Why Post-Cardiac Arrest Interventions Often Fail: Therapeutic Amenability and the Rapidly Closing Window of Neuroprotection.

Hypoxic-ischemic brain injury remains the leading cause of death and neurological disability after cardiac arrest. Although targeted temperature management (TTM) and other neuroprotective strategies have demonstrated promising results in preclinical studies, large randomized controlled trials have largely failed to show consistent clinical benefit. This review examines two major limitations that may contribute to these translational failures: delayed initiation of therapy beyond a time-limited therapeutic window and the lack of baseline injury severity stratification. Evidence from both experimental and clinical studies suggests that the opportunity to modify neurological injury may be confined to the first few hours after return of spontaneous circulation (ROSC). Delayed intervention may occur after irreversible neuronal injury, microvascular dysfunction, and impaired cerebrovascular autoregulation have already become established. In addition, cardiac arrest survivors represent a heterogeneous population. Patients with minimal injury may recover with standard supportive care, whereas those with severe irreversible injury are unlikely to benefit from neuroprotective interventions. Patients with moderate-severity brain injury may represent the subgroup most likely to respond to targeted therapies. Ultra-early stratification using neuroimaging, electroencephalography, circulating biomarkers, and clinical risk scores may help identify patients with therapeutic potential. This review proposes that future post-cardiac arrest research should integrate both time-sensitive intervention strategies and early injury severity stratification. Large prospective studies and randomized controlled trials are needed to determine not only whether interventions are effective, but also when they should be initiated and which patients are most likely to benefit.