Impact of Esketamine on Delayed Neurocognitive Recovery in Older Patients

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.

• Esketamine 1 (Drug), also known as 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.
• Esketamine 2 (Drug), also known as Esketamine dose 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.
• Esketamine 3 (Drug), also known as 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.
• Normal saline (Drug), also known as 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.

Primary outcomes

• Incidence of dissociative symptoms [Up to 4 days 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 frrom 0 to 24 with higher scores indicating more severe dissociative symptoms; a score >=3 indicates presence of dissociative symptoms).

Secondary outcomes

• Incidence of emergence delirium [At 30 minutes after extubation]: 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).
• Incidence of postoperative delirium [Up to 4 days after surgery]: 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.
• Incidence of delayed neurocognitive recovery [Up to 5 days after surgery]: 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.

Other outcomes

• Area under curve of dissociative symptom severity at various timepoints after surgery [Up to 4 days 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).
• Area under curve of pain intensity at various timeoints after surgery [Up to 4 days 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).
• Scores of subjective sleep quality after surgery [Up to 4 days 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).
• Severity of anxiety after surgery [Up to 5 days 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).
• Severity of depressive symptoms after surgery [Up to 5 days 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).
• Length of hospital stay after surgery [Up to 30 days after surgery]: Length of hospital stay after surgery
• Incidence of postoperative neurocognitive disorder [At 30 days after surgery]: 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.
• Incidence of complications within 30 days after surgery [Up to 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.

Sex: All, ages: 65 Years to 90 Years, 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.

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• Dong-Xin Wang, MD, PhD, Principal investigator, Peking University First Hospital