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Patients in the intensive care unit (ICU) often develop anxiety and agitation, sleep disturbances, and delirium. Delirium occurrence is associated with worse early and long-term outcomes. Dexmedetomidine and ketamine are recommended for sedation and analgesia in postoperative ICU patients, but each may induce side effects. The sedative effects of dexmedetomidine can help mitigate the neuropsychiatric side effects of esketamine. Recent studies showed that dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing side effects. This trial is designed to test the hypothesis that dexmedetomidine-esketamine combination for sedation and analgesia in postoperative ICU patients may reduce delirium.
An estimated 300 million surgical procedures are performed globally each year. Patients who have complex conditions and an elevated risk of postoperative complications frequently require admission to the intensive care unit (ICU). Among these, a subset are admitted to ICU with an endotracheal tube and continue to receive mechanical ventilation. Sleep disturbances are highly prevalent in ICU patients due to environmental factors, underlying diseases, therapeutic interventions, and pain-related stimuli.
Mechanical ventilation, painful stimulation, and sleep disturbances are important risk factors of delirium in ICU patients. Delirium is an acutely occurred brain dysfunction symdrome characteristized with fluctuating disturbances in attention, cognition, and consciousness, and is reported to occur in up to 80% of ICU patients with mechanical ventilation. Delirium occurrence is associated with worse outcomes, including prolonged mechanical ventilation, extended ICU and hospital stays, increased healthcare burden and costs, and elevated mortality risk, as well as long-term sequelae including cognitive decline, reduced quality of life, and decreased survival.
Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. It exerts effects by activating the endogenous sleep-promoting pathways, inducing a state like non-rapid eye movement sleep. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine, a more potent enantiomer of ketamine, has a higher affinity for the NMDA receptor and is approximately twice as potent as ketamine. Both dexmedetomidine and ketamine are recommended for sedation and analgesia in postoperative ICU patients. However, sedative dose dexmedetomidine is associated with bradycardia and hypotension. Even low-dose esketamine can induce neuropsychiatric side effects such as dissociation, hallucinations, and nightmares.
The sedative effects of dexmedetomidine can help mitigate the neuropsychiatric side effects of esketamine. Recent studies showed that low-dose dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing side effects. It is hypothesized that dexmedetomidine-esketamine combination for sedation and analgesia in postoperative ICU patients may reduce delirium.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dexmedetomidine | Active Comparator | Sedation is provided with dexmedetomidine (4 μg/ml dexmedetomidine) for up to 7 days or until discharge from the ICU. |
|
| Dexmedetomidine-esketamine combination | Experimental | Sedation is provided with dexmedetomidine-esketamine combination (2 μg/ml dexmedetomidine and 1 mg/ml esketamine) combination for up to 7 days or until discharge from the ICU. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine | Drug | For patients with endotracheal intubation, nighttime (20:00-06:00) sedation is initiated with 0.2 μg/kg/h dexmedetomidine and increased/decreased by 0.1 μg/kg/h dexmedetomidine every 15 min, until the Richmond Agitation-Sedation Scale (RASS) reaches -2 to -1, maximal infusion rate reaches 0.7 μg/kg/h dexmedetomidine, or adverse reactions occur. Daytime (06:00-20:00) sedation is provided as above when considered necessary, with a target RASS score of -2 to +1. For patients without endotracheal intubation, nighttime (20:00-06:00) sedation is initiated with 0.10 μg/kg/h dexmedetomidine and increased/decreased by 0.05 μg/kg/h dexmedetomidine every 15 min, until the RASS reaches -1, maximal infusion rate reaches 0.2 μg/kg/h dexmedetomidine, or adverse reactions occur. Daytime (06:00-20:00) sedation is typically not provided. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of delirium within 7 days | Delirium will be assessed twice daily (8:00-10:00, 18:00-20:00) for 7 days or until hospital discharge. Patients with endotracheal intubation will be assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Patients without endotracheal intubation will be assessed with the 3-Minute Diagnostic Assessment for Delirium using the Confusion Assessment Method (3D-CAM). Positive result of delirium assessments at any timepoint is defined as occurrence of delirium. | Up to 7 days after surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Total sleep time (TST) on the first postoperative night | Total sleep time will be monitored using an actigraphy device. | From 20:00 on the night of surgery to 06:00 the next morning |
| Postoperative pain score within 7 days |
| Measure | Description | Time Frame |
|---|---|---|
| Length of stay in hospital after surgery | Length of stay in hospital after surgery | Up to 30 days after surgery |
| Incidence of major complications within 30 days | Major complications are defined as new-onset medical conditions other than delirium that are deemed harmful and require therapeutic intervention, that is grade II or higher on the Clavien-Dindo classification. |
Inclusion Criteria:
Exclusion Criteria:
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| 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 |
|---|---|---|---|
| 38918408 | Background | Wang S, Yu X, Cheng L, Ren W, Wen G, Wu X, Lou H, Ren X, Lu L, Hermenean A, Yao J, Li B, Lu Y, Wu X. Dexmedetomidine improves the circulatory dysfunction of the glymphatic system induced by sevoflurane through the PI3K/AKT/DeltaFosB/AQP4 pathway in young mice. Cell Death Dis. 2024 Jun 25;15(6):448. doi: 10.1038/s41419-024-06845-w. | |
| 39328423 |
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| ID | Term |
|---|---|
| D003693 | Delirium |
| ID | Term |
|---|---|
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Dexmedetomidine-esketamine combination | Drug | For patients with endotracheal intubation, nighttime (20:00-06:00) sedation is initiated with 0.1 μg/kg/h dexmedetomidine and 0.05 mg/kg/h esketamine, increased/decreased by 0.05 μg/kg/h dexmedetomidine and 0.025 mg/kg/h esketamine every 15 min, until the RASS reaches -2 to -1, maximal infusion rate reaches 0.35 μg/kg/h dexmedetomidine and 0.175 mg/kg/h esketamine, or adverse reactions occur. Daytime (06:00-20:00) sedation is provided as above when considered necessary, with a target RASS score of -2 to +1. For patients without endotracheal intubation, nighttime (20:00-06:00) sedation is initiated with 0.05 μg/kg/h dexmedetomidine and 0.025 mg/kg/h esketamine, and increased/decreased by 0.025 μg/kg/h dexmedetomidine and 0.0125 mg/kg/h esketamine every 15 min, until the RASS reaches -1, maximal infusion rate reaches 0.1 μg/kg/h dexmedetomidine and 0.05 mg/kg/h esketamine, or adverse reactions occur. Daytime (06:00-20:00) sedation is typically not provided. |
|
|
Pain intensity will be assessed twice daily (8:00-10:00, 18:00-20:00) for 7 days or until hospital discharge, using the 11-point Numeric Rating Scale (NRS; 0 = no pain, 10 = worst pain) or the Behavioral Pain Scale (BPS; range 4-16, with higher scores indicating more severe pain; for patients with deep sedation).
| Up to 7 days after surgery |
| Postoperative subjective sleep quality within 7 days | Subjective sleep quality will be assessed once daily (08:00-10:00) for 7 days or until hospital discharge, using an 11-point Numeric Rating Scale (0 = best sleep, 10 = worst sleep) | Up to 7 days after surgery |
| Length of stay in the ICU | Length of stay in the ICU | Up to 30 days after surgery |
| Up to 30 days after surgery |
| Incidence of cognitive dysfunction at 30 days | Cognitive function is assessed with the Montreal Cognitive Assessment-telephone version (T-MoCA; score ranges from 0 to 22, with higher score indicating better cognitive function). A decline of 1 standard deviation (SD) or more from baseline is defined as having cognitive dysfunction. | At 30 days after surgery |
| Concentration of amyloid-β peptide 42 (Aβ42) in plasma (part of patients) | Concentration of amyloid-β peptide 42 (Aβ42) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of phosphorylated tau at threonine 217 (Tau-PT217) in plasma (part of patients) | Concentration of phosphorylated tau at threonine 217 (Tau-PT217) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of phosphorylated tau at threonine 181 (Tau-PT181) in plasma (part of patients) | Concentration of phosphorylated tau at threonine 181 (Tau-PT181) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of S100 calcium binding protein B (S100B) in plasma (part of patients) | Concentration of S100 calcium binding protein B (S100B) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of glial fibrillary acidic protein (GFAP) in plasma (part of patients) | Concentration of glial fibrillary acidic protein (GFAP) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of interleukin-1 beta (IL-1β) in plasma (part of patients) | Concentration of interleukin-1 beta (IL-1β) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of interleukin-6 (IL-6) in plasma (part of patients) | Concentration of interleukin-6 (IL-6) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of interleukin-10 (IL-10) in plasma (part of patients) | Concentration of interleukin-10 (IL-10) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Concentration of tumor necrosis factor-alpha (TNF-α) in plasma (part of patients) | Concentration of tumor necrosis factor-alpha (TNF-α) in plasma on the morning of the 1st postoperative day | On the morning of the 1st postoperative day |
| Dong R, Liu W, Han Y, Wang Z, Jiang L, Wang L, Gu X. Influencing factors of glymphatic system during perioperative period. Front Neurosci. 2024 Sep 12;18:1428085. doi: 10.3389/fnins.2024.1428085. eCollection 2024. |
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| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |