The action of drugs on cardiac output

630

TTIE

AI\IERI('AS

HEART

JOCRNAL

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Glyke, D. D., rind Ncill, J. M.: Tile Determination of Bases in Blood and Other Solution8 by Vacuum Extraction and Manometrie Measurement, Jour. Biol. Chem., 1924, lxi, 523. sBlnlock, A. : A Rubber Mask for the Determination of the Oxwen Consumution 1 of’the Dog, Jour. Lab. and Clin. Med., 1927, xii, 378. “l”Blaloek, Alfred: Personal communication. llHiggin8 and Mean8 : The Effects of Certain Drugs on the Respirations and Gaseous Metabolism in Normal Human Subjects, Jour. Pharm. and Exper. Therap., 1915, vii, 1. 1Vushny : On the Pharmacology of the Respiratory Center, Jour. Pharm. and Exper. Therap., 1913, iv, 363. IsBinz : Arch. Extwr. Path. and Pharm.. 1SiS. ix. 31. l*Heintz: Inaug. hiss., Bonn, 1890. ’ ’ 1~~Imperes : Arch. internat. de Pharm. et de Theran.. 1899. ri. l-19. 1INewburgh: The Use of Strychnine and Caffeine 18 Car&o-, Arch. Int. Mwl., 1914, sir, 769.

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JI.D.,

TINSLEY

CARDIAC

CHARLES

RANDOLPH I\~ABHVILLE,

OUTPUT C)UTPUT

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DOGS”

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IIARRISON,

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M.D.

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I

T Id our belief that the n1inut.e cardiac out,put. accurately determined, affords an excellent standard by which t,he condition of the circulatory mechanism as a whole may be judged, as well as a relative index for the work of the heart. Elalockl has shown that the cardiac output changes in response to hemorrhage before the pulse rate and before the mean blood pressure. We have found it a delicate indicator which may respond rapidly to such drugs and physiological conditions as protluce less striking changes in the many other factors by which the &rculat.ion has been studied. Hence, we have chosen to study some of the drugs whose act.ion (or, in some cases, supposed act,ion) on the circulation is responsible for their therapeutic use. A number of these investigations hare been reportecl. The present paper deals with the eft’ect of epinq~hrin. It has been shown by many workers and is generally accepted that epinephrin, by its action on t.he sympathetic nerve endings, causes vasoconstriction (and hence a rise in blood pressure) and cardiac acceleration. Further, it is known that the drug is rapidly oxidized in the bocly and t.hat, therefore, its effect is of very short cluration. These *From

the

Department

of Medicine,

Vanderbilt

Universit>-.

Nashville.

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views are expressed by Sollmannz after thorough review of the literature. Little work has been done, however, on the etYect of t.he drug on the cardiac output. Odaira3 found that “small doses” (0.03-0.15 mg. per kg.) increased cardiac output and oxygen consumption, that “large doses ’ ’ (over 0.15 mg. per kg.) decreased both, and that “intermediate closes ” had no effect. It is worthy of remark that Odaira’s smallest dose (0.03 mg. per kg.) is equivalent to a very large therapeutic dose (2.1 cc. of a %ooo solution for a man weighing 154 pounds), and that this dose and those in its immediate vicinity caused an increase in cardiac output. Lyon and Sands,4 using. the method of Davies and Meakins,j dcmonstrated an increased cardiac outnut in man following the administra-

t,ion of epinephrin, and Smith, Miller and Gr’aber,” studying the coronary flow in perfused rabbits’ hearts, found a decreased flow with a concentration of the drug of 1 to 200,000,000 but an increased flow with higher concentrations. METllOD

All t.he csl)erimcnts here rcljorted were done on trained, unnarcotized male dogs. Cardiac output leas determined by the Fick principle as described in previous papers.7 In all experiments, one or more cont,rol determinations were done after the animal had been on the table thirty minutes or longer. Epinephrin” was then given, intravenously in some experiments, subcutaneously in others. In all but t.wo of the former group, another determination was done within one t.o three minutes of the injection; in the latt.er, fifteen minutes were allowed to elapse *Adrenalin

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(Parke-Davis)

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in all

experiments.

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beforr the next. tleternlinatioll. Vurther observations were then made to study the duration of the drug’s (affect. In all except two experiments the dose used was 0.05 mg. per kg. of hod>- weight. In these two, 0.025 nig. per kg. werC given iiitra~enousl~. In all, twenty experiments were done on six trained dogs. Three of these experiments were discarded on account of failure t.o obtain duplicate conbrol determinations or because the animals struggled. RESULTS

A. Intravemus ild),lilristl.ation.-In the four experiments in which determinations were done immediately after the drug was given, the cardiac output. was increased 59 per cent and 27 per cent respectiTrely 60 33

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following a dose of 0.05 nlg. per kg. and 15 per cent in two experiments following a dose of 0.025 mg. per kg. In all these experiments there was an increase in oxygen consumption, but never relatively as great as the increase in cardiac output. Seven minutes or longer after an intravenous injection of epil nephrin, the minute cardiac output ivas within 7 per cent of the control det.erminabions, which is not greater than the limits of error of the method. In the single exception, there was a decrease of 11 per cent. twenty-t,hree minutes after inject,ion following an increase of 27 per cent one minute after injection. The results of these experiments are shown graphically

in Fig. 1.

The pulse rate was elevated in all experiment-s, the average increase being 56 beats per minute immediately after injection, and it remained elerat.ed 32 beats per minute (average) after the cardiac output had returned to normal. (hi Sevc’ral ex]JeIhlelltS :I11 hitid decrease in pulse rate occ77rrcd Trhile the drug was lwing given. This was, however, of only a few seconds’ dnration.) B. XuBcutnneoirs .~tlnLinisf,.nfioI~.-177 seven of the ele\Pn eslwriments in which the drug was given suhcutaneonsl~-, there was an incrc;lse varying from 10 to 59 per cent in minute cardiac output. fifteen minutes after injection. The average increase was 32 per cent. The oxygen consumption increased here also, bnt in only one experiment w:ls this increase relatively more than that in cardiac ont.put. Subsequent det.erminations in these experiments were somewhat variable. In three experiments, the cardiac out.pnt. hacl returned to or below normal within 40 minntes of injection. but. all others remained above normal for at least 60 minntes and two for 11.5and 210 mi7777tes, respectively. In the remaining four experiments, the cardiac ontput. decreased from 6 to 24’per cent. Three of these experiments were upon the same clog. (V56, Fig. 2). The other dog (V’iO, Fig. 2) whose output, decreased 8 per cent, was snbjected to the same experiment. fonr d:lys later, at which time his output. was increased 21 lwr cent fifteen minutes after injection and 50 per rent thirty-five minntes after injection. He was, however, the single dog ment.iont~d above whose osygen consumption increased relatively more than his cardiac o77tpnt. The pulse rate increased and remainecl elevated in most. of the esperiments but. the average increase was only 15 beats per minute. The results of these experiments are shown in Fig. 2. DISCUSSION The doses of epinephrin atlministered by IIS, 0.05 and o.&?j 111~.[JCl’ kg., are eqnivalent. to 3.5 c.c. and 1.75 e.(‘.. wspccti\-e1.v for ai1 nclnlt man. It is apparent from these csl)erinients that the iminrdi;rtc~ el’fevt of snch closesis to eaiise a7i’increa~r in the ontpnt of the normal dog’s heart, whether the dr77g be given intravr7lously or s~7bc7~ti~~leo77sl~. The chief clinical 77seof rpinephrin for its circulatory elects is in combating acute circulatory failure, nsnally linen-n as “ shock, ” whicll results from hemorrhage, tranma, pro’lonpwl auesthesin and similar acute debilit.ating conditions. If we grant that the effect. of the drug is the same in man ancl the dog (and this is highly l)robable, for it is a physiological product common to both and, f~~rthermor~, has sirnila~ effects upon the blood prcssnre and pulse rate of both), there seemsto be a very reasonable basis for snch a usage, for Blaloclr’ has shown that there is a decreased cardiac outl)nt in hemorrhagic i‘sl~ocl;” in th.e dog.

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JOURNAL

On the other ‘hand, however, t.here are at. least two objections to this method of treatment : First, the durat,ion of the drug’s effect, when given intravenously, is little more than moment.ary, and, when given subcutaneously, it is very variable in both ext.ent. and duration. Secondly, the cardiac output in many of our ex1~eriment.s showed a tendency to return to b&w its original level, once the brief effect of the drug had disappeared. Thus, if the reaction of man be the same, cpinephrin not, only may be wholly inadequate in the serious condit.ions, for which it is used, but may ultimately (or even very quickly) become actually harmful. Haeberlin8 has recommended frequent. repeated subcutaneous injections of epinephrin in ” grave toxic weakness ” of the circulation, which we may interpret as being similar to the “shock” here in question, and it. is ctuite possible that such a method might be beneficial. In so far as the customary- use of the drug is concerned, however, we believe that t.he facts here presented indicate that epinephrin, if used at all in the treatment of acute circulatory failure, should be em ployed with great care and only as a temporary measure to uphold the patient’s circulation until more valuable procedures, such as blood transfusion and saline infusion, can be employed.

Epinephrin, given both intravenously and subcutaneously, has been shown to increase the cardiac output of normal unnarcotized dogs, as determined by the Pick method. The degree of increase after both methods of administration*has varied from 10 per cent to 59 per cent. The duration of the effect has been less than seven minut,es after intravenous administration, and very variable after subcutaneous administration. One dog showed a decrease in cardiac output on three occasions after being given the drug. It has been suggested that epincphrin may be inefl’ectire and possibly tlangrrous in the treatment of acute circulatory failure. REFERENCES C’ommunicntion. Alfred : Pcrsoual Torald: A Manual of Pharmncologr, ed. ‘7, 1922, Pl~il:~~lclpl~i:~, \Y. H. Saunders Co., p. 385. Wdnirn, T. : Tohoku Jour. Exp. Med., 1923, ii, 30.i. .11,ym, Tl. Murray, and Sands, J:mr : Am. Jour. Physiol., lO?.i, lxsi, .XH. ,?Davies, TJ. W., and Mexkins, d.: lIcart, 1!+22, ix, 191. Am. J~ur . :I.‘l:vsiol., t;Smith, F. M., Miller, C:. It., an11 (;rnher, 1’. C.: 192(i, l-xxvii, 1. . ;TJnrrison, T. R.. and Leon:wl, B. W.: Jour. Cliu. Iuves., 1926, iii, 1; :11no Blnlock, A.. nut1 Harrison. T. K.: Am. Jour. l’lysiol., 1927, lxxx, lZ7. ‘Blalock, ~Sollmnn,