Coronary heart disease (CHD) causes about 103 000 myocardial infarctions per year and it is the most common cause of death in the UK with around 80 000 people dying from CHD in 2010 (www.bhf.org.uk). The overall economic cost of CHD in the UK is estimated to be about £7 billion a year, with 27% due to direct healthcare costs, 47% to productivity losses, and 26% to the informal care of people with CHD. Coronary artery bypass graft (CABG) surgery is indicated in patients with severe CHD. About 17 000 of these CABG procedures were performed in the UK in 2011. In addition, about 10 500 cardiac valve procedures were performed in 2011 and the overall mortality rate after open-heart surgery was about 3% (http://bluebook.scts.org). Owing to the ageing population, more patients undergoing CABG, valve surgery, or both present with comorbidities, such as diabetes, hypertension, and more complex CHD.1 This leads to a higher risk of postoperative myocardial injury,2 renal injury,3 stroke,4 and delirium,5 which are all associated with increased mortality or diminished quality of life.
Therefore, optimization of cardiac, renal, and cerebral protection during cardiac surgery will be beneficial, especially for those patients at greater risk.
In cardiac anaesthesia, potentially reversible myocardial injury caused by ischaemia–reperfusion injury can be limited by pre-conditioning.6 Interestingly, volatile anaesthetics have the potential to protect the myocardium by anaesthetic preconditioning,7 and in addition have the potential to provide renal and cerebral protection.8,9
However, so far, despite a myriad of proof-of-concept trials and many meta-analyses, there is no evidence suggesting that volatile anaesthetics are beneficial with regard to clinical outcome in cardiac anaesthesia, when compared with i.v. anaesthetics: two meta-analyses tell us they are,10,11 and two suggest they are not.12,13 Consequently, there is currently a high variability in anaesthetic techniques in cardiac surgery, including total i.v. anaesthesia, volatile anaesthetics only, or a mixture of both.
How do volatile anaesthetics protect the myocardium, the kidneys, and the brain?
Myocardial protection from acute ischaemic injury by volatile anaesthetics was first described with halothane in the 1970s in dogs.14 In the 1980s, evidence of the potential protection by volatile anaesthetics from myocardial ischaemia was obscured by experimental findings that volatile anaesthetics cause ‘coronary steal’ and thus ischaemia by vasodilation, resulting in reduced myocardial blood flow in the ischaemic myocardium.15–18 The proposed ‘coronary steal’ phenomenon was refuted only in the 1990s,19–21 and myocardial protection by preconditioning confirmed experimentally for the first time in 1997.22–24
Volatile anaesthetics protect the myocardium by several plausible mechanisms: e.g. by delaying the opening of the mitochondrial permeability transition pore (mPTP),25 stimulating the opening of mitochondrial ATP-sensitive potassium (KATP) channels,24 alteration of G protein-coupled receptor activity and cellular kinase signalling, and by regulating reactive oxygen species production.7 It has also been demonstrated recently that volatile anaesthetics provide endothelial protection by preventing tumour necrosis factor (TNF)-α-induced adhesion molecule expression.26,27 In addition to protection of the myocardium, experimental studies have demonstrated that volatile anaesthetics provide renal and cerebral protection from ischaemia–reperfusion injury8,9 and this has also been shown in patients undergoing cardiac surgery.28,29
In summary, based on experimental evidence, there are proof-of-concept studies demonstrating potential cardiac, renal, and cerebral protection, but so far there has been no large-scale clinical trial investigating the clinical outcome of the potentially protective effects.
Volatile anaesthetic preconditioning: how do we assess clinical outcome?
Commonly, clinical outcome can only be studied meaningfully in large multicentre trials.30,31 Clinical outcome in cardiac surgery is often assessed in clinical trials by looking at the incidence of major adverse cerebral and cardiovascular (CV) events and death (MACCE, CV death, myocardial infarction, revascularization, stroke), which has an incidence of about 12–20%.32,33
The size of the reduction in negative clinical outcomes by an intervention (effect size) in cardiac surgical trials is usually between 27% and 30%.32,34–36 Clinical effects of anaesthetic preconditioning may be slightly higher, with meta-analyses reporting volatile anaesthetic-induced reductions in mortality by 50% (from 2.6% to 1.3%),11 reductions in myocardial infarction by 47%, reduced use of postoperative inotropes by 69%,10 and the reduction in biomarker-derived infarct size by 36.6%.12
A well-designed multicentre trial based on experimental evidence investigating clinical outcome is the quintessence in translational research. A pragmatic clinical trial addressing relevant perioperative clinical outcome questions needs to include a multiprofessional team with experienced clinical trial managers, apart from statisticians and clinicians. UK funding bodies, such as the National Institute for Health Research (NIHR), are eager to fund pragmatic and feasible trials assessing clinical outcome based on preliminary evidence.
Therefore, the time appears to be right to go ahead not only with a pragmatic large-scale clinical multicentre trial investigating anaesthetic preconditioning and clinical outcome, but also with other relevant clinical outcome-related hypotheses in anaesthesia and perioperative medicine.
Declaration of interest