A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics

The purpose of this Phase I study is to determine the safety of a drug called dexmedetomidine (DEX) as part of a balanced general anesthetic and sedative strategy for neonates and infants undergoing corrective cardiac surgery that requires the use of cardiopulmonary bypass for congenital cardiac problems. This study will also design and validate a dosing schema for the use of DEX as described above.

Study Overview

• Status: Completed
• Conditions: Tetralogy of Fallot; Transposition of the Great Arteries; Ventricular Septal Defect
• Intervention / Treatment: Drug: Dexmedetomidine

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Childrens Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, age 0 to 180 days at the time of surgery.
2. Diagnosis of: D-transposition of the great arteries (with or without ventricular septal defect), or tetralogy of Fallot, or ventricular septal defect (with or without associated atrial septal defect and/or patent ductus arteriosus)
3. Scheduled for complete corrective two-ventricle surgical repair with cardiopulmonary bypass.

Exclusion Criteria:

• 1. Less than 37 completed weeks' gestational age at birth for the Neonatal age group (0-21 days); less than 36 completed weeks' gestational age at birth for the Infant age group (22-180 days).

  2. Enrollment in the PHN Collaborative Learning Study, if tetralogy of Fallot 91-180 days of age only.

  3. Known or suspected hepatic dysfunction; AST and ALT >3X upper limit of normal at the time of screening within 72 hours of operation.

  4. Known or suspected renal dysfunction; serum creatinine > 0.8 mg/dL after 7 days of age, >1.2 mg/dL if <7 days of age, within 72 hours of operation.

  5. Preoperative administration of DEX or clonidine within 72 hours of operation.

  6. Major congenital anomaly(ies) outside the cardiovascular system that in the investigator's opinion would potentially affect safety or pharmacokinetics.

  7. Preoperative central nervous system injury resulting in clinical signs and symptoms: coma, seizures, hemiparesis.

  8. Planned period of deep hypothermic circulatory arrest. 9. History of second or third degree heart block. 10. Sinus or junctional bradycardia below 80 BPM sustained for greater than 15 minutes within 72 hours of operation. 11. Junctional rhythm sustained for greater than 15 minutes within 72 hours of operation.

  12. Hypotension defined as mean arterial blood pressure below 35 mm Hg for 0-21 day old neonatal patients, and below 40 mm Hg for 22-180 day old infant patients sustained for greater than 15 minutes within 72 hours of operation.

  13. History of cardiac arrest or ECMO cannulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neonate dosing cohort 1; Neonate dexmedetomidine dosing cohort 1	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Neonate dosing cohort 2; Neonate dexmedetomidine dosing cohort 2	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Neonate dosing cohort 3; Neonate dexmedetomidine dosing cohort 3	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Neonate dosing cohort 4; Neonate dexmedetomidine dosing cohort 4	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Neonate dosing cohort 5; Neonate dexmedetomidine dosing cohort 5	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Infant dosing cohort 1; Infant dexmedetomidine dosing cohort 1	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Infant dosing cohort 2; Infant dexmedetomidine dosing cohort 2	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Infant dosing cohort 3; Infant dexmedetomidine dosing cohort 3	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Infant dosing cohort 4; Infant dexmedetomidine dosing cohort 4	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl
Experimental: Infant dosing cohort 5; Infant dexmedetomidine dosing cohort 5	Drug: Dexmedetomidine; Other Names: Precedex, dexmedetomidine HCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The occurrence of a safety event that is possibly, probably or definitely related to DEX administration	The occurrence of any of the following that is possibly, probably, or definitely related to DEX administration: Bradycardia; Heart block; Junctional rhythm; Hypotension; Excessive sedation; Cardiac arrest or ECMO cannulation; Serious Adverse Event (SAE) Both the DEX dose, and DEX exposure will be assessed for associations with the primary outcome.	Within 4 hours after DEX adminstration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of DEX	Plasma concentrations of dex obtained intraoperatively and up to 36 hours post-operatively will be used to create drug dosing models. These models will then be evaluated to determine how effective they are at achieving targeted plasma concentration levels.	Intraoperatively and up to 36 hours post-operatively

Collaborators and Investigators

• Sponsor: HealthCore-NERI
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Zuppa AF, Nicolson SC, Wilder NS, Ibla JC, Gottlieb EA, Burns KM, Stylianou M, Trachtenberg F, Ni H, Skeen TH, Andropoulos DB; Pediatric Heart Network Investigators. Results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery. Br J Anaesth. 2019 Dec;123(6):839-852. doi: 10.1016/j.bja.2019.06.026. Epub 2019 Oct 14.

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2014
• Primary Completion (Actual): October 16, 2017
• Study Completion (Actual): October 17, 2017

Study Registration Dates

• First Submitted: July 30, 2013
• First Submitted That Met QC Criteria: July 31, 2013
• First Posted (Estimate): August 2, 2013

Study Record Updates

• Last Update Posted (Actual): March 23, 2018
• Last Update Submitted That Met QC Criteria: March 21, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Pediatric corrective cardiac surgery
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Septal Defects; Tetralogy of Fallot; Transposition of Great Vessels; Heart Septal Defects, Ventricular; 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: PHN-DEX