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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Acute Kidney Injury; Congenital Heart Disease
• Intervention / Treatment: Drug: gases Nitric Oxide (gNO)

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: gNO Group; 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); 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.
No Intervention: Control Group; Participants in the control group will receive standard conduction of cardiopulmonary bypass.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2019
• Primary Completion (Actual): October 20, 2019
• Study Completion (Actual): October 20, 2019

Study Registration Dates

• First Submitted: March 19, 2019
• First Submitted That Met QC Criteria: February 5, 2020
• First Posted (Actual): February 6, 2020

Study Record Updates

• Last Update Posted (Actual): February 6, 2020
• Last Update Submitted That Met QC Criteria: February 5, 2020
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Renal Insufficiency; Cardiovascular Abnormalities; Heart Diseases; Wounds and Injuries; Acute Kidney Injury; Heart Defects, Congenital; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: CIN001-gNO to prevent AKI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes