Nitrite Infusion in High Risk Patients Undergoing Cardiopulmonary Bypass

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the efficacy of intravenous sodium nitrite compared with placebo in reducing the occurrence of CSA-AK as diagnosed by KDIGO criteria during the first 72 hrs after cardiac surgery in high-risk patients undergoing cardiac surgery. Secondary objectives are to determine whether IV sodium nitrite achieves adequate pharmacokinetics (PK) in patients undergoing cardiac surgery with the use of CPB.

Detailed Description
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Acute kidney injury is one of the most untoward consequences of cardiac-surgery with the use of CPB. As such it is associated with a high mortality and morbidity and health care expense. Unfortunately, currently, there is no effective preventive or treatment strategy for cardiac surgery-associated (CSA) AKI other than renal replacement therapy. It is postulated that a major mechanism of CSA-AKI is created by the ischemia reperfusion injury (IRI) resulting from aortic cross clamping and unclamping. This creates a cascade of events culminating in inflammation, microvascular dysfunction and tubular cell maladaptation and eventually renal tissue damage. Current treatment modalities that target the microcirculation such as blood pressure and cardiac output fails to prevent renal abnormalities and as such may be deleterious to the renal tissue microcirculation. The PI hypothesizes that a therapeutic strategy that limits IRI such as the administration of inhaled nitric oxide (NO) or sodium nitrite (NaNO2) would ameliorate CSA-AKI by limiting inflammatory injury to the kidney. The anion nitrite (NO2-) releases NO in biological systems and has been demonstrated to inhibit IR injury in the heart, liver and kidneys created by various pathologic states1-3 and improve outcomes in patients with acute myocardial infarction, in patients with pulmonary hypertension and is the putative active mediator of protection in liver-transplantation patients receiving inhaled nitric oxide4. The objective of this study is to determine whether the NO donor, nitrite will prevent I/R injury in patients at high risk of development of CSA-AKI undergoing open-heart surgery with cardiopulmonary bypass.

Official Title
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Randomized, Controlled, Double-blinded Pilot Study: Nitrite Infusion in High Risk Patients Undergoing Cardiopulmonary Bypass

Conditions
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Acute Kidney Injury

Intervention / Treatment
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* Drug: Saline
* Drug: Sodium Nitrite


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients CCFS score ≥ 6 (Table 1) Patients admitted to UAB cardiac intensive care unit (CICU) following elective cardiac surgery with cardiopulmonary bypass under general endotracheal anesthesia 19 years old Estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 Exclusion Criteria: Prisoners directly admitted from a correctional facility. Children < 19 years or under 50 kg body weight if age is unknown. Patients enrolled in a concurrent ongoing interventional, randomized clinical trial. Patients with end stage renal disease or preexisting GFR <30 mL/min/1.73 m2 or need for dialysis. 34 Patients with end stage heart disease on the cardiac transplant list. Patients undergoing procedures without the use of CPB All transplant patients. Patients on ventricular assist devices. Patients undergoing emergency procedures. Patients with glucose 6-dehydrogenase deficiency Pregnancy

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control group<br>saline infusion will be administered after induction of general anesthesia | Drug: Saline<br>* A placebo (saline infusion) will be administered after induction of general anesthesia.<br>Drug: Sodium Nitrite<br>* Sodium nitrite infusion at a 267 mcg/kg/hr. will start after induction of general anesthesia via a dedicated IV line for 6 hrs.<br>* Other names: NaNO2;|
| Active Comparator: Sodium Nitrite<br>sodium nitrite will start after induction of general anesthesia via a dedicated IV line for 6 hrs. | Drug: Saline<br>* A placebo (saline infusion) will be administered after induction of general anesthesia.<br>Drug: Sodium Nitrite<br>* Sodium nitrite infusion at a 267 mcg/kg/hr. will start after induction of general anesthesia via a dedicated IV line for 6 hrs.<br>* Other names: NaNO2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitrite Metabolome Levels | Measuring nitrite, nitrate, and nitrosothiols levels | baseline to 73 hrs post-operatively | 
| Biomarkers of Hemolysis | Measuring hemolysis indicators heme, Hb, hemopexin, and hemopectin | baseline to 73 hrs post-operatively | 
| Biomarkers of Kidney Injury | Measuring kidney injury indicators creatine, neutrophil-associated gelatinase, lipocalin (NGAL) | baseline to 73 hrs post-operatively | 
| Cell Cycle Stress | Measuring cell cycle arrest biomarkers TIMP-2, IGFBP-7 | baseline to 73 hrs post-operatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers of Hepatic injury | Measuring serum AST and ALT | baseline to 24 hours post-operatively | 
| Biomarkers of Kidney Injury | Measuring kidney injury indicators creatine, neutrophil, lipocalin (NGAL) | baseline to 24 hours post-operatively | 
| Cell Cycle Stress | Measuring cell cycle arrest biomarkers TIMP-2, IGFBP-7 | baseline to 24 hours post-operatively | 
| Biomarkers of Myocardial Injury | Measuring myocardial injury indicators troponin and CKMB | baseline to 24 hours post-operatively | 
| Urine Output | Measuring total urine output | baseline to 73 hrs post-operatively | 
| Vasopressors Usage | Percentage of vasopressor usage between the control and intervention | baseline to 73 hrs post-operatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nitric Oxide, Sodium Nitrite, Cardiopulmonary bypass, cardioplegic cardiac arrest, coronary revacularization