BACKGROUND: Postoperative delirium (POD) is a frequent and serious complication, particularly in older adults undergoing major surgery. Pharmacologic prevention remains limited. This study aimed to evaluate whether perioperative ketamine or esketamine reduces POD incidence and to explore optimal administration strategies. METHODS: We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to January 2025 for randomized controlled trials (RCTs) comparing perioperative ketamine or esketamine with placebo or standard care. The primary outcome was POD incidence (risk ratio [RR]). Subgroup, meta‑regression, and trial sequential analysis (TSA) were performed. Sensitivity analyses addressed active comparators and unit‑of‑analysis issues. RESULTS: Twenty-five RCTs (3344 patients) were included (ketamine: 9; esketamine: 16). Both agents reduced POD risk versus control (ketamine: RR 0.69, 95% CI, 0.49–0.98, P = .04; esketamine: RR 0.58, 95% CI, 0.36–0.95, P = .03). Benefit was more evident with high-dose regimens (single bolus: ketamine >0.5 mg/kg or esketamine >0.25 mg/kg; cumulative dose: ketamine >1.0 mg/kg or esketamine >0.5 mg/kg), bolus-plus-infusion, and in major surgery. The effect was observed when POD was assessed 2 to 7 days postoperatively, but not within 24 hours. TSA indicated that current evidence remains inconclusive due to insufficient information size. Dizziness risk increased (RR 1.45, 95% CI, 1.14–1.84, P = .002), while postoperative depressive symptoms decreased (RR 0.78, 95% CI, 0.63–0.96, P = .02; based on 2 studies, 493 patients). CONCLUSIONS: Perioperative ketamine and esketamine show a potential signal for POD reduction, particularly with optimized dosing in high‑risk patients. However, the evidence is currently inconclusive, and increased dizziness risk precludes routine recommendation. Large, multicenter RCTs are urgently needed.
