Long-term Follow-up of Dexmedetomidine-esketamine and tDCS for Neurocognitive Complications After Surgery

Official title

Long-term Follow-up of Perioperative Dexmedetomidine-esketamine Combination and Transcranial Direct Current Stimulation for Prevention of Neurocognitive Complications in Older Patients After Non-cardiac Surgery

Overview

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.

Detailed description

Neurocognitive complications, mainly delirium and neurocognitive disorders, are common cerebral complications in older patients after surgery. Occurrence of neurocognitive complications is associated with prolonge hospital stay and increased in-hospital death. Furthermore, occurrence of neurocognitive complications is associated with adverse long-term outcomes, including cognitive decline, poor quality of life, and reduced long-term survival.

Dexmedetomidine is a highly selective alpha 2 adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. Available evidence showed that perioperative dexmedetomidine decreased early postoperative neurocognitive complications in older patients, possibly by improving analgesia and sleep quality and relieving surgery-related inflammation. 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 esketamine is effective in improving analgesia and sleep quality and relieving surgery-related stress response. However, even subanesthetic ketamine or esketamine increases neuropsychiatric side effects.

In clinical practice, dexmedetomidine-esketamine combination has been used for premedication in children and postoperative analgesia in adults and showed additive or synergistic effects. An ongoing trial conducted by the investigators plan to test the hypothesis that perioperative use of dexmedetomidine-esketamine combination may prevent postoperative neurocognitive complications in older patients. It is reasonable to hypothesize that perioperative dexmedetomdine-esketamine might also have favorable effects on long-term outcomes.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique and increasingly used for treatment of various neurological diseases. Studies in the perioperative settings showed that perioperative use of tDCS improved sleep quality and reduced delirium occurrence early after surgery. The ongoing trial coducted by the investigators plan to test the hypothesis that perioperative use of tDCS may reduce postoperative neurocognitive complications in older patients. Perioperative tDCS might also have favorable effects on long-term outcomes.

This long-term follow-up of the ongoing 2×2 factorial trial aims to investigate the effects of perioperative dexmedetomidine-esketamine combination and tDCS on long-term outcomes in older patients after noncardiac surgery.

Interventions

• 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 expected end surgery. Postoperative patient-controlled analg
• 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 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-
• 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 f
• 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 periphera

Primary outcome measures

• Incidence of postoperative neurocognitive disorders (pNCD) at 3 months [Time frame: At 3 months after surgery]

Secondary outcome measures (1)

• Event-free survival [Time frame: Up to 1 year after surgery of the last enrolled patient]

Eligibility criteria

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, 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;
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

China · 6 centers

• Peking University First Hospital — Beijing
• Fujian Medical University Union Hospital — Fuzhou
• Peking University Shenzhen Hospital — Shenzhen
• Xijing Hospital, Air Force Medical University — Xi'an
• First Affilited Hospital, School of Medicine, Zhejiang University — Hangzhou
• Second Affilited Hospital, School of Medicine, Zhejiang University — Hangzhou

Publications

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. PMID 19097774
• Tao M, Yang J, Liu R, Zhang S, Han Y, Li C, Wei Q, Chen D, Fang J, Zhang H, Wang Y, Liu H, Cao JL. Efficacy of transcranial direct current stimulation for improving postoperative quality of recovery in elderly patients undergoing lower limb major arthroplasty: a randomized controlled substudy. Front Neurol. 2024 Jan 24;15:1327558. doi: 10.3389/fneur.2024.1327558. eCollection 2024. PMID 38327619
• Rodrigues NB, McIntyre RS, Lipsitz O, Lee Y, Cha DS, Shekotikhina M, Vinberg M, Gill H, Subramaniapillai M, Kratiuk K, Lin K, Ho R, Mansur RB, Rosenblat JD. A simplified 6-Item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions. J Affect Disord. 2021 Mar 1;282:160-164. doi: 10.1016/j.jad.2020.12.119. Epub 2020 Dec 29 PMID 33418362
• Shinall MC Jr, Arya S, Youk A, Varley P, Shah R, Massarweh NN, Shireman PK, Johanning JM, Brown AJ, Christie NA, Crist L, Curtin CM, Drolet BC, Dhupar R, Griffin J, Ibinson JW, Johnson JT, Kinney S, LaGrange C, Langerman A, Loyd GE, Mady LJ, Mott MP, Patri M, Siebler JC, Stimson CJ, Thorell WE, Vincent SA, Hall DE. Association of Preoperative Patient Frailty and Operative Stress With Postoperative PMID 31721994
• Zisapel N, Nir T. Determination of the minimal clinically significant difference on a patient visual analog sleep quality scale. J Sleep Res. 2003 Dec;12(4):291-8. doi: 10.1046/j.0962-1105.2003.00365.x. PMID 14633240
• Martin S, Chandran A, Zografos L, Zlateva G. Evaluation of the impact of fibromyalgia on patients' sleep and the content validity of two sleep scales. Health Qual Life Outcomes. 2009 Jul 10;7:64. doi: 10.1186/1477-7525-7-64. PMID 19591683
• Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4. PMID 2748771
• Wang W, Bian Q, Zhao Y, Li X, Wang W, Du J, Zhang G, Zhou Q, Zhao M. Reliability and validity of the Chinese version of the Patient Health Questionnaire (PHQ-9) in the general population. Gen Hosp Psychiatry. 2014 Sep-Oct;36(5):539-44. doi: 10.1016/j.genhosppsych.2014.05.021. Epub 2014 Jun 6. PMID 25023953

Identifiers

NCT: NCT07576543 · 2026-1219-LT · 82293644

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗