Clinical trial NCT06468436: Dexmedetomidine-Esketamine Combination for Sedation and Analgesia in ICU Patients
Official title: Effect of Dexmedetomidine-Esketamine Combination for Sedation and Analgesia on Delirium in ICU Patients With Mechanical Ventilation: A Multicenter Randomized Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Aged
Intensive Care Units
Ventilators, Mechanical
Dexmedetomidine
Esketamine
Delirium
Keywords: Aged
Intensive Care Units
Ventilators, Mechanical
Dexmedetomidine
Esketamine
Delirium
Lead sponsor: Peking University First Hospital
Sponsor class: OTHER
Collaborators: name: Peking University International Hospital
name: Tianjin Medical University General Hospital
First posted: 2024-06-21
Enrollment: 1508
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of delirium within 7 days
timeFrame: Up to 7 days after enrollment
Secondary outcomes:
measure: Days alive without delirium or come during the 7-day period
timeFrame: Up to 7 days after enrollment
measure: Ventilator-free days within 30 days
timeFrame: Up to 30 days after enrollment
measure: Length of stay in the ICU
timeFrame: Up to 30 days after enrollment
measure: 30-day all-cause mortality
timeFrame: Up to 30 days after enrollment
Other outcomes:
measure: Proportion of patients without delirium
timeFrame: Up to 7 days after enrollment
measure: Proportion of patients without delirium or coma
timeFrame: Up to 7 days after enrollment
measure: Length of stay in hospital after enrollment
timeFrame: Up to 30 days after enrollment
measure: Incidence of major complications within 30 days
timeFrame: Up to 30 days after enrollment
measure: Incidence of cognitive dysfunction at 30 days
timeFrame: At 30 days after enrollment
measure: Quality of life at 30 days
timeFrame: At 30 days after enrollment
Locations:
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University International Hospital
state: Beijing
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
state: Tianjin
Study officials:
affiliation: Peking University First Hospital
name: Dong-Xin Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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