Intranasal Dexmedetomidine-esketamine Combination and Postoperative Cognitive Recovery in Older Patients
Impact of Intranasal Dexmedetomidine-esketamine Combination on Neurocognitive Recovery in Older Patients After Noncardiac Surgery: a Randomized, Double-blind, and Placebo-controlled Trial
Postoperative neurocognitive disorders, including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in older patients undergoing surgery and are associated with worse outcomes. Intranasal dexmedetomidine, esketamine, and their combination have been used in clinical practice to improve sleep quality and analgesia. A preliminary study suggested lower rates of emergence delirium and POD/dNCR in older patients receiving perioperative intranasal dexmedetomidine-esketamine. This randomized controlled trial is designed to test the hypothesis that perioperative administration of an intranasal dexmedetomidine-esketamine combination improves neurocognitive recovery in older patients undergoing noncardiac surgery.
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
Postoperative neurocognitive disorders, including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in older patients undergoing surgery and are associated with prolonged hospitalization, worse functional recovery, and increased mortality. Disturbed sleep is a modifiable contributor: perioperative sleep disruption may amplify neuroinflammation, pain, and opioid requirements, creating a feed-forward loop that promotes neurocognitive complications.
Dexmedetomidine, a highly selective α2-adrenergic agonist, mimics aspects of physiological non-rapid eye movement (NREM) sleep. Intranasal dexmedetomidine has been used to improve perioperative sleep in older patients. Esketamine, the S-enantiomer of ketamine, provides analgesia and has rapid antidepressant effects. Intranasal esketamine is approved for treatment-resistant depression. Combined use of subanesthetic doses of esketamine and dexmedetomidine shows synergy in analgesia and anxiolysis, with fewer neuropsychiatric adverse effects.
Combining low doses of both agents for intranasal administration therefore targets several mechanisms implicated in POD and dNCR simultaneously (sleep restoration, analgesia, anxiolysis, and potentially reduced opioid consumption) via a noninvasive route feasible on surgical wards. A preliminary study suggested lower rates of emergence delirium and POD/dNCR in older patients receiving perioperative intranasal dexmedetomidine-esketamine.
This randomized controlled trial is designed to test the hypothesis that perioperative administration of an intranasal dexmedetomidine-esketamine combination improves neurocognitive recovery in older patients undergoing noncardiac surgery.
Tipo di studio
Iscrizione (Stimato)
Fase
- Fase 4
Contatti e Sedi
Contatto studio
- Nome: Dong-Xin Wang, MD, PhD
- Numero di telefono: 86 10 83572784
- Email: wangdongxin@hotmail.com
Backup dei contatti dello studio
- Nome: Huai-Jin Li, MD
- Numero di telefono: 86 10 83572460
- Email: sophie.lee.coffee@gmail.com
Luoghi di studio
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Beijing Municipality
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Beijing, Beijing Municipality, Cina, 100034
- Peking University First Hospital
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Contatto:
- Huai-Jin Li, MD
- Numero di telefono: +8613488659162
- Email: sophie.lee.coffee@gmail.com
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
Inclusion Criteria:
- Age ≥65 years.
- Scheduled to undergo noncardiac surgery under general anesthesia with an expected operative duration >1 hour.
- Planned hospital stay of at least 1 day.
Exclusion Criteria:
- Nasal disease precluding intranasal administration (e.g., rhinitis, nasal polyps, or nasal congestion of any cause).
- Pre-existing schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis.
- Inability to communicate preoperatively due to coma, severe dementia, or language disorder.
- History of craniocerebral injury or neurosurgery.
- Pre-existing sleep-disordered breathing (diagnosed sleep apnea or high risk of moderate-to-severe sleep apnea on the STOP-Bang questionnaire).
- History of hyperthyroidism or pheochromocytoma.
- Preoperative LVEF <30%, sick sinus syndrome, severe sinus bradycardia (heart rate <50 beats/min), or second-degree or higher atrioventricular block without a pacemaker.
- Severe hepatic dysfunction (Child-Pugh class C), severe renal impairment requiring preoperative dialysis, or ASA physical status ≥IV.
- Planned postoperative ICU admission.
- Known allergy or hypersensitivity to dexmedetomidine and/or esketamine.
- Any other condition that, in the judgment of the investigator, makes the patient unsuitable for enrollment.
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Prevenzione
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Quadruplicare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
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Sperimentale: DEX-ESK group
Participants in this group will receive intranasal administration of a dexmedetomidine-esketamine combination at bedtime (8-9 pm) three times: the night before surgery, the night of surgery, and the first postoperative night. |
Participants in this group will receive intranasal administration of a dexmedetomidine-esketamine combination at bedtime (8-9 pm) three times: the night before surgery, the night of surgery, and the first postoperative night.
Altri nomi:
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Comparatore placebo: Placebo group
Participants in this group will receive intranasal administration of placebo (0.9% saline) at bedtime (8-9 pm) three times: the night before surgery, the night of surgery, and the first postoperative night. |
Participants in this group will receive intranasal administration of placebo (0.9% saline) at bedtime (8-9 pm) three times: the night before surgery, the night of surgery, and the first postoperative night.
Altri nomi:
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Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
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Incidence of delayed neurocognitive recovery (dNCR) on postoperative day 4.
Lasso di tempo: Up to 4 days after surgery.
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Cognitive function will be assessed with the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better function) before surgery and on postoperative day 4 or at hospital discharge, whichever occurs first. Delayed neurocognitive recovery (dNCR) is defined as a decline from baseline of >1 SD in MoCA score. |
Up to 4 days after surgery.
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Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
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Incidence of postoperative delirium within 3 days after surgery.
Lasso di tempo: Up to 3 days after surgery.
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Delirium will be assessed twice daily during the first 3 postoperative days using the 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) in non-intubated patients and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in intubated patients. |
Up to 3 days after surgery.
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Incidence of delayed neurocognitive recovery (dNCR) on postoperative day 30.
Lasso di tempo: At 30 days after surgery.
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Cognitive function will be assessed with the Telephone Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher scores indicating better function) before surgery and on postoperative day 30. Delayed neurocognitive recovery (dNCR) is defined as a decline from baseline of >1 SD in T-MoCA score. |
At 30 days after surgery.
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Collaboratori e investigatori
Sponsor
Investigatori
- Investigatore principale: Dong-Xin Wang, MD, PhD, Peking University First Hospital
Pubblicazioni e link utili
Pubblicazioni generali
- Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16.
- 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.
- Khan BA, Perkins AJ, Gao S, Hui SL, Campbell NL, Farber MO, Chlan LL, Boustani MA. The Confusion Assessment Method for the ICU-7 Delirium Severity Scale: A Novel Delirium Severity Instrument for Use in the ICU. Crit Care Med. 2017 May;45(5):851-857. doi: 10.1097/CCM.0000000000002368.
- 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.
- Duan X, Coburn M, Rossaint R, Sanders RD, Waesberghe JV, Kowark A. Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta-analysis with trial sequential analysis of randomised controlled trials. Br J Anaesth. 2018 Aug;121(2):384-397. doi: 10.1016/j.bja.2018.04.046. Epub 2018 Jun 22.
- Jun JH, Kim KN, Kim JY, Song SM. The effects of intranasal dexmedetomidine premedication in children: a systematic review and meta-analysis. Can J Anaesth. 2017 Sep;64(9):947-961. doi: 10.1007/s12630-017-0917-x. Epub 2017 Jun 21.
- Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sanchez E, Gutierrez-Rojas L, Meana JJ. Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs. 2018 May;32(5):411-420. doi: 10.1007/s40263-018-0519-3.
- 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.
- Gleason LJ, Schmitt EM, Kosar CM, Tabloski P, Saczynski JS, Robinson T, Cooper Z, Rogers SO Jr, Jones RN, Marcantonio ER, Inouye SK. Effect of Delirium and Other Major Complications on Outcomes After Elective Surgery in Older Adults. JAMA Surg. 2015 Dec;150(12):1134-40. doi: 10.1001/jamasurg.2015.2606.
- Silva AR, Regueira P, Albuquerque E, Baldeiras I, Cardoso AL, Santana I, Cerejeira J. Estimates of Geriatric Delirium Frequency in Noncardiac Surgeries and Its Evaluation Across the Years: A Systematic Review and Meta-analysis. J Am Med Dir Assoc. 2021 Mar;22(3):613-620.e9. doi: 10.1016/j.jamda.2020.08.017. Epub 2020 Oct 1.
- Uusalo P, Seppanen SM, Jarvisalo MJ. Feasibility of Intranasal Dexmedetomidine in Treatment of Postoperative Restlessness, Agitation, and Pain in Geriatric Orthopedic Patients. Drugs Aging. 2021 May;38(5):441-450. doi: 10.1007/s40266-021-00846-6. Epub 2021 Mar 16.
- Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versatile tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020 Oct;33(5):633-638. doi: 10.1097/ACO.0000000000000916.
- Wolff K, Winstock AR. Ketamine : from medicine to misuse. CNS Drugs. 2006;20(3):199-218. doi: 10.2165/00023210-200620030-00003.
- Sapkota A, Khurshid H, Qureshi IA, Jahan N, Went TR, Sultan W, Alfonso M. Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus. 2021 Aug 21;13(8):e17352. doi: 10.7759/cureus.17352. eCollection 2021 Aug.
- 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.
- 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.
- Crocker E, Beggs T, Hassan A, Denault A, Lamarche Y, Bagshaw S, Elmi-Sarabi M, Hiebert B, Macdonald K, Giles-Smith L, Tangri N, Arora RC. Long-Term Effects of Postoperative Delirium in Patients Undergoing Cardiac Operation: A Systematic Review. Ann Thorac Surg. 2016 Oct;102(4):1391-9. doi: 10.1016/j.athoracsur.2016.04.071. Epub 2016 Jun 22.
- Pereira JV, Aung Thein MZ, Nitchingham A, Caplan GA. Delirium in older adults is associated with development of new dementia: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2021 Jul;36(7):993-1003. doi: 10.1002/gps.5508. Epub 2021 Feb 27.
- Cortese GP, Burger C. Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer's disease. Behav Brain Res. 2017 Mar 30;322(Pt B):269-279. doi: 10.1016/j.bbr.2016.08.027. Epub 2016 Aug 17.
- 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.
- Zhang Y, Shan GJ, Zhang YX, Cao SJ, Zhu SN, Li HJ, Ma D, Wang DX; First Study of Perioperative Organ Protection (SPOP1) investigators. Propofol compared with sevoflurane general anaesthesia is associated with decreased delayed neurocognitive recovery in older adults. Br J Anaesth. 2018 Sep;121(3):595-604. doi: 10.1016/j.bja.2018.05.059. Epub 2018 Jul 27.
- Ha A, Krasnow RE, Mossanen M, Nagle R, Hshieh TT, Rudolph JL, Chang SL. A contemporary population-based analysis of the incidence, cost, and outcomes of postoperative delirium following major urologic cancer surgeries. Urol Oncol. 2018 Jul;36(7):341.e15-341.e22. doi: 10.1016/j.urolonc.2018.04.012. Epub 2018 May 24.
- Ma X, Chu H, Han K, Shao Q, Yu Y, Jia S, Wang D, Wang Z, Zhou Y. Postoperative delirium after transcatheter aortic valve replacement: An updated systematic review and meta-analysis. J Am Geriatr Soc. 2023 Feb;71(2):646-660. doi: 10.1111/jgs.18104. Epub 2022 Nov 23.
- Shi Z, Mei X, Li C, Chen Y, Zheng H, Wu Y, Zheng H, Liu L, Marcantonio ER, Xie Z, Shen Y. Postoperative Delirium Is Associated with Long-term Decline in Activities of Daily Living. Anesthesiology. 2019 Sep;131(3):492-500. doi: 10.1097/ALN.0000000000002849.
- Yokoyama C, Yoshitnai K, Ogata S, Fukushima S, Matsuda H. Effect of postoperative delirium after cardiovascular surgery on 5-year mortality. JA Clin Rep. 2023 Oct 13;9(1):66. doi: 10.1186/s40981-023-00658-0.
- Xu J, Jian J, Zhang Y, Wu J, Qiu Y. The efficacy of nasal administration of esketamine in patients having moderate-to-severe pain after preoperative CT-guided needle localization: a randomized, double-blind, placebo-controlled trial. Front Med (Lausanne). 2024 Apr 9;11:1344160. doi: 10.3389/fmed.2024.1344160. eCollection 2024.
- Lin X, Chen Y, Zhang P, Chen G, Zhou Y, Yu X. The potential mechanism of postoperative cognitive dysfunction in older people. Exp Gerontol. 2020 Feb;130:110791. doi: 10.1016/j.exger.2019.110791. Epub 2019 Nov 23.
- Goldberg TE, Chen C, Wang Y, Jung E, Swanson A, Ing C, Garcia PS, Whittington RA, Moitra V. Association of Delirium With Long-term Cognitive Decline: A Meta-analysis. JAMA Neurol. 2020 Nov 1;77(11):1373-1381. doi: 10.1001/jamaneurol.2020.2273.
- Li A, Yuen VM, Goulay-Dufay S, Sheng Y, Standing JF, Kwok PCL, Leung MKM, Leung AS, Wong ICK, Irwin MG. Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine. Br J Anaesth. 2018 May;120(5):960-968. doi: 10.1016/j.bja.2017.11.100. Epub 2018 Feb 2.
- Katz MJ, Wang C, Nester CO, Derby CA, Zimmerman ME, Lipton RB, Sliwinski MJ, Rabin LA. T-MoCA: A valid phone screen for cognitive impairment in diverse community samples. Alzheimers Dement (Amst). 2021 Feb 5;13(1):e12144. doi: 10.1002/dad2.12144. eCollection 2021.
- Khaled M, Sabac D, Fuda M, Koubaesh C, Gallab J, Qu M, Lo Bianco G, Shanthanna H, Paul J, Thabane L, Marcucci M. Postoperative pain and neurocognitive outcomes after noncardiac surgery: a systematic review and dose-response meta-analysis. Br J Anaesth. 2025 Jan;134(1):89-101. doi: 10.1016/j.bja.2024.08.032. Epub 2024 Oct 11.
- 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.
- 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.
- Zhang ZR, Li YZ, Wu XQ, Chen WJ, Xu J, Zhao WH, Gong XY. Postoperative cognitive dysfunction in elderly postcardiac surgery patients: progress in rehabilitation application research. Front Rehabil Sci. 2024 Dec 17;5:1525813. doi: 10.3389/fresc.2024.1525813. eCollection 2024.
- 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.
- 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.
- 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.
- Vasunilashorn SM, Guess J, Ngo L, Fick D, Jones RN, Schmitt EM, Kosar CM, Saczynski JS, Travison TG, Inouye SK, Marcantonio ER. Derivation and Validation of a Severity Scoring Method for the 3-Minute Diagnostic Interview for Confusion Assessment Method--Defined Delirium. J Am Geriatr Soc. 2016 Aug;64(8):1684-9. doi: 10.1111/jgs.14234. Epub 2016 Jul 4.
- Wei Q, Du B, Liu Y, Cao S, Yin S, Zhang Y, Ye R, Bai T, Wu X, Tian Y, Hu P, Wang K. The Montreal cognitive assessment: normative data from a large, population-based sample of Chinese healthy adults and validation for detecting vascular cognitive impairment. Front Neurosci. 2024 Jul 31;18:1455129. doi: 10.3389/fnins.2024.1455129. eCollection 2024.
- Chen C, Zhai R, Yang S, Xiong X, Lu J, Tang G, Tang S, Shi Y, Zhu Z, Chen D, Shi J. Preventive Effect of Preoperative Intranasal Dexmedetomidine for Postoperative Delirium in Elderly Patients with Sleep Disorders Undergoing Major Noncardiac Surgery: A Randomized, Triple-Blind, Placebo-Controlled Trial. Drug Des Devel Ther. 2025 Dec 6;19:10821-10834. doi: 10.2147/DDDT.S559012. eCollection 2025.
- He E, Dong Y, Jia H, Yu L. Relationship of sleep disturbance and postoperative delirium: a systematic review and meta-analysis. Gland Surg. 2022 Jul;11(7):1192-1203. doi: 10.21037/gs-22-312.
- Varpaei HA, Farhadi K, Mohammadi M, Khafaee Pour Khamseh A, Mokhtari T. Postoperative cognitive dysfunction: a concept analysis. Aging Clin Exp Res. 2024 Jun 21;36(1):133. doi: 10.1007/s40520-024-02779-7.
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