Alterations in regional contractility following cardiopulmonary bypass with intraoperative ischemia

Alterations in regional contractility following cardiopulmonary bypass with intraoperative ischemia Coronary occlusion during cardiopulmonary bypass has been used in place of aortic occlusion to perform coronary artery anastomoses, but the effect of this procedure on distal myocardial function has not been evaluated. Regional myocardial function was examined with the use of ultrasonic crystals in 20 dogs subjected to this technique to compare normothermic and hypothermic (30° C) bypass in both beating and fibrillating hearts. We found a significant decline in the velocity of contraction of the distal segment in fibrillating compared to beating hearts (p < 0.01). Hypothermia prevented this decline in the beating, but not the fibrillating, hearts. With respect to contractile function in the distal myocardial segment, local occlusion techniques cause an injury similar to that reported for aortic cross-clamping.

Vincent A. Gaudiani, M . D . , Howard J. Smith, M.D., and Stephen E. Epstein, M . D . , Bethesda, Md.

±J ecause brief periods of myocardial ischemia are required during many cardiac operations, considerable attention has been focused on the effects of ischemia on postoperative ventricular function. Most prior studies, however, have utilized a global model of myocardial ischemia and have assessed myocardial function in terms of total cardiac performance. Less information is available concerning the effects of regional coronary artery occlusion during cardiopulmonary bypass, a technique used to perform distal coronary artery bypass anastomoses. 1 The present study was designed to compare the relative effects of normothermia versus hypothermia and of ventricular fibrillation versus the beating heart on regional ventricular function following brief periods of ischemia during cardiopulmonary bypass. Previous reports have demonstrated that pairs of small ultrasonic crystals implanted in the myocardium accurately measure myocardial segment length. 2 , 3 The pattern of segmental shortening recorded by the crystals can be analyzed to determine the rate and extent of From the Clinic of Surgery and Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 20014. Received for publication Feb. 16, 1978. Accepted for publication March 29, 1978. Address for reprints: Stephen E. Epstein, M.D., Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 20014

70

SEGMENT LENGTH (cm)

1.5r 2.0 L

^ J ,A V\ MILD

MOD

SEVERE

Fig. 1. Ischemic damage. Tracings of original data showing normal segmental contractile pattern (C) and increasing degrees of ischemic dysfunction. Vertical lines mark the period of mechanical systole. segment shortening. In this study, these crystals were used to measure regional contractile function before and after local coronary occlusion on cardiopulmonary bypass. Methods Adult foxhounds of either sex (weight 18 to 20 kilograms) were anesthesized with sodium pentobarbital (20 to 25 mg. per kilogram given intravenously) and ventilated with room air through a cuffed endotracheal tube. Normal saline was infused at a rate of 50 ml. per hour throughout the study. A left lateral thoractomy was performed through the fifth intercostal space, and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery (LAD) was dissected free and prepared for occlusion with a silk thread and snare, at a level approximately 2 cm. below its origin but above a major diagonal branch. Arterial and

Volume 76 Number 1 July, 1978

Alterations

in regional contractility

71

10

1.05 1.00

0.90 C3 lil

0.80

TIME (min) (0 refers to time of occlusion)

Fig. 2. Normothermic beating hearts. See text. CPB, Cardiopulmonary bypass. VVm, Normalized velocity of contraction in the first one third of systole. EDLn, Normalized enddiastolic segment length. MSLn, Normalized mean systolic segment length. AL, Mean systolic shortening. central venous pressures were recorded through polyethylene catheters advanced to the descending thoracic aorta and inferior vena cava. Left ventricular (LV) pressure was recorded through a pressure line placed through the apex of the cavity with the LV vent (vide infra). The pressure recordings together with Lead II of the electrocardiogram were displayed on a Sanborn 350 recorder. Miniature ultrasonic crystals were made from 3 MHz piezoelectric material (LTZ5, Transducer Products, Torrington, Conn.) and thin, insulated wire. Each crystal was dipped in liquid plastic to create a crude lens (producing divergence of the ultrasound beam) and mounted to a fine wire stent to stabilize its position in the myocardium. A pair of such crystals (diameter = 2 mm.) was placed 1 to 2 cm. apart and 5 to 6 mm. deep in the anterior LV wall below the first diagonal branch of the LAD perpendicular to the long axis of the ventricle; the crystals were aligned for optimum transmission of ultrasound energy. The emitter crystal of each pair was stimulated with a ! KHz pulse train so that the resultant ultrasonic pulsed beam induced a re-

TIME (min) (0 refers to time of occlusion)

Fig. 3. Normothermic fibrillating hearts. See text. Abbreviations as in Fig. 2. sponse in the receptor crystal. The transmission time of the ultrasound beam was converted electronically to an analogue signal that was displayed on the recorder; the signal was calibrated with a pair of crystals mounted on a caliper in a water bath. Changes in segment length were displayed from positive to negative so that all normal systolic events (pressure and segmental shortening) were unidirectional. The onset of systole and diastole was determined from the LV pressure waveform. Before the LV pressure line was placed, or when the LV was empty on cardiopulmonary bypass, the timing of systolic contraction was derived from the electrocardiogram and its measured relation to the normal pressure wave. After 30 minutes, to allow full hemostasis, the animals were given 10,000 units of sodium heparin for anticoagulation. Control recordings of arterial pressure, heart rate, electrocardiogram, and contractile pattern were obtained. Total cardiopulmonary bypass was then instituted with a Sarns pediatric roller pump and a Temptrol pediatric oxygenator primed with heparinized whole blood. Venous return was collected through a

The Journal of Thoracic and Cardiovascular Surgery

7 2 Gaudiani, Smith, Epstein

10

10 £

5

>

c

>

-5

1.10

1.00 X I-

a o.9o -

0.80 -

30 40 30 40 TIME (min) (0 refers to time of occlusion)

Fig. 4. Hypothermic beating hearts. See text. Abbreviations as in Fig. 2. right atrial connula and returned to the dog through a femoral artery cannula. An LV vent with a pressure recording line was inserted through the apex of the LV and secured with a purse-string suture. The total pump flow (1,500 to 1,800 ml. per minute) was adjusted to maintain a stable mean arterial pressure of 70 to 80 mm. Hg. Cardiac temperature was recorded with a thermistor probe placed in the pericardial cradle in contact with the epicardium. Cardiopulmonary bypass was then discontinued and the normal circulation was restored. The LV vent and cannulas were left in situ. At this stage, the preparation was discarded if the pattern of regional contraction was abnormal (Fig. 1). Four groups, each comprising five dogs, were studied. Groups I and II were studied with the use of normothermic bypass. Both groups underwent a 10 minute and a 30 minute period of ischemia. In Groups III and IV, a single 30 minute ischemic episode at 30° C. (systemic hypothermia) on cardiopulmonary bypass was used. In Groups I and III the hearts were beating during the entire study. In Groups II and IV the hearts were electrically fibrillated immediately before the ischemic

TIME (min) (0 refers to time of occlusion)

Fig. 5. Hypothermic fibrillating hearts. See text. Abbreviations as in Fig. 2. episodes, and they fibrillated spontaneously for the duration of the ischemia. In all groups the pattern of injury to contractile function was examined after discontinuing cardiopulmonary bypass. Experimental protocols for each group will be described and are diagrammed in Figs. 2 to 6. Group I: Normothermic by pass-beating heart. In five dogs (dogs 1 to 5) changes in regional function were studied during and after two periods of cardiopulmonary bypass with the body temperature controlled at 37 to 38° C. In the first period, the LAD was occluded after 3 to 5 minutes of stable cardiopulmonary bypass with an LV pressure of 0 mm. Hg. Recordings of contractile function were obtained during 11 minutes of occlusion and for 15 minutes after release. Cardiopulmonary bypass was discontinued 30 seconds after reperfusion; the heart rapidly resumed function in 20 to 30 seconds. Blood volume was adjusted to bring the central venous pressure and mean arterial pressure as closely as possible to the control levels. After a stabilization period of 30 minutes, a second period of cardiopulmonary bypass was established, and the LAD was occluded for 30 minutes. Cardiopulmonary bypass was again discontinued after 30 seconds of

Volume 76 Number 1 July, 1978

Alterations in regional contractility

PERCENT RECOVERY OF V1/3n 10 MIN ISCHEMIA NORMOTHERMIA

30 MIN ISCHEMIA HYPOTHERMIA

HEARTS BEATING HEARTS FIBRILLATING

13

RELATIVE CHANGE IN MEAN SYSTOLIC SHORTENING (AD 10 MIN ISCHEMIA NORMOTHERMIC

30 MIN ISCHEMIA HYPOTHERMIC

HEARTS BEATING HEARTS FIBRILLATING

100 -

Fig. 6. Summary of the findings of this study. V!6n, a measure of early systolic dyskinesia, showed good recovery after 10 minutes of normothermic and 30 minutes of hypothermic ischemia in beating hearts, moderate impairment in the 10 minute normothermic, fibrillating hearts, and marked impairment in both of the 30 minute normothermic groups as well as the 30 minute fibrillating group. Similar trends are apparent with respect to the less sensitive measure, mean systolic shortening (AZJ. See tables for significance values.

reperfusion, and contractile function was studied for 15 minutes. Group II: Normothermic bypass-fibrillating heart. In five dogs (dogs 6 to 10) a protocol identical to that used in the normothermic beating group was undertaken, except that ventricular fibrillation was induced immediately prior to LAD occlusion. Ventricular fibrillation was induced by momentarily stimulating the right ventricle with a 40 Hz pulsed direct current (DC) shock (6 to 8 volts) with a bipolar electrode. Sinus rhythm was restored by DC cardioversion with a 10 watt-second shock at 30 seconds after both 10 and 30 minute LAD occlusions; cardiopulmonary bypass was then discontinued immediately. Group III: Hypothermic bypass-beating heart. In five dogs (dogs 11 to 15) regional function was obtained during a control period and again after a 5 minute period of cardiopulmonary bypass at 37° C. without coronary occlusion. The dogs were then core-cooled to 30° C. on cardiopulmonary bypass over a 10 minute period, and the LAD was occluded for 30 minutes with the heart beating. On release of the LAD occlusion, temperature was maintained at 30° C. for an additional 10 minutes before rewarming to 37° C. over the next 20 minutes. Regional contractility was recorded 5 minutes after establishing normal circulation at control heart rate and arterial pressure. Group IV: Hypothermic bypass-fibrillating

heart. In five dogs (dogs 16 to 20) a protocol indentical to that used in the hypothermic beating group was undertaken with the addition of ventricular fibrillation as in Group II just prior to LAD occlusion. After 30 minutes of occlusion, reperfusion was begun, DC cardioversion was carried out within 30 seconds, and the dogs were then treated exactly as in Group III. Analysis of contractile pattern Segmental contractile function was assessed by measuring the end-diastolic segment length (EDL), the end-systolic segment length, and the lengths after one third and two thirds of systole; these four measurements were then averaged to give the mean systolic segment length (MSL). The mean systolic change in length (AL) was defined as (EDL-MSL). The mean velocity of shortening over the first third of systole (VVi) was calculated from the change in length over the first third of systole. Both VV3 and MSL were chosen as parameters that describe the pattern of segmental contraction rather than as indices of segmental power or work. Thus V/3 was chosen as an index that assessed early systolic dyskinesia, and MSL (and hence AL) was used as a measurement of mean shortening. EDL, MSL, AL, and V/3 were then normalized by dividing them by the control EDL, to give EDLn, MSLn, Ln, and V/3n. Thus by definition, control EDLn = 1.00 cm. All data are presented as mean ± standard error of

The Journal of Thoracic and Cardiovascular Surgery

7 4 Gaudiani, Smith, Epstein

Table I. Hemodynamic and contractile data (normothermic) Ten minutes of ischemia Beating C HR AP V'/in AL

195 110 6.7 0.08

±5 ±6 ± 1.7 ± 0.02

Fibrillating 15 min. 180 101 5.1 0.07

± rt ± ±

9 8 1.9 0.01

NS NS NS NS

15 min.

C

P 154 100 13.9 0.11

± + ± ±

10 6 1.8 0.01

183 100 8.8 0.09

± ± ± ±

10 7 1.6 0.01

P NS NS

* *

Legend: C, Control, p, Significance (control versus 15 minutes after reperfusion). HR, Heart rate. AP, Arterial pressure. V l/3n. Normalized velocity of contraction in the first one third of systole. AL, Mean systolic shortening. *p <0.01 (control versus 15 minutes after reperfusion).

the mean unless indicated otherwise. Significance of change or difference was tested by paired or unpaired Student's t test. Results Group I: Normothermic bypass-beating heart. At the beginning of the study period, the mean heart rate in these five dogs was 195 ± 5 beats per minute and the arterial pressure was 110 ± 6 mm. Hg. Epicardial temperature was 37° C. The pattern of regional contractile function recorded from the crystals in the anterior left ventricular wall was normal: MSLn 0.92 ± 0.02 cm. and VVSn 6.7 ± 1.7 mm. per second per centimeter; by definition, EDLn was 1.00 cm. Cardiopulmonary bypass emptied the heart and thereby reduced EDLn to 0.85 ± 0.03 cm. (p < 0.01) and MSLn to 0.84 ± 0.02 cm. (p < 0.01); there was minimal effective systolic shortening (V'/3n = 0.2 ± 0.9 mm. per second per centimeter and AL = 0.0 ± 0.005); mean arterial pressure was 79.6 ± 10.8 mm. Hg. The LAD was then occluded for 10 minutes. Bypass was discontinued 30 seconds after release of the occluded artery. Heart rate and arterial pressure measured 15 minutes after termination of bypass were not significantly different from control values, and regional contractile function returned to a pattern similar to that of control (V'/3 = 5.1 ± 1.9 mm. per second per centimeterandAL = 0.07 ± 0.01). In addition, there was no deterioration in contractile function over the next 15 minutes. A second period of bypass was then begun during which the LAD was occluded for 30 minutes. After release of the occlusion and cessation of bypass, VVi was 2.2 ± 3.8 mm. per second per centimeter after 1 minute of reperfusion, and it fell to - 1 . 6 ± 2.6 mm. per second per centimeter over the next 15 minutes (p < 0.01). Thus 10 minutes of ischemia during normothermic bypass had no significant effect on contractile function.

Recovery after 30 minutes was poor, and deterioration followed in every case. The data are displayed in Figs. 2 and 6 and listed in Table I. Group II: Normothermic bypass-fibrillating heart. A second group of five dogs subjected to the identical surgical preparation had heart rates and arterial pressures similar to those of animals in Group I. Initial VVS was higher than in Group I (13.9 ± 1.8 mm. per second per centimeter). Cardiopulmonary bypass emptied the heart as in the first group of dogs, and the heart was fibrillated with a brief electrical stimulus. The coronary artery was released after 10 minutes of ischemia, the hearts were defibrillated, and bypass was discontinued immediately. After 2 minutes of reperfusion, VVS had fallen from control in all animals to a mean 8.3 ± 2.1 mm. per second per centimeter (p < 0.01), and AL had fallen in all animals from 0.11 ± 0.01 to 0.09 ± 0.01 cm. (p < 0.01). These values remained unchanged over the next 13 minutes. During a second period of normothermic bypass with ventricular fibrillation, the LAD was occluded for 30 minutes. Two minutes after reperfusion, V'/3n declined from control to 1.7 ± 4.0 mm. per second per centimeter, and it fell further to - 1 . 4 ± 1.7 mm. per second per centimeter after 15 minutes (p < 0.01). AL had fallen from its control value of 0.09 ± 0.01 to 0.04 ± 0.02 cm. (p < 0.01). These data are displayed in Figs. 3 and 6 and listed in Table I. Thus recovery was impaired in both the 10 minute and the 30 minute periods of ischemic fibrillation, and after the 30 minute interval there was deterioration in VVSn during 15 minutes of reperfusion similar to that seen after 30 minutes of ischemia with the heart beating. Group III: Hypothermic bypass-beating heart. A third group of five dogs with similar values of heart rate, arterial pressure, and contractile function was core-cooled on cardiopulmonary bypass from 37° C. to

Volume 76 Number 1 July, 1978

15

Alterations in regional contractility

Thirty minutes of ischemia Fibrillating

Beating / min.

C 180 101 5.1 0.07

± ± ± ±

9 8 1.9 0.01

15 min.

198 ±4 99 ± 7 2.2 ± 3.8 0.04 ± 0.03

190 105 -1.6 0.03

± ± ± ±

3 6 2.6 0.01

NS NS * *

183 100 8.8 0.05

± ± ± ±

75 min.

1 min.

C

P

175 89 1.7 0.03

10 7 1.6 0.01

± ± ± ±

2 8 4.0 0.01

177 97 -1.4 0.04

± ± ± ±

3 9 1.7 0.02

P NS NS

* *

Table II. Hemodynamic and contractile data (hypothermic) Thirty minutes of ischemia Beating

Fibrillating

C HR AP V'/sn AL

176 100 10.6 0.09

± ± ± ±

15 min. 9 6 2.1 0.01

147 96 9.8 0.10

± ± ± ±

11 6 1 0.01

*

15 min.

C

P NS NS NS

162 94 7.8 0.08

± ± ± ±

6 4 0.9 0.01

137 91 0 0.06

± ± ± ±

10 5 2.1 0.01

P

*

NS

*t

NS

For legend see Table I. *p <0.01 (control versus 15 minutes after reperfusion). tp <0.01 (beating versus fibrillating hearts).

30° C. Heart rate slowed from 176 ± 9 to 120 ± 2 beats per minute. The LAD was occluded with the hearts beating at this slower rate. After 30 minutes of ischemia, bypass was discontinued as discribed previously. Arterial pressure was returned to control levels, but heart rate was slower (147 ± 11 beats per minute than control. Contractile function was unchanged (Table II; data are illustrated in Figs. 4 and 6). Group IV: Hypothermic bypass-fibrillating heart. In five dogs hypothermic bypass was instituted as in Group III. Hearts were then fibrillated by a brief stimulus. The LAD occluded for 30 minutes. After the discontinuation of bypass, Win had fallen to 0.0 ± 2.1 mm. per second per centimeter, which was significantly less than control (p < 0.01) and significantly less than WVm in the hypothermic beating group (p < 0.01). As in Group III, arterial pressure was unchanged from control, but heart rate was slower. These data are shown in Figs. 5 and 6 and in Table II. Discussion Both aortic occlusion and individual coronary artery occlusion have been utilized clinically to perform coronary artery anastomoses. Although substantial data have been accumulated on the myocardial effects of global ischemia, less information has been available

concerning regional ischemia. We found that a 10 minute period of regional myocardial ischemia induced during normothermic cardiopulmonary bypass depressed contractile function only when ventricular fibrillation accompanied the ischemic episode. During 30 minute periods of ischemia, hypothermia (30° C.) prevented ischemic damage in the beating heart, but not the fibrillating heart. Normothermic regional ischemia for 30 minutes caused equally severe ischemic damage in either rhythm. Thus it appears that normothermic ischemia of this duration produces damage too intense to be influenced by cardiac rhythm. Certain aspects of our model require amplification. First, the hypothermic groups were permitted additional time on cardiopulmonary bypass while rewarming was accomplished. In contrast, the normothermic groups resumed function and were tested immediately after the ischemic episode. This difference was necessary in order to rewarm the dogs, and it may tend to overestimate the protective effects of hypothermia compared to normothermia. It does not, however, alter the comparison between beating and fibrillating hypothermic groups, because the two were treated identically. Second, 30° C. hypothermia, while perhaps not optimal clinical hypothermia,13 conforms to the moderate

7 6 Gaudiani, Smith, Epstein

hypothermia often used in both experimental and clinical applications. This degree of hypothermia also provided significantly more protection to the beating than the fibrillating heart. Our results are generally compatible with observations made after global ischemia during cardiopulmonary bypass, particularly with respect to the effects of ventricular fibrillation. Reis, Cohn, and Morrow4 showed that maintained fibrillation caused more myocardial depression than spontaneous fibrillation. With the development of the microsphere blood flow technique Hottenrott, Maloney, and Buckberg5 demonstrated the deleterious effect of maintained fibrillation on regional myocardial flow. Subsequently, they6 observed the effects of low coronary perfusion pressures and hypothermia on the bypassed fibrillating heart. Baird and colleagues7 found identical effects on regional flow with sustained and spontaneous fibrillation, but regional perfusion remained adequate as long as perfusion pressure was sufficiently high. However, in a regionally ischemic model such as we employed, perfusion pressure to the ischemic segment is sharply reduced, and the increased myocardial wall tension imposed by ventricular fibrillation could compress collateral channels to the ischemic segment and thereby magnify the ischemic insult.6- 9 ' I0 Where our results differ from those of other investigators, the difference may be explained by the method used to detect ischemia. Schaff and colleagues,11,12 for instance, using microsphere flows and intramyocardial oxygen tensions, have shown that regional myocardial ischemia occurs distal to a critical coronary stenosis in the bypassed, fibrillating heart, but that these changes are reversed when the hearts are defibrillated. The return of these parameters to normal may not imply that mechanical myocardial activity has resumed normal function. In fact, in groups of dogs subjected to 30 minutes of normothermic ischemia in this study, function deteriorated as reperfusion proceeded. Although experimental models are different, this discrepancy suggests that resumption of normal pressure and flow to the myocardium may not immediately reverse the myocardial injury sustained during the ischemic episode. With respect to the effects of hypothermia, our results differ from those of McConnell and associates,10 who showed that ischemia, as defined by diminished regional flow and lactate production, is more likely to occur in hypoperfused beating hearts during hypothermia than during normothermia. The results of the present study are not consistent with this concept. In the beating heart, 30 minutes of regional ischemia dur-

The Journal of Thoracic and Cardiovascular Surgery

ing cardiopulmonary bypass at 30° C. resulted in no depression of contractile function after restoration of coronary flow and termination of bypass. In contrast, the same experiment conducted at 37° C. resulted in marked reduction of contractile function. This difference in results may be related to differences in experimental models. However, it might also reflect a difference between the methods used to detect ischemia in the two studies. McConnell and coworkers10 defined ischemia mainly by a reduction in regional myocardial flow and detection of lactate production as measured during ischemia. These methods may not always serve as an accurate reflection of ischemia. For example, regional flow may be low but not cause myocardial injury if it is accompanied by a reduction in myocardial oxygen requirements. In addition, Brazier and co-workers6 have shown that lactate measurements during hypoperfusion may not accurately reflect the state of anaerobic metabolism, as a pronounced washout of myocardial lactate occurs when perfusion pressure is subsequently raised to normal levels. Our approach was predicated on the consideration that the most relevant effect of ischemia is its impact on myocardial function after the ischemia is relieved and the heart is working. The present study was designed to elucidate contractile changes in a myocardial segment made ischemic during cardiopulmonary bypass. No direct comparison of the virtues of global versus regional ischemia to obtain a dry operative field can be made. However, the ultrasonic technique documents a pattern of injury which conforms with concepts derived from models of globally ischemic hearts. Therefore, the clinical implications of regional ischemia should be similar to those of global ischemia.8 This technique also demonstrates that ventricular fibrillation increases ischemic injury during brief periods of normothermic ischemia as well as longer periods of hypothermic ischemia. Since there are, as yet, no experimental data to suggest that limiting the ischemic insult to a segment of myocardium will affect the incidence of postoperative myocardial infarction or low-output syndrome, it appears that regional occlusion techniques suffer the same drawbacks as aortic occlusion. Finally, we estimate that the maximal ischemic injury measured in this study was of moderate severity, because all hearts could be weaned from bypass without pharmacologic support and maintain a blood pressure similar to that measured before the insult. The hemodynamic response to ischemia must depend upon many variables, including the metabolic state of the heart before operation, the duration of the insult and

Volume 76 Number 1 July, 1978

rhythm during the insult, and the amount of myocardium involved. In our study, duration appeared to dominate, because a differential effect of fibrillation could not be detected in the group subjected to 30 minutes of normothermic ischemia. Even if these variables are known, it remains to specify the biochemical and morphologic sequence after ischemia which determines whether the involved segment will survive. Further investigation will determine if the regionally ischemic model offers additional insights into these processes. REFERENCES 1 Ellis RJ, Kligfield P, Gay W, Ebert PA: Distal coronary artery bypass. Local occlusion vs. ischemic arrest. Surgery 78:424-429, 1975 2 Theroux P, Franklin D, Ross J Jr, Kemper US: Regional myocardial function during acute coronary artery occlusion and its modification by pharmacologic agents in the dog. Circ Res 35:896-908, 1974 3 Theroux P, Ross J Jr, Franklin D, Kemper US, Sasayama S: Regional myocardial function in the conscious dog during acute coronary occlusion and responses to morphine, propranolol, nitroglycerin, and lidocaine. Circulation 53:302-314, 1976 4 Reis RL, Cohn LH, Morrow AG: Effects of induced ventricular fibrillation on ventricular performance and cardiac metabolism. Circulation 35:Suppl 1:234-243, 1967 5 Hottenrott C, Maloney JV Jr, Buckberg G: Studies of the effects of ventricular fibrillation on the adequacy of regional myocardial flow I. Electrical vs. spontaneous fibrillation. J THORAC CARDIOVASC SURG 68:615-625,

1974 6 Brazier JR, Cooper N, McConnell DH, Buckberg G:

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Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. III. Effects of temperature, time, and perfusion pressure in fibrillating hearts. J THORAC CARDIOVASC SURG 73:102-109, 1977

7 Baird R, Dutka F, Okumori M, de la Rocha A, Goldbach MM, Hill TJ, MacGregor DC: Surgical aspects of regional myocardial blood flow and myocardial pressure. J THORAC CARDIOVASC SURG 69:17-29, 1975

8 Buckberg GD, Olinger GN, Mulder DG, Maloney JV Jr: Depressed postoperative cardiac performance. J THORAC CARDIOVASC SURG 70:974-988, 1975

9 Buckberg G, Brazier JR, Nelson RL, Goldstein SM, McConnell DH, Cooper N: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. I. The adequately perfused beating, fibrillating, and arrested heart. J THORAC CARDIOVASC SURG 73:87-94, 1977

10 McConnell DH, Brazier JR, Cooper N, Buckberg G: 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 THORAC CARDIOVASC SURG 73:95-101, 1977

11 Schaff H, Flaherty JT, Ciardullo R, Gott VL: Effects of a critical coronary artery stenosis on regional myocardial blood flow in a fibrillating heart. Fed Proc 35:346, 1976 12 Schaff HV, Ciardullo R, Flaherty JT, Brawley RK, Gott VL: Myocardial ischemia distal to criticial coronary stenosis during cardiopulmonary bypass: Fibrillating vs. beating nonworking heart. Surg Forum 27:248-250, 1976 13 Tyers GFO, Williams EH, Hughes HC Jr, Waldhausen JA: Optimal myocardial hypothermia at 10 to 15° C. Surg Forum 27:233-234, 1976