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

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)

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.

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.

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.