Dexmedetomidine-Esketamine Combination for Sedation and Analgesia in ICU Patients

Delirium Clinical Trial

Official title:

Effect of Dexmedetomidine-Esketamine Combination for Sedation and Analgesia on Delirium in ICU Patients With Mechanical Ventilation: A Multicenter Randomized Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06468436
• Other study ID #: 2024-239
• Status: Not yet recruiting
• Phase: N/A
• Start date: July 2024
• Est. completion date: December 2030

Study information

• Verified date: June 2024
• Source: Peking University First Hospital
• Contact: Dong-Xin Wang, MD, PhD
• Phone: 8610 83572784
• Email: wangdongxin[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1508
• Est. completion date: December 2030
• Est. primary completion date: June 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Aged
• Delirium
• Dexmedetomidine
• Esketamine
• Intensive Care Units
• Ventilators, Mechanical

Intervention

Drug:
• Dexmedetomidine-Esketamine Combination
For patients with invasive ventilation, nighttime sedation (20:00-06:00) is provided with an initial infusion rate of [0.05×kg] ml/h which is increased by [0.025×kg] ml/h every 10 min, until the Richmond Agitation-Sedation Scale (RASS) reaches -2 to -1, maximal infusion rate reaches [0.175×kg] ml/h, or adverse reactions occur. Daytime sedation (06:00-20:00) is provided as above when considered necessary by the ICU physicians, with a target RASS score of -2 to +1. For patients with non-invasive ventilation (including high-flow nasal oxygenation) or without assisted ventilation, nighttime sedation (20:00-06:00) is provided with an initial infusion rate of [0.0125×kg] ml/h which is increased by [0.0125×kg] ml/h every 10 min, until the RASS reaches -1, maximal infusion rate reaches [0.05×kg] ml/h, or adverse reactions occur. Daytime sedation (06:00-20:00) is typically not required but is provided when considered necessary by the ICU physicians, with a target RASS score of -1 to +1.
• Dexmedetomidine
For patients with invasive ventilation, nighttime sedation (20:00-06:00) is provided with an initial infusion rate of [0.05×kg] ml/h which is increased by [0.025×kg] ml/h every 10 min, until the Richmond Agitation-Sedation Scale (RASS) reaches -2 to -1, maximal infusion rate reaches [0.175×kg] ml/h, or adverse reactions occur. Daytime sedation (06:00-20:00) is provided as above when considered necessary by the ICU physicians, with a target RASS score of -2 to +1. For patients with non-invasive ventilation (including high-flow nasal oxygenation) or without assisted ventilation, nighttime sedation (20:00-06:00) is provided with an initial infusion rate of [0.0125×kg] ml/h which is increased by [0.0125×kg] ml/h every 10 min, until the RASS reaches -1, maximal infusion rate reaches [0.05×kg] ml/h, or adverse reactions occur. Daytime sedation (06:00-20:00) is typically not required but is provided when considered necessary by the ICU physicians, with a target RASS score of -1 to +1.

Locations

Country	Name	City	State
China	Peking University First Hospital	Beijing	Beijing
China	Peking University International Hospital	Beijing	Beijing
China	Tianjin Medical University General Hospital	Tianjin	Tianjin

Sponsors (3)

Lead Sponsor	Collaborator
Peking University First Hospital	Peking University International Hospital, Tianjin Medical University General Hospital

Country where clinical trial is conducted

China, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Proportion of patients without delirium within 14 days	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 14-day period after enrollment or until hospital discharge.	Up to 14 days after enrollment
Other	Proportion of patients without delirium or coma within 14 days	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.	Up to 14 days after enrollment
Other	Length of stay in hospital after enrollment	Length of stay in hospital after enrollment.	Up to 30 days after enrollment
Other	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.	Up to 30 days after enrollment
Other	Cognitive function 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).	At 30 days after enrollment
Other	Quality of life at 30 days	Quality of life is assessed with the World Health Organization Quality of Life brief version (WHOQOL-BREF), a 24-item questionnaire that assesses the quality of life in physical, psychological, and social relationship, and environmental domains. The score ranges from 0 to 100 for each domain, with higher score indicating better function.	At 30 days after enrollment
Primary	Incidence of delirium within 14 days	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 14-day period after enrollment or until hospital discharge. Positive result of delirium assessments at any timepoint is defined as occurrence of delirium.	Up to 14 days after enrollment
Secondary	Days alive without delirium or come during the 14-day period	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.	Up to 14 days after enrollment
Secondary	Ventilator-free days within 30 days	Mechanical ventilation includes both invasive and non-invasive ventilation, but do not include high-flow nasal oxygenation.	Up to 30 days after enrollment
Secondary	Length of stay in the ICU	Length of stay in the ICU.	Up to 30 days after enrollment
Secondary	30-day all-cause mortality	30-day all-cause mortality.	Up to 30 days after enrollment