Viewpoints
Extracorporeal Membrane Oxygenation for Acute
Respiratory Distress Syndrome: EOLIA and Beyond
Robert H. Bartlett, MD
Key Words: acute respiratory distress syndrome; clinical trial;
EOLIA; extracorporeal membrane oxygenation
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E
xtracorporeal membrane oxygenation (ECMO) has been
standard treatment for cardiac failure and respiratory
failure in neonates and children for decades. The use of
ECMO for adults with severe respiratory failure was limited to
a few specializing centers until 2008. In 2008–2009, ECMO was
very successful in the management of severe acute respiratory
distress syndrome (ARDS) due to viral pneumonia in the H1N1
worldwide pandemic (1). New devices became available in 2009
which were much simpler, safer, and easier to use than the origi-
nal ECMO devices (2). In 2010, the CESAR trial was published
(3). This study showed major survival advantage to the ECMO
arm of the trial which included a detailed protocol of care plus
ECMO if needed (in a single center) compared with the best
available care in the country. In addition, there have been two
matched pairs trials of ECMO in H1N1, both of which show a
survival advantage to care in an ECMO center, with ECMO sup-
port if needed (4, 5). These trials have been discussed at length
in the literature (6). The basic conclusion is that patients with
severe ARDS should be transferred to ECMO centers. Survival
for severe ARDS in these centers is 65–75%. Meanwhile, the
overall outcomes for ARDS have not changed in 30 years (7, 8).
The mortality is 40% for all comers and 30% for patients with-
out major comorbidities. If ECMO were used for the patients at
high risk of dying with ARDS, and most of them survived, the
overall mortality would be decreased from 40% to 20%.
The EOLIA trial was designed in 2008 to determine whether
ECMO applied early in severe ARDS gave better results than
continuing conventional care (9). The protocol for conven-
tional care ventilator management was defined in this trial. In
the conventional care arm, ECMO was permitted if conven-
tional care failed. There were two endpoints: 1) a “key endpoint
“of treatment failure between the two arms of the trial (defining
Department of Surgery, University of Michigan, Ann Arbor, MI.
Dr. Bartlett disclosed that he does not have any potential conflicts of interest.
For information regarding this article, E-mail: robbar@umich.edu
Copyright © 2018 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000003444
114 www.ccmjournal.org January 2019 • Volume 47 • Number 1
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
death and crossover to rescue ECMO as treatment failure) and
2) the actual mortality in the two arms of the trial (which was
considered the primary endpoint). The trial was powered at
300 patients to detect a 20% difference between the arms of
the study. The results were examined by a data safety monitor-
ing board at intervals of 60 patients. When 240 patients were
entered in the trial, the DSMB reported a major difference in
the key endpoint between the two randomized groups. Treat-
ment failure in the early ECMO group was 35%, and treatment
failure in the conventional care (plus late ECMO) group was
58%. The predicted 20% difference in treatment failure which
powered the study was a good estimate. The statistical signifi-
cance favoring ECMO was p value equals to 0.001.
However, the actual mortality for early ECMO was 35%,
but in the control arm, it was 46% (not 58%). This difference
was not quite statistically significant (p = 0.09). The reason for
the difference in treatment failure versus the actual survival
was that 35 patients in the conventional care group were man-
aged with ECMO as rescue treatment when conventional care
was failing. Forty-three percent of those patients ultimately
survived. The study had become a study of early versus late
ECMO. Now the investigators had an ethical dilemma. If the
trends continued, the actual survival percentage would reach
statistical significance with only a few more patients entered
into the study. (Nine more patients were entered into the study
while the 240 patient analysis was underway. The actual sur-
vival significant difference was now p = 0.07) However, that
would require randomizing patients to the conventional care/
late ECMO arm which they had just proven was inferior based
on the key endpoint. Some patients would be assigned to a
treatment, which would be more likely to result in death. The
investigators developed a complex mathematical model to
predict the likelihood of reaching a 20% difference in survival
if they continued the study to 300 patients (described in the
supplement). They concluded that reaching a 20% difference
was unlikely, so they recommended stopping the study for effi-
cacy of preventing treatment failure but futility to show a 20%
difference in actual survival. They did not apply the model to
predict the likely result of continuing to 300 patients. That
would have shown a 12% survival difference which was statis-
tically significant, which would have shown efficacy for both
endpoints. They published the article concluding that ECMO
was not effective in ARDS.

Even the editors of the New England Journal where the study
was published were disappointed that this approach was taken
based on the report of the DSMB (10). They pointed out two
important lessons from this trial: “DSMBs should consider the
wider context of a trial—alternative analyses may adjust for
aspects of the trial that do not follow the design,” and “a tradi-
tionally negative trial may well be informative with a thought-
ful post hoc analysis.” As summarized by the editors of the
New England Journal (10), ECMO probably has some benefit
in severe ARDS based on this trial. My thoughtful post hoc
analysis is that the 11% difference in survival comparing early
ECMO to conventional care with late rescue ECMO will prob-
ably (p = 0.07) be considered clinically significant by intensiv-
ists and payers for healthcare in severe ARDS.
What is the status of ECMO for severe ARDS after the
EOLIA trial? The recommendations from the CESAR trial
and the two matched pairs trials is that patients with severe
ARDS should be managed in ECMO centers. The EOLIA trial
indicates that ECMO should be used promptly when high-risk
criteria are met, rather than as late rescue therapy when death
from ARDS or multiple organ failure is imminent. Hence,
these studies have provided the “evidence” that ECMO is now
in the standard algorithm for the management of ARDS.
Should another trial of ECMO in ARDS be conducted?
If so, how should it be designed? Based on the four modern
ARDS ECMO trials (4–6, 9), it seems unethical to conduct
another ECMO versus conventional care trial in which ECMO
is not permitted in the conventional care arm. The next study
of ECMO for severe ARDS could:
1) Design a tighter definition of mortality risk in severe ARDS.
The EOLIA trial invented three different new entry criteria
based on gas exchange. The CESAR used the Murray Score
(11), but that score was developed before the concept of
ventilator-induced lung injury was recognized. Two other
mortality score prediction scores for adult ARDS have been
proposed and evaluated (APSS [12] and AOI [13]).
2) Evaluate very early ECMO (when plateau pressure exceeds
25 cm H2O or driving pressure [14] exceeds 12 cm H2O,
for example) compared with continuing conventional care
including a late ECMO arm based on specific criteria. This
was the study design of the Schumacher et al (15) trial of
ECMO in neonatal respiratory failure which we conducted
25 years ago. In that study, infants with severe respiratory
failure were identified. Our scoring system was called the
ARDS with ECMO. Oxygenation index of 40 carried an
80% mortality with conventional care. In this study, infants
who had an oxygenation index of 20 with 50% mortality
risk were randomized to go on to ECMO at that time or
continue on conventional treatment. Infants in the con-
ventional treatment group who developed a score of 40
proceeded to ECMO support. In that trial of early versus
conventional care versus late ECMO, the survival in all
groups was the same (90%). However, the infants managed
with early ECMO recovered more quickly, had less ICU and
hospital days, less expense, and less severe neurologic injury.
Critical Care Medicine www.ccmjournal.org 115
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Viewpoints
The EOLIA trial was similar to the neonatal trial, although
there was no requirement to proceed to rescue ECMO when
criteria defining failure of conventional care were met.
3) Compare ECMO with awake ambulatory management to
ECMO to heavy sedation. There are indications that man-
agement of patients with minimal sedation, spontaneous
breathing, and rehabilitation produces better survival results
than continued heavy sedation in these patients (16, 17).
The average length of ECMO in the EOLIA trial was 16 ± 14
days. In that trial, ECMO was terminated when the investigators
thought that recovery was not possible because of prolonged
duration, right heart failure, sepsis, or multiple organ failure.
In recent years, it has been recognized that some patients with
severe ARDS can be successfully transplanted (18) or will
recover to normal lung function after months of extracorpo-
real support (19). The actual survival with this approach of
very long ECMO is unknown, but it seems that overall sur-
vival will be greater than 65%. A new study of ECMO in ARDS
should take this approach to management into account.
ECMO for respiratory failure is the only intervention of
life support in fatal critical illness which has been studied in
a randomized fashion compared with conventional care (20).
We have examined the 10 ECMO trials with particular atten-
tion to study design related to the logistics and ethics of studies
of life support systems in which the endpoint is death (20). We
recommend that any future studies of ECMO in ARDS should
be conducted either as matched pairs trials or using adap-
tive designs that shift the treatment assignment to the more
favorable treatment as the trial proceeds. The original adap-
tive design trials in acute fatal illness were trials of ECMO in
neonatal respiratory failure. These trials were criticized by cli-
nicians at the time (21) but are now recognized as an innova-
tive approach to addressing the ethical dilemmas in studies in
which the endpoint is death (22).
BEYOND EIOLA
Whether more clinical trials of ECMO in ARDS are done or
not, ARDS patients who are at high risk of dying will be man-
aged with ECMO. ECMO should be used early in the course
rather than as late rescue treatment. These patients will be
managed awake and with spontaneous breathing and ongoing
rehabilitation. Transplantation will be considered for patients
who have been on ECMO more than a month or more (18).
A decision to transplant will be tempered by the realization
that the lung might recover to normal function over several
months or a year (19, 23). How can we identify which long-
term ECMO patients will recover? Clearly, 6-month support
with ECMO is better than lung transplantation and lifelong
immunosuppression.
The possibility of lung recovery in acute ARDS after months
of ECMO support is a new phenomenon. The identification of
the factors involved, the frequency of late recovery, the basic
biology, and the best management methods are all to be deter-
mined in the next several years. When we have these answers,
Bartlett
we will know the implications to the management of severe
ARDS with ECMO.
This should not be surprising. Most patients with acute
anuric renal failure supported by dialysis regain normal func-
tion after many months of dialysis support. Some patients with
profound myocardial failure supported by ventricular assist
devices (VADs) recover cardiac function while awaiting heart
transplant.
Although we are learning about late lung recovery with
ECMO support, we have also created a new clinical problem.
Currently, these patients are managed in ICUs, creating ethi-
cal, financial, and resource utilization issues. Aside from these
important questions, whereas we are learning about this,
important ICU beds are needed for new early acute critical
care and postoperative patients. Even if lung centers are devel-
oped that can handle 10 or 20 prolonged ECMO patients, they
will be rapidly over loaded if these trends continue.
Therefore, a high priority is to learn to manage these
patients out of the ICU in chronic care facilities, maybe even
at home. There was a time when hemodialysis for acute renal
failure was only done in ICUs. There was a time when VAD
patients stayed in the ICU until a heart donor was available,
which was often several months. Although it currently seems
unsafe and perhaps outrageous, major research should focus
on managing ECMO support in patients with total lung fail-
ure out of the ICU. The next step in artificial lung research is
not safer extracorporeal systems but wearable or implantable
artificial lungs that are so safe and effective that patients can be
managed out of the ICU or even at home for prolonged peri-
ods. Several laboratories and companies are working on this
concept. It can be clinical within 5 years.
Wearable artificial lungs for unresolved ARDS have to
address both gas exchange and right heart failure due to high
pulmonary vascular resistance. There are two approaches: pul-
monary artery (PA) to left atrium (LA) access and right atrium
(RA) to PA access. PA to LA access requires a thoracotomy,
direct vascular cannulation, transcutaneous blood access con-
duits, and a low resistance membrane lung. A blood pump
is not required. Systemic blood gases are determined by the
amount of flow through the device (100% oxyhemoglobin sat-
uration and PCO2 around 30 mm Hg) related to the amount of
flow through the native nonfunctional lungs (venous blood).
By adjusting the composition and flow of the “sweep” gas, the
arterial blood gases can be maintained at normal values. The
higher the pulmonary vascular resistance, the higher the flow
through the membrane lung, so the strain on the right ventricle
is autoregulated depending on pulmonary vascular resistance.
This approach has been used clinically since 2007 as a bridge to
lung transplant (24). The Novalung oxygenator is used because
it has the lowest resistance of commercially available adult size
device. It does not have a heat exchange component, which is
included in other commercial devices. The advantage of PA-LA
is that there is no blood pump. The disadvantage is that any
thromboemboli go directly into the systemic circulation.
The RA to PA approach generally requires a thoracotomy,
with direct cannulation of the RA and PA, transcutaneous
116 www.ccmjournal.org January 2019 • Volume 47 • Number 1
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
vascular access conduits, a blood pump, and a membrane
lung. Systemic blood gases are determined by the amount of
flow through the device (100% oxyhemoglobin saturation and
PCO2 around 30 mm Hg) related to the amount of flow through
the native nonfunctional lungs (venous blood). By adjusting
the amount of pump-driven blood flow and composition
and flow of the “sweep” gas, the arterial blood gases can be
maintained at normal values. The pump forces blood through
the nonfunctional, high resistance lungs, relieving strain on
the right ventricle. Recently one company is marketing a RA
to PA cannula that is placed via the jugular vein, avoiding a
thoracotomy and we are awaiting data on long-term use (25).
The RA to PA approach has been used many times (26). Any
commercial oxygenator can be used. The longest ECMO run
with recovery used direct access RA to PA for more than a year
(K. Nelson, unpublished observations, 2018). The advantage
of the RA to PA approach is that emboli go into the pulmo-
nary circulation. The disadvantage is that a portable pump is
required.
The wearable membrane lung will always be paracorporeal
with transcutaneous conduits (rather than implanted under
the skin) because the membrane lung will have to be changed
when clotting occurs in the device (typically monthly). Sys-
temic anticoagulation is required, and bleeding is always a risk.
Either approach can be used with commercially available can-
nulas, pumps, and membrane lungs (albeit “off-label” in the
United States). Several labs and companies are working on
complete wearable lung systems for long-term use.
CONCLUSIONS
The EOLIA trial combined with other trials of ECMO in severe
ARDS has established ECMO as a standard step in the algo-
rithm for managing ARDS when other treatment is failing.
EOLIA demonstrated that ECMO should be used promptly
when failure to respond is recognized as opposed to late res-
cue. Future studies of ECMO in ARDS should focus on better
methods of identifying the 30–40% of patients who are at high
risk of death early in the course and using that information to
define the timing and methods of ECMO support. Some ARDS
patients supported with ECMO will be transplanted or recover
to normal function after months of ECMO support. This gives
urgency to research efforts to get chronic ECMO patients out
of the ICU, or out of the hospital. The development of wear-
able artificial lungs addresses this goal.
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