Sedation Efficacy of Dexmedetomidine Versus Midazolam in Critically Ill Ventilated Children

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.

Study Overview

• Status: Recruiting
• Conditions: Mechanically Ventilated, Critically Ill Children
• Intervention / Treatment: Drug: Precedex; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Maysaa Assaf, BSc; Phone Number: 77548 519-685-8500; Email: maysaa.assaf@lhsc.on.ca

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • Children's Hospital - London Health Sciences Centre
      • Contact: Maysaa Assaf, BSc; Phone Number: 77548 519-685-8500; Email: maysaa.assaf@lhsc.on.ca
      • Principal Investigator: Douglas D Fraser, MD/PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age is 1 month to 18 years inclusive
2. The patient is intubated and is expected to remain intubated for at least the next 48 hours
3. The patient has not been receiving mechanical ventilation for more than 72 hours
4. 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:

1. Admission is a consequence of suspected or proven drug overdose
2. Patient is receiving dialysis
3. Known pregnancy or lactation
4. Neuromuscular blockade other than for intubation
5. General anesthesia in the 24 hours prior to study initiation
6. 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
7. Acute hepatitis or severe liver disease
8. Known history of sensitivity to midazolam and/or dexmedetomidine or their constituents
9. Systolic blood pressure (SBP) below 5th percentile for two consecutive measurements
10. Heart rate (HR) below 5th percentile for two consecutive measurements
11. 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
12. Previous enrollment into the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Economic Analysis	The investigators will perform an economic evaluation during this pilot trial. This will be cost estimate analysis based on approximate costs incurred daily in the PCCU. Costs will be determined at discharge from estimated cost per day of admission to the PCCU.	Up to 90 days post-randomization

Collaborators and Investigators

• Sponsor: Douglas Fraser
• Investigators: Principal Investigator: Douglas D Fraser, MD., PhD, Lawson Health Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2021
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: August 28, 2019
• First Submitted That Met QC Criteria: September 6, 2019
• First Posted (Actual): September 9, 2019

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: sedation, delirium, pediatric, critical care
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; 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; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Dexmedetomidine
• Other Study ID Numbers: PEDSED01

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