Neurocognitive complications, mainly delirium and neurocognitive disorders, are common cerebral complications in older patients after surgery and associated with worse long-term outcomes. An ongoing 2×2 factorial trial conducted by the investigators plan to test the effects of perioperative dexmedetomidine-esketamine combination and transcranial direct current stimulation (tDCS) on postoperative neurocognitive complications in older patients. This long-term follow-up of the ongoing trial aims to investigate the effects of perioperative dexmedetomidine-esketamine combination and tDCS on long-term outcomes in older patients after noncardiac surgery.
Aged 65 to 90 years;
Preoperative Mini-Mental State Examination (MMSE) score < 27 points, indicating possible cognitive impairment ranging from mild to moderate;
Scheduled to undergo elective non-cardiac, non-neurosurgical surgery under general anesthesia, with an expected surgical duration > 1 hour;
Required patient-controlled intravenous analgesia (PCIA) after surgery.
Preoperative inability to communicate due to coma, severe dementia, endstage disease, or language impairment;
History of schizophrenia, epilepsy, Parkinson's disease, brain trauma/surgery, or myasthenia gravis;
Presence of metal implants in the intracranial or cervical region (such as cochlear implants, aneurysm clips, deep brain stimulation electrodes), or skin damage or severe skin disease on the head;
Severe cardiac dysfunction (left ventricular ejection fraction < 30%), comorbid with sick sinus syndrome, severe bradycardia (heart rate < 50 bpm), or second-degree or higher atrioventricular block, or implantation of a cardiac pacemaker;
Factorial
Dex-Esk
DrugDexmedetomidine-esketamine combination (1 μg/mL dexmedetomidine and 0.5 mg/mL esketamine) will be administered after anesthesia induction, firstly as a loading dose at a rate of \[0.4 x body weight (kg)\] mL/h for 30 minutes (0.2 μg/kg dexmedetomidine and 0.1 mg/kg esketamine), followed by a maintenance infusion at a rate of \[0.1 x body weight (kg)\] mL/h (0.1 μg/kg/h dexmedetomidine and 0.05 mg/kg/h esketamine) until one hour before expected end surgery. Postoperative patient-controlled analgesia will be established with a 100 mL mixture (containing 1.0 μg/mL sufentanil, 1.25 μg/mL dexmedetomidine, and 0.25 mg/mL esketamine in normal saline), programmed to deliver 2-mL boluses with an 8-minute lockout interval and an 1-mL/h background infusion, and provided for 48 hours (at least 24 hours).
Placebo
DrugPlacebo (normal saline) will be administered after anesthesia induction, firstly as a loading dose at a rate of \[0.4 x body weight (kg)\] mL/h for 30 minutes, followed by a maintenance infusion at a rate of \[0.1 x body weight (kg)\] mL/h until one hour before expected end surgery. Postoperative patient-controlled analgesia will be established with a 100 mL mixture (containing 1.0 μg/mL sufentanil in normal saline), programmed to deliver 2-mL boluses with an 8-minute lockout interval and an 1-mL/h background infusion, and provided for 48 hours (at least 24 hours).
Active tDCS
DeviceActive transcranial direct current stimulation (tDCS) will be administered using a battery-powered stimulator. The anode will be positioned over the left dorsolateral prefrontal cortex (DLPFC, F3) and the cathode over the right supraorbital region (Fp2). The stimulation intensity will be set at 2.0 mA, featuring a 30-second linear ramp-up at the beginning and a 30-second ramp-down at the end of each session. Each participant will receive a total of three 20-minute sessions of active tDCS. The first session will be provided at 40 minutes after extubation in the post-anesthesia care unit. Two other sessions will be provided on postoperative days 1 and 2 (between 10:00 and 12:00 am).
Sham tDCS
DeviceSham transcranial direct current stimulation (tDCS) will be administered using a battery-powered stimulator. The anode will be positioned over the left dorsolateral prefrontal cortex (DLPFC, F3) and the cathode over the right supraorbital region (Fp2). To ensure blinding, the device will deliver a initial 30-second ramp-up to 2.0 mA followed immediately by a 30-second ramp-down to 0 mA. The device remains "ON" for the remaining 19 minutes with no effective current output, mimicking the peripheral scalp sensation without delivering cortical modulation. Each participant will receive a total of three 20-minute sessions of sham tDCS. The first session will be provided at 40 minutes after extubation in the post-anesthesia care unit. Two other sessions will be provided on postoperative days 1 and 2 (between 10:00 and 12:00 am).
Incidence of postoperative neurocognitive disorders (pNCD) at 3 months
Cognitive function will be assessed at baseline and at 3 months after surgery using the Telephone version of Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher scores indicating better cognitive function）. Postoperative neurocognitive disorders (pNCD) is defined as: a \|Z\| value of decline in T-MoCA score ≥1.96. Z value = \[(change from baseline in T-MoCA score in a surgical patient - mean change from baseline in T-MoCA scores in the non-surgical group)\] / (standard deviation of change from baseline in T-MoCA scores in the non-surgical group).
Event-free survival
Time interval from index surgery to cancer recurrence/metastasis/progression, new-onset cancer, new-onset serious illness (requiring hospitalization), or all-cause death, whichever comes first.
Overall survival
Time interval from index surgery to all-cause death.
Recurrence-free survival
Time interval from index surgery to cancer recurrence/metastasis/progression or all-cause death, whichever comes first.
Activities of daily living score
Daily living activities will be assessed with the activities of daily living (ADL; scores range from 1 to 56, with higher scores indicating worse ability of daily living).
Incidence of postoperative neurocognitive disorders (pNCD) at 6 months and 1 year
Cognitive function will be assessed at baseline and at 6 months and 1 year after surgery using the Telephone version of Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher scores indicating better cognitive function）. Postoperative neurocognitive disorders (pNCD) is defined as: a \|Z\| value of decline in T-MoCA score ≥1.96. Z value = \[(change from baseline in T-MoCA score in a surgical patient - mean change from baseline in T-MoCA scores in the non-surgical group)\] / (standard deviation of change from baseline in T-MoCA scores in the non-surgical group).
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Peking University First Hospital
Lead sponsor
Peking University Shenzhen Hospital
Collaborator
Second Affiliated Hospital, School of Medicine, Zhejiang University
Collaborator
Fujian Medical University Union Hospital
Collaborator
The First Affiliated Hospital of Air Force Medicial University
Collaborator
Zhejiang University
Collaborator
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