Cardiac arrest represents a major clinical problem that is associated with extremely high mortality. In the United States alone, over 300,000 out-of-hospital and over 200,000 in-hospital cardiac arrests occur on an annual basis according to recent estimates.1 Unfortunately, only approximately 10% of patients with out-of-hospital cardiac arrest survive.1 Survival is even more dismal when the duration of the arrest is prolonged.2
Conventional cardiopulmonary resuscitation (CPR) has been the cornerstone of initial management of cardiac arrest. In light of the dismal outcomes associated with cardiac arrest despite the use of conventional CPR, alternative modes of therapy have been sought. The use of extracorporeal life support (ECLS), and more specifically extracorporeal membrane oxygenation (ECMO), in the management of cardiac arrest is appealing because it provides immediate hemodynamic support after it is initiated, resulting in instantaneous delivery of oxygen and substrate to ischemic tissues. Ongoing support can be provided while the profound acidosis and other metabolic derangements that occur as a result of the arrest are corrected. Furthermore, myocardial stunning and pulmonary edema are common consequences of cardiac arrest, even if resuscitation is possible. Extracorporeal membrane oxygenation can provide support until the heart and lungs recover, thereby preventing ongoing organ injury and progression along the downward spiral of multisystem organ dysfunction. Finally, there is an underlying cause for every cardiac arrest. Since ECMO provides hemodynamic support and oxygenation, it provides a window of opportunity for the cause of the arrest to be sought out and treated, providing a potential critical step toward recovery.
In a meta-analysis published in 2009, Cardarelli et al.3 examined data available from studies published between 1990 and 2007 on the use of ECMO in adult patients suffering from a witnessed cardiac arrest. Studies reporting on out-of-hospital cardiac arrest were excluded. Their search yielded 11 clinical series and nine case reports. In aggregate, these publications provided data on 135 patients. The median age of this group of patients was 56 years, ranging between 18 and 83 years old. The overall survival to hospital discharge was 40%. The authors found that younger patients had significantly better survival than older patients and there was a trend toward worse survival in patients that underwent prolonged CPR (greater than 30 minutes) before the initiation of ECMO. Complication rates and neurologic outcomes were not well documented. While subject to the inherent limitations of this type of study, this meta-analysis suggested that the use of ECLS-assisted CPR (ECPR) could potentially serve as a useful adjunct to conventional CPR, particularly in young patients and when extracorporeal circulation was expeditiously instituted.
In another study published in 2009, data on adult patients that underwent ECPR between 1992 and 2007 were extracted from the Extracorporeal Life Support Organization (ELSO) registry, an international database that collects data from ECMO centers on a voluntary basis.4 Data on 295 patients were analyzed. This data represented 11% of ECMO uses reported to the ELSO registry over that period of time. The median age was 52 years and the majority of patients were males. Cardiac disease was the most common cause of arrest, including acute myocardial infarction, cardiomyopathy, and myocarditis. Pulmonary embolus, respiratory disease, and accidental injury caused the majority of the remaining arrests. Survival to hospital discharge in this retrospective analysis was 27%.
ECPR for In-Hospital Cardiac Arrest
In the time since these retrospective studies were performed, the published literature has evolved substantially, including publication of larger prospective trials of ECPR in both in-hospital and out-of-hospital cardiac arrest (Table 1). The first trials focused on patients with in-hospital cardiac arrest. In 2008, Chen et al. 5 published a prospective observational study that utilized propensity matching to compare survival to hospital discharge of patients that underwent ECLS-assisted CPR compared with those that underwent conventional CPR from 2004 to 2006. The trial included patients 18 to 75 years old with a witnessed arrest of presumed cardiac origin that underwent CPR for longer than 10 minutes. Patients were excluded if they had pre-existing severe neurologic injury, terminal malignancy, trauma complicated by uncontrolled hemorrhage, do-not-resuscitate (DNR) order, or the inability to wean from cardiopulmonary bypass. The decision to call for ECLS was made by the attending physician running the code. The average duration from call to ECMO team arrival was 5–7 minutes during the day and 15–30 minutes at night. Hypothermia as an adjunct to postarrest care was not employed in this study. A total of 59 patients were included in the ECPR group and 113 in the conventional CPR group. In an analysis of unmatched patients, those receiving ECPR were more likely to survive to discharge than patients treated with conventional CPR only (28.8% vs. 12.3%). This survival benefit was statistically significant at discharge, 30 days, and 1 year. To account for baseline differences in the two groups, propensity matching was performed and 46 patients were included from each group (either ECPR or conventional CPR). After propensity matching, survival analysis demonstrated superior survival in the ECPR group compared with the conventional CPR group at both 30 days and 1 year. A multivariate regression analysis of the raw data demonstrated that factors associated with survival included ventricular tachycardia (VT) or ventricular fibrillation (VF) as the initial rhythm, as opposed to pulseless electrical activity (PEA) or asystole, and use of ECPR. A longer duration of CPR was negatively associated with survival. While this was not a randomized trial, this study provides a direct, prospective comparison of ECPR versus conventional resuscitation alone for patients suffering from in-hospital cardiac arrest at a single center. Despite its nonrandomized nature, the use of both propensity matching and a multivariate regression analysis strengthen the authors’ findings. The use of these techniques is particularly important given the differences in both the baseline characteristics and subsequent interventions of the patient populations studied.
In a single center retrospective observational study, Shin et al.6 analyzed 406 adult patients between 18 and 80 years old with in-hospital cardiac arrest that underwent either conventional CPR or ECPR after 10 minutes of refractory arrest between 2003 and 2009. Patients with neurologic injury, intracranial hemorrhage, malignancy, trauma, pre-existing irreversible organ injury, or DNR status were excluded. A total of 85 patients underwent ECPR and 321 underwent conventional CPR. The decision to initiate ECPR was made by the attending physician in charge of the arrest team. Clear criteria on the use of ECPR were not outlined. While this was a retrospective analysis, propensity matching was used to control for bias and confounding factors. After propensity matching, 60 patients were included in each group and baseline variables were well matched between the groups. Rates of survival to discharge and survival at 6 months with minimal neurologic impairment were superior in the ECPR group compared with the conventional CPR group. However, it should be noted that those in the ECPR group were more likely to undergo an intervention postarrest than those in the conventional CPR group, including percutaneous coronary intervention (PCI; 25.0% vs. 3.3%), which may have significantly influenced survival. A multivariate analysis was also used in an attempt to eliminate any residual bias. ECLS-assisted CPR was consistently found to be an independent predictor of survival at discharge and at 6 months. The large number of patients included in this study as well as the use of both propensity matching and a multivariate analysis are strengths of this study. However, it has a number of limitations. It is a retrospective, nonrandomized study from a single center. Despite the use of multivariate analysis and propensity matching, hidden bias may persist. Since the decision to employ ECPR was made at the discretion of the physician in charge, variables that were not measured or not included in the matching process may have factored into the decision. The authors acknowledge that did not adjust for variables that may be important, such as the response time of the CPR team. While their findings are credible, these limitations must be considered. Of note, in a later publication examining the same patient population, the authors found that the survival benefit of ECPR persisted at a 2 year time interval.10
ECPR for Out-of-Hospital Cardiac Arrest
Compared with in-hospital cardiac arrest, the circumstances associated with cardiac arrests that occur in the community provide additional challenges. The time from the arrest until CPR is initiated may be longer in out-of-hospital cardiac arrest. The quality of the CPR may be more variable during out-of-hospital cardiac arrests, as trained providers may or may not be immediately available. Finally, the prehospital transport time may delay the initiation of ECPR. For these reasons, out-of-hospital cardiac arrest continues to represent a very difficult clinical problem and poses significant obstacles to the successful use of ECPR.
Wang et al.8 prospectively collected data on 230 patients that suffered a cardiac arrest and were treated with ECPR. Of these 230 patients, 31 of the arrests occurred outside of the hospital and 199 occurred in a hospital setting. The authors compared outcomes between patients undergoing ECPR who suffered in-hospital versus out-of-hospital cardiac arrest. As would be expected, the duration from the onset of the arrest to the initiation of ECMO was longer in the out-of-hospital cardiac arrest group compared with the in-hospital arrest group. Despite this longer duration, the authors found that survival to discharge and survival with a good neurologic outcome was similar in both groups. It should be noted that there were important differences in both baseline characteristics as well as the subsequent interventions that the patients underwent. The patients in the out-of-hospital group were younger, more frequently treated with postarrest therapeutic hypothermia, and more likely to undergo PCI. A multivariate analysis was performed and revealed that younger age, initial rhythm of VT or VF (as opposed to systole or PEA), and a shorter duration from onset of arrest to the initiation of ECLS were predictive of survival. This prospective analysis by Wang et al.8 suggests that similar survival can be achieved after out-of-hospital cardiac arrest compared with in-hospital cardiac arrest when ECPR is employed. Given the disparities that exist in the patient populations in this study, as well as the differences in the adjunct treatments that they received along with ECPR, further study will be required to more definitively establish this point.
In a retrospective study, Haneya et al.11 analyzed data on 85 consecutive patients that underwent ECPR. Of these patients, 59 had a cardiac arrest in the hospital and 26 suffered from an out-of-hospital cardiac arrest. Outcomes were compared between the two groups. The overall survival to discharge was 34.1%, with 42.4% of patients from the in-hospital group surviving and only 15.4% of patients in the out-of-hospital group surviving. As would be expected, the duration of CPR in the out-of-hospital arrest group was significantly longer than that of the in-hospital cardiac arrest group (70 vs. 25 minutes, respectively). A multivariate analysis was performed in this study and factors that were significantly associated with survival included short duration of CPR, lower serum lactate levels, and higher serum pH at the time of ECMO initiation. No direct comparison is made between the use of ECPR and conventional CPR in this study. Furthermore, in contradiction to the study by Wang et al.,8 this study suggests that survival after out-of-hospital cardiac arrest is worse compared with in-hospital cardiac arrest despite the use of ECLS. While the study by Haneya et al. 11 is admittedly smaller and data was collected retrospectively, the difference in the findings between these two studies highlights the need for more research on the use of ECPR for out-of-hospital cardiac arrest. Since no direct comparison is made between ECPR and conventional CPR for out-of hospital cardiac arrest in either study, it is impossible to draw conclusions about the benefit of ECPR over conventional CPR based on data from these studies.
In 2013, Maekawa et al. 7 published an analysis of a prospective observational study examining survival in 162 patients that suffered out-of-hospital cardiac arrest and underwent either ECPR or conventional CPR at a tertiary care center in Japan. Three-month survival with good neurologic outcome was the primary endpoint. Propensity matching was used and after matching, there were 24 patients in each group. The authors found better survival in the ECPR group (29.2%) compared with the conventional CPR group (8.3%). A Kaplan–Meier survival analysis demonstrated significantly better survival in the ECPR group at 3 months. Pupil diameter on hospital arrival was identified as a central predictor of survival in this analysis. In this direct comparison of ECPR to conventional CPR for patients with out-of hospital cardiac arrest, outcomes were more favorable when ECPR was employed. It should be noted that this trial was also not randomized. While propensity matching was used, the number of patients in the matched groups was relatively small.
In another study, by Sakamoto et al.,9 a comparison of ECPR versus conventional CPR alone for patient suffering from out-of hospital cardiac arrest was performed. This multicenter prospective observational study was conducted in Japan. A total of 46 hospitals were involved in the study. All hospitals involved in the trial were major medical centers with the capability of performing interventions such as PCI and therapeutic hypothermia. Each hospital was asked to conduct either ECPR (26 centers) or conventional CPR (20 centers) based on their usual operational strategy. Patients included in the study were adult patients with OHCA with VT or VF as their initial rhythm. Of note, unwitnessed arrests were included and only about half of the patients in each group received bystander CPR. A total of 454 patients were enrolled, with 260 in the ECPR group and 194 in the conventional CPR group. An intention-to-treat analysis demonstrated significantly better survival in the ECPR group compared with the conventional CPR group at 1 month (12.3% vs. 1.5%) and 6 months (11.2% vs. 2.6%). This trial represents one of the largest trials conducted to date to evaluate the effectiveness of ECPR. Furthermore, it provides a direct comparison of ECPR compared with conventional CPR for patients suffering from out-of hospital cardiac arrest. However, it also has several limitations. One major shortcoming of the study is that providing the choice of either ECPR or conventional CPR as the sole mode of therapy used at a particular center may introduce significant bias that cannot be corrected for with statistical techniques. Although the use of postarrest modalities was conducted according to protocol, a significantly greater proportion of patients in the ECPR group underwent therapeutic hypothermia and significantly more patients in the ECPR group underwent intraaortic balloon pump insertion. These limitations need to be considered when interpreting this data.
ECPR as a Component of a Cardiac Arrest Bundle
Another recent prospective observational trial involved ECMO as part of a bundled package of care for cardiac arrest patients.12 The bundle in this trial, referred to as the “CHEER trial” consisted of mechanical CPR, therapeutic hypothermia, ECMO, and early coronary angiography, and PCI if indicated. More specifically, mechanical CPR was delivered with an Autopulse device (ZOLL, Chelmsford, MA). Hypothermia was initiated with 2 L cooled saline immediately followed by maintenance at 33°C for 24 hours. Percutaneous femoral cannulation for veno-arterial ECMO was performed in the emergency department. Interestingly, small cannulas were employed (17 French and 15 French) and ECMO flows of only 3 L/minute were utilized. Early consideration was given to coronary angiography or CT angiogram. This was a smaller trial with a total of only 26 patients, of which 15 suffered an in-hospital cardiac arrest and 11 patients suffered an out-of-hospital cardiac arrest. There were nine survivors (60%) from the in-hospital cardiac arrest group and five (45%) from the out-of-hospital group. It should be noted that two of the out-of-hospital survivors had return of spontaneous circulation (ROSC) before ECMO support. These results are promising and warrant further investigation. However, this trial also has a number of important limitations. First, this trial was nonrandomized and there was no control group. In addition, the sample size was small. Finally, because a group of therapies were incorporated into a bundle, the contribution of any single component to the outcomes achieved is unclear.
Summary and Future Direction
Taken together, the results of these trials provide evidence that suggests that the use of ECPR may improve survival in appropriately chosen patients suffering a cardiac arrest. Collection of prospective data and the utilization of statistical methods including propensity matching and multivariate analyses strengthen these findings but cannot entirely exclude the possibility of bias. While the data from these trials is promising, at least one large randomized trial testing the hypothesis that ECPR improves survival in cardiac arrest will be required before it is broadly accepted and implemented.
Currently, randomized trials to evaluate the use of ECLS are in progress. In a single-center randomized trial that is being conducted in Vienna, Austria, adult patients with witnessed out-of-hospital cardiac arrest with immediate bystander CPR and without ROSC after 15 minutes are being randomized to two groups.13 One group will receive standard advanced cardiac life support (ACLS). The second group will undergo ACLS with the addition of a protocol involving ongoing resuscitation during transport to the emergency department and then emergent initiation of ECLS. Each group will consist of 20 patients. The rates of sustained restoration of circulation, survival to 24 hours, ICU discharge, and hospital discharge, as well as neurologic outcomes, will be compared between the groups.
In a multicenter, randomized trial currently being conducted in Prague, Czech Republic, adult patients with witnessed out-of-hospital cardiac arrest and without ROSC after 5 minutes of ACLS are being randomized to receive either standard therapy or an aggressive protocol including immediate initiation of CPR with a mechanical compression device and intranasal cooling.14,15 According to this protocol, patients are then transported directly to the catheterization lab at a participating center and ECLS is initiated if no contraindications exist. After ECLS is initiated, the patients are cooled and invasive investigation is performed immediately. The primary outcome will be survival with minimal neurologic disability. The target enrollment is estimated at 170 patients. The results of both of these trials will undoubtedly be of great interest and are anxiously awaited.
In addition to data from randomized, controlled clinical trials supporting its use, a number of obstacles must be overcome for ECPR to achieve its potential as therapeutic modality. Strategies to achieve rapid and efficient cannulation and initiation of ECLS will need to be developed. The logistics behind ensuring that appropriate equipment and personnel are available must be worked out at each center offering ECPR. The optimal methods and protocols for reperfusion after cannulation, mechanical ventilation during ECLS, anticoagulation, and temperature management during ECLS will require ongoing refinement. Ongoing research into other areas of postarrest patient management is necessary to better care for patients that have undergone ECPR.
It is clear that there is a broad array of underlying pathologies that may cause or contribute to cardiac arrest. Furthermore, cardiac arrest may occur in diverse patient populations. Defining appropriate candidates that have the highest probability to benefit from ECPR will be a critical to the successful implementation of ECPR as a therapeutic modality. Current data indicate that younger patients, patients with VT or VF as the initial rhythm, and those with short duration of arrest before initiation of ECLS are most likely to survive (Table 2).5–7,10,11 By targeting the patient populations that are likely to benefit from ECPR, higher success rates can be anticipated. More emphasis on defining the patient populations that are most likely to benefit from ECPR will be of greater importance as health care resources become more limited. As global experience with ECPR continues to grow, the criteria used to choose patients as candidates for ECPR are likely to become more precisely defined.
When a cardiac arrest occurs, effective delivery of oxygen and metabolites to all organ systems ceases. Some organs, such as the kidneys, have an enormous capacity for recovery. In contrast, irreversible neurologic injury may be sustained rapidly if the brain is deprived of blood flow. To prevent catastrophic and potentially unrecoverable neurologic injury, as well as dysfunction of other organ systems, timely restoration of circulation in patients in cardiac arrest is critical. Accordingly, the duration between arrest and institution of ECLS has been identified as a key determinant of survival in several studies in the current literature.16 Given the importance of rapid establishment of circulatory flow, several pediatric centers have developed rapid response ECLS teams with good results.17–19 Important aspects of these rapid response teams include rapid notification and availability of team members, stocking and locating carts with materials necessary for cannulation in immediately available locations, and maintenance of ECMO circuits primed with crystalloid for immediate use. These features may prove useful for efficient institution of ECPR for adults as well.
A particularly important issue for the success of an ECPR program is the availability of providers skilled at cannulation and initiation of ECMO at all times. At many institutions, ECMO is initiated solely by cardiac surgeons or intensivists. One way to help ensure that skilled providers are available is to expand the pool of providers that are capable of cannulating patients. Initiation of ECMO by emergency physicians for patients with out-of-hospital cardiac arrest has been reported with good results.20 Training emergency physicians to cannulate patients and initiate ECMO not only provides an additional pool of specialists but also allows ECPR to be carried out by the providers first encountering patients with out-of-hospital cardiac arrest.
Given the poor results that some have observed with patients suffering from out-of-hospital cardiac arrest that are cannulated after reaching a hospital, prehospital ECLS has been explored as a potential alternative strategy.21–23 Initiation of ECLS in the field for cardiac arrest presents a number of additional challenges that must be considered. First, a triage system must be in place to identify appropriate candidates and dispatch a team capable of responding. To respond to a call, all equipment and materials must be available and transported to the scene, including items that would be immediately available in a hospital setting such as gowns, gloves, and drapes. In addition to these basic necessities, all of the equipment required for ECLS would need to be transported, including cannulas, wires, pumps, and oxygenators. Having back up equipment available would also be prudent in case of equipment failure, damage, or accidental contamination. Cannulation can be difficult in the setting of a cardiac arrest. In the field, it may be even more challenging. Lighting, patient positioning, and the surrounding environment may by suboptimal. As such, an experienced provider capable of both open and percutaneous approaches would be most ideally suited. Finally, transport of patients on ECLS can be dangerous. Accidental decannulation is a risk. Cannulas must be well secured to prevent this disastrous complication. In obese patients, even cannulas well secured at the level of the skin have the potential for decannulation; however, the use of longer cannulas may mitigate this risk. While the speed of this approach has appeal, both the feasibility and broad applicability of institution of ECLS in the field will require substantially more investigation.
Effective ECPR depends upon efficient institution of ECLS, an important component of which is cannula insertion. Delays in cannula insertion result in delays in restoring circulation. A cannulation complication, resulting in bleeding or arterial dissection, can be potentially disastrous, particularly in a patient that is in full arrest. Utilization of smaller cannulas may facilitate insertion and potentially reduce vascular complications. Recent data suggest that the use of smaller cannulas can be effective for veno-arterial ECMO in adult patients with cardiogenic shock or cardiac arrest.12,24 More research will be required to determine whether the use of smaller cannulas truly helps avoid vascular complications and whether they allow for adequate flow. One might envision the use of a hybrid procedure suite with advanced imaging capabilities for the initial treatment of cardiac arrest patients. In appropriately selected patients, cannulation could be carried out under fluoroscopy. Further diagnostic and potentially therapeutic procedures, such as coronary angiography and PCI, could then be performed immediately after instituting ECLS without the need to transport the patient throughout the hospital. Future research will also need to focus on the development of technology to facilitate cannula insertion to make the process faster, safer, and more broadly applicable.
While better identification of appropriate candidates for ECPR, rapid institution of ECLS, and safer and more efficient cannulation techniques are areas of potential investigation that may result in ongoing improvement in outcomes after ECPR, advances in care of the cardiac arrest patient before and post-ECLS will also lead to better outcomes. Before initiation of ECLS, effective conventional CPR is critical. It is clear that the timing and quality of CPR can impact survival in cardiac arrest patients. Mechanical CPR devices have been developed and have demonstrated promise in preclinical trials. However, clinical benefit in the use of automated devices to deliver CPR has not been definitively established.25–27 Therapeutic hypothermia has been considered as an important postarrest care modality for over a decade. With the publication of the Targeted Temperature Management trial by Nielsen in 2013, the optimal goal temperature for general postarrest patients has been questioned.28 It is difficult to extrapolate this data to the ECPR population and more research is needed to determine best practices. Determining which patients treated with EPCR will benefit from early PCI is critically important. Studies have shown that acute coronary occlusion is common in patients with sudden cardiac arrest and that immediate coronary angiography and PCI (as indicated) in patients with ST-elevation myocardial infarction (STEMI) is beneficial.29,30 Proper incorporation of PCI into ECPR algorithms, including appropriate timing, for patients both with and without STEMI is thus of significant importance. Understanding and implementing other optimal postarrest care targets including a standardized search for reversible causes and appropriate neurologic assessment and prognostication will also undoubtedly contribute optimizing outcomes after ECPR. Ongoing postarrest research, particularly in the areas of neuroprotection and neuroprognostication, may also prove to be of value.
Outcomes after cardiac arrest are unsatisfactory. Previously published case reports and small series have suggested that ECPR might be beneficial as an adjunct to conventional CPR for patients with refractory cardiac arrest. More recently, a number of larger series, including some prospective studies, have been published and provide further evidence for a role for ECPR in the management of cardiac arrest. While the results of these studies are promising, it is clear that more data is required to establish a definitive role for ECLS in the management of the patient suffering from cardiac arrest. Randomized studies designed to evaluate the role of ECPR as a component of cardiac arrest management are underway. Ongoing research on the optimal application of ECPR, as well as further study on logistical hurdles and postarrest management, will likely contribute to continued improvements in outcomes after cardiac arrest.
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