Early neurofilament light chain supports escala-tion decision-making in comatose cardiac arrest patients

Background

Out-of-hospital cardiac arrest (OHCA) has high mortality, mainly from hypoxic–ischemic brain injury. In patients hemodynamically unstable after return of spontaneous circulation, escalation to advanced therapies such as renal replacement therapy or, less commonly, mechanical circulatory support may be considered. However, these decisions are often made while patients are deeply sedated and mechanically ventilated, before reliable neurological assessment is feasible.

Neurofilament light chain (NfL) is a sensitive biomarker of hypoxic–ischemic neuronal injury and measurement of NfL at 24 hours may provide an early, quantitative estimate of cerebral injury severity prior to clinical awakening.

Purpose

To determine if 24-hour NfL discriminates neurological from non-neurological death following OHCA and to define a clinically actionable threshold to support early escalation decision-making.

Methods

This post-hoc exploratory analysis was conducted within the BOX trial (NEJM 2022), which included comatose adults resuscitated from OHCA. Plasma NfL was measured 24 hours after return of spontaneous circulation, and results were blinded to treating clinicians. Cardiac index (CI)and pulmonary wedge pressure were recorded by a pulmonary artery catheter (PCWP) at 24 hours. One-year mortality was classified as neurological or non-neurological by assessors blinded to NfL concentrations. Discrimination was assessed using ROC analysis with AUC and 95% confidence intervals. A high-specificity threshold (≥95%) for neurological death was prespecified.

Results

Of 789 patients, 523 patients had a 24-hour NfL measurement and for these patients neurological death occurred in 127 (24.3%), non-neurological death in 38 (7.3%), and 358 (68.5%) survived to one year. Twenty-four–hour NfL showed excellent discrimination for neurological death versus all other outcomes (AUC 0.97, 95% CI 0.95–0.99), see Figure 1. A prespecified high-specificity threshold (lowest cutoff achieving ≥95% specificity) was NfL ≥875 pg/mL, yielding sensitivity 94.5% and specificity 95.2% (PPV 86.3%, NPV 98.2%; accuracy 95.0%).

Among non-survivors alive at 24 hours (n=165), NfL discriminated neurological from non-neurological death (AUC 0.86, 95% CI 0.78–0.95); applying the same 875 pg/mL threshold, 71.1% (27/38) of non-neurological deaths had NfL below the cutoff (Figure 2).

CI and PCWP did not discriminate all-cause mortality vs survivors; among non-survivors CI modestly discriminated neurological vs non-neurological death (AUC 0.73, 95% CI 0.63–0.83

Conclusion

Twenty-four–hour NfL differentiates neurological from non-neurological death with good accuracy and provides early quantification of hypoxic–ischemic brain injury before clinical awakening. This ability to distinguish neurological irreversibility from potentially reversible causes may help inform the clinician on escalation decisions in patients with salvageable neurological prognosis.Figure 1.Figure 2.