Abstract
Among the interesting articles in Perfusion this month is a review of the effect of adenosine on the myocardial inflammatory response to ischaemia and reperfusion. 1 It investigates this effect as a possible contributory factor in the purported benefits of adenosine-containing cardioplegia.
Cardioplegia is a divisive issue among cardiac surgeons; some avoiding it whenever possible, some developing new solutions in an attempt to overcome its perceived adverse effects, but most happy to use the currently available solutions routinely. It has a slightly controversial history. Melrose and Bentall’s team at the Royal Postgraduate Medical School are usually credited with developing a clinically usable potassium-rich solution to arrest the heart in the 1950s and the use of ‘high-potassium’ cardioplegia became widespread over the following years. It was designed to provide good surgical conditions rather than to protect the heart, causing a depolarising cardiac arrest by increasing the extracellular potassium concentration. Towards the end of that decade, enough concerns about the safety of the technique - mainly resistant ventricular fibrillation and myocardial necrosis - had been raised that its use was abandoned. Cardiac surgery continued using techniques such as aortic occlusion with or without direct coronary perfusion or hypothermic cardiac arrest induced by topical cooling. These remained the preferred practice into the 1970s. 2
Meanwhile, the investigation of chemical cardioplegia continued, especially in Europe. The first high-potassium cardioplegic solutions had been based on potassium chloride. Melrose had thought that the excess chloride was responsible for the resistant ventricular fibrillation and used potassium citrate as the basis for his solutions, but research showed that the citrate ion was reducing available calcium and magnesium. Various solutions composed of potassium and magnesium chlorides, procaine (as a membrane stabiliser), mannitiol (to reduce oedema) culminated in the development of the St Thomas’ Hospital solution in the UK and Gay and Ebert’s solution in the USA; both were high-potassium solutions, but had normal osmolarity, in contrast to the hyperosmolar Melrose solution. By the end of the 1970s, high-potassium cardioplegia was used by the vast majority of cardiac surgeons. Although there have been modifications of cardioplegic techniques (retrograde and/or continuous cardioplegia), the only real change in the solution used has been in the widespread adoption of blood as a vehicle for the high-potassium cardioplegia.
That is not to say that the high-potassium technique was universally accepted. Research continued and high-potassium solutions were blamed for vasoconstriction, endothelial injury, platelet aggregation, ventricular dysfunction and dysrhythmias. It is not surprising that alternative cardioplegic solutions have been sought. Drugs that open the ATP-associated potassium channels or block calcium have been included in solutions, but these have been in addition to rather than as a replacement for the potassium content. Some drugs have been evaluated as non-depolarising alternatives to high-potassium solutions. Bretschneider developed a hyponatraemic, hyperkalaemic solution, containing histidine, tryptophan, ketoglutarate, magnesium and mannitiol. This hyperpolarising cardioplegia has become popular in paediatric surgery under the tradename Custodiol. 3
Adenosine, which causes a hyperpolarising cardiac arrest, has also been investigated in several clinical trials. When added to high-potassium cardioplegia, it was found safe, but with no obvious clinical benefit.4-7 Two small trials8,9 comparing adenosine with high-potassium blood cardioplegia showed the adenosine solution to be clinically satisfactory, but not obviously better than the conventional cardioplegia, except that it was associated with a reduced incidence of post-operative atrial fibrillation in one of the trials. 9
Laboratory investigation has found that the combination of lidocaine and adenosine is more protective than either alone, with optimum benefit at normokalaemia. 10 In a canine model of cardiopulmonary bypass, haemodynamic recovery from an hour of ischaemia with adenosine-lidocaine cardioplegia was at least as good as after high-potassium cardioplegia. 11 So far, this has only been used clinically in hyperkalaemic mixtures. In a randomised clinical trial of 80 adult patients published in 2012, a high-potassium cardioplegia with adenosine, lidocaine, magnesium and insulin was superior to the standard practice of high-potassium blood cardioplegia, in the sense of better post-bypass cardiac output, reduced troponin release, less blood and blood product use and shorter length of hospital stay. 12 In another randomised study involving 134 paediatric patients, a cardioplegic solution containing adenosine with moderate hyperkalemia was associated with reduced post-operative serum troponin concentrations compared to high-potassium solutions with or without adenosine. 13 In spite of these reports, it has not caught on and other clinical experience is very limited. 14
Why has a technique supported by good laboratory evidence and which has been shown to protect human hearts better than conventional therapy not been adopted more widely? Most surgeons do not see enough of a clinical problem with current cardioplegia to warrant any change to a working, widely-accepted system. The job is stressful enough as it is and who wants to go out on a limb with a new technique? The review by Boros et al. 1 brings together evidence that may make some surgeons wonder whether adenosine cardioplegia could prevent the unexpectedly dysfunctional heart seen after, say, two in a hundred bypasses. It will take a lot more clinical experience to convince them that none of the other 98 would be worse off.