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

Phase 1

Completed

Conditions: Atrial Septal Defect
Ventricular Septal Defect
Atrioventricular Septal Defect

Interventions: Drug: Intravenous L-Citrulline
Drug: Placebo of Intravenous L-Citrulline

Registration Number: NCT01120964

Lead Sponsor: Asklepion Pharmaceuticals, LLC

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.

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

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

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intravenous L-Citrulline	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.
Placebo of Intravenous L-Citrulline	Placebo of Intravenous L-Citrulline	Placebo administered according to the same schedule as L-citrulline

Primary Outcome Measures

Name	Time	Method
L-citrulline Plasma Levels	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.	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.

Secondary Outcome Measures

Name	Time	Method
Postoperative Invasive Mechanical Ventilation (Mean and SD)	Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs first	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.
Postoperative Invasive Mechanical Ventilation (Median and Range)	Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first	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.
Total Duration of Respiratory Support	Baseline to discharge or Day 30, whichever occurs first	Analysis included any invasive and non-invasive respiratory support required during the study period
Postoperative Intravenous Inotrope Duration	Measured at 48 hours	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.
Length of Hospitalization	Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred first
Total Inotrope Score	PICU admission until Hour 48	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.
Time on Vasoactive Medications	Hour 0 to Hour 48	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
Total Vasoactive Score	Hour 0 to Hour 48	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.
Length of ICU Stay	Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred first	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
Composite Endpoint: Cessation of Positive Pressure Ventilation and of Inotrope Therapy	Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred first	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.
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 or Day 30, whichever occurred first	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.
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	Measured at 28 days post surgical repair	28-day postoperative survival and survival to discharge
Number of Patients With Clinically Significant Hypotension.	Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.	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.

Trial Locations

Locations (2): Washington University Children's Hospital
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Saint Louis, Missouri, United States
Cincinnati Children's Hospital Medical Center
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Cincinnati, Ohio, United States