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Intermittent myocardial ischemia during cardiopulmonary bypass
Intermittent myocardial ischemia during cardiopulmonary bypass George Benzing, III, M.D., James Stockert, Ph.D., Ed Nave, M.S.E.E., and Samuel Kaplan, M.D., Cincinnati, Ohio
DUring the surgical treatment of patients with congenital heart disease who require cardiopulmonary bypass, intervals of myocardial ischemia are sometimes used'? to provide a bloodless operative field and a relaxed myocardium. Previous investigations of cardiac performance in man' and dogsv" suggest that interruption of coronary blood flow for long periods of time is associated with moderate depression of cardiac function. In the interest of preserving myocardial function, it appears better to use intermittent myocardial ischemia': 5 rather than a long single interval of cardiac anoxia. The duration of the interval of coronary flow permitted between periods of myocardial ischemia has been selected at least in part on an empiric basis. The purpose of this study was to determine the effects of a total of 45 minutes of myocardial ischemia on left ventricular function of dogs subjected to cardiopulmonary bypass at 32° c.lO In one group of animals, the 45 minutes of ischemia were divided into three 15 minute periods, with two 5 minute intervals of coronary flow. In another group, two 45 second intervals of coronary flow were interspersed similarly. The method of study was chosen to simulate the From the Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio. Supported in part by the Heart Association of Southwestern Ohio and the Kinnard Foundation. Received for publication June 6, 1972. Address for reprints: George Benzing, III, M.D., The Children's Hospital, Cincinnati, Ohio 45229.
108
situation which occurs during clinical perfusion.
Materials and methods Thirty-seven mongrel dogs weighing 12 to 28 kilograms were studied after they were anesthetized with sodium pentobarbital (30 mg. per kilogram). A satisfactory plane of anesthesia was maintained with morphine sulfate. Body temperature was maintained at 37° C., and arterial blood pH was kept within normal physiologic limits. After endotracheal intubation, positive-pressure ventilation was accomplished with 50 per cent oxygen. The chest was opened by a median sternotomy incision. Aortic pressure was obtained from a strain gauge attached to a catheter inserted in the right internal mammary artery. An electromagnetic flow probe was placed around the root of the aorta. Left ventricular and left atrial pressures were sensed via catheters placed in these chambers. Blood flow and pressures were recorded as the filling pressure of the left ventricle was increased serially by rapid transfusion of warmed blood as previously described' in plotting Frank-Starling ventricular function curves. Instantaneous left ventricular power was calculated by multiplying instantaneous left ventricular pressure minus left ventricular end-diastolic pressure by instantaneous aortic flow. The product was averaged electronically to obtain mean left ventricular power. Systemic vascular resistance was computed by dividing mean aortic pressure by mean aortic blood flow.
Volume 65 Number 1
Intermittent myocardial ischemia during bypass
1 09
January, 1973
After data for a control ventricular function curve had been obtained, the dog was placed on total cardiopulmonary bypass." Venous inflow was derived by caval cannulation, and arterial return was accomplished by bilateral femoral cannulation. After body temperature had been reduced to 32° C., the left ventricle was drained. Myocardial ischemia was produced by cross-clamping the root of the aorta. Fifteen dogs, Group I, were permitted 5 minutes of coronary flow by release of the aortic clamp after each 15 minute interval of myocardial ischemia for a total of 45 minutes of total cardiac anoxia. Group II animals, consisting of 13 dogs, were allowed only 45 seconds of coronary flow after each 15 minute period of ischemia, but they also had a total of 45 minutes of cardiac anoxia. After three 15 minute intervals of myocardial ischemia with two periods of coronary flow, the clamp was removed and body temperature was restored to 37° C. All dogs of Groups I and II were subjected to a total of 45 minutes of cardiac ischemia. A control group of 9 dogs was subjected to the same duration of cardiopulmonary bypass as the dogs of Groups I and II but with no intervals of myocardial ischemia. Thirty minutes after cardiopulmonary bypass, a second ventricular function curve was obtained in all animals. Systemic vascular resistance was regulated! to the same level that existed during the control run at the same left ventricular filling pressure. The change in left ventricular performance was determined by expressing the maximum attained mean left ventricular power following myocardial ischemia as a per cent of the original maximal attainable mean left ventricular power. The effects of 45 minutes of cardiac anoxia on these two groups of dogs were compared to the results in the control group of dogs, which were subjected to cardiopulmonary bypass of the same total duration at 32° C. Results
The results obtained in the three groups of dogs are summarized in Table I. The control group of dogs retained 84 per cent of the original maximal attainable mean left
Table I. Maximum attained mean left ventricular (LV) power Maximal attained LV power (Gm.-M./min.) Before Dog No.
Weight (Kg.)
perju-
sion
After perju- Per cent sion of original
Control group
1 2 3 4 5 6 7 8 9 Mean ± S.D.
16.4 27.7 13.6 17.7 20.4 14.5 18.2 17.7 19.0
7,800 13,200 9,300 10,800 11,400 12,200 11,200 11,600 9,300
7,600 12,000 8,100 9,100 9,600 10,100 8,600 8,900 6,800
97.5 91.0 87.0 84.3 84.2 83.0 76.8 76.6 73.1 83.7 ± 7.63
23.2 18.2 17.7 18.1 16.8 18.1 19.1 17.7 19.1 18.2 17.0 17.3 19.6 18.2 16.4
7,900 7,900 8,600 10,600 9,600 12,600 10,400 13,600 10,000 8,200 10,400 9,600 8,300 9,500 7,500
5,100 5,000 5,400 6,500 5,600 7,100 5,600 7,100 4,900 3,900 4,700 4,200 3,300 3,700 2,900
64.5 63.4 62.8 61.3 58.3 56.3 53.8 52.2 49.0 47.5 45.1 43.8 39.8 39.0 38.7 51.7 ± 9.2
12.7 20.5 15.4 15.9 17.7 15.5 16.4 21.4 19.1 20.0 19.6 20.5 19.1
9,300 13,900 8,900 9,400 11,400 12,000 9,500 7,800 11,400 12,000 7,000 10,800 14,400
6,000 7,100 4,500 4,300 5,100 4,900 3,800 3,000 4,200 3,200 1,800 2,300 2,600
64.5 51.0 50.6 45.8 44.7 40.8 40.0 38.5 36.8 26.7 26.1 21.3 18.1 38.8 ± 13.2
Group I
1 2
3
4 5 6 7 8 9 10 11 12 13 14 15 Mean ± S.D. Group II
1 2 3 4 5 6
7 8 9 10 11 12 13 Mean± S.D.
Legend: For description of groups, see text. S.D., Standard deviation.
1 10
The Journol of Thorocic ond Cordiovosculor Surgery
Benzing et al.
ventricular power. An average of 52 per cent of maximal attained left ventricular power capacity was retained by dogs of Group I, in which 5 minutes of coronary flow were permitted for each 15 minutes of ischemia. In contrast, dogs of Group II, allowed only 45 seconds of coronary flow, retained an average of 38 per cent of the original work capacity of the heart. According to Duncan's" Multiple Range Test, the control group differed statistically from Groups I (p < 0.01) and II (p < 0.01) in the retention of left ventricular power. Furthermore, dogs of Group I retained significantly more ventricular function than Group II dogs (p < 0.05). Of the Group I dogs, the least retention of ventricular power was 38 per cent. In contrast, 4 dogs of Group II retained less than 30 per cent of the original maximal left ventricular power.
This report is the first to demonstrate statistically in dogs that longer intervals of coronary flow (e.g., 5 minutes) offer more benefit in preserving postoperative heart function than do short intervals (e.g., 45 seconds). We have previously shown" that following 45 minutes of uninterrupted myocardial ischemia only 33.6 per cent of the original maximal attained mean left ventricular power persisted. Dogs which were permitted 5 minute intervals of coronary flow retained statistically greater ventricular function than did those subjected to 45 minutes of continuous ischemia. The findings of this investigation support the concept that the use of 5 minutes of coronary flow after each 15 minute interval of myocardial ischemia is advantageous in preserving cardiac function during the surgical repair of congenital cardiac defects in man.
Discussion
Summary The effects of intermittent 5 minute and 45 second intervals of coronary flow each 15 minutes of myocardial ischemia for a total of 45 minutes during total cardiopulmonary bypass were evaluated by ventricular function curves. Dogs which were permitted 5 minutes of coronary flow for each 15 minute period of cardiac anoxia retained 52 per cent of original maximal mean left ventricular power. Only 38 per cent of myocardial function was retained by those allowed 45 seconds of coronary flow for each 15 minutes of ischemia. This study suggests that 5 minute intervals of coronary flow after each 15 minute interval of myocardial ischemia offer a significant advantage in the preservation of cardiac function during cardiopulmonary bypass.
These studies were performed under circumstances similar to those used during surgical correction of cardiac defects in patients. Obviously, the effects of ventriculotomy!' and myocardial trauma necessary to repair cardiac defects may impose further impairment of the patient's cardiac performance. Moderately severe alteration of canine cardiac ultrastructure has been observed following 30 minutes of continuous ischemia.': I'. Jr. Jennings and colleagues" observed necrosis in the myocardium of dogs in which 25 minutes or more of myocardial ischemia was produced by temporary occlusion of the circumflex branch of the left coronary artery. Previous work of Greenberg and Edmunds'> suggests that postoperative recovery of dogs is difficult if 40 per cent or less of the original function is retained. Studies of human myocardial performance- demonstrated that decreased levels of retention of ventricular performance are associated with higher mortality rates. In some instances, inotropic agents aid in survival of patients with moderately severe impairment of myocardial function."
REFERENCES I Kirklin, J. W., and Karp, R. B.: The Tetralogy
of Fallot, From a Surgical Viewpoint, Philadelphia, 1970, W. B. Saunders Company. 2 Benzing, G., III, Helmsworth, I., Stockert, I., and Kaplan, S.: Human Myocardial Performance During Surgical Treatment of Cardiac Defects, 1. THoRAc. CARDIOVASC. SURG. 59: 800, 1970. 3 Bernhard, W. P., Schwartz, H. F., and Mal-
Volume 65 Number 1
Intermittent myocardial ischemia during bypass
111
January, 1973
4
5
6 7
8
9
10
lick, N. P.: Intermittent Cold Coronary Perfusion As an Adjunct to Open Heart Surgery, Surg, Gyneco!. Obstet. 111: 744, 1960. Benzing, G., III, Stockert, I., DeForest, D., and Kaplan, S.: Effect of Myocardial Ischemia on Left Ventricular Function After Hypothermic Cardiopulmonary Bypass, I. THORAC. CARDIOVASC. SURG. 56: 241, 1968. Ebert, P. A., Greenfield, L. I., Austen, W. G., and Morrow, A. G.: Experimental Comparison of Methods for Protecting the Heart During Aortic Occlusion, Ann. Surg. 155: 25, 1962. Levitsky, S., Sloane, R., Mullin, E., McIntosh, C., and Morrow, A.: Normothermic Myocardial Anoxia, Ann. Thorac. Surg. 11: 229, 1971. Buja, M., Levitsky, S., Ferrans, V., Souther, S., Roberts, W., and Morrow, A.: Acute and Chronic Effects of Normothermic Anoxia on Canine Hearts, Circulation 43: 144, 1971. Stoney, R. I., and Roe, B. B.: Ventricular Function After Induced Intermittently Ischemic Ventricular Fibrillation: Effect of Moderate Hypothermia, I. THORAC. CARDIOVASC. SURG. 48: 838, 1964. Bolooki, H., Rooks, I. I., Viera, C. E., Smith, B., Mobin-Uddin, K., Lombardo, C. R., and Jude, I. R.: Comparison of the Effect of Temporary or Permanent Myocardial Ischemia on Cardiac Function and Pathology, 1. THORAC. CARDIOVASC. SURG. 56: 590, 1968. Sarnoff, S. I., and Berglund, E.: Starling's Law of the Heart Studied by Simultaneous
11
12 13
14
15
16
17
18
Right and Left Ventricular Function Curves in the Dog, Circulation 9: 706, 1954. Clark, L. C., r-., Hoover, F., and Gollan, F.: A Large Capacity, All-Glass Dispersion Oxygenator and Pump, Rev. Sci. Instrum, 23: 748, 1952. Duncan, D. B.: Multiple Range and Multiple "F" Tests, Biometrics 11: 1, 1955. Greenberg, I. I., and Edmunds, L. H., Ir.: Effect of Myocardial Ischemia at Varying Temperatures on Left Ventricular Function and Tissue Oxygen Tension, I. THORAC. CARDIOVASCo SURG. 42: 84, 1961. Benzing, G., III, Baker, R. A., Stockert, 1., DeForest, D., and Kaplan, S.: Cardiotomy and Ventricular Function, I. THORAC. CARDIOVASCo SURG. 53: 303, 1967. Partin, I. S., Partin, I. C., and Benzing, G., III: Early Mitochondrial Alterations in Dog Hearts Following Three Periods of Total Aortic Occlusion of Cardiopulmonary Bypass, Proc. Electron Microscope Soc., 1971. Partin, I. S., Benzing, G., III, and Partin, I. C.: Quantitative Fine Structural Changes in Dog Heart Following Cardiopulmonary Bypass, I. Mo!. Cell. Cardio!. 4: 345, 1972. Jennings, I., Sommers, H., Smyth, G., Flack, H., and Linn, H.: Myocardial Necrosis Induced by Temporary Occlusion of a Coronary Artery in the Dog, Arch. Patho!. 70: 68, 1960. Benzing, G., III, Stockert, I., Nave, E., and Kaplan, S.: Myocardial Ischemia and Cardiopulmonary Bypass, Cardiovasc. Res. In press.
DUring the surgical treatment of patients with congenital heart disease who require cardiopulmonary bypass, intervals of myocardial ischemia are sometimes used'? to provide a bloodless operative field and a relaxed myocardium. Previous investigations of cardiac performance in man' and dogsv" suggest that interruption of coronary blood flow for long periods of time is associated with moderate depression of cardiac function. In the interest of preserving myocardial function, it appears better to use intermittent myocardial ischemia': 5 rather than a long single interval of cardiac anoxia. The duration of the interval of coronary flow permitted between periods of myocardial ischemia has been selected at least in part on an empiric basis. The purpose of this study was to determine the effects of a total of 45 minutes of myocardial ischemia on left ventricular function of dogs subjected to cardiopulmonary bypass at 32° c.lO In one group of animals, the 45 minutes of ischemia were divided into three 15 minute periods, with two 5 minute intervals of coronary flow. In another group, two 45 second intervals of coronary flow were interspersed similarly. The method of study was chosen to simulate the From the Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio. Supported in part by the Heart Association of Southwestern Ohio and the Kinnard Foundation. Received for publication June 6, 1972. Address for reprints: George Benzing, III, M.D., The Children's Hospital, Cincinnati, Ohio 45229.
108
situation which occurs during clinical perfusion.
Materials and methods Thirty-seven mongrel dogs weighing 12 to 28 kilograms were studied after they were anesthetized with sodium pentobarbital (30 mg. per kilogram). A satisfactory plane of anesthesia was maintained with morphine sulfate. Body temperature was maintained at 37° C., and arterial blood pH was kept within normal physiologic limits. After endotracheal intubation, positive-pressure ventilation was accomplished with 50 per cent oxygen. The chest was opened by a median sternotomy incision. Aortic pressure was obtained from a strain gauge attached to a catheter inserted in the right internal mammary artery. An electromagnetic flow probe was placed around the root of the aorta. Left ventricular and left atrial pressures were sensed via catheters placed in these chambers. Blood flow and pressures were recorded as the filling pressure of the left ventricle was increased serially by rapid transfusion of warmed blood as previously described' in plotting Frank-Starling ventricular function curves. Instantaneous left ventricular power was calculated by multiplying instantaneous left ventricular pressure minus left ventricular end-diastolic pressure by instantaneous aortic flow. The product was averaged electronically to obtain mean left ventricular power. Systemic vascular resistance was computed by dividing mean aortic pressure by mean aortic blood flow.
Volume 65 Number 1
Intermittent myocardial ischemia during bypass
1 09
January, 1973
After data for a control ventricular function curve had been obtained, the dog was placed on total cardiopulmonary bypass." Venous inflow was derived by caval cannulation, and arterial return was accomplished by bilateral femoral cannulation. After body temperature had been reduced to 32° C., the left ventricle was drained. Myocardial ischemia was produced by cross-clamping the root of the aorta. Fifteen dogs, Group I, were permitted 5 minutes of coronary flow by release of the aortic clamp after each 15 minute interval of myocardial ischemia for a total of 45 minutes of total cardiac anoxia. Group II animals, consisting of 13 dogs, were allowed only 45 seconds of coronary flow after each 15 minute period of ischemia, but they also had a total of 45 minutes of cardiac anoxia. After three 15 minute intervals of myocardial ischemia with two periods of coronary flow, the clamp was removed and body temperature was restored to 37° C. All dogs of Groups I and II were subjected to a total of 45 minutes of cardiac ischemia. A control group of 9 dogs was subjected to the same duration of cardiopulmonary bypass as the dogs of Groups I and II but with no intervals of myocardial ischemia. Thirty minutes after cardiopulmonary bypass, a second ventricular function curve was obtained in all animals. Systemic vascular resistance was regulated! to the same level that existed during the control run at the same left ventricular filling pressure. The change in left ventricular performance was determined by expressing the maximum attained mean left ventricular power following myocardial ischemia as a per cent of the original maximal attainable mean left ventricular power. The effects of 45 minutes of cardiac anoxia on these two groups of dogs were compared to the results in the control group of dogs, which were subjected to cardiopulmonary bypass of the same total duration at 32° C. Results
The results obtained in the three groups of dogs are summarized in Table I. The control group of dogs retained 84 per cent of the original maximal attainable mean left
Table I. Maximum attained mean left ventricular (LV) power Maximal attained LV power (Gm.-M./min.) Before Dog No.
Weight (Kg.)
perju-
sion
After perju- Per cent sion of original
Control group
1 2 3 4 5 6 7 8 9 Mean ± S.D.
16.4 27.7 13.6 17.7 20.4 14.5 18.2 17.7 19.0
7,800 13,200 9,300 10,800 11,400 12,200 11,200 11,600 9,300
7,600 12,000 8,100 9,100 9,600 10,100 8,600 8,900 6,800
97.5 91.0 87.0 84.3 84.2 83.0 76.8 76.6 73.1 83.7 ± 7.63
23.2 18.2 17.7 18.1 16.8 18.1 19.1 17.7 19.1 18.2 17.0 17.3 19.6 18.2 16.4
7,900 7,900 8,600 10,600 9,600 12,600 10,400 13,600 10,000 8,200 10,400 9,600 8,300 9,500 7,500
5,100 5,000 5,400 6,500 5,600 7,100 5,600 7,100 4,900 3,900 4,700 4,200 3,300 3,700 2,900
64.5 63.4 62.8 61.3 58.3 56.3 53.8 52.2 49.0 47.5 45.1 43.8 39.8 39.0 38.7 51.7 ± 9.2
12.7 20.5 15.4 15.9 17.7 15.5 16.4 21.4 19.1 20.0 19.6 20.5 19.1
9,300 13,900 8,900 9,400 11,400 12,000 9,500 7,800 11,400 12,000 7,000 10,800 14,400
6,000 7,100 4,500 4,300 5,100 4,900 3,800 3,000 4,200 3,200 1,800 2,300 2,600
64.5 51.0 50.6 45.8 44.7 40.8 40.0 38.5 36.8 26.7 26.1 21.3 18.1 38.8 ± 13.2
Group I
1 2
3
4 5 6 7 8 9 10 11 12 13 14 15 Mean ± S.D. Group II
1 2 3 4 5 6
7 8 9 10 11 12 13 Mean± S.D.
Legend: For description of groups, see text. S.D., Standard deviation.
1 10
The Journol of Thorocic ond Cordiovosculor Surgery
Benzing et al.
ventricular power. An average of 52 per cent of maximal attained left ventricular power capacity was retained by dogs of Group I, in which 5 minutes of coronary flow were permitted for each 15 minutes of ischemia. In contrast, dogs of Group II, allowed only 45 seconds of coronary flow, retained an average of 38 per cent of the original work capacity of the heart. According to Duncan's" Multiple Range Test, the control group differed statistically from Groups I (p < 0.01) and II (p < 0.01) in the retention of left ventricular power. Furthermore, dogs of Group I retained significantly more ventricular function than Group II dogs (p < 0.05). Of the Group I dogs, the least retention of ventricular power was 38 per cent. In contrast, 4 dogs of Group II retained less than 30 per cent of the original maximal left ventricular power.
This report is the first to demonstrate statistically in dogs that longer intervals of coronary flow (e.g., 5 minutes) offer more benefit in preserving postoperative heart function than do short intervals (e.g., 45 seconds). We have previously shown" that following 45 minutes of uninterrupted myocardial ischemia only 33.6 per cent of the original maximal attained mean left ventricular power persisted. Dogs which were permitted 5 minute intervals of coronary flow retained statistically greater ventricular function than did those subjected to 45 minutes of continuous ischemia. The findings of this investigation support the concept that the use of 5 minutes of coronary flow after each 15 minute interval of myocardial ischemia is advantageous in preserving cardiac function during the surgical repair of congenital cardiac defects in man.
Discussion
Summary The effects of intermittent 5 minute and 45 second intervals of coronary flow each 15 minutes of myocardial ischemia for a total of 45 minutes during total cardiopulmonary bypass were evaluated by ventricular function curves. Dogs which were permitted 5 minutes of coronary flow for each 15 minute period of cardiac anoxia retained 52 per cent of original maximal mean left ventricular power. Only 38 per cent of myocardial function was retained by those allowed 45 seconds of coronary flow for each 15 minutes of ischemia. This study suggests that 5 minute intervals of coronary flow after each 15 minute interval of myocardial ischemia offer a significant advantage in the preservation of cardiac function during cardiopulmonary bypass.
These studies were performed under circumstances similar to those used during surgical correction of cardiac defects in patients. Obviously, the effects of ventriculotomy!' and myocardial trauma necessary to repair cardiac defects may impose further impairment of the patient's cardiac performance. Moderately severe alteration of canine cardiac ultrastructure has been observed following 30 minutes of continuous ischemia.': I'. Jr. Jennings and colleagues" observed necrosis in the myocardium of dogs in which 25 minutes or more of myocardial ischemia was produced by temporary occlusion of the circumflex branch of the left coronary artery. Previous work of Greenberg and Edmunds'> suggests that postoperative recovery of dogs is difficult if 40 per cent or less of the original function is retained. Studies of human myocardial performance- demonstrated that decreased levels of retention of ventricular performance are associated with higher mortality rates. In some instances, inotropic agents aid in survival of patients with moderately severe impairment of myocardial function."
REFERENCES I Kirklin, J. W., and Karp, R. B.: The Tetralogy
of Fallot, From a Surgical Viewpoint, Philadelphia, 1970, W. B. Saunders Company. 2 Benzing, G., III, Helmsworth, I., Stockert, I., and Kaplan, S.: Human Myocardial Performance During Surgical Treatment of Cardiac Defects, 1. THoRAc. CARDIOVASC. SURG. 59: 800, 1970. 3 Bernhard, W. P., Schwartz, H. F., and Mal-
Volume 65 Number 1
Intermittent myocardial ischemia during bypass
111
January, 1973
4
5
6 7
8
9
10
lick, N. P.: Intermittent Cold Coronary Perfusion As an Adjunct to Open Heart Surgery, Surg, Gyneco!. Obstet. 111: 744, 1960. Benzing, G., III, Stockert, I., DeForest, D., and Kaplan, S.: Effect of Myocardial Ischemia on Left Ventricular Function After Hypothermic Cardiopulmonary Bypass, I. THORAC. CARDIOVASC. SURG. 56: 241, 1968. Ebert, P. A., Greenfield, L. I., Austen, W. G., and Morrow, A. G.: Experimental Comparison of Methods for Protecting the Heart During Aortic Occlusion, Ann. Surg. 155: 25, 1962. Levitsky, S., Sloane, R., Mullin, E., McIntosh, C., and Morrow, A.: Normothermic Myocardial Anoxia, Ann. Thorac. Surg. 11: 229, 1971. Buja, M., Levitsky, S., Ferrans, V., Souther, S., Roberts, W., and Morrow, A.: Acute and Chronic Effects of Normothermic Anoxia on Canine Hearts, Circulation 43: 144, 1971. Stoney, R. I., and Roe, B. B.: Ventricular Function After Induced Intermittently Ischemic Ventricular Fibrillation: Effect of Moderate Hypothermia, I. THORAC. CARDIOVASC. SURG. 48: 838, 1964. Bolooki, H., Rooks, I. I., Viera, C. E., Smith, B., Mobin-Uddin, K., Lombardo, C. R., and Jude, I. R.: Comparison of the Effect of Temporary or Permanent Myocardial Ischemia on Cardiac Function and Pathology, 1. THORAC. CARDIOVASC. SURG. 56: 590, 1968. Sarnoff, S. I., and Berglund, E.: Starling's Law of the Heart Studied by Simultaneous
11
12 13
14
15
16
17
18
Right and Left Ventricular Function Curves in the Dog, Circulation 9: 706, 1954. Clark, L. C., r-., Hoover, F., and Gollan, F.: A Large Capacity, All-Glass Dispersion Oxygenator and Pump, Rev. Sci. Instrum, 23: 748, 1952. Duncan, D. B.: Multiple Range and Multiple "F" Tests, Biometrics 11: 1, 1955. Greenberg, I. I., and Edmunds, L. H., Ir.: Effect of Myocardial Ischemia at Varying Temperatures on Left Ventricular Function and Tissue Oxygen Tension, I. THORAC. CARDIOVASCo SURG. 42: 84, 1961. Benzing, G., III, Baker, R. A., Stockert, 1., DeForest, D., and Kaplan, S.: Cardiotomy and Ventricular Function, I. THORAC. CARDIOVASCo SURG. 53: 303, 1967. Partin, I. S., Partin, I. C., and Benzing, G., III: Early Mitochondrial Alterations in Dog Hearts Following Three Periods of Total Aortic Occlusion of Cardiopulmonary Bypass, Proc. Electron Microscope Soc., 1971. Partin, I. S., Benzing, G., III, and Partin, I. C.: Quantitative Fine Structural Changes in Dog Heart Following Cardiopulmonary Bypass, I. Mo!. Cell. Cardio!. 4: 345, 1972. Jennings, I., Sommers, H., Smyth, G., Flack, H., and Linn, H.: Myocardial Necrosis Induced by Temporary Occlusion of a Coronary Artery in the Dog, Arch. Patho!. 70: 68, 1960. Benzing, G., III, Stockert, I., Nave, E., and Kaplan, S.: Myocardial Ischemia and Cardiopulmonary Bypass, Cardiovasc. Res. In press.