The role of excitotoxicity in post-cardiac arrest brain injury

Post-cardiac arrest brain injury (PCABI) remains the leading cause of neurological disability and death following cardiac arrest. While considerable improvements have been made in achieving return of spontaneous circulation (ROSC) following cardiac arrest, effective neuroprotective therapies have lagged behind. This review examines the potential utility of targeting early glutamate-mediated excitotoxicity and explores why previous neuroprotective strategies have failed to improve clinical outcomes.

Preclinical models have recognized glutamate-mediated excitotoxicity as a key mechanism contributing to early ischemia-reperfusion injury following cardiac arrest. Early interruption of this excitotoxic cascade may preserve vulnerable neurons and mitigate downstream secondary brain injury. Emerging therapies targeting glutamate have demonstrated mixed but encouraging early clinical results. We propose that these therapies should be integrated into a broader multimodal neuroprotective strategy that adapts to the evolving pathophysiology of PCABI.

The failure of neuroprotective therapies after cardiac arrest may reflect delayed therapeutic delivery rather than the absence of viable biological targets. Future progress will require improved characterization of human cerebral ischemia, earlier implementation of neuroprotective interventions, and therapies that are tailored to the evolving biology of PCABI.