Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients

Peking University

Status and phase: Not yet enrolling; Phase 4

Conditions: Delayed Neurocognitive Recovery; Esketamine; Elderly; Noncardiac Surgery; Postoperative Delirium

Treatments: Drug: Esketamine 3; Drug: Normal saline; Drug: Esketamine 2; Drug: Esketamine 1

Study type: Interventional

Funder types: Other

Identifiers

NCT07523334

2026-0166

Details and patient eligibility

About

Esketamine is frequently used during the perioperative period for supplemental analgesia. Small sample size trials showed that subanesthetic dose esketamine may decrease postoperative neurocognitive complications. However, conflicting results exist and optimal dose of esketamine remains to be determined. This dose-exploring pilot trial is designed to evaluate the safety and efficacy of three different perioperative esketamine dosing regimens in older patients undergoing major non-cardiac surgery. The primary purpose is to explore the optimal dosing strategy that produce maximal neurocognitive benefits with minimal adverse neuropsychiatric symptoms.

Full description

Postoperative neurocognitive complications including delirium and delayed neurocognitive recovery are common in older patients after major surgery and associated with worse early and long-term outcomes. Risk factors of neurocognitive complications are multiple. Predisposing factors include older age, low education, and cognitive decline. Precipitating factors include major surgery, high dose opioids, severe pain, and sleep disturbances. The underlying mechanisms are not totally clear but may include surgery-related stress response and inflammation.

Ketamine is a noncompetitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist and has been used as an anesthetic and analgesic for decades. Esketamine is the S-enantiomer of ketamine and has an analgesic potent of approximately 2 times of that of ketamine. Available studies showed that subanesthetic dose ketamine/esketamine may reduce delirium and/or delayed neurocognitive recovery. However, conflicting results exist. Furthermore, even subanesthetic dose ketamine/esketamine may produce neuropsychiatric symptoms which are harmful for neurocognitive recovery.

This dose-exploring pilot trial is designed to evaluate the safety and efficacy of three different perioperative esketamine dosing regimens in older patients undergoing major non-cardiac surgery. The primary purpose is to explore the optimal dosing strategy that produce maximal neurocognitive benefits with minimal adverse neuropsychiatric symptoms.

Enrollment: 120 estimated patients

Sex: All

Ages: 65 to 90 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. Aged >=65 but <= 90 years;
2. Scheduled to undergo non-cardiac surgery with an expected duration of >= 2 hours under general anesthesia;
3. Requiring patient-controlled intravenous analgesia (PCIA) after surgery.

Exclusion criteria

1. Unable to communicate preoperatively due to visual or auditory impairment, language barrier, or severe dementia;
2. Comorbid with schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
3. Traumatic brain injury or neurosurgery;
4. Severe hepatic dysfunction (Child-Pugh Class C), severe renal dysfunction (receiving dialysis preoperatively), or American Society of Anesthesiologists physical status classification >= Ⅳ;
5. Expected admission to the Intensive Care Unit with endotracheal intubation after surgery;
6. Anaphylaxis to esketamine;
7. Participation in other clinical studies, or any other conditions that are considered unsuitable to be involved in the study.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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120 participants in 4 patient groups, including a placebo group

Esketamine dose 1

Experimental group

Description:

During anesthesia, a loading dose esketamine (0.5 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.1 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.05 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.25 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (0.5 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.25 mg/h esketamine) background infusion, and used for up to 48 hours.

Treatment:

Drug: Esketamine 1

Esketamine dose 2

Experimental group

Description:

During anesthesia, a loading dose esketamine (1 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.2 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.1 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.5 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (1 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.5 mg/h esketamine) background infusion, and used for up to 48 hours.

Treatment:

Drug: Esketamine 2

Esketamine dose 3

Experimental group

Description:

During anesthesia, a loading dose esketamine (1.5 mg/ml) 0.4 ml/kg will be infused over 30 minutes (0.3 mg/kg) after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h (0.15 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with esketamine (0.75 mg/ml) and sufentanil (1 ug/ml), programmed to deliver 2-ml bolus (1.5 mg esketamine) with a 8-10-minute lock-out time and a 1-ml/h (0.75 mg/h esketamine) background infusion, and used for up to 48 hours.

Treatment:

Drug: Esketamine 3

Placebo

Placebo Comparator group

Description:

During anesthesia, a loading dose placebo (normal saline) 0.4 ml/kg will be infused over 30 minutes after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with sufentanil (1 ug/ml), programmed to deliver 2-ml bolus with a 8-10-minute lock-out time and a 1-ml/h background infusion, and used for up to 48 hours.

Treatment:

Drug: Normal saline