Neurologic Prognostication After Cardiac Arrest Using Brain Biomarkers

Abstract

IMPORTANCE Brain injury biomarkers released into circulation from the injured neurovascular unit are important prognostic tools in patients with cardiac arrest who develop hypoxic ischemic brain injury (HIBI) after return of spontaneous circulation (ROSC).OBJECTIVE To assess the neuroprognostic utility of bloodborne brain injury biomarkers in patients with cardiac arrest with HIBI.DATA SOURCES Studies in electronic databases from inception to September 15, 2021. These databases included MEDLINE, Embase, Evidence-Based Medicine Reviews, CINAHL, Cochrane Database of Systematic Reviews, and the World Health Organization Global Health Library.STUDY SELECTION Articles included in this systmatic review and meta-analysis were independently assessed by 2 reviewers. We included studies that investigated neuron-specific enolase, S100 calcium-binding protein β, glial fibrillary acidic protein, neurofilament light, tau, or ubiquitin carboxyl hydrolase L1 in patients with cardiac arrest aged 18 years and older for neurologic prognostication. We excluded studies that did not (1) dichotomize neurologic outcome as favorable vs unfavorable, (2) specify the timing of blood sampling or outcome determination, or (3) report diagnostic test accuracy or biomarker concentration.DATA EXTRACTION AND SYNTHESIS Data on the study design, inclusion and exclusion criteria, brain biomarkers levels, diagnostic test accuracy, and neurologic outcome were recorded. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.MAIN OUTCOMES AND MEASURES Summary receiver operating characteristic curve analysis was used to calculate the area under the curve, sensitivity, specificity, and optimal thresholds for each biomarker. Risk of bias and concerns of applicability were assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. RESULTSWe identified 2953 studies, of which 86 studies with 10 567 patients (7777 men [73.6] and 2790 women [26.4]; pooled mean [SD] age, 62.8 [10.2] years) were included. Biomarker analysis at 48 hours after ROSC demonstrated that neurofilament light had the highest predictive value for unfavorable neurologic outcome, with an area under the curve of 0.92 (95% CI, 0.84-0.97). Subgroup analyses of patients treated with targeted temperature management and those who specifically had an out-of-hospital cardiac arrest showed similar results (targeted temperature management, 0.92 [95% CI, 0.86-0.95] and out-of-hospital cardiac arrest, 0.93 [95% CI, 0.86-0.97]).CONCLUSIONS AND RELEVANCE Neurofilament light, which reflects white matter damage and axonal injury, yielded the highest accuracy in predicting neurologic outcome in patients with HIBI at 48 hours after ROSC.

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…These data are consistent with an AUC of 0.96 for NfL in a smaller study (Meyer et al, 2022). As demonstrated before for TBI (Gao et al, 2020b), timing of sampling was relevant with blood NfL levels continuing to rise from 24 to 72 h after the event (Figure 3d in (Hoiland et al, 2022)).…”

“…There have been 33 meta‐analyses on the wealth of data on Nf as a biomarker for neurodegeneration over the past 15 years (Agah et al, 2018; Alagaratnam, Widekind, et al, 2021; Angelopoulou et al, 2021; Arneth & Kraus, 2022; Cai & Huang, 2018; Choong et al, 2019; Cong et al, 2021; Forgrave et al, 2019; Gao et al, 2020b; Ge et al, 2018; Hoiland et al, 2022; Hu et al, 2017; Jin et al, 2019; Karantali, Kazis, Chatzikonstantinou, et al, 2021; Karantali, Kazis, McKenna, et al, 2021; Katayama et al, 2020; Koychev et al, 2021; Li et al, 2016; Liu et al, 2022; Liu, Chen, et al, 2020; Martin et al, 2019; Mondello et al, 2021; Peng et al, 2022; Petzold et al, 2007; Rübsamen et al, 2022; Sako et al, 2015; Sferruzza et al, 2021; Wang et al, 2019; Wang et al, 2020a; Wang et al, 2020b; Xu et al, 2016; Zhang et al, 2022; Zhao et al, 2019; Zhou et al, 2021).…”

“…One meta‐analysis tested the prognostic value of a range of biomarkers in cardiac arrest (Hoiland et al, 2022). The summary receiver operating curve characteristic analyses (Figure 2a–f in (Hoiland et al, 2022)) showed an AUC of 0.92 for blood NfL levels ( n = 935) for predicting unfavourable outcome.…”

“…One meta‐analysis tested the prognostic value of a range of biomarkers in cardiac arrest (Hoiland et al, 2022). The summary receiver operating curve characteristic analyses (Figure 2a–f in (Hoiland et al, 2022)) showed an AUC of 0.92 for blood NfL levels ( n = 935) for predicting unfavourable outcome. This was a better AUC compared to NSE (0.84, n = 4898), S100B (0.85, n = 1724), GFAP (0.77, n = 911), tau (0.89, n = 792) or Ubiquitin carboxyl hydrolase L1 (0.88, n = 702).…”

Correlations Between EEG Spectral Power and Cerebral Perfusion in Adults Undergoing Extracorporeal Membrane Oxygenation

“…Numerous studies of patients with HIBI link elevated blood biomarkers of damaged neurons (neuron-specific enolase, NSE), axons (neurofilament light, NFL), and astrocytes (glial fibrillary acid protein, GFAP) to poor neurologic outcomes. (Diaz-Arrastia et al, 2020, Hoiland et al, 2022, Stammet, 2017) The NVU is comprised of these cell types together with pericytes and capillary endothelium, implicating it as the site of injury in patients with HIBI. (Iadecola, 2017) Under normal circumstances, neuronal activity contributes to the endothelial production of vasodilators including nitric oxide, prostanoids, and adenosine, all of which act to regulate cerebral blood flow.…”