Sedation Efficacy of Dexmedetomidine Versus Midazolam in Critically Ill Ventilated Children

Study Overview
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Brief Summary
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There is a significant lack of adequately powered randomized clinical trial (RCT) data to determine the comparative safety and effectiveness of sedative treatments in pediatric patients. In many centres the standard of care for sedation in pediatric critical care unit (PCCU) patients includes the use of benzodiazepines despite the known negative effects of increased patient agitation and delirium, which can contribute to longer PCCU and hospital length of stay (LOS). The use of an alternative sedative, dexmedetomidine may reduce negative effects in this population. As such, the investigators plan to conduct a well designed comparative RCT to determine the most effective and safest sedative in this vulnerable population utilizing clinical assessments of sedation levels and delirium instance, electroencephalography (EEG) analysis and patient important outcomes.

Official Title
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Sedation Efficacy of Dexmedetomidine Versus Midazolam in Critically Ill Ventilated Children

Conditions
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Mechanically Ventilated, Critically Ill Children

Intervention / Treatment
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* Drug: Precedex
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age is 1 month to 18 years inclusive The patient is intubated and is expected to remain intubated for at least the next 48 hours The patient has not been receiving mechanical ventilation for more than 72 hours The patient must already be receiving an opioid infusion per PCCU Guidelines for Sedation & Analgesia for Procedures Outside O.R. and need additional sedation. Exclusion Criteria: Admission is a consequence of suspected or proven drug overdose Patient is receiving dialysis Known pregnancy or lactation Neuromuscular blockade other than for intubation General anesthesia in the 24 hours prior to study initiation An acquired Central Nervous System (CNS) condition (i.e. encephalitis, traumatic brain injury) resulting in ongoing dysfunction or an acquired condition resulting in ongoing dysfunction Acute hepatitis or severe liver disease Known history of sensitivity to midazolam and/or dexmedetomidine or their constituents Systolic blood pressure (SBP) below 5th percentile for two consecutive measurements Heart rate (HR) below 5th percentile for two consecutive measurements Death is deemed to be imminent or inevitable during the admission and either the intensivist or substitute decision maker is not committed to full active resuscitation Previous enrollment into the study

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 17 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexmedetomidine<br> | Drug: Precedex<br>* Precedex, dexmedetomidine hydrochloride, IV, 4mcg/mL, infusion duration determined by the clinical care team<br>* Other names: dexmedetomidine;|
| Active Comparator: Midazolam<br> | Drug: Midazolam<br>* Midazolam, IV, 5mg/mL (for patients more than 10kg), 1mg/mL (for patients 2-10kg), infusion duration determined by the clinical care team<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target Sedation Range | The percentage of time spent within target sedation range, defined as COMFORT Behaviour Scale score of 11-22, which will be assessed at minimum every 4 hours. | Up to 14 days post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delirium | Prevalence of delirium using the Cornell Assessment of Pediatric Delirium (CAPD) tool | Up to 14 days post-randomization | 
| Delirium | Duration of delirium using the Cornell Assessment of Pediatric Delirium (CAPD) tool | Up to 14 days post-randomization | 
| Delirium | Prevalence of delirium using raw and quantitative EEG | Up to 14 days post-randomization | 
| Delirium | Duration of delirium using raw and quantitative EEG | Up to 14 days post-randomization | 
| Duration of mechanical ventilation | Mechanical ventilation-free days through day 28 will be calculated as 28 minus the duration of mechanical ventilation. Participants who die, are still receiving mechanical ventilation, or are transferred from the PCCU still receiving mechanical ventilation by day 28 will be censored at 28 days and assigned zero mechanical ventilation-free days | Up to 28 days post-randomization | 
| PCCU Length of Stay | Length of stay will be calculated from the time of PCCU admission to the time of PCCU discharge. | Up to 90 days post-randomization | 
| Hospital Length of Stay | Hospital Length of Stay will be calculated from the time of PCCU admission to the time of physical hospital discharge. | Up to 90 days post-randomization | 
| Adverse event (AE) occurrence | Documentation of treatment related adverse events including blood pressure/heart rate changes requiring decreasing or discontinuation of study drug or intervention, delirium requiring medical treatment, any unplanned extubation or line removals, aspirations, ulcerations, etc.determined to result from inadequate sedation | Randomization to 90 days post-randomization | 
| Quantification of sleep stages and sleep quality assessment | Visual and automated scoring of sleep stages from EEG recordings Stage 1 sleep: scored when more than 15 seconds of the epoch is made up of theta activity (4to7 Hz) Stage 2 sleep: predominant theta activity (4 to 7 Hz) and occasional quick bursts of faster activity Stage 3/4 sleep: marked by high-amplitude slow waves Rapid eye movement (REM) sleep: characterized by low-amplitude, mixed-frequency theta waves, intermixed with some alpha waves (usually 1 to 2 Hz slower than wake). | Up to 14 days post-randomization | 
| Pharmacokinetics - Maximum plasma concentration (Cmax) | Maximum plasma concentration (Cmax) | Up to 14 days post-randomization | 
| Pharmacokinetics - Area under the plasma concentration-time curve (AUC) | Area under the plasma concentration-time curve (AUC) | Up to 14 days post-randomization | 
| Use of open label boluses for sedation - number | Number of boluses (opioid and benzodiazepine) administered during the treatment period | Up to 14 days post-randomization | 
| Use of open label boluses for sedation - total dose | Total dose of boluses (opioid and benzodiazepine) administered during the treatment period | Up to 14 days post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sedation, delirium, pediatric, critical care