Dexmedetomidine-esketamine and tDCS for Prevention of Neurocognitive Complications After Surgery

Perioperative Use of Dexmedetomidine-esketamine Combination and Transcranial Direct Current Stimulation for Prevention of Neurocognitive Complications in Older Patients After Non-cardiac Surgery: a 2×2 Factorial Trial

Neurocognitive complications, mainly delirium and neurocognitive disorders, are common cerebral complications in older patients after surgery and associated with worse outcomes. In previous studies, perioperative use of dexmedetomidine-esketamine combination improved analgesia and sleep quality after surgery. Perioperative use of transcranial direct current stimulation (tDCS) also improved sleep quality and reduced delirium occurrence early after surgery. This 2×2 factorial trial is designed to investigate the effects of perioperative dexmedetomidine-esketamine combination and tDCS on early postoperative neurocognitive recovery and delirium occurrence in older patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Surgery; Dexmedetomidine; Transcranial Direct Current Stimulation; Older Patients; Esketamine; Perioperative Neurocognitive Disorders
• Intervention / Treatment: Device: Active tDCS; Device: Sham tDCS; Drug: Dex-Esk; Drug: Placebo

Detailed Description

Alone with aging population, the number of older patients undergoing surgery is also increasing. Neurocognitive complications, mainly delirium and neurocognitive disorders, are common cerebral complications in older patients after surgery and associated with worse outcomes. Risk factors of postoperative neurocognitive complications are multifactorial and include predisposing and precipitating factors. Of these, older age and pre-existing cognitive decline are important predisposing factors; surgical trauma, postoperative pain, and postoperative sleep disturbances are important precipitating factors.

Dexmedetomidine is a highly selective alpha 2 adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. Perioperative use of dexmedetomidine improves analgesia and sleep quality after surgery, an relieves surgery-related stress response and inflammation. Accumulating evidence showed that perioperative dexmedetomidine decreased early postoperative delirium and delayed neurocognitive recovery in older patients. The effect of perioperative dexmedetomidine is dose-dependent; however, routine dose dexmedetomidine increases bradycardia and hypotension which are potentially harmful to older patients.

Ketamine is a noncompetitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist and has been used as an anesthetic and analgesic for decades. Esketamine is the S-enantiomer of ketamine and twice as potent as racemic ketamine. Recent studies found that subanesthetic dose of ketamine or esketamine is effective in improving analgesia and sleep quality and relieving depression; it also attenuated surgery-related stress response. However, even subanesthetic ketamine or esketamine increases neuropsychiatric side effects and is not recommended to be used alone for analgesia and sedation.

In clinical practice, the sedative effect of exmedetomidine is used to relieve the neuropsychiatric side effects of ketamine/esketamine, and the sympathomimetic effect of ketamine/esketamine can be used to counteract the sympatholytic effect of dexmedetomidine. Combination of dexmedetomidine and esketamine has been used for premedication in children and postoperative analgesia in adults and showed additive or synergistic effects. The investigators hypothesize that perioperative combined use of low dose dexmedetomidine and esketamine may be more effective in preventing postoperative delirium and delayed neurocognitive recovery in older patients.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique and increasingly used for treatment of various neurological diseases such as neurodevelopmental disorders and post-stroke dysphagia. Preliminary studies in the perioperative settings showed that perioperative use of tDCS improved sleep quality and reduced delirium occurrence early after surgery. The investigators hypothesize that perioperative use of tDCS may help reduce early postoperative delayed neurocognitive recovery in older patients.

This 2×2 factorial trial is designed to investigate the effects of perioperative dexmedetomidine-esketamine combination and tDCS on early postoperative neurocognitive recovery and delirium occurrence in older patients.

• Study Type: Interventional
• Enrollment (Estimated): 1160
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Dong-Xin Wang, MD, PHD; Phone Number: 86 10 83572784; Email: wangdongxin@hotmail.com
• Study Contact Backup: Name: Zhen-Zhen Xu, MD; Phone Number: 86 10 83572460; Email: zjxvzhenzhen@126.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100034
      • Peking University First Hospital
      • Contact: Zhen-Zhen Xu, MD; Phone Number: 86 10 83572460; Email: zjxvzhenzhen@126.com
      • Contact: Dong-Xin Wang, MD, PhD; Phone Number: +86 10 83572784; Email: wangdongxin@hotmail.com
  • Fujian
    • Fuzhou, Fujian, China, 362011
      • Fujian Medical University Union Hospital
      • Contact: Dan-Feng Zhang, MD; Email: mazui1234@163.com
  • Guangdong
    • Shenzhen, Guangdong, China, 518036
      • Peking University Shenzhen Hospital
      • Contact: Tao Luo, MD; Email: 496855048@qq.com
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Xijing Hospital, Air Force Medical University
      • Contact: Zhi-Hong Lu, MD; Email: deerlu23@163.com
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310006
      • First Affilited Hospital, School of Medicine, Zhejiang University
      • Contact: Dian-San Su, MD; Email: diansansu@yahoo.com
    • Hangzhou, Zhejiang, China, 310009
      • Second Affilited Hospital, School of Medicine, Zhejiang University
      • Contact: Min Yan, MD; Email: zryanmin@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• Preoperative inability to communicate due to coma, severe dementia, end-stage 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;
• Uncontrolled hyperthyroidism or pheochromocytoma;
• Severe liver dysfunction (Child-Pugh class C), severe renal dysfunction (requiring dialysis), or ASA classification ≥ IV;
• Allergy to dexmedetomidine or esketamine;
• Participation in other clinical studies within the past 3 months;
• Other conditions that are deemed unsuitable for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dex-Esk + active tDCS; Participants will receive dexmedetomidine-esketamine (Dex-Esk) combination and active transcranial direct current stimulation (tDCS).	Device: Active tDCS; Active 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).; Other Names: Active transcranial direct current stimulation; Drug: Dex-Esk; Dexmedetomidine-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 the expected end of 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).; Other Names: Dexmedetomidine-esketamine combination
Experimental: Dex-Esk + sham tDCS; Participants will receive dexmedetomidine-esketamine (Dex-Esk) combination and sham (placebo) transcranial direct current stimulation (tDCS).	Device: Sham tDCS; Sham 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).; Other Names: Sham transcranial direct current stimulation; Drug: Dex-Esk; Dexmedetomidine-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 the expected end of 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).; Other Names: Dexmedetomidine-esketamine combination
Experimental: Placebo + active tDCS; Participants will receive placebo (normal saline) and active transcranial direct current stimulation (tDCS).	Device: Active tDCS; Active 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).; Other Names: Active transcranial direct current stimulation; Drug: Placebo; Placebo (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 the expected end of 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).; Other Names: Normal saline
Placebo Comparator: Placebo + sham tDCS; Participants will receive placebo (normal saline) and sham (placebo) transcranial direct current stimulation (tDCS).	Device: Sham tDCS; Sham 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).; Other Names: Sham transcranial direct current stimulation; Drug: Placebo; Placebo (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 the expected end of 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).; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of delayed neurocognitive recovery (dNCR)	Cognitive function will be assessed at baseline and at 5 days after surgery (or before hospital discharge) using the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better cognitive function). Delayed neurocognitive decline (dNCR) is defined as: a |Z| value of decline in MoCA score ≥1.96. Z value = [(change from baseline in MoCA score in a surgical patient - mean change from baseline in MoCA score in the non-surgical group)] / (standard deviation of change from baseline in MoCA score in the non-surgical group).	At 5 days after surgery or before hospital discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative delirium	Delirium will be assessed twice daily (8-10 am and 6-8 pm) using the 3-Dimensional Confusion Assessment Method (3D-CAM) for patients without intubation or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) for patients with intubation.	Up to 4 days after surgery
Incidence of postoperative neurocognitive disorders (pNCD)	Cognitive function will be assessed at baseline and at 30 days after surgery using the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better cognitive function). Postoperative neurocognitive disorders (pNCD) is defined as: a |Z| value of decline in MoCA score ≥1.96. Z value = [(change from baseline in MoCA score in a surgical patient - mean change from baseline in MoCA score in the non-surgical group)] / (standard deviation of change from baseline in MoCA score in the non-surgical group).	At 30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early postoperative pain intensity	Pain intensity will be assessed twice daily (8-10 am and 6-8 pm) both at rest and with movement (coughing or turning over) using an 11-point Numeric Rating Scale (NRS; scores range from 0 to 10 where 0=no pain and 10=the worst pain). Pain intensity early after surgery will be summarized as the area under the curve (AUC) using the trapezoidal method.	Up to 4 days after surgery
Length of hospital stay (LOS) after surgery	From the day of surgery until the day of hospital discharge.	Up to 30 days after surgery
Incidence of postoperative complications within 30 days	Postoperative complications are defined as new-onset conditions that are deemed harmful and required therapeutic intervention, i.e., grade II or above on the Clavien-Dindo classification.	Up to 30 days after surgery
Subjective sleep quality at 30 days after surgery	Subjective sleep quality at 30 days will be assessed using the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating poorer sleep quality).	At 30 days after surgery
Early postoperative subjective sleep quality	Subjective sleep quality will be assessed once daily (8-10 am) using an 11-point Numeric Rating Scale (NRS; scores range from 0 to 10 where 0=the best sleep and 10=the worst sleep. Subjective sleep quality early after surgery will be summarized as the cumulative score of subjective sleep quality during the first 4 postoperative nights.	Up to 4 nights after surgery

Collaborators and Investigators

• Sponsor: Peking University First Hospital
• Collaborators: Second Affiliated Hospital, School of Medicine, Zhejiang University; Fujian Medical University Union Hospital; Zhejiang University; Peking University Shenzhen Hospital; The First Affiliated Hospital of Air Force Medicial University
• Investigators: Principal Investigator: Dong-Xin Wang, MD, PhD, Peking University First Hospital

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Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: May 2, 2026
• First Submitted That Met QC Criteria: May 3, 2026
• First Posted (Actual): May 8, 2026

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Surgery; Dexmedetomidine; Esketamine; Transcranial direct current stimulation; Older patients; Perioperative neurocognitive disorders
• Additional Relevant MeSH Terms: Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Saline Solution
• Other Study ID Numbers: 2026-1219; 82293644 (Other Grant/Funding Number: National Natural Science Foundation of China)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No