Two recent large clinical outcome studies investigating the role of remote ischaemic preconditioning in cardiac surgery have been contemporaneously published in the New England Journal of Medicine. Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart) [
54] and Effect of Remote Ischaemic Preconditioning on Clinical Outcomes in CABG Surgery (ERICCA) [
27]. Both of these studies sought to determine the efficacy of remote ischaemic conditioning (four cycles of 5 min upper limb ischaemia wrought by inflation of a blood pressure cuff to 200 mmHg and 5 min reperfusion with cuff deflation) in patients undergoing open-heart surgery and on-pump cardio-pulmonary bypass. With broadly similar primary end-points of death (any cause in RIPHeart, cardiovascular in ERICCA), rates of non-fatal MI and cerebrovascular accident, neither study was able to demonstrate a positive outcome for these measures. Curiously, in contrast to earlier clinical CABG trials, even differences in troponin release were not significantly different between control and active treatment groups. The reasons for the inability of these trials to reproduce the clear efficacy of basic and earlier, smaller clinical trials are unclear. One potential explanation may be an interval improvement in surgical and anaesthetic management protocols that has led to improved cardiovascular morbidity and mortality outcomes that has been observed over the last three decades [
60,
66]. Indeed, recent innovations in surgical myocardial preservation techniques, such as combined antegrade and retrograde myocardial perfusion during bypass, are associated with smaller peri-operative myocardial injury [
12]. Thus speculatively, optimisation of surgical and anaesthetic techniques may have led to a progressively smaller peri-procedural myocardial injury in patients undergoing CABG and valve surgery in recent years. With smaller peri-procedural injury, a type 1 statistical error is the likely consequence for studies in which power calculations are based on historical measures of myocardial injury and complications. Reduction of peri-procedural injury represents a genuine success for current surgical, anaesthetic and medical management strategies for the benefit of patients, but it also presents a diminishing target for additional benefit from conditioning-type cardioprotective interventions.
The converse argument is that current anaesthetic practice may be interfering with the cardioprotective mechanisms triggered by interventions such as remote ischaemic conditioning. Support for such a hypothesis can be found in comparable troponin release profiles in studies published over the last decade. Early, proof of concept trials consistently demonstrate an approximate 30 % reduction in the area under the troponin release profile curve over 48–72 h—with Troponin-T (TnT) peaks at 6–12 h consistently in the range of 700 ng/L in control patients. Interestingly, control patients in both RIPHeart and ERICCA have comparable TnT release profiles to these historical trials, but in contrast to the earlier studies, remote ischaemic preconditioning had lost its efficacy in reducing the release of this biomarker (ERICCA had a 10 % lower total troponin T release in patients who received remote ischemic preconditioning, an effect that was lost following multiple imputation analysis for missing data points). It has been argued that anaesthetic agents such as propofol may interfere with the canonical conditioning pathway [
44] and more than 90 % of patients in ERICCA and all by protocol in RIPHeart, received propofol in preference to volatile anaesthesia. While the role of propofol is contentious (potentially cardioprotective in some settings, but largely neutral in CABG [
62]) and biomarker release is not a clinical outcome, it may be relevant that absence of attenuation of troponin release by RIPC occurred in the two studies that did not demonstrate an outcome benefit, implicating a loss of biological effect [
34]. Therefore, despite the neutral outcomes of RIPHeart and ERICCA, important questions remain unanswered in the context of cardiac surgery and the optimal anaesthetic management in the pre-, peri- and post-operative phases. Moreover, various peri-operative anaesthetic management strategies, from propofol anaesthesia to the administration of nitric oxide donors [e.g., intravenous glyceryl tri-nitrate (GTN) [
42]; currently prospectively investigated in the ERIC-GTN trial [
26]], require systematic careful investigation. In the presence of a cocktail of anaesthetic agents that may both inhibit canonical conditioning and are themselves cardioprotective, it is perhaps unsurprising that the demonstration of additional protection has become extremely difficult and perhaps also unnecessary. Moreover, there are concerns regarding both the nature of peri-procedural myocardial injury (i.e., how much is due to ischaemia/reperfusion injury versus direct mechanical tissue injury and perioperative inflammation) and the relevance of the relatively small release of troponin seen following cardiac surgery to clinical outcome has consequently cast doubt on the relevance of modern cardiac surgery as a model in which to test cardioprotective strategies, although the impact of conditioning strategies upon other post-surgical endpoints such as quality of life [
22] has yet to be fully evaluated. The group considered that conditions that lead to greater myocardial injury (for example, acute ST-elevation myocardial infarction) would represent a better target for clinical study, with the potential for greater response to cardioprotective strategies in which to demonstrate efficacy.
Therefore, while further investigations into the myocardial benefit of remote ischaemic conditioning in cardiac surgery are not a high priority, it was felt by the group that close scrutiny and a more structured investigation into the optimal anaesthetic management of CABG patients is certainly warranted.