Nitrite Mediated Cardioprotection During Coronary Artery Bypass Surgery

Study Overview
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Brief Summary
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The purpose of this study is to determine whether sodium nitrite administration 24 hours prior to or during coronary artery bypass surgery protects the heart better from lack of blood flow which occurs as part of this type of operation. The study will also determine what the mechanisms of this cardioprotection are.

Detailed Description
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In recent years, there has been much interest in sodium nitrite as a cytoprotective agent in in vitro and animal models. A recent study undertaken in a canine model of myocardial infarction demonstrated a 50% reduction in myocardial injury following the administration of sodium nitrite prior to the ischemic event. In humans, the setting of coronary artery bypass surgery lends itself well to study potential cytoprotective agents. During cardiac surgery, the heart undergoes a period of ischemia allowing the surgeons to operate on the heart. This is followed by a period of reperfusion which in itself can add to cellular injury. Such injury can hinder post-operative myocardial recovery. The aim of this pilot study is to determine whether the cardioprotective effects of sodium nitrite demonstrated in animal models are translated in humans and to determine the exact underlying mechanisms of this cytoprotection. Patients undergoing coronary artery bypass grafting surgery who give written, informed consent will receive sodium nitrite 24 hours prior to surgery, during cardiac surgery or placebo. Myocardial injury will be assessed through the measurement of biochemical markers such as troponin T. Cardiac biopsy samples will be obtained to determine underlying molecular mechanisms of this cardioprotection. The other aim of this pilot study is to determine what dose of sodium nitrite (i.e. 0.2mcg/kg/min or 1mcg/kg/min) is optimal for cardioprotection. This study will form pilot data also for a larger clinical trial with clinical endpoints.

Official Title
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Mechanisms of Nitrite Mediated Cardioprotection in Coronary Artery Bypass Surgery

Conditions
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Coronary Artery Bypass Surgery

Intervention / Treatment
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* Drug: sodium nitrite
* Drug: 0.9% sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing elective first time multi-vessel coronary artery bypass surgery Older than 18 years of age Exclusion Criteria: Significant psychiatric /neurological impairment that might prevent adherence to the requirements of the protocol or the ability to give informed consent Inability to read the Information Sheet. Redo operation Age >80 years Pregnancy Renal Impairment requiring pre-operative renal support Diabetes Mellitus Intended heart valve or additional surgery Episodes of angina or ischemia within 48hours prior to the procedure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sodium nitrite 24 hours before<br> | Drug: sodium nitrite<br>* 0.2mcg/kg/min or 1mcg/kg/min intravenous for 30minutes at 1ml/min<br>|
| Experimental: sodium nitrite during surgery<br> | Drug: sodium nitrite<br>* 0.2mcg/kg/min or 1mcg/kg/min intravenous for 30minutes at 1ml/min<br>|
| Placebo Comparator: 0.9% sodium chloride<br> | Drug: 0.9% sodium chloride<br>* intravenous 0.9% sodium chloride over 30minutes at 1ml/min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Troponin T | Biochemical marker of myocardial injury | 72 hours post release of aortic cross clamp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Troponin T |  | 6 hours post release of aortic cross clamp | 
| troponin T |  | 12 hours post release of aortic cross clamp | 
| Troponin T |  | 24 hours post release of aortic cross clamp | 
| Troponin T |  | 48 hours post release of aortic cross clamp | 
| Creatinine Kinase myocardial Fraction (CKMB) |  | 6 hours post release of aortic cross clamp | 
| Creatinine Kinase myocardial Fraction (CKMB) |  | 12 hours post release of aortic cross clamp | 
| Creatinine Kinase myocardial Fraction (CKMB) |  | 24 hours post release of aortic cross clamp | 
| Creatinine Kinase myocardial Fraction (CKMB) |  | 48 hours post release of aortic cross clamp | 
| Creatinine Kinase myocardial Fraction (CKMB) |  | 72 hours post release of aortic cross clamp | 
| venous methemoglobinaemia | study drug means both sodium nitrite and placebo | immediately before infusion of study drug | 
| plasma 8-isoprostane |  | before aortic cross clamp administration | 
| Nitric oxide metabolites in cardiac tissue |  | before aortic cross clamp application | 
| Cardiac output studies |  | upto 12 hours after release of aortic cross clamp | 
| inotrope usage |  | up to 12 hours after release of aortic cross clamp | 
| venous methemoglobinemia | Study drug could be sodium nitrite or placebo and each infusion last 30minutes. | immediately after infusion of study drug. | 
| Nitric oxide metabolites in cardiac tissue |  | before release of aortic cross clamp | 
| Nitric oxide metabolites in cardiac tissue |  | 10minutes after release of aortic cross clamp | 
| Plasma 8 isoprostane levels |  | 5minutes after discontinuation of cardiopulmonary bypass | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sodium nitrite, coronary artery bypass surgery, cardioprotection, myocardial injury