Correlation of blood biomarkers with microstructural brain injury in survivors of out-of-hospital cardiac arrest

Abstract

In-hospital mortality among resuscitated out-of-hospital cardiac arrest (OHCA) patients remains high. Identifying patients who will benefit from intensive care while avoiding prolonged, potentially unnecessary treatments is essential. Blood-based biomarkers provide a novel method for evaluating brain injury. The ability of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), neuron-specific enolase (NSE) and total-tau (t-tau) to measure white and grey matter injury is unestablished in comatose OHCA survivors treated with targeted temperature management (TTM) or xenon combined with TTM. We examined correlations between the biomarkers and white and grey matter injury assessed with diffusion tensor imaging (DTI). This was a randomised, single-blind, phase 2 clinical drug trial involving two multi-purpose intensive care units in Finland. It was conducted between August 2009 and March 2015. One hundred and ten comatose OHCA patients aged 24 to 76 years were randomly assigned to either inhaled xenon treatment combined with 24-hour TTM (33°C) (n=55, xenon group) or TTM alone (n=55, control group). MRI data were available from 96 patients, with a median imaging time of 53 hours (interquartile range, 47-64 hours) after OHCA. Biomarker data were obtained from 105 patients. In the control group of 48 patients, after adjusting for age, sex and site, a disruption of white matter microintegrity as measured by decreased fractional anisotropy FA of DTI, the primary endpoint of the trial, showed a significant negative correlation with NfL at 24 h, 48 h and 72 h (ρ -0.28 – -0.37; p<0.05), NSE at 48 h and 72 h (ρ -0.30 – -0.35; p <0.05) and t-tau only at 72 h (ρ -0.30; p <0.05). In the xenon group (n = 48), these correlations were absent at all timepoints. The NfL–FA partial correlations showed progressive divergence between the xenon and control groups, with a statistically significant between-group difference observed at 72 h (ρ = −0.37 vs. ρ = 0.14; p = 0.016). Cortical or basal ganglia grey matter mean diffusivity did not have consistent correlation with biomarker levels at different time points. No statistically significant differences were found between the xenon and control groups in the adjusted geometric mean levels of GFAP, NfL, NSE, or t-tau at various time points following OHCA. In conclusion, NfL correlated with fractional anisotropy in controls but not in the xenon group. This between-group difference reached significance at 72 h, suggesting that xenon may modify the relationship between axonal injury and white matter microstructure after OHCA. Trial registration - clinicaltrials.gov identifier: NCT00879892