Extracorporeal Cardiopulmonary Resuscitation – Focusing on the truly refractory cardiac arrest population

Abstract

To date, there have been three randomized trials (RCT) examining the utility of Extracorporeal Cardiopulmonary Resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA). The first published was the ARREST trial, which suggested a dramatic increase in neurologically intact survival in patients with refractory ventricular arrhythmias.[[1]Yannopoulos D. et al.Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.Lancet. 2020; 396: 1807-1816Abstract Full Text Full Text PDF PubMed Google Scholar] The second was the Hyperinvasive Approach to Out of Hospital Cardiac Arrest trial, which trended towards a survival benefit with good neurologic outcomes, but did not reach statistical significance.[[2]Belohlavek J. et al.Effect of Intra-arrest Transport, Extracorporeal Cardiopulmonary Resuscitation, and Immediate Invasive Assessment and Treatment on Functional Neurologic Outcome in Refractory Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.JAMA. 2022; 327: 737-747Crossref PubMed Scopus (80) Google Scholar] Finally, the INCEPTION trial was recently published and failed to demonstrate benefit for ECPR.[[3]Suverein M.M. et al.Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest.N Engl J Med. 2023; 388: 299-309Crossref PubMed Scopus (15) Google Scholar] Following the publication of the ARREST and Hyperinvasive trials, the most recent systematic review on ECPR noted that, while the certainty of evidence remained low, these trials suggested potential benefit.[[4]Holmberg M.J. et al.Extracorporeal cardiopulmonary resuscitation for cardiac arrest: An updated systematic review.Resuscitation. 2023; 182109665Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] The subsequent publication of the INCEPTION trial has led to much debate about the utility of ECPR for OHCA. This debate has focused on whether larger trials may generate the statistical power needed to capture the benefit of ECPR, whether a lack of strict protocolization between centers in the INCEPTION trial led to longer times to ECMO cannulation thus limiting their ability to demonstrate benefit, or whether specific patient subsets that might benefit from this therapy have yet to be identified. While we agree that larger trials with strict protocols and improved times to ECMO cannulation may demonstrate statistically improved outcomes, we believe the three trials have already demonstrated significant benefit for a specific patient population – those without pre-hospital return of spontaneous circulation (ROSC). While each of the trials attempted to assess whether utilizing ECPR for refractory OHCA improved outcomes, their ability to capture a population of patients in refractory arrest varied. While the ARREST trial had 0% of patients with pre-hospital ROSC, the Hyperinvasive trial had 27% of patients in the hyperinvasive group and 44% of patients in the standard group, and the INCEPTION trial had 26% of patients in the ECPR group and 31% of patients in the conventional CPR group with pre-hospital ROSC, respectively. It should be noted that while all 3 trials allowed inclusion of patients with pre-hospital ROSC, the ARREST trial randomized patients on hospital arrival, while the Hyperinvasive and INCEPTION trials randomized in the field. The presence of sustained pre-hospital ROSC indicates those patients are no longer in refractory arrest and are, therefore, unlikely to receive the planned intervention (i.e., ECPR). We believe this may have diluted the treatment effect seen in the Hyperinvasive and INCEPTION trials.[2Belohlavek J. et al.Effect of Intra-arrest Transport, Extracorporeal Cardiopulmonary Resuscitation, and Immediate Invasive Assessment and Treatment on Functional Neurologic Outcome in Refractory Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial.JAMA. 2022; 327: 737-747Crossref PubMed Scopus (80) Google Scholar, 3Suverein M.M. et al.Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest.N Engl J Med. 2023; 388: 299-309Crossref PubMed Scopus (15) Google Scholar] This is supported by a subsequent secondary analysis of the Hyperinvasive trial, examining patients without pre-hospital ROSC, where survival with good neurologic outcome was significantly higher in the ECPR group.[[5]Rob D. et al.Extracorporeal versus conventional cardiopulmonary resuscitation for refractory out-of-hospital cardiac arrest: a secondary analysis of the Prague OHCA trial.Crit Care. 2022; 26: 330Crossref Scopus (8) Google Scholar] We believe the ARREST trial[[1]Yannopoulos D. et al.Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.Lancet. 2020; 396: 1807-1816Abstract Full Text Full Text PDF PubMed Google Scholar] and the secondary analysis of the Hyperinvasive trial[[5]Rob D. et al.Extracorporeal versus conventional cardiopulmonary resuscitation for refractory out-of-hospital cardiac arrest: a secondary analysis of the Prague OHCA trial.Crit Care. 2022; 26: 330Crossref Scopus (8) Google Scholar] demonstrate benefit because they capture the purpose of ECPR, which is to serve as a rapidly implemented rescue therapy for refractory but reversible cardiac arrest. Future trials should attempt to limit inclusion of patients with sustained pre-hospital ROSC in order to study this population directly (e.g. by pre-hospital initiation of ECPR or randomization on hospital arrival).