Extracorporeal membrane oxygen (ECMO) is well established as a resuscitative adjunct or treatment modality in severe respiratory failure (1), refractory cardiogenic shock (2,3), and during sudden cardiac arrest (4,5)—where it can be applied during active chest compressions and is known as extracorporeal cardiopulmonary resuscitation (ECPR). Acknowledging some controversy over optimal use, we can observe that survival on ECMO is better among patients who are alive and have a pulse at the time of cannulation than among patients who are not and do not. Further, among patients who receive ECMO, be it for respiratory failure, cardiogenic shock, or cardiac arrest, observational data suggest earlier initiation (6–8) and initiation among lower severity of illness (9) is generally associated with better outcomes. What is relatively unknown is exactly how early.

It is against this brief summary of adult ECMO that we discuss the significance of signs of life (SOL) among patients who have cardiac arrest. SOL are physical manifestations of cerebral activity, and include gasping, movement, and pupillary reflexes. It has been previously shown that +SOL during cardiac arrest resuscitation are associated with improved outcomes, although data are sparse (10,11). Furthermore, research into the prognostic value of these SOL has been limited given the rarity of the outcome of interest (survival), and the fact that a given prognostic factor (e.g., SOL) has limited utility in situations where we cannot control the outcome. In the situation of out-of-hospital cardiac arrest (OHCA), by 20 minutes of refractory arrest, only 5% of patients survive (12); prognostic factors are not needed when the outcome is nonmodifiable death.

Enter ECPR, and patients can be kept hemodynamically alive on ECMO for days or more, when their condition was otherwise nonsurvivable. Now the utility of a given prearrest or intra-arrest prognostic factor for the outcome of survival becomes much more useful.

In this issue of Critical Care Medicine, Bunya et al (13) analyzed 1395 adults from the Study of Advanced Cardiac Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan (SAVE-J) cohort, examining the prognostic value of SOL upon hospital arrival for patients with OHCA who then received ECPR. The authors examined the occurrence rate of SOL upon hospital arrival, and the value of these SOL as independent predictors of neurologically intact survival. Their findings are thematically consistent with previous ECPR studies that demonstrated a survival association with gasping (14), and transient return of spontaneous circulation (15); Bunya et al (13) found that +SOL upon hospital arrival were individually and cumulatively associated with dramatically higher survival for each added SOL. The adjusted odds ratio (aOR) of survival increased from a baseline aOR of 1 (0 SOL) to 4.7 (1 SOL) to 18.66 (2+ SOL). Furthermore, the authors demonstrated that survival outcomes were stratified by initial rhythm when patients had at least 1 SOL, with 12.5% survival for asystole, 27.3% for pulseless electrical activity (PEA), and 42.2% for ventricular fibrillation (VF).

It should be noted that these survival statistics are artificially inflated compared with an otherwise unrestricted ECPR cohort, that is, as has been done with other studies out of the SAVE-J cohort (16,17), the analysis a priori removed patients whom the authors identified as having noncardiac etiologies, diagnosed after the fact. Many of these etiologies (aortic dissection, aneurysm, primary cerebral disorder) are likely nonsurvivable if presenting with sudden cardiac arrest. Removing these “nonrecoverable” patients does bias the population, functionally enriching it for potential survivors. Although it inflates the survival numbers, it also cleans up the analysis, tightening the scientific relationship between pre-ECPR prognostic features such as SOL, and eventual outcome. This is not bad, as long as it is acknowledged and considered. It leads to a better understanding of the science, but lower generalizability of the prognostic factors.

This functional enrichment for survival might partially explain the higher survival seen in this study compared with a 2021 study by Debaty et al (18) from Paris which demonstrated that SOL at any point of the resuscitation were associated with an adjusted odds 7.35 for neurologically intact survival, with 12% and 23% survival (nonshockable/shockable) if +SOL, compared with 0% and 4% without.

Bunya et al (13) make a point of the significance of restricting their analysis to patients who had SOL after hospital arrival, rather than at any point of the arrest. It means that patients had to have had consistently sufficient perfusion to not only avoid irreversible ischemia throughout the resuscitation, but then were able to achieve sufficient cerebral blood flow upon hospital arrival to elicit neurologic activity and corresponding motor movement.

This last point may be the most important conclusion—the suggestion that patients who exhibit SOL during resuscitation are not quite dead yet. The theoretical construct goes something like this: SOL occur in response to brain activity. Brain activity requires some cerebral blood flow and that that particular portion of the brain has thus far escaped death, which indicates that the perfusion up to that point was at least sufficient to prevent irreversible neurologic death.

Stepping back, the hypothesis that these patients still have at least partial preserved cerebral blood flow and brain activity is more radical than one might initially think. Most cardiac arrest (and ECPR patients) either do not have preserved cerebral blood flow, or already sustained irreversible neurologic injury. Many patients already demonstrate signs of brainstem injury (dilated pupils, agonal breaths) and myocardial injury (asystole and PEA) early on in the resuscitation—and never normalize—despite receiving perfusion through CPR, or even full ECMO. This irreversibly injured population may constitute ~60% of ECPR patients, which is still less than the typical proportion of adult ECPR patients who die.

Another demonstration of the value of the SOL in prognosticating survival is that the survival numbers in the no-SOL group are low, even comparable to the historical outcomes in the SAVE-J dataset (16,19). By removing patients who had +SOL, it is easy to see how the no-SOL group had survival of 5% (PEA and asystole) and 9% (VF). Further, the patients with +SOL had much higher survival by rhythm than typically observed (42% VF, 27% PEA) for ECPR.

Coming back to the initial rhythm, let us consider the finding that survival was stratified by initial rhythm among patients with +SOL. Initial rhythm has been a reliable predictor of outcome in just about all previous studies of ECPR, although in this analysis, the initial rhythm fell out of the multivariate model after adding SOL. A potential reason for this could be due to the knowledge that initial rhythm not only correlates with etiology (20,21), but also correlates with duration of no-flow (22,23), with VF becoming less common over time. As patients with SOL upon hospital arrival have had cerebral blood flow since arrest sufficient to avoid neurologic death of the region generating the movement, this temporally late prognostic factor (+SOL) may subsume the prognostic value of the initial rhythm. Although the demonstration that survival was still stratified by initial rhythm shows that initial rhythm retains some value. As a take away for the clinician, patients with initial VF and at least 1 SOL upon hospital arrival had a nearly 50% probability of neurologically intact survival when treated with ECPR.

The demonstration by Bunya et al (13) of the value of SOL upon hospital survival in prognosticating neurologic intact survival, and our discussion of the physiologic implications of +SOL, taken together beg the question of why we are not initiating ECPR—or ECMO writ large—earlier. I suggest that the answer is a combination of the aspirational “we certainly should be” and the pragmatic “it’s both logistically difficult and will lead to harm if done too early.” Earlier ECPR implementation requires patients get to the hospital faster, or that ECPR goes to them. Both have been demonstrated (24,25), but neither is easy. Even if we take the cardiac arrest out of the picture and look at respiratory and cardiac ECMO, there are legitimate concerns around implementing ECMO too early. ECMO has a known rate of complications, including structural (26,27) and hemorrhagic (28), and despite examples to the contrary (29), the majority of patients do not have high levels of mobilization (30,31), which is associated with, and may lead to, better outcomes.

In summary, this study by Bunya et al (13) demonstrates that +SOL upon hospital arrival, in a multicenter cohort of adult patients who did eventually receive ECPR and had nonsurvivable etiologies excluded, are strongly and cumulatively associated with neurologically intact survival. As we can surmise that these patients had intact cerebral perfusion throughout the resuscitation, we now have more data that getting ECMO if you are not quite fully dead is better than if you are already fully dead. It sounds elementary, but as clinicians, we still struggle with it. There is an optimal time of initiation, and that time is early in the course of cardiac arrest, or critical illness—just not too early, where the complications and side effects from ECMO add unnecessary risk. Identifying this optimal balance, for various patients and conditions, should drive prospective research and trials. The closer we get to it, the better patients will do.

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