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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

ConditionsDexmedetomidineKetamineAnalgesiaRespiratory TherapyIntensive Care Units (ICUs)AgitationSedation and Analgesia
Trial statusNot yet recruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexAll
Age18-80
SponsorThe First Affiliated Hospital with Nanjing Medical University

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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.

Disqualifiers

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;

Trial design

Design model

Parallel

Treatments tested in this trial

  • 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.

  • 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.

Treatment groups

356 Participants
are divided into 2 treatment groups
Group A: Esketamine combined with dexmedetomidineExperimental treatment 1 intervention
Group B: DexmedetomidineActive comparator 1 intervention

Trial outcomes

Primary outcomes

1

A hierarchical composite endpoint within 7 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 7 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 7. 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 7.

Time frame
Usually within 7 days

Secondary outcomes

1

The number of ventilator-free and/or delirium free days (the number of days without a positive CAM-ICU) at day 7

Time frame
Usually within 7 days
2

Delirium recurrence rate

The occurrence of a new positive CAM-ICU assessment following at least one negative CAM-ICU assessment after initial delirium resolution.

Time frame
Usually within 7 days
3

Open-label rescue of Antipsychotic Medications (e.g., haloperidol, olanzapine) in the first 7 days.

Time frame
Usually within 7 days
4

The length of ICU stay

Time frame
Usually within 28 days

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

The First Affiliated Hospital with Nanjing Medical University

Lead sponsor

Source ClinicalTrials.gov

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