Effect of Low-dose EsketaMine on dElirium in High-risk Elderly Patients uNdergoing elecTive Surgery (ELEMENT)

Summary

Delirium is an acutely occurred neurocognitive disorder characterized by fluctuating symptoms of inattention, altered consciousness and cognitive dysfunction. Delirium is reported to occur in 4% to 65% of postoperative patients depending on the population, and is especially common in older patients. Postoperative delirium is disturbing to patients and their families, and it is a strong predictor of both early and long-term worse outcomes including increased non-delirium complications, increased perioperative mortality, shortened overall survival, declined cognitive function, and lowered quality of life. Although ketamine/esketamine has anti-inflammatory and neuroprotective effects, evidence on its efficacy in reducing postoperative delirium remains inconsistent and inconclusive. Existing studies are limited by heterogeneity, small sample sizes, single-center designs, and a focus on specific type of surgery. Research on elderly high-risk patients is lacking, and most studies administer the drug intraoperatively, with limited exploration of postoperative use. The optimal dosing and timing for POD prevention are unclear. This study aims to carry out a multicenter, single-blind, placebo-controlled, large-sample randomized controlled trial assessing the effect of low-dose esketamine, given intraoperatively and postoperatively, on delirium in elderly high-risk patients undergoing major non-cardiac surgery.

Timeline

Start

2025-02-12

Primary completion

2027-06

Completion

2027-07

Publications

• Background Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 2017 Sep 26;318(12):1161-1174. doi: 10.1001/jama.2017.12067.
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• Background Salluh JI, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, Serafim RB, Stevens RD. Outcome of delirium in critically ill patients: systematic review and meta-analysis. BMJ. 2015 Jun 3;350:h2538. doi: 10.1136/bmj.h2538.
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• Background 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.
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• Background Zhao J, Zhang R, Wang W, Jiang S, Liang H, Guo C, Qi J, Zeng H, Song H. Low-dose ketamine inhibits neuronal apoptosis and neuroinflammation in PC12 cells via alpha7nAChR mediated TLR4/MAPK/NF-kappaB signaling pathway. Int Immunopharmacol. 2023 Apr;117:109880. doi: 10.1016/j.intimp.2023.109880. Epub 2023 Feb 27.
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• Background Xiong X, Shao Y, Chen D, Chen B, Lan X, Shi J. Effect of Esketamine on Postoperative Delirium in Patients Undergoing Cardiac Valve Replacement with Cardiopulmonary Bypass: A Randomized Controlled Trial. Anesth Analg. 2024 Oct 1;139(4):743-753. doi: 10.1213/ANE.0000000000006925. Epub 2024 Mar 6.
• Background Ma J, Wang F, Wang J, Wang P, Dou X, Yao S, Lin Y. The Effect of Low-Dose Esketamine on Postoperative Neurocognitive Dysfunction in Elderly Patients Undergoing General Anesthesia for Gastrointestinal Tumors: A Randomized Controlled Trial. Drug Des Devel Ther. 2023 Jun 29;17:1945-1957. doi: 10.2147/DDDT.S406568. eCollection 2023.
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• Background Bornemann-Cimenti H, Wejbora M, Michaeli K, Edler A, Sandner-Kiesling A. The effects of minimal-dose versus low-dose S-ketamine on opioid consumption, hyperalgesia, and postoperative delirium: a triple-blinded, randomized, active- and placebo-controlled clinical trial. Minerva Anestesiol. 2016 Oct;82(10):1069-1076. Epub 2016 Jun 21.
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• Background Zhang Y, Chen R, Tang S, Sun T, Yu Y, Shi R, Wang K, Zeng Z, Liu X, Meng Q, Xia Z. Diurnal variation of postoperative delirium in elderly patients undergoing esketamine anesthesia for elective noncardiac surgery: a randomized clinical trial. Int J Surg. 2024 Sep 1;110(9):5496-5504. doi: 10.1097/JS9.0000000000001642.
• Background Huang C, Yang R, Xie X, Dai H, Pan L. Effect of small dose esketamine on perioperative neurocognitive disorder and postoperative depressive symptoms in elderly patients undergoing major elective noncardiac surgery for malignant tumors: A randomized clinical trial. Medicine (Baltimore). 2024 Oct 18;103(42):e40028. doi: 10.1097/MD.0000000000040028.
• Background Ma CB, Zhang CY, Gou CL, Liang ZH, Zhang JX, Xing F, Yuan JJ, Wei X, Zhang YB, Wang ZY. Effect of Low-Dose Esketamine on Postoperative Delirium in Elderly Patients Undergoing Total Hip or Knee Arthroplasty: A Randomized Controlled Trial. Drug Des Devel Ther. 2024 Nov 26;18:5409-5421. doi: 10.2147/DDDT.S477342. eCollection 2024.
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• Background Ren Q, Hua L, Zhou X, Cheng Y, Lu M, Zhang C, Guo J, Xu H. Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inflammatory Factors in Colorectal Cancer Patients. Front Pharmacol. 2022 Apr 5;13:818822. doi: 10.3389/fphar.2022.818822. eCollection 2022.

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