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

Purpose

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).