Comparing extracorporeal cardiopulmonary resuscitation with conventional cardiopulmonary resuscitation: A meta-analysis

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Review article

Comparing extracorporeal cardiopulmonary resuscitation with conventional cardiopulmonary resuscitation: A meta-analysis夽 Su Jin Kim a , Hyun Jung Kim b , Hee Young Lee c , Hyeong Sik Ahn b , Sung Woo Lee a,∗ a

Department of Emergency Medicine, College of Medicine, Korea University Hospital, Seoul, Republic of Korea Institute for Evidence-based Medicine, The Korean Branch of Australasian Cochrane Center, Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Republic of Korea c Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea b

a r t i c l e

i n f o

Article history: Received 29 October 2015 Received in revised form 19 December 2015 Accepted 19 January 2016 Keywords: Out-of-hospital cardiac arrest In-hospital cardiac arrest Extracorporeal cardiopulmonary resuscitation Conventional cardiopulmonary resuscitation Cerebral performance category Meta-analysis

a b s t r a c t Introduction: The objective was to determine whether extracorporeal cardiopulmonary resuscitation (ECPR), when compared with conventional cardiopulmonary resuscitation (CCPR), improves outcomes in adult patients, and to determine appropriate conditions that can predict good survival outcome in ECPR patients through a meta-analysis. Methods: We searched the relevant literature of comparative studies between ECPR and CCPR in adults, from the MEDLINE, EMBASE, and Cochrane databases. The baseline information and outcome data (survival, good neurologic outcome at discharge, at 3–6 months, and at 1 year after arrest) were extracted. Beneficial effect of ECPR on outcome was analyzed according to time interval, location of arrest (outof-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA)), and pre-defined population inclusion criteria (witnessed arrest, initial shockable rhythm, cardiac etiology of arrest and CPR duration) by using Review Manager 5.3. Cochran’s Q test and I2 were calculated. Results: 10 of 1583 publications were included. Although survival to discharge did not show clear superiority in OHCA, ECPR showed statistically improved survival and good neurologic outcome as compared to CCPR, especially at 3–6 months after arrest. In the subgroup of patients with pre-defined inclusion criteria, the pooled meta-analysis found similar results in studies with pre-defined criteria. Conclusion: Survival and good neurologic outcome tended to be superior in the ECPR group at 3–6 months after arrest. The effect of ECPR on survival to discharge in OHCA was not clearly shown. As ECPR showed better outcomes than CCPR in studies with pre-defined criteria, strict indications criteria should be considered when implementation of ECPR. © 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction Survival to hospital discharge rates are less than 10% and 20% respectively for out-of-hospital cardiac arrest (OHCA) and inhospital cardiac arrest (IHCA), and good neurologic survival rates vary widely, from 50% to 85% of survivors according to regional variations.1–4 Extracorporeal cardiopulmonary resuscitation (ECPR), either during conventional cardiopulmonary resuscitation (CCPR) or when repetitive arrest events without return of spontaneous

夽 A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2016.01.019. ∗ Corresponding author at: Department of Emergency Medicine, College of Medicine, Korea University, Inchon-ro 73, Seongbuk-gu, Seoul 02841, Republic of Korea. E-mail address: [email protected] (S.W. Lee).

circulation (ROSC) for more than 20 min, is considered an alternative resuscitative method for patients who have a presumed reversible etiology of arrest (acute myocardial infarction, pulmonary embolism, etc.) who show no response despite advanced cardiac life support in emergency department, intensive care unit and catheterization room.5–7 ECPR may preserve myocardial viability by enhancing coronary blood flow, thus increasing the chance of ROSC.8 As ECPR provides sufficient perfusion to vital organs until an effective cardiac output has been recovered, thus preventing organ failure, ECPR, compared to CCPR, may improve survival and neurological outcome long-term post-arrest. However, the advantages of ECPR as an alternative method to CCPR for increasing survival rate and attaining good cerebral performance category (CPC) score are still controversial, especially in OHCA, as well as in IHCA. Moreover, outcomes of CCPR, despite standardized guidelines, show a multitude of discrepancies, with varying resuscitative

http://dx.doi.org/10.1016/j.resuscitation.2016.01.019 0300-9572/© 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Kim SJ, et al. Comparing extracorporeal cardiopulmonary resuscitation with conventional cardiopulmonary resuscitation: A meta-analysis. Resuscitation (2016), http://dx.doi.org/10.1016/j.resuscitation.2016.01.019

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methods and strategies depending on regional variations and emergency response systems.9 ECPR also has shown a wide range results due to its relatively limited indications and differing protocols. This is especially true in OHCA patients, which differ from IHCA cases in terms of characteristics of patients, common etiologies of arrest, pre-existing disease, low-flow time, bystander CPR quality.10,11 Furthermore, the invasively high cost of ECPR and its applicability to only a limited patient population both play a considerable role in determining outcome. Although there are several studies regarding ECPR survival rates and neurological outcomes, evidence on conditions for predicting beneficial effects of ECPR compared to CCPR is lacking.12–14 Therefore, we performed an updated meta-analysis of observational studies, addressing whether ECPR, compared with CCPR, improves survival outcome and good neurological outcome (CPC 1, 2) in adult patients with cardiac arrest according to time interval after arrest (at discharge, 3–6 months, and 1 year). In addition, we analyzed outcomes of subgroups according to location of arrest (OHCA and IHCA). The primary objective was to determine whether ECPR results in better outcome than CCPR, regardless of time interval and location of arrest. Our secondary objective was to determine adequate predictors of better outcome in ECPR versus CCPR through subgroup analysis. Methods We used multiple comprehensive databases to find literature comparing outcomes of ECPR and CCPR. This study is based on the Cochrane Review Methods.15 Data source & literature searches We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from August 1965 until February 2015 without restrictions on language or year of publication or type of publication. Further studies were additionally included from March 31 to July 31, 2015 during the review process. The following keywords and MeSH were searched through Medline: “heart arrest”, “extracorporeal membrane oxygenation”, and “resuscitation” (See Appendix 1 for the comprehensive list). Search strategies were adapted for other databases based on the MEDLINE strategy. After the initial electronic search, we hand-searched further relevant articles and bibliographies from identified studies. Articles identified were assessed individually for inclusion. Study selection Studies were assessed for inclusion independently by two reviewers (SJK and SWL) based on pre-defined selection criteria. Two reviewers independently assessed the titles and abstracts of included studies and then assessed the reports to ensure that they met our inclusion criteria. Any disagreement was discussed by the two reviewers. We excluded reports that did not completely fulfill our inclusion criteria. Studies were included in our meta-analysis if they contained (1) adult (age ≥ 16 years) patients, (2) with either in-hospital or out-of-hospital cardiac arrest, (3) comparative study data between ECPR as the intervention group and CCPR as the control group, and (4) reported outcomes (survival and neurological outcome at discharge, 3–6 month, and 1 year after arrest). We excluded any studies that (1) contained only non-comparative outcomes of either ECPR or CCPR, (2) included cases with cardiogenic shock or postcardiac surgery, (3) included pediatric patients (age < 16 years), (4) were comprised of a majority of arrest events caused by trauma, avalanche, hanging and/or drowning or (5) Do-Not-Attempt

Resuscitation (DNAR) cases. Studies that were duplicates of the same patient cohort were not included. Data extraction The two reviewers independently extracted data from each study using a predefined data extraction form. Any disagreement was resolved by discussion. The following variables were extracted from studies: (1) demographic, clinical, and treatment characteristics (e.g., inclusion criteria of studies, number of arrest patients in ECPR and CCPR groups, study location), (2) number of patients with reported outcomes (survival outcome at discharge, at 3–6 months, at over 1 year and good neurologic outcome at discharge, at 3–6 months, at over 1 year in comparative groups), (3) location of arrest, (4) study period, and (5) ECPR indications. When not otherwise specified, we considered 30-day survival as survival to hospital discharge. Good neurologic outcome was defined as a Glasgow–Pittsburgh CerebralPerformance Category (CPC) score of 1 or 2 on the 5-category scale. If the above variables were not mentioned in the studies, we asked corresponding authors for the data via email. Assessment of methodological quality Two reviewers independently assessed the methodological qualities for each study using the Newcastle–Ottawa Scale for cohort studies. Any unresolved disagreements between reviewers were resolved through discussion or review from the third author (HYL). As tests for funnel plot asymmetry are generally only performed when at least 10 studies are included in the meta-analysis, publication bias was not assessable. Statistical analysis The main outcome was survival to hospital discharge and good neurologic outcome at discharge. The denominator for calculating rates of survival to hospital discharge was the number of adult patient with arrest. For dichotomous outcomes (survival rate, event rate of good neurologic outcome), data were pooled using Mantel–Haenszel method random-effects weighting, and the results were expressed as relative risks (RR) and 95% confidence intervals (CI). RR was used for survival events and good neurologic outcome, not for mortality. To estimate heterogeneity, we estimated the I2 statistic, with values of 25%, 50%, and 75% considered low, moderate, and high, respectively. We conducted planned subgroup analyses according to (1) OHCA and IHCA, (2) selectively limited inclusions of the study population, such as cases of witnessed arrest, or cases with initial rhythm of ventricular fibrillation (VF)/ventricular tachycardia (VT), or presumed cardiac etiology or CPR duration >10–20 min. Sensitivity analysis was performed by the Newcastle–Ottawa scale, or through consideration of article quality through publication type. We used Review Manager version 5.3 for these analyses. Cochran’s Q test and I2 were calculated. Results Identification of studies Searches of the databases yielded 1583 articles, excluding duplicates (Fig. 1). Of these, 1555 publications were excluded upon initial screening as it was clear from the title and abstract that they did not fulfill the selection criteria. For the remaining 28 articles, we obtained full manuscripts, and following scrutiny of these, we identified potentially relevant studies. Publications were further excluded if they were (1) duplicate data, (2) outcome

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Fig. 1. Flowchart of meta-analysis.

from the same editorial or comments, (3) studies including noncomparative outcome, post-cardiac surgery or cardiogenic shock without distinction from cardiac arrest (Appendix 2). Although the study by Nagao et al. reported survival to discharge in both ECPR and CCPR cases, the population only included OHCA patients with poor predicted outcome (Glasgow Coma Scale of 3–5) on arrival at the ED, and was therefore excluded due to inappropriate inclusion criteria.16 Therefore the total 14 publications were eligible, included in the review and 10 of 14 were full publications (Fig. 1). Study characteristics and patient populations (Table 1) Table 1 displays study characteristics and variables. The year of publication of the studies ranged from 2008 to 2014. Although CPR guidelines were updated in 2005 and 2010, as the meta-analysis was conducted from 2000 to 2013, it was not possible to stratify the analysis according to the years CPR guidelines were updated. The studies were conducted in Korea (n = 4), Japan (n = 4), Taiwan (n = 4), Germany (n = 1) and Austria (n = 1). 6 studies included patients with in-hospital cardiac arrest.17–22 Six studies included patients with out-of-hospital cardiac arrest.23–29 Siao et al. included data with both in-hospital and out-of-hospital cardiac arrest.30 All studies used CPC scoring to assess neurologic outcome, with CPC scores of 1 or 2 being considered good neurologic outcomes. The report by Tanno et al. restricted the definition of good neurological outcome to a CPC score of 1.23 The study populations of Chen et al. and Lin et al. were duplicates, as Lin et al. included a portion of the population of Chen’s study with a slightly different design.18,19 Similarly, the population of Nagao et al. was included in the study by Sakamoto et al.25,27

The study population of Shin et al. was also a duplicate.20,21 Duplicate data was excluded, but if the reported outcome did not overlap for subgroups, such as time interval, the data was included in the analysis. All of the studies defined inclusion criteria as cases with brief no-flow time (witnessed arrest or initial rhythm of VF/VT) and CPR duration over 10–20 min without ROSC, except the studies of Kim et al. Kim reported comparative results using both crude and propensity-matched data. Kim et al. analyzed a large, diverse population including all adult OHCA patients, with the exception of trauma and DNAR cases.24 Propensity-matched data of the Kim et al. study was used to analyze the effect of ECPR versus CCPR with other studies. 5 studies showed complications related to ECPR, such as bleeding, infection at cannulation site, 2 studies showed the data of complication related to post-resuscitation (Appendix 3). Although 4 of the 14 publications had all documented available outcomes for review in ECPR and CCPR groups, we excluded 4 publications including abstract-only publications to meta-analysis.22,25,28,29 8 comparative studies of 10 publications reported the outcome of an overall 2280 patients. The total number of patients with ECPR was 641, and that of CCPR was 1639. Quality of the included studies (appendix 4) Although 7 of 8 studies were registry-based, other study based on medical reviews may have a risk of selection bias. Sensitivity analysis, however, did not show any difference. As the studies with only crude data may increase risk of bias in comparability, analysis was performed based on the studies with propensity score matching. Propensity-matched data to adjust for confounders were

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4 Table 1 Characteristic of studies included in the meta-analysis. Study identification

Author

Publication year

Population (n)

OHCA/IHCAa

Study type

Location

Study period

Chu 2014

Chu et al.

2014

IHCA

Observational cohort

Taiwan

2006.1–2010.7.1

Chen 2008

Chen et al.

2008

IHCA

Observational cohort Propensity score matching

Taiwan

2004.1–2006.12

Lin et al.

2010

ECPRb (43) CCPRb (23) ECPR (59) CCPR (113) mECPRc (46) mCCPRc (46) ECPR (55) CCPR (63)

IHCA

Shin 2011

Shin et al.

2011

Observational cohort Propensity score matching Observational Cohort Propensity score matching

Tanno 2008

Shin et al. Tanno et al.

2013 2008

Kim 2014

Kim et al.

2014

Maekawa 2013

Maekawa et al.

2013

Sakamoto 2014

Sakamoto et al. Siao et al.

2014

Siao 2015

2015

Excluded abstract-only publications Leick et al. Leick 2014

2014

Nagao 2014

Nagao et al.

2014

Chung 2012

Chung et al.

2012

Schober 2014

Schober et al.

2014

a b c

ECPR (85) CCPR (321) mECPR (60) mCCPR (60) ECPR (66) CCPR (332) ECPR (55) CCPR (444) mECPR (52) mCCPR (52) ECPR (53) CCPR (109) mECPR (24) mCCPR (24) ECPR (260) CCPR (194) ECPR (20) CCPR (40)

IHCA

ECPR (52) CCPR (272) mECPR (52) mCCPR (52) EPCR (165) CCPR (115) ECPR (12) CCPR (26) ECPR (12) CCPR (257)

Type of publication

2004.1–2006.12

Korea

2003.1–2009.6

Medical chart review Observational Cohort Observational Cohort Propensity score matching

Japan

2001.1–2004.9

Korea

2006.5–2013.12

OHCA

Observational Cohort Propensity score matching

Japan

2000.1–2004.9

OHCA

Observational Cohort

Japan

2008.10–2012.3

OHCA/IHCA

Medical chart review

Taiwan

2011.9–2013.9

IHCA

Medical chart review Propensity score matching

Germany

Not reported

Abstract only

OHCA

Observational Cohort

Japan

Not reported

Abstract only

OHCA

Medical chart review

Korea

2010.4–2011.8

Abstract only

OHCA

Not reported

Austria

2002–2012

Abstract only

OHCA OHCA

OHCA; Out-of-hospital cardiac arrest, IHCA; In-hospital cardiac arrest. ECPR; Extracorporeal cardiopulmonary resuscitation, CCPR; conventional cardiopulmonary resuscitation. mECPR; matched Extracorporeal cardiopulmonary resuscitation, mCCPR; matched conventional cardiopulmonary resuscitation.

used in 4 studies of 6 publications, excluding two publications with overlapped data.18–22,24,26 Adequacy of follow-up was documented in 3 studies. As subgroup analysis according to publication type did not show any difference, the results of meta-analysis including abstract-only publications were supplemented by Appendices 5 and 6. Survival and good neurologic outcome stratified by time interval after arrest Survival outcome stratified by time interval after arrest (hospital discharge, 3–6 months and 1 year after arrest) Overall survival tended to be higher in ECPR than CCPR, especially at 3–6 months (RR 2.60, 95% CI 1.57–4.30) in the studies using propensity-matched data (RR 1.86, 95% CI 0.99–3.50 at discharge; and RR 1.96, 95% CI 1.00–3.87 at 1 year) (Fig. 2A). Comparative studies with crude data showed better overall survival outcome in ECPR than in CCPR, at discharge, at 3–6 months and at 1 year in Table 2. Good neurologic outcome stratified by time interval after arrest (hospital discharge, 3–6 months and 1 year after arrest) In the analysis with matched data, overall good neurologic outcome at discharge, at 3–6 months and at 1 year, was higher in ECPR

than CCPR (RR 3.12, 95% CI 1.46–6.66; RR 4.65, 95% CI 2.00–10.81,; RR 2.63, 95% CI 1.11–6.21) (Fig. 2B). ECPR studies also revealed higher rates of good neurologic outcome according to time interval in comparative studies with crude data at discharge, at 3–6 months and at 1 year (Table 2). Survival and good neurologic outcome stratified by location of arrest (OHCA and IHCA) Survival outcome stratified by location of arrest (OHCA and IHCA) The study of Siao et al. was not included due to mixed OHCA and IHCA data. Survival to hospital discharge and survival outcome at 3–6 months in studies with matching data resulted in outcomes with ECPR, compared with CCPR, in IHCA groups (RR 2.37, 95% CI 1.35–4.15 at discharge, Fig. 3A; RR 2.54, 95% CI 1.38–4.66 at 3–6 months, Fig. 3B). ECPR showed higher survival rate at 3– 6 months after arrest in OHCA patients (RR 2.74, 95% CI 1.13–6.67, Fig. 3B). However, the beneficial effect of ECPR compared with CCPR in OHCA patients was not clear for survival to hospital discharge (RR 1.45, 95% CI 0.41–5.16, Fig. 3A). There were no statistical differences among subgroups of OHCA and IHCA for survival to discharge and at 3–6 months. Even when crude data was used for OHCA and IHCA survival to discharge, ECPR showed superior results over CCPR. Furthermore, with a subgroup difference, the ECPR in the OHCA group

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Fig. 2. Forest plot of studies with propensity-matched data, reporting outcome by time interval after arrest. (A) Forest plot of studies reporting survival outcome. (B) Forest plot of studies reporting a good neurologic outcome.

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Table 2 Analysis of survival and good neurologic outcome in studies using crude data. Subgroup

Study number

Survival outcome stratified by time interval arrest after arrest 6 At discharge At 3–6 months

5

At 1 year after arrest

4

Good neurologic outcome stratified by time interval after arrest 4 At discharge At 3–6 months

4

At 1 year after arrest

3

Survival to discharge stratified by location of arrest OHCA 2 IHCA

3

Good neurologic outcome stratified by location of arrest 1 OHCA IHCA a

2

Total participants

Risk ratio

95% CI

Heterogeneity within group I2 (%)

ECPRa (520) CCPRa (800) ECPR (523) CCPR (1069) ECPR (207) CCPR (497)

2.77

2.01–3.83

35

3.16

2.23–4.49

36

2.25

1.62–3.14

0

3.68

2.29–5.19

28

3.49

2.19–5.55

22

3.15

1.76–5.64

36

ECPR (313) CCPR (303) ECPR (187) CCPR (457)

4.52

2.81–7.26

0

2.48

1.79–3.42

0

ECPR (260) CCPR (194) ECPR (144) CCPR (434)

7.96

2.47–25.61

(–)

3.03

1.92–4.80

17

ECPRa (424) CCPRa (668) ECPR (464) CCPR (956) ECPR (164) CCPR (474)

Subgroup differences I2 (%) 0

0

76.2

55.9

ECPR; Extracorporeal cardiopulmonary resuscitation, CCPR; conventional cardiopulmonary resuscitation

appeared more effective than in the IHCA group (RR 4.52, 95% CI 2.81–7.26 in OHCA; RR 2.48, 95% CI 1.79–3.42 in IHCA, I2 76.2%) (Table 2). Good neurologic outcome stratified by location of arrest (OHCA and IHCA) In studies with matched data, in both OHCA and IHCA groups, ECPR showed better outcomes for good neurologic outcome at discharge and at 3–6 months. (RR 8.00, 95% CI 1.04–61.71 in OHCA and RR 2.72, 95% CI 1.21–6.13 in IHCA at discharge, Fig. 4A) (RR 4.64, 95% CI 1.41–15.25 in OHCA and RR 4.67, 95% CI 1.41–15.41 in IHCA at 3–6 months, Fig. 4B). There were no subgroup differences of OHCA and IHCA at discharge and at 3–6 months. ECPR in OHCA showed higher good neurologic outcome of ECPR in IHCA despite the use of crude data (RR 7.96, 95% CI 2.47–25.61 in OHCA; RR 3.03, 95% CI 1.92–4.80 in IHCA, I2 55.9%) (Table 2). Analysis of subgroups for survival to discharge stratified by inclusion criteria The apparently better ratio of neurologic outcome at discharge in ECPR also showed differences in the studies limited to any inclusion criteria versus study without any limitation of study population (Table 3, Appendix 3). Outcomes in studies with witnessed arrest versus studies whether witnessed or not There was no statistical difference in the studies with witnessed arrest and the studies including other criteria, i.e. whether witnessed or not (I2 0%, Table 3A). Outcomes in studies with initial shockable rhythm versus studies without limitation of initial rhythm Survival to hospital discharge also did not show a statistical difference between studies including initial shockable rhythm and

other studies including other criteria with all types of arrest rhythm (I2 0%, Table 3B). The benefit of ECPR in the studies limited to ‘witnessed arrest or initial shockable rhythm’ was not different from studies without limitation of being witnessed and initial rhythm (I2 38.8%, Table 3C). Outcomes in studies limited to presumed cardiac etiology of arrest versus all etiologies There was no difference in relative ratio of survival to hospital discharge in the studies with arrest cases limited only to presumed cardiac etiology compared to those that included all reversible etiologies (I2 0%, Table 3D). Outcomes in studies limited to CPR duration over 10–20 min versus without limitation of CPR duration Comparing these studies, the benefit of ECPR was different in studies without any limitation of study population (I2 90.8%, Table 3E). Discussion In a meta-analysis using only studies that included propensitymatched data, the survival to discharge of ECPR showed a rate twice as high as compared to CCPR. The analysis of survival outcome, when stratified by time interval, showed ECPR maintaining a beneficial effect, at 3–6 months after arrest, in overall studies. ECPR also demonstrated superior neurological outcomes over CCPR. The 3–6 month post-arrest outcome was markedly better than at discharge in the ECPR group. This can be especially significant because the time of discharge was not consistent across the patient population, and therefore the 3–6 month post-arrest period may be a more objective metric of comparison. CCPR results in 25% of adequate cardiac output, and the rate of favorable neurologic outcome, as well as survival discharge, decreases according to the prolongation of cardiopulmonary resuscitation (CPR) duration.3,31 As ECPR provides sufficient perfusion to vital organs such as the brain and the injured

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Fig. 3. Forest plot of studies with propensity-matched data, reporting survival outcome stratified by location of arrest. (A) Forest plot of studies reporting survival to discharge in OHCA and IHCA. (B) Forest plot of studies reporting survival at 3–6 months after arrest in OHCA and IHCA.

myocardium, the window for effective resuscitation duration can be extended.26 ECPR may also increase long-term survival by ensuring adequate oxygenated blood delivery to vital end-organs until effective cardiac output has been recovered, thus preventing organ failure.32 In analysis using propensity-matched data, ECPR showed lower survival to discharge rates in OHCA when compared to IHCA (Fig. 3A). Although ECPR showed a tendency for beneficial results with moderate heterogeneity when compared to CCPR, the beneficial effect of ECPR compared with CCPR in OHCA patients was not clear for survival to discharge. However, ECPR demonstrated a 3–6 months survival rate that was double that of CCPR with low heterogeneity in both OHCA and IHCA. These results were similar to results of the ILCOR systematic review.33 While survival to hospital discharge rates in CCPR are known to be less than 10% and 20% respectively, for OHCA and IHCA,1–4

the survival rates of ECPR were reported at 4–36% of adult OHCA, and 34–46% for adult IHCA.13,20,34 The favorable outcomes of ECPR for IHCA have been reported,18,35–38 but several recent studies report conflicting experiences with ECPR in cases of OHCA similar to our results.16,23,26,39 Certain comparative studies of ECPR outcomes in OHCA and IHCA reported that there tended to be more benefit of ECPR in IHCA.11,13 However, such reports compared outcomes of ECPR in OHCA versus IHCA, and did not study the benefit of ECPR when compared with CCPR. The studies of Wang and Kagawa showed no difference of survival or neurologic outcome between OHCA and IHCA, despite tendencies of more chronic pre-existing comorbidities and older age in IHCA, and less pre-existing diseases, younger age, longer noflow and low-flow duration, more cardiac etiology of arrest, and prehospital emergency medical system variables, in OHCA.10,40 The effect of ECPR at survival to discharge in OHCA may not

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Fig. 4. Forest plot of studies with propensity-matched data, reporting good neurologic outcome stratified by location of arrest. (A) Forest plot of studies reporting at discharge in OHCA and IHCA. (B) Forest plot of studies reporting at 3–6 months after arrest in OHCA and IHCA.

be clear due to many influencing factors, when compared with IHCA.33 The benefit of ECPR in a good neurologic outcome at discharge was more pronounced in OHCA than in IHCA, even though ECPR at survival to discharge in OHCA was not clearly beneficial compared with CCPR. It may originate from different patient characteristics of OHCA patients, who are generally of younger age, less chronic comorbidities and more sudden cardiac origin of etiology in OHCA, when compared with IHCA patients.10,40 Candidate selection for ECPR are important factors for comparability between ECPR and CCPR to evaluate beneficial effect of ECPR. The magnitude of the ECPR effect is more dependent on patient characteristics and prehospital variables which contribute to candidate selection, not less on location of arrest. The beneficial effect of ECPR on good neurologic outcome tended to be higher than on survival outcome, especially at 3–6 months after arrest. It is similar to several

reports that survivors of ECPR, especially in study population with therapeutic hypothermia, had tendency of excellent neurological outcome. 16,32,41 Our comparative studies limited inclusion based on factors such as CPR duration (over 10–20 min), witnessed arrest, initial shockable rhythm, or presumed cardiac etiology. The detailed indications of ECPR, as well as inclusion criteria of study populations, differ across various studies. Common contraindications of ECPR were cases with severe trauma, terminal malignancy, severe irreversible neurologic deficit, arrest due to irreversible causes, incurable chronic disease and DNAR cases. Variable, flexible indications were applied to select patients for ECPR, especially in OHCA. We conducted subgroup analysis, stratified by inclusion criteria of the study population to identify conditions that lead to ECPR candidates with better outcome. The report of Kim et al. used both crude data and propensity-matched

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Table 3 Analysis of subgroups in studies using crude data.

data, and the crude data included a diverse non-trauma OHCA study population without limitation.24 Subgroup analysis based on the crude data of Kim’s study may compare the relative beneficial effect of ECPR in studies with strict patient selection criteria.24 Predefined inclusion criteria was defined as witnessed arrest, initial shockable rhythm or CPR duration. Witnessed arrest and shockable rhythm can be interpreted as brief no-flow durations or presumed cardiac etiology of arrest. The beneficial effects of ECPR in the study without any selection criteria were not shown in subgroup analysis. Although critical, definite differences were not shown in the subgroup analysis, certain preferences for ECPR candidate selection may be derived from the analysis. There was no difference in groups limited to one criterion and in groups without limitation of defined criterion; there was no single criterion that was a dominant factor in determining outcome. The studies with selection criteria regardless of any type showed the benefit of ECPR. ‘Presumed cardiac arrest’ can be an ambiguous term, and so the 2014 update to the Utstein resuscitation registry recommends etiology to be reported as medical (presumed cardiac or unknown other medical etiology), traumatic, drug overdose, drowning or electrocution.42 Reversible causes of cardiac arrest can be difficult to recognize, especially in OHCA cases. The etiology of the arrest must be carefully evaluated when selecting ECPR patients for possible contraindications. It is also important to begin early,

multifaceted approaches to correct underlying causes after ECPR implementation.41 CPR duration in particular, which is representative of lowflow time, can serve as an index to explain the refractoriness to CCPR.31,43 The probability of survival to discharge, especially with a good neurologic outcome, tends to decrease with longer CPR durations (>16 min in only CCPR).3,44 ECPR cannot replace CCPR, but alternative resuscitative strategies such as ECPR are needed to increase probability of survival with good neurologic outcome, after prolonged CPR.3,45 CPR duration > 10 min in IHCA and >15–30 min in OHCA were defined as selection criteria in our studies despite the lack of clear evidence. Although the pertinent indications have not been established, considerations for factors including brief CPR duration, witnessed arrest or initial shockable rhythm are necessary when performing candidate selection.46 ECPR may be considered in patients with brief no-flow time and a reversible cause of cardiac arrest, and recent recommendation is focused on selecting patients with suspected potentially reversible etiology during a limited period.6,47,48 Limitations Our study has several limitations as the small numbers of observational studies with possibility of unbalanced confounders

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were included. We attempted to use high quality studies with propensity-matched data as much as possible, however, it is necessary to consider limitations with insufficient number of study and heterogeneity in clinical application. International guidelines on CPR change every 5 years, and we attempted to identify differences in CPR application according to guideline updates. However, the period of studies could not be strictly stratified according to cutoffs of 2005 and 2010, and furthermore there were no detectable alterations in the outcomes of ECPR versus CCPR cases over time attributable to guidelines updates. As medical centers with the facilities and resources for ECPR have a higher likelihood to provide high quality of care, the effect of ECPR may induce bias toward better outcome in included studies, and this effect must be considered in evaluating the benefit of ECPR. Also, the differences in the availability and quality of ECPR teams, hospital facilities, infrastructure, emergency response system, the characteristics of patients undergoing arrest, the systematic accessibility to ECPR (healthcare insurance, cost, underlying local cultural background) could all play a role despite the use of propensity score matching.49

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Conclusions ECPR may give a chance for better survival and neurologic outcome than CCPR, especially at 3–6 months and location of arrest, although the beneficial effect of ECPR on survival to hospital discharge in the studies with OHCA were not clearly shown. To predict better outcomes of ECPR over CCPR, rigorous criteria for candidate selection are necessary. Strict limited inclusion and a multifaceted approach with ECPR experts to develop evidence-based standardized protocols will be necessary in the future. Conflict of interest statement The authors declare that they have no competing interests. Acknowledgments We would like to thank Eusang Ahn for the assistance in English proofreading. Financially nothing to be declared. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.resuscitation. 2016.01.019. References 1. Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-ofhospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2010;3:63–81. 2. Meaney PA, Nadkarni VM, Kern KB, Indik JH, Halperin HR, Berg RA. Rhythms and outcomes of adult in-hospital cardiac arrest. Crit Care Med 2010;38:101–8. 3. Reynolds JC, Frisch A, Rittenberger JC, Callaway CW. Duration of resuscitation efforts and functional outcome after out-of-hospital cardiac arrest: when should we change to novel therapies? Circulation 2013;128:2488–94. 4. Goldberger ZD, Chan PS, Berg RA, et al. Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study. Lancet 2012;380:1473–81. 5. Travers AH, Rea TD, Bobrow BJ, et al. Part 4: CPR overview: 2010 American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S676–84. 6. Cave DM, Gazmuri RJ, Otto CW, et al. Part 7: CPR techniques and devices: 2010 American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122:S720–8. 7. Brown KL, Dalton HJ. Extracorporeal cardiopulmonary resuscitation: ECPR. In: Annich GM, editor. ECMO extracorporeal cardiopulmonary support in critical

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