Perioperative esketamine for prevention of postoperative sleep disturbance after anesthesia: a systematic review and meta-analysis of randomized controlled trials

Background Postoperative sleep disturbance (PSD) is a common complication after general anesthesia and is associated with delayed recovery and other adverse postoperative outcomes. Perioperative esketamine may improve postoperative sleep, but current evidence remains inconclusive. This systematic review and meta-analysis assessed the efficacy and safety of perioperative esketamine for preventing PSD in adults undergoing surgery under general anesthesia. Methods PubMed, Embase, the Cochrane Library, and CNKI were searched from inception to 10 March 2026, for randomized controlled trials comparing perioperative esketamine with placebo or non-esketamine controls. The primary outcomes were the incidence of Postoperative sleep disturbance on postoperative day 1, 2, 3, and 7. Secondary outcomes included common perioperative adverse events. Risk ratios (RRs) with 95% confidence intervals were pooled using a random-effects model. Risk of bias, certainty of evidence, and robustness of key findings were assessed using the Cochrane Risk of Bias tool, GRADE, trial sequential analysis, and leave-one-out sensitivity analyses. Results Twenty-two randomized controlled trials were included. Esketamine significantly reduced PSD incidence on POD1 (RR = 0.58, 95% CI: 0.51–0.66; I 2 = 0%), POD2 (RR = 0.40, 95% CI: 0.28–0.58; I 2 = 0%), and POD3 (RR = 0.55, 95% CI: 0.45–0.68; I 2 = 9%), but not on POD7 (RR = 0.77, 95% CI: 0.55–1.08). Although statistical heterogeneity was low, clinical heterogeneity should be considered because of differences in surgical populations, patient characteristics, esketamine regimens, and sleep assessment methods. Subgroup analyses generally supported the early postoperative benefit, whereas POD3 findings stratified by preoperative sleep status should be interpreted cautiously. No statistically significant differences were observed in the analyzed adverse events, but safety evidence remains limited. Sensitivity analyses and trial sequential analysis supported the robustness of POD1 and POD3 findings. The certainty of evidence for early PSD outcomes was moderate. Conclusion Perioperative esketamine may reduce early PSD incidence, particularly from POD1 to POD3. However, evidence mainly reflects subjective binary PSD outcomes, while effects on objective sleep parameters and longer-term sleep recovery remain uncertain. Further high-quality, multicenter trials using standardized and objective sleep assessments are needed. Clinical Trial Registration PROSPERO (CRD420261364623).