What is the role of Extracorporeal Membrane Oxygenation (ECMO) in managing severe adult respiratory failure according to the CESAR trial?

Critical Appraisal of the CESAR Trial for DrNB Examination

Overview and Primary Findings

The CESAR trial demonstrated that transferring adults with severe but potentially reversible respiratory failure (Murray score >3.0 or pH <7.20) to a specialized ECMO center significantly improved survival without severe disability at 6 months (63% vs 47%, RR 0.69, p=0.03), representing one additional survivor for every six patients treated. 1, 2

Study Design and Methodology

Key Design Elements

• Randomization structure: 180 patients randomized 1:1 to either referral for ECMO consideration (n=90) or continued conventional management at their original centers (n=90) 1, 2
• Inclusion criteria: Adults aged 18-65 years with severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure 1
• Primary outcome: Death or severe disability at 6 months after randomization 1, 2
• Intervention: Transfer to single specialized center (Glenfield Hospital, Leicester) for ECMO consideration, not guaranteed ECMO treatment 1, 2

Actual Treatment Received

• Only 68 of 90 patients (75%) randomized to ECMO arm actually received ECMO 1, 2
• Reasons for not receiving ECMO: 3 died before transfer, 2 died in transit, 16 improved with conventional treatment by ECMO team, 1 required amputation preventing heparinization 2

Major Limitations and Critical Flaws

Design-Related Limitations

The most significant limitation is that CESAR was not a pure comparison of ECMO versus conventional ventilation, but rather a comparison of transfer to a specialized center versus staying at the original hospital. 3

• Lack of standardized ventilator management in control arm: No specific management protocol was mandated for conventional treatment centers, introducing substantial heterogeneity 3
• Incomplete application of intervention: 24% of patients randomized to ECMO never received it, yet analysis was intention-to-treat 3
• Co-intervention with high-volume center transfer: Impossible to separate ECMO benefit from benefits of specialized center care 3
• Composite primary endpoint: Used "disability-free survival" rather than mortality alone, complicating interpretation 3

Temporal and Contextual Limitations

The CESAR trial predated establishment of prone positioning as standard therapy, and its use was limited in this trial, making results less applicable to modern ARDS management. 3

• Trial conducted before lung-protective ventilation was universally standardized 3
• Modern adjunctive therapies (prone positioning, neuromuscular blockade, higher PEEP strategies) were not systematically applied in control arm 3
• Certainty of evidence downgraded from moderate to low for indirectness due to these limitations 3

Generalizability Concerns

There is considerable variability in center experience, pre-ECMO care, and outcomes, leading to uncertainty about real-world generalizability beyond high-volume expert ECMO centers. 3

• Both CESAR and subsequent trials conducted at high-volume, expert ECMO centers 3
• Outcomes differ significantly by institutional case volume and experience 3
• Centers caring for >20-25 cases per year have significantly better outcomes 4

Economic Evaluation

Cost-Effectiveness Analysis

• ECMO patients incurred average total costs of £73,979 versus £33,435 for conventional management (UK prices, 2005) 2
• Lifetime model predicted cost per QALY of £19,252 (95% CI £7,622-£59,200) at 3.5% discount rate 1, 2
• ECMO gained 0.03 QALYs at 6-month follow-up, with lifetime QALYs of 10.75 for ECMO versus 7.31 for conventional group 1, 2
• Costs to patients and families were higher for ECMO allocation 2

Current Guideline Interpretation

American Thoracic Society Position (2024)

The ATS suggests use of VV-ECMO in selected patients with severe ARDS, but this is a conditional recommendation with low certainty of evidence, specifically citing CESAR's limitations. 3

Recommended Patient Selection Criteria

• Reversible etiologies of respiratory failure 3
• Very severe hypoxemia (PaO₂/FiO₂ ratio <80 mm Hg) or hypercapnia (pH <7.25 with PaCO₂ >60 mm Hg) despite optimal conventional management 3
• Early in ARDS course (<7 days) 3, 4
• Few risk factors for futility of treatment 3

Prerequisite Therapies Before ECMO Consideration

Less invasive therapies must be optimized before considering VV-ECMO: lung-protective ventilation, higher PEEP, neuromuscular blockade, and prone positioning. 3

• These interventions may obviate need for ECMO escalation 3
• CESAR's failure to standardize these therapies in control arm is a major criticism 3

Historical Context and Evolution

Earlier Evidence (2017 Guidelines)

• 2017 ATS/ERS/SCCM guidelines stated "additional evidence is necessary to make a definitive recommendation for or against the use of ECMO" 3
• Recommended ongoing research rather than routine clinical use 3
• Noted CESAR's mortality difference was not statistically significant (RR 0.75,95% CI 0.53-1.06) 3

Subsequent Evidence

• Pooled analysis of two RCTs (429 patients total) demonstrated VV-ECMO probably decreased mortality and increased organ support-free days 3
• Second trial (249 patients) used protocolized ventilator management in control arm with encouraged prone positioning and neuromuscular blockade 3

Common Pitfalls in Interpretation

What CESAR Actually Demonstrated

1. Transfer to specialized center improved outcomes, not necessarily ECMO itself 3
2. Expert team management matters - 16 patients improved without ECMO after transfer 2
3. Results apply to referral strategy, not isolated ECMO intervention 3

What CESAR Did NOT Demonstrate

1. Benefit of ECMO when modern lung-protective strategies optimized 3
2. Outcomes in centers without high volume and expertise 3
3. Benefit when prone positioning routinely used 3

Implementation Considerations for Clinical Practice

Resource and System Requirements

• ECMO is resource-intensive regarding staffing, equipment, and costs, potentially diverting resources from other institutional needs 3
• Should be provided in high-volume, dedicated centers with regional organization 3
• Mobile ECMO teams and transfer networks should be established 3, 4
• Learning curve requires at least 20 cases for competence 4

Health Equity Concerns

• Disparities in patient selection based on insurance status, income, and gender have been reported 3
• Variable access to ECMO centers has serious implications for health equity 3

Examination Key Points

Strengths to Emphasize

• First adequately powered RCT showing mortality benefit in severe respiratory failure 1, 2
• Pragmatic design reflecting real-world referral decisions 1, 2
• Comprehensive economic evaluation demonstrating cost-effectiveness 1, 2
• Survival benefit (66% vs historical 42-55%) was clinically meaningful 5

Weaknesses to Emphasize

• Confounding by co-intervention (specialized center care) 3
• Non-standardized control arm ventilation 3
• 24% crossover (randomized to ECMO but didn't receive it) 3
• Outdated context (pre-prone positioning era) 3
• Limited generalizability beyond expert centers 3

Current Clinical Application

• CESAR supports conditional recommendation for VV-ECMO in highly selected severe ARDS patients at experienced centers 3
• Must exhaust conventional therapies first 3
• Transfer to ECMO-capable center should be considered when feasible 3, 4
• Certainty of evidence remains low due to CESAR's methodological limitations 3