Coronary heart disease (CHD) is the leading cause of death in the UK, accounting for 124,000 deaths in 2006 ( CHD is estimated to cost the UK economy over £7.9 billion a year, of which 45% is due to direct health care costs (the cost of hospital care and drugs), and 40% attributed to productivity losses (due to CHD mortality and morbidity), and 15% due to the informal care of such patients ( As such, improving health outcomes in patients with CHD is a major priority of the NHS as outlined in the National Service Framework for Coronary Heart Disease and embodied in several clinical guidelines and technology appraisals issued by NICE.

Coronary Artery Bypass Graft (CABG) surgery remains the procedure of choice for coronary artery revascularisation in a large number of CHD patients particularly in patients with triple vessel coronary artery disease as highlighted in the recently published SYNTAX study, which demonstrated that CABG surgery is superior to percutaneous coronary intervention (PCI) in this patient group. About 20,000 first time CABG operations are performed in the UK each year with an overall operative mortality risk of about 1.0% for elective CABG surgery (The Society of Cardiothoracic Surgeons of Great Britain and Ireland National Adult Cardiac Surgical Database Report 2003). Innovative treatment strategies are required to reduce myocardial injury and improve clinical outcomes in patients undergoing CABG surgery, and in this regard, one potential approach is remote ischaemic preconditioning.

Remote ischaemic preconditioning

Remote ischaemic preconditioning (RIC) describes a phenomenon in which the application of brief episodes of non-lethal ischaemia and reperfusion to an organ (such as the kidney, liver or small intestine) or tissue (such as skeletal muscle) protects the heart against a sustained episode of lethal ischaemia-reperfusion injury (IRI). The discovery that the RIC stimulus could be reproduced by applying brief episodes of ischaemia and reperfusion to the upper or lower limb, has facilitated its recent translation from animal studies into the clinical arena.

MacAllister and co-workers first demonstrated the concept of RIC in human volunteers using a non-invasive RIC stimulus, comprising inflating a blood pressure cuff applied to the upper arm to 200 mmHg for 5 minutes (to induce brief ischaemia) and deflating the cuff for 5 minutes (to induce brief reperfusion); a cycle which was repeated two more times. This RIC stimulus attenuated ischaemia-induced endothelial dysfunction in the contralateral arm arising from a 20 minute episode of sustained cuff inflation. Cheung and co-workers were the first to apply this RIC protocol in the clinical arena, in a study in which four-5 minute cycles of lower limb ischaemia and reperfusion reduced myocardial injury, improved airway resistance and decreased inotrope score in children undergoing cardiac surgery. Recently, we demonstrated that three-5 minute cycles of upper limb ischemia and reperfusion reduced myocardial injury (43% reduction in serum troponin-T released over 72 hours) in adult patients undergoing elective coronary artery bypass graft plus or minus valve (CABG with or without valve) surgery. This last proof-of-concept clinical study forms the pilot data for the current research proposal.

Most recently, RIC using lower limb ischaemia and reperfusion has also been reported to be beneficial in terms of cardiac, renal and neurological protection in the setting of elective surgery for abdominal aortic aneurysm (AAA), and surgery for cervical decompression. Ali and colleagues demonstrated that invasive lower limb ischemia using two-10 minute episodes of iliac artery occlusion reduced myocardial injury (as indicated by a 27% reduction in serum

troponin-I) and preserved renal function during elective AAA surgical repair. Hoole and co-workers have recently reported that RIC using brief ischaemia and reperfusion of the arm reduced the peri-procedural myocardial injury associated with elective PCI for stable coronary artery disease (CAD). Finally, Botker and co-workers have recently demonstrated that the RIC using four-5 minute cuff inflations/deflations administered in the ambulance reduced myocardial infarct size in ST-elevation myocardial infarction patients undergoing primary PCI. In the current research protocol, we will be using this particular RIC protocol i.e. four 5 minute cycles of cuff inflation and deflation.

Therefore, although several proof-of-concept studies have been published, whether RIC can impact on clinical outcomes and improve patient healthcare in higher-risk patients undergoing CABG with or without valve surgery is unknown and is the subject of the current research study.


The intervention being assessed is RIC, which refers to the phenomenon in which brief non-lethal episodes of ischaemia and reperfusion in an organ or tissue are able to protect the heart, kidney and brain against a subsequent lethal episode of ischaemia-reperfusion injury).

RIC, which will be applied after anaesthesia induction, comprises the inflation of a standard blood pressure cuff, or any other CE approved equipment which becomes available, applied to the upper arm to 200mmHg for 5 minutes and then deflating it for 5 minutes, a cycle which will be repeated 4 times in total. For patients with systolic blood pressures >185mmHg, the cuff will be inflated to at least 15mmHg above the patient’s systolic blood pressure.

The sham RIC (control group), which will be applied after anaesthesia induction, will also use a standard blood pressure cuff, or any other CE approved equipment which becomes available. The sham RIC protocol is described as follows: The air valve on the blood pressure cuff is first opened such that the cuff is not inflated on squeezing the attached bulb. The bulb will then be squeezed for a duration of 15 seconds to give the impression that the cuff is being inflated. After 5 minutes the air valve will be closed to give the impression that the cuff in being deflated. After 5 minutes, the air valve will be opened again and the bulb squeezed as before, a cycle which will be repeated 4 times in total. These interventions will be undertaken after the induction of anaesthesia and will not prolong the anaesthetic time or delay the onset of surgery.

There are unlikely to be any problems with compliance given that the non-invasive RIC intervention is applied after anaesthesia induction, and is a single intervention administered at one time-point.

Primary objective

To determine the effect of RIC on Major Adverse Cardiac and Cerebral Events (MACCE) 12

months after cardiac surgery. MACCE include cardiovascular (CV) death, myocardial infarction,

revascularisation, and stroke.

Secondary objectives

To determine the effects of RIC on: 1. 30 day MACCE 2. All cause death 3. Peri-operative myocardial injury (Troponin T in the first 72 hours post-surgery) 4. Peri-operative renal injury (creatinine and 24 hours serum Neutrophil Gelatinase Associated Lipocalin (NGAL)) post-surgery

5. Length of Intensive Therapy Unit (ITU) stay

6. Inotrope score

7. Hospital stay

8. 6 minute walk test

9. Quality of life

10. Echo Substudy: Left ventricular ejection fraction

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