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

Browse trials for

• Heart Septal Defects, Atrial 85
• Heart Septal Defects, Ventricular 59

Heart Septal Defects, Atrial

85 studies on the registry are indexed under Heart Septal Defects, Atrial; 22 are open to participants now.

This study's enrollment of 22 is below the median of 93 across 50 interventional studies indexed under Heart Septal Defects, Atrial.

Lead sponsor

Asklepion Pharmaceuticals, LLC is the lead sponsor of 7 studies on the registry; 1 is open to participants now.

Study arms

• 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

Interventions

• DrugIntravenous L-Citrulline
• DrugPlacebo of Intravenous L-Citrulline

  Placebo of intravenous L-Citrulline given at the same prescribed times as L-Citrullne Drug

Primary outcomes

1. 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.

   Time frame: 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 outcomes

1. 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.

   Time frame: Measured in hours from the end of surgery until extubation, or Day 30, whichever occurs first

2. 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.

   Time frame: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first

3. Total Duration of Respiratory Support

   Analysis included any invasive and non-invasive respiratory support required during the study period

   Time frame: Baseline to discharge or Day 30, whichever occurs first

4. 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.

   Time frame: Measured at 48 hours

5. 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.

   Time frame: PICU admission until Hour 48

6. 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

   Time frame: Hour 0 to Hour 48

7. 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.

   Time frame: Hour 0 to Hour 48

8. 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

   Time frame: Measured in hours from the end of surgery to discharge from ICU or Day 30, whichever occurred first

9. 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.

   Time frame: Until cessation of positive pressure ventilation and of inotrope therapy or Day 30, whichever occurred first

10. Length of Hospitalization

    Time frame: Measured from the day of surgery until discharge from hospital or Day 30, whichever occurred first

11. 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.

    Time frame: Measured in hours from the end of surgery until extubation or Day 30, whichever occurred first

12. Duration of Chest Tube Drainage

    Time frame: Measured in hours from the end of surgery until removal of chest tubes or Day 30, whichever occurred first

13. Volume of Chest Tube Drainage

    Time frame: Measured in milliliters from the end of surgery until removal of chest tubes or Day 30, whichever occurred first

14. Survival

    28-day postoperative survival and survival to discharge

    Time frame: Measured at 28 days post surgical repair

15. 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.

    Time frame: Mean Arterial Blood pressure as continuously monitored postoperatively in the PCCU (Hour 0 to Hour 24) during Citrulline or Placebo infusion.

Other outcomes

1. 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.

   Time frame: Baseline to Hour 48

2. 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.

   Time frame: Baseline to Hour 48

Baseline characteristics