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Extracorporeal cardiopulmonary resuscitation for cardiac arrest: An updated systematic review

Open AccessPublished:December 12, 2022DOI:https://doi.org/10.1016/j.resuscitation.2022.12.003

      Abstract

      Objectives

      To provide an updated systematic review on the use of extracorporeal cardiopulmonary resuscitation (ECPR) compared with manual or mechanical cardiopulmonary resuscitation during cardiac arrest.

      Methods

      This was an update of a systematic review published in 2018. OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched for randomized trials and observational studies between January 1, 2018, and June 21, 2022. The population included adults and children with out-of-hospital or in-hospital cardiac arrest. Two investigators reviewed studies for relevance, extracted data, and assessed bias. The certainty of evidence was evaluated using GRADE.

      Results

      The search identified 3 trials, 27 observational studies, and 6 cost-effectiveness studies. All trials included adults with out-of-hospital cardiac arrest and were terminated before enrolling the intended number of subjects. One trial found a benefit of ECPR in survival and favorable neurological status, whereas two trials found no statistically significant differences in outcomes. There were 23 observational studies in adults with out-of-hospital cardiac arrest or in combination with in-hospital cardiac arrest, and 4 observational studies in children with in-hospital cardiac arrest. Results of individual studies were inconsistent, although many studies favored ECPR. The risk of bias was intermediate for trials and critical for observational studies. The certainty of evidence was very low to low. Study heterogeneity precluded meta-analyses. The cost-effectiveness varied depending on the setting and the analysis assumptions.

      Conclusions

      Recent randomized trials suggest potential benefit of ECPR, but the certainty of evidence remains low. It is unclear which patients might benefit from ECPR.

      Keywords

      Introduction

      Out-of-hospital cardiac arrest (OHCA) affects over 350,000 individuals in the United States
      • Tsao C.W.
      • Aday A.W.
      • Almarzooq Z.I.
      • et al.
      Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association.
      and 275,000 individuals in Europe
      • Gräsner J.T.
      • Lefering R.
      • Koster R.W.
      • et al.
      EuReCa ONE-27 Nations, ONE Europe, ONE Registry: A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe.
      • Berdowski J.
      • Berg R.A.
      • Tijssen J.G.
      • Koster R.W.
      Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies.
      each year. In-hospital cardiac arrest (IHCA) occurs in an estimated 290,000 patients in the United States per year.
      • Holmberg M.J.
      • Ross C.E.
      • Fitzmaurice G.M.
      • et al.
      Annual Incidence of Adult and Pediatric In-Hospital Cardiac Arrest in the United States.
      Cardiac arrest is associated with high mortality and morbidity, with approximately 10% of individuals with OHCA and 30% of patients with IHCA surviving to hospital discharge.
      • Andersen L.W.
      • Holmberg M.J.
      • Berg K.M.
      • Donnino M.W.
      • Granfeldt A.
      In-Hospital Cardiac Arrest: A Review.
      Extracorporeal cardiopulmonary resuscitation (ECPR) is an advanced rescue therapy recognized by both the American Heart Association (AHA)
      • Panchal A.R.
      • Bartos J.A.
      • Cabañas J.G.
      • et al.
      Part 3: Adult Basic and Advanced Life Support, American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
      • Topjian A.A.
      • Raymond T.T.
      • Atkins D.
      • et al.
      Part 4: Pediatric Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.
      and the European Resuscitation Council (ERC)
      • Van de Voorde P.
      • Turner N.M.
      • Djakow J.
      • et al.
      European Resuscitation Council Guidelines 2021: Paediatric Life Support.
      • Soar J.
      • Böttiger B.W.
      • Carli P.
      • et al.
      European Resuscitation Council Guidelines 2021: Adult advanced life support.
      to support circulation in selected patients with refractory cardiac arrest. Although ECPR may extend the time in which reversible causes of cardiac arrest can be treated, the benefit of applying ECPR as well as the optimal patient selection and timing of the procedure remain uncertain.
      The previous systematic review on the use of ECPR for cardiac arrest, published by the International Liaison Committee on Resuscitation (ILCOR) in 2018, stated that the evidence was inconclusive.
      • Holmberg M.J.
      • Geri G.
      • Wiberg S.
      • et al.
      Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
      Twenty-five observational studies (22 in adults and 3 in children) and no randomized trials were identified at the time of the previous review. With evidence from three randomized trials becoming available, an updated systematic review of the literature is needed.
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      The aim of this study was to perform an updated systematic review on the use of ECPR compared with manual or mechanical cardiopulmonary resuscitation (CPR) during cardiac arrest to inform the international guidelines.

      Methods

      Protocol and registration

      The protocol was prospectively submitted to the International Prospective register of Systematic Reviews (PROSPERO) (CRD42022341077) on June 21, 2022. The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      The PROSPERO protocol and PRISMA checklist are provided in the Supplementary Content.

      Eligibility criteria and outcomes

      This was an update of a systematic review addressing the same topic in 2018.
      • Holmberg M.J.
      • Geri G.
      • Wiberg S.
      • et al.
      Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
      The specific study question was framed using the PICO (Population, Intervention, Comparison, Outcome) format: in adults (≥18 years) and children (<18 years) with cardiac arrest in any setting (out-of-hospital or in-hospital), does ECPR including extracorporeal membrane oxygenation or cardiopulmonary bypass during cardiac arrest, compared to manual or mechanical CPR, change clinical outcomes.
      Relevant outcomes were selected for the review based on the data reported in the literature, including survival and favorable neurological outcome. Outcomes with similar time frames were combined into single categories (mid-term: intensive care unit discharge, hospital discharge, 30-days, and 1-month; long-term: 3-months, 6-months, and 1-year). Long-term survival reported as hazard ratios were also considered irrespective of the length of follow-up. Descriptive data were obtained from randomized trials on cannulation success, loss of limb and amputations, brain death, and organ donations.
      Return of spontaneous circulation (ROSC) was not included as an outcome given that ROSC is difficult to meaningfully define in this population. A favorable neurological outcome was generally defined as a modified Rankin Scale score of 0–3 or a Cerebral Performance Category score of 1–2 indicating that the patient does not need assistance with activities of daily living.
      New randomized controlled trials, non-randomized controlled trials, and observational studies (cohort studies and case-control studies) with a control group (patients not receiving ECPR) were included. Ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, and unpublished studies were not included. Studies assessing cost-effectiveness were included for a descriptive overview. All languages were considered if there was an English abstract or an English full-text article.
      Studies exclusively assessing the use of extracorporeal membrane oxygenation (ECMO) for cardiac or respiratory failure after sustained ROSC were not included. Studies assessing ECMO for deep hypothermia (or other conditions) were only included if cardiac arrest was documented.

      Information sources and search strategy

      The following electronic databases were searched between January 1, 2018, and June 21, 2022: OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials. The bibliographies of included articles were reviewed for potential additional articles. The search strategy for each database is provided in the protocol. To identify ongoing or unpublished randomized trials, the International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.Gov were searched on October 5, 2022. Additional details are provided in the Supplementary Methods.

      Study selection

      Pairs of two reviewers independently screened all titles and abstracts retrieved from the systematic search. Any disagreement regarding inclusion or exclusion were resolved via discussion between the reviewers and with a third reviewer as needed. The Kappa-values for inter-observer variance was calculated. A third reviewer reviewed all excluded titles and abstracts to ensure optimized sensitivity given that the Kappa-value between the initial pairs of reviewers was below 0.60. Two reviewers then independently reviewed all the full-text reports of the publications passing the first level of screening. Any disagreement regarding eligibility was resolved via discussion.

      Data collection and data items

      Two reviewers extracted data from individual manuscripts using a predefined standardized data extraction form. Any discrepancies in the extracted data were identified and resolved via discussion. Missing statistical parameters and variance measures of importance (odds ratios and confidence intervals) were calculated if the data permitted.

      Risk of bias in individual studies

      Two reviewers independently assessed the risk of bias for the included studies. Risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool for randomized trials
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      and using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for observational studies
      • Sterne J.A.
      • Hernán M.A.
      • Reeves B.C.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.
      . Any disagreement was resolved via discussion. Risk of bias was assessed for each outcome within studies. If the bias was different for outcomes this was noted. Additional considerations regarding bias assessments are provided in the Supplementary Methods.

      Data synthesis

      Studies were assessed for clinical (participants, interventions, and outcomes), methodological (study design or risk of bias), and statistical (forest plots, Chi-squared statistics, and I2 statistics) heterogeneity. Separate meta-analyses for randomized trials and observational studies were planned as described in the protocol.

      Confidence in cumulative evidence

      The certainty in the overall evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      based on studies identified in the previous
      • Holmberg M.J.
      • Geri G.
      • Wiberg S.
      • et al.
      Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
      and present systematic review. GRADEpro (McMaster University, 2022) was used for drafting of the GRADE tables.

      Results

      Overview

      The search identified 5573 unique records of which 84 full-text manuscripts were assessed for eligibility (Fig. 1). A total of 35 articles were identified, including 3 trials, 27 observational studies, and 6 cost-effectiveness studies (one was also an observational study).
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      • Métrailler-Mermoud J.
      • Hugli O.
      • Carron P.N.
      • et al.
      Avalanche victims in cardiac arrest are unlikely to survive despite adherence to medical guidelines.
      • Nakashima T.
      • Noguchi T.
      • Tahara Y.
      • et al.
      Patients With Refractory Out-of-Cardiac Arrest and Sustained Ventricular Fibrillation as Candidates for Extracorporeal Cardiopulmonary Resuscitation - Prospective Multi-Center Observational Study.
      • Shiba D.
      • Hifumi T.
      • Tsuchiya M.
      • et al.
      Pneumonia and Extracorporeal Cardiopulmonary Resuscitation Followed by Targeted Temperature Management in Patients With Out-of-Hospital Cardiac Arrest - Retrospective Cohort Study.
      • Bartos J.A.
      • Grunau B.
      • Carlson C.
      • et al.
      Improved Survival With Extracorporeal Cardiopulmonary Resuscitation Despite Progressive Metabolic Derangement Associated With Prolonged Resuscitation.
      • Bougouin W.
      • Dumas F.
      • Lamhaut L.
      • et al.
      Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study.
      • Braumann S.
      • Nettersheim F.S.
      • Hohmann C.
      • et al.
      How long is long enough? Good neurologic outcome in out-of-hospital cardiac arrest survivors despite prolonged resuscitation: a retrospective cohort study.
      • Shin Y.S.
      • Kim Y.J.
      • Ryoo S.M.
      • et al.
      Promising candidates for extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest.
      • Yoshida T.
      • Fujitani S.
      • Wakatake H.
      • et al.
      Exploratory Observational Study of Extracorporeal Cardiopulmonary Resuscitation for Nonshockable Out-Of-Hospital Cardiac Arrest Occurring After an Emergency Medical Services Arrival: SOS-KANTO 2012 Study Report.
      • Fukushima K.
      • Aoki M.
      • Nakajima J.
      • et al.
      Favorable prognosis by extracorporeal cardiopulmonary resuscitation for subsequent shockable rhythm patients.
      • Jeong D.
      • Lee G.T.
      • Park J.E.
      • et al.
      Extracorporeal Life-support for Out-of-hospital Cardiac Arrest: A Nationwide Multicenter Study.
      • Mørk S.R.
      • Bøtker M.T.
      • Christensen S.
      • Tang M.
      • Terkelsen C.J.
      Survival and neurological outcome after out-of-hospital cardiac arrest treated with and without mechanical circulatory support.
      • Kitada M.
      • Kaneko T.
      • Yamada S.
      • Harada M.
      • Takahashi T.
      Extracorporeal cardiopulmonary resuscitation without target temperature management for out-of-hospital cardiac arrest patients prolongs the therapeutic time window: a retrospective analysis of a nationwide multicentre observational study in Japan.
      • Nakajima M.
      • Kaszynski H.R.
      • Goto H.
      • et al.
      Current trends and outcomes of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Japan: A nationwide observational study.
      • Yamada S.
      • Kaneko T.
      • Kitada M.
      • Harada M.
      • Takahashi T.
      Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.
      • Kim S.J.
      • Han K.S.
      • Lee E.J.
      • Lee S.J.
      • Lee J.S.
      • Lee S.W.
      Association between Extracorporeal Membrane Oxygenation (ECMO) and Mortality in the Patients with Cardiac Arrest: A Nation-Wide Population-Based Study with Propensity Score Matched Analysis.
      • Mandigers L.
      • Scholten E.
      • Rietdijk W.J.R.
      • et al.
      Survival and neurological outcome with extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest caused by massive pulmonary embolism: A two center observational study.
      • Patricio D.
      • Peluso L.
      • Brasseur A.
      • et al.
      Comparison of extracorporeal and conventional cardiopulmonary resuscitation: a retrospective propensity score matched study.
      • Shinar Z.
      • Plantmason L.
      • Reynolds J.
      • et al.
      Emergency Physician-Initiated Resuscitative Extracorporeal Membrane Oxygenation.
      • Kwon S.S.
      • Park B.W.
      • Lee M.H.
      • et al.
      Role and Prognosis of Extracorporeal Life Support in Patients Who Develop Cardiac Arrest during or after Office-Based Cosmetic Surgery.
      • Stoll S.E.
      • Paul E.
      • Pilcher D.
      • Udy A.
      • Burrell A.
      Hyperoxia and mortality in conventional versus extracorporeal cardiopulmonary resuscitation.
      • Ohbe H.
      • Isogai S.
      • Jo T.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Extracorporeal membrane oxygenation improves outcomes of accidental hypothermia without vital signs: A nationwide observational study.
      • Patel J.K.
      • Meng H.
      • Qadeer A.
      • Parikh P.B.
      Impact of Extracorporeal Membrane Oxygenation on Mortality in Adults With Cardiac Arrest.
      • Ohbe H.
      • Ogura T.
      • Matsui H.
      • Yasunaga H.
      Extracorporeal cardiopulmonary resuscitation for acute aortic dissection during cardiac arrest: A nationwide retrospective observational study.
      • Meert K.
      • Telford R.
      • Holubkov R.
      • et al.
      Paediatric in-hospital cardiac arrest: Factors associated with survival and neurobehavioural outcome one year later.
      • Taeb M.
      • Levin A.B.
      • Spaeder M.C.
      • Schwartz J.M.
      Comparison of Pediatric Cardiopulmonary Resuscitation Quality in Classic Cardiopulmonary Resuscitation and Extracorporeal Cardiopulmonary Resuscitation Events Using Video Review.
      • Meert K.
      • Slomine B.S.
      • Silverstein F.S.
      • et al.
      One-year cognitive and neurologic outcomes in survivors of paediatric extracorporeal cardiopulmonary resuscitation.
      • Hamzah M.
      • Othman H.F.
      • Almasri M.
      • Al-Subu A.
      • Lutfi R.
      Survival outcomes of in-hospital cardiac arrest in pediatric patients in the USA.
      • Bharmal M.I.
      • Venturini J.M.
      • Chua R.F.M.
      • et al.
      Cost-utility of extracorporeal cardiopulmonary resuscitation in patients with cardiac arrest.
      • Dennis M.
      • Zmudzki F.
      • Burns B.
      • et al.
      Cost effectiveness and quality of life analysis of extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest.
      • Gravesteijn B.Y.
      • Schluep M.
      • Voormolen D.C.
      • et al.
      Cost-effectiveness of extracorporeal cardiopulmonary resuscitation after in-hospital cardiac arrest: A Markov decision model.
      • Kawashima T.
      • Uehara H.
      • Miyagi N.
      • et al.
      Impact of first documented rhythm on cost-effectiveness of extracorporeal cardiopulmonary resuscitation.
      • Matsuoka Y.
      • Goto R.
      • Atsumi T.
      • et al.
      Cost-effectiveness of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: A multi-centre prospective cohort study.
      No additional studies were identified after reviewing the references of included studies. The search for ongoing or unpublished randomized trials identified 4 records (Table 1).
      Figure thumbnail gr1
      Fig. 1PRISMA diagram. Chart illustrating the flow of articles. Of 5573 titles and abstracts, 84 full-text articles were assessed for eligibility, and 35 articles were included in the review. a Including one of the observational studies
      Table 1Overview of registered randomized trials
      TitleCountryEstimated completionTreatmentControlPatientsStatus
      Status obtained through correspondence with the principal investigators
      Emergency Cardiopulmonary Bypass for Cardiac Arrest (ECPB4OHCA)AustriaDecember 2020Emergency CPBStandard treatment40Terminated early due to low enrollment
      A Comparative Study Between a Pre-Hospital and an In-Hospital Circulatory Support Strategy in Refractory Cardiac Arrest (APACAR2)

      Lamhaut L. A Comparative Study Between a Pre-Hodspital and an In-hospital Circulatory Support Strategy in Refractory Cardiac Arrest. ClinicalTrials.Gov. Accessed October 19, 2022. https://clinicaltrials.gov/ct2/show/NCT02527031.

      FranceJuly 2020Prehospital ECMOIn-hospital ECMO65Completed
      Early Initiation of Extracorporeal Life Support in Refractory Out-of-Hospital Cardiac Arrest (INCEPTION)

      Van De Poll M. Early Initiation of Extracorporeal Life Support in Refractory Out-of-Hospital Cardiac Arrest. ClinicalTrials.Gov. Accessed October, 19, 2022. https://clinicaltrials.gov/ct2/show/NCT03101787.

      NetherlandsFebruary 2022ECPR upon ED arrivalStandard treatment134Completed
      On-Scene Initiation of Extracorporeal Cardiopulmonary Resuscitation During Refractory Out-of-Hospital Cardiac Arrest (ON-SCENE)

      Miranda D. On-Scene Initiation of Extracorporeal Cardiopulmonary Resuscitation During Refractory Out-of-Hospital Cardiac Arrest. ClinicalTrials.Gov. Accessed October, 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04620070.

      NetherlandsJanuary 2026Prehospital ECPRStandard treatment390Recruiting
      CPB: cardiopulmonary bypass; ECMO: extracorporeal membrane oxygenation; ECPR: extracorporeal cardiopulmonary resuscitation; ED: emergency department
      a Status obtained through correspondence with the principal investigators
      Study heterogeneity precluded any meaningful meta-analyses for both randomized trials and observational studies. A descriptive overview of the studies is provided below. Additional study characteristics, patient characteristics, and results of individual studies are provided in the data extraction sheets in the Supplementary Content.

      Randomized trials

      Three trials comparing an ECPR strategy to local standard care were identified.
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      All trials included adult patients with OHCA. There was some heterogeneity in the patient populations and interventions between the trials (Table 2, Table 3 and Table S1). Yannopoulos et al. included 30 cardiac arrests with a shockable rhythm, randomized patients upon arrival to the Emergency Department, and found a benefit of ECPR in survival and favorable neurological status.
      • 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.
      Hsu et al. included 15 cardiac arrests
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      and Belohlavek et al. included 264 cardiac arrests
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      with any rhythm, randomized patients in the prehospital setting, and found no statistically significant differences in outcomes, although there was a strong signal towards benefit in the larger trial.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      The intervention group obtained immediate access to a catheterization laboratory in the trials by Yannopoulos et al. and Belohlavek et al.
      • 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.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      All trials were terminated prior to enrolling the intended number of subjects. Effect measures could not be estimated for all outcomes in all trials due to a limited number of events. ECPR was initiated in 42% to 80% of patients in the treatment groups. The mean time from cardiac arrest to ECPR ranged from 59 to 66 minutes. The risk of bias was assessed as intermediate for trials due to the lack of blinding (Table S2).
      Table 2Characteristics of randomized trials.
      StudyCountryCentersTime of inclusionMain inclusion criteriaLocation of randomizationECPR locationECMO in treatment groupLocation of cannulationPhysician performing cannulationTime to ECMO
      Yannopoulos, 2020
      • 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.
      USA12019–2020Age 18–75, initial shockable rhythm, no ROSC after 3 shocks, transfer time to ED < 30 minEDIn-hospital80%FemoralCardiologist59 min

      (SD: 28)
      Hsu, 2021
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      USA12017–2020Age 18–70, initial shockable rhythm or witnessed, persistent cardiac arrest after rhythm analysis and shock if indicated, transfer time to ED < 30 minPrehospitalIn-hospital42%FemoralEmergency physician66 min

      (SD: 17)
      Belohlavek, 2022
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      Czech Republic12013–2020Age 18–65, witnessed, cardiac cause, at least 5 min of ACLS, time to cath. lab < 60 minPrehospitalIn-hospital66%FemoralCardiologist61 min



      (IQR: 55, 70)
      ECMO: extracorporeal membrane oxygenation; ROSC: return of spontaneous circulation; ED: emergency department; Cath. Lab.: catheterization laboratory; ECPR: extracorporeal cardiopulmonary resuscitation; ACLS: advanced cardiac life support.
      Table 3Main results of randomized trials
      StudyPatientsTreatmentControlMid-term survival
      Mid-term defined as hospital discharge or 30 days
      Mid-term favorable neurological outcome
      Mid-term defined as hospital discharge or 30 days
      Long-term survival
      Long-term defined as 3 months or 6 months
      Long-term favorable neurological outcome
      Long-term defined as 3 months or 6 months
      TreatmentControlTreatmentControlTreatmentControlTreatmentControl
      Yannopoulos, 2020
      • 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.


      30Access to cath. lab and ECPR upon hospital arrivalStandard ACLS in the ED6/14 (43%)



      1/15



      3/14



      0/15 (0%)



      6/14 (43%)



      0/15 (0%)



      6/14 (43%)



      0/15 (0%)



      Hsu, 2021
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.


      15Expedited transport to ECPR capable EDStandard ACLS on site0/12 (0%)



      1/3 (33%)



      0/12



      0/3 (0%)



      0/12 (0%)



      1/3 (33%)



      0/12 (0%)



      0/3 (0%)



      Belohlavek, 2022
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.


      264Intra-arrest transport to cardiac center for ECPRStandard ACLS on site52/124 (42%)



      43/132 (33%)



      38/124 (31%)



      24/132 (18%)



      41/124 (33%)



      33/132 (25%)



      39/124 (32%)



      29/132 (22%)



      ECPR: extracorporeal cardiopulmonary resuscitation; ED: emergency department; ACLS: advanced cardiac life support
      a Mid-term defined as hospital discharge or 30 days
      b Long-term defined as 3 months or 6 months

      Observational studies in adults

      There were 23 observational studies in adults.
      • Métrailler-Mermoud J.
      • Hugli O.
      • Carron P.N.
      • et al.
      Avalanche victims in cardiac arrest are unlikely to survive despite adherence to medical guidelines.
      • Nakashima T.
      • Noguchi T.
      • Tahara Y.
      • et al.
      Patients With Refractory Out-of-Cardiac Arrest and Sustained Ventricular Fibrillation as Candidates for Extracorporeal Cardiopulmonary Resuscitation - Prospective Multi-Center Observational Study.
      • Shiba D.
      • Hifumi T.
      • Tsuchiya M.
      • et al.
      Pneumonia and Extracorporeal Cardiopulmonary Resuscitation Followed by Targeted Temperature Management in Patients With Out-of-Hospital Cardiac Arrest - Retrospective Cohort Study.
      • Bartos J.A.
      • Grunau B.
      • Carlson C.
      • et al.
      Improved Survival With Extracorporeal Cardiopulmonary Resuscitation Despite Progressive Metabolic Derangement Associated With Prolonged Resuscitation.
      • Bougouin W.
      • Dumas F.
      • Lamhaut L.
      • et al.
      Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study.
      • Braumann S.
      • Nettersheim F.S.
      • Hohmann C.
      • et al.
      How long is long enough? Good neurologic outcome in out-of-hospital cardiac arrest survivors despite prolonged resuscitation: a retrospective cohort study.
      • Shin Y.S.
      • Kim Y.J.
      • Ryoo S.M.
      • et al.
      Promising candidates for extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest.
      • Yoshida T.
      • Fujitani S.
      • Wakatake H.
      • et al.
      Exploratory Observational Study of Extracorporeal Cardiopulmonary Resuscitation for Nonshockable Out-Of-Hospital Cardiac Arrest Occurring After an Emergency Medical Services Arrival: SOS-KANTO 2012 Study Report.
      • Fukushima K.
      • Aoki M.
      • Nakajima J.
      • et al.
      Favorable prognosis by extracorporeal cardiopulmonary resuscitation for subsequent shockable rhythm patients.
      • Jeong D.
      • Lee G.T.
      • Park J.E.
      • et al.
      Extracorporeal Life-support for Out-of-hospital Cardiac Arrest: A Nationwide Multicenter Study.
      • Mørk S.R.
      • Bøtker M.T.
      • Christensen S.
      • Tang M.
      • Terkelsen C.J.
      Survival and neurological outcome after out-of-hospital cardiac arrest treated with and without mechanical circulatory support.
      • Kitada M.
      • Kaneko T.
      • Yamada S.
      • Harada M.
      • Takahashi T.
      Extracorporeal cardiopulmonary resuscitation without target temperature management for out-of-hospital cardiac arrest patients prolongs the therapeutic time window: a retrospective analysis of a nationwide multicentre observational study in Japan.
      • Nakajima M.
      • Kaszynski H.R.
      • Goto H.
      • et al.
      Current trends and outcomes of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Japan: A nationwide observational study.
      • Yamada S.
      • Kaneko T.
      • Kitada M.
      • Harada M.
      • Takahashi T.
      Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.
      • Kim S.J.
      • Han K.S.
      • Lee E.J.
      • Lee S.J.
      • Lee J.S.
      • Lee S.W.
      Association between Extracorporeal Membrane Oxygenation (ECMO) and Mortality in the Patients with Cardiac Arrest: A Nation-Wide Population-Based Study with Propensity Score Matched Analysis.
      • Mandigers L.
      • Scholten E.
      • Rietdijk W.J.R.
      • et al.
      Survival and neurological outcome with extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest caused by massive pulmonary embolism: A two center observational study.
      • Patricio D.
      • Peluso L.
      • Brasseur A.
      • et al.
      Comparison of extracorporeal and conventional cardiopulmonary resuscitation: a retrospective propensity score matched study.
      • Shinar Z.
      • Plantmason L.
      • Reynolds J.
      • et al.
      Emergency Physician-Initiated Resuscitative Extracorporeal Membrane Oxygenation.
      • Kwon S.S.
      • Park B.W.
      • Lee M.H.
      • et al.
      Role and Prognosis of Extracorporeal Life Support in Patients Who Develop Cardiac Arrest during or after Office-Based Cosmetic Surgery.
      • Stoll S.E.
      • Paul E.
      • Pilcher D.
      • Udy A.
      • Burrell A.
      Hyperoxia and mortality in conventional versus extracorporeal cardiopulmonary resuscitation.
      • Ohbe H.
      • Isogai S.
      • Jo T.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Extracorporeal membrane oxygenation improves outcomes of accidental hypothermia without vital signs: A nationwide observational study.
      • Patel J.K.
      • Meng H.
      • Qadeer A.
      • Parikh P.B.
      Impact of Extracorporeal Membrane Oxygenation on Mortality in Adults With Cardiac Arrest.
      • Ohbe H.
      • Ogura T.
      • Matsui H.
      • Yasunaga H.
      Extracorporeal cardiopulmonary resuscitation for acute aortic dissection during cardiac arrest: A nationwide retrospective observational study.
      Fourteen studies included patients with OHCA,
      • Métrailler-Mermoud J.
      • Hugli O.
      • Carron P.N.
      • et al.
      Avalanche victims in cardiac arrest are unlikely to survive despite adherence to medical guidelines.
      • Nakashima T.
      • Noguchi T.
      • Tahara Y.
      • et al.
      Patients With Refractory Out-of-Cardiac Arrest and Sustained Ventricular Fibrillation as Candidates for Extracorporeal Cardiopulmonary Resuscitation - Prospective Multi-Center Observational Study.
      • Shiba D.
      • Hifumi T.
      • Tsuchiya M.
      • et al.
      Pneumonia and Extracorporeal Cardiopulmonary Resuscitation Followed by Targeted Temperature Management in Patients With Out-of-Hospital Cardiac Arrest - Retrospective Cohort Study.
      • Bartos J.A.
      • Grunau B.
      • Carlson C.
      • et al.
      Improved Survival With Extracorporeal Cardiopulmonary Resuscitation Despite Progressive Metabolic Derangement Associated With Prolonged Resuscitation.
      • Bougouin W.
      • Dumas F.
      • Lamhaut L.
      • et al.
      Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study.
      • Braumann S.
      • Nettersheim F.S.
      • Hohmann C.
      • et al.
      How long is long enough? Good neurologic outcome in out-of-hospital cardiac arrest survivors despite prolonged resuscitation: a retrospective cohort study.
      • Shin Y.S.
      • Kim Y.J.
      • Ryoo S.M.
      • et al.
      Promising candidates for extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest.
      • Yoshida T.
      • Fujitani S.
      • Wakatake H.
      • et al.
      Exploratory Observational Study of Extracorporeal Cardiopulmonary Resuscitation for Nonshockable Out-Of-Hospital Cardiac Arrest Occurring After an Emergency Medical Services Arrival: SOS-KANTO 2012 Study Report.
      • Fukushima K.
      • Aoki M.
      • Nakajima J.
      • et al.
      Favorable prognosis by extracorporeal cardiopulmonary resuscitation for subsequent shockable rhythm patients.
      • Jeong D.
      • Lee G.T.
      • Park J.E.
      • et al.
      Extracorporeal Life-support for Out-of-hospital Cardiac Arrest: A Nationwide Multicenter Study.
      • Mørk S.R.
      • Bøtker M.T.
      • Christensen S.
      • Tang M.
      • Terkelsen C.J.
      Survival and neurological outcome after out-of-hospital cardiac arrest treated with and without mechanical circulatory support.
      • Kitada M.
      • Kaneko T.
      • Yamada S.
      • Harada M.
      • Takahashi T.
      Extracorporeal cardiopulmonary resuscitation without target temperature management for out-of-hospital cardiac arrest patients prolongs the therapeutic time window: a retrospective analysis of a nationwide multicentre observational study in Japan.
      • Nakajima M.
      • Kaszynski H.R.
      • Goto H.
      • et al.
      Current trends and outcomes of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Japan: A nationwide observational study.
      • Yamada S.
      • Kaneko T.
      • Kitada M.
      • Harada M.
      • Takahashi T.
      Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.
      6 studies included patients with either OHCA or IHCA,
      • Kim S.J.
      • Han K.S.
      • Lee E.J.
      • Lee S.J.
      • Lee J.S.
      • Lee S.W.
      Association between Extracorporeal Membrane Oxygenation (ECMO) and Mortality in the Patients with Cardiac Arrest: A Nation-Wide Population-Based Study with Propensity Score Matched Analysis.
      • Mandigers L.
      • Scholten E.
      • Rietdijk W.J.R.
      • et al.
      Survival and neurological outcome with extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest caused by massive pulmonary embolism: A two center observational study.
      • Patricio D.
      • Peluso L.
      • Brasseur A.
      • et al.
      Comparison of extracorporeal and conventional cardiopulmonary resuscitation: a retrospective propensity score matched study.
      • Shinar Z.
      • Plantmason L.
      • Reynolds J.
      • et al.
      Emergency Physician-Initiated Resuscitative Extracorporeal Membrane Oxygenation.
      • Kwon S.S.
      • Park B.W.
      • Lee M.H.
      • et al.
      Role and Prognosis of Extracorporeal Life Support in Patients Who Develop Cardiac Arrest during or after Office-Based Cosmetic Surgery.
      • Stoll S.E.
      • Paul E.
      • Pilcher D.
      • Udy A.
      • Burrell A.
      Hyperoxia and mortality in conventional versus extracorporeal cardiopulmonary resuscitation.
      and in 3 studies the setting of cardiac arrest was unclear.
      • Ohbe H.
      • Isogai S.
      • Jo T.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Extracorporeal membrane oxygenation improves outcomes of accidental hypothermia without vital signs: A nationwide observational study.
      • Patel J.K.
      • Meng H.
      • Qadeer A.
      • Parikh P.B.
      Impact of Extracorporeal Membrane Oxygenation on Mortality in Adults With Cardiac Arrest.
      • Ohbe H.
      • Ogura T.
      • Matsui H.
      • Yasunaga H.
      Extracorporeal cardiopulmonary resuscitation for acute aortic dissection during cardiac arrest: A nationwide retrospective observational study.
      Years of patient inclusion ranged from 2004 to 2022. ECPR was assessed in the prehospital setting in 1 study
      • Bougouin W.
      • Dumas F.
      • Lamhaut L.
      • et al.
      Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study.
      and in the in-hospital setting in the remaining studies. The setting of ECPR was unclear in 4 studies.
      • Kitada M.
      • Kaneko T.
      • Yamada S.
      • Harada M.
      • Takahashi T.
      Extracorporeal cardiopulmonary resuscitation without target temperature management for out-of-hospital cardiac arrest patients prolongs the therapeutic time window: a retrospective analysis of a nationwide multicentre observational study in Japan.
      • Nakajima M.
      • Kaszynski H.R.
      • Goto H.
      • et al.
      Current trends and outcomes of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest in Japan: A nationwide observational study.
      • Yamada S.
      • Kaneko T.
      • Kitada M.
      • Harada M.
      • Takahashi T.
      Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.
      • Kim S.J.
      • Han K.S.
      • Lee E.J.
      • Lee S.J.
      • Lee J.S.
      • Lee S.W.
      Association between Extracorporeal Membrane Oxygenation (ECMO) and Mortality in the Patients with Cardiac Arrest: A Nation-Wide Population-Based Study with Propensity Score Matched Analysis.
      The number of patients analyzed ranged from 25 to 253,806, the number of exposed patients receiving ECPR ranged from 7 to 5612, and the proportion of exposed patients receiving ECPR ranged from 2% to 66%. The median age of exposed patients ranged from 31 to 72 years. Twelve studies reported the number of patients receiving targeted temperature management or coronary procedures. Results of individual studies were inconsistent, although many studies favored ECPR (Fig. S1). This risk of bias was assessed as critical for all observational studies, primarily due to the risk of confounding and selection bias (Table S3 and the Supplementary Methods).

      Observational studies in children

      There were 4 observational studies in children.
      • Meert K.
      • Telford R.
      • Holubkov R.
      • et al.
      Paediatric in-hospital cardiac arrest: Factors associated with survival and neurobehavioural outcome one year later.
      • Taeb M.
      • Levin A.B.
      • Spaeder M.C.
      • Schwartz J.M.
      Comparison of Pediatric Cardiopulmonary Resuscitation Quality in Classic Cardiopulmonary Resuscitation and Extracorporeal Cardiopulmonary Resuscitation Events Using Video Review.
      • Meert K.
      • Slomine B.S.
      • Silverstein F.S.
      • et al.
      One-year cognitive and neurologic outcomes in survivors of paediatric extracorporeal cardiopulmonary resuscitation.
      • Hamzah M.
      • Othman H.F.
      • Almasri M.
      • Al-Subu A.
      • Lutfi R.
      Survival outcomes of in-hospital cardiac arrest in pediatric patients in the USA.
      All studies included patients with IHCA. Years of inclusion ranged from 2000 to 2017. ECPR was assessed in the in-hospital setting in all studies. The number of patients analyzed ranged from 17 to 20,654, the number of exposed patients receiving ECPR ranged from 6 to 1670, and the proportion of exposed patients receiving ECPR ranged from 8% to 55%. The median age was only reported in 1 study as 2.5 years. Three studies reported the number of patients receiving targeted temperature management or coronary procedures. Studies generally favored no ECPR although the confidence intervals were wide (Fig. S2). The risk of bias was assessed as critical for all observational studies, primarily due to the risk of confounding and selection bias (Table S4 and the Supplementary Methods).

      Cost-effectiveness studies

      Six cost-effectiveness studies were identified
      • Bharmal M.I.
      • Venturini J.M.
      • Chua R.F.M.
      • et al.
      Cost-utility of extracorporeal cardiopulmonary resuscitation in patients with cardiac arrest.
      • Dennis M.
      • Zmudzki F.
      • Burns B.
      • et al.
      Cost effectiveness and quality of life analysis of extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest.
      • Gravesteijn B.Y.
      • Schluep M.
      • Voormolen D.C.
      • et al.
      Cost-effectiveness of extracorporeal cardiopulmonary resuscitation after in-hospital cardiac arrest: A Markov decision model.
      • Kawashima T.
      • Uehara H.
      • Miyagi N.
      • et al.
      Impact of first documented rhythm on cost-effectiveness of extracorporeal cardiopulmonary resuscitation.
      • Matsuoka Y.
      • Goto R.
      • Atsumi T.
      • et al.
      Cost-effectiveness of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: A multi-centre prospective cohort study.
      including 1 observational study that performed a cost analysis.
      • Ohbe H.
      • Ogura T.
      • Matsui H.
      • Yasunaga H.
      Extracorporeal cardiopulmonary resuscitation for acute aortic dissection during cardiac arrest: A nationwide retrospective observational study.
      The number of patients analyzed ranged from 32 to 796. The perspective, time horizon, assumed costs, effect of ECPR, and utility varied considerably between the studies. The reported incremental cost-effectiveness ratios of ECPR were converted to euros (EUR) and accounted for inflation until 2022. The calculated incremental cost-effectiveness ratios ranged from 12,254 to 155,739 EUR per quality-adjusted life year in individual studies (Table S5).

      Certainty in the overall evidence

      The certainty in the evidence was assessed as low for adults with OHCA (Table 4) and as very low for adults with IHCA (Table S6) based on the randomized trials. The certainty in the evidence was assessed as very low for children with OHCA (Table S7) and children with IHCA (Table S8) based on the observational studies in the previous
      • Holmberg M.J.
      • Geri G.
      • Wiberg S.
      • et al.
      Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
      and present systematic review. Observational studies in adults were not used to assess the certainty in the evidence given that new evidence from randomized trials was available.
      Table 4Certainty of evidence for randomized trials in adults with out-of-hospital cardiac arrest.
      OutcomesStudiesRisk of BiasInconsistencyIndirectnessImprecisionOther
      Includes assessment of publication bias and magnitude of the effect
      Overall
      Survival to hospital discharge or 30 days3 studies
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      Not seriousSerious
      Some inconsistencies in effect sizes
      Not seriousSerious
      Although no pooled estimate was calculated, the small sample sizes led to wide confidence intervals
      NoneLow
      Survival to 3 months or 6 months3 studies
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      Not seriousSerious
      Some inconsistencies in effect sizes
      Not seriousSerious
      Although no pooled estimate was calculated, the small sample sizes led to wide confidence intervals
      NoneLow
      Favorable neurological outcome at hospital discharge or 30 days3 studies
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      Not seriousSerious
      Some inconsistencies in effect sizes
      Not seriousSerious
      Although no pooled estimate was calculated, the small sample sizes led to wide confidence intervals
      NoneLow
      Favorable neurological outcome at 3 months or 6 months3 studies
      • 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.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      Not seriousSerious
      Some inconsistencies in effect sizes
      Not seriousSerious
      Although no pooled estimate was calculated, the small sample sizes led to wide confidence intervals
      NoneLow
      a Includes assessment of publication bias and magnitude of the effect
      b Some inconsistencies in effect sizes
      c Although no pooled estimate was calculated, the small sample sizes led to wide confidence intervals

      Discussion

      This systematic review provides an update on the use of ECPR compared with manual or mechanical CPR during cardiac arrest. The search identified 3 trials, 27 observational studies (23 in adults and 4 in children), and 6 cost-effectiveness studies published between 2018 and 2022. This review adds to the previous systematic review which identified 25 observational studies prior to 2018.
      • Holmberg M.J.
      • Geri G.
      • Wiberg S.
      • et al.
      Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
      The purpose of ECPR is to provide circulatory and respiratory support in cardiac arrest, thereby extending the time for recovery, diagnostics, and treatment of potentially reversible causes. Although the application of ECPR appears to have increased over the past decade, data on the potential benefit in cardiac arrest has until recently been limited to observational studies and case series.
      • Abrams D.
      • MacLaren G.
      • Lorusso R.
      • et al.
      Extracorporeal cardiopulmonary resuscitation in adults: evidence and implications.
      The paucity of randomized trials, the very-low certainty in the available evidence, and the substantial resources associated with the procedure led to a weak recommendation in the previous cardiac arrest guidelines by ILCOR.
      • Wyckoff M.H.
      • Singletary E.M.
      • Soar J.
      • et al.
      2021 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Neonatal Life Support; Education, Implementation, and Teams; First Aid Task Forces; and the COVID-19 Working Group.
      No meta-analyses were conducted of the 3 trials included in this review due to heterogeneity in the included patient populations and interventions, as well as a very low number of events for many outcomes. Yannopoulos et al. included cardiac arrests with an initial shockable rhythm refractory to defibrillation attempts, randomized patients after arrival at the hospital, and found a substantial benefit of ECPR in survival and favorable neurological status.
      • 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.
      Hsu et al. and Belohlavek et al. included cardiac arrests with any initial rhythm, randomized patients during ongoing resuscitation in the prehospital setting, and found no significant differences in outcomes.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      • Belohlavek J.
      • Smalcova J.
      • Rob D.
      • 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.
      The primary outcomes were defined as survival to hospital discharge in the trial by Yannopoulos et al., time to Emergency Department arrival or ECPR initiation in the trial by Hsu et al., and favorable neurological status at 180 days in the trial by Belohlavek et al.
      There is a possibility that the trials were underpowered to detect a clinical important difference for some outcomes as all trials were terminated early leading to wide confidence intervals. Moreover, the different trial settings and healthcare systems make the results difficult to generalize and the findings should be interpreted cautiously in the context of the logistical and geographical constraints within each trial. For example, the trial by Belohlavek et al. may better reflect settings where resuscitation for those not receiving ECPR is continued on-scene, which has been associated with improved outcomes compared to intra-cardiac arrest transport in observational studies.
      • Grunau B.
      • Kime N.
      • Leroux B.
      • et al.
      Association of Intra-arrest Transport vs Continued On-Scene Resuscitation With Survival to Hospital Discharge Among Patients With Out-of-Hospital Cardiac Arrest.
      Similarly, the trial by Yannopoulos et al. may better reflect settings where all patients are equally likely to be transported to the hospital during ongoing resuscitation. The patients included in the 3 trials were highly selected with only 6–10% of all screened patients being eligible for enrollment and randomization. The study populations may, therefore, reflect variations in ECPR eligibility criteria and patient selection within each trial. Ongoing trials are pending to assess the effect of initiating ECPR on-scene which will be informative for settings where this is possible.
      The included observational studies were all assessed to have a critical risk of bias, mainly due to confounding and selection bias for similar reasons as described in the previous ILCOR systematic review.
      • Holmberg M.J.
      • Geri G.
      • Wiberg S.
      • et al.
      Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review.
      This is further illustrated by the wide range of effect estimates obtained from observational studies in adults with odds ratios ranging from 0.24 (95%CI: 0.13, 0.46) to 43.1 (95%CI: 10.0, 185) for survival and from 0.33 (95%CI: 0.14, 0.76) to 70.4 (95%CI: 9.38, 528) for favorable neurological status. Many studies provided only unadjusted results, did not adjust adequately for potential confounding factors which increases the risk for residual confounding, or adjusted for post-cardiac arrest characteristics which cannot be direct confounders of the relationship between ECPR and outcomes.
      • Schisterman E.F.
      • Cole S.R.
      • Platt R.W.
      Overadjustment bias and unnecessary adjustment in epidemiologic studies.
      For some studies, patient selection was strongly related to the intervention and outcome, thereby, introducing collider bias.
      • Holmberg M.J.
      • Andersen L.W.
      Collider Bias.
      Very few studies adequately controlled for the timing of ECPR, may have led to resuscitation time bias – a bias occurring when patients with short duration of resuscitation (potentially due to ROSC) cannot receive the intervention.
      • Andersen L.W.
      • Grossestreuer A.V.
      • Donnino M.W.
      “Resuscitation time bias”-A unique challenge for observational cardiac arrest research.
      Resuscitation time bias was considered an issue of confounding in the previous ILCOR systematic review but determined to be more related to selection bias in this review. Although many studies attempted to control for this bias by including the duration of resuscitation in the statistical model, this is problematic as time is also a mediator on the causal pathway between ECPR and outcomes. The above issues illustrate some of the limitations in addressing this question using observational data and the need for additional randomized trials.
      ECPR is a resource intensive and costly procedure that is only available in selected settings. Despite the well-known costs, there have until recently been no formal analysis to assess the cost-effectiveness of the intervention. The cost-effectiveness studies included in this review were all conducted prior to publication of any randomized trial, meaning that many of the assumptions used for the analyses (such as the effect size of the intervention) were either based on expert opinion, theoretical models, or observational data. As illustrated by the results of the individual studies, these assumptions have led to very wide incremental cost-effectiveness ratios (the difference in the cost divided by the difference in the effect between ECPR and no ECPR) ranging from 12,254 to 155,739 EUR per quality-adjusted life year, which makes the trade-offs between costs and benefits difficult to assess. More rigorous cost-effectiveness studies using data from the recently published trials are needed to inform the appropriate application of ECPR in different settings.
      This systematic review should be interpreted in the context of some limitations. First, the interrater reliability for review of the literature was low (Kappa = 0.45) reflecting the difficulty in identifying relevant studies. However, we did not identify any additional studies through our subsequent review of excluded records, review of references of included studies, and discussion with content experts. Second, the decisions related to the risk of bias assessments were, at least in part, subjective and dependent on the reviewer. Third, we did not evaluate the optimal patient selection, indication, timing, and prognostication related to ECPR. Whether patient selection criteria should be more narrow or wider than those reported in the 3 randomized trials remains unknown, although a consensus statement have been published by the Extracorporeal Life Support Organization in an attempt to guide clinicians.
      • Richardson A.S.C.
      • Tonna J.E.
      • Nanjayya V.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation in Adults. Interim Guideline Consensus Statement From the Extracorporeal Life Support Organization.
      Lastly, we had originally planned to conduct meta-analyses, but determined that this was not feasible due to heterogeneity, a low number of events for many outcomes, and methodological challenges with few trials included.

      Conclusions

      Recent randomized trials suggest potential benefit of ECPR, but the certainty of evidence remains low. It is unclear which patients might benefit from ECPR.

      Conflicts of Interest

      Cindy H. Hsu was the lead investigator of the EROCA trial and was, therefore, not involved in the bias assessment of that study.
      • Hsu C.H.
      • Meurer W.J.
      • Domeier R.
      • et al.
      Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest (EROCA): Results of a Randomized Feasibility Trial of Expedited Out-of-Hospital Transport.
      None of the remaining authors have any conflicts of interest to report.

      Acknowledgments

      The authors would like to thank Katherine M. Berg and Ian Drennan for reviewing the manuscript. Mathias J. Holmberg, Asger Granfeldt, Anne-Marie Guerguerian, Claudio Sandroni, Cindy H. Hsu, and Lars W. Andersen are task force members of the International Liaison Committee on Resuscitation.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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