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NCT07377981

PHASE4

Efficacy and Safety of Esketamine Combined With Dexmedetomidine in Non-Invasive ICU Patients With Hyperactive Delirium (ESSENTIAL Trial): Protocol of a Randomized Controlled Trial

Sponsor: The First Affiliated Hospital with Nanjing Medical University

View on ClinicalTrials.gov

Summary

This investigator-initiated, randomized, controlled, single-blind, superiority trial aims to assess the efficacy and safety of esketamine combined with dexmedetomidine for the management of agitation or delirium in intensive care unit (ICU) patients receiving non-invasive respiratory support. The primary endpoint is a clinically prioritized hierarchical composite endpoint within 28 days, including intubation or tracheostomy, delirium duration, and agitation duration.

Key Details

Gender

All

Age Range

18 Years - 80 Years

Study Type

INTERVENTIONAL

Enrollment

388

Start Date

2026-07-01

Completion Date

2029-01-01

Last Updated

2026-05-29

Healthy Volunteers

Conditions

Dexmedetomidine Ketamine Analgesia Respiratory Therapy Intensive Care Units (ICUs)Agitation Sedation and Analgesia

Interventions

DRUG

Esketamine combined with dexmedetomidine

Participants will receive esketamine at 0.125-0.20 mg/(kg·h) combined with dexmedetomidine at 0.2-0.5 μg/kg/h. Sedation will be targeted to maintain a RASS score between -1 and +1, prioritizing light sedation while ensuring adequate control of agitation. Drug titration will follow a protocolized, stepwise approach to minimize inter-physician variability: - If RASS ≥ +2, the esketamine infusion rate will be preferentially increased within the predefined range. - If agitation persists at the upper esketamine dose, dexmedetomidine may be increased within its allowed range. - If RASS between -1 and +1, the current dose will be maintained. - If RASS ≤ -2, esketamine will be reduced or temporarily discontinued first, followed by reduction of dexmedetomidine if necessary.

DRUG

Dexmedetomidine

Participants will receive dexmedetomidine at 0.2-0.5 μg/kg/h. Sedation will be targeted to maintain a Richmond Agitation-Sedation Scale (RASS) score between -1 and +1, prioritizing light sedation while ensuring adequate control of agitation. Drug titration will follow a protocolized, stepwise approach to minimize inter-physician variability: - If RASS ≥ +2, dexmedetomidine infusion will be increased within the predefined range. - If RASS ≤ -2, dexmedetomidine will be reduced or temporarily discontinued. Continuous infusion will be maintained for at least 36 hours after resolution of delirium, or until ICU discharge if earlier, to reduce the risk of relapse.

Inclusion Criteria: 1. Age ≥18 years and ≤80 years at the time of randomization; 2. Hospitalized in the ICU (with an expected ICU stay \>24 hours); 3. Patients with hyperactive delirium: meeting criteria for Confusion Assessment Method for the ICU (CAM-ICU)\[19\] positivity (i.e., acute onset or fluctuating course plus inattention, and at least one secondary criterion-disorganized thinking or altered level of consciousness) and having agitation which is diagnosed if the Richmond Agitation-Sedation Scale (RASS) score\[20\] is superior or equal to +1. (The RASS and CAM-ICU are used to assess sedation and delirium levels. Hyperactive delirium is defined as CAM-ICU positive with RASS \> +1); 4. Receiving non-invasive respiratory support (eg. high-flow nasal cannula, CPAP, or non-invasive ventilation) at least for \>24 hours. Exclusion Criteria: 1. Known or suspected allergy or Contraindications to any of the study drugs; 2. Severe arrhythmias (e.g., ventricular fibrillation, second- or third-degree atrioventricular block, sick sinus syndrome, ventricular tachycardia, QTc interval ≥470 ms, severe bradycardia (heart rate \<40 beats per minute), etc.), or left ventricular ejection fraction (LVEF) \<30%; 3. Recent administration of esketamine, dexmedetomidine or haloperidol within previous 72 hours. 4. Pregnancy or lactation; 5. Conditions that may affect efficacy assessment or cognitive function testing, such as blindness, deafness, aphasic, or coma patients; 6. History of epilepsy or seizures; 7. Patients with an estimated survival period of less than 48 hours as judged by the investigator; 8. Neuropsychiatric conditions per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) that may introduce bias (e.g., active substance use disorder, psychosis, etc.), including alcoholism, drug abuse, or use of psychotropic medications; 9. Patients receiving non-invasive respiratory support via a tracheostomy; 10. Patients with untreated or inadequately treated hyperthyroidism; 11. Severe hepatic insufficiency (Child-Pugh grade C); 12. Severe renal dysfunction, defined as: chronic renal insufficiency with a glomerular filtration rate (GFR) ≤ 29 mL/min/1.73 m²; or subjects on long-term maintenance hemodialysis or peritoneal dialysis; 13. A history of sleep disorders requiring medical intervention within the past month; 14. Patients or their legally authorized representatives (family members) who are unable to cooperate or unwilling to provide written informed consent; 15. Other conditions deemed unsuitable for inclusion by the investigators.

Locations (1)

The First Affiliated Hospital with Nanjing Medical University

Nanjing, Jiangsu, China