Luciano Candilio

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery

BACKGROUND Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).

Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial

Objectives Remote ischaemic preconditioning (RIPC), using brief cycles of limb ischaemia/reperfusion, is a non-invasive, low-cost intervention that may reduce perioperative myocardial injury (PMI) in patients undergoing cardiac surgery. We investigated whether RIPC can also improve short-term clinical outcomes. Methods One hundred and eighty patients undergoing elective coronary artery bypass graft (CABG) surgery and/or valve surgery were randomised to receive either RIPC (2–5 min cycles of simultaneous upper arm and thigh cuff inflation/deflation; N=90) or control (uninflated cuffs placed on the upper arm and thigh; N=90). The study primary end point was PMI, measured by 72 h area under the curve (AUC) serum high-sensitive troponin-T (hsTnT); secondary end point included short-term clinical outcomes. Results RIPC reduced PMI magnitude by 26% (−9.303 difference (CI −15.618 to −2.987) 72 h hsTnT-AUC; p=0.003) compared with control. There was also evidence that RIPC reduced the incidence of postoperative atrial fibrillation by 54% (11% RIPC vs 24% control; p=0.031) and decreased the incidence of acute kidney injury by 48% (10.0% RIPC vs 21.0% control; p=0.063), and intensive care unit stay by 1 day (2.0 days RIPC (CI 1.0 to 4.0) vs 3.0 days control (CI 2.0 to 4.5); p=0.043). In a post hoc analysis, we found that control patients administered intravenous glyceryl trinitrate (GTN) intraoperatively sustained 39% less PMI compared with those not receiving GTN, and RIPC did not appear to reduce PMI in patients given GTN. Conclusions RIPC reduced the extent of PMI in patients undergoing CABG and/or valve surgery. RIPC may also have beneficial effects on short-term clinical outcomes, although this will need to be confirmed in future studies. Trial registration number ClinicalTrials.gov ID: NCT00397163.

Protection of organs other than the heart by remote ischemic conditioning.

Organ or tissue dysfunction due to acute ischemia–reperfusion injury (IRI) is the leading cause of death and disability worldwide. Acute IRI induces cell injury and death in a wide variety of organs and tissues in a large number of different clinical settings. One novel therapeutic noninvasive intervention, capable of conferring multiorgan protection against acute IRI, is ‘remote ischemic conditioning’ (RIC). This describes an endogenous protective response to acute IRI, which is triggered by the application of one or more brief cycles of nonlethal ischemia and reperfusion to one particular organ or tissue. Originally discovered as a therapeutic strategy for protecting the myocardium against acute IRI, it has been subsequently demonstrated that RIC may confer protection against acute IRI in a number of different noncardiac organs and tissues including the kidneys, lungs, liver, skin flaps, ovaries, intestine, stomach and pancreas. The discovery that RIC can be induced noninvasively by applying the RIC stimulus to the skeletal tissue of the upper or lower limb has facilitated its application to a number of clinical settings in which organs and tissues are at high risk of acute IRI. In this article, we review the experimental studies that have investigated RIC in organs and tissues other than the heart, and we explore the therapeutic potential of RIC in preventing organ and tissue dysfunction induced by acute IRI.

A retrospective analysis of myocardial preservation techniques during coronary artery bypass graft surgery: are we protecting the heart?

BackgroundRetrograde perfusion into coronary sinus during coronary artery bypass graft (CABG) surgery reduces the need for cardioplegic interruptions and ensures the distribution of cardioplegia to stenosed vessel territories, therefore enhancing the delivery of cardioplegia to the subendocardium. Peri-operative myocardial injury (PMI), as measured by the rise of serum level of cardiac biomarkers, has been associated with short and long-term clinical outcomes. We conducted a retrospective analysis to investigate whether the combination of antegrade and retrograde techniques of cardioplegia delivery is associated with a reduced PMI than that observed with the traditional methods of myocardial preservation.MethodsFifty-four consecutive patients underwent CABG surgery using either antegrade cold blood cardioplegia (group 1, n = 28) or cross-clamp fibrillation (group 2, n = 16) or antegrade retrograde warm blood cardioplegia (group 3, n = 10). The study primary end-point was PMI, evaluated with total area under the curve (AUC) of high-sensitivity Troponin-T (hsTnT), measured pre-operatively and at 6, 12, 24, 48 and 72 hours post-surgery. Secondary endpoints were acute kidney injury (AKI) and inotrope scores, length of intensive care unit (ICU) and hospital stay, new onset atrial fibrillation (AF) and clinical outcomes at 6 weeks (death, non-fatal myocardial infarction, coronary artery revascularization, stroke).ResultsThere was evidence that mean total AUC of hsTnT was different among the three groups (P = 0.050). In particular mean total AUC of hsTnT was significantly lower in group 3 compared to both group 1 (-16.55; 95% CI: -30.08, -3.01; P = 0.018) with slightly weaker evidence of a lower mean hsTnT in group 3 when compared to group 2 (-15.13; 95% CI -29.87, -0.39; P = 0.044). There was no evidence of a difference when comparing group 2 to group 1 (-1.42,; 95% CI: -12.95, 10.12, P = 0.806).ConclusionsOur retrospective analysis suggests that, compared to traditional methods of myocardial preservation, antegrade retrograde cardioplegia may reduce PMI in patients undergoing first time CABG surgery.

Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality

Objective We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGALpre-op) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. Methods This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72 hours was defined using the International Kidney Disease: Improving Global Outcomes classification. Results 1371 out of 1612 patients had data on sNGALpre-op. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGALpre-op (30.5%, 41.5% and 45.9%, respectively, p<0.001). There was also an increase in both cardiovascular and all-cause mortality from the first to the third tertile of sNGALpre-op, linear trend test with adjusted p=0.018 and p=0.013, respectively. The adjusted HRs for those in the second and third tertiles of sNGALpre-op compared with the first tertile were 1.60 (95% CI 0.78 to 3.25) and 2.22 (95% CI 1.13 to 4.35) for cardiovascular mortality, and 1.25 (95% CI 0.71 to 2.22) and 1.91 (95% CI 1.13 to 3.25) for all-cause mortality at 1 year. Conclusion In a cohort of high-risk adult patients undergoing cardiac surgery, there was an increase in postoperative AKI and 1-year mortality from the first to the third tertile of preoperative serum NGAL. Those in the last tertile (>220 ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1 year. Clinical trial registration NCT101247545; Post-results.

Is there a role for ischaemic conditioning in cardiac surgery

Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Coronary artery bypass graft (CABG) surgery is the revascularisation strategy of choice in patients with diabetes mellitus and complex CAD. Owing to a number of factors, including the ageing population, the increased complexity of CAD being treated, concomitant valve and aortic surgery, and multiple comorbidities, higher-risk patients are being operated on, the result of which is an increased risk of sustaining perioperative myocardial injury (PMI) and poorer clinical outcomes. As such, new treatment strategies are required to protect the heart against PMI and improve clinical outcomes following cardiac surgery. In this regard, the heart can be endogenously protected from PMI by subjecting the myocardium to one or more brief cycles of ischaemia and reperfusion, a strategy called “ischaemic conditioning”. However, this requires an intervention applied directly to the heart, which may be challenging to apply in the clinical setting. In this regard, the strategy of remote ischaemic conditioning (RIC) may be more attractive, as it allows the endogenous cardioprotective strategy to be applied away from the heart to the arm or leg by simply inflating and deflating a cuff on the upper arm or thigh to induce one or more brief cycles of ischaemia and reperfusion (termed “limb RIC”). Although a number of small clinical studies have demonstrated less PMI with limb RIC following cardiac surgery, three recently published large multicentre randomised clinical trials found no beneficial effects on short-term or long-term clinical outcomes, questioning the role of limb RIC in the setting of cardiac surgery. In this article, we review ischaemic conditioning as a therapeutic strategy for endogenous cardioprotection in patients undergoing cardiac surgery and discuss the potential reasons for the failure of limb RIC to improve clinical outcomes in this setting. Crucially, limb RIC still has the therapeutic potential to protect the heart in other clinical settings, such as acute myocardial infarction, and it may also protect other organs against acute ischaemia/reperfusion injury (such as the brain, kidney, and liver).

Remote Ischemic Preconditioning: Would You Give Your Right Arm to Protect Your Kidneys?

Address correspondence to Derek Hausenloy, MD, PhD, Duke-National University of Singapore, 8 College Road, Singapore 169857. E-mail: derek.hausenloy@duke-nus.edu.sg 2015 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2015.08.018 The incidence of acute kidney injury (AKI) following cardiac bypass surgery can be as high as 30%, and even an increase in serum creatinine level smaller than the criterion for AKI after cardiac surgery is associated with increased postsurgical morbidity and mortality. Although the cause of AKI following surgery is multifactorial and the precise underlying mechanisms are unclear, acute tubular injury is the predominant pathology in severe cases of AKI. Although numerous strategies have been investigated to minimize AKI during cardiac surgery, there is currently no effective renoprotective intervention in clinical use. In this context, remote ischemic preconditioning (RIPC), which refers to the phenomenon whereby transient nonlethal episodes of ischemia and reperfusion to a remote organ or tissue confer multiorgan protection against a sustained episode of ischemiareperfusion to an organ of interest, may hold promise. Results of studies investigating the potential for RIPC, performed using transient limb ischemia and reperfusion, to reduce the incidence of AKI following cardiac surgery have been inconsistent. It is therefore not surprising that the recently published study titled “Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial” by Zarbock et al in the Journal of the American Medical Association has attracted significant attention.

Atrial Fibrillation in the Intensive Care Setting

Atrial fibrillation (AF) is the commonest cardiac arrhythmia both in the general population and in the intensive care unit (ICU) setting. Its incidence continues to rise, affecting up to 10% of patients admitted to a general ICU and up to 50% of those admitted to a cardiac ICU. Uncontrolled AF has detrimental effects on the cardiovascular system, including heart failure, thromboembolic events, reduced quality of life and prolonged hospital stay. This article reviews the risk factors for developing AF, possible underlying mechanisms, clinical features and diagnosis, and focuses particularly on its management according to the latest guidelines with a specific focus on the ICU patient. We also discuss novel anticoagulants that will revolutionise the management of antithrombotic therapy in AF patients by replacing warfarin.

107 Remote ischaemic preconditioning and human atrial trabeculae in the diabetic heart

Introduction Remote ischaemic preconditioning (RIPC) using brief cycles of upper or lower limb ischaemia and reperfusion has been reported to protect the heart against ischaemia-reperfusion injury (IRI). Previous studies suggest that the diabetic heart is more resistant to the cardioprotective effects of myocardial ischaemic preconditioning. Whether the diabetic heart is amenable to RIPC is unknown and is investigated in this study. Methods Non-diabetic and diabetic patients undergoing elective coronary artery bypass graft (CABG) surgery were randomised to receive three different treatment protocols after the induction of anaesthesia: (1) Control—no RIPC; (2) RIPC1 comprising 3-five min cycles of upper arm cuff inflation/deflation; or (3) RIPC2 comprising 2-five min cycles of simultaneous upper and lower limb cuff inflations/deflations (total 4). A section of the right atrial appendage was harvested, from which atrial trabeculae were isolated and subjected to 90 min simulated ischaemia and 120 min simulated reperfusion, at the end of which the recovery of baseline contractile function was determined. Results Atrial trabeculae harvested from diabetic (N=13 patients) and non-diabetic control patients (N=20 patients) were demonstrated to recover 24.5%±2.4% and 29.3%±1.3% of baseline contractile function, respectively. Prior treatment of patients with RIPC1 increased the recovery of function in both non-diabetic (50.4%±1.9%; p<0.05) and diabetic (41.6%±1.9%; p<0.05) patients. Interestingly, the stronger RIPC2 stimulus resulted in a greater recovery of function in both non-diabetic (59.3%±1.9%; p<0.05) and diabetic (50.7%±2.1%; p<0.05) patients. As a positive control direct hypoxic preconditioning (HPC) of atrial trabeculae also improved the recovery of function (56.4%±1.8% with HPC vs 27.5%±1.7% in control; N=10 patients; p<0.05). The administration of the MEK-Erk1/2 inhibitors U0126 and PD98059 at the onset of reperfusion abrogated the protective effect in both non-diabetic (30.9%±0.8% U0126 and 31.3%±0.8% PD98059; p>0.05) and diabetic (28.6%±0.9% U0126 and 30.0%±1.2% PD98059; p>0.05) atrial trabeculae. Conclusion We demonstrate for the first time that in vivo RIPC can protect ex vivo atrial trabeculae against simulated IRI. Both non-diabetic and diabetic atrial trabeculae were amenable to RIPC protection. Increasing the intensity of the RIPC stimulus resulted in greater functional recovery. The pro-survival kinase MEK-Erk1/2 appears to contribute to RIPC protection in human atria trabeculae.

124 MULTI-LIMB REMOTE ISCHAEMIC PRECONDITIONING REDUCES MYOCARDIAL INJURY IN DIABETIC PATIENTS UNDERGOING CORONARY ARTERY BYPASS SURGERY

Background Diabetic patients undergoing coronary artery bypass surgery (CABG) are at higher risk of peri-operative myocardial injury (PMI) with subsequent worse short and long-term clinical outcomes. Remote ischaemic preconditioning (RIPC), in which the application of one or more brief cycles of non-lethal ischaemia and reperfusion to an organ or tissue protects the heart against a lethal episode of acute ischaemia-reperfusion injury, has emerged as a non-invasive, low-cost therapeutic intervention for protecting the heart in patients undergoing CABG surgery. However, both experimental and clinical studies have demonstrated that the diabetic heart presents an increased resistance to the protective effects of RIPC. Whether by increasing the preconditioning stimulus we can protect diabetic patients undergoing CABG surgery is unknown. Methods and results 87 consecutive diabetic patients undergoing elective CABG surgery were recruited into two substudies. In the first substudy (N=53), patients were randomised to receive either standard RIPC protocol (3–5 min cycles of upper arm cuff inflation to 200 mm Hg with intervening 5 min deflation, N=26) or control (uninflated cuff placed on the upper arm for 30 min, N=27) following anaesthesia induction. In the second substudy (N=34), patients were randomised to receive either an enhanced RIPC stimulus (2–5 min cycles of simultaneous upper arm and thigh cuff inflation to 200 mm Hg with intervening 5 min deflation, N=17) or control (uninflated cuffs placed on the upper arm and thigh for 20 min, N=17). PMI was calculated as area-under-the-curve (AUC) of troponin-T (TnT), measured pre-operatively and 6, 12, 24, 48, 72 h post-surgery. In the first substudy with standard preconditioning protocol, there was no difference in the 72 h TnT AUC between control and RIPC (AUC was respectively 22.17 µg/l and 22.22 µg/l, p=0.98). However, in the second substudy and with the application of the enhanced preconditioning stimulus, we observed a significant reduction in the 72 h TnT AUC in the RIPC group compared to control (31.73 µg/l vs 19.63 µg/l respectively, p=0.022). Conclusions An enhanced preconditioning stimulus by multi-limb RIPC reduces PMI in diabetic patients undergoing CABG surgery. Larger multicentre studies are being conducted to confirm these studies.