ARTICLE: Suverein MM, Delnoji TSR, Lorusso R, et al. Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest. N Engl J Med. 2023;388(4):299-309.
OBJECTIVE
To compare the effects of extracorporeal CPR (eCPR) versus conventional CPR (cCPR) on survival with favorable 30-day neurological outcomes in refractory out-of-hospital cardiac arrest (OHCA) due to ventricular arrhythmias
BACKGROUND
A major cause of out-of-hospital cardiac arrests are ventricular arrhythmias such as ventricular fibrillation (VF) or ventricular tachycardia (VT). Early, high-quality chest compressions and external defibrillation give the best opportunity for return of spontaneous circulation (ROSC).1 If these measures fail, however, the chance of survival with cCPR declines rapidly with time. Treatment of the underlying disorder such as via coronary artery angioplasty is key, though the ability to perform these life-saving interventions without ROSC is limited. In eCPR, intravascular cannulas are placed in the femoral vessels and connected to a heart-lung machine during resuscitation, restoring circulation and oxygenation during cardiac arrest. This limits hypoxic brain injury and other organ damage, buying time for the identification and potential treatment of the underlying cardiac arrest.
Two recent trials have found mixed evidence on the effect that eCPR has on survival with good neurologic outcomes for patients with out-of-hospital ventricular cardiac arrest. A 2012 single-center study based in the Czech Republic (“Prague OHCA study”) was terminated early for futility, as 31.5% of the patients in the eCPR group survived with favorable neurologic outcome at 6 months as compared to 22% in the control group which was not statistically significant.2 Conversely, in the ARREST (Advanced Reperfusion Strategies for Refractory Cardiac Arrest) trial published out of a single center in the US in 2020, the study was terminated early because of superiority of the intervention group: survival to discharge occurred in 43% in the group that received eCPR as compared to 7% in the standard ACLS group.3 The INCEPTION trial was conducted to address this discrepancy in outcomes.
DESIGN
Multicenter, randomized, controlled trial conducted in the Netherlands from May 2017 through February 2021. Patients were enrolled at 10 cardiosurgical centers served by 12 emergency medical services (EMS). Based on prior trial data, it was hypothesized that 30-day survival with favorable neurologic outcome would increase from 8-30% with use of eCPR, requiring at least 49 patients per group to give the trial 80% power to detect such a difference with a significance level of 0.05.
INCLUSION CRITERIA
- Patients aged 18-70 years old and who had witnessed, refractory OHCA with initial ventricular arrhythmias (VF/VT)
- The arrhythmia had to be diagnosed by the EMS provider or detected as a shockable rhythm by an automated external defibrillator (AED)
- Basic life support had to be performed unless the arrest had been witnessed by the EMS provider who initiated advanced life support
- The cardiac arrest had to persist despite 15 minutes of advanced life support
EXCLUSION CRITERIA
- ROSC with sustained hemodynamic recovery within 15 minutes
- Terminal heart failure (New York Heart Association class III or IV)
- Severe pulmonary disease (grade III or IV on the Chronic Obstructive Pulmonary Disease Global Initiative for Obstructive Lung Disease criteria)
- Disseminated oncologic disease
- Obvious or suspected pregnancy
- Bilateral femoral bypass surgery
- Known contraindications for eCPR
- Known advance health care directive prohibiting resuscitation or invasive ventilation
- Expected time interval of more than 60 minutes between the initial cardiac arrest to the initiation of the cannulation procedure
If the cardiac arrest persisted after 15 minutes of ACLS, EMS initiated intra-arrest transport to a hospital. Patients then underwent randomization and the patient information was relayed to the teams at the receiving hospital. Upon patient arrival, inclusion/exclusion criteria were reviewed and patients were placed into the two treatment arms. Post-resuscitation care was delivered according to current guidelines and institutional protocols.
PRIMARY OUTCOME
Favorable neurologic outcome at 30 days as defined as a Cerebral Performance Category score of 1 or 2 (normal or disabled but independent). This was assessed by an independent neurologist who was blinded to trial-group assignments.
SECONDARY OUTCOMES
Duration of CPR before ROSC, total duration of CPR, duration of time in the ICU, duration of hospitalization, 30-day survival, 6-month survival, Cerebral Performance Category score 6 months after the OHCA, the reason for discontinuation of treatment, and the duration of mechanical ventilation.
KEY RESULTS
The mean age of the patients was 54 in the eCPR group and 57 in the cCPR group. 90% and 89% of patients in the two groups were men, respectively. The mean time from start of cardiac arrest to arrival to an emergency department was 36 minutes and 38 minutes, respectively.
Primary outcome
Of the 160 total patients randomized in this study, 70 received eCPR and 64 received cCPR; 26 did not meet inclusion criteria. At 30 days, 14 of 70 (20%) in the eCPR group had a Cerebral Performance Category score of 1 or 2 compared to 10 of 62 (16%) in the conventional CPR group. The odds ratio was 1.4 with a 95% confidence interval (0.5 to 3.5) and P=0.52. There was a similar number of serious adverse events per patient between the two groups.
Secondary outcomes
eCPR was associated with a higher proportion of patients who survived until admission until the ICU as compared to cCPR. A similar proportion of patients in the two groups survived until hospital discharge and had similar survival with favorable neurologic outcome at 6 months. The main reason for discontinuation in the eCPR group was a neurologically unfavorable prognosis whereas for the cCPR group it was lack of further treatment options.
LIMITATIONS
- The application of this study may be limited to large metropolitan areas because obtaining regular experience with eCPR outside of these areas may be difficult
- EMS was aware of the trail which may have prompted them to proceed to intra-arrest transport earlier than usual
- 90% of the patients were male and some of the inclusion criteria may have skewed the male-to-female ratio
- Early randomization led to a considerable number of patients who had achieved ROSC between random assignment and hospital arrival
- Early randomization led to screen failures and post randomization exclusions and the actual time-to-cannulation was not used as a post randomization exclusion criterion, since it only applied to one group.
- Masking of treatment assignments was impossible, leading to crossovers by 3 patients, all of whom died despite receiving eCPR.
- There was no standardization of protocols for eCPR and post-resuscitation care which were instead left to current institutional guidelines, though this may also increase the generalizability of the results
- Median interval between hospital admission and start of ECMO cannulation was 16 minutes (after a median of 36 minutes to arrive to the hospital after cardiac arrest). These median intervals are longer than those in the ARREST and Prague OHCA study.
EM TAKE-AWAYS
In this multicenter, pragmatic RCT, eCPR and cCPR had similar effects on survival with favorable neurologic outcome at 30 days in patients with refractory OHCA due to ventricular arrhythmia. More studies need to be done showing clear benefits before eCPR becomes standard practice. In particular, hospital systems seeking to implement successful eCPR programs should consider investing in highly experienced, multidisciplinary teams and coordinating EMS logistics to minimize the time to eCPR initiation.
REFERENCES
- Blom MT, Beesems SG, Homma PCM, et al. Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators. Circulation. 2014;130:1868-1875.
- Belohlavek J, Kucera K, Jarkovsky J, et al. Hyperinvasive approach to out-of hospital cardiac arrest using mechanical chest compression device, prehospital intraarrest cooling, extracorporeal life support and early invasive assessment compared to standard of care: a randomized parallel groups comparative study proposal: “Prague OHCA study.” J Transl Med. 2012;10:163-163.
- Yannopoulos D, Bartos J, Raveendran G, et al. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single center, open-label, randomized controlled trial. Lancet. 2020;396:1807-1816.