612.I73:6I2.I3. mammary and mediastinal vessels tied off. The thoracic wall on the left

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1 612.I73:6I2.I3 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. By H. BAR CROFT (Harmsworth Scholar, St Mary's Hospital, London). (From the Physiological Laboratory, Cambridge.) THE methods for the measurement of the output of the heart have hitherto, for the most part, dealt only with variations which take place over a considerable period of time. The cardiometer has yielded valuable results. The method has several objections; the cardiometer is not easily adjusted and if badly adjusted yields fallacious results; it presses on the coronary veins; the analysis of the records is laborious. The mechanical stromuhr [Barcroft, H. 1929] and the thermo-electric methods [Rein, 1928; Gesell, 1926] give accurate and continuous measurements of the variations which take place over intervals of a few seconds, and therefore open up quite new possibilities of detailed investigation of the cardiac output. This paper describes changes in the output of the dog's heart which can be produced by various manipulative procedures. An accurate collection of such data is of value because it provides a number of definite and simple facts which any theory of the circulation must be able to explain. METHOD. Dogs weighing approximately 10 kg. were used. Morphia was injected half an hour before the experiment, and anesthesia produced by a mixture of equal parts chloroform and ether. Artificial respiration was established. A cannula attached to a burette was inserted into the femoral vein. The chest was opened and the azygos vein, internal mammary and mediastinal vessels tied off. The thoracic wall on the left side was divided from the sternum to the head of the ribs between the fourth and fifth ribs. The ribs were pulled widely apart and secured to the table with string. Ligatures on the great vessels were laid ready. Heparin, 0-25 g., dissolved in warmed saline solution, was injected through the burette. The arrangement of tubes and cannule attached to the stromuhr is shown diagrammatically in Fig. 1. The stromuhr was filled with warmed defibrinated blood from another animal. The tubes

2 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. A, B and C were clamped with Spencer-Wells' forceps. The thoracic aorta and i.v.c. were simultaneously clamped. A ligature round the arch of the aorta was pulled firmly towards the head to prevent bleeding, and a -+- shaped cut was made in the upper part of the thoracic aorta between the occlusions. The cannula D was placed in the cut, pressed against the back of the aorta and slid upwards towards the head of the animal; the top flaps of the cut opened and directly the cannula was above the cut it was ligatured in place. The cannula E was inserted into the same cut and was ligatured G E F D in the descending part of the thoracic aorta. The Spencer-Wells' forceps at A B B was removed. Air in the central cannula was caught in the stromuhr and could be released at will. The H screw clamp at F was loosened and the Spencer-Wells at A removed, air, above the clamp on the thoracic C aorta was driven out through F. The clamps on the thoracic aorta and i.v.c. were simultaneously removed. Some defibrinated blood was S I injected through the burette if there ij had been any bleeding. The arterial pressure manometer was attached at C; if the blood pressure was below 80 mm. Hg more blood was injected UN immediately to prevent the risk of cardiac fibrillation. The cannula G was inserted into the peripheral end of a cutin the brachiocephalicartery Fig. ments 1. Apparatus in which theused systemic in the output experi- of and the clamp H removed. The left the dog's heart was recorded. Detailed subclavian artery was tied off. The explanation in text. intercostal vessels opening from that part of the thoracic aorta between the two cannulae were ligatured. Blood flowed from the heart into the stromuhr and thence into the thoracic aorta or brachiocephalic artery. Thus the total systemic output was recorded. The following data were collected from observations made during sixteen different experiments. 281

3 282 H. BARCROFT. I. COMPLETE OCCLUSION OF THE THORACIC AORTA. In 1886 de Jager published a paper showing that complete occlusion of the thoracic aorta caused increase in the arterial and venous bloodpressures. He supposed that the paradoxical increase in the venous blood-pressure might have been caused by a collapse of the vessels supplied by the thoracic aorta accompanied by a transference of blood through the i.v.c. into the rest of the vascular system. He did not measure the systemic output. Burton-Opitz [1921] measured the blood flow through the s.v.c. before and after complete occlusion of the thoracic aorta. His observations show that complete occlusion of the thoracic aorta increased the flow through the s.v.c. He did not measure the total systemic output. Tigerstedt [1909] measured the systemic output in dogs and found increase in the output after stimulation of the splanchnic nerve. I have not been able to find any observations on the systemic output before and after complete occlusion of the thoracic aorta. The typical effects produced by complete occlusion of the thoracic aorta in this series of experiments can be seen in Table I. TABLE I. Percentage changes in systemic output Total no. Average observed after complete occlusion of obser- percentage of thoracic aorta vations change Vagi intact +40, +38, +36, +33, 0, 0, 0, 0, -3, -15, , -30, -35 Vagi cut +53, +50, +40, +30, +27, +25, +25, +25, , +25, +25, +22, +20, +20, +20, +20, +20, +15, +15, +10, +10 Brain destroyed + 150, + 60, + 60, + 60, + 33, + 30, + 30, +25, , +20, +20, +15, +15, +10,0, 0, 0, 0, -5, -5, - 15, - 15, - 15, -20, -20, -25 The striking fact is that after section of the vagi occlusion of the thoracic aorta has always produced increase in the total systemic output. This is shown in Fig. 2. This increase in the systemic output, after occlusion of the thoracic aorta, has been observed in spite of fairly high initial blood-pressures. Thus in one experiment the blood-pressures before occlusion were 120, 105, 95, 85 and 80 mm. Hg respectively, the systemic outputs before occlusion were 880, 920, 720, 690 and 750 c.c. per minute respectively and the percentage increases in the output after occlusion were 25, 20, 25, 25, and 25 respectively. The fact that this increase in the systemic output after complete occlusion of the thoracic aorta is not observed more frequently when the vagi are intact must be that these nerves participate in some vascular reflex which sometimes prevents such a possibility.

4 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. 283 Factor responsible foir increase in systemic output after complete occlusion of the thoracic aorta. In four experiments the blood supply to the brain was cut off till the rise in the blood-pressure caused by cerebral anaemia could no longer be elicited. The brain was then considered to have been destroyed. Fig. 2. Thoracic aorta completely occluded at X and released at Y. BP. Arterial bloodpressure. BP=O. Arterial blood-pressure base line. S. Stromuhr record. 22 c.c. passed through the stromuhr during the interval between successive vertical strokes. T. Time in seconds. Stromuhr recording total systemic output. This tracing shows that complete occlusion of the thoracic aorta causes increase in systemic output when the vagi are cut. ( x 2.) There was a considerable fall in the blood-pressure; but in the majority of cases, as Table I shows, occlusion of the thoracic aorta still produced increase in the systemic output. It seemed therefore necessary to look for some other factor. The immediate cause for the great increase in the flow through the vessels supplied by the brachiocephalic artery after complete occlusion of the thoracic aorta was not difficult to find. This cause was found to be the drainage of blood from the occluded area and its transference to

5 284 H. BARCROFT. the remainder of the vascular system. For if the thoracic aorta and i.v.c. were occluded simultaneously the systemic output was greatly diminished. This is shown in Fig. 3. Thus increase in the systemic output after occlusion of the thoracic aorta alone was dependent upon the fact that the i.v.c. was patent. This could only mean that, after occlusion of the thoracic aorta alone, a quantity of blood passed through the i.v.c. into the heart and was responsible for increasing the systemic output. Fig. 3. Thoracic aorta and inferior vena cava simultaneously occluded at X and released at Y. PBP. Pulmonary blood-pressure. At X the puhnonary blood-pressure fell 4-5 cm. of water. BP. Arterial blood-pressure. S. Stromuhr record. 22 c.c. passed through the stromuhr during the interval between successive vertical strokes. BP=O. Arterial blood-pressure ba-se line. T'. Time in seconds. Stromuhr recording total systemic output. This tracing shows; that simultaneous occlusion of the thoracic aorta and inferior vena cava causes increase in arterial blood-pressure and decrease in systemic output. (x 1-96.) de Jager [1886] supposed that after occlusion of the thoracic aorta blood flowed on through the i.v.c. This experiment provides actual proof for de Jager's hypothesis. Measurement of blood redistribution after complete occlusion of the thoracic aorta. The following principle has been employed. Starting with an initial blood-pressure of, say, BP, Fig. 3, the thoracic aorta and i.v.c. were occluded simultaneously. The blood-pressure rose, say, to the extent shown

6 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. 285 between X and Y, Fig. 3. (I do not think attention has been drawn to the rise in the blood-pressure observable after simultaneous occlusion of the thoracic aorta and i.v.c., experimental evidence of its significance will be found later in this paper.) The exact value of the blood-pressure between X and Y was noted. All clamps were removed and if the animal was in good condition the blood-pressure returned to its original value BP. The thoracic aorta alone was then occluded. The blood-pressure rose to a much higher value than that shown between X and Y, Fig. 3. After the bloodpressure had reached its maximum the transference of blood through the i.v.c. was considered to have been completed. The i.v.c. was then occluded; blood was withdrawn from the brachiocephalic artery through the tube F, Fig. 1, till the blood-pressure dropped to and remained at the value between X and Y, Fig. 3. It is probable that the quantity of blood removed represented approximately the quantity which had travelled through the i.v.c. after occlusion of the thoracic aorta. Two values obtained for this were 43 and 46 c.c. No attempt has been made to measure the relative quantities of blood given up by different organs after occlusion of the thoracic aorta. It seems probable that the splanchnic area would be the chief source. It also seems probable that active constriction of the splanchnic area would express more blood than is yielded by passive collapse and hence that greater effects might be produced on the systemic output. MacKeith, Pembrey, Spurrell, Warner and Westlake [1921]; Barcroft and Stephens [1927]; and Barcroft and Florey [1929] have proved that splanchnic constriction accompanies exercise, and Krogh [1912] has given an important account of the significance of blood redistribution during exercise. II. COMPLETE OCCLUSION OF THE BRACHIOCEPHALIC ARTERY. Burton-Opitz [1921].occluded the brachiocephalic artery and found that the blood flow through the i.v.c. was increased. The typical change in the systemic output after occlusion of the brachiocephalic artery in this series of experiments is shown in Table II. These results show that the typical effect of complete occlusion of the brachiocephalic artery is a slight decrease in the systemic flow. Vascular reflexes occur after occlusion of the brachiocephalic artery when the vagi are intact or cut but have not been observed after destruction of the brain.

7 286 H. BARCROFT. TABLE II. Percentage changes in systemic output Total no. Average observed after complete occlusion of obser- percentage of brachiocephalic artery vations change Vagi intact + 38, + 10, + 5, + 5, + 5, 0, 0, 0, - 5, - 5, , - 5, - 5, - 5, - 10, - 10, - 20, - 25, -25, -33 Vagi cut +50, +45, +20, +15, +15, +10, +5,0, , -5, -5, -5, -10, -10, -10, -10, - 10, - 15, - 15, - 20, - 20, - 20, - 20, -25, -30 Brain destroyed 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, , 0, 0, 0, - 5, -5, -5 -,-5, - 5, -5, - 5, - 5, -5, -10, -10, -10, -20 III. COMPLETE OCCLUSION OF THE SUPERIOR VENA CAVA. A decided drop in the systemic output was found in all types of experiments. The output was decreased by approximately 50 p.c. of its initial value. IV. COMPLETE OCCLUSION OF THE INFERIOR VENA CAVA. A profound drop in the systemic output was found in all experiments. The output decreased by approximately 75 p.c. of its initial value. This fact is well known already [B ur t o n -O p i t z, 1921]. Some measurements of the redistribution of the blood after clamping the I.v.c. have been made. The method used was a modification of the method which has already been described for the measurement of the redistribution after complete occlusion of the thoracic aorta. These measurements show that, after occlusion of the I.v.C., in one experiment 48 c.c. entered the thoracic aorta and 47 c.c. in another. In many experiments the observations were taken in the following order: thoracic aorta alone occluded; brachiocephalic artery alone occluded; s.v.c. alone occluded; i.v.c. alone occluded. The typical result showed that the systemic output was increased by occlusion of the thoracic aorta; slightly decreased by occlusion of the brachiocephalic artery; further decreased by occlusion of the s.v.c.; most decreased by occlusion of the i.v.c. These facts, among others, have been taken into consideration in the construction of an artificial peripheral vascular system which is believed to embody the essential physical properties of the animal's peripheral vascular system. The nature and behaviour of this peripheral vascular system when attached to the animal's heart will be described in a future paper.

8 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. 287 V. SIMULTANEOUS COMPLETE OCCLUSION OF THE THORACIC AORTA AND INFERIOR VENA CAVA. I have not been able to find any data in the literature concerning the output, arterial blood-pressure and redistribution of blood after this procedure. Fig. 3 shows that after simultaneous occlusion of these vessels the blood-pressure rises and the systemic output is diminished. This has been observed in all experiments. Great care was taken to perform the occlusions simultaneously, so that no blood could reach the heart through the I.v.c. after occlusion of the thoracic aorta. Fig. 4. Thoracic aorta and inferior vena cava simultaneously occluded at X and released at Y. BP. Arterial blood-pressure. BP=O. Arterial blood-pressure base line. S. Stromuhr record. 22 c.c. passed through the stromuhr during the interval between successive vertical strokes. T'. Time in seconds. Stromuhr recording blood flow through brachiocephalic artery only. This tracing shows that simultaneous occlusion of the thoracic aorta and inferior vena cava increases the arterial blood-pressure and increases the flow through the brachiocephalic artery. ( x 2.37.) In some experiments the stromuhr was placed in the brachiocephalic artery only; Fig. 4 shows that simultaneous occlusion of these vessels then causes rise in arterial blood-pressure accompanied by increase in flow through the brachiocephalic artery. The same results were always obtainable when the brain was destroyed. Factor responsible for increase in arterial blood-pressure and increase in flow through brachiocephalic artery after simultaneous occlusion of thoracic aorta and i.v.c. Apparently this phenomenon could be explained by a concomitant

9 288 H. BARCROFT. transference of blood from the heart and lungs of the animal to the vessels supplied by the brachiocephalic artery. On a priori grounds such a transference might be explained by the fact that the diminished systemic output might cause: 1. Some collapse of the vascular bed of the lung. Daly [1928] has shown that, other things being equal, the volume of blood in the lungs is a function of the blood flow through the lungs. 2. Some decrease in the volume of blood in the heart. Patterson, Piper and Starling [1914] have shown that the volume of blood in the heart is a function of the output of the heart. This will, however, be counteracted to an unknown extent by the rise in the blood-pressure. -~~~~~~~~~~ Fig. 5. Arrangement of vascular system used for experiment described intext. A. Brachiocephalic artery. a. Superior vena cava. D. Inferior vena cava. E. Thoracic aorta. S. Stromuhr. B. Resistance on heart lung apparatus. B. Screw clamp on tube from reservoir of heart-lung apparatus to inferior vena cava. The clamps were applied at B and E. If this was the true explanation then the greater the diminution in the flow through the heart and lungs, consequent upon simultaneous occlusion of the thoracic aorta and i.v.c., the greater should be the transference of blood to the brachiocephalic artery, and the greater the rise in blood-pressure in and flow through that artery. This was then put to the test. The arrangement used is shown in Fig. 5. In the otherwise intact animal the peripheral parts of the heart-lung apparatus [Patterson and Starling, 1914] were substituted for the vessels connecting the thoracic aorta with the i.v.c. At the commencement of each observation in the series described below the blood-pressure was the same and was made so by adjustments of the resistance R. Since the arterial bloodpressure was constant, the flow through the brachiocephalic artery was

10 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. 289 always the same and was recorded by the stromuhr at the position S. The flow round the artificial circuit representing the body vessels could be set at any value by adjusting the screw clamp B. The pulmonary pressure was recorded. Starting in each case with as nearly the same conditions of blood-pressure and flow through the brachiocephalic artery, the tubes representing the thoracic aorta and i.v.c. were simultaneously clamped: (1) During a small flow round the artificial circuit. 80 c.c. per minute. Tracing 1. Fig. 6. (2) During a medium flow round the artificial circuit. 355 c.c. per minute. Tracing 2. Fig. 6. (3) During a large flow round the artificial circuit. 555 c.c. per minute. Tracing 3. Fig. 6. These tracings show that after occluding the artificial circuit at both ends: (1) The increase in the arterial blood-pressure, (2) The increase in the flow through the brachiocephalic artery, (3) The decrease in the pulmonary blood-pressure varied directly with the initial flow round the artificial circuit. The greater the flow round the artificial circuit, the greater was the diminution in the work of the heart and in the pulmonary flow when this circuit was occluded at both ends. Hence the greater the quantity of blood transferred to the brachiocephalic artery. In some experiments after the pressure in, and flow through, the brachiocephalic artery had been increased in the manner just described, blood was withdrawn from it (at the stromuhr S, Fig. 5) till the blood flow and blood-pressure fell to their initial values (which they did simultaneously). Thus in one observation the initial flow round the circuit representing the body was 675 c.c. per minute and after clamping this circuit of! the removal of 51 c.c. restored the blood flow and the blood-pressure to its initial value, in another observation an initial flow of 80 c.c. per minute necessitated the removal of 18 c.c. It is probable that these quantities represent approximately the quantities of blood which were transferred from the heart and lungs to the vessels of the brachiocephalic artery. In the experiment just described the animal's brain had been destroyed. Exactly comparable phenomena have been observed after simultaneous occlusion of the brachiocephalic artery and s.v.c.

11 290 H. BARCROFT. 7-

12 CARDIAC OUTPUT AND BLOOD DISTRIBUTION. 291 SUMMARY. 1. The systemic output of the heart has been measured in dogs with the mechanical stromuhr. 2. Complete occlusion of the thoracic aorta increases the systemic output after section of the vagi. 3. This is shown to be due to a transference of blood from the vessels supplied by the thoracic aorta to the remainder of the vascular system. 4. Simultaneous occlusion of the thoracic aorta and i.v.c. causes increase in the blood-pressure and in the flow through the brachiocephalic artery. 5. This is shown to be due to the transference of a quantity of blood from the cardio-pulmonary system to the remainder of the vascular system. I am very grateful to Prof. Barcroft and Dr Anrep for their help and criticism. REFERENCES. Barcroft, H. (1929). J. Phy8iol. 67, 402. Barcroft, J. and Florey, H. (1929). J. Physiol. 68, 181. Barcroft, J. and Stephens, J. G. (1927). J. Phy8iol. 64, 1. Burton-Opitz, R. (1921). Amer. J. Physiol. 58, 226. Daly, I. de B. (1928). J. Phy8iol. 65, 422. de Jager, S. (1886). J. Phy8iol. 7, 130. Gesell, R. (1926). Amer. J. Phy8iol. 79, 61. Krogh, A. (1912). Skand. Arch. Phy8iol. 27, 227. MacKeith, N. W., Pembrey, M. S., Spurrell, W. R., Warner, E. C. and Westlake, H. J. W. J. (1921). Proc. Roy. Soc. B, 95, 413. Patterson, S. W., Piper, H. and Starling, E. H. (1914). J. Physiol. 48, 465. Patterson, S. W. and Starling, E. H. (1914). J. Phy8iol. 48, 357. Rein, H. (1928). Z. Biol. 87, 394. Tigerstedt, C. (1909). Skand. Arch. Phy8iol. 22, 120.