11 6I2. I34. I CERTAIN EFFECTS OF PULMONARY GAS EMBOLISM BY INDERJIT SINGH (From the Physiological Laboratory, Cambridge, and the Medical College, Rangoon University) (Received December 9, 1935) DUNN [1920], working with Barcroft, showed that a considerable proportion of the pulmonary vessels could be blocked without diminution in the blood flow through the lungs. Torracca [1922] briefly described the morbid anatomical findings after the intravenous injection of considerable quantities of oxygen to guinea-pigs. Binger, Brow and Branch [1924a, b] studied the cause of the respiratory disturbances produced during pulmonary embolism, while B arry [1929] investigated the electrocardiographic and respiratory changes in pulmonary gas embolism. The present experiments are in continuation of work on the intravenous injection of oxygen [Singh, 1935], certain of the effects of pulmonary gas embolism being studied in detail. EFFECT ON CIRCULATION (a) Cardiac output. This was determined on three urethanized cats by Henderson's cardiometric method. The calibration was done with a syringe [Barcroft, 1934] worked at the same frequency as the heart. The effects on the stroke volume, the pulse rate and the resultant cardiac output are given in Figs. 1-3. Figs. 1 and 2 show a fall in cardiac output followed by a rise. Fig. 3 shows a rise without a preceding fall. Later the cardiac output may return to the original value (Figs. 1 and 3) or may continue to be raised (Fig. 2). The preliminary fall in cardiac output is associated with a rise of venous pressure and therefore appears to be due to blocking of pulmonary vessels. The subsequent increase in blood flow is presumably due to opening of other vessels and may be regarded as compensatory in character. But it takes place whether or not there is a preliminary decrease. The preliminary decrease cannot therefore be
12 I. SINGH regarded as a necessary cause of the subsequent dilatation, and some other cause must be sought; this cause might be a reflex originated by the emboli themselves. Period of injection Time in min. Fig. 1. Effects of injection of air, 1 c.c. per min.; weight of cat 1650 g. (b) Systemic arterial blood-pressure. This shows variations parallel with those of the cardiac output. There is usually a fall of blood-pressure followed by a rise, which may or may not persist. The factor which determines the general blood-pressure seems to be the cardiac output. Most of the changes are determined purely by mechanical considerations, a fall followed by a rise of blood-pressure being also produced if the
EFFECTS OF PULMONARY GAS EMBOLISM pulmonary capillaries are occluded by raising the intra-alveolar pressure [Sharpey-Schafer, 1933]. (c) Pulmonary circulation. The blood-pressure in the pulmonary artery is raised in cats and dogs, and in the former even if 1 c.c. of air is 124- I I I I I I I Stroke volume of heart in c.c 13 I*16 80 Cardiac output in c.c. per min. Pulse-ate 68-64- 1. 4 5 6 7 8 9 10 Period of injection Time in mn. Fig. 2. Effects of injection of air, 1*5 c.c. per min.; weight of cat 1690 g. injected. The increase is due to blockage of the pulmonary arterioles and to the increased cardiac output resulting from pulmonary embolism. Compensatory dilatation of the blood vessels in the lungs occurs, due partly to rise in pulmonary blood-pressure and the increased output of the heart. Mild asphyxial convulsions were produced in three decapitated cats by partial occlusion of the pulmonary capillaries brought about by
14 I. SINGH raising the intra-alveolar pressure [Sharpey-Schafer and Bain, 1933]. Embolism was then produced and the asphyxial convulsions ceased because the resulting stimulation of the heart overcame the increased intra-alveolar pressure. The compensation thus produced overshot the requirements of the body, for if a certain dose of oxygen or air produced asphyxial convulsions, a larger dose did not do so after compensation Period of injection Time in min. Fig. 3. Effects of injection of air, 2 c.c. per min.; weight of cat 1650 g. had been established (Table I). These experiments show that a considerable number of pulmonary arterioles may be blocked without any diminution in the pulmonary blood flow, as found by Dunn [1920] and Elaggart and Walker [1923]. The accelerated circulation through the lungs after embolism may explain certain phenomena which have been noted clinically by some observers and refuted theoretically by others. Tunnicliffe and Stebbing in 1916 gave small quantities of oxygen intravenously to three patients. They reported the presence of a churning sound over the precordium and state that the clinical condition was improved in two
EFFECTS OF PULMONARY GAS EMBOLISM 15 TABLE I Amount of oxygen No. of injected in 10 min. observation c.c. Convulsions 1 5 Absent 2 6 Present 3 7 Absent 4 8 Absent 5 9 Present 6 10 Present 7 11 Present 8 12 Present and death cases. The amount given (10-20 c.c. per min. for periods of 10-15 min. separated by pauses of 2-3 min.) could have had very little effect in raising the oxygen content of the arterial blood, the normal oxygen requirement for an adult being about 250-300 c.c. per min. The improvement must have been brought about by circulatory acceleration owing to the presence of bubbles in the lungs. Similar phenomena in patients receiving intravenous oxygen [East and Bain, 1931] were probably due to the same cause. EFFECT ON PULMONARY GASEOUS EXCHANGE AND METABOLIC RATE The oxygen consumption of six decapitated cats was measured before, during and after the production of embolism, using the method described by Singh [1932, 1934]. The results are shown in Table II. During the TABLE II Oxygen consumption per 10 min. (c.c.) Wt. of Before injection During After injection cat in,- injec-, -A No. g. 1 2 3 tion 1 2 3 4 5 6 1 1600 112 113 112 103 121 113 112 112-2 1600 113 113 113 96 130 121 117 113 113 112 3 1450 124 126 124 109 143 132 128 124 124 124 4 2000 126 124 122 105 139 128 114 112 112 5 2000 112 114 112 84 131 123 118 112 111 112 6 2650 195 196 194 207 211 200 196 193 193 191 Temperature 260 C. Pressure 760 mm. Hg. Dose of oxygen injected = 10 c.c. in 10 min. period of injection there is a sharp decline in the oxygen respired through the lungs, due to the blockage of blood vessels with gas emboli. As redistribution of blood takes place, owing to compensatory dilatation and opening up of other blood vessels, the oxygen consumption rises considerably but soon returns to the value before the injection. If the metabolism was declining previous to the injection, then the necessary correction has to be made [Singh, 1932, 1934]. During the injection, as
16 I. SINGH the pulmonary vessels are blocked, an oxygen debt is incurred and is repaid when the vascular compensation takes place. The repayment takes place in two stages, a rapid and a slow one. The seat of blockage seems to be the arterioles and not the capillaries, as any gas present in the latter would easily diffuse out into the alveoli. The metabolic rate shows a rise of about 5 p.c. In calculating the effect on metabolism, the fluctuations in gaseous exchange produced by the occlusion of the pulmonary vessels have to be taken into account. The effects on oxygen consumption are shown in Table II. Cat No. 2 consumed 12 c.c. in excess of what was required to repay the debt set up during the period of injection. The same is noted in other experiments. In cat No. 6 there was no decline as is usually produced by embolism, but the oxygen consumption rose from 194 c.c. per 10 min. before to 207 c.c. in the 10-min. period of injection and 211 c.c. in the subsequent observation. Here the rise in metabolism had overshadowed the decline due to pulmonary obstruction. From the above it is obvious that figures representing oxygen consumption in a cat during embolism are the algebraical sum of changes produced by a rising metabolism, a diminished gas exchange due to pulmonary obstruction and the repayment of oxygen debt when compensation has been established. The first and the last tend to raise the figure while the second tends to lower it. During the period of the injection, these factors may produce a decline in the oxygen consumption greater than, less than, or equal to the quantity of oxygen injected. The subsequent observation will show a rise compared with that obtained before the injection, thus indicating embolism. A minor degree of embolism may produce no change in the oxygen consumption, dilatation of blood vessels proceeding pari passu with obstruction, thus producing no oxygen debt and no rise in metabolism. EFFECT ON RESPIRATION Bronchial spasm. Dunn [1920] from histological sections hadobserved irregular narrowing of the lumina of the bronchioles due to local thickening of the musculature. This was also observed by Binger, Brow and Branch [1924a] in lungs of embolized as well as normal dogs. They concluded that such findings do not prove the presence of bronchial spasm during embolism. An experiment on a pithed cat was therefore carried out to determine directly the existence of any spasm. Using the Dixon- Brodie oncometric method the changes in lung volume during artificial respiration were recorded. The result is shown in Fig. 4. The spasm was temporary. It was less after 0-2 mg. of atropine in 1 c.c. of saline in-
EFFECTS OF PULMONARY GAS EMBOLISM travenously and was immediately abolished by 1 c.c. of 1/10,000 adrenaline. Binger, Brow and Branch, from measurement of the residual air, found reduction in lung volume, but ascribed it as due to hypostasis, aedema and swelling of the capillaries. But the diminution in lung volume as measured by the Dixon-Brodie oncometric method comes on almost immediately after the embolism is produced, the time being too short for such vascular complications as mentioned above. It was shown that adrenaline increases the blood flow through the lungs and 17 m!~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~4 Fig. 4. Lung volume. A. Bronchial spasm mn a cat produced by injecting 8 c.c. of air at the rate of 2 c.c. per min. B. Spasm still occurs after 0-2 mg. of atropine intravenously. C. Spasm is relieved immediately by 1 c.c. of 1/10,000 adrenaline intravenously. Time in seconds. adr =adrenaline. this retards their exrpansion during respiration [Dixon and Ransom, 1914], s0 that if the diminution in lung volume be due to the presence of vascular complications, it should be aggravated rather than relieved by adrenaline. The action of this drug proves that a genuine spasm of the bronchial musculature occurs. The spasm is independent of any reflex through the vagus from the medulla, as the latter was destroyed before the exrperiment. It is also independent of any local axcon reflexr through the vagus, since it is still well defined when the vagus endings are paralysed by atropine. This spasm resembles the one produced by inhalation of volatile substances described by Dixon and Ransom [1921] and poisonous gases [Dunn, 1920]. PH. Lxx2x2VII. 2
18 I. SINGH Effect on respiratory movements. The effect on the frequency and amplitude of the respiratory movements is variable. Both the frequency and amplitude may diminish, resulting in apnoea with standstill either in inspiration or midway between inspiration and expiration. As the apncea persists, gasping movements are superadded. The apncea is relieved immediately on cutting the vagi. The frequency may be increased without any change in amplitude or, with an increase in frequency, the amplitude may be increased or diminished. All these changes in the respiratory movements are abolished if the vagi are cut. From this Dunn [1920] concluded that the presence of emboli in some way interfered with the Hering-Breuer reflex, and section of the vagi blocked certain afferent peripheral impulses initiated by the presence of starch Euemboli. Binger, Brow and Branch [1924a] showed that Fig. 5. Rapid shallow breathing produced by stimulating central end of cut vagus. (Stimulated between signals.) vagotomy slows the tachypncea of central origin, and such slowing does not necessarily imply the blocking of afferent irritative impulses, hence the slowing produced by starch tachypncea cannot be used as evidence for the existence of such impulses. That the respiratory changes as a result of pulmonary embolism are produced by afferent impulses in the vagi can be shown by the fact that most of them can be elicited if the central end of a cut vagus is stimulated electrically. Thus apnoea can be reproduced, as shown by the classical experiment of Head, by stimulation of the central end of the cut vagus. Rapid shallow breathing-such as may result from embolism (Fig. 8 B)-can be reproduced in a similar manner (Fig. 5). This indicates that the respiratory changes in embolism are producedby afferent impulses due to stimulation of the vagal terminations in the lungs. ACTION OF ADRENALINE The three principal results of pulmonary gas embolism are the reduction in the quantity of oxygen respired leading to asphyxia, bronchial spasm and disordered respiration. Various drugs were tried to
EFFECTS OF PULMONARY GAS EMBOLISM counteract these effects, and it was found that adrenaline affected all three. (a) Effect on asphyxia. When embolism is produced, the quantity of oxygen respired by the animal diminishes. This diminution is not due to a decline in metabolism per se, but to pulmonary blockage, as is evident from Table II. It was mentioned above that one of the factors in bringing about compensatory dilatation of blood vessels after embolism is the increase in the pulmonary blood-pressure. It is therefore probable that anything that increases the latter will tend to increase the compensatory dilatation of the pulmonary blood vessels. The asphyxia will also be relieved if more blood circulates in unit time owing to an increase in the output of the heart. Since adrenaline raises the pulmonary blood-pressure [Sharpey-Schafer, 1933] and also stimulates the heart, it was administered to three cats after producing so great a blockage of the pulmonary vessels that no more compensation occurred. The results of an experiment are shown in Fig. 6. Adrenaline immediately raised the amount of oxygen respired but the effect was only temporary, as the action of the drug is temporary. But the amount of oxygen respired after adrenaline may continue greater than before its administration, showing either that it accentuates the vascular compensation in embolism or that it drives the gas embpli through the arterioles into the lung capillaries. It is doubtful if the gas ever escapes into the systemic circulation, as it would diffuse out into the alveoli when it reaches the capillaries of the lungs. After adrenaline, a greater quantity of gas can be injected without apparently producing any effect on the oxygen respired, and a larger dose of gas than usual is required to bring about an equivalent reduction. It would be expected that, after all the blood vessels of the lungs are dilated to their maximum capacity, blockage of some of them would not be succeeded by any compensatory phenomena as described above. Thus a cat whose oxygen consumption was 124 c.c. in 10 min. had it reduced to 85 c.c. by injecting oxygen. This was followed by the usual compensatory phenomena, and the oxygen consumption was restored to its original value. After adrenaline a reduction to 85 c.c. was followed by death. This would have a bearing in certain inflammatory diseases of the lungs, wherein there would be inflammatory dilatation of blood vessels so that embolism would be less completely compensated than if the lungs were not inflamed. The increase in metabolism due to adrenaline may counteract the advantage gained by the increased compensation it produces. The animal may be asphyxiated on injection of adrenaline so that it is thrown into 2-2 19
20 I. SINGH convulsions. This action is only temporary. In embolism of the lungs the oxygen respirated by an animal may be diminished to such an extent that the animal lies just on the verge of a convulsive attack. Increase in metabolism will now result in metabolic asphyxia, so that the injection of adrenaline will produce convulsions, as the latter raises the metabolism. (P İ 6 6., 170-8- 0 0 0...I g 140-80- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 30 60 90 120 150 Time in min. -%I I JV. ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Fig. 6. Relief of embolic asphyxia by adrenaline. 1, 2, 3. Normal 02 consumption. 4. Result of embolism; 02 injected at the rate of 1-5 c.c. per min. 5. Repayment of oxygen debt. 6. Result of embolism of a greater degree than 4. 7. Shows lack of compensation. 8. Result of adrenaline 1 c.c. 1/10,000; 02 consumption rises to normal. 9. Effect of adrenaline passes off. 10, 11, 12. Level of 02 consumption higher than 6and 7, showing permanent benefit by adrenaline. 13. Effect ofembolism. 14. Showing lack of compensation. 15. Effect of adrenaline. 16. Effect of adrenaline passes off. Cat dies. (b) Effect on disordered respiration. Adrenaline in cats, dogs and rabbits produces effects opposite to those produced by embolism. Thus if the frequency and amplitude of respiration be increased as a result of embolism, adrenaline decreases them (Fig. 7). The effect of adrenaline may be transient or permanent, the permanent action probably being due as already stated to removal of the emboli from the arterioles. If the frequency is increased with diminished amplitude, adrenaline restores
EFFECTS OF PULMONARY GAS EMBOLISM -21 the normal respiration though the frequency may be slightly greater than before embolism (Fig. 8). Apncea produced by embolism is immediately relieved by adrenaline (Fig. 9). In high concentrations (1 in 1000) Fig. 7. A. Normal respiration (cat). B. Effect of pulmonary embolism; tracing about half a minute after injection. C. Effect of 0-5 c.c. of 1/10,000 adrenaline intraveno.usly. (Respiration recorded by means of a tambour connected with another tambour with a piece of cork on its diaphragm pressing in the intercostal angle.) Adrenaline acts almost immediately. Fig. 8. A. Normal respiration (dog). B. Effect of pulmonary embolism; tracing about half a minute after injection. C. Effect of 1 c.c. of 1/10,000 adrenaline intravenously. (Respiration recorded by a lever connected to a pin in the intercostal angle by means of a string over the pulley.) Adrenaline acts almost immediately. Fig. 9. Apncea produced by pulmonary embolism is relieved by adrenaline 1 c.c. 1/10,000. Adrenaline injected at signal. adrenaline may produce apncea temporarily before the above effects are manifest. Mellanby and Huggett [1923] found that adrenaline abolishes the dyspnoea produced by oxygen want and excess of CO2.
22 1. SINGH Occasionally adrenaline may aggravate temporarily the embolic effects on respiration. This is probably due to increasea friction between the emboli and blood vessels owing to rise in pulmonary blood-pressure. SUMMARY AND CONCLUSIONS 1. A minor degree of pulmonary gas embolism accelerates the circulation. 2. Oxygen consumption is diminished during the period of blockage, but exceeds and then returns to the normal when vascular compensation occurs. During the period of blockage oxygen debt is set up which is repaid subsequently. 3. Metabolism is increased by about 5 p.c. by pulmonary embolism. 4. Adrenaline relieves embolic asphyxia, spasm and disordered respiration, but this effect may be counteracted by the increase in metabolic rate due to the adrenaline. In conclusion I wish to thank Prof Sir Joseph Barcroft for criticism and advice. REFERENCES Barcroft, J., Flexner, L. B. and McClurkin, T. (1934). J. Phy8il. 82, 498. Barry, D. T. (1929). C. R. Soc. Biol., Paris, 101, 123. Binger, C. A. L., Brow, G. L. and Branch, A. (1924a). J. Clin. Invest. 1, 127. Binger, C. A. L., Brow, G. L. and Branch, A. (1924b). Ibid. 1, 155. Bourne, G. and Smith, R. G. (1927). Amer. J. Phy8iol. 83, 329. Dixon, W. E. and Ransom, F. (1914). J. Pharmacol., Baltimore, 5, 539. Dixon, W. E. and Ransom, F. (1921). J. Phy8iol. 54, 384. Dunn, J. S. (1920). Quart. J. exp. Med. 13, 129. East, C. F. T. and Bain, C. W. C. (1931). Recent Advancem in Cardiology, p. 203, 2nd ed. London. Haggart, G. E. and Walker, A. M. (1923). Arch. Surg. 6, 674. Mellanby, J. and Huggett, A. St G. (1923). J. Phy8iol. 57, 395. Schafer, E. A. (1916). Endocrine Organ8, p. 58. London. Sharpey-Schafer, E. (1933). Quart. J. exp. Phy8iol. 22, 95. Sharpey-Schafer, E. and Bain, W. (1933). Ibid. 22, 101. Singh, I. (1932). Ibid. 22, 193. Singh, I. (1934). Ibid. 23, 45. Singh, I. (1935). J. Phy8iol. 84, 315. Torracca (1922). Reform. Med. 38, 985. (Quoted by Bourne and Smith (1927), Amer. J. Physiol. 83, 329.) Tunnicliffe, F. W. and Stebbing, G. F. (1916). Lancet, 2, 321.