Dexmedetomidine to Lessen Intensive Care Unit (ICU) Agitation

Study Overview
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Brief Summary
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The primary aim of the DahLIA trial is to determine, in patients with ICU-associated delirium and agitation who are otherwise pathophysiologically stable (as defined), the number of ventilator-free hours in the incident ICU admission in the 7 days following commencement of trial medication, in patients randomised to receive dexmedetomidine or placebo while receiving all other aspects of standard care. The null hypothesis assumes no difference in the median number of ventilator-free hours in this ICU admission in the following 7 days, between patients receiving dexmedetomidine and placebo for ICU-associated agitation and delirium.

Official Title
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A Randomised, Double-blind, Multi-centre Placebo Controlled Trial of Dexmedetomidine for Patients With Agitation and Delirium in the Intensive Care Unit

Conditions
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Delirium

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be eligible for the study if, in the opinion of the treating clinician, they continue to require mechanical ventilation only because their degree of agitation requires such a high dose of sedative medication (midazolam or propofol, the only commonly used specific sedatives in our unit) that extubation is not possible, AND in the opinion of their treating intensivist their agitation is so severe as to make lessening their sedation unsafe. These criteria will be objectively quantified as follows: they have required either mechanical restraint and/or anti-delirium or sedative medication in the 4 hours prior to seeking consent AND their Confusion Assessment Method for the ICU (CAM-ICU) test is positive for delirium in the 4 hours prior to seeking consent AND their Motor Activity Assessment Scale (MAAS) score is 5 or more in the 4 hours prior to seeking consent, confirming psychomotor agitation AND their SOFA score is less than or equal to 5 in the 4 hours prior to seeking consent, predicting a mortality or around 5%. Exclusion Criteria: Age less than 18 years old Pregnancy or breastfeeding Advanced dementia (in the premorbid state requiring professional nursing care) Open or closed head injury Death is deemed imminent and inevitable The patient has previously been enrolled in the DahLIA study Patients who could not be extubated, or who would be intubated within the following 48 hours, even if delirium or agitation were corrected. This will include: Patients receiving high dose opioid for analgesia (not sedation) ( > 40 mg/morphine/day) Patients shortly to return to the operating theatre Patients undergoing repeated invasive procedures, in whom it is desirable to maintain deep sedation Patients likely to require ongoing airway protection or control, or ventilatory support (for example, spinal patients with an inadequate vital capacity) Known allergy to haloperidol or alpha 2 agonists

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexmedetomidine<br>Dexmedetomidine will be administered intravenously as a maintenance infusion of 0.2 to 1.5 mcg/kg/hour, commencing at 0.5 mcg/kg/hour and titrated according to effect, for as long as deemed necessary by the treating physician. Specifically, the study medication may be (as recommended by the manufacturer) continued after extubation, and if discontinued may be restarted at any time up until ICU discharge. The clinician will have the option of using a loading dose of 1.0 mcg/kg IV over 20 minutes, as recommended by the manufacturer. Bedside nursing staff will adjust drug infusion rates as necessary, in consultation with the treating physician, aiming to achieve a Riker Sedation-Agitation Scale 20 score of 4. | Drug: Dexmedetomidine<br>* Dexmedetomidine will be administered intravenously as a maintenance infusion of 0.2 to 1.5 mcg/kg/hour, commencing at 0.5 mcg/kg/hour and titrated according to effect, for as long as deemed necessary by the treating physician. Specifically, the study medication may be (as recommended by the manufacturer) continued after extubation, and if discontinued may be restarted at any time up until ICU discharge. The clinician will have the option of using a loading dose of 1.0 mcg/kg IV over 20 minutes, as recommended by the manufacturer. Bedside nursing staff will adjust drug infusion rates as necessary, in consultation with the treating physician, aiming to achieve a Riker Sedation-Agitation Scale 20 score of 4.<br>* Other names: Precedex;|
| Placebo Comparator: Saline placebo<br>An identical syringe to that in the intervention arm, but which does not contain dexmedetomidine, will be provided. The initial rate of infusion and subsequent adjustments will be the same as in the dexmedetomidine group. | Drug: Saline placebo<br>* An identical syringe containing only saline with no dexmedetomidine added will be supplied. Initial rate of infusion and subsequent adjustments will be the same as in the active comparator group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free hours | The primary outcome measure for the study will be the number of ventilator-free hours in the incident ICU admission in the 7 days following commencement of trial medication, in patients randomised to receive dexmedetomidine or normal saline placebo while receiving all other aspects of standard care. | 7 days following randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to ICU discharge |  | On hospital discharge, or 6 months (whichever is sooner) | 
| Overall ICU length of stay |  | On hospital discharge, or 6 months (whichever is sooner) | 
| Time to first extubation |  | On hospital discharge, or 6 months (whichever is sooner) | 
| Time taken to achieve a satisfactory sedation score | Time taken to achieve RASS score -2 to +1 and RIKER score 3 or 4 | 7 days following randomisation | 
| %ICU time spent with a satisfactory sedation score | %ICU time spent with RASS -2 to +1 and RIKER 3 or 4 | 7 days following randomisation | 
| %ICU time spent with a satisfactory delirium score | % time spent with a negative CAM-ICU assessment | 7 days following randomisation | 
| Time taken to achieve a satisfactory agitation score | Time taken to achieve a MAAS score 2-4 | 7 days following randomisation | 
| %ICU time spent with a satisfactory agitation score | %ICU time spent with a MAAS score 2-4 | 7 days following randomisation | 
| Need for supplementary sedative medication | total infusion time, mean hourly dose and total dose of propofol, morphine and midazolam. | 7 days following randomisation | 
| Need for mechanical restraint | Time to first not requiring restraint and % ICU time spent without mechanical restraint in the 7 days following commencement of trial medication | 7 days following randomisation | 
| Need for supplementary antipsychotic medication | Number of doses and total mg delivered of haloperidol, olanzapine, quetiapine, or other anti-psychotic medication as prescribed by the treating physician | 7 days following randomisation | 
| Need for tracheostomy | Tracheostomy deemed to be necessary by the treating physician, and actually performed. | On hospital discharge, or 6 months (whichever is sooner) | 
| Acute hospital length of stay | Total duration of admission to the acute hospital, prior to discharge to home or a skilled or unskilled nursing facility. | On hospital discharge, or 6 months (whichever is sooner) | 
| Discharge destination | Discharge to home, a skilled nursing facility, residential care, a physical rehabilitation facility, or death. | On hospital discharge, or 6 months (whichever is sooner) | 
| Daily SOFA score | Daily SOFA score with recording of the component parts | 7 days following randomisation | 
| ICU mortality | ICU mortality | On hospital discharge, or 6 months (whichever is sooner) | 
| Hospital mortality | Death in the acute care hospital | On hospital discharge, or 6 months (whichever is sooner) | 
| Duration and rate of vasopressor support | total infusion time, and mean hourly dose of noradrenaline and any other inotrope or vasopressor | 7 days following randomisation | 
| Need for insertion of a new central venous catheter to facilitate vasopressor / inotropic support |  | 7 days following randomisation | 
| Requirement for reintubation | Reintubation of the trachea to facilitate airway protection or mechanical ventilation, as indicated in the opinion of the treating physician | On hospital discharge, or 6 months (whichever is sooner) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Delirium, Intensive Care Unit, Dexmedetomidine