Safety and Efficacy of Esketamine - Dexmedetomidine Combination Versus Dexmedetomidine Monotherapy for Hyperactive Delirium in ICU Patients on Non-Invasive Respiratory Support (SEED-NIRS Trial): Study Protocol of a Randomized Controlled Trial

NCT07377981 | Not Yet Recruiting Phase 4

• 1 other identifier: 2025-SR-1088
• Study Type: interventional
• Target: 388
• Locations: 1 country
• Sites: 1

Brief 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.

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)

• A hierarchical composite endpoint within 14 days, including intubation or tracheostomy, delirium duration, and agitation duration

  The hierarchical components, ranked in order of clinical importance, are as follows: 1. All-cause endotracheal intubation or tracheostomy within 14 days. 2. Duration of delirium is defined as the number of days from randomization to the first sustained resolution of delirium, where sustained resolution is defined as CAM-ICU negative for ≥36 consecutive hours. Follow-up for delirium duration is censored at the earliest of: * sustained resolution of delirium (CAM-ICU negative for ≥36 hours), * endotracheal intubation or tracheostomy, * death, or * day 14. 3. Duration of agitation is defined as the cumulative number of hours with a RASS score ≥ +1 from randomization up to the earliest of: * resolution of agitation, * endotracheal intubation or tracheostomy, * death, or * day 14.

  Usually within 14 days

Secondary Outcomes (8)

• The number of ventilator-free and/or delirium free days (the number of days without a positive CAM-ICU) at day 14

  Usually within 14 days

• Delirium recurrence rate

  Usually within 14 days

• Open-label rescue of Antipsychotic Medications (e.g., haloperidol, olanzapine) in the first 14 days.

  Usually within 14 days

• The length of ICU stay

  Usually within 14 days

• All-cause mortality at day 14

  Usually within 14 days

Study Arms (2)

Esketamine combined with dexmedetomidine

EXPERIMENTAL

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: Esketamine combined with dexmedetomidine

Dexmedetomidine

ACTIVE COMPARATOR

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.

Drug: Dexmedetomidine

Interventions

Esketamine combined with dexmedetomidine DRUG

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.

Also known as: E+D

Esketamine combined with dexmedetomidine

Dexmedetomidine DRUG

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.

Also known as: D

Dexmedetomidine

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years and ≤80 years at the time of randomization;
• Hospitalized in the ICU (with an expected ICU stay \>24 hours);
• 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);
• Receiving non-invasive respiratory support (eg. high-flow nasal cannula, CPAP, or non-invasive ventilation) at least for \>24 hours.

You may not qualify if:

• Known or suspected allergy or Contraindications to any of the study drugs;
• 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%;
• Recent administration of esketamine, dexmedetomidine or haloperidol within previous 72 hours.
• Pregnancy or lactation;
• Conditions that may affect efficacy assessment or cognitive function testing, such as blindness, deafness, aphasic, or coma patients;
• History of epilepsy or seizures;
• Patients with an estimated survival period of less than 48 hours as judged by the investigator;
• 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-invasive respiratory support via a tracheostomy;
• Patients with untreated or inadequately treated hyperthyroidism;
• 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;
• Patients or their legally authorized representatives (family members) who are unable to cooperate or unwilling to provide written informed consent;

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: August 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029
• Last Updated: July 2, 2026

Record last verified: 2026-05

Locations

CN (1)