Melania M. Bembea

Objectives: To develop and internally validate a multivariable prediction model for survival to hospital discharge after pediatric extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital cardiac arrest (IHCA), and to use this model to derive risk-standardized survival rates (RSSRs) and quantify between-hospital variation in outcomes. Design: Retrospective multicenter cohort study. Setting: Hospitals contributing to the Extracorporeal Life Support Organization (ELSO) registry between 2020 and 2023. Patients: Children (< 18 yr) treated with ECPR for IHCA. Interventions: None. Measurements and Main Results: Eligible patients were identified from the ELSO Registry and split into derivation ( N = 1060) and validation ( N = 317) cohorts using a hospital-stratified split to preserve within-hospital clustering. Survival prediction models were derived using penalized logistic regression with the least absolute shrinkage and selection operator. A full-event model incorporating 14 routinely available clinical variables demonstrated fair discrimination (area under the curve, 0.728 in the derivation cohort and 0.678 in the validation cohort) and good calibration (observed-to-expected ratio, 0.995; Brier score, 0.222 in the validation cohort). This model was embedded in a multilevel logistic regression model to generate hospital-level RSSRs for centers reporting five or more ECPR cases. Between-hospital variation was quantified using the median odds ratio, which was 1.30 (95% CI, 1.11–1.93), indicating significant differences in survival likelihood between centers after adjusting for patient-level risk. Conclusions: In a large, international cohort of pediatric ECPR patients, we developed and internally validated a clinically interpretable model for survival to hospital discharge. The model performance as a discriminator likely limits its use as a standalone tool for clinical decision-making. However, strong internal calibration allowed for determination of hospital-level RSSRs, which revealed significant inter-hospital variability. These findings demonstrate the feasibility of developing a risk-adjustment model capable of estimating hospital-level RSSRs. Additional external validation and evaluation of residual case-mix differences are needed before such models can be used for benchmarking across pediatric ECPR centers.

Importance: Timely identification of acute brain injury (ABI) in children receiving extracorporeal membrane oxygenation (ECMO) support is critical for early neuroprotective interventions. Objectives: To determine if elevations in plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and tau levels in children receiving ECMO precede new ABI confirmed by neuroimaging, and if they are associated with mortality and functional outcomes. Design, Setting, and Participants: This was a prospective observational cohort study conducted from 2019 to 2023, with 18-month follow-up completed in 2025. Children aged 2 days to younger than 18 years at ECMO cannulation were recruited from 11 US children’s hospitals. Study data were analyzed from May to August 2025. Exposures: GFAP, NfL, and tau measured in plasma samples collected serially during the ECMO course. Main Outcomes and Measures: Unfavorable short-term outcome was a composite of in-hospital mortality or discharge Pediatric Cerebral Performance Category score of 3 or greater with decline of at least 1 point from baseline. Unfavorable long-term outcome was a composite of mortality or Vineland Adaptive Behavior Scales, third edition, composite score less than 85 at 18 months after ECMO. Results: This study included 219 participants (224 ECMO courses; 1089 serial blood samples). Median age was 11 months (IQR, 30 days-9 years), and 121 (54%) were male. Among 60 ECMO courses with new ABI during the ECMO course, GFAP and NfL levels increased significantly, by 6.4% (95% CI, 1.4%-11.6%) and 16.1% (95% CI, 10.5%-22.0%), respectively, for each 24 hours preceding neuroimaging diagnosis of new ABI. Geometric means for GFAP, NfL, and tau were all significantly higher in those with unfavorable vs favorable outcome at hospital discharge for both the first sample receiving ECMO and peak levels during ECMO support. A 2-fold increase in GFAP and NfL levels from first sample receiving ECMO was significantly associated with unfavorable outcome after adjusting for baseline GFAP and NfL levels, age, and ECMO indication (GFAP adjusted hazard ratio [aHR], 1.48; 95% CI, 1.22-1.79; NfL aHR, 1.43; 95% CI, 1.14-1.79). Similar models for tau showed no significant association with outcomes. Conclusions and Relevance: Results suggest that GFAP and NfL may be promising candidates for real-time neurologic monitoring in children receiving ECMO and may aid in diagnosis, association with outcomes, and potentially guiding neuroprotective strategies.

Background Cyclohexanone is a volatile organic compound known to be toxic to humans and animals, used in the medical setting as a solvent sealer for intravenous (IV) fluid administration devices. We aimed to determine exposure sources as well as plasma and urine levels of cyclohexanone and metabolites in critically ill infants and children. Methods We prospectively enrolled children in a single center pediatric intensive care unit (ICU) (n = 66), and conducted a secondary analysis of a multicenter trial in premature neonates (n = 69). Cyclohexanone and its predominant metabolites, trans-1,2-cyclohexanediol and trans-1,4-cyclohexanediol, were measured serially in medical fluids, plasma, and urine. Results Cyclohexanone was detected in all IV solutions used in standard ICU care (IV fluids, medications, dialysate and red blood cell bags, n = 53 fluid samples). Cyclohexanone and metabolites were higher in urine versus plasma in both cohorts. In premature neonates, plasma and urine cyclohexanone concentrations were highest on day of randomization, while metabolite concentrations were highest on days 7–14. Conclusions Currently, cyclohexanone may represent an inevitable exposure to children who require intensive care inclusive of IV fluid and medication administration devices. Further studies are needed to develop replacement or mitigation strategies for cyclohexanone exposure in the vulnerable neonatal and pediatric ICU populations. Impact Direct bloodstream exposure to cyclohexanone in the hospital environment has been poorly described in the healthcare setting. Cyclohexanone was present in all tested types of intravenous solutions used in standard intensive care (intravenous fluids, medications, dialysate and stored red blood cell bags). In a single center pediatric intensive care unit cohort and a multicenter neonatal intensive care unit cohort, cyclohexanone and its metabolites were detected in every blood and urine sample tested. In a multicenter neonatal intensive care unit cohort, plasma and urine cyclohexanone concentrations were highest on day 1 of admission and metabolite concentrations were highest on days 7–14.

Background: Pediatric respiratory syncytial virus (RSV)–related acute lower respiratory tract infection (LRTI) commonly requires hospitalization. The Clinical Progression Scale–Pediatrics (CPS-Ped) measures level of respiratory support and degree of hypoxia across a range of disease severity, but it has not been applied in infants hospitalized with severe RSV-LRTI. Methods: We analyzed data from a prospective surveillance registry of infants hospitalized for RSV-related complications across 39 pediatric intensive care units in the United States from October through December 2022. We assigned CPS-Ped (0 = discharged home at respiratory baseline to 8 = death) at admission and days 2–7, 10, and 14. We identified predictors of clinical improvement (CPS-Ped ≤2 or 3-point decrease) by day 7 using multivariable log-binomial regression models and estimated the sample size (80% power) to detect 15% between-group clinical improvement with CPS-Ped versus hospital length of stay (LOS). Results: Of 585 hospitalized infants, 138 (23.6%) received invasive mechanical ventilation (IMV) and 1 died. Failure to clinically improve by day 7 occurred in 205 (35%) infants and was associated with age <3 months, prematurity, underlying respiratory condition, and IMV in the first 24 hours in the multivariable analysis. The estimated sample size per arm required for detecting a 15% clinical improvement in a potential study was 584 using CPS-Ped clinical improvement versus 2031 for hospital LOS. Conclusions: CPS-Ped can be used to capture a range of disease severity and track clinical improvement in infants who develop RSV-related critical illness and could be useful for evaluating therapeutic interventions for RSV.

OBJECTIVES: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus. DATA SOURCES: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill neonates and children. DATA EXTRACTION: Within each of the eight subgroups, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: Following the systematic review of MEDLINE, EMBASE, and Cochrane Library databases from January 1988 to May 2021, and the consensus process for clinical recommendations and consensus statements, PEACE panel experts constructed research priorities using the Child Health and Nutrition Research Initiative methodology. Twenty research topics were prioritized, falling within five domains (definitions and outcomes, therapeutics, anticoagulant monitoring, protocolized management, and impact of the ECMO circuit and its components on hemostasis). CONCLUSIONS: We present the research priorities identified by the PEACE expert panel after a systematic review of existing evidence informing clinical care of neonates and children managed with ECMO. More research is required within the five identified domains to ultimately inform and improve the care of this vulnerable population.

In this two-center prospective cohort study of children on ECMO, we assessed a panel of plasma brain injury biomarkers using exploratory factor analysis (EFA) to evaluate their interplay and association with outcomes. Biomarker concentrations were measured daily for the first 3 days of ECMO support in 95 participants. Unfavorable composite outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category > 2 with decline ≥ 1 point from baseline. EFA grouped 11 biomarkers into three factors. Factor 1 comprised markers of cellular brain injury (NSE, BDNF, GFAP, S100β, MCP1, VILIP-1, neurogranin); Factor 2 comprised markers related to vascular processes (vWF, PDGFRβ, NPTX1); and Factor 3 comprised the BDNF/MMP-9 cellular pathway. Multivariable logistic models demonstrated that higher Factor 1 and 2 scores were associated with higher odds of unfavorable outcome (adjusted OR 2.88 [1.61, 5.66] and 1.89 [1.12, 3.43], respectively). Conversely, higher Factor 3 scores were associated with lower odds of unfavorable outcome (adjusted OR 0.54 [0.31, 0.88]), which is biologically plausible given the role of BDNF in neuroplasticity. Application of EFA on plasma brain injury biomarkers in children on ECMO yielded grouping of biomarkers into three factors that were significantly associated with unfavorable outcome, suggesting future potential as prognostic instruments.

BACKGROUND: Red blood cell (RBC) transfusions are used frequently in pediatric patients admitted to the intensive care unit (ICU) after cardiac surgery. To improve data-driven transfusion decision-making in the ICU, we conducted a retrospective analysis to assess the effect of RBC transfusion on cerebral and somatic regional oxygenation (rSO2). METHODS: We evaluated post- versus pre-RBC transfusion cerebral rSO2 and somatic rSO2 in all consecutive pediatric patients (age >28 days to 50%. When restricting analysis to the first (index) transfusion after arrival to the ICU from the operating room (administered at a median of 1.15 postoperative days [25th–75th percentile, 0.84–1.93]), between-patient pretransfusion hemoglobin was not associated with pretransfusion crSO2 but within-patient posttransfusion versus pretransfusion hemoglobin difference was significantly associated with posttransfusion versus pretransfusion crSO2 difference (mean posttransfusion versus pretransfusion crSO2 difference, 2.54; 95% confidence interval, 0.50–4.48). CONCLUSIONS: In this study, neither cerebral nor somatic rSO2 increased significantly post- versus pre-RBC transfusion in pediatric cardiac surgery patients admitted to the ICU after biventricular repairs. However, almost three-quarters of transfusions administered when pretransfusion crSO2 was below the critical threshold of 50% resulted in a posttransfusion crSO2 >50%. In addition, the significant within-patient change in crSO2 in relation to the change in posttransfusion versus pretransfusion hemoglobin in the immediate postoperative period suggests that a personalized approach to transfusion following within-patient trends of crSO2 rather than absolute between-patient values may be an important focus for future research.