Yes, The EOLIA Trial Was Technically Negative But…

It should not be used as “evidence” that ECMO for severe hypoxia is “unproven.”

First of all, everyone should download the Critical Matters podcast, hosted by my good friend Dr. Sergio Zanotti. It is an excellent resource for great discussions about Critical Care Medicine and its practice.

In a recent episode, the management of refractory hypoxemia was discussed, and the main message was quite clear: veno-venous extracorporeal membrane oxygenation (VV-ECMO) should not be used if the patient was not proned first.

After I listened to it, I reached out a world renown Critical Care expert and asked him if he also agreed that ECMO should not precede proning, and he said:

I wouldn’t do V-V ECMO before proning

I must admit that this answer gave me a bit of distress.

They based these statements on the recently published EOLIA trial. This post gives an excellent rundown of the results of the trial and what they mean. Here is the gist of the findings:

Outcome

• Primary outcome: No statistical difference in mortality at day 60
• ECMO group 44/124 (35%) vs Control group 57/125 (46%)
• Relative risk, 0.76; 95% confidence interval [CI], 0.55 to 1.04; P=0.09

Secondary outcomes:

• Compared to control group, the ECMO group had:
• Lower relative risk of treatment failure 0.62 (95% CI, 0.47 to 0.82; P<0.001)
• Treatment failure was defined as death by day 60 in patients in the ECMO group, and as crossover to ECMO or death in patients in the control group
• Lower risk of Renal replacement therapy (RRT) at day 60 (50 vs. 32 days; median difference, 18 days; 95% CI, 0 to 51)
• Underwent less proning (59 vs. 46 days; median difference, 13 days; 95% CI, 5 to 59)
• Cross over to ECMO occurred in 35/125 (28%) of control patients
• Occurred at median 4 days (IQR 1 to 7)
• Median PaO2:FiO2 51 mmHg (IQR 46 to 61), median SaO2 77% (IQR 74 to 87), median lactate was 3.2 mmol/L (1.5–6.2)
• 9 patients had cardiac arrest, 7 had right heart failure, 11 received RRT
• 7 underwent venoarterial (VA) ECMO (and 6 had E-CPR)
• 60 day mortality was higher in cross over patients than rest of controls: 20/35 (57%) in cross over patients vs 90 (41%) in remaining cross over patients
• The hazard ratio for death within 60 days, for the ECMO group compared to controls after adjusting for selective crossover with the rank-preserving structural failure time analysis, was 0.51 (95% CI, 0.24 to 1.02; P=0.055) (supplemental analysis)

Adverse Events. Compared to control patients, ECMO patients had

• More severe thrombocytopenia (<20,000 platelets per cubic millimeter; 27% vs. 16%; ARR 11 %; 95% CI, 0 to 21)
• More bleeding events (defined as ≥1 RBC transfusion: 46% vs. 28%; ARR 18%; 95% CI, 6 to 30
• Less ischaemic stroke (no patients vs. 5%; ARR -5%; 95% CI, −10 to −2)

So, does this mean that the trial was “negative,” that VV-ECMO is “unproven”?

Hardly.

Yes, technically, the trial results were negative. The mortality difference did not reach statistical significance. The trend, however, was quite strong favoring ECMO. The post also summarized well the issues with interpretation of the results, especially given the fact that 28% of patients in the control group crossed over to ECMO:

High cross over rate of controls

• The 28% cross over rate resulted a reduction of separation between the two arms, and diluted the ECMO treatment effect. This potentially impacted the trial in the following ways:
• The cross over complicates the interpretation of the two arms in an intention to treat analysis. It also introduces a potential bias against the ECMO group in the secondary risk of treatment failure analysis, as ECMO was initiated much later and in sicker patients than the rest of the controls

If these patients didn’t get ECMO, all of them would have died. “Well,” one can say, “they all would have died anyway.” Not true. Of the 35 patients who crossed over, 15 survived. That’s a big deal.

To my mind, this trial adds to the positive results of the CESAR trial published in 2009. It would be interesting to see what combining the two trials would show as sort of a “meta analysis.”

Here is the another thing about ECMO. Again, yes, proning has good data that it works and saves lives. And the EOLIA trial was technically a negative trial. At the same time, we need to realize something: most of the medical care in the US (and the world), is delivered in the community setting. The same goes with my main hospital: it’s a community hospital. Yes, it has a high powered (and award-winning) ICU, but it’s still a community hospital.

The centers that did proning were highly experienced at proning. They have done it a lot, and they know what they are doing to make sure it’s done safely. You can’t always translate that to every single community hospital, with staff that is not as experienced at proning.

“Well, develop a protocol.”

Sure, that can always be done. But if a center can easily, safely, and feasibly do ECMO for refractory hypoxia, then what’s the harm? Certainly, I wouldn’t use the EOLIA trial as “proof” that ECMO doesn’t work.

Further, if I can maintain adequate oxygenation with, say, airway pressure release ventilation (APRV) and neuromuscular blockade, why would I risk proning the patient? Same goes with ECMO, actually. If I’m doing the job with advanced mechanical ventilation, why would I go to ECMO? It does have real risks, and they can harm patients. I don’t take this risk for granted.

Still, I’m a believer in ECMO. I’ve seen it work. And my experience with proning has been less successful, and I fully admit they we likely didn’t prone soon enough. That said, at my institution, I can easily start ECMO if conventional mechanical ventilation and neuromuscular blockade fails to improve. I’d much rather do this than prone, and I think the data supports this view, the p-value notwithstanding.

The real question is this: OK, I convince the surgeons to hook the patient up to ECMO. Now what? That is a discussion for another day.

The opinions expressed in this post are my own and do not reflect those of my employer or the organizations with which I am affiliated.