Hrev_master [page 24] [Emergency Care Journal 2023; 19:11274] Emergency Care Journal 2023; volume 19:11274 Abstract The use of continuous positive airway pressure (CPAP) in COVID-19 hypoxemic respiratory failure (h-ARF) under a strict protocol has been described to be highly efficient. However, early prediction of failure is crucial to avoid delayed intubation. Lower PaCO2 values may represent a higher inspiratory effort and, there- fore, may help identify patients at greatest risk of CPAP failure. Aim of this study was to observe the PaCO2 trend of COVID-19 patients with h-ARF before and after the initial treatment with hel- met-CPAP. A case series study was conducted from November 2020 to March 2021. All adult patients with h-ARF secondary to COVID-19 treated with helmet-CPAP and eligible for endotracheal intubation were observed. Of a total of 54 patients, 32 (59.3%) underwent intubation. Seven (12.9%) patients died in the ETI group, and none in the non-ETI group. Median PaO2/FiO2 ratio on admission was 91mmHg [IQR 68-185] vs. 104mmHg [IQR 85-215] (p=0.137) in the ETI e non-ETI group, respectively. No differences were found either for PaCO2 values on admission (31.5mmHg [IQR 27-35] vs. 29.3mmHg [IQR 27.7-40]) and for PaCO2 variations after 120 minutes of CPAP (+2.38 mmHg ± 3.65 vs. +2.73 mmHg ± 3.96). Changes in PaCO2 values were observed during an initial helmet-CPAP trial, but no differences were found in those undergo- ing endotracheal intubation as compared to the others. Introduction The use of continuous positive airway pressure (CPAP) in COVID-19 respiratory failure under a strict protocol has been described to be highly efficient. However, early prediction of fail- ure is crucial to avoid delayed intubation.1–3 Even though risk fac- tors have previously been proposed to predict CPAP failure, a lead- ing role is played by a high respiratory drive, whose accurate mea- surement, especially its non-invasive evaluation, remains a chal- lenge.4–7 In the Emergency Department (ED), clinical evaluation with respiratory parameters and blood gases are the first useful tools helping healthcare professionals, nurses, and physicians, firstly to assess the degree of respiratory distress at arrival, and subsequently to monitor the response to CPAP treatment over time.8,9 COVID-19 patients with hARF often present with an increased respiratory drive and low arterial carbon dioxide tension (PaCO2) values due to hypoxia, impaired respiratory mechanics, and inflammatory stimulus. Recently, in a post hoc analysis of the HENIVOT trial, evalu- ating helmet noninvasive ventilation as compared with a high-flow nasal cannula, patients with a PaCO2 < 35 mmHg had a greater benefit from helmet non-invasive ventilation in terms of endotra- cheal intubation (ETI) than patients with normal or higher PaCO2 (³ 35 mmHg).10 The authors postulated that lower PaCO2 values might represent a higher inspiratory effort and therefore may help identify patients who are at the greatest risk for non-invasive treat- ment failure during spontaneous breathing.10 Anyway, so far, no one has demonstrated that the PaCO2 trend, in addition to other non-invasive respiratory parameters, may help evaluate the patient’s response to CPAP. The aim of this case series was to describe the PaCO2 trend of COVID-19 patients undergoing a first helmet-CPAP (H-CPAP) treatment in the emergency department according to a local proto- Correspondence: Nicolò Capsoni, Department of Emergency Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy. E-mail: nicolo.capsoni@gmail.com Key words: helmet; CPAP; non-invasive ventilation; COVID-19; hypoxemic respiratory failure Contributions: NC, CA, and AB, data analysis and interpretation; DP, SG and GT, data collection; NC and DP, significant contribu- tions to manuscript writing. All authors read and approved the final manuscript. Conflict of interest: the authors declare no potential conflict of inter- est, and all authors conform accuracy. Availability of data and materials: the datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and informed consent: the study was approved by the local ethical committee of Milano Area 3 (approval number 338- 18052022). Owing to retrospective and de-identified data collection, the need for informed consent was waived. Acknowledgments: we would like to thank our NIV Group, all doc- tors and nurses of ASST Niguarda, for their great effort. Received for publication: 24 February 2023. Accepted for publication: 28 April 2023. 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; 19:11274 doi:10.4081/ecj.2023.11274 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, 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 manufacturer is not guaranteed or endorsed by the publisher. Evaluation of PaCO2 trend in COVID-19 patients undergoing helmet CPAP in the emergency department Nicolò Capsoni,1 Daniele Privitera,1 Chiara Airoldi,2 Silvia Gheda,1 Annamaria Mazzone,1 Gianluca Terranova,1 Filippo Galbiati,1 Andrea Bellone1 1Department of Emergency Medicine, ASST Grande Ospedale Metropolitano Niguarda, Milan; 2Department of Translation Medicine, University of Piemonte Orientale, Novara, Italy No n- co mm er cia l u se on ly col. Other respiratory parameters, H-CPAP failure, defined as the need for ETI, and in-hospital mortality were also assessed. Materials and Methods This case series was conducted between 13th November 2020 and 3rd March 2021 in the Emergency Department of the ASST Niguarda Hospital, Milan, Italy. The study was approved by the local ethical committee of Milano Area 3 (approval number 338- 18052022). Owing to retrospective and de-identified data collec- tion, the need for informed consent was waived. Patients admitted to the ED with ARF due to COVID-19 pneu- monia treated with H-CPAP, according to our local protocol and eligible for ETI, were included in the study.11 Diagnosis of COVID-19 pneumonia was made if typical computed tomography scan patterns were present (ground-glass opacities, crazy-paving pattern, consolidations) and a SARS-CoV2 infection was con- firmed by positive real-time reverse transcriptase-polymerase chain reaction assay of the nasopharyngeal swab.12 Inclusion criteria were age 18 years or older, preserved state of consciousness defined as Kelly ≤ 3, stable hemodynamics, SpO2 level < 94% and respiratory rate (RR) ≥ 28 despite oxygen therapy supplied for at least 15 minutes through a face mask, according to our local protocol. Exclusion criteria were the need for immediate intubation, altered state of consciousness, hemodynamic instability defined as systolic pressure <90 mmHg unresponsive to fluids replacement or requiring amines and/or major arrhythmias, inability to protect the airways, recent surgery on the skull or esophagus, trauma and cran- iofacial burns, and undrained pneumothorax. Patients who received a Do Not Intubate (DNI) order due to extremely poor functional status prior to admission, very low predicted probability of hospital survival and comorbidities, were also excluded. The ETI eligibility and the decision to intubate the patient was based on a multidisciplinary discussion between the emergency physician in charge and the critical care physician, after discussion with the senior ICU physician when necessary. Clinical criteria were mainly used for ETI: respiratory arrest, respiratory pauses with loss of consciousness, severe hemodynamic instability, septic shock, multi-organ failure, need for sedation, worsening of vigi- lance (an increase of the Kelly scale >3), persistence or worsening of respiratory distress (presence of use of accessory respiratory muscles or paradoxical abdominal movement), PaO2/FiO2 value reduction and muscular exhaustion despite CPAP/non-invasive ventilation treatment. CPAP local protocol All the enrolled patients started a 120 minutes trial H-CPAP, following a local protocol, with a strict nursing evaluation and monitoring. CPAP was delivered through the helmet and high- flow-generating devices, able to deliver a minimum of 60 L/min flow required to match the patient’s inspiratory flow and avoid CO2 rebreathing.13 Air-oxygen blenders (“BLENDER”; RM/145-2, Flow-Meter S.p.A., Levate, Italy), turbine (Monnal T75, Air Liquide Medical Systems, Paris, France), and three Venturi sys- tems (EasyFlow, Dimar, Mirandola, Italy; 9293/D, Harol, S. Donato Milanese, Italy; Whisperflow, Philips Respironics, Murrysville, PA, USA) were used, according to the availability of the moment.14 The initial settings were a PEEP of 7.5 cm/H20, a Flow ≥ 60L/min and a FiO2 titrated to reach a SpO2 ≥ 94% and a RR ≤ 25 bpm. PEEP was increased by 2.5 cm/H2O up to a maximum of 12,5 cm/H2O every 30 minutes in case of failure to reach the RR target. To limit air contamination, HME or electrostatic filters were applied at the expiratory port of the helmet-CPAP, and because of PEEP increase inside the helmet due to the filter application, PEEP was monitored with a manometer every different step up.15,16 To increase patient comfort, counterweights instead of shoulder straps and earplugs were used, and nurses focused their attention on the interventions that contribute to increasing the patient’s comfort to maximize the acceptability of the interface.17 Data collection Vital signs and ventilation parameters were prospectively recorded before the CPAP trial was started and then every 30 min- utes until the end of the trial. SpO2, RR, PEEP, FiO2 and body tem- perature were recorded before the CPAP trial was started and then every 30 min until the end of the trial (t0 - t30 e t60 e t90 e t120). Arterial blood gases were recorded before and after 120 minutes of CPAP. Demographics, comorbidities, and clinical findings at admis- sion were recorded. Patients were followed until hospital discharge. Data analysis Sociodemographic variables and clinical data were reported as absolute and relative frequencies for categorical variables, while for numerical ones, the mean, and the corresponding standard deviation (SD) or median and interquartile range (IQR) were reported as appropriate. To explore the association between ETI and sociodemographic and clinical variables X2 test or Fisher’s exact test, and the student or Mann-Whitney U test were used. Then, parameters related to the use of CPAP (FiO2, PEEP, RR, and SpO2) were evaluated in time using a mixed model for repeat- ed measures to compared ETI and non-ETI group. Particularly, each parameter was considered as outcome and time was included as covariate; Beta and 95% confidence intervals [95% CI] were reported. A graphical representation was also reported to better visualize the time trend in each group. The significant threshold was set to 0.05 (two-tailed and all statistical analyses were per- formed using the SAS software (version 9.4). Results A total of 54 patients were observed. Forty-six (85.2%) were males, and the mean age was 62 years. Comorbidities and clinical findings are reported in Table 1. The median PaO2/FiO2 was 100 mmHg [72.5-192.5], and the median PaCO2 was 32.9 [29-35] mmHg. Twenty-two patients (40.7%) underwent ETI after the first trial of H-CPAP. There was no difference in PaO2/FiO2 ratio values between ETI and non-ETI groups (91 mmHg [IQR 68-185] vs. 104 mmHg [IQR 85-215], p=0.137, respectively). No differences were found either for PaCO2 values on admission (31.5mmHg [IQR 27- 35] vs 29.3mmHg [IQR 27.7-40], p=0.399, respectively) and for PaCO2 variations after the CPAP trial (mean 2.38mmHg ±3.65 vs 2.73 mmHg ±3.96, p=0.556, respectively). ETI was performed after 1 [0-4] day of CPAP. Respiratory and CPAP-related parameters (PEEP, FiO2, RR, and SpO2) and their variation over time are shown in Figure 1, while in supplementary material we reported the value of parame- ters in time. Considering the models with CPAP-related parameters and ETI as a covariate, statistically significant changes between the Article [Emergency Care Journal 2023; 19:11274] [page 25] No n- co mm er cia l u se on ly two groups were found for PEEP (p=0.03) and SpO2 (p=0.046). Particularly, the ETI groups than non-ETI had a higher value of PEEP of 0.58 [95% CI 0.05; 1.11] and lower value of SpO2 of -1.00 [-1.98; -0.01]. No significant changes were found for FiO2 (p=0.084) and RR (p=0.102). Of 54 patients, 7 (12.9%) died, all of them after ETI, whereas 39 (72.2%) were discharged, and 8 ETI patients (14.8%) were lost during follow-up because they trans- ferred to other hospitals. The median length of hospital stay was for ETI and not ETI patients 33 [18-47] vs 16 [8-23] days - p=0.0032, respectively. Discussion As known, non-invasive ventilation failure is an independent risk factor for death in patients with hARF.18,19 Although burdened by the risk of treatment failure, in real-life experience, a first short CPAP trial was often attempted in the ED in patients with hARF due to COVID-19 to ameliorate hypoxia and dyspnea while pro- ceeding with the first diagnostic tests and while evaluating ETI eli- gibility and need.1,2 A careful selection of patients and strict bed- side monitoring are mandatory during the first hours of CPAP trial to assess the response in terms of gas exchange and respiratory dis- tress. Different CPAP protocols previously proposed a progressive upgrade of oxygen and respiratory support with a strict clinical patients monitor.1,2 Clinical evaluation of respiratory distress and mechanics, respiratory parameters, and blood gases are often the only non-invasive bedside instruments available to ED clinicians and nurses to roughly quantify the degree of respiratory failure and inspiratory effort during CPAP treatment. As postulated by Grieco et al.,10 lower PaCO2 values may represent a higher inspiratory effort. Therefore, in our study, we evaluated PaCO2 values and trends as potential simple bedside surrogates of increased respira- tory drive in COVID-19 patients during CPAP treatment. Most of our patients had severe respiratory failure (PaO2/FiO2 ratio 100 mmHg [72.5-192.5]) with significant hypocapnia (PaCO2 32,9 mmHg [29-35]). We observe a general increase in PaCO2 after 120 minutes of the CPAP trial, with a reduction of RR and an increase of SpO2, with no significant difference in those undergoing ETI compared to the others. Statistically significant changes between the two groups were found for PEEP and SpO2. According to our protocol, higher values of PEEP were applicated to patients with persistent respiratory distress and higher RR, thus suffering a more severe respiratory failure. Therefore, the higher PEEP and lower SpO2 values probably reflected a higher severity of the disease. The generalizability of our results is undoubtedly limited by the retrospective study design and the small sample size. Furthermore, we evaluated the PaCO2 trend after 120 minutes, given that a longer CPAP trial in hARF could have delayed ETI Article Figure 1. PEEP, Respiratory Rate, SpO2, and FiO2 values over time in the ETI group (blue line) and non-ETI group (red line). PEEP, pos- itive end-expiratory pressure; RR, respiratory rate; FiO2, fraction of inspired oxygen; SpO2, peripheral oxygen saturation. [page 26] [Emergency Care Journal 2023; 19:11274] No n- co mm er cia l u se on ly and have been harmful. It could be reasonable to evaluate a PaCO2 improvement after a longer time-lapse. Moreover, other PaCO2 determinants besides the hypoxemic stimulus correction should be considered. However, based on our knowledge, this is the first study in which the PaCO2 trend was evaluated after 120 minutes of a standardized CPAP trial. Non-invasive repeatable and easy-to- implement monitoring methods to assess the inspiratory effort and evaluate the risk of CPAP failure are needed to guide clinicians. Among these diaphragmatic ultrasound, allowing the evaluation of diaphragmatic mass and thickening fraction, represents an interest- ing new bedside tool.20,21 The hypothesis that a lower PaCO2 may represent a higher inspiratory effort and that its trend may help to evaluate CPAP response is interesting and need well-sized observational studies to be evaluated. Conclusions Changes in PaCO2 values were observed during the first closed-monitored CPAP trial, but no difference was found in those undergoing ETI compared to others. Larger studies are necessary to confirm our results, evaluate the efficacy of non-invasive surro- gate parameters to assess the inspiratory effort and guide clinicians and nurses treating hARF with CPAP. References 1. Brusasco C, Corradi F, Dazzi F, et al. The use of continuous positive airway pressure during the second and third waves of the COVID-19 pandemic. ERJ Open Res 2023;9:00365-2022. 2. Brusasco C, Corradi F, Di Domenico A, et al. Continuous pos- itive airway pressure in COVID-19 patients with moderate- Tosevere respiratory failure. Eur Res J 2021;57:10-13. 3. Corradi F, Brusasco C. The puzzle of non-invasive respiratory support in COVID-19. Minerva Anestesiologica 2023;89:7-9. 4. Winck JC, Scala R. Non Invasive Respiratory Support Therapies in COVID-19 Related Acute Respiratory Failure: Looking at the Neglected Issues. Arch Bronconeumol 2021;57:9-10. 5. Bellani G, Grasselli G, Cecconi M, et al. Noninvasive ventila- tory support of patients with covid-19 outside the intensive care units (ward-covid). Ann Am Thor Soc 2021;18:1020-6. 6. Tonelli R, Fantini R, Tabbì L, et al. Early inspiratory effort assessment by esophageal manometry predicts noninvasive ventilation outcome in de novo respiratory failure: A pilot study. Am J Resp Critical Care Med 2020;202:558-67. 7. Spinelli E, Marongiu I, Mauri T. Control of Respiratory Drive by Noninvasive Ventilation as an Early Predictor of Success. Am J Res Critical Care Med 2020;202:1737-8. 8. Bose E, Hoffman L, Hravnak M. Monitoring cardiorespiratory instability: Current approaches and implications for nursing Article [Emergency Care Journal 2023; 19:11274] [page 27] Table 1. Baseline characteristics, clinical findings, blood gas analysis and outcomes of the study population and of the ETI and non-ETI group. All (n=54) ETI (n=22) Non-ETI (n=32) Females 8 (14.81) 2 (9.09) 6 (18.75) Age, mean (±SD) 62.24 (±9.88) 57.18 (±10.06) 65.72 (±8.23) Comorbidities Obesity, n (%) 12 (22.22) 3 (13.64) 9 (28.13) Hypertension, n (%) 28 (51.85) 11 (50.00) 17 (53.13) Diabetes, n (%) 6 (11.11) 1 (4.55) 5 (15.63) Immunosuppression, n (%) 4 (7.41) 1 (4.55) 3 (9.38) Active cancer, n (%) 2 (3.70) 1 (4.55) 1 (3.13) Pulmonary disease, n (%) 4 (7.41) 3 (13.64) 1 (3.13) Heart disease, n (%) 8 (14.81) 3 (13.64) 5 (15.63) Chronic renal failure, n (%) 3 (5.56) 0 3 (9.38) Autoimmune disease, n (%) 1 (1.85) 0 1 (3.13) Symptoms Fever, n (%) 39 (72.22) 17 (77.27) 22 (68.75) Cough, n (%) 19 (35.19) 9 (40.91) 10 (31.25) Dyspnea, n (%) 47 (87.04) 20 (90.91) 27 (84.38) Asthenia and/or myalgia, n (%) 14 (25.93) 10 (45.45) 4 (12.50) Dysgeusia and/or anosmia, n (%) 2 (3.70) 2 (9.09) 0 Days from symptoms onset to hospital admission, median [IQR] 2 [2-3] 3 [2-3] 2 [1-3] Blood gas analysis before CPAP trial pH 7,47 [7,44-7,49] 7,48 [7,45-7,49] 7,46 [7,44-7,50] PaCO2, mmHg 32,9 [29-35] 31,5 [27-34,9] 29.3 [27,7-34] PaO2/FiO2 ratio, mmHg 100 [72,5-192,5] 91 [68-185] 104 [85-215] PaCO2 variations after 120 minutes of CPAP treatment, mean (±SD) +2,38 mmHg (±3,65) +2,73 mmHg (±3,96) Outcomes In-hospital mortality, n (%) 7 (12,9%) 7 (50%) 0 Days of length of stay, median [IQR] 23 [12-33] 33 [18-47] 16 [8-23] Days of NIV, median [IQR] 5 [1-9] 1 [0-4] 7 [4-12] N, number; FiO2: fraction of inspired oxygen; SpO2, peripheral oxygen saturation; CPAP, continuous positive airway pressure; NIV, non-invasive ventilation. No n- co mm er cia l u se on ly practice. Intens Critical Care Nurs 2016;34:12-9. 9. Privitera D, Mazzone A, Vailati P, et al. Improving Helmet CPAP Use During COVID-19 Pandemic: A Multidisciplinary Approach in the Emergency Department. Dimens Crit Care Nurs 2022;41:178-81. 10. Grieco DL, Menga LS, Cesarano M, et al. Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial. JAMA 2021;325:1731- 43. 11. Privitera D, Angaroni L, Capsoni N, et al. Flowchart for non- invasive ventilation support in COVID-19 patients from a northern Italy Emergency Department. Intern Emerg Med 2020;15:767-71. 12. Chung M, Bernheim A, Mei X, et al. CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV). Radiology 2020;295:202-7. 13. Bellani G, Patroniti N, Greco M, et al. The use of helmets to deliver non-invasive continuous positive airway pressure in hypoxemic acute respiratory failure. Minerva Anestesiol 2008;74:651-6. 14. Privitera D, Capsoni N, Zadek F, et al. Flow generators for hel- met CPAP: Which to prefer? A bench study. Intensive Crit Care Nurs 2023;74:103344. 15. Cabrini L, Landoni G, Zangrillo A. Minimise nosocomial spread of 2019-nCoV when treating acute respiratory failure. Lancet 2020;395:685. 16. Privitera D, Capsoni N, Zadek F, et al. The Effect of Filters on CPAP Delivery by Helmet. Respir Care 2022;67:995-1001. 17. Lucchini A, Elli S, Bambi S, et al. How different helmet fixing options could affect patients' pain experience during helmet- continuous positive airway pressure. Nurs Crit Care 2019;24: 369-74. 18. Bellani G, Laffey JG, Pham T, et al. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study. Am J Respir Crit Care Med 2017;195:67-77. 19. Demoule A, Girou E, Richard JC, Taille S, Brochard L. Benefits and risks of success or failure of noninvasive ventila- tion. Intensive Care Med 2006;32:1756-65. 20. Corradi F, Isirdi A, Malacarne P, et al. Low diaphragm muscle mass predicts adverse outcome in patients hospitalized for COVID-19 pneumonia: An exploratory pilot study. Minerva Anestesiologica 2021;87:432-8. 21. Corradi F, Vetrugno L, Orso D, et al. Diaphragmatic thickening fraction as a potential predictor of response to continuous pos- itive airway pressure ventilation in COVID-19 pneumonia: A single-center pilot study. Respir Physiol Neurobiol 2021;284: 103585. Article [page 28] [Emergency Care Journal 2023; 19:11274] No n- co mm er cia l u se on ly