Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery

NCT ID: NCT00335244

Last Updated: 2015-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 77 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-05-31
• Study Completion Date: 2009-12-31

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.

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.

Conditions

Heart Defects, Congenital; Hypertension, Pulmonary

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

1

Intravenous L-citrulline

Group Type: EXPERIMENTAL

L-citrulline

Intervention Type: DRUG

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

2

Placebo of intravenous L-citrulline

Group Type: PLACEBO_COMPARATOR

Placebo of intravenous L-citrulline

Intervention Type: DRUG

Placebo of intravenous L-citrulline

Interventions

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

Intervention Type: DRUG

Placebo of intravenous L-citrulline

Placebo of intravenous L-citrulline

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

1. AVSD repair

2. VSD repair

3. Bidirectional Glenn

4. Modified Fontan

5. 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

• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University

OTHER

Sponsor Role: collaborator

Asklepion Pharmaceuticals, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fredrick E. Barr, MD, MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

R01HL073317-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB# 060197

Identifier Type: -

Identifier Source: secondary_id

409

Identifier Type: -

Identifier Source: org_study_id