Dexmedetomidine Pharmacokinetics in Neonates During Therapeutic Hypothermia

Dexmedetomidine Use During Therapeutic Hypothermia Treatment for Neonates With Hypoxic-ischemic Encephalopathy: The Cool DEX Study

The goal of this proposal is to profile the pharmacokinetics of dexmedetomidine in newborns ≥36 weeks post-menstrual age during therapeutic hypothermia for hypoxic-ischemic encephalopathy.

Study Overview

• Status: Completed
• Conditions: Hypoxic-ischemic Encephalopathy
• Intervention / Treatment: Drug: Dexmedetomidine

Detailed Description

The goal of this proposal is to determine the pharmacokinetics (PK) of dexmedetomidine (DEX) in newborns in the neonatal intensive care unit (NICU) receiving therapeutic hypothermia (TH) for moderate to severe hypoxic-ischemic encephalopathy (HIE). In newborns with HIE, TH for 72 hours is the standard therapy to mitigate brain damage. Most HIE patients receive mechanical ventilation during TH and are thus sedated with morphine. Unfortunately, morphine has negative side effects and does not specifically prevent shivering. Prevention of shivering is critical to success of TH, as shivering negates cooling. DEX is a particularly promising alternative sedative because it does prevent shivering and is already used in NICUs for sedation and pain management. In newborns, DEX PK data in the setting of TH is not available and needs to be determined to properly dose DEX for HIE patients.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98015
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Newborns 36 weeks gestation or older with moderate to severe hypoxic-ischemic encephalopathy identified and treated with therapeutic hypothermia in the Seattle Children's Hospital neonatal intensive care unit.
2. Cooled infants who are initially intubated and mechanically ventilated.
3. Infants anticipated to require 72 hrs of continuous sedation and/or treatment to prevent shivering.
4. Subject's parent(s) or legal guardian(s) has/have voluntarily signed and dated the informed consent document approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).

Exclusion Criteria:

1. Known chromosomal anomalies.
2. Newborns without central lines (e.g., lines not needed or unable to be successfully placed) or without a peripheral arterial line.
3. Patients with known cyanotic congenital heart defects
4. Patients who are participating in another clinical trial.
5. Patients who received DEX prior to enrollment in the study
6. At the discretion of the Investigator, subjects in whom the risk of Dexmedetomidine treatment is expected to exceed its benefits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine group; Neonates with hypoxic-ischemic encephalopathy will receive a dexmedetomidine maintenance infusion of 0.4 mcg/kg/hr during treatment with therapeutic hypothermia and during re-warming (78 hours total).	Drug: Dexmedetomidine; Dexmedetomidine infusion; Other Names: Precedex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) parameter of area under the curve (AUC)	Estimate PK parameter of AUC in newborns ≥36 weeks post-menstrual age with hypoxic-ischemic encephalopathy treated with a continuous dexmedetomidine infusion during therapeutic hypothermia.	Day 1 to Day 4
Pharmacokinetic (PK) parameter of clearance	Estimate PK parameter of clearance in newborns ≥36 weeks post-menstrual age with hypoxic-ischemic encephalopathy treated with a continuous dexmedetomidine infusion during therapeutic hypothermia.	Day 1 to Day 4
Pharmacokinetic (PK) parameter of terminal half-life	Estimate PK parameter of terminal half-life in newborns ≥36 weeks post-menstrual age with hypoxic-ischemic encephalopathy treated with a continuous dexmedetomidine infusion during therapeutic hypothermia.	Day 1 to Day 4
Pharmacokinetic (PK) of volume of distribution	Estimate PK parameter of volume of distribution in newborns ≥36 weeks post-menstrual age with hypoxic-ischemic encephalopathy treated with a continuous dexmedetomidine infusion during therapeutic hypothermia.	Day 1 to Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of dexmedetomidine at preventing shivering	Measure number of morphine doses given for shivering in neonates receiving a continuous dexmedetomidine infusion during therapeutic hypothermia for hypoxic-ischemic encephalopathy.	Day 1 to Day 3
Safety of dexmedetomidine in neonatal subjects. (composite outcome will include: adverse events, physical examination findings, and vital signs)	Safety assessments will include: adverse events, physical examination findings, vital signs including continuous heart rate, blood pressure, respiratory rate, and pulse oximetry monitoring in neonates receiving a continuous dexmedetomidine infusion during therapeutic hypothermia for hypoxic-ischemic encephalopathy.	Day 1 to Day 4

Collaborators and Investigators

• Sponsor: Seattle Children's Hospital
• Investigators: Principal Investigator: Ryan M McAdams, MD, Seattle Children's Hospital

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: August 6, 2015
• First Submitted That Met QC Criteria: August 18, 2015
• First Posted (Estimate): August 20, 2015

Study Record Updates

• Last Update Posted (Estimate): January 12, 2017
• Last Update Submitted That Met QC Criteria: January 10, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Dexmedetomidine; Neonate; Central Nervous System Agents; Analgesics; Adrenergic Agents; Central Nervous System Depressants; Therapeutic Hypothermia; Adrenergic Agonists; Hypoxic-ischemic Encephalopathy; Adrenergic alpha-2 Receptor Agonists
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Body Temperature Changes; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypothermia; Hypoxia-Ischemia, Brain; 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: 15647

Plan for Individual participant data (IPD)

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