rIPC Group Research Articles

Ticagrelor potentiates cardioprotection by remote ischemic preconditioning: the ticagrelor in remote ischemic preconditioning (TRIP) randomized clinical trial

ObjectiveRemote ischemic preconditioning (RIPC) reduces periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) through various pathways, including an adenosine-triggered pathway. Ticagrelor inhibits adenosine uptake, thus may potentiate the effects of RIPC. This randomized trial tested the hypothesis that ticagrelor potentiates the effect of RIPC and reduces PMI, assessed by post-procedural troponin release. MethodsPatients undergoing PCI for non-ST elevation acute coronary syndromes were 1:1 randomized to ticagrelor (TG-Group) or clopidogrel (CL-Group). Within each treatment, patients were 1:1 randomized to a RIPC (RIPC-Group) or a control group (CTRL-Group). The primary endpoint was the difference between post- and pre-procedural troponin at 24 h following PCI, termed deltaTnI. ResultsDuring a 12-month period, 138 patients were included in the study (34 in the CL-CTRL group, 34 in the TG-CTRL group, 35 in the CL-RIPC group, and 35 in the TG-CTRL group). There was a significant difference in deltaTnI between the study groups [ TG-RIPC:0.04 (0–0.16), CL-CTRL:0.10 (0.03–0.43), CLRIPC:0.11 (0.03–0.89), and TG-CTRL:0.24 (0.06–0.47); p = 0.007]. Eight patients (22.9%) in the TG-RIPC group developed type 4a myocardial infarction (MI), compared to 14 (40%) in the CL-RIPC group, 13 (38.2%) in the CL-CTRL group, and 19 (55.9%) in the TG-CTRL group (p = 0.048). A significant interaction between antiplatelet group allocation and RIPC on deltaTnI was observed [F (1,134) = 7.509; p = 0.007]. In multivariate analysis, the interaction between RIPC and ticagrelor treatment was independently associated with a lower incidence of Type 4a MI. ConclusionOur results demonstrate an interaction between ticagrelor and RIPC, which may potentiate the cardioprotective effects of RIPC during PCI by reducing PMI.

Identification of serum exosomal metabolomic and proteomic profiles for remote ischemic preconditioning

BackgroundRemote ischemic preconditioning (RIPC) refers to a brief episode of exposure to potential adverse stimulation and prevents injury during subsequent exposure. RIPC has been shown to increase tolerance to ischemic injury and improve cerebral perfusion status. Exosomes have a variety of activities, such as remodeling the extracellular matrix and transmitting signals to other cells. This study aimed to investigate the potential molecular mechanism of RIPC-mediated neuroprotection.MethodsSixty adult male military personnel participants were divided into the control group (n = 30) and the RIPC group (n = 30). We analyzed the differential metabolites and proteins in the serum exosomes of RIPC participants and control subjects.ResultsEighty-seven differentially expressed serum exosomal metabolites were found between the RIPC and control groups, which were enriched in pathways related to tyrosine metabolism, sphingolipid metabolism, serotonergic synapses, and multiple neurodegeneration diseases. In addition, there were 75 differentially expressed exosomal proteins between RIPC participants and controls, which involved the regulation of insulin-like growth factor (IGF) transport, neutrophil degranulation, vesicle-mediated transport, etc. Furthermore, we found differentially expressed theobromine, cyclo gly-pro, hemopexin (HPX), and apolipoprotein A1 (ApoA1), which are associated with neuroprotective benefits in ischemia/reperfusion injury. In addition, five potential metabolite biomarkers, including ethyl salicylate, ethionamide, piperic acid, 2, 6-di-tert-butyl-4-hydroxymethylphenol and zerumbone, that separated RIPC from control individuals were identified.ConclusionOur data suggest that serum exosomal metabolites are promising biomarkers for RIPC, and our results provide a rich dataset and framework for future analyses of cerebral ischemia‒reperfusion injury under ischemia/reperfusion conditions.

Ischemic preconditioning does not prevent placental dysfunction induced by fetal cardiac bypass.

Remote ischemic preconditioning (rIPC) has been applied to attenuate tissue injury. We tested the hypothesis that rIPC applied to fetal lambs undergoing cardiac bypass (CB) reduces fetal systemic inflammation and placental dysfunction. Eighteen fetal lambs were divided into three groups: sham, CB control, and CB rIPC. CB rIPC fetuses had a hindlimb tourniquet applied to occlude blood flow for four cycles of a 5-minperiod, followed by a 2-minreperfusion period. Both study groups underwent 30 min of normothermic CB. Fetal inflammatory markers, gas exchange, and placental and fetal lung morphological changes were assessed. The CB rIPC group achieved higher bypass flow rates (p < .001). After CB start, both study groups developed significant decreases in PaO2 , mixed acidosis, and increased lactate levels (p < .0004). No significant differences in tissular edema were observed on fetal lungs and placenta (p > .391). Expression of Toll-like receptor 4 and intercellular adhesion molecule-1in the placenta and fetal lungs did not differ among the three groups, as well as with vascular cell adhesion molecule-1(VCAM-1) of fetal lungs (p > .225). Placental VCAM-1 expression was lower in the rIPC group (p < .05). Fetal interleukin-1 (IL-1) and thromboxane A2 (TXA2) levels were lower at 60 min post-CB in the CB rIPC group (p < .05). There were no significant differences in tumor necrosis factor-α, prostaglandin E2, IL-6, and IL-10 plasma levels of the three groups at 60-minpost-bypass (p > .133). Although rIPC allowed increased blood flow during fetal CB and decreasedIL-1 and TXA2 levels and placental VCAM-1, it did not prevent placental dysfunction in fetal lambs undergoing CB.

Remote ischemic preconditioning can extend the tolerance to extended drug-coated balloon inflation time by reducing myocardial damage during percutaneous coronary intervention

BackgroundRemote ischemic preconditioning (RIPC) alleviates myocardial ischemia-reperfusion injury (IRI) that occurs during percutaneous coronary intervention (PCI) and increases the myocardial tolerance to ischemia and hypoxia. Prolonged inflation time of drug-coated balloons (DCBs) can improve the treatment effects of PCI and the long-term prognosis of patients. This study investigated whether preoperative RIPC improves the tolerance to extended DCB inflation time. Methods and resultsOverall, 345 patients with coronary artery disease (CAD) were enrolled; 90, 96, 83, and 76 of these were randomized into the upper limb RIPC, lower limb RIPC, upper limb control, and lower limb control groups, respectively. Their baseline data were collected. Data on cardiac markers were analyzed. The DCB inflation time was recorded. The baseline data and cardiac marker levels before operation did not differ between RIPC and control groups. The post-PCI high-sensitivity troponin-T levels were lower in the RIPC groups (35.81 ± 14.02 and 34.65 ± 14.86 pg/mL) than in the control groups (41.63 ± 18.31 and 42.24 ± 14.38 pg/mL) (P = 0.001). The DCB inflation tolerance time was higher in the lower limb RIPC group (120 s [120,120]) than in the upper limb RIPC group (120 s [110,120]), and was the lowest in the upper limb control (100 s [90, 120]) and the lower limb control (100 s [90, 115]) groups (P < 0.001). ConclusionsRIPC reduces the level of myocardial damage that occurs during PCI and prolongs tolerance to increased DCB inflation time. The larger the ischemic area in RIPC, the better the improvement in the tolerance to extended DCB inflation time.

Limb Remote Ischemic Preconditioning Applied During Sevoflurane Anesthesia Does Not Protect the Lungs in Patients Undergoing Adult Heart Valve Surgery.

Two consistent overall cell protective preconditioning treatments should provide more protection. We hypothesized that limb remote ischemic preconditioning (RIPC, second preconditioning stimulus) applied during sevoflurane inhalation (first preconditioning stimulus) would provide more protection to the lungs of patients undergoing adult heart valve surgery. In this randomized, placebo-controlled, double-blind trial, 50 patients were assigned to the RIPC group or the placebo group (1:1). Patients in the RIPC group received three 5-min cycles of 300 mmHg cuff inflation/deflation of the left-side lower limb before aortic cross-clamping. Anesthesia consisted of opioids and propofol for induction and sevoflurane for maintenance. The primary end point was comparison of the postoperative arterial-alveolar oxygen tension ratio (a/A ratio) between groups. Secondary end points included comparisons of pulmonary variables, postoperative morbidity and mortality and regional and systemic inflammatory cytokines between groups. In the RIPC group, the a/A ratio and other pulmonary variables exhibited no significant differences throughout the study period compared with the placebo group. No significant differences in either plasma or bronchoalveolar lavage levels of TNF- α were noted between the groups at 10 min after anesthetic induction and 1 h after cross-clamp release. The percentage of neutrophils at 12 h postoperation was significantly increased in the RIPC group compared with the placebo group (91.34±0.00 vs. 89.42±0.10, P = 0.023). Limb RIPC applied during sevoflurane anesthesia did not provide additional significant pulmonary protection following adult valvular cardiac surgery.

Remote Ischemic Post-Conditioning may Improve Post-Stroke Cognitive Impairment: A Pilot Single Center Randomized Controlled Trial

Background and PurposeWe aimed to demonstrate the tolerability and feasibility and the effect of remote ischemic post-conditioning on cognitive functioning in patients with post-stroke cognitive impairment. MethodsThis was a single-center, randomized, outcome-blinded, placebo-controlled trial, randomized 1:1 to receive 4 cycles of remote ischemic post-conditioning or a sham procedure for 7 days. The primary outcome measure was tolerability and feasibility of remote ischemic post-conditioning. Secondary outcomes to measure the neurological function with national institute of health stroke scale and the cognitive impairment with Montreal Cognitive Assessment scale and Alzheimer's disease assessment scale-cognitive (at baseline, 90 days, 180 days). Results48 patients (24 RIPC and 24 Control) were recruited. remote ischemic post-conditioning was well tolerated with 90 out of 96 cycles completed in full. 4 patients experienced vascular events in the control group: 3 cerebrovascular and 1 cardiovascular event versus only 2 cerebrovascular events in the RIPC group. We showed the similar result in the neurological function with national institute of health stroke scale score with no statistically significant differences between RIPC and control group at baseline (P = 0.796) and 90 days (P = 0.401) and 180 days (P = 0.695). But compare with baseline, it was significantly difference in the control and RIPC group at 90 days (P < 0.05) and 180 days (P < 0.05). The comparison of Montreal Cognitive Assessment scale between two groups both showed that P > 0.05 at baseline which was no statistical difference, but P < 0.05 at 90 days and 180 days which were significant statistical difference. The comparison of Alzheimer's disease assessment scale-cognitive between two groups showed that P > 0.05 at baseline (P = 0.955) and 90 days (P = 0.138) was no statistical difference, but P = 0.005<0.05 at 180 days was significant statistical difference. ConclusionsThe remote ischemic post-conditioning for post-stroke cognitive impairment was well tolerated, safe and feasible. The remote ischemic post-conditioning may improve neurological and cognitive outcomes in patients with post-stroke cognitive impairment. A larger trial is warranted. (Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: ChiCTR1800015231.)

Effect of remote ischaemic preconditioning on walking in people with multiple sclerosis: double-blind randomised controlled trial

BackgroundRemote ischaemic preconditioning (RIPC) is the exposure of body parts to brief periods of circulatory occlusion and reperfusion. Recent studies have also shown that RIPC can improve exercise performance in...

English

INTRODUCTION: Acute kidney injury following receipt of iodinated contrast (CI-AKI) has been referred to as contrast induced nephropathy. There are various preventive measures for CI-AKI like 1. use of less nephrotoxic contrast agents, 2. use of pharmacological agents to counteract the toxic effects of contrast media, 3. administration of IV fluids to expand the intravascular space and enhance dieresis. This study shows whether ischemic preconditioning, transient brief episodes of ischemia before a subsequent prolonged ischemia / reperfusion injury is useful to reduce the incidence of CI-AKI. AIMS AND OBJECTIVES: To assess if remote ischemic preconditioning reduces the incidence of CI-AKI in patients with STEMI undergoing coronary angiogram. MATERIALS & METHODS: This is a prospective, single blind, randomized, sham-controlled parallel group study conducted among 100 randomly selected patients who are admitted in Govt. Rajaji Hospital, Madurai with STEMI. Patients are divided into two groups (test and control). Control group will undergo CAG without RIPC and those in the test group will undergo CAG after undergoing RIPC by three cycles of ischemia/ reperfusion of upper arm, achieved by 5 minute cuff inflation at 20 mm Hg above SBP followed by 5 minutes of complete cuff deflation. Both sets of patients are hydrated with normal saline infusion. Necessary haematological, biochemical, radiological investigations are performed and serum creatinine will be serially monitored in the next 72 hrs. RESULTS: Of the 50 patients in the control group 18 developed CI-AKI and of the 50 in test group 8 developed CI-AKI. This shows that RIPC was associated with a lower incidence of CIAKI and the difference was statistically significant. CONCLUSION: Not only was the incidence of CIAKI lower in RIPC group, but the mean rise in serum creatinine was also lower which would further reduce the duration of hospital stay and short term mortality. Thus RIPC can serve as a cost efficient tool in the lowering of occurrence of CI-AKI in patients undergoing contrast imaging.

The effect of remote ischemic pre-conditioning on pulmonary vascular pressure and gas exchange in healthy humans during hypoxia

This study investigated whether rIPC alters the typical changes in pulmonary arterial pressure, pulmonary gas exchange associated with exercise in hypoxia. Methods16 healthy adults were randomized to either rIPC treatment (n = 8) or control (n = 8). Afterward, subjects performed supine ergometry at constant load (30 W, 40˜50 rpm) for 25 min during hypoxia (12.5% O2). Following a 90˜120 min rest, either rIPC or sham treatment was performed, which was then followed by post-assessment exercise. Throughout exercise, pulmonary arterial systolic pressure (PASP) and mean pulmonary arterial pressure (mPAP) were measured via echocardiography, while pulmonary gas exchange was being assessed. ResultsThe rICP group demonstrated improved PASP and mPAP (p < 0.05), whereas the control group did not. Additionally, breathing efficiency (VE/VCO2) and end-tidal CO2 (PETCO2) were improved in rIPC group (p < 0.05), but not in controls. ConclusionThese data suggest that rIPC contributes to reduced pulmonary arterial pressure, and improved pulmonary gas exchange during hypoxic exercise. However, follow-up studies are needed to apply these findings to patient care settings.

Tobacco smoking protective effect via remote ischemic preconditioning on myocardial damage after elective percutaneous coronary intervention: Subanalysis of a randomized controlled trial

BackgroundRemote ischemic preconditioning (RIPC) is promising for preventing periprocedural myocardial damage (pMD) in patients undergoing percutaneous coronary intervention (PCI). However, the impact of RIPC on pMD on smokers is not well elucidated. The aim of this study was to investigate an association between tobacco smoking and RIPC on pMD in patients planning to undergo PCI. MethodsThis study used data from a multicenter randomized controlled trial involving patients with stable angina who planned to undergo elective PCI. We analyzed data for 262 patients in the control (n = 133) and upper-limb RIPC (n = 129) groups, including 166 current or former smokers. The major outcome was the pMD incidence following PCI, with pMD defined as an elevated level of highly sensitive cardiac troponin T or a creatine kinase myocardial band 12 or 24 h after PCI. ResultsThe incidence of pMD was significantly lower in the upper-limb RIPC group than in the control group (28/83 patients [33.8%] vs. 43/83 patients [51.8%], respectively; p = 0.018). In a multiple logistic regression model, tobacco smoking was an independent predictor of interacting with and enhancing the effect of RIPC on reducing the incidence of pMD after PCI (regression coefficient, −0.4 [95% confidence interval, −0.74 to −0.082]; p = 0.015). ConclusionsTobacco smoking may have a beneficial effect on RIPC against pMD after PCI.

Effect of Combined Treatment of Ketorolac and Remote Ischemic Preconditioning on Renal Ischemia-Reperfusion Injury in Patients Undergoing Partial Nephrectomy: Pilot Study.

We evaluated postoperative renal function in patients with/without combined therapy of ketorolac and remote ischemic preconditioning during partial nephrectomy. Sixteen patients were randomly allocated to either the ketorolac combined with RIPC group (KI, n = 8) or control group (n = 8). The KI group received both remote ischemic preconditioning before surgery and intravenous ketorolac of 1 mg/kg before renal artery clamping. Renal parameters were measured before induction, after anesthesia induction, and 2, 12, 24, 48, and 72 h after renal artery declamping. Acute kidney injury was assessed by Acute Kidney Injury Network criteria. The estimated glomerular filtration rate decreased in both groups, but then increased significantly at 48 h and 72 h after declamping only in the KI group compared to 24 h (p = 0.001 and p = 0.016). Additionally, it was higher at 48 h and 72 h after declamping in the KI group compared to the control group (p = 0.025 and p = 0.044). The incidence of acute kidney injury was significantly reduced in the KI group (13%) compared to the control group (83%) (p = 0.026). FENa was markedly increased at 2 h after declamping, and recovered in both groups, but it was more significant at 12 h after declamping in the KI group (p = 0.022). Urinary N-acetyl-1-β-D-glucosoaminidase and serum neutrophil gelatinase-associated lipocalin were similar (p = 0.291 and p = 0.818). There is a possibility that combined therapy of ketorolac and remote ischemic preconditioning prior to ischemia may alleviate renal dysfunction and reduce the incidence of acute kidney injury in patients undergoing partial nephrectomy.

Remote ischemic preconditioning in myocardial protection in hemodialysis patients.

BackgroundRemote ischemic preconditioning (RIPC) is a procedure that generates a brief period of ischemia followed by reperfusion. The role of RIPC in protecting myocardial ischemia during hemodialysis is not yet established. The aim of the study was to evaluate RIPC myocardial protection as evaluated by ultrasensitive I troponin in hemodialysis outpatients.Patients and methodsA double-blind randomized trial with two groups: intervention submitted to RIPC and control group without RIPC. Intervention group received RIPC in three consecutive hemodialysis sessions. Blood samples were taken before and after each session. Blood urea nitrogen for calculation of single-pool Kt/v and ultrasensitive I troponin were measured to evaluate dialysis adequacy and myocardial injury.ResultsA total of 47 patients were randomized. About 60.8% were men and 54% were diabetic. The mean single-pool Kt/v was 1.51 in the intervention group and 1.49 in control. The ultrasensitive troponin I measured no significant change from the time of collection: before or after dialysis.ConclusionThe RIPC applied in three consecutive sessions did not demonstrate superiority to control, therefore another study tested RIPC in 12 consecutive sessions with a positive result in myocardial protection. In our study, more than half of the patients were diabetic. Diabetic patients have a trend to show a lower response to RIPC because of the greater presence of collateral coronary circulation. In summary, in this model there was no interference of RIPC in ultrasensitive troponin I values, but troponin had a high negative predictive value for myocardial infarction in all tested models.

Randomized clinical trial of remote ischaemic preconditioning versus no preconditioning in the prevention of perioperative myocardial infarction during open surgery for ruptured abdominal aortic aneurysm.

BackgroundRemote ischaemic preconditioning (RIPC) has been suggested as a means of protecting vital organs from reperfusion injury during major vascular surgery. This study was designed to determine whether RIPC could reduce the incidence of perioperative myocardial infarction (MI) during open surgery for ruptured abdominal aortic aneurysm (AAA). Secondary aims were to see if RIPC could reduce 30‐day mortality, multiple organ failure, acute intestinal ischaemia, acute kidney injury and ischaemic stroke.MethodsThis randomized, non‐blinded clinical trial was undertaken at three vascular surgery centres in Denmark. Patients who had open surgery for ruptured AAA were randomized to intervention with RIPC or control in a 1 : 1 ratio. Postoperative complications and deaths were registered, and ECG and blood samples were obtained daily during the hospital stay.ResultsOf 200 patients randomized, 142 (72 RIPC, 70 controls) were included. There was no difference in rates of perioperative MI between the RIPC and control groups (36 versus 43 per cent respectively), or in rates of organ failure. However, in the per‐protocol analysis 30‐day mortality was significantly reduced in the RIPC group (odds ratio 0·46, 95 per cent c.i. 0·22 to 0·99; P = 0·048).ConclusionRIPC did not reduce the incidence of perioperative MI in patients undergoing open surgery for ruptured AAA. Registration number: NCT00883363 ( http://www.clinicaltrials.gov).

387 Ischemic Preconditioning Reduces the Incidence of Postoperative Ischemic Lesions in Patients Undergoing Surgical Resection of Brain Tumors

Abstract INTRODUCTION Postoperative ischemia is a frequent phenomenon in patients with brain tumors and is associated with postoperative neurological deficits and impaired overall survival. Previous clinical and experimental studies have shown that the application of a brief ischemic stimulus not only in the target organ but also in a remote tissue can prevent ischemia. We hypothesized that remote ischemic preconditioning (rIPC) in patients with brain tumors undergoing elective surgical resection reduces the incidence of postoperative ischemic tissue damage and its consequences. METHODS Sixty patients were randomly assigned to two groups, with 1:1 allocation, stratified after tumor type (glioma or metastasis) and previous treatment with radiotherapy. Remote ischemic preconditioning was induced by inflating a blood pressure cuff placed on the upper arm three times for 5 minutes at 200 mmHg in the treatment group after induction of anesthesia. Between the cycles, the blood pressure cuff was released to allow reperfusion. In the control group no preconditioning was performed. Early postoperative MR images were evaluated blinded to randomization for the presence of ischemia and its volume. RESULTS &gt;Fifty-eight of the 60 patients were assessed for occurrence of postoperative ischemia. Of these 58 patients, 44 (75.9%) had new postoperative ischemic lesions. The incidence of new postoperative ischemic lesions was significantly higher in the control group (87.1%) (27/31) than in the rIPC group (63.0%) (17/27) (P = 0.03). The median infarct volume was 0.36 cm3 (IR: 0.0- 2.35) in the rIPC group compared with 1.30 cm3 (IR: 0.29- 3.66) in the control group (P = 0.09). CONCLUSION Application of rIPC significantly reduced the incidence of postoperative ischemic tissue damage in patients undergoing elective brain tumor surgery. This is the first study indicating a benefit of rIPC in brain tumor surgery.

Impact of ischemic preconditioning on surgical treatment of brain tumors: a single-center, randomized, double-blind, controlled trial

BackgroundPostoperative ischemia is a frequent phenomenon in patients with brain tumors and is associated with postoperative neurological deficits and impaired overall survival. Particularly in the field of cardiac and vascular surgery, the application of a brief ischemic stimulus not only in the target organ but also in remote tissues can prevent subsequent ischemic damage. We hypothesized that remote ischemic preconditioning (rIPC) in patients with brain tumors undergoing elective surgical resection reduces the incidence of postoperative ischemic tissue damage and its consequences.MethodsSixty patients were randomly assigned to two groups, with 1:1 allocation, stratified by tumor type (glioma or metastasis) and previous treatment with radiotherapy. rIPC was induced by inflating a blood pressure cuff placed on the upper arm three times for 5 min at 200 mmHg in the treatment group after induction of anesthesia. Between the cycles, the blood pressure cuff was released to allow reperfusion. In the control group no preconditioning was performed. Early postoperative magnetic resonance images (within 72 h after surgery) were evaluated by a neuroradiologist blinded to randomization for the presence of ischemia and its volume.ResultsFifty-eight of the 60 patients were assessed for occurrence of postoperative ischemia. Of these 58 patients, 44 had new postoperative ischemic lesions. The incidence of new postoperative ischemic lesions was significantly higher in the control group (27/31) than in the rIPC group (17/27) (p = 0.03). The median infarct volume was 0.36 cm3 (interquartile range (IR): 0.0–2.35) in the rIPC group compared with 1.30 cm3 (IR: 0.29–3.66) in the control group (p = 0.09).ConclusionsApplication of rIPC was associated with reduced incidence of postoperative ischemic tissue damage in patients undergoing elective brain tumor surgery. This is the first study indicating a benefit of rIPC in brain tumor surgery.Trial registrationGerman Clinical Trials Register, DRKS00010409. Retrospectively registered on 13 October 2016.

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

BackgroundRemote 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.MethodsIn 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).ResultsWe 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).ConclusionMany 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.Trial registrationThe Netherlands Trial Register: NTR2915; Registered 25 Mei 2011.

Effects of delayed remote ischemic preconditioning on peri-operative myocardial injury in patients undergoing cardiac surgery — A randomized controlled trial

BackgroundRemote ischemic preconditioning (RIPC) has two time windows for organ protection: acute and delayed. Previous studies have mainly focused on the acute time window to evaluate organ protection by RIPC. We evaluated myocardial protection by delayed RIPC in adult patients undergoing cardiac surgery. MethodsA total of 160 adult patients undergoing cardiac surgery with cardiopulmonary bypass were randomized to receive either delayed RIPC (four cycles of 5min of ischemia followed by 5min of reperfusion by inflation to 200mmHg and deflation of a blood pressure cuff on the upper arm) or the control treatment 24–48h before surgery. The primary endpoint was post-operative troponin I levels serially measured for 72h. Secondary endpoints included post-operative serum creatinine levels, acute kidney injury, and composite complications. ResultsThere were no significant differences in post-operative troponin I values. The incidence of acute kidney injury, defined by the Acute Kidney Injury Network staging system, was lower in the delayed RIPC group compared to the control group (30.0% vs. 47.5%; relative risk, 0.768; 95% confidence interval, 0.599–0.985; p=0.023). Moreover, the occurrence of composite complications was lower in the delayed RIPC group compared with the control group (65.0% vs. 81.3%; relative risk, 0.536; 95% confidence interval, 0.311–0.924; p=0.020). ConclusionsWhile RIPC did not provide cardioprotective effects in patients undergoing cardiac surgery, it appeared to reduce acute kidney injury, as well as the rate of composite complications.

Possible Underlying Mechanisms of the Renoprotective Effect of Remote Limb Ischemic Preconditioning Against Renal Ischemia/Reperfusion Injury: A Role of Osteopontin, Transforming Growth Factor-Beta and Survivin

Background: It has been documented that remote limb ischemic preconditioning (rIPC) protect kidneys against renal ischemia/reperfusion (I/R). We hypothesized that osteopontin (OPN), transforming growth factor beta (TGF-β), apoptotic proteins (survivin and caspase-3) and oxidative stress play role in the renoprotective effects of rIPC. Materials and Methods: Fifty-four male Sprague-Dawley rats were randomized into 3 equal groups: sham group, I/R group (left renal 45 min ischemia) and rIPC group (as I/R group with 3 cycles of left hind limb ischemia just before renal ischemia). Each group was subdivided into 24, 48 and 72 h groups according to the time of sacrifice. We measured serum creatinine and blood urea nitrogen (BUN) at the baseline and end points. Also, left kidney was harvested at study end points for assessment of the expression of OPN, TGF-β, apoptotic proteins (survivin and caspase-3) and oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD)) in kidney tissues and histopathological examination. Results: Serum creatinine and BUN levels and histopathological damage score were significantly lower in rIPC group than I/R group (p < 0.005). Also, compared to I/R group, the levels of MDA and the expression of OPN, TGF-β and caspase-3 in kidney tissues were significantly lower in rIPC group, while the levels of SOD and GSH and the expression of survivin in kidney tissues were significantly higher in rIPC group at all time points (p ≤ 0.05). Conclusions: rIPC exhibited protective effects against renal I/R injury which might be due to inhibition of OPN expression, inflammatory cytokine TGF-β and caspase-3 and activation of anti-apoptotic protein survivin as well as improvement of oxidative stress in kidney tissues.

Effect of remote ischemic preconditioning on myocardial injury and inflammatory response induced by ablation for atrial fibrillation: A randomized controlled trial

BackgroundRemote ischemic preconditioning (RIPC) has been suggested to reduce postoperative release of cardiac and inflammatory markers in patients undergoing cardiac surgery. This study aimed to evaluate the effect of RIPC on nonischemic myocardial damage and inflammatory response in patients undergoing radiofrequency catheter ablation for paroxysmal atrial fibrillation (AF). MethodsSeventy-two patients with drug-refractory paroxysmal AF undergoing radiofrequency catheter ablation were randomized into RIPC or control groups. RIPC (intermittent arm ischemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) was performed once daily on 2 consecutive days before the ablation and immediately before ablation. Cardiac troponin-I (cTnI), high-sensitive C-reactive protein (hs-CRP), and interleukin (IL)-6 levels were measured before RIPC/sham RIPC, after the ablation, and 24 and 72h later. The early recurrence of atrial fibrillation (ERAF) in the two groups was observed over the subsequent 3months. ResultsRadiofrequency ablation resulted in a significant rise in cTnI, hs-CRP, and IL-6 in both groups, which persisted for 72h. The RIPC group showed a lower increase in cTnI (P<0.001), hs-CRP (P=0.003), and IL-6 (P=0.008) than the control and tended to have a lower risk of ERAF (hazard ratio [HR]=0.77, 95% confidence interval [CI]: 0.32–1.88). ConclusionsThese results show that RIPC before ablation for paroxysmal AF significantly reduces the increase in cTnI, hs-CRP, and IL-6 associated with the procedure and results in a lower risk of ERAF. These findings suggest that RIPC could provide cardioprotection against nonischemic myocardial damage.

Remote ischemic preconditioning in patients undergoing cardiovascular surgery: Evidence from a meta-analysis of randomized controlled trials

BackgroundRemote ischemic preconditioning (RIPC) has been associated with reduced risk of myocardial injury in patients undergoing cardiovascular surgery, but uncertainty about clinical outcomes remains, particularly in the light of 2 recent large randomized clinical trials (RCTs) which were neutral. We performed a meta-analysis to evaluate the efficacy of RIPC on clinically relevant outcomes in patients undergoing cardiovascular surgery. MethodsWe searched PubMed, Cochrane CENTRAL, EMBASE, EBSCO, Web of Science and CINAHL databases from inception through November 30, 2015. RCTs that compared the effects of RIPC vs. control in patients undergoing cardiac and/or vascular surgery were selected. We calculated summary random-effect odds ratios (ORs) and 95% confidence intervals (CI). ResultsThe analysis included 5652 patients from 27 RCTs. RIPC reduced the risk of myocardial infarction (MI) (OR 0.72, 95% CI, 0.52 to 1.00; p=0.05; number needed to treat (NNT)=42), acute renal failure (OR 0.73, 95% CI, 0.53 to 1.00; p=0.05; NNT=44) as well as the composite of all cause mortality, MI, stroke or acute renal failure (OR 0.60, 95% CI, 0.39 to 0.90; p=0.01; NNT=25). No significant difference between RIPC and the control groups was observed for the outcome of all-cause mortality (OR 1.10, 95% CI, 0.81 to 1.51). Randomization to RIPC group was also associated with significantly shorter hospital stay (weighted mean difference −0.15days; 95% CI −0.27 to −0.03days). ConclusionsRIPC did not decrease overall mortality, but was associated with less MI and acute renal failure and shorter hospitalizations in patients undergoing cardiac or vascular surgery.