Low-dose Dexmedetomidine in Mechanically Ventilated ICU Patients

Study Overview
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Brief Summary
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For patients undergoing mechanical ventilation, light sedation is better than deep sedation for the outcomes, which is manifested as shortened length of ICU stay, shortened duration of mechanical ventilation, and decreased mortality. In a recent study of the investigators, low-dose dexmedetomidine without sedative effects (0.1 ug/kg/h) improved sleep quality and reduced the incidence of delirium in elderly patients admitted to the ICU after surgery. The investigators hypothesize that, for ICU patients with prolonged mechanical ventilation, low-dose dexmedetomidine infusion (0.1 ug/kg/h) may also be effective in decreasing delirium. The purpose of this study is to investigate whether low-dose dexmedetomidine infusion can reduce the incidence of delirium in ICU patients with prolonged duration of mechanical ventilation (>= 24 hours).

Detailed Description
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Delirium is an acutely occurred and transient brain dysfunction characterized with cognitive dysfunction, lowered consciousness, disturbed attention, abnormal psychoactivity, and disordered sleep-wake rhythm. Delirium is frequent in mechanically ventilated patients in the intensive care unit (ICU), with reported incidences up to 70% or 87%. Possible reasons leading to delirium include the intervention-heavy environment of the ICU, mechanical ventilation and sleep disturbances. The occurrence of delirium is associated with worse outcomes including prolonged mechanical ventilation and ICU stay, increased complications, prolonged hospital stay, higher mortality, and elevated medical expenses. It is also associated with worse long-term outcomes including declined cognitive function, lowered life quality, and elevated long-term mortality. Dexmedetomidine is a high selective alpha-2 adrenoceptor agonist with anxiolytic, sedative and analgesic effects. When used for sedation in mechanically ventilated patients (dose range 0.2-1.4 ug/kg/h), it reduces the consumption of other sedatives and analgesics, ameliorates the rhythm and structure of sleep, and decreases the occurrence of delirium. In recent studies of the investigators, low-dose dexmedetomidine infusion (0.1 ug/kg/h) ameliorated sleep quality; for elderly patients admitted to the ICU after surgery, prophylactic low-dose dexmedetomidine infusion reduced the incidence of delirium (for patients with mechanical ventilation: 28.8% with placebo vs. 11.5% with dexmedetomidine, P<0.0001; for patients without mechanical ventilation: 15.1% with placebo vs. 6.3% with dexmedetomidine, P=0.014). For patients undergoing mechanical ventilation, light sedation is better than deep sedation for the outcomes, which is manifested as shortened length of ICU stay, shortened duration of mechanical ventilation, and decreased mortality. Some authors even reported that no sedation (analgesia only) provides better outcome than light sedation, because it further shortens the durations of mechanical ventilation and ICU stay. In the above studies of the investigators, the recruited patients were less severe because the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was low (mean score from 10.2 to 10.6) and the duration of mechanical ventilation was short (median 6.9 hours in the control group). The investigators hypothesize that, for ICU patients with prolonged mechanical ventilation, low-dose dexmedetomidine infusion (0.1 ug/kg/h) may also be effective in improving sleep and decreasing delirium. The purpose of this study is to investigate whether low-dose dexmedetomidine infusion can reduce the incidence of delirium in ICU patients with prolonged duration of mechanical ventilation (>= 24 hours).

Official Title
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Low-dose Dexmedetomidine for Delirium Prevention in Mechanically Ventilated Patients in Intensive Care Unit: a Multicenter, Randomised, Double-blinded, Placebo-controlled Trial

Conditions
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Adult Disease, Intensive Care Unit Syndrome, Mechanical Ventilation Complication, Delirium, Dexmedetomidine

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Placebo (normal saline)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aged 18 years or older; admitted to the ICU; with expected duration of mechanical ventilation of more than 24 hours. Exclusion Criteria: refused to participate; aged less than 18 years; pregnant; preoperative history of schizophrenia, epilepsy, Parkinsonism, or myasthenia gravis; inability to communicate in the preoperative period (coma, profound dementia, or language barrier); brain injury or neurosurgery; known preoperative left ventricular ejection fraction less than 30%, sick sinus syndrome, severe sinus bradycardia (<50 beats per min [bpm]), or second degree or greater atrioventricular block without pacemaker; severe hepatic dysfunction (Child-Pugh class C); severe renal dysfunction (undergoing dialysis before surgery); less likely to survive for more than 24 hours.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine group<br>Dexmedetomidine is infused at a rate of 0.1 ug/kg/h for a maximum of 3 days. | Drug: Dexmedetomidine<br>* Dexmedetomidine is administered as a continuous intravenous infusion at a rate of 0.025 mL/kg per h (0.1 μg/kg per h) from study recruitment in the ICU for no more than 72 hours.<br>* Other names: Dexmedetomidine hydrochloride;|
| Placebo Comparator: Placebo group<br>Placebo (normal saline) is infused at a same rate as in the dexmedetomidine group for a maximum of 3 days. | Drug: Placebo (normal saline)<br>* Placebo (normal saline) is administered as a continuous intravenous infusion at a rate of 0.025 mL/kg per h from study recruitment in the ICU for no more than 72 hours.<br>* Other names: Normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of delirium within the first 7 days after enrollment | Assessment twice daily (in the morning from 0600 h to 1000 h and in the evening from 1800 h to 2000 h) with the Confusion Assessment Method for the ICU (CAM-ICU). | From enrollment until 7 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of mechanical ventilation | Duration of mechanical ventilation after study enrollment. | From enrollment until extubation or 30 days. | 
| Length of stay in the ICU | Length of stay in the ICU after study enrollment. | From enrollment until ICU discharge or 30 days. | 
| Length of stay in the hospital | Length of stay in the hospital after study enrollment. | From enrollment until hospital discharge or 30 days. | 
| Occurrence of non-delirium complications | Occurrence of complications other than delirium after study enrollment. | From enrollment until 30 days. | 
| All-cause 30-day mortality | All-cause 30-day mortality after study enrollment. | On the 30th day after enrollment. | 
| 30-day cognitive function | Assessed with the Telephone Interview of Cognitive Status-Modified (TICS-m). | On the 30th day after enrollment. | 
| 30-day life quality | Assessed with the WHOQOL-Bref. | On the 30th day after enrollment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult, Intensive care unit, Mechanical ventilation, Delirium, Dexmedetomidine