Efficacy and Safety of Esketamine Combined With Dexmedetomidine in Non-Invasive ICU Patients With Hyperactive Delirium (ESSENTIAL Trial): Protocol of a Randomized Controlled Trial (ESSENTIAL)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Analgesia; Ketamine; Dexmedetomidine; Agitation; Respiratory Therapy; Sedation and Analgesia; Intensive Care Units (ICUs)
• Intervention / Treatment: Drug: Esketamine combined with dexmedetomidine; Drug: Dexmedetomidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 388
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Xiangrong Zuo; Phone Number: +86 13913979197; Email: zuoxiangrong@njmu.edu.cn

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • The First Affiliated Hospital with Nanjing Medical University
      • Contact: Xiangrong Zuo; Phone Number: +86 13913979197; Email: zuoxiangrong@njmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Esketamine combined with dexmedetomidine; 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; 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.; Other Names: E+D
Active Comparator: Dexmedetomidine; 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; 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.; Other Names: D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A hierarchical composite endpoint within 28 days, including intubation or tracheostomy, delirium duration, and agitation duration	The hierarchical components, ranked in order of clinical importance, are as follows: All-cause endotracheal intubation or tracheostomy within 28 days: the HACOR score will be assessed at enrollment (H0) and subsequently twice daily (between 08:00-10:00 and 16:00-18:00), with intervals exceeding 6 hours between assessments.; 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, orday 28.; 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, orday 28.	Usually within 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Athens Insomnia Scale (AIS) Score	All enrolled patients will complete the AIS before receiving the study medication. The AIS will be administered again on the first morning after 24 hours of medication (at 10:00) and subsequently every morning (at 10:00), with all scores recorded.	Usually within 30 days
Pain Assessment using the Critical-Care Pain Observation Tool (CPOT) or Visual Enhanced Numeric Rating Scale（NRS-V)	Pain scores will be assessed at 15 minutes, 2 hours, 4 hours, and 24 hours after initiation of the study medication, and subsequently once every 24 hours.	Usually within 30 days
The number of ventilator-free and/or delirium free days (the number of days without a positive CAM-ICU) at day 28		Usually within 14 days
Delirium recurrence rate	The occurrence of a new positive CAM-ICU assessment following at least one negative CAM-ICU assessment after initial delirium resolution.	Usually within 14 days
Open-label rescue of Antipsychotic Medications (e.g., haloperidol, olanzapine) in the first 28 days.		Usually within 14 days
The length of ICU stay		Usually within 14 days
All-cause mortality at day 7 and day 28		Usually within 14 days
Incidence of Adverse Events	This includes electrocardiographic abnormalities (bradycardia, arrhythmia, myocardial ischemia, tachycardia, or QTc prolongation), hypotension or hypertension requiring any vasoactive medication, respiratory distress or apnea, and delirium-related complications (such as unplanned removal of catheters, tubes, or drains, increased secretions, etc.).	Usually within 14 days

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: January 12, 2026
• First Submitted That Met QC Criteria: January 28, 2026
• First Posted (Actual): January 30, 2026

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Analgesia; Ketamine; Dexmedetomidine; Agitation; Respiratory Therapy; Sedation and analgesia; Intensive Care Units (ICUs)
• Additional Relevant MeSH Terms: Aberrant Motor Behavior in Dementia; Neurologic Manifestations; Nervous System Diseases; Behavioral Symptoms; Neurobehavioral Manifestations; Dyskinesias; Psychomotor Disorders; Perceptual Disorders; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Psychomotor Agitation; Agnosia; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Dexmedetomidine; Fumigant 93
• Other Study ID Numbers: 2025-SR-1088

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No