The Pharmacology and Hemodynamics of Dexmedetomidine in Children With Congenital Heart Disease

• Sponsor: Children's National Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00480740
• Collaborator: (none)
• Enrollment: 41
• Location: 1
• Arms: 3
• Duration (Months): 58
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the pharmacokinetics, pharmacodynamics, and pharmacogenomics of dexmedetomidine in the following three pediatric patient populations: patients with bi-directional cavopulmonary anastomosis or a Fontan procedure, patients who have had a cardiac transplant, and patients with otherwise normal physiology who are undergoing closure of a patent ductus arteriosis or atrial septal defect.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Transplant; Patent Ductus Arterious; Atrial Septal Defect; Bidirectional Cavopulmonary Anastomosis	Drug: Dexmedetomidine	Phase 3

Detailed Description

While opioid analgesia is currently the mainstream for management of pain in the perioperative setting, it often leads to significant morbidity, including opioid tolerance and hyperalgesia. Looking at ways to decrease the need for opioids with the use of adjunct medications allows for the long-term goal of decreasing physiologic tolerance in children. This is especially relevant in the pediatric congenital heart population.

Dexmedetomidine is in a class of drugs known as alpha-2 agonists and is known to provide analgesia, attenuate opioid tolerance and inhibit the sympathetic stress response. While there are numerous published case studies of dexmedetomidine validating its effectiveness and safety, the pharmacologic and pharmacodynamic profile has not been established.

This study will examine the hemodynamics, pharmacokinetics, and pharmacogenomics of dexmedetomidine in patients with congenital heart disease. The dose-ranging effect of dexmedetomidine will also be investigated. The three groups being studied will be: patients with bi-directional cavopulmonary anastomosis or a Fontan procedure, patients who have had a cardiac transplant, and patients with otherwise normal physiology who are undergoing closure of a patent ductus arteriosis or atrial septal defect.

Comparison: Compare both invasive and noninvasive hemodynamic parameters at baseline sevoflurane and during maintenance dosing on dexmedetomidine. The pharmacokinetics of dexmedetomidine in the pediatric population following escalating loading doses and continuous infusion at timed intervals will be estimated. The efficacy of dexmedetomidine will be estimated by the amount of rescue doses of propofol that are given.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Pharmacology of Dexmedetomidine in Children With Congenital Heart Disease
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cardiac Transplant diagnostic cardiac catheterization in children with a transplanted heart	Drug: Dexmedetomidine; Dexmedetomidine load of 1 microgram/kilogram over 10 minutes, followed by a 1 microgram/kilogram/hour infusion during the time of catheterization; Other Names: Precedex
Experimental: Fontan procedure diagnostic cardiac catheterization in children with a transplanted ventricle	Drug: Dexmedetomidine; Dexmedetomidine load of 1 microgram/kilogram over 10 minutes, followed by a 1 microgram/kilogram/hour infusion during the time of catheterization; Other Names: Precedex
Other: Normal Physiology diagnostic cardiac catheterization in children with normal cardiac physiology	Drug: Dexmedetomidine; Dexmedetomidine load of 1 microgram/kilogram over 10 minutes, followed by a 1 microgram/kilogram/hour infusion during the time of catheterization; Other Names: Precedex

Outcome Measures

Primary Outcome Measures

1. Changes in Hemodynamic Variables Recorded During Administration of Sevoflurane + Dexmedetomidine. [Up to 24 hours following cardiac catheterization]

   Non-inferiority was shown when differences at steady-state (dexmedetomidine + sevoflurane) compared to baseline (sevoflurane alone) and its associated 95% confidence interval fell completely within the range of plus or minus 20%.The 95% confidence interval was normalized by subtracting the baseline values. Bispectral Index: monitors electroencephalographic and electromyographic parameters to monitor the depth of anesthesia.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• age is birth to 18 years

• or = 6 kg.

• American Society of Anesthesiology (ASA) I, II, or III

• undergone prior cardiac transplant, Fontan or has a patent ductus arterious or atrial septal defect.

• scheduled for cardiac catheterization

Exclusion Criteria:

• subject or family history of malignant hyperthermia

• known hepatic disorder determined by history physical exam or laboratory tests

• pregnant or lactating female

• receiving inotropic agents or has a pacemaker

• weighs less than 6 kg.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's National Medical Center	Washington	District of Columbia	United States	20010

Sponsors and Collaborators

• Children's National Research Institute

Investigators

• Principal Investigator: Julia C Finkel, MD, Children's National Research Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

• Finkel JC, Elrefai A. The use of dexmedetomidine to facilitate opioid and benzodiazepine detoxification in an infant. Anesth Analg. 2004 Jun;98(6):1658-1659. doi: 10.1213/01.ANE.0000113547.34160.A5.
• Finkel JC, Johnson YJ, Quezado ZM. The use of dexmedetomidine to facilitate acute discontinuation of opioids after cardiac transplantation in children. Crit Care Med. 2005 Sep;33(9):2110-2.

• Responsible Party: Julia Finkel, MD, Children's National Research Institute
• ClinicalTrials.gov Identifier: NCT00480740
• Other Study ID Numbers: IRB# 3908
• First Posted: May 31, 2007
• Last Update Posted: Jun 26, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Julia Finkel, MD, Children's National Research Institute: Dexmedetomidine; Congenital heart disease; pharmacokinetics; pharmacodynamics; pediatric; Bidirectional cavopulmonary anastomosis; Fontan physiology; Cardiac transplant
• Additional relevant MeSH terms: Heart Diseases; Heart Defects, Congenital; Heart Septal Defects, Atrial; Dexmedetomidine

Study Results

Participant Flow

Recruitment Details	Patients were recruited from cardiology outpatient clinic. The study is anticipating to enroll 104 patients.
Pre-assignment Detail	74 subjects assessed for eligibility, 9 were excluded; 12 did not meet inclusion criteria; 12 refused to enroll; resulting in 41 subjects enrolled

Arm/Group Title	Normal Physiology	Cardiac Transplant	Fontan Physiology
Arm/Group Description	diagnostic cardiac catheterization in children with normal cardiac physiology	diagnostic cardiac catheterization in children with a transplanted heart	diagnostic cardiac catheterization in children with a transplanted ventricle
Period Title: Overall Study
STARTED	26	9	6
COMPLETED	26	9	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Normal Physiology	Cardiac Transplant	Fontan Physiology	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	26	9	6	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.3 (4)	11 (4.5)	5.5 (3.3)	6.9 (6.2)
Sex: Female, Male (Count of Participants)
Female	17 65.4%	3 33.3%	2 33.3%	22 53.7%
Male	9 34.6%	6 66.7%	4 66.7%	19 46.3%
Weight (kg) (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	19.1 (14.3)	35.2 (17.8)	21.4 (8.7)	27.3 (13.6)
American Society of Anesthesiology (ASA) physical status classification (participants) [Number]
ASA 1	18 69.2%	0 0%	0 0%	18 43.9%
ASA 2	8 30.8%	9 100%	0 0%	17 41.5%
ASA 3	0 0%	0 0%	6 100%	6 14.6%
Primary diagnosis (participants) [Number]
ASD	10 38.5%	0 0%	0 0%	10 24.4%
PDA	16 61.5%	0 0%	0 0%	16 39%
PA with IVS	0 0%	2 22.2%	0 0%	2 4.9%
HLHS	0 0%	2 22.2%	2 33.3%	4 9.8%
Unbalanced AVC	0 0%	1 11.1%	0 0%	1 2.4%
Cardiomyopathy	0 0%	4 44.4%	0 0%	4 9.8%
Tricuspid Atresia	0 0%	0 0%	2 33.3%	2 4.9%
DORV	0 0%	0 0%	1 16.7%	1 2.4%
Ebstein's anomaly	0 0%	0 0%	1 16.7%	1 2.4%

Outcome Measures

1. Primary Outcome

Title	Changes in Hemodynamic Variables Recorded During Administration of Sevoflurane + Dexmedetomidine.
Description	Non-inferiority was shown when differences at steady-state (dexmedetomidine + sevoflurane) compared to baseline (sevoflurane alone) and its associated 95% confidence interval fell completely within the range of plus or minus 20%.The 95% confidence interval was normalized by subtracting the baseline values. Bispectral Index: monitors electroencephalographic and electromyographic parameters to monitor the depth of anesthesia.
Time Frame	Up to 24 hours following cardiac catheterization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Physiology	Cardiac Transplant	Fontan Physiology
Arm/Group Description	diagnostic cardiac catheterization in children with normal cardiac physiology	diagnostic cardiac catheterization in children with a transplanted heart	diagnostic cardiac catheterization in children with a transplanted ventricle
Measure Participants	26	9	6
Heart Rate	-0.14	-0.16	-0.21
Systolic Pressure	0.15	0.18	0.22
Diastolic Pressure	0.23	0.19	0.09
Mean Pressure	0.23	0.16	0.08
Bispectral Index	0.04	0.16	-0.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Physiology, Cardiac Transplant, Fontan Physiology
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Noninferiority of dexmedetomindine plus sevoflurane compared with the baseline (sevoflurane alone) for any given variable was reached when the difference (steady-state [dexmedetomidine + sevoflurane]-baseline [sevoflurane0]/baseline [sevoflurane]0 and its associated 95% confidence interval (CI) fell completely withing the range of +/-20% indicated by the gray column.
Statistical Test of Hypothesis	p-Value	0.05
	Comments	The original study design was powered to achieve at least 80% power to detect noninferiority with the two-tailed alpha level set at 0.05 for data with two measurements.
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	from study start through followup
Arm/Group Title	Cardiac Transplant		Fontan Procedure		Normal Physiology
Arm/Group Description	Dexmedetomidine: Dexmedetomidine load of 1 microgram/kilogram over 10 minutes, followed by a 1 microgram/kilogram/hour infusion during the time of catheterization		Dexmedetomidine: Dexmedetomidine load of 1 microgram/kilogram over 10 minutes, followed by a 1 microgram/kilogram/hour infusion during the time of catheterization		control group Dexmedetomidine: Dexmedetomidine load of 1 microgram/kilogram over 10 minutes, followed by a 1 microgram/kilogram/hour infusion during the time of catheterization
All Cause Mortality
	Cardiac Transplant		Fontan Procedure		Normal Physiology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cardiac Transplant		Fontan Procedure		Normal Physiology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/6 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Cardiac Transplant		Fontan Procedure		Normal Physiology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/6 (0%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.