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Ann Thorac Surg 1998;66:755-761
© 1998 The Society of Thoracic Surgeons
a Department of Anesthesiology, Oulu University Hospital, Oulu, Finland
b Department of Thoracic Surgery, Oulu University Hospital, Oulu, Finland
c Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
Accepted for publication March 7, 1998.
Address reprint requests to Dr Peuhkurinen, Department of Internal Medicine, Kuopio University Hospital, PO 1777, 70211, Kuopio, Finland
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Abstract |
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Methods. Twenty patients undergoing an elective coronary bypass procedure were randomized to receive antegrade or retrograde mild hypothermic blood cardioplegia. Transventricular differences in oxygen extraction, lactate production, and pH were monitored during aortic cross-clamping, and myocardial biopsy specimens were taken from both ventricles before cannulation and 15 minutes after aortic declamping for analysis of adenine nucleotides and their breakdown products. The extent of myocardial injury was estimated by monitoring postoperative leakage of troponin T and the MB isoenzyme of creatine kinase. Hemodynamic recovery and postoperative complications were noted.
Results. The preoperative characteristics of the two groups were similar. Oxygen extraction and lactate production in the right ventricular myocardium were higher in the retrograde group. In this group, the right ventricle also extracted more oxygen and produced more lactate and acid than did the left ventricle. Tissue levels of adenine nucleotides tended to decrease in both ventricles during operation, with no differences between them. The level of adenosine catabolites did increase somewhat in the right ventricular myocardium of the retrograde cardioplegia group after aortic declamping. There was a tendency for more prominent efflux of troponin T and the MB isoenzyme of creatine kinase in the retrograde group. Nevertheless, the postoperative course was uneventful in both groups.
Conclusions. Retrograde mild hypothermic blood cardioplegia leads to metabolic changes compatible with right ventricular ischemia. Nevertheless, tissue levels of high-energy phosphates are well preserved, and the postoperative course seems to be unproblematic. Care should be taken when retrograde normothermic blood cardioplegia is provided for patients with right ventricular hypertrophy, poor right ventricular function, or severe preoperative myocardial ischemia.
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Introduction |
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Controversy over the uniformity of the protective capacity of retrograde blood cardioplegia still exists, however. This concern is based largely on findings that a large percentage of retroperfusate is shunted through the arteriosinusoidal system and thebesian veins into the ventricular cavities as nonnutritive flow, leading to nonhomogeneous distribution of cardioplegia and inadequate protection of the right ventricle and the posterior left ventricles [4–10]. Approximately one quarter of human hearts have a cardiac vein tributary draining the dorsal wall of the right ventricle and entering the coronary sinus near its orifice. Retroperfusion through this vein is endangered if the balloon-tipped coronary sinus catheter is positioned too distally [7]. The occasional need to discontinue cardioplegia can also predispose the myocardium to ischemia, especially when normothermic cardioplegia is used [11–13]. Despite these theoretical pitfalls, good clinical results have generally been achieved with retrograde cardioplegia even in the case of hypertrophied hearts [12, 14, 15].
We conducted a prospective, randomized trial to study the homogeneity of myocardial protection during antegrade or retrograde mild hypothermic blood cardioplegia. Metabolic changes in the right and the left ventricular myocardium were monitored during the aortic cross-clamp period by repeatedly determining the transventricular gradients for oxygen content, lactate production, and pH. In addition, myocardial biopsy specimens for the measurement of adenosine triphosphate and its degradation products were taken from the right and the left anterior myocardium before cannulation and 15 minutes after aortic declamping. The extent of global myocardial injury was estimated by monitoring the postoperative leakage of troponin T and the isoenzyme of MB (CK-MB). Immediate creatine kinase hemodynamic recovery and postoperative complications were also recorded.
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Material and methods |
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Anesthesia and perfusion
Anesthesia was induced and maintained principally as described previously [15]. A membrane oxygenator was used (Compactflo; Dideco, Mirandola, Italy). The hematocrit was kept higher than 28% during cardiopulmonary bypass, pump flow was 1.8 to 2.4 L · min-1 · m-2, and mean arterial pressure was kept at 60 to 80 mm Hg with the aid of nitroglycerin or phenylephrine hydrochloride. The systemic temperature of the patients was maintained at 32° to 33°C. Anesthesia and perfusion were performed by two experienced anesthesiologists (P.K.K. and K.T.K.).
Surgical technique
All operations were done by the same experienced cardiac surgeon (M.V.K.L.). Cardiopulmonary bypass was established with a single two-stage atrial cannula and an ascending aortic cannula. A cardioplegia delivery cannula with venting and pressure-monitoring ports (DLP Inc, Grand Rapids, MI) and a coronary cardioplegic adapter for vein graft infusions were used in the antegrade group. The heart was arrested in an antegrade manner in both groups. A coronary sinus catheter with a manually inflatable balloon (DLP Inc) in the retrograde group and a pediatric sinus catheter (DLP Inc) in the antegrade group were positioned using the closed transatrial technique before initiation of cardiopulmonary bypass. The catheter was placed as proximally as possible under visual control. In the antegrade cardioplegia group, the pediatric sinus catheter was inserted well to the left in the coronary sinus to collect samples representing outflow drainage from the left ventricular myocardium, and the middle cardiac vein in the diaphragmatic wall of the right ventricle was cannulated in the distal direction with a miniature central venous catheter to collect samples representing outflow drainage from the right ventricular myocardium.
The vein graft to the right coronary artery was always anastomosed first and the left internal mammary artery, last. All the distal and proximal anastomoses were performed during a single period of aortic cross-clamping.
Cardioplegia
The same aspartate- and glutamate– enriched cardioplegic solution was used in both groups. The composition of the solution has been published in detail elsewhere [15]. One part of solution and 9 parts of blood (1:9) were delivered using a commercial cardioplegia set (CSC 14; Dideco). After aortic cross-clamping, hearts in both groups were arrested by inducing antegrade normothermic cardioplegia with extra KCl at 300 mL/min for 5 minutes, with the aortic root pressure kept lower than 60 mm Hg. Thereafter, the temperature was lowered to 30° to 31°C, and cardioplegic solution was infused by either the antegrade (group 1) or the retrograde route (group 2). Aortic root pressure was monitored continuously in the antegrade group and maintained at less than 45 mm Hg. In the retrograde group, cardioplegia administration was switched to retrograde delivery after arrest of the heart and continued at 200 mL/min. Coronary sinus pressure was monitored continuously and maintained lower than 40 mm Hg. Cardioplegia had to be interrupted occasionally to improve visualization or in cases of aortic valve incompetence caused by the lifting of the heart. The aortic root was vented continuously during retrograde cardioplegia, but no vent was used in the antegrade group. A final normothermic cardioplegia infusion (hot shot) was used in both groups.
Myocardial biopsies
Transmural myocardial biopsies for the measurement of adenosine triphosphate and its degradation products were done in all patients using a Tru-Cut needle (William Schmidt, Inc, Valencia, CA). The biopsy specimens were taken from the left anterior and the right inferior ventricular myocardium at points that were normal in appearance. The first specimen was obtained before cannulation and the second, 15 minutes after aortic declamping. The biopsy specimens were placed in sterilized Eppendorf tubes, which were immediately immersed in liquid nitrogen and kept there until analyzed. The frozen myocardial biopsy samples were pulverized and extracted with 0.5 mL of 8% (wt/vol) HClO4 in 40% (vol/vol) ethanol precooled to -20°C, and the extraction was repeated with 6% (wt/vol) HClO4. The filtrates were neutralized to pH 6 with 3.75 mol/L K2CO3, containing 0.5 mol/L triethanolamine hydrochloride.
Hemodynamics
Heart rate, mean arterial pressure, central venous pressure, pulmonary artery wedge pressure, and cardiac output by the thermodilution technique were measured before induction of anesthesia, on arrival in the intensive care unit, 4 hours later, 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
Blood samples were taken simultaneously from the cardioplegia line (inflow), the middle cardiac vein (outflow from the right ventricle), and the distal coronary sinus catheter (outflow from the left ventricle) in the antegrade group and correspondingly from the cardioplegia line (inflow), through the vein graft of the right coronary artery near its distal anastomosis (outflow from the right ventricle), and from the aortic root (outflow of mainly the left ventricle) in the retrograde group. The samples were obtained after completion of the distal anastomosis of the first left-sided vein graft, before the anastomosis of the left internal mammary artery to the left anterior descending coronary artery, and (3) before aortic declamping.
Oxygen content and pH were determined with a 288 blood gas system (Ciba-Corning, Medfield, MA). Lactate production was assayed using an electrode-based lactate analyzer (model 1500; Yellow Springs Instrument Co, Inc, Yellow Springs, OH). The transventricular pH and lactate differences and oxygen extraction were calculated.
Troponin T (TnT) was measured by a manual version of an enzyme-linked immunosorbent assay specific for cardiac TnT (Boehringer Mannheim, Mannheim, Germany) and CK-MB, by a monoclonal antibody technique (AxSYM CK-MB Reagent Pack; Abbott Laboratories, North Chicago, IL). The areas under the curves of the postoperative serum levels of CK-MB and TnT were calculated by summing the areas under the graph between each pair of consecutive observations (trapezoidal rule). Samples for TnT measurement were collected 4, 12, and 24 hours after aortic declamping, and samples for CK-MB measurement were collected at 4-hour intervals for the first 24 hours after aortic cross-clamping and then at 48 hours.
Adenine nucleotides (adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate) and their breakdown products (xanthine, hypoxanthine, inosine, and adenosine) were assayed from tissue extracts using high-pressure liquid chromatography as previously described [16].
Postoperative follow-up
Electrocardiograms were made daily postoperatively and 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, left bundle-branch block, or poor R-wave progression associated with simultaneous elevations of TnT to more than 3.5 µg/L and CK-MB to more than 60 IU/L [14]. Patients were considered to have low-output syndrome whenever the systolic blood pressure was lower than 90 mm Hg and the cardiac index was less than 2 L · min-1 · m-2 despite adequate preload, inotropic support, and reduction in afterload. Postoperative morbidity and mortality were analyzed on day 30 after operation.
Statistical analysis
The statistical analyses were performed using the Statistica package program, version 5.0 (StatSoft, Tulsa, OK). The unpaired Student t test and 
2 test were used to compare the clinical variables between the two groups, and multiple analysis of variance was used to test time-dependent changes in the measured variables. The resulting design was a 2 (group) by 3 (time) by 2 (ventricles) analysis of variance. Group was a between-group factor, and time and ventricles were repeated measures factors. When the F values indicated that significant differences were present, Scheffé’s post-hoc test was used. The data are presented as the mean ± the standard deviation. Significance was assumed when the p value was less than 0.05.
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Results |
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Metabolic changes
Blood samples for the analysis of oxygen content, lactate production, and pH were taken simultaneously from the cardioplegia line, the middle cardiac vein, and the coronary sinus in the antegrade group and from the cardioplegia line, the right-sided vein graft, and the aortic root in the retrograde group, and the outflow-inflow differences representing both ventricles were subsequently calculated.
Oxygen extraction in the right ventricle was higher in the retrograde cardioplegia group, and it also increased during aortic cross-clamping (p < 0.001) (Table 2; Fig 1). On the other hand, oxygen extraction on the left ventricular side was similar in both groups. Lactate efflux from the right ventricle was higher in the retrograde group during aortic cross-clamping (p = 0.013), and there was a relatively large variation between patients (six values exceeding 2.0 mmol/L in 3 patients with the highest value being 4.06 mmol/L), although the flow of cardioplegia was kept constant at 200 mL/min (Fig 2; see Table 2). Lactate production in the left ventricle remained similar in both groups, although ischemia was of longer duration in the antegrade group. The transventricular pH differences resembled those of lactate (p = 0.014 between groups for the right ventricle) (see Table 2).
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Peak levels of CK-MB and TnT were similar in both groups (29.7 ± 8.30 IU/L versus 29.7 ± 16.0 IU/L and 0.69 ± 0.64 µg/L versus 0.95 ± 0.79 µg/L, respectively, in the antegrade and retrograde groups), but the calculated areas under the curves of CK-MB and TnT within the first 24 postoperative hours tended to be higher in the retrograde cardioplegia group (400 ± 256 IU/L versus 291 ± 85 IU/L and 14.4 ± 10.8 µg/L versus 9.3 ± 5.2 µg/L, respectively). None of the patients sustained a perioperative myocardial infarction, as all the measured TnT values were lower than 3.5 µg/L and the CK-MB values were lower than 60 U/L [14]. There was no mortality in the series.
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Comment |
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Menasché and coworkers [18] studied metabolic changes in the myocardium during aortic valve replacement operations and concluded that retrograde mild hypothermic blood cardioplegia is able to preserve hypertrophied myocardium. Their samples for the analysis of blood gases, oxygen content, and lactate concentration were obtained from the coronary sinus (inflow) and the left coronary ostium (outflow from the left ventricle), however, and not from the right coronary ostium, so that little could be said about the preservation of right ventricular metabolism.
In another study, Menasché and his group [14] adopted a different approach when studying coronary bypass patients and took blood samples from the radial artery, the right ventricle, and the coronary sinus within 1 minute of retrograde cardioplegia during antegrade washout of metabolites and found no differences in lactate concentrations. This study can be criticized for several reasons. First, the trial was not a randomized, comparative one. Second, the samples were taken only after the end of retrograde cardioplegia, not during it. Third, the washout of myocardial metabolites during antegrade cardioplegia is, in our experience, very efficient, and the peak levels of lactate decrease rapidly [19]. Fourth, the right ventricular blood samples are diluted with blood derived from thebesian flow and collaterals, which is almost impossible to quantify. Although the conclusions based on the metabolic data from this study [14] can be faulted, it is clear from the hemodynamic data that right ventricular function recovered equally well in the retrograde warm and antegrade cold cardioplegia groups.
Our present results demonstrate that the right ventricular myocardium extracted more oxygen and produced more lactate and acid than the left ventricle during retrograde mild hypothermic blood cardioplegia. On the other hand, there were no significant differences in right and left ventricular metabolism in the antegrade cardioplegia group. In addition, left ventricular metabolism behaved similarly in both cardioplegia groups (see Table 2; Figs 1, 2), even though the ischemia time (cardioplegia off) was significantly longer in the antegrade group.
We studied patients having elective coronary artery bypass grafting without aortotomy or valve replacement. Therefore, selective sampling from the right and left coronary ostia was ethically undesirable. We realize that retrograde outflow samples taken from the aortic root represent a mixture of blood cardioplegia draining off both coronary ostia and cardioplegia shunted directly from the left ventricle and collaterals, but Allen and coauthors [8] measured right ostial drainage and found it to be only about 6% of left ostial drainage using the same delivery rate of retrograde cardioplegia as we did. The lactate differences between the aortic root (outflow) and the cardioplegia line (inflow) during retrograde cardioplegia in our patients were 0.4 mmol/L on average, which is of the same magnitude as measured between the coronary sinus catheter and left coronary ostium by Menasché and coworkers [14]. Thus, the mixing effect of right coronary drainage during retrograde cardioplegia is probably of minor importance in our results and does not affect the conclusions. In fact, without the mixing effect, the differences would have been even more marked. To avoid mixing of blood derived from the right and left ventricles, the pediatric coronary sinus catheter was positioned as far distally as possible in the antegrade group. Therefore, the samples from that catheter can be taken to represent blood draining from the left anterior myocardium through the great cardiac vein.
There was quite a lot of variation in oxygen extraction and lactate production between individual patients, especially for the right ventricle during retrograde cardioplegia. The reasons for this are not obvious, but one possible explanation is that the distribution of retrograde blood cardioplegia and its protective capacity vary according to the individual venous anatomy, which is hard to predict.
Although oxygen extraction, lactate production, and acidosis were more prominent in the right ventricular myocardium during retrograde cardioplegia, the tissue levels of high-energy phosphates were similar in both groups and did not decrease during aortic cross-clamping (see Table 3). Increases in the tissue levels of adenosine, inosine, xanthine, and hypoxanthine are sensitive indicators of a decreased energy state, and their levels increased somewhat in the right ventricular myocardium in the retrograde group after aortic declamping (see Table 3). Although the increase was modest, it can be taken to represent a somewhat decreased energy state in the right ventricle [16]. Our results are in accordance with those of Hoffenberg and associates [13], who demonstrated increased levels of myocardial inorganic phosphate and decreased levels of creatine phosphate during retrograde normothermic blood cardioplegia in isolated porcine hearts studied with phosphorus 31 magnetic resonance spectroscopy. The relatively well preserved adenine nucleotide levels in our study, however, explain the good clinical results obtained with retrograde cardioplegia by us and others [2, 13, 15, 18–20].
The peak CK-MB and TnT values did not differ between the two groups, but the areas under the curves of CK-MB and TnT tended to be larger in the retrograde group. The right ventricular ejection fraction was not measured, but there were no differences in the right or left ventricular stroke work index between groups (results not shown). Nor were there any major postoperative complications in the series.
In conclusion, we demonstrated that retrograde mild hypothermic blood cardioplegia leads to anaerobic metabolism in the right ventricular myocardium. Tissue levels of high-energy phosphates are relatively well preserved, however, which is probably the cornerstone for uneventful recovery of function. Our patients did not have valvular disease leading to right or left ventricular hypertrophy, and we used mild hypothermia, which in our hands seems to be more protective than normothermia [15]. Care should be taken when retrograde normothermic blood cardioplegia is used in patients with right ventricular hypertrophy, poor right ventricular function, or severe myocardial ischemia.
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