Effects of esketamine on postoperative delirium in adult patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Postoperative delirium (POD) is a common perioperative complication linked to poor prognosis. As the S-enantiomer of racemic ketamine, esketamine exhibits neuroprotective potential, yet its overall efficacy and safety for perioperative neurocognitive protection await systematic confirmation. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to November 8, 2025, for randomized controlled trials (RCTs) examining esketamine's effect on POD in patients under elective general anesthesia. Meta-analyses were conducted via Stata/MP 18.0: risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data, and mean differences (MD) or standardized mean differences (Cohen's d) with 95% CIs for continuous outcomes. Cochrane RoB 2.0 Tool assessed bias risk in included studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was adopted to evaluate the certainty of all evidence. RESULTS: Twenty-two RCTs involving 2,860 patients were included. Perioperative esketamine administration significantly reduced POD incidence (RR = 0.57, 95% CI: 0.43 to 0.75; p < 0.001), and this protective effect was consistent across subgroups (age, surgical type, dosing regimen). Esketamine also decreased delayed neurocognitive recovery (dNCR) incidence (RR = 0.60, 95% CI: 0.44 to 0.82; p < 0.01), improved short-term postoperative recovery quality (QoR-15 score, MD = 4.80, 95% CI: 1.06 to 8.55; p < 0.01), and reduced serum IL-6 (Cohen's d = -1.47, 95% CI: -2.40 to -0.55; p < 0.01) and S100β (Cohen's d = -0.85, 95% CI: -1.49 to -0.20; p = 0.01) levels at 1 day postoperatively. Additionally, it reduced postoperative agitation, with no obvious elevation in overall adverse event incidence. Studies with follow-up < 3 days showed no significant POD benefit, and no effect on NSE levels was observed. GRADE assessment yielded low or very low certainty for all outcomes, attributed to clinical heterogeneity, single-region study population, inconsistent outcome assessment, and limited secondary data. CONCLUSION: Perioperative esketamine exerts favorable neuroprotective and recovery-improving effects in Chinese surgical populations, reducing POD, dNCR, postoperative neuroinflammation, neuronal injury, and agitation with a safe adverse event profile. Restricted by geographical homogeneity, substantial heterogeneity, and low GRADE evidence certainty, further high-quality international multicenter trials are required to validate and standardize its clinical application. SYSTEMATIC REVIEW REGISTRATION: This systematic review has been formally registered. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251184190.