Low-dose esketamine for postoperative fatigue after gynecological laparoscopic surgery: a randomized controlled trial

BACKGROUND: Postoperative fatigue is a prevalent complication delaying early recovery after gynecological laparoscopic surgery, with no proven effective interventions. To investigate the effect of continuous intraoperative low-dose esketamine on postoperative fatigue in patients undergoing gynecological laparoscopic surgery. METHODS: This single-center, double-blind, randomized placebo-controlled trial enrolled 116 elective gynecological laparoscopic surgery patients, randomly assigned 1:1 to the esketamine group (0.2 mg·kg⁻¹·h⁻¹ esketamine infusion during surgery, n = 58) or control group (equal volume normal saline, n = 58). The primary outcome was the incidence of postoperative fatigue on postoperative day 1 (POD1, Chalder Fatigue Scale score ≥ 4). Secondary outcomes included Chalder Fatigue Scale scores, 15-item Quality of Recovery (QoR-15) scores, Visual Analogue Scale (VAS) pain scores, perioperative drug consumption, and safety events. RESULTS: In the primary intention-to-treat analysis, the incidence of POD1 postoperative fatigue was 23.3% (14/60) in the esketamine group and 40.0% (24/60) in the control group (risk difference - 16.7%, OR = 0.46, 95% CI 0.21-1.01, P = 0.050). Esketamine group had significantly lower POD1 fatigue scores, better recovery quality and pain control on POD1 and POD3, reduced intraoperative sufentanil and ephedrine consumption, (all P < 0.05). No significant differences in adverse events were observed between groups (all P > 0.05). CONCLUSION: Intraoperative low-dose esketamine shows a favorable effect on reducing postoperative fatigue, and significantly improves recovery quality and analgesia, without increasing adverse events in patients undergoing gynecological laparoscopic surgery. The primary ITT analysis shows a borderline significant reduction in fatigue incidence, which is supported by a statistically significant result in the per-protocol sensitivity analysis. TRIAL REGISTRATION: This study was prospectively registered at the Chinese Clinical Trial Registry (ChiCTR, https://www.chictr.org.cn/showproj.html?proj=290957), with the clinical trial registration number ChiCTR2500112382, and the registration date is November 13, 2025.