Extracorporeal membrane oxygenation (ECMO) in patients with severe COVID-19 adult respiratory distress syndrome: a systematic review and meta-analysis
Authors: Elsayed Hany Hasan , Hassaballa Aly Sherif , Ahmed Taha Aly , Gumaa Mohammed , Sharkawy Hazem Youssef 
Published: April 2021

Abstract
Background
COVID 19 is the most recent cause of adult respiratory distress syndrome (ARDS). Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients failing conventional mechanical ventilation, but its role is still controversial. We conducted a systematic review and meta-analysis on ECMO for COVID-associated ARDS to study its outcome.

Main body
CENTRAL, MEDLINE/PubMed, Cochrane Library, and Scopus were systematically searched from inception to May 28, 2020. Studies reporting five or more patients with COVID-19 infection treated venovenous with ECMO were included. The main outcome assessed was mortality and ICU/hospital discharge. Baseline, procedural, outcome, and validity data were systematically appraised and pooled with random-effect methods. The validity of all the included observational studies was appraised with the Newcastle Ottawa scale. Meta-regression and publication bias were tested. This trial was registered with PROSPERO under registration number CRD42020183861.
From 1647 initial citations, 34 full-text articles were analyzed and 12 studies were selected, including 194 patients with confirmed COVID-19 infection requiring ICU admission and venovenous ECMO treatment. Median Newcastle-Ottawa scale was 6 indicating acceptable study validity. One hundred thirty-six patients reached an endpoint of weaning from ECMO with ICU/hospital discharge or death while the rest were still on ECMO or in the ICU. The median Berlin score for ARDS prior to starting ECMO was III. Patients received mechanical ventilation before ECMO implementation for a median of 4 days and ECMO was maintained for a median of 13 days. In hospital and short-term mortality were highly variable among the included studies ranging between 0 and 100%. Random-effect pooled estimates suggested an overall in-hospital mortality risk ratio of 0.49 (95% confidence interval 0.259 to 0.721; I2 = 94%). Subgroup analysis according to country of origin showed persistent heterogeneity only in the 7 Chinese studies with pooled estimate mortality risk ratio of 0.66 (I2 = 87%) (95% CI = 0.39-0.93), while the later larger studies coming from the USA showed pooled estimate mortality risk ratio of 0.41 (95% CI 0.28-0.53) with homogeneity (p=0.67) similar to France with a pooled mortality risk ratio of 0.26 (95% CI 0.08-0.43) with homogeneity (p=0.86). Meta-regression showed only younger age as a predictor of mortality (p=0.02). Publication bias was excluded by visualizing the funnel plot of standard error, Egger’s test with p=0.566, and Begg and Mazumdar test with p=0.373.

Conclusion
The study included the largest number of patients with outcome findings of ECMO in this current pandemic. Our findings showed that the use of venovenous ECMO at high-volume ECMO centers may be beneficial for selected COVID 19 patients with severe ARDS. However, none of the included studies involve prospective randomized analyses; and therefore, all the included studies were of low or moderate quality according to the Newcastle-Ottawa scale. In the current era and environment of the pandemic, it will likely be very challenging to conduct a prospective randomized trial of ECMO versus no-ECMO for COVID-19. Therefore, the information contained in this systematic review of the literature is valuable and provides important guidance.

Trial registration
The study protocol link is at www.crd.yorl.ac.uk/PROSPERO under registration number CRD42020183861.