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.
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: 1. 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'. 2. The effects of the trial intervention will not be attributable to changes in frailty, activity or baseline organ dysfunction. 3. The trial intervention will not result in long-term adverse changes in cardiometabolic status. 4. Metabolic preconditioning will confer protection against post-cardiac surgery kidney injury by increasing the expression of genes that promote renal tubular homeostasis. 5. 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. 6. Metabolic preconditioning will confer protection against post-cardiac surgery endothelial dysfunction by increasing the expression of genes that promote endothelial homeostasis.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
116
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.
University of Leicester
Leicester, Leicestershire, United Kingdom
RECRUITINGChange of Serum Creatinine level
Measurement of Serum Creatinine level and expressed as umol/L.
Time frame: 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.
Time frame: Baseline, 0-6, 6-12, 24, 48 and 72 hours post-operatively
Post-surgery organ injury: Sepsis-related Organ Failure
Sepsis-related Organ Failure Assessment (SOFA) Score. Range 0-3, 3 being the worse score
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: Daily for 5 days from Baseline
Post-surgery organ injury: Kidney Injury
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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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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 frame: 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 frame: 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 frame: 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 frame: 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.
Time frame: Within 24 hours of surgery
Clinical events: Acute Lung Injury
Measurement of PaO2/FiO2 ratio and expressed in kPa/L.
Time frame: 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 frame: 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 frame: 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 frame: 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 frame: 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 frame: 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 frame: 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 frame: 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 frame: 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
Time frame: 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 frame: 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
Time frame: 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.
Time frame: 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.
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: 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.
Time frame: 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.
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: 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.
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 microRNA.
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: 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.
Time frame: 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)
Time frame: 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.
Time frame: Baseline,1 day before surgery, 6-12, 24 and 48 hours post-operatively.