Investigation Into the Role of GTN & RIPC in Cardiac Surgery

Study Overview
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Brief Summary
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The purpose of this study is to determine whether Glyceryl Trinitrate (GTN) reduces injury to the heart during heart-lung bypass surgery in combination with the newer technique of remote ischaemic preconditioning (RIPC).

Detailed Description
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Ischaemic heart disease is a leading cause of mortality in the western world. A number of patients undergo coronary artery bypass graft (CABG) surgery as treatment for ischaemic heart disease. With the rise of interventional procedures, patients who are coming to have CABG surgery are higher risk1. Remote ischaemic preconditioning (RIPC) has been shown to reduce perioperative myocardial injury (PMI) in patients having CABG even when cold blood cardioplegia or intermittent cross clamp fibrillation is used as cardioprotective measures. These patients have a general anaesthetic with multiple infusions including Glyceryl Trinitrate (GTN). The use of GTN in these patients is based on theoretical assumptions of coronary vasodilation pre operatively along with maintaining graft potency postoperatively. We intend to investigate the effect of GTN in patients undergoing cardiac surgery being subjected to RIPC in its role as a Nitric Oxide (NO) donor. Exogenous NO has been shown to be cardioprotective in animal models.

Official Title
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The Effect of Remote Ischaemic Preconditioning and Glyceryl Trinitrate on Peri-operative Myocardial Injury in Cardiac Bypass Surgery Patients (ERIC-GTN Study)

Conditions
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Myocardial Reperfusion Injury

Intervention / Treatment
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* Other: Remote ischaemic preconditioning
* Drug: IV Normal saline
* Drug: IV Glyceryl trinitrate 2-5ml/h


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years all patients admitted for on- pump CABG and/or valve surgery Able to give consent Exclusion Criteria: Allergies to excipients of IMP and placebo Chronic Renal failure (eGFR<30 ml/min/kg) Severe liver disease Peripheral arterial disease Pregnant or lactating women

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Group 1 Control (65 patients)<br>Sham Remote ischaemic preconditioning with IV normal saline 2-5ml/hour. | Drug: IV Normal saline<br>* Normal saline IV started prior to knife to skin at a rate of 2-5 mls/h and stopped just after weaning off bypass.<br>|
| Active Comparator: Group 2 (65 patients)<br>Patients administered a Remote Ischaemic preconditioning protocol (three-5 min cycles of simultaneous inflation to cuffs placed on upper arm and thigh) prior to surgery and IV normal saline 2-5 mL/h during surgery. | Other: Remote ischaemic preconditioning<br>* 3 cycles of 5 minutes to arm and legs<br>Drug: IV Normal saline<br>* Normal saline IV started prior to knife to skin at a rate of 2-5 mls/h and stopped just after weaning off bypass.<br>|
| Experimental: Group 3 GTN (65 patients):<br>Patients administered sham simulated Remote Ischaemic Preconditioning protocol prior to surgery and IV Glyceryl Trinitrate 2-5ml/h during surgery. | Drug: IV Glyceryl trinitrate 2-5ml/h<br>* IV GTN given during surgery started prior to knife to skin and stopped after weaning off cardiopulmonary bypass.<br>|
| Experimental: • Group 4 RIPC+GTN (65 patients):<br>Patients administered Remote Ischaemic Preconditioning protocol and IV Glyceryl Trinitrate during surgery | Other: Remote ischaemic preconditioning<br>* 3 cycles of 5 minutes to arm and legs<br>Drug: IV Glyceryl trinitrate 2-5ml/h<br>* IV GTN given during surgery started prior to knife to skin and stopped after weaning off cardiopulmonary bypass.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Troponin T area under the curve | Troponin T area under the curve will be calculated using blood samples collected at 0,6,12,24,48 and 72 hours plotting it against time to calculated AUC. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inotrope/Vasopressor requirements peri-operatively | The inotrope score will be calculated as follows: Dosages (in μg/kg/min) of [Dopamine + Dobutamine] + [(Adrenaline + Noradrenaline + Isoproterenol + Isoproterenol) x 100] + [(Enoximone + Milrinone) x 15] | Post-operative day 1,2,3 and 4 | 
| Ventilator dependence post operatively | The duration of endotracheal intubation will be noted in hours. Re-intubation rates will be calculated by noting down the number of patients requiring re-intubation and comparing this amongst the 4 groups. | Post-operative day 1,2,3 and 4 | 
| Incidence of Acute Kidney Injury assessed using biomarkers | Serum creatinine levels will be noted in the first 3 days postoperatively. If a patient requires renal replacement therapy, this will be recorded and comparisons made amongst the groups. Hourly urine output and daily urine volumes for the duration of ITU stay will be recorded. | Post-operative day 1,2,3 and 4 | 
| Length of ITU stay | A record of stay in days will be noted | Average 4 days | 
| Length of hospital stay | Duration of hospital stay will be recorded in days | Average 14 days | 
| Incidence of post-operative atrial fibrillation | Atrial fibrillation will be diagnosed using ECG. A record of the number of patients developing AF post operatively, the intervention used to treat it and whether or not the patient reverted to sinus rhythm prior to ITU discharge will be documented | Post-operative day 1,2,3 and 4 |