Neuron-Specific Enolase for Neurological Prognostication After Cardiac Arrest in the Era of Targeted Temperature Management: A Systematic Review and Meta-Analysis.

Background/Objectives: Neuron-specific enolase (NSE) is one of the most extensively investigated biomarkers for neurological prognostication after cardiac arrest. However, uncertainty remains regarding the influence of targeted temperature management (TTM) on NSE kinetics, optimal prognostic thresholds, and predictive accuracy. This systematic review and meta-analysis aimed to evaluate the prognostic performance of NSE and assess the impact of TTM on its clinical utility in contemporary post-resuscitation care. Methods: A systematic search of PubMed/MEDLINE, Embase, and Scopus was conducted to identify studies published between January 2000 and April 2026. Literature screening, data extraction, and quality assessment were performed in accordance with the PRISMA 2020 statement. Methodological quality was assessed using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool, when applicable. Quantitative synthesis was performed for studies reporting sufficiently homogeneous area under the receiver operating characteristic curve (AUC) data. Results: Twenty-one studies met the eligibility criteria and were included in the qualitative synthesis, of which seven were eligible for quantitative analysis. NSE demonstrated good overall prognostic performance for predicting neurological outcome after cardiac arrest, with a pooled AUC of 0.868 (95% CI: 0.849-0.885) and no significant between-study heterogeneity (I2 = 0%). Prognostic performance was generally highest when NSE was measured between 48 and 72 h after return of spontaneous circulation. Considerable variability was observed in reported prognostic thresholds, particularly across different TTM strategies. Serial NSE measurements and multimodal neuroprognostication approaches consistently improved predictive performance. Conclusions: NSE provides good prognostic accuracy for neurological outcome prediction after cardiac arrest and remains clinically valuable in patients managed with TTM. Serial measurements obtained between 48 and 72 h after return of spontaneous circulation appear to provide the greatest prognostic value. NSE should be interpreted as part of a multimodal neuroprognostication strategy rather than as a standalone predictor.