The Val-CARD Trial

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.