Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients

Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients Undergoing Non-cardiac Surgery: a Two-center, Dose-exploring Pilot Trial

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.

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.

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.