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Detrimental effects of interrupting warm blood cardioplegia during coronary revascularization
Detrimental effects of interrupting warm blood cardioplegia during coronary revascularization Warm blood cardioplegia has emerged as a substitute for cold blood cardioplegia as a method of myocardial protection. However, the continuous infusion of blood in this technique may obscure the operative field and necessitate interruption of warm blood cardioplegia. This experimental study was therefore undertaken to determine whether interrupting warm blood cardioplegia durihg coronary revascularization would increase myocardial damage. In 30 adult pigs, the second and third diagonal vessels were occluded with snares for 90 minutes. All animals underwent cardiopulmonary bypass and 45 minutes of cardioplegic arrest. During the period of cardioplegic arrest, 10 pigs received intermittent antegrade/retrograde infusion of cold blood cardioplegic solution (4° C), 10 pigs received continuous retrograde infusion of warm blood cardioplegic solution (370 C) at 100 ml/min, and 10 pigs received retrograde infusion of warm blood cardioplegic solution that was interrupted for three 7-minute periods. After aortic unclampihg, the coronary snares were released and all hearts were reperfused for 180 minutes, Interrupting retrograde warm blood cardioplegia resulted in more tissue acidosis durihg cardioplegic arrest (6.20 ± 0.16 interrupted retrograde warm blood cardioplegia and 6.45 ± 0.12 continuous retrograde warm blood cardioplegia, both p < 0.05 compared with 6.98 ± 0.17 intermittent antegrade and retrograde cold blood cardioplegia), decreased echocardiographic wall-motion scores (4 [normal] to -1 [dyskinesis]; 2.06 ± 0.30 interrupted retrograde warm blood cardioplegia, p < 0.05 compared with 3.30 ± 0.40 intermittent antegrade and retrograde cold blood cardioplegia, 2.80 ± 0.40 continuous retrograde warm blood cardioplegia), and increased tissue necrosis as measured by the area of necrosis/area at risk (38 % ± 5% interrupted retrograde warm blood cardioplegia, p < 0.05 compared with 21 % ± 2 % intermittent antegrade and retrograde cold blood cardioplegia; 25 % ± 2 % continuous retrograde warm blood cardioplegia). We concluded that interrupting warm blood cardioplegia during coronary revascularization diminishes the effectiveness of warm blood cardioplegia and results in increased ischemic damage. (J THoRAc CARDIOVASC SURG 1993;106:357-61)
Hiroshi Matsuura, MD, Harold L. Lazar, MD, Xi Ming Yang, MD, Samuel Rivers, BS, Patrick R. Treanor, CCP, and Richard J. Shemin, MD, Boston, Mass.
Wrm blood cardioplegia has emerged as a substitute for cold blood cardioplegia as a method of myocardial protection.!" In a previous experimental study' we showed that with an acute coronary occlusion, warm blood cardioplegic solution must be administered retro-
From the Department of Cardiothoracic Surgery, Boston University Medical Center, The University Hospital, Boston, Mass. Received for publication May 18, 1992. Accepted for publication Aug. 6, 1992. Address for reprints: Harold L. Lazar, MD, Department of Cardiothoracic Surgery, The University Hospital, Suite B404, 88 East Newton S1. Boston, MA 02118. Copyright
v
1993 by Mosby-Year Book, Inc.
0022-5223/93 $1.00
+ .10
12/1/41796
gradely and continuously but does not provide myocardial protection superior to that achieved with intermittent antegrade/retrograde cold blood cardioplegia (A/RCBC). The continuous infusion of warm blood cardioplegic solution may obscure the operative field, necessitating the interruption of cardioplegia. However, the effects of interrupting warm blood cardioplegia during the revascularization of acutely ischemic myocardium are unknown. This experimental study was therefore undertaken to determine whether interrupting warm blood cardioplegia during coronary revascularization increases myocardial damage. Methods Preparation. Thirty adult pigs (28 to 32 kg) were premedicated intramuscularly with ketamine (15 rug/kg of body
357
The Journal of Thoracic and Cardiovascular Surgery August 1993
3 5 8 Matsuura et at.
weight) and acepromazine; 0.5 rng/kg), anesthetized with chloralose (75 rug/kg), and subjected to positive-pressure endotracheal ventilation. A median sternotomy was performed, and catheters were placed into the aorta and superior vena cava for monitoring systemic arterial and venous pressures and administering fluids. The azygos vein was ligated, and the animals were heparinized (3 rug/kg). The second and third diagonal vesselsjust distal to the takeoff of the left anterior descending coronary artery were then occluded with snares for 90 minutes. Intravenous lidocaine was used to treat ventricular arrhythmias. Inotropic agents were not administered. After the 90-minute period of coronary occlusion, all animals underwent total cardiopulmonary bypass with a No. 20 cannula in the femoral artery and a No. 36 venous return catheter in the right atrium, as previously described," A catheter was inserted into the left atrium to infuse volume to vary left ventricular end-diastolic pressure (L VEDP). Mean arterial blood pressure during cardiopulmonary bypass ranged from 65 to 75 mm Hg and pump flow was kept at 80 nil/kg per minute. The average hematocrit level was 27% ± 2%, and pH was maintained at 7.41 ± 0.03. After cardiopulmonary bypass was begun, all hearts were arrested for 45 minutes with a 4:1 ratio of blood to cardioplegic solution to reach a hematocrit levelof20%; the pH was 7.60, and the initial potassium concentration was 25 mEq/L. After the initial 300 ml of cardioplegic solution was infused, the potassium concentration was lowered to 10 mEq/L. During cardioplegic arrest, three different cardioplegic techniques were used. A/RCBC.Cold blood cardioplegic solution (4° C) was administered in 10 pigs; half was delivered through a catheter in the ascending aorta, and half was delivered in a retrograde fashion through a coronary sinus catheter (DLP, Inc., Grand Rapids, Mich.). The initial dose was 10 ml/kg of body weight, which was followed by additional boluses of 5 ml/kg administered every 20 minutes. These animals also underwent continuous topical hypothermia with the use of iced saline solution and were systemically cooled to 30° C. Continuous retrograde warm blood cardioplegia. In 10 pigs, continuous retrograde warm blood cardioplegia (R WBC) was achieved through a coronary sinus catheter (37° C; 100 ml/rnin). These animals did not undergo topical or systemic hypothermia. Systemic temperature was maintained at 37° C. Interrupted retrograde warm blood cardioplegia. Interrupted retrograde warm blood cardioplegia (I/RWBC) in 10 pigs included three different 7-minute periods of interruption: at 8, 23, and 38 minutes into the 45-minute crossclamp period. After the 45-minute period of cardioplegic arrest, the crossclamp was removed and the coronary snares were released. All hearts were then reperfused on cardiopulmonary bypass at 37° C for 180 minutes. Measurements and data analysis. Electrocardiographic leads were used to measure heart rate and monitor electrical activity during arrest. LVEDP was recorded with a piezoelectric Mikro-Tip catheter pressure transducer (Millar Instruments, Inc., Houston, Tex.) inserted via a stab wound in the left ventricular apex. Systemic body temperature was measured with a rectal temperature probe (Yellow Springs Instrument Co., Yellow Springs, Ohio). Coronary sinus pressure was measured with the retrograde cardioplegia catheter. Myocardial tissue pH was measured on-line as previously described.' Tissue pH probes (Khuri Tissue Ischemia Monitor; Vascular Technology Inc., North Chelmsford, Mass.) were
inserted into the center of the area of risk beyond the coronary occlusions. The pH was standardized according to myocardial temperature, which was measured simultaneously with a temperature probe inserted next to the pH probe. Preischemic pH measurements were made after a 30-minute period of equilibration and then recorded on-line with myocardial temperature during the periods of coronary occlusion, cardioplegic arrest, and reperfusion. The pH values were recorded for each experiment and then averaged for all experiments in each cardioplegia group. Wall-motion scores were obtained from two-dimensional echocardiographic sections through the area at risk, as previously described.s-f Left ventricular end-diastolic volume (LVEDV) measurements were obtained by planimetry of a perpendicular long-axis length and a short-axis area obtained from a hand-held 3.5 mHz ultrasound transducer (ATL, Tempe, Ariz.). Short-axis sections were used to assess segmental wall-motion changes. The ventricle was arbitrarily divided into eight anatomic areas and wall motion was analyzed qualitatively by a numeric score (4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, 1 = severe hypokinesis, 0 = akinesis, and -1 = dyskinesis). Echocardiographic sections for wall-motion analysis were obtained at a constant afterload (mean arterial pressure = 65 mm Hg). Only sections with the same LVEDV during the preischemic, coronary occlusion, and reperfusion periods were used for analysis to ensure similar preload conditions. Measurements were made by an experienced echocardiographer, Dr. Sheilah Bernard, who had no knowledge of the particular cardioplegia technique used. Data were averaged for the periods of preischemia, coronary occlusion, and reperfusion for each experiment and, in turn, for each cardioplegia group. The area at risk and area of necrosis were determined by histochemical staining techniques with 2,3,5-triphenyltetrazolium chloride after 180 minutes of reperfusion, as previously described." They were calculated for each experiment and then averaged for each cardioplegia group. Statistical evaluation of the three cardioplegia groups was computed by means of analysis of variance. Differences in variables measured in a continuous scale within each group were assessed by paired Student's t test. Differences in variables between two different cardioplegia groups were assessed with nonpaired Student's t test. All data were expressed as the mean ± standard error. Data were considered significant at p < 0.05. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).
Results The results are summarized in Figs. 1 to 3. All hearts achieved electromechanical arrest within 45 seconds of aortic crossclamping. Some electrical activity was noted in 7 of 10 animals in the IjRWBC group during the interruption of cardioplegia. Electrical activity was extinguished after cardioplegia was reinstituted, although flows as high as 150 to 200 mljmin were required in the first 2 minutes to cease all electrical activity in some ani-
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 2
Matsuura et ai.
o Antegrade/Retrograde CBC a Retrograde WBC • Interrupted Retrograde WBC ·p<0.05 from Retrograde WBC Interrupted Retrograde WBC
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i gOmin Coronary Occlusion
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·p<0.05 from Interrupted Retrograde WBC
- 1 . . . 1 . . - - , - - - - , - - - - - , - -_ _.,-__ Preiscnernia
180min Hepertuslon
Fig. 1. Myocardial pH values decreased from preischemic values inthe threecardioplegia groupsduringperiodof coronary occlusion. After 45 minutes of cardioplegic arrest, hearts that underwent antegrade/retrograde cold blood cardioplegia (CBC) had significantly higher pH values. Lowest pH values were seen in interrupted/retrograde warm blood cardioplegia (WBC) group. pH Values were similar in all cardioplegia groups after 180 minutes of reperfusion but remained lower than preischemic values. WBC, Warm bloodcardioplegia; CBC, cold blood cardioplegia.
esc
gamin Coronary Occjusion
60min Reperlusion
180mln Reperfusion
Fig. 2. Wall-motion scores decreased in all cardioplegia groupsduring the periodof coronaryocclusion. After 180 minutes of reperfusion, hearts protectedwith antegrade/retrograde CBC had significantly higher wall-motion scores than did the interrupted/retrograde WBC group. Wall-motion score: 4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, I = severe hypokinesis, 0 = akinesis, -1 = dyskinesis. WBC, Warm blood cardioplegia; CBC, cold blood cardioplegia.
100
mals. Coronary sinus pressures remained below 50 mm Hg, and aortic root pressure never exceeded 60 mm Hg during cardioplegic infusions. Serum potassium levels remained below 5.5 mliq/L during reperfusion in all hearts. Myocardial pH. The pH changes in the area at risk beyond the coronary occlusions are summarized in Fig. 1. During the preischemic period, pH values were similar in all hearts (7.57 ± 0.07 A/RCBC; 7.53 ± 0.05 RWBC, 7.44 ± 0.10 I/RWBC). After 90 minutes of coronary occlusion, all three groups had significant decreases in pH from preischemic values (6.47 ± 0.10 A/RCBC, 6.47 ± 0.13 RWBC,6.35 ± 0.06I/RWRC;p < 0.0001 from preischemic values). After 45 minutes of cardioplegic arrest, pH increased significantly in the hearts that underwent A/RCBC (6.47 ± 0.10 versus 6.98 ± 0.17; p < 0.02). pH values remained the same in the continuous RWBC group (6.47 ± 0.13 versus 6.45 ± 0.12; not significant [NS]) and actually decreased in the I/RWBC group, although this difference was not statistically significant (6.35 ± 0.06 versus 6.20 ± 0.16; NS). The pH values were significantly higher in the intermittent A/RCBC group compared with those in the warm blood cardioplegia groups after 45 minutes of aortic crossclamping (6.98 ± 0.17 A/RCBC, P < 0.05 compared with 6.45 ± 0.12 RWBC and 6.20 ± 0.16 I/RWBC). After 180 minutes of reperfusion, pH values were similar in all cardioplegia groups but remained lower than preis-
·p<0.05 from Interrupted Retrograde WBC
a Antegrade/Retrograde CBC
Retrograde WBC
Interrupted Retrograde WBC
Fig. 3. Hearts protected with interrupted/retrograde warm blood cardioplegia (WBC) had a significantly higher area of necrosis than did other cardioplegia groups. WBC, Warm blood cardioplegia; CBC, cold blood cardioplegia.
chemic levels (6.85 ± 0.15 A/RCBC, 6.80 ± 0.10 RWBC, 6.85 ± 0.21 I/RWBC; P < 0.01 from preischemic values). Wall-motion scores. All cardioplegia groups had normal wall-motion scores during the preischemic period (Fig. 2). After 90 minutes of coronary occlusion, all hearts showed a significant decrease in wall-motion scores in the area at risk (2.1 ± 0.3 A/RCBC, 2.5 ± 0.3 R WBC, 2.6 ± 0.2 I/RWBC; P < 0.001 from preischemic values). After 180 minutes of reperfusion, wall-motion scores in the area at risk decreased in the I/RWBC group, and these hearts had significantly lower wall-motion
3 6 0 Matsuura et al.
scores than did those of the intermittent AjRCBC group (2.1 ± 0.3 IjRWBC, p < 0.05 compared with 3.3 ± 0.1 AjRCBC and 2.8 ± 0.4 RWBC). Furthermore, wall-motion scores in nonischemic areas of the myocardium were also significantly lower in the IjRWBC hearts compared with the AjRCBC and continuous RWBC hearts (2.35 ± 0.40 IjRWBC, p < 0.05 compared with 3.78 ± 0.13 AjRCBC and 3.36 ± 0.27 RWBC). Area of necrosisjarea at risk. The area of myocardium at risk was similar in all three cardioplegia groups (13% ± 3% AjRCBC, 14% ± 1% AjRCBC, 16% ± 2% IjRWBC). The calculations of the area of necrosis within the area at risk are shown in Fig. 3. Hearts protected with IjRWBC had a significantly higher area of necrosis than did the intermittent AjRCBC and continuous RWBC hearts (21% ± 2% AjRCBC and 25% ± 2% R WBC, both p < 0.05 compared with 38% ± 5% IjRWBC). Discussion The continuous infusion of warm blood cardioplegic solution during ischemic arrest theoretically avoids periods of ischemia and subsequent reperfusion damage. However, the presence of an acute coronary occlusion may result in heterogeneous distribution of cardioplegic solution, thus predisposing the warm heart to further ischemic damage. Our previous studies and those of others 5, 9, 10 have shown that under these conditions antegrade warm blood cardioplegia results in significantly less myocardial protection than does continuous RWBe. Nevertheless, if visualization is impaired and the warm blood cardioplegia must be stopped, further ischemic damage is possible. Furthermore, our earlier studies' showed that continuous R WBC did not result in myocardial protection that was superior to that achieved with intermittent AjRCBC. Hence, if RWBC must be interrupted, theoretically it must be able to achieve the same degree of protection as intermittent AjRCBe. This experimental study sought to answer this question by using a model that simulates the events that occur after a failed percutaneous transluminal coronary angioplasty in which a coronary artery is suddenly occluded. The retrograde infusion of warm blood cardioplegic solution was stopped during three separate periods, as it would have been had visualization been impaired during the construction of three distal coronary anastomoses. The volume of solution for intermittent AjRCBC was similar to that used in our clinical practice, and the volume of solution for continuous warm blood cardioplegia was based on the studies of Lichtenstein and Salerno and their associates-? and our earlier investigations'
The Journal of Thoracic and Cardiovascular Surgery August 1993
After 90 minutes of coronary occlusion, all three cardioplegia groups had comparable depression in wall-motion scores and tissue pH. However, during the period of aortic crossclamping, pH trends were different in each cardioplegia group (Fig. 1). The pH values rose significantly in the hearts protected with intermittent AjRCBe. Hypothermia could have contributed to the higher pH values in this group; however, the studies of Khuri and others I 1-13 have shown that the failure of pH to increase during hypothermic cardioplegic arrest is a sensitive predictor of postischemic myocardial dysfunction. Il - 13 Hence, the higher pH values in the area at risk indicated adequate myocardial protection in these hearts by means of an intermittent AjRCBC technique. Throughout the period of cardioplegic arrest in the area at risk, hearts protected with continuous RWBC maintained a stable pH compared with pH values immediately before crossclamping. Although pH values were lower during arrest in the continuous R WBC hearts than in the AjRCBC hearts, this does not mean that the former were more acidotic. This condition was reflected in the areas of necrosis of the two groups, which were not statistically different. In contrast, pH values continued to decrease during the period of cardioplegic arrest in hearts protected with IjRWBe. Although there was no statistically significant difference in the mean pH values of the continuous RWBC group (6.45 ± 0.12) and the IjRWBC group (6.20 ± 0.16) during cardioplegic arrest, physiologic significance may exist because Khuri and associates!' have shown that irreversible tissue damage in the canine myocardium occurs when pH values approach 6.20. After 3 hours of reperfusion, wall-motion scores in the area at risk were lowest in the I jRWBC group (Fig. 2). These scores were significantly lower than those of the intermittent AjRCBC group. In addition, wall-motion scores were also significantly lower in nonischemic areas that underwent IjRWBe. These changes in pH and wall motion were reflected in the percentage of area of necrosis, which was significantly higher in the IjRWBC group when compared with the other groups (Fig. 3). Since the introduction of warm blood cardioplegia to clinical practice, techniques such as "gas jets" have been introduced in an attempt to provide better visualization of the operative field without interrupting cardioplegia. 14 In some instances, it may be possible to maintain flow through the completed vein graft to the area at risk while interrupting blood flow to less critical areas of the myocardium. These techniques may help to limit ischemic damage when warm blood cardioplegia must be interrupted. Nevertheless, our results indicate that interrupting R WBe during the revascularization of acutely ischemic myocardium results in more tissue acidosis dur-
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 2
ing cardioplegic arrest, lower postischemic wall-motion scores, and increased tissue necrosis in the area at risk. Furthermore, the wall-motion scores in nonischemic areas suggest that interrupting RWBC may also be detrimental to other regions of the myocardium. Histologic staining was not done in these areas, but it is conceivable that this depressed wall motion may represent stunned myocardium. Nevertheless, these data imply that hearts undergoing IRWBC are at higher risk for developing wall-motion abnormalities in both acutely ischemic and nonischemic areas of the myocardium. This study suggests that surgeons using warm blood cardioplegia techniques should make every effort to limit periods of anoxia during the revascularization of acutely ischemic myocardium. It also suggests that when cardioplegia must be interrupted for extended periods during coronary revascularization, AjRCBC results in superior regional and global myocardial protection than can be achieved with interrupted warm blood cardioplegia techniques. The secretarial assistance of Ms. Ellie LaBombard in the preparation of this manuscript is greatly appreciated. REFERENCES I. Lichtenstein SV, Ashe KA, Dalati HE, Cusimano RJ, Panas A, Slutsky AS. Warm heart surgery. J THORAC CARDIOVASC SURG 1991;101:269-74. 2. Salerno TA, Houck JP, Barrozo CAM, et al. Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991;51:245-7. 3. Lichtenstein SV, Fremis SE, Abel JG, Christakis GT, Salerno TA. Technical aspects of warm heart surgery. J Cardiac Surg 1991;6:278-85. 4. Lichtenstein SV, Abel JG, Salerno TA. Warm heart surgery and results of operation for recent myocardial infarction. Ann Thorac Surg 1991;52:455-60.
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5. Matsuura H, Lazar HL, Yang XM, et al. Warm versus cold blood cardioplegia: Is there a difference? Surg Forum 1991;50:231-2. 6. Haan C, Lazar HL, Bernard S, Rivers S, Zallnick J, Shemin RJ. Superiority of retrograde cardioplegia after acute coronary occlusion. Ann Thorac Surg 1991;51:40812. 7. Lazar HL, Khoury T, Rivers S. Improved distribution of cardioplegia with pressure controlled intermittent coronary sinus occlusion (PICSO). Ann Thorac Surg 1988;46:2027.
8. Wyatt HL, Heng MK, Meerbaum S. Cross-sectional echocardiography. II. Analysis of mathematical models for quantifying volume of the formalin-fixed left ventricle. Circulation 1980;61:1119-25. 9. Misare BD, Krukenkamp IB, Lazar ZP, LevitskyS. Antegrade warm continuous blood cardioplegia exacerbates acute regional ischemic injury. Surg Forum 1991;50:2324.
10. Misare BD, Krukenkamp IB, Lazar ZP, Levitsky S. Retrograde is superior to antegrade continuous warm blood cardioplegia for acute cardiac ischemia. Circulation 1991;84(Suppl):1I687. II. Lange R, Kloner RA, Zierler M, Carlson N, Seiler M, Khuri SF. Time course of ischemic alterations during normothermic and hypothermic arrest and its reflection by on-line monitoring of tissue pH. J THoRAc CARDIOVASC SURG 1983;86:418-34. 12. Khuri SF, Josa M, Martson W, et al. First report of intramyocardial pH in man. II. Assessment of adequacy of myocardial preservation. J THORAC CARDIOVASC SURG 1983;86:667-78. 13. Takach TJ, Glassman LR, Ribakove GH, Clark RE. Continuous measurement of intramyocardial pH: correlation to functional recoveryfollowingnormothermic and hypothermic global ischemia. Ann Thorac Surg 1986;42:31-6. 14. Teoh KH, Panos AL, Harmantas AA, Lichtenstein SV, Salerno TA. Optimal visualization of coronary artery anastomoses by gas jet. Ann Thorac Surg 1991;52:564.
Hiroshi Matsuura, MD, Harold L. Lazar, MD, Xi Ming Yang, MD, Samuel Rivers, BS, Patrick R. Treanor, CCP, and Richard J. Shemin, MD, Boston, Mass.
Wrm blood cardioplegia has emerged as a substitute for cold blood cardioplegia as a method of myocardial protection.!" In a previous experimental study' we showed that with an acute coronary occlusion, warm blood cardioplegic solution must be administered retro-
From the Department of Cardiothoracic Surgery, Boston University Medical Center, The University Hospital, Boston, Mass. Received for publication May 18, 1992. Accepted for publication Aug. 6, 1992. Address for reprints: Harold L. Lazar, MD, Department of Cardiothoracic Surgery, The University Hospital, Suite B404, 88 East Newton S1. Boston, MA 02118. Copyright
v
1993 by Mosby-Year Book, Inc.
0022-5223/93 $1.00
+ .10
12/1/41796
gradely and continuously but does not provide myocardial protection superior to that achieved with intermittent antegrade/retrograde cold blood cardioplegia (A/RCBC). The continuous infusion of warm blood cardioplegic solution may obscure the operative field, necessitating the interruption of cardioplegia. However, the effects of interrupting warm blood cardioplegia during the revascularization of acutely ischemic myocardium are unknown. This experimental study was therefore undertaken to determine whether interrupting warm blood cardioplegia during coronary revascularization increases myocardial damage. Methods Preparation. Thirty adult pigs (28 to 32 kg) were premedicated intramuscularly with ketamine (15 rug/kg of body
357
The Journal of Thoracic and Cardiovascular Surgery August 1993
3 5 8 Matsuura et at.
weight) and acepromazine; 0.5 rng/kg), anesthetized with chloralose (75 rug/kg), and subjected to positive-pressure endotracheal ventilation. A median sternotomy was performed, and catheters were placed into the aorta and superior vena cava for monitoring systemic arterial and venous pressures and administering fluids. The azygos vein was ligated, and the animals were heparinized (3 rug/kg). The second and third diagonal vesselsjust distal to the takeoff of the left anterior descending coronary artery were then occluded with snares for 90 minutes. Intravenous lidocaine was used to treat ventricular arrhythmias. Inotropic agents were not administered. After the 90-minute period of coronary occlusion, all animals underwent total cardiopulmonary bypass with a No. 20 cannula in the femoral artery and a No. 36 venous return catheter in the right atrium, as previously described," A catheter was inserted into the left atrium to infuse volume to vary left ventricular end-diastolic pressure (L VEDP). Mean arterial blood pressure during cardiopulmonary bypass ranged from 65 to 75 mm Hg and pump flow was kept at 80 nil/kg per minute. The average hematocrit level was 27% ± 2%, and pH was maintained at 7.41 ± 0.03. After cardiopulmonary bypass was begun, all hearts were arrested for 45 minutes with a 4:1 ratio of blood to cardioplegic solution to reach a hematocrit levelof20%; the pH was 7.60, and the initial potassium concentration was 25 mEq/L. After the initial 300 ml of cardioplegic solution was infused, the potassium concentration was lowered to 10 mEq/L. During cardioplegic arrest, three different cardioplegic techniques were used. A/RCBC.Cold blood cardioplegic solution (4° C) was administered in 10 pigs; half was delivered through a catheter in the ascending aorta, and half was delivered in a retrograde fashion through a coronary sinus catheter (DLP, Inc., Grand Rapids, Mich.). The initial dose was 10 ml/kg of body weight, which was followed by additional boluses of 5 ml/kg administered every 20 minutes. These animals also underwent continuous topical hypothermia with the use of iced saline solution and were systemically cooled to 30° C. Continuous retrograde warm blood cardioplegia. In 10 pigs, continuous retrograde warm blood cardioplegia (R WBC) was achieved through a coronary sinus catheter (37° C; 100 ml/rnin). These animals did not undergo topical or systemic hypothermia. Systemic temperature was maintained at 37° C. Interrupted retrograde warm blood cardioplegia. Interrupted retrograde warm blood cardioplegia (I/RWBC) in 10 pigs included three different 7-minute periods of interruption: at 8, 23, and 38 minutes into the 45-minute crossclamp period. After the 45-minute period of cardioplegic arrest, the crossclamp was removed and the coronary snares were released. All hearts were then reperfused on cardiopulmonary bypass at 37° C for 180 minutes. Measurements and data analysis. Electrocardiographic leads were used to measure heart rate and monitor electrical activity during arrest. LVEDP was recorded with a piezoelectric Mikro-Tip catheter pressure transducer (Millar Instruments, Inc., Houston, Tex.) inserted via a stab wound in the left ventricular apex. Systemic body temperature was measured with a rectal temperature probe (Yellow Springs Instrument Co., Yellow Springs, Ohio). Coronary sinus pressure was measured with the retrograde cardioplegia catheter. Myocardial tissue pH was measured on-line as previously described.' Tissue pH probes (Khuri Tissue Ischemia Monitor; Vascular Technology Inc., North Chelmsford, Mass.) were
inserted into the center of the area of risk beyond the coronary occlusions. The pH was standardized according to myocardial temperature, which was measured simultaneously with a temperature probe inserted next to the pH probe. Preischemic pH measurements were made after a 30-minute period of equilibration and then recorded on-line with myocardial temperature during the periods of coronary occlusion, cardioplegic arrest, and reperfusion. The pH values were recorded for each experiment and then averaged for all experiments in each cardioplegia group. Wall-motion scores were obtained from two-dimensional echocardiographic sections through the area at risk, as previously described.s-f Left ventricular end-diastolic volume (LVEDV) measurements were obtained by planimetry of a perpendicular long-axis length and a short-axis area obtained from a hand-held 3.5 mHz ultrasound transducer (ATL, Tempe, Ariz.). Short-axis sections were used to assess segmental wall-motion changes. The ventricle was arbitrarily divided into eight anatomic areas and wall motion was analyzed qualitatively by a numeric score (4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, 1 = severe hypokinesis, 0 = akinesis, and -1 = dyskinesis). Echocardiographic sections for wall-motion analysis were obtained at a constant afterload (mean arterial pressure = 65 mm Hg). Only sections with the same LVEDV during the preischemic, coronary occlusion, and reperfusion periods were used for analysis to ensure similar preload conditions. Measurements were made by an experienced echocardiographer, Dr. Sheilah Bernard, who had no knowledge of the particular cardioplegia technique used. Data were averaged for the periods of preischemia, coronary occlusion, and reperfusion for each experiment and, in turn, for each cardioplegia group. The area at risk and area of necrosis were determined by histochemical staining techniques with 2,3,5-triphenyltetrazolium chloride after 180 minutes of reperfusion, as previously described." They were calculated for each experiment and then averaged for each cardioplegia group. Statistical evaluation of the three cardioplegia groups was computed by means of analysis of variance. Differences in variables measured in a continuous scale within each group were assessed by paired Student's t test. Differences in variables between two different cardioplegia groups were assessed with nonpaired Student's t test. All data were expressed as the mean ± standard error. Data were considered significant at p < 0.05. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).
Results The results are summarized in Figs. 1 to 3. All hearts achieved electromechanical arrest within 45 seconds of aortic crossclamping. Some electrical activity was noted in 7 of 10 animals in the IjRWBC group during the interruption of cardioplegia. Electrical activity was extinguished after cardioplegia was reinstituted, although flows as high as 150 to 200 mljmin were required in the first 2 minutes to cease all electrical activity in some ani-
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 2
Matsuura et ai.
o Antegrade/Retrograde CBC a Retrograde WBC • Interrupted Retrograde WBC ·p<0.05 from Retrograde WBC Interrupted Retrograde WBC
7.50
359
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'5
650
600 I Preischemia
i gOmin Coronary Occlusion
i 45min Caruiopleqic Arrest
i
·p<0.05 from Interrupted Retrograde WBC
- 1 . . . 1 . . - - , - - - - , - - - - - , - -_ _.,-__ Preiscnernia
180min Hepertuslon
Fig. 1. Myocardial pH values decreased from preischemic values inthe threecardioplegia groupsduringperiodof coronary occlusion. After 45 minutes of cardioplegic arrest, hearts that underwent antegrade/retrograde cold blood cardioplegia (CBC) had significantly higher pH values. Lowest pH values were seen in interrupted/retrograde warm blood cardioplegia (WBC) group. pH Values were similar in all cardioplegia groups after 180 minutes of reperfusion but remained lower than preischemic values. WBC, Warm bloodcardioplegia; CBC, cold blood cardioplegia.
esc
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60min Reperlusion
180mln Reperfusion
Fig. 2. Wall-motion scores decreased in all cardioplegia groupsduring the periodof coronaryocclusion. After 180 minutes of reperfusion, hearts protectedwith antegrade/retrograde CBC had significantly higher wall-motion scores than did the interrupted/retrograde WBC group. Wall-motion score: 4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, I = severe hypokinesis, 0 = akinesis, -1 = dyskinesis. WBC, Warm blood cardioplegia; CBC, cold blood cardioplegia.
100
mals. Coronary sinus pressures remained below 50 mm Hg, and aortic root pressure never exceeded 60 mm Hg during cardioplegic infusions. Serum potassium levels remained below 5.5 mliq/L during reperfusion in all hearts. Myocardial pH. The pH changes in the area at risk beyond the coronary occlusions are summarized in Fig. 1. During the preischemic period, pH values were similar in all hearts (7.57 ± 0.07 A/RCBC; 7.53 ± 0.05 RWBC, 7.44 ± 0.10 I/RWBC). After 90 minutes of coronary occlusion, all three groups had significant decreases in pH from preischemic values (6.47 ± 0.10 A/RCBC, 6.47 ± 0.13 RWBC,6.35 ± 0.06I/RWRC;p < 0.0001 from preischemic values). After 45 minutes of cardioplegic arrest, pH increased significantly in the hearts that underwent A/RCBC (6.47 ± 0.10 versus 6.98 ± 0.17; p < 0.02). pH values remained the same in the continuous RWBC group (6.47 ± 0.13 versus 6.45 ± 0.12; not significant [NS]) and actually decreased in the I/RWBC group, although this difference was not statistically significant (6.35 ± 0.06 versus 6.20 ± 0.16; NS). The pH values were significantly higher in the intermittent A/RCBC group compared with those in the warm blood cardioplegia groups after 45 minutes of aortic crossclamping (6.98 ± 0.17 A/RCBC, P < 0.05 compared with 6.45 ± 0.12 RWBC and 6.20 ± 0.16 I/RWBC). After 180 minutes of reperfusion, pH values were similar in all cardioplegia groups but remained lower than preis-
·p<0.05 from Interrupted Retrograde WBC
a Antegrade/Retrograde CBC
Retrograde WBC
Interrupted Retrograde WBC
Fig. 3. Hearts protected with interrupted/retrograde warm blood cardioplegia (WBC) had a significantly higher area of necrosis than did other cardioplegia groups. WBC, Warm blood cardioplegia; CBC, cold blood cardioplegia.
chemic levels (6.85 ± 0.15 A/RCBC, 6.80 ± 0.10 RWBC, 6.85 ± 0.21 I/RWBC; P < 0.01 from preischemic values). Wall-motion scores. All cardioplegia groups had normal wall-motion scores during the preischemic period (Fig. 2). After 90 minutes of coronary occlusion, all hearts showed a significant decrease in wall-motion scores in the area at risk (2.1 ± 0.3 A/RCBC, 2.5 ± 0.3 R WBC, 2.6 ± 0.2 I/RWBC; P < 0.001 from preischemic values). After 180 minutes of reperfusion, wall-motion scores in the area at risk decreased in the I/RWBC group, and these hearts had significantly lower wall-motion
3 6 0 Matsuura et al.
scores than did those of the intermittent AjRCBC group (2.1 ± 0.3 IjRWBC, p < 0.05 compared with 3.3 ± 0.1 AjRCBC and 2.8 ± 0.4 RWBC). Furthermore, wall-motion scores in nonischemic areas of the myocardium were also significantly lower in the IjRWBC hearts compared with the AjRCBC and continuous RWBC hearts (2.35 ± 0.40 IjRWBC, p < 0.05 compared with 3.78 ± 0.13 AjRCBC and 3.36 ± 0.27 RWBC). Area of necrosisjarea at risk. The area of myocardium at risk was similar in all three cardioplegia groups (13% ± 3% AjRCBC, 14% ± 1% AjRCBC, 16% ± 2% IjRWBC). The calculations of the area of necrosis within the area at risk are shown in Fig. 3. Hearts protected with IjRWBC had a significantly higher area of necrosis than did the intermittent AjRCBC and continuous RWBC hearts (21% ± 2% AjRCBC and 25% ± 2% R WBC, both p < 0.05 compared with 38% ± 5% IjRWBC). Discussion The continuous infusion of warm blood cardioplegic solution during ischemic arrest theoretically avoids periods of ischemia and subsequent reperfusion damage. However, the presence of an acute coronary occlusion may result in heterogeneous distribution of cardioplegic solution, thus predisposing the warm heart to further ischemic damage. Our previous studies and those of others 5, 9, 10 have shown that under these conditions antegrade warm blood cardioplegia results in significantly less myocardial protection than does continuous RWBe. Nevertheless, if visualization is impaired and the warm blood cardioplegia must be stopped, further ischemic damage is possible. Furthermore, our earlier studies' showed that continuous R WBC did not result in myocardial protection that was superior to that achieved with intermittent AjRCBC. Hence, if RWBC must be interrupted, theoretically it must be able to achieve the same degree of protection as intermittent AjRCBe. This experimental study sought to answer this question by using a model that simulates the events that occur after a failed percutaneous transluminal coronary angioplasty in which a coronary artery is suddenly occluded. The retrograde infusion of warm blood cardioplegic solution was stopped during three separate periods, as it would have been had visualization been impaired during the construction of three distal coronary anastomoses. The volume of solution for intermittent AjRCBC was similar to that used in our clinical practice, and the volume of solution for continuous warm blood cardioplegia was based on the studies of Lichtenstein and Salerno and their associates-? and our earlier investigations'
The Journal of Thoracic and Cardiovascular Surgery August 1993
After 90 minutes of coronary occlusion, all three cardioplegia groups had comparable depression in wall-motion scores and tissue pH. However, during the period of aortic crossclamping, pH trends were different in each cardioplegia group (Fig. 1). The pH values rose significantly in the hearts protected with intermittent AjRCBe. Hypothermia could have contributed to the higher pH values in this group; however, the studies of Khuri and others I 1-13 have shown that the failure of pH to increase during hypothermic cardioplegic arrest is a sensitive predictor of postischemic myocardial dysfunction. Il - 13 Hence, the higher pH values in the area at risk indicated adequate myocardial protection in these hearts by means of an intermittent AjRCBC technique. Throughout the period of cardioplegic arrest in the area at risk, hearts protected with continuous RWBC maintained a stable pH compared with pH values immediately before crossclamping. Although pH values were lower during arrest in the continuous R WBC hearts than in the AjRCBC hearts, this does not mean that the former were more acidotic. This condition was reflected in the areas of necrosis of the two groups, which were not statistically different. In contrast, pH values continued to decrease during the period of cardioplegic arrest in hearts protected with IjRWBe. Although there was no statistically significant difference in the mean pH values of the continuous RWBC group (6.45 ± 0.12) and the IjRWBC group (6.20 ± 0.16) during cardioplegic arrest, physiologic significance may exist because Khuri and associates!' have shown that irreversible tissue damage in the canine myocardium occurs when pH values approach 6.20. After 3 hours of reperfusion, wall-motion scores in the area at risk were lowest in the I jRWBC group (Fig. 2). These scores were significantly lower than those of the intermittent AjRCBC group. In addition, wall-motion scores were also significantly lower in nonischemic areas that underwent IjRWBe. These changes in pH and wall motion were reflected in the percentage of area of necrosis, which was significantly higher in the IjRWBC group when compared with the other groups (Fig. 3). Since the introduction of warm blood cardioplegia to clinical practice, techniques such as "gas jets" have been introduced in an attempt to provide better visualization of the operative field without interrupting cardioplegia. 14 In some instances, it may be possible to maintain flow through the completed vein graft to the area at risk while interrupting blood flow to less critical areas of the myocardium. These techniques may help to limit ischemic damage when warm blood cardioplegia must be interrupted. Nevertheless, our results indicate that interrupting R WBe during the revascularization of acutely ischemic myocardium results in more tissue acidosis dur-
The Journal of Thoracic and Cardiovascular Surgery Volume 106, Number 2
ing cardioplegic arrest, lower postischemic wall-motion scores, and increased tissue necrosis in the area at risk. Furthermore, the wall-motion scores in nonischemic areas suggest that interrupting RWBC may also be detrimental to other regions of the myocardium. Histologic staining was not done in these areas, but it is conceivable that this depressed wall motion may represent stunned myocardium. Nevertheless, these data imply that hearts undergoing IRWBC are at higher risk for developing wall-motion abnormalities in both acutely ischemic and nonischemic areas of the myocardium. This study suggests that surgeons using warm blood cardioplegia techniques should make every effort to limit periods of anoxia during the revascularization of acutely ischemic myocardium. It also suggests that when cardioplegia must be interrupted for extended periods during coronary revascularization, AjRCBC results in superior regional and global myocardial protection than can be achieved with interrupted warm blood cardioplegia techniques. The secretarial assistance of Ms. Ellie LaBombard in the preparation of this manuscript is greatly appreciated. REFERENCES I. Lichtenstein SV, Ashe KA, Dalati HE, Cusimano RJ, Panas A, Slutsky AS. Warm heart surgery. J THORAC CARDIOVASC SURG 1991;101:269-74. 2. Salerno TA, Houck JP, Barrozo CAM, et al. Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991;51:245-7. 3. Lichtenstein SV, Fremis SE, Abel JG, Christakis GT, Salerno TA. Technical aspects of warm heart surgery. J Cardiac Surg 1991;6:278-85. 4. Lichtenstein SV, Abel JG, Salerno TA. Warm heart surgery and results of operation for recent myocardial infarction. Ann Thorac Surg 1991;52:455-60.
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5. Matsuura H, Lazar HL, Yang XM, et al. Warm versus cold blood cardioplegia: Is there a difference? Surg Forum 1991;50:231-2. 6. Haan C, Lazar HL, Bernard S, Rivers S, Zallnick J, Shemin RJ. Superiority of retrograde cardioplegia after acute coronary occlusion. Ann Thorac Surg 1991;51:40812. 7. Lazar HL, Khoury T, Rivers S. Improved distribution of cardioplegia with pressure controlled intermittent coronary sinus occlusion (PICSO). Ann Thorac Surg 1988;46:2027.
8. Wyatt HL, Heng MK, Meerbaum S. Cross-sectional echocardiography. II. Analysis of mathematical models for quantifying volume of the formalin-fixed left ventricle. Circulation 1980;61:1119-25. 9. Misare BD, Krukenkamp IB, Lazar ZP, LevitskyS. Antegrade warm continuous blood cardioplegia exacerbates acute regional ischemic injury. Surg Forum 1991;50:2324.
10. Misare BD, Krukenkamp IB, Lazar ZP, Levitsky S. Retrograde is superior to antegrade continuous warm blood cardioplegia for acute cardiac ischemia. Circulation 1991;84(Suppl):1I687. II. Lange R, Kloner RA, Zierler M, Carlson N, Seiler M, Khuri SF. Time course of ischemic alterations during normothermic and hypothermic arrest and its reflection by on-line monitoring of tissue pH. J THoRAc CARDIOVASC SURG 1983;86:418-34. 12. Khuri SF, Josa M, Martson W, et al. First report of intramyocardial pH in man. II. Assessment of adequacy of myocardial preservation. J THORAC CARDIOVASC SURG 1983;86:667-78. 13. Takach TJ, Glassman LR, Ribakove GH, Clark RE. Continuous measurement of intramyocardial pH: correlation to functional recoveryfollowingnormothermic and hypothermic global ischemia. Ann Thorac Surg 1986;42:31-6. 14. Teoh KH, Panos AL, Harmantas AA, Lichtenstein SV, Salerno TA. Optimal visualization of coronary artery anastomoses by gas jet. Ann Thorac Surg 1991;52:564.