Three recent reports have examined pediatric ECPR survival predictors [2, 13, 20]. Thiagarajan et al. have reviewed the largest series of pediatric ECPR cases known [20]. According to their report, the overall survival of all pediatric ECPR patients in the ELSO registry between 1992 and 2005 was 38%. The survival rate among those patients receiving ECPR for cardiac reasons was 42%. Although our survival rate is lower, our patients’ illness severity and complexity of disease may not be comparable to those of patients in the ELSO registry. The majority of our patients had recent cardiothoracic surgery.

Although Alsoufi et al. have reviewed the second largest series of pediatric ECPR cases known, pre-ECMO laboratory variables were not examined [2]. Our data, however, are consistent with the finding that gender does not affect survival to hospital discharge. Furthermore, our survival rate to hospital discharge, although lower, is comparable (23 vs. 34%). In another report, Huang and colleagues reviewed a series of 26 pediatric ECPR patients, including a number of clinical and laboratory variables [13]. A higher survival rate (41%) was reported, despite our similar ECPR specialist availability and patient population.

The higher survival rate reported by Alsoufi et al. [2] is likely unrelated to the presence of an in-house ECMO specialist and/or perfusionist at all times at the Hospital for Sick Children in Toronto. Although UCLA Medical Center differs in that an ECMO perfusionist is not in-house at all times, our CPR duration times are very similar to those reported by Alsoufi and colleagues. In the report by Alsoufi et al., however, ECPR is considered within 10 min of starting CPR. Likewise, our CPR durations were also similar to those reported by Huang and colleagues [13], but they had discussed the possible advantages of ECPR with staff, and the goal was to activate ECPR for appropriate patients after 10–15 min of refractory CPR. Although the survival benefit of a rapid response ECMO team does not appear statistically evident upon analysis of a report by Duncan et al. [9], this may be related to the small number of patients analyzed.

Mattel Children’s Hospital UCLA does not have an official policy outlining the requirements needed to initiate ECPR. We speculate that educating staff and having a goal of activating or at least considering ECPR for appropriate patients early during CPR may introduce a selection bias. In other words, a physician may reject a potential ECPR candidate earlier due to a probable irreversible reason for the cardiac arrest. By then selecting a patient for ECPR because of a probable reversible reason for the cardiac arrest, the physician may be improving his or her institution’s ECPR survival rate. We also speculate that educating staff and having a goal of activating or at least considering ECPR for appropriate patients early during CPR may improve or expedite the delivery of ancillary care, such as antibiotic or blood product administration. Although further investigation is needed to confirm these hypotheses, we speculate that being familiar with the potential advantages of ECPR and educating staff should, at least intuitively, improve ultimate survival to discharge.

Pre-ECMO serum phosphorus concentration was found to be significantly lower among survivors to hospital discharge, even after log age adjustment. In addition, ROC/discriminant analysis identified the pre-ECMO serum phosphorus concentration as the most accurate continuous variable in predicting survival to hospital discharge or death. To our knowledge, these findings have not been reported previously. We further note that serum phosphorus concentrations among survivors to hospital discharge were not lower due to dialysis, as survivors to hospital discharge were not receiving dialysis at the time of their arrest.

We speculate that a serum phosphorus concentration in a compromised cardiac output state may be inversely related to a patient’s metabolic reserve, as supported by Kupriyanov et al. in a porcine model of myocardial ischemia [14]. Increased phosphorus has also been observed in dogs (subjected to cardiac arrest) during CPR and following circulatory return [3]. Furthermore, increased phosphorus has also been seen after giving lactic acid to dogs [19]. The fact that specific CPR ABG pCO₂ and bicarbonate concentration thresholds were also found to be highly accurate in predicting survival to hospital discharge or death by ROC/discriminant analysis lends support to this metabolic theory. Furthermore, a classification tree analysis, using, in part, a pre-ECPR phosphorus concentration threshold of 5.5 mg/dl and a CPR ABG base excess concentration threshold of –13 mmol/l, yielded a highly accurate model of predicting ECPR survival to hospital discharge or death, with a lower pre-ECMO phosphorus concentration and a higher CPR ABG base excess concentration associated with survival. Empirically, adequate ventilation, cardiac output, and end-organ perfusion, as reflected in normal CPR ABG pCO₂, bicarbonate, and base excess concentrations, should be associated with patient survival. In other words, inadequate ventilation, cardiac output, and end-organ perfusion typically lead to acidemia from an increased pCO₂ concentration and a decreased bicarbonate concentration as reflected in a decreased base excess concentration. Our findings regarding CPR ABG pCO ₂ , bicarbonate and base excess concentrations are consistent with this theory with regard to survival to discharge. This unexpected finding regarding phosphorus, however, requires validation.

Our finding conflicts, however, with other published reports and, therefore, requires validation. In a pediatric ECPR report by Huang and colleagues, the prevalence of “renal failure” (as defined by a low urine output or a fall in creatinine clearance) after ECMO initiation was significantly higher among nonsurvivors despite its having been similar prior to CPR. [13]. In another report, although Allan and colleagues found no difference in blood urea nitrogen or creatinine concentrations between survivors and nonsurvivors in their study of pediatric ECMO use associated with cardiac catheterization, 3 patients among their study population of 22 were not ECPR recipients [1].

ROC/discriminant analysis is a powerful statistical tool which identifies thresholds for continuous variables in cases of dichotomous outcomes, while maximizing sensitivity and specificity. This analysis may be particularly useful in clinical situations, where clinicians might be presented with a particular laboratory value and desire to predict the likelihood of one of two possible outcomes. ROC/discriminant analysis of our data, in addition to identifying a pre-ECMO phosphorus concentration threshold, also identified CPR ABG pCO₂ and CPR ABG bicarbonate concentration thresholds as highly accurate predictors of survival to hospital discharge or death. Both CPR ABG pCO₂ and CPR ABG bicarbonate concentrations likely reflect the adequacy of resuscitative ventilation, cardiac output, and end-organ perfusion and, thereby, the effectiveness of CPR in our patient population. This conclusion, however, is only speculative and requires further investigation. Similarly, the identification of a pre-ECMO phosphorus concentration threshold and a CPR arterial base excess concentration threshold in the multivariate analysis also supports our speculation that effective CPR is the major contributor to ECPR survival to discharge. For as discussed earlier, inadequate ventilation, cardiac output, and end-organ perfusion typically lead to acidemia from an increased pCO₂ concentration and a decreased bicarbonate concentration as reflected in a decreased base excess concentration. Our findings regarding CPR ABG pCO₂, bicarbonate, and base excess concentrations are consistent with this theory with regard to survival to discharge. These laboratory tests may be surrogates for objective measurements of CPR performance, such as chest compression depth or ventilation frequency. Furthermore, by extension, those patients undergoing ineffective CPR may suffer proportionately more end-organ damage during CPR, thereby increasing their likelihood of mortality despite having survived cannulation. Interestingly, similar to our results, pre-ECPR acid–base status does appear to be associated with survival according to a report by Thiagarajan and colleagues [20]. ECPR survivors tended to have a lower pre-ECMO ABG pCO₂ concentration (P = 0.06) and a significantly higher pre-ECMO ABG pH (P = 0.001).

Whether CPR duration influences survival to discharge following ECPR is controversial. Two recent pediatric reports have shown that CPR duration is not significantly associated with death [2, 17]. Our CPR duration times are comparable to these reports. Huang et al., however, showed a significant association between longer CPR duration and death among pediatric ECPR recipients [13]. In their report, ECPR “activation time” (“time from cardiac arrest to calling the ECMO team”) took significantly longer for those patients who ultimately did not survive. In addition, a large adult ECPR study has indicated that a CPR duration <60 min is significantly associated with survival [6]. Our series would suggest that CPR duration does not affect survival to discharge among pediatric patients receiving ECPR. We speculate that this may be due to the fact that effective CPR depends, in part, on qualified providers, adequate vascular access, ready availability of resuscitation medications and equipment, and optimal hemodynamic monitoring. These are typically present in tertiary-care settings, such as ours. As a result, we speculate that CPR duration is likely less important to ECPR survival to discharge than the effectiveness of that CPR, perhaps reflected by, as we speculate, CPR ABG pCO₂, bicarbonate, and base excess concentrations, for example. This is only a hypothesis, however, requiring further investigation.

ECMO duration did not differ significantly between survivors to hospital discharge and nonsurvivors. This finding is consistent with other reports [2, 5, 13, 17]. At our institution, although the timing of ECMO decannulation procedures varied widely and an intracranial hemorrhage is generally a contraindication to ECMO continuation, this finding may indicate that providing adequate pre-ECMO oxygen delivery affects overall survival to hospital discharge more than the ECMO course, itself, and any ECMO complications.

Our retrospective, historical cohort case series has a number of limitations potentially affecting the ability to generalize our findings to other institutions, providers, and patients. Our study population, although largely homogeneous, was relatively small. A larger sample size may be required to see larger or additional differences between survivors to hospital discharge and nonsurvivors. Also, all of our patients suffered in-hospital cardiac arrests, which are associated with improved survival to discharge, compared to out-of-hospital arrests [8, 18, 21]. Furthermore, multiple medical providers were involved in the care of these patients, and variations in medical and surgical care undoubtedly occurred, before, during, and after cannulation. We also did not analyze any potentially available follow-up records, including neurological and developmental evaluations. Finally, the number of physicians who rejected potential ECPR candidates due to probable irreversible reasons for their cardiac arrest (selection bias) is unknown.

ECPR is a potentially lifesaving intervention, but one that carries significant risks. Lower pre-ECMO phosphorus and creatinine concentrations were associated with survival to hospital discharge in our patients. Furthermore, CPR arterial pCO₂, bicarbonate, and base excess concentration thresholds may aid in the prediction of patient survival to discharge or death.

We believe that a large, multicenter, prospective cohort study is required to sufficiently validate whether these pre-ECPR variables or others are predictive of survival to hospital discharge. Selection bias, however, may be difficult to eliminate. Such a study could potentially identify differences among certain subgroups of patients with specific diagnoses. Additional data fields should be collected as well.

We strongly caution against generalizing these findings to other patients. Validation of these results and further investigation are needed. At the very least, this study provides statistical methods and a framework for analyzing this clinical dilemma. Given the interplay of many variables and the complexity of human physiology, a multivariate model is likely to provide the most guidance. Fortunately, the laboratory variables found to be associated with survival to hospital discharge in this report are readily available in the modern medical setting. Given the limitations discussed, however, pediatric cardiologists, intensivists, and surgeons should continue to rely on clinical judgment when evaluating potential ECPR recipients. As our data support, ECPR should remain an option to health-care providers in cases of refractory pediatric cardiac arrest, even if CPR duration is lengthy.