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High Dose Vitamin C in Cardiac Surgery Patients

Sponsor
Virginia Commonwealth University (Other)
Overall Status
Terminated
CT.gov ID
NCT02762331
Collaborator
(none)
6
Enrollment
1
Location
2
Arms
14.3
Actual Duration (Months)
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Coronary artery bypass grafting (CABG) is the most common procedure performed by cardiac surgeons. Post-operative atrial fibrillation (AF) is the most common adverse event following CABG, experienced in 20-50% of patients; the highest incidence of AF occurs by the third post-operative day. Reduction of AF by various drugs is moderately effective, but involves either rate control with beta blockers or rate conversion with amiodarone after the myocardial damage processes initiating AF have already occurred. Decreasing the incidence of post-operative AF, and hence the morbidity and mortality of high-risk CABG patients, could be more fruitfully approached by targeting the upstream combined processes of inflammation and coagulation activation induced by the surgical insult and associated ischemia-reperfusion (I/R). We propose that cell damage induced by oxidative stress and I/R injury could be prevented and/or inhibited by antioxidant supplementation. Specifically the investigators hypothesize that high-dose intravenous (IV) vitamin C supplementation will ameliorate ROS and therefore damp down upstream inflammatory processes, leading to a reduction of downstream adverse events with demonstrable links to inflammation processes, such as AF.

Condition or Disease Intervention/Treatment Phase
  • Drug: Ascorbic Acid
  • Drug: Placebo
 Phase 1

Detailed Description

Coronary artery bypass grafting (CABG) is the most common procedure performed by cardiac surgeons. More complicated surgeries were enabled by the development of cardiopulmonary bypass (CPB) in the 1930s; CABG procedures increased to peak at over 500,000 in 2000, although numbers have decreased somewhat in the last decade. In 2010 over 150,000 major cardiac procedures involved CABG; 18,008 involved both aortic valve replacement and CABG; 2,378 involved mitral valve replacement and CABG; and 4,635 involved mitral valve repair and CABG. This procedure is costly; in 2010 mean hospital charges for CABG and valve procedures were $124,404 and $171,270 with a mean length of hospital stay of 9 and 11 days and an in-hospital death rate of 1.8% and 3.9%, respectively.

Post-operative atrial fibrillation (AF) is the most common adverse event following CABG, experienced in 20-50% of patients; the highest incidence of AF occurs by the third post-operative day. Post-operative AF is associated with overall poorer prognosis resulting 4-fold increase in disabling stroke and cognitive impairment, 3-fold risk of cardiac-related death, and increased length of hospital stay. These risks are increased by the changing composition of the patient population over the last 10 years: patients are older and sicker, and are presenting with more complex disease states and co-morbidities, such as severe coronary artery disease (CAD), congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), diabetes, previous cardiac surgeries with mechanical support device placements, and complex pharmacological histories. A higher prevalence of AF with increased transfusions among CPB patients has also been reported, suggesting a link with increased plasma load of inflammatory markers and mediators from transfused red cells. Reduction of AF by various drugs is moderately effective, but involves either rate control with beta blockers or rate conversion with amiodarone after the myocardial damage processes initiating AF have already occurred.

Decreasing the incidence of post-operative AF, and hence the morbidity and mortality of high-risk CABG patients, could be more fruitfully approached by targeting the upstream combined processes of inflammation and coagulation activation induced by the surgical insult and associated ischemia-reperfusion (I/R). During CPB, the heart is subjected to ischemic periods of varying duration. The cardiac tissue at that point is electrically resting and its metabolic demands are accordingly low. However, there is also a severely diminished supply of oxygen and nutrients. This results in slow but direct myocardium cellular damage, which increases as ischemia duration increases. However, after reperfusion with oxygenated blood, oxidative stress actually peaks because of accumulated oxidative substrates and cellular depletion of reductive compounds. Cardiac damage related to ischemia-reperfusion will be exacerbated in the presence of co-morbidities, such as diabetes and CAD, which are pathologies with a significant reactive oxygen species (ROS) injury component. High levels of ROS in the myocardium contribute to both electrical and structural remodeling of the cardiac muscle, resulting in the development of AF.

I/R-related oxidative stress and ROS activation contribute to cell damage by modifying protein DNA and phospholipids, resulting in lipid peroxidation and thiol-group oxidation, which in turn are linked to the induction of inflammatory cascades. Lipids are important small-molecule metabolites that have roles in a wide variety of physiological processes. The lipidome of eukaryotic cells contains thousands of lipid entities that structurally and chemically regulate cell membranes, store energy, or are precursors of bioactive metabolites. Defects in lipid regulation and metabolism are therefore significant contributors to disease pathophysiology. In particular, eicosanoids are lipid mediators linking coagulation and inflammatory pathways; intracellular oxidant species are essential mediators in eicosanoids synthesis pathways. Thus lipidomic analyses are a potential novel tool for the identification of drivers of underlying pathogenesis and new diagnostic biomarkers.

During CABG, total peroxide (TP) and oxidative stress index approximately double Increased post-bypass plasma levels of inflammatory markers such as C-reactive protein (CRP) and platelets and leukocyte activation have been observed during CPB. Increases in oxidative stress associated with CPB are correlated with a reduction in total plasma antioxidant capacity. These observations are of interest because an antioxidant is a molecule that inhibits the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When the chain reaction occurs in a cell, it can cause damage or death to the cell. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by auto-oxidation; hence antioxidants are often reducing agents. The investigators propose that cell damage induced by oxidative stress and I/R injury could be prevented and/or inhibited by antioxidant supplementation. Specifically the investigators hypothesize that high-dose intravenous (IV) vitamin C supplementation will ameliorate ROS and therefore damp down upstream inflammatory processes, leading to a reduction of downstream adverse events with demonstrable links to inflammation processes, such as AF. Vitamin C is an viable therapeutic candidate because it is a powerful antioxidant with an excellent safety profile, and an emerging history of reducing inflammatory markers in both critically ill and traumatically injured patients. Scattered trials have indicated possible benefits of vitamin C in reducing incidence of post-CABG AF (see Literature search). An antioxidant such as vitamin C acts as a scavenger of intracellular oxidant species; as these are essential mediators in eicosanoids synthesis pathways, it is expected that vitamin C supplementation would decrease the thrombotic potential of eicosanoid-mediated pathways, such as the thromboxane (TBX) production pathway. Impaired cardiac blood flow and clot formation associated with AF contributes to congestive heart failure and stroke; therefore reduction of thrombotic potential is another essential feature for the proposed therapeutic agent.

The proposed pilot study described below represents a marked advance on previously-reported trials in that (a) study design is directed towards minimization of systemic bias, and (b) the investigators will perform simultaneous comparisons of multivariate inflammatory and coagulation profile changes over the immediate post-operative time period when inflammatory changes are expected to be at a maximum. The novelty of this approach is the systems-level analysis of lipids and their interacting moieties; new technology allows for rapid quantitative analysis of over 150 lipid mediators in a sample, time and cost effective manner.

Study Design

Study Type:
Interventional
Actual Enrollment :
6 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Basic Science
Official Title:
Pilot Study to Assess Effect of High Dose Ascorbic Acid (Vitamin C) on Inflammation Reduction in Cardiac Surgery Patients.
Actual Study Start Date :
Jan 1, 2017
Actual Primary Completion Date :
Mar 13, 2018
Actual Study Completion Date :
Mar 13, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Vitamin C

Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours.

Drug: Ascorbic Acid
Comparing safety and efficacy of IV Vitamin C in CABG patients
Other Names:
  • Vitamin C

    		•
    Placebo Comparator: Normal saline

    Intravenous normal saline 50 mL every six hours for 48 hours

    Drug: Placebo
    Placebo intervention
    Other Names:
  • Normal Saline

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Plasma Inflammatory Biomarkers [48 hours]

      Change in baseline inflammatory biomarkers including TNF-alpha, C-reactive protein, and interleukin-6 will be measured at 6, 24, and 48 hours following first administration of study drug.

    2. Urinary Inflammatory Biomarker [24 hours]

      Change in baseline urine concentrations for neutrophil gelatinase-associated lipocalin (NGAL) will be measured at 6 and 24 hours.

    Secondary Outcome Measures

    1. Occurence of Atrial Fibrillation [48 hours]

      Atrial fibrillation is a common complication of CABG surgery. We will monitor EKG status for development of atrial fibrillation for 48 hours post-op.

    2. Coagulation Biomarkers [48 hours]

      Change in baseline coagulation biomarkers including thrombomodulin, fibrinogen, platelets and clotting parameters from thromboelastography will be measured at 6, 24, and 48 hours following the first administration of the study drug.

    3. Lipidomic Biomarkers [24 hours]

      Change in baseline lipidomic biomarkers including free fatty acids, eicosanoids, 3-polyunsaturated fatty acid-derived lipid mediators, phospholipid substrates of cytosolic PLA2α, and isoprostanes will be measured at 6- and 24 hours following administration of the study drug.

    4. Development of Renal Calculi [48 hours]

      We will assess for develop of renal calculi as a safety measure.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Age ≥18 years

    • Scheduled for elective non-emergent valve repair or replacement, or multi-vessel CABG surgery

    • No known coagulopathy prior to surgery

    Exclusion Criteria:

    • Emergency cardiac surgery

    • Ejection fraction < 35%

    • Presence of autoimmune disease or currently receiving immunosuppressant therapy

    • History of renal calculi

    • Renal dysfunction (pre-operative creatinine clearance < 40 mL/min, or serum creatinine greater than 1.8 mg/dl)

    • Known bleeding diathesis

    • Active infection, cancer or tumor

    • Prior history of atrial fibrillation

    • Single CABG procedure (one involved coronary vessel)

    • Prisoner

    • Pregnant

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Virginia Commonwealth University Health System Richmond Virginia United States 23298

    Sponsors and Collaborators

    • Virginia Commonwealth University

    Investigators

    • Principal Investigator: Donald F Brophy, PharmD, Virginia Commonwealth University

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Virginia Commonwealth University
    ClinicalTrials.gov Identifier:
    NCT02762331
    Other Study ID Numbers:
    • HM20000539
    First Posted:
    May 4, 2016
    Last Update Posted:
    Jun 24, 2019
    Last Verified:
    Mar 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Virginia Commonwealth University
    Vitamin C
    Coronary Artery Bypass Grafting
    Atrial Fibrillation
    Cardiac Valve Repair
    Additional relevant MeSH terms:
    Atrial Fibrillation
    Heart Valve Diseases
    Ascorbic Acid

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Period Title: Overall Study
    STARTED 4 2
    COMPLETED 4 2
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Vitamin C Normal Saline Total
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients 4 subjects total Age: Between 32 and 72 1 Female 3 Male 1 Black or African American/Non-Hispanic 3 White/Non-Hispanic Region of enrollment: USA Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention 2 subjects total Age: 50; 74 2 Males 2 White/Non-Hispanic Region of enrollment: USA Total of all reporting groups
    Overall Participants 4 2 6
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    3
    75%
    1
    50%
    4
    66.7%
    >=65 years
    1
    25%
    1
    50%
    2
    33.3%
    Sex: Female, Male (Count of Participants)
    Female
    1
    25%
    0
    0%
    1
    16.7%
    Male
    3
    75%
    2
    100%
    5
    83.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    4
    100%
    2
    100%
    6
    100%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    25%
    0
    0%
    1
    16.7%
    White
    3
    75%
    2
    100%
    5
    83.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    4
    100%
    2
    100%
    6
    100%

    Outcome Measures

    1. Primary Outcome
    Title Plasma Inflammatory Biomarkers
    Description Change in baseline inflammatory biomarkers including TNF-alpha, C-reactive protein, and interleukin-6 will be measured at 6, 24, and 48 hours following first administration of study drug.
    Time Frame 48 hours

    Outcome Measure Data

    Analysis Population Description
    Samples were collected but not analyzed due to study termination. This study was terminated because the therapy was proven effective by larger studies.
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Measure Participants 0 0
    2. Primary Outcome
    Title Urinary Inflammatory Biomarker
    Description Change in baseline urine concentrations for neutrophil gelatinase-associated lipocalin (NGAL) will be measured at 6 and 24 hours.
    Time Frame 24 hours

    Outcome Measure Data

    Analysis Population Description
    Samples were collected but not analyzed due to study termination. This study was terminated because the therapy was proven effective by larger studies.
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Measure Participants 0 0
    3. Secondary Outcome
    Title Occurence of Atrial Fibrillation
    Description Atrial fibrillation is a common complication of CABG surgery. We will monitor EKG status for development of atrial fibrillation for 48 hours post-op.
    Time Frame 48 hours

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Measure Participants 4 2
    Count of Participants [Participants]
    0
    0%
    0
    0%
    4. Secondary Outcome
    Title Coagulation Biomarkers
    Description Change in baseline coagulation biomarkers including thrombomodulin, fibrinogen, platelets and clotting parameters from thromboelastography will be measured at 6, 24, and 48 hours following the first administration of the study drug.
    Time Frame 48 hours

    Outcome Measure Data

    Analysis Population Description
    Samples were collected but not analyzed due to study termination. This study was terminated because the therapy was proven effective by larger studies.
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Measure Participants 0 0
    5. Secondary Outcome
    Title Lipidomic Biomarkers
    Description Change in baseline lipidomic biomarkers including free fatty acids, eicosanoids, 3-polyunsaturated fatty acid-derived lipid mediators, phospholipid substrates of cytosolic PLA2α, and isoprostanes will be measured at 6- and 24 hours following administration of the study drug.
    Time Frame 24 hours

    Outcome Measure Data

    Analysis Population Description
    Samples were collected but not analyzed due to study termination. This study was terminated because the therapy was proven effective by larger studies.
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Measure Participants 0 0
    6. Secondary Outcome
    Title Development of Renal Calculi
    Description We will assess for develop of renal calculi as a safety measure.
    Time Frame 48 hours

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention
    Measure Participants 4 2
    Count of Participants [Participants]
    0
    0%
    0
    0%

    Adverse Events

    Time Frame Investigators will determine daily if any clinical adverse experiences occur during the period from informed consent through study hour 48 and will be followed up through resolution, resolved with sequelae, unresolvable or death.
    Adverse Event Reporting Description No adverse events occured
    Arm/Group Title Vitamin C Normal Saline
    Arm/Group Description Intravenous ascorbic acid 50 mg/kg in 50 mL normal saline every six hours for 48 hours. Ascorbic Acid: Comparing safety and efficacy of IV Vitamin C in CABG patients 4 subjects total Age: Between 32 and 72 1 Female 3 Male 1 Black or African American/Non-Hispanic 3 White/Non-Hispanic Region of enrollment: USA No Adverse Events Intravenous normal saline 50 mL every six hours for 48 hours Placebo: Placebo intervention 2 subjects total Age: 50; 74 2 Males 2 White/Non-Hispanic Region of enrollment: USA No Adverse Events
    All Cause Mortality
    Vitamin C Normal Saline
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/2 (0%)
    Serious Adverse Events
    Vitamin C Normal Saline
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/2 (0%)
    Other (Not Including Serious) Adverse Events
    Vitamin C Normal Saline
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/2 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Donald Brophy, PharmD
    Organization Virginia Commonwealth University
    Phone (804) 827-1455
    Email dbrophy@vcu.edu
    Responsible Party:
    Virginia Commonwealth University
    ClinicalTrials.gov Identifier:
    NCT02762331
    Other Study ID Numbers:
    • HM20000539
    First Posted:
    May 4, 2016
    Last Update Posted:
    Jun 24, 2019
    Last Verified:
    Mar 1, 2019