M.D Alain Combes
email: alain.combes@aphp.fr

M.D Giles J Peek

M.D David Hajage

MSc Pollyanna Hardy

M.D.; Darryl Abrams

M.D Matthieu Schmidt

M.D Agnès Dechartres

Diana Elbourne

ECMO for severe acute respiratory distress syndrome: systematic review and individual patient data meta-analysis

Keywords: Extracorporeal Membrane Oxygenation, Acute Respiratory Distress Syndrome, Adult patients, individual patient data meta-analysis

ECMO for severe acute respiratory distress syndrome:

systematic review and individual patient data meta-analysis.

Introduction

Ventilatory management of patients with severe acute respiratory distress syndrome (ARDS) has improved over the last decades with a strategy combining low tidal volume (VT) ventilation, [1] high positive end-expiratory pressure (PEEP), [2,3] neuromuscular blocking agents [4] and prone positioning. [5] However, ventilator-induced lung injury (VILI) may persist in these patients since a recent and large epidemiological study showed that their hospital mortality was still 46%. [6] Recently, even higher mortality was reported for patients with severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) infection who needed invasive mechanical ventilation. [START_REF] Cummings | Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study[END_REF][START_REF] Yang | Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study[END_REF][START_REF] Wang | Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China[END_REF] Venovenous extracorporeal membrane oxygenation (ECMO) providing full blood oxygenation, CO2 elimination and combined with more gentle ventilation has benefited from major technological advances in the last 15 years. [START_REF] Brodie | Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review[END_REF][START_REF] Schmidt | Mechanical Ventilation ! 19[END_REF] In 2009, favourable outcomes were reported in patients who received ECMO during the influenza A (H1N1) pandemic.[12-14] The Conventional Ventilator Support vs Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Failure (CESAR) trial [15,16] showed that transfer to an ECMO centre was associated with fewer deaths or severe disabilities at 6 months compared with conventional mechanical ventilation (37% vs. 53%; p 0 = 0.03), although 6 month mortality was not significantly reduced (37% vs. 45%; p = 0.07). The more recent ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial showed a non-statistically significant reduction in 60-day mortality with ECMO (35% vs. 46%; p = 0.09).[17] However, neither trial was separately powered to detect a 10-15% survival benefit with ECMO.

We performed a systematic review with an individual patient data meta-analysis of randomised controlled trials comparing ECMO to conventional mechanical ventilation in patients with severe ARDS. The primary objective was to evaluate the effect of ECMO on 90-day mortality.

Secondary objectives included the evaluation of ECMO for other clinical outcomes and in prespecified subgroups for the primary outcome.

! 6

Methods

Study Design

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Individual Patient Data (PRISMA-IPD checklist in eTable 1 in the Supplement) and the protocol was registered in PROSPERO (CRD42019130034).

Eligibility criteria

We included all randomised controlled trials (RCTs) evaluating venovenous ECMO in the experimental group and conventional ventilatory management in the control group, that included patients with ARDS fulfilling the American-European Consensus Conference definition [18] or the Berlin definition for ARDS, [19] and that were published or whose primary completion date was after 2000. [START_REF] Brodie | Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review[END_REF]20,[START_REF] Combes | Fifty Years of Research in ARDS. Is Extracorporeal Circulation the Future of Acute Respiratory Distress Syndrome Management?[END_REF] This choice was justified by the major improvements in intensive care treatments and in ECMO technology that occurred in the last two decades. Additional information on selection criteria is provided in the Supplement.

Search strategy

We searched MEDLINE via PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (Central) from January 1, 2000 to September 30, 2019 using a search algorithm developed for the purpose of this study and adapted to each database (eTable 2 in the Supplement). We also searched trial registries including ClinicalTrials.gov and the International Clinical Trial Registry Platform (ICTRP) for completed and ongoing trials, conference proceedings of major critical care ! 7 societies and screened reference lists of identified articles as well as systematic or narrative reviews on the topic (see the Supplement).

Selection and data collection

Selection was conducted independently by two reviewers (DA and MS) on titles and abstracts first and then, on the full text. For each included RCT, the corresponding author was contacted to provide fully anonymized individual patient data as well as format, coding and definition of any variables.

Risk of bias in each trial was evaluated by two independent reviewers (DH and AD) using the updated version of the risk-of-bias tool developed by Cochrane [START_REF] Sterne | RoB 2: a revised tool for assessing risk of bias in randomised trials[END_REF] (see the Supplement).

Study outcomes

The primary endpoint was mortality 90 days after randomisation. Main secondary endpoints comprised time to death up to 90 days after randomisation, treatment failure up to 90 days, defined as crossover to ECMO or death for patients in the control group, and death for patients in the ECMO group, number of days alive and out-of-hospital between randomisation and day 90, number of days alive without mechanical ventilation, renal replacement therapy and vasopressor support between randomisation and day 90. Other preplanned secondary outcomes comprised mortality at 28 and 60 days after randomisation, number of days alive and out of the ICU between randomisation and day 90, number of days alive without respiratory failure, neurological failure, cardiovascular failure, liver failure, renal failure and coagulation failure, defined as the corresponding component sequential organ failure assessment (SOFA) score greater than 2 between randomisation and day 90. Data related to patients' management, causes of death and safety outcomes were also described (see the Supplement).

! 8 Statistical Analysis

The statistical analysis was performed for each outcome of interest using individual patient data. An intention-to-treat analysis was used for all outcomes, whereby all patients were analysed in the groups to which they were randomised. The measures of treatment effect were risk ratios for binary outcomes, hazard ratios for time-to-event outcomes and mean differences for quantitative outcomes.

The primary endpoint was defined as a binary outcome and analysed using both one-step (as primary analysis) and two-steps (as sensitivity analysis) methods. [START_REF] Tierney | Chapter 26: Individual participant data[END_REF] In the one-step method, we analysed both studies simultaneously to obtain the combined treatment effect with 95% CIs and p-value by using a generalized linear mixed effect model to account for the clustering of data within each trial with a random effect. In the two steps method, we first analysed separately each trial using individual patient data before combining them using a random effects meta-analysis model to account for variability between studies. A two-step method was used for all secondary outcomes. Heterogeneity was evaluated with the Cochran's Q-test, I 2 statistic and between study variance τ 2 . Survival curves for the time to death up to 90 days were generated using individual patient data and the Kaplan-Meier method.

We conducted sensitivity analyses for the primary outcome in different populations (per-protocol, astreated). The per-protocol population included all randomised patients having received the treatment attributed by randomisation (i.e., patients having received ECMO in the ECMO arm and patients not having received ECMO in the control arm). The as-treated population compared patients receiving ECMO to those who did not receive ECMO, whatever the randomisation arm. A sensitivity analysis excluding trials at high risk of bias was also planned.

We explored whether the effect of ECMO on 90-day mortality varied according to baseline patient characteristics (see the Supplement). For each subgroup, the treatment-subgroup interaction was tested in the one-step model. For quantitative baseline characteristics, we used the median values to ! 9 define the subgroups. All these subgroup analyses were pre-planned (PROSPERO, CRD42019130034).

Alpha risk was set at 5% for the primary outcome. For all secondary outcomes, we did not correct for multiple testing. As such, subgroup and sensitivity analyses should be considered as exploratory.

All the analyses were performed with the use of R software version 3.6.1 (R Foundation).

The quality of evidence for the 7 most important outcomes was graded with GRADEpro GDT (GRADEpro GDT: GRADEpro Guideline Development Tool

Results

Selection process and general characteristics

From the 1179 references identified by the search strategy, we included two randomised controlled trials fulfilling our eligibility criteria -CESAR and EOLIA. [15,17] Reasons for exclusion are reported in eFigure 1 of the Supplement. The two trials provided individual patient data for all randomised patients (429 overall, 180 in CESAR and 249 in EOLIA), and there was no eligible trial not providing individual patient data. Detailed characteristics of the two trials are reported in eTable 3 in the Supplement.

Comparison of patient characteristics at randomisation did not show baseline imbalance between groups (Table 1 and eTable 4 and 5 in the Supplement). The main disorder leading to study entry was severe hypoxia (in 88% of the patients, with a mean (±SD) PaO2:FIO2 of 75±34 mm Hg). The main cause of ARDS was pneumonia (>60% of the patients) and 39% had 3 or more organs failing at randomisation. Of the 214 patients randomised to the ECMO groups, 189 (88%) received ECMO (98% and 76% in EOLIA and CESAR, respectively). Rescue extracorporeal gas exchange was used ! 10 for 36 (17%) of the 215 control patients (35 patients crossed over to ECMO in EOLIA, and 1 to pumpless arteriovenous CO2 removal in CESAR that was a protocol violation by the conventional management team as rescue extracorporeal gas exchange was not part of the CESAR trial design).

Risk of bias was judged low in both trials (eFigure 2 in the Supplement).

Primary Outcome

By day 90, 77 (36%) ECMO-group and 103 (48%) control group patients had died (relative risk, 0.75, 95% confidence interval, 0.60 to 0.94; p = 0.013) (Table 2 and Figure 1). Results were similar in the one-step and two-steps models. There was no evidence of heterogeneity across studies (p = 0.640, I 2 =0%, τ 2 =0.000).

Secondary Outcomes

The hazard ratio for death within 90 days after randomisation in the ECMO group, as compared with the control group, was 0.65 (95% CI, 0.49 to 0.88) (Fig. 2). The relative risk of treatment failure, defined as death by day 90 for the ECMO-group and death or crossover to ECMO for the control group was 0.65 (0.52 to 0.80) (Table 2 and eFigure 3 in the Supplement). At 90 days, ECMO-group patients had more days alive without ventilation (40 vs 31 days, mean difference, 8 days; 95% CI, 2 to 15) and out of the ICU (36 vs 28 days, mean difference, 8 days; 95% CI, 2 to 14) than those in the control group (Table 2 and eFigure 4 in the Supplement).

At day 60 post-randomisation (90-day follow-up was not available for the following outcomes in EOLIA), patients in the ECMO group had more days alive without vasopressors (35 vs 28 days, mean difference, 8 days; 95% CI, 3 to 13), renal replacement therapy (35 vs 28 days, mean difference, 7 days; 95% CI, 2 to 13) and neurological failure (38 vs 31 days, mean difference, 7 days; ! 11 95% CI, 2 to 13) than those in the control group (Table 2 and eFigure 5 in the Supplement). Prone positioning and low-volume low-pressure mechanical ventilation were applied to 71% and 85% of control group patients, respectively (Table 3). Multiorgan failure and respiratory failure were the main causes of death in both groups (Table 3), while a cannulation-related fatal complication occurred in 3 of the 225 patients who received ECMO. Of the 214 patients randomised to ECMO, 7 (3%) died before ECMO could be established. Additional data on secondary outcomes are provided in Tables 2 and3 and eFigure 6 in the Supplement.

Sensitivity and subgroup analyses

The relative risks of death at day 90 post-randomisation according to the per-protocol and as-treated analyses were 0.75 (95% CI, 0.60 to 0.94) and 0.86 (95% CI, 0.68 to 1.09), respectively (eFigure 7 in the Supplement). The only significant treatment-covariate interaction identified in subgroup analyses was the number of organs failing at randomisation with RR=0.53 (95% CI 0.36-0.78) among patients with 1-2 organ failures and RR=1.00 (95% CI 0.78-1.30) among patients with 3 or more organ failures, p = 0.006 for interaction (Figure 3). There was no evidence to suggest a differential treatment effect for any other subgroups.

Quality of Evidence

The Summary Of Findings Table reporting the evaluation of the quality of evidence for the 7 most important outcomes is presented in eTable 6 in the Supplement. The level of evidence was high for mortality at 90 days, time to death and treatment failure.

Discussion

! 12

In this individual patient data meta-analysis of patients with severe ARDS included in the CESAR [15] and EOLIA[17] randomised trials, there is strong evidence to suggest that early recourse to ECMO leads to a reduction in 90-day mortality and less treatment failure compared with conventional ventilatory support. Patients randomised to ECMO also had more days alive out of the ICU and without respiratory, cardiovascular, renal and neurological failure.

The benefit of ECMO in severe ARDS patients has long been debated. [START_REF] Li | Unproven and Expensive before Proven and Cheap: Extracorporeal Membrane Oxygenation versus Prone Position in Acute Respiratory Distress Syndrome[END_REF][START_REF] Schmidt | ECMO for immunosuppressed patients with acute respiratory distress syndrome: drawing a line in the sand[END_REF][START_REF] Fernando | Mortality and costs following extracorporeal membrane oxygenation in critically ill adults: a population-based cohort study[END_REF][START_REF] Fan | Less is More: not (always) simple-the case of extracorporeal devices in critical care[END_REF] Because of highly challenging design and conduct issues, only four randomised trials of extracorporeal life support for adult patients with acute respiratory failure have been performed in the last 5 decades. [15,17,[START_REF] Zapol | Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study[END_REF][START_REF] Morris | Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome[END_REF] Our meta-analysis included only the two most recent trials (CESAR[15] and EOLIA[17]) since major advances in ICU care and in ECMO techniques have occurred in the past 15 years making the two older trials not relevant for comparison. [START_REF] Brodie | Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review[END_REF]20,[START_REF] Combes | Fifty Years of Research in ARDS. Is Extracorporeal Circulation the Future of Acute Respiratory Distress Syndrome Management?[END_REF] In addition the two older trials did not use venovenous ECMO. One used venoarterial ECMO [START_REF] Zapol | Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study[END_REF] and one used low-flow veno-venous extracorporeal CO2 removal. [START_REF] Morris | Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome[END_REF] Characteristics of patients included in EOLIA and CESAR were comparable regarding ARDS aetiology and disease severity at randomisation. Patients were enrolled early after the initiation of invasive mechanical ventilation and rates of control patients being proned and receiving low-volume low-pressure mechanical ventilation were high. Both EOLIA and CESAR trials showed a comparable survival benefit with ECMO, but neither was individually powered to detect a reasonable survival difference between groups. Specifically, the data safety monitoring board of EOLIA, following pre-specified guidance using a sequential design with a two-sided triangular test based on 60-day mortality, recommended stopping the trial for futility after 75% of the maximal sample size had been enrolled because the probability of demonstrating a 20% absolute risk reduction in mortality with ECMO was considered unlikely. Our meta-analysis, which includes a much larger number of patients and shows higher survival with ECMO in both the intention-to-treat and per-protocol analyses provides strong evidence about the benefit of ECMO in severe ARDS. Our ! 13 results also extend the conclusions of a post-hoc Bayesian analysis of EOLIA indicating a very high probability of ECMO success in severe ARDS patients, ranging from 88% to 99% depending on the chosen priors. [START_REF] Goligher | Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc Bayesian Analysis of a Randomized Clinical Trial[END_REF] Our results are consistent with two previous aggregated data meta-analyses in the field: one was a network meta-analysis considering different interventions whose impact is limited by the lack of direct comparisons [START_REF] Aoyama | Assessment of Therapeutic Interventions and Lung Protective Ventilation in Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis[END_REF] and the other focused on ECMO. [START_REF] Munshi | Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis[END_REF] Our IPD meta-analyses goes beyond these two previous studies and provides a stronger evidence on the benefit of ECMO in ARDS for the following reasons. IPD meta-analyses provides a higher level of evidence than aggregated data meta-analyses because they are independent of the quality of reporting in included studies and allow evaluation of other important outcomes such as time to death and number of days without organ failures. [START_REF] Tierney | Individual Participant Data (IPD) Meta-analyses of Randomised Controlled Trials: Guidance on Their Use[END_REF][START_REF] Tierney | Comparison of aggregate and individual participant data approaches to meta-analysis of randomised trials: An observational study[END_REF] In this study, we showed that, beyond mortality, duration and severity of organ failures also favoured ECMO, and these results were highly consistent between the two studies. This observation provides insights into the potential pathophysiological mechanisms of ECMO-associated benefits in severe ARDS. [START_REF] Brodie | Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review[END_REF] Although extracorporeal gas exchange may rescue some patients dying of profound hypoxemia or in whom high pressure mechanical ventilation has become dangerous, minimization of lung stress and strain associated with positive pressure ventilation may drive most of the improved outcomes observed under ECMO. [START_REF] Brodie | Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review[END_REF] Ultraprotective ventilation with very low VTs, driving pressures and respiratory rates, [START_REF] Abrams | Mechanical Ventilation for Acute Respiratory Distress Syndrome during Extracorporeal Life Support. Research and Practice[END_REF] and therefore minimized overall mechanical power transmitted to lung alveoli [START_REF] Neto | Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts[END_REF] may reduce ventilator-induced lung injury, pulmonary and systemic inflammation and ultimately organ failure leading to death. These data also reinforce the recent recommendation of the World Health Organization (WHO), [START_REF]Clinical management of severe acute respiratory infection when COVID-19 disease is suspected[END_REF] and the Surviving Sepsis Campaign [START_REF] Alhazzani | Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)[END_REF] to consider ECMO support in coronavirus disease 2019 (COVID-19)-related ARDS with refractory hypoxemia if lung protective mechanical ventilation was insufficient to support the patient. [START_REF] Schmidt | Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study[END_REF] ! 14 Meta-analyses of individual patient data can also explore outcomes in important subgroups and suggest which population may derive the greatest benefit of a specific intervention, which is very limited in aggregated data meta-analyses. [START_REF] Fisher | Meta-analytical methods to identify who benefits most from treatments: daft, deluded, or deft approach?[END_REF] In this study, the mortality of patients with only one or two organs failing at randomisation was almost halved with ECMO (22% vs. 41%) while it was not substantially different between groups in patients with ≥3 organ failures (P=0.006 for interaction). This finding suggests that veno-venous ECMO may not be able to improve the outcomes of ARDS patients with severe shock and multiple organ failure. In EOLIA, patients with baseline PaO2:FIO2 >66 mmHg or those enrolled due to severe respiratory acidosis and hypercapnia, seemed to derive the greatest benefit of ECMO. [17] This analysis has several limitations. First, inclusion criteria were more stringent for the EOLIA trial, in which, for example, ventilator optimization (FIO2>80%, VT at 6 ml/kg predicted body weight and PEEP >10 cm H2O) was mandatory before enrolment. However, it should be noted that baseline patient characteristics were comparable regarding ARDS severity at inclusion (eTable 4 in the Supplement). Second patient management was not similar in the two studies. In CESAR, 24% of patients randomised to the ECMO arm did not receive ECMO and there was no standardized protocol for mechanical ventilation in the control group. Conversely, in EOLIA, 98% of patients randomised to ECMO received the intervention, the mechanical ventilation strategy in the control group followed a strict protocol, and rescue ECMO was applied to 28% of control group patients who had developed refractory hypoxemia. However, this meta-analysis showed a significantly lower mortality with ECMO in the per-protocol analysis including only patients in whom ECMO had been initiated in the ECMO arm and patients not having ECMO in the control arm. This analysis minimizes the aforementioned management differences, since the least severe patients who did not receive ECMO after MV optimization in CESAR were excluded from the ECMO arm and the most severe patients who needed rescue ECMO in EOLIA were excluded from the control arm. In ! 15 contrast, ECMO was not associated with a mortality benefit in the as-treated population, but such an analysis strongly disadvantages the ECMO group, which includes the most severe control patients rescued by ECMO. Second, this meta-analysis does not provide detailed data on ECMO-related safety endpoints since they were not reported in CESAR. Death directly related to ECMO cannulation was rare in both studies and the rates of stroke and major bleeding were also low in EOLIA, in which a restrictive anticoagulation strategy was applied.[17] Third, no long-term outcomes beyond 90 days post-randomisation were analysed although the CESAR trial[15] and a retrospective cohort of ARDS patients [START_REF] Schmidt | The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome[END_REF] reported satisfactory long-term health-related quality-oflife after ECMO. Fourth, only the CESAR trial provided a cost-effectiveness analysis that suggested a benefit of the transfer of ARDS patients to a centre with an ECMO-based management protocol.

[15] Our results, showing improved survival, with more days alive out of the ICU and without the need for major organ support are in line with CESAR's cost-effectiveness data. Fifth, many conditions such as MV duration >7 days prior to ECMO or major comorbidities were exclusion criteria for enrolment in both CESAR and EOLIA. The indication to initiate ECMO should therefore be carefully evaluated in these situations. Lastly, ECMO should be used in experienced centres and only after proven conventional management of severe ARDS (including lung protective mechanical ventilation and prone positioning) have been applied and failed, [START_REF] Abrams | ECMO for ARDS: from salvage to standard of care?[END_REF] except when hypoxemia is immediately life-threatening, or when the patient is too unstable for prone positioning. [START_REF] Maclaren | Saying no until the moment is right: initiating ECMO in the EOLIA era[END_REF] In conclusion, this meta-analysis of individual patient data of the CESAR and EOLIA trials showed strong evidence of a clinically meaningful benefit of early ECMO in severe ARDS patients.

Another large study of ECMO appears unlikely in this setting and future research should focus on the identification of patients most likely to benefit from ECMO and optimization of treatment strategies after ECMO initiation [START_REF] Guervilly | Prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial?[END_REF].

! 16

The trial was registered at PROSPERO (CRD42019130034) on May 1 st 2019. The CESAR trial was supported by the UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health See the Supplement for the list of EOLIA and CESAR collaborators. the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, PEEP positive end-expiratory pressure.

Conflict of interest statement

Missing data were <3% for patients' characteristics at randomisation, except for predicted mortality, respiratory system compliance and Murray score (see eTable 5 in the Supplement).

! 25 MV, mechanical ventilation; number of organ failed (0 to 6) defined as the corresponding component sequential organ failure assessment (SOFA) score > 2; APACHE2 (CESAR) and SAPS2 (EOLIA) scores were both translated to predicted probability of ICU mortality.

! 30

CESAR

The CESAR trial was supported by the UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

CESAR Collaborators

III. SUPPLEMENTARY DATA 1. METHODS

Ethical Aspects

The study protocol for the systematic review and IPD meta-analysis was approved by the relevant Only patient characteristics and outcomes already evaluated in the trials were combined in this systematic review and meta-analysis.

independent

Study Design

The protocol followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols (PRISMA-P) and was registered in PROSPERO (CRD42019130034).

Eligibility criteria

Type of Studies

We included only randomised controlled trials (RCTs) published or whose primary completion date is after 2000. This choice is justified by major progress in intensive care treatment in general and in ECMO techniques in particular that have considerably modified the prognosis of patients. [2] We considered all types of RCTs whether they are published or not and whatever their language of publication.

Population

We included trials of patients with ARDS fulfilling the American-European Consensus Conference definition [3] or the Berlin definition for ARDS, [4] who were endotracheally intubated and who had signs of severe hypoxemia or hypercapnia.

We

Intervention in the Experimental Group

We included trials evaluating in the experimental group early veno-venous cannulation and ECMO initiation with adjustment of mechanical ventilator settings to allow low-volume, low-pressure ventilation.

Intervention in the Control Group

We included trials evaluating in the control group conventional ventilatory management.

Data Sources

Electronic Search

We S1.

We also searched trial registries including ClinicalTrials.gov and the International Clinical Trial Registry Platform (ICTRP) for completed and ongoing trials.

Additional Searches

We screened conference proceedings of major critical care societies (American Thoracic Society We also screened reference lists of identified articles as well as systematic or narrative reviews on the topic and contact experts for further eligible trials.

Selection Process

Selection was conducted by two independent reviewers (DA and MS) on titles and abstracts first and then, on the full text. Any discrepancies between the reviewers was discussed with the help of a third reviewer whenever necessary to reach a consensus on studies to be included.

We initially planned to use the first version of the tool but the updated version was made available while we were conducting this systematic review and we decided to use this updated version. We evaluated the following domains: risk of bias arising from the randomisation process (using full-text articles and IPD), risk of bias due to deviations from the intended interventions (using full-text articles and protocols), risk of bias due to missing outcome data (using full-text articles and IPD), risk of bias in measurement of the outcome (using full-text articles and protocols), risk of bias in selection of the reported result (using full-text articles, protocols and registration). We focused on our primary outcome for this evaluation.

Study Outcomes and planned analyses

The primary endpoint was mortality 90 days after randomisation in the intention-to-treat population.

The following outcomes were defined as secondary endpoints of interest: time to death up to 90 days after randomisation, treatment failure up to 90 days, defined as crossover to ECMO or death for patients in the control group, and death for patients in the ECMO group, number of days alive and out of hospital, between randomisation and day 90, number of days alive without mechanical ventilation, renal replacement therapy and vasopressor support between randomisation and day 90. Only outcomes already evaluated in trials were combined in meta-analyses. There were no additional data collected for this systematic review and individual patient data meta-analysis.

Study Outcomes Modified or Not Evaluated in Meta-Analysis Because of Unavailability in

Included Studies

Because only two trials were eligible and included, we combined in the meta-analysis only predefined outcomes available in both trials. In EOLIA, [1] the day-by-day follow-up was limited to Day 60, except for mortality, mechanical ventilation, and ICU/hospital duration. Thus, the timeframe was shrunk up to day 60 for the following outcomes: number of days alive without RRT, number of days alive without vasopressors, number of days alive without respiratory failure, number of days alive without neurological failure, and number of days alive without cardiovascular failure.

Number of days alive without liver failure, number of days alive without renal failure, and number of days alive without coagulation failure were not available in the CESAR study, [5] these outcomes were thus excluded from the meta-analysis.

Statistical Analysis

The statistical analysis was performed for each outcome of interest using individual patient data. An intention-to-treat analysis was used for all outcomes, whereby all randomised patients were analyzed in the groups to which they were randomised. The measures of treatment effect were risk ratios for binary outcomes, hazard ratios for time-to-event outcomes and mean differences for quantitative outcomes. The primary endpoint, mortality up to 90 days, was defined as a binary outcome. For the primary endpoint, the analysis involved both one step (as primary analysis) and two steps (as sensitivity analysis) methods. In the one step method, we analyzed all studies simultaneously to obtain the combined treatment effect with 95% CIs and p-values by using a generalized linear mixed effect model to account for the clustering of data within each trial with a random effect. In the two steps method, we first analyzed separately each study using IPD before combining them using a random effects meta-analysis model to account for variability between studies. For convenience reasons and due to the number of analyses, only the two-step method was used for all secondary endpoints. Heterogeneity was evaluated with the Cochran's Q-test, I 2 and between study variance τ 2 .

Survival curves for the time to death up to 90 days were generated using IPD and the Kaplan-Meier method.

Sensitivity analyses according to different populations of analysis (per-protocol, as-treated)

were conducted. The per-protocol population included all randomised patients having received the treatment attributed by randomisation (i.e., patients having received ECMO in the ECMO arm and patients not having ECMO in the control arm). The as-treated population compared patients receiving ECMO to those who did not receive ECMO, whatever the randomisation arm. We planned a sensitivity analysis excluding trials at high risk of bias for each domain but we did not conduct it because only two trials were included and because they were judged at low risk of bias.

We explored whether the effect of ECMO on 90 day mortality varies according to the following baseline characteristics: age, gender, partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FIO2), interval between initiation of mechanical ventilation and randomisation, driving pressure, respiratory system compliance, positive end-expiratory pressure (PEEP), pH, number of organs failed, Murray score, acute physiology score and chronic health (APACHE) II or SAPS II predicted mortality, pneumonia vs. other etiologies of ARDS and use of prone position. For each subgroup, the treatment-subgroup interaction was tested in the one step model. For quantitative baseline characteristics, we used the median values to define the subgroups.

All these subgroup analyses (except for the subgroup of patients who received lung protective ventilation) were preplanned as registered in the PROSPERO database (CRD42019130034). We added a post hoc exploratory analysis of 90-d mortality restricted to patients having received lung protective ventilation. Alpha risk was set at 5%. We defined a single primary outcome and did not correct alpha risk for multiple testing. As such all secondary outcomes, subgroup and sensitivity analyses should be considered as exploratory. All analyses involved use of R version 3.6.1.

Grading of the Evidence

For each key outcome (the primary outcome and the 6 most important prespecified secondary outcomes), the quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach and GRADEpro GDT ((GRADEpro GDT:

GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by

Evidence Prime, Inc.). Available from gradepro.org). A summary of findings table (Table S5) summarizes these results.

The primary outcome was mortality up to 90 days after randomisation. The 6 most relevant secondary outcomes were defined as:

• Time to death up to 90 days after randomisation;

• Treatment failure up to 90 days, defined as crossover to ECMO or death for patients in the control group, and death for patients in the ECMO group;

• Number of days alive and out of hospital, between randomisation and day 90;

• Number of days alive without mechanical ventilation between randomisation and day 90;

• Number of days alive without renal replacement therapy between randomisation and day 90;

• Number of days alive without vasopressor support between randomisation and day 90. 12 Strength s and limitatio ns 25 Discuss any important strengths and limitations of the evidence including the benefits of access to IPD and any limitations arising from IPD that were not available.

TABLES eTable 1. PRISMA-IPD checklist of items to include when reporting a systematic review and meta-analysis of individual participant data (IPD).

PRISMA-IPD

13-14

Conclusi ons 26 Provide a general interpretation of the findings in the context of other evidence.

14-15

Implicati ons A4 Consider relevance to key groups (such as policy makers, service providers and service users). Consider implications for future research.

14-15

  The study was supported by the Direction de la Recherche Clinique et de l'Innovation (DRCI), Assistance Publique-Hopitaux de Paris (APHP), with a grant from the French Ministry of Health (CRC 2018, #18021). The EOLIA trial was supported by the Direction de la Recherche Clinique et du Développement (DRCD), Assistance Publique-Hôpitaux de Paris (APHP), with a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique number, PHRC 2009 081224), the EOLIA Trial Group, the Réseau Européen en Ventilation Artificielle (REVA) and the International ECMO Network (ECMONet, http://www.internationalecmonetwork.org).

Figure legend Figure 1 .

 legend1 Figure legend

Figure 2 .

 2 Figure 2. Kaplan-Meier survival estimates in the intention-to-treat population of the time to

Figure 3 .

 3 Figure 3. Subgroup analyses for the primary outcome according to baseline characteristics.

Figure 1 ! 31

 131 Figure 1

Figure 2 ! 32

 232 Figure 2

Figure 3 ! 33 I

 333 Figure 3

  Adfield, S Ainley, E Allen, D Altman, C Armstrong, M Aslam, J Aulakh, F Bage, A Bailey, K Bailey, D Bagnall, J Baldwin, F Barchard, L Barton, J Bean, JM Bellin, S Bennett, M Bennett, K Berry, F Bertasius, B Bray, E Britton-Smith, L Burgoyne, J Cadwallader, G Calder, C Calder, M Calleja, J Cardy, B Carr, J Chambers, P Chambers, A Chan, F Clemens, L Clements, E Coates, A Collins, JR Colvin D Connolly, W Cook, H Cooper, N Cooper, K Coulson, C Crocker, A Culpepper, GL Dabuco, L Davies, J Davies, T Dexter, K Diallo, J Dickson, W Doherty, R Doll, Y Doyle, M Drummond, P Duncan, M Dunlop, D Edbrooke, WC Edmondson, D Elbourne, M Esmail, L Evans, T Evans J Everatt, G Faulkner, J Fawcett, D Field, G Findlay, R Firmin, D Francis, M Garfield, M Garrioch, D Goldhill, S Gower, K Greatorex, P Grice, V Gupta, B Gutteridge, P Hale, D Handley, I Hamilton, P Hardy, C Harland, D Harling, P Harris, R Harris, S Harris, C Harvey, J Hawkins, J Herring, C Hibbert, D Higgins, J Hilton, S Holden, A Holmes, S Holbeck, M Hope, J Hunter, E Hutcheon, JD Hutchinson, A Jackson D Jayson,E Jones, N Jones, BJ Jenkins, B Keeling, L Kehoe D Kelly, D Kennedy, M Kermack, D Kerr, H Killer, A King, V Knights, R Kyte, T Leach, CA Lee, J Lee, W Lee, G Levens,M Levitt, J Lewis, J Little, R Lo, M Longshaw, T Mason, G Masterson, D Macrae, E Maggs, S Maisey, S Maguire, K Marchant, L Morgan, A Markham, L Marriot, A Martin, N Mathew, F McAuley, C McCulloch, J McHugh, V McLean, G McMillan, C McMullen, G McPherson, S Michael, K Miller, J Morton, M Mugford, D Muir, W Nganasurian, D Niblett, A Normington, S Nourse, P Oats, I O'Connor, D O'Malley,J O'Riordan, K Owen,V Page, M Parfitt, M Patten, G Peek, M Pepperman, D Piercy, M Platt, K Price, W Price, H Proctor, T Proctor, L Randall, A Read, H Reading, J Redfern, R Reeves, J Rhodes, C Richardson, J Rigg, P Ritchie, C Roberts, K Roberts, N Roberts, S Robertson, M Ross, T Rowan, H Rymell, R Saad, T Samuel, J Sanderson-Mann, T Schiavone, J Scott, J Scriven, L Shaikh, R Sharawi, E Shearer, A Sheward, P Sinfield, P Sigston, R Slater, I Smith, L Smith, M Smith, M Smith, N Smith, S Smith, M Smithies, S Snelson, AW Sosnowski, P Spiers, M Spittal, T Stambach, B Soutar, J Sutherland, S Swire,S Tabener, C Tarrant, A Tattersfield, C Taylor, I Taylor, M Taylor, A Tebbat, B Tehan, M Thalanany, L Thomas, J Thomas, J Thomas, A Tinsley, R Tiruvoipati, K Tomlin, G Toovey. A Truesdale, D Turner, A Turley, P Tyler, L Twohey, N Volpe, L Wadsworth, C Wareham, H Watkinson, D Watson, C Waldmann, A Walker, G Walker, J Webb, N Webster, S Westwell, M Willis, A Wilson, L Williams, L Woodbridge, P Wootton, N Worral, RP Wroth.

(

  ATS), European Society of Intensive Care Medicine (ESICM), Society of Critical Care Medicine (SCCM) and International Symposium on Intensive Care and Emergency Medicine (ISICEM) for the last 5 years.

Other secondary outcomes included mortality at 28

 28 and 60 days after randomisation, number of days alive and out of the ICU between randomisation and day 90, number of days alive without respiratory failure, neurological failure, cardiovascular failure, liver failure, renal failure and coagulation failure, defined as the corresponding component sequential organ failure assessment (SOFA) score greater than 2 between randomisation and day 90.Description of patients' management in each group included duration of ECMO support up to 90 days, durations of ICU and hospital stay, rate of patients who received and duration of inhaled nitric oxide, recruitment maneuvers, prone position, high frequency oscillation ventilation, almitrine infusion and low-volume low-pressure ventilation strategy up to 90 days post-randomisation. Causes of death were analyzed and deaths directly attributed to the ECMO procedure were defined as those occurring in the setting of ECMO-device failure: massive gas emboli, cardiac arrest due to massive circuit clotting, septic shock due to ECMO cannulation-site infection, cerebral or meningocerebral hemorrhage, pneumothorax during cannula insertion, or massive hemorrhage requiring transfusion of at least ≥10 units of pack red blood cells. Safety outcomes included: pneumothorax, stroke, ECMO cannula insertion-site infections, cannula thrombosis, ECMO circuit change, intravascular hemolysis, ventilator-associated pneumonia, severe hemorrhagic complications and red blood cells transfusion.

eFigure 2 . 8 .

 28 Risk of bias in the trials included in the analysis. eFigure 3. Forest plot (A) and Kaplan-Meier survival estimates (B) in the intention-to-treat population of the time to treatment failure within the first 90 study days. day free-days of renal replacement therapy (A), vasopressors (B), and neurological failure (C). Neurological failure was defined by the number of days without neurological depression requiring system monitoring/support' in CESAR study and the neurologic component of the sequential organ failure assessment (SOFA) score greater than 2. Post-hoc analysis of 90-day mortality in the subgroup of patients who received lung protective ventilation.

eTable 4 .

 4 Characteristics of the patients at randomisation in the 2 included trials and in the individual patient data meta-analysis.

  ECMO denotes extracorporeal membrane oxygenation, ARDS the acute respiratory distress syndrome, PaO2 partial pressure of arterial oxygen, FiO2 the fraction of inspired oxygen, PaO2/FIO2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, PEEP positive end-expiratory pressure, LVLP MV, low-volume low-pressure mechanical ventilation, iNO inhaled nitric oxide, and ICU intensive care unit.

eTable 5 .

 5 Missing data for characteristics of the patients included in the 2 trials and in the metaanalysis † number of organ failed (0 to 6) defined as the corresponding component sequential organ failure ) score > 2. ‡ APACHE2 (CESAR) and SAPS2 (EOLIA) scores were both translated to predicted probability of ICU mortality.ECMO denotes extracorporeal membrane oxygenation, ARDS the acute respiratory distress syndrome, PaO2 partial pressure of arterial oxygen, FiO2 the fraction of inspired oxygen, PaO2/FIO2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, PEEP positive end-expiratory pressure, LVLP MV, low-volume low-pressure mechanical ventilation, iNO inhaled nitric oxide, and ICU intensive care unit.

  [Software]; McMaster University, 2015 (developed by Evidence Prime, Inc.; Available from gradepro.org).

Table 1 . Characteristics of the patients at randomisation. *

 1 Alain Combes reports grants from Getinge, personal fees from Getinge, Baxter and Xenios outside the submitted work. Matthieu Schmidt reports lecture fees from Getinge, Drager and Xenios outside the submitted work. The other authors declare that they have no conflicts of interest related to the purpose of this manuscript.

	! 18

Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, Hibbert CL, Truesdale A, Clemens F, Cooper N, Firmin RK, Elbourne D, (2009) Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 374: 1351-1363 16. Peek GJ, Elbourne D, Mugford M, Tiruvoipati R, Wilson A, Allen E, Clemens F, Firmin R, Hardy P, Hibbert C, Jones N, Killer H, Thalanany M, Truesdale A, (2010) Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR). Health technology assessment (Winchester, England) 14: 1-46 17. Combes A, Hajage D, Capellier G, Demoule A, Lavoue S, Guervilly C, Da Silva D, Zafrani L, Tirot P, Veber B, Maury E, Levy B, Cohen Y, Richard C, Kalfon P, Bouadma L, Mehdaoui H, Beduneau G, Lebreton G, Brochard L, Ferguson ND, Fan E, Slutsky AS, Brodie D, Mercat A, (2018) Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med 378: 1965-1975 18. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R, (1994) The American-European Consensus Conference on ARDS. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med 190: 488-496 ! 20 ECMO denotes extracorporeal membrane oxygenation, ARDS the acute respiratory distress syndrome, PaO2 partial pressure of arterial oxygen, FiO2 the fraction of inspired oxygen, PaO2/FIO2

Table 2 .

 2 Endpoints.! 26 ‡ Day-by-day follow-up was limited to Day 60 in the EOLIA trial £ Neurological failure was defined by the number of days without neurological depression requiring system monitoring/support' in CESAR study and the neurologic component of the sequential organ failure assessment (SOFA) score greater than 2.

	Data are mean (SD) or number (%).
	ECMO denotes extracorporeal membrane oxygenation, ICU intensive care unit and RRT renal
	replacement therapy.

* The width of confidence intervals have not been adjusted for multiplicity and should not be used to infer definitive treatment differences. † Free-days were calculated assigning zero free-days to patients who died during the follow-up period.

Table 3 . Patients' management and other outcomes.

 3

	Data are mean (SD) or number (%); see eTable 5 in the Supplement for missing data.

* For patients who received ECMO. † From randomisation to Day 60.

ECMO denotes extracorporeal membrane oxygenation, LVLP MV, low-volume low-pressure mechanical ventilation, iNO inhaled nitric oxide, and ICU intensive care unit.

  ethics committees: in France, Comité de Protection des Personnes CPP Ile de France VI, Pitié-Salpêtrière, on 04/19/2018, Ref #12 and in the UK by the Ethics committee of the London School of Hygiene and Tropical Medicine, on 04/12/2019, LSHTM Ethics Ref: 17159.

  searched MEDLINE via PubMed, EMBASE and the Cochrane Central Register of Controlled

	Trials (Central) from 2000 (see justification above) to 30 September 2019 using a search algorithm
	developed for the purpose of this study and adapted to each database. The search algorithm included
	both key-words relevant to this topic and free text words as well as the sensitive filter developed by
	the Cochrane Collaboration to identify RCTs. The search algorithm for MEDLINE via PubMed is
	reported in Table

denote new items that are additional to standard PRISMA items. A4 has been created as a result of re-arranging content of the standard PRISMA statement to suit the way that systematic review IPD meta-analyses are reported.

  Describe all methods of identifying published and unpublished studies including, as applicable: which bibliographic databases were searched with dates of coverage; details of any hand searching including of conference proceedings; use of study registers and agency or company databases; contact with the original research team and experts in the field; open adverts and surveys. Give the date of last search or elicitation. Describe how the information and variables to be collected were chosen. List and define all study level and participant level data that were sought, including baseline and follow-up information. If applicable, describe methods of standardising or translating variables within the IPD datasets to ensure common scales or measurements across studies. For each comparison and for each main outcome (benefit or harm), for each individual study report the number of eligible participants for which data were obtained and show simple summary data for each intervention group (including, where applicable, the number of events), effect estimates and confidence intervals. These may be tabulated or included on a forest plot. Give results of any additional analyses (e.g. sensitivity analyses). If applicable, this should also include any analyses that incorporate aggregate data for studies that do not have IPD. If applicable, summarise the main meta-analysis results following the inclusion or exclusion of studies for which IPD were not available.

	Identifyi Results	7 7 20 Fig 1
	ng of
	studies -individua		Suppl eFig
	informati on l studies		. 7-8 2-6
	sources
	Results	21 Present summary effects for each meta-analysis undertaken, including	Fig 1
	Section/ topic Identifyi of ng studies -search synthese s	Ite m No 8 Present the full electronic search strategy for at least one database, Checklist item confidence intervals and measures of statistical heterogeneity. State including any limits used, such that it could be repeated. whether the analysis was pre-specified, and report the numbers of studies and participants and, where applicable, the number of events on which it is based.	eTabl Repor ted on page eFig e 2 2-6
	Study Title selection	9 State the process for determining which studies were eligible for When exploring variation in effects due to patient or study inclusion. characteristics, present summary interaction estimates for each	7
	Title processe s	characteristic examined, including confidence intervals and measures of 1 Identify the report as a systematic review and meta-analysis of individual participant data. statistical heterogeneity. State whether the analysis was pre-specified. State whether any interaction is consistent across trials.	Suppl . 7-8
	Data collectio n processe Risk of s bias across studies Data items Risk of bias across studies analyses al Addition	10 Describe how IPD were requested, collected and managed, including any processes for querying and confirming data with investigators. If IPD were not sought from any eligible study, the reason for this should be Provide a description of the direction and size of effect in terms meaningful to those who would put findings into practice. stated (for each such study). 22 Present results of any assessment of risk of bias relating to the If applicable, describe how any studies for which IPD were not available were dealt with. This should include whether, how and what aggregate data were sought or extracted from study reports and publications (such accumulated body of evidence, including any pertaining to the availability and representativeness of available studies, outcomes or other variables. as extracting data independently in duplicate) and any processes for obtaining and confirming these data with investigators. 11 Suppl 7; Suppl . 7-8 10 NA . 8 15 Specify any assessment of risk of bias relating to the accumulated body of studies, outcomes or other variables. evidence, including any pertaining to not obtaining IPD for particular 23 10-11
	Addition	16 Describe methods of any additional analyses, including sensitivity	9
	al analyses Discussion	analyses. State which of these were pre-specified.	Suppl
	IPD Summary	A1 Describe what aspects of IPD were subject to data checking (such as 24 Summarize the main findings, including the strength of evidence for each	Suppl . 13
	integrity evidence Results of	sequence generation, data consistency and completeness, baseline imbalance) and how this was done. main outcome.	. 7-9
	Introduction Rational e 3 Describe the rationale for the review in the context of what is already known. Objectiv es 4 Provide an explicit statement of the questions being addressed with reference, as applicable, to participants, interventions, comparisons, Risk of bias assessme nt in individua 12 Describe methods used to assess risk of bias in the individual studies and Study 17 Give numbers of studies screened, assessed for eligibility, and included in selection the systematic review with reasons for exclusions at each stage. Indicate whether this was applied separately for each outcome. If applicable, describe how findings of IPD checking were used to inform the assessment. Report if and how risk of bias assessment was used in any and IPD the number of studies and participants for which IPD were sought and for obtained which IPD were obtained. For those studies where IPD were not available, give the numbers of studies and participants for which aggregate data data synthesis. were available. Report reasons for non-availability of IPD. Include a flow l studies. diagram. Specifica tion of 13 State all treatment comparisons of interests. State all outcomes Study 18 For each study, present information on key study and participant addressed and define them in detail. State whether they were pre-outcomes and study design (PICOS). Include any hypotheses that relate to particular types of participant-level subgroups. Methods outcome s and effect measure specified for the review and, if applicable, whether they were primary/ main or secondary/additional outcomes. Give the principal measures of effect (such as risk ratio, hazard ratio, difference in means) used for each outcome. for each study. Where applicable, also report similar study characteristics source, and if applicable duration of follow-up). Provide (main) citations ristics participants, demographic data, unavailability of outcomes, funding characte characteristics (such as description of interventions, numbers of	6 9 7 eFig Suppl . 10 1 6 7-8 eTabl . 11-12 Suppl e 4
	Protocol s	5 Indicate if a protocol exists and where it can be accessed. If available, for any studies not providing IPD.	7
	and registrati on integrity IPD	provide registration information including registration number and were none. registry name. Provide publication details, if applicable. A3 Report any important issues identified in checking IPD or state that there	NA
	Eligibilit y criteria Risk of bias within studies A1 -A3 © Reproduced with permission of the PRISMA IPD Group, which encourages sharing and 6 Specify inclusion and exclusion criteria including those relating to participants, interventions, comparisons, outcomes, study design and characteristics (e.7 Suppl . 7-8 19 Present data on risk of bias assessments. If applicable, describe whether data checking led to the up-weighting or down-weighting of these assessments. Consider how any potential bias impacts on the robustness of meta-analysis conclusions. 9 eFig 2
	reuse for non-commercial purposes

g. years when conducted, required minimum followup). Note whether these were applied at the study or individual level i.e. whether eligible participants were included (and ineligible participants excluded) from a study that included a wider population than specified by the review inclusion criteria. The rationale for criteria should be stated.

Search algorithm for the MEDLINE via PubMED search.

	eTable 2. 1. Extracorporeal membrane oxygenation [mh] eTable 3.
	2. "Extracorporeal membrane oxygenation" [tiab]
	3. ECMO [tiab]
	4. "extracorporeal life support" [tiab]
	5. "extracorporeal gas exchange" [tiab]
	6. respiratory insufficiency [mh]
	7. Respiratory distress syndrome, adult [mh]
	8. "respiratory insufficiency" [tiab]
	9. "respiratory failure" [tiab]
	10. "respiratory distress syndrome" [tiab]
	11. randomized controlled trial [pt]
	12. controlled clinical trial [pt]
	13. randomized [tiab]
	14. placebo [tiab]
	15. drug therapy [sh]
	16. randomly [tiab]
	17. trial [tiab]
	18. groups [tiab]
	19. 11 OR 12 OR13 OR 14 OR 15 OR 16 OR 17 OR 18
	20. animals [mh] NOT humans [mh]
	21. 19 NOT 20
	22 1 OR 2 OR 3 OR 4 OR 5
	23 6 OR 7 OR 8 OR 9 OR 10
	24 21 AND 22 AND 23
	Funding
	Funding	27 Describe sources of funding and other support (such as supply of IPD), and	15
		the role in the systematic review of those providing such support.

Summury of the trial design of the 2 included studies.

	First	Setting Design Recrui	Population Interventio	Interven	Primar	Number of
	autho			tment		n in the	tion in	y	patients
	r,			period		experiment	the	outco	randomised
	year					al group	control	me
							group
	Peek,	UK,	Pragmat	July	-Aged	Transfer to	Best	Death	180
	2009	multice ntre trial (103 centres )	ic RCT 1:1 ratio	2001-August 2006	18-65 years -Severe but potentially reversible failure respiratory	ECMO centre and ECMO using percutaneo mode with venovenous	critical care practice with volume using low advice on	or severe disabili ty at 6 months	ECMO group: 90 Control group: 90
					-Murray	us	low
					score ≥ 2.5 or hypercapni	cannulation	pressure ventilatio n strategy
					a with pH
					<7.20
	Comb	Internat	RCT	Decem	-ARDS	ECMO	Ventilator	Mortali	249
	es, 2018	ional (France , USA, Austral ia,	1:1 ratio Sequenti al design	ber 2012, April 2017	-Endotrache al intubation	with percutaneo us venovenous cannulation	y treatment according to the increased	ty at 60 days	ECMO group: 124 Control group: 125
		Canada	with		-		recruitme
		),	pre-		Ventilation		nt
		multice	specifie		<7 days		strategy
		ntre trial (43 centres	d stopping rules		-Disease-criteria severity		of the EXPRES S trial
		)

eTable 6: Summary of findings table.

  We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

		Anticipated absolute effects * (95%
	Outcomes GRADE Working Group grades of evidence Anticipated absolute effects * (95% CI) Risk with Control Risk with ECMO Control High certainty: Outcomes CI) Risk with Risk with ECMO	Relative effect (95% CI) Relative effect (95% CI)	№ of participants (studies) № of participants (studies)	Certainty of the evidence (GRADE) Certainty of the evidence (GRADE)	Comments Comments
			359 per 1 000				Despite the low number of
	Mortality up to 90 days after randomization follow up: 90 Explanations days a. there was imprecision	479 per 1 000	(287 to 450)	RR 0.75 (0.60 to 0.94)	429 (2 RCTs)	⨁⨁⨁⨁ HIGH	included studies, there was a high level of evidence because results were highly consistent in both studies, with no heterogeneity. Both studies
							had a low risk of bias.
			NaN per				Despite the low number of
	Time to death up to 90 days after randomization follow up: 90 days	0 per 1 000	1 000 (NaN to NaN)	HR 0.65 (0.49 to 0.88)	429 (2 RCTs)	⨁⨁⨁⨁ HIGH	included studies, there was a high level of evidence because results were highly consistent in both studies, with no heterogeneity. Both studies
							had a low risk of bias.
			360 per 1 000				Despite the low number of
	Treatment failure		(288 to 443)				included studies, there was a high level of
	up to 90 days follow up: 90	553 per 1 000		RR 0.65 (0.52 to 0.80)	429 (2 RCTs)	⨁⨁⨁⨁ HIGH	evidence because results were highly consistent in
	days						both studies, with no
							heterogeneity. Both studies
							had a low risk of bias.
	Number of days alive and out of hospital follow up: 90	The mean number of days alive and out of hospital was 18	MD 4 days more (1 fewer to 9 more)	-	429 (2 RCTs)	⨁⨁⨁◯ MODERATE a	Results were downgraded because of imprecision
	days	days
	Number of days alive without mechanical ventilation days follow up: 90	31 days The mean number of days alive without mechanical ventilation was	MD 8 days more (2 more to 15 more)	-	429 (2 RCTs)	⨁⨁⨁◯ MODERATE a	Results were downgraded because of imprecision
	Number of days alive without renal replacement therapy	The mean number of days alive without renal replacement	MD 7 days more (2 more to 13 more)	-	429 (2 RCTs)	⨁⨁⨁◯ MODERATE a	Results were downgraded because of imprecision
	follow up: 60	therapy was 28
	days	days
	Number of days alive without vasopressor support days follow up: 60	days The mean number of days alive without vasopressor support was 28	MD 8 days more (3 more to 13 more)	-	429 (2 RCTs)	⨁⨁⨁◯ MODERATE a	Results were downgraded because of imprecision

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; HR: Hazard Ratio; MD: Mean difference

Acknowledgement

We thank Mrs Elizabeth Allen for her help in preparing the data of the CESAR trial.

! 17

Supplementary online material ECMO for severe acute respiratory distress syndrome: systematic review and individual patient data metaanalysis Authors:

Alain Combes, M.D., Ph.D.; 1,2 Giles J Peek, M.D., FRCS CTh.; 3 David Hajage, M.D., Ph.D.; 4 Pollyanna Hardy, MSc; 5 Darryl Abrams, M.D.; 6,7 Matthieu Schmidt, M.D., Ph.D.; 1,2 Agnès Dechartres, M.D., Ph.D.; 4 Diana Elbourne, Msc., Ph.D. 8 Authors affiliations: 1 Endnote (Thomson Reuters) was used to manage references and conduct the selection process.

Supplementary online material

Data Collection Process

For each included RCT, the corresponding author was contacted by email to request individual patient data. The members of the team conducted the two most important RCTs in the topic (EOLIA [1] and CESAR [5]). For each RCT, we asked for fully anonymized IPD for all randomised participants as well as format, coding and signification of any variables. To check data and ensure reproducibility of results, we re-analyzed each included trial in collaboration with each principal investigator, data manager and statistician. In particular, we evaluated data consistency and completeness as well as baseline imbalance (for risk of bias assessment as detailed below). We reviewed the individual study protocols, case report forms and definition of variables to harmonize databases. Whenever necessary, we transformed variables to have homogeneous variable coding across trials in order to merge IPD into one single database.

We planned a strategy in case we identified eligible RCTs but could not obtain individual patient data but this situation was not encountered. Two reviewers would have independently extracted for each outcome of interest, aggregated data from the full text of each RCT with discrepancies solved by discussion with the help of a third reviewer whenever necessary. We would conduct a sensitivity analysis to account for these trials using a two-step approach.

Risk of Bias

For each eligible RCT, risk of bias was evaluated independently by two reviewers using the updated version of the Risk of bias tool developed by the Cochrane Collaboration [6] (www.cochrane.org).

A B

Synthesis methods 14 Describe the meta-analysis methods used to synthesize IPD. Specify any statistical methods and models used. Issues should include (but are not restricted to):

• Use of a one-stage or two-stage approach.

• How effect estimates were generated separately within each study and combined across studies (where applicable).

• Specification of one-stage models (where applicable) including how clustering of patients within studies was accounted for.

• Use of fixed or random effects models and any other model assumptions, such as proportional hazards.

• How (summary) survival curves were generated (where applicable).

• Methods for quantifying statistical heterogeneity (such as I 2 and τ 2 ).

• How studies providing IPD and not providing IPD were analysed together (where applicable).

• How missing data within the IPD were dealt with (where applicable).

8-9

Suppl . 12-14 Explorati on of variation in effects A2 If applicable, describe any methods used to explore variation in effects by study or participant level characteristics (such as estimation of interactions between effect and covariates). State all participant-level characteristics that were analysed as potential effect modifiers, and whether these were pre-specified. 9 Suppl . 13