Perioperative esketamine-containing strategies and postoperative neurocognitive outcomes in older surgical patients: a systematic review and meta-analysis of randomized controlled trials with certainty assessment.

BACKGROUND: Postoperative delirium (POD) is a common neurocognitive complication after surgery in older adults and is associated with adverse clinical outcomes. Esketamine, the S-enantiomer of ketamine and an N-methyl-D-aspartate (NMDA) receptor antagonist with established analgesic effects and potential anti-inflammatory properties, may therefore influence postoperative neurocognitive outcomes. However, the efficacy of ketamine-containing perioperative strategies for preventing POD remains uncertain. METHODS: This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement and registered in PROSPERO (CRD420261370159). Randomized controlled trials evaluating perioperative esketamine in adults aged ≥ 60 years undergoing surgery were included. The primary outcome was POD incidence. Secondary outcomes included postoperative cognitive dysfunction or delayed neurocognitive recovery, postoperative nausea and vomiting, and psychiatric adverse events. Random-effects models, subgroup analyses, exploratory exposure-response analyses, and GRADE certainty assessments were performed. RESULTS: Seventeen randomized controlled trials involving 2,914 participants were included, with eleven trials contributing to the primary POD analysis. Esketamine-containing perioperative regimens were associated with reduced POD incidence compared with control interventions (OR = 0.57, 95% CI 0.40-0.82; P = 0.002; I² = 45.8%). Four studies evaluating postoperative cognitive dysfunction or delayed neurocognitive recovery suggested a possible reduction (OR = 0.39, 95% CI 0.22-0.71; P = 0.002; I² = 0.0%), but evidence certainty was very low. Esketamine was associated with reduced postoperative nausea and vomiting (OR = 0.49, 95% CI 0.32-0.75; P = 0.001), without increased psychiatric adverse events (OR = 1.41, 95% CI 0.67-2.96; P = 0.37). Exploratory exposure-response analysis showed no significant association between cumulative esketamine exposure and POD risk. CONCLUSIONS: Perioperative esketamine may be associated with reduced POD incidence in older surgical patients; however, given heterogeneity in perioperative management and limited certainty of evidence, these findings should be interpreted cautiously and require confirmation in future standardized trials. TRIAL REGISTRATION: PROSPERO CRD: 420261370159. Retrospectively registered.