The Postcardiac Arrest Inflammatory Response: Mechanisms and Therapeutic Targets

Abstract

Postcardiac arrest syndrome is a complex multisystem disorder that evolves after return of spontaneous circulation and remains a major determinant of morbidity and mortality following out-of-hospital cardiac arrest. Beyond anoxic brain injury and transient myocardial dysfunction, many patients develop a systemic ischemia/reperfusion response with endothelial and microvascular dysfunction, vasoplegia, and immune dysregulation—features that contribute to shock and organ failure. Hemodynamic instability is often mixed with low systemic vascular resistance despite preserved or recovering cardiac output, but management is still largely supportive and centered on achieving a target mean arterial pressure. An increasing understanding of the central role of inflammation, including gastrointestinal barrier disruption, cytokine release, complement activation, nitric oxide–cGMP signaling, and immune phenotypic heterogeneity has prompted evaluation of targeted adjunctive therapies. However, randomized trials of immunomodulators and other vasoactive strategies have yielded mixed results, reflecting biological heterogeneity and limited phenotypic stratification. This review synthesizes contemporary understanding of the inflammatory and hemodynamic mechanisms underpinning postcardiac arrest syndrome, examines current and emerging pharmacologic strategies, and highlights priorities for future investigation, including mechanistic phenotyping, prospective biobanking, and prospective trial requirements to guide more precise management strategies in postcardiac arrest care.