The Lancet OCTOBER 17, 2009

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

Giles J Peek, Miranda Mugford, Ravindranath Tiruvoipati, et al. (CESAR trial collaboration)

Bottom Line

The CESAR trial demonstrated that a referral strategy to a specialist center for consideration of ECMO significantly improved the composite outcome of survival without severe disability at 6 months compared to conventional ventilation in patients with severe, potentially reversible respiratory failure.

Key Findings

1. The primary composite outcome (death or severe disability at 6 months) occurred in 37% (33/90) of the ECMO referral group compared to 53% (44/87) in the conventional management group (Relative Risk 0.69; 95% CI 0.05-0.97; P=0.03).

2. Only 75% (68/90) of patients randomized to the ECMO arm actually received the intervention, indicating the trial assessed a strategy of specialist center referral rather than direct ECMO administration.

3. Mortality at 6 months was 36% in the ECMO referral arm compared to 48% in the conventional management arm.

4. The intervention was estimated to be cost-effective with a modeled lifetime cost per Quality-Adjusted Life-Year (QALY) of £19,252.

Study Design

Design

RCT

Open-Label

Sample

180

Patients

Duration

6 mo

Median

Setting

Multicenter, UK

Population Adults (18-65 years) with severe, potentially reversible respiratory failure defined by a Murray score ≥3.0 or uncompensated hypercapnia with pH <7.2 despite optimal conventional ventilation.

Intervention Transfer to a specialist center for consideration of ECMO, including standardized ECMO protocols.

Comparator Continued conventional ventilatory management at the referring hospital.

Outcome Death or severe disability (defined as confinement to bed and inability to wash or dress alone) at 6 months post-randomization.

Study Limitations

• The trial utilized a pragmatic design comparing a referral-based strategy to standard care, confounding the direct therapeutic effect of ECMO with the effect of specialist center management.

• Adherence to the intervention was incomplete, as 24% of the intervention group never received ECMO.

• Ventilatory management was not strictly standardized, with significantly higher rates of low-volume, low-pressure ventilation observed in the ECMO referral group (93%) compared to the conventional group (70%).

• The sample size was smaller than originally planned, and the composite nature of the primary outcome led to ongoing debate regarding the true magnitude of mortality benefit versus disability reduction.

Clinical Significance

The CESAR trial provided the landmark evidence supporting the establishment of regional ECMO referral networks, suggesting that patients with severe, reversible respiratory failure benefit from transfer to specialized centers, likely through a combination of ECMO technology and expert multidisciplinary management.

Historical Context

Prior to CESAR, adult ECMO was largely discredited following negative randomized trials in the 1970s and 1990s. CESAR utilized modern extracorporeal technology and a regionalized strategy, fundamentally changing clinical practice and serving as a critical precursor to later trials like EOLIA, which aimed to refine the role of ECMO in severe acute respiratory distress syndrome.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

The CESAR trial highlights the concept of 'lung rest.' What is the physiological mechanism by which Extracorporeal Membrane Oxygenation (ECMO) facilitates this, and why is it beneficial in severe ARDS?

Key Response

ECMO performs gas exchange (O2 uptake and CO2 removal) outside the body. This allows clinicians to use 'ultra-protective' ventilation settings—minimizing tidal volumes and airway pressures—which reduces Ventilator-Induced Lung Injury (VILI), such as volutrauma and barotrauma, giving the native lungs time to heal from the initial inflammatory insult.

Resident

A patient with severe pneumonia has a Murray Lung Injury Score of 3.2 despite optimized conventional ventilation. According to the CESAR trial's inclusion criteria and management strategy, what is the next most appropriate step in their care, and why?

Key Response

The CESAR trial demonstrated that referral to a specialist center for consideration of ECMO improved outcomes. The Murray Score (incorporating PaO2/FiO2, PEEP, lung compliance, and CXR quadrants) helps quantify ARDS severity; a score >3.0 indicates a high risk of death where the benefit of specialized ECMO-center care likely outweighs the risks of transfer.

Fellow

A primary criticism of the CESAR trial is its 'referral-based' design. How does the fact that 24% of the intervention group never actually received ECMO complicate the interpretation of the trial's results regarding the efficacy of the ECMO circuit itself?

Key Response

Because it was an intention-to-treat analysis of a referral strategy, the benefit seen could be attributed to the specialized ARDS care (e.g., standardized lung-protective ventilation, prone positioning) provided at the specialist center rather than the ECMO circuit itself. This makes it difficult to isolate the pump's specific therapeutic contribution compared to just 'better' conventional care at a high-volume center.

Attending

Reflecting on the CESAR results alongside the later EOLIA trial, how should the organizational model of 'regionalized' severe respiratory failure centers change our approach to patients failing conventional therapy in community hospitals?

Key Response

CESAR suggests that the 'center effect'—centralizing expertise in high-volume units—is critical. Attendings should advocate for early stabilization and transport to specialized centers before the patient develops irreversible multi-organ failure or high-pressure-induced lung injury, as the benefit is derived from the entire package of specialist care, not just the rescue ECMO.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The CESAR trial used a composite primary endpoint of 'death or severe disability at 6 months.' From a clinimetric perspective, why is the inclusion of 'severe disability' essential for evaluating ECMO, and how might the 'Pragmatic' nature of the trial design affect the statistical power of this specific endpoint?

Key Response

Severe respiratory failure survivors often face significant neurocognitive and physical morbidities. Including disability ensures the intervention isn't just 'deferring death' to a state of poor quality of life. However, pragmatic trials with heterogeneous control group management (lack of standardized ventilation in non-specialist centers) can increase variance, potentially requiring larger sample sizes to maintain power for composite outcomes.

Journal Editor

As a reviewer, how would you address the lack of a standardized ventilation protocol in the control arm of the CESAR trial, and does this 'performance bias' compromise the internal validity of the study?

Key Response

A major threat to validity is that the control group received 'conventional management' at the discretion of the local center, which may not have met the ARDSNet standard of 6mL/kg tidal volumes. This creates a 'straw man' comparison where ECMO is compared to potentially sub-optimal care, possibly exaggerating the treatment effect of the specialist center arm.

Guideline Committee

CESAR was the first major trial to include a formal economic assessment of ECMO. How should the finding of an incremental cost-effectiveness ratio (ICER) of £19,252 per QALY influence international guidelines for the resource-intensive adoption of ECMO programs?

Key Response

The ICER fell below the typical threshold (e.g., NICE's £20k-£30k/QALY), suggesting ECMO is cost-effective in developed health systems for this specific population. This supports 'Strong' recommendations for regionalized ECMO referral pathways in guidelines, provided the systems can replicate the specialist center model used in the trial to ensure the high-cost intervention is used efficiently.

Clinical Landscape

Noteworthy Related Trials

2000

ALIVE Trial

n = 140 · AJRCCM

Tested

Extracorporeal CO2 removal (ECCO2R)

Population

Patients with severe acute respiratory failure

Comparator

Conventional mechanical ventilation

Endpoint

Survival to hospital discharge

Key result: The study demonstrated improved survival rates in patients treated with extracorporeal CO2 removal combined with low-frequency positive-pressure ventilation.

2013

PROSEVA Trial

n = 466 · NEJM

Tested

Prone positioning

Population

Patients with severe ARDS

Comparator

Supine positioning

Endpoint

28-day mortality

Key result: Early application of prone positioning significantly reduced 28-day mortality in patients with severe ARDS.

2018

EOLIA Trial

n = 249 · NEJM

Tested

Early extracorporeal membrane oxygenation (ECMO)

Population

Patients with severe acute respiratory distress syndrome (ARDS)

Comparator

Conventional mechanical ventilation with crossover to ECMO

Endpoint

60-day mortality

Key result: The trial did not meet its primary endpoint of significantly lower 60-day mortality, though it showed a trend toward benefit.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis