Vitamin C in Cardiac Surgery Patients

Study Overview
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Brief Summary
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Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery that increases the incidence of stroke, kidney injury and death. Vitamin C has been shown to decrease the incidence of POAF follow cardiac surgery, but the optimal dose has not been identified. With this project, the investigators plan to gather pharmacokinetic and dose-response data for vitamin C in the cardiac surgery population. The investigators plan to conduct a small interventional pilot study investigating the pharmacokinetics and pharmacodynamics of Vitamin C in patients undergoing coronary artery bypass graft (CABG) surgery. Patients enrolled will receive an intravenous dose of Vitamin C the day before surgery and the day after. Patients will have blood samples obtained with each dose for analysis of vitamin C concentrations and several biomarkers of oxidative stress. Analysis of samples will be performed within the Department of Pharmaceutical Sciences at Wilkes University.

Detailed Description
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The pathophysiology of post-operative atrial fibrillation (POAF) in cardiac surgery patients has not been fully elucidated, but inflammation and oxidative stress are associated with its occurrence. Increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and production of glutathione and nitrotyrosine have been found to occur in animal models of atrial fibrillation and patients who develop POAF. Similarly, malondialdehyde (MDA), a biomarker of lipid peroxidation, has also been shown to increase during cardiac surgery, and be significantly more elevated in patients who develop POAF. Cardiac surgery patients supplemented with ascorbic acid have reduced expression of NADPH oxidase and levels of MDA, glutathione and nitrotyrosine, and reduced POAF rates. Ascorbic acid supplementation has demonstrated a significant reduction in POAF in small clinical trials enrolling patients undergoing cardiac surgery. Collectively, these findings show that ascorbic acid prevents POAF in a novel way compared to recommended therapies such as beta-blockers and amiodarone, without the risk of significant side effects. However, the doses of ascorbic acid utilized in clinical trials have been found to inadequately suppress the production of inflammatory markers associated with POAF. Therefore, the maximum effect of ascorbic acid for POAF prevention may not have been realized in clinical trials published to date. These suboptimal responses may be attributable to known variances in medication pharmacokinetics in the cardiac surgery population that lead to reduced medication bioavailability, metabolism and elimination. The variation in ascorbic acid pharmacokinetics in this population is unknown. Thus, the contribution of the proposed research is expected to be determination of the pharmacokinetic profile of ascorbic acid and its concentration-response relationship with oxidative biomarkers associated with POAF in the cardiac surgery population.

Official Title
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Advancing the Cardiovascular Science of Vitamin C in Cardiac Surgery Patients

Conditions
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Coronary Artery Bypass Graft Surgery

Intervention / Treatment
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* Drug: Ascorbic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 21 to 79 years of age admitted to Geisinger Wyoming Valley (GWV) and scheduled to undergo urgent CABG Planned utilization of cardiopulmonary bypass during the surgical procedure Exclusion Criteria: Body mass index greater than 30 kg/m2 Estimated creatinine clearance less than 30 ml/min History of persistent or permanent atrial fibrillation Condition associated with oxidative stress or inflammation (e.g. chronic rheumatic, inflammatory or neoplastic disease, recent infection, etc.) Currently taking corticosteroids, non-steroidal anti-inflammatory drugs or deferoxamine History of oxalate kidney stones Currently pregnant History of allergic reaction to ascorbic acid products Currently taking any herbals or supplements (not including a multivitamin or calcium) Enrolled in another research study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 79 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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ascorbic Acid<br>4 patients will receive 15 mg/kg of ascorbic acid IV the day before and after CABG surgery; 4 patients will receive 30 mg/kg of ascorbic acid IV the day before and after CABG surgery. The maximum dose of ascorbic acid will be 2 g. | Drug: Ascorbic Acid<br>* Ascorbic acid doses will be mixed in 100 mL normal saline and infused over 60 minutes. The postoperative dose will be given on postoperative day #1.<br>* Other names: Vitamin C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ascorbate maximum serum concentration (Cmax) | Maximum serum concentration of ascorbate obtained after drug administration. | 1 year | 
| Half-life of serum ascorbate (T1/2) | The amount of time is takes for the serum concentration of ascorbate to decrease by half. | 1 year | 
| Elimination rate constant of ascorbate (Ke) | The rate at which ascorbate is eliminated from the body | 1 year | 
| Area under the concentration-time curve for serum ascorbate (AUC) | Describes the overall concentration in the body given an administered dose of ascorbic acid. | 1 year | 
| Change in biomarker concentrations | This will consist of the concentrations of NADP+, NADPH, MDA, GGS and nitrotyrosine in blood and atrial tissue samples. | Change within 24 hours; preoperative compared to postoperative | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ascorbic acid, Vitamin C, Postoperative atrial fibrillation, coronary artery bypass graft