Nitric Oxide During Cardiopulmonary Bypass in Neonates to Reduce Risk of Acute Kidney Injury

Study Overview
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Brief Summary
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Acute kidney injury following cardiac surgery for congenital heart defects in children is a major cause of both short- and long-term morbidity and mortality, affecting up to 60% of high risk patients. Despite effort, to date, no successful therapeutic agent has gained widespread success in preventing this postoperative decline in renal function. Based on preliminary data available in the literature, we hypothesize that nitric oxide (gNO), administered during cardiopulmonary bypass (CPB), may reduce the risk of acute kidney injury (AKI) via mechanisms of reduced inflammation and vasodilation. In this pilot study, 40 neonates undergoing cardiac surgery will be randomized to receive intraoperative administration of 20 ppm of nitric oxide to the oxygenator of the cardiopulmonary bypass circuit or standard CPB with no additional gas.

Official Title
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Efficacy of Nitric Oxide Administration During Cardiopulmonary Bypass in Neonates at Reducing the Risk of Acute Kidney Injury: a Preliminary Double-blind Randomized Controlled Trial

Conditions
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Acute Kidney Injury, Congenital Heart Disease

Intervention / Treatment
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* Drug: gases Nitric Oxide (gNO)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates (≤31 days) undergoing cardiac surgery with cardiopulmonary bypass for congenital heart disease Exclusion Criteria: 1. Failure to obtain informed consent from parent/guardian, Clinical signs of preoperative persistent elevated pulmonary vascular resistance, Emergency surgery, Episode of cardiac arrest within 1 week before surgery, Recent treatment with steroids and/or a condition that may require treatment with steroids (excluding steroid administration specifically for CPB), Use of inhaled NO (iNO) immediately prior to surgery, Structural renal abnormalities by ultrasound, Preoperative AKI, Use of other investigational drugs, Weight less than <2.2 kg, Gestational age <36 weeks, Major extracardiac congenital anomalies.

Ages Eligible for Study
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Maximum Age: 31 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Each of the 40 participants will be stratified based on type of lesion (single ventricle vs. biventricular lesions) and block randomized into 1 of 2 study arms: treatment arm (receiving intraoperative administration of 20 ppm of gNO to the oxygenator of the CPB circuit) and control arm (standard CPB conduct).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: gNO Group<br>Participants in the treatment group will receive gNO added to the oxygenator gas flow at 20 ppm throughout the duration of cardiopulmonary bypass. | Drug: gases Nitric Oxide (gNO)<br>* Participants in the intervention group will receive gNO blended into the fresh gas flow of the cardiopulmonary bypass (CPB) oxygenator and maintained at 20 ppm via an Ikaria INO Max DSIR (Mallinckrodt Pharmaceuticals, St. Louis, Missouri, USA), with continuous sampling of NO and NO2 concentration from a port adjacent to the oxygenator. The gNO delivery will be initiated when the patient is on CPB and stopped once the patient comes off CPB.<br>|
| No Intervention: Control Group<br>Participants in the control group will receive standard conduction of cardiopulmonary bypass. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Kidney Injury | Occurrence of acute kidney defined by the Kidney Disease Improving Global Outcomes (KDIGO) diagnostic classification (employing both serum creatinine and urine output criteria). | up to 72 hours postoperative | 
| Glomerular Filtration Rate | Postoperative glomerular filtration rate (GFR) measured using serum cystatin C. | up to 72 hours postoperative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Structural Kidney Injury | Assessed by measurement of urine biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18) liver-type fatty acid-binding protein (L-FABP), and urinary nitrate. | up to 72 hours postoperative | 
| Low cardiac output syndrome (LCOS) | Occurence of low cardiac output syndrome (LCOS) defined as any of the following at any time during the first 48 hours postoperative: Lactate >6mmol/l and central venous saturation (ScvO2) <60% (or SaO2-ScvO2 difference greater than 35% in a single ventricle), Vasoactive inotropic score (VIS)24 ≥ 10, Extracorporeal Membrane Oxygenation (ECMO). | up to 48 hours postoperative | 
| Duration of mechanical ventilation | hours/days | up to 2 weeks from admission to CICU to extubation | 
| Length of cardiac intensive care unit (CICU) stay | days | up to 2 weeksfrom admission to CICU to discharge from CICU | 
| Length of hospital stay | days | up to 30 days from hospital admission to discharge | 
| Inotrope free days | days | up to 30 days after surgery to CICU discharge | 
| ECMO free days | Extracorporeal Membrane Oxygenation free days | up to 2 weeks after surgery to CICU discharge | 
| Closed sternum days | days | up to 2 weeks from postoperative CICU admission to discharge | 
| Time to negative fluid balance | hours/days | up to 2 weeks from CICU admission to outcome reached | 
| Urine Output | ml | up to two weeks from CICU admission to discharge | 
| Use of peritoneal dialysis | yes/no | up to two weeks from CICU admission to discharge | 
| Cardiac arrest | yes/no | up to two weeks from CICU admission to discharge | 
| Use of postoperative inhaled Nitric Oxide (iNO) | yes/no, indication, dose | up to two weeks from CICU admission to discharge |