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

Official title

Effect of Perioperative Low-dose EsketaMine on dElirium in High-risk Elderly Patients uNdergoing elecTive Major Non-cardiac Surgery: a Multi-center Randomized Trial (ELEMENT Trial)

Overview

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.

Detailed description

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.

The mechanism of delirium remains unclear, with neuroinflammation playing a significant role. Emerging evidence suggests anesthetic drug selection may influence the incidence of delirium. Ketamine, a non-competitive NMDA receptor antagonist, exhibits anti-inflammatory and neuroprotective properties by reducing TNF-α, IL-6, IL-1β, p-TAU, and S100B levels, mitigating oxidative stress, and inhibiting neuronal autophagy via the PI3K/AKT/mTOR pathway, thereby potentially preserving cognitive function. Clinical studies exploring ketamine's role in postoperative delirium have yielded mixed results. A retrospective study involving ICU patients undergone abdominal surgery found low-dose ketamine reduced delirium risk by 43% after propensity score matching. In cardiac surgery patients, a single dose of ketamine during induction decreased delirium incidence from 31% to 3%. However, a large international multicenter RCT in patients aged ≥60 undergoing major surgery found no reduction in delirium with pre-induction ketamine. A meta-analysis of eight RCTs also reported no preventive effect, though significant heterogeneity and inconsistent diagnostic criteria were noted. Perioperative ketamine use was consistently found safe, with no increase in adverse events such as nausea, vomiting, respiratory depression, or psychiatric symptoms.

Esketamine, the S-(+)-enantiomer of ketamine, has higher bioavailability, a shorter elimination half-life, and fewer side effects. It is effective in general anesthesia, postoperative analgesia, and ICU sedation, and can be used alone for minor procedures or combined with general or regional anesthesia. As an adjunct, it reduces the need for sedatives (e.g., propofol, midazolam) and opioids, minimizes hemodynamic fluctuations and respiratory depression, and improves anesthesia safety. Esketamine may prevent postoperative delirium, as suggested by emerging evidence. A single dose (0.25 mg/kg) before induction reduced delirium incidence in cardiac surgery patients from 44.6% to 23.2%. In elderly patients undergone gastrointestinal cancer surgery, intraoperative infusion (0.25 mg/kg at induction, then 0.125 mg/kg/h until 20 minutes before the end of surgery) decreased delayed neurocognitive recovery but not delirium. Conversely, postoperative esketamine (1 mg/kg) reduced delirium incidence from 40% to 13.3% in another RCT involving elderly patients undergone gastrointestinal surgery. In patients after major abdominal surgery, mini-dose esketamine (0.015 mg/kg/h for 48 hours) significantly lowered ICU delirium scores compared to low-dose esketamine or placebo. Two meta-analyses of 13 and 17 RCTs, respectively, reported reduced delirium incidence with perioperative esketamine usage, though evidence quality was limited by small sample sizes and heterogeneity. Recent studies showed mixed results. A single-center RCT of 426 elderly surgical patients found no reduction in delirium with 0.2 mg/kg esketamine at induction. In 209 patients aged ≥60 undergone tumor resection, 0.5 mg/kg at induction and 2 mg/kg PCIA postoperatively did not reduce delirium but may improve 90-day cognitive function. Similarly, a single-center RCT of 260 elderly patients after arthroplasty surgery found no benefit with esketamine administered at induction (0.2 mg/kg), intraoperatively (0.125 mg/kg/h), and postoperatively (0.5 mg/kg PCIA). Despite inconsistent findings, esketamine is safe in total, with no increased risk of adverse effects such as respiratory depression, nausea, vomiting, or psychiatric symptoms.

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.

Interventions

• Drug Esketamine
  Esketamine (1mg/ml) will be administered at a loading dose of 0.2 mg/kg, namely at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with a formulation consisting of esketamine 50mg and sufentanil 200 μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2
• Drug Normal saline
  Normal saline will be administered at a infusion rate of 1.2ml/kg/h over 10 minutes after induction, then a maintenance infusion rate of 0.1 mg/kg/h until 40 minutes before the end of the surgery. For postoperative analgesia, patient-controlled intravenous analgesia (PCIA) is prepared with sufentanil 200μg, diluted to a total volume of 200 ml. The background dose is set at 2 ml/h, with a bolus dose of 2 ml and a lockout interval of 15 minutes.

Primary outcome measures

• The incidence of delirium within 5 days after surgery [Time frame: Up to 5 days after surgery]
• Quality of recovery on postoperative day 1 (Sub-study) [Time frame: On postoperative day 1]

Secondary outcome measures (11)

• Intensity of pain during the first 3 postoperative days [Time frame: Up to 3 days after surgery]
• Use of opioids during the first 3 postoperative days [Time frame: Up to 3 days after surgery]
• Cognitive function at 30 days after surgery [Time frame: At the end of 30 days after surgery]
• The incidence of delayed neurocognitive recovery [Time frame: At the end of 30 days after surgery]
• Death rate at 30 days after surgery [Time frame: At the end of 30 days after surgery]
• Quality of recovery on postoperative day 3 (Sub-study) [Time frame: On postoperative day 3]
• Postoperative gastrointestinal intolerance during the first 2 postoperative days (Sub-study) [Time frame: Up to 2 days after surgery]
• Postoperative gastrointestinal dysfunction during the first 2 postoperative days (Sub-study) [Time frame: Up to 2 days after surgery]
• Quality of recovery at 30 days after surgery (Sub-study) [Time frame: At the end of 30 days after surgery]
• HADS score at 30 days after surgery (Sub-study) [Time frame: At the end of 30 days after surgery]
• Sleep quality at 30 days after surgery (Sub-study) [Time frame: At the end of 30 days after surgery]

Eligibility criteria

Inclusion criteria

• Age ≥65 years and <90 years;
• Scheduled to undergo major non-cardiac surgery.
• Fulfill at least one of risk factors as follows: history of stroke; history of delirium; hypertension; congestive heart failure; coronary artery disease; atrial fibrillation; peripheral artery disease; chronic obstructive pulmonary disease; obstructive sleep apnea; diabetes; chronic kidney disease; anemia; malnutrition; hypoalbuminemia; chronic pain; anxiety and depression; poor sleep quality; smoke; alcoholism.
• Scheduled to receive patient-controlled intravenous analgesia (PCIA).

Exclusion criteria

• Refuse to participate;
• Preoperative history of epilepsy, myasthenia gravis, Parkinson's disease, intracranial hypertension, delirium, schizophrenia, or other psychiatric diseases;
• Inability to communicate in the preoperative period because of coma, profound dementia, or language barrier;
• Preoperative uncontrolled severe hypertension (baseline SBP>180 mmHg or DBP>110 mmHg);
• Preoperative history of hyperthyroidism and pheochromocytoma;
• Acute cardiovascular event occurring within 30 days before surgery;
• Severe hepatic dysfunction (Child-Pugh class C), renal dysfunction (required preoperative dialysis), or expected survival ≤24 hours;
• Scheduled to undergo organ transplantation, vascular surgery, neurosurgery;
• Receiving treatment with ketamine or esketamine;
• Contradiction to ketamine or esketamine;
• Other situations where the investigator or physician considers the patient ineligible for the study.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Prevention

Study locations

China · 6 centers

• Fujian Provincial Hospital — Fuzhou
• Sun Yat-sen University Cancer Center — Guangzhou
• Nanfang Hospital, Southern Medical University — Guangzhou
• The First Affiliated Hospital of JiNan University — Guangzhou
• The Eighth Affliated Hospital of Southern Medical Universily — Guangzhou
• Ganzhou People's Hospital — Ganzhou

Publications

• 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. PMID 28973626
• Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesth Analg. 2011 May;112(5):1202-11. doi: 10.1213/ANE.0b013e3182147f6d. Epub 2011 Apr 7. PMID 21474660
• Lindroth H, Bratzke L, Purvis S, Brown R, Coburn M, Mrkobrada M, Chan MTV, Davis DHJ, Pandharipande P, Carlsson CM, Sanders RD. Systematic review of prediction models for delirium in the older adult inpatient. BMJ Open. 2018 Apr 28;8(4):e019223. doi: 10.1136/bmjopen-2017-019223. PMID 29705752
• Balas MC, Happ MB, Yang W, Chelluri L, Richmond T. Outcomes Associated With Delirium in Older Patients in Surgical ICUs. Chest. 2009 Jan;135(1):18-25. doi: 10.1378/chest.08-1456. Epub 2008 Nov 18. PMID 19017895
• 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. PMID 26041151
• Moskowitz EE, Overbey DM, Jones TS, Jones EL, Arcomano TR, Moore JT, Robinson TN. Post-operative delirium is associated with increased 5-year mortality. Am J Surg. 2017 Dec;214(6):1036-1038. doi: 10.1016/j.amjsurg.2017.08.034. Epub 2017 Sep 20. PMID 28947274
• 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. PMID 27344279
• Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008 Sep;65(3):229-38. doi: 10.1016/j.jpsychores.2008.05.019. PMID 18707945

Identifiers

NCT: NCT06817239 · NFEC-2025-016

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗