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Predictors of Survival for Nonhighly Selected Patients Undergoing Resuscitation With Extracorporeal Membrane Oxygenation After Cardiac Arrest

Pabst, Dirk*; El-Banayosy, Aly; Soleimani, Behzad*; Brehm, Christoph, E.*

doi: 10.1097/MAT.0000000000000644
Clinical Critical Care

In several case reports and case series, extracorporeal membrane oxygenation during chest compression (CPR) has been shown to be a reasonable tool to improve outcome of patients under resuscitation. Although recommendations for extracorporeal cardiopulmonary resuscitation (ECPR) include younger patients with shockable rhythm and short previous CPR-time, it remains unclear if nonhighly selected patients have a similar outcome. Aim of this study was to determine outcome in our nonhighly selected patient population treated with ECPR and investigate possible predictors of survival. We made a retrospective single-center study of adults who underwent ECPR for in-hospital cardiac arrest between June 2008 and September 2016. Outcome and predictors of survival were identified. In this period of time, 59 patients underwent ECPR due to cardiac arrest. Fifteen patients (25.4%) survived discharge of which all had a good neurological outcome (cerebral performance category ≤ 2). Survival to discharge of patients with shockable rhythm (ventricular fibrillation or ventricular tachycardia) was 40.7%. Serum lactate ≥ 8, pulseless electrical activity (PEA) or asystole and male gender could be identified as predictors for low survival rate. Age, body mass index, renal replacement–dependent kidney injury had no significant influence on survival outcome. Mean CPR-time was 41.1 minutes (interquartile range, ±29.25 minutes). Extracorporeal membrane oxygenation seems to be a useful tool to improve the outcome of CPR also in nonhighly selected patients when compared with CPR alone and could be considered in patients with refractory cardiac arrest also after longer previous CPR-time. Serum lactate and heart rhythm should be taken into account for patient selection.

From the *Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania

Department of MCS Cardiothoracic Surgery, INTEGRIS Baptist Medical Center, Oklahoma City, Oklahoma.

Submitted for consideration February 2017; accepted for publication in revised form June 2017.

Disclosure: The authors have no conflicts of interest to report.

Correspondence: Dirk Pabst, Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033-0850. Email: dpabst@pennstatehealth.psu.edu.

Current resuscitation strategies for cardiac arrest include electrical defibrillation, chest compression (CPR), and Advanced Cardiac Life Support (ACLS) medications. Although electrical defibrillation and CPR are fairly effective in the early minutes after cardiac arrest, the addition of ACLS medications seem not to show significant survival benefits.1 , 2 A strategy is debated in recent discussions proposing extracorporeal membrane oxygenation as a tool to improve the outcome of CPR after cardiac arrest (ECPR) that might show better short- and long-term survival over conventional cardiopulmonary resuscitation (CCPR).3 , 4 Although high-quality randomized control trial data do not exist to prove the better outcome after using ECPR, a number of observational studies suggest a benefit for these patients.5 A recently published meta-analysis including 3,098 cardiac arrest patients confirmed this suggestion by showing an increase of 30 day survival of up to 13%.6 Kim et al.7 showed in another meta-analysis with high-quality data that the survival to hospital discharge, when using ECPR almost doubled when compared with patients who underwent CCPR. Despite these benefits of ECPR, it also has significant ethical implications,8 and it remains debatable which patient should receive this invasive and costly technique. Many ECPR programs exclude patients from ECPR with presumably weak outcome criteria like initial rhythm asystole, total arrest time of more than 60 minutes, and suspicion of shock due to sepsis. However, most of these criteria are not supported by significant study data. Conclusive predictors for better outcome in ECPR could simplify decision which patients to treat with ECPR.

We retrospectively examined outcome of a single-center trial on a group of “less high selected” patients who received ECPR after cardiac arrest and were trying to determine predictors for good outcome.

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Methods

This retrospective single-center study includes 59 patients who received placement of VA extracorporeal membrane oxygenation (ECMO) during resuscitation for refractory cardiac arrest between June 2008 and September 2016. Refractory cardiac arrest was defined as a sudden cessation of normal cardiac function in which mechanical CPR did not lead to a return of spontaneous circulation within the first 10 minutes of being initiated. The procedure of the further treatment was discussed with the family and/or power of attorney directly after ECPR was done and patients advance directive wishes were addressed.

Only patients who received an ECMO cannula placement during chest compressions were included in this study. Information obtained through the “Cerner Health Facts® database” (Cerner Corporation, Kansas City, MO) including age, sex, body mass index (BMI), initial heart rhythm during arrest, reason for cardiogenic shock, time of chest compressions, location of cardiac arrest, maximum lactate levels, creatinine levels before ECMO placement, maximum troponin levels and ECMO complications were compiled and analyzed with regard to patients survival to discharge.

All 59 patients received mechanical CPR in accordance with the ACLS guidelines of the American Heart Association before receiving ECMO support. The ECMO circuits that were utilized in this study consisted of a Quadrox oxygenator (Maquet Cardiovascular; Wayne, NJ) and either a Rotaflow® centrifugal pump (Maquet Cardiovascular; Wayne, NJ) or a Centrimag® centrifugal pump (Levitronix LLC, Waltham, MA). Attending intensivists or attending cardiac surgeons in the hospital setting performed all ECMO cannulations. The cannulation technique utilized for each patient was at the discretion of the performing physician, with a peripheral catheter placement in both the femoral artery and the femoral vein by percutaneous Seldinger technic being the preferred cannulation method. Subsequent management and care of the patient was performed by the Heart and Vascular Institute Critical Care Unit team of ECMO specialized nurses, nurse practitioners, and intensivists. Extracorporeal membrane oxygenation flows and inotrope dosing (epinephrine, dobutamine, or milrinone) were adjusted appropriately to maintain mean arterial pressures > 65 mm Hg and arterial saturations > 93%.

Most patients were treated with “target temperature management” (TTM) after resuscitation for a goal temperature of 32–34°C for 24 hours according to the institutional TTM protocol.

Neurological status was described with the cerebral performance category (CPC). Good neurological outcome was defined as CPC 1 and CPC 2.9

Results were reported as percentages, means ± standard deviations, and/or medians and interquartile ranges. Categorical data were analyzed using a Pearson’s χ2 test of independence or a Fisher’s exact test when appropriate. Conversely, continuous data were analyzed using a Mann–Whitney U test. Kaplan–Meier survival curves were constructed to examine differences in survival over time between patient groups with heart rhythm previous to ECMO implantation as PEA/asystole, (shockable) ventricular rhythm, or unknown rhythm as well as survival over time for all patients. Subsequently, values between each pair were compared for statistical significance using the log-rank test. All tests were two-tailed, and statistical significance was defined by a p value of < 0.05. IBM SPSS Statistics (IBM Corporation, Armonk, NY) was used for the statistical analyses in this study.

Extracorporeal cardiopulmonary resuscitation score developed by Park et al. 10 was identified. For this score, identification of age, shockable rhythm, CPR time, arterial pulse pressure, and Sequential Organ Failure Assessment (SOFA) score was done.

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Results

In the time period between June 2008 and September 2016, we performed 59 VA ECMOs under mechanical resuscitation for refractory cardiac arrest; characteristics of these patients are summarized in Table 1. The mean patient age was 57 years (range, 19–80 years). Forty patients (67.8%) were male. The mean patient BMI was 32.8 (SD ± 10.7). Twenty eight (47.5%) presented with ventricular tachycardiac rhythm (ventricular tachycardia or ventricular fibrillation) at the time of decision for VA ECMO placement was made. Sixteen patients (27.1%) had PEA, seven patients (11.9%) had an asystolie, and in 8 patients (13.6%) initial rhythm was not reliably documented.

Table 1

Table 1

Twenty-nine patients (49.2%) had a myocardial infarction that was proven in electrocardiogram (ECG) and/or in coronary angiography afterward. In 10 patients (16.9%), myocardial infarction was assumed due to history and/or elevated troponine but could not be proven by ECG signs or coronary angiography. Four of these patients had a very high troponine level (> 16.24 ng/mL), four patients had a significant elevated level (> 0.13 ng/mL), and in one patient the troponine was not determined. In four patients (6.8%) pulmonary embolism was diagnosed as reason for cardiogenic shock. Five patients (8.5%) had an acute allograft rejection after heart transplantation. Two patients (3.4%) had an acute heart failure with history of nonischemic cardiomyopathy. Two patients (3.4%) were diagnosed with a septic shock in the aftermaths. Seven patients (11.9%) had other reason for cardiac arrest or a reliable diagnose could not be accomplished.

Eighteen patients (30.5%) were in the intensive care unit during ECPR, and 16 patients (27.1%) were in the cardiac catheter laboratory. Other locations were the emergency department, operation room, ordinary ward, or computed tomography (CT) scan. In nine patients (15.3%), resuscitation and ECMO placement were done in an outside hospital where more detailed information of the exact location could not be reliably evaluated.

In the majority of patients (98.3%), a peripheral cannulation was done.

Table 2 shows the outcome variables. The survival to discharge was 25.4%. In 14 cases (23.7%), the patients passed away during the first day after resuscitation. In five patients (8.5%), ECMO flow could not be established under CPR due to technical problems with cannulation in the first 75 minutes after cardiac arrest, and these patients were pronounced dead.

Table 2

Table 2

Mean initial ECMO flow was 3.99 L/min (SD ± 1.18 L/min).

The average time on ECMO was 6 days (range, 0–33 days). Two patients (3.4%) were bridged to a left ventricular assist device, and one patient was bridged to a total artificial heart (TAH). One patient was intermittently bridged on “AB5000 Ventricular Assist Device” (Abiomed Inc, Danvers, MA) that could be explanted after the heart function improved. One of the two left ventricular assist device (LVAD) patients passed away during the same hospital admission. The other LVAD patient and the TAH patient could be successfully heart transplanted during the course of the following 2 years.

Daily plasma hemoglobin (pHb) was taken to detect hemolysis. Nineteen patients (32.2%) had hemolysis during their ECMO run, defined as plasma hemoglobin level > 50 mg/dL.11 There was no significant difference in survival rate between patients with proven hemolysis and ECMO patients without hemolysis. In 36 patients (61.0%), blood culture was taken during ECMO treatment. In three patients (5.1%), bacteremia could be discovered. Other ECMO-related complications were significant groin bleedings leading to blood transfusion in seven patients. Two patients had severe groin bleeding in which surgical intervention was needed. In one patient, a surgical vessel repair was done, the other patient needed a fasciotomy due to compartment syndrome. Limb ischemia occurred in three patients. In one patient, thrombectomy was done. In no patient, amputation was necessary.

Twenty-seven patients (45.8%) had to be treated with renal replacement therapy (RRT). Four patients (6.8%) already had indication for RRT before their cardiac arrest.

Seven patients (46.7%) of the survived discharged patients went on continuous renal replacement therapy (CRRT) during the hospital admission. In three patients (18.8%), RRT-dependent terminal kidney failure (chronic kidney disease (CKD) stage 5) remained as diagnose in the following up visits. Table 3 shows the follow up of the discharged patients.

Table 3

Table 3

Of the 16 patients, which survived hospital discharge, all patients had a good neurological outcome defined as CPC score 1 or 2. Figure 1 shows the Kaplan–Meier analysis survival over the first year of the patient group in which ECMO was explanted at least 1 year before data were collected. The 1-year survival of the discharged patients was 73.3%.

Figure 1

Figure 1

Twenty-three patients had asystolie or PEA as initial rhythm. The survival rate of these patients was significantly lower (n = 2; 8.7%). In 27 patients, a shockable rhythm (ventricular tachycardia or ventricular fibrillation) was seen as initial rhythm. These patients showed a survival to discharge rate of 40.7% (n = 11). Figure 2 shows the Kaplan–Meier 1-year survival curve separated by initial heart rhythm.

Figure 2

Figure 2

Patients with serum lactate level of ≥ 8 mmol/L had a significant lower survival to discharge when compared with patients with lower lactate levels (13.3% vs. 45.0%).

Male gender also showed significant lower survival to discharge rate (17.5% vs. 42.1%).

Maximum lactate values of ≥ 8 mmol/L and PEA or asystole as heart rhythm by time of decision were significant risk factors for in-hospital mortality. In this patient cohort, we could not find significance to mortality in age, troponine level, baseline plasma creatinine, BMI, location of CPR, or reasons for cardiogenic shock. Surprisingly, there was no significant difference between groups of shorter and longer CPR-time in the outcome of survival. This was tested for groups more and less than 30 and 60 minutes of CPR-time. Potential predictors for survival and complications of the patients are listed in Table 4 and Table 5.

Table 4

Table 4

Table 5

Table 5

ECPR score10 could be identified in 33 patients. The mean ECPR score was 9.06 (minimum 5; maximum 13). Forty percentage of the patients with an ECPR score of > 10 survived when compared with 17.4% to patients with an ECPR score of ≤ 10.

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Discussion

In the last years, ECMO treatment has grown widely as a rescue therapy with several indications like cardiogenic shock, acute respiratory distress syndrome (ARDS), and other reasons.

It was described that VA ECMO placement during CPR could improve the outcome of patients undergoing cardiac arrest.3 , 4

According to the registry from the Extracorporeal Life Support Organization (ELSO) as of July 2016, 2,885 adult patients have received VA ECMO during ECPR. Survival to discharge rate was 29% in these patients.11 We found a survival rate of 25.4% in our institution and therefore are in the range of the documented ELSO data.

Other publications describe a survival to discharge rate from 13% to 54%.12–20 In many publications, inclusion criteria are well selected and exclude patients with asystolie or PEA as initial heart rhythm.15 , 20 Bellezzo et al. 20 defined not only persistent cardiopulmonary arrest as inclusion criteria but also shock (systolic blood pressure < 70 mm Hg) refractory to standard therapies. Other reasons for high variation of the outcome between studies could be different comorbidities, different percentage of VT/pVT. In our study, all patients were placed on ECMO under ongoing mechanical compression (ECPR) and a high number of patients with asystolie or PEA were included. The survival rate of patients without asystolie or PEA as initial rhythm in our study is 40.7% and is significantly different from the survival to discharge from the patients with asystolie or PEA (8.7%; p = 0.04).

Extracorporeal cardiopulmonary resuscitation is an invasive procedure, which requires resources including costs for staff and equipment. It should be clearly defined when patients likely would benefit from this procedure and when the resources, risk, and poor outcome does not justify the initiation of VA ECMO during CPR. Which outcome in a certain patient group justifies the initiation of this treatment needs to be discussed. However, knowing predictors for poor outcome might help to simplify the decision in which patient ECPR should be tried. Even if some studies show some predictors for poor survival rates (for example age ≤ 66 years, shockable arrest rhythm, lactate acid, CPR to ECMO pump-on time between (≤ 45 minutes) and comorbidity10), guidelines that propose in which patient groups ECMO placement during CPR should be initiated are still missing.

In our patient cohort, lactate ≥ 8 mmol/L and as mentioned above cardiac rhythm of PEA or asystole were significant predictors for low survival rate. We did not find a significant age boarder, which limited the outcome in our study group.

We could show that patients even with PEA and asystole at the time of ECPR could survive. Therefore, a nonshockable rhythm by itself should not be an exclusion criterion for ECMO placement and other criteria should be taken into account and also have to be identified in further studies.

Questionable is still after how many minutes of CPR outcome is futile and when attempt of ECPR should be avoided or withdrawn. Kelly et al. 21 described two cases with good neurological outcome after 176 minutes and 97 minutes cardiopulmonary resuscitation before extracorporeal rescue. The CPR time in our study cohort was up to 75 minutes. Surprisingly, we did not find a significant correlation between CPR time and survival rate.

Although ECPR can increase survival rates after cardiac arrest, it could also result in poor postresuscitation neurological status, and the data for this are still poor. Studies reported high serum lactic acid levels before ECMO not only as predictors for poor survival rate but also for poor neurological outcome.22 In our data, all survivors of discharge had a good neurological outcome with CPC of 1 or 2.

It is still unclear which role acute kidney injury might play in terms of survival rate. Oliguria seen during the first 24 hours after ECMO may be an independent predictor of mortality.23 In our patient cohort, there was no significant higher mortality for patient needed CRRT during admission.

The reason for the cardiac arrest also did not show any differences in outcome. Some studies mention that the outcome of ECPR in adult patients for septic shock is controversial.24 , 25 In our cohort, we had two patients in whom septic shock was diagnosed as reason for cardiac arrest in the aftermath. Both patients did not survive hospital discharge.

Patients undergoing ECMO support through femoral vessels, especially under CPR are prone to complications.26–28 The incidence of complications in our cohort was comparable with complications reported in other publications.26 , 28 , 29 Most complications include femoral artery injuries and were manageable. Severe complication was limb ischemia needed fasciectomy and severe groin bleeding needing immediate intervention, but no amputation. Hemolysis during extracorporeal membrane oxygenation is a known complication.30 Daily pHb levels were measured. Elevated pHb could be seen in 19 patients (32.2%), which had no significant influence on survival to discharge rate.

Experience of the provider (especially in terms of cannulation) could influence a successful placement of the cannulas and therefore increase the outcome.29 Technical challenge during CPR is particularly to place the arterial cannula because due to low flow the vessel is often small and under ongoing CPR difficult to detect. In this study, in five patients (8.5%) ECMO support could not be established. Most of our patients who were placed on ECMO in the cardiac catheter laboratory already had femoral arterial access that were used for placing the ECMO cannula. Anyway, there was no significant difference in mortality between patients who were cannulated in the cardiac catheter laboratory and patients who were placed somewhere else on ECMO.

Our study has some limitations. Nine patients were cannulated in other hospitals and were transported for further care to our institution. Values for variables like first detected rhythm on CPR, baseline creatinine, troponine were sometimes difficult to evaluate in these patients.

Chest compression time was well documented in 42 patients. In 17 patients, no reliable CPR time was documented.

Male gender was a significant predictor for poor survival in our cohort. Reasons for this remain unclear, and it might be reevaluated in cohorts of bigger studies.

Park et al. 10 developed a score to monitor survival to discharge in patients after ECPR. The score ranges from 3 to 15 and includes the age of the patient, shockable arrest rhythm, CPR time, post-ECMO arterial pulse pressure, and the SOFA score. When the ECPR score was > 10, the sensitivity and specificity for prediction of survival to discharge in Parks study were 89.6% and 75.0%, respectively.

The ECPR score could be identified in 33 patients in this cohort. Ten patients had an ECPR score of > 10. Forty percentage of these patients survived to discharge when compared with 17.4% of the patient with an ECPR score less than 10. Although there was a remarkable difference in survival between these two groups, our patients did not reach the significant difference in outcome expected by ECPR score. One reason might be the smaller cohort in our study. Anyhow, the ECPR score has already shown in a bigger cohort that it can be a useful tool for clinical providers.10

Although this study did not find any significant difference in the survival outcome between groups with longer and shorter CPR time, we believe that shortening time to establish a sufficient blood circle is important in patients with cardiac arrest. Logistic structures might improve survival rate by shortening time of CPR. Several case series could even show that prehospital placement of ECMO is successfully possible27 , 31 , 32 and might be considered as a challenge for future ECMO programs.

The results of this study do not deviate much from the published ELSO data. Slightly lower survival to discharge results can be explained mainly with the higher number of patients having PEA/asystole while ECMO placement. Demographic differences in matters of age do not seem to play an important role in our study since we did not see a clear cutoff point for age.

In conclusion, we showed that ECMO after cardiac arrest could be successful even in a nonhighly selected group of patients. In patients with high serum lactate levels, PEA or asystole presenting as initial heart rhythm, ECPR should be carefully considered since these were predictors for poor outcome in our study.

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Keywords:

ECPR; ECMO; survival; outcome

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