Suverein MM, Delnoij TSR, Lorusso R, et al. Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest. N Engl J Med. 2023 Jan 26;388(4):299-309
Background
In refractory cardiac arrest, the addition of extracorporeal membrane oxygenation to conventional cardiopulmonary life support (e-CPR) may help maintain organ perfusion and alleviate neurological damage. Besides, it offers a window of opportunity to identify the underlying cause and apply therapeutic interventions, including coronary revascularization.
Two previous randomized controlled trials (RCTs) have evaluated the efficacy of e-CPR in patients who suffered out-of-hospital cardiac arrest. The ARREST trial was stopped after the enrollment of 30 patients as early results favored e-CPR (1). However, there were few survivors in either group (six in the e-CPR group and a lone survivor in the conventional group). The Prague e-CPR trial, including 256 patients, was terminated prematurely for futility, although a favorable 6-month survival was higher with e-CPR (31.5% vs. 22%) (2). Against this background, the INCEPTION trial investigators conducted this trial to assess survival with a favorable neurological outcome with e-CPR compared to conventional CPR among patients who sustained out-of-hospital cardiac arrest with a ventricular arrhythmia as the initial rhythm (3).
Population/design
The INCEPTION trial was an RCT conducted between May 2017 and February 2021, including 10 cardiosurgical centers served by 12 emergency medical services in the Netherlands. Adult patients 18–70 years old were eligible if they had sustained a witnessed, refractory, out-of-hospital cardiac arrest with ventricular fibrillation, ventricular tachycardia, or any other shockable initial rhythm. Refractory cardiac arrest was defined as failure to attain return of spontaneous circulation (ROSC) within 15 minutes of arrest. Patients were randomized in a 1:1 ratio to e-CPR or conventional CPR.
Excluded
The trial excluded patients who attained ROSC within 15 minutes, those with terminal heart failure, severe COPD, disseminated malignancy, pregnancy, bilateral femoral bypass surgery, other known contraindications for e-CPR, or an expected duration of >60 minutes between cardiac arrest and cannulation. Patients with a poor neurological state at baseline were also excluded.
Inclusion criteria were reviewed after arrival to the hospital. Patients who were randomized to e-CPR but took more than 60 minutes for cannulation were included. E-CPR was not performed If ROSC was achieved before initiation but were analyzed based on an intention-to-treat basis. Post-resuscitation care including targeted temperature management and conduct of extracorporeal circulation was based on institutional protocols according to current guidelines.
E-CPR group
Percutaneous or surgical cannulation of the femoral vein and the femoral artery was carried out. The e-CPR circuit was chosen based on local availability. A distal cannula for lower limb perfusion was encouraged, but not mandatory. Chest compressions were carried out throughout this period with minimal interruption.
Post-resuscitation care
Targeted temperature management at 33–36 C for 24 hours was carried out in both groups. Normothermia was maintained for 72 hours. Mechanical ventilation was aimed to maintain normal PaO2 and PCO2 levels. The target mean arterial pressure was set at 65–70 mm Hg. Coronary angiography was performed as appropriate. The decision to cease treatment was left to the clinician.
Sample size
The authors hypothesized an improvement in the 30-day survival with a favorable neurological outcome from 8 to 30% with e-CPR and calculated an initial sample size of 49 patients in each group. However, as several patients who were assigned to e-CPR achieved ROSC before cannulation, the sample size was revised to 134 patients, 67 in each group.
Results
A total of 160 patients underwent randomization; 26 were excluded – the reasons for exclusion were unwitnessed arrest, age >70 years old, unshockable initial rhythm, and attainment of ROSC in <15 min. In the primary analysis, 70 patients were included from the e-CPR group, and 63 from the conventional group. The mean age was 54 vs. 57 years in the e-CPR vs. control groups; nearly 90% of subjects in both groups were male. Both groups were well matched at baseline regarding co-morbidities.
Other important baseline characteristics
| Characteristic | e-CPR (70 patients) | Conventional (63 patients) |
| Witnessed arrest (no, %) | 68 (97) | 63 (98) |
| CPR within 5 min (no, %) | 69 (99) | 61 (95) |
| Arrest-ambulance time (min) | 8±4 | 8±4 |
| Arrest-ER arrival (min) | 36±12 | 38±11 |
| No of defibrillations | 8±5 | 9±6 |
In the e-CPR group, 18/70 patients did not receive the intervention as planned. Among these patients, a stable ROSC was achieved without e-CPR in 13, logistic failure occurred in three, while treatment was discontinued in three. In the remaining 62, cannulation and extracorporeal circulation was successful in 46 (88%) of patients. Three patients crossed over from the conventional to the e-CPR group. A stable ROSC was achieved in 18/70 (26%) in the e-CPR group and 20/64 (31%) in the conventional CPR group.
Important clinical outcomes
| Outcome | e-CPR (70 patients) | Conventional (63 patients) | OR (95% CI) |
| Primary outcome: 30-d survival with CPC 1 or 2 (independent ADLs)(no, %) | 14 (20) | 10 (16) | 1.4 (0.5–3.5) |
| 3-month survival with CPC 1 or 2 | 12 (18) | 9 (14) | 1.5 (0.6–3.8) |
| 6-month survival with CPC 1 or 2 | 14 (20%) | 10 (16) | 1.3 (0.5–3.3) |
E-CPR was associated with a higher survival to ICU admission. Survival to ICU and hospital discharge were similar between the two groups.
Adverse events per patient were similar in both groups. Discontinuation of treatment was carried out in 80% of patients in both groups. The reason for discontinuation were unfavorable neurological state, multiorgan failure, cannulation of ECLS failure, and non-availability of further treatment options.
Limitations
- In the e-CPR group, 18/70 (25.7%) patients did not receive the intervention as planned; among them, a stable ROSC was achieved in 13 patients. However, analysis was by intention-to-treat (these patients were included in the e-CPR group for analysis)
- Although the time to cannulation was set to 60 minutes, it was delayed in some patients; however, these patients were not excluded from the trial
- Initiation of e-CPR was unsuccessful in 6 patients
- Three patients in the conventional group crossed over to e-CPR; again, analysis was by intention-to-treat. However, there were no survivors among these patients.
- One patient in each arm was lost to follow-up
- Neurological assessment could be over the phone; this may have led to incomplete assessment
- Lack of blinding could have led to bias
Summary
The currently available evidence from three RCTs does not support the routine use of e-CPR in patients who suffer out-of-hospital cardiac arrest. It holds promise as an intervention for the future. However, the efficacy of e-CPR needs to be established in larger, more robust studies with adequate statistical power. Until then, this technique cannot be routinely recommended among patients who sustain out-of-hospital cardiac arrest.
References
- 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 centre, open-label, randomised controlled trial. Lancet. 2020 Dec 5;396(10265):1807-1816. doi: 10.1016/S0140-6736(20)32338-2. Epub 2020 Nov 13. PMID: 33197396; PMCID: PMC7856571.
- 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 Aug 10;10:163. doi: 10.1186/1479-5876-10-163. PMID: 22883307; PMCID: PMC3492121.
- Suverein MM, Delnoij TSR, Lorusso R, et al. Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest. N Engl J Med. 2023 Jan 26;388(4):299-309
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