Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery

Sponsor

Asklepion Pharmaceuticals, LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT00335244

Collaborator

Vanderbilt University (Other)

Enrollment

Location

Arms

Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This clinical trial will determine the safety and effectiveness of intravenous L-citrulline in children undergoing cardiopulmonary bypass during heart surgery. Participants will be randomly assigned to either L-citrulline or a placebo (a substance that has no medicine in it).

Citrulline is a protein building block in the body that can convert into another substance, nitric oxide (NO), which controls blood pressure in the lungs. Increased blood pressure in the lungs can be an important surgical problem; it may also lead to problems following surgery, such as severe high blood pressure in the lungs (pulmonary hypertension), increased time spent on a breathing machine, and a longer stay in the intensive care unit (ICU). The hypothesis of this study is that perioperative supplementation with intravenous citrulline will increase plasma citrulline, arginine and NO metabolites and prevent elevations in the postoperative PVT leading to a decrease in the duration of postoperative invasive mechanical ventilation.

Condition or Disease	Intervention/Treatment	Phase
Heart Defects, Congenital Hypertension, Pulmonary	Drug: L-citrulline Drug: Placebo of intravenous L-citrulline	Phase 3

Detailed Description

Increased pulmonary vascular tone (PVT) can complicate the postoperative course of the following five surgical procedures for congenital heart defects: 1) unrestrictive ventricular septal defect (VSD) repair; 2) atrioventricular septal (AVSD) repair; 3) arterial switch procedure for transposition of the great arteries (TGA); 4) bidirectional Glenn shunt procedure; and 5) Fontan procedure for single ventricle lesions. PVT is partially controlled by NO. Arginine, the precursor to NO, is a product of the urea cycle. Preliminary data have been presented regarding 169 infants and children who have undergone one of six previous surgical procedures. It was found that urea cycle function and plasma arginine levels were significantly decreased in all participants. Furthermore, participants with increased PVT had significantly lower arginine levels compared to participants with normal PVT. Finally, a genetic single nucleotide polymorphism (SNP) in the rate limiting urea cycle enzyme (carbamyl phosphate synthetase I [CPSl T1405N]) appeared to affect postoperative plasma arginine levels and PVT. The hypothesis is that genetic polymorphisms in the rate limiting urea cycle enzyme CPSl, and other important enzymes in the urea cycle, influence the availability of NO precursors. It is further hypothesized that perioperative enhancement of urea cycle function with the key urea cycle intermediate (citrulline) will increase plasma arginine and NO metabolites and prevent elevations in PVT.

Study Design

Study Type:

Interventional

Actual Enrollment :

77 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

A Phase III Single-Blind, Randomized, Placebo Controlled, Clinical Trial to Determine the Safety and Efficacy of Intravenous L-Citrulline Versus Placebo in Children Undergoing Cardiopulmonary Bypass

Study Start Date :

May 1, 2006

Actual Primary Completion Date :

Dec 1, 2009

Actual Study Completion Date :

Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Intravenous L-citrulline	Drug: L-citrulline 150mg bolus X 1 after initiation of cardiopulmonary bypass followed by continuous infusion of 9mg/kg/hr IV, starting 4 hours post bolus administration and ending at 48 hours continuous infusion or discharge from the PCCU
Placebo Comparator: 2 Placebo of intravenous L-citrulline	Drug: Placebo of intravenous L-citrulline Placebo of intravenous L-citrulline

Arm

Intervention/Treatment

Experimental: 1

Intravenous L-citrulline

Drug: L-citrulline

150mg bolus X 1 after initiation of cardiopulmonary bypass followed by continuous infusion of 9mg/kg/hr IV, starting 4 hours post bolus administration and ending at 48 hours continuous infusion or discharge from the PCCU

Placebo Comparator: 2

Placebo of intravenous L-citrulline

Drug: Placebo of intravenous L-citrulline

Placebo of intravenous L-citrulline

Outcome Measures

Primary Outcome Measures

Duration of postoperative mechanical ventilation in hours compared between treatment groups. [Measured in hours from the end of surgery until extubation]

Secondary Outcome Measures

Incidence of increased PVT (defined as a sustained mean pulmonary artery pressure greater than 20 mm Hg for at least 2 hours, measured during the first 48 hours [Measured in hours from the end of surgery until extubation]
Postoperative intravenous inotrope score [Measured at 48 hours]
Length and volume of chest tube drainage [Measured in hours from the end of surgery until removal of chest tubes]
Length of ICU stay [Measured in hours from the end of surgery to discharge from ICU]
Length of hospitalization [Measured from the day of surgery until discharge from hospital]
Survival [Measured at 30 days post surgical repair]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Undergoing cardiopulmonary bypass surgery with 1 of the following 5 procedures:

AVSD repair
VSD repair
Bidirectional Glenn
Modified Fontan
Arterial switch

Exclusion Criteria:

Pulmonary artery or vein abnormalities not being addressed surgically
Preoperative requirement for mechanical ventilation or intravenous inotrope support
Any condition that might interfere with study objectives, as determined by the investigator
Pregnant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

Asklepion Pharmaceuticals, LLC
Vanderbilt University

Investigators

Principal Investigator: Fredrick E. Barr, MD, MSCI, Vanderbilt University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Asklepion Pharmaceuticals, LLC

ClinicalTrials.gov Identifier:

NCT00335244

Other Study ID Numbers:

409
R01HL073317-01
IRB# 060197

First Posted:

Jun 9, 2006

Last Update Posted:

Feb 2, 2015

Last Verified:

Jan 1, 2015

Additional relevant MeSH terms:

Hypertension, Pulmonary

Heart Defects, Congenital

Congenital Abnormalities

Study Results

No Results Posted as of Feb 2, 2015