EOLIA: ECMO for Severe ARDS (2018)

“In patients with very severe ARDS, 60-day mortality was not significantly lower with ECMO than with a strategy of conventional ventilation that included ECMO as rescue therapy.”

  • The EOLIA Trial Investigators

1. Publication Details

  • Trial Title: Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome
  • Citation: Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018;378(21):1965-1975. DOI: 10.1056/NEJMoa1800385
  • Published: May 24, 2018, in The New England Journal of Medicine
  • Author: Alain Combes, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • ARDS, Extracorporeal Membrane Oxygenation (ECMO), Mechanical Ventilation, Respiratory Failure, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with very severe ARDS (Population), does a strategy of early initiation of venovenous ECMO (Intervention) compared to a strategy of continued conventional mechanical ventilation with the option for rescue ECMO (Comparison) reduce 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Extracorporeal membrane oxygenation (ECMO) can provide life support for patients with the most severe forms of ARDS. The CESAR trial (2009) had suggested a benefit for a strategy of referral to an ECMO center, but it did not directly compare ECMO to optimal medical management within the same expert centers.
  • Knowledge Gap: It was unknown if the ECMO device and procedure itself provided a survival benefit when compared to a strategy of expertly managed, protocolized conventional ventilation that still allowed for ECMO as a last-resort rescue therapy.
  • Proposed Hypothesis: The authors hypothesized that a strategy of early ECMO would be superior to a strategy of conventional mechanical ventilation in reducing 60-day mortality in patients with very severe ARDS.

5. Study Design and Methods

  • Design: A multicenter, international, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 64 intensive care units (ICUs) in France, the United States, and other countries.
  • Trial Period: Enrollment ran from October 2011 to January 2017.
  • Population:
    • Inclusion Criteria: Adult patients with very severe ARDS, defined by one of three criteria: a PaO2:FiO2 ratio of <50 for >3 hours, a PaO2:FiO2 of <80 for >6 hours, or an arterial pH <7.25 with a PaCO2 ≥60 for >6 hours.
    • Exclusion Criteria: Included high-pressure or high-FiO2 ventilation for >7 days, contraindications to anticoagulation, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients were randomized to receive immediate initiation of venovenous ECMO.
  • Control: Patients were randomized to continue with a protocolized strategy of conventional mechanical ventilation, which included the use of neuromuscular blockers and prone positioning. Crossover to rescue ECMO was permitted if the patient developed refractory hypoxemia.
  • Management Common to Both Groups: All patients were managed in expert centers with a standardized, lung-protective ventilation strategy.
  • Power and Sample Size: The authors calculated that a sample size of 331 patients would provide 80% power to detect a 20% absolute risk reduction in 60-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 60 days.
    • Secondary Outcomes: Included failure of the assigned treatment strategy (defined as death or crossover to ECMO in the control group) and the incidence of complications.

6. Key Results

  • Enrollment and Baseline: 249 patients were randomized (124 to ECMO and 125 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped for futility by the data and safety monitoring board after the second interim analysis, as it was deemed unlikely to show a significant difference in the primary outcome.
  • Primary Outcome: There was no significant difference in 60-day mortality. 44 of 124 patients (35%) in the ECMO group died, compared with 57 of 125 patients (46%) in the control group (p=0.09).
  • Secondary Outcomes: A key finding was the very high rate of crossover: 35 patients (28%) in the control group received rescue ECMO due to refractory hypoxemia. The risk of treatment failure was significantly lower in the ECMO group.
  • Adverse Events: The incidence of bleeding complications was significantly higher in the ECMO group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 60 days: 0.76 (95% CI, 0.55 to 1.04; P-value: 0.09).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.76.
      • Clinical Meaning: An RR of 0.76 suggests a 24% lower relative risk of death in the ECMO group, but this result was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.55 to 1.04.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. The true effect could range from a 45% benefit to a 4% harm.
    • P-value: The p-value of 0.09 is above the 0.05 threshold, indicating the result is not statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 46% – 35% = 11%.
      • Clinical Meaning: For every 100 patients treated with early ECMO, there was a non-significant trend towards about 11 fewer deaths.
  • Subgroup Analyses: A post-hoc Bayesian analysis of the trial suggested a high probability (96%) that early ECMO was superior to the control strategy.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a critical clinical question. The use of a highly protocolized conventional ventilation strategy in the control arm was a major strength.
  • Generalizability: The inclusion of 64 diverse, expert centers increases the applicability of the findings to similar high-level care settings.
  • Patient-Centered Outcomes: The primary outcome of 60-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias. The high rate of crossover from the control arm to rescue ECMO is a major limitation that makes the results difficult to interpret and likely biased the result towards the null (i.e., made it harder to find a difference).
  • External Validity (Generalizability): The trial was conducted exclusively in expert centers with a high volume of ARDS and ECMO patients. The results are not generalizable to less experienced centers.
  • Other: The trial was stopped early for futility and was therefore underpowered to definitively rule out a smaller, but still potentially important, treatment effect. The p-value of 0.09 is a major point of discussion.

10. Conclusion of the Authors

  • The authors concluded that in patients with very severe ARDS, 60-day mortality was not significantly lower with early ECMO than with a strategy of conventional ventilation that included ECMO as a rescue therapy.

11. To Summarize

  • Impact on Current Practice: This trial, despite being technically “negative,” has been highly influential. The strong trend towards benefit, combined with the high crossover rate, has been interpreted by many in the critical care community as supportive evidence for the use of early ECMO in this highly select, severely ill population.
  • Specific Recommendations:
    • Patient Selection: For adult patients with very severe ARDS who are failing optimized conventional mechanical ventilation in an expert center.
    • Actionable Intervention: The results support considering early initiation of ECMO in this specific population.
  • What This Trial Does NOT Mean: This trial does NOT mean that ECMO should be used for all patients with ARDS. Its findings are specific to the sickest patients being managed in expert centers.
  • Implementation Caveats: The use of ECMO is a complex, high-risk, and resource-intensive therapy that should only be performed at experienced, high-volume centers.

12. Context and Related Studies

  • Building on Previous Evidence: The EOLIA trial (2018) was a direct successor to the CESAR trial (2009). While CESAR tested a “strategy of referral,” EOLIA was designed to test the efficacy of the ECMO device itself against optimal medical care within the same expert centers.
  • Influence on Subsequent Research: The complex and debated results of EOLIA have spurred further research and meta-analyses, which have generally supported a mortality benefit for ECMO in very severe ARDS.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is how to best interpret the non-significant primary outcome in the face of the very high crossover rate.
  • Future Directions: Future research is focused on better identifying which patients with severe ARDS are most likely to benefit from ECMO and on optimizing the timing and delivery of this complex therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a high-stakes intervention for the sickest patients in the ICU.
  • Methods: The multicenter RCT design was appropriate. The main methodological limitation is the very high rate of crossover to rescue ECMO in the control arm, which severely complicates the interpretation of the intention-to-treat analysis and likely biased the result towards finding no difference. The trial was also stopped early and was underpowered.
  • Results: The study reported a non-significant difference in its primary outcome, but with a strong trend towards benefit (p=0.09) and a large absolute risk reduction of 11%. This “negative” result is a classic example of how a p-value alone can be misleading.
  • Conclusions and Applicability: The authors’ statistically conservative conclusion is a fair reflection of the primary outcome data. However, many experts in the field interpret the totality of the evidence from this trial (including the high crossover rate and the Bayesian analysis) as being supportive of early ECMO. The findings are only applicable to high-volume, expert ECMO centers.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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