Open access Protocol Awake prone positioning of hypoxaemic patients with COVID-19: protocol for a randomised controlled open-­label superiority meta-­trial Elsa Tavernier ‍ ‍,1,2 Bairbre McNicholas,3,4 Ivan Pavlov,5 Oriol Roca,6,7 Yonatan Perez,8 John Laffey,3,4 Sara Mirza,9 David Cosgrave,3,4 David Vines,9 Jean-­Pierre Frat,10 Stephan Ehrmann,8 Jie Li ‍ ‍9 To cite: Tavernier E, ABSTRACT McNicholas B, Pavlov I, et al. Strengths and limitations of this study Introduction Prone positioning (PP) is an effective first-­ Awake prone positioning line intervention to treat patients with moderate to severe of hypoxaemic patients ►► This pragmatic design will deal with the recruitment acute respiratory distress syndrome (ARDS) receiving with COVID-19: protocol for difficulties that could occur in the individual trials invasive mechanical ventilation, as it improves gas a randomised controlled given the uncertainties of the international dynamics open-­label superiority exchanges and reduces mortality. The use of PP in awake of the COVID-19 pandemic. meta-­trial. BMJ Open spontaneous breathing patients with ARDS secondary to ►► The collaborative interim analysis plan at the level 2020;10:e041520. doi:10.1136/ COVID-19 was reported to improve oxygenation in few of the meta-­trial will enable an earlier data analysis bmjopen-2020-041520 retrospective trials with small sample size. High-­level compared with the individual study level or to a ret- evidence of awake PP for hypoxaemic patients with ►► Prepublication history and rospective meta-­analysis. COVID-19 patients is still lacking. supplemental material for this ►► Besides synthesising the effect size estimates, it paper is available online. To Methods and analysis The protocol of this meta-­trial also considers the aspect of replication: results be- view these files, please visit is a prospective collaborative individual participant data ing consistent across trials is a strength in favour of the journal online (http://​dx.​doi.​ meta-­analysis of randomised controlled open label a robust treatment effect over different conditions. org/​10.​1136/​bmjopen-​2020-​ superiority trials. This design is particularly adapted to a ►► The lack of blinding of trial participants, care pro- 041520). rapid scientific response in the pandemic setting. It will viders and outcome assessors is an unavoidable take place in multiple sites, among others in USA, Canada, Received 11 June 2020 limitation of the study design. Ireland, France and Spain. Patients will be followed up for Revised 08 September 2020 28 days. Patients will be randomised to receive whether Accepted 06 October 2020 awake PP and nasal high flow therapy or standard medical treatment and nasal high flow therapy. Primary outcome (ICU), mortality rates of up to 42% have been is defined as the occurrence rate of tracheal intubation described.3 As of 6 June 2020, 51.2% of the 6128 or death up to day 28. An interim analysis plan has been UK hospitalised patients with COVID-19 that set up on aggregated data from the participating research required advanced respiratory support died3 groups. and 36% mortality was reported for invasively Ethics and dissemination Ethics approvals were obtained in all participating countries. Results of the meta-­ ventilated COVID-19 patients in a single centre trial will be submitted for publication in a peer-­reviewed in Atlanta.4 journal. Each randomised controlled trial was registered High flow nasal cannula (HFNC) oxygen individually, as follows: NCT04325906, NCT04347941, therapy provides oxygen-­rich heated humidi- NCT04358939, NCT04395144 and NCT04391140. fied gas to the patient’s nose at flow rates suffi- cient to deliver a constant, precisely set high fraction of inspired oxygen (FiO2). HFNC INTRODUCTION washes out the dead space carbon dioxide, © Author(s) (or their Background and rationale provides a low level of positive end-­expiratory employer(s)) 2020. Re-­use COVID-19 is an emerging infectious disease that pressure and decreases breathing frequency permitted under CC BY-­NC. No commercial re-­use. See rights was first reported in Wuhan, China, and had and work of breathing.5 6 In hypoxaemic and permissions. Published by subsequently spread worldwide. As of 6 June respiratory failure, HFNC use is associated BMJ. 2020, more than 6 million cases were confirmed with lower mortality, lower rates on endo- For numbered affiliations see globally, and close to 0.4 million deaths were tracheal intubation and improved oxygen- end of article. reported.1 Nearly 20% of patients experienced ation.7–9 It has been extensively used early in Correspondence to hypoxemia, which was the primary reason for the COVID-19 outbreak in China.10 Dr Elsa Tavernier; hospitalisation.2 In patients with severe disease Prone positioning (PP) of mechanically ​elsa.​tavernier@​univ-​tours.​fr who were admitted to the intensive care unit ventilated patients is an effective first-­ line Tavernier E, et al. BMJ Open 2020;10:e041520. doi:10.1136/bmjopen-2020-041520 1 Open access intervention to treat patients with moderate to severe acute two parallel groups and a primary endpoint of thera- respiratory distress syndrome (ARDS) receiving invasive peutic failure at day 28. mechanical ventilation, as it improves gas exchanges and reduces mortality.11 12 There is limited evidence to support Study setting awake PP of patients treated with HFNC. Two small studies This meta-­trial will include patients with severe COVID-19 showed that PP was feasible in spontaneously breathing pneumonia treated with HFNC in the ICU, in emergency patients.13 14 In one of them, PP combined with HFNC departments, in high-­dependency units and on medical resulted in higher arterial partial pressure of oxygen (PaO2) wards of participating hospitals. A full list of participating to FiO2 ratios than HFNC alone.13 However, not all hypox- institutions is available in each individual trial record on​ aemic patients with COVID-19 responded to awake PP.15 In ClinicalTrials.​gov. The original protocols are in online a retrospective study of 610 patients from China,16 a multi- supplemental files 1-4). pronged intervention that included early and aggressive use of HFNC and non-­invasive ventilation (NIV) along with PP Eligibility criteria for awake patients resulted in lower overall mortality (3.33%, All adult patients with proven (or clinically suspected, as compared with 4.34% in a nearby province). A very low pending microbiological confirmation) COVID-19 pneu- percentage of patients required mechanical ventilation monia who require treatment with HFNC are eligible for (<1%, as compared with the national average of 2.3%,17 in a this trial. population that included 10% of critically ill patients). The Eligibility criteria for potential trial participants are authors highlighted that mortality was lower than in a previ- described in table 1. ously reported cohort study of patients with ARDS performed at the same institution prior to the pandemic,18 although is Recruitment not clear if the two populations were comparable in terms of Due to the rapidly evolving pandemic situation, we have a disease severity. Since the outbreak, the use of awake PP with strong uncertainty about the pace of enrolment. We antic- different oxygen modalities has been described in case series ipate this international collaboration to lead to better reports by teams from the USA, France, Italy and China.19–23 recruitment than individual trials studying the same However, none of them provided high-­level evidence of the population. Other individual RCTs may be added into effects on patients’ outcome. this meta-­trial study, as long as inclusion criteria, main Based on the potential beneficial mechanisms of HFNC outcomes and trial interventions are sufficiently similar. and PP, early use of PP combined with HFNC to avoid the need for intubation in COVID-19 patients with moderate Interventions to severe ARDS needs to be further investigated. Control group Due to the urgent need to find effective treatments for The patients in the control groups will be treated COVID-19, this meta-­trial will gather together several trials according to the same standard of care and receive the launched independently at the beginning of the COVID-19 same oxygenation support with HFNC as in the interven- pandemic. As of 6 May 2020, eight randomised trials eval- tion groups, but they will not be asked to remain in prone uating the efficacy of PP in patients with COVID-19 were position. Details for each trial are presented in table 2. registered on ​ClinicalTrials.​gov. Early in the pandemic, we organised a meeting with the investigators and methodol- Intervention description ogists of the teams whose trials planned to include similar The patients in the intervention groups will turn in prone populations to address the same question of the effects of position with the help and under the supervision of a PP. We have decided to combine our recruitment capabili- caregiver to ensure that they are predominantly on their ties and design an international meta-­trial.24 25 This protocol chest rather than on their side. Patients will be asked to includes a common analysis plan for the primary endpoint remain in prone position as long as they can and as close with four interim analysis in order to obtain early evidence. as possible to 16 hours or more per day or more. Objectives Criteria for continuing or modifying allocated interventions The primary objective is to demonstrate the efficacy of Proning procedure will continue as long as the patient is PP combined with HFNC in terms of treatment failure in the following oxygen conditions: rate at 28 days, defined as a combination of (1) death and ►► PaO2/FiO2 below 200 or SpO2 (peripheral oximetry (2) intubation, in awake and spontaneously breathing saturation) to FiO2 ratio below 235 in the Irish trial. patients with suspected or confirmed COVID-19 infection. ►► PaO2/FiO2 (or SpO2/FiO2) below 300 mm Hg (or 315) in the French and Spanish trials. ►► PaO2/FiO2 below 200 mm Hg or SpO2/FiO2 below METHODS AND ANALYSIS 240 in the Canadian and American trial. Trial design Proning will be left at the discretion of the clinician in This meta-­ trial is designed as a collaborative indi- case of intubation. vidual participant prospective data meta-­analysis of five Proning will be interrupted in case of discharge or randomised controlled open-­label superiority trials with death. 2 Tavernier E, et al. BMJ Open 2020;10:e041520. doi:10.1136/bmjopen-2020-041520 Open access Table 1 Eligibility criteria in each trial USA and Canada Ireland France and Spain Inclusion criteria 1. COVID-19 pneumonia based on the 1. Suspected or confirmed 1. Adult patient suffering from COVID-19 Ccenters for Disease Control guidelines. COVID-19 infection. pneumonia according to the diagnostic 2. Presence of acute hypoxaemic respiratory 2. Bilateral Infiltrates on chest criteria in effect at the time of inclusion or failure. X-­ray very strongly suspected. 3. Acute onset within 7 days of insult or new SpO2 <94% on FiO2 40% by ei- 2. Patient treated by nasal high flow therapy. (within 7 days) or worsening respiratory ther venturi facemask or HFNC 3. Moderate or severe ARDS: bilateral symptoms. 3. Respiratory rate <40 breath/min. radiological opacities not explained entirely 4. Bilateral opacities on chest X-­ray or CT 4. Written informed consent. by effusions, atelectasis or nodules; acute scanner not fully explained by effusions, hypoxaemia with worsening within the seven lobar or lung collapse, or nodules. previous days, not entirely explained by left 5. Cardiac failure not the primary cause of ventricular failure; PaO2/FiO2 ratio <300 mm acute respiratory failure. Hg (or equivalent SpO2/FiO2). 6. Written informed consent 4. Written informed consent in France and oral 7. PaO2/FiO2 ratio <200 mm Hg or SpO2/FiO2 consent in Spain. <240 with HFNC at 50 L/min and peripheral capillary oxygen saturation (SpO2) maintained at 92%–95%. Exclusion 1. Patients with a consistent SpO2 <80% when 1. Age <18 years. 1. Indication for immediate tracheal intubation. criteria evaluated with a FiO2 of 0.6, or signs of 2. Uncooperative or likely to be 2. Significant acute progressive circulatory respiratory fatigue (respiratory rate >40/ unable to lie on abdomen for insufficiency. min, partial pressure of carbon dioxide 16 hours. 3. Impaired consciousness, confusion and (PaCO2)>50 mm Hg/pH <7.30 and obvious 3. Vomiting or bowel obstruction. restlessness. accessory respiratory muscle use). 4. Palliative care. 4. Body mass index >40 kg/m2. 2. Immediate need for intubation (PaO2/FiO2 5. Multiorgan failure. 5. Chest trauma or other contraindication to <50 mm Hg or SpO2/FiO2 <90, unable to 6. Standard contraindications to PP. protect airway or mental status change). PP including the presence of 6. Pneumothorax. 3. Haemodynamic instability (sustained an open abdominal wound, 7. Vulnerable person: safeguard of justice, systolic blood pressure <90 mm Hg, unstable pelvic fracture, curatorship or tutorship known at inclusion. sustained mean blood pressure below spinal lesions and instability, 8. Pregnant or lactating woman. 65 mm Hg or requirement for vasopressor). pregnancy >20/40 gestation and 4. Unable to collaborate with HFNC/PP with brain injury without monitoring agitation or refusal of HFNC/PP. of intracranial pressure. 5. Chest trauma or any contraindication for PP. 6. Pneumothorax. 7. Age <18 years. 8. Pregnant. 9. Body mass index >40 kg/m2. ARDS, acute respiratory distress syndrome; FiO2, fraction of inspired oxygen; HFNC, high flow nasal cannula; PaO2, partial pressure of oxygen; PP, prone positioning. The following guidance is provided concerning the –– Lack of improvement of signs of respiratory muscle need for tracheal intubation to perform invasive mechan- fatigue. ical ventilation. Intubation is recommended in case of7: –– Development of copious tracheal secretions. 1. Signs of persisting or worsening respiratory failure, de- –– Hypercapnic respiratory acidosis with a pH below fined by at least two of the following criteria: 7.25. –– Respiratory rate above 40 breaths/min. Table 2 Standard management in each trial USA and Canada Ireland France and Spain HFNC will be initiated at 50 L/min (AIRVO2 or Control patients will receive full HFNC adapted for an SpO2 of 90%–95%. Optiflow, Fisher & Paykel Healthcare Limited, standard care. Except in case of poor tolerance by the patient Auckland, New Zealand) with temperature set a minimum gas flow rate of 50 L/min will be at 37°C. Nasal cannula size will be determined set initially. Weaning of the HFNC will first be by the patient’s nostril size (≤50%). FiO2 will be performed reducing FiO2 down to 0.4 before adjusted to maintain SpO2 at 92%–95%. Flow reducing the gas flow rate. In clinically stable and temperature will be adjusted based on patients with a FiO2 less than or equal to 0.4 patient’s comfort and clinical response. and a gas flow rate less than or equal to 30 L/ min, an attempt will be made to switch to standard oxygen therapy at 4–6 L/min. FiO2, fraction of inspired oxygen; HFNC, high flow nasal cannula. Tavernier E, et al. BMJ Open 2020;10:e041520. doi:10.1136/bmjopen-2020-041520 3 Open access SpO2 below 90% at FiO2 ≥0.8 for more than 5 min –– ►► Association between time of onset and outcome. without technical dysfunction. 2. Haemodynamic instability. Other measures 3. Deterioration of neurological status. In the PP groups complications will be recorded; compli- For patients who meet the intubation criteria in cations include skin breakdown, device removal or the HFNC and HFNC+PP groups, a trial of NIV might desaturation during position change (within 28 days of be allowed according to the physician’s preference in randomisation). patients with signs of persisting or worsening respiratory Plans for assessment and collection of outcomes failure and no other organ dysfunction before performing Protocol explanation will be provident to study sites endotracheal intubation and invasive ventilation. Reasons during a dedicated online or physical meeting. Assess- for intubation will be recorded as well. ment and collection of outcomes will be performed by Strategies to improve adherence to interventions investigators, physicians, nurses and research assistants The number of sessions and the total time spent in prone trained and used to deal with patients with hypoxaemia position will be collected per 24-­hour period, and encour- without additional training required. SpO2/FiO2 ratio agement will be provided. assessment requires the SpO2 to be equal of less than 97%. The primary outcome (intubation or death) is easily Relevant concomitant care permitted or prohibited during the retrieved from patients’ charts. Bedside sheets are made trial available to simplify data recording. Each individual study No prohibitions during the trial. coordinator is responsible for data quality control. Provisions for post-trial care Statistical methods Post-­trial care will be standard care through the standard Sample size healthcare system from each country. We assume the primary outcome rate to be between 60% and 70% in the control group. The meta-­analysis is Outcomes designed to demonstrate superiority of PP over control The primary outcome is therapeutic failure within 28 with 90% power and a one-­sided type I error rate of 2.5. days of randomisation, defined as intubation (successful For a fixed design with no interim analysis and a sample or attempted) or death. size of 836, the maximum detectable risk ratio will be between 0.847 and 0.814 (a difference of failure rates of Secondary outcomes about 11% between groups). For the same assumptions, ►► Days spent in the ICU and in the hospital (within 28 asymmetric two-­sided group sequential analysis requires days of randomisation). a sample size of 1000, for five interim analyses (including ►► Mortality in the ICU and in the hospital (within 28 the last analysis). Bounds were determined using a Kim-­ days of randomisation). DeMets spending function with parameters 0.75 for effi- ►► Primary outcome (intubation of death) among cacy and 3 for futility. This provides an aggressive Pocock patients receiving NIV in each randomisation groups. superiority bound and a conservative O’Brien Fleming ►► Time of escalation of therapy (in case of NIV use). bound for futility (figure 1). Sample sizes were computed ►► Length of HFNC therapy use in those patients who using the packages epiR and gsDesign in R software. succeeded with HFNC (efficacy). ►► Length of HFNC therapy in those patients who fail Randomisation with HFNC (safety). All patients who give consent for participation and who ►► Ventilator-­free days within the first 28 days. fulfil the inclusion criteria will be randomised. For each ►► Need for rescue treatments in those patients who trial, a professional statistician not involved in patient need to be intubated. recruitment will generate the allocation sequence. ►► Need for tracheotomy. Participants will be randomly assigned to either control ►► Organ failure different from respiratory failure. or experimental group with a 1:1 allocation as per a ►► Number of protocol violations. computer-­ generated randomisation schedule stratified ►► Time to intubation or death. by site and using varying block sizes. The American trial ►► Response to prone position: prechange and will also be stratified by ARDS severity (moderate vs postchange of SpO2/FiO2 ratio, respiratory rate and severe), and French and Spanish trial will also be strati- ROX index (SpO2/(FiO2 × respiratory rate). As a fied by the therapeutic use of the PP prior to inclusion. practical alternative to PaO2/FiO2, SpO2/FiO2 has In four trials, participants will be randomised using an been shown to have a strong linear relationship in online central randomisation system. In the Canadian moderate to severe ARDS.26 27 trial, allocation concealment will be ensured using on-­site ►► Duration of participation will be limited to 28 days sealed opaque envelopes. By the very nature of the inter- after randomisation for each patient. ventions and design, trial participants, care providers, ►► Daily duration with PP in the first 3 days after outcome assessors and data analysts could not be blinded enrolment. to interventions. 4 Tavernier E, et al. BMJ Open 2020;10:e041520. doi:10.1136/bmjopen-2020-041520 Open access 400 (200 in each arm), 600 (300 in each arm), 800 (400 in each arm) and 1000 the last possible analysis. The interim analyses define rules for stopping the trials early for the statistical reasons of established efficacy or futility on the primary outcome. Two professional academic statisticians will conduct all interim analyses (blind duplicates). At each interim analysis, the Z statistics for a difference of binary endpoints is computed from the data of the two arms and is compared with the efficacy and futility bounds given in figure 1. If the value of Z is higher than the interim analysis specific upper bound (or lower than the lower bound), the trials will be considered to be stopped for reasons of demonstrated efficacy (or futility), and data will be published as soon as possible to inform the clinical and scientific community; otherwise the trials will continue. Figure 1 Efficacy and futility stopping boundaries: analyses are planned every 200 patients randomised in the various trials. The interim analyses define rules for stopping the Methods for additional analyses (eg, subgroup analyses) trials early for the statistical reasons of established efficacy We plan to conduct a subgroup analysis on the severity or futility on the primary outcome. Bounds were determined of ARDS: PaO2/FiO2 ratio below 150 mm Hg, PaO2/FiO2 using a Kim-­DeMets spending function with an aggressive ratio above 150 mm Hg (or equivalent SpO2/FiO2 ratio). Pocock superiority and a conservative O’Brien Fleming We will test if the treatment effects differ with severity of bound for futility. ARDS by putting their main effect and interaction terms in the logistic regression. Statistical methods for primary and secondary outcomes Adjusted analyses will be nested in the intervention We plan a prospective meta-­analysis of individual data. group to evaluate the effect of duration of PP on the risk Common variables from all datasets will be gathered and of intubation or death, as well as the analysis of prog- combined to conduct the analysis. A detailed analysis nostic factors associated with PP such as comorbidities, plan will be a priori defined. The primary analysis will be age, body mass index and so on. performed on an intent-­to-­treat basis. A sensitivity analysis will be performed on a per-­protocol set described below. Methods in analysis to handle protocol non-adherence and any Baseline patient characteristics will be presented by statistical methods to handle missing data country and treatment group. The comparison between We do not expect any patient to be lost to follow-­up. intervention arms will be synthesised using mixed-­effects The only missing data could relate to patients who with- models with a random effect on the trial: a mixed-­effects draw their consent. In this case, we will perform multiple logistic regression for the primary outcome and any binary outcome. A survival analysis will be performed imputations on the primary outcome. We will analyse the on mortality and any other time-­to-­event outcome, using primary outcome using two analysis sets: the intention-­to-­ a gamma-­frailty term on each trial in a Cox regression treat set, considering all patients as randomised regard- model providing that the assumption of proportional less of whether they performed the prone position, and hazards is verified. Regarding adverse events, descrip- the per-­protocol analysis set. The per-­protocol set will tive statistics (percentages) will be estimated. We plan to only include patients who spent at least 1 hour in prone assess statistical heterogeneity between countries by visual position after randomisation without intubation or death. inspection of the forest plots, which will also present per-­ Patients in the intervention group who spent less than country analyses, and by calculating the Q and I² statistics. 1 hour daily in PP and patients in the control group who remained more than 1 hour at least 1 day in PP will be Interim analyses excluded. We chose a Kim-­ spending approach28 29 DeMets alpha-­ rather than other methods such as a triangular test for its simplicity of implementation and for the continuous stopping boundaries enabling to be more flexible in ETHICS AND DISSEMINATION managing interim analysis if the design of the trial were Ethics and consent to change as a result of an unexpected development of Ethics approval was obtained in all five participating the epidemic. countries. Informed consent will be obtained according Analyses are planned when the total number of to local regulations in each trial. Local investigators will randomised patients with the primary outcome available obtain either verbal or electronic consent. Documenta- from the various trials reaches 200 (100 in each arm), tion of consent will be either written or electronic. Tavernier E, et al. BMJ Open 2020;10:e041520. doi:10.1136/bmjopen-2020-041520 5 Open access Data management, transfer and deposition Contributors BM, IP, OR, YP, JoL, SM, DC, J-­PF, SE and JiL conceived the trials. ET The details of data management procedures can be provided methodological expertise in the meta-­trial design and prepared the first draft of this study protocol. BM, IP, OR, YP, JoL, SM, DC, J-­PF, SE and JiL contributed found in the original protocols (online supplemental to the rewriting; all of the authors approved the final manuscript and reviewed it for files). Each investigator is responsible for the confiden- important intellectual content. tiality of the data collected during his or her trial. The Funding This work was supported by OpenAI. (3180 18th St, San Francisco, CA data sets will use pseudonymised data. Interim analyses 94110, USA; no grant number), Rice Foundation (8600 Gross Point Rd, Skokie, will be performed by centralising the aggregated data IL 60077, USA; no grant number), Fisher & Paykel (15 Maurice Paykel Place, East Tamaki, Auckland 2013 New Zealand; grant number PO 480003859) and of the primary endpoint per trial. The confidentiality of the French ministry of health (14 Avenue Duquesne, 75 350 Paris, France; grant data will be preserved when the coded, depersonalised number API20/T001). data will be transmitted and stored at the location of the Competing interests IP has been a speaker for Fisher & Pakyel Healthcare within statistician in charge of the final analysis. the last 3 years. All compensation was paid to the charitable foundation at the hospital where he works, and he did not personally receive any compensation. JL Steering committee discloses research support from Fisher & Paykel Healthcare for another research The steering committee will be responsible for reporting project. SE received unrestricted research grants, travel fee reimbursements and speaker fees from Fisher & Paykel Healthcare, consulting fees from La and interpreting the result of the interim analysis and the Diffusion Technique Française, consulting fees and unrestricted research grants final analysis. The steering committee will be composed from Aerogen Ltd and an unrestricted research grant from Hamiton medical. OR of principal investigators and statistician from all sites and provides consultancy to Hamilton Medical but he did not receive any personal fee. may be completed by independent investigators without All compensation were received by the Institute of Research of his Institution. He received speaker fees by Air Liquide. J-­PF reports grants from the French Ministry any competing interest. This study will be reported in of Health; grants, personal fees and non-­financial support from Fisher & Paykel accordance with the Consolidated Standards of Reporting Heathcare; personal fees and non-­financial support from SOS oxygene, outside the Trials statement for non-­ pharmacological trials and submitted work. published in peer-­reviewed journals. Patient consent for publication Not required. Provenance and peer review Not commissioned; externally peer reviewed. Dissemination strategy Supplemental material This content has been supplied by the author(s). It has The results of the study will be presented in national not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been and international conferences and published via a peer-­ peer-­reviewed. Any opinions or recommendations discussed are solely those reviewed journal. of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content Data sharing statement includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, Deidentified data will be made available on reasonable terminology, drug names and drug dosages), and is not responsible for any error request discussed among the steering committee. and/or omissions arising from translation and adaptation or otherwise. Open access This is an open access article distributed in accordance with the Study status Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which At the time of submitting for publication, the study was permits others to distribute, remix, adapt, build upon this work non-­commercially, collecting data. and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use Author affiliations is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. 1 Clinical Investigation Center, INSERM 1415, CHRU Tours, Tours, Centre, France ORCID iDs 2 Methods in Patients-­Centered Outcomes and Health Research, INSERM UMR 1246, Elsa Tavernier http://​orcid.​org/​0000-​0003-​0798-​1182 Nantes, Loire-­Atlantique, France Jie Li http://​orcid.​org/​0000-​0003-​0121-​1291 3 Department of Anaesthesia and Intensive Care Medicine, School of Medicine, National University of Ireland Galway, Galway, Ireland 4 Department of Anaesthesia, University Hospital Galway, Saolta University Hospital Group, Galway, Ireland 5 Department of Emergency Medicine, Hopital de Verdun, Montreal, Quebec, Canada 6 REFERENCES Critical Care Department, Vall d'Hebron University Hospital, Vall d'Hebron Research 1 WHO. Coronavirus disease (COVID-19) Dashboard. 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