The utility of brain biomarkers in predicting survival and neurological outcomes in pediatric patients after cardiac arrest: A systematic review and meta-analysis

Abstract

Background: Cardiac arrest in children is associated with high morbidity and mortality, primarily due to neurological injury. Biomarkers linked to brain injury, released into circulation from compromised elements of the neurovascular unit, act as significant prognostic indicators in patients suffering from hypoxic-ischemic brain injury (HIBI) subsequent to the restoration of spontaneous circulation (ROSC) after pediatric cardiac arrest. The aim of this systematic review and meta-analysis is to evaluate the prognostic utility of brain injury biomarkers in predicting neurological outcomes and survival in patients following cardiac arrest in the pediatric population.

Methods: Bibliographic databases (PubMed, the Cochrane Library, and Embase) were searched from their inception to November 2024. A random-effect model was used for all analyses.

Results: Our meta-analysis demonstrates significant associations between various biomarkers and survival or neurological outcomes after cardiac arrest. Neuron-specific enolase (NSE) levels were consistently elevated in non-survivors and patients with unfavorable neurological outcomes, with pronounced differences observed on Days 2 and 3 (e.g., Day 3 mean difference: -88.48, 95%CI: -146.77 to -30.19, P = 0.003). Emerging biomarkers, including UCH-L1 and GFAP, showed striking differences, such as elevated UCH-L1 levels on Day 1 (mean difference: -415.41, 95%CI: -474.41 to -356.61, P < 0.001) and GFAP levels exceeding 4000 ng/mL in non-survivors on Day 2 (P < 0.001).

Conclusions: Our findings underscore the significant prognostic value of biomarkers in predicting survival and neurological outcomes following cardiac arrest. Neuron-specific enolase (NSE) consistently demonstrated its reliability across multiple time points, while emerging biomarkers like UCH-L1 and GFAP showed promising potential for early outcome stratification.

Keywords: S100β protein; brain markers; cardiac arrest; meta-analysis; neuron-specific enolase; survival.

Figure 1

PRISMA flow chart of the included studies

Figure 2

Group differences in brain biomarkers between survivors and patients who died (patients who survived [blue circles] and died [red squares]) outcomes at 0-, 24-, 48-, and 72-hours after return of spontaneous circulation report the mean concentration and spread (SD). Each graph notes the number of patients and studies included in determining the mean and standard deviation for each point. A. Neuron-specific enolase: Y-axis: NSE [conc] (μg/L), X-axis: Hours from ROSC; B. S100 Calcium binding protein B: Y-axis: S100B [conc] (μg/L), X-axis: Hours from ROSC; C. Neurofilament light chain: Y-axis: NFL [conc] (pg/mL), X-axis: Hours from ROSC; D. Ubiquitin C-terminal hydrolase L1: Y-axis: UCH-L1 [conc] (pg/mL), X-axis: Hours from ROSC; E. Tau protein: Y-axis: Tau [conc] (pg/mL), X-axis: Hours from ROSC; F. Glial fibrillary acidic protein: Y-axis: GFAP [conc] (pg/mL), X-axis: Hours from ROSC

Figure 3

Group differences in brain biomarkers between patients with favorable and unfavorable neurologic outcome (patients with favorable [blue circles] and unfavorable [red squares] outcomes) at 0-, 24-, 48-, and 72-hours after return of spontaneous circulation report the mean concentration and spread (SD). Each graph notes the number of patients and studies included in determining the mean and standard deviation for each point. Biomarkers at different time points after ROSC (return of spontaneous circulation). A. Neuron-specific enolase (NSE): Y-axis: NSE [conc] (μg/L), X-axis: Hours from ROSC, Trend: Increase in NSE levels over time, especially in the red dashed-line group; B. S100 Calcium binding protein B (S100B): Y-axis: S100B [conc] (μg/L), X-axis: Hours from ROSC, Trend: Initial increase followed by a decrease; C. Neurofilament light chain (NFL): Y-axis: NFL [conc] (pg/mL), X-axis: Hours from ROSC, Trend: Significant increase over time, particularly in the red dashed-line group; D. Ubiquitin C-terminal hydrolase L1 (UCH-L1): Y-axis: UCH-L1 [conc] (pg/mL), X-axis: Hours from ROSC, Trend: Increase up to 24–48 hours, then stabilization; E. Tau protein: Y-axis: Tau [conc] (pg/mL), X-axis: Hours from ROSC, Trend: Significant differences between groups, large variability in values; F. Glial fibrillary acidic protein (GFAP): Y-axis: GFAP [conc] (pg/mL), X-axis: Hours from ROSC, Trend: Gradual increase in values over time. Red dashed line — possibly indicates a group with poor prognosis. Blue dashed line — possibly indicates a group with better prognosis. All graphs represent mean values with confidence intervals