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Use of Extracorporeal Membrane Oxygenation for Adults in Cardiac Arrest (E-CPR): A Meta-Analysis of Observational Studies

Cardarelli, Marcelo G.*; Young, Andrew J.†; Griffith, Bartley*

doi: 10.1097/MAT.0b013e3181bad907
Clinical Cardiovascular

Published data on the use of extracorporeal membrane oxygenation (ECMO) as a supportive measure during or immediately after cardiopulmonary resuscitation (CPR) in adults (older than18 years) shows mixed results. To assess the clinical outcomes of the use of ECMO in this modality and to look for predictors of mortality, we performed a meta-analysis (MA) of individual patients collected from observational studies. An electronic PubMed search restricted to English-language publications between 1990 and 2007, using a consensus restrictive criterion, retrieved 141 titles. After full text evaluation, 11 clinical series and nine case reports were considered appropriate and included in our MA. Data on 135 individually identified adult patients (male:female = 1.6:1) were collected. Median age for the group was 56 years (range 18–83), and the median ECMO run was 54 hours (range 0–3881). Overall survival to hospital discharge was 40% (54 of 135). The most common diagnosis leading to cardiac arrest was acute myocardial infarction (46 of 135 patients). Compared with the youngest group (17–41 years), odds ratio (OR) for mortality was higher for age group 41–56 years (OR 2.9 95%; CL, 1.6–8.2) and those older than 67 years (OR 3.4%; 95% CL, 1.2–9.7). Duration of ECMO support measured in days was also a predictor of mortality, with significant better outcome for those supported between 0.875 and 2.3 days (OR 0.2; 95% CL, 0.07–0.6). There was a negative trend in survival when manual CPR lasted >30 minutes without prompt ECMO initiation (OR 1.9; 95% CL, 0.9–4.2). This work confirms the expectations for a better survival when E-CPR is used in younger patients, for shorter periods of time and after expeditious implementation during or immediately after manual CPR. Neurologic sequelae and other major complications, although suspected to be high, are poorly described in the reviewed literature.

From the *Department of Surgery, University of Maryland, Baltimore, Maryland; and †Department of Surgery, Virginia Commonwealth University, Richmond, Virginia.

Submitted for consideration June 2009; accepted for publication in revised form July 2009.

Reprint Requests: Marcelo Cardarelli, MD, MPH, Division of Cardiac Surgery, 22 South Greene Street, Suite N4W94, Baltimore, MD 21201. Email: mcard001@umaryland.edu.

Since the original description by Bartlett et al.1 in 1976, indications for the use of extracorporeal membrane oxygenation (ECMO) have greatly expanded. One such indication has been the use of ECMO as a supportive therapy for manual cardiopulmonary resuscitation (CPR) in the presence of cardiac arrest in adults, a methodology also known as E-CPR. Much has been written about the use of ECMO within this context but little more than anecdotal case reports and brief clinical series are available in the scientific literature, and none recommend or discourage its deployment based on evidence-based criteria. Our review of the literature and meta-analysis (MA) had the primary objective of finding predictors of mortality for adult patients in these extreme conditions.

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Methods

Search Strategy

After a review and exemption by the institutional review board, we performed an electronic database search of PubMed from January 1990 to March 2007 with the following search terms: ECMO, extracorporeal life support (ECLS), heart arrest, resuscitation, cardiopulmonary resuscitation (CPR) and using the limit function for “humans.” One reviewer (A.Y.) read all 141 abstracts retrieved during the original search to identify articles appropriate for full text evaluation. When no abstract was available, the full article was reviewed. All selected articles, a total of 20 publications, that met the pre-established criteria were included.

Once an article was accepted for inclusion in the MA, individual patients were identified from each publication, and a unique identifier was assigned. Data on a number of variables (demographic, hospital course, and survival to discharge) were tracked and recorded for each individually identified patient.

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Inclusion Criteria

All case reports and observational studies reporting on adults (older than 18 years) treated with ECMO after a witnessed cardiac arrest were considered and individually evaluated.

We rigorously defined cardiac arrest as the need for chest compressions or defibrillation being administered for a nonperfusing cardiac rhythm.

Publications in languages other than English were excluded. Studies reporting out-of-hospital cardiac arrest and/or uncertainty regarding onset time of the cardiac arrest were not included. Studies describing the use of ECMO as an elective therapy for patients with deteriorating circulation but not in cardiac arrest were also excluded. To achieve further accuracy in our estimations, individual authors of articles that fell short of our inclusion criteria were contacted to request a full set of data for each patient. If, after contacting the author, the individual patient data was still insufficient to validate our statistical analysis, then those studies were dismissed.

Information on the authors, institution, population, and dates were checked to identify duplicate publications. Duplicated patients in consecutive reports from the same institution or author were excluded. Patient data not reported in the original article but available in the duplicated article was included without duplicating patients. Our search yielded 141 titles, leading to 68 abstracts considered appropriate for full text evaluation, of which 20 articles were included in the MA (11 clinical series and nine case reports).2–21 The most frequent reasons for exclusion were failing the predetermined inclusion criteria, patients younger than 18 years, and inability to obtain detailed patient information. For a bibliographic search explanation see Figure 1.

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Statistical Analysis

Unadjusted odds ratios (OR) of dying before hospital discharge were calculated using logistic regression with single independent variables. Those independent variables associated with hospital mortality were included in the development of a multiple logistic regression models (SAS System Software package). When needed, Student's t test was used for comparing mean values among groups.

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Rationale for Selection and Coding of Data

Because of the number of nonstandardized diagnoses reported in the included series and to facilitate analysis, we created a classification system with 15 diagnostic groups. Table 1 shows diagnoses and survival for all groups with n > 1 patient. Single case reports, although included in the MA, are not included in this table. Sex, ECMO relationship to a surgical procedure, ECMO deployment under 30′, ECMO modality (venous/venous or arterial/venous), presence of any complication, and survival to discharge were collected as dichotomous values. Age, weight, duration of CPR, ECMO timing, setup time, cannulation technique, cannulation site, setting of ECMO initiation, length on ECMO, and outcome were entered as continuous values. A list of all the variables collected and their data format is available in Table 2.

Variables for which information was lacking in a large proportion of the patients were not included in the MA. These included technique used for left heart decompression, reason for withdrawal of ECMO support, and ultimate cause of death.

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Results

Data from the 135 individually identified patients described in the included articles were abstracted into the MA (male:female = 1.6:1). All the included patients had in common treatment with E-CPR as a rescue modality after suffering a witnessed cardiac arrest.

Overall survival to hospital discharge for patients who underwent ECMO support after cardiac arrest was 40% (54 of 135). Survival was higher, although not enough to be statistically significant for females (46.5%).

Sixty-seven patients (49.6%) were successfully weaned from ECMO support, but only 54 of them were discharged alive from the hospital, with an attrition rate of 19.4% (13 patients) between ECMO discontinuation and discharge. Patients who were not discharged home after ECMO withdrawal included two patients on whom ECMO was used as a bridge to transplant and both were discharged alive. Four cases, where ECMO was used as a bridge to a ventricular assist device, had a 50% discharge home. The rest of the patients in the group either died while on mechanical support or had ECMO withdrawn because of major complications or family request.

Manual CPR in the 102 patients for whom data were available had a mean duration of 40 minutes (range 1′–180′). Some patients were placed on ECMO after a short period of CPR because of low cardiac output, despite recovery of cardiac rhythm. Although not statistically significant, there was a trend toward better survival for those who had CPR for <30′ before ECMO was instituted (OR 1.9; 95% CL, 0.9–4.2). In 21 patients, ECMO was initiated while full manual CPR was still in place, and 10 patients survived to hospital discharge (47.6%).

Median ECMO run was 54 hours (range 0–3881), with females having a significantly shorter run (p = 0.04). For the purpose of this analysis, duration of ECMO support was measured in days, and patients were divided into four equivalent groups. When evaluated in this fashion, the group sustained by ECMO between 0.875 and 2.3 days displayed a trend toward higher survival (61%) with lower OR for mortality (OR 0.2; 95% CL, 0.07–0.6) compared with the rest (Table 3).

Median age was 56 years (range 18–83). Age group was also a mortality risk. Patients for whom age was available (n = 133) were divided into four similar groups. Compared with group 1 (age 17–40), OR for mortality was significantly higher for group 2 (41–56 years) (OR 2.9; 95% CL, 1.6–8.2) and group 4 (older than 67 years) (OR 3.4; 95% CL, 1.2–9.7) and higher, although not significantly, for group 3 (Table 4).

The overall occurrence of complications was not well described in the articles included in our MA. Prevalence of major clinical complications was specifically mentioned in 15 of 135 patients, and absence of any complications was specifically addressed in only six patients. The existence of complications of any type was not addressed at all in the rest of the included patients (n = 114), seriously limiting our ability to draw any conclusions on that topic. According to data from studies other than those included in our MA, the occurrence of complications as a result of the use of E-CPR is a relatively common phenomenon. Frequent blood and blood products transfusions (47%), multiorgan system failure (30.4%), and an incidence of neurologic events of variable severity ranging between 5.6% and 17.5% seem to be the most commonly described complications.22,23

Information on the hospital setting at which E-CPR was initiated was available only for 82 patients. In most cases (50 of 82), E-CPR was started in the intensive care unit with only 12 survivors to discharge (24%). A second group of patients (n = 23) suffering from myocardial infarction or pulmonary embolization required emergency E-CPR to be instituted in the catheterization laboratory, and 10 of those patients survived to discharge (43.4%). A small group (n = 4) had ECMO implemented in the operating room with no survivors. Finally, a second small group (n = 5) needed E-CPR in the emergency department setting to treat deep hypothermia, acute myocardial infarction, and left internal mammary graft avulsion. Three patients (60%) survived to hospital discharge in this group. No significant conclusion could be drawn from the information on hospital setting because of small size of the samples and the variety of the initial diagnosis.

The information on the site of cannulation for ECMO and its relationship to survival was very limited in the majority of articles reviewed for this MA, and therefore no firm conclusion could be drawn. The only piece of solid information was that survival to discharge for 45 patients connected to ECMO through femoral cannulation was 55.5% (25 patients). For the purpose of comparison, we may speculate that all patients treated with E-CPR after postcardiotomy arrest (50% survival) were indeed cannulated through the sternotomy. If that was the case, the relationship between survival and cannulation site might be irrelevant.

The relationship between mortality and the diagnosis that originated the cardiac arrest was difficult to establish because of the large number of diagnoses and the low number of patients for many of those diagnoses. In the three largest groups, acute myocardial infarction (n = 46), pulmonary embolus (n = 21), and postcardiotomy arrest (n = 24), the rates of survival to discharge were 36.9%, 57%, and 50%, respectively.

Lower hospital survival (25% and 33%, respectively) was observed in a group of patients with cardiac arrest due to left ventricular rupture (n = 4) and a heterogeneous group of patients (n = 6) that included arrest due to nontraumatic pulmonary causes (adult respiratory distress syndrome, Werner granulomatosis, and Hanta virus). Except for cardiac arrest after a traumatic injury to the lungs (n = 6) with a survival of 50%, the results of E-CPR were rather dismal for other small groups. Viral cardiomyopathy (n = 7), acute heart transplant failure (n = 5), and arrest due to refractory arrhythmias (n = 3) had no survivors.

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Study Limitations

Meta-analyses based on observational studies are frequently unable to extract the patient's data without the inherent biases of the original studies, (i.e., the retrospective design in all the studies included in our MA).24 Another common problem affecting this form of MA is a phenomenon called ecological bias, a type of statistical error by which patients included in the MA may not be representative of the population subjected to similar treatment but not included in the MA.24 To assess our MA for ecological bias, we reviewed the results among 165 adult patients with cardiac arrest treated with E-CPR from studies not included in our MA and found an overall survival rate similar to ours (37.6%).22,25,26

Authors often reported on complications as a simple rate and without further specification or not at all. Studies included in our analysis had limited information on the specific complications, and therefore their occurrence should be looked as an underestimation.

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Discussion

Historically, survival for witnessed arrests has benefited from significantly better results than for nonwitnessed arrests (25% vs. 7%, respectively), likely due to a swift implementation of manual CPR.27 Overall survival to hospital discharge after cardiac arrest is significantly low (22.4%) even in series, showing a high initial CPR survival (48.3%).28 Because of these poor results, mechanical extracorporeal ventilation and support of the perfusion of end organs during cardiac arrest (E-CPR) have been advocated for improving hospital survival.

Early animal research indicated that the use of some form of extracorporeal circulation had the potential to become an effective intervention for resuscitation when conventional techniques of precordial compression and external defibrillation fail to reverse cardiac arrest.29

Similarly, the initial clinical results of the use of E-CPR in small groups of patients with reversible diseases were encouraging.30 Results of E-CPR were particularly hopeful in the pediatric arena, where the experience in the use of ECMO for rescue therapy started earlier.31

Although the use of E-CPR in adults has gained some momentum, its implementation has been based on personal experiences and the availability of vast technical and human resources, rather than evidence-based criteria.

In our review, duration of manual CPR before implementation of ECMO seems to behave as a limiting factor regarding the measured outcome. Our findings, although not statistically significant, show a negative trend on hospital survival as the length of manual CPR extends beyond the initial 30 minutes. A number of authors in the pediatric E-CPR literature have speculated that an expeditious institution of ECMO should shorten the duration of manual CPR consequently influencing clinical outcomes; however, none of those studies found a significant difference in the duration of manual CPR between survivors and nonsurvivors.32,33 Our findings regarding duration of manual CPR seem to be in accordance with those reported by Chen et al.25 and is not included in our MA. They reported a statistically significant difference in survival (p < 0.05) on adults treated with E-CPR depending on whether the manual portion of the CPR remained below or went above 60 minutes (survival rate of 48% and 11.5%, respectively).

Age stratification demonstrated a trend of lower mortality in the youngest adults. We might speculate that the relationship between age and mortality is likely the result of the relationship between the age of the patient and the specific diagnosis leading toward the cardiac arrest event, although we present no significant evidence on that regard. Although we verified a trend favoring hospital survival among a younger group of patients (mean 51.2 years), no statistically significant difference was evident (p = 0.09) when we compared them with those who did not survive to hospital discharge (mean 56 years). These findings are similar to those reported by Saito et al.26 who found no statistical difference (p = 0.86) in the survival rates of patients younger and older than 75 years (44.3% and 41.7%, respectively) treated with E-CPR. A larger sample size may be needed to observe the effects of age over mortality.

Mortality for those with cardiac arrest due to heart transplant failure (n = 5) was 100%. Although lacking statistical value because of the small number of cases, this outcome was surprisingly worse than we expected. Although the original studies did not expand on the subject, one potential explanation for the lack of recovery reserve seen in failed cardiac grafts could be the presence of pulmonary hypertension or the increasingly common use of marginal organs. Other authors have found E-CPR as a beneficial solution for failing cardiac grafts, although in the large majority of patients, it was instituted as a preventive rather than as an emergency measure.34

A possible critique to this type of study is the long timespan over which the included studies were published (1990–2007) and the ensuing changes in patient management and technology. To assess the impact of improvements in technology and critical care management, we divided the identifiable population from the included studies into two groups. Those treated with E-CPR between January 1990 and December 1998 (group I) with a total of 89 cases and those treated with E-CPR between January 1999 and March 2007 (group II), which included 41 cases. Survival to discharge was 30% for group I and 59% for group II (p < 0.001), confirming that recent technological and management changes have had a strong influence on hospital discharge.

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Conclusion

The use of E-CPR in the face of witnessed cardiopulmonary arrest in adults might increase the chances of leaving the hospital alive up to 40%. Survival seems to be improved when E-CPR is used in younger patients for shorter periods of time and after an expeditious implementation. Instances of cardiopulmonary arrest treated with E-CPR with the best chances of hospital survival were pulmonary emboli, trauma, and postcardiotomy arrest. Neurologic sequelae and other major complications, although likely high, are poorly described in the reviewed literature. Recommendations on how to improve the survival to hospital discharge for patients undergoing E-CPR should focus on shortening of ECMO deployment time and refining neuroprotective strategies. A dedicated team of experts available on a 24/7 basis and preprimed equipment on stand-by seem to answer the deployment issue.35 A rapid cooling protocol for patients undergoing manual CPR seems to be the best neuroprotective strategy available until ECMO can be initiated.36,37 Before embarking on the costly task of instituting an ECMO program for adults, healthcare systems should carefully evaluate the comparative effectiveness of E-CPR compared with manual CPR alone.

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