An Exploratory Study of the Efficacy and Safety of Esketamine and Dexmedetomidine in Non-Intubated ICU Patients With Hyperactive Delirium: Protocol of a Randomized Controlled Trial

NCT07377981 | Not Yet Recruiting Phase 4 DMC

• 1 other identifier: 2025-SR-1088
• Study Type: interventional
• Target: 132
• Locations: 1 country
• Sites: 1

Brief Summary

This investigator-initiated, randomized, controlled, 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 the duration of delirium.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Duration of Delirium (Time with positive CAM-ICU)

  RASS assessments were performed at the 1st, 2nd, and 3rd hours (H1, H2, H3) after the administration of the study or control drug to randomized enrolled patients, followed by an assessment frequency of once every 2 hours thereafter, with scores recorded accordingly. If a patient who has become CAM-ICU negative and achieved an RASS score between -2 and +1 experiences a sudden recurrence of agitation or delirium, CAM-ICU and RASS assessments will be performed immediately and then repeated hourly until the patient is again CAM-ICU negative with an RASS between -2 and +1, or until non-invasive respiratory support is discontinued for any reason.

  Usually within 30 days

Secondary Outcomes (9)

• Duration of Agitation (Time with RASS > +1)

  Usually within 30 days

• Endotracheal Intubation and Mechanical Ventilation Rate

  Usually within 30 days

• 28-day Mortality Rate

  Usually within 30 days

• ROX Index and SpO₂/FiO₂ Ratio

  Usually within 30 days

• Length of ICU Stay

  Usually within 30 days

Study Arms (2)

Esketamine combined with dexmedetomidine

EXPERIMENTAL

Patients will receive a loading dose of esketamine at 0.1 mg/kg (subanesthetic dose) without a concomitant loading dose of dexmedetomidine. This will be followed by a continuous intravenous infusion (pump-driven) of esketamine at 0.125-0.20 mg/(kg·h) (subanesthetic dose) combined with dexmedetomidine at 0.2-0.5 μg/kg/h. The infusion will be maintained until the patient fulfills the criteria of both a negative CAM-ICU assessment and a RASS score between -2 and +1.

Drug: Esketamine combined with dexmedetomidine

Dexmedetomidine

ACTIVE COMPARATOR

Patients will receive a loading dose of normal saline (0.1 mL/kg), without a loading dose of dexmedetomidine. This will be followed by a continuous intravenous infusion (pump-driven) of normal saline at an equivalent volume to the esketamine infusion rate (simulating 0.125-0.20 mg/(kg·h)), combined with dexmedetomidine at 0.2-0.5 μg/kg/h. The infusion will be continued until the patient meets both criteria: a negative CAM-ICU assessment and a RASS score between -2 and +1.

Drug: Dexmedetomidine

Interventions

Esketamine combined with dexmedetomidine DRUG

Patients will receive a loading dose of esketamine at 0.1 mg/kg (subanesthetic dose) without a concomitant loading dose of dexmedetomidine. This will be followed by a continuous intravenous infusion (pump driven) of esketamine at 0.125-0.20 mg/(kg·h) (subanesthetic dose) combined with dexmedetomidine at 0.2-0.5 μg/kg/h. The infusion will be maintained until the patient fulfills the criteria of both a negative CAM ICU assessment and a RASS score between -2 and +1.

Also known as: E+D

Esketamine combined with dexmedetomidine

Dexmedetomidine DRUG

Patients will receive a loading dose of normal saline (0.1 mL/kg), without a loading dose of dexmedetomidine. This will be followed by a continuous intravenous infusion (pump driven) of normal saline at an equivalent volume to the esketamine infusion rate (simulating 0.125-0.20 mg/(kg·h)), combined with dexmedetomidine at 0.2-0.5 μg/kg/h. The infusion will be continued until the patient meets both criteria: a negative CAM ICU assessment and a RASS score between -2 and +1.

Also known as: D

Dexmedetomidine

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years and ≤90 years;
• Hospitalized in the Intensive Care Unit (ICU) or receiving ICU-level care (with an expected ICU stay \>24 hours);
• Patients with hyperactive delirium: meeting criteria for CAM-ICU 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 a Richmond Agitation-Sedation Scale (RASS) score \> +1. (The RASS and the Confusion Assessment Method for the ICU (CAM-ICU) are used to assess sedation and delirium levels. Hyperactive delirium is defined as CAM-ICU positive with RASS \> +1);
• Receiving non-intubated respiratory support (for \>12 hours);
• Body Mass Index (BMI) between 18 kg/m² and 30 kg/m² for each patient.

You may not qualify if:

• Known or suspected allergy to any of the study drugs;
• Acute myocardial infarction, severe arrhythmias (e.g., ventricular fibrillation, second- or third-degree atrioventricular block, sick sinus syndrome, ventricular tachycardia, QTc interval ≥470 ms, etc.), or left ventricular ejection fraction (LVEF) \<30%;
• Severe bradycardia (heart rate \<40 beats per minute) with significant symptoms and hemodynamic instability;
• Pregnancy or lactation;
• Conditions that may affect efficacy assessment or cognitive function testing, such as blindness or deafness;
• History of epilepsy or seizures;
• Severe central nervous system disorders (e.g., cerebrovascular accident, coma, etc.);
• 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;
• Patients receiving non-intubated respiratory support via a tracheostomy;
• Patients with untreated or inadequately treated hyperthyroidism;
• Patients with poorly controlled hypertension (resting systolic/diastolic blood pressure \>180/100 mmHg);
• Patients or their legally authorized representatives (family members) who are unable to cooperate or unwilling to provide written informed consent;
• Severe hepatic insufficiency (Child-Pugh grade C);
• 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;
• A history of sleep disorders requiring medical intervention within the past month;

Sponsors & Collaborators

• The First Affiliated Hospital with Nanjing Medical University: lead

Study Sites (1)

The First Affiliated Hospital with Nanjing Medical University

Nanjing, Jiangsu, 210000, China

Location

MeSH Terms

Conditions

Agnosia; Psychomotor Agitation

Interventions

Dexmedetomidine; Fumigant 93

Condition Hierarchy (Ancestors)

Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Dyskinesias; Psychomotor Disorders; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Xiangrong Zuo

CONTACT

+86 13913979197; zuoxiangrong@njmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2026
• First Posted: January 30, 2026
• Study Start (Estimated): June 2, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029
• Last Updated: April 13, 2026

Record last verified: 2025-12

Locations

CN (1)