An Exploratory Study of the Efficacy and Safety of Esketamine and Dexmedetomidine in Non-Intubated ICU Patients With Hyperactive Delirium

Inclusion Criteria:

1. Age ≥18 years and ≤90 years;
2. Hospitalized in the Intensive Care Unit (ICU) or receiving ICU-level care (with an expected ICU stay \>24 hours);
3. 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);
4. Receiving non-intubated respiratory support (for \>12 hours);
5. Body Mass Index (BMI) between 18 kg/m² and 30 kg/m² for each patient.

Exclusion Criteria:

1. Known or suspected allergy to any of the study drugs;
2. 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%;
3. Severe bradycardia (heart rate \<40 beats per minute) with significant symptoms and hemodynamic instability;
4. Pregnancy or lactation;
5. Conditions that may affect efficacy assessment or cognitive function testing, such as blindness or deafness;
6. History of epilepsy or seizures;
7. Severe central nervous system disorders (e.g., cerebrovascular accident, coma, etc.);
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-intubated respiratory support via a tracheostomy;
10. Patients with untreated or inadequately treated hyperthyroidism;
11. Patients with poorly controlled hypertension (resting systolic/diastolic blood pressure \>180/100 mmHg);
12. Patients or their legally authorized representatives (family members) who are unable to cooperate or unwilling to provide written informed consent;
13. Severe hepatic insufficiency (Child-Pugh grade C);
14. 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;
15. A history of sleep disorders requiring medical intervention within the past month;
16. Other conditions deemed unsuitable for inclusion by the investigators.