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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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-controlle
• Препарат 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 an
• Устройство 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 f
• Устройство 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 periphera

Первичные конечные точки

• Incidence of delayed neurocognitive recovery (dNCR) [Срок оценки: At 5 days after surgery or before hospital discharge]

Вторичные конечные точки (2)

• Incidence of postoperative delirium [Срок оценки: Up to 4 days after surgery]
• Incidence of postoperative neurocognitive disorders (pNCD) [Срок оценки: At 30 days after surgery]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Факторный дизайн

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Китай · 6 центров

• Peking University First Hospital — Пекин
• Fujian Medical University Union Hospital — Фучжоу
• Peking University Shenzhen Hospital — Шэньчжэнь
• Xijing Hospital, Air Force Medical University — Сиань
• First Affilited Hospital, School of Medicine, Zhejiang University — Ханчжоу
• Second Affilited Hospital, School of Medicine, Zhejiang University — Ханчжоу

Публикации

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Идентификаторы

NCT: NCT07576517 · 2026-1219 · 82293644

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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