Efficacy and safety of perioperative intravenous esketamine for the prevention of postoperative sleep disturbance and reduction of its incidence in adult surgical patients: a systematic review, meta-analysis, and trial sequential analysis of randomiz

Abstract Background Postoperative sleep disturbance (PSD) is a common complication hindering recovery. Esketamine, an S (+)-enantiomer of ketamine, has shown potential in improving sleep and mood, but its specific efficacy in preventing PSD remains to be quantitatively synthesized. This study aims to evaluate the efficacy and safety of perioperative esketamine in preventing PSD and reducing its incidence in adult surgical patients using meta-analysis and trial sequential analysis (TSA). Methods We searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov from inception to August 20, 2026, for RCTs comparing perioperative esketamine with a normal saline placebo control regarding the incidence of PSD in patients undergoing various surgical procedures. Primary outcomes were PSD incidence on postoperative days (POD) 1 and 3. Secondary outcomes included sleep, anxiety, depression, and pain scores, as well as intraoperative remifentanil consumption, quality of recovery and adverse events. TSA was conducted to verify the conclusiveness of the evidence. Results A total of 15 RCTs involving 1,863 patients were included. Esketamine significantly reduced the incidence of PSD on POD1 and POD3. TSA confirmed these primary outcomes as conclusive. It also significantly decreased the incidence of PSD on POD7 although TSA indicated that the current evidence for this late time point remains inconclusive due to limited sample size. Furthermore, esketamine significantly improved subjective sleep quality and overall quality of recovery, while alleviating pain, reducing early anxiety, and decreasing intraoperative remifentanil consumption. However, these therapeutic benefits did not extend to postoperative depression scores. Subgroup analyses revealed consistent efficacy across elderly (≥ 60 years) and non-elderly patients. Continuous intraoperative infusion and other administration routes demonstrated comparable protective effects, and sub-anesthetic infusion rates below 0.5 mg/kg/h were sufficient to achieve clinical benefits. No significant differences were found regarding the incidence of adverse events between groups. Conclusion Perioperative esketamine safely and effectively reduces the incidence of PSD. Low dose administration including continuous infusion below 0.5 mg/kg/h serves as an effective preventive option demonstrating consistent efficacy across both elderly patients aged 60 years or older and younger populations. Trial registration CRD420251250904.