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.

Delirium is defined as an acute disturbance in attention and consciousness that develops over a short period of time and is accompanied by other cognitive impairments, such as memory deficits, disorientation, or perceptual abnormalities. It represents the most common clinical manifestation of acute brain dysfunction in the intensive care unit (ICU). Based on psychomotor activity, delirium is classified into three subtypes: hyperactive, hypoactive, and mixed. Hyperactive delirium is the most readily recognized form, characterized by agitation, emotional lability, hallucinations, or delusions. Patients with this subtype often exhibit impulsive behaviors-such as attempting to remove intravenous lines in the ICU-which can lead to serious injury or life-threatening situations. Furthermore, agitation induces a state of physiological stress, amplifies neuroendocrine responses, increases organ load, and may exacerbate the underlying illness. For instance, it can elevate blood pressure, raise heart rate, and increase oxygen consumption, potentially triggering cardiac or cerebrovascular events in patients with preexisting conditions. During episodes of agitation or delirium, inflammatory markers such as IL 6, IL 8, IL 2, and CRP are elevated. The rise in pro inflammatory cytokines activates microglia, leading to further release of inflammatory mediators and creating a vicious cycle that exacerbates neuroinflammation. According to the Chinese Guidelines for Pain and Sedation in Adult ICU Patients, delirium is a risk factor for poor prognosis in ICU patients, not only increasing mortality and extending hospital stay but also imposing a significant economic burden. Given these adverse consequences, the early management of delirium in the ICU is particularly important.

Treatment strategies for delirium include non pharmacological approaches, such as those incorporated into bundled care models like the ABCDE bundle, which have been shown to support recovery. While the ABCDE bundle is supported by high quality evidence regarding its efficacy and safety, its complexity often makes full implementation challenging in clinical practice, leading to greater reliance on pharmacological interventions. Pharmacological prevention may include supplements such as melatonin to improve sleep quality and avoid sleep deprivation associated delirium. The selective melatonin receptor agonist ramelteon shortens sleep latency and promotes sleep maintenance by modulating signals from the suprachiasmatic nucleus, thereby potentially reducing delirium incidence. However, some studies have found no significant difference in delirium incidence compared with placebo, and robust evidence for its efficacy remains lacking. Another approach involves the use of antipsychotics such as haloperidol or olanzapine. Nevertheless, research indicates that haloperidol does not significantly shorten delirium duration and may be associated with higher six month mortality. High dose haloperidol can also induce cardiotoxicity, including QT interval prolongation, torsades de pointes, and hypotension. Additionally, GABA receptor agonists like benzodiazepines are used for sedation and anxiolysis in critically ill patients, yet prolonged use is believed to increase the risk of delirium. Dexmedetomidine, a potent and highly selective α 2 adrenergic receptor agonist, offers sedative, analgesic, anxiolytic, and opioid sparing properties. It is widely used in clinical practice and, compared with other sedatives, demonstrates advantages in reducing postoperative complications and shortening hospital length of stay. A prospective study in patients with type II respiratory failure receiving non intubated respiratory support compared dexmedetomidine, propofol, and remifentanil for sedation and analgesia. The dexmedetomidine group showed lower rates of non intubated respiratory support failure, lower mortality, and shorter ICU and hospital stays. However, no current guidelines recommend dexmedetomidine for managing agitation or delirium occurring during non intubated respiratory support.

Non intubated respiratory support is widely used in clinical practice, yet its failure rate is considerable. Studies report failure rates ranging from 15% to 38%-and up to 50% in some settings-among patients with acute respiratory failure. A proportion of these failures can be attributed to agitation or delirium during therapy. For example, one study found that 18.1% of ICU patients developed delirium during non intubated positive pressure ventilation, and delirium was independently associated with ventilatory failure. Poor tolerance due to anxiety or discomfort is considered a key driver of non intubated respiratory support failure. Another study reported an 18.18% incidence of delirium in patients receiving sequential high flow nasal cannula oxygen therapy after extubation. For cases of ventilatory failure secondary to agitation or delirium during non intubated support, moderate sedation is a recommended strategy to improve success rates. Although dexmedetomidine can reduce agitation duration in non intubated ICU patients, its effect on shortening delirium duration or preventing intubation remains uncertain, as suggested by the 4D trial in patients with hyperactive delirium. Moreover, dexmedetomidine significantly increases the risk of bradycardia and hypotension, and its labeling notes additional side effects such as headache, dry mouth, nausea, vomiting, and abnormal body temperature fluctuations.

Ketamine, a phencyclidine derivative, provides hemodynamically stable anesthesia through central sympathetic stimulation without significant respiratory depression. The combination of ketamine and dexmedetomidine has been associated with better mask or helmet compliance, faster sedation onset, and improved hemodynamic stability. Mechanistically, ketamine increases extracellular norepinephrine and dopamine concentrations in a time and dose dependent manner, whereas dexmedetomidine can cause bradycardia and vasodilation. Thus, their combination may produce counter balancing effects, yielding a net "negative negative positive" outcome. A multimodal regimen such as esketamine combined with dexmedetomidine for managing agitation or delirium during non intubated respiratory support could offer a promising approach to achieve rapid sedation, reduce delirium incidence, and maintain hemodynamic stability.

Esketamine, the S enantiomer of racemic ketamine, is considered approximately two to three times more potent than the racemate and is associated with a more favorable adverse effect profile, including fewer psychotomimetic symptoms. Low dose esketamine has been shown to reduce the incidence and severity of extubation related cough in patients undergoing laryngoscopic surgery and to decrease postoperative delirium incidence and pain levels in elderly surgical patients. In frail elderly patients undergoing laparoscopic radical resection for gastrointestinal tumors, low dose esketamine lowered delirium associated biomarker concentrations and effectively reduced postoperative delirium incidence. Currently, the combination of esketamine and dexmedetomidine has been employed in various settings, including intraoperative anesthesia, pediatric procedural sedation, gastrointestinal endoscopy, trauma analgesia, and mechanical ventilation. However, its utility for delirium occurring during non intubated respiratory support has not been formally evaluated. Our research group's earlier work confirmed that the combination is safe and effective for sedation in mechanically ventilated ICU patients, reducing ICU length of stay and time to awakening without increasing hypotension or bradycardia, compared with dexmedetomidine alone. Building on these preliminary findings, this study will investigate the efficacy and safety of esketamine combined with dexmedetomidine for the management of hyperactive delirium in ICU patients receiving non intubated respiratory support, with the aim of providing new insights to improve delirium related outcomes in critically ill patients.

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 <40 beats per minute), etc.), or left ventricular ejection fraction (LVEF) <30%;
3. Recent administration of esketamine, dexmedetomidine or haloperidol within previous 72 hours.
4. Pregnancy or lactation;
5. Conditions that may affect efficacy assessment or cognitive function testing, such as blindness, deafness, aphasic, or coma patients;
6. History of epilepsy or seizures;
7. Patients with an estimated survival period of less than 48 hours as judged by the investigator;
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-invasive respiratory support via a tracheostomy;
10. Patients with untreated or inadequately treated hyperthyroidism;
11. Severe hepatic insufficiency (Child-Pugh grade C);
12. 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;
13. A history of sleep disorders requiring medical intervention within the past month;
14. Patients or their legally authorized representatives (family members) who are unable to cooperate or unwilling to provide written informed consent;
15. Other conditions deemed unsuitable for inclusion by the investigators.