Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol

Phase IB Double Blind, Randomized, Placebo Controlled Clinical Trial to Determine the Pharmacokinetics and Safety of a Revised Protocol of Intravenous L-Citrulline (Citrupress®) 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.

The objective of this study is to determine in a randomized placebo controlled phase IB multicenter clinical trial if a revised protocol of intravenous L-citrulline delivery given perioperatively achieves a plasma citrulline level of > 100 umol/L in children undergoing surgical repair of an atrial septal defect,ventricular septal defect or an atrioventricular septal defect.

Study Overview

• Status: Completed
• Conditions: Atrial Septal Defect; Atrioventricular Septal Defect; Ventricular Septal Defect
• Intervention / Treatment: Drug: Intravenous 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. It is 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): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 6 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Informed Consent signed by the subject's legal representative
2. Subjects < 6 years old
3. Subjects undergoing cardiopulmonary bypass for repair of an atrial septal defect, a ventricular septal defect or an atrioventricular septal defect

Exclusion Criteria:

1. Pulmonary artery or vein abnormalities being addressed surgically
2. Preoperative requirement for invasive mechanical ventilation or intravenous inotrope support
3. Any condition which, in the opinion of the investigator, might interfere with study objectives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intravenous L-Citrulline; IV bolus of 150 mg/kg L-citrulline at the initiation of bypass, followed by L-citrulline (200 μmol/L) addition to the filtration or hemoconcentration replacement fluid used during bypass. Plus L-citrulline (20 mg/kg) bolus 30 minutes after decannulation from bypass, immediately followed by 9 mg/kg/h continuous L-citrulline infusion for 48 hours.	Drug: Intravenous L-Citrulline
PLACEBO_COMPARATOR: Placebo of Intravenous L-Citrulline; Placebo administered according to the same schedule as L-citrulline	Drug: Placebo of Intravenous L-Citrulline; Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
L-citrulline Plasma Levels	Citrulline Blood Levels: 1. Baseline sample in OR prior to Cardiopulmonary Bypass prior to administration of first bolus of Citrulline or Placebo 2. Immediately after Bolus 1 administered in Operating Room. 3. 30 minutes after separation from Cardiopulmonary Bypass; immediately prior to administration of Bolus 2 and start of continuous infusion of Citrulline or Placebo. 4. Six hours after after start of infusion. 5. 12 hours after start of infusion. 6. 24 hours after start of infusion. 7. 48 hours after start of infusion; or whenever infusion is discontinued if prior to 48 hours.	Measured in seven blood sample time points from the beginning of surgery until end of IV Citrulline Infusion; at either 48 hours postoperatively or at extubation, whichever comes first.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative Invasive Mechanical Ventilation (Mean and SD)	Duration of postoperative invasive mechanical ventilation was derived as the time in hours from separation from cardiopulmonary bypass until endotracheal extubation. If a patient required reintubation within 24 hours after extubation, the reintubation time was added in the main analysis. In a second analysis, the reintubation time was not included.	Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs first
Postoperative Invasive Mechanical Ventilation (Median and Range)	Duration of postoperative invasive mechanical ventilation was derived as the time in hours from separation from cardiopulmonary bypass until endotracheal extubation. If a patient required reintubation within 24 hours after extubation, the reintubation time was added in the main analysis. In a second analysis, the reintubation time was not included.	Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first
Total Duration of Respiratory Support	Analysis included any invasive and non-invasive respiratory support required during the study period	Baseline to discharge or Day 30, whichever occurs first
Postoperative Intravenous Inotrope Duration	The length of time on IV inotropes was documented from the time of first use after surgery until completion of the study medication at Hour 48 (i.e., duration of inotrope use was maximally 48 hours). Patients still receiving inotropes at Hour 48 were censored.	Measured at 48 hours
Total Inotrope Score	The inotrope dose was calculated each hour postoperatively from the time of PICU admission until the completion of study drug using the following scoring system: Dopamine (μg/kg/min) x 1 plus Dobutamine (μg/kg/min) x 1 plus Milrinone (μg/kg/min) x10 plus Epinephrine (Adrenaline) (μg/kg/min) x 100 plus Phenylephrine (μg/kg/min) x 100 plus Norepinephrine (Noradrenaline) (μg/kg/min) x 100 = Total inotrope score An ANOVA was performed. Additionally a repeated measures analysis of variance was used to compare total inotrope score between placebo and citrulline.	PICU admission until Hour 48
Time on Vasoactive Medications	The total number of hours on vasoactive medications, including nitroglycerin, nitroprusside and vasopressin, was calculated from the end of surgery until the discontinuation of vasoactive medications or end of study medication (Hour 48), whichever occurred first	Hour 0 to Hour 48
Total Vasoactive Score	Vasoactive score is reflective of the pharmacological support required by the cardiovascular system and is a good predictor of mortality and morbidity in patients undergoing bypass surgery. A lower vasoactive score represents less pharmacological support and would indicate a lower risk for a poor clinical outcome. Therefore, any treatment effect would be indicated by a lower score in the citrulline group when compared to the placebo group. In this study, the score was calculated post-operatively from the time of separation from bypass until the completion of study drug. Vasoactive score was calculated using the following formula: Total Vasoactive Score = nitroglycerin dose + nitroprusside dose + vasopressin dose The minimum value is zero (i.e., no vasoactive drugs administered), but it is not possible to define a maximum as this is wholly dependent upon the dose of each vasoactive drug administered.	Hour 0 to Hour 48
Length of ICU Stay	Duration of ICU stay was analyzed once as the total number of postoperative hours spent in the ICU and once as the total number of postoperative hours that a patient required postoperative mechanical ventilator or continuous intravenous inotrope or vasodilator support. The latter combination of parameters represents another surrogate endpoint for ICU stay	Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred first
Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy	The composite endpoint comprised the longer of the duration of positive pressure ventilatory support or of inotrope therapy. Since inotrope use was only documented until Hour 48 after surgery (end of study medication treatment), patients with inotrope use continuing until Hour 48 and with mechanical ventilation duration of ≤48 h were censored at this time point. If mechanical ventilation was continued beyond the 48-hour time point, the duration of mechanical ventilation was used in the analysis.	Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred first
Length of Hospitalization		Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred first
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	There were insufficient data to analyze ECHO measurements in summary statistics. Additionally, most images were of very low quality and the data from ECHO evaluations were insufficient to determine whether the affected patients had pulmonary hypertension.	Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first
Duration of Chest Tube Drainage		Measured in hours from the end of surgery until removal of chest tubes or Day 30, whichever occurred first
Volume of Chest Tube Drainage		Measured in milliliters from the end of surgery until removal of chest tubes or Day 30, whichever occurred first
Survival	28-day postoperative survival and survival to discharge	Measured at 28 days post surgical repair
Number of Patients With Clinically Significant Hypotension.	Age specific mean arterial blood pressure (MAP) limits compared between the citrulline and placebo groups will be used to determine significant hypotension. Defined as MAP below a specific age-based value (infants and age 1 year, 40; ; age 2 years, 44; age 3 years, 47; age 4 years, 50; age 5 years, 52; age 6 years, 53), that lasted greater than 30 minutes and was unresponsive to therapeutic interventions such as fluid administration (volume bolus) and increasing inotropic support.	Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arginine Concentrations	Citrulline is the precursor of arginine and nitric oxide. Nominal sampling times were Baseline, Post-bolus 1, Pre-bolus 2, and Hours 2, 6, 12, 24 and 48.	Baseline to Hour 48
Nitric Oxide Concentrations	Citrulline is the precursor of arginine and nitric oxide. Nominal sampling times were Baseline, Post-bolus 1, Pre-bolus 2, and Hours 2, 6, 12, 24 and 48.	Baseline to Hour 48

Collaborators and Investigators

• Sponsor: Asklepion Pharmaceuticals, LLC
• Investigators: Study Chair: Frederick E Barr, MD, Batson Children's Hospital, University of Mississippi Medical Center; Principal Investigator: Catherine Krawczeski, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Allan Doctor, MD, St. Louis Children's Medical Center

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (ACTUAL): April 1, 2012
• Study Completion (ACTUAL): April 1, 2012

Study Registration Dates

• First Submitted: May 6, 2010
• First Submitted That Met QC Criteria: May 9, 2010
• First Posted (ESTIMATE): May 11, 2010

Study Record Updates

• Last Update Posted (ACTUAL): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 21, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Septal Defects; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Endocardial Cushion Defects
• Other Study ID Numbers: CIT-002-01