Regional centers could provide extracorporeal cardiopulmonary resuscitation to improve survival
The most promising way to refine our current extracorporeal cardiopulmonary resuscitation (ECPR) systems and improve survivability in out-of-hospital cardiac arrest is to include standardized EMS protocols across multiple systems to support regional ECPR centers, an idea backed by a recent trial.
The Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest study, known as the INCEPTION trial, created a lot of excitement in emergency medicine, generating discussion and hope that analysis will continue to pave the best path forward for ECPR and extracorporeal membrane oxygenation (ECMO) programs. (N Engl J Med. 2023;388:299; https://bit.ly/3YrkFhR.)
This trial was the first randomized, controlled multicenter model to examine ECPR versus conventional CPR for out-of-hospital cardiac arrest caused by ventricular dysrhythmia. The authors' work disproved their hypothesis that current ECPR guidelines could be implemented effectively across more diverse hospital systems.
Some experts have said this negative trial shows that ECPR may not be quite ready for prime time, but a careful consideration of the study, especially in light of previous research, helps to provide us with a roadmap forward as we build better systems to help support ECPR success. (N Engl J Med. 2023;388:370; https://bit.ly/3ZnZG0p.)
The INCEPTION trial provides us with the data to examine the feasibility of larger EMS systems using protocols to play an integral role in more widespread access to ECPR. This feasibility would support a model of busy regional centers becoming the most successful at ECPR before any wider spread hospital utilization occurs. These centers would also act as hubs for research to help understand what else may lead to increased survivability and improved outcomes with ECPR. (N Engl J Med. 2023;388:299; https://bit.ly/3YrkFhR.)
Previous studies, including multiple cohort studies, the ARREST trial (The Lancet. 2020;396:1807; https://bit.ly/3EW21Yr), and the Prague OHCA trial (J Transl Med. 2012;10:163; http://bit.ly/3F2V8Vb) have shown varying levels of support for ECPR. Multiple cohort studies seemed to support the concept of ECPR, but the ARREST trial was the first randomized controlled study to compare ECPR with CPR for OHCA from ventricular dysrhythmias.
ARREST was terminated early due to the superiority of ECPR during the enrollment. Meanwhile, the Prague OHCA trial compared ACLS on scene with a hyperinvasive resuscitation bundle involving ECPR. It was terminated early for futility. This mixed data set may at first glance make the INCEPTION trial look like the nail in the coffin of ECPR, but I think a closer examination of this trial in the context of the previous publications really will pave the path for better ECPR program development. (N Engl J Med. 2023;388:299; https://bit.ly/3YrkFhR; Lancet. 2020;396:1807; https://bit.ly/3EW21Yr; J Transl Med. 2012;10:163; http://bit.ly/3F2V8Vb; Resuscitation. 2010;81:968 https://bit.ly/3ymLCZ7; Resuscitation. 2014;85:762; https://bit.ly/3ZIBR3d; Resuscitation. 2012;83:1331; https://bit.ly/3ycoD3b; Resuscitation. 2012;83:966; https://bit.ly/3L1UHOS.)
The INCEPTION trial took place in the Netherlands from May 2017 through February 2021 with the trial halted in 2019 during the first coronavirus outbreak. The trial enrolled 160 patients ages 18 to 70 years old with a median age of 54 in the ECPR group and 57 in the CPR group, very similar to the patients in the previous trials. The inclusion and exclusion criteria were also similar. The trial differed from previous studies in that it enrolled these patients across 12 emergency medical services and 10 hospitals. The Netherlands trial had 25 ambulance regions and 16 cardiothoracic centers, and it was able to cover about 8.5 million people over about 3500 square miles.
Twenty-six of the 160 patients randomized did not meet the inclusion criteria at time of admission and were excluded. The final trial population was composed of 70 patients in the extracorporeal CPR group and 64 patients in the conventional CPR group. This was an intention-to-treat trial, and 18 patients in the ECPR group did not receive ECPR. Cannulation and circulation were successful in 46 of 52 patients; six patients failed, five from procedural complications and one from failure to establish adequate flow on ECMO.
No patients in the conventional CPR group had sustained return of spontaneous circulation before reaching the ED, and crossover to extracorporeal CPR occurred in three patients for whom ECPR was successfully established. This led to 52 of the initial 64 patients receiving the assigned treatment in the conventional CPR group.
The primary outcome for this study was 30-day survival with a cerebral performance category of 1 or 2 as assessed by an independent neurologist. Two patients in the conventional CPR group were not assessed at 30 days. Fourteen of the 70 patients in the ECPR group met the primary outcome compared with 10 of the 62 patients in the conventional CPR group. This difference of 20 percent compared with 16 percent was not statistically significant.
Unsurprisingly, a higher proportion of patients in the ECPR group survived until admission to the ICU compared with the conventional CPR group. Similar proportions of patients in the groups, however, survived until hospital discharge, and similar proportions had favorable neurologic outcomes at six months.
A Closer Look at the Numbers
Compared with the ARREST trial, the INCEPTION trial should be considered a feasibility study examining the prehospital strategies successfully employed across a larger EMS system. ARREST was the only study of the three randomized, controlled trials examining the efficacy of ECPR to show favorable outcomes with ECPR. It demonstrated superiority of ECPR with 43 percent survival-to-discharge compared with a seven percent survival-to-discharge in the control group.
INCEPTION and ARREST used similar prehospital strategies, but the ARREST trial was conducted at a single mature ECMO center served by three emergency medical services, while the INCEPTION trial was conducted across 10 cardiosurgical centers served by 12 emergency medical services. Closely examining the time intervals demonstrates that the EMS strategies employed during the INCEPTION trial were effective, the time-of-arrest-to-ED-arrival was 36 minutes in the ECPR group and 38 minutes in the conventional CPR group. The time to the ED was similar to the ARREST trial's data despite serving a larger catchment area. (N Engl J Med. 2023;388:299; https://bit.ly/3YrkFhR; Lancet. 2020;396:1807; https://bit.ly/3EW21Yr; Resuscitation. 2019;138:235; http://bit.ly/3YqvaSy; Resuscitation. 2015;95:100; https://bit.ly/3L5k6Y0.)
The INCEPTION trial also demonstrated that ECPR is not yet ready to be employed across a broad network of hospitals. When we examine the time of arrest to the time of ECLS flow established in the ECPR patients, the ARREST trial had a median time of 59 minutes in the ECPR group while the INCEPTION trial had a median time of 74 minutes. The INCEPTION trial authors explained that these time differences likely reflect differences in factors such as team experience, logistics, and caseload.
An examination of the supplemental data put these differences in stark relief. The INCEPTION trial had only two centers with more than 20 patients placed on ECPR during the entire study, essentially three years due to the time lost from the pandemic. Six of the centers involved in the study initiated ECPR on 10 or less patients during the entire study. The ARREST trial in contrast enrolled and initiated ECPR on 14 patients over just 10 months. It is clear with the current ECPR guidelines and equipment that more experienced providers are able to vastly sway outcomes. (N Engl J Med. 2023;388:299; https://bit.ly/3YrkFhR; Lancet. 2020;396:1807; https://bit.ly/3EW21Yr.)
A Roadmap Forward
I hope the excitement surrounding publication of the INCEPTION trial continues to lead to a deeper dive into these protocols and programs. Despite this essentially being a negative trial for ECPR, it still laid the groundwork for the feasibility of similar EMS protocols playing an integral role in larger health systems.
The study demonstrated that investment into regional ECPR centers of excellence rather than bringing ECPR into every community ED could increase survival. The best direction we can take now is to foster the growth of a limited number of mature ECMO centers where they can gain enough experience to master this therapy.
Smaller ECMO centers may be feasible with time and research, but the data now point to increases in survival being linked to more experienced providers and centers. Acceptance and understanding of the utility and limitations of ECPR will help to refine future research with the goal of continuing to advance our utilization and understanding of the impact of ECPR.
If those conclusions hold true, EMS and EMS protocols will need to advance to support these specialized centers best and help them to grow their catchment areas. This seems to me to be an exciting prospect for emergency medicine and our EMS specialized colleagues.
Dr. Sabolickis an emergency medicine and critical care physician and core faculty at Albert Einstein Healthcare Network in Philadelphia. Follow her on Twitter@ERCC_Erin.