Efficacy and Safety of Dexmedetomidine During Weaning From Analgesia and Sedation in PICU (TIP-15-01)

Study Overview
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Brief Summary
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This interventional study evaluates the efficacy of dexmedetomidine during weaning from analgesic and sedative drugs in reducing the occurrence of the withdrawal syndrome in PICU. All enrolled patients will undergo the same weaning regimen one half will receive dexmedetomidine while the other will receive a placebo.

Detailed Description
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Children admitted to PICU need of analgesic and sedative drugs. Prolonged treatment can lead to undesirable effects as dependence and tolerance. Patients that have developed dependence may develop the withdrawal syndrome (WS) during the analgesics and sedatives weaning process. Withdrawal symptoms are due to central nervous system excitement, gastrointestinal disturbance, and sympathetic system activation. The incidence of withdrawal syndrome is variable between 17 and 57% a recent study reported an incidence of 64.6% of WS in Italian PICUs. The prevention strategies are addressed to the restriction of drug exposure and to the gradual tapering of infusion. However, these strategies have weak evidence of effectiveness. In this study, the investigators hypothesize that dexmedetomidine may be useful and effective during the weaning of analgosedation drugs in PICU, in preventing the withdrawal syndrome. The primary aim of the study is to evaluate the efficacy of dexmedetomidine in reducing the occurrence of the WS. Secondary aims are to evaluate the dexmedetomidine safety during the weaning, the effective dose range, and the efficacy in reducing the duration of the weaning, of the mechanical ventilation, and of the length of PICU stay. Efficacy will be compared among pediatric age groups, gender, race, Pediatric Index of Mortality (PIM3) score, and length of the analgosedation treatment. Patients admitted to the PICU that meets the inclusion criteria, will be randomly assigned to one of the two treatment groups: treatment A (dexmedetomidine) or treatment B (placebo). Twenty-four hours before the start of the weaning an intravenous infusion of dexmedetomidine/placebo will start. After 24 hours of dexmedetomidine infusion, the weaning regimen will begin following the subsequent indications: 10% reduction of the dose every 12 hours. The withdrawal assessment tool version 1 (WAT-1) is the selected scale to evaluate the occurrence of the WS. Patients with a score of WAT-1 <3 continue the weaning regimen. Patients with a score ≥3 increase the dose of dexmedetomidine/placebo until the next WAT-1 score control and temporarily stop the planned 10% dose reduction. If the next WAT-1 score decreased by at least 1 point from the previous score, the weaning program restarted (10% reduction) without further changes in the dose of dexmedetomidine/placebo until the subsequent score. The 'acute withdrawal crisis' will be treated with a rescue dose of the opioid and/or benzodiazepine in use repeatable until resolution of the crisis. Once analgesics and sedatives weaning is complete, dexmedetomidine will gradually discontinue. Five days after discharge from PICU, a follow-up visit will be performed. The sample size estimate is 80 participants for each of the two groups for a total of 160 patients recruited within a period of two years.

Official Title
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Efficacy and Safety of Dexmedetomidine During Weaning From Analgesia and Sedation in Pediatric Intensive Care Unit. A Multicenter, Double-blind, Randomized Controlled Trial.

Conditions
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Withdrawal Syndrome

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Continuous analgesic and sedative endovenous treatment for at least 5 days Invasive or non-invasive mechanical ventilation Clinical conditions that allow by clinical judgment the start of analgosedation weaning Post-natal age ≥ 7 days and PMA beyond the 37 weeks Written informed consent obtained Exclusion Criteria: Hemodynamic instability Cardiac bundle-branch block of 2 or 3 degree Hypersensitivity to the alpha-agonists Persistent fever of unknown origin or sensitivity to malignant hyperthermia Use of alpha-agonist (clonidine or dexmedetomidine) in the last 30 days

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum 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<br>Dexmedetomidine 100 mcg/ml concentrate solution. Continuous iv infusion. Start dose 0.4 mcg/kg/h, increases by 0.2 mcg/kg/h until 0.8 mcg/kg/h (half dose for neonates). If withdrawal symptoms appear the dose can be increased to a maximum of 1.4 mcg/Kg/h. | Drug: Dexmedetomidine<br>* intravenous infusion<br>* Other names: Dexdor, Precedex;|
| Placebo Comparator: Placebo<br>saline solution for IV infusion. The administration of infusion will follow the experimental drug. | Drug: Placebo<br>* intravenous infusion of physiological saline solution to mimic dexmedetomidine infusion<br>* Other names: physiological saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Withdrawal Assessment Tool (WAT-1) scale | WAT-1 score recorded every 12 hours.The score ranges from 0 to 12, a score ≥3 indicates the presence of signs/symptoms of withdrawal. | time 0 start dexmedetomidine and every 12 hours post-start dexmedetomidine for 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in heart rate | changes in heart rate will be recorded when their value differs more than 20% by the patient's baseline values. | 0,1, 2, 12, 24 hours post-start dexmedetomidine and then every 12 hours for 7 days | 
| Change in Systolic Blood Pressure | changes in Systolic Blood Pressure will be recorded when their value differs more than 20% by the patient's baseline values. | 0,1, 2, 12, 24 hours post-start dexmedetomidine and then every 12 hours for 7 days | 
| Change in Diastolic Blood Pressure | changes in Diastolic Blood Pressure will be recorded when their value differs more than 20% by the patient's baseline values. | 0,1, 2, 12, 24 hours post-start dexmedetomidine and then every 12 hours for 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatrics, dexmedetomidine, analgesia, sedation, pediatric intensive care unit, abstinence syndrome, assessment tool