Currently, despite significant advancements in understanding cardiac diseases over the past four decades, only 1 in 10 patients with OHCA survive. In Spain, approximately 50,000 cases of cardiac arrest (CA) occur annually, with about 3/5 taking place outside hospitals, ultimately resulting in a high number of deaths, around 45,000. Patients with the highest survival probability are those with ventricular fibrillation (VF), which can potentially be reversed through electrical cardioversion (ECV). However, even among these, up to half may experience refractory VF, which foretells an unfavorable prognosis due to rapid multi-organ failure onset if cardiopulmonary resuscitation (CPR) maneuvers fail to reverse this state early.
CPR supplemented with veno-arterial ECMO, also known as extracorporeal CPR, has been proposed as an option for patients with VF refractory to conventional CPR. Naturally, the feasibility of this approach largely depends on the medical emergency system available within a specific geographic region. However, the efficacy and safety of extracorporeal CPR remain inconclusive, as most available data comes from single-center study series. In fact, the latest European resuscitation guideline assigns a very low level of evidence to extracorporeal CPR.
In this multicenter, randomized controlled trial conducted in the Netherlands, patients with OHCA were assigned to receive extracorporeal CPR or conventional CPR (standard advanced cardiac life support). Eligible patients were aged between 18 and 70, had received bystander CPR, presented with an initial ventricular arrhythmia, and had not achieved return of spontaneous circulation within 15 minutes after CPR initiation. The primary outcome was survival with a favorable neurological outcome, defined as a Cerebral Performance Category score of 1 or 2 (range 1–5, with higher scores indicating more severe disability) at 30 days. Analyses were performed on an intention-to-treat basis. Of the 160 randomized patients, 70 were assigned to receive extracorporeal CPR and 64 to receive conventional CPR. Twenty-six patients were excluded for not meeting inclusion criteria at hospital admission. At 30 days, 14 patients (20%) in the extracorporeal CPR group were alive with a favorable neurological outcome, compared to 10 patients (16%) in the conventional CPR group (OR = 1.4; p = 0.52). The number of serious adverse events per patient was similar in both groups.
The authors concluded that, in patients with refractory OHCA, extracorporeal CPR and conventional CPR yielded similar effects on survival with a favorable neurological outcome.
COMMENTARY:
The INCEPTION study under review concluded that extracorporeal CPR offers no significant advantage over conventional CPR in terms of the primary outcome. Without yet delving into these apparently disappointing results, the article provides invaluable information on the use of extracorporeal CPR in OHCA settings. The study’s rigorous methodology presents an unparalleled opportunity for future research with greater statistical power. The randomization involved 160 patients with “witnessed” OHCA, a detail that may go unnoticed but is crucial for approximating the time elapsed since CA onset. For inclusion in the study, patients had to present a shockable rhythm (e.g., VF) and a lack of return of spontaneous circulation after 15 minutes of CPR initiation. Another noteworthy aspect is that the study was conducted in the Netherlands, where emergency response teams arrived at the patient’s side in approximately 8 minutes, with hospital arrival occurring an average of 35 minutes after CA onset—figures that are difficult to exceed in most countries. Additionally, the median time from CA onset to initiation of VA-ECMO was 74 minutes; while also brief, this timeframe may be insufficient to yield substantial benefits after over an hour of CPR. Finally, I would emphasize that the trial’s primary endpoint was survival with a favorable neurological outcome, referring to adequate brain function that enables at least minimal independence in daily activities; analyzing survival alone would be uninformative if neurological sequelae preclude a normal life.
Before the INCEPTION study, the efficacy of extracorporeal CPR compared to conventional CPR had only been assessed in two randomized controlled trials (RCTs) with contradictory results. The ARREST trial was prematurely terminated due to favorable outcomes in patients receiving ECMO (a 36% increase in survival rate compared to conventional CPR). Although the inclusion criteria in the ARREST study were similar to those in INCEPTION, there are notable differences. The ARREST study included only 30 patients before its premature termination, thus increasing the probability that any findings might have resulted from chance due to the small sample size. Unlike ARREST, the INCEPTION trial involved multiple centers, making it more representative of real-world conditions if extracorporeal CPR were to become more accessible. Belohlavek et al., in another RCT conducted in Prague analyzing extracorporeal CPR, concluded that it did not improve outcomes compared to conventional CPR. This study was also terminated early due to the lack of significant differences in its primary endpoint of survival with a favorable neurological outcome at 180 days (32% vs. 22% in favor of extracorporeal CPR among 256 evaluated patients). Unlike ARREST, this study was conducted in a single center but with a much larger sample size (264 patients). Furthermore, like INCEPTION, it was conducted in a setting with a well-developed emergency response system, and ECMO was implemented within reasonable, short times.
The results from the three RCTs seem contradictory and may be disappointing. However, this does not necessarily imply that extracorporeal CPR is ineffective in certain cases. Overall, data from the three RCTs indicate a numerical advantage in the primary outcome of increased survival without severe neurological disability, favoring the use of extracorporeal CPR. I believe most medical professionals would agree that VA-ECMO is an effective tool in managing patients in refractory CA, as long as it is implemented promptly in a hospital setting with trained personnel, potentially significantly improving survival odds compared to conventional CPR. Nevertheless, despite its availability in hospitals with the best medical resources, the actual times from the onset of OHCA to VA-ECMO initiation in these hospitals are, in most cases, too long to demonstrate plausible benefits, possibly due to irreversible multi-organ damage.
The newly published 2023 Spanish Cardiogenic Shock (CS) code aims to implement early mechanical circulatory support (MCS) nationwide for patients with CS. However, the actual implementation of an effective protocol faces challenges due to non-uniform assistance, action heterogeneity, and the lack of a standardized approach in our country. If favorable clinical evidence for extracorporeal CPR were to be established in the future, implementing a real and effective extracorporeal CPR code would likely be an immensely complex challenge.
Thus, based on currently available data, generalized use of extracorporeal CPR in patients suffering refractory OHCA cannot be recommended. Larger-scale studies with strong statistical power are needed to appropriately evaluate the impact of extracorporeal CPR in this specific clinical context.
REFERENCES:
Suvrein MM, Delnoij TSR, Lorusso R, Brandon Bravo Bruinsma GJ, Otterspoor L, et al. Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest. N Engl J Med. 2023 Jan 26;388(4):299-309. doi: 10.1056/NEJMoa2204511
Martínez-Sellés M, Hernández-Pérez FJ, Uribarri A, Martín Villén L, Zapata L, Alonso JJ, et al. Cardiogenic shock code 2023. Expert document for a multidisciplinary organization that allows quality care. Rev Esp Cardiol (Engl Ed). 2022 Dec 21(22)00330-9. English, Spanish. doi: 10.1016/j.rec.2022.10.014.
