Hrev_master [page 10] [Emergency Care Journal 2023; 19:10810] Emergency Care Journal 2023; volume 19:10810 Abstract Much research, both pathophysiological and clinical, has been produced on septic shock during the last 20 years. Nevertheless, many aspects of treatment are still controversial, among these the approach to the administration of fluids and vasopressors. Moreover, most clinical research on septic shock was produced in the ICU setting on mechanically ventilated and invasively moni- tored patients, a situation hardly comparable to that of most emer- gency rooms throughout the world. In this non-systematic review, the basic pathophysiological concepts and the most important mes- sages from clinical studies will be summarized, with the aim to identify the baseline skills and knowledge necessary for a first approach to septic shock patients in the emergency room. Introduction Knowledge of pathophysiology and clinical trials are the land- marks of modern medical practice. Unfortunately, pathophysiological knowledge is often incom- plete, and the results of clinical trials may be at odds with each other. The practicing physician must therefore strive to critically use the information derived from these two branches of research to respond as well as possible to each patient’s needs. Many important studies, both pathophysiological and clinical, have been conducted over the past twenty years. Consequently, the approach to patients in septic shock has improved and mortality has fallen,1 yet controversies are still open as many important ques- tions need answers and additional research.2 Moreover, most clini- cal research on septic shock was produced in the ICU setting on mechanically ventilated and invasively monitored patients, a situ- ation hardly comparable to that of most Emergency Departments (ED) throughout the world. This article summarizes the most important aspects of the administration of fluids and vasopressors, based on a personal selection from the endless literature on the topic, to propose as a conclusion some operational suggestions for daily medical practice in the ED. Macro and microcirculation in septic shock Sepsis is a life-threatening organ dysfunction caused by a dys- regulated host response to infection. From the perspective of macrocirculation, septic shock is a distributive shock characterized by increased venous capacitance and decreased Systemic Vascular Resistance (SVR). The reduction in parietal tone and increased capacitance of the venous circulation has the most significant hemodynamic effect,3,4 because about 75% of the blood volume circulates in the veins. As the disease advances, almost half the patients with septic shock develop a cardiomyopathy5,6 which can significantly impair ventricular function, affecting the Cardiac Output (CO). Turning to microcirculation, a complex interaction between pro and anti-inflammatory and coagulative phenomena7 produces endothelial dysfunction, glycocalyx degradation, altered blood cell rheology, and imbalance between the levels of vasodilating and vasoconstricting substances, altering the matching of blood flow to tissue demand.8 It has been demonstrated that sepsis is associated with reduced microvascular density, an increased number of non- perfused small vessels, and heterogeneity among microcirculatory areas. The direction, extent, and duration of these reactions are determined by factors related to the host (genetics, age, co-pathol- ogy, immunodepression) and the pathogen (microbial load and vir- ulence). Macrocirculatory status can be assessed by the direct or indi- rect measurement of parameters such as Stroke Volume (SV), Central Venous Pressure (CVP), and Blood Pressure (BP).9 However, CVP and BP have only a low to moderate predictive Correspondence: Daniele Coen, Emergency Department, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Tel.: +39.339.8954101. E-mail: dacoen53@gmail.com Key words: fluid resuscitation; vasopressors; septic shock; preload; stressed volume; emergency department. Financial support: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest: the author declares no conflict of interest. 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. Informed consent: not applicable. Received for publication: 22 August 2022. Revision received: 5 February 2022. Accepted for publication: 14 February 2022. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2023 Licensee PAGEPress, Italy Emergency Care Journal 2023; 19:10810 doi:10.4081/ecj.2023.10810 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organiza- tions, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its man- ufacturer is not guaranteed or endorsed by the publisher. Fluids and vasopressors in septic shock: basic knowledge for a first approach in the emergency department Daniele Coen Emergency Department, Grande Ospedale Metropolitano Niguarda, Milan, Italy No n- co mm er cia l u se on ly power in assessing response to treatment, being reliable only for very significant variations of their values.10,11 Although SV is a much better indicator, its measurement requires expertise, and its accuracy in predicting response to treatment is higher for sedated and mechanically ventilated patients for whom hemodynamic and respiratory parameters can be more precisely evaluated. Microcirculatory alterations are more difficult to assess because their assessment relies on semiquantitative measurements that are difficult to apply in emergency, such like the direct visualization of the sublingual capillary network.12 Because an improvement in macrocirculation does not necessarily correspond to an improve- ment in microcirculation and peripheral perfusion, the most useful parameters for guiding therapy remain, despite some controver- sy,13-15 those that assess tissue oxygenation trends (lactate, ScvO2, veno-arterial PCO2 gradient)16 in addition to clinical parameters (level of consciousness, urinary output, and capillary refill time - CRT).17-18 In a recent trial, patients randomized to CRT-guided resuscitation fared as well or better compared with patients ran- domized to lactate-guided therapy.19 In conclusion, no single measurement best identifies the sever- ity of the shock, nor how an individual patient will respond to fluid administration and other treatments. A combination of clinical signs, hemodynamic parameters, and laboratory tests will continue to be used by physicians according to their level of expertise and the availability of diagnostic instruments. The determinants of cardiac output Cardiac output is determined by preload, inotropism, and after- load. Inotropism and preload are directly related to CO, while afterload has an inverse relation. Therefore, when BP falls in front of no change (or an increase) in CO, the primary problem must be a decrease in SVR. On the contrary, when BP falls and CO falls too, the primary problem stays with CO and the next question is whether CO fell because of a decrease in inotropism or in venous return.3,20 It is unanimously agreed that the administration of fluids and vasopressors has the main clinical goal of enhancing CO through an increase of preload. When this is not the case, they are at best useless and can be detrimental. The return of systemic venous blood to the heart is determined by the difference between Mean Venous Filling Pressure (MSFP) and Central Venous Pressure (CVP).3,12 MSFP is the pressure that would be measured at each point in the circulatory system (exclud- ing the heart and pulmonary circulation) if the heart stopped and blood was redistributed instantaneously so that the pressure was the same at each point. Mean venous filling pressure tends to remain constant even for large changes in CO, is not clinically measurable, and is estimated to be between 7 and 12 mmHg in humans.3 MSFP is determined by intravascular volume and venous tone. Intravascular volume can be considered as consisting of two parts. The first one, which represents about 85% of the total volume (Vt) exerts no pressure on the vascular walls and theoretically repre- sents the volume that corresponds to an MSFP=0. For this reason, it is referred to as the unstressed volume (Vu). The second one, rep- resenting the remaining 15% of Vt, exerts the hydrostatic pressure responsible for MSFP and is consequently referred to as the stressed volume (Vs).21 As we will see later, fluids increase Vs replenishing the venous circulation, while vasopressors act on Vs inducing venous constriction. The role of blood pressure and peripheral resistance BP plays an important role in determining organ blood flow and therefore it is often used as a surrogate index of tissue perfu- sion, although this cannot be considered a reliable practice.22 Blood pressure is the product of CO and systemic vascular resistances, but it is the vascular resistances of each specific organ that deter- mine regional flows. Thus, the distribution of local arterial resis- tances is the major determinant of where blood goes. If the distri- bution of vascular resistances changes, blood flow will perfuse the different organs proportionally to the dilation of their arteriolar cir- culation. The use of vasopressors to induce constriction in the arte- rioles is based on the assumption that resistance will increase less in vital organs, such as the brain, kidney, and heart, because of the play of local neuronal and hormonal signals, thus favouring the flow to these districts. Unfortunately, however, in septic patients the ability to autoregulate vascular tone is often impaired.23 Thus, it is difficult to foresee the effects that the administration of adrenergic agents may have on regional flows. Moreover, while systemic resistances can be calculated by invasive methods or derived by SV and CVP, regional vascular resistances cannot be measured nor calculated in the clinical setting. The physiological and pharmacological basis of treatment with fluids and vasoactive drugs The generalized vasoplegia that characterizes septic shock causes a reduction in venous tone with an increase in vascular bed capacitance. As a consequence, when physiological compensation mechanisms are inadequate, both stressed volume and preload are reduced. This situation can be managed in one of two ways: increasing intravascular volume with fluids or increasing venous tone with vasopressors. More often, the decision is made to admin- ister both, to balance the positive and undesirable effects of the two interventions. Fluids Crystalloids are the fluids of choice because they have a better benefit/risk ratio than colloids.24 Recent meta-analyses are con- flicting as to whether balanced crystalloid solutions are superior to saline, but most authors recommend their use since saline causes hyperchloremic metabolic acidosis when given rapidly or in large volumes and may increase the risk of acute kidney injury.25-27 The main problem with crystalloids is their limited stay in the intravas- cular space and rapid passage into the interstitium of more than three-quarters of the administered volume. This is further promot- ed by sepsis-induced alterations in endothelial permeability.28 Interstitial edema hampers oxygen transport to the tissues and can be a serious clinical problem because it may affect the lung parenchyma and increase intra-abdominal pressure. Finally, fluid administration may be ineffective in patients with left ventricular failure who reach the plateau phase of the Frank-Starling curve very early (Figure 1). In this case, the effect of preload on stroke volume may be little or absent, when not counterproductive. The evaluation of fluid responsiveness, especially outside the ICU, is a much-discussed item that goes beyond the aims of this review.29 Measuring SV modification after passive leg raising or a fluid bolus administration is the preferred method when instrumen- tation and expertise are available. Echocardiography is probably the best option to measure SV in the ED setting, since the number Review [Emergency Care Journal 2023; 19:10810] [page 11] No n- co mm er cia l u se on ly of emergency doctors trained in this technique is growing, while other non-invasive approaches are either too clumsy to use or sim- ply too little diffused. Other measures, like respiratory diameter variation of the inferior vena cava, require confirmatory studies and are reliable in non-ventilated patients only for very significant changes.30 Yet, most patients in septic shock do show a complete inspiratory collapse of the inferior vena cava, and this can be used as a proxy indicator of fluid responsiveness, or at least of the patient’s capability to tolerate a further fluid bolus. Lastly, it is important to point out that being a fluid responder doesn’t neces- sarily mean requiring fluids. Most people who are well and in hemodynamic equilibrium will respond to fluids, but this is not a good reason to treat them. Vasopressors The choice generally falls on norepinephrine31 which has a higher a1-receptor affinity and safety profile than dopamine and adrenaline.32,33 Noradrenaline mainly affects CO by reducing the capacitance of the venous circulation, thus increasing stressed vol- ume and venous return. The problem with noradrenaline (especial- ly at the higher doses) is an increase in SVR which could cause an excessive load for a failing heart, despite the positive inotropic effect of this drug.34 Lastly, the effect of vasopressors on septic shock is difficult to foresee, considering that an altered response to adrenergic stimulation is often encountered in patients with over- whelming bacterial infections.35 Inotropes Administration of dobutamine has a sound pathophysiological basis and is employed in patients with septic shock that persists after adequate fluid loading and administration of noradrenaline, because of its important inotropic effect.36 Undesirable effects of dobutamine include increased myocardial O2 consumption and its action on the AV node that can increase heart rate in patients with AF.37 Before moving on to clinical studies, it may be helpful to sum- marize the main messages of this very concise overview on the pathophysiology and pharmacology of septic shock. Data on macrocirculation and hemodynamics corroborate the importance of both fluids and vasopressor drugs in improving preload and CO. However, they also show that the efficacy of fluids on preload decreases approaching the plateau phase of the Frank-Starling curve and that this happens much earlier in patients with left ven- tricular failure. Because of the risk of pulmonary edema, fluid administration to these patients should be particularly careful. Noradrenaline finds a strong rationale in its positive effects on preload and there are sound reasons to support its use in the early stage of septic shock, following initial fluid replenishment. Lastly, the analysis of microcirculatory changes, which are complex, vari- able, and not directly measurable, cautions against the illusion that a standardized (“one fits all”) treatment can be used, and reminds us of the importance of an individualized therapeutic approach. Epidemiological data Epidemiological data clearly show that mortality from sepsis has fallen over the past two decades, although the incidence of this syndrome has not declined.1 They also show that mortality is relat- ed to factors such as the site of infection (e.g., lung more than uri- nary tract), age (in England, nearly 80% of patients who die from sepsis are over 75 years old), and a state of fragility. An interesting editorial from a few years ago, based on English data, points out that sepsis is often the terminal event of a severe and debilitating chronic disease.38 However, epidemiological data suffer from important limitations. Firstly, they relate mostly to Western coun- tries with advanced healthcare systems and are based mainly on registers of deaths from the hospital settings. Secondly, following major international initiatives to combat sepsis (e.g., Surviving Sepsis Campaign), attention to the problem has increased and many more patients have been recognized as septic. A higher denominator may therefore be responsible for an apparent reduc- tion in mortality.39 To better understand the role that fluids and vasopressor drugs have played in improving mortality from septic shock, it is then necessary to examine the results of clinical trials. Observational studies and controlled clinical trials Fluids Most studies on fluids in the treatment of sepsis and septic shock are observational studies and as such suffer from important limitations. The populations studied are often not homogeneous with each other (in terms of age, site of infection, co-pathologies, and the severity of septic picture) and have been enrolled predom- inantly in intensive care units. Consequently, many studies exclude the large proportion of subjects who, for various reasons, are treat- ed outside the ICU and who account for most cases in daily prac- tice. Analysing these studies in chronological order, one can recog- nize first of all a long series of papers with historical controls that, referring to the pivotal study by Rivers in 2001 (see below),40 con- firm that patients treated according to the Early Goal-Directed Therapy (EGDT) have lower mortality than patients treated with a “traditional” approach.41-44 Without going into too much detail, suf- fice it to say that the EGDT protocol required the administration of fluids until CVP values = 8-12 mmHg were reached and consid- ered the administration of vasopressors only after this step was completed. An adequate central venous saturation was the ultimate Review [page 12] [Emergency Care Journal 2023; 19:10810] Figure 1. Frank-Starling curve in the normal and insufficient heart. No n- co mm er cia l u se on ly goal. The EGDT approach was strongly criticized in later years,45- 48 but this did not prevent it from becoming the reference for inter- national guidelines for almost 15 years.49 In 2017, though, an important paper documented that almost all the benefits shown by the observational studies on EGDT could be attributed to the earli- er administration of antibiotic treatment, a likely by-product of the growing attention to speed up all therapeutic interventions.50 A second set of observational studies grew out of concern that the EGDT approach could lead to the harmful overuse of fluids. These studies collectively documented that a positive fluid balance at 12-48 hours after diagnosis is associated with increased mortal- ity.51,52 Other studies showed that a higher cumulative fluid balance was associated with the subsequent development of major adverse kidney events.53,54 This new awareness stimulated a progressive reversal of fluid administration protocols in septic shock and renewed interest in the early administration of vasopressor drugs. Among Randomized Clinical Trials (RCT), three large studies which challenged the results of the original EGDT trial should be mentioned, if only for their size. All three studies (ARISE, ProMISe, and ProCESS)55-57 failed to demonstrate a benefit with EGDT. Nevertheless, their results are difficult to interpret since they were conducted about 15 years after the original study by Rivers, when the general approach to septic patients had already changed profoundly. It is important to notice that in all EGDT stud- ies, patients received more than 2 L of fluids before randomization, and at least 2 L more during the first 6 hours of treatment (Table 1). More interesting, with regard to our topic, are several smaller studies that specifically investigated the amount of fluids to be given in the acute phase of septic shock.58,59 Most studies that compared a restrictive versus a liberal use of fluids pointed towards a beneficial effect of fluid restriction, but they were not powered to reach statistical significance. In most cases, however, these studies enrolled patients who had already been admitted to the ICU and for whom the quantity of fluids administered before admission was not always clearly reported. Of particular interest is a pilot study that enrolled patients at the time of their arrival at the emergency department. In this study, patients in both groups had received approximately 35/mL/Hg of crystalloids at the time of enrolment and remained in shock, so the difference between the two groups was limited to the hours following randomization. Patients randomized to restrictive treatment received, in the first 24 hours, half the fluids that were administered to controls, with no difference in mortality and with a suggestive reduction (although not statistically significant) in ICU stay and hours of mechanical ventilation and amine administration. It must be emphasized, how- ever, that in this study patients both in the treated and in the control group received much less fluid (respectively 7.8 ± 13.3 and 16.6 ± 23.2 mL/Kg in the first 24 hours) than in each of the four random- ized EGDT studies (Table 1). Two recent, randomized studies of adequate numerosity have given a very important contribution to settling the problem since neither demonstrated any clinically sig- nificant advantage (or disadvantage) for patients treated with a restrictive fluid approach.60,61 Considering that in both studies patients had received 1 to 3 L crystalloids before randomization, the message seems to be that after an initial resuscitative bolus, and as far as the first 24 hrs of treatment are concerned, the amount of fluids administered is not such an important determinant of out- come. The Surviving Sepsis Campaign guidelines recommend initiat- ing 30 mL/kg of IV crystalloids to patients with suspected sepsis within 1-3 hours in case of hypotension or lactate level greater than or equal to 4 µmol/L. Although this is a strong recommendation, it is based upon evidence of low quality. Moreover, specific subpop- ulations might need different approaches. For instance, patients with hypotension but normal lactate (which should not be consid- ered in septic shock according to the Sepsis 3 definitions) have a better outcome and might need a less aggressive approach.62 On the other hand, studies aiming to normalize lactate levels in normoten- sive patients have given conflicting results.63,64 In clinical practice, determining the optimal amount of fluid to be administered remains a critical issue that might never find a solution appropriate for every case.64 There is growing agreement that a four-step pro- tocol (Figure 2) should be adopted in most situations, with an aggressive initial approach, followed by optimization and quick reduction in the subsequent hours and days.65,66 Vasopressors Studies on vasopressors are far fewer in number and even less conclusive than those on volemic replenishment. As in the case of fluids, there are no clinical studies comparing patients treated or untreated with vasopressors, but only comparisons between differ- ent drugs and timing of treatment. Noradrenaline is the drug of choice according to the Surviving Sepsis Campaign guidelines and this advice is compatible with available data on the efficacy and side effects of different vasopres- sors.67 Vasopressin has also been studied as an adjunctive treatment or first-line therapy, with unevenresults. As to the timing of admin- istration, provisional conclusions from the scanty available evi- dence can be summarized by saying that early treatment with vaso- pressors (<2h from the onset of shock) seems to be associated with Review Table 1. Fluid administration in the 4 randomized trials on EGDT. Fluids (mL) RIVERS (2001) ARISE (2014) PROCESS (2014) PROMISE (2015) Pre-random ? 2515±1244 2254±1472 1950 0-6h 4981±2984 2226±1363 2805±1957 2000 6-72 8625±5162 4274±3071 4458±3878 3623 Total 13606±8146 8753±5730 9517±7307 7573 [Emergency Care Journal 2023; 19:10810] [page 13] Figure 2. Four-step approach to fluid administration in shock. No n- co mm er cia l u se on ly a more favorable prognosis.68,69 An interesting retrospective large study suggests that the best effect of vasoactive amines can be obtained by starting their administration no earlier than 1 hour and no later than 6 hours after the diagnosis and following an initial fluid replenishment of at least 1000 mL.70 Other studies document that higher doses or a more protracted time of treatment are asso- ciated with higher mortality,71,72 but this evidence is affected by the fact that it is generally the most severe patients who receive the most intense and prolonged drug treatment. Finally, a possible neg- ative immunomodulatory effect of noradrenaline has been dis- cussed.73 Clinical documentation for dobutamine is also sparse and inconclusive although guidelines continue to recommend it in patients with impaired inotropism and poor response to fluids and noradrenaline. In the large EGDT studies, dobutamine was used in about 1% of patients in the control group and 10-15% of patients in the EGDT group with no difference in mortality. Moreover, sev- eral studies seem to document a positive effect of b-blockers in patients with septic shock, making it even more problematic to employ a drug with a strong b-agonist activity.74 Sepsis at the end of life Although sepsis and septic shock can occur at any age, almost 80% of deaths in British hospitals concern patients >75 years of age. The high incidence of frailty and severe comorbidities makes most sepsis-related deaths not directly attributable to sepsis, nor preventable through timely therapeutic interventions. In a point prevalence study in British hospitals including 521 patients with sepsis and 136 deaths, only 40 deaths were directly or possibly attributable to sepsis.75 Of these, 77.5% were in patients who had substantial frailty, and 70% were in patients who were considered not to resuscitate in the event of cardiac arrest. A US study estimat- ed that only 12% of sepsis deaths were possibly-to-definitely pre- ventable.76 Although it is difficult to retrieve data on the percentage of patients with septic shock who are directly admitted from the ED to the ICU, it is a common experience that the very elderly and frailest patients are often admitted to general wards. This limits the monitoring capability as well as the aggressiveness of therapy. A practical approach to the early therapy of septic shock in the ED As we have seen, a substantial number of patients with septic shock are not admitted to the ICU because of frailty and severe comorbidities. It is thus of the utmost importance that the chance of a patient being admitted to the ICU is evaluated early. When ICU seems a concrete possibility, the intensivists should be informed and involved from the very early stages of therapy. When ICU admission is not envisaged, the clinical approach must be car- ried out within the frame of the available monitoring equipment and physicians’ expertise. Basic competence in sonography is the minimum standard acceptable for ED physicians called to treat patients in septic shock. Competence in echocardiography to esti- mate SV would be a welcome addition. Both the physiology of macrocirculation and microcirculation and the results of clinical trials confirm that fluids and vasopres- sors are indicated and effective in the treatment of septic shock. As we have seen, the most recent data tend to favour an earlier initia- tion of vasopressors than previously advised. In evaluating the approach to fluid administration, one must consider that ED physi- cians face septic patients with hypotension that are not always sim- ilar to those treated in clinical trials (that by definition are enrolled only after a first ineffective bolus of crystalloids). As a conse- quence, although the administration of 30 mL/Kg of crystalloids in the first 3 hours is still recommended by the Surviving Sepsis Campaign guidelines and sounds reasonable as a first approach, it might be appropriate to evaluate the efficacy of volume expansion as early as after the first 1000 mL of crystalloids. Particular atten- tion should be paid to patients with left ventricular failure, in whom volemic expansion has little effect on preload and may cause pulmonary edema. A respiratory collapse >50% of the infe- rior vena cava is an acceptable sign that the patient will tolerate a further fluid bolus, though not the best way to evaluate fluid responsiveness. Repeated pulmonary ultrasound may help identify the early signs of interstitial edema. The lack of a consistent correlation between improved hemo- dynamic values and tissue oxygenation status suggests that macro- circulation-related parameters (PA, CVP, SV when available) be always evaluated in the light of tissue perfusion sensitive parame- ters (level of consciousness, urinary output, CRT, lactates, SVcO2). CRT is an old, but recently revaluated assessment that is easy to perform, can be repeated frequently, and might be particu- larly appropriate for the ED setting. After the first 1000 mL, crystalloids should be preferentially administered in boluses of 250-500 mL followed by the revalua- tion of the patient’s vital parameters and one or more among IVC and pulmonary sonography, SV, CRT. As a rough guide, it could be kept in mind that patients enrolled in the major clinical studies on septic shock received an average of 4 L of crystalloids in the first 6 hours, with a rapid reduction thereafter. Noradrenaline is the vasopressor of choice and, when neces- sary, it can be first administered in a peripheral vein.77 The addition of other vasopressors (adrenaline or vasopressin) is acceptable in patients who do not respond to noradrenaline. The use of inotropic drugs has a rationale in case of left ventricular insufficiency and an inadequate response to fluids and noradrenaline, although it is not supported by appropriate clinical trials. Echocardiography may help identify patients that could better respond to inotropes.78 This treatment, as well as the administration of adrenaline, should be constantly monitored and reserved for patients followed in an intensive care setting. Since an early and appropriate antimicrobial treatment has the best correlation with prognosis, ED physicians should pay the utmost attention to identifying and possibly removing the source of infection. Early cultures and initiation of antibiotic treatment are also of paramount importance. Finally, the very frail patients in whom sepsis is the final event of advanced chronic disease should be spared unnecessary clinical aggressiveness and be started on palliative care early. References 1. Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis. Crit Care 2020;24:239. 2. Lat I, Coopersmith CM, De Backer D. The Surviving Sepsis Campaign: fluid resuscitation and vasopressor therapy research priorities in adult patients. Crit Care Med 2021;49: Review [page 14] [Emergency Care Journal 2023; 19:10810] No n- co mm er cia l u se on ly 623-35. 3. Magder S. Bench-to-bedside review: An approach to hemody- namic monitoring--Guyton at the bedside. Crit Care 2012;16:236. 4. Persichini R, Lai C, Teboul JL, et al. Venous return and mean systemic filling pressure: physiology and clinical applications. Crit Care 2022;26:150. 5. Sato R, Nasu M. A review of sepsis-induced cardiomyopathy. J Intensive Care 2015;3:48. 6. L’Heureux M, Sternberg M, Brath L, et al. Sepsis-induced car- diomyopathy: a comprehensive review. Curr Cardiol Rep 2020;22:35. 7. Yadav H, Cartin-Ceba R. Balance between hyperinflammation and immunosuppression in sepsis. Semin Respir Crit Care Med 2016;37:42–50. 8. Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med 2010;363:689-91. 9. Bentzer P, Griesdale DE, Boyd J, et al. Will this hemodynam- ically unstable patient respond to a bolus of Intravenous fluids? JAMA 2016;316:1298-1309. 10. Eskesen TG, Wetterslev M, Perner A: Systematic review including re-analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness. Intensive Care Med 2016;42:324–32. 11. Airapetian N, Maizel J, Alyamani O, et al. Does inferior vena cava respiratory variability predict fluid responsiveness in spontaneously breathing patients? Critical Care 2015;19:400 12. Assessment of sublingual microcirculation in critically ill patients: consensus and debate. Dilken O, Ergin B, Ince C. Ann Transl Med 2020;8:793 13. Hernandez G, Bellomo R, Bakker J. The ten pitfalls of lactate clearance in sepsis. Intensive Care Med 2019;45:82-85 14. Textoris J, Fouché L, Wiramus S, et al. High central venous oxygen saturation in the latter stages of septic shock is associ- ated with increased mortality. Crit Care 2011;15:R176. 15. Gattinoni L, Vasques F, Camporota L, et al. Understanding lac- tatemia in human sepsis: potential impact for marly Management. Am J Respir Crit Care Med 2019;200:582-9. 16. Vincent JL, Quintairos ESA, Couto L Jr, Taccone FS. The value of blood lactate kinetics in critically ill patients: a sys- tematic review. Crit Care 2016;20:257 17. Yasufumi O, Morimura N, Shirasawa A, et al. Quantitative capillary refill time predicts sepsis in patients with suspected infection in the emergency department: an observational study. J Intensive Care 2019;7:29 18. Castro R, Kattan E, Ferri G, et al. Effects of capillary refill time-vs. lactate-targeted fluid resuscitation on regional, micro- circulatory and hypoxia-related perfusion parameters in septic shock: a randomized controlled trial. Ann Intensive Care 2020;10:150. 19. Zampieri FG, Damiani LP, Bakker J, et al: Effect of a resusci- tation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: A Bayesian reanalysis of the ANDROMEDA-SHOCK trial. Am J Respir Crit Care Med 2020;201:423–29. 20. Magder S, Brengelmann GL. Point: Counterpoint: the classic Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correct. J Appl Physiol 2006;101:1523–27. 21. Spiegel R. Stressed vs. unstressed volume and its relevance to critical care practitioners. Clin Exp Emerg Med 2016;3:52-4. 22. Magder SA. The highs and lows of blood pressure: toward meaningful clinical targets in patients with shock. Crit Care Med 2014;42:1241–51. 23. Carrara M, Herpain A, Baselli G, Ferrario M. Vascular decou- pling in septic shock: the combined role of autonomic nervous system, arterial stiffness, and peripheral vascular tone. Front Physiol 2020;11:594. 24. Bayer O, Reinhart K, Sakr Y, et al. Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison. Crit Care Med 2011;39: 1335–42. 25. Hammond DA, Lam SW, Rech MA, et al. Balanced crystal- loids versus saline in critically ill adults: A systematic review and meta-analysis. Ann Pharmacother 2020;54:5–13 26. Xue M, Zhang X, Liu F, et al: Effects of chloride content of intravenous crystalloid solutions in critically ill adult patients: a meta-analysis with trial sequential analysis of randomized trials. Ann Intensive Care 2019;9:30 27. Hammond DA, Lam SW, Rech MA, et al. Balanced crystal- loids versus saline in critically ill adults: a systematic review and meta-analysis. Ann Pharmacother 2020;54:5-13. 28. Nunes TS, Ladeira RT, Bafi AT, et al. Duration of hemodynam- ic effects of crystalloids in patients with circulatory shock after initial resuscitation. Ann Intensive Care 2014;4:25 29. Bentzer P, Griesdale DE, Boyd, J, et al. Will this hemodynam- ically unstable patient respond to a bolus of intravenous fluids? JAMA 2016;316:1298-1309. 30. Preau S, Bortolotti P, Colling D, et al.Diagnostic accuracy of the inferior vena cava collapsibility to predict fluid responsive- ness in spontaneously breathing patients with sepsis and acute circulatory failure. Crit Care Med 2017;45:e290–7. 31. Hernandez G, Teboul JL, Bakker J. Norepinephrine in septic shock. Intensive Care Med 2019;45:687–9. 32. Avni T, Lador A, Lev S, et al. Vasopressors for the treatment of septic shock: systematic review and meta-analysis. PLoS One 2015;10:e0129305. 33. Vasu TS, Cavallazzi R, Hirani A, et al . Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials. J Intensive Care Med 2012;27:172-8 . 34. Uhel F, van der Poll T. Norepinephrine in septic shock: a mixed blessing. Am J Respir Crit Care Med 2020;202:788–9. 35. Levy B, Collin S, Sennoun N, et al. Vascular hyporesponsive- ness to vasopressors in septic shock: From bench to bedside. Intensive Care Med 2010;36:2019–29. 36. Hernandez G, Bruhn A, Luengo C, et al. Effects of dobutamine on systemic, regional and microcirculatory perfusion parame- ters. Intensive Care Med 2013;39:1435–43. 37. Sato R, Nasu M. Time to re-think the use of dobutamine in sep- sis. J Intensive Care 2017;5:65. 38. Singer M, Inada-Kim M, Shankar-Hari M. Sepsis hysteria: excess hype and unrealistic expectations. Lancet 2019;394: 1513-14. 39. Rhee C, Klompas M. Sepsis trends: increasing incidence and decreasing mortality, or changing denominator? J Thorac Dis 2020;12:S89-S100. 40. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed ther- apy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77. 41. Gao F, Melody T, Daniels DF, et al. The impact of compliance with 6-hour and24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care 2005;9:R764-R770. 42. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Review [Emergency Care Journal 2023; 19:10810] [page 15] No n- co mm er cia l u se on ly Crit Care Med 2010;38:367-74. 43. Rivers E. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock: what a sep- sis pilot must consider before taking flight with your next patient. Crit Care Med 2006;34:1247. 44. Prasad PA, Shea ER, Shiboski S, et al. Relationship between a sepsis intervention bundle and in-hospital mortality among hospitalized patients: a retrospective analysis of real-world data. Anesth Analg 2017;125:507-13. 45. Marik PE, Cavallazzi R. Does the central venous pressure pre- dict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med 2013;41:1774–81. 46. Kumar A, Anel R, Bunnell E, et al. Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects. Crit Care Med 2004;32:691–9. 47. Delaney A. Protocolized sepsis care is not helpful for patients. Crit Care Med 2017;45:473-5. 48. Jones AE. Unbundling early sepsis resuscitation. Ann Emerg Med 2014;63:654-5. 49. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for the management of sep- sis and septic shock: 2016. Crit Care Med 2017;43:304–77. 50. Kalil AC, Johnson DV, Lisco SJ, Su JN. Early goal-directed therapy for sepsis: a novel solution for discordant survival out- comes in clinical trials. Crit Care Med 2017;45:607–14. 51. Sakr Y, Rubatto Birri PN, Kotfis K, et al. Intensive Care Over Nations Investigators: higher fluid balance increases the risk of death from sepsis: Results from a large international audit. Crit Care Med 2017;45:386–94. 52. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011;39:259–265. 53. Kellum JA, Chawla LS, Keener C, et al. ProCESS and ProGReSS-AKI Investigators.The effects of alternative resus- citation strategies on acute kidney injury in patients with septic Shock. Am J Respir Crit Care Med 2016;193:281-7. 54. Mele A, Cerminara E, Häbel H, et al. Fluid accumulation and major adverse kidney events in sepsis: a multicenter observa- tional study. Ann Intensive Care 2022;12:62. 55. ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506. 56. Mouncey PR, Osborn TM, Power GS Trial of early, goal- directed resuscitation for septic shock. N Engl J Med 2015; 372:1301-11. 57. The ProCESS Investigators. A randomized trial of protocol- based care for early septic shock. N Engl J Med 2014;370: 1683-93. 58. Meyhoff TS, Møller MH, Hjortrup PB, et al. Lower vs higher fluid volumes during initial management of sepsis: A system- atic review with meta-analysis and trial sequential analysis. Chest 2020;157:1478–96. 59. Hjortrup PB, Haase N, Bundgaard H, et al. CLASSIC Trial Group; Scandinavian Critical Care Trials Group. Restricting vol- umes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multi- centre feasibility trial. Intensive Care Med 2016;42:1695-705. 60. Meyhoff TS, Hjortrup PB, Wetterslev J, et al. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med 2022;386:2459-70. 61. National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, et al. Early restrictive or liberal fluid management for sepsis-Induced hypotension. N Engl J Med. 2023;388:499-510. 62. Hernandez G, Bruhn A, Castro R, Pedreros C, et al. Persistent sepsis-induced hypotension without hyperlactatemia: a distinct clinical and physiological profile within the spectrum of septic shock. Crit Care Res Pract 2012;2012:536852. 63. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lac- tate-guided therapy in intensive care unit patients: a multicen- ter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182:752-61. 64. Hernandez G, Luengo C, Bruhn A, et al. When to stop septic shock resuscitation: clues from a dynamic perfusion monitor- ing. Ann Intensive Care 2014,4:30. 65. Hoste EA, Maitland K, Brudney CS, et al. Four phases of intra- venous fluid therapy: a conceptual model. Br J Anaesth 2014;113:740-7. 66. Malbrain MLNG, Langer T, Annane D, et al. Intravenous fluid therapy in the perioperative and critical care setting: Executive summary of the International Fluid Academy (IFA). Ann Intensive Care 2020;10:64. 67. Avni T, Lador A, Lev S, et al. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One 2015;10:e0129305. 68. Permpikul C, Tongyoo S, Viarasilpa T, et al. Early use of nore- pinephrine in septic shock resuscitation (CENSER): a random- ized trial. Am J Resp Crit Care Medicine 2019;199:1097-05. 69. Li Y, Li H, Zhang D. Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-anal- ysis. Critical Care 2020;24:488. 70. Waechter J, Kumar A, Lapinsky SE, et al. for the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study. Crit Care Med 2014;42:2158-68. 71. Takala J. Should we target blood pressure in sepsis? Crit Care Med 2010;38:S613–S619. 72. Martin C, Medam S, Antonini F, et al. Norepinephrine: not too much, too long. Shock 2015;44:305–9. 73. Stolk RF, van der Poll T, Angus DC, et al. Potentially inadver- tent immunomodulation: norepinephrine use in sepsis. Am J Respir Crit Care Med 2016;194:550–8. 74. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013;310:1683–91. 75. Kopczynska M, Sharif B, Cleaver S, et al. Sepsis-related deaths in the at-risk population on the wards: attributable frac- tion of mortality in a large point-prevalence study. BMC Res Notes 2018;11:720. 76. Rhee C, Jones TM, Hamad Y, et al. Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals. JAMA Netw Open 2019;2:e187571. 77. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care 2015;30:653.e9–653.e17 78. Corradi F, Via G, Tavazzi G. What's new in ultrasound-based assessment of organ perfusion in the critically ill: expanding the bedside clinical monitoring window for hypoperfusion in shock. Intensive Care Med 2020;46:775-9. Review [page 16] [Emergency Care Journal 2023; 19:10810] No n- co mm er cia l u se on ly