Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome Associated with COVID-19: An Emulated Target Trial Analysis

Abstract

Rationale: Whether patients with coronavirus disease (COVID-19) may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. Objectives: To estimate the effect of ECMO on 90-day mortality versus IMV only. Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO versus no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (Pa_O2/Fi_O2 < 80 or Pa_CO2 ⩾ 60 mm Hg). We controlled for confounding using a multivariable Cox model on the basis of predefined variables. Measurements and Main Results: A total of 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability on Day 7 from the onset of eligibility criteria (87% vs. 83%; risk difference, 4%; 95% confidence interval, 0-9%), which decreased during follow-up (survival on Day 90: 63% vs. 65%; risk difference, -2%; 95% confidence interval, -10 to 5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand and when initiated within the first 4 days of IMV and in patients who are profoundly hypoxemic. Conclusions: In an emulated trial on the basis of a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and regions with ECMO capacities specifically organized to handle high demand.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; emulated target trial; extracorporeal membrane oxygenation.

Figure 1.

Study flow chart. The flowchart describes at each landmark time (defined as the first seven days from invasive mechanical ventilation initiation) the number of patients considered for eligibility, the number of patients who met the eligibility criteria of the emulated trial, and the number of patients who initiated extracorporeal membrane oxygenation (ECMO). One patient can contribute several times to the “Did not initiate ECMO” group but only once to the “initiated ECMO” group. CC = complete cases; COVID-ICU = large French cohort of 4,244 critically ill patients admitted in intensive care unit for coronavirus disease; IMV = invasive mechanical ventilation; MI = number of cases after multiple imputations of missing data (median [min/max]); SAPS II = simplified acute psychology score.

Figure 2.

Marginal survival curves for patients who are (A) extracorporeal membrane oxygenation (ECMO)-treated versus patients treated without ECMO. (B) Patients receiving ECMO treatment in low- or high-ECMO volume centers versus patients treated without ECMO (SA8). The number at-risk is the median number among multiply imputed datasets. The evaluation cohort is composed of unique individuals the first time they meet eligibility criteria. The pooled database is composed of potentially repeated individuals obtained by pooling the data from the seven sequential trials.