Dexmedetomidine-Esketamine Combination for Sedation and Analgesia in ICU Patients

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Delirium; Dexmedetomidine; Aged; Intensive Care Units; Esketamine; Ventilators, Mechanical
• Intervention / Treatment: Drug: Dexmedetomidine-Esketamine Combination; Drug: Dexmedetomidine

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 Type: Interventional
• Enrollment (Estimated): 1508
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dong-Xin Wang, MD, PhD; Phone Number: 8610 83572784; Email: wangdongxin@hotmail.com
• Study Contact Backup: Name: Xian Su, MD, PhD; Phone Number: 8610 83575138; Email: suxxxx@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100034
      • Peking University First Hospital
      • Principal Investigator: Dong-Xin Wang, MD, PhD
      • Contact: Dong-Xin Wang, MD, PhD; Phone Number: 8610 83572784; Email: wangdongxin@hotmail.com
      • Contact: Xian Su, MD, PhD; Phone Number: 8610 83575138; Email: suxxxx@126.com
    • Beijing, Beijing, China, 102206
      • Peking University International Hospital
      • Contact: Gang Li, MD; Phone Number: +86 13521809822; Email: ligang@pkuih.edu.cn
      • Contact: Hong-Xun Yuan, MD; Phone Number: +86 13601199951; Email: yuanhongxun@pkuih.edu.cn
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • Tianjin Medical University General Hospital
      • Contact: Ke-Liang Xie, MD; Phone Number: +86 15332112099; Email: xiekeliang2009@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	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.; Other Names: Dexmedetomidine hydrochloride; Esketamine hydrochloride
Active Comparator: 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.	Drug: 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.; Other Names: Dexmedetomidine hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of delirium within 7 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 7-day period after enrollment or until hospital discharge. Positive result of delirium assessments at any timepoint is defined as occurrence of delirium.	Up to 7 days after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Length of stay in the ICU	Length of stay in the ICU.	Up to 30 days after enrollment
30-day all-cause mortality	30-day all-cause mortality.	Up to 30 days after enrollment
Days alive without delirium or come during the 7-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 7 days after enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of stay in hospital after enrollment	Length of stay in hospital after enrollment.	Up to 30 days after enrollment
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
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
Proportion of patients without delirium	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.	Up to 7 days after enrollment
Proportion of patients without delirium or coma	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 7 days after enrollment
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 enrollment

Collaborators and Investigators

• Sponsor: Peking University First Hospital
• Collaborators: Peking University International Hospital; Tianjin Medical University General Hospital
• Investigators: Principal Investigator: Dong-Xin Wang, MD, PhD, Peking University First Hospital

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: June 15, 2024
• First Submitted That Met QC Criteria: June 15, 2024
• First Posted (Actual): June 21, 2024

Study Record Updates

• Last Update Posted (Actual): July 31, 2025
• Last Update Submitted That Met QC Criteria: July 28, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Dexmedetomidine; Intensive Care Units; Aged; Delirium; Esketamine; Ventilators, Mechanical
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Neurotransmitter Agents; Hypnotics and Sedatives; Psychotropic Drugs; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Antidepressive Agents; Esketamine; Dexmedetomidine
• Other Study ID Numbers: 2024-239

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No