Extracorporeal Cardiopulmonary Resuscitation

Evidence and Implications

Background: Around the world, survival rates after cardiac arrest range between <14% for in-hospital (IHCA) and <10% for out-of-hospital cardiac arrest (OHCA). This situation could potentially be improved by using extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (CPR), i.e. by extracorporeal cardiopulmonary resuscitation (ECPR).

Methods: A selective literature search of Pubmed and Embase using the searching string ((ECMO) OR (ECLS)) AND (ECPR)) was carried out in February 2023 to prepare an up-to-date review of published trials comparing the outcomes of ECPR with those of conventional CPR.

Results: Out of 573 initial results, 12 studies were included in this review, among them three randomized controlled trials comparing ECPR with CPR, involving a total of 420 patients. The survival rates for ECPR ranged from 20% to 43% for OHCA and 20% to 30.4% for IHCA. Most of the publications were associated with a high degree of bias and a low level of evidence.

Conclusion: ECPR can potentially improve survival rates after cardiac arrest compared to conventional CPR when used in experienced, high-volume centers in highly selected patients (young age, initial shockable rhythm, witnessed cardiac arrest, therapy-refractory high-quality CPR). No general recommendation for the use of ECPR can be issued at present.

Globally, survival rates after cardiac arrest range between <14% and <10% for in-hospital cardiac arrest (IHCA) and for out-of-hospital cardiac arrest (OHCA), respectively (1, 2).

In Germany, the annual incidence of cardiac arrest exceeds 60 000 cases (3). Survival to discharge from hospital continues to be low; for out-of-hospital cardiac arrest, it is under 10% (1).

Extracorporeal systems have already been used in the past to restore circulation in an effort to improve survival (4, 5, 6). Extracorporeal cardiopulmonary resuscitation (ECPR) has been defined as resuscitation from cardiac arrest using venoarterial extracorporeal membrane oxygenation (VA ECMO). Given that in this case, ECMO placement is performed under resuscitation conditions, a high level of professional expertise and increased material resources are required (7).

With the publication of INCEPTION in 2023, ARREST in 2021 and HYPERINVASIVE in 2022, three randomized controlled trials (RCTs) with significant numbers of patients are now available, comparing cardiopulmonary resuscitation (CPR) with ECPR in the OHCA patient population (8, 9, 10).

In this review, we compare and interpret data on the effect of ECPR on survival after cardiac arrest with conventional Advanced Life Support (ALS) data. In addition, we define patient groups most likely to benefit from ECPR.

Physiology and complications of treatment with venoarterial ECMO

VA ECMO involves percutaneous puncture of the inguinal blood vessels and placement of large-bore cannulas. Blood is drained from the inferior vena cava, pumped through an oxygenator and reinfused into the systemic circulation via the femoral artery. Given the large foreign surface area, systemic continuous intravenous anticoagulation is mandatory. VA ECMO creates an artificial retrograde aortic blood flow (Figure 1).

Figure 1

Therapeutic principle of peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO)

During circulatory failure in the absence of cardiac ejection, ECMO can transport oxygenated blood to the coronary arteries and cerebral blood vessels, substituting 100% of the cardiac output (depending on the size and weight of the patient), whereas a maximum of 20% to 25% of the cardiac output can be generated when using manual chest compressions alone (11). In most cases, hemodynamic stabilization of the patient is achieved by VA ECMO, allowing to perform additional diagnostic studies (for example, coronary angiography).

The most common complication of peripheral VA ECMO is bleeding at the cannulation site, potentially occurring in about 21% to 40% of cases (12). In addition, the rate of thrombosis may be increased in about 15% of cases, with associated risk of ischemic stroke (13, 14).

Furthermore, placement of large-bore cannulas in the inguinal blood vessels is associated with an increased risk of vascular complications, such as perforation, dissection, pseudoaneurysm formation, and lower-limb ischemia, in up to 17% of cases (15, 16, 17). Most notably, acute lower-limb ischemia following cannulation is a fatal complication and may result in amputation of the affected limb in up to 5% of cases (18).

Further complications of VA ECMO include local infection (7%–20 %) (19), Harlequin syndrome (reduced oxygen supply to specific regions of the body) (20) and acute renal failure in up to 60% of cases (21).

Endpoints for evaluation of extracorporeal cardiopulmonary resuscitation

Survival is the endpoint typically used to evaluate the success of an intervention in patients with cardiac arrest. However, survival alone is not an adequate measure of successful treatment outcome. Therefore, it is important to assess the neurological status of survivors, using neurological function-related indices such as the Cerebral Performance Categories (CPC) scale and the Modified Rankin Score (mRS) (22). Both tools allow to assess a patient using a multi-level scale (CPC 1; no or minimal neurological impairment; CPC 2: slight neurological impairment; CPC 3: severe neurological impairment; CPC 4: persistent vegetative state; CPC 5: dead). The mRS scale consists of seven levels, ranging from 0 (no symptoms) to 6 (dead).

Regrettably, however, these scales are not consistently applied in the literature.

According to a large US analysis of approximately 600 000 cases of OHCA, the proportion of patients potentially eligible for ECPR is 1.7% to 3.7% of all cases (23). Applied to Germany, this would correspond to 1080 to 2256 patients per year. This underscores the relatively low rate of potential ECPR candidates compared to the total number of cases of cardiac arrest.

Methods

A selective literature search of Pubmed and Embase using the search string ((ECMO) OR (ECLS)) AND (ECPR)) was carried out in February 2023 to prepare an up-to-date review of relevant studies comparing the survival rates of conventional CPR with those of ECPR by direct group comparison. The initial search generated a total of 573 hits. First, case reports and reviews were excluded. Studies primarily analyzing populations of hypothermic patients, trauma patients and other patients with circulatory instability not primarily related to cardiac causes were excluded

Relevant studies not identified by our search string but cited in the references of identified studies or reviews were also included. Subsequently, the included studies were reviewed by two authors (CG and ML) independently and assessed for their relevance based on their title, abstract and, if necessary, by content of the manuscript. The two lists were then reconciled. Studies listed by one reviewer only were included or excluded by consensus. A total of 12 studies were eligible for inclusion in our review (Table 1).

Table 1

Current evidence on the basis of selected published studies

Levels of evidence and risk of bias

Apart from the three randomized controlled trials (RCTs), which randomized a total of 420 patients (ECPR = 209, CPR = 211), the available literature consists of retrospective studies.

In the retrospective studies, the risk of bias was consistently appraised as “critical” due to confounding and that of the RCTs as “moderate“ due to the lack of blinding of the patients to the treatment. Thus, when looking at the available studies collectively, it can be clearly stated that the overall level of evidence related to ECPR is low (24, 25).

Evidence 

In-hospital cardiac arrest (IHCA)

To date, no prospective RCT on the use of ECPR in patients with IHCA has been published. Table 1 presents a selection of the most important retrospective observational studies. Chen et al. analyzed ECPR in 135 IHCA patients and reported an overall survival of 34.1% (30.3% when limited to CPC 1 or CPC2) at the time of discharge from hospital (5). The average manual cardiopulmonary resuscitation duration until ECMO (low-flow time) was 55.7 ± 27.0 minutes.

Propensity score matching was performed based on the findings of the initially conducted study to analyze the potential benefits of ECPR (6). After propensity-score matching, survival to discharge in patients with CPC 1–2 was 23.7% for ECPR compared to 10.6% for CPR. Analysis of the 46 matched pairs found a significantly higher survival-to-discharge rate among patients treated with ECPR (hazard ratio [HR]: 0.51; [95% confidence interval: 0.35; 0.74]; p<0.0001). However, the proportion of patients who underwent percutaneous coronary intervention (PCI) was higher among ECPR patients (17.4% ECPR versus 6.5% CPR).

An analysis by Shin et al. showed that with 20% versus 5% the 2-year survival rate for ECPR (n = 85) was higher compared to CPR (n = 321) (16). In the ECPR group, younger age, shorter low-flow time and subsequent cardiac intervention were associated with more favorable outcomes.

In a meta-analysis, 195 pairs were assessed by propensity score matching. An absolute risk difference of 13% in favor of ECPR was found for neurologically intact 30-day survival (26).

Based on a dataset of more than 1000 patients, Tonna et al. developed a risk score for the use of ECPR in patients with IHCA and demonstrated that time of day when resuscitation occurred, presence of a shockable rhythm, normal renal function, and postoperative cardiac surgical status, as well as short resuscitation duration were associated with a survival benefit (27).

Out-of-hospital cardiac arrest with in-hospital ECMO placement

A total of three RCTs evaluating the efficacy of ECPR in OHCA have been published to date (Table 1).

Published in 2020, ARREST (8), conducted in Minneapolis, was the first RCT comparing ECPR with conventional CPR. Randomizing 30 patients, the study showed that ECPR (n = 15) was superior to CPR (n = 15) in respect of neurologically intact survival at six months. The study was terminated early by the competent monitoring authority in the light of the significantly increased survival rates with ECPR (43% versus 7%; risk difference 36.2 percentage points, [3.7; 59.2]) and rates of CPC 1–2 at three and six months.

Likewise, HYPERINVASIVE compared ECPR (n = 124) with conventional CPR (n = 132) in OHCA (9). While the authors from Prague did not find a statistically significant difference for survival at the time of discharge in the overall cohort (22% CPR versus 31.5% ECPR, p = 0.09), they showed that the proportion of patients with CPC 1–2 was significantly greater after ECPR (18.2% versus 30.6%; p = 0.02) and that ECPR was additionally associated with a significant survival benefit in patients who underwent prolonged (>45 minutes) resuscitation (20 survivors versus 6 survivors, p = 0.018). In view of the intention-to-treat protocol, it should be noted when interpreting these results that 11 of 124 patients who were initially assigned to the CPR group nevertheless received ECMO treatment but were still counted as part of the CPR group in terms of the primary end point. In addition, it is important to note that in HYPERINVASIVE the survival rate of patients with conventional CPR after OHCA was high (22%; international comparison: <10%).

In January 2023, Suverein et al. published the first multicenter RCT, INCEPTION, comparing ECPR with conventional CPR at ten centers in the Netherlands (10). After inclusion of 160 patients, a non-significant survival benefit was found for ECPR at 30 days (odds ratio [OR] 1.4; [0.5; 3.5]; p = 0.52). The mean time from resuscitation event to ECMO treatment was 74 [63; 87] minutes, compared to 61 [55; 70] minutes in HYPERINVASIVE and 59 [31; 87] minutes in ARREST. In addition, the reported rate of failed cannulation attempts (13.7%) was comparably high. The authors attributed this to differences in team experience, logistics and case numbers at the various centers (INCEPTION: 2.82 patients per year; HYPERINVASIVE: 26.9; ARREST: 36). The authors acknowledged that no mandatory treatment protocol was in place for rescue services and hospital staff.

Out-of-hospital cardiac arrest with prehospital ECMO placement

Some centers attempted to implement ECMO already in the out-of-hospital situation to address the challenge of reducing the low-flow time until ECMO initiation. The largest related study was conducted in Paris and compared ECPR (n = 525, of these 136 with prehospital ECMO) with conventional CPR (n = 12 666). It found no significant difference in survival at the time of hospital discharge (8.4% versus 8.6%; no survival difference at the time of discharge between prehospital and in-hospital ECMO placement) despite significant differences between the two patient groups (ECPR patients were younger and had higher rates of bystander CPR and initial shockable rhythm) (17). The authors attributed the finding that ECPR did not offer a significant survival benefit over CPR to comparably longer resuscitation times and a lower rate of return of spontaneous circulation (ROSC) events as well as patient selection in the ECPR group.

The lack of a positive result highlights the limitations of prehospital ECMO placement in OHCA in a real-world situation, including the complexity of logistics and the need for appropriate patient selection.

Which patient groups may benefit from ECPR?

The studies discussed above identified factors that were associated with a poorer prognosis for survival in patients with ECPR: older age, prolonged low-flow time and initial non-shockable rhythm (Box) (6, 16, 17, 28, 29).

Box

Overview of exemplary inclusion criteria for ECPR, according to the 2021 ELSO Consensus Statement

A pooled subgroup analysis of ARREST and HYPERINVASIVE data showed that patients with prolonged CPR (low-flow time ≥ 45 minutes) significantly benefited from ECPR (30).

Further factors associated with improved 180-day survival in both groups include: male sex, age 55 years and older, initial shockable rhythm (ventricular fibrillation or ventricular tachycardia) and witnessed cardiac arrest (30). This had already been shown in retrospective studies (31, 32). About one-third of patients from ARREST and HYPERINVASIVE with low-flow times of 60 minutes, were still alive 180 days after study inclusion.

These data show that the initial ECG has a comparatively high predictive power for the neurologically intact survival of patients requiring resuscitation. None of the published RCTs showed a positive effect of ECPR on initial non-shockable rhythms (asystole and pulseless electrical activity).

In both ARREST and HYPERINVASIVE, about 95% of patients with no initial shockable rhythm died, regardless of group assignment. Given the comparatively poor prognosis, the decision to use ECPR in patients with initial non-shockable rhythm should be made on a case-by-case basis; so far, no general recommendation for a specific patient group can be made (30).

Based on their retrospective analysis, Lunz et al. also concluded that the consistent application of strict inclusion criteria for ECPR (age ≤ 65 years, cardiac arrest with bystander CPR, no severe comorbidities, and the ability to initiate ECMO within one hour of cardiac arrest) is associated with a potentially doubled chance of survival (initially 19%, after application of selection criteria 38%, corresponds to 105 of 423 patients) (28).

These findings suggest that it may be possible to achieve improved survival without neurological impairment with ECPR despite prolonged low-flow time. However, these results show strong correlation with patient- and center-specific factors (31).

Ethical questions

The increasing use of ECMO systems, however narrowly indicated, will drive up the numbers of patients for whom there is no realistic prospect of recovery (“bridge-to-nowhere”). Conventional CPR may be discontinued, if these efforts are deemed futile. Possibly, ECPR should be considered an extension of CPR and hence be entitled to the same discretion. ECMO therapy can be terminated by the medical staff or the treatment team if a neurologically intact outcome and self-determined life cannot be achieved. However, it is virtually impossible to adequately predict permanent neurological functional impairment after cardiac arrest and the level of evidence of the published studies on the topic is particularly low (33).

Availability of resources and system design

The resources required to establish a successful ECPR program are considerable and comprise access to equipment (Table 2) as well as availability of specialized staff. The site where ECPR is performed—either in an in-hospital setting (emergency department, operating room, catheterization laboratory, intensive care unit, ward) or an out-of-hospital setting (Figure 2)—is crucial for staffing and the selection and storage of the required material. A position paper has already been published with a detailed description of the resources required (34). Centers performing ECPR in OHCA should have protocols in place that define the responsibilities of the rescue services and the receiving hospital to accelerate ECPR when the patient has arrived in the emergency department or catheterization laboratory. For example, in Germany, interdisciplinary treatment pathways, the definition of minimum standards and quality controls in the CPR procedure are already put in place in the context of the certification of Cardiac Arrest Centers by the German Resuscitation Council (GRC). By the end of 2022, more than 100 hospitals had already been certified (35).

Figure 2

Flow chart of ECPR

Table 2

Technical overview of the most frequently used ECMO systems in Germany

In addition, the lack of monitoring technologies and the consequential lack of specific therapeutic strategies after ECMO placement is a major challenge in the management of these patients and subject of current research (36).

Conclusions

Overall, the conclusion can be drawn that significantly higher survival rates are possible in highly selected patient populations (young age, initial shockable rhythm, witnessed cardiac arrest, refractory high-quality CPR) with the use of ECPR in experienced centers. However, no general undifferentiated recommendation for the use of ECPR in OHCA can be issued at present. The further establishment of specialized care structures and the continuous patient-specific advancement of ECPR therapy appear particularly desirable and promising with regard to the future quality of care for post-resuscitation patients.

Conflict of interest statement
JSP is the inventor of a resuscitation manikin designed for eCPR training (DE 10 2020 202 272 and DE 10 2018 120 960; proprietor: Resuscitec GmbH). While conducting basic experimental research on cerebral perfusion during extracorporeal cardiopulmonary resuscitation, he received material support from Resuscitec GmbH, Raumedic AG and GS Elektromedizinische Geräte G. Stemple GmbH. There is also a research grant from the German Research Foundation (DFG) supporting the research described (PO 2520/1–1).

The remaining authors declare that no conflict of interest exists.

Manuscript received on 13 March 2023, revised version accepted on 4 August 2023.

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Dr. Christopher Gaisendrees, MD
Klinik und Poliklinik für Herzchirurgie,
herzchirurgische Intensivmedizin und Thoraxchirurgie, Uniklinik Köln
Kerpener Straße 62, 50937 Köln, Germany

Cite this as:
Gaisendrees C, Pooth JS, Luehr M, Sabashnikov A, Yannopoulos D, Wahlers T: Extracorporeal cardiopulmonary resuscitation—evidence and implications. Dtsch Arztebl Int 2023; 120: 703–10. DOI: 10.3238/arztebl.m2023.0189

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