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.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Delirium; Elderly; Noncardiac Surgery; Esketamine; Delayed Neurocognitive Recovery
• Intervention / Treatment: Drug: Esketamine 1; Drug: Esketamine 2; Drug: Esketamine 3; Drug: Normal saline

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Dong-Xin Wang, MD, PhD; Phone Number: +86 13910731903; Email: wangdongxin@hotmail.com
• Study Contact Backup: Name: Jia-Hui Ma, PhD; Email: mjh@bjmu.edu.cn

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100034
      • Peking University First Hospital
      • Contact: Jia-Hui Ma, PhD; Email: mjh@bjmu.edu.cn
  • Tianjing
    • Tanjing, Tianjing, China, 300052
      • Tianjin Medical University General Hospital
      • Contact: Yi-Ze Li, MD; Email: liyizelisa@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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.	Drug: Normal saline; 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.; Other Names: Placebo
Experimental: Esketamine dose 1; 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.	Drug: Esketamine 1; 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.; Other Names: Esketamine dose 1
Experimental: Esketamine dose 2; 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.	Drug: Esketamine 2; During anesthesia, a loading dose esketamine (1.0 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.; Other Names: Esketamine dose 2
Experimental: Esketamine dose 3; 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.	Drug: Esketamine 3; 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.; Other Names: Esketamine dose 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dissociative symptoms	Dissociative symptoms will be assessed at 30 minutes after extubation and then twice daily (8:00-10:00, 18:00-20:00) during the first 4 days after surgery, using the 6-item Clinician Administered Dissociative State Scale (CADSS-6; scores range frrom 0 to 24 with higher scores indicating more severe dissociative symptoms; a score >=3 indicates presence of dissociative symptoms).	Up to 4 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of delayed neurocognitive recovery	Cognitive function will be assessed with the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better function) at baseline and on the 5th day/before hospital discharge after surgery. Delayed neurocognitive recovery is defined as |Z| score of MoCA decline >=1.96. Z score = (MoCA change of patients - MoCA change of normal control)/standard deviation of MoCA change of normal control.	Up to 5 days after surgery
Incidence of emergence delirium	Emergence delirium will be assessed at 30 minutes after extubation, during stay in the postanesthesia care unit, using the Confusion Assessment Methods for the Intensive Care Unit (CAM-ICU).	At 30 minutes after extubation
Incidence of postoperative delirium	Postoperative delirium will be assessed twice daily (8:00-10:00, 18:00-20:00) during the first 4 days after surgery, using the 3-Minute Diagnostic Interview for the Confusion Assessment Method (3D-CAM) for non-intubated patients or the Confusion Assessment Methods for the Intensive Care Unit (CAM-ICU) for intubated patients.	Up to 4 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay after surgery	Length of hospital stay after surgery	Up to 30 days after surgery
Incidence of complications within 30 days after surgery	Postoperative complications are defined as new-onset condition that are deemed harmful and required therateutic intervention, i.e., class II or higher on the Clavien-Dindo classification.	Up to 30 days after surgery
Incidence of postoperative neurocognitive disorder	Cognitive function will be assessed with the Telephone Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher scores indicating better function) at baseline and on the 30th day after surgery. Postoperative neurocognitive disorder is defined as |Z| score of T-MoCA decline >=1.96. Z score = (T-MoCA change of patients - T-MoCA change of normal control)/standard deviation of T-MoCA change of normal control.	At 30 days after surgery
Area under curve of dissociative symptom severity at various timepoints after surgery	Dissociative symptoms will be assessed at 30 minutes after extubation and then twice daily (8:00-10:00, 18:00-20:00) during the first 4 days after surgery, using the 6-item Clinician Administered Dissociative State Scale (CADSS-6; scores range from 0 to 24 with higher scores indicating more severe dissociative symptoms; a score >=3 indicates presence of dissociative symptoms).	Up to 4 days after surgery
Area under curve of pain intensity at various timeoints after surgery	Pain intensity will be assessed at 30 minutes after extubation and then twice daily (8:00-10:00, 18:00-20:00) during the first 4 days after surgery, using the Numeric Rating Scale (NRS; scores range from 0 to 10 with 0=no pain at all and 10=the worst pain).	Up to 4 days after surgery
Scores of subjective sleep quality after surgery	Subjective sleep quality will be assessed once daily (8:00-10:00) during the first 4 days after surgery, using the Numeric Rating Scale (NRS; scores range from 0 to 10 with 0=the best sleep quality and 10=the worst sleep quality).	Up to 4 days after surgery
Severity of anxiety after surgery	Severity of anxiety will be assessed on the 5th day or before hospital discharge after surgery, using the Generalized Anxiety Disorde-7 (GAD-7; scores range from 0 to 21 with higher scores indicating more severe anxiety).	Up to 5 days after surgery
Severity of depressive symptoms after surgery	Severity of depressive symptoms will be assessed on the 5th day or before hospital discharge after surgery, using the Patient Health Questionnaire-9 (PHQ-9; scores range from 0 to 27 with higher scores indicating more severe depressive symptoms).	Up to 5 days after surgery

Collaborators and Investigators

• Sponsor: Peking University First Hospital
• Collaborators: Tianjin Medical University General Hospital
• Investigators: Principal Investigator: Dong-Xin Wang, MD, PhD, Peking University First Hospital

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 4, 2026
• First Submitted That Met QC Criteria: April 4, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Esketamine; Postoperative delirium; Older patients; Noncardiac surgery; Delayed neurocognitive recovery
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Emergence Delirium; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Saline Solution
• Other Study ID Numbers: 2026-0166

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No