The PRE-OP ENERGY Trial

Study Overview
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Brief Summary
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The PRE-OP ENERGY Trial proposes to test the overarching hypothesis that a pre-surgery high energy diet will protect patients against organ damage during cardiac surgery with cardiopulmonary bypass.

Detailed Description
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PRE-OP ENERGY is a single centre, unblinded, parallel group, randomised controlled trial of a pre-operative high energy diet, versus a control group receiving standard care. The trial will test a number of specific hypotheses: A pre-surgery high energy diet will protect against post-cardiac surgery organ failure by altering the pre-surgery cardiometabolic state, a process referred to as 'metabolic preconditioning'. The effects of the trial intervention will not be attributable to changes in frailty, activity or baseline organ dysfunction. The trial intervention will not result in long-term adverse changes in cardiometabolic status. Metabolic preconditioning will confer protection against post-cardiac surgery kidney injury by increasing the expression of genes that promote renal tubular homeostasis. Metabolic preconditioning will confer protection against post-cardiac surgery myocardial injury by increasing the expression of genes that promote myocardial mitochondrial homeostasis via effects on chromatin histone deacetylation. Metabolic preconditioning will confer protection against post-cardiac surgery endothelial dysfunction by increasing the expression of genes that promote endothelial homeostasis.

Official Title
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A Randomised Controlled Trial of a Pre-operative High Energy Diet for the Prevention of Organ Injury in Cardiac Surgery: The PRE-OP ENERGY Trial

Conditions
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Cardiac Valve Disease, Coronary Artery Disease, Organ Failure, Multiple

Intervention / Treatment
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* Dietary Supplement: High energy diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ALL of the following: Adult cardiac surgery patients (≥18 years) undergoing cardiac surgery (CABG, Valve, or CABG and Valve) with cardiopulmonary bypass. BMI<30 Able, in the opinion of the investigator, and willing to give informed consent. Do not have diagnosed coeliac disease Able to understand English Exclusion Criteria: Any of the following: Urgent, emergency or salvage procedure Patients with end stage renal failure defined as an estimated Glomerular Filtration rate (eGFR) <15 mL/min/1.73 m2 calculated from the Modification of Diet in Renal Disease equation,1 or patients who are on long-term haemodialysis or have undergone renal transplantation. Patients with persistent or chronic atrial fibrillation. Patients with severe liver dysfunction; hepatitis, cirrhosis, jaundice. Women who are pregnant or who may become pregnant in the intraoperative period. Patients who are participating in another interventional clinical trial. Unable, in the opinion of the investigator, or unwilling to give informed consent. Have diagnosed coeliac disease Unable to understand English Exclusion criteria for optional MRI research procedure: Permanent pacemaker or ICD Brain Aneurysm Clip Implanted neural stimulator Cochlear implant (specific implant must be checked that it is MR safe) Ocular foreign body (e.g. metal shavings) unless removed Other implanted medical devices: (e.g. Swan Ganz catheter) Insulin pump Retained metal shrapnel or bullet Claustrophobia

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Unblinded randomised controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group A: Control<br>Standard Care | |
| Experimental: Group B: High energy diet<br>High energy diet for 8-12 weeks pre-surgery | Dietary Supplement: High energy diet<br>* An overfeeding regime of 135% required energy intake per day, set from baseline energy requirements consisting of high (saturated) fat snacks, added to the usual diet, supervised by a dietitian.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Serum Creatinine level | Measurement of Serum Creatinine level and expressed as umol/L. | Baseline, 0-6, 6-12, 24, 48, 72, and up to 96 hours post-operatively | 
| Change of Serum Troponin I level | Measurement of Serum Troponin level and expressed as ng/L. | Baseline, 0-6, 6-12, 24, 48 and 72 hours post-operatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-surgery organ injury: Sepsis-related Organ Failure | Sepsis-related Organ Failure Assessment (SOFA) Score. Range 0-3, 3 being the worse score | Baseline, pre-operatively, 0-6, 6-12, 24, 48, 72 and 96 hours post-operatively | 
| Post-surgery organ injury: Kidney Injury (Urinary Biomarkers) - NGAL (Neutrophil gelatinase associated lipocalcin) | Urine samples will be analysed for biomarkers of renal injury. Measurement of NGAL level will be expressed as μg/L. | Baseline, 1 day pre-op, 6-12, 24 and 48 hours post-operatively | 
| Post-surgery organ injury: Kidney Injury (Urinary Biomarkers) - microRNA (Neutrophil gelatinase associated lipocalcin) | Urine samples will be analysed for biomarkers of renal injury. Measurement of microRNA in urine samples will be represented by the frequency (%) of identified microRNA. | Baseline, 1 day pre-op, 6-12, 24 and 48 hours post-operatively | 
| Post-surgery organ injury: Kidney Injury | Absolute change from baseline for serum creatinine | Daily for 5 days from Baseline | 
| Post-surgery organ injury: Kidney Injury | Serum creatinine and eGFR in all patients using the Modification of Diet in Renal Disease equation. The following is the IDMS-traceable MDRD Study equation (for creatinine methods calibrated to an IDMS reference method) GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American) The equation does not require weight or height variables because the results are reported normalized to 1.73 m2 body surface area, which is an accepted average adult surface area. | At 6 weeks and then 3 months post-surgery | 
| Post-surgery organ injury: Lung Injury using the Berlin ARDS Score | Using the Berlin ARDS score, the measurement of Arterial Alveolar oxygen ratio expressed in kPa/L. | Baseline, immediately pre-surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-operatively | 
| Post-surgery organ injury: GI Tract injury (Biomarker) - 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. | Baseline, pre-assessment, pre-operatively, 0-6 and at 6-12, 24, 48, 72 and 96 hours post-operatively. | 
| Post-surgery organ injury: GI Tract injury (Biomarker) - 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. | Baseline, pre-assessment, pre-operatively, 0-6 and at 6-12, 24, 48, 72 and 96 hours post-operatively. | 
| Post-surgery organ injury: GI Tract injury (Biomarker) - 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. | Baseline, pre-assessment, pre-operatively, 0-6 and at 6-12, 24, 48, 72 and 96 hours post-operatively. | 
| Post-surgery organ injury: GI Tract injury (Biomarker) - 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. | Baseline, pre-assessment, pre-operatively, 0-6 and at 6-12, 24, 48, 72 and 96 hours post-operatively. | 
| Post-surgery organ injury: GI Tract injury (Biomarker) - 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. | Baseline, pre-assessment, pre-operatively, 0-6 and at 6-12, 24, 48, 72 and 96 hours post-operatively. | 
| Assessment of resource use: Extubation | Time until extubation | Time (hours) measured from the start of surgery to extubation (up to 30 days) | 
| Assessment of resource use: Intensive Care Unit | Length of stay in Intensive Care Unit. Number of hours between admission and discharge from the High Dependency Unit (HDU) | Time (hours) measured from the start of surgery to discharge from ICU (up to 30 days) | 
| Assessment of resource use: Hospital Stay | Length of stay in hospital. Number of days between admission and discharge from the hospital | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Sepsis | Sepsis will be defined as suspected or documented infection and an acute change in total SOFA score ≥2 points consequent to the infection. For the purposes of the trial suspected or documented infection will be defined as the commencement of intravenous antibiotics. The rise in SOFA score will be assessed within 72 hours of the commencement of antibiotics. Range of SOFA is 0 to 3, 3 being the worse. For the purposes of the study suspected or documented infection will be defined as the commencement of intravenous antibiotics. The rise in SOFA score will be assessed within 72 hours of the commencement of antibiotics. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Peak lactate | Peak lactate within 24 hours of surgery and time to resolution of hyperlactataemia (arterial serum lactate >2.5 mmol/L) post peak. | Within 24 hours of surgery | 
| Clinical events: Acute Lung Injury | Measurement of PaO2/FiO2 ratio and expressed in kPa/L. | Baseline, immediately pre-surgery, 0-6, 6-12, 24, 48, 72 and 96 hours post-operatively | 
| Clinical events: Low cardiac output | Low cardiac output, defined as new intra-or postoperative intra-aortic balloon pump insertion or a cardiac index of <2.2 L/min/ m2 refractory to appropriate intravascular volume expansion after correction or attempted correction of any dysrhythmias, or the administration of the inotropes Dobutamine, Enoximone, Milrinone or Levosimendan. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Stroke | Stroke; diagnosed by brain imaging (CT or MRI), in association with new onset focal or generalized neurological deficit (defined as deficit in motor, sensory or co-ordination functions) | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Acute Liver Injury - AST (Aspartate Transaminase) | Acute liver injury will be defined as an acute derangement of liver enzymes three times the upper limit of normal, or a serum amylase concentration >1000 ng/m. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Acute Liver Injury - ALT (Alanine Transaminase) | Acute liver injury will be defined as an acute derangement of liver enzymes three times the upper limit of normal, or a serum amylase concentration >1000 ng/m. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Acute Liver Injury - Bilirubin | Acute liver injury will be defined as an acute derangement of liver enzymes three times the upper limit of normal, or a serum amylase concentration >1000 ng/m. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Acute Liver Injury - Alkaline Phosphatase | Acute liver injury will be defined as an acute derangement of liver enzymes three times the upper limit of normal, or a serum amylase concentration >1000 ng/m. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Acute Liver Injury - Serum Amylase | Acute liver injury will be defined as an acute derangement of liver enzymes three times the upper limit of normal, or a serum amylase concentration >1000 ng/m. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Acute Intestinal Injury | Acute intestinal injury will be defined a radiological, operative or post-mortem evidence of gut ischaemia. | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| Clinical events: Rate of mortality | Rate of mortality at 30-days and 1 year from the date of surgery | Within 30-days from surgery and at 1 year from surgery | 
| Clinical events: A composite endpoint Organ Injury, Mortality and Sepsis | As above for description of organ injury, mortality and sepsis | Time (days) measured from the start of surgery to discharge from hospital (up to 90 days) | 
| 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 will be recorded | Blood loss at 6 hours post-operatively | 
| Mechanism study: Mitochondrial 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. | At time of surgery | 
| Mechanism study: microRNA isolation of microvessels from tissue biopsies | The findings will be represented by the frequency (%) of identified microRNA. 50-100 mg biopsies obtained from pedicled left internal mammary artery biopsies. | 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. | At time of surgery | 
| Mechanism study: Mitochondrial 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. | At time of surgery | 
| Mechanism study: microRNA isolation in 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 microRNA. | 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. | At time of surgery | 
| Mechanism study: Mitochondrial 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. | 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 microRNA. | 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. | 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. | Baseline,1 day before surgery, 6-12, 24 and 48 hours post-operatively. | 
| Mechanism study: Measurement of microRNA in urine samples | The findings will be represented by the frequency (%) of identified microRNA. | Baseline,1 day before surgery, 6-12, 24 and 48 hours post-operatively. | 
| Mechanism study: Measurement of histone acetylation in urine samples | The findings will be reported as acetylated H3 (ug/mg) over time (hours) | Baseline,1 day before surgery, 6-12, 24 and 48 hours post-operatively. | 
| 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. | Baseline,1 day before surgery, 6-12, 24 and 48 hours post-operatively. |