sigmoid curve was obtained by plotting the fall of blood-pressure rapid fall of blood-pressure after a quick i.v. injection was followed

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1 : : THE INFLUENCE OF SODIUM EVIPAN ON THE HEART AND CIRCULATION. By S. C. DAS. From the Department of Pharmacology, University of Edinburgh. (Received for publication 8th May 1941.) AMONGST the barbiturates, sodium evipan is very widely used and has gained popularity as an intravenous anesthetic. Kennedy and Narayana [1935] obtained with evipan a fall of blood-pressure in cats. Bor and Storm [1935] reported that 25 mg./kg. of evipan caused anesthesia in monkeys, but did not affect cardiac activity and bloodpressure if injected slowly. Tournade and Joltrain [1936] obtained a fall of blood-pressure after evipan and also studied the factors concerned in its production. Stanley-Nowak [1938], from his study of vasomotor and aortic sinus reflexes in dogs, concluded that evipan had "no depressing effect on blood-pressure." In view of the importance of the subject, a detailed study of the effect of evipan on heart and circulation was undertaken to clear these differences of opinion. Cats under ether and chloralose aneesthesia were mainly used for these experiments; decerebrate and decapitate animals were also used. The intravenous injection of evipan produced a fall of bloodpressure in every case. The extent of the fall varied with the initial pressure: the higher this pressure, the greater being the fall. The effects of a wide range of dosage were measured in one group of experiments. Different animals differed in sensitiveness, but in all cases a sigmoid curve was obtained by plotting the fall of blood-pressure (in mm.) against the logs of the doses (mg./kg.) used (fig. 1). The rapid fall of blood-pressure after a quick i.v. injection was followed by a slow recovery. In cases where fairly large doses were repeated several times, the blood-pressure after recovery failed to reach the original level. Vogt [1930] reported similar experience in her experiments with veronal in cats. The effects of different rates of injection were next studied. The same quantity produced less fall of blood-pressure if injected in divided doses at short intervals of a few seconds than when given in one dose. A slow continuous injection of more than 1 mg./kg. per minute produced a slow and steadily increasing fall of blood-pressure, but the maximum fall caused by the total quantity given in this way was much less than if given by single or interrupted injections. A continuous 103

2 104 Das infusion avoids a high concentration of the drug caused by a single big injection and hence produces decidedly less depressant effect. An intra-arterial injection also avoids a sudden excess of the drug on the heart, and it was found that when injected into the femoral artery the effect produced was similar to that produced by slow intravenous injection, namely, a slow fall of blood-pressure followed by a still slower recovery. Intra-arterial injections introduce another factor 83. p? 410,, A,s.-c 30 / J0 /12 14 Le9. ciose o' Ev/p9a(n y//7 ) FiG. 1.-Relation between log. dose sodium evipan in mg./kg. (abscissa) and fall of blood-pressure (mm. Hg) in cats (ordinate). A, B, and C are curves obtained in three different animals. -the probable loss by diffusion or destruction of some of the drug before it reaches the general circulation. The effect of injection into portal vein was also tried and found to be less than when injected into the systemic vein. This was partly due to dilution of the drug in the liver and partly to detoxication in the liver. Results of similar nature were obtained by continuous injection into the portal vein and the aorta. The next group of experiments were directed towards the analysis of the cause of fall of blood-pressure. That the fall of blood-pressure after evipan was not due to the ph of the solution was shown by the fact that Ringer's solution buffered to the same ph as the evipan solution did not cause a fall, whereas even 2-0 mg./kg. of evipan dissolved in the same quantity of fluid caused an appreciable fall of blood-pressure. Kennedy and Narayana [1935] stated that they did not observe vagal depression after evipan, but Tournade and Joltrain [1936]

3 The Influence of Sodium Evipan on the Heart and Circulation 105 reported diminished vagal activity after evipan, as vagal stimulation produced less slowing of heart's rate after evipan than before it. The author found that vagal stimulation produced less fall of blood-pressure after evipan than before it, thus confirming Tournade and Joltrain's finding. Stanley-Nowak [1934] reported suppression of the carotid sinus reflex by numal, pernocton, and evipan. The carotid sinus reflex was found by the author to be depressed after evipan, but even after a dose of 20 mg./kg. it was not completely suppressed. Tournade and Joltrain [1936] recorded the effects of splanchnic stimulation on kidney volume and- observed paresis of peripheral vasomotor apparatus after evipan. The author also obtained similar evidence of weakening of vasomotor activity after evipan by comparing the pressor response obtained before and after evipan, when stimuli of same intensity were given to the sciatic nerve exposed and placed on the shielded electrodes of a secondary coil. The effect on blood-vessels was determined by perfusion of a leg in situ with the animal's own blood. Dixon's pump, as adopted by Robson and Schild [1938], was used with heparin as anticoagulant. The venous outflow was not interfered with. Blood from the central end of the femoral artery was delivered into the perfusion apparatus which rhythmically pumped it onwards into the peripheral end of the artery, thus resembling the natural pumping of the heart, which it substituted with the advantage that it eliminated the depressant action of the drug on the heart that would diminish the peripheral arterial pressure. Carotid pressure was recorded as well as the perfusion pressure. After the perfusion pressure ran steady for some time, 10 mg./kg. of evipan was injected into the femoral vein of the other leg. This caused a fall of the systemic pressure as usual, and also a fall in the perfusion pressure. The rate and force of the pump being constant, a fall in the perfusion pressure indicated vasodilatation. After section of the sciatic and femoral nerves of the perfused leg, the same dose produced less fall of the perfusion pressure. The fall in this latter case was a measure of the direct vasodilatation, whereas the greater fall before section of the nerves represented the combined effects of depression of vasomotor tonus and direct vasodilator effect (fig. 2 (I) and (II)). Direct vasodilatation was also observed on adding evipan to a closed-circuit perfusion, the venous outflow of the perfused leg feeding the perfusion apparatus (fig. 2 (III)). The evidence of this direct vasodilatation effect of evipan is in keeping with Lepper's observation [1924] on the effect of veronal on the perfused isolated rabbit's ear. Kennedy and Narayana [1935] perfused the isolated frog's heart with evipan and reported that 1 in 4000 of evipan reduced the contractions by 10 per cent., whilst 1 in 1000 caused complete inhibition. Sodium evipan has a higher ph value than frog's Ringer. and unless

4 106 Das the evipan solution is buffered to the same ph as frog's Ringer the results cannot be relied on. These authors did not state whether they brought their evipan solution to the correct ph. The author measured the effects of evipan on frog's heart. The evipan solution was buffered to the same ph as frog's Ringer and each concentration was allowed sufficient time to develop its maximum effect. On the auricle strip of the frog, a concentration of 1 in 100,000 of evipan produced no appreciable change, 1 in 50,000 produced about F1G. 2. Perfusion of femnorl artery of eat's leg in situ. BP = blood-pressuire an(l PP perftusiorn preslire. A =iinj( tion into feniornal veiln of so(diiiiii xvipan (10 ing.!kg.). B an(il C injection inito perfused arter-y of 0O3 c.c. saline anird 10 mng.,kg. soclitinu evipan in O03 cc.. saline respectixvely. Time: I (.uirn. =90 sees. I. Sciatic an(d feriioral nerves of perftuse(d leg intact. Vaso(lilatation prodtuced by injection as indicate(d by the fall in perfusion pressure. II. Sciatic and(i feinoral nerves of perfuse(d leg cut. The fall in perfusion pressuire is reditced. IIT. The ev-ipan injection cauises a slhort initial rise, probably due to the fluid intro(tice(l and(i tlis is followed by vaso-dilatation. 10 per cent. inhibition, 1 in 20,000 about 20 to 25 per cent., 1 in 10,000 about 40 per cent., 1 in 500()0 about (Go per cent., anid 1 in 2000 about 95 to 100 per cent. inhibition. Recovery followted washouts if not lelayed too long. A range of 25 to 30) times increase in concentration was thus necessary to cause from just appreciable inhibition to complete inhibition. If the percentages of depression are plotted against the logs of the concentrations, an S-shaped curve is obtained (fig. 3). Tournade and Joltrain [1936] made plethysmographic measuremnents of the dog's heart. They found that evipan produced dilatation and incomplete contraction, and also obtained evidence of toxic and fatigue effect. The author studied the effects of evipan on the cat's heart, and used the Cushny-myocardiograph to record auricular and

5 The Influence of Sodium Evipan on the Heart and Circulation 107 ventricular contractions simultaneously with the carotid pressure. :Moderate doses produced marked depressant effects on auricular and /UJr 80F 0 0 2c 'Z, Fia. 3. Relation betxween log. concentration of sodium evipan (abscissa) and per cent. depressioni of contraction of frog's isolated aturicle strip (ordiinate). I Fia. 4. Action of intravenous evipan ontl cat's heart in sitzt. Myocardiographic recor(ls of aturicle (A) and venitricle (V); blood-pressure (C). Intravenous sodium evipan, 2 mg./kg. at 2, 5 mg./kg. at 5. Tracings I. and 11. from different cats. Timne: 1 cmn. = 2 min. ventricular contractions. Even a dose of 2 mg./kg. which was only just sufficient to cause an appreciable effect on carotid pressure, produced an appreciable diminution of the auricular contraction (fig. 4).

6 108 Das This shows that the cardiac factor contributes towards the fall of blood-pressure not only in the case of large and toxic doses (as pointed FIG. 5. Effects on heart and blood-pressure of bleeding and of intravenous evipan. A and V: Myocardiographic records of auricle and ventricle. B.P.: bloodpressure. Time: 1 cm. =2 min. I. Rapid bleeding of 5 c.c./kg. (cat i, 3 kg. B.W.). II. Rapid bleeding of 5 c.c./kg. ((at ii, 3-5 kg. B.W.). III. and IV. Intravenous injection of sodium evipan into cat ii. 10 mg./kg. and 40 mg./kg. respectively. The latter injection produced death. FIG. 6. Transient nat,ure of action of evipan on cat's heart. Records as in fig. 5). Time: 1 cm. = 2 min. I., II., and III. Injections of sodium evipan 10, 20, and 30 mg./kg. respectively. The animal had previously received several doses of sodium evipan. out by Vogt [1930] in the case of veronal), but also in cases of small doses of evipan. That the diminution of contraction of the auricle and the ventricle after evipan was a contributory factor towards the production of fall

7 The Influence of Sodium Evipan on the Heart and Circulation 109 of blood-pressure, and was not simply an effect of the fall of bloodpressure brought on by other causes, was proved by showing that a well-defined fall of blood-pressure caused by drawing about 15 c.c. of blood from a femoral artery did not affect auricular or ventricular contraction, whereas a dose of evipan producing a much smaller fall of blood-pressure caused definite depression of auricle and ventricle (fig. 5). The depressant effect of evipan was observed to be more marked on the auricle than on the ventricle. By repeating large doses of evipan several times, during an experiment, complete inhibition of the auricle and extreme depression of the ventricle were obtained, but whereas the ventricle slowly recovered, the auricle paralysis persisted (fig. 6). DIscusSION. Different factors co-operate in the production of the fall of bloodpressure by evipan and other barbiturates. Most workers agree that vasodilatation is an important factor, and some believe vasomotor paresis to be the chief contributory cause. There is also a direct dilator effect on the blood-vessels, as demonstrated by the perfusion experiments. According to Vogt, the cardiac factor comes into play only in cases of severe depression from large doses. It appears that proper consideration has not been given to the part played by the heart in the production of the fall of blood-pressure, probably owing to paucity of accurate quantitative data. Tournade and Joltrain relied on the information given by Kennedy and Narayana, whose method, as already stated, was defective, but the author's experiments show that moderate doses of evipan produce a direct depressant action on the mammal's heart. The usual human dosage of sodium evipan is 3 c.c. of 10 per cent. solution given quickly, followed by a further 5 c.c. to complete the induction. These quantities correspond respectively to 4 mg./kg. and 10 mg./kg. for an 80 kg. individual. These doses in the cat produce a well-marked depression of auricular and ventricular contractions. If the blood volume of man be taken as 10 per cent. of the body weight, the doses mentioned will produce concentrations in the blood in the heart of at least 1 in 10,000 and 1 in 25,000. These concentrations produce respectively 40 and 15 per cent. depression of the isolated frog's auricle. The experiments on both the isolated frog's auricle and the intact mammal agree therefore in showing that sodium evipan in therapeutic doses can produce direct cardiac depression. It is well known that a large dose of evipan rapidly injected intravenously may lead to respiratory arrest. Apart from the risk of respiratory depression, there is also a sudden though short-lived severe circulatory depression, following such rapid administration of evipan

8 110 The Influence of Sodium Evipan on the Heart and Circulation and this probably co-operates with respiratory failure in producing a fatal ending in cases of sudden deaths immediately after a big dose of evipan quickly administered. SUMMARY. 1. Intravenous injection of sodium evipan always causes a fall of blood-pressure. This fall is not due to the reaction of the solution, but is partly due to vasodilation and partly to cardiac depression. 2. Perfusion of cat's leg in situ gives evidence of direct vasodilatation as well as of vasomotor depression. 3. Auricle strip of frog shows 10 per cent. depression with 1 in 50,000 of evipan, 25 per cent. with 1 in 20,000, 40 per cent. with 1 in 10,000, 60 per cent. with 1 in 5000, and 95 to 100 per cent. with 1 in 2000 concentration. 4. Myocardiographic record of cat's heart in situ indicates auricular and ventricular depression even with small doses of evipan, showing that the cardiac factor plays a definite part in causing a fall of bloodpressure. 5. This depressant effect on circulatory system can be minimised to a great extent by giving the dose in fractions at short intervals, and still better by continuous intravenous infusion. The author gratefully acknowledges his indebtedness to Professor A. J. Clark for his advice and help throughout the course of his work. REFERENCES. BOR, A. H., and STORM, C. J. (1935). Trans. Far-East. Ass. trop. Med. 11, 675. KENNEDY, W. P., and NARAYANA, B. (1935). Quart. J. exp. Physiol. 24, 69. LEPPER, L. (1924). Pfluigers Arch. 204, 498. ROBSON, J., and SCHILD, H. 0. (1938). J. Phsiol. 92, 9. STANLEY-NOWAK, J. G. (1934). C.R. Soc. Biol. 116, 642. STANLEY-NOWAK, J. G. (1938). Arch. int. Pharmacodyn. 60, 118. TOURNADE, A., and JOLTRAIN, E. (1935). C.R. Soc. Biol. 119, 240. TOURNADE, A., and JOLTRAIN, E. (1936). Ancesth. Anaig. 2, 290. VOGT, M. (1930). Arch. exp. Path. Pharm. 152, 341.