Wu_2026_Drug.Des.Devel.Ther_20_614204

BACKGROUND: Postoperative delirium (POD) affects 4-53% of elderly surgical patients, and is linked to prolonged hospitalization, functional decline, and elevated mortality. Traditional benzodiazepines are confirmed POD risk factors due to accumulation of long-acting metabolites. Remimazolam, an ultra-short-acting benzodiazepine metabolized by tissue esterases, is a promising alternative. However, existing reviews pool heterogeneous surgical populations, and overlook procedure-specific pathophysiology as well as the confounding effect of flumazenil reversal on delirium assessment. METHODS: We performed a focused literature search of PubMed/MEDLINE, Embase, and the Cochrane Library to June 2026, using terms including remimazolam, postoperative delirium, elderly, and surgery. Randomized controlled trials (RCTs), cohort studies, meta-analyses, and mechanistic studies were included, with reference lists hand-searched. Data were synthesized narratively, with emphasis on orthopedic surgery, frailty stratification, and mechanistic plausibility. RESULTS: Recent RCTs in frail elderly surgery patients show remimazolam does not significantly raise POD incidence compared with propofol, consistent with pooled meta-analytic findings. Remimazolam reduces intraoperative hypotension and vasopressor requirements, which are independent POD risk factors. Its potential neuroprotective mechanisms include attenuated systemic inflammation, microglial M2 polarization, preserved cerebral perfusion, and maintained sleep architecture. Routine flumazenil reversal in multiple trials is a key methodological confounder that may mask early emergence delirium. Remimazolam retains class-related risks such as respiratory depression, with limited long-term ICU data and unproven cost-effectiveness. CONCLUSION: Remimazolam does not increase POD in elderly surgical patients versus propofol or dexmedetomidine, while offering better hemodynamic stability. It serves as a valuable option for frail patients with cardiovascular comorbidities undergoing high-risk orthopedic procedures. Future RCTs should standardize frailty assessment, apply flumazenil-free delirium screening windows, enroll cognitively vulnerable populations, and evaluate long-term cognitive and cost outcomes.