Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass

Study Overview
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Brief Summary
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Around 7500 neonates born yearly in the United States have complex congenital heart disease that require surgical repair in the first few days of life. The complexity of the surgical repair requires long periods of cardiopulmonary bypass (CPB) and the use of intermittent periods of low flow or complete circulatory arrest. The immature neonatal vital organs are more prone to the complications of the cardiopulmonary bypass circulation, namely ischemia/reperfusion (I/R) injury and systemic inflammatory response. Inhaled nitric oxide (NO) is used frequently in neonates for the treatment of pulmonary hypertension, Additionally, many studies have shown that NO has an anti-inflammatory effect by reducing I/R injury and endothelial dysfunction. The purpose of this pilot study is to assess the efficacy of NO administration via the CPB circuit in attenuating the CPB induced I/R injury and systemic inflammatory reaction in neonates undergoing repair of complex congenital heart defects. Specific goals will be to demonstrate that NO use via CPB will: Decrease markers of I/R injury and systemic inflammatory response. Decrease platelet activation leading to reduced postoperative bleeding and transfusion requirements. Decrease postoperative organ dysfunction, and hence decrease operative mortality and postoperative morbidity. Twelve neonates undergoing repair of complex congenital heart defects will receive NO via the CPB circuit, for the duration of surgery. They will be compared to a control group of 12 similar patients. Serum levels of different ischemic reperfusion injury and inflammatory markers will be measured at different time points after surgery and will be correlated with different end organ function tests and clinical course in the postoperative period. The results will be compared between the two groups to try to determine the clinical benefit of NO administration through CPB circuit.

Official Title
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Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass.

Conditions
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Ischemia/Reperfusion Injury After Neonatal Cardiac Surgery, Inflammatory Reaction After Neonatal Cardiac Surgery

Intervention / Treatment
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* Drug: Inhaled Nitric Oxide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates, age 0-30 days Full term, > 37 weeks gestation Birth weight ≥ 2.6 kg Exclusion Criteria: Preoperative sepsis Preoperative renal dysfunction Preoperative intracranial hemorrhage Chromosomal abnormalities and/or genetic syndromes Prior intervention (catheter based or surgical)

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 30 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitric oxide on CPB<br>neonates receiving inhaled NO into the cardiopulmonary bypass circuit during cardiac surgery | Drug: Inhaled Nitric Oxide<br>* delivering inhaled Nitric Oxide into the cardiopulmonary bypass circuit during neonatal cardiac surgery<br>* Other names: study group;|
| Placebo Comparator: control<br>neonates not receiving inhaled NO into the cardiopulmonary bypass | Drug: placebo<br>* inhaled Nitric Oxide not delivered to the cardiopulmonary bypass circuit during neonatal cardiac surgery<br>* Other names: control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive   Increase From Pre-op) | The primary study endpoints are to evaluate whether NO delivered through the neonatal cardiopulmonary bypass (CPB) circuit can decrease various biochemical markers of ischemia/reperfusion injury and oxidative damage. Markers to be analyzed will include cardiac troponin I, interleukins (IL), tumor necrosis factor, N-terminal prohormone for brain natriuretic peptide (NT-proBNP),lactate dehydrogenase (LDH), plasma anti-oxidant levels, plasma malondialdehyde (MDA) levels. | Pre-op baseline and up to 12 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Fluid Balance at 48 Hours | The secondary study endpoints are to evaluate whether NO delivered through the neonatal CPB circuit can decrease the clinical signs of ischemia/reperfusion injury and/or cardiac dysfunction. Clinical parameters (post surgery) include inotropic support, fluid balances, diuretic support, ventilator times, and length of ICU stay will be evaluated. | 48 hours post surgery | 
| Time Until Start of Diuretic Therapy | hours until start of diuretic therapy | Pre-op to 72 hours post surgery | 
| Inotropic Score Day 1 | The Inotropic Score is an objective clinical tool used to quantify the need for cardiovascular support in children and adolescents after surgery and to predict prognosis of pediatric septic shock (higher score predicts higher risk or worse prognosis).The Inotropic Score is low if <= 20, intermediate if 21-30, and high if > 30. Formula used in the study: Daily inotropic score (mcg/kg/min) = Dopamine drip dose+ dobutamine drip dose+ (milrinone drip dose times 10) + (epinephrine drip dose times 100 ) | 24 hours post surgery | 
| Length of Intubation and PSHU Stay | Days to extubation and Pediatric Surgical Heart Unit (PSHU) length of stay (LOS) as measuring patient surgical outcomes. | Surgery to discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemia/reperfusion injury