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

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.

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 \