High Dose Vitamin C in Cardiac Surgery Patients
Status: | Terminated |
---|---|
Conditions: | Atrial Fibrillation, Cardiology |
Therapuetic Areas: | Cardiology / Vascular Diseases |
Healthy: | No |
Age Range: | 18 - 70 |
Updated: | 4/17/2018 |
Start Date: | January 1, 2017 |
End Date: | March 13, 2018 |
Pilot Study to Assess Effect of High Dose Ascorbic Acid (Vitamin C) on Inflammation Reduction in Cardiac Surgery Patients.
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.
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.
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.
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.
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
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