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.