Statistical Methods in Medical Research.

Following an acute myocardial infarction (AMI), early coronary artery reperfusion remains the most effective means of limiting the eventual infarct size. The resultant left ventricular systolic function is a critical determinant of the patient's clinical outcome. Despite current myocardial reperfusion strategies and ancillary antithrombotic and antiplatelet therapies, the morbidity and mortality of an AMI remain significant, with the number of patients developing cardiac failure increasing, necessitating the development of novel strategies for cardioprotection which can be applied at the time of myocardial reperfusion to reduce myocardial infarct size. In this regard, the Reperfusion Injury Salvage Kinase (RISK) Pathway, the term given to a group of pro-survival protein kinases (including Akt and Erk1/2), which confer powerful cardioprotection, when activated specifically at the time of myocardial reperfusion, provides an amenable pharmacological target for cardioprotection. Preclinical studies have demonstrated that an increasing number of agents including insulin, erythropoietin, adipocytokines, adenosine, volatile anesthetics natriuretic peptides and 'statins', when administered specifically at the time of myocardial reperfusion, reduce myocardial infarct size through the activation of the RISK pathway. This recruits various survival pathways that include the inhibition of mitochondrial permeability transition pore opening. Interestingly, the RISK pathway is also recruited by the cardioprotective phenomena of ischemic preconditioning (IPC) and postconditioning (IPost), enabling the use of pharmacological agents which target the RISK pathway, to be used at the time of myocardial reperfusion, as pharmacological mimetics of IPC and IPost. This article reviews the origins and evolution of the RISK pathway, as part of a potential common cardioprotective pathway, which can be activated by an ever-expanding list of agents administered at the time of myocardial reperfusion, as well as by IPC and IPost. Preliminary clinical studies have demonstrated myocardial protection with several of these pharmacological activators of the RISK pathway in AMI patients undergoing PCI. Through the use of appropriately designed clinical trials, guided by the wealth of existing preclinical data, the administration of pharmacological agents which are known to activate the RISK pathway, when applied as adjuvant therapy to current myocardial reperfusion strategies for patients presenting with an AMI, should lead to improved clinical outcomes in this patient group.

Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection.

Background: Experimental studies have related the cardioprotective effects of sevoflurane both to preconditioning properties and to beneficial effects during reperfusion. In clinical studies, the cardioprotective effects of volatile agents seem more important when administered throughout the procedure than when used only in the preconditioning period. The authors hypothesized that the cardioprotective effects of sevoflurane observed in patients undergoing coronary surgery with cardiopulmonary bypass are related to timing and duration of its administration. Methods: Elective coronary surgery patients were randomly assigned to four different anesthetic protocols (n = 50 each). In a first group, patients received a propofol based intravenous regimen (propofol group). In a second group, propofol was replaced by sevoflurane from sternotomy until the start of cardiopulmonary bypass (SEVO pre group). In a third group, propofol was replaced by sevoflurane after completion of the coronary anastomoses (SEVO post group). In a fourth group, propofol was administered until sternotomy and then replaced by sevoflurane for the remaining of the operation (SEVO all group). Postoperative concentrations of cardiac troponin I were followed during 48 h. Cardiac function was assessed perioperatively and during 24 h postoperatively. Results: Postoperative troponin I concentrations in the SEVO all group were lower than in the propofol group. Stroke volume decreased transiently after cardiopulmonary bypass in the propofol group but remained unchanged throughout in the SEVO all group. In the SEVO pre and SEVO post groups, stroke volume also decreased after cardiopulmonary bypass but returned earlier to baseline values than in the propofol group. Duration of stay in the intensive care unit was lower in the SEVO all group than in the propofol group. Conclusion: In patients undergoing coronary artery surgery with cardiopulmonary bypass, the cardioprotective effects of sevoflurane were clinically most apparent when it was administered throughout the operation.

Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration

BACKGROUND: Sevoflurane has been shown to protect against myocardial ischemia and reperfusion injury in animals. The present study investigated whether these effects were clinically relevant and would protect left ventricular (LV) function during coronary surgery. METHODS: Twenty coronary surgery patients were randomly assigned to receive either target-controlled infusion of propofol or inhalational anesthesia with sevoflurane. Except for this, anesthetic and surgical management was the same in all patients. A high-fidelity pressure catheter was positioned in the left ventricle and the left atrium. LV response to increased cardiac load, obtained by leg elevation, was assessed before and after cardiopulmonary bypass (CPB). Effects on contraction were evaluated by analysis of changes in dP/dt(max). Effects on relaxation were assessed by analysis of the load dependence of myocardial relaxation (R = slope of the relation between time constant tau of isovolumic relaxation and end-systolic pressure). Postoperative concentrations of cardiac troponin I were followed during 36 h. RESULTS: Before CPB, leg elevation slightly increased dP/dt(max) in the sevoflurane group (5 +/- 3%), whereas it remained unchanged in the propofol group (1 +/- 6%). After CPB, leg elevation resulted in a decrease in dP/dt(max) in the propofol group (-5 +/- 4%), whereas the response in the sevoflurane group was comparable to the response before CPB (5 +/- 4%). Load dependence of LV pressure fall (R) was similar in both groups before CPB. After CPB, R was increased in the propofol group but not in the sevoflurane group. Troponin I concentrations were significantly lower in the sevoflurane than in the propofol group. CONCLUSIONS: Sevoflurane preserved LV function after CPB with less evidence of myocardial damage in the first 36 h postoperatively. These data suggest a cardioprotective effect of sevoflurane during coronary artery surgery

Sevoflurane but not propofol preserves myocardial function in coronary surgery patients

Desflurane and Sevoflurane in Cardiac Surgery: A Meta-Analysis of Randomized Clinical Trials

It is known that volatile anaesthetics protect myocardial tissue against ischaemic and reperfusion injury in vitro. In this investigation, we have determined the effects of the inhalation anaesthetics, enflurane, isoflurane, sevoflurane and desflurane, administered only during early reperfusion, on myocardial reperfusion injury in vivo. Fifty chloralose-anaesthetized rabbits were subjected to 30 min of occlusion of a major coronary artery followed by 120 min of reperfusion. Left ventricular pressure (LVP, tip-manometer), cardiac output (CO, ultrasonic flow probe) and infarct size (triphenyltetrazolium staining) were determined. During the first 15 min of reperfusion, five groups of 10 rabbits each received 1 MAC of enflurane (enflurane group), isoflurane (isoflurane group), sevoflurane (sevoflurane group) or desflurane (desflurane group), and 10 rabbits served as untreated controls (control group). Haemodynamic baseline values were similar between groups (mean LVP 106 (SEM 2) mm Hg; CO 281(7) ml min-1). During coronary occlusion, LVP and CO were reduced to the same extent in all groups (LVP 89% of baseline; CO 89%). Administration of inhalation anaesthetics during early reperfusion further reduced both variables, but they recovered after discontinuation of the anaesthetics to values not different from control animals. Infarct size was reduced from 49 (5)% of the area at risk in the control group to 32 (3)% in the desflurane group (P = 0.021), and to 36 (2)% in the sevoflurane group (P = 0.097). In the enflurane group, infarct size was 39 (5)% (P = 0.272). Isoflurane had no effect on infarct size (48 (5)%, P = 1.000). The results show that desflurane and sevoflurane markedly reduced infarct size and therefore can protect myocardium against reperfusion injury in vivo. Enflurane had only a marginal effect and isoflurane offered no protection against reperfusion injury in vivo. These different effects suggest different protective mechanisms at the cellular level.

Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo.

Free oxygen radicals and intracellular calcium homeostasis play important roles in the development of myocardial reperfusion injury. Propofol is a radical scavenger with calcium channel blocking properties. We have investigated the effects of propofol on myocardial reperfusion injury. We used an isolated rat heart model where heart rate, ventricular volume and perfusion pressure were constant. The left anterior descending coronary artery (LAD) was occluded for 30 min and reperfused for 2 h. We studied an untreated control group, an Intralipid group (l μl ml −1 ) and a propofol group (Intralipid I μl ml −1 and propofol l μg ml −1 ) ( n = 12 each). Drugs were infused for 20 min starting 5 min before reperfusion. We measured left ventricular developed pressure (LVDP), coronary flow and infarct size. LAD occlusion reduced mean LVDP from 129 (SEM 4) to 36 (3) mm Hg and mean coronary flow from 12.2 (0.3) to 5.2 (0.2) ml min −1 . During reperfusion, LVDP recovered to 98 (4) mm Hg and coronary flow to 11.9 (0.4) ml min −1 . Haemodynamic variables were similar in all groups. Propofol had no effect on infarct size compared with the Intralipid group (25.0 (3.7) vs 26.9 (3.3)% of the area at risk; P =0.89). Infarct size in the Intralipid group tended to be smaller compared with the control group (34.8 (3.2)%; P =0.19). We conclude that propofol, at a clinically relevant concentration, provided no protective effect against myocardial reperfusion injury in the rat heart in vitro .

Effect of propofol on reperfusion injury after regional ischaemia in the isolated rat heart

BACKGROUND: In skeletal muscle, dantrolene reduces free cytosolic calcium by inhibiting calcium release from the sarcoplasmic reticulum. A similar effect in ischemic-reperfused heart cells would protect myocardial tissue against reperfusion injury. We tested the hypothesis that dantrolene infusion during reperfusion protects the heart against reperfusion injury. METHODS: Isovolumetric beating rat hearts were subjected to 30 min of ischemia followed by 60 min of reperfusion. Left ventricular (LV) developed pressure (LVDP) and creatine kinase release (CKR) were determined as indices of myocardial performance and cellular injury, respectively. In the treatment groups, dantrolene (25 (DAN25) or 100 (DAN100) micromol l(-1)) was infused during the first 15 min of reperfusion; control hearts received the respective concentration of the vehicle (mannitol (CON25, CON100), each group n=7). To investigate the effects of dantrolene on reperfusion injury in vivo, 18 chloralose-anesthetized rabbits were subjected to 30 min occlusion and 180 min reperfusion of a major coronary artery. LV pressure (LVP), cardiac output (CO), and infarct size were determined. During the last 5 min of ischemia, nine rabbits received 10 mg kg(-1) dantrolene intravenously (DAN). Another nine rabbits received the vehicle (dimethylsulfoxide) and served as controls (CON). RESULTS: In isolated rat hearts, there was no recovery of LVDP in any group. Total CKR during 1 h of reperfusion was 845+/-76 (CON100) and 550+/-81 U g(-1) dry mass (DAN100, P <0.05). In rabbits in vivo, hemodynamic baseline values were similar between groups (CON vs. DAN: LVP, 99+/-6 (mean+/-SEM) vs. 91+/-6mm Hg, P=0.29; CO, 252+/-26 vs. 275+/-23 ml min(-1), P= 0.53). During coronary artery occlusion, LVP and CO were reduced in both groups (CON: LVP, 89+/-3%; CO, 90+/-5% of baseline values) and LVP did not recover to baseline values during reperfusion (51+/-5% (CON) vs. 67+/-7% (DAN) of baseline, P=0.10). Infarct size was 41+/-4% of the area at risk in controls and 37+/-6% in dantrolene treated hearts (P=0.59). CONCLUSIONS: Dantrolene reduced CKR, indicating an attenuation of lethal cellular reperfusion injury in isolated rat hearts. However, in the rabbit in vivo, there was no effect on the extent of reperfusion injury after regional myocardial ischemia

T. Comfère

Papers

Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo.

Effect of propofol on reperfusion injury after regional ischaemia in the isolated rat heart

Effect of dantrolene in an in vivo and in vitro model of myocardial reperfusion injury.