The Val-CARD trial aims to answer the question: "Does the drug sodium valproate reduce complications affecting the heart and kidneys in patients having heart operations?" Sodium valproate is a drug commonly used in the treatment of epilepsy. Recently it has been shown to protect against heart and kidney damage in laboratory tests. This has led to trials evaluating whether it can prevent heart and kidney damage in patients. The investigators wish to evaluate whether treatment with sodium valproate for a short period can reduce levels of organ damage following heart surgery by measuring this in blood tests, exercise tests, a special x-ray measuring body fat content, a walk exercise and muscle strength tests. The investigators now want to establish if sodium valproate works by making the heart and kidney more resistant to any injury that results from the use of the heart lung machine.
This trial is a single centre, unblinded, randomised controlled trial of pre-surgery sodium valproate versus standard care (no treatment). The trial has two phases. In the first phase - the dose finding phase, 40 patients will be randomised (1:1:1:1) to three different treatment doses versus a control group of standard care (no treatment). A single sodium valproate dose will be selected based on the evaluation of compliance, toxicity and levels of Histone Deacetylase inhibition. In the second phase, the efficacy of this dose at preventing myocardial and kidney injury will then be compared to untreated controls using a 1:1 randomised parallel group design in a further 82 patients. In an optional research procedure during the efficacy phase of the trial (Phase 2) cardiometabolic status (cardiac function and visceral adiposity) will be evaluated using MRI scanning. Patients will be screened by the investigators to assess eligibility for entry into the trial. Eligible patients undergoing cardiac surgery with CPB who consent to participate will be randomly allocated using concealed allocation as follows: In the dose finding phase of the trial patient will be randomised in a 1:1:1:1 ratio to: 1. GROUP A: Standard care (no treatment) 2. GROUP B: Sodium valproate at a target dose of 15 mg/kg per day for 1-2 weeks pre-surgery. 3. Group C: Sodium valproate at a target dose of 15 mg/kg per day for 4-6 weeks pre-surgery. 4. Group D: Sodium valproate at a target dose of 25 mg/kg per day for 4-6 weeks pre-surgery. In the efficacy phase of the trial patients will be randomised in a 1:1 ratio to: 1. GROUP A: Standard care (no treatment) 2. GROUP B, C or D: Sodium valproate at a target dose as determined by the dose finding phase of the trial. The Val-CARD Trial proposes to test the overarching hypothesis that pre-surgery administration of sodium valproate will protect patients against organ damage that occurs during cardiac surgery with cardiopulmonary bypass. The trial will test a number of specific hypotheses: 1. Pre-surgery sodium valproate will reduce the risk of post cardiac surgery organ failure. 2. Short-term (1-2 weeks) pre-surgery treatment with sodium valproate at a target dose of 15mg/kg/day will have different pharmacokinetics but comparable tolerability and protective effects on myocardial and renal signaling to long-term (4-6 weeks) treatment at a target dose of 15mg/kg/ day or 25mg/kg/day. 3. Sodium valproate will reduce the risk of post cardiac surgery myocardial injury by increasing the expression of genes that promote myocardial mitochondrial homeostasis via effects on chromatin histone deacetylation. 4. Sodium valproate will reduce the risk of post cardiac surgery acute kidney injury (AKI) by increasing the expression of genes that promote renal tubular homeostasis. 5. Sodium valproate will reduce the risk of post cardiac surgery endothelial dysfunction by increasing the expression of genes that promote endothelial homeostasis. 6. The trial interventions will be tolerated by patients and will not result in long-term adverse changes in cardiometabolic status.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
122
Treatment with Sodium Valproate vs. Control Discovery phase - 4 arms: 15 mg/kg for 1-2 weeks; 15mg/kg for 4-6 weeks; 25 mg/kg for 4-6 weeks; Control Efficiency phase - 2 arms: Treatment group selected from previous phase; Control
Glenfield Hospital
Leicester, Leicestershire, United Kingdom
RECRUITINGChange of Serum Creatinine level
Measurement of serum creatinine level and expressed as umol/L.
Time frame: Baseline, 2 weeks, 4 weeks, 0-6, 6-12, 24, 48, 72, and 96 hours post-operatively
Change of Serum Troponin I level
Measurement of serum Troponin level and expressed as ng/L.
Time frame: Baseline, at 0-6, 6-12, 24, 48 and 72 hours post-operatively
Change in Multiple organ dysfunction - Sepsis-related Organ Failure Assessment (SOFA) Score)
Range 0-3, 3 being the worse score
Time frame: Baseline, 4 weeks, 0-6, 24, 48, 72 and 96 hours
NGAL (Neutrophil gelatinase associated lipocalcin)
Measurement of NGAL level and expressed as μg/L.
Time frame: Baseline, day before surgery, 6-12, 24 and 48 hours post-surgery.
Lung Injury - Arterial alveolar oxygen (PaO2/FiO2) ratios
Measurement of PaO2/FiO2 ratio and expressed in kPa/L.
Time frame: Baseline, day before surgery, 24, 48, 72 and 96 hours post-surgery.
AST (Aspartate Transaminase)
Measurement of AST levels in serum and expressed in IU/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.
Time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
ALT (Alanine Transaminase)
Measurement of ALT levels in serum and expressed in IU/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.
Time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Bilirubin
Measurement of Bilirubin levels in serum and expressed in μmol/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.
Time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Alkaline Phosphatase
Measurement of Alkaline Phosphatase levels in serum and expressed in IU/L. Acute liver injury will be defined as an acute derangement of three times the upper limit of normal.
Time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Serum Amylase
Measurement of Amylase levels in serum and expressed in IU/L. Acute pancreatitis will be defined as a serum amylase concentration \>1000 ng/ml.
Time frame: Baseline, day before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Assessment of resource use - Time until extubation
Time frame: Time (hours) measured from the start of surgery - to extubation (up to 30 days)
Length of stay in Intensive Care Unit
Number of hours between admission and discharge from the Intensive Care Unit (ICU).
Time frame: Time (hours) measured from the start of surgery to discharge from ICU (up to 30 days)
Length of Stay in Hospital
Number of days between the date of surgery and discharge from the hospital.
Time frame: Time (days) measured from the start of surgery to discharge from hospital (up to 90 days)
Sepsis
Sepsis is defined as: Suspected or documented infection and an acute change in total Sepsis-related Organ Failure Assessment (SOFA) score ≥2 points consequent to the infection. Range of SOFA is 0 to 3, 3 being the worse score.
Time frame: Baseline, 4 weeks before surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-surgery
Rate of mortality
Rate of mortality at 30-day and 1 year from the date of surgery.
Time frame: Within 30-days from surgery and at 1 year from surgery
Bleeding and Transfusion
The total number of units of red cells and other blood components transfused during the operative period and post-operative hospital stay
Time frame: Intra-operative and between time of surgery and hospital discharge up to two weeks
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Adverse events as assessed for type and severity by CTCAE v4.0
Time frame: Post-operative up to 3 months follow-up from time of surgery
Mechanism study: Mithocondrial function of microvessels from tissue biopsies
50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.
Time frame: At time of surgery
Mechanism study: microRNAs isolation from microvessels
The findings will be represented by the frequency (%) of identified microRNAs. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.
Time frame: At time of surgery
Mechanism study: Chromatin Immunoprecipitation (ChIP) of microvessels from tissue biopsies
To identify protein binding sites that may help identify functional elements in the genome. Findings will be represented by the number (n) of binding sites. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies.
Time frame: At time of surgery
Mechanism study: Mithocondrial function measured in right atrium myocardium tissue biopsies
50-100 mg myocardial biopsies will be obtained from the right atrium at surgery. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.
Time frame: At time of surgery
Mechanism study: microRNA isolation from right atrium myocardium tissue biopsies
50-100 mg myocardial biopsies will be obtained from the right atrium at surgery. The findings will be represented by the frequency (%) of identified microRNAs.
Time frame: At time of surgery
Mechanism study: Chromatin Immunoprecipitation (ChIP) in right atrium myocardium tissue biopsies
50-100 mg myocardial biopsies will be obtained from the right atrium at surgery. To identify protein binding sites that may help identify functional elements in the genome. Findings will be represented by the number (n) of binding sites.
Time frame: At time of surgery
Mechanism study: Mithocondrial function measured in adipose tissue biopsies
Adipose tissue collected from epicardial fat at time of surgery. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.
Time frame: At time of surgery
Mechanism study: microRNA isolation in adipose tissue biopsies
Adipose tissue collected from epicardial fat at time of surgery. The findings will be represented by the frequency (%) of identified microRNAs.
Time frame: At time of surgery
Mechanism study: Chromatin Immunoprecipitation (ChIP) in adipose tissue biopsies
Adipose tissue collected from epicardial fat at time of surgery. To identify protein binding sites that may help identify functional elements in the genome. Findings will be represented by the number (n) of binding sites.
Time frame: At time of surgery
Mechanism study: Measurement of microvesicles in urine samples
Identification of microvesicles. The findings will be represented by the frequency (%) of each identified microvesicle.
Time frame: 1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Measurement of microRNAs in urine samples
The findings will be represented by the frequency (%) of identified microRNAs.
Time frame: 1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Measurement of histone acetylation in urine samples
The findings will be reported as acetylated H3 (ug/mg) over time (hours)
Time frame: 1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Measurement of gene expression in urine samples
Whole genome sequencing will be achieved through ATAC sequencing. The identified genes will be characterised by average expression count over ATAC.
Time frame: 1 day before surgery, 12 and 24 hours following surgery
Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac Function
Assessment of cardiac function, by assessing ventricular function. This will be expressed as ejection fraction (%). Intravenous contrast will be administered via an indwelling venous catheter.
Time frame: Baseline, 1 day before surgery and 3 months following surgery
Mechanism study: Cardiac Magnetic Resonance Imaging - Cardiac adiposity content
Assessment of cardiac adiposity content. A percentage of adipose tissue over total body mass will be calculated. Intravenous contrast will be administered via an indwelling venous catheter.
Time frame: Baseline, 1 day before surgery and 3 months following surgery
Mechanism study: Cardiac Magnetic Resonance Imaging - Visceral adiposity content
Assessment of visceral adiposity content. A percentage of adipose tissue over total body mass will be calculated. Intravenous contrast will be administered via an indwelling venous catheter.
Time frame: Baseline, 1 day before surgery and 3 months following surgery
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