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In this meta-analysis of individual patient data in severe ARDS, 90-day mortality was significantly lowered by ECMO compared with conventional management. Patients randomised to ECMO had more days alive out of the ICU and without respiratory, cardiovascular, renal and neurological failure

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 [7,30]. 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 [31] and the other focused on ECMO [32]. 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 [33, 34].

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 [10]. 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 [10]. Ultraprotective ventilation with very low VTs, driving pressures and respiratory rates [35], and, therefore, minimized overall mechanical power transmitted to lung alveoli [36] 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) [37], and the Surviving Sepsis Campaign [38] 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 [39].

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 [40]. 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. 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 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 day post-randomisation were analysed although the CESAR trial [15] and a retrospective cohort of ARDS patients [41] reported satisfactory long-term health-related quality-of-life 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 [42], except when hypoxemia is immediately life-threatening, or when the patient is too unstable for prone positioning [43].

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 [44].

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, #18,021).

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 081,224), the EOLIA Trial Group, the Réseau Européen en Ventilation Artificielle (REVA) and the International ECMO Network (ECMONet, https://www.internationalecmonetwork.org).

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.