Abstract Body: Background: The prognostic value of serum biomarkers after out-of-hospital cardiac arrest (OHCA) depends on the timing, but the physiological basis for this temporal variation remains unclear. We investigated whether blood–brain barrier (BBB) integrity and biomarker-specific properties explain the time-dependent differences in prognostic performance.
Methods: We analyzed prospectively collected registry data from comatose adult OHCA survivors who underwent paired serum and cerebrospinal fluid (CSF) measurements of neuron-specific enolase (NSE; 47 kDa) and S100 calcium-binding protein B (S100B; 21 kDa) at 0 (H0), 24 (H24), 48 (H48), and 72 (H72) h after return of spontaneous circulation. BBB disruption was assessed using the CSF/serum albumin quotient (Q_A). Prognostic performance for poor neurological outcome at 6 months (Cerebral Performance Category 3–5) was evaluated with area under the receiver operating characteristic curve (AUC) analysis.
Results: Among 111 patients (59% poor outcome), 646 serum and 620 CSF samples were analyzed. BBB disruption was more severe in the poor outcome group at all timepoints (all P<0.001), peaking at H24 (Q_A 0.0282 [IQR 0.0150–0.120]) and remaining elevated at H72 (0.0228 [IQR 0.0147–0.0598]). In the poor outcome group, serum S100B levels peaked at H0 (0.80 ng/mL [IQR 0.39–2.81]) and declined despite a persistent elevation in CSF levels at or above the upper detection limit (≥30 ng/mL, denoted as the assay maximum). Conversely, NSE levels progressively increased in both compartments, with serum and CSF levels increasing in parallel over time (Fig. 1). Serum NSE concentrations showed a time-dependent improvement in prognostic accuracy, peaking at H72 (AUC 0.88), whereas S100B concentrations maintained stable performance across all timepoints (AUCs 0.79–0.85, all P > 0.4) (Fig. 2). Notably, the prognostic performance of S100B remained relatively consistent regardless of BBB disruption severity, whereas NSE showed progressively improved predictive accuracy with increased BBB disruption (Fig. 3).
Conclusions: Serum NSE levels closely reflect the degree of BBB disruption and CSF levels, while S100B exhibits a transient early-phase profile, with decreased serum detectability over time, even in the presence of sustained CSF elevation or severe BBB disruption. These findings highlight the importance of interpreting biomarker kinetics across compartments and timepoints rather than relying on molecular weight or BBB status alone.