Sedation With Dexmedetomidine-esketamine Combination and Delirium in ICU Patients

Effect of Sedation With Dexmedetomidine-esketamine Combination on Delirium in Postoperative ICU Patients: a Randomized Controlled Pilot Trial

Patients in the intensive care unit (ICU) often develop anxiety and agitation, sleep disturbances, and delirium. Delirium occurrence is associated with worse early and long-term outcomes. Dexmedetomidine and ketamine are recommended for sedation and analgesia in postoperative ICU patients, but each may induce side effects. The sedative effects of dexmedetomidine can help mitigate the neuropsychiatric side effects of esketamine. Recent studies showed that dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing side effects. This trial is designed to test the hypothesis that dexmedetomidine-esketamine combination for sedation and analgesia in postoperative ICU patients may reduce delirium.

An estimated 300 million surgical procedures are performed globally each year. Patients who have complex conditions and an elevated risk of postoperative complications frequently require admission to the intensive care unit (ICU). Among these, a subset are admitted to ICU with an endotracheal tube and continue to receive mechanical ventilation. Sleep disturbances are highly prevalent in ICU patients due to environmental factors, underlying diseases, therapeutic interventions, and pain-related stimuli.

Mechanical ventilation, painful stimulation, and sleep disturbances are important risk factors of delirium in ICU patients. Delirium is an acutely occurred brain dysfunction symdrome characteristized with fluctuating disturbances in attention, cognition, and consciousness, and is reported to occur in up to 80% of ICU patients with mechanical ventilation. Delirium occurrence is associated with worse outcomes, including prolonged mechanical ventilation, extended ICU and hospital stays, increased healthcare burden and costs, and elevated mortality risk, as well as long-term sequelae including cognitive decline, reduced quality of life, and decreased survival.

Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. It exerts effects by activating the endogenous sleep-promoting pathways, inducing a state like non-rapid eye movement sleep. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Esketamine, a more potent enantiomer of ketamine, has a higher affinity for the NMDA receptor and is approximately twice as potent as ketamine. Both dexmedetomidine and ketamine are recommended for sedation and analgesia in postoperative ICU patients. However, sedative dose dexmedetomidine is associated with bradycardia and hypotension. Even low-dose esketamine can induce neuropsychiatric side effects such as dissociation, hallucinations, and nightmares.

The sedative effects of dexmedetomidine can help mitigate the neuropsychiatric side effects of esketamine. Recent studies showed that low-dose dexmedetomidine-esketamine combination improved analgesia and sleep quality without increasing side effects. It is hypothesized that dexmedetomidine-esketamine combination for sedation and analgesia in postoperative ICU patients may reduce delirium.

Inclusion Criteria:

1. Aged 60 years or older;
2. Admitted to the intensive care unit (ICU) after surgery;
3. Expected to stay in the ICU for at least one night.

Exclusion Criteria:

1. History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis;
2. Presence of preoperative delirium, or inability to communicate due to coma, severe dementia, or language barrier;
3. Previously diagnosed obstructive sleep apnea, judged to be at high risk of moderate-to-severe obstructive sleep apnea according to the STOP-Bang questionnaire, or have a body mass index >30 kg/m²;
4. Preoperative left ventricular ejection fraction <30%, sick sinus syndrome, severe sinus bradycardia (heart rate <50 bpm), second-degree or higher atrioventricular block without a pacemaker, or systolic blood pressure <90 mmHg despite use of vasopressors;
5. Comorbid with hyperthyroidism or pheochromocytoma;
6. Severe liver dysfunction (Child-Pugh Class C), severe renal dysfunction (requiring dialysis), or expected survival ≤24 hours;
7. After traumatic brain injury or neurosurgery;
8. Allergy to dexmedetomidine and/or esketamine;
9. Other conditions that are considered unsuitable for study participation.