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

NCT07576543 | Not Yet Recruiting Phase 4 DMC

• 2 other identifiers: 2026-1219-LT82293644
• Study Type: interventional
• Target: 1,160
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Older Patients; Surgery; Dexmedetomidine; Esketamine; Transcranial Direct Current Stimulation; Cognitive Function; Survival

Keywords

Older patients; Surgery; Dexmedetomidine; Esketamine; Transcranial direct current stimulation; Cognitive function; Survival

Outcome Measures

Primary Outcomes (1)

• 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).

  At 3 months after surgery

Secondary Outcomes (1)

• Event-free survival

  Up to 1 year after surgery of the last enrolled patient

Other Outcomes (4)

• Overall survival

  Up to 1 year after surgery of the last enrolled patient

• Recurrence-free survival

  Up to 1 year after surgery of the last enrolled patient

• Activities of daily living score

  At 3 months, 6 months, and 1 year after surgery

Study Arms (4)

Dex-Esk + active tDCS

EXPERIMENTAL

Participants will receive dexmedetomidine-esketamine (Dex-Esk) combination and active transcranial direct current stimulation (tDCS).

Drug: Dex-Esk; Device: Active tDCS

Dex-Esk + sham tDCS

EXPERIMENTAL

Participants will receive dexmedetomidine-esketamine (Dex-Esk) combination and sham (placebo) transcranial direct current stimulation (tDCS).

Drug: Dex-Esk; Device: Sham tDCS

Placebo + active tDCS

EXPERIMENTAL

Participants will receive placebo (normal saline) and active transcranial direct current stimulation (tDCS).

Drug: Placebo; Device: Active tDCS

Placebo + sham tDCS

PLACEBO COMPARATOR

Participants will receive placebo (normal saline) and sham (placebo) transcranial direct current stimulation (tDCS).

Drug: Placebo; Device: Sham tDCS

Interventions

Dex-Esk DRUG

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 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).

Also known as: Dexmedetomidine-esketamine combination

Dex-Esk + active tDCS; Dex-Esk + sham tDCS

Placebo DRUG

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-mL/h background infusion, and provided for 48 hours (at least 24 hours).

Also known as: Normal saline

Placebo + active tDCS; Placebo + sham tDCS

Active tDCS DEVICE

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).

Also known as: Active transcranial direct current stimulation

Dex-Esk + active tDCS; Placebo + active tDCS

Sham tDCS DEVICE

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).

Also known as: Sham transcranial direct current stimulation

Dex-Esk + sham tDCS; Placebo + sham tDCS

Eligibility Criteria

• Age: 65 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Peking University First Hospital: lead
• 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

Study Sites (6)

Peking University First Hospital

Beijing, Beijing Municipality, 100034, China

Location

Fujian Medical University Union Hospital

Fuzhou, Fujian, 362011, China

Location

Peking University Shenzhen Hospital

Shenzhen, Guangdong, 518036, China

Location

Xijing Hospital, Air Force Medical University

Xi'an, Shaanxi, 710032, China

Location

First Affilited Hospital, School of Medicine, Zhejiang University

Hangzhou, Zhejiang, 310006, China

Location

Second Affilited Hospital, School of Medicine, Zhejiang University

Hangzhou, Zhejiang, 310009, China

Location

Related Publications (84)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 Mortality. JAMA Surg. 2020 Jan 1;155(1):e194620. doi: 10.1001/jamasurg.2019.4620. Epub 2020 Jan 15.

  PMID: 31721994 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969 Autumn;9(3):179-86. No abstract available.

  PMID: 5349366 BACKGROUND

• Lai Y, Zhao M, Jiang C, Du X, Wang Z, Zhang J, Bai Y, Xu B, Zhang W, Tang R, Sang C, Long D, Dong J, Ma C. Validation of T-MoCA in the Screening of Mild Cognitive Impairment in Chinese Patients With Atrial Fibrillation. Front Cardiovasc Med. 2022 Jun 22;9:896846. doi: 10.3389/fcvm.2022.896846. eCollection 2022.

  PMID: 35811734 BACKGROUND

• Wong A, Nyenhuis D, Black SE, Law LS, Lo ES, Kwan PW, Au L, Chan AY, Wong LK, Nasreddine Z, Mok V. Montreal Cognitive Assessment 5-minute protocol is a brief, valid, reliable, and feasible cognitive screen for telephone administration. Stroke. 2015 Apr;46(4):1059-64. doi: 10.1161/STROKEAHA.114.007253. Epub 2015 Feb 19.

  PMID: 25700290 BACKGROUND

• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.

  PMID: 15817019 BACKGROUND

• Creavin ST, Wisniewski S, Noel-Storr AH, Trevelyan CM, Hampton T, Rayment D, Thom VM, Nash KJ, Elhamoui H, Milligan R, Patel AS, Tsivos DV, Wing T, Phillips E, Kellman SM, Shackleton HL, Singleton GF, Neale BE, Watton ME, Cullum S. Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations. Cochrane Database Syst Rev. 2016 Jan 13;2016(1):CD011145. doi: 10.1002/14651858.CD011145.pub2.

  PMID: 26760674 BACKGROUND

• Kunicki ZJ, Ngo LH, Marcantonio ER, Tommet D, Feng Y, Fong TG, Schmitt EM, Travison TG, Jones RN, Inouye SK. Six-Year Cognitive Trajectory in Older Adults Following Major Surgery and Delirium. JAMA Intern Med. 2023 May 1;183(5):442-450. doi: 10.1001/jamainternmed.2023.0144.

  PMID: 36939716 BACKGROUND

• Li C, Tao M, Chen D, Wei Q, Xiong X, Zhao W, Tan W, Yang J, Han Y, Zhang H, Zhang S, Liu H, Cao JL. Transcranial Direct Current Stimulation for Anxiety During Laparoscopic Colorectal Cancer Surgery: A Randomized Clinical Trial. JAMA Netw Open. 2024 Apr 1;7(4):e246589. doi: 10.1001/jamanetworkopen.2024.6589.

  PMID: 38635271 BACKGROUND

• Granger KT, Spies C, Caswell S, Hadzidiakos D, Speidel S, Slooter AJ, Kant I, Piper SK, van Montfort SJ, Barnett JH, Moran PM, Borchers F. Pre-surgical memory impairment is associated with risk of postoperative cognitive dysfunction in a large geriatric cohort. JAR Life. 2025 Feb 7;14:100002. doi: 10.1016/j.jarlif.2025.100002. eCollection 2025.

  PMID: 40046643 BACKGROUND

• Tao M, Zhang S, Han Y, Li C, Wei Q, Chen D, Zhao Q, Yang J, Liu R, Fang J, Li X, Zhang H, Liu H, Cao JL. Efficacy of transcranial direct current stimulation on postoperative delirium in elderly patients undergoing lower limb major arthroplasty: A randomized controlled trial. Brain Stimul. 2023 Jan-Feb;16(1):88-96. doi: 10.1016/j.brs.2023.01.839. Epub 2023 Jan 20.

  PMID: 36682718 BACKGROUND

• Yang X, Wei YF, Ye CH, Tian WD, Li XY, Hu YJ, Chen LP. Effect of preoperative transcranial direct current stimulation on postoperative delirium in elderly patients following laparoscopic surgery. World J Psychiatry. 2025 Oct 19;15(10):107298. doi: 10.5498/wjp.v15.i10.107298. eCollection 2025 Oct 19.

  PMID: 41112611 BACKGROUND

• Zahed M, El Menawy Z, Elmesalmi M, Elnaggar N, Ahmed F, Azaz RM, Elkilany A, Elhabbak SI, Amer SH, Adel M. Non-pharmacological Perioperative Interventions for the Prevention of Postoperative Delirium in Elderly Patients Undergoing Hip and Knee Arthroplasty Surgery: A Systematic Review. Cureus. 2025 Dec 17;17(12):e99475. doi: 10.7759/cureus.99475. eCollection 2025 Dec.

  PMID: 41487800 BACKGROUND

• Yang J, Tao M, Liu R, Fang J, Li C, Chen D, Wei Q, Xiong X, Zhao W, Tan W, Han Y, Zhang H, Liu H, Zhang S, Cao J. Effect of transcranial direct current stimulation on postoperative sleep disturbance in older patients undergoing lower limb major arthroplasty: a prospective, double-blind, pilot, randomised controlled trial. Gen Psychiatr. 2024 Mar 27;37(2):e101173. doi: 10.1136/gpsych-2023-101173. eCollection 2024.

  PMID: 38562406 BACKGROUND

• Prathum T, Chantanachai T, Vimolratana O, Laksanaphuk C, Apiworajirawit I, Aneksan B, Latthirun K, Yang CT, Klomjai W. A systematic review and meta-analysis of the impact of transcranial direct current stimulation on cognitive function in older adults with cognitive impairments: the influence of dosage parameters. Alzheimers Res Ther. 2025 Feb 4;17(1):37. doi: 10.1186/s13195-025-01677-y.

  PMID: 39905569 BACKGROUND

• Gomez-Garcia N, Alvarez-Barrio L, Leiros-Rodriguez R, Soto-Rodriguez A, Andrade-Gomez E, Hernandez-Lucas P. Transcranial direct current stimulation for post-stroke dysphagia: a meta-analysis. J Neuroeng Rehabil. 2023 Dec 11;20(1):165. doi: 10.1186/s12984-023-01290-w.

  PMID: 38082316 BACKGROUND

• Salehinejad MA, Ghanavati E, Glinski B, Hallajian AH, Azarkolah A. A systematic review of randomized controlled trials on efficacy and safety of transcranial direct current stimulation in major neurodevelopmental disorders: ADHD, autism, and dyslexia. Brain Behav. 2022 Sep;12(9):e2724. doi: 10.1002/brb3.2724. Epub 2022 Aug 8.

  PMID: 35938945 BACKGROUND

• Cocco S, Podda MV, Grassi C. Role of BDNF Signaling in Memory Enhancement Induced by Transcranial Direct Current Stimulation. Front Neurosci. 2018 Jun 26;12:427. doi: 10.3389/fnins.2018.00427. eCollection 2018.

  PMID: 29997473 BACKGROUND

• Zhang H, Zheng X, Zhang B. Anti-Inflammatory Pathways Mediating tDCS's Effects on Neuropathic Pain. Biology (Basel). 2025 Jul 20;14(7):892. doi: 10.3390/biology14070892.

  PMID: 40723449 BACKGROUND

• Shin DW, Fan J, Luu E, Khalid W, Xia Y, Khadka N, Bikson M, Fu BM. In Vivo Modulation of the Blood-Brain Barrier Permeability by Transcranial Direct Current Stimulation (tDCS). Ann Biomed Eng. 2020 Apr;48(4):1256-1270. doi: 10.1007/s10439-020-02447-7. Epub 2020 Jan 8.

  PMID: 31916126 BACKGROUND

• Tan M, Feng Z, Chen H, Min L, Wen H, Liu H, Hou J. Transcranial direct current stimulation regulates phenotypic transformation of microglia to relieve neuropathic pain induced by spinal cord injury. Front Behav Neurosci. 2023 Apr 4;17:1147693. doi: 10.3389/fnbeh.2023.1147693. eCollection 2023.

  PMID: 37081929 BACKGROUND

• Cavaleiro C, Martins J, Goncalves J, Castelo-Branco M. Memory and Cognition-Related Neuroplasticity Enhancement by Transcranial Direct Current Stimulation in Rodents: A Systematic Review. Neural Plast. 2020 Feb 25;2020:4795267. doi: 10.1155/2020/4795267. eCollection 2020.

  PMID: 32211039 BACKGROUND

• Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000 Sep 15;527 Pt 3(Pt 3):633-9. doi: 10.1111/j.1469-7793.2000.t01-1-00633.x.

  PMID: 10990547 BACKGROUND

• Zhang Y, Cui F, Ma JH, Wang DX. Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after scoliosis correction surgery: a double-blind randomised trial. Br J Anaesth. 2023 Aug;131(2):385-396. doi: 10.1016/j.bja.2023.05.001. Epub 2023 Jun 9.

  PMID: 37302963 BACKGROUND

• Wen CY, Bao J, Zhou Y, Mu DL, Ding T. Combined Esketamine and Dexmedetomidine Decreases the Risk of Postoperative Delirium in Neurosurgical Pediatrics: A Randomized Controlled Trial. Drug Des Devel Ther. 2025 Sep 30;19:8865-8877. doi: 10.2147/DDDT.S550647. eCollection 2025.

  PMID: 41049041 BACKGROUND

• Lu X, Tang L, Lan H, Li C, Lin H. A Comparison of Intranasal Dexmedetomidine, Esketamine or a Dexmedetomidine-Esketamine Combination for Induction of Anaesthesia in Children: A Randomized Controlled Double-Blind Trial. Front Pharmacol. 2022 Jan 27;12:808930. doi: 10.3389/fphar.2021.808930. eCollection 2021.

  PMID: 35185548 BACKGROUND

• Junior AB Jr, Bendazzoli PS, Ferreira Melo FW Jr, Porto Franco RM, de Sousa Rocha EM, Matos Lima RD, Brondi EB. Efficacy and Safety of the Ketamine-Dexmedetomidine Combination in Adult Sedation and Anesthesia: A Systematic Review and Single-Arm Meta-Analysis of Randomized Controlled Trials. Cureus. 2025 Nov 21;17(11):e97432. doi: 10.7759/cureus.97432. eCollection 2025 Nov.

  PMID: 41431543 BACKGROUND

• Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):521-546. doi: 10.1097/AAP.0000000000000808.

  PMID: 29870458 BACKGROUND

• Amer M, Hylander Moller M, Alshahrani M, Shehabi Y, Arabi YM, Alshamsi F, Ingi Sigurethsson M, Rehn M, Chew MS, Kalliomaki ML, Lewis K, Al-Suwaidan FA, Al-Dorzi HM, Al-Fares A, Alsadoon N, Bell CM, Groth CM, Parke R, Mehta S, Wischmeyer PE, Al-Omari A, Olkkola KT, Alhazzani W. Ketamine Analgo-sedation for Mechanically Ventilated Critically Ill Adults: A Rapid Practice Guideline from the Saudi Critical Care Society and the Scandinavian Society of Anesthesiology and Intensive Care Medicine. Anesth Analg. 2025 Aug 1;141(2):309-326. doi: 10.1213/ANE.0000000000007173. Epub 2025 Jul 14.

  PMID: 39207913 BACKGROUND

• Su X, Chen L, Zhao Y, Li C, Liu S, Wang Z, Zhu J, Yuan X, Tian Y, Tian S. Impact of perioperative esketamine on the perioperative neurocognitive dysfunction: a systematic review and meta-analysis of randomised controlled studies. BMJ Open. 2025 May 21;15(5):e095695. doi: 10.1136/bmjopen-2024-095695.

  PMID: 40398929 BACKGROUND

• Li Y, Peng Q, Lu J, Hu L, Zhou H. Cognitive Change Associated with Anesthesia and Surgery: An Introduction to POCD for Neuroscientists. J Integr Neurosci. 2025 Jul 23;24(7):36785. doi: 10.31083/JIN36785.

  PMID: 40767006 BACKGROUND

• Zhang S, Bai C, Xu M, Li Y, Han Y, Jin Y, Zhao X. Clinical Benefits and Challenges of Esketamine in Elderly Patients During the Perioperative Period. Drug Des Devel Ther. 2025 Sep 13;19:8251-8263. doi: 10.2147/DDDT.S536813. eCollection 2025.

  PMID: 40969846 BACKGROUND

• Chen P, Qian K, Zhu K, Xiaoqing L, Dajin L. Esketamine modulates postoperative biochemical markers of oxidative stress, inflammation, and immune dysregulation in laparoscopic colorectal cancer surgery. J Med Biochem. 2025 Aug 21;44(5):1020-1027. doi: 10.5937/jomb0-56862.

  PMID: 40951888 BACKGROUND

• Qiu D, Wang XM, Yang JJ, Chen S, Yue CB, Hashimoto K, Yang JJ. Effect of Intraoperative Esketamine Infusion on Postoperative Sleep Disturbance After Gynecological Laparoscopy: A Randomized Clinical Trial. JAMA Netw Open. 2022 Dec 1;5(12):e2244514. doi: 10.1001/jamanetworkopen.2022.44514.

  PMID: 36454569 BACKGROUND

• Yao M, Fang B, Yang J, Chen P, Chen F. Esketamine combined with sufentanil versus sufentanil in patient-controlled intravenous analgesia: a meta-analysis. Front Pharmacol. 2024 Feb 7;15:1247646. doi: 10.3389/fphar.2024.1247646. eCollection 2024.

  PMID: 38384296 BACKGROUND

• Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, Bhatia A, Davis FN, Hooten WM, Cohen SP. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):456-466. doi: 10.1097/AAP.0000000000000806.

  PMID: 29870457 BACKGROUND

• Zhu M, Xu S, Ju X, Wang S, Yu X. Effects of the Different Doses of Esketamine on Postoperative Quality of Recovery in Patients Undergoing Modified Radical Mastectomy: A Randomized, Double-Blind, Controlled Trial. Drug Des Devel Ther. 2022 Dec 16;16:4291-4299. doi: 10.2147/DDDT.S392784. eCollection 2022.

  PMID: 36561309 BACKGROUND

• Mion G, Himmelseher S. Esketamine: Less Drowsiness, More Analgesia. Anesth Analg. 2024 Jul 1;139(1):78-91. doi: 10.1213/ANE.0000000000006851. Epub 2024 Jan 31.

  PMID: 38295061 BACKGROUND

• Trimmel H, Helbok R, Staudinger T, Jaksch W, Messerer B, Schochl H, Likar R. S(+)-ketamine : Current trends in emergency and intensive care medicine. Wien Klin Wochenschr. 2018 May;130(9-10):356-366. doi: 10.1007/s00508-017-1299-3. Epub 2018 Jan 10.

  PMID: 29322377 BACKGROUND

• Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay MA, Baker GB, Dursun SM. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020 May 11;10:2045125320916657. doi: 10.1177/2045125320916657. eCollection 2020.

  PMID: 32440333 BACKGROUND

• Wolff K, Winstock AR. Ketamine : from medicine to misuse. CNS Drugs. 2006;20(3):199-218. doi: 10.2165/00023210-200620030-00003.

  PMID: 16529526 BACKGROUND

• Sun P, Liang XQ, Chen NP, Ma JH, Zhang C, Shen YE, Zhu SN, Wang DX. Impact of mini-dose dexmedetomidine supplemented analgesia on sleep structure in patients at high risk of obstructive sleep apnea: a pilot trial. Front Neurosci. 2024 Oct 2;18:1426729. doi: 10.3389/fnins.2024.1426729. eCollection 2024.

  PMID: 39416950 BACKGROUND

• Ashraf MW, Uusalo P, Scheinin M, Saari TI. Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration. Clin Pharmacokinet. 2020 Nov;59(11):1467-1482. doi: 10.1007/s40262-020-00900-3.

  PMID: 32462542 BACKGROUND

• Verret M, Le JBP, Lalu MM, Jeffers MS, McIsaac DI, Nicholls SG, Turgeon AF, Ramchandani R, Li H, Hutton B, Zivkovic F, Graham M, Le M, Geist A, Berube M, O'Hearn K, Gilron I, Poulin P, Daudt H, Martel G, McVicar J, Moloo H, Fergusson DA. Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis. Br J Anaesth. 2024 Sep;133(3):615-627. doi: 10.1016/j.bja.2024.06.007. Epub 2024 Jul 16.

  PMID: 39019769 BACKGROUND

• Fondeur J, Escudero Mendez L, Srinivasan M, Hamouda RK, Ambedkar B, Arzoun H, Sahib I, Mohammed L. Dexmedetomidine in Prevention of Postoperative Delirium: A Systematic Review. Cureus. 2022 Jun 3;14(6):e25639. doi: 10.7759/cureus.25639. eCollection 2022 Jun.

  PMID: 35812638 BACKGROUND

• Strada AL, Tevay A, Scoggins M, Gonzalez K. Dexmedetomidine for Postoperative Delirium Prevention in the Older Adult: An Integrative Review. AANA J. 2024 Oct 1;92(5):383-389.

  PMID: 39361485 BACKGROUND

• Wang K, Wu M, Xu J, Wu C, Zhang B, Wang G, Ma D. Effects of dexmedetomidine on perioperative stress, inflammation, and immune function: systematic review and meta-analysis. Br J Anaesth. 2019 Dec;123(6):777-794. doi: 10.1016/j.bja.2019.07.027. Epub 2019 Oct 24.

  PMID: 31668347 BACKGROUND

• Li B, Li Y, Tian S, Wang H, Wu H, Zhang A, Gao C. Anti-inflammatory Effects of Perioperative Dexmedetomidine Administered as an Adjunct to General Anesthesia: A Meta-analysis. Sci Rep. 2015 Jul 21;5:12342. doi: 10.1038/srep12342.

  PMID: 26196332 BACKGROUND

• Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2012 Jun;116(6):1312-22. doi: 10.1097/ALN.0b013e31825681cb.

  PMID: 22546966 BACKGROUND

• Wang L, Liang XQ, Sun YX, Hua Z, Wang DX. Effect of perioperative dexmedetomidine on sleep quality in adult patients after noncardiac surgery: A systematic review and meta-analysis of randomized trials. PLoS One. 2024 Dec 5;19(12):e0314814. doi: 10.1371/journal.pone.0314814. eCollection 2024.

  PMID: 39636906 BACKGROUND

• Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet. 2017 Aug;56(8):893-913. doi: 10.1007/s40262-017-0507-7.

  PMID: 28105598 BACKGROUND

• Dilmen OK, Meco BC, Evered LA, Radtke FM. Postoperative neurocognitive disorders: A clinical guide. J Clin Anesth. 2024 Feb;92:111320. doi: 10.1016/j.jclinane.2023.111320. Epub 2023 Nov 8.

  PMID: 37944401 BACKGROUND

• Lahiri NK, Vuckovic N, Sidhu AS, Li J, Sun Y, Naiken S, Curtis SJ, Bisch E, Bolda R, Nagra PS, Mann G, Gonzales AE, Smith L, Anderson BP, Liu Z, Adams DC, Meng L. Patterns of prevention effectiveness in postoperative neurocognitive disorder and delayed neurocognitive recovery research: a systematic review with meta-regression of randomised trials. Br J Anaesth. 2025 Aug;135(2):340-359. doi: 10.1016/j.bja.2025.04.021. Epub 2025 Jun 5.

  PMID: 40480916 BACKGROUND

• Hu Z, Zhang F, Liao Q, Ouyang W. The Glymphatic System: A Potential Pathophysiological Focus for Perioperative Neurocognitive Disorder. Explor Res Hypothesis Med. 2021;6(1):24-27. doi: 10.14218/ERHM.2020.00041.

  BACKGROUND

• Travica N, Aslam H, O'Neil A, Lane MM, Berk M, Gamage E, Walder K, Liu ZSJ, Segasby T, Marx W. Brain derived neurotrophic factor in perioperative neurocognitive disorders: Current evidence and future directions. Neurobiol Learn Mem. 2022 Sep;193:107656. doi: 10.1016/j.nlm.2022.107656. Epub 2022 Jul 2.

  PMID: 35792324 BACKGROUND

• Cheng C, Wan H, Cong P, Huang X, Wu T, He M, Zhang Q, Xiong L, Tian L. Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders. J Neuroinflammation. 2022 Dec 12;19(1):297. doi: 10.1186/s12974-022-02656-y.

  PMID: 36503642 BACKGROUND

• Maisat W, Yuki K. The Role of Damage-Associated Molecular Patterns in Perioperative Neurocognitive Disorders: A Narrative Review. Anesth Analg. 2026 Feb 1;142(2):312-325. doi: 10.1213/ANE.0000000000007682. Epub 2025 Aug 5.

  PMID: 40763077 BACKGROUND

• Yang T, Velagapudi R, Terrando N. Neuroinflammation after surgery: from mechanisms to therapeutic targets. Nat Immunol. 2020 Nov;21(11):1319-1326. doi: 10.1038/s41590-020-00812-1. Epub 2020 Oct 19.

  PMID: 33077953 BACKGROUND

• Chen L, Au E, Saripella A, Kapoor P, Yan E, Wong J, Tang-Wai DF, Gold D, Riazi S, Suen C, He D, Englesakis M, Nagappa M, Chung F. Postoperative outcomes in older surgical patients with preoperative cognitive impairment: A systematic review and meta-analysis. J Clin Anesth. 2022 Sep;80:110883. doi: 10.1016/j.jclinane.2022.110883. Epub 2022 May 24.

  PMID: 35623265 BACKGROUND

• Weiss Y, Zac L, Refaeli E, Ben-Yishai S, Zegerman A, Cohen B, Matot I. Preoperative Cognitive Impairment and Postoperative Delirium in Elderly Surgical Patients: A Retrospective Large Cohort Study (The CIPOD Study). Ann Surg. 2023 Jul 1;278(1):59-64. doi: 10.1097/SLA.0000000000005657. Epub 2022 Aug 1.

  PMID: 35913053 BACKGROUND

• Park S, Kim J, Ha Y, Kim KN, Yi S, Koo BN. Preoperative mild cognitive impairment as a risk factor of postoperative cognitive dysfunction in elderly patients undergoing spine surgery. Front Aging Neurosci. 2024 Jan 12;16:1292942. doi: 10.3389/fnagi.2024.1292942. eCollection 2024.

  PMID: 38282693 BACKGROUND

• Aldecoa C, Bettelli G, Bilotta F, Sanders RD, Aceto P, Audisio R, Cherubini A, Cunningham C, Dabrowski W, Forookhi A, Gitti N, Immonen K, Kehlet H, Koch S, Kotfis K, Latronico N, MacLullich AMJ, Mevorach L, Mueller A, Neuner B, Piva S, Radtke F, Blaser AR, Renzi S, Romagnoli S, Schubert M, Slooter AJC, Tommasino C, Vasiljewa L, Weiss B, Yuerek F, Spies CD. Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients. Eur J Anaesthesiol. 2024 Feb 1;41(2):81-108. doi: 10.1097/EJA.0000000000001876. Epub 2023 Aug 30.

  PMID: 37599617 BACKGROUND

• Ren X, Huiqiao L, Wu Y, Zhang T, Chen P, Li L, Zhao G, Wang F. Perioperative neurocognitive disorders: a comprehensive review of terminology, clinical implications, and future research directions. Front Neurol. 2025 Aug 26;16:1526021. doi: 10.3389/fneur.2025.1526021. eCollection 2025.

  PMID: 40933055 BACKGROUND

• Needham MJ, Webb CE, Bryden DC. Postoperative cognitive dysfunction and dementia: what we need to know and do. Br J Anaesth. 2017 Dec 1;119(suppl_1):i115-i125. doi: 10.1093/bja/aex354.

  PMID: 29161395 BACKGROUND

• Nilsson U, Amirpour A, Lampi M, Guenna Holmgren A, Markovic G, Zecevic E, Nomm M, Drakenberg A, Claesson Lingehall H, Damen T, Martinik A, Saarijarvi M, Bergman L, Eckerblad J; PeriBrainCare. Older Patients' Postoperative Neurocognitive Recovery: A Narrative Review. Clin Interv Aging. 2025 Dec 16;20:2579-2591. doi: 10.2147/CIA.S559531. eCollection 2025.

  PMID: 41425754 BACKGROUND

• Suraarunsumrit P, Srinonprasert V, Kongmalai T, Suratewat S, Chaikledkaew U, Rattanasiri S, McKay G, Attia J, Thakkinstian A. Outcomes associated with postoperative cognitive dysfunction: a systematic review and meta-analysis. Age Ageing. 2024 Jul 2;53(7):afae160. doi: 10.1093/ageing/afae160.

  PMID: 39058915 BACKGROUND

• Mohanty S, Gillio A, Lindroth H, Ortiz D, Holler E, Azar J, Boustani M, Zarzaur B. Major Surgery and Long Term Cognitive Outcomes: The Effect of Postoperative Delirium on Dementia in the Year Following Discharge. J Surg Res. 2022 Feb;270:327-334. doi: 10.1016/j.jss.2021.08.043. Epub 2021 Oct 29.

  PMID: 34731730 BACKGROUND

• Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, Gravenstein JS. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology. 2008 Jan;108(1):18-30. doi: 10.1097/01.anes.0000296071.19434.1e.

  PMID: 18156878 BACKGROUND

• Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD, Langeron O, Johnson T, Lauven PM, Kristensen PA, Biedler A, van Beem H, Fraidakis O, Silverstein JH, Beneken JE, Gravenstein JS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet. 1998 Mar 21;351(9106):857-61. doi: 10.1016/s0140-6736(97)07382-0.

  PMID: 9525362 BACKGROUND

• Alhamdah Y, Li WY, Nagappa M, Yan E, He D, Sarieplla A, Englesakis M, Elias Z, Chan MTV, Wang DX, Chung F. Perioperative approaches to prevent delayed neurocognitive recovery and postoperative neurocognitive disorder in older surgical patients: A systematic review and meta-analysis of randomized controlled trials. J Anaesthesiol Clin Pharmacol. 2025 Jan-Mar;41(1):3-14. doi: 10.4103/joacp.joacp_396_23. Epub 2024 Oct 16.

  PMID: 40026724 BACKGROUND

• Fenta E, Teshome D, Kibret S, Hunie M, Tiruneh A, Belete A, Molla A, Dessie B, Geta K. Incidence and risk factors of postoperative delirium in elderly surgical patients 2023. Sci Rep. 2025 Jan 9;15(1):1400. doi: 10.1038/s41598-024-84554-2.

  PMID: 39789093 BACKGROUND

• Vacas S, Canales C, Deiner SG, Cole DJ. Perioperative Brain Health in the Older Adult: A Patient Safety Imperative. Anesth Analg. 2022 Aug 1;135(2):316-328. doi: 10.1213/ANE.0000000000006090. Epub 2022 May 18.

  PMID: 35584550 BACKGROUND

• Thedim M, Vacas S. Postoperative Delirium and the Older Adult: Untangling the Confusion. J Neurosurg Anesthesiol. 2024 Jul 1;36(3):184-189. doi: 10.1097/ANA.0000000000000971. Epub 2024 Apr 29.

  PMID: 38683185 BACKGROUND

• Li YW, Li HJ, Li HJ, Zhao BJ, Guo XY, Feng Y, Zuo MZ, Yu YP, Kong H, Zhao Y, Huang D, Deng CM, Hu XY, Liu PF, Li Y, An HY, Zhang HY, Wang MR, Wu YF, Wang DX, Sessler DI; Peking University Clinical Research Program Study Group. Delirium in Older Patients after Combined Epidural-General Anesthesia or General Anesthesia for Major Surgery: A Randomized Trial. Anesthesiology. 2021 Aug 1;135(2):218-232. doi: 10.1097/ALN.0000000000003834.

  PMID: 34195765 BACKGROUND

• Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, Oh ES, Crosby G, Berger M, Eckenhoff RG; Nomenclature Consensus Working Group. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Br J Anaesth. 2018 Nov;121(5):1005-1012. doi: 10.1016/j.bja.2017.11.087. Epub 2018 Jun 15.

  PMID: 30336844 BACKGROUND

• Kong H, Xu LM, Wang DX. Perioperative neurocognitive disorders: A narrative review focusing on diagnosis, prevention, and treatment. CNS Neurosci Ther. 2022 Aug;28(8):1147-1167. doi: 10.1111/cns.13873. Epub 2022 Jun 1.

  PMID: 35652170 BACKGROUND

• Krause BM, Sabia S, Manning HJ, Singh-Manoux A, Sanders RD. Association between major surgical admissions and the cognitive trajectory: 19 year follow-up of Whitehall II cohort study. BMJ. 2019 Aug 7;366:l4466. doi: 10.1136/bmj.l4466.

  PMID: 31391161 BACKGROUND

• Kainz E, Juilfs N, Harler U, Kahl U, Mewes C, Zollner C, Fischer M. The impact of cognitive reserve on delayed neurocognitive recovery after major non-cardiac surgery: an exploratory substudy. Front Aging Neurosci. 2023 Nov 23;15:1267998. doi: 10.3389/fnagi.2023.1267998. eCollection 2023.

  PMID: 38076537 BACKGROUND

MeSH Terms

Interventions

Saline Solution

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Dong-Xin Wang, MD, PhD

  Peking University First Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dong-Xin Wang, MD, PHD

CONTACT

86 10 83572784; wangdongxin@hotmail.com

Zhen-Zhen Xu, MD

CONTACT

86 10 83572460; zjxvzhenzhen@126.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 3, 2026
• First Posted: May 8, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2031
• Last Updated: May 8, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (6)