CESAR: ECMO for Severe Adult Respiratory Failure (2009)

“We conclude that transferring adult patients with severe but potentially reversible respiratory failure to a single centre specialising in the treatment of severe respiratory failure with ECMO is safe and, compared with conventional management, can improve survival without severe disability.”

  • The CESAR Trial Investigators

1. Publication Details

  • Trial Title: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial
  • Citation: Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363. DOI: 10.1016/S0140-6736(09)61069-2
  • Published: October 17, 2009, in The Lancet
  • Author: Giles J. Peek, M.D.
  • Funding: The UK National Institute for Health Research Health Technology Assessment programme.

2. Keywords

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

3. The Clinical Question

  • In adult patients with severe but potentially reversible respiratory failure (Population), does a strategy of transferring the patient to a single expert ECMO center for consideration of ECMO (Intervention) compared to continued conventional management at the referring hospital (Comparison) improve the outcome of death or severe disability at 6 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Extracorporeal membrane oxygenation (ECMO) provides life support for patients with severe respiratory failure refractory to conventional mechanical ventilation. However, its use was controversial due to high costs, complexity, and a lack of high-quality evidence. Previous randomized trials in the 1970s and 1990s had failed to show a benefit.
  • Knowledge Gap: It was unknown if modern ECMO technology, when delivered at a single, high-volume, expert center as part of a comprehensive care strategy, could improve patient-centered outcomes compared to conventional ventilation managed at multiple non-specialist centers.
  • Proposed Hypothesis: The authors hypothesized that a strategy of referral and transfer to a single ECMO-capable center would be superior to continued conventional management in reducing the rate of death or severe disability at 6 months.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 182 ICUs in the United Kingdom for recruitment, with a single expert ECMO center for the intervention.
  • Trial Period: Enrollment ran from July 2001 to August 2006.
  • Population:
    • Inclusion Criteria: Adult patients (18-65 years) with severe but potentially reversible respiratory failure, defined by a Murray score ≥3.0 or a pH <7.20.
    • Exclusion Criteria: Included high-pressure or high-FiO2 ventilation for >7 days, contraindications to heparinization, and any condition making 6-month survival unlikely.
  • Intervention: Patients were randomized to be considered for transfer to a single, designated expert center (Glenfield Hospital) for management, which included the potential use of ECMO.
  • Control: Patients were randomized to continue receiving conventional management at the referring hospital.
  • Management Common to Both Groups: The control group was managed with the goal of optimizing conventional ventilation. In the intervention group, not all patients received ECMO; the decision was made by the expert center team.
  • Power and Sample Size: The authors calculated that a sample size of 180 patients would provide 80% power to detect a 20% absolute risk reduction in the primary outcome. (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: A composite of death or severe disability (defined as confinement to bed and inability to wash and dress) at 6 months after randomization.
    • Secondary Outcomes: Included the actual use of ECMO, duration of ventilation, and cost-effectiveness.

6. Key Results

  • Enrollment and Baseline: 180 patients were randomized (90 to the ECMO strategy group and 90 to the conventional management group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: A significantly lower proportion of patients in the ECMO strategy group met the primary outcome. 33 of 90 patients (37%) in the conventional management group died or were severely disabled, compared with 24 of 90 patients (27%) in the ECMO strategy group. However, after adjusting for missing primary outcome data, the result was reported as: 63% of patients in the ECMO group survived without disability, compared with 47% in the conventional group (p=0.03).
  • Secondary Outcomes: In the intervention arm, 68 of the 90 patients (76%) actually received ECMO.
  • Adverse Events: One patient in the ECMO group had a cerebral hemorrhage during transport.

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 patients who died or had severe disability at 6 months.
  • Key Statistic(s) Reported: Relative Risk (RR) for death or severe disability: 0.69 (95% CI, 0.47 to 1.02, p=0.07). The primary analysis reported in the abstract is based on survival without disability: 63% vs 47% (p=0.03).
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.03 for the primary outcome of survival without disability is 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 of Good Outcome in Intervention Group) – (Risk of Good Outcome in Control Group)
      • Calculation: ARR = 63% – 47% = 16%.
      • Clinical Meaning: For every 100 patients managed with the ECMO referral strategy, about 16 additional patients survived without severe disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.16 = 6.25, which is rounded down to 6.
      • Clinical Meaning: You would need to refer 6 patients to an expert ECMO center to achieve one additional good outcome (survival without severe disability).
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: As a multicenter, randomized controlled trial, it provided the first high-quality evidence in decades on the role of ECMO.
  • Generalizability: The pragmatic design, recruiting from 182 ICUs, makes the findings highly generalizable to a national healthcare system.
  • Patient-Centered Outcomes: The primary outcome of death or severe disability at 6 months is a robust and highly relevant patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded. The most significant limitation is that it was a trial of a “strategy of care” (referral to an expert center) and not a direct trial of the ECMO device itself. The control group did not receive the same level of protocolized, expert ventilation management as the intervention group.
  • External Validity (Generalizability): The results are specific to a system with a single, highly experienced ECMO referral center and may not be applicable to systems with multiple, less experienced centers.
  • Other: The high rate of crossover (24% of the control group received ECMO at their own centers) and the fact that not all patients in the intervention arm received ECMO complicates the interpretation of the results.

10. Conclusion of the Authors

  • Transferring adult patients with severe but potentially reversible respiratory failure to a single expert center for consideration of ECMO is safe and improves the primary outcome of survival without severe disability at 6 months.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial that revived interest in ECMO and led to the development of regional ECMO centers and networks worldwide. It established the “ECMO as a strategy” concept.
  • Specific Recommendations:
    • Patient Selection: For adult patients (age <65) with severe but potentially reversible respiratory failure who are failing conventional ventilation.
    • Actionable Intervention: The results support the development of and referral to regional, high-volume, expert ECMO centers.
  • What This Trial Does NOT Mean: This trial does NOT prove that the ECMO device itself is superior to conventional ventilation. It proves that management at an expert center that has ECMO as an option is superior to conventional management at a non-expert center.
  • Implementation Caveats: The success of the strategy is dependent on having a well-organized referral network and a high-volume, expert ECMO center.

12. Context and Related Studies

  • Building on Previous Evidence: The CESAR trial (2009) was designed to overcome the limitations of earlier negative ECMO trials by standardizing care at a single expert center.
  • Influence on Subsequent Research: The positive but complex findings of this trial, particularly the criticism that it was a “strategy” trial, directly led to the design of the EOLIA trial (2018), which was a true patient-level randomization to either ECMO or continued expert conventional ventilation within the same centers.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not answer the key question of whether ECMO itself is superior to a strategy of optimized conventional ventilation when both are delivered by an expert team.
  • Future Directions: The EOLIA trial (2018) was the direct successor to this study, designed to answer the question that CESAR left unresolved.

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 pragmatic RCT design was a strength for assessing a complex healthcare strategy. However, the major methodological limitation is the confounding of the intervention (ECMO) with the location and expertise of care (a single expert center). The control arm did not receive the same level of protocolized care, which is a significant source of potential bias.
  • Results: The study reported a statistically significant benefit in its primary patient-centered outcome. The NNT of 6 suggests a large and clinically important treatment effect.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their data, but it must be interpreted as a trial of a “care bundle” or “strategy” rather than just a device. The findings are most applicable to healthcare systems that can support a similar model of regional expert referral 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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