Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery

Hypertension, Pulmonary Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00335244
• Other study ID #: 409
• Secondary ID: R01HL073317-01IR
• Status: Completed
• Phase: Phase 3
• First received: June 7, 2006
• Last updated: January 26, 2015
• Start date: May 2006
• Est. completion date: December 2009

Study information

• Verified date: January 2015
• Source: Asklepion Pharmaceuticals, LLC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 77
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 17 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Congenital Abnormalities
• Heart Defects, Congenital
• Hypertension, Pulmonary

Intervention

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 of intravenous L-citrulline
Placebo of intravenous L-citrulline

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Asklepion Pharmaceuticals, LLC	Vanderbilt University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of postoperative mechanical ventilation in hours compared between treatment groups.		Measured in hours from the end of surgery until extubation	Yes
Secondary	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	Yes
Secondary	Postoperative intravenous inotrope score		Measured at 48 hours	No
Secondary	Length and volume of chest tube drainage		Measured in hours from the end of surgery until removal of chest tubes	No
Secondary	Length of ICU stay		Measured in hours from the end of surgery to discharge from ICU	No
Secondary	Length of hospitalization		Measured from the day of surgery until discharge from hospital	No
Secondary	Survival		Measured at 30 days post surgical repair	No