Ischemic Preconditioning Does Not Improve Myocardial Preservation During Off-Pump Multivessel Coronary Operation

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1 Ischemic Preconditioning Does Not Improve Myocardial Preservation During Off-Pump Multivessel Coronary Operation Hannu J. Penttilä, MD, Martti V. K. Lepojärvi, MD, PhD, Päivi K. Kaukoranta, MD, PhD, Kai T. Kiviluoma, MD, PhD, Kari V. Ylitalo, MD, PhD, and Keijo J. Peuhkurinen, MD, PhD Departments of Anesthesiology and Cardio-Thoracic Surgery, Oulu University Hospital, Oulu, Department of Medical Biochemistry, Oulu University, Oulu, and Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland Background. The value of ischemic preconditioning during coronary operations has remained controversial. The aim of this study was to evaluate the effects of ischemic preconditioning on myocardial energy metabolism and tissue injury during off-pump multivessel coronary surgery. Methods. Eleven patients with preceding preconditioning were compared with 11 patients without it. The preconditioning group underwent a 5-minute period of ischemia followed by a 5-minute reperfusion period before coronary occlusion for each of the first two anastomoses. Results. The transmyocardial differences (coronary sinus arterial) in inosine and the sum of adenine degradation products increased in both groups, but the differences in xanthine and hypoxanthine increased only in the preconditioning group. Myocardial lactate production increased to a maximum of 0.09 mmol/l with preconditioning and to a maximum of 0.17 mmol/l without it. Transmyocardial ph differences increased to 0.03 U in both groups. The maximum postoperative concentration of creatine kinase-mb mass was 14.8 g/l with preconditioning and 6.3 g/l without preconditioning, and that of troponin I 7.4 g/l and 5.2 g/l, respectively. There were no statistically significant differences between the groups, however. Conclusions. Ischemic preconditioning of 5 minutes followed by reperfusion of 5 minutes during off-pump multivessel coronary artery surgery did not prevent myocardial metabolic derangement and tissue injury and thus cannot be routinely recommended. (Ann Thorac Surg 2003;75: ) 2003 by The Society of Thoracic Surgeons Ischemic preconditioning (IPC), defined as protection of the myocardium by inducing a short ischemic period before a subsequent longer period of ischemia, was first described by Murry and colleagues [1]. Since then, the phenomenon has been confirmed in numerous animal studies, but despite intensive research, its basic cellular mechanisms are not yet fully understood [2, 3]. Preinfarction angina in humans has been found to act like IPC because it preserves left ventricular function, even without collateral coronary artery circulation [4]. Coronary artery angioplasty has been a popular model in studying IPC in human subjects, but the results are conflicting [5 7]. In coronary artery bypass grafting (CABG) performed with cardiopulmonary bypass, IPC has been found to be effective during intermittent aortic crossclamping [8, 9] or with normothermic or mild hypothermic cardioplegia but not with cold cardioplegia [10 12], although several conflicting results also exist [13 16]. In a rat model, IPC alone had similar protective effects as cardioplegia [17] and also ensured optimal myocardial Accepted for publication Oct 16, Address reprint requests to Dr Penttilä, Department of Anesthesiology, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland; hannu.penttila@tyks.fi. protection when the delivery of cardioplegic solution was impaired [18]. In CABG without cardiopulmonary bypass, the coronary artery to be grafted is usually occluded during the suturing of the distal anastomosis, and the ischemic periods are longer than those in coronary angioplasty, thus offering a model to study the effects of IPC in human subjects. The aim of this prospective, randomized study was to evaluate whether preconditioning has a protective effect against ischemia-induced derangement of myocardial energy metabolism and tissue injury during multivessel CABG on a beating heart. Material and Methods Patients The study was approved by the Ethical Committee of Oulu University Hospital. Thirty-three patients with coronary artery disease considered suitable for CABG without cardiopulmonary bypass were included in the series after written informed consent had been obtained. The exclusion criteria were ongoing ischemia, acute myocardial infarction less than 1 month previously, poorly controlled diabetes, serum creatinine level higher than 2003 by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Science Inc PII S (02)

2 Ann Thorac Surg PENTTILÄ ET AL 2003;75: ISCHEMIC PRECONDITIONING DURING OPCAB mol/l, chronic atrial fibrillation, and aortic or mitral valvular disease. The patients were randomly assigned to three study groups: 22 patients were operated on off pump, of which 11 (study group) were preconditioned with regional ischemia before the construction of each of the first two anastomoses, and 11 patients (control group) were operated on without preconditioning. The patients in the third group (11 patients) were operated conventionally on pump. This on-pump group previously has been compared with the off-pump group without IPC (control group of the present study) in order to evaluate the effects of cardiopulmonary bypass and cardioplegia on myocardial injury and energy preservation [19]. Only the off-pump patients, with or without IPC, were included in this study to evaluate the effects of IPC during off-pump operations. Anesthesia All patients were anesthetized by the same experienced cardiac anesthesiologist (H.J.P.). All medications except salicylates were allowed without interruption until the day of the operation. Salicylates were withdrawn 1 to 2 weeks before the operation, except in 4 patients, 1 in the control group and 3 in the IPC group. Premedication consisted of oral diazepam (10 to 20 mg), intramuscular morphine (7 to 10 mg), and oral dipyridamole (200 mg). The radial artery was cannulated, and a Swan-Ganz pulmonary artery catheter (Baxter Healthcare Corp, Santa Ana, CA) for continuous monitoring of cardiac output and mixed venous oxygen saturation was introduced. Anesthesia was induced with propofol (1.1 to 2.8 mg/kg) and fentanyl (3.2 to 6.2 g/kg). Muscle relaxation was achieved with pancuronium (0.07 to 0.11 mg/kg). The patients lungs were ventilated with 30% to 50% oxygen in air, and anesthesia was maintained with propofol (1.3 to 5.2 mg kg 1 h 1 ), alfentanil (21.2 to 45.5 g kg 1 h 1 ), and sevoflurane (minimal alveolar concentration 0.7 to 1.9). All patients received 20 mg of intravenous dipyridamole before the beginning of the operation. The patients were given heparin, 1 mg/kg, for anticoagulation, and additional heparin was given when needed to maintain the activated coagulation time above 300 seconds. Heparinization was reversed with protamine sulfate (50 to 100 mg). Intraoperative myocardial ischemia was evaluated by continuous automatic monitoring of the ST segment in the modified leads V5 and II and by observing the appearance of a V wave in the pulmonary artery wedge pressure curve. Ischemia, if present, was treated with intravenous nitroglycerine. If the patient did not respond to nitroglycerine, an intracoronary flow-through catheter was inserted. The mean arterial blood pressure was maintained above 50 mm Hg with phenylephrine hydrochloride and enhanced intravenous fluid infusion. After the vein grafts were harvested, the patient was actively heated by placing a thermoblanket over the lower body to raise the core temperature above 36 C. Fig 1. Study design and blood sampling schedule. (IPC ischemic preconditioning [an ischemic period of 5 minutes followed by reperfusion for 5 minutes]; Time [T] 0 before bypass grafting; T 1 T 2 immediately after the completion of the first two distal anastomoses; T 3 T 4 5 and 15 minutes after the suturing of the last anastomosis; T 5 T 6 2 and 8 hours after the suturing of the last anastomosis; T 7 T 10 first to fourth postoperative day.) Surgical Technique All operations were performed by the same experienced cardiac surgeon (M.V.K.L). A conventional midline sternum-splitting incision was used, and a coronary sinus catheter (Pediatric RCSP Cannula, Grand Rapids, MI) was introduced through the right atrial wall before suturing the anastomoses. Pericardial traction sutures and elevating gauze pads were used to facilitate visibility and access to either the left or the right side of the heart. Hemostatic silicone loops (Retract-O-Tape, Quest Medical Inc, Allen, TX) were used to obstruct the coronary artery for IPC. The IPC consisted of an ischemic period of 5 minutes followed by a reperfusion period of 5 minutes. The first IPC was performed before the first coronary artery closure for suturing the distal anastomosis and the second before the second closure (Figure 1). The following coronary closures were performed without preceding preconditioning. A commercial mechanical suction stabilizer (Octopus, Medtronic, Medtronic Inc, Minneapolic, MN) and

3 1248 PENTTILÄ ET AL Ann Thorac Surg ISCHEMIC PRECONDITIONING DURING OPCAB 2003;75: Table 1. Demographics and Perioperative Course Variable n or Mean (95% Confidence Interval) Without IPC Age (y) 59.0 ( ) 59.5 ( ) Body mass index (kg/m 2 ) 30.6 ( ) 27.2 ( ) New York Heart Association class (II/III/IV) 0/10/1 1/10/0 Diseased vessels (1/2/3) 0/5/6 1/6/4 Myocardial infarctions (0/1/2) 6/3/2 6/5/0 Ejection fraction 50% 2 1 The total number of bypassed coronaries (RCA/LAD/Cx) 11/8/15 10/15/6 Patients (n) receiving 2/3/4/5 bypass grafts 4/3/3/1 4/5/2/0 Operation time (min) 242 ( ) 231 ( ) Total ischemia time (min) 50.3 ( ) 41.6 ( ) IPC Cx circumflex coronary artery and/or its branches; IPC ischemic preconditioning; LAD left anterior descending coronary artery and/or its branches; RCA right coronary artery and/or its branches. moist air blower were used to facilitate the construction of distal anastomoses, and coronary artery probes were used to diminish the bleeding of the target artery. The left internal thoracic artery was used as a bypass graft in every patient. The most severely diseased coronary artery was always grafted first. The grafted coronary arteries are shown in Table 1, and the first and the second bypass grafts in Figure 2. The proximal anastomoses of vein grafts were finished with the aid of a partially occluding aortic side clamp. Laboratory Data and Electrocardiogram Intraoperative blood samples were withdrawn simultaneously from the arterial catheter and the coronary sinus Fig 2. Coronary occlusion times (means and 95% confidence intervals), ischemic preconditionings for the first two bypass grafts, and a list of the first two bypassed coronaries. (CI confidence interval; Cx circumflex coronary artery and its branches; Dg diagonal coronary artery; IPC ischemic preconditioning; LAD left anterior descending coronary artery; RCA right coronary artery and its branches; T 0 T 2 sampling times [Fig 1].) catheter (T 0 T 4 in Fig 1). Oxygen and carbon dioxide tensions and ph were determined with a 288 blood gas system (Ciba Corning Diagnostics Corp, Walpole, MA), and oxygen content was calculated as follows: 1.39 hemoglobin concentration oxygen saturation oxygen tension. Transcardiac differences of ph and carbon dioxide tension were determined, and myocardial oxygen extraction was calculated from the oxygen content values. Lactate was assayed by using an electrode-based lactate analyzer (YSI model 1500; Yellow Springs Instrument Co, Inc, Yellow Springs, OH), and transcardiac differences were calculated. To measure the plasma levels of adenosine triphosphate (ATP) degradation products (adenosine, inosine, hypoxanthine, and xanthine), blood samples were drawn into a syringe containing dipyridamole solution. The samples were processed and the metabolites were assayed as described earlier [20], and the transcardiac concentration differences in the ATP degradation products were calculated. After the operation, the electrocardiogram was recorded, and the mass of the isoenzyme MB of creatine kinase (CK-MBM) and cardiac troponin I (TnI) were measured (T 0 and T 5 T 10 in Fig 1). CK-MBM and TnI were analyzed by using microparticle enzyme immunoassay technology (AxSYM, Abbott Laboratories, North Chicago, IL). The electrocardiograms were evaluated by the same experienced cardiologist (K.J.P.), who was blinded to the group assignment of the patients. Perioperative myocardial infarction was defined as either new Q waves or ischemic ST-segment changes with a concomitant elevation of CK-MBM above 30 g/l or TnI levels above 15 g/l [21]. Statistics Statistical analyses were performed by using the Statistica package software, version 5.1 (StatSoft, Inc, Tulsa, OK). The t test for independent changes was used for single continuous variables, and a cross-table was used for single categoric variables to test the differences between the groups. Analysis of variance with contrast

4 Ann Thorac Surg PENTTILÄ ET AL 2003;75: ISCHEMIC PRECONDITIONING DURING OPCAB 1249 analysis was used to analyze the time-dependent variance within the groups and the differences between the groups when repeated measures were made. In the case of non-normal distribution, nonparametric Kruskal- Wallis test was used. The data are presented as means and 95% confidence intervals (CIs). Significance was assumed when the p value was less than Results The two study groups had similar preoperative characteristics and operative courses. The total ischemia time was increased in the IPC group because of the two preconditioning periods. However, there were no differences between the groups in the total ischemia times or in the ischemic times during the suturing of the first two bypass grafts (Table 1 and Fig 2). Myocardial Energy Metabolism The transmyocardial differences in inosine and the sum of ATP degradation products increased significantly without IPC during the construction of the anastomoses (p 0.01 and p 0.04, respectively). In addition to inosine and the sum of ATP degradation products, the transcardiac differences in xanthine and hypoxanthine also increased significantly in the IPC group (p 0.006, p 0.004, p 0.009, and p 0.04, respectively). However, there were no statistically significant differences between the groups (Table 2). The highest value of myocardial lactate production in the IPC group was 0.09 mmol/l (95% CI, 0.01 to 0.17 mmol/l) after the suturing of the first distal anastomosis, with the increase from the initial level being statistically significant (p 0.05). Without IPC, the increase of myocardial net lactate production was statistically significant only after the suturing of the second distal anastomosis (p 0.04), with the maximum value being 0.17 mmol/l (95% CI, 0.07 to 0.27 mmol/l; Fig 3). The transcardiac ph difference increased significantly in both groups (p with IPC, and p 0.01 without it), with the highest value being 0.03 U (95% CI, 0.02 to 0.05 U) in both groups (Figure 3). There were no statistically significant differences between the groups in lactate production or transcardiac ph differences. Myocardial oxygen extraction decreased evenly during and after the construction of the anastomoses from 69.0 ml o 2 /L blood (95% CI, 58.6 to 79.4 ml o 2 /L blood) to 49.7 ml o 2 /L blood (95% CI, 39.7 to 59.8 ml o 2 /L blood) with preceding preconditioning, and from 66.6 (95% CI, 58.0 to 75.3 ml o 2 /L blood) to 43.5 ml o 2 /L blood (95% CI, 37.6 to 49.5 ml o 2 /L blood) without IPC (p 0.001). The oxygen saturation of hemoglobin in coronary sinus blood did not differ between groups, ranging between 39.3% and 77.9%. The transmyocardial difference in blood carbon dioxide tension decreased (p 0.001) from the initial value of 0.81 kpa (95% CI, 0.64 to 0.97 kpa) to 0.66 kpa (95% CI, 0.52 to 0.81 kpa) without IPC, and from 0.79 kpa (95% CI, 0.59 to 0.99 kpa) to 0.74 kpa (95% CI, 0.61 to 0.86 kpa) with IPC. Creatine Kinase-MB Mass and Troponin I The maximum values of CK-MBM were 14.8 g/l (95% CI, 4.9 to 24.7 g/l) with IPC and 6.3 g/l (95% CI, 5.0 to 7.6 g/l) without it. Maximum serum TnI concentrations were 7.4 g/l (95% CI, 3.7 to 11.2 g/l) with IPC and 5.2 g/l (95% CI, 2.6 to 7.8 g/l) without it. The highest values of both myocardial injury markers in both groups were recorded at 8 hours after the construction of the last anastomosis, and there were no statistically significant differences between the groups (Figure 4). One patient without preconditioning was considered to have had perioperative myocardial infarction and was excluded from the analyses of CK-MBM and TnI. Perioperative Course There were no differences between groups in STsegment changes during construction of the anastomoses. Four patients in each group received intravenous nitroglycerine, and 2 of these patients (1 in each group) also had an intracoronary flow-through catheter inserted. One patient without preconditioning received nitroglycerine to decrease his modestly elevated pulmonary artery pressure, and the others were considered to be ischemic. All the patients received phenylephrine hydrochloride to maintain arterial pressure above 50 mm Hg. The lowest mean arterial blood pressure was 62 mm Hg (95% CI, 54 to 70 mm Hg) in the IPC group and 60 mm Hg (95% CI, 55 to 65 mm Hg) without IPC. The lowest cardiac index and mixed venous saturation were 1.9 L/m 2 per minute (95% CI, 1.6 to 2.1 L/m 2 per minute) and 1.6 L/m 2 per minute (95% CI, 1.5 to 1.8 L/m 2 per minute) and 69% (95% CI, 62% to 75%) and 67% (95% CI, 62% to 72%), respectively. One patient in each group required defibrillation to restore sinus rhythm. One patient without preconditioning had new anterolateral Q waves in electrocardiogram with concomitant CK-MBM and TnI increases (273 g/l and g/l, respectively) and was considered to have had a perioperative myocardial infarction. The hemodynamic recovery of this patient was uneventful, however. Four patients without IPC had nonspecific postoperative changes in electrocardiogram indicating pericardial irritation. Three patients with and 1 patient without IPC developed atrial fibrillation after the operation and were converted to sinus rhythm with the -blocking agents amiodarone hydrochloride or ibutilide fumarate. One patient with IPC and 2 patients without IPC received dopamine after the operation, mainly as a treatment for modest hypotension. Only one patient (without IPC) had a cardiac index below 2.2 L/m 2. The mean time to tracheal extubation after the operation was 4.3 hours (95% CI, 3.3 to 5.4 hours) in the IPC group and 4.1 hours (95% CI, 3.4 to 4.9 hours) in the control group. One patient with IPC had mild weakness in the right arm because of a small hemorrhagic brain infarction, which was confirmed with computed tomography. All patients were moved from the intensive care unit to the ward on the first postoperative day, and there were no other

5 1250 PENTTILÄ ET AL Ann Thorac Surg ISCHEMIC PRECONDITIONING DURING OPCAB 2003;75: Table 2. Transcardiac Concentration Differences (Coronary Sinus Artery) of Adenosine Triphosphate Degradation Products a Xanthine ( mol/l) Hypoxanthine ( mol/l) Inosine ( mol/l) IPC Without IPC IPC Without IPC IPC Without IPC T ( ) 0.29 ( ) 1.37 ( ) 1.33 ( ) 0.62 ( ) 0.72 ( ) T ( ) 1.20 ( ) 1.96 ( ) 5.98 ( ) 2.47 ( ) 2.32 ( ) T ( ) 4.55 ( ) 6.64 ( ) 0.80 ( ) 2.02 ( ) 3.70 ( ) T ( ) 4.61 ( ) 2.51 ( ) 0.95 ( ) 0.85 ( ) 4.73 ( ) T ( ) 2.62 ( ) 5.82 ( ) 3.16 ( ) 0.82 ( ) 1.68 ( ) a Results are mean and 95% confidence intervals. The increases in xanthine, hypoxanthine, inosine, and the total of ATP degradation products were significant in the IPC group (p 0.009, p 0.04, p 0.006, and p 0.004, respectively). The transcardiac differences in inosine and the sum of the degradation products increased significantly in the group without IPC (p 0.01 and p 0.04). There were no significant differences between the groups, however. IPC ischemic preconditioning; T 0 before the anastomoses; T 1 after the first distal anastomosis; T 2 after the second distal anastomosis; T 3 5 minutes after completing all the anastomoses; T 4 15 minutes after completing all the anastomoses (Fig 1). major complications during the 5- to 7-day in-hospital period. Comment Off-pump coronary operations offer some advantages over operations with cardiopulmonary bypass and are gaining popularity. The promising results of IPC attempt to predispose the beating myocardium to regional shortterm ischemia before occluding the coronary artery in order to use the benefits of IPC. We evaluated the effects of IPC on myocardial energy metabolism and tissue injury during off-pump coronary operations. The two study groups were comparable with respect to demographics, perioperative courses, and the ischemic burden for the first two bypass grafts (Figure 2). The transcardiac differences in serum ATP degradation products increased only slightly, with the increases being equal in the two groups. This demonstrates that the overall energy state of the myocardium was relatively well maintained during the suturing of the first two bypass grafts. Lactate and acid production are well-accepted indicators of ischemic metabolism. The overall increases in myocardial lactate production and the transcardiac ph differences were slight, and there were no statistically significant differences between the groups. The highest lactate production level occurred after the suturing of the first distal anastomosis in the IPC group and after the second one in the control group (Figure 3). It seems that a 5-minute ischemia period followed by a 5-minute reperfusion period is not enough to provide protection, although a tendency of lower lactate peaking was seen in the IPC group. Iliodromitis and colleagues [22] showed that preconditioning reduces infarct size in rabbits when IPC was repeated up to four times, after which the infarct size increased. The IPC response, however, is species dependent, and the strength of the stimulus and the number of IPC repetitions needed to initiate the preconditioning in human subjects is largely unknown. One IPC cycle of 5 plus 5 minutes was chosen, because this cycle is most often used in studies of ischemic preconditioning. In off-pump operations, it also acts as a test occlusion for ischemic changes before the final coronary occlusion for suturing of the distal anastomosis. Multiple repetitions of the IPC cycle would have significantly increased the operation time, which we regarded as unethical for the patients. In our study, there were no statistically significant differences between groups in the postoperative levels of CK-MBM and TnI, although there was a slight tendency for higher levels of both markers and larger variations in the IPC group. There were 2.8 distal anastomoses and coronary artery occlusions without IPC and 3.1 distal anastomoses and 5.1 coronary occlusions with IPC, including the two occlusions for preconditioning. Thus, the slightly higher level and larger variation of CK-MBM and TnI with IPC can be explained by the larger number of coronary occlusions and the longer cumulative ischemic time. We conclude that IPC, as done in our study, was not beneficial when the operation was done on a beating heart. The results of our study do not exclude the possibility of IPC counteracting impaired myocardial function during ischemia or postoperative stunning, although both seem unlikely in the light of the data on tissue injury markers. Also, cardiac output and mixed venous oxygen saturation were measured continuously during the operations, and they did not show any significant decrease. In this context it is interesting that Malkowski and colleagues [23] did not detect functional improvement in left ventricular wall motion after IPC performed during minimally invasive CABG. Bufkin and colleagues [24] also did not find any improvements in left ventricular function in a canine model. Conversely, the same group found that an IPC period of 5 minutes followed by a reperfusion period of 5 minutes decreased neutrophil accumulation, endothelial dysfunction, and apoptosis [24 26]. Continuous intravenous infusion of hypnotics, analgesics, and phenylephrine hydrochloride during the operations might have induced pharmacologic preconditioning [2, 3]. In addition, use of dipyridamole may recruit

6 Ann Thorac Surg PENTTILÄ ET AL 2003;75: ISCHEMIC PRECONDITIONING DURING OPCAB 1251 Table 2. Continued Adenosine ( mol/l) Total ( mol/l) IPC Without IPC IPC Without IPC 0.32 ( ) 0.18 ( ) 2.40 ( ) 2.52 ( ) 0.40 ( ) 0.36 ( ) ( ) 9.86 ( ) 0.28 ( ) 0.60 ( ) ( ) 8.04 ( ) 0.06 ( ) 0.51 ( ) 4.19 ( ) 9.76 ( ) 0.23 ( ) 0.23 ( ) ( ) 7.69 ( ) endogenous protective mechanisms through increased extracellular adenosine levels and specific receptor occupation. Whether any pharmacologic preconditioning occurred in our patients is impossible to say. Moreover, it is an essential status of the clinical practice in which IPC does not seem to offer any benefits in light of this study. The use of potential preconditioning mimicking agents, as well as the blood sampling protocol, was similar in both study groups, however. There was one small perioperative cerebral infarction in the IPC group and one myocardial infarction in the group without IPC. The patient with myocardial infarction was excluded from the analyses of CK-MBM and TnI because the purpose of this study was to evaluate overall Fig 3. Myocardial lactate production (top) and transcardiac ph difference (bottom) (median, 25% and 75% percentiles, and non-outlier range) before grafting (T 0 ), after the completion of the first (T 1 ) and second (T 2 ) distal anastomoses, and five (T 3 ) and 15 (T 4 ) minutes after the completion of all the anastomoses (Fig 1). The increase in myocardial lactate production was significant after the first anastomosis (p 0.05) with ischemic preconditioning and after the second anastomosis without preconditioning (p 0.04). The increase of the transcardiac ph difference was significant in both groups (p 0.001). There were no differences between the groups. (IPC ischemic preconditioning.) Fig 4. Plasma levels of creatine kinase-mb (CK-MB) mass (top) and cardiac troponin I (bottom) (median, 25% and 75% percentiles, and non-outlier range) before construction of the anastomoses (T 0 ), at 2 (T 5 ) and 8 (T 6 ) hours after the suturing of the last anastomosis, and on the next 4 days (T 7 T 10 ) (Fig 1). There were no statistically significant differences between the groups. (IPC ischemic preconditioning.)

7 1252 PENTTILÄ ET AL Ann Thorac Surg ISCHEMIC PRECONDITIONING DURING OPCAB 2003;75: myocardial preservation during operations with normal courses. Both patients with major complications recovered well, and there were no other major complications during the 1-week in-hospital period. Otherwise, the postoperative courses in the two groups were similar. In conclusion, IPC of 5-minute regional ischemia followed by 5-minute reperfusion did not prevent metabolic perturbations, as evaluated by transcardiac differences of ATP degradation products, lactate, and ph. Neither did IPC reduce myocardial injury evaluated by serum levels of CK-MBM and TnI during multivessel CABG on a beating heart, and thus it cannot be routinely recommended. This study was supported by a grant from the Inari and Reijo Holopainen Foundation. We are grateful to Marja-Leena Lehtonen for her assistance in analyzing the ATP degradation products, and the staff of the operative and postoperative intensive care units of Oulu University Hospital. References 1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74: Yellon DM, Baxter GF, Garcia-Dorado D, Heusch G, Sumeray MS. Ischaemic preconditioning: present position and future directions (Review). Cardiovasc Res 1998;37: Perrault LP, Menasché P. Preconditioning during cardiac surgery. In: Marber MS, Yellon DM, eds. Ischaemia: preconditioning and adaptation. BIOS Scientific Publishers, Oxford, 1996: Nakagawa Y, Ito H, Kitakaze M, et al. Effect of angina pectoris on myocardial protection in patients with reperfused anterior wall myocardial infarction: retrospective clinical evidence of preconditioning. J Am Coll Cardiol 1995; 25: Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW, Herrmann HC, Laskey WK. Adaptation to ischemia during percutaneous transluminal coronary angioplasty: clinical, hemodynamic, and metabolic features. Circulation 1990;82: Eltchaninoff H, Cribier A, Tron C, et al. Adaptation to myocardial ischemia during coronary angioplasty demonstrated by clinical, electrocardiographic, echocardiographic, and metabolic parameters. Am Heart J 1997;133: Ylitalo K, Airaksinen J, Ikäheimo M, Ruskoaho H, Peuhkurinen K. No evidence for ischemic preconditioning during repeated vessel occlusion in coronary angioplasty. Int J Cardiol 1996;55: Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993;342: Alkhulaifi AM, Yellon DM, Pugsley WB. Preconditioning the human heart during aorto-coronary bypass surgery. Eur J Cardiothorac Surg 1994;8: Valen G, Takeshima S, Vaage J. Preconditioning improves cardiac function after global ischemia, but not after cold cardioplegia. Ann Thorac Surg 1996;62: Cleveland JC, Meldrum DR, Rowland RT, Banerjee A, Harken AH. Preconditioning and hypothermic cardioplegia protect human heart equally against ischemia. Ann Thorac Surg 1997;63: Cremer J, Steinhoff G, Karck M, et al. Ischemic preconditioning prior to myocardial protection with cold blood cardioplegia in coronary surgery. Eur J Cardiothorac Surg 1997;12: Perrault LP, Menasché P, Bel A, et al. Cardiopulmonary bypass, myocardial management, and support techniques. Ischemic preconditioning in cardiac surgery: A word of caution. J Thorac Cardiovasc Surg 1996;112: Kaukoranta PK, Lepojärvi MPK, Ylitalo KV, Kiviluoma KT, Peuhkurinen KJ. Normothermic retrograde blood cardioplegia with or without preceding ischemic preconditioning. Ann Thorac Surg 1997;63: Lu EX, Chen SX, Yuan MD, et al. Preconditioning improves myocardial preservation in patients undergoing open heart operations. Ann Thorac Surg 1997;64: Illes RW, Swoyer KD. Prospective, randomized clinical study of ischemic preconditioning as an adjunct to intermittent cold blood cardioplegia. Ann Thorac Surg 1998;65: Kolocassides KG, Galiñanes M, Hearse DJ. Ischemic preconditioning, cardioplegia or both? J Mol Cell Cardiol 1994;26: Galiñanes M, Argano V, Hearse DJ. Can ischemic preconditioning ensure optimal myocardial protection when delivery of cardioplegia is impaired? Circulation 1995;92(Suppl II:II): Penttilä HJ, Lepojärvi MVK, Kaukoranta PK, Kiviluoma KT, Ylitalo KV, Peuhkurinen KJ. Myocardial metabolism and hemodynamics during coronary surgery without cardiopulmonary bypass. Ann Thorac Surg 1999;67: Penttilä HJ, Lepojärvi MVK, Kiviluoma KT, Kaukoranta PK, Hassinen IE, Peuhkurinen KJ. Myocardial preservation during coronary surgery with and without cardiopulmonary bypass. Ann Thorac Surg 2001;71: Alyanakian MA, Dehoux M, Chatel D, et al. Cardiac troponin I in diagnosis of perioperative myocardial infarction after cardiac surgery. J Cardiothorac Vasc Anesth 1998;12: Iliodromitis EK, Kremastinos DT, Katritsis DG, Papadopoulos CC, Hearse DJ. Multiple cycles of preconditioning cause loss of protection in open-chest rabbits. J Mol Cell Cardiol 1997;29: Malkowski MJ, Kramer CM, Parvizi ST, et al. Transient ischemia does not limit subsequent ischemic regional dysfunction in humans: a transesophageal echocardiographic study during minimally invasive coronary artery bypass surgery. J Am Coll Cardiol 1998;31: Bufkin BL, Shearer ST, Vinten-Johansen J, et al. Preconditioning during simulated MIDCABG attenuates blood flow defects and neutrophil accumulation. Ann Thorac Surg 1998;66: Wang NP, Bufkin BL, Nakamura M, et al. Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis. Ann Thorac Surg 1999;67: Thourani VH, Nakamura M, Duarte IG, et al. Ischemic preconditioning attenuates postischemic coronary artery endothelial dysfunction in a model of minimally invasive direct coronary artery bypass grafting. J Thorac Cardiovasc Surg 1999;117: INVITED COMMENTARY Experimentally preconditioning is the most powerful mode of protection against ischemia-reperfusion injury known. In cardiac surgery with cardiopulmonary bypass and cardioplegia, most studies conclude that preconditioning improves myocardial preservation [1]. Only a few investigations have studied ischemic preconditioning in off-pump coronary artery bypass grafting (OPCAB) [2, 3], and the present study is an important contribution to this 2003 by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Science Inc PII S (03)