From Bench to Bedside: New Frontiers in Understanding and Treating Postoperative Delirium

Postoperative delirium is a frequent and serious neurocognitive complication in older surgical patients, characterized by acute impairments in attention, awareness, and cognition. It is associated with increased morbidity, prolonged hospitalization, and persistent cognitive decline. In this narrative review, we synthesize translational research on biological mechanisms underlying delirium and emerging targeted interventions. We conducted a comprehensive search of major biomedical databases, with no date restrictions but prioritizing publications from 2018 to 2025. The multifactorial pathophysiology involves dysregulated cholinergic and dopaminergic signaling, systemic and neuroinflammation, oxidative stress, and metabolic disturbances. Pre-existing cognitive impairment and frailty emerge as key clinical risk factors linked to these mechanisms. Aged rodent models replicate delirium-like cognitive deficits and validate mechanistic pathways, while human neuroimaging studies demonstrate disrupted functional connectivity in attentional and consciousness networks. Genomic and proteomic analyses have identified candidate biomarkers for early detection and risk stratification, and genetic variants associated with inflammation and neurodegeneration contribute to individual vulnerability. Emerging therapies targeting inflammation, microglial activation, mitochondrial function, and neurotransmitter balance show promise in preclinical studies, although clinical trials report mixed results. We advocate integrating basic science with clinical care through thorough preoperative assessment, multicomponent non-pharmacological strategies, and mechanism-based preventive measures to reduce the burden of postoperative delirium.