Effects of Esketamine and Magnesium Sulfate on Postoperative Fatigue Syndrome in Patients Undergoing Laparoscopic Cholecystectomy: A Randomized, Double-Blind, Placebo-Controlled, 2×2 Factorial Trial

Jie Zhou, Qian Liu, Lei Wang, Lulu Shen, Wenzhuang Zheng, Chenglan XieDepartment of Anesthesiology, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, Jiangsu, 223002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chenglan Xie, Department of Anesthesiology, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, Jiangsu, 223002, People’s Republic of China, Tel +86 13776701556, Email xiechenglan@163.comPurpose: This 2× 2 factorial trial aimed to evaluate the main effects and interaction of esketamine and magnesium sulfate on postoperative fatigue syndrome (POFS) in patients undergoing laparoscopic cholecystectomy (LC).Patients and Methods: In this randomized, double-blind, 2× 2 factorial trial, 128 patients scheduled for elective LC were randomized to receive intravenous esketamine (0.25 mg/kg load, 0.125 mg/kg/h maintenance), magnesium sulfate (30 mg/kg load, 10 mg/kg/h maintenance), both, or placebo. The primary outcome was the Christensen Fatigue Scale (CFS) score on postoperative day 1 (POD 1). Secondary outcomes included longitudinal CFS and Identity-Consequence Fatigue Scale (ICFS) scores, Quality of Recovery-15 (QoR-15), pain scores, intraoperative hemodynamics, anesthetic consumption, and safety profiles. All randomized participants were included in the primary intention-to-treat analysis. Main effects and interactions were evaluated using generalized linear models (GLM), generalized estimating equations, and linear mixed-effects models. ClinicalTrials.gov: NCT07131033 (registered August 13, 2025).Results: Of the 128 randomized patients, 10 were excluded, leaving 118 in the per-protocol set, which was used only as a descriptive sensitivity analysis. Based on the prespecified factorial GLM, both esketamine and magnesium sulfate exhibited significant main effects in reducing POD 1 CFS scores (esketamine: mean difference [MD], − 1.12; 95% confidence interval [CI], − 1.69 to − 0.55; P < 0.001; magnesium sulfate: MD, − 0.69; 95% CI, − 1.26 to − 0.12; P = 0.018), with no significant interaction (P = 0.592). In the longitudinal analysis, esketamine reduced CFS scores on POD 1 (MD, − 1.17; P = 0.001), whereas the magnesium sulfate contrast at POD 1 was not statistically significant after Bonferroni correction (MD, − 0.71; P = 0.300). Neither drug significantly affected ICFS scores (P > 0.05). Esketamine improved QoR-15 scores on POD 1 and POD 2, with MDs of 10.41 (P < 0.001) and 4.60 (P = 0.001) points, respectively. Magnesium sulfate improved QoR-15 scores on POD 1 by 7.48 points (P < 0.001) but not on POD 2. Both interventions decreased early postoperative pain and intraoperative propofol and remifentanil consumption (P < 0.001). Magnesium sulfate significantly prolonged extubation time (MD, 1.69 min; 95% CI, 0.26 to 3.12; P = 0.021), whereas esketamine did not reach statistical significance; neither agent significantly increased PACU stay. No significant differences were observed in prespecified adverse events.Conclusion: In this 2× 2 factorial trial, perioperative esketamine was associated with reduced acute postoperative fatigue and improved early recovery after laparoscopic cholecystectomy, whereas the magnesium sulfate effect was significant in the GLM model but not confirmed by the corrected longitudinal analysis. Both agents had anesthetic-sparing and early analgesic effects, and no significant esketamine–magnesium interaction was detected for the primary outcome. Magnesium sulfate was also associated with intraoperative hemodynamic changes.Keywords: esketamine, magnesium sulfate, postoperative fatigue syndrome, postoperative pain, laparoscopic cholecystectomy, factorial design