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| Name | Class |
|---|---|
| Tianjin Medical University General Hospital | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Esketamine dose 1 | Experimental | 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. |
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| Esketamine dose 2 | Experimental | 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. |
|
| Esketamine dose 3 | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Esketamine 1 | Drug | 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. |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dong-Xin Wang, MD, PhD | Contact | +86 13910731903 | wangdongxin@hotmail.com | |
| Jia-Hui Ma, PhD | Contact | mjh@bjmu.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Dong-Xin Wang, MD, PhD | Peking University First Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Peking University First Hospital | Beijing | Beijing Municipality | 100034 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33889433 | Background | Brodier EA, Cibelli M. Postoperative cognitive dysfunction in clinical practice. BJA Educ. 2021 Feb;21(2):75-82. doi: 10.1016/j.bjae.2020.10.004. Epub 2020 Dec 24. No abstract available. | |
| 12170047 | Background | Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, Kuipers HM, Hanning CD, Siersma VD, Kristensen D, Canet J, Ibanaz MT, Moller JT; ISPOCD2 Investigators. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology. 2002 Jun;96(6):1351-7. doi: 10.1097/00000542-200206000-00014. |
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| ID | Term |
|---|---|
| D000071257 | Emergence Delirium |
| ID | Term |
|---|---|
| D003693 | Delirium |
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
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| ID | Term |
|---|---|
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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| Placebo | Placebo Comparator | 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. |
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| Esketamine 2 | Drug | 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. |
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| Esketamine 3 | Drug | 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 | 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. |
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|
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 |
| 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 |
| 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 |
| Length of hospital stay after surgery | Length of hospital stay after surgery | 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 |
| 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 |
| Tianjin Medical University General Hospital | Tanjing | Tianjing | 300052 | China |
|
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| D009422 |
| Nervous System Diseases |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |