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Multicenter Study
. 2022 Sep 1;5(9):e2230518.
doi: 10.1001/jamanetworkopen.2022.30518.

Association of Blood-Based Brain Injury Biomarker Concentrations With Outcomes After Pediatric Cardiac Arrest

Ericka L Fink  1   2   3 , Patrick M Kochanek  1   2   3 , Ashok Panigrahy  4 , Sue R Beers  5 , Rachel P Berger  2   3 , Hülya Bayir  1   2   3   6 , Jose Pineda  7 , Christopher Newth  7 , Alexis A Topjian  8 , Craig A Press  9 , Aline B Maddux  10 , Frederick Willyerd  11 , Elizabeth A Hunt  12   13 , Ashley Siems  12   13 , Melissa G Chung  14 , Lincoln Smith  15 , Jesse Wenger  16 , Lesley Doughty  16 , J Wesley Diddle  17 , Jason Patregnani  18 , Juan Piantino  19 , Karen Hallermeier Walson  20 , Binod Balakrishnan  21 , Michael T Meyer  21 , Stuart Friess  22 , David Maloney  1 , Pamela Rubin  1 , Tamara L Haller  23 , Amery Treble-Barna  24 , Chunyan Wang  23 , Robert R S B Clark  1   2   3 , Anthony Fabio  23 ; Personalizing Outcomes After Child Cardiac Arrest (POCCA) Investigators
Collaborators, Affiliations
Multicenter Study

Association of Blood-Based Brain Injury Biomarker Concentrations With Outcomes After Pediatric Cardiac Arrest

Ericka L Fink et al. JAMA Netw Open. .

Abstract

Importance: Families and clinicians have limited validated tools available to assist in estimating long-term outcomes early after pediatric cardiac arrest. Blood-based brain-specific biomarkers may be helpful tools to aid in outcome assessment.

Objective: To analyze the association of blood-based brain injury biomarker concentrations with outcomes 1 year after pediatric cardiac arrest.

Design, setting, and participants: The Personalizing Outcomes After Child Cardiac Arrest multicenter prospective cohort study was conducted in pediatric intensive care units at 14 academic referral centers in the US between May 16, 2017, and August 19, 2020, with the primary investigators blinded to 1-year outcomes. The study included 120 children aged 48 hours to 17 years who were resuscitated after cardiac arrest, had pre-cardiac arrest Pediatric Cerebral Performance Category scores of 1 to 3 points, and were admitted to an intensive care unit after cardiac arrest.

Exposure: Cardiac arrest.

Main outcomes and measures: The primary outcome was an unfavorable outcome (death or survival with a Vineland Adaptive Behavior Scales, third edition, score of <70 points) at 1 year 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 days 1 to 3 after cardiac arrest. Multivariate logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were performed to examine the association of each biomarker with outcomes on days 1 to 3.

Results: Among 120 children with primary outcome data available, the median (IQR) age was 1.0 (0-8.5) year; 71 children (59.2%) were male. A total of 5 children (4.2%) were Asian, 19 (15.8%) were Black, 81 (67.5%) were White, and 15 (12.5%) were of unknown race; among 110 children with data on ethnicity, 11 (10.0%) were Hispanic, and 99 (90.0%) were non-Hispanic. Overall, 70 children (58.3%) had a favorable outcome, and 50 children (41.7%) had an unfavorable outcome, including 43 deaths. On days 1 to 3 after cardiac arrest, concentrations of all 4 measured biomarkers were higher in children with an unfavorable vs a favorable outcome at 1 year. After covariate adjustment, NfL concentrations on day 1 (adjusted odds ratio [aOR], 5.91; 95% CI, 1.82-19.19), day 2 (aOR, 11.88; 95% CI, 3.82-36.92), and day 3 (aOR, 10.22; 95% CI, 3.14-33.33); UCH-L1 concentrations on day 2 (aOR, 11.27; 95% CI, 3.00-42.36) and day 3 (aOR, 7.56; 95% CI, 2.11-27.09); GFAP concentrations on day 2 (aOR, 2.31; 95% CI, 1.19-4.48) and day 3 (aOR, 2.19; 95% CI, 1.19-4.03); and tau concentrations on day 1 (aOR, 2.44; 95% CI, 1.14-5.25), day 2 (aOR, 2.28; 95% CI, 1.31-3.97), and day 3 (aOR, 2.04; 95% CI, 1.16-3.57) were associated with an unfavorable outcome. The AUROC models were significantly higher with vs without the addition of NfL on day 2 (AUROC, 0.932 [95% CI, 0.877-0.987] vs 0.871 [95% CI, 0.793-0.949]; P = .02) and day 3 (AUROC, 0.921 [95% CI, 0.857-0.986] vs 0.870 [95% CI, 0.786-0.953]; P = .03).

Conclusions and relevance: In this cohort study, blood-based brain injury biomarkers, especially NfL, were associated with an unfavorable outcome at 1 year after pediatric cardiac arrest. Additional evaluation of the accuracy of the association between biomarkers and neurodevelopmental outcomes beyond 1 year is needed.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fink reported receiving grants from the Neurocritical Care Society and personal fees from the American Board of Pediatrics and the Child Neurology Society outside the submitted work. Dr Kochanek reported having a patent pending for a method to improve neurological outcomes in temperature-managed patients outside the submitted work. Dr Berger reported having patents pending for angle biosensors and biomarkers in infant brain injury outside the submitted work. Dr Press reported receiving grants and personal fees from Marinus Pharmaceuticals outside the submitted work. Dr Hunt reported receiving grants from the American Heart Association and Inspire Pharmaceuticals and owning a patent for an end-tidal CO2 simulator outside the submitted work. Dr Piantino reported receiving personal fees from Applied Cognition outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
ICU indicates intensive care unit; PCPC, Pediatric Cerebral Performance Category; PI, primary investigator; and VABS-3, Vineland Adaptive Behavior Scales, third edition. aChildren may have met 1 or more criteria that made them ineligible for the study. bCriteria regarding likelihood of survival were determined by site research personnel; therefore, it was inappropriate to approach these patients for enrollment. cInformed consent from a parent or guardian was required for participation, and patient assent was obtained when appropriate.
Figure 2.
Figure 2.. Log-Transformed Biomarker Concentrations Overall and by Outcome Group
The Vineland Adaptive Behavior Scales, third edition (VABS-3) provides age-corrected standard scores (mean [SD], 100 [15] points) for individuals from birth through age 90 years in 4 domains (communication, daily living, socialization, and motor skills) and an overall adaptive behavior composite score, with higher scores denoting better functioning. A favorable outcome was defined as a VABS-3 overall adaptive behavior composite score of ≥70 points, and an unfavorable outcome was defined as a VABS-3 overall adaptive behavior composite score of <70 points or death. P < .001 for each comparison (with the exception of GFAP on day 1 [P = .002]) using a Kruskal-Wallis test. Circles represent outlier data points, diamonds represent statistically significant associations, and whiskers represent 95% CIs. GFAP indicates glial fibrillary acidic protein; NfL, neurofilament light; UCH-L1, ubiquitin carboxyl-terminal esterase L1.
See this image and copyright information in PMC

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