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

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

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.

Study Overview

• Status: Terminated
• Conditions: Withdrawal Syndrome
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy, 40138
    • PICU Policlinico S.Orsola-Malpighi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine; 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; intravenous infusion; Other Names: Dexdor, Precedex
Placebo Comparator: Placebo; saline solution for IV infusion. The administration of infusion will follow the experimental drug.	Drug: Placebo; intravenous infusion of physiological saline solution to mimic dexmedetomidine infusion; Other Names: physiological saline solution

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Opioid dose	verification of adherence to weaning regimen	7 days
Change in Sedative dose	verification of adherence to weaning regimen	7 days

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Collaborators: Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Azienda Ospedaliera di Padova
• Investigators: Study Chair: Maria C. Mondardini, MD, Azienda Ospedaliero Universitaria di Bologna Policlinico S.Orsola-Malpighi

Publications and helpful links

General Publications

• Amigoni A, Mondardini MC, Vittadello I, Zaglia F, Rossetti E, Vitale F, Ferrario S, Savron F, Coffaro G, Brugnaro L, Amato R, Wolfler A, Franck LS; Network of Paediatric Intensive Care Unit Study Group (TIPNet). Withdrawal Assessment Tool-1 Monitoring in PICU: A Multicenter Study on Iatrogenic Withdrawal Syndrome. Pediatr Crit Care Med. 2017 Feb;18(2):e86-e91. doi: 10.1097/PCC.0000000000001054.
• Mondardini MC, Daverio M, Caramelli F, Conti G, Zaggia C, Lazzarini R, Muscheri L, Azzolina D, Gregori D, Sperotto F, Amigoni A. Dexmedetomidine for prevention of opioid/benzodiazepine withdrawal syndrome in pediatric intensive care unit: Interim analysis of a randomized controlled trial. Pharmacotherapy. 2022 Feb;42(2):145-153. doi: 10.1002/phar.2654. Epub 2021 Dec 21.
• Mondardini MC, Sperotto F, Daverio M, Caramelli F, Gregori D, Caligiuri MF, Vitale F, Cecini MT, Piastra M, Mancino A, Pettenazzo A, Conti G, Amigoni A. Efficacy and safety of dexmedetomidine for prevention of withdrawal syndrome in the pediatric intensive care unit: protocol for an adaptive, multicenter, randomized, double-blind, placebo-controlled, non-profit clinical trial. Trials. 2019 Dec 11;20(1):710. doi: 10.1186/s13063-019-3793-6.

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2018
• Primary Completion (Actual): January 18, 2020
• Study Completion (Actual): January 18, 2020

Study Registration Dates

• First Submitted: August 17, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 30, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: pediatrics; dexmedetomidine; sedation; analgesia; assessment tool; pediatric intensive care unit; abstinence syndrome
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Substance Withdrawal Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: EudraCT 2015-002114-80 OsSC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No