- 146 - Extracorporeal 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. New devices became available in 2009 which were much simpler, safer, and easier to use than the original ECMO devices. In 2010, the CESAR trial was published. 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 support if needed.
Meanwhile, the overall outcomes for ARDS have not changed in 30 years.
The ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial was designed in 2008 to determine whether ECMO applied early in severe ARDS gave better results than continuing con- ventional care (Table 1). The protocol for conventional care ven- tilator management was defined in this trial. In the conventional care arm, ECMO was permitted if conventional care failed.
There were two endpoints: 1) a “key end point“ of treatment failure between the two arms of the trial (defining death and crossover to rescue ECMO as treatment failure) and 2) the ac- tual 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.
However, the actual mortality for early ECMO was 35%, but in the control arm, it was 46%. This difference was not quite statistically significant (p = 0.09) (Figure 1). The reason for the difference in treatment failure versus the actual survival was that 35 patients in the conventional care group were managed with ECMO as rescue treatment when conventional care was failing, with 20 of these patients (57%) dying.
ECMO, 새로운 희망인가?
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조 영 재
Advanced Course : 호흡기
Table 1. Overview of the four completed and published randomized clinical trials on ECMO in acute respiratory distress syndrome
－ 조영재, ECMO, 새로운 희망인가? －
- 147 - Even the editors of the New England Journal of Medicine where the study was published were disappointed that this ap- proach was taken based on the report of the DSMB. They point- ed 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 traditionally negative trial may well be informative with a thoughtful post hoc analysis.” As summarized by the editors of the Journal, ECMO probably has some benefit in severe ARDS based on this trial. In fact, a predefined secondary composite endpoint revealed a somewhat different picture: the relative risk of treatment failure (death in the ECMO group, and death or crossover to ECMO in the control group) was 0.62 in favor of ECMO treatment (44% ECMO vs 72% control; 95% CI 0.47–
0.82; p<0.001).
Some experts propose a two-step approach that should be tak- en going forward: 1) a follow-up to elucidate the long term (one-year) survival and cost-adjusted quality of life of the EOLIA trial patients; and 2) a new prospective, randomized, multicenter, international trial with an adjusted sample size of at least 622 patients to account for the expected actual effect size, which based by using the actual results for 60-day mortal- ity (35% ECMO vs 46% control, α=0.05, power 80%) reveals a modest estimated total sample size of 622 patients (311 per group). However, that is simply not possible because as a rescue
in the emergency setting, an RCT of ECMO versus non-ECMO in severe hypoxemia is ethically unacceptable and comparable to one in situations such as CPR. Instead, comparing ECMO to non-ECMO to decrease ventilator-induced lung injury in stable ARDS requires first a realistic estimate of the mortality attribut- able to mechanical ventilation. EOLIA was planned assuming that protective mechanical ventilation per se has a 20% mortal- ity, while ECMO itself has a zero risk of mortality. Negative trials do not indicate whether a given intervention is useless, but simply fail to confirm the hypothesis. Moreover, Calculations based on the characteristics of the patients in EOLIA show that at least 622 patients would be required for a study with suffi- cient power to detect a significant 11% absolute mortality reduc- tion in ECMO from 46% mortality of non-ECMO patients. With the enrolment rate of the CESAR trial (0.03 patients/unit/month) or the EOLIA trial (0.058 patients/unit/month) and 100 partic- ipating units, such a study would take 17 or 9 years, respectively.
Instead, we can believe that two aspects of EOLIA deserve closer consideration: results and feasibility and utility of ECMO trials. The results of this study should have proved or disproved two hypotheses: 1) Emergency ECMO improves outcome by
“buying time” in extremely hypoxemic patients. Of the 35 pa- tients switched from conventional therapy to rescue ECMO (median SaO2 77%; nine cardiac arrest events), 15 survived. It is unlikely that they would have survived without ECMO, re- gardless of the statistical relevance of these observations. 2) ECMO improves outcome by reducing the invasiveness of me- chanical ventilation. During ECMO, tidal volume was reduced by 43% and respiratory rate by 23%, while PEEP remained es- sentially unchanged. This represents an estimated 66% reduction in the mechanical power applied to the lungs (from 28 J/min to 10 J/min). This reduction was associated with a higher surviv- al rate (81/124 patients) in the ECMO group (vs 68/125 con- trols). The next study of ECMO for severe ARDS could: 1) Design a tighter definition of mortality risk in severe ARDS. 2) Evaluate very early ECMO compared with continuing conven- tional care including a late ECMO arm based on specific criteria. 3) Compare ECMO with awake ambulatory manage- Figure 1. Kaplan–Meier Survival Estimates in the
Intention-to-Treat Population during the First 60 Days of the EOLIA Trial.
－ 2018년 대한내과학회 추계학술대회 －
- 148 - ment to ECMO to heavy sedation. In recent years, it has been recognized that some patients with severe ARDS can be success- fully transplanted or will recover to normal lung function after months of extracorporeal support. The actual survival with this approach of very long ECMO is unknown, but it seems that overall survival will be greater than 65%. A new study of ECMO in ARDS should take this approach to management into account.
What is the status of ECMO for severe ARDS after or be- yond 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.
Especially, the possibility of lung recovery in acute ARDS af- ter months of ECMO support is a new phenomenon. 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 ethical, financial, and re- source 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 developed that can handle 10 or 20 prolonged ECMO patients, they will be rapidly over load- ed if these trends continue. Therefore, a high priority is to learn to manage these patients out of the ICU in chronic care facili- ties, may be even at home. Although it currently seems unsafe and perhaps outrageous, major research should focus on manag- ing ECMO support in patients with total lung failure out of the ICU. The next step in artificial lung research is not safer ex- tracorporeal 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 periods.
Wearable artificial lungs for unresolved ARDS have to ad- dress both gas exchange and right heart failure due to high pul- monary vascular resistance. There are two approaches: pulmo- nary artery (PA) to left atrium (LA) access and right atrium (RA) to PA access. Both accesses require a thoracotomy, direct
Figure 2. Radiographic development of the heart silhouette over time in chest x-rays on the day of right ventricular assist device (RVAD) deployment (left) and on day 35 (right). Filled black arrows mark the pulmonary artery cannula, whereas empty arrows denote the tip of the draining cannula.
－ 조영재, ECMO, 새로운 희망인가? －
- 149 - vascular cannulation, transcutaneous blood access conduits, and a low resistance membrane lung. However, a blood pump is not required in the case of PA to LA access, but he disadvantage is that any thromboemboli go directly into the systemic circulation. In the case of RA to PA access ('oxy'RVAD, Figure 2), there is vice versa. The wearable membrane lung will always be “paracorporeal” with transcutaneous conduits (rather than im- planted under the skin) because the membrane lung will have to be changed when clotting occurs in the device (typically monthly). Systemic anticoagulation is required, and bleeding is always a risk.
Finally, when should ECMO not be offered—where in the sand should the line be drawn? Conditions with expected surviv- al rates of < 30%? < 10%? In attempting to answer this ques- tion, it should first be acknowledged that survival to hospital discharge is not the most important outcome measure, but rather
‘good long-term survival’—adequate neurological, psychological and functional recovery coupled to an acceptable quality of life, recognizing that there are many plausible definitions and sub- jective components of this. lives. Second, intensive care clini- cians should not regard themselves as the sole arbiters of re- source allocation and thus decide who receives or is denied ECMO based on a hazy, imprecise prediction of the patient’s chances of survival coupled to a potentially misguided sense of distributive justice. In addition to the clinician’s view as to the likely short-term outcome, other variables which should be con- sidered include institutional experience, resources and policies;
discussions with the patient’s next-of-kin; an assessment of the likely long-term survival, function and quality of life; and the availability and quality of rehabilitation, aftercare and home sup- port, which vary enormously across different parts of the planet.
Lastly, if clinicians always reject high-risk ECMO candidates, they will never learn whether some of them could ever have been saved, given more time or new management strategies.
Until it can be established with greater certainty what the like- lihood of ‘good long-term survival’ is by conducting compre- hensive follow-up studies of ECMO patients, what can be done today when the next high-risk ECMO patient is referred? It is
often easier to say “no” than “yes”, but we should not always opt for the path of least resistance (Table 2).
Choosing to offer ECMO in such circumstances is predicated on serving the patient’s best interests and seeks to balance the benefits of attempting a heroic rescue versus the risks of provid- ing futile care and prolonging suffering. These are difficult deci- sions, need to be tailored to individual patient and institutional circumstances and are often best not made alone. Thankfully, there is often time to decide in advance whether a given patient will be offered ECMO in the event they deteriorate. Discussions with ICU colleagues, both senior and junior, and liaising with ECMO directors in national or international centers experienced in managing specific conditions may be fruitful.
In summary, with the encouraging aspects of the EOLIA trial in mind, we can already see a light at the end of the tunnel.
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Table 2. Checklist prior to initiating high-risk ECMOa
