Extracorporeal Membrane Oxygenation for COVID-19

A Systematic Review and Meta-Analysis

Kollengode Ramanathan; Kiran Shekar; Ryan Ruiyang Ling; Ryan P. Barbaro; Suei Nee Wong; Chuen Seng Tan; Bram Rochwerg; Shannon M. Fernando; Shinhiro Takeda; Graeme MacLaren; Eddy Fan; Daniel Brodie

Disclosures

Crit Care. 2021;25(211) 

In This Article

Discussion

This systematic review and meta-analysis examined the use of ECMO in adult patients with COVID-19 during the first year of the pandemic. The pooled in-hospital mortality in 1896 patients with COVID-19 who predominantly had severe ARDS and were supported with ECMO was 37%, and this estimate was based on high certainty evidence. Mortality was slightly lower (35.7%) in patients exclusively receiving VV ECMO. This pooled mortality rate is comparable to the mortality rates seen in ECMO treated patients in the ECMO to Rescue Lung Injury in Severe ARDS [EOLIA] and Conventional ventilation or ECMO for Severe Adult Respiratory failure [CESAR] trials[44,45] as well as the recent individual patient data meta-analysis of the two randomised controlled trials evaluating the use of VV ECMO in patients with ARDS from non-COVID etiologies (32.1 vs. 36%).[46] The pooled mean duration of ECMO support in COVID-19 patients was 16 days, and the pooled mean ICU length of stay was 29 days. A large proportion of patients received neuromuscular blockade (96.2%) and were positioned prone (84.5%) prior to initiation of ECMO. The patients more commonly suffered renal, mechanical and infectious complications, and the complication rates in COVID-19 patients were similar to those seen in the EOLIA trial.[44] The review also identified increasing age as a risk factor for increased mortality.

The use and efficacy of ECMO in pandemics have been previously reported.[1–3] The incidence of ECMO use in patients with 2009 influenza A(H1N1)-associated ARDS in Australia and New Zealand was estimated to be 2–6 cases per million,[1,8] whereas 6% of critically ill patients were supported with ECMO for MERS-CoV-associated ARDS.[4] A meta-analysis of the studies that reported on the use of ECMO for the 2009 influenza A(H1N1) pandemic showed an overall mortality of 35% in a relatively younger population (mean age 40 years).[2] Patients with MERS-CoV who were supported with ECMO had a higher reported mortality of 40–70%.[3] By comparison, this review demonstrated that the cumulative mortality for patients with COVID-19 receiving ECMO support was 37.1% in a group of patients who were older (mean age 51.6 years) and were predominantly men. These results may also alleviate some concerns regarding VV ECMO use in the context of COVID-19-related ARDS.[13,47] During a pandemic, ECMO use will be subject to resource availability, given that prolonged ECMO support may be needed in these patients and the ELSO guidelines provide recommendations to assist clinicians in selecting patients judiciously in order to maximise benefit to patients with available resources.[7,8] Our meta-regression analysis showed that outcomes appear worse in patients with increasing age. Clinicians may have to exercise considerable discretion when offering ECMO to older patients during a pandemic where resources may be stretched, with no definitive age cut-off to guide this decision-making.

Interestingly, greater duration of ECMO support and illness severity (SOFA score) were not independently associated with death. The duration of VV ECMO support was longer when compared with patients in the EOLIA trial receiving ECMO (median: 15.92 days vs 11 days). Prolonged ECMO runs outside COVID-19 have been reported with good success.[48] However, the association between prolonged ECMO duration and improved mortality seen in this study stems likely from immortal time bias[49](49), commonly reported in observational studies. For patients on ECMO, such individuals must survive long enough to be weaned off, whereas their peers have no minimum survival requirements. The mean duration of mechanical ventilation prior to ECMO was 4.4 days and was not associated with mortality in the meta-regression analysis. Higher SOFA score was not an independent predictor for death in this review, a finding that contradicts previously published experience.[50] SOFA scores in patients requiring ECMO for COVID-19 can be variable, depending on their underlying phenotype.[51] Therefore, caution should be exercised when placing patients with advanced extrapulmonary organ failures on ECMO. Even though VV ECMO appears to be a viable therapy, the potential need for prolonged ECMO support may be a significant consideration when selecting patients during the pandemic. Other uncertainties regarding the long-term outcomes and the maximum duration of ECMO where recovery is still possible remain and may become clearer as more data becomes available.[52]

Strengths of this study include robust inclusion criteria and relevant exclusion criteria. Our review included 22 studies covering 6 geographical regions. We reduced confounding by elucidating factors correlating with mortality via subgroup analysis and meta-regression. Single-centre data that overlapped with international registries were excluded thereby avoiding duplication of data. We assessed study quality using a validated tool and assessed certainty in our estimates using GRADE. Nonetheless, we recognise several limitations of this study. Firstly, we included studies written only in English for the review. The variability in ECMO initiation and management across centres and regions as well as additional variability during the pandemic may have contributed to increased heterogeneity in our results. The outcomes of patients who were still in hospital or on ECMO at the time of publication were not known. Given that most of these studies were single-centre retrospective studies, these aspects could have introduced various confounders given the lack of risk adjustment or propensity score weighting. Even though the paper from ELSO registry contributed to a majority of patients in the review, the overall weightage to the entire analysis was only 12%, highlighting that the data were not skewed by one study. In addition, manuscripts published from centres that contributed to the ELSO registry report were excluded to avoid duplication. Meta-regression analyses are also inherently constrained by a lack of power, resulting in an increased risk of type 2 errors. This is further compounded by the fact that certain important variables, such as pre-ECMO SOFA scores, were only available in 11 studies, which might reduce the strength of the association between these variables and mortality Nonetheless, there was no publication bias in the studies included and JBI critical appraisal deemed most of the articles as high quality and suitable for inclusion while the GRADE assessment suggested a high certainty of evidence for the primary outcome.

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