EOLIA

In Review

Combes A, et al. "Extracorporeal membrane oxygenation for severe Acute respiratory distress syndrome". The New England Journal of Medicine. 2018. 378(21):1965-1975.
PubMed • Full text

Clinical Question

Do patients with very severe ARDS refractory to traditional therapies benefit from early initiation of venovenous ECMO?

Bottom Line

Early initiation of VV ECMO does not provide a mortality benefit to patients with very severe ARDS compared to conventional ARDS strategies with rescue ECMO therapy.

Major Points

Given the critical condition of ARDS patients with refractory hypoxia, multiorgan failure, and the dangers of ventilator-induced lung injury, the use of venovenous extracorporeal membrane oxygenation (VV ECMO) has seen increased utilization. Previous retrospective case-control studies have shown decreased rates of mortality associated with VV ECMO use in patients with severe ARDS leading to the Extracorporeal Life Support Organization recommending VV ECMO initiation in patients with PaO2/FiO2 < 100 despite utilization of advanced strategies for oxygenation . A randomized control trial on ECMO vs. conventional management showed referral to an ECMO center (but not necessarily initiation of ECMO) was associated with lower mortality, however the direct benefit of VV ECMO use has remained controversial in terms of mortality benefit .

The EOLIA trial was an multi-center, randomized, open-label trial which randomized patients with severe ARDS to receiving early VV ECMO or conventional mechanical ventilation with an option to use ECMO as a rescue therapy. The trial was planned to enroll 331 patients, however was stopped at 240 patients during a planned interim analysis after no statistically significant mortality benefit was detected between the two trial groups. The 60-day mortality was 35% in the ECMO group and 46% in the control group (p = 0.09). Secondary outcomes favored the early VV ECMO group including lower relative risk of treatment failure (death or crossover to ECMO group), lower number of days prone, lower rates of renal failure, and lower rates of cardiac failure. There was a high proportion of patients (35 patients, 28%) from the control group who ultimately required VV ECMO.

While the EOLIA trial did not show a statistically significant decrease in mortality, the high rate of crossover from the control group makes it difficult to analyze conventionally. There was a clear benefit seen in most secondary outcomes and a trend towards significance in the primary outcome as well. This has led to much controversy and debate about the results of this trial, which remains ongoing. Given the significant period of time required to recruit sufficient participants, it is unlikely there will be a further RCT on this topic. Overall, VV ECMO remains a reasonable option to utilize in severe ARDS which has failed conventional mechanical ventilation strategies.

Guidelines

Extracorporeal Life Support Organization (2017) indications for VV ECMO

• Hypoxic respiratory failure when PaO2/FiO2 <100 and FiO2 >0.9 despite optimal care for 6 hours or less. Suggested that ECMO be instituted within 1-2 days of presentation.
• Respiratory acidosis despite high plateau pressures (>30cmH2O)
• Severe air leak syndromes
• Pre-lung transplant patients

Design

• International, open-label, randomized, controlled trial
• N=249
  • Early VV ECMO (N=121)
  • Conventional ARDS treatment (N=125) with 35 patients ultimately receiving rescue VV ECMO therapy
• Setting: 23 centers internationally
• Enrollment: October 2012 to April 2017
• Follow-up period: 90 days
• Analysis: Intention-to-treat
• Primary outcome: 60-day mortality

Population

Inclusion Criteria

Severe ARDS according to usual criteria AND 1 of the 3 following criteria:

• PaO2/FiO2 ratio <50mmHg with FiO2 >80% for 3 hours despite optimization of mechanical ventilation and despite attempts at rescue maneuvers (Inhaled nitric oxide, recruitment maneuvers, prone positioning, HFO ventilation, or almitrine infusion)
• PaO2/FiO2 ratio <80mmHg with FiO2 >80% for 6 hours despite optimization of mechanical ventilation and despite attempts at rescue maneuvers (Inhaled nitric oxide, recruitment maneuvers, prone positioning, HFO ventilation, or almitrine infusion)
• pH <7.25 with PaCO2 >60mmHg for 6 hours resulting from mechanical ventilation settings adjusted to keep Pplat <32cmH2O

Exclusion Criteria

• Mechanical ventilation for >7 days
• Age <18 years
• Pregnancy
• Weight >1kg/cm or BMI >45kg/m2
• Chronic respiratory disease requiring oxygen therapy or mechanical assistance
• Cardiac failure requiring VA ECMO
• History of heparin-induced thrombocytopenia
• Malignancy with prognosis <5 years
• Moribund patient on day of randomization
• Cardiac arrest with resultant coma
• Irreversible neurological pathology
• Decision to limit medical interventions
• Unable to successfully cannulate femoral or jugular veins for ECMO
• CardioHelp device not available

Baseline Characteristics

From the VV ECMO group

• Demographics: Age 52 years, male sex 70%
• Illness stratification: SOFA 10.8, median time since intubation 34 hours
• Cause of ARDS: Bacterial pneumonia 44%, viral pneumonia 21%, other 35%
• Ventilation characteristics: P/F Ratio 73 mm Hg, PEEP 11.7 cm H₂O
• Arterial blood pH: 7.24
• Advanced treatments (ECMO group vs. Conventional group)
  • Prone positioning = 56% vs. 62%
  • Inhaled nitric oxide = 52% vs. 54%
  • Recruitment maneuvers = 18% vs. 27%
  • Neuromuscular blockade = 92% vs. 96%

Interventions

• Experimental arm: VV ECMO started as soon as possible (median time = 3.3 hours) with ventilation settings of ACVC, FiO2 = 0.3-0.6, PEEP >10, Plateau pressure of <24cmH2O, RR 10-30
• Control arm: ACVC ventilation with TV maximum of 6ml/kg of ideal body weight, Pplat <30cmH2O. If refractory hypoxemia is present, can use advanced strategies including inhaled Nitric Oxide, prone positioning, HFO ventilation, and almitrine
  • Patients in the control arm are able to cross-over to ECMO if refractory hypoxemia (SaO2 <80% for >6 hours) despite advanced therapies

Outcomes

Comparisons are early VV ECMO vs. conventional therapy.

Primary Outcomes

60-day mortality

35% vs. 46% (RR 0.76; 95% CI 0.55-1.04; P=0.09)

Secondary Outcomes

Treatment failure at 60 days (Death for ECMO group vs. death or switch to ECMO for conventional group)

35% vs. 58% (RR 0.62; 95% CI 0.47-0.82; P<0.001)

90-day mortality

37% vs. 47%

Median length of ICU stay

23% vs. 18%

Median days free from mechanical ventilation

23 days vs. 3 days

Median days free from renal replacement therapy

50 days vs. 32 days

Adverse Events

Pneumothorax

15% vs. 13%

Thrombocytopenia

40% vs. 32%

Bleeding leading to transfusion

46% vs. 28% (Massive transfusion: 2% vs. 1%)

Stroke (ischemic or hemorrhagic)

2% vs. 6%

Criticisms

• There was a relatively large proportion of patients who ultimately received ECMO within the control group. This was inevitable and expected particularly given the high rate of mortality associated with ARDS and the potential benefit that was present with use of VV ECMO. This high rate of crossover potentially confounded the primary outcome results leading to underappreciation for the benefit of early VV ECMO.
• Trial was stopped early for futility and unable to reach the pre-specified 331 patients for statistical analysis

Funding

Direction de la Recherche Clinique et du Développement and the French Ministry of Health