Multimodal cardioprotective strategy in cardiac surgery (the ProCCard trial): Study protocol for a multicenter randomized controlled trial

Cardiac surgery with cardiopulmonary bypass (CPB) induces, consecutive to aortic clamping–unclamping, myocardial damage related to ischemia-reperfusion. The most common myocardial protection technique involves administration of a cardioplegic solute into the coronary arteries. Nevertheless, elevated postoperative cardiac troponin release remains a marker of poor prognosis after cardiac surgery [1, 2]. Many studies have, therefore, attempted to reduce myocardial ischemia-reperfusion injuries during CPB.

The protective effect of ischemic preconditioning was first described in 1986 by Murry et al. [3]. This process involves applying transient brief episodes of ischemia before subsequently sustained ischemia to render the myocardium more resistant to an ischemic insult. More recently, similar interventions applied at the onset of reperfusion, a process named postconditioning by analogy with preconditioning, have been described [4]. Since these first publications, a very large number of experimental studies have been carried out to characterize these phenomena and to understand their mechanisms. In a second stage, several clinical studies have attempted to reproduce these results in humans, with rather mixed results [5]. Most studies have been done in patients undergoing CPB. However, these specific clinical conditions, such as the major inflammatory processes induced by the heart–lung machine, the influence of the anesthetic agents, or the specificity of each cardiac surgical procedure, may complicate the interpretation of the results of such studies. Moreover, all the clinical studies that have been done to date have tested a single factor of myocardial protection, such as the administration of cyclosporine, the beneficial effects of anesthesia by means of halogenated volatile anesthetics, or the effect of remote ischemic preconditioning (RIPC) [6‐8]. The biological effect of a single cardioprotective procedure might not be strong enough for translation into heterogeneous routine clinical situations, conversely to standardized experimental models.

The combination of multiple cardioprotective procedures offers the potential for increasing the biological and clinical effects of cardioprotection. Experimental work has found a synergistic effect of cardioprotection. However, no clinical study has sought to combine the beneficial effects of several techniques of cardioprotection in patients undergoing heart surgery with CPB [9, 10].

The present study evaluates the effect of a bundle of care combining several cardioprotective techniques during cardiac surgery. We seek to evaluate the effect and feasibility of adding different simple and patient-safe procedures compared to standard of care to reduce myocardial damage in patients undergoing CPB.

Cardioprotective strategies of preconditioning and postconditioning during cardiac surgery with CPB have shown very promising and consistent results in experimental models and small clinical studies. In larger groups of patients in randomized studies, however, these cardioprotective strategies have failed to show any significant clinical benefit [3‐5]. Experimental studies clearly demonstrated the benefit of halogenated volatile anesthetics before ischemia (halogen-induced preconditioning) and at the onset of reperfusion (halogen-induced postconditioning) [9, 14]. De Hert et al. [7] showed in patients undergoing coronary artery surgery the cardioprotective effects of sevoflurane when administered throughout the operation. Unfortunately, we and others did not find such a protective effect of halogenated volatile anesthetics in other clinical studies [15, 16]. RIPC is another example of this recurring problem. Initially, Hausenloy et al. [8] demonstrated that RIPC reduced serum troponin T release in patients undergoing coronary artery bypass graft surgery. Similarly, Zarbock et al. [17] reduced the rate of perioperative acute kidney injury by applying RIPC in patients undergoing cardiac surgery. Unfortunately, ERICCA and RIPHeart, two large-scale multicenter trials, did not confirm the previous results [18, 19].

These results of disappointing clinical studies raise questions because most of the experimental works in standardized models are positive. In addition, the human myocardium, under experimental conditions, is just as sensitive to preconditioning as other species [20]. Nevertheless, it must be kept in mind that clinical conditions, especially during cardiac surgery, are very different from experimental studies. In a clinical setting, many confounders can affect the efficacy of cardioprotective strategies. Many surgical procedures are performed in older patients and the protective effects of conditioning decline with age [21]. The preoperative drug treatments prescribed to patients can also interfere with the cellular mechanisms of conditioning. The major inflammatory response to CPB is another source of confusion [22]. Finally, postoperative serum troponin release, which is often the primary outcome of the clinical studies, is also related to the type of cardiac procedure [23].

On the other hand, clinical studies have focused on only one conditioning factor, such as the effect of cyclosporine administration, the potential beneficial effect of halogenated volatile anesthetics, or the protective effect of RIPC. However, experimental studies have highlighted that a synergy exists between the different conditioning triggers. We previously demonstrated that the combination of a concentration of halogenated volatile anesthetics that did not produce cardioprotection alone was able to reduce the time threshold required for ischemic postconditioning [9]. There is also a link between hyperglycemia, a phenomenon commonly encountered during cardiac surgery, and the preconditioning effect of halogenated volatile anesthetics [24, 25]. Beneficial effects of simvastatin, when added to ischemic preconditioning, restored cardioprotection even in hyperglycemic animals [10]. So, it seemed important to carry out a study evaluating the interest of combining several cardioprotective factors in order to develop an intraoperative cardioprotective strategy.

The biological effect of a single cardioprotective procedure might not be strong enough for translation into heterogeneous routine clinical situations compared to standardized experimental models. The combination of multiple cardioprotective procedures offers the potential for increasing the biological and clinical effects of cardioprotection.

All the cardioprotective procedures we are combining in this protocol were chosen carefully. The purpose was to combine easily applicable procedures with potential synergistic effects. As mentioned by previous studies, the beneficial effect of RIPC is potentially amplified during halogenated anesthesia. Kottenberg et al. [26] conducted a study during coronary artery bypass graft surgery. Three cycles of 5 min upper arm ischemia/5 min reperfusion decreased the troponin AUC by 50% during isoflurane anesthesia but had no effect under propofol anesthesia. The same results were confirmed later in a larger study [27]. We therefore decided that patients in the “treated group” would be anesthetized with sevoflurane and would also benefit from a RIPC protocol. In parallel, the frequency of perioperative dysglycemia is underestimated in cardiac surgery and its impact on postoperative morbidity and mortality is unquestionable [24]. Because hyperglycemia can impair the myocardial tolerance to ischemia-reperfusion and knowing that insulin is cardioprotective, we included these parameters in the bundle of care of the ProCCard study, in conjunction with RIPC and sevoflurane [28]. Based on the study of Duncan et al. [29], we chose to keep the intraoperative blood glucose threshold at 8 mmol/l in order to avoid any hypoglycemia. Our objective was to control the patient’s glycemia, rather than to conduct a hyperinsulinemic management protocol, as recently proposed [30]. The moment of reperfusion, which corresponds to the aortic unclamping, is also a double-edged sword. Temporary acidosis at the time of reperfusion can limit infarct size by delaying the opening of the mitochondrial permeability transition pore [11]. We have therefore ensured that the pH level is in the low range of clinically acceptable values to limit the “pH paradox” phenomenon [12, 31]. The final procedure in this bundle of care is a gentle reperfusion protocol. Controlled reperfusion after an ischemic period protects the myocardium, probably by the activation of the phosphatidylinositol 3-kinase–Akt pathway [32]. We therefore decided to limit reperfusion injuries by a gradual restoration of the theoretical CPB flow over 2 min.

In conclusion, the ProCCard study will be the first multicenter randomized controlled trial aiming to assess the role of a bundle of care combining several cardioprotective procedures to reduce myocardial damage in patients undergoing CPB.

The ProCCard trial is currently recruiting patients (protocol version 3, September 3, 2018). The first patient was included on January 3, 2018. The expected inclusion period is 24 months. Recruitment will be completed approximately at the end of 2019.