Dexmedetomidine-Esketamine Combination for Sedation and Analgesia in ICU Patients

Not Applicable

Not yet recruiting

• Conditions: Intensive Care Units; Esketamine; Aged; Ventilators, Mechanical; Dexmedetomidine; Delirium
• Interventions: Drug: Dexmedetomidine-Esketamine Combination; Drug: Dexmedetomidine

• Registration Number: NCT06468436
• Lead Sponsor: Peking University First Hospital

Brief Summary

Patients with mechanical ventilation in the intensive care unit (ICU) often develop anxiety and agitation, sleep distuebances, and delirium. Delirium occurrence is associated with worse early and long-term outcomes. Dexmedetomidine and ketamine are recommended for sedation and analgesia in ICU patients, but each may induce side effects. The sedative effects of dexmedetomidine can help mitigate the psychiatric side effects of esketamine. Recent studies showed that dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing psychiatric side effects. This trial is designed to test the hypothesis that dexmedetomidine-esketamine combination for sedation and analgesia in ICU patients with mechanical ventilation may reduce delirium and improve respiratory recovery.

Detailed Description

Patients with respiratory failure or other severe conditions often require non-invasive or invasive mechanical ventilation in the Intensive Care Unit (ICU). The uncomfortable stimulation produced by mechanical ventilation may lead to anxiety and agitation of patients and adverse consequences such as ventilator asynchrony, increased oxygen consumption, stress responses, self-extubation, and potentially prolonged mechanical ventilation. The above factors, together with the ICU environment, underlying illnesses, treatment measures, and painful procedures, often result in sleep disturbances in ICU patients.

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 duration, 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, the more potent enantiomer of ketamine, has a higher affinity for the NMDA receptor and is approximately twice as potent as ketamine, with a lower incidence of adverse effects. Both dexmedetomidine and ketamine are recommended for sedation and analgesia in ICU patients. However, sedative dose dexmedetomidine is associated with bradycardia and hypotension. Even low-dose esketamine can induce psychotropic side effects such as dissociation, hallucinations, and nightmares.

The sedative effects of dexmedetomidine can help mitigate the psychiatric side effects of esketamine. Recent studies showed that dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing psychiatric side effects. It is hypothesized that dexmedetomidine-esketamine combination for sedation and analgesia in ICU patients with mechanical ventilation may reduce delirium and improve respiratory recovery.

Study Timeline

• Study First Submitted: 2024-06-15
• Study First Submitted QC: 2024-06-15
• Study First Posted: 2024-06-21
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-04
• Last Update Posted: 2024-10-08
• Study Start: 2024-11
• Primary Completion: 2030-06
• Study Completion: 2030-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1508

Inclusion Criteria

1. Aged ≥18 years;
2. Receiving invasive or non-invasive mechanical ventilation in the ICU, with an expected duration ≥24 hours;
3. Require sedation as judged by ICU physicians.

Exclusion Criteria

1. Pregnant or lactating women;
2. History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
3. Unable to communicate due to coma, severe dementia, or language barrier prior to invasive/non-invasive mechanical ventilation;
4. After stroke, hypoxic encephalopathy, traumatic brain injury, or neurosurgery;
5. Comorbid with hyperthyroidism or pheochromocytoma;
6. Left ventricular ejection fraction <30%, sick sinus syndrome, severe sinus bradycardia (heart rate <50 bpm), second-degree or higher atrioventricular block without a pacemaker, or systolic blood pressure <90 mmHg despite use of vasopressors;
7. Severe liver dysfunction (Child-Pugh Class C), severe renal dysfunction (requiring dialysis), or expected survival ≤24 hours;
8. Allergy to dexmedetomidine and/or esketamine, or any other conditions that are considered unsuitable for study participation.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dexmedetomidine-Esketamine Combination	Dexmedetomidine-Esketamine Combination	Sedation-analgesia is provided with dexmedetomidine-esketamine combination for up to 14 days or until discharge from the ICU. The formulation consists of dexmedetomidine 200 μg/2 ml and esketamine 100 mg/4 ml, diluted with normal saline to a total volume of 50 ml, resulting in a dexmedetomidine concentration of 4 μg/ml and an esketamine concentration of 2 mg/ml.
Dexmedetomidine	Dexmedetomidine	Sedation-analgesia is provided with dexmedetomidine for up to 14 days or until discharge from the ICU. The formulation consists of dexmedetomidine 200 μg/2 ml, diluted with normal saline to a total volume of 50 ml, resulting in a dexmedetomidine concentration of 4 μg/ml.

Primary Outcome Measures

Name	Time	Method
Incidence of delirium within 7 days	Up to 7 days after enrollment	Delirium is assessed twice daily with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or the 3-Minute Diagnostic Assessment for Delirium using the Confusion Assessment Method (3D-CAM) during the 7-day period after enrollment or until hospital discharge. Positive result of delirium assessments at any timepoint is defined as occurrence of delirium.

Secondary Outcome Measures

Name	Time	Method
Days alive without delirium or come during the 7-day period	Up to 7 days after enrollment	Delirium is assessed twice daily with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or the 3-Minute Diagnostic Assessment for Delirium using the Confusion Assessment Method (3D-CAM). Coma is defined as Richmond Agitation Sedation Scale (score ranges from -5 \[unarousable\] to +4 \[combative\] and 0 indicates alert and calms) of -4 or -5. Positive results at any timepoint is defined as occurrence of delirium or coma.
Ventilator-free days within 30 days	Up to 30 days after enrollment	Mechanical ventilation includes both invasive and non-invasive ventilation, but do not include high-flow nasal oxygenation.
Length of stay in the ICU	Up to 30 days after enrollment	Length of stay in the ICU.
30-day all-cause mortality	Up to 30 days after enrollment	30-day all-cause mortality.

Trial Locations

Locations (3)

Tianjin Medical University General Hospital; 🇨🇳 Tianjin, Tianjin, China

Peking University International Hospital; 🇨🇳 Beijing, Beijing, China

Peking University First Hospital; 🇨🇳 Beijing, Beijing, China