Differentiating Late Awakeners from Non-Awakeners in Comatose Cardiac Arrest Survivors: Diagnostic Value of Multimodal Monitoring in Patients with Indeterminate Prognosis

<b>Background</b>: Current guidelines recommend prognostication at 72 h after cardiac arrest, yet a subset of patients (Late Awakeners) recover consciousness after this window. This study investigated diagnostic markers to distinguish Late Awakeners from those with permanent poor outcomes (Non-Awakeners) to prevent premature withdrawal of life-sustaining therapy. <b>Methods</b>: We analyzed adult OHCA patients treated with TTM from 2009 to 2019 who remained comatose (Glasgow Coma Scale Motor score < 6) at 72 h. Patients were categorized as Late Awakeners (obeyed commands > 72 h) or Non-Awakeners. The diagnostic performance of maximal Neuron-Specific Enolase (NSE) levels within 72 h and brainstem reflexes was assessed using receiver operating characteristic (ROC) analysis. Model calibration was evaluated using the Hosmer-Lemeshow test, and internal validation was performed using bootstrap resampling. <b>Results</b>: Of 213 patients comatose at 72 h, 20 (9.4%) were identified as Late Awakeners. The median time to awakening was 4.4 days (IQR 3.4-8.3) from ROSC. Late Awakeners exhibited significantly preserved corneal reflexes (85.0% vs. 20.2%) compared to Non-Awakeners. The optimal NSE cut-off value to predict late awakening was <89.5 ng/mL (Sensitivity 95.0%, Specificity 50.3%, AUC 0.801). A multimodal approach combining NSE < 90 ng/mL and preserved corneal reflexes achieved a high specificity of 93.2% and an AUC of 0.899 (optimism-corrected: 0.896) for predicting late recovery. At six-month follow-up, 74.3% of Late Awakeners achieved good neurological outcome (CPC 1-2). <b>Conclusions</b>: Approximately 9% of patients comatose at 72 h eventually regain consciousness with favorable long-term outcomes. A multimodal diagnostic model combining intermediate NSE thresholds and preserved brainstem reflexes can effectively identify these Late Awakeners, suggesting that observation should be extended for patients fitting this profile.