Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension, Pulmonary; Heart Defects, Congenital
• Intervention / Treatment: Drug: L-citrulline; Drug: Placebo of intravenous L-citrulline

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 Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Duration of postoperative mechanical ventilation in hours compared between treatment groups.	Measured in hours from the end of surgery until extubation

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Asklepion Pharmaceuticals, LLC
• Collaborators: Vanderbilt University
• Investigators: Principal Investigator: Fredrick E. Barr, MD, MSCI, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: June 7, 2006
• First Submitted That Met QC Criteria: June 7, 2006
• First Posted (Estimate): June 9, 2006

Study Record Updates

• Last Update Posted (Estimate): February 2, 2015
• Last Update Submitted That Met QC Criteria: January 26, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Cardiovascular Abnormalities; Hypertension; Congenital Abnormalities; Hypertension, Pulmonary; Heart Defects, Congenital
• Other Study ID Numbers: 409; R01HL073317-01 (U.S. NIH Grant/Contract); IRB# 060197