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.
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).
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);
Parallel
Esketamine
DrugEsketamine (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 ml and a lockout interval of 15 minutes.
Normal saline
DrugNormal 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.
The incidence of delirium within 5 days after surgery
Delirium is assessed twice daily (8-10 am and 6-8 pm) with The Confusion Assessment Method (CAM) for non-intubated patients or The confusion assessment method for the Intensive Care Unit (CAM-ICU) for intubated patients.
Quality of recovery on postoperative day 1 (Sub-study)
Quality of recovery is assessed once daily (6-8 pm) with 15-item Quality of Recovery Scale (QoR-15).
Intensity of pain during the first 3 postoperative days
Intensity of pain will be assessed twice after surgery with the Behavioral Pain Scale and Numeric Rating Scale (an 11- point scale where 0 indicates no pain and 10 the worst pain).
Use of opioids during the first 3 postoperative days
Include opioids used for PCIA and supplemental analgesics.
Cognitive function at 30 days after surgery
Cognitive function is assessed with the Telephone-Montreal Cognitive Assessment (T-MoCA) (a 22-point scale, with higher score indicating better function).
The incidence of delayed neurocognitive recovery
A decline in the T-MoCA score by 1 standard deviation (SD) or more from the baseline is considered delayed neurocognitive recovery.
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