Nitrite Mediated Cardioprotection During Coronary Artery Bypass Surgery

Mechanisms of Nitrite Mediated Cardioprotection in Coronary Artery Bypass Surgery

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.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Bypass Surgery
• Intervention / Treatment: Drug: sodium nitrite; Drug: 0.9% sodium chloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Recruiting
    • University Hospitals Birmingham NHS Trust
    • Contact: Sayqa Arif, MBChB; Phone Number: 0044(1)214145916; Email: s.arif@bham.ac.uk
    • Sub-Investigator: Sayqa Arif, MBChB
    • Principal Investigator: Robert S Bonser, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Birmingham NHS Foundation Trust
• Investigators: Principal Investigator: Michael P Frenneaux, MD, University of Aberdeen

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Anticipated): January 1, 2012
• Study Completion (Anticipated): July 1, 2012

Study Registration Dates

• First Submitted: March 30, 2010
• First Submitted That Met QC Criteria: April 1, 2010
• First Posted (Estimate): April 2, 2010

Study Record Updates

• Last Update Posted (Estimate): April 2, 2010
• Last Update Submitted That Met QC Criteria: April 1, 2010
• Last Verified: January 1, 2010

More Information

Terms related to this study

• Keywords: myocardial injury; coronary artery bypass surgery; cardioprotection; sodium nitrite
• Other Study ID Numbers: RRK3719; RG/04/005/14168 (Other Grant/Funding Number: British Heart Foundation); 09/H1207/7 (Other Identifier: South Birmingham Research and Ethics Committee)