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Ann Thorac Surg 1997;63:1268-1274
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Normothermic Retrograde Blood Cardioplegia With or Without Preceding Ischemic Preconditioning

Departments of Anesthesiology, Thoracic Surgery, and Internal Medicine, Oulu University Hospital, Oulu, Finland

Accepted for publication November 8, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Background. Preconditioning has been suggested as the most powerful mechanism of myocardial protection against prolonged ischemia. However, whether preconditioning offers additional benefits over cardioplegia during coronary artery bypass grafting is not known.

Methods. Thirty patients undergoing coronary artery bypass grafting were randomized into two groups. After aortic cross-clamping, group 1 received antegrade blood and blood cardioplegia followed by normothermic retrograde blood cardioplegia (controls), whereas group 2 patients were subjected to 5 minutes of global ischemia followed by reperfusion with antegrade and retrograde blood cardioplegia (preconditioned). The transcardiac differences in oxygen saturation, pH, and lactate were measured during cardiopulmonary bypass. Myocardial biopsy specimens were taken from half of the patients for adenosine triphosphate determination. The extent of myocardial injury was estimated by monitoring the postoperative leakage of creatine kinase-MB and troponin T. Immediate hemodynamic recovery and postoperative complications were also observed.

Results. The 5-minute preconditioning induced marked lactate and acid production, and myocardial adenosine triphosphate levels tended to decrease. The hearts continued to produce lactate and acid during retrograde cardioplegia, but the transcardiac pH and lactate differences were similar in both groups. Adenosine triphosphate level measured at the end of the cross-clamp period was decreased to a half and one third of the preclamp values in the control and preconditioned groups, respectively. The postoperative creatine kinase-MB and troponin T effluxes tended to be more elevated in the preconditioned group, yet hemodynamic recovery and the number of postoperative complications were similar in both groups.

Conclusions. The results show that a 5-minute preconditioning ischemia does not offer any additional benefits over normothermic retrograde blood cardioplegia during coronary artery bypass grafting.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Protection against prolonged ischemia by one or more preceding short ischemic and reperfusion episodes, a phenomenon known as ischemic preconditioning, was first described by Murry and associates [1]. Increased tolerance of a later, potentially lethal, episode of ischemia is manifested by better preservation of the myocardial energy state, delayed onset of irreversible cell injury, limitation of infarct size, better recovery of contractile function, and fewer reperfusion arrhythmias [2–5].

Optimal myocardial protection during coronary artery bypass grafting relies on adequate delivery of the cardioplegic solution to all parts of the heart. Because the areas distal to complete coronary artery occlusions or severely stenosed vessels are poorly protected by antegrade cardioplegia, retrograde administration through the coronary sinus has emerged as a good alternative in these cases [6, 7]. The occasional need to discontinue retrograde blood cardioplegia predisposes the myocardium to ischemic damage, especially when normothermic cardioplegia is used [8]. There has been some concern about the possibility of inhomogenous distribution of retrograde cardioplegia [9] with inadequate protection of the right ventricle and the posterior left ventricular septum [10], which means that use of this mode of cardioplegia can lead to unintentional ischemia, at least in some areas of the myocardium.

Although ischemic preconditioning has been investigated in animal models simulating coronary artery bypass grafting [11, 12], human studies are rare [13, 14]. We decided to conduct a prospective clinical trial to compare normothermic retrograde blood cardioplegia with and without ischemic preconditioning. The aim was to investigate whether a 5-minute period of global ischemia preceding normothermic cardioplegia is able to precondition the myocardium and thus offer additional protection during elective coronary artery bypass grafting. Altogether 30 patients with coronary artery disease undergoing elective bypass grafting were randomized to undergo normothermic retrograde blood cardioplegia alone or in combination with an initial 5 minutes of global ischemia. The transcardiac differences in oxygen content, lactate, and pH were monitored before, during, and after aortic cross-clamping. Myocardial biopsy specimens for measurement of tissue adenosine triphosphate (ATP) level were taken before aortic cross-clamping, 5 minutes after cross-clamping, and at the end of the cross-clamping period. The extent of myocardial injury was estimated by monitoring the postoperative leakage of troponin T (TnT) and creatine kinase-MB (CK-MB). Immediate hemodynamic recovery and postoperative complications were also recorded.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Patients
This research was approved by the Ethical Committee of Oulu University Hospital, and the patients gave their informed written consent before the operation. Thirty patients admitted for elective aortocoronary bypass grafting were randomized into two groups: normothermic retrograde blood cardioplegia with (group 1) and without (group 2) preceding ischemic preconditioning. The exclusion criteria were ejection fraction less than 0.40, significant left main stenosis, and unstable angina pectoris.

	Anesthesia

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
All medications were allowed without interruption until the day of operation. Premedication consisted of oral diazepam (0.2 mg/kg) and intramuscular morphine (0.15 mg/kg), given 1 hour preoperatively. Before induction of anesthesia the left radial artery was cannulated and a Swan-Ganz pulmonary artery catheter was introduced through the right innominate vein. A standardized anesthetic technique was used with continuous infusion of propofol (4 mg • kg^-1 • h^-1) and alfentanil (0.05 mg • kg^-1 • h^-1). Patients were also given fentanyl (0.5 mg) at induction of anesthesia. Pancuronium (0.1 mg/kg) was used for muscle relaxation, and the patients were ventilated with 40% oxygen/air. Enflurane was used when needed. Heparin (3 mg/kg) was given before aortic cannulation for cardiopulmonary bypass. The activated clotting time was always kept at more than 460 seconds during perfusion. Heparinization was reversed with protamine sulfate (3 mg/kg) after decannulation.

	Surgical Technique

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
The operations were performed by the same experienced cardiac surgeon (M.P.K.L.). Cardiopulmonary bypass was established with a single two-stage atrial cannula and ascending aortic cannula. A cardioplegic cannula with venting and pressure monitoring ports (DLP Inc, Grand Rapids, MI) was used for initial antegrade cardioplegia delivery. A retrograde coronary sinus catheter with a manually inflatable balloon (DLP Inc) was positioned using the closed transatrial technique before initiation of the full cardiopulmonary bypass. The distal and proximal anastomoses of the grafts were performed during a single period of aortic cross-clamping.

	Perfusion

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
A membrane oxygenator was used (Compactflow; Dideco, Mirandola, Italy). The hematocrit was maintained at more than 28% during cardiopulmonary bypass, pump flow was 2.4 L • min^-1 • m^-2, and mean arterial pressures were kept at 60 to 80 mm Hg with the aid of nitroglycerin or phenylephrine hydrochloride. The systemic temperature of the patients was kept at 37°C. All the anesthesias and perfusions were taken care of by two experienced anesthesiologists (P.K.K. and K.T.K.).

	Cardioplegia

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
The same aspartate-glutamate-enriched cardioplegic solution was used in both groups. The detailed composition of the cardioplegia has been published previously [15]. One part of the solution in 7 parts of blood (1:7) was delivered by a commercial cardioplegia set (D 720; Dideco). Before arresting the hearts in the preconditioning group were rendered ischemic for 5 minutes by clamping the aorta and keeping the aortic root pressure at zero by means of continuous venting. All the preconditioned hearts continued to beat in sinus rhythm throughout this period, and none started to fibrillate. After the preconditioning ischemia, the hearts were reperfused for 5 minutes with antegrade blood and thereafter arrested by inducing antegrade normothermic cardioplegia with extra KCl at 300 mL/min for 5 minutes, keeping the aortic root pressure at more than 60 mm Hg. Whenever electrical activity reappeared, extra potassium boluses were administered into the cardioplegia line. In the control group the aortic cross-clamp was followed by two antegrade infusions, first with normothermic blood and then with blood cardioplegia. The infusion rates and aortic root pressure were kept similar to those in the preconditioning group. After arresting the hearts, the cardioplegia was switched to retrograde and continued at 200 mL/min in both groups (Fig 1). Coronary sinus pressure was monitored continuously and maintained at less than 40 mm Hg throughout the retrograde cardioplegia. Occasionally, cardioplegia had to be interrupted for short periods to improve visibility during construction of the distal anastomosis. The aortic root was vented continuously during retrograde cardioplegia.

View larger version (17K): [in this window] [in a new window]   Fig 1. . Design of the research. The letters (A, B, C) indicate the times when myocardial biopsy specimens were taken, and the numbers (1–10) indicate those for blood sampling. The first and last three blood samples were taken at fixed points in time (see Material and Methods section), samples 4 to 7 at 29 ± 1.4 minutes, 43 ± 1.5 minutes, 61 ± 2.5 minutes, and 76 ± 3.1 minutes, and 26 ± 1.6 minutes, 39 ± 2.0 minutes, 58 ± 2.4 minutes, and 74 ± 3.6 minutes after aortic cross-clamping in the control (C) and preconditioned (PC) groups, respectively. (CPL = cardioplegia.)

	Myocardial Biopsies

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

	Hemodynamics

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Heart rate, mean arterial pressure, central venous pressure, pulmonary artery wedge pressure, and cardiac output by the thermodilution technique were measured before the induction of anesthesia, when the patients arrived at the intensive care unit, 4 hours afterward, and the next morning. Cardiac index, stroke index, right and left ventricular stroke work indices, and pulmonary and systemic vascular resistances were calculated using standard formulas.

	Laboratory Data

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Blood samples were taken simultaneously from the cardioplegia line and aortic root. Oxygen and carbon dioxide tensions, pH, and oxygen saturation were determined with a 288 blood gas system (Ciba-Corning, Medfield, MA). Lactate was assayed using an electrode-based lactate analyzer (YSI model 1500; Yellow Springs Instrument Co, Inc, Yellow Springs, OH). The MB isoenzyme of CK (CK-MB) was measured by an electrophoretic method (REP, Helena Laboratories, Beaumont, TE), and TnT by a manual version of an enzyme-linked immunosorbent assay specific for cardiac TnT (Boehringer Mannheim, Mannheim, Germany). Oxygen content was calculated as 1.39 hemoglobin concentration x oxygen saturation + 0.003 oxygen tension. The differences in oxygen contents between the inflow and outflow samples were multiplied by the cardioplegic flow rate to calculate myocardial oxygen consumption during the cross-clamp period. The transcardiac pH and lactate differences were also calculated. The areas under the curves of the transcardiac lactate differences and postoperative serum levels of CK-MB and TnT were calculated by adding the areas under the graph between each pair of consecutive observations (trapezoidal rule).

Blood samples were obtained: (1) just before aortic cross-clamping, (2) 1 and (3) 4 minutes after the initiation of antegrade cardioplegia, (4–7) after completion of the first four distal anastomoses, and (8–10) 1, 5, and 15 minutes after declamping (Fig 1). In the cases with only three distal anastomoses, sample 7 was taken after construction of the first proximal anastomosis at approximately the same time point as the fourth distal anastomosis was completed in the other cases. Samples for the CK-MB and TnT assays were collected every 4 hours for the first 48 hours after aortic cross-clamping.

Adenosine triphosphate was assayed in the myocardial biopsy extracts enzymatically.

	Postoperative Follow-up

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
The postoperative course was followed, and daily electrocardiograms were analyzed by the same cardiologist (K.J.P.), who was blinded as to the group to which the patient had been assigned. Perioperative myocardial infarction was defined as the appearance of new Q waves, a left bundle-branch block, or poor R wave progression associated with simultaneous elevations of CK-MB level at more than 60 IU/L and TnT level more than 3.5 g/L [15, 16]. Patients were considered to be suffering from low output syndrome whenever systolic blood pressure was less than 90 mm Hg and the cardiac index was less than 2 L • min^-1 • m^-2 despite an adequate preload, inotropic support, and reduction of the afterload. Postoperative morbidity and mortality were analyzed on day 30 after the operation.

	Statistical Analysis

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
The statistical analyses were performed using the CSS statistical package program (StatSoft, Tulsa, OK). The unpaired Student's t test and ² test were used when comparing clinical variables between the two groups, and analysis of variance for repeated measures to test time-dependent changes in the measured variables. When the F values indicated that significant differences were present, Scheffé's post-hoc test was used. Pearson's correlation was used to measure the relation between two or more variables. The data are presented as means ± standard error of the mean. Significance was assumed when the p value was less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Patients
The preconditioning and control groups had similar preoperative characteristics, without any significant differences with respect to the New York Heart Association classification of angina, risk factors for coronary artery disease, previous myocardial infarctions, medication, number of diseased vessels, or ejection fraction (Table 1).

	Perioperative Course

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

	Metabolic Changes

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
There were no significant differences in myocardial oxygen consumption between the groups. The average oxygen consumption during delivery of antegrade cardioplegia was 11.7 ± 1.3 mL/min and 10.9 ± 1.1 mL/min in the control and preconditioned groups, respectively, whereas the corresponding values were 5.5 ± 0.8 mL/min and 5.5 ± 0.6 mL/min during retrograde cardioplegia. Oxygen consumption was somewhat higher than observed by us for normothermic retrograde cardioplegia delivered at lower rate than in this study [15]. The samples for the analysis of acid-base balance and lactate determination were taken simultaneously from the proximal coronary sinus and aortic root, and the outflow-inflow differences were calculated. The hearts had already produced some lactate while on cardiopulmonary bypass before aortic cross-clamping, but the 5-minute preconditioning caused a marked net efflux of lactate and tissue acidosis, therefore the transcardiac pH and lactate differences were still much higher in the preconditioning group than in the control group 1 minute after starting the delivery of antegrade cardioplegia (0.18 ± 0.02 U/L versus 0.08 ± 0.03 U/L, p < 0.001, and 2.16 ± 0.20 mmol/L versus 0.64 ± 0.20 mmol/L, p < 0.001). The pH and lactate differences during aortic cross-clamp and retrograde blood cardioplegia were similar in both groups. It should be noted that lactate production reverted to lactate extraction soon after aortic declamping in the preconditioned group, whereas the control group continued to produce lactate. This was not reflected in the pH differences, however (Figs 2, 3). The areas under the curves for the overall transcardiac pH and lactate differences did not differ significantly.

View larger version (36K): [in this window] [in a new window]   Fig 2. . Inflow and outflow concentrations of lactate. The sampling times are the same as in Figure 1. p < 0.0001 for both groups with analysis of variance for repeated measurements. At sampling point 2, 6 minutes after aortic cross-clamping, the preconditioned group was producing more lactate (**p < 0.001, Scheffé's test). The values are means ± standard error of the mean; n = 15 for both groups. (Black bars = preconditioned; Open bars = control.)

View larger version (34K): [in this window] [in a new window]   Fig 3. . Inflow and outflow pH values. The sampling times are the same as in Figure 1. The transcardiac pH difference was higher in the preconditioned group at sampling point two (**p < 0.001, Scheffé's test). Symbols are as in Figure 2. The values are means ± standard error of the mean; n = 15 for both groups.

View larger version (13K): [in this window] [in a new window]   Fig 4. . Levels of myocardial adenosine triphosphate (ATP). Adenosine triphosphate level was lower in the control group than in the preconditioned group before aortic cross-clamping and 5 minutes thereafter (**p < 0.001). There was a decrease in the adenosine triphosphate content during aortic cross-clamping within both groups (##p < 0.001, ###p < 0.0001). The values are means ± standard error of the mean; n = 7 for controls and n = 6 for preconditioned hearts.

	Tissue Injury

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

View larger version (25K): [in this window] [in a new window]   Fig 5. . Postoperative levels of serum troponin T and creatine kinase-MB (CK-MB). These levels tended to be higher in the preconditioned group (closed circles) than in the control group (open circles), but the difference was not statistically significant.

	Hemodynamic Recovery

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Heart rate increased postoperatively and remained higher than preoperatively in both groups, whereas mean arterial pressure decreased, but only transiently. Central venous and pulmonary capillary wedge pressures tended to decrease in both groups. The cardiac and stroke indices decreased immediately after the operations, but recovered quickly, whereas the right and left ventricular stroke work indices decreased but did not recover completely during the observation period. The need for inotropes was similar in the two groups. Systemic vascular resistance tended to decrease postoperatively, whereas pulmonary vascular resistance increased, but was normalized within the observation period. There were no group differences in any of the hemodynamic variables measured. In general the hemodynamic changes resembled those observed in our previous study with normothermic retrograde blood cardioplegia [15].

	Postoperative Course

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
There were two reoperations for bleeding in the preconditioning group, and one in the control group on account of a suspicion of graft occlusion. One patient in the control group had low output syndrome upon arrival to the intensive care unit, but recovered during the next 6 hours without an intraaortic balloon pump. The number of other postoperative complications did not differ significantly between the groups. The incidence of supraventricular arrhythmias was 40% and 47% in the preconditioning and control groups, respectively. One right bundle-branch block was observed in the preconditioning group and two in the control group, but all of them were transient in nature. One patient in the control group had hemiplegia and aphasia 1 day after the operation and was diagnosed to have suffered from a cerebral infarction. There were two infections in the preconditioning group: one wound infection in the leg and one mediastinitis. Both infections were treated with success. There was no mortality in the series.

	Comment

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
The results of this study demonstrate that the hearts rendered ischemic for 5 minutes shortly before arrest and initiation of retrograde cardioplegia did not do any better than the control hearts. The transcardiac differences in pH and lactate during aortic cross-clamp did not differ in the groups, and the ATP levels at the end of the aortic cross-clamp period were similarly decreased. The myocardial tissue injury estimated on the basis of the CK-MB and TnT effluxes tended to be more prominent in the preconditioned group. In fact, 3 patients in this group suffered from small perioperative non-Q-wave myocardial infarctions in terms of the predetermined criteria. Finally, the preconditioned and control hearts recovered equally well functionally, and there were no major differences in postoperative complications.

Galiñanes and colleagues [11] recently demonstrated with rat hearts that ischemic preconditioning combined with antegrade crystalloid cardioplegia offers some additional protection as compared with cardioplegia alone, when coronary arteries were occluded proximally. When Yellon and associates [13] examined the effect of preconditioning, induced with two 3-minute ischemic episodes (each followed by 2 minutes of reperfusion) produced by cross-clamping the aorta and with the heart paced at 90 beats/min, on human myocardial ATP levels after a 10-minute period of cross-clamping with ventricular fibrillation, they found that the preconditioned hearts had a higher ATP content after the longer ischemic insult than those not exposed to preceding brief ischemic episodes. Neither of these human studies, although providing evidence suggesting that preconditioning may have favorable metabolic effects during coronary artery bypass grafting, evaluated the effects of preconditioning on myocardial damage, recovery of contractile function after operation, postoperative morbidity, and ultimately mortality.

We do not have any definite explanations for the different results obtained here relative to previous reports [11–14], but it may well be that the species studied, the presence or absence of cardioplegia itself, or the mode of cardioplegia (blood versus crystalloid), its temperature (cold versus warm), delivery route (antegrade versus retrograde), or delivery rate can affect the protective capability of adjunctive ischemic preconditioning. Yellon [13] and Alkhulaifi [14] and their colleagues, studying human subjects, used intermittent aortic cross-clamping and ventricular fibrillation without cardioplegia, and Galiñanes and associates [11] used antegrade crystalloid cardioplegia (St. Thomas`s cardioplegic solution) on rats. We have made an earlier investigation into the changes in the myocardial energy state and its relations to lipid peroxidation during intermittent antegrade blood cardioplegia, in which cardioplegia was delivered for a few minutes after each distal anastomosis had been constructed at about 15-minute intervals. The relative release of purines and malondialdehyde tended to decrease upon repeated ischemia and reperfusion, suggesting less degradation of myocardial adenylates toward the end of the aortic cross-clamp period [17, 18]. This could be taken to represent one form of ischemic preconditioning.

The present preclamp myocardial ATP levels were lower in the control group than in the preconditioned group, and they were also somewhat lower in the controls than those observed by Yellon and colleagues [13]. It may be that the hearts were more ischemic before the aortic cross-clamp in the control group, as net lactate production in these hearts was also somewhat greater at this time point (see Fig 2). Normothermic retrograde blood cardioplegia could not prevent deterioration of the myocardial energy state during aortic cross-clamping, the relative decrease in myocardial ATP content being more prominent in the preconditioned group.

One could argue that interrupting the retrograde blood cardioplegia, as was done in this study, could precondition the myocardium during retrograde cardioplegia, and this would reduce the differences between the two groups. However, there is no evidence to support this. The average length of ischemia caused by interruptions of retrograde cardioplegia was 2.1 and 1.9 minutes in the control and preconditioned groups, respectively, which is probably close to the minimum time that could induce preconditioning [19]. It has been suggested that glycogen depletion induced by preconditioning ischemia limits the decrease in pH during a subsequent ischemic period, although this is not necessarily the major mechanism of tissue protection [20]. We did not observe any progressive decrease in the transcardiac pH or lactate differences during retrograde blood cardioplegia, which suggests unaltered rates of glycolysis and speaks against preconditioning during this period (see Figs 2, 3).

It is interesting that the hearts preconditioned with a 5-minute period of global ischemia preceding cardioplegia started to extract lactate after aortic declamping, whereas control hearts continued to produce lactate. This could have been attributable to depleted glycogen stores at the end of the aortic cross-clamp period, as the overall lactate efflux was greater in the preconditioned hearts. Another possibility is the better recovery of oxidative metabolism in these hearts.

Minor perioperative tissue damage and small myocardial infarctions during aortocoronary bypass grafting are difficult to diagnose. Cardiac TnT has been suggested as being more sensitive and specific for this purpose [16]. Three of our patients had CK-MB levels at more than 60 IU/L and TnT levels at more than 3.5 g/L in one or more of the serum samples taken at 4-hour intervals for 48 hours after aortic declamping, and they can be taken to have suffered from small perioperative infarctions. All of these patients belonged to the preconditioning group, and this was the major reason for the more significant CK-MB and TnT effluxes in this group. On the other hand, there were some patients with CK-MB levels between 60 and 100 IU/L who had TnT levels well below 3.5 g/L. Although we do not have any definite explanations for this finding, it seems to us that TnT is a more specific indicator of myocardial injury during cardiac operation and that isolated CK-MB levels of 60 to 100 IU/L do not justify the diagnosis of perioperative myocardial infarction.

In spite of the metabolic derangements and tissue injury during aortic cross-clamp the hemodynamic recovery was uncomplicated and the number of postoperative complications low in both patient groups. These facts strongly suggest that normothermic retrograde blood cardioplegia is a good alternative for myocardial protection during coronary artery bypass grafting and that preconditioning before arrest does not offer any additional benefits under the conditions of the present study.

Evidence has been put forward that ischemic preconditioning exists in humans, increasing the tolerance of the myocardium for ischemia during coronary artery bypass grafting when performed using intermittent aortic cross-clamping [13, 14]. Our results demonstrate, however, that preconditioning ischemia preceding cardiac arrest and the initiation of retrograde warm blood cardioplegia did not offer any additional protection for the myocardium. On the contrary, the data suggest that somewhat less tissue injury was recorded in the group receiving cardioplegia alone. Hemodynamic recovery and the number of postoperative complications were both similar in the two patient groups. In spite of the negative results obtained, we believe that the potential for recruiting endogenous protective mechanisms and ischemic preconditioning should be tested in future clinical series using different strategies for myocardial protection during coronary artery bypass grafting.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
This study was supported by grants from the Finnish Foundation for Cardiovascular Research.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 
Address reprint requests to Dr Peuhkurinen, Division of Cardiology, Department of Internal Medicine, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland.

	References

Top Footnotes Abstract Introduction Material and Methods Anesthesia Surgical Technique Perfusion Cardioplegia Myocardial Biopsies Hemodynamics Laboratory Data Postoperative Follow-up Statistical Analysis Results Perioperative Course Metabolic Changes Tissue Injury Hemodynamic Recovery Postoperative Course Comment Acknowledgments References

 

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