JOURNAL
OF SURGICAL
RESEARCH
53,98-l@!
(19%‘)
Improved Distribution of Antegrade Cardioplegic Solution with Simultaneous Coronary Sinus Occlusion Following Acute Coronary Artery Occlusion SHU-CHING SUN, M.D., MAURIZIO DIACO, M.D., GREGORY S. COUPER, M.D., PAOLO MASETTI, M.D., RITA G. LAURENCE, B.S., AND LAWRENCE H. COHN, M.D. Department
of Surgery,
Brigham
& Women’s Hospital,
Haruard
Medical School, Boston, Massachusetts
02115
Submitted for publication December 27, 1990
This study was designed to evaluate the distribution of cardioplegic solution infused antegradely with simultaneous coronary sinus occlusion. After 1 hr LAD occlusion, sheep were placed on cardiopulmonary bypass. Hearts were arrested with 300 ml of cold cardioplegia and replenished with two additional doses. In group I (n = lo), antegrade cardioplegia (ACP) was given alone; in group II (n = Q), ACP was given in combination with simultaneous coronary sinus occlusion. Microspheres were infused into the cardioplegic line to determine the antegrade distribution of the solution, while a different microsphere was injected into the anterior interventricular vein to detect the venous backflow of the solution. The data showed that myocardium distal to LAD occlusion in group II received more antegrade (0.17 + 0.02 versus 0.06 ? 0.02 mlJgJmin, P ~0.01, in subendocardium; and 0.15 + 0.03 versus 0.09 ? 0.02 ml/g/min, P = NS, in subepicardium) and retrograde (2181 + 455 P ~0.01, in subendocardium; versus 0 counts/g/min, P ~0.01, in and 2,146 f 527 versus 0 countsJgJmin, subepicardium) distribution of cardioplegic solution in comparison to group I. We therefore conclude that simultaneous coronary sinus occlusion significantly improves the distribution of antegrade cardioplegic solution to the regionally occluded myocardium by increasing collateral flow as well as venous backflow. o 1992 AcademicPress, Inc.
INTRODUCTION
Despite the known advantages of cold cardioplegia administered in an antegrade fashion, the presence of coronary stenosis restricts adequate delivery of cardioplegic solution beyond the diseased area of the myocardium [l-4]. We have previously reported a method of antegrade cardioplegia with simultaneous coronary sinus occlusion as a modality for more homogenous cardioplegic delivery [5]. This is performed by tightening a snare around the 0022-4804/92$4.00 Copyright 0 1992 by AcademicPress,Inc. All rights of reproductionin any form reserved.
98
proximal coronary sinus during cardioplegic infusion at the aortic root. Our preliminary results have shown that experimental animals treated with this method had more uniform myocardial cooling, better recovery of regional function, and a lower percentage of occluded myocardium becoming necrotic after acute coronary oc22s clusion and surgical reperfusion. The current study was designed to extend our’experiment to quantitate the distribution of cardioplegic solution with this method following acute coronary artery occlusion. The specific purposes of this study were to provide direct evidence to answer the following questions: (1) would elevation of coronary sinus pressure by coronary sinus occlusion improve the distribution of antegrade cardioplegic solution to the occluded myocardium? and (2) if so, did the improved distribution occur antegrade through the collateral vessels or retrograde through the venous channels, or both? Answers to these questions would help us understand more precisely the mechanism of the action of this method. METHODS
Animal
Preparation
Young sheep, weighing 24 to 32 kg, were assigned to one of two experimental groups. Sheep in group I (n = 10) were subjected to the infusion of cardioplegic solution at the aortic root; for those in group II (n = 9), antegrade infusion was combined with simultaneous coronary sinus occlusion. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 85-23, revised 1985). The sheep were anesthetized with thiopental sodium (30 mg/kg), and ventilated with a constant-volume respirator. A catheter was placed into the right femoral artery for systemic pressure measurement. The mean arterial pressure was kept between 80 and 90 mm Hg. Arterial blood gases were determined hourly and maintained
SUN
ET AL.: ANTEGRADE
CARDIOPLEGIA
LAD occlusion
FIG. 1. Experimental model showing method of creating a partial coronary sinus occlusion and method of introducing radiolabeled microspheres into the anterior interventricular vein to detect venous backflow distribution of cardioplegic solution.
within physiologic ranges. Electrocardiogram was monitored continuously. A sternotomy was performed and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery (LAD) was dissected at its mid portion and snared with a silicone loop for subsequent occlusion. The left hemiazygous vein was ligated. Two 19-gauge catheters were inserted directly into the coronary sinus through separate purse string sutures approximately 5 mm apart. One was connected to a Statham PlOEZ pressure transducer for the measurement of coronary sinus pressure. Another one was advanced into the anterior interventricular vein (AIV) close to the site of proposed LAD occlusion for a subsequent injection of radiolabeled microspheres. The coronary sinus was encircled near its junction with the right atrium with a No. 0 coated vicryl stitch, which was snared with a latex tube 5 mm o.d. for its subsequent occlusion in group II (Fig. 1). After 60 min of LAD occlusion, the animal was systemically heparinized (2 mg/kg), and placed on cardiopulmonary bypass (CPB) by cannulating the right atrium and the left femoral artery. The perfusion rate was adjusted to keep the systemic pressure between 40 and 50 mm Hg. The body temperature was cooled to 30°C. After aortic cross-clamping, cold cardioplegic solution was administered by an infusion pump at a rate of 150 ml/min into the aortic root. Sheep in group II received the cardioplegic infusion in the same manner as those in group I, but the coronary sinus was partially occluded for the entire period of infusion. To create a partial coronary sinus occlusion, a probe, 2 mm in diameter, was selected to be placed externally on the posterior free wall of the coronary sinus where the snare stitch was placed. After the snare was tightened over the probe, the probe was withdrawn, and, according to our pilot study, an approximately 85% subtotal coronary sinus occlusion created (Fig. 1). Coronary sinus pressure was measured during each cardioplegic infusion.
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A total volume of 600 ml of 4 to 6°C crystalloid cardioplegic solution containing 28 mEq/liter potassium chloride was divided into three doses. The first dose of 300 ml of cardioplegic solution was infused immediately after aortic cross-clamping and 150 ml each after 10 and 20 min. The antegrade distribution of cardioplegic solution was determined quantitatively by injecting approximately 200,000 ‘13T in radiolabeled microspheres (10 -+ 2 pm) into the infusion line for the first dose of cardioplegic solution. The possible venous back flow distribution of cardioplegic solution was detected by injection of 2 ml (approximately 200,000) 46Sc-radiolabeled microspheres (10 f 2 pm) into the AIV catheter over a period of 1 min, starting 30 set after infusing the first dose of cardioplegic solution. After 30 min of aortic occlusion, the LAD was released, the aorta unclamped, and the heart allowed to beat for 30 min on CPB. The occluded area of myocardium was determined by injecting 30 ml of monastryl blue dye into the left atrium with the LAD reoccluded to provide a clear visual demarcation between the nonperfused myocardial tissue distal to the occlusion and the perfused myocardial tissue. The heart was then excised. The atrium and valvular tissue were cut away, and the remaining heart was sliced into 5-mm thick transverse sections parallel to the atrioventricular groove. Transmural strips from the middle two occluded slices and two slices of the right ventricle were used to analyze the distribution of cardioplegic solution from four regions: (1) central ischemic region, (2) the left ventricular free wall, (3) the interventricular septum, and (4) the right ventricular free wall. Each of these strips was further divided into three equal portions. The middle portion was discarded and an inner subendocardial third and an outer subepicardial third were weighed and counted together with cardioplegic reference samples in a multichannel gamma counter (Model 1195, Searle Radiographics, Inc., Des Plaines, IL). Antegrade distribution of cardioplegic solution was calculated and expressed as milliliters per gram of wet tissue per minute. The venous backflow distribution of cardioplegic solution was expressed as counts of 46Sc per gram of wet tissue per minute. All data were expressed as means ? standard error of the mean. Differences were tested by analysis of variance, with subsequent pairwise comparisons by the Bonferroni adjusted t test. Results were considered statistically significant at a P value less than 0.05.
RESULTS
Global cardioplegic arrest occurred rapidly in all animals. No bleeding, heart block, or other conduction abnormalities were associated with coronary sinus occlusion technique.
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TABLE Antegrade Occluded Endo
LAD
segment
Epi
Group I Group II P value
0.06 + 0.02 0.17 + 0.02 0.05
0.09 f 0.02 0.15 + 0.03 NS
Note. Endo, subendocardial standard
53, NO. 1, JULY
0.60 + 0.13 1.28 + 0.10 0.05
Endo
Epi bl/g/min)
2.08k 0.26 1.90 k 0.24 NS
flow; Epi, subepicardial
1.69 ~0.18 1.42 k 0.18 NS
1992
1
of Cardioplegic
LV
Endo/Epi ratio
(mlldmin)
Distribution
VOL.
Solution RV
EndoiEpi ratio
Epi
Endo
1.45 + 0.15 1.36 k 0.19 NS
1.46 f 0.16 1.22 + 0.16 NS
Endo
Endo/Epi ratio
W/g/min)
1.30-c 0.15 1.46 + 0.23 NS
flow; Endo/Epi
IVS
1.08 k 0.09 1.02 + 0.07 NS
ratio, the ratio of subendocardial
Epi
Endo/Epi ratio
W/g/min) 1.93 + 0.26 1.99 C 0.25 NS
subepicardial
1.62 ? 0.19 1.64 ? 0.19 NS
1.20 + 0.09 1.30 ? 0.22 NS
flow. Values are means +
error of the mean.
Coronary Sinus Pressure The baseline coronary sinus pressure was 1.0 f 0.6 mm Hg for the experimental animals. During cardioplegic infusion, no significant change in coronary sinus pressure (2.2 f 0.5 mm Hg) occurred in group I. In group II, coronary sinus pressure rose to a mean of 25.8 * 1.8 mm Hg (P ~0.01) during cardioplegic infusion and then fell to the basal level after release of coronary sinus occlusion. Distribution
of Cardioplegic
Solution
In both groups, the normally perfused left ventricle, right ventricle, and interventricular septum received similar amounts of antegrade cardioplegic solution. The ratios of endo/epi cardioplegic flow were slightly greater than 1.0 in all these regions. Although there was a tendency toward more cardioplegic distribution to the left ventricle and interventricular septum than to the right ventricle, no significant differences existed among comparable myocardial layers in each group. With LAD occlusion, the antegrade distribution of cardioplegic solution to the regionally ischemic myocardium was reduced profoundly as compared with normally perfused regions in both groups (P ~0.05). In group I, this reduction was more marked in the subendocardium than in the subepicardium, leading to a significant decrease in the endo/ epi ratio (0.60 -+ 0.13, P ~0.05). Conversely, no such change in endo/epi ratio was observed in group II (1.28 + 0.10, P = NS). When comparison was made between the two groups, nearly a threefold increase in subendocardial distribution (0.17 f 0.02 ml/g/min versus 0.06 + 0.02 ml/g/min, P ~0.05) and a 150% increase in subepicardial distribution (0.15 f 0.03 ml/g/min versus 0.09 + 0.02 ml/g/min, P = NS) of cardioplegic solution through collateral vessels were found in the occluded myocardium in group II than in group I. The difference in endo/ epi ratio between the two groups was also significant (1.28 +- 0.10 versus 0.60 f 0.13, P ~0.05) (Table 1). No counts of 46Sc were detected in any regions of group I hearts. In contrast, much higher counts of 46Sc were detected in both layers of regionally ischemic myocardium in group II hearts in subendocardium (2,181 +-
455 counts/g/min) and in subepicardium (2,146 + 527 counts/g/min) with an endo/epi ratio of 1.02 f 0.37, indicating the effective retrograde arrival of cardioplegic solution to the myocardium subtended by the occluded LAD (Table 2). Counts of 46Sc could be occasionally detected in some other regions of group II hearts, but never exceeded 220 counts/g/min. DISCUSSION
The protection of regionally ischemic myocardium secondary to acute or chronic coronary obstruction due to unequal distribution of cardioplegic solution remains a concern in cardiac surgery [l-4]. Methods, such as intra-aortic infusion of cardioplegic solution under higher pressure [6], or the use of large infusion volumes [7] to enhancing collateral cardioplegic flow to the jeopardized myocardium and the use of coronary sinus as an alternative route for cardioplegic delivery [B-11] have been described to overcome this problem. The underlying concept of these interventions is that regional myocardial protection can be, at least partially, achieved if enough cardioplegic solution is provided for the occluded segment. We have previously reported that antegrade cardioplegia with simultaneous coronary sinus occlusion is a valuable modality for more homogeneous cardioplegic delivery and may provide better regional myocardial
TABLE
2
Venous Backflow Distribution Solution in the Occluded
of Cardioplegic LAD Segment Epi
Endo (counts/g/min) Group I Group II P value
0 2181 f 455 0.01
0 2146 + 527 0.01
Endo/Epi
ratio
1.02 + 0.37 -
Note. Endo, subendocardial counts; Epi, subepicardial counts; Endo/Epi ratio, the ratio of subendocardial/subepicardial counts. Values are means + standard error of the mean.
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protection as compared with standard antegrade cardioplegia in a model of acute coronary artery occlusion [5]. In this current study, using radiolabeled microsphere technique, we have demonstrated, for the first time, that antegrade cardioplegia with coronary sinus occlusion not only induces backflow of cardioplegic solution through the venous system but also increases the cardioplegic delivery through the collateral vessels to the regionally occluded myocardium. This demonstration provides us a sound basis to understand more precisely the mechanism of this method in a setting of acute regionally occluded myocardium. Several previous studies [l, 3, 121 have used microsphere technique to examine the distribution of cardioplegic solution administered at the onset of global ischemic arrest. It was found that the patterns of the distribution of antegrade cardioplegic solution was homogeneous and similar to the distribution of baseline coronary blood flow. Hilton et al. [l] and Heineman et al. [3] also found that when coronary artery was experimentally occluded during cardioplegic infusion, much less collateral flow was detected in the occluded segment, and that poor regional myocardial cooling during infusion and significant dysfunction after reperfusion resulted. These findings parallel ours in the group I hearts of this study where only antegrade infusion was used. There was only 0.08 ml/g/min of cardioplegic solution reaching the occluded myocardium after 2 min of infusion at a rate of 150 ml/min, only 3% of the level of the adjacent normally perfused myocardium. We found that collaterally delivered cardioplegic solution increased by more than 100% when the coronary sinus was subtotally occluded as compared with group I. The increase in collateral cardioplegic flow to the occluded myocardium may result from the positive effect of coronary sinus occlusion on the aortic root pressure. With coronary sinus occlusion, outflow impedance within the coronary system increases. This may result in slower runoff through the unobstructed coronary arteries and cause some elevation of aortic root pressure. It is generally agreed that higher aortic infusion pressure may open up more collateral vessels and provide more cardioplegic solution beyond occluded arteries [6]. This may explain the reason why coronary sinus occlusion has an effect of increasing antegrade distribution of cardioplegic solution to the occluded myocardium as shown in this study. The degree of collateralization is variable and is not significant in the sheep model with acute coronary artery occlusion. Despite the superiority of collateral distribution in the group II hearts, the absolute volume of cardioplegic solution received by occluded myocardium through collateral vessels was limited. It was only about 9% of the level of adjacent normally perfused myocardium. In view of the significant improvement of regional myocardial recovery demonstrated previously in the animals treated by antegrade cardioplegia with simultaneous coronary sinus occlusion [5], it is reasonable to
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believe that except for the small increase in collateral flow, there exists another approach to provide functionally adequate cardioplegic solution to protect the segment in jeopardy in this model. By introducing a small amount (2 ml/min) of a second radiolabeled microsphere (46Sc) into the AIV, we successfully demonstrated the venous backflow of cardioplegic solution to the occluded myocardium and differentiate it from the collateral flow in this model. High counts of 46Sc were detected in both subendocardium and subepicardium of the occluded segment in the group II hearts, from which the transmural cardioplegic distribution with a favorable endo/epi ratio of 1.26 -+ 0.37% was obtained. Since the concentration of the injected 46Sc-labeled microspheres was changed after they were mixed with the venous return of cardioplegic solution, it prevented us from assessing the absolute volume of the backflow cardioplegic distribution to the myocardium. During antegrade cardioplegic infusion, the immediate effect of coronary sinus occlusion is the elevation of coronary sinus pressure. Although the outflow impedance increases in the whole heart due to coronary sinus occlusion, the pressure gradient in the normally perfused coronary system remains from the arterial side to the venous side to allow cardioplegic drainage. However, in the myocardium subtended by an occluded coronary artery, this relationship changes. With a very low intraarterial pressure, the pressure gradient in the occluded myocardium may reverse from the venous side to the arterial side. This may cause the venous return of cardioplegic solution to redistribute retrogradely to the occluded segment-with the myocardial bed acting as a “sink.” This proposed mechanism is supported by the microsphere data of this experiment. We assume that with the combination of antegrade cardioplegia and coronary sinus occlusion, the increased volume of cold cardioplegic solution reaching the occluded segment may washout the accumulated toxic metabolites, supply energy products, and reduce metabolic rate within the occluded myocardium. In addition, the flow rate of cardioplegic solution in the coronary system will become slower and may cause better heat and substance exchanges between the cold solution and the normally perfused or regionally occluded myocardium. All or some of these factors may contribute to preserve the occluded myocardium for an improved recovery after reperfusion as we demonstrated previously [5]. Two additional technical points about this method warrant discussion. First, at a given infusion rate, the degree of coronary sinus occlusion is the major determinant of coronary sinus pressure. The optimal coronary sinus pressure is still uncertain for this method. Although a higher coronary sinus pressure may promote more cardioplegic solution to the occluded myocardium, an excessive pressure may cause venous damage and edema formation. We adopted a subtotal coronary sinus occlusion combined with an infusion rate of about 150
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ml/min in this study. It created a coronary sinus pressure of 25.8 k 1.2 mm Hg, which is well within the generally accepted safe range of pressure for coronary sinus interventions [8, 9, 13-151. Second, since the coronary arterial system cannot be used as a temporary “venous” runoff during antegrade cardioplegia with coronary sinus occlusion, we vented the left heart to avoid the potential wall tension which might be caused by the accumulation of the drained solution through the thebesian channels in the left ventricle. ACKNOWLEDGMENT The authors wish to thank Robert Appleyard, Ph.D., for his comments during preparation of the manuscript and his assistance with the statistical analysis.
REFERENCES 1.
2. 3.
4.
5.
6.
7.
Codd, J. E., Wiens, R. D., Kaiser, G. C., Barner, H. B., Tyras, D. H., Mudd, J. G., and Willman, V. L. Late sequelae ofperioperative myocardial infarction. Ann. Thorac. Surg. 26: 208, 1978. Ochsner, J. L. Adequacy of myocardial protection. Ann. Thorac. Surg. 28: 315,1979. Landymore, R. W., Tice, D., Trehan, N., and Spencer, F. Importance of topical hypothermia to ensure uniform myocardial cooling during coronary artery bypass. J. Thorac. Cardiovasc. Surg. 82: 832,198l. Grodin, C. M., Helias, J., Vouhe, P. R., and Robert, P. Influence of a critical coronary artery stenosis on myocardial protection through cold potassium cardioplegia. J. Thorac. Cardiouasc. Surg. 82: 608,198l. Sun, S. C., Raza, S. T., Tam, S. K. C., Laurence, R. G., and Cohn, L. H. Effects of antegrade cardioplegic infusion with simultaneously controlled coronary sinus occlusion on preservation of regionally ischemic myocardium after acute coronary artery occlusion and reperfusion. J. Thorac. Cardiouasc. Surg. 96: 626, 1988. Johnson, R. E., Dorsey, L. M., Moye, S. J., Hatcher, C. R., Jr., and Guyton, R. A. Cardioplegic infusion. The safe limits of pressure and temperature. J. Thorac. Cardiouasc. Surg. 81: 851, 1981. Engelman, R. M., Rousou, J. H., and Lemeshow, S. High volume crystalloid cardioplegia: an improved method of myocardial preservation. J. Thorac. Cardiouasc. Surg. 86: 87, 1983.
8.
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1992
Menasche, P., Kural, S., Fauchet, M., Lavergne, A., Commin, P., Bercot, M., Touchot, B., Georgiopoulos, G., and Piwnica, A. Retrograde coronary sinus perfusion: a safe alternative for ensuring cardioplegic delivery in aortic valve surgery. Ann. Thorac. Surg. 34: 647,1982. g, Gundry, S. R., and Kirsh, M. M. A comparison of retrograde cardioplegia versus antegrade cardioplegia in the presence of coronary artery obstruction. Ann. Thorac. Surg. 38: 124, 1984. 10. Silverman, N. A., Schmitt, G., Levitsky, S., and Feinberg, H. Effect of coronary artery occlusion on myocardial protection by retroperfusion of cardioplegic solutions. J. Surg. Res. 39: 164, 1985. 11. Diehl, J. T., Eichhorn, E. J., Konstam, M. A., Payne, D. D., Dresdale, A. R., Bojar, R. M., Rastegar, H., Stetz, J. J., Salem, D. N., Connolly, R. J., and Cleveland, R. J. Efficacy of retrograde coronary sinus cardioplegia in patients undergoing myocardial revascularization: A prospective randomized trial. Ann. Thorac. Surg. 45: 595, 1988. *‘T Partington, I‘. M. T., Acar, C., Buckberg, G. D., Julia, P., Kofsky, E. R., and Bugyi, H. I. Studies of retrograde cardioplegia. I. Capillary blood flow distribution to myocardium supplied by open and occluded arteries. J. Thoruc. Cardiouasc. Surg. 97: 605,1989. 13. Zile, M. R., Neill, W. A., Gaasch, W. H., Oxendine, J., Apstein, C. S., Weinberg, E., and Bing, 0. H. L. Distribution of a neutral cardioplegic vehicle during the development of ischemic myocardial contracture. J. Mol. Cell. Cardiol. 19: 977, 1987. 14. Tilton, R. G., Larson, K. B., Udell, J. R., Sobel, B. E., and Williamson, J. R. External detection of early microvascular dysfunction after no-flow ischemia followed by reperfusion in isolated rabbit hearts. Circ. Res. 52: 210, 1983. 15. Bush, L. R., Buja, M., Samowitz, W., Rude, R. E., Wathen, M., Tilton, G. D., Willerson, J. T. Recovery of left ventricular segmental function after long-term reperfusion following temporary coronary occlusion in conscious dogs. Circ. Res. 53: 248, 1983. 16 Lavallee, M., Cox, D., Patrick, T. A., and Vatner, S. F. Salvage of myocardial function by coronary artery reperfusion 1, 2 and 3 hours after occlusion in conscious dogs. Circ. Res. 53: 235,1983. 17. Schaper, J., Walter, P., Scheld, H., and Hehrlein, F. The effects of retrograde perfusion of cardioplegic solution in cardiac operations. J. Thoruc. Curdiouasc. Surg. 90: 882, 1985. 18 Mori, F., Ivey, T. D., Tabayashi, K., Thomas, R., and Misbach, G. A. Regional myocardial protection by retrograde coronary sinus infusion of cardioplegic solution. Circulation 74(Pt 2):III 116,1986. D. G., Kostuk, 19. Guiraudon, G. M., Campbell, C. S., McLellan, W. J., Purves, P. D., MacDonald, J. L., Cleland, A. G., and Tadros, N. B. Retrograde coronary sinus versus aortic root perfusion with cold cardioplegia: randomized study of levels of cardiac enzymes in 40 patients. Circulation 74(pt 2):III 105, 1986.
OF SURGICAL
RESEARCH
53,98-l@!
(19%‘)
Improved Distribution of Antegrade Cardioplegic Solution with Simultaneous Coronary Sinus Occlusion Following Acute Coronary Artery Occlusion SHU-CHING SUN, M.D., MAURIZIO DIACO, M.D., GREGORY S. COUPER, M.D., PAOLO MASETTI, M.D., RITA G. LAURENCE, B.S., AND LAWRENCE H. COHN, M.D. Department
of Surgery,
Brigham
& Women’s Hospital,
Haruard
Medical School, Boston, Massachusetts
02115
Submitted for publication December 27, 1990
This study was designed to evaluate the distribution of cardioplegic solution infused antegradely with simultaneous coronary sinus occlusion. After 1 hr LAD occlusion, sheep were placed on cardiopulmonary bypass. Hearts were arrested with 300 ml of cold cardioplegia and replenished with two additional doses. In group I (n = lo), antegrade cardioplegia (ACP) was given alone; in group II (n = Q), ACP was given in combination with simultaneous coronary sinus occlusion. Microspheres were infused into the cardioplegic line to determine the antegrade distribution of the solution, while a different microsphere was injected into the anterior interventricular vein to detect the venous backflow of the solution. The data showed that myocardium distal to LAD occlusion in group II received more antegrade (0.17 + 0.02 versus 0.06 ? 0.02 mlJgJmin, P ~0.01, in subendocardium; and 0.15 + 0.03 versus 0.09 ? 0.02 ml/g/min, P = NS, in subepicardium) and retrograde (2181 + 455 P ~0.01, in subendocardium; versus 0 counts/g/min, P ~0.01, in and 2,146 f 527 versus 0 countsJgJmin, subepicardium) distribution of cardioplegic solution in comparison to group I. We therefore conclude that simultaneous coronary sinus occlusion significantly improves the distribution of antegrade cardioplegic solution to the regionally occluded myocardium by increasing collateral flow as well as venous backflow. o 1992 AcademicPress, Inc.
INTRODUCTION
Despite the known advantages of cold cardioplegia administered in an antegrade fashion, the presence of coronary stenosis restricts adequate delivery of cardioplegic solution beyond the diseased area of the myocardium [l-4]. We have previously reported a method of antegrade cardioplegia with simultaneous coronary sinus occlusion as a modality for more homogenous cardioplegic delivery [5]. This is performed by tightening a snare around the 0022-4804/92$4.00 Copyright 0 1992 by AcademicPress,Inc. All rights of reproductionin any form reserved.
98
proximal coronary sinus during cardioplegic infusion at the aortic root. Our preliminary results have shown that experimental animals treated with this method had more uniform myocardial cooling, better recovery of regional function, and a lower percentage of occluded myocardium becoming necrotic after acute coronary oc22s clusion and surgical reperfusion. The current study was designed to extend our’experiment to quantitate the distribution of cardioplegic solution with this method following acute coronary artery occlusion. The specific purposes of this study were to provide direct evidence to answer the following questions: (1) would elevation of coronary sinus pressure by coronary sinus occlusion improve the distribution of antegrade cardioplegic solution to the occluded myocardium? and (2) if so, did the improved distribution occur antegrade through the collateral vessels or retrograde through the venous channels, or both? Answers to these questions would help us understand more precisely the mechanism of the action of this method. METHODS
Animal
Preparation
Young sheep, weighing 24 to 32 kg, were assigned to one of two experimental groups. Sheep in group I (n = 10) were subjected to the infusion of cardioplegic solution at the aortic root; for those in group II (n = 9), antegrade infusion was combined with simultaneous coronary sinus occlusion. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 85-23, revised 1985). The sheep were anesthetized with thiopental sodium (30 mg/kg), and ventilated with a constant-volume respirator. A catheter was placed into the right femoral artery for systemic pressure measurement. The mean arterial pressure was kept between 80 and 90 mm Hg. Arterial blood gases were determined hourly and maintained
SUN
ET AL.: ANTEGRADE
CARDIOPLEGIA
LAD occlusion
FIG. 1. Experimental model showing method of creating a partial coronary sinus occlusion and method of introducing radiolabeled microspheres into the anterior interventricular vein to detect venous backflow distribution of cardioplegic solution.
within physiologic ranges. Electrocardiogram was monitored continuously. A sternotomy was performed and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery (LAD) was dissected at its mid portion and snared with a silicone loop for subsequent occlusion. The left hemiazygous vein was ligated. Two 19-gauge catheters were inserted directly into the coronary sinus through separate purse string sutures approximately 5 mm apart. One was connected to a Statham PlOEZ pressure transducer for the measurement of coronary sinus pressure. Another one was advanced into the anterior interventricular vein (AIV) close to the site of proposed LAD occlusion for a subsequent injection of radiolabeled microspheres. The coronary sinus was encircled near its junction with the right atrium with a No. 0 coated vicryl stitch, which was snared with a latex tube 5 mm o.d. for its subsequent occlusion in group II (Fig. 1). After 60 min of LAD occlusion, the animal was systemically heparinized (2 mg/kg), and placed on cardiopulmonary bypass (CPB) by cannulating the right atrium and the left femoral artery. The perfusion rate was adjusted to keep the systemic pressure between 40 and 50 mm Hg. The body temperature was cooled to 30°C. After aortic cross-clamping, cold cardioplegic solution was administered by an infusion pump at a rate of 150 ml/min into the aortic root. Sheep in group II received the cardioplegic infusion in the same manner as those in group I, but the coronary sinus was partially occluded for the entire period of infusion. To create a partial coronary sinus occlusion, a probe, 2 mm in diameter, was selected to be placed externally on the posterior free wall of the coronary sinus where the snare stitch was placed. After the snare was tightened over the probe, the probe was withdrawn, and, according to our pilot study, an approximately 85% subtotal coronary sinus occlusion created (Fig. 1). Coronary sinus pressure was measured during each cardioplegic infusion.
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CORONARY
SINUS
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A total volume of 600 ml of 4 to 6°C crystalloid cardioplegic solution containing 28 mEq/liter potassium chloride was divided into three doses. The first dose of 300 ml of cardioplegic solution was infused immediately after aortic cross-clamping and 150 ml each after 10 and 20 min. The antegrade distribution of cardioplegic solution was determined quantitatively by injecting approximately 200,000 ‘13T in radiolabeled microspheres (10 -+ 2 pm) into the infusion line for the first dose of cardioplegic solution. The possible venous back flow distribution of cardioplegic solution was detected by injection of 2 ml (approximately 200,000) 46Sc-radiolabeled microspheres (10 f 2 pm) into the AIV catheter over a period of 1 min, starting 30 set after infusing the first dose of cardioplegic solution. After 30 min of aortic occlusion, the LAD was released, the aorta unclamped, and the heart allowed to beat for 30 min on CPB. The occluded area of myocardium was determined by injecting 30 ml of monastryl blue dye into the left atrium with the LAD reoccluded to provide a clear visual demarcation between the nonperfused myocardial tissue distal to the occlusion and the perfused myocardial tissue. The heart was then excised. The atrium and valvular tissue were cut away, and the remaining heart was sliced into 5-mm thick transverse sections parallel to the atrioventricular groove. Transmural strips from the middle two occluded slices and two slices of the right ventricle were used to analyze the distribution of cardioplegic solution from four regions: (1) central ischemic region, (2) the left ventricular free wall, (3) the interventricular septum, and (4) the right ventricular free wall. Each of these strips was further divided into three equal portions. The middle portion was discarded and an inner subendocardial third and an outer subepicardial third were weighed and counted together with cardioplegic reference samples in a multichannel gamma counter (Model 1195, Searle Radiographics, Inc., Des Plaines, IL). Antegrade distribution of cardioplegic solution was calculated and expressed as milliliters per gram of wet tissue per minute. The venous backflow distribution of cardioplegic solution was expressed as counts of 46Sc per gram of wet tissue per minute. All data were expressed as means ? standard error of the mean. Differences were tested by analysis of variance, with subsequent pairwise comparisons by the Bonferroni adjusted t test. Results were considered statistically significant at a P value less than 0.05.
RESULTS
Global cardioplegic arrest occurred rapidly in all animals. No bleeding, heart block, or other conduction abnormalities were associated with coronary sinus occlusion technique.
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TABLE Antegrade Occluded Endo
LAD
segment
Epi
Group I Group II P value
0.06 + 0.02 0.17 + 0.02 0.05
0.09 f 0.02 0.15 + 0.03 NS
Note. Endo, subendocardial standard
53, NO. 1, JULY
0.60 + 0.13 1.28 + 0.10 0.05
Endo
Epi bl/g/min)
2.08k 0.26 1.90 k 0.24 NS
flow; Epi, subepicardial
1.69 ~0.18 1.42 k 0.18 NS
1992
1
of Cardioplegic
LV
Endo/Epi ratio
(mlldmin)
Distribution
VOL.
Solution RV
EndoiEpi ratio
Epi
Endo
1.45 + 0.15 1.36 k 0.19 NS
1.46 f 0.16 1.22 + 0.16 NS
Endo
Endo/Epi ratio
W/g/min)
1.30-c 0.15 1.46 + 0.23 NS
flow; Endo/Epi
IVS
1.08 k 0.09 1.02 + 0.07 NS
ratio, the ratio of subendocardial
Epi
Endo/Epi ratio
W/g/min) 1.93 + 0.26 1.99 C 0.25 NS
subepicardial
1.62 ? 0.19 1.64 ? 0.19 NS
1.20 + 0.09 1.30 ? 0.22 NS
flow. Values are means +
error of the mean.
Coronary Sinus Pressure The baseline coronary sinus pressure was 1.0 f 0.6 mm Hg for the experimental animals. During cardioplegic infusion, no significant change in coronary sinus pressure (2.2 f 0.5 mm Hg) occurred in group I. In group II, coronary sinus pressure rose to a mean of 25.8 * 1.8 mm Hg (P ~0.01) during cardioplegic infusion and then fell to the basal level after release of coronary sinus occlusion. Distribution
of Cardioplegic
Solution
In both groups, the normally perfused left ventricle, right ventricle, and interventricular septum received similar amounts of antegrade cardioplegic solution. The ratios of endo/epi cardioplegic flow were slightly greater than 1.0 in all these regions. Although there was a tendency toward more cardioplegic distribution to the left ventricle and interventricular septum than to the right ventricle, no significant differences existed among comparable myocardial layers in each group. With LAD occlusion, the antegrade distribution of cardioplegic solution to the regionally ischemic myocardium was reduced profoundly as compared with normally perfused regions in both groups (P ~0.05). In group I, this reduction was more marked in the subendocardium than in the subepicardium, leading to a significant decrease in the endo/ epi ratio (0.60 -+ 0.13, P ~0.05). Conversely, no such change in endo/epi ratio was observed in group II (1.28 + 0.10, P = NS). When comparison was made between the two groups, nearly a threefold increase in subendocardial distribution (0.17 f 0.02 ml/g/min versus 0.06 + 0.02 ml/g/min, P ~0.05) and a 150% increase in subepicardial distribution (0.15 f 0.03 ml/g/min versus 0.09 + 0.02 ml/g/min, P = NS) of cardioplegic solution through collateral vessels were found in the occluded myocardium in group II than in group I. The difference in endo/ epi ratio between the two groups was also significant (1.28 +- 0.10 versus 0.60 f 0.13, P ~0.05) (Table 1). No counts of 46Sc were detected in any regions of group I hearts. In contrast, much higher counts of 46Sc were detected in both layers of regionally ischemic myocardium in group II hearts in subendocardium (2,181 +-
455 counts/g/min) and in subepicardium (2,146 + 527 counts/g/min) with an endo/epi ratio of 1.02 f 0.37, indicating the effective retrograde arrival of cardioplegic solution to the myocardium subtended by the occluded LAD (Table 2). Counts of 46Sc could be occasionally detected in some other regions of group II hearts, but never exceeded 220 counts/g/min. DISCUSSION
The protection of regionally ischemic myocardium secondary to acute or chronic coronary obstruction due to unequal distribution of cardioplegic solution remains a concern in cardiac surgery [l-4]. Methods, such as intra-aortic infusion of cardioplegic solution under higher pressure [6], or the use of large infusion volumes [7] to enhancing collateral cardioplegic flow to the jeopardized myocardium and the use of coronary sinus as an alternative route for cardioplegic delivery [B-11] have been described to overcome this problem. The underlying concept of these interventions is that regional myocardial protection can be, at least partially, achieved if enough cardioplegic solution is provided for the occluded segment. We have previously reported that antegrade cardioplegia with simultaneous coronary sinus occlusion is a valuable modality for more homogeneous cardioplegic delivery and may provide better regional myocardial
TABLE
2
Venous Backflow Distribution Solution in the Occluded
of Cardioplegic LAD Segment Epi
Endo (counts/g/min) Group I Group II P value
0 2181 f 455 0.01
0 2146 + 527 0.01
Endo/Epi
ratio
1.02 + 0.37 -
Note. Endo, subendocardial counts; Epi, subepicardial counts; Endo/Epi ratio, the ratio of subendocardial/subepicardial counts. Values are means + standard error of the mean.
SUN
ET AL.: ANTEGRADE
CARDIOPLEGIA
protection as compared with standard antegrade cardioplegia in a model of acute coronary artery occlusion [5]. In this current study, using radiolabeled microsphere technique, we have demonstrated, for the first time, that antegrade cardioplegia with coronary sinus occlusion not only induces backflow of cardioplegic solution through the venous system but also increases the cardioplegic delivery through the collateral vessels to the regionally occluded myocardium. This demonstration provides us a sound basis to understand more precisely the mechanism of this method in a setting of acute regionally occluded myocardium. Several previous studies [l, 3, 121 have used microsphere technique to examine the distribution of cardioplegic solution administered at the onset of global ischemic arrest. It was found that the patterns of the distribution of antegrade cardioplegic solution was homogeneous and similar to the distribution of baseline coronary blood flow. Hilton et al. [l] and Heineman et al. [3] also found that when coronary artery was experimentally occluded during cardioplegic infusion, much less collateral flow was detected in the occluded segment, and that poor regional myocardial cooling during infusion and significant dysfunction after reperfusion resulted. These findings parallel ours in the group I hearts of this study where only antegrade infusion was used. There was only 0.08 ml/g/min of cardioplegic solution reaching the occluded myocardium after 2 min of infusion at a rate of 150 ml/min, only 3% of the level of the adjacent normally perfused myocardium. We found that collaterally delivered cardioplegic solution increased by more than 100% when the coronary sinus was subtotally occluded as compared with group I. The increase in collateral cardioplegic flow to the occluded myocardium may result from the positive effect of coronary sinus occlusion on the aortic root pressure. With coronary sinus occlusion, outflow impedance within the coronary system increases. This may result in slower runoff through the unobstructed coronary arteries and cause some elevation of aortic root pressure. It is generally agreed that higher aortic infusion pressure may open up more collateral vessels and provide more cardioplegic solution beyond occluded arteries [6]. This may explain the reason why coronary sinus occlusion has an effect of increasing antegrade distribution of cardioplegic solution to the occluded myocardium as shown in this study. The degree of collateralization is variable and is not significant in the sheep model with acute coronary artery occlusion. Despite the superiority of collateral distribution in the group II hearts, the absolute volume of cardioplegic solution received by occluded myocardium through collateral vessels was limited. It was only about 9% of the level of adjacent normally perfused myocardium. In view of the significant improvement of regional myocardial recovery demonstrated previously in the animals treated by antegrade cardioplegia with simultaneous coronary sinus occlusion [5], it is reasonable to
WITH
CORONARY
SINUS
OCCLUSION
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believe that except for the small increase in collateral flow, there exists another approach to provide functionally adequate cardioplegic solution to protect the segment in jeopardy in this model. By introducing a small amount (2 ml/min) of a second radiolabeled microsphere (46Sc) into the AIV, we successfully demonstrated the venous backflow of cardioplegic solution to the occluded myocardium and differentiate it from the collateral flow in this model. High counts of 46Sc were detected in both subendocardium and subepicardium of the occluded segment in the group II hearts, from which the transmural cardioplegic distribution with a favorable endo/epi ratio of 1.26 -+ 0.37% was obtained. Since the concentration of the injected 46Sc-labeled microspheres was changed after they were mixed with the venous return of cardioplegic solution, it prevented us from assessing the absolute volume of the backflow cardioplegic distribution to the myocardium. During antegrade cardioplegic infusion, the immediate effect of coronary sinus occlusion is the elevation of coronary sinus pressure. Although the outflow impedance increases in the whole heart due to coronary sinus occlusion, the pressure gradient in the normally perfused coronary system remains from the arterial side to the venous side to allow cardioplegic drainage. However, in the myocardium subtended by an occluded coronary artery, this relationship changes. With a very low intraarterial pressure, the pressure gradient in the occluded myocardium may reverse from the venous side to the arterial side. This may cause the venous return of cardioplegic solution to redistribute retrogradely to the occluded segment-with the myocardial bed acting as a “sink.” This proposed mechanism is supported by the microsphere data of this experiment. We assume that with the combination of antegrade cardioplegia and coronary sinus occlusion, the increased volume of cold cardioplegic solution reaching the occluded segment may washout the accumulated toxic metabolites, supply energy products, and reduce metabolic rate within the occluded myocardium. In addition, the flow rate of cardioplegic solution in the coronary system will become slower and may cause better heat and substance exchanges between the cold solution and the normally perfused or regionally occluded myocardium. All or some of these factors may contribute to preserve the occluded myocardium for an improved recovery after reperfusion as we demonstrated previously [5]. Two additional technical points about this method warrant discussion. First, at a given infusion rate, the degree of coronary sinus occlusion is the major determinant of coronary sinus pressure. The optimal coronary sinus pressure is still uncertain for this method. Although a higher coronary sinus pressure may promote more cardioplegic solution to the occluded myocardium, an excessive pressure may cause venous damage and edema formation. We adopted a subtotal coronary sinus occlusion combined with an infusion rate of about 150
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ml/min in this study. It created a coronary sinus pressure of 25.8 k 1.2 mm Hg, which is well within the generally accepted safe range of pressure for coronary sinus interventions [8, 9, 13-151. Second, since the coronary arterial system cannot be used as a temporary “venous” runoff during antegrade cardioplegia with coronary sinus occlusion, we vented the left heart to avoid the potential wall tension which might be caused by the accumulation of the drained solution through the thebesian channels in the left ventricle. ACKNOWLEDGMENT The authors wish to thank Robert Appleyard, Ph.D., for his comments during preparation of the manuscript and his assistance with the statistical analysis.
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