Laparoscopic cholecystectomy (LC), while minimally invasive, triggers postoperative fatigue syndrome (POFS) through mechanisms including ischemia-reperfusion injury, neuroendocrine stress (sustained cortisol elevation), and inflammation-driven mitochondrial dysfunction (IDO-mediated kynurenine production). Esketamine, an NMDA receptor antagonist, counteracts POFS by blocking central sensitization, suppressing neuroinflammation (e.g., microglial IL-6 release), and enhancing neuroplasticity via BDNF/TrkB upregulation. Magnesium sulfate complements this by antagonizing NMDA/voltage-gated calcium channels to reduce inflammation and calcium overload, while optimizing cellular energy metabolism as an ATPase cofactor and alleviating muscle spasms. Crucially, their combination holds synergistic potential: esketamine targets central fatigue pathways, while magnesium addresses peripheral metabolic and muscular components. This study aims to determine their individual and interactive effects on POFS, recovery quality, and sleep outcomes in LC patients, establishing an efficient, safe strategy to accelerate postoperative rehabilitation.

This randomized, double-blind trial investigated the effects of esketamine and magnesium sulfate on postoperative fatigue syndrome in patients undergoing laparoscopic cholecystectomy. Using computer-generated randomization and sealed envelopes, 120 patients were allocated in a 1:1:1:1 ratio to four groups: Group E received intravenous esketamine (0.25 mg/kg over 10 min pre-induction followed by 0.25 mg/kg/h); Group M received magnesium sulfate (30 mg/kg over 10 min pre-induction followed by 10 mg/kg/h); Group EM received both drugs concurrently at the specified doses; and Group C received volume-matched normal saline. Patients, attending anesthesiologists, and outcome assessors remained blinded to group assignment throughout the study, with intraoperative management handled by a separate non-investigating anesthesiologist to preserve blinding integrity.

The patients were routinely fasted for 6 h and abstained from drinking for 2 h preoperatively. All patients were not anesthetized with premedication. After admission, patients were routinely administered oxygen by mask, peripheral venous access was opened and cardiac monitoring, including noninvasive blood pressure, pulse oximetry, electrocardiogram, body temperature and entropy index, was routinely performed. Both groups were routinely rapidly induced with midazolam 0.05 mg/kg, propofol 1.5 mg/kg, rocuronium bromide 1mg/kg, and sufentanil 0.5 μg/kgrespectively. Preoxygenation was administered for 3 min followed by endotracheal intubation and connection to a ventilator with 50％ oxygen of 2.0 L/min for respiratory control. Setting parameters: tidal volume 6～8 ml/kg, inspiratory ratio 1:2, control PETCO2 at 35～40 mmHg. During anaesthesia maintenance, remifentanil 0.1-0.5 ug/kg/min, sevoflurane (1%-3%) and propofol 4-12 mg/kg/h were continuously infused in all three groups.Sevoflurane (1%-3%), and Propofol 4-12 mg/kg/h were continuously infused in all three groups.A four-channel microinfusion pump was used for synchronous intravenous infusion. Each drug was administered through an independent channel to avoid drug interactions, and the drugs were continuously infused during the operation until the end of the surgery. The appropriate depth of anesthesia (entropy index RE/SE 40-60) was maintained by adjusting the infusion rate of propofol and remifentanil. At the appropriate depth of anaesthesia, vasoactive drugs (ephedrine, phenylephrine, nitroglycerin) can be administered to regulate blood pressure.After the operation, the patient was immediately transferred to the PACU. when the patient regained consciousness and could breathe on his own, the tracheal tube was removed. In the PACU, 30 mg of ketorolac tromethamine was administered intravenously to relieve analgesia if the patient's NRS score was >3 or if the patient required analgesia.

Inclusion Criteria:

• Age between 18 and 65 years
• American Society of Anesthesiologists (ASA) classification I-II
• Patients scheduled for LC under general anaesthesia and with a procedure duration of less than 60 minutes.

Exclusion Criteria:

• Patients who do not sign the informed consent;
• patients with severe diseases of major organs such as the heart, brain, lungs, liver, and kidneys;
• patients with adverse drug reactions to esketamine or magnesium sulfate;
• patients with uncontrolled hypertension or hyperthyroidism;
• patients with endocrine and metabolic diseases or neurological diseases;
• pregnant or lactating women;
• long-term users of sedatives, analgesics, or long-term alcohol abusers;
• patients with a history of mental illness, language communication barriers, or inability to understand the content of the experiment;
• patients with difficult airways during anesthesia induction requiring a change in the conventional intubation method;
• patients with sinus bradycardia or atrioventricular block;
• patients with concurrent cholangitis, biliary obstruction, or pancreatitis.

The randomization sequence was generated by a computer and handed over in sealed opaque sequentially numbered envelopes. The envelope was opened by anaesthetist not involved in the study and drugs were dispensed as per the allocation card. The configured drugs were then handed over to experienced anaesthetists who were not aware of the subgroups