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Influence of perfusion pressure on oxygen supply and demand in beating empty hypertrophied dog hearts
JOURNAL
OF SURGICAL
RESEARCH
33, 103- 111 (1982)
Influence of Perfusion Pressure on Oxygen Supply and Demand in Beating Empty Hypertrophied Dog Hearts’ YOSHITO
AKIRA Division
KAWACHI, M.D.,* RYUJI TOMINAGA, M.D., MOCHIKAZU YOSHITOSHI, SESE, M.D., KOUICHI TOKUNAGA, M.D., AND MOTOOMI NAKAMURA, and Cardiovascular of Cardiovascular Surgery, *Research Institute of Angiocardiology Kyushu Universiiy Faculty of Medicine, Fukuoka 812. Japan Submitted
for publication
M.D., M.D.*
Clime. and
April 23, 198I
As cardiopulmonary bypass is frequently accompanied by hypotension, the effect of varying perfusion pressure (30, 60, and 90 mm Hg) on the adequacy and distribution of coronary flow was studied under conditions of a normothermic beating empty state, of normal and hypertrophied hearts of 20 mongrel dogs, using the radioactive microsphere technique. In the normal hearts, 30 mmHg caused a 47% (P i 0.005 to prebypass) reduction of left ventricular coronary Row but did not change flow distribution (ENDO/EPI flow ratio: 1.01); increasing mean perfusion pressure from 30 to 90 mm Hg did not alter the oxygen consumption but did increase the coronary flow and decrease the oxygen extraction ratio. In the hypertrophied hearts, 30 and 60 mm Hg perfusion pressures resulted in a redistribution of flow away from the subendocardium (ENDO/EPI flow ratio: 0.82 and 0.87, respectively, P < 0.02 to prebypass). An increase in perfusion pressure from 30 to 60 mm Hg resulted m a significant increase in oxygen uptake (4.0 vs 5.6 cc/100 g/min, respectively, P < 0.02). An increased perfusion pressure of 90 mmHg resulted in a sufficient subendocardial Row and an augmentation of the oxygen uptake. These results indicate that subendocardial underperfusion occurs in the beating empty hypertrophied heart, under conditions of lower perfusion pressures (30 and 60 mm Hg), but that such can be improved by increasing the perfusion pressure to 90 mmHg. In contrast, the subendocardial underperfuston does not occur with a perfusion pressure of 30 mm Hg in normal hearts.
might be contraindicated as myocardial edema may occur [7, 81, and a pressure Although there are numerous experiments lower than 50 mmHg should be maintained. on the beating empty state in the normal On the contrary, the oxygen-debt repayment heart [ 15, 18, 221, few studies have been is accomplished by a beating empty heart at done on the hypertrophied heart [ 1, 2, 131. over 80 mm Hg [5]. In the open beating In clinical cases of a hypertrophied heart, heart with left ventricular hypertrophy, the a lower perfusion pressure often accompaoptimal myocardial oxygen delivery can be nies a decreased peripheral vascular resisachieved at a “line pressure” of over 110 tance or a decreased flow rate. For myocarmm Hg [ 121. Thus, the perfusion pressure dial protection, attention should be given to appears to be inconsistent with regard to preventing reperfusion injury [6, 9, 10, 231 protection of reperfusion injury and oxygenand “oxygen-debt repayment” [9, 161 after debt repayment. We have studied the hethe aortic clamp is released. Upon initiation modynamics and metabolism at various perof reperfusion of the anoxic myocardium, a fusion pressures in a beating empty state of higher perfusion pressure ( 100 mm Hg) the hypertrophied heart to determine whether ’ This study was supported by a grant from the Minischemia would occur at a lower perfusion istry of Education (357416), Japan. pressure and whether improvement would * To whom correspondence and reprint requests should occur under conditions of a higher pressure. be addressed at: Dtvision of Cardiovascular Surgery, Our observations were then compared with Kyushu University Faculty of Medicine, Maidashi 3-lI, Higashi-ku, Fukuoka 812, Japan. findings in normal hearts. INTRODUCTION
103
0022-4804/82/080103-09so1.00/0 Copyright 0 1982 by Academic Press, Inc. All rights of reproduction in any form reserved
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RESEARCH: VOL. 33, NO. 2, AUGUST 1982
METHODS
Twenty mongrel dogs were anesthetized with sodium pentobarbital (25 mg/kg, iv), and additional doses were given as required, before the cardiopulmonary bypass. The dogs were ventilated with oxygen-rich gas mixtures. Catheters with side-holes were inserted into the left carotid artery for aorticroot pressure monitoring, into the right femoral artery for reference blood sampling, and into the right femoral vein for drug injection. A bilateral thoracotomy was performed to expose the heart. Sodium heparin was then administered (300 III/kg, iv). A catheter was inserted in the left atrium for microsphere injection and pressure monitoring. Left ventricular intracavitary pressure was obtained using a microtip pressure transducer (Miller Co.) inserted through the left ventricular apex. In some dogs, a coronary sinus catheter was inserted. Cardiopulmonary bypass was instituted by diverting systemic and coronary venous blood into a bubble oxygenator, respectively, then returning it via the right carotid artery. The extracorporeal circuit was primed with fresh heparinized homologous blood. The esophageal temperature was maintained at normothermia using a heat exchanger. The left ventricle was vented with a cannula placed through the left ventricular apex, and the right ventricle with a cannula placed directly into the outflow tract. The main pulmonary artery was occluded. Left ventricular and/ or left atria1 pressure was monitored continuously to assure the adequacy of venting. Heart rate was maintained spontaneously. If required, sodium bicarbonate was given to maintain the arterial pH within normal ranges. Two experimental groups were prepared. Group I (normal or nonhypertrophied left ventricle): This group included 13 adult dogs weighing 9 to 14 kg. Group II (hypertrophied left ventricle): This group included 7 dogs in which banding of the ascending aorta had been performed when the dogs were about 2 months old, a time when they
weighed between 1.7 and 4.8 (mean 3.0) kg. After 11 months, they weighed 7 to 13 (mean 8.8) kg and were thus suitable for experimental cardiopulmonary bypass studies. Beating, working heart. After thoracotomy, control measurements were obtained, under stable conditions and when the heart was beating prior to institution of the cardiopulmonary bypass. Beating, nonworking (empty) heart. Following the cardiopulmonary bypass, the hearts were vented and allowed to beat but without externally related work. A series of measurements were done at perfusion pressures of 30,60, and 90 mm Hg. The required pressures were maintained by regulating the perfusion flow rate. Measurements were made after each perfusion pressure had been maintained for approximately 15 min. For measurements of coronary blood flow, we prepared radioactive microspheres (3M Co.) 9 f 1 pm in diameter labeled with 14’Ce, “0, %r, and 46Sc.At selected times during the experiments, 2,000,OOO microspheres were injected into the left atrium under a beating working condition or into the arterial perfusion line under beating nonworking conditions. The left ventricular free wall, excluding the region around the vent (apex), was further divided into the papillary muscles and three layers with an approximately equal thickness, namely, subendocardial, midmyocardial, and subepicardial layers. All sections were weighed (wet weight, accurate to 1 mg). The tissues and blood samples were placed in separate vials and counted in a well-type scintillation detector connected to a multichannel pulse height analyzer (Nuclear Chicago). Total and regional flows were calculated from the equation flow to the tissue =
(counts in the tissue) X (flow in the reference sample) counts in the reference sample
Two blood samples were obtained anaerobically from the aortic catheter and cor-
KAWACHI
ET AL.: PERFUSION
PRESSURE
AND
CORONARY
105
FLOW
onary sinus catheter, in the beating working condition, or from the arterial perfusion line and the right ventricular drainage line, in the beating nonworking state. Analyses of pH and POZ were performed immediately using a blood gas analyzer (Corning, Model 165). Oxygen content (0, Cont.), whole heart oxygen consumption (MVO,), and myocardial oxygen extraction (0, Ext.) were calculated from the equations O2 Cont. = 1.34 X Hb X %02 Sat. + 0.003 x PO* ) MVOl = CBF X (A - v), and O2 Ext. = (A - V)/A x 100, where Hb = Ht/3.1, %02 Sat. is the percentage oxygen saturation determined using a Severinghaus blood gas calculator,3 CBF is the coronary blood flow by the microsphere technique, A is the arterial oxygen content, and Vis the coronary venous oxygen content. Data were analyzed using Student’s t test for group data and paired t test for paired data. P < 0.05 was considered the lower level of significance. Data were expressed as the mean + 1 SEM with some exceptions. RESULTS
Hypertrophy of the left ventricle in group II was evident in the wall thickness and the relatively small cavity. The aortic areas in square millimeters were as follows: stenotic, 19 f 10 SD; infrastenotic, 8 1 + 20 SD. Left ventricle with septum (LV)/right ventricular free wall (RV) weight ratios were 2.83 + 0.22 SD in intact dogs and 3.84 + 0.43 SD in banded dogs (P < 0.001). All banded dogs had LV weights exceeding the values predicted on the basis of the RV weights for normal adult dogs (Fig. 1). There was no significant difference between the two groups 3 PO2 - Oxygen saturation percentage nomogram for whole blood (radiometer code 984-204).
l
!
0
10
20
RV FREE WALL WEIGHT
LVH
30 (9)
FIG. 1. Relation of left ventricular (LV) weight including the ventricular septum to right ventricular (RV) free wall weight. In 26 normal dogs in which 13 were in group I, the regression line is y = 2.36X + 7.9, r = 0.9363 (P < 0.01). Solid line is mean LV/RV weight ratio, and dotted lines indicate 95.45% variation from this.
with regard to experimental conditions, except for the heart rate (Table 1). We assessedthe accuracy of our microsphere technique by comparing the calculated coronary blood flow and the simultaneously measured coronary venous drainage volume (Fig. 2). There was no difference between the two groups. Left ventricular jlow. Total flow of the beating working heart was 68 f 6 ml/100 g/min in group I and 92 f 12 ml/ 100 g/min
106
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RESEARCH:
VOL. 33, NO. 2, AUGUST
TABLE EXPERIMENTAL
Aortic pressure Cm) (mm Hg)
1982
1 CONDITIONS
Heart rate (beats/ min)
Hem&wit W)
Esophageal temperature (“C)
pa02 (Torr)
PH.
p.co* (Torr)
Group I Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
93 35 62 87
+ f k f
6 1.7 1.1 1.4
166Lt 5 131 f 8* 141 f 11; 142 + 6*
39 32 32 32
k f f +-
1 2 2 2
36.6 35.9 36.0 36.7
+ f f f
0.4 0.8 0.8 0.3
7.30 1.46 7.35 7.34
- 7.43 - 7.54 - 7.50 - 7.46
353 491 431 312
+ f f f
48 22 35 35
31 24 27 28
+ 3 3~ 4 f 3 * 2
Group II Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
87 31 60 91
+ * + +
5 0.9 0.4 1.3
162f 9 162 + 11 171 f 9 165 f 11
31 30 30 30
k f iT +
2 1 1 2
36.4 36.6 37.1 37.3
+ f 2 f
0.5 0.4 0.3 0.2
7.22 7.31 7.31 7.31
-
507 419 418 395
+ f + *
13 35 25 31
34 23 28 29
f k f f
Note. All values are means f SEMs. Prebypass is the beating working 90 mm Hg are the required perfusion pressures for bypass, respectively. *P < 0.02 to group II.
in group II, with no significant difference (Table 2). Coronary flow of the beating empty heart increased in proportion to the
7.35 7.50 1.39 7.40
heart before the cardiopulmonary
bypass; 30, 60, and
perfusion pressure, in both groups. Coronary flow in group II was markedly greater than that in group I (P < 0.05 at 30 mm Hg, P
120 7 :
80 -
A Normal 0 LVH Ofl 0
,:..::
I 20
40
I 60
MEASUREDCBF
80
4 100
120
(ml./min.)
FIG. 2. Accuracy of the microsphere technique. Horizontal axis: measured coronary venous drainage volume in the beating empty state. Vertical axis: coronary blood flow calculated by the microsphere method. Solid line is the regression line: y = 0.890X + 4.5, r = 0.9820 (P ( 0.01). Dotted lines indicate 20% variation
from
the line of identity.
2 1 2 2
KAWACHI
ET AL.: PERFUSION PRESSURE AND CORONARY
FLOW
107
TABLE 2 CORONARYBLOODFLOW AND DISTRIBUTIONIN DOGS Whole heart (ml/100 g/min) Group I Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg Group II Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
61f
5
34 f 49k 67f
4* 5 I
82f 492 90+
11
129 f
Left ventricle (ml/ 100 g/min)
68k 36+ 5lk 67k
6 4% 6 7
92+12 56+ I** 98 + 5tt
6 5
2**
143 f
4***-tt
LV ENDO/EPI flow ratio 1.01 f 0.03 1.01 f 0.02 1.11 + 0.03 1.18 f 0.03*
1.01 + 0.03 0.82 + O.O5****t 0.87 + O.O3***,tt
1.21 + 0.13
Note. See Table 1. * P < 0.005, **P < 0.05, ***P < 0.02 compared to control. t P < 0.005, ‘I-I P -=z0.001 compared to group I.
< 0.001 at 60 and 90 mm Hg). When the perfusion pressure was lowered to 30 mm Hg, the total flow fell significantly in both groups (P < 0.005 in group I, P < 0.05 in group II). Regional flow. In group I, the papillary 200
r
muscle flow was the highest in the three regions, in both the beating working and beating empty heart, particularly at 30 mm Hg (Fig. 3). In group II, the subepicardial flow was the highest at 30 and 60 mm Hg in the beating nonworking condition (P < 0.02).
A Normal 0 LVH
3LL w 2looL.., w I‘.... I......., p E z;: P Lp _.__.__ p ‘-.’ r-f < z
50-
p-. . ...p
.._p
2 z
0 PM EN00 EPI
PM END0 EPI
PM END0 EPI
PREBYPASS
30
60
PERFUSION PRESSURE
PM END0 EPI 90 h.Hg)
FIG. 3. Left ventricular regional blood flow (see text). PM is papillary muscle, END0 is endocardium, and EPI is epicardium of the left ventricle.
108
JOURNAL OF SURGICAL RESEARCH: VOL. 33, NO. 2, AUGUST 1982 TABLE 3 OXYGEN CONSUMPTION AND OXYGEN EXTRACTION OF THE WHOLE HEART IN DOGS
MVO~ (cc/ 100 g/min) Group I Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
6.2 t 2.1 + 2.8 + 2.6 k
Group II Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
4.0 f 0.1 5.6 f 0.4~88 6.2 f 1.115
0.5 0.2. 0.3* 0.2*
Oxygen extraction (sl,) 57 + 3 54 f 4 40 f 4-r 29 -t 3$ 62 + 5 45 f 5tt 33 + 4$
Nore. See Table 1. * P < 0.01 to control. ?P < 0.02, VP < 0.05 to 30 mm Hg. $ P < 0.005 to 60 mm Hg. $ P -z 0.001, @P < 0.01 to group I.
When the perfusion pressure was increased volved in external work, the MVOz was sigto 90 mm Hg, the papillary muscle and nificantly higher at 60 than at 30 mm Hg subendocardial tlow increased to levels over (5.6 -+ 0.4 vs 4.0 f 0.1 cc/100 g/min, P the subepicardial flow. In the beating work- c 0.02). There was no significant augmentation between 60 and 90 mm Hg. There was ing condition, the endocardial/epicardial (ENDO/EPI) flow ratio was 1.01 _+0.03 in a significant difference between the two both groups (Table 2). This ratio increased groups under beating nonworking condifrom 1.Ol + 0.02 to 1.18 f 0.03 in group I, tions at 60 and 90 mm Hg (P < 0.001 and when the perfusion pressure was increased < 0.01, respectively), but no difference at from 30 to 90 mm Hg (P < 0.005). In con- 30 mm Hg. Oxygen extraction fell significantly in trast, the ENDO/EPI flow ratios were lowered to 0.82 f 0.05 and 0.87 f 0.03 in group both groups when the perfusion pressure inII at 30 and 60 mm Hg, respectively (P creased from 30 to 60 and from 60 to 90 mm < 0.02 to control), but the ratio was in- Hg, respectively (Table 3). In group I, there creased to 1.21 f 0.13 at 90 mm Hg. There were significant differences between a beatwas a significant difference between the two ing working condition and a beating empty groups at 30 and 60 mm Hg (P < 0.005 and condition at 60 and 90 mm Hg (P < 0.01 < 0.00 1, respectively). and < 0.001, respectively). The oxygen extraction was significantly higher in group II Myocardial oxygen consumption. When the normal heart was under the condition of than in group I at each perfusion pressure. external work, the MVOz was 6.2 f 0.5 cc/ DISCUSSION 100 g/min (Table 3). In the beating empty heart, MYOz resulted in a significant fall We followed the method of O’Kane et al. (P < 0.01) with no change, despite increases [20] to produce a state of hypertrophy in in the perfusion pressure: 2.7 f 0.2, 2.8 dogs. Left ventricular hypertrophy in clinical + 0.3, and 2.6 -+ 0.2 cc/100 g/min at 30,60, cases is the result of aortic stenosis; thereand 90 mm Hg, respectively. When the hy- fore, the coronary arterial system does not pertrophied heart was beating but not in- participate in the hypertrophic process. The
KAWACHI
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hypertrophy induced in our dogs was the heart, there was no maldistribution of myresult of supravalvular stenosis and the cor- ocardial flow, even at 30 mm Hg. These reonary arteries were enlarged and consider- sults show that perfusion pressures of 30 and ably swollen. We divided the heart into sec- 60 mm Hg wll induce an ischemia due to tions following the method of Fulton et al. inadequate oxygen delivery even though the [ 111.The wet weight of the myocardium was hypertrophied heart is in a beating empty used for the microsphere technique and the state. However, this ischemia can be allerelation of the left ventricle with septum viated by increasing the perfusion pressure weight to right ventricular free wall weight to 90 mm Hg. The hypertrophied ventricle was considered to express the extent of left can be adequately perfused at 90 mm Hg ventricular hypertrophy. In the heart of each in the beating empty state. On the contrary, in the intact heart, a perfusion pressure of dog in group II, left ventricular hypertrophy could be thus induced. We identified the cor- 30 mm Hg offers adequate oxygen delivery, onary blood Row calculated by the micro- and higher pressures (60 and 90 mm Hg) sphere method [ 3, 19, 241 and the measured will supply a larger amount of oxygen to the coronary venous drainage volume as being myocardium. Our findings in the intact heart do not almost equal. Differences exceeding 20% between the paired flows were included in differ significantly from data reported by the lower flow. others [ 15, 18, 221. Because a diseased Subendocardial ischemia without coro- myocardium, as in casesof chronic left vennary artery obstruction may be the result of tricular hypertrophy, is more susceptible discrepancies between metabolic needs and to intraoperative injury [ 14, 211, the subavailable blood supply [4]. Ischemia may endocardial underperfusion and ischemia also occur with a reduced myocardial oxygen may occur, despite a beating empty state, consumption, if the coronary flow is impeded in hypertrophied hearts. Other investigators have found that oxy[ 131. Measurements of myocardial oxygen consumption may be misleading unless the gen consumption per gram of tissue was adequacy of oxygen delivery is assessedsi- greater in hypertrophied hearts [ 2 11. On the multaneously. In the hypertrophied ventri- other hand, Marchetti et al. [ 171 showed cle, an increase in the perfusion pressure (or that coronary flow and oxygen consumption coronary flow) from 30 to 60 mm Hg in- per gram of myocardium in animals with creased myocardial oxygen consumption sig- cardiac hypertrophy were not significantly nificantly, and a further increase to 90 different from those in the normal hearts. mmHg further augmented it. In contrast, in Under conditions of a beating empty state the intact heart, an increase in the perfusion we noted that the hypertrophied heart conpressure from 30 to 90 mm Hg did not in- sumed almost twice as much oxygen; howcrease the oxygen consumption and there ever, such may be overestimated because was an increased coronary flow and de- tachycardia accompanies a hypertrophied creased oxygen extraction ratio. With a di- heart. In beating nonworking conditions of version of flow away from the endocardium the hypertrophied heart, the coronary flow (reduced ENDO/EPI flow ratio), underper- per gram of tissue increased markedly, more fusion of the subendocardium ensues to- oxygen was extracted from the flow per gram gether with metabolic, electrocardiographic. of tissue, and, as a result, the oxygen conmicroscopic, hemodynamic, and/or func- sumption increased. The hypertrophied heart tional signs of ischemia [4, 13, 18, 221. In probably demands more oxygen than normal the hypertrophied heart, the ENDO/EPI hearts; therefore, a deficiency in oxygen deRow ratio was significantly low at 30 and 60 livery due to redistribution of coronary flow mmHg, but augmentation to 90 mmHg occurs particularly in the subendocardial reshowed a definite improvement. In the intact gion when the perfusion pressure is lowered.
110
JOURNAL
OF SURGICAL
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CONCLUSION
From our experiments using the beating empty heart under conditions of various perfusion pressure, we conclude that: 1. In the hypertrophied heart, subendocardial ischemia occurs at lower perfusion pressures (30 and 60 mm Hg) but will improve by increasing the pressure to 90 mm Hg. 2. In the normal heart, a lower perfusion pressure (30 mm Hg) does not result in subendocardial ischemia. 3. In beating nonworking conditions, the hypertrophied heart has a larger blood flow per gram. minute, oxygen extraction, and oxygen consumption per gram. minute than does the normal heart. ACKNOWLEDGMENTS We thank Ms. Y. Tanaka for excellent technical assistance and M. Ohara of Kyushu University for editing the manuscript.
REFERENCES 1. Allard, J. R., Shizgal. H. M., and Dobell, A. R. C. Distribution of myocardial blood flow during cardiopulmonary bypass in normal and hypertrophied left ventricles. Surg. Forum 24: 178, 1973. 2. Baird, R. J., Dutka, F., Okumori, M., de la Rocha, A., Goldbach, M. M., Hill, T. J., and MacGregor, D. C. Surgical aspects of regional myocardial blood flow and myocardial pressure. J. Thoruc. Curdiovast. Surg. 69: 17, 1975. 3. Buckberg, G. C., Luck, J. C., Payne, D. B., Hoffman, J. I. E., Archie, J. P., and Fixler, D. E. Some sources of error in measuring regional blood flow with radioactive microspheres. J. Appl. Physiol. 31: 598, 1971. 4. Buckberg, G. D., Fixler, D. E., Archie, J. P., and Hoffman, J. I. E. Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ. Rex 30: 67, 1972. 5. Buckberg, G. D., Olinger, G. N., Mulder, D. G., and Maloney, J. V., Jr. Depressed postoperative cardiac performance-Prevention by adequate myocardial protection during cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 70: 914, 1975. 6. Buckberg, G. D. Left ventricular subendocardial necrosis. Ann. Thorac. Surg. 24: 379, 1977. 1. Engelman, R. M., Spencer, F. C., Adler, S., Gouge, T. H., Chandra, R., and Boyd, A. D. Effect of nor-
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mothermic anoxic arrest on coronary blood flow distribution of pigs. Surg. Forum 25: 176, 1974. 8. Engelman, R. M., Adler, S., Gouge, T. H., Chandra, R., Boyd, A. D., and Baumann, F. G. The effect of normothermic anoxic arrest and ventricular fibrillation on the coronary blood flow distribution of the pig. J. Thorac. Curdiovasc. Surg. 69: 858, 1975. Engelman, R. M., Chandra, R., Baumann, F. G., 9’ and Goldman, R. A. Myocardial reperfusion, a cause of ischemic injury during cardiopulmonary bypass. Surgery 80: 266, 1976. 10. Follette, D. M., Fey, K. H., Steed, D. L., Foglia, R. P., and Buckberg, G. D. Reducing reperfusion injury with hypocalcemic, hyperkalemic, alkalotic blood during reoxygenation. Surg. Forum 29: 284, 1978. I I. Fulton, R. M., Hutchinson, E. C., and Jones, A. M. Ventricular weight in cardiac hypertrophy. Brit. Heart J. 14: 413, 1952. 12. Harris, E. A., Parimelazhagan, K. N.. Seelye, E. R., and Barratt-Boyes, B. G. Optimization of coronary perfusion rate during cardiac surgery in man. J Thorac. Cardiovasc. Surg. 77: 662, 1979. 13. Hottenrott, C. E., Towers, B., Kurkji, H. J., Maloney, J. V., and Buckberg, G. The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J. Thoruc. C’urdiovasc. Surg. 66: 742. 1973. 14. Iyengar, S. R. K., Ramchand, S., Charrette, E. J. P., Iyengar, C. K. S., and Lynn, R. B. Anoxic cardiac arrest: An experimental and clinical study of its effects. Part I. J. Thornc. Cardiovasc. Surg. 66: 722, 1973. 15. Kleinman, L. H., Yarbrough, J. W., Symmonds, J. B., and Wechsler, A. S. Pressure-flow characteristics of the coronary collateral circulation during cardiopulmonary bypass. Effects of hemodilution. J. Thorac. Curdiovasc. Surg. 75: 17, 1978. 16. Lazar, H. L., Foglia. R. P., Manganaro, A. J., and Buckberg, G. D. Detrimental effects of premature use of inotropic drugs to discontinue cardiopulmonary bypass. Surg. Forum 29: 276, 1978. 17. Marchetti, G. V., Merlo, L., Noseda, V., and Visioli, 0. Myocardial blood flow in experimental cardial hypertrophy in dogs. Curdiovusc. Res. 7: 519, 1973. 18. McConnell, D. H., Brazier, J. R., Cooper, N., and Buckberg, G. D. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. II. Ischemia during moderate hypothermia in continually perfused beating hearts. J. Thoruc. Cardiovusc. slug. 73: 95, 1977. 19. Nakamura, M., Nakagaki, 0.. Nose, Y., Fukuyama, T., and Kikuchi, Y. Effects of nitroglycerine and dipyridamole on regional myocardial blood flow. Basic Res. Cardiol. 73: 482, 1978.
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20. O’Kane, H. O., Geha, A. S., Kleiger, R. E., Abe, T., Salaymeh, M. T., and Malik, A. B. Stable left ventricular hypertrophy in the dog. Experimental production, time course, and natural history. J. Thorac. Cardiovasc. Surg. 65: 264, 1973. 2 1. Reitz, B. A. Laboratory evaluation of intraoperative myocardial protection. The need for appropriate animal models. Ann. Thorac. Surg. 20: 7, 1975. 22. Schaff, H. V., Ciardullo, R. C., Flaherty, J. T., and Gott, V. L. Development of regional myocardial ischemia distal to a critical coronary stenosis during cardiopulmonary bypass: Comparison of the fibril-
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lating vs. the beating non-working states. Surgq 83: 57, 1978. 23. Smith, H. J., Kent, K. M., and Epstein, S. E. Contractile damage from reperfusion after transient ischemia in the dog. J. Thorac. Cardiovasc. Surg. 75: 452, 1978. 24. Utley, J., Carlson, E. L., Hoffman, J. I. E., Martinez, H. M., and Buckberg, G. D. Total and regional myocardial blood flow measurements with 25~, 15p, 9~. and filtered I- 10 diameter microspheres and antipyrine in dogs and sheep. Circ. Rex 34: 391, 1974.
OF SURGICAL
RESEARCH
33, 103- 111 (1982)
Influence of Perfusion Pressure on Oxygen Supply and Demand in Beating Empty Hypertrophied Dog Hearts’ YOSHITO
AKIRA Division
KAWACHI, M.D.,* RYUJI TOMINAGA, M.D., MOCHIKAZU YOSHITOSHI, SESE, M.D., KOUICHI TOKUNAGA, M.D., AND MOTOOMI NAKAMURA, and Cardiovascular of Cardiovascular Surgery, *Research Institute of Angiocardiology Kyushu Universiiy Faculty of Medicine, Fukuoka 812. Japan Submitted
for publication
M.D., M.D.*
Clime. and
April 23, 198I
As cardiopulmonary bypass is frequently accompanied by hypotension, the effect of varying perfusion pressure (30, 60, and 90 mm Hg) on the adequacy and distribution of coronary flow was studied under conditions of a normothermic beating empty state, of normal and hypertrophied hearts of 20 mongrel dogs, using the radioactive microsphere technique. In the normal hearts, 30 mmHg caused a 47% (P i 0.005 to prebypass) reduction of left ventricular coronary Row but did not change flow distribution (ENDO/EPI flow ratio: 1.01); increasing mean perfusion pressure from 30 to 90 mm Hg did not alter the oxygen consumption but did increase the coronary flow and decrease the oxygen extraction ratio. In the hypertrophied hearts, 30 and 60 mm Hg perfusion pressures resulted in a redistribution of flow away from the subendocardium (ENDO/EPI flow ratio: 0.82 and 0.87, respectively, P < 0.02 to prebypass). An increase in perfusion pressure from 30 to 60 mm Hg resulted m a significant increase in oxygen uptake (4.0 vs 5.6 cc/100 g/min, respectively, P < 0.02). An increased perfusion pressure of 90 mmHg resulted in a sufficient subendocardial Row and an augmentation of the oxygen uptake. These results indicate that subendocardial underperfusion occurs in the beating empty hypertrophied heart, under conditions of lower perfusion pressures (30 and 60 mm Hg), but that such can be improved by increasing the perfusion pressure to 90 mmHg. In contrast, the subendocardial underperfuston does not occur with a perfusion pressure of 30 mm Hg in normal hearts.
might be contraindicated as myocardial edema may occur [7, 81, and a pressure Although there are numerous experiments lower than 50 mmHg should be maintained. on the beating empty state in the normal On the contrary, the oxygen-debt repayment heart [ 15, 18, 221, few studies have been is accomplished by a beating empty heart at done on the hypertrophied heart [ 1, 2, 131. over 80 mm Hg [5]. In the open beating In clinical cases of a hypertrophied heart, heart with left ventricular hypertrophy, the a lower perfusion pressure often accompaoptimal myocardial oxygen delivery can be nies a decreased peripheral vascular resisachieved at a “line pressure” of over 110 tance or a decreased flow rate. For myocarmm Hg [ 121. Thus, the perfusion pressure dial protection, attention should be given to appears to be inconsistent with regard to preventing reperfusion injury [6, 9, 10, 231 protection of reperfusion injury and oxygenand “oxygen-debt repayment” [9, 161 after debt repayment. We have studied the hethe aortic clamp is released. Upon initiation modynamics and metabolism at various perof reperfusion of the anoxic myocardium, a fusion pressures in a beating empty state of higher perfusion pressure ( 100 mm Hg) the hypertrophied heart to determine whether ’ This study was supported by a grant from the Minischemia would occur at a lower perfusion istry of Education (357416), Japan. pressure and whether improvement would * To whom correspondence and reprint requests should occur under conditions of a higher pressure. be addressed at: Dtvision of Cardiovascular Surgery, Our observations were then compared with Kyushu University Faculty of Medicine, Maidashi 3-lI, Higashi-ku, Fukuoka 812, Japan. findings in normal hearts. INTRODUCTION
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0022-4804/82/080103-09so1.00/0 Copyright 0 1982 by Academic Press, Inc. All rights of reproduction in any form reserved
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METHODS
Twenty mongrel dogs were anesthetized with sodium pentobarbital (25 mg/kg, iv), and additional doses were given as required, before the cardiopulmonary bypass. The dogs were ventilated with oxygen-rich gas mixtures. Catheters with side-holes were inserted into the left carotid artery for aorticroot pressure monitoring, into the right femoral artery for reference blood sampling, and into the right femoral vein for drug injection. A bilateral thoracotomy was performed to expose the heart. Sodium heparin was then administered (300 III/kg, iv). A catheter was inserted in the left atrium for microsphere injection and pressure monitoring. Left ventricular intracavitary pressure was obtained using a microtip pressure transducer (Miller Co.) inserted through the left ventricular apex. In some dogs, a coronary sinus catheter was inserted. Cardiopulmonary bypass was instituted by diverting systemic and coronary venous blood into a bubble oxygenator, respectively, then returning it via the right carotid artery. The extracorporeal circuit was primed with fresh heparinized homologous blood. The esophageal temperature was maintained at normothermia using a heat exchanger. The left ventricle was vented with a cannula placed through the left ventricular apex, and the right ventricle with a cannula placed directly into the outflow tract. The main pulmonary artery was occluded. Left ventricular and/ or left atria1 pressure was monitored continuously to assure the adequacy of venting. Heart rate was maintained spontaneously. If required, sodium bicarbonate was given to maintain the arterial pH within normal ranges. Two experimental groups were prepared. Group I (normal or nonhypertrophied left ventricle): This group included 13 adult dogs weighing 9 to 14 kg. Group II (hypertrophied left ventricle): This group included 7 dogs in which banding of the ascending aorta had been performed when the dogs were about 2 months old, a time when they
weighed between 1.7 and 4.8 (mean 3.0) kg. After 11 months, they weighed 7 to 13 (mean 8.8) kg and were thus suitable for experimental cardiopulmonary bypass studies. Beating, working heart. After thoracotomy, control measurements were obtained, under stable conditions and when the heart was beating prior to institution of the cardiopulmonary bypass. Beating, nonworking (empty) heart. Following the cardiopulmonary bypass, the hearts were vented and allowed to beat but without externally related work. A series of measurements were done at perfusion pressures of 30,60, and 90 mm Hg. The required pressures were maintained by regulating the perfusion flow rate. Measurements were made after each perfusion pressure had been maintained for approximately 15 min. For measurements of coronary blood flow, we prepared radioactive microspheres (3M Co.) 9 f 1 pm in diameter labeled with 14’Ce, “0, %r, and 46Sc.At selected times during the experiments, 2,000,OOO microspheres were injected into the left atrium under a beating working condition or into the arterial perfusion line under beating nonworking conditions. The left ventricular free wall, excluding the region around the vent (apex), was further divided into the papillary muscles and three layers with an approximately equal thickness, namely, subendocardial, midmyocardial, and subepicardial layers. All sections were weighed (wet weight, accurate to 1 mg). The tissues and blood samples were placed in separate vials and counted in a well-type scintillation detector connected to a multichannel pulse height analyzer (Nuclear Chicago). Total and regional flows were calculated from the equation flow to the tissue =
(counts in the tissue) X (flow in the reference sample) counts in the reference sample
Two blood samples were obtained anaerobically from the aortic catheter and cor-
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FLOW
onary sinus catheter, in the beating working condition, or from the arterial perfusion line and the right ventricular drainage line, in the beating nonworking state. Analyses of pH and POZ were performed immediately using a blood gas analyzer (Corning, Model 165). Oxygen content (0, Cont.), whole heart oxygen consumption (MVO,), and myocardial oxygen extraction (0, Ext.) were calculated from the equations O2 Cont. = 1.34 X Hb X %02 Sat. + 0.003 x PO* ) MVOl = CBF X (A - v), and O2 Ext. = (A - V)/A x 100, where Hb = Ht/3.1, %02 Sat. is the percentage oxygen saturation determined using a Severinghaus blood gas calculator,3 CBF is the coronary blood flow by the microsphere technique, A is the arterial oxygen content, and Vis the coronary venous oxygen content. Data were analyzed using Student’s t test for group data and paired t test for paired data. P < 0.05 was considered the lower level of significance. Data were expressed as the mean + 1 SEM with some exceptions. RESULTS
Hypertrophy of the left ventricle in group II was evident in the wall thickness and the relatively small cavity. The aortic areas in square millimeters were as follows: stenotic, 19 f 10 SD; infrastenotic, 8 1 + 20 SD. Left ventricle with septum (LV)/right ventricular free wall (RV) weight ratios were 2.83 + 0.22 SD in intact dogs and 3.84 + 0.43 SD in banded dogs (P < 0.001). All banded dogs had LV weights exceeding the values predicted on the basis of the RV weights for normal adult dogs (Fig. 1). There was no significant difference between the two groups 3 PO2 - Oxygen saturation percentage nomogram for whole blood (radiometer code 984-204).
l
!
0
10
20
RV FREE WALL WEIGHT
LVH
30 (9)
FIG. 1. Relation of left ventricular (LV) weight including the ventricular septum to right ventricular (RV) free wall weight. In 26 normal dogs in which 13 were in group I, the regression line is y = 2.36X + 7.9, r = 0.9363 (P < 0.01). Solid line is mean LV/RV weight ratio, and dotted lines indicate 95.45% variation from this.
with regard to experimental conditions, except for the heart rate (Table 1). We assessedthe accuracy of our microsphere technique by comparing the calculated coronary blood flow and the simultaneously measured coronary venous drainage volume (Fig. 2). There was no difference between the two groups. Left ventricular jlow. Total flow of the beating working heart was 68 f 6 ml/100 g/min in group I and 92 f 12 ml/ 100 g/min
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TABLE EXPERIMENTAL
Aortic pressure Cm) (mm Hg)
1982
1 CONDITIONS
Heart rate (beats/ min)
Hem&wit W)
Esophageal temperature (“C)
pa02 (Torr)
PH.
p.co* (Torr)
Group I Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
93 35 62 87
+ f k f
6 1.7 1.1 1.4
166Lt 5 131 f 8* 141 f 11; 142 + 6*
39 32 32 32
k f f +-
1 2 2 2
36.6 35.9 36.0 36.7
+ f f f
0.4 0.8 0.8 0.3
7.30 1.46 7.35 7.34
- 7.43 - 7.54 - 7.50 - 7.46
353 491 431 312
+ f f f
48 22 35 35
31 24 27 28
+ 3 3~ 4 f 3 * 2
Group II Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
87 31 60 91
+ * + +
5 0.9 0.4 1.3
162f 9 162 + 11 171 f 9 165 f 11
31 30 30 30
k f iT +
2 1 1 2
36.4 36.6 37.1 37.3
+ f 2 f
0.5 0.4 0.3 0.2
7.22 7.31 7.31 7.31
-
507 419 418 395
+ f + *
13 35 25 31
34 23 28 29
f k f f
Note. All values are means f SEMs. Prebypass is the beating working 90 mm Hg are the required perfusion pressures for bypass, respectively. *P < 0.02 to group II.
in group II, with no significant difference (Table 2). Coronary flow of the beating empty heart increased in proportion to the
7.35 7.50 1.39 7.40
heart before the cardiopulmonary
bypass; 30, 60, and
perfusion pressure, in both groups. Coronary flow in group II was markedly greater than that in group I (P < 0.05 at 30 mm Hg, P
120 7 :
80 -
A Normal 0 LVH Ofl 0
,:..::
I 20
40
I 60
MEASUREDCBF
80
4 100
120
(ml./min.)
FIG. 2. Accuracy of the microsphere technique. Horizontal axis: measured coronary venous drainage volume in the beating empty state. Vertical axis: coronary blood flow calculated by the microsphere method. Solid line is the regression line: y = 0.890X + 4.5, r = 0.9820 (P ( 0.01). Dotted lines indicate 20% variation
from
the line of identity.
2 1 2 2
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TABLE 2 CORONARYBLOODFLOW AND DISTRIBUTIONIN DOGS Whole heart (ml/100 g/min) Group I Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg Group II Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
61f
5
34 f 49k 67f
4* 5 I
82f 492 90+
11
129 f
Left ventricle (ml/ 100 g/min)
68k 36+ 5lk 67k
6 4% 6 7
92+12 56+ I** 98 + 5tt
6 5
2**
143 f
4***-tt
LV ENDO/EPI flow ratio 1.01 f 0.03 1.01 f 0.02 1.11 + 0.03 1.18 f 0.03*
1.01 + 0.03 0.82 + O.O5****t 0.87 + O.O3***,tt
1.21 + 0.13
Note. See Table 1. * P < 0.005, **P < 0.05, ***P < 0.02 compared to control. t P < 0.005, ‘I-I P -=z0.001 compared to group I.
< 0.001 at 60 and 90 mm Hg). When the perfusion pressure was lowered to 30 mm Hg, the total flow fell significantly in both groups (P < 0.005 in group I, P < 0.05 in group II). Regional flow. In group I, the papillary 200
r
muscle flow was the highest in the three regions, in both the beating working and beating empty heart, particularly at 30 mm Hg (Fig. 3). In group II, the subepicardial flow was the highest at 30 and 60 mm Hg in the beating nonworking condition (P < 0.02).
A Normal 0 LVH
3LL w 2looL.., w I‘.... I......., p E z;: P Lp _.__.__ p ‘-.’ r-f < z
50-
p-. . ...p
.._p
2 z
0 PM EN00 EPI
PM END0 EPI
PM END0 EPI
PREBYPASS
30
60
PERFUSION PRESSURE
PM END0 EPI 90 h.Hg)
FIG. 3. Left ventricular regional blood flow (see text). PM is papillary muscle, END0 is endocardium, and EPI is epicardium of the left ventricle.
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JOURNAL OF SURGICAL RESEARCH: VOL. 33, NO. 2, AUGUST 1982 TABLE 3 OXYGEN CONSUMPTION AND OXYGEN EXTRACTION OF THE WHOLE HEART IN DOGS
MVO~ (cc/ 100 g/min) Group I Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
6.2 t 2.1 + 2.8 + 2.6 k
Group II Prebypass (control) 30 mm Hg 60 mm Hg 90 mm Hg
4.0 f 0.1 5.6 f 0.4~88 6.2 f 1.115
0.5 0.2. 0.3* 0.2*
Oxygen extraction (sl,) 57 + 3 54 f 4 40 f 4-r 29 -t 3$ 62 + 5 45 f 5tt 33 + 4$
Nore. See Table 1. * P < 0.01 to control. ?P < 0.02, VP < 0.05 to 30 mm Hg. $ P < 0.005 to 60 mm Hg. $ P -z 0.001, @P < 0.01 to group I.
When the perfusion pressure was increased volved in external work, the MVOz was sigto 90 mm Hg, the papillary muscle and nificantly higher at 60 than at 30 mm Hg subendocardial tlow increased to levels over (5.6 -+ 0.4 vs 4.0 f 0.1 cc/100 g/min, P the subepicardial flow. In the beating work- c 0.02). There was no significant augmentation between 60 and 90 mm Hg. There was ing condition, the endocardial/epicardial (ENDO/EPI) flow ratio was 1.01 _+0.03 in a significant difference between the two both groups (Table 2). This ratio increased groups under beating nonworking condifrom 1.Ol + 0.02 to 1.18 f 0.03 in group I, tions at 60 and 90 mm Hg (P < 0.001 and when the perfusion pressure was increased < 0.01, respectively), but no difference at from 30 to 90 mm Hg (P < 0.005). In con- 30 mm Hg. Oxygen extraction fell significantly in trast, the ENDO/EPI flow ratios were lowered to 0.82 f 0.05 and 0.87 f 0.03 in group both groups when the perfusion pressure inII at 30 and 60 mm Hg, respectively (P creased from 30 to 60 and from 60 to 90 mm < 0.02 to control), but the ratio was in- Hg, respectively (Table 3). In group I, there creased to 1.21 f 0.13 at 90 mm Hg. There were significant differences between a beatwas a significant difference between the two ing working condition and a beating empty groups at 30 and 60 mm Hg (P < 0.005 and condition at 60 and 90 mm Hg (P < 0.01 < 0.00 1, respectively). and < 0.001, respectively). The oxygen extraction was significantly higher in group II Myocardial oxygen consumption. When the normal heart was under the condition of than in group I at each perfusion pressure. external work, the MVOz was 6.2 f 0.5 cc/ DISCUSSION 100 g/min (Table 3). In the beating empty heart, MYOz resulted in a significant fall We followed the method of O’Kane et al. (P < 0.01) with no change, despite increases [20] to produce a state of hypertrophy in in the perfusion pressure: 2.7 f 0.2, 2.8 dogs. Left ventricular hypertrophy in clinical + 0.3, and 2.6 -+ 0.2 cc/100 g/min at 30,60, cases is the result of aortic stenosis; thereand 90 mm Hg, respectively. When the hy- fore, the coronary arterial system does not pertrophied heart was beating but not in- participate in the hypertrophic process. The
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hypertrophy induced in our dogs was the heart, there was no maldistribution of myresult of supravalvular stenosis and the cor- ocardial flow, even at 30 mm Hg. These reonary arteries were enlarged and consider- sults show that perfusion pressures of 30 and ably swollen. We divided the heart into sec- 60 mm Hg wll induce an ischemia due to tions following the method of Fulton et al. inadequate oxygen delivery even though the [ 111.The wet weight of the myocardium was hypertrophied heart is in a beating empty used for the microsphere technique and the state. However, this ischemia can be allerelation of the left ventricle with septum viated by increasing the perfusion pressure weight to right ventricular free wall weight to 90 mm Hg. The hypertrophied ventricle was considered to express the extent of left can be adequately perfused at 90 mm Hg ventricular hypertrophy. In the heart of each in the beating empty state. On the contrary, in the intact heart, a perfusion pressure of dog in group II, left ventricular hypertrophy could be thus induced. We identified the cor- 30 mm Hg offers adequate oxygen delivery, onary blood Row calculated by the micro- and higher pressures (60 and 90 mm Hg) sphere method [ 3, 19, 241 and the measured will supply a larger amount of oxygen to the coronary venous drainage volume as being myocardium. Our findings in the intact heart do not almost equal. Differences exceeding 20% between the paired flows were included in differ significantly from data reported by the lower flow. others [ 15, 18, 221. Because a diseased Subendocardial ischemia without coro- myocardium, as in casesof chronic left vennary artery obstruction may be the result of tricular hypertrophy, is more susceptible discrepancies between metabolic needs and to intraoperative injury [ 14, 211, the subavailable blood supply [4]. Ischemia may endocardial underperfusion and ischemia also occur with a reduced myocardial oxygen may occur, despite a beating empty state, consumption, if the coronary flow is impeded in hypertrophied hearts. Other investigators have found that oxy[ 131. Measurements of myocardial oxygen consumption may be misleading unless the gen consumption per gram of tissue was adequacy of oxygen delivery is assessedsi- greater in hypertrophied hearts [ 2 11. On the multaneously. In the hypertrophied ventri- other hand, Marchetti et al. [ 171 showed cle, an increase in the perfusion pressure (or that coronary flow and oxygen consumption coronary flow) from 30 to 60 mm Hg in- per gram of myocardium in animals with creased myocardial oxygen consumption sig- cardiac hypertrophy were not significantly nificantly, and a further increase to 90 different from those in the normal hearts. mmHg further augmented it. In contrast, in Under conditions of a beating empty state the intact heart, an increase in the perfusion we noted that the hypertrophied heart conpressure from 30 to 90 mm Hg did not in- sumed almost twice as much oxygen; howcrease the oxygen consumption and there ever, such may be overestimated because was an increased coronary flow and de- tachycardia accompanies a hypertrophied creased oxygen extraction ratio. With a di- heart. In beating nonworking conditions of version of flow away from the endocardium the hypertrophied heart, the coronary flow (reduced ENDO/EPI flow ratio), underper- per gram of tissue increased markedly, more fusion of the subendocardium ensues to- oxygen was extracted from the flow per gram gether with metabolic, electrocardiographic. of tissue, and, as a result, the oxygen conmicroscopic, hemodynamic, and/or func- sumption increased. The hypertrophied heart tional signs of ischemia [4, 13, 18, 221. In probably demands more oxygen than normal the hypertrophied heart, the ENDO/EPI hearts; therefore, a deficiency in oxygen deRow ratio was significantly low at 30 and 60 livery due to redistribution of coronary flow mmHg, but augmentation to 90 mmHg occurs particularly in the subendocardial reshowed a definite improvement. In the intact gion when the perfusion pressure is lowered.
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CONCLUSION
From our experiments using the beating empty heart under conditions of various perfusion pressure, we conclude that: 1. In the hypertrophied heart, subendocardial ischemia occurs at lower perfusion pressures (30 and 60 mm Hg) but will improve by increasing the pressure to 90 mm Hg. 2. In the normal heart, a lower perfusion pressure (30 mm Hg) does not result in subendocardial ischemia. 3. In beating nonworking conditions, the hypertrophied heart has a larger blood flow per gram. minute, oxygen extraction, and oxygen consumption per gram. minute than does the normal heart. ACKNOWLEDGMENTS We thank Ms. Y. Tanaka for excellent technical assistance and M. Ohara of Kyushu University for editing the manuscript.
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mothermic anoxic arrest on coronary blood flow distribution of pigs. Surg. Forum 25: 176, 1974. 8. Engelman, R. M., Adler, S., Gouge, T. H., Chandra, R., Boyd, A. D., and Baumann, F. G. The effect of normothermic anoxic arrest and ventricular fibrillation on the coronary blood flow distribution of the pig. J. Thorac. Curdiovasc. Surg. 69: 858, 1975. Engelman, R. M., Chandra, R., Baumann, F. G., 9’ and Goldman, R. A. Myocardial reperfusion, a cause of ischemic injury during cardiopulmonary bypass. Surgery 80: 266, 1976. 10. Follette, D. M., Fey, K. H., Steed, D. L., Foglia, R. P., and Buckberg, G. D. Reducing reperfusion injury with hypocalcemic, hyperkalemic, alkalotic blood during reoxygenation. Surg. Forum 29: 284, 1978. I I. Fulton, R. M., Hutchinson, E. C., and Jones, A. M. Ventricular weight in cardiac hypertrophy. Brit. Heart J. 14: 413, 1952. 12. Harris, E. A., Parimelazhagan, K. N.. Seelye, E. R., and Barratt-Boyes, B. G. Optimization of coronary perfusion rate during cardiac surgery in man. J Thorac. Cardiovasc. Surg. 77: 662, 1979. 13. Hottenrott, C. E., Towers, B., Kurkji, H. J., Maloney, J. V., and Buckberg, G. The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass. J. Thoruc. C’urdiovasc. Surg. 66: 742. 1973. 14. Iyengar, S. R. K., Ramchand, S., Charrette, E. J. P., Iyengar, C. K. S., and Lynn, R. B. Anoxic cardiac arrest: An experimental and clinical study of its effects. Part I. J. Thornc. Cardiovasc. Surg. 66: 722, 1973. 15. Kleinman, L. H., Yarbrough, J. W., Symmonds, J. B., and Wechsler, A. S. Pressure-flow characteristics of the coronary collateral circulation during cardiopulmonary bypass. Effects of hemodilution. J. Thorac. Curdiovasc. Surg. 75: 17, 1978. 16. Lazar, H. L., Foglia. R. P., Manganaro, A. J., and Buckberg, G. D. Detrimental effects of premature use of inotropic drugs to discontinue cardiopulmonary bypass. Surg. Forum 29: 276, 1978. 17. Marchetti, G. V., Merlo, L., Noseda, V., and Visioli, 0. Myocardial blood flow in experimental cardial hypertrophy in dogs. Curdiovusc. Res. 7: 519, 1973. 18. McConnell, D. H., Brazier, J. R., Cooper, N., and Buckberg, G. D. Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. II. Ischemia during moderate hypothermia in continually perfused beating hearts. J. Thoruc. Cardiovusc. slug. 73: 95, 1977. 19. Nakamura, M., Nakagaki, 0.. Nose, Y., Fukuyama, T., and Kikuchi, Y. Effects of nitroglycerine and dipyridamole on regional myocardial blood flow. Basic Res. Cardiol. 73: 482, 1978.
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20. O’Kane, H. O., Geha, A. S., Kleiger, R. E., Abe, T., Salaymeh, M. T., and Malik, A. B. Stable left ventricular hypertrophy in the dog. Experimental production, time course, and natural history. J. Thorac. Cardiovasc. Surg. 65: 264, 1973. 2 1. Reitz, B. A. Laboratory evaluation of intraoperative myocardial protection. The need for appropriate animal models. Ann. Thorac. Surg. 20: 7, 1975. 22. Schaff, H. V., Ciardullo, R. C., Flaherty, J. T., and Gott, V. L. Development of regional myocardial ischemia distal to a critical coronary stenosis during cardiopulmonary bypass: Comparison of the fibril-
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lating vs. the beating non-working states. Surgq 83: 57, 1978. 23. Smith, H. J., Kent, K. M., and Epstein, S. E. Contractile damage from reperfusion after transient ischemia in the dog. J. Thorac. Cardiovasc. Surg. 75: 452, 1978. 24. Utley, J., Carlson, E. L., Hoffman, J. I. E., Martinez, H. M., and Buckberg, G. D. Total and regional myocardial blood flow measurements with 25~, 15p, 9~. and filtered I- 10 diameter microspheres and antipyrine in dogs and sheep. Circ. Rex 34: 391, 1974.