Ann Thorac Surg 1997;64:1256-1262
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Does Retrograde Administration of Blood Cardioplegia Improve Myocardial Protection During First Operation for Coronary Artery Bypass Grafting?
Michel Carrier, MD,
L. Conrad Pelletier, MD,
Norman R. Searle, MD
Departments of Surgery and Anesthesia, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
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Abstract
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Background. The objective of this study was to evaluate the value of retrograde blood cardioplegia in coronary artery bypass grafting.
Methods. In 1994 and 1995, 224 patients undergoing first-time isolated coronary artery bypass grafting were randomized to antegrade (112 patients, group 1) or retrograde (112 patients, group 2) administration of blood cardioplegia. In group 1, 76 patients were given warm cardioplegia (at 33°C) and 36 had cold cardioplegia (<20°C), whereas in group 2 cardioplegia was warm in 77 patients and cold in 35. The two randomization groups had similar demographic and angiographic characteristics. The number of grafted coronary arteries averaged 2.9 ± 0.7 in group 1 and 2.8 ± 0.7 in group 2. Total duration of cardiopulmonary bypass (78 ± 23 and 75 ± 21 minutes) and of aortic cross-clamping (47 ± 16 and 46 ± 16 minutes), total volume of infusion of the crystalloid component of cardioplegia (988 ± 297 and 1016 ± 595 mL), and total duration of infusion of cardioplegia (23 ± 10 and 22 ± 11 minutes) were similar (p > 0.05).
Results. There was no death in group 1 and one in group 2 as a result of a pulmonary embolus, for a global early mortality of 0.45%. The numbers of perioperative myocardial infarction (5 versus 3), congestive heart failure (4 versus 5), postoperative hemorrhage (4 versus 4), and stroke (1 versus 2) were also similar (p > 0.05). Release curves of total creatine kinase, creatine kinase–MB by serum activity and mass concentration, and troponin T were not significantly different (p > 0.05) between the two groups. For the 216 patients without perioperative myocardial infarction, peak enzyme release of creatine kinase–MB at 24 hours averaged 23 ± 22 and 20 ± 18 IU/L, and that of troponin T averaged 1.1 ± 1.1 and 1.3 ± 1.5 µg/L at 6 hours for the antegrade and the retrograde groups, respectively (p > 0.05).
Conclusions. Our results indicate no evidence that the retrograde method of cardioplegic infusion improves myocardial protection during first operation for isolated coronary revascularization compared with the usual antegrade route.
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Introduction
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See also page 1262.
It is now generally accepted that blood cardioplegia is the method of choice for myocardial protection during cardiac operations [1]. However, the temperature and route of administration of the perfusate to be used for optimal results remain controversial. In a previous study, warm (33°C) and cold (<20°C) blood cardioplegia administered antegrade through the aortic root were found to give similar clinical results in first-time coronary artery bypass grafting operations. However, a higher incidence of spontaneous return of sinus rhythm on unclamping of the aorta and a lower postoperative release of myocardial creatine kinase (CK) MB isoenzyme and troponin T was shown with warm cardioplegic protection of the myocardium [2].
In an editorial comment, Menasché [3] suggested that a combined antegrade and retrograde approach may be safer and more effective in obtaining a more uniform myocardial distribution of blood cardioplegia, as reported in previous studies [4, 5]. However, the superiority of this technique compared with the more conventional antegrade route of infusion has not been convincing in several other clinical trials [6–9]. In addition, there are indications suggesting that retrograde cardioplegia may not provide adequate protection of the right ventricle [10].
The aim of the present study was to assess the value of retrograde administration of blood cardioplegia for myocardial protection during first isolated coronary artery bypass grafting operations, in a prospective randomized clinical trial using postoperative morbidity and mortality and changes in the release of biochemical markers of myocardial ischemia as end points.
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Patients and Methods
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Study Population
In 1994 and 1995, 224 patients undergoing elective first operation for isolated coronary artery bypass grafting at the Montreal Heart Institute were randomly attributed to antegrade (group 1) or retrograde (group 2) routes of administration of blood cardioplegia. After the patient had agreed to participate in the study and signed an informed consent form, assignment to one of the two treatment groups was done by a perfusionist. Randomization was done just before the beginning of the operation, so that group allocation was blinded to the patient, using blocks of four for equal sample size in the two groups. There were 187 men and 37 women, aged 40 to 80 years (mean 61.5 years). Patients with any of the following were excluded: (1) operation within 7 days of an acute myocardial infarction; (2) urgent operation for acute coronary occlusion at angioplasty; (3) emergent surgical procedures performed outside of normal working hours; (4) reoperations for myocardial revascularization; and (5) coronary operations associated with any other cardiac surgical procedures. The study sample size in each group was based on a projected decrease of 50% in the mean maximum value of postoperative troponin T serum level, as reported in a previous study [2], with an 
error of 0.05, a ß error of 0.20, and a power of 80%. In a trial comparing warm with cold blood cardioplegia [2], a decrease of troponin T release greater than 50% was shown in patients treated with warm compared with those treated with cold cardioplegia. In the present study, we hypothesized that a difference of 50% in the postoperative release of troponin T between the two groups would become significant in decreasing ischemic events during cardioplegia.
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Surgical Techniques
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The operation was performed according to standard surgical techniques. Internal mammary artery and saphenous vein grafts were used in all but 8 patients (3.6%); 5 in the antegrade and 3 in the retrograde group had only double internal mammary artery grafts. The number of bypassed vessels averaged 2.9 per patient. All proximal anastomoses to the aorta were performed with partial occlusion of the ascending aorta with a Beck's clamp. Cardiopulmonary bypass was performed using moderate hemodilution, with a hematocrit level between 20% and 25%, and mild systemic hypothermia by permitting body temperature to drift down progressively to 33°C, the core temperature being thereafter maintained at that level with a heat exchanger until the aorta was unclamped.
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Myocardial Protection
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The cardioplegic solution was infused either through a 14F double-lumen needle (Medtronic Inc, Grand Rapids, MI) in the ascending aorta or through a 14F retrograde coronary sinus catheter with a self-inflating balloon (Research Medical Inc, Midvale, UT) introduced blindly through the lateral wall of the right atrium before initiation of cardiopulmonary bypass. Proper positioning of the catheter was verified by palpation of its tip in the coronary sinus and by recording of sinus pressure through the side part of the catheter. With the catheter in place, compression of the coronary sinus resulted in an increase in venous pressure between 30 and 50 mm Hg. The cardioplegia infusion set (CardioMed Supplies Inc, Gormley, Ontario, Canada) consisted of two inflow lines for the mixing of the crystalloid solution with blood from the arterial circuit. One liter of Ringer's lactate solution containing either 80 mmol (high K) or 40 mmol (low K) potassium, 20 g mannitol, 80 mg lidocaine hydrochloride, and 1.9 mL of 8.4% sodium bicarbonate solution to obtain a pH of 7.4 was used as the crystalloid cardioplegic solution to be mixed with blood in the proportion of 1:4.
After cross-clamping of the ascending aorta, induction of cardioplegic arrest was performed in all patients of the two groups by antegrade infusion of 300 mL of the high-potassium solution during a period of 3 to 5 minutes, at a perfusion pressure not exceeding 250 mm Hg in the infusion line, and at the same temperature as the cardiopulmonary bypass perfusate (33°C, warm cardioplegia). Diastolic arrest was usually obtained before termination of the initial infusion. Thereafter and for the remainder of the procedure, repeat intermittent infusions of 200 to 300 mL of low-potassium solution were administered after each distal anastomosis, either through the antegrade cannula (group 1) or through the retrograde catheter (group 2). In the latter group, the perfusion pressure in the coronary sinus was kept less than 40 mm Hg during the infusion period.
In 71 patients (31.7%), electromechanical activity of the heart persisted after the injection of 300 to 400 mL of high-potassium solution. The cardioplegic mixture was then cooled by immersing the heat exchanger of the infusion line in ice to decrease the solution temperature to less than 20°C (cold cardioplegia).
Potassium serum level was determined at 30-minute intervals throughout the surgical procedure. When potassium levels exceeded 6 mmol/L (normal range, 3.5 to 4.9 mmol/L) after the aorta was unclamped, furosemide was administered intravenously at a dose of 20 mg. Routine care and monitoring procedures were used during the postoperative period.
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Markers of Myocardial Ischemia and Diagnosis of Perioperative Myocardial Infarction
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Blood samples for determination of serum levels of total CK, the catalytic activity and mass concentrations of its MB isoenzyme (CK-MB), and troponin T were taken at the beginning of the operation, and at 1, 3, 6, 12, 24, and 48 hours after chest closure. Total CK serum level (normal range, 24 to 195 IU/L) and, after inhibition of the monomer with a monoclonal antibody, CK-MB isoenzyme serum catalytic activity (normal range, 0 to 30 IU/L) were measured by standard methods using a Hitachi 717 analyzer and reagents from Boehringer-Mannheim (Mannheim, Germany). The serum CK-MB isoenzyme mass assay (normal range, 0 to 5 µg/L) was performed by an enzyme-immunoassay method with a Stratus 11 analyzer and reagents from Baxter Corp. (Miami, FL). The cardiac troponin T serum concentration (normal range, 0 to 0.02 µg/L) was determined with an enzyme immunoassay using an ES300 analyzer and reagents from Boehringer-Mannheim.
Electrocardiographic tracings were obtained the day before operation, on arrival in the intensive care unit, and on postoperative days 1, 2, and 3. A myocardial pyrophosphate scan was performed 48 to 72 hours after operation in patients with abnormal increases in CK-MB serum level without electrocardiographic changes indicative of a new myocardial infarction.
The diagnosis of perioperative myocardial infarction was based on the presence of two of the following criteria: (1) a new Q wave or the disappearance of the R wave persisting on two consecutive postoperative electrocardiographic tracings; (2) peak CK-MB serum activity higher than 100 IU/L; (3) peak CK-MB mass serum level in excess of 100 µg/L; or (4) a positive myocardial pyrophosphate scan [11].
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Data Analysis
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Analysis of continuous data was performed with the Student's t test and the two-way analysis of variance test for repeated measures. The 
2 test was used for the comparison of discontinuous data. The Wilcoxon's test was used for the comparison of the number of diseased vessels between the two groups. The level of statistical significance was established at 95%. The two groups of patients were established according to the intent-to-treat approach. Therefore, for data analysis, crossover patients to the other treatment group were kept with the initial group they had been randomized to. Data are expressed as mean and standard deviation.
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Results
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Preoperative Profile of the Patients
The two cohorts of patients had similar preoperative clinical characteristics with no significant differences (Table 1
). The majority of patients had a history of previous myocardial infarction and almost 50% of the series were admitted to the hospital with a diagnosis of unstable angina. Of the following high-risk factors, one was present in 50% of the patients: (1) age older than 70 years; (2) unstable angina requiring continuous intravenous infusion of nitroglycerin and heparin up to the day of operation; (3) severe left ventricular dysfunction with an ejection fraction of less than 0.3; (4) recent myocardial infarction (8 to 30 days before operation); and (5) failure of coronary angioplasty within the same hospitalization. Significant stenosis (
50% of the lumen) of the left main coronary artery was present in 46 of the 224 patients (20.5%), and 150 patients (67%) presented with three-vessel disease. Close to one third of all patients had significant left ventricular dysfunction at ventriculography. However, the extent and severity of coronary artery disease was similar between the two groups (p > 0.05, Table 1).
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Surgical Procedures
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There was no significant difference between groups in regard to the number of bypassed vessels, completeness of revascularization, duration of aortic cross-clamping and total cardiopulmonary bypass, and core temperature (Table 2). With an average of 2.9 grafted vessels per patient, complete revascularization was achieved in 85% of the patients.
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Cardioplegia Infusion
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The total volume of crystalloid solution infused was similar in the two groups and maximum intraoperative potassium serum levels were identical (Table 3). Because of the inability to achieve complete and sustained cardiac arrest with the infusion of cardioplegia at 33°C, cold cardioplegia at temperatures between 10° and 20°C had to be administered to 36 (32%) and 35 (31%) patients of groups 1 and 2, respectively, a similar proportion (p > 0.05). Total duration of infusion of the cardioplegic solution was also very similar between groups (23 and 22 minutes, p > 0.05) and infusion time corresponded to 49% and 48% of the period of aortic cross-clamping, respectively.
The method used for myocardial protection failed in a total of 12 patients (5.4%). In 2 patients of the antegrade group (1.8%), electromechanical activity of the heart persisted despite cooling of the cardioplegic solution, and complete arrest was obtained only after retrograde infusion of cold cardioplegia. On the other hand, in 10 patients of the retrograde group (8.9%), it was not possible to cannulate the coronary sinus or to maintain the retrograde catheter in the proper position, therefore precluding the use of the retrograde route. In the latter patients, the surgical procedure was completed using cardioplegic infusions through the antegrade route only. The failure rate was significantly higher (p = 0.02) with the retrograde route (Table 3
).
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Postoperative Morbidity and Mortality
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The incidence of stroke, arrhythmias, and mediastinal hemorrhage that required surgical exploration was similar between groups (Table 4). There was no significant difference in the need for pharmacologic or mechanical support postoperatively. Likewise, there was no difference (p > 0.05) in the incidence of postoperative congestive heart failure (3.6% versus 4.5%) and of perioperative myocardial infarction (4.5% versus 2.7%).
There was a single early death in the whole series (30-day mortality, 0.45%), which occurred in the retrograde group and was caused by pulmonary embolism 2 weeks after operation.
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Biochemical Markers of Myocardial Damage and Ischemia
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Total serum CK activity peaked 24 hours postoperatively at 790 ± 559 IU/L and 840 ± 722 IU/L in the antegrade and retrograde groups, respectively. Peak values and release curves of total CK were not significantly different (p > 0.05) (Fig 1).
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Fig 1. . Postoperative changes in total creatine kinase (CK) serum level in 224 patients. There is no significant (NS) difference between the release curves of the two groups. Data shown as mean ± standard deviation
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In the 216 patients without perioperative myocardial infarction, the release curves of CK-MB isoenzyme measured either as serum activity (Fig 2) or as mass concentration (Fig 3) were very similar between the two groups (p > 0.05), with average level around 20 IU or 20 µg/L at 6, 12, and 24 hours. There was a slightly higher rise in CK-MB activity level at 1 hour, most probably because of the effect of hemolysis, as this early peak was not present when using the CK-MB mass determination technique, which remains unaffected by intracellular red cell products. A peak release of CK-MB at 24 hours with either technique of greater than 50 IU or 50 µg/L occurred in 15 group 1 patients (13.4%) and 9 group 2 patients (8%), including 8 patients with myocardial infarction in whom CK-MB peaked greater than 100, and 16 patients with peak CK-MB between 50 and 100, indicating a smaller degree of myocardial damage. There was no statistical difference between groups (p > 0.05).
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Fig 2. . Postoperative changes in creatine kinase-MB (CK-MB) isoenzyme serum activity level in 216 patients without perioperative myocardial infarction. There is no significant (NS) difference in the release curves between the two groups. Data shown as mean ± standard deviation
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Fig 3. . Postoperative changes in creatine kinase-MB (CK-MB) mass concentration in 216 patients without perioperative myocardial infarction. There is no significant (NS) difference between the release curves of the two groups. Data shown as mean ± standard deviation
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Among patients without infarction, troponin T serum level peaked 6 hours postoperatively at 1.1 ± 1.1 and 1.3 ± 1.5 µg/L in groups 1 and 2, respectively. Neither peak values nor release curves differed significantly between groups (p > 0.05) (Fig 4).
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Fig 4. . Postoperative changes in cardiac troponin T serum level in 216 patients without perioperative myocardial infarction. The release curves are not significantly (NS) different between the two groups. Data shown as mean ± standard deviation
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Subgroup of Patients With Left Main Coronary Stenosis
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Among the 46 patients with significant disease of the left main coronary artery, 26 were in the antegrade group and 20 in the retrograde. There was no death and only one perioperative myocardial infarction, which occurred in the former group. Peak release of CK-MB at 24 hours (24 ± 21 versus 21 ± 17 IU/L) and of troponin T at 6 hours (0.9 ± 0.7 versus 0.9 ± 0.6 µg/L) was very similar in both groups (p > 0.05).
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Comment
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Several clinical studies indicate that retrograde cardioplegia provides adequate myocardial protection in the human [6–9]. Evidence of a more homogenous distribution of cardioplegia is suggested with the retrograde route [4, 5, 12]. In the presence of complete coronary artery occlusion, this method would appear to result in a better perfusion of the ischemic myocardial area [13]. However, most of these data were obtained in a small number of patients. In randomizing 1,001 patients (retrograde warm cardioplegia), Martin and colleagues [14] obtained excellent myocardial protection that compared favorably with cold crystalloid techniques for coronary bypass grafting. No failure of cannulation of the coronary sinus nor crossover from the warm to the cold group were reported in this series. However, the authors stressed the fact that in several patients of the warm group it had been difficult to achieve and maintain complete electromechanical arrest of the heart. In the present study, there was a 9% failure rate of retrograde cannulation (crossover to the antegrade group) and a 32% failure rate of warm cardioplegia (cooling of cardioplegia to <20°C).
More recently, studies have shown that the right ventricular myocardium is poorly perfused with retrograde cardioplegic infusion in the human [10, 15]. Uneven distribution of cardioplegia administered through the coronary sinus has also been found in the experimental animal, confirming the findings of clinical studies that the right ventricle and posterior septum are particularly at risk [16, 17]. In the normal porcine heart, retrograde warm cardioplegia causes a transition to ischemic metabolism in the myocardium [18]. These results have stimulated the use of combined and simultaneous antegrade and retrograde infusion of cardioplegia to alleviate the problem of uneven distribution [19–21]. However, Shirai and colleagues [22] found that myocardial function was better preserved with alternate compared with simultaneous antegrade and retrograde cardioplegic infusions, although the latter method was more practical with a lesser risk of coronary air embolism.
The present study indicates no improvement of myocardial protection with the use of the retrograde route compared with the more usual antegrade infusion. The release of myocardial cell proteins indicating myocardial damage was very similar between the two groups. Even in the higher risk group of 46 patients with left main coronary artery disease, no significant differences between the two methods were found. Although the study was not designed with sufficient power to discriminate for clinical events, there was no difference in mortality and morbidity between the two groups. Using the retrograde route did not result in a shorter aortic cross-clamping time, and the total infusion volumes of the crystalloid solute were similar, as were the maximum potassium serum levels observed at the time of unclamping the aorta. We opted for intermittent infusions of cardioplegia rather than for continuous perfusion to obtain better visualization during construction of coronary anastomoses. As a result, cardioplegia was infused during approximately 50% of the time the aorta was clamped in both groups, leaving an average total of 24 ± 6 minutes without coronary perfusion. Because the number of coronary anastomoses averaged three per patient, each unperfused period between cardioplegic infusions averaged 8 ± 2 minutes. These results are similar to previous reports in which continuous rather than intermittent cardioplegic infusions were used [7–9, 12–14]. Nevertheless, we cannot exclude the possibility that different results may have been observed with continuous perfusion.
The present study was designed with sufficient statistical power to show decreases in cardiac enzyme release similar to the differences observed in a previous study comparing warm and cold blood cardioplegia [2]. The two groups did not differ significantly in regard to their preoperative clinical and angiographic profile, surgical characteristics, and cardioplegic solution infusions other than the route of administration. None of the postoperative variables used as end points differed between groups. Only the failure rate of the method was significantly higher with the retrograde technique, which may be related to the blind transatrial method of cannulation used in the study.
In conclusion, although there is no advantage to the routine use of retrograde administration of cardioplegia for first coronary artery bypass grafting operations, our results stress the need to adapt temperature and route of infusion of the cardioplegic solution to the need of each clinical situation and use the various approaches as complementary methods rather than as competing techniques. Because we found no benefits to retrograde infusion, a greater failure rate than with antegrade infusion, and a higher cost because of the additional perfusion lines and cannulae, we do not routinely use this method of myocardial protection for first-time myocardial revascularization. Antegrade intermittent administration of warm or cold blood cardioplegia in the aortic root remains our method of choice for patients having first-time, isolated coronary artery bypass grafting.
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Acknowledgments
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We acknowledge the help of Mrs. Carole Jézina and Johanne Marquis in the recruitment of patients, data collection, and database management for this study, and thank Dr Yves Leclerc for contributing some of his patients to the study.
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Footnotes
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presented at the Thirty-third Annual Meeting of the society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.
Address reprint requests to Dr Carrier, Department of Surgery, Montreal Heart Institute, 5000 Belanger St E, Montreal, PQ H1T 1C8, Canada.
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References
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Abstract
Introduction
