Blood-Based Brain Injury Biomarkers to Prognosticate Outcome after Pediatric Cardiac Arrest
Authors: Fink Ericka L , Kochanek Patrick M. , Panigrahy Ashok , Beers Sue R. , Berger Rachel P. , Bayir Hülya , Pineda Jose , Newth Christopher , Topjian Alexis A , Press Craig A. , Maddux Aline B. , Willyerd Frederick , Hunt Elizabeth A , Duval-Arnould Jordan , Siems Ashley , Chung Melissa G , Smith Lincoln , Wenger Jesse , Doughty Leslie , Diddle J. Wesley , Patregnani Jason , Piantino Juan , Walson Karen Hallermeier , Balakrishnan Binod , Meyer Michael T. , Friess Stuart , Maloney David , Rubin Pamela , Haller Tamara L. , Treble-Barna Amery , Wang Chunyan , Clark Robert R.S.B. , Fabio Anthony ,   the POCCA Investigators
Published: March 2022

Background

Prognostication after cardiac arrest in children is challenging due to a lack of validated methods to evaluate direct brain injury. The objective of this multicenter study was to analyze biomarker accuracy to prognosticate outcome 1 year post-arrest.

Methods

Fourteen U.S. centers enrolled 164 children ages 48 h - 17 years with pre-arrest Pediatric Cerebral Performance Category score of 1-3 who were admitted to an intensive care unit after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase-L1 (UCH-L1), neurofilament light (NfL), and Tau concentrations were measured in blood samples from post-arrest days 1-3 using Quanterix™ Simoa 4-Plex assay, Billerica, MA. Unfavorable outcome was death or survival with Vineland Adaptive Behavioral Scale-Third Edition score < 70 at 1 year. We analyzed area under receiver operator curve (AUROC) and performed multivariate logistic regressions to determine the association of each biomarker with outcome on days 1-3.

Results

Fifty of 120 children with primary outcomes available had an unfavorable outcome, including 43 deaths. Compared to those with favorable outcomes, more children with unfavorable outcome had out-of-hospital (36% vs. 70%) and unwitnessed (7% vs. 46%) events, p<0.05. For days 1-3, concentrations of all four measured biomarkers were increased in children with an unfavorable vs. favorable outcome, p<0.05. On post-arrest day 1, NfL demonstrated the best outcome classification (AUROC 0.731 [95% confidence interval 0.642, 0.820]) while UCH-L1 performed best on days 2 (0.860 [0.785, 0.935]) and 3 (0.837 [0.747, 0.926]). After covariate adjustment, NfL concentrations on day 1 (odds ratio 5.9 [95% confidence interval 1.8, 19.2], day 2 (11.9 [3.8, 36.9]), and day 3 (10.2 [3.1, 33.3]), UCH-L1 on day 2 (11.3 [3.0, 42.4]) and day 3 (7.6 [2.1, 27.1]), GFAP on day 2 (2.3 [1.2, 4.5]) and day 3 (2.2 [1.2, 4.0]), and tau on day 1 (2.4 [1.1, 5.3]), day 2 (2.3 [1.3, 4.0]), and day 3 (2.0 [1.2, 3.6]) were associated with unfavorable outcome, p<0.05.

Conclusions

Blood-based brain injury biomarkers accurately prognosticated death or unfavorable adaptive behavior composite outcome at 1 year after pediatric cardiac arrest. Accuracy of biomarkers to predict neurodevelopmental outcomes beyond 1 year should be evaluated.

Clinical Trial Registration

URL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534

Clinical Perspective

What is new?

In children who suffered a cardiac arrest, post-arrest blood levels of neurofilament light, ubiquitin carboxyl-terminal esterase-L1, glial fibrillary acidic protein, and tau predicted death or unfavorable adaptive behavior composite outcome at 1 year.

Neurofilament light was the best performing biomarker to predict outcome on day 1 while ubiquitin carboxyl-terminal esterase-L1 performed best on days 1 and 2.

What are the clinical implications?

Blood-based brain injury biomarkers should be considered for clinical use to aid in prognostication after pediatric cardiac arrest.

Biomarker levels should be assessed as tools to aid in the prediction of neurodevelopmental outcomes beyond one year.