Dexmedetomidine plus esketamine may reduce postoperative delirium and injuryCombined dexmedetomidine and esketamine may protect brain function after surgery

Perioperative neurocognitive disorders (PND), including postoperative cognitive dysfunction (POCD) and postoperative delirium (POD), are common complications after surgery and are associated with poor clinical outcomes. This systematic review and meta-analysis aimed to evaluate the effects of perioperative combined administration of dexmedetomidine and esketamine on postoperative neurocognitive function and perioperative recovery outcomes. PubMed, Embase, Web of Science, Cochrane Library, CNKI, and the Chinese Medical Journal Full-text Database were systematically searched from database inception to April 2026. Randomized controlled trials and prospective cohort studies evaluating perioperative dexmedetomidine combined with esketamine were included. The primary outcomes were postoperative neuronal injury biomarkers and cognitive function scores. Secondary outcomes included postoperative delirium, postoperative nausea and vomiting (PONV), and postoperative pain scores. Meta-analysis was performed using RevMan and Stata software, and evidence quality was assessed using the GRADE approach. Eight studies involving 1,118 patients were included, comprising seven randomized controlled trials and one prospective cohort study. Compared with controls, combined dexmedetomidine and esketamine was associated with lower postoperative 24-h serum neuron-specific enolase (NSE) levels (SMD = −0.95, 95% CI: −1.16 to −0.73, I2 = 18%) and S-100β levels (SMD = −1.17, 95% CI: −1.39 to −0.95, I2 = 0%). The combined intervention was also associated with higher MMSE scores (SMD = 0.84, 95% CI: 0.05 to 1.63, I2 = 91%) and MoCA scores (SMD = 0.49, 95% CI: 0.20 to 0.79, I2 = 19%). In addition, the risks of POD (RR = 0.45, 95% CI: 0.29 to 0.70, I2 = 0%) and PONV (RR = 0.50, 95% CI: 0.35 to 0.72, I2 = 0%) were lower, and early postoperative pain scores were lower in the combined intervention group (SMD = −0.51, 95% CI: −0.87 to −0.14, I2 = 69%). Sensitivity analyses demonstrated stable results. According to the GRADE assessment, the quality of evidence ranged from moderate to low, and the 24-h cognitive test scores should be interpreted as short-term postoperative assessments. The findings suggest that perioperative combined administration of dexmedetomidine and esketamine may be associated with attenuated postoperative neuronal injury, improved early cognitive function, and reduced risks of POD, PONV, and pain. Further high-quality multicenter randomized controlled trials are warranted to confirm these preliminary findings.