PHYSIOLOGIC PRINCIPLES OF CORONARY PERFUSION

PHYSIOLOGIC PRINCIPLES OF C O R O N A R Y PERFUSION Robert F. Shaw, M.D. (by invitation),

Paul Mosher, B.A.* (by

John Ross, Jr., M.D. (by invitation),

Julian I. Joseph, M.D. (by

and Arnold

S. J. Lee, B.S. (by invitation),

(Sponsored

by George H. Humphreys,

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New

York, N.

II, New York, N.

invitation), invitation),

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the past year, this laboratory has studied various aspects of the perfusion characteristics of the myocardial vascular bed. This report is a summary of the findings of a series of related experiments which, taken as a group, suggest certain principles that might be helpful in deciding how best to perfuse coronary arteries, especially during aortic valvular surgery. URING

THE RELATION OF CORONARY BLOOD FLOW TO PERFUSION PRESSURE1

Studies were conducted in 22 open-chest anesthetized dogs in whom perfusion pressure in the left circumflex coronary artery could be varied, independent of aortic pressure. The circumflex coronary artery was cannulated and perfused either from a cannulated femoral artery or from a pressurized reservoir of mixed donor arterial blood, by means of the extracorporeal circuit illustrated (Fig. 1). Body and perfusion temperatures were maintained constant by heating pads and the countercurrent heat exchangers shown. Blood volume was held constant by matched bleeding from a femoral vein whenever perfusion was conducted from the arterial reservoir. In addition to central venous and perfusion temperatures, four hemodynamic parameters were continuously measured and recorded. These were coronary perfusion pressure, central arterial pressure, left ventricular pressure (Statham strain gauges), and coronary blood flow (Shipley-Wilson rotameter). In addition, the electrical ventricular pressure signal was fed into an integrating circuit which was balanced to accumulate voltage only during systole and discharged every 10 seconds. This technique provided a simple, convenient method of integrating continuously the systolic pressure generated by the myocardium over ten-second intervals (VPI), which, in the absence of gross changes in end-diastolic ventricular volume, is a sensitive index of the level of cardiac effort. 2 ' 3 From the Department of Surgery, College of Physicians and Surgeons and the Bio-Medical Engineering Laboratory, Electronics Research Laboratories, School of Engineering and Applied Sciences, Columbia University, New York, N. Y. The various aspects of this work were supported by U. S. Public Health Service Research Grant H-5032 and National Aeronautics and Space Administration Research Grant NsG-112-61. Read at the Forty-second Annual Meeting of The American Association for Thoracic Surgery at St. Louis, Mo., April 16-18, 1962. *U. S. Public Health Service Post-Sophomore Research Fellow. 608

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By means of this experimental preparation, it was possible to subject the myocardial bed to a series of sudden pressure-steps while the level of cardiac function was maintained constant. The response of the coronary bed to a sudden change in perfusion pressure was similar in all experiments. In Pig. 2, a recording of a sudden increase of perfusion pressure from 100 to 140 mm. Hg is reproduced. The step-up in perfusion pressure is accompanied by an abrupt increase in coronary flow, which quickly begins to return toward its former value as vasoconstriction intervenes. In a matter of seconds, coronary flow is very near its initial level despite the considerable difference in the two perfusion pressures. In addition to the rapid return of flow toward its previous level during an interval of approximately 10 seconds, an oscillation of flow with a period of approximately 10 seconds is noted.

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Pig. 1.—Schematic representation of the extracorporeal circuit used for the study of auto-regulation of coronary blood flow. Perfusion of the coronary artery is carried out either from the left femoral artery (Line A) or from the arterial reservoir. The reservoir is filled intermittently from the right femoral artery.

Fig. 3 demonstrates the transient response to a sudden decrement in perfusion pressure from 100 to 75 mm. Hg. Once again, flow rapidly returns toward its initial level, this time as a consequence of vasodilation. Once again, oscillations occurred. The damped oscillations routinely observed are characteristic of feedback control systems. If the stabilized flow values after compensation are plotted against perfusion pressure for a series of pressure steps conducted at a constant level of cardiac effort, a post-compensation steady-state pressure-flow curve for the coronary bed is obtained (Pig. 4). It will be noted that over a physiologic range of perfusion pressures, flow is maintained at a constant level, independent of pressure. In each of the 14 experiments in which a sufficient number of pressure steps could be imposed (10 to 20) while indices of cardiac work re-

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mained constant, a similar curve was obtained. The average pressure at the lower end of this regulated range was 70 mm. Hg for all 14 experiments, and the average for the upper end was 144 mm. Hg. The average maximum deviation of flow over this wide pressure range was ±7 per cent. Below and above the regulated range, flow is dependent upon perfusion pressure. 150

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oL Fig-. 2.—Coronary flow: transient response to sudden increment in coronary perfusion pressure. Coronary flow abruptly increases but vasoconstriction rapidly intervenes to return coronary flow toward its previous level.

Fig:. 3.—Coronary flow: transient response to sudden decrement in coronary perfusion pressure. Coronary flow abruptly falls off but almost immediately begins to return to its previous level as vasodilation occurs.

These studies demonstrate an active intrinsic mechanism that regulates blood flow to the myocardium. In the anesthetized, thoracotomized state, this mechanism is capable of adjusting blood flow quite precisely, if perfusion pressure is maintained between 70 to 145 mm. Hg. In general, above and below these average values, the regulatory mechanism fails. THE RELATION OF CORONARY FLOW TO CARDIAC EFFORT1

I n 5 experiments conducted as described above, following the determination of steady-state pressure-flow curves, the level of cardiac effort was increased or decreased by aortic constriction, transfusion, or controlled hemorrhage. A

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series of pressure steps was then imposed at a new stable work level. The results in all 5 experiments were similar. An augmentation of coronary effort caused coronary flow to be regulated at a higher level (Fig. 5), and a decrease in cardiac effort caused coronary flow to be regulated at a lower level. 70

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Fig. 4.—Postcompensation steady-state pressure-flow curve for coronary circulation under condition of constant cardiac work. In this experiment, pressure was changed in consecutive 10 mm. Hg steps. Increments (.open circles) and decrements (2 runs, closed circles and X's) from an initial pressure of 115 mm. Hg. ^ . 120

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Pig- 5.—The relation of the regulated level of coronary blood flow to the level of myocardial function. In this experiment, following determination of the postcompensation steadystate pressure-flow curve (closed circles), cardiac effort was increased by partial occlusion of the thoracic aorta and the curve re-determined (open circles) a t this stable augmented level of cardiac work. The higher level at which coronary flow is regulated is apparent.

Thus, the level at which coronary blood flow is regulated is related to the level of cardiac effort and, presumably, to myocardial needs. THE DELETERIOUS EFFECT OF CORONARY OVERPERFUSION4

The effects of coronary underperfusion are well known. studied the effects of coronary overperfusion.

We have recently

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In 12 open-chest anesthetized dogs, the left common coronary artery was cannulated with a Gregg cannula and perfused from a pressure-regulated reservoir which continuously received blood from a femoral artery. Perfusion pressure and temperature were monitored just proximal to the coronary cannula. Perfusion was conducted at levels of 100, 150, 200, 250, and 300 mm. Hg for periods of 30 to 90 minutes. Table I summarizes the results of gross and microscopic pathologic examination following perfusion. The average mean systemic pressure after thoracotomy, but prior to experimental intervention, was 133 mm. Hg. No impressive pathologic evidence of damage was observed for perfusion pressures less than

Fig. 6.—Photograph of heart after left coronary perfusion a t 300 mm. Hg for 90 min. (Exper. 13, Table I ) . Heart has been opened by the method of Schlesinger and the left ventricle is seen to the right. The appearance of severe hemorrhages in the left ventricle and septum are in obvious contrast to the appearance of the right ventricle. TABLE I. L E F T CORONARY ARTERY PERFUSION-RELATION OF PERFUSION MYOCARDIAL HEMORRHAGE* PREINTERPERFUSION VENTION SYSTEMIC PRES SURE PRESSURE (MM. (MM. HG) Ho) 110 100 150 170-200 200 200 250 250 300 300

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CORONARY PERFUSTON

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200 mm. Hg. However, all hearts perfused at levels of 200 mm. Hg or greater showed gross evidence of myocardial hemorrhage. At 200 mm. Hg, the hemorrhages were punctate and scattered over the myocardium nourished by the left coronary artery. As perfusion pressures increased, the size and number of the hemorrhagic areas increased. In the hearts perfused at 300 mm. Hg, the hemorrhagic areas were almost confluent (Fig. 6), and, in those two perfusions, left ventricular failure supervened at 40 and 45 minutes.

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Pig:. 7.—Replotting of coronary artery steady-state pressure-flow curve for a constant level of cardiac function with flow on the abscissa, demonstrating- the narrow physiologic flow and pressure range. THE CONDUCT OF CORONARY PERFUSION

These studies suggest that, if offered blood at a physiologic head of pressure, the myocardial bed will adjust its own flow to an appropriate level. Autoregulation has been demonstrated in the bypassed as well as the working heart. If perfusion pressure is too high, or too low, the autoregulatory mechanism will fail. If perfusion pressure is too high, loss of integrity of the vascular tree and myocardial hemorrhages can be expected. Recent work in other laboratories has demonstrated similar autoregulatory mechanisms operative in brain, 5 kidney, 6 and muscle.7 These studies argue for the general advisability of maintaining mean pressure levels of at least 70 mm. Hg during total body perfusions conducted at normothermia. Coronary perfusion becomes a special problem during aortic valvular surgery. The limited myocardial reserve often seen in these patients and the lengthy periods frequently required for repair suggest that optimal coronary perfusion technique may be worthy of consideration.

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If coronary perfusion is to be performed from a line tapping-off the main arterial line, it is well to remember that even though coronary cannulas are considerably smaller than femoral cannulas, the pressure drop across a coronary cannula is but a small fraction of the pressure drop across a femoral cannula. This is due to the fact that the resistance of the vascular bed of each coronary artery is roughly forty times that of the total systemic circulation. Perfusion line pressures are often in the neighborhood of 300 mm. Hg. A fixed resistance in the coronary line is helpful in protecting the myocardium from high pressures, but is less than optimal in its inability to adjust for changes in cardiac state and flow requirements. For example, a resistance may be added to the coronary line that will decrease perfusion pressure from 270 to 90 mm. Hg, at a time that total coronary flow is at a level of 300 c.c. per minute. However, if increased cardiac need diminishes vascular resistance by 50 per cent, flow will not increase as normally to 600 c.c. per minute, but only to 360 c.c. per minute and perfusion pressure will drop to 54 mm. Hg. Alternatively, perfusing from a separate pump at a pre-selected flow rate is not without difficulties. The steady-state pressure-flow curve demonstrates how precisely one must estimate flow to perfuse at reasonable pressures (Fig. 7). And, of course, coronary flow requirements may vary with time. If the flow estimate is low, hypoxia will occur. If the estimate is high, the response to excessive coronary flow, as we have seen in Fig. 2, is vasoconstriction. Since by this perfusion mode, flow rate is fixed, vasoconstriction will result in an elevated perfusion pressure. T H E AUTOMATIC P E R F U S I O N PRESSURE REGULATOR 7

These considerations have led us to develop the automatic perfusion pressure regulator (APPR) (Fig. 8). The APPR is a small self-contained hydraulic servo-system which, when placed in a perfusion line, will automatically maintain perfusion pressure close to a pre-set value despite wide fluctuations in either the pressure or flow presented to it. I t has been designed so that an index of outflow is apparent on its dial indicator, and malposition of coronary cannulas causing obstruction to flow can be discerned. The A P P R operates by automatically controlling the resistance to blood flow of a section of silicone rubber tubing which is part of its flow circuit. The perfusion line to the patient is in communication with a small silicone rubber bellows which pushes against a compression spring, the force of which determines the perfusion pressure. The height of the bellows actuates a lever arm which squeezes the segment of silicone rubber tubing so that any change in the height of the bellows will alter the resistance to blood flow through the tubing. The conductance of this segment of tubing is directly proportional to the height of the bellows over the total range of bellows movement of y± in. (50 c.c.). The apparatus is designed to control either the entire output of a pump, returning the superfluous output to the pump's inlet (bypass mode), or to control a minor branch of pump output (tap-off mode). All of the parts which come into contact with blood can be autoclaved as a single, assembled unit which

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Pig. 8.—The automatic perfusion pressure regulator which maintains perfusion pressure within a narrow pre-set range despite wide fluctuations in either pressure or flow presented to it.

Pig. 9.—The direct reading manometer for measurement of mean intravasoular or perfusion line pressures.

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can be freely handled by the surgical team after sterilization. The maximum blood volume contained in the APPR is 75 c.c; there is no blood-gas interface and no possibility of air embolus. A small direct-reading manometer has been designed 8 (Fig. 9) to be used in conjunction with the APPR or in any situation where mean pressure is to be monitored but not recorded. SUMMARY

1. An active intrinsic mechanism operative within the myocardium regulates coronary blood flow, independent of perfusion pressure, over a physiologic pressure range. In the anesthetized, thoracotomized dog, this pressure range is 70 to 145 mm. Hg. In general, the regulatory mechanism fails at higher and lower pressures. 2. The level at which coronary flow is regulated is related to the level of cardiac effort and, presumably, to myocardial needs. 3. Elevated perfusion pressures may result in capillary rupture, hemorrhage into the myocardium and compromised cardiac function. 4. The hydraulics of cardiopulmonary bypass are such that: (a) the pressure drop across a coronary cannula is a fraction of the pressure drop across a larger femoral cannula; (b) the insertion of a fixed resistance in a coronary line perfused from the main arterial line protects the mycoardium from elevated pressures but cannot compensate for variations in coronary vascular resistance; and (c) when conducting coronary perfusion from a separate pump, only a narrow flow range permits perfusion in the physiologic range of pressures. 5. An automatic perfusion pressure regulator has been designed which maintains perfusion pressure in a narrow range despite wide variations in either the pressure or flow rate presented to it. The authors are indebted to Dr. John B. Price, Jr., Miss Patricia McFate, and Mr. William Baum for their participation in various phases of these studies. REFERENCES

1. Mosher, P., Ross, J., J r . McFate, P . A., and Shaw, E. F . : Autoregulation in the Control of Coronary Blood Flow. ( I n press.) 2. Feinberg, H., Katz, L. N., and Boyd, E . : Determinants of Coronary Flow and Myocardial Oxygen Consumption, Am. J . Physiol. 202: 45, 1962. 3. Sarnoff, S. J., Braunwald, E. Welch, G. H., Jr., Vase, R. B., Stainsby, W. N., and Macruz, R.: Hemodynamie Determinants of Oxygen Consumption of the Heart With Special Reference to the Tension-Time Index, Am. J . Physiol. 192: 148, 1958. 4. Shaw, R. F., Baum, W. M., and Joseph, J. I.: Pathologic Effects of Coronary Overperperfusion. (In press.) 5. Machowicz, P . B., Sabo, G., Lin, G., Rapela, C. E., and Green, H. D.: Effects of Varying Cerebral Arterial Pressure on Cerebral Venous Flow, Physiologist 4: 68, 1961. 6. Schmid, H. E., Jr., and Spencer, M. P . : Characteristics of Pressure-Flow Regulation bv the Kidney, J. Appl. Physiol. 17: 201, 1962. 7. Stainsby, W. N., and Renkin, E. M.: Autoregulation of Blood Flow in Resting Skeletal Muscle, Am. J. Physiol. 201: 117, 1961. 8. Shaw, R. F., and Lee, A. S. J . : An Automatic Perfusion Pressure Regulator for Total Body and Regional Perfusion. ( I n press.) 9. Shaw, R. F., and Lee, A. S. J . : A Direct Reading Manometer for the Measurement of Mean I n t r a v a s c u l a r Pressures. (In press.) (For Discussion, see page 633)