This multicenter retrospective study was conducted to collect and analyze data on pediatric patients who underwent ECMO insertion in Korea. We reviewed the medical records of all patients who received ECMO for any indication between January 2012 and December 2021, as detailed in the initial report [2]. A total of 10 centers that possessed eligible cardiac-related medical ECMO cases and agreed to participate in this subgroup analysis were included in the study.

The methodology for data collection has been described in detail in the previous report [2]. Pediatric patients under 18 years of age were included in the study. Data were collected on demographics, clinical characteristics, and outcomes. The data included laboratory results, echocardiographic findings, heart rhythm data, urine output, and other relevant clinical parameters. For this subgroup analysis, we focused on patients with severe heart failure necessitating ECMO support, excluding those in a post-cardiotomy state. This patient group, referred to as the "cardiac-related medical group," included conditions such as acute myocarditis, cardiomyopathy, congenital heart disease, and others (e.g., malignant arrhythmia).

We also paid particular attention to the application of extracorporeal cardiopulmonary resuscitation (ECPR), which was defined according to the ELSO guidelines as the initiation of ECMO during conventional cardiopulmonary resuscitation with manual or mechanical chest compressions, or within 20 minutes of return of spontaneous circulation without ongoing compressions [3].

While the previous report provided an overview of individual outcomes, this study specifically targeted the clinical characteristics of the cardiac-related medical group and their association with in-hospital outcomes. The primary in-hospital outcomes assessed were survival to discharge and death. Patients were classified as having survived to discharge if they were discharged alive from the hospital, irrespective of whether they were discharged to home or transferred to another facility. However, transfers while still on ECMO support were not classified as survival to discharge. ECMO weaning was considered successful if the patient survived for at least 48 hours after ECMO removal.

We explored potential correlations between ECMO outcomes and various clinical features, including laboratory parameters (e.g., lactate, B-type natriuretic peptide [BNP], N-terminal prohormone of brain natriuretic peptide [NT-proBNP], creatine kinase-MB [CK-MB]), which were measured immediately before ECMO insertion or on the same day; 24-hour urine output following ECMO initiation; the use of dialysis; and patient information immediately prior to ECMO insertion, such as left ventricular ejection fraction (LVEF) and heart rhythm.

Data were analyzed using IBM SPSS statistics for Windows version 30 (IBM Corp.). Descriptive statistics were presented as medians with interquartile ranges for continuous variables or frequencies with percentages for categorical variables. Group comparisons were performed using the chi-square test for nominal variables and the Mann-Whitney U-test for continuous variables, as most data did not follow a normal distribution. Binary logistic regression analysis was conducted to examine the association between pre-ECMO rhythms and mortality. The independent variable was the rhythm type at the time of ECMO insertion, classified into seven predefined groups. The dependent variable was mortality. Odds ratios (ORs) with 95% CIs were calculated to estimate the likelihood of mortality associated with each rhythm group, with normal sinus rhythm serving as the reference category.

The in-hospital outcomes of patients with cardiac-related medical conditions are shown in Table 2. More than three-quarters of non-ECPR patients were successfully weaned from ECMO, and 68% of them survived to discharge. In contrast, ECPR patients exhibited worse in-hospital outcomes, as expected, with higher mortality rates and lower survival to discharge. However, the number and distribution of heart transplantations did not differ significantly between the non-ECPR and ECPR groups. Among patients awaiting transplantation, one of three patients in the non-ECPR group and the only patient in the ECPR group died while on the waiting list.

Various clinical features were analyzed for their association with mortality. Non-survivors exhibited higher lactate levels before ECMO insertion, lower 24-hour urine output immediately after ECMO initiation, and a higher prevalence of dialysis use (Table 3, Fig. 1A and B). However, other parameters, such as BNP, NT-proBNP, CK-MB, and LVEF prior to ECMO insertion, did not show statistically significant differences between survivors and non-survivors. Additionally, the timing and duration of dialysis were not significantly associated with mortality (Table 3, Fig. 1C-F). Notably, in a subgroup analysis of patients diagnosed with acute myocarditis, pre-ECMO LVEF was significantly higher in survivors than in non-survivors (median LVEF, 18.15% in non-survivors vs. 29.86% in survivors, p=0.043) (Supplementary Table 1).

The distribution of heart rhythms immediately prior to ECMO insertion is shown in Fig. 2, categorized by in-hospital outcomes. The heart rhythms were classified into seven groups: ventricular tachycardia (VT)/ventricular fibrillation (VF), atrial fibrillation/atrial flutter, high-degree atrioventricular (AV) block, sinus bradycardia (heart rate <60 bpm), pulseless electrical activity (PEA)/asystole, normal sinus rhythm, and others. Normal sinus rhythm was the most common rhythm at the time of ECMO insertion, followed by VT/VF (Fig. 2). Logistic regression analysis revealed that PEA/asystole was associated with a significantly higher likelihood of mortality, with a 9.6-fold increased risk compared to normal sinus rhythm (Table 4). Other heart rhythms, however, were not significantly associated with mortality.

Our analysis confirmed several previously identified risk factors for mortality. Non-survivors had higher lactate levels before ECMO insertion, lower urine output within 24 hours after initiation, and a higher prevalence of dialysis (Table 3). These findings corroborate previous studies highlighting the prognostic value of lactate levels, acute kidney injury, and poor urine output [5-7,9]. Additionally, the rate of lactate clearance has been identified as a dynamic predictor of mortality, suggesting that both static and dynamic lactate metrics are critical for prognosis [12]. However, it is important to acknowledge that elevated lactate levels might also reflect poor pre-ECMO clinical status, potentially due to delayed ECMO initiation, which could lead to further lactate accumulation. In this context, our findings underscore the potential importance of early ECMO initiation to mitigate the progression of metabolic derangement and improve patient outcomes.

However, traditional cardiac markers such as BNP, NT-proBNP, CK-MB, and pre-ECMO LVEF did not show significant predictive value in this study. While this may suggest that these markers are not reliable risk factors in the context of pediatric ECMO for cardiac-related medical indications, it is also possible that this result reflects the limitations of missing data or patient heterogeneity. In particular, the lack of simultaneous testing for BNP and NT-proBNP across most centers resulted in insufficient data to draw reliable conclusions. Interestingly, when analyzing a relatively homogeneous patient group with acute myocarditis separately, pre-ECMO LVEF was found to have a significant association with mortality. This result is consistent with findings from a previous study. Tuan et al. [13] identified LVEF at 48 hours, platelet count, and protein levels as predictors of mortality in patients with acute myocarditis. Their study also analyzed patients receiving ECMO and highlighted LVEF at 48 hours, a high vasoactive-inotropic score, and lactate at 24 hours post-ECMO as significant risk factors. In contrast, a study by Sun et al. [14] on children with acute myocarditis receiving venoarterial ECMO identified peak serum creatinine and peak CK-MB during ECMO as prognostic factors, unlike our findings. These discrepancies may stem from differences in study design, patient populations, or clinical practices, and underscore the need for further research to confirm these associations.

Heart rhythm immediately before ECMO insertion showed a significant association with in-hospital outcomes. Normal sinus rhythm was more prevalent in survivors, whereas PEA/asystole was predominant in non-survivors (Fig. 2). Logistic regression analysis revealed that PEA/asystole was associated with a 9.6-fold higher likelihood of mortality compared to normal sinus rhythm (Table 4). Other rhythms, including VT/VF, high-degree AV block, sinus bradycardia, and others, were not significantly associated with mortality. Few studies have evaluated pre-ECMO heart rhythm as a prognostic factor in pediatric patients, but findings from adult studies support the protective role of normal sinus rhythm before ECMO initiation (OR, 0.374) [15]. Our results suggest that PEA/asystole remains a critical risk factor for mortality, while other rhythms may not independently predict outcomes.

This study has several limitations. First, data loss due to the emergency nature of ECMO procedures and the retrospective study design may have affected the reliability of certain parameters, such as lactate, CK-MB, BNP, NT-proBNP, and LVEF. Additionally, analysis for troponin I and troponin T could not be performed due to a high proportion of missing data. However, the consistency of lactate levels as a prognostic factor suggests that the most critical predictors were not overlooked. Second, since not all major centers participated in this study on ECMO for pediatric patients with cardiac-related medical conditions, selection bias may exist, and the study results may not fully represent current ECMO practices in Korea. Therefore, the generalizability of our findings is limited.

Building upon the recent study that first reported on the practice and outcomes of pediatric ECMO in Korea, our study provides focused insights into the outcomes and risk factors specific to pediatric cardiac-related medical ECMO patients. The results are consistent with findings from previous studies, identifying the pre-ECMO lactate level, 24-hour urine output post-ECMO, use of dialysis, and PEA/asystole as significant risk predictors. This study is expected to offer clinicians valuable insights into managing pediatric ECMO patients with cardiac-related medical indications, aiding in more accurate prognostic predictions and improved decision-making. Furthermore, it serves as a foundational step toward future prospective studies to further advance the understanding and management of this patient population.