A randomized trial of remote ischemic preconditioning and control treatment for cardioprotection in sevoflurane-anesthetized CABG patients

Rianne Nederlof, Nina C. Weber, Nicole P. Juffermans, Bas A. M. J. de Mol, Markus W. Hollmann, Benedikt Preckel, Coert J. Zuurbier

Remote ischemic preconditioning (RIPC) efficacy is debated. Possibly, because propofol, which has a RIPC-inhibiting action, is used in most RIPC trials. It has been suggested that clinical efficacy is, however, present with volatile anesthesia in the absence of propofol, although this is based on one phase 1 trial only. Therefore, in the present study we further explore the relation between RIPC and cardioprotection with perioperative anesthesia restricted to sevoflurane and fentanyl, in CABG patients without concomitant procedures. In a single-center study, we aimed to randomize 46 patients to either RIPC (3x5 min inflation of a blood pressure cuff around the arm) or control treatment (deflated cuff around the arm). Blood samples were obtained before and after RIPC to evaluate potential RIPC-induced mediators (Interleukin (IL)-6, IL-10, Tumor Necrosis Factor-α, Macrophage Inhibitory Factor). An atrial tissue sample was obtained at cannulation of the appendix of the right atrium for determination of mitochondrial bound hexokinase II (mtHKII) and other survival proteins (Akt and AMP-activated protein kinase α). In blood samples taken before and 6, 12 and 24 h after surgery cardiac troponin T (cTnT) and C-reactive protein (CRP) were determined. Surgery was strictly performed under sevoflurane anesthesia (no propofol). We actually randomized 16 patients to control treatment and 13 patients to RIPC. The mean 24 h area under the curve (AUC) cTnT was 11.44 (standard deviation 4.66) in the control group and 10.90 (standard deviation 4.73) in the RIPC group (mean difference 0.54, 95% CI -3.06 to 4.13; p = 0.76). The mean 24 h AUC CRP was 1319 (standard deviation 92) in the control group and 1273 (standard deviation 141) in the RIPC group (mean difference 46.2, 95% CI -288 to 380; p = 0.78). RIPC was without effect on survival proteins in atrial tissue samples obtained before surgery (mitochondrial hexokinase, Akt and AMPK) and inflammatory mediators obtained before and immediately after RIPC (IL-6, IL-10, TNF-α, macrophage migration inhibitory factor). Many factors can interfere with the outcome of RIPC. Trying to correct for this led to strict inclusion criteria, which, in combination with a decreased institutional frequency of CABG without concomitant procedures and a change in institutional anesthetic regimen away from volatile anesthetics towards total intravenous anesthesia, caused slow inclusion and halting of this trial after 3 years, before target inclusion could be reached. Therefore this study is underpowered to prove its primary goal that RIPC reduced AUC cTnT by < 25%. Nevertheless, we have shown that the effect of RIPC on 24 h AUC cTnT, in cardiac surgery with anesthesia during surgery restricted to sevoflurane/fentanyl (no propofol), was between a decrease of 27% and an increase of 36%. These findings are not in line with previous studies in this field. The Netherlands Trial Register: NTR2915 ; Registered 25 Mei 2011.