No. 4883.

MARCH 31, 1917.

The Lumleian LecturesON

MODERN ASPECTS OF HEART DISEASE.Delivered before the Royal College of Physicians of London

BY G. A. SUTHERLAND, M.D. EDIN.,F.R.C.P. LOND.,

PHYSICIAN TO THE HAMPSTEAD AND NORTH-WEST LONDON HOSPITAL;PHYSICIAN TO THE PADDINGTON GREEN CHILDREN’S HOSPITAL.

LECTURE IllyDeLwered on JtfarcPt 20th.

MR. PRESIDENT AND GENTLEMEN,-Although new methodsof treatment of heart disease have been introduced, it is

questionable whether any addition of great value has beenmade to the armamentarium of our predecessors. The

advantages of rest, of suitable diet, and of digitalis werewell known to them. What has been done is to analyse andtest more exactly the measures which are beneficial and todefine with more precision the conditions and the cases fortheir suitable application.

., CARDIAC TONICS."

The term- cardiac tonic" is still in common use and is

’employed somewhat indefinitely. It is applied to drugswhich are supposed to stimulate or increase the contractilepower of the heart. Some cardiac tonics are supposed toact directly on the musculature and others through thenerves of the heart. If one takes a list of the so-calledcardiac tonics and tries to ascertain the exact action of theindividual drugs it will be difficult to state precisely whatspecial result is to be looked for. Digitalis and its allies,strophanthus and squills, stand apart from all the others inthis respect.

Balfour (1897) held that the fundamental action of thedigitalis group was to increase the elasticity of the muscularfibre of the heart, so that it expanded more slowly and con-tracted more perfectly. Broadbent (1897) considered thatdigitalis caused a more complete expulsion of their contentsby the energetic contraction of the ventricles, and alsoimproved the suction action during diastole, thus with-

drawing the blood which had been dammed back in theveins. Brunton found that digitalis acted on the cardiacmuscle, on the intrinsic cardiac nerves, on the vagus centrein the medulla, and also on the arterioles. We do not findany clinical proof of the accuracy of these views. Therewas no precise knowledge of the underlying changes incardiac failure which digitalis is specially fitted to remedy.Each authority seemed to draw his conclusions from few andimperfect observations, or even to make his observations forthe purpose of supporting his previously formed conclusions.In many cases what would now be regarded as the out-

standing changes in cardiac failure were relegated to anentirely subsidiary position.

It is interesting to note that 20 years ago the specialsymptoms which called for digitalis had been recognised.These may be summed up as cyanosis and dropsy, with arapid, irregular pulse and breathlessness. This condition ismost frequently due to auricular fibrillation, and is still theone in which the action of digitalis is most clearly demon-strated. Digitalis was used as a cardiac tonic, and havingbeen found benpficial in this special type of case it came tobe used indiscriminately in all forms of severe illness withcardiac weakness. When I was a house physician it wouldhave been regarded as almost criminal to let a patient diewithout giving digitalis, whether the disease was pneumonia,typhoid fever, or pernicious ansemia. We believed thatdigitalis was the great cardiac tonic and always suitable ifcardiac failure threatened. Other cardiac tonics and stimu-lants have had their day and are still used by those whobelieve they have seen good results follow from their use.Amongst them may be mentioned strychnine, caffeine,camphor, adrenalin, and pituitrin. The exact mode of theiraction on the heart, if any, has not been determined, and thetype of case suitable for their application has not been clearly1 Lectures I. and II. were published in THE LANCET of March 17th

(p. 401) and 24th (p. 437), 1917.No. 4883.

differentiated. Digitalis, however, holds its own’ in thepresent as in the past.

EFFECTS OF DIGITALIS IN VARIOUS CONDITIORTS.

Progress has been made, and although differences of

opinion may still exist we are a good deal nearer the answersto the questions why to use digitalis, when to use it, and howto use it. The progress of scientific medicine is often

delayed by the existence of unscientific beliefs, and theemployment of digitalis in heart disease is an illustration.The one outstanding fact about the action of digitalis whichhas been fully established is that it slows the action of theheart under certain conditions. I propose to consider howthis slowing is brought about ; what effects follow from theslowing; and whether the ascertained beneficial effects fromdigitalis are not to be explained solely as the result of thiscardiac slowing. In doing so no attempt will be made todispute the various effects on the cardiac muscle obtained byphysiologists and pharmacologists in their experimental workwith large doses of digitalis. The pharmacologist cannotproduce in animals those changes in the tissues and func-tions of the heart which are the result of disease, nor canhe form any estimate as to what the results of digitalisin therapeutic doses will be in the treatment of cardiacdisease.

In ordinary language slowing of the heart means slowingof the rate of contraction of the left ventricle, and this isestimated clinically by the pulse-rate or, if necessary, byauscultation of the heart, We have already seen that anincrease in the ventricular rate or a serious disturbance ofthe cardiac rhythm is never primarily ventricular in origin.The ventricle follows but does not lead the cardiac rate orrhythm, which is always initiated in some part of the supra-ventricular tissues. In diseased conditions an increase ofrate or a disturbance of rhythm is also started in the supra-ventricular tissues. Consequently it would appear that treat-ment should be directed to the supra-ventricular tissues fromwhich the disturbance proceeds.Here are two further points to be considered. First, it

has not been shown that digitalis in medicinal doses-andwe are dealing solely with digitalis as a therapeutic agent-has any direct effect on the wall of the left ventricle. Con-

sequently we must not assume that digitalis acts on theventricular muscle. Secondly, it has been shown that theslowing action of digitalis is through the vagus nerve, butit has not been shown that the vagus has any direct actionon the musculature of the left ventricle. These two pointswill be discussed more fully later. Meantime, assumingthem to be true, we draw this conclusion-that digitalisslows the rate of the left ventricle without’ acting on theventricle ; and that it produces its effect through the vagusnerve, which also has no direct action on the left ventricle.It therefore follows that as the rate of the left ventricle isdependent on impulses proceeding from other parts (thesupra-ventricular tissues), the action of digitalis throughthe vagus must be on these supra-ventricular tissues. In an

attempt to slow the ventricular rate through the supra-ventricular tissues, there are two possible lines of action:

(1) to check the rate of impulse discharge at some over-

active centre, or (2) to block some of the rapid contractileimpulses at the conducting tissues so that a diminishednumber of them reach the ventricle. Clinically it can beshown. that in slowing the heart rate this is the mode ofaction of digitalis, as in the following types of cases.

I. Wzth Normal Rhythm anil Rapid Reg1Ûar Action.CASE I.-A girl of 11 years had suffered from several

attacks of rheumatic fever with cardiac involvement. Aftersix weeks at a convalescent home she was readmitted tohospital because of increasing dyspnoea and rapid cardiacaction. For the previous three weeks the cardiac rate hadaveraged 120 to 130 beats per minute. She had not beenable to be out of bed for a fortnight owing to breathlessness.There was no pyrexia and no evidence of active rheumatic

infection. The cardiac rate was rapid, averaging 124, andregular, and the rhythm was normal. Praecordial pulsationwas strong and the apex beat was felt 1 inches outside thenipple line, while the right side of the heart was feltpulsating to the right of the sternum. The murmurspresent indicated mitral and aortic regurgitation. The liverwas enlarged, extending 2 inches below the costal margin.After a fortnight’s rest in bed and salicylate treatment

there was no improvement, and it was resolved to try theeffect of digitalis in slowing the heart-rate. In 12 days therate had fallen to 68, the amount of digitalis taken in that

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time having been 12 granules of digitalin (Nativelle), igr. 1/240 in each. Four days after the digitalis treatment iwas begun the heart was beating regularly at 80 per minute, Iand with a normal rhythm, as shown by the tracings. Atthe end of the course the apex beat was felt inchoutside the nipple line, and’ the right border of the heartdid not extend beyond the right margin of the sternum.The liver edge was just palpable at the costal margin. Thepatient expressed herself as feeling very well, and was allowedoat of b3d, when she found she could walk about withoutany breathlessness. The action of the digitalis was success-fully maintained after she left the hospital by small doses ofdigitalin. In this case the diminution in the size of thewhole heart, coincidently with the slowing of the rate, wasvery striking.

This type of case is a common one in adolescent life.Rheumatic infection has led to carditis, in which myo-cardium, pericardium, and endocardium may be involvedsingly or in combination. Active signs of rheumatic infec-tion (fever, are ab3ent, b there is a persistently rapidcardiac action, the rate being from 120 to 140 at rest. Inmild cases there are symptoms of cardiac weakness, as

shown by the languor, disinclination for exertion, andshortness of breath when any exertion is made. In moresevere cases symptoms of cardiac failure may be presentand the breathing distressed, even when the patient is inbed. The rapid cardiac action seems to be an importantfactor in producing the cardiac weakness which leads tothese symptoms. Digitalis grips the vagus nerve and stimu-lates its inhibitory action which tells on the first centre

reached-namely, the sino-auricular node. The rate ofimpulse discharge here is diminished and a slower rate ofthe heart is established at the sinus, which leads to theslower ventricular rate. In cases of this kind, and they arenot uncommon, we find no evidence of any direct action ofdigitalis on the contraction of the left ventricle or on therate of the left ventricle. We trace the slower and strongercontractions of the ventricle directly to the slower cardiacrate established at the sino-auricular node.

II. With Auricular Rhythm and Rapid Regzclcvr Action.CASE 2.-A boy of 10 had suffered for some years from

occasional attacks of paroxysmal tachycardia. They hadbecome more frequent and more persistent until at the endof an attack lasting for a month signs of cardiac failure setin. Apart from the cardiac condition, there was no evidenceof disease in any part of the body, and he had never shownany sign of rheumatic infection.The heart rate was 180 per minute and regular. Therewas diffuse prmcordial pulsation, not forcible, and con-

siderable dilatation of the heart to right and left. Strongvenous pulsation was to be seen and felt in the neck. Asoft svstolic murmur was audible over the prseoordia. Theradial pulse was very small, feeble, and rapid, but appar-ently all the cardiac pulsations reached the wrist. Thebreathing was laboured and the ears were dusky. Theliver was enlarged and free fluid was present in theperitoneum, while there was some cedema of the lowerextremities and of the abdominal wall. Tracings showed anabnormal cardiac rhythm which was not of sinus origin butarose somewhere in the supra-ventricular tissues and mostprobably in the auricles.After moderate doses of digitalis the cardiac rate fell to 96,

the action was much stronger, and the dilatation was lessmarked. Diuresis set in, the dropsical symptoms rapidlydisappeared, and the boy felt much relieved as regards hisbreathing. On stopping the digitalis, however, the rapidcardiac rate quickly returned, and this happened after eachsuccessive course of digitalis. An effort was therefore madeto establish a firmer hold on the cardiac rate by means ofdigitalis. He was ordered 45 drops of the tincture ofdigitalis daily, and during 19 days he took 11 drachms inall, a dose being omitted occasionally when nausea orheadache was present. This had the effect of producingmarked instability of the cardiac rate, so that it changedfrom fast to slow with great frequency, on the slighteststimulus, and usually without any recognisable cause. Thepatient stated that he could always change the rate by 1

breathing deeply. In the fast periods the rate was always ithe same, 170 to 180 per minute, and the abnormal auricularrhythm was present. In the slow periods the heart ratewould at one time be 42 and at another a normal one of 80,while in both cases a normal rhythm would be present. Afew days later the normal rate became established with veryfew and brief periods of tachycardia. ’

We had here a case of very rapid cardiac action, theimpulse starting presumably in the auricular tissues, and theventricle eventually showing signs of exhaustion from over-action. There was no evidence of rheumatic or other

infection, and the heart was sound until the onset of thetaohycardia. Here again digitalis would appear to have.gripped the site of impulse formation in the auricle, passingby the sino-auricular node which was thrown out of actionby the new focus, but large doses of the drug and a largetotal amount were required before the inhibitory effect ofthe vagus was fully developed. The large doses were-probably rendered necessary by the fact that the centre ofdisturbance was a particularly active one, as shown by the-severity and the persistence of the tachycardia.III. With A2cricular Rhythm and Rapid Irregular Action.In the form of auricular fibrillation this is a common.

condition, and the beneficial action of digitalis is now wellknown. How it acts would appear to be as follows: Thesino-auricular node is out of action as auricular fibrillationis a state in which multiple stimuli originate all over the-auricles and dominate the cardiac rhythm. Fibrillationitself is so firmly established that the vagus has no effect inchecking it. The inhibitory action of the vagus may beregarded as passing over the heart until it reaches the-auriculo-ventricular node and bundle, which convey the-stimuli from the auricles to the ventricles, and producingthere diminution of the conducting power (conductivity), the-so-called partial heart-block. By this means many of theimpulses passing towards the ventricle are checked en routa,the rate of ventricular stimulation is lessened, and the rateof the ventricular contractions gradually falls.

It may be objected that there is no proof here that this isthe action of digitalis in auricular fibrillation, but few whohave studied the subject have failed to accept the explana-tion. The inference has this further in its favour. Thefibrillary contractions continue unaffected in the auriclesand the ventricular contractions continue of the same kind’as before, so that only the junctional tissues remain. Onthem digitalis and the vagus are known to act. It may be-said that the mere slowing of the ventricular rate inauricular fibrillation does not explain the good results fromdigitalis, and that the drug has a real tonic " action on theheart muscle. A case like the following has a bearing onthis question.CASE 3.-A married woman of 30 years sought advice

because of increasing shortness of breath on exertion,.although she was still carrying on her usual house duties..She had had rheumatic fever in childhood. The heartshowed the characteristic signs of mitral stenosis in theform of a well-marked presystolic thrill and murmur. Therewas no left-sided dilatation, but the right side of the heart-was somewhat enlarged. The cardiac action was regular at84 beats per minute. The pulse was small and regular. Thecondition was, in fact, such as it might have been found on,examination at any time during the previous 10 years,except that the right side of the heart was slightly moreenlarged. The treatment ordered was largely negative-namely, the avoidance of anything inducing cardiac effort,for it has been my experience that no benefit is derived fromdrug treatment at this stage of mitral stenosis.The patient was not seen again for three months, when*

she gave the following history. Up to 10 days previouslyshe had gone on with her housework as usual. That night,.about an hour after falling asleep, she woke with urgent,breathlessness, and could not lie down. She felt the heart.beat rapidly and thumping at times. The distress of the,dyspnoea had gradually diminished and she had finally been.able to come to the hospital.The dyapncea. was still present, but she could lie down..

The pulse was extremely feeble and rapid, with occasionalstronger beats, but was very difficult to count. The cardiacrate was 140 and the action was grossly irregular-the so-called delirium cordis. The heart was much dilated, the,liver was enlarged, and there was slight cyanosis. At theapex a systolic murmur was audible, and there was no traceof a presystolic thrill or murmur. Two days later she wasadmitted to hospital, when the pulse was found to be 140 perminute and very irregular. On the following morning shewoke feeling that all dyspnoea had gone. This was clearlydue to the spontaneous cessation of the attack of auricularfibrillation. The pulse was 96 and regular. I saw her nextday when she was lying in bed without any sign of cardiac.distress. The pulse was 90 and regular. There was a well-marked presystolic thrill and murmur at the apex, indicatingthe return of definite auricular contractions. The liver wasnormal in size. In a few days she was out of bed and goingabout the ward.

’

Two months later the patient had another attack of ca.rdiafailure with similar symptoms, and was readmitted.Tracings showed the characteristic adial and venous curves.of auricular fibrillation. The cardiac rate was 140 and th6

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action very irregular. On full doses of digitalis the heart Islowed down, and later on moderate doses the rate was kept Iunder 90. Although the patient’s symptoms had been Ientirely relieved by digitalis the fibrillation and cardiac irregularity persisted. !

Here a flist attack of fibrillation passed off, and with itscessation the signs of cardiac failure rapidly subsided. Noone will suggest that the cessation of fibrillation was

accompanied by any special increase of contractile power inthe ventricle, except that the rapid rate may have produceda certain amount of exhaustion. But the ventricle was leftin peace-that is to say, it was freed from the showers ofstimuli which were reaching it from above, and by reason ofthe slower rate its contractions became stronger. In asecond attack digitalis secured the same result-namely, aslowing of the ventricular rate, and when that was estab-lished the signs of cardiac failure again disappeared. Thefibrillation persisted, but the exhausting effects of its rapidrate were held in check. The only difference between theresults in the two attacks was that in the first instancethe heart reverted to a normal rhythm and rate, while inthe other an abnormal rhythm of the heart and an irregularaction of the ventricle persisted. These are not factors ofthe first importance provided that the ventricular rate isnormal or slow.

IV. With Normal Rhythm and Slow Regular Action.We may refer to the action of digitalis when the cardiac

rate is normal and a sinus rhythm is present, and symptomsof cardiac failure have developed. This condition is mosc

frequently met with in degenerative forms of cardiac disease,and after middle life. If one pushes digitalis here theusual result is to produce partial heart-block or sinus

irregularity ; the ventricular rate may be a few beats slower,but the chief effect is to substitute an irregular ventricularaction for a regular. Even if this is not injurious if notpushed to an extreme, it is not at all an advantage, for aregular rhythm with harmonious interaction of auricles andventricles is always to be preferred. This type of case doesnot, as a rule, show any benefit from digitalis, save that ifdropsy is present a diuretic effect may follow, possibly dueto an irritant action on the kidneys.

V. With Â1trioula7’ Rhythm and Slo7v Irregular Action.Cases of auricular fibrillation are sometimes met with in

which the ventricular rate is slow and irregular. They havealways appeared to me to be of a mild type of cardiacfailure-that is to say, the subjects do not present thesevere symptoms of heart failure seen in fibrillating caseswith rapid ventricular action. They may have a limitedcardiac response to effort, traceable rather to cardiacdegeneration than to the fibrillation. One may infer thatin such cases the degeneration has attacked the auriculo-ventricular bundle, and has already produced a condition ofpartial heart-block, so that the conducting tissues will allowof the passage of only a limited number of the stimuliwhich are coming from the auricles. Consequently in suchcases one would not expect any benefit from digitalis, whosespecial action has already been anticipated by the changesresulting from disease, and in my experience digitalis is ofno use. In some of these cases when the patient exertshimself the ventricular rate is greatly accelerated andsymptoms of distress are then evoked. Digitalis may dogood in this condition by preventing the acceleration of ratethrough an increase of the block in the conducting tissues.If digitalis had any direct effect on the contractile tissues ofthe heart it ought to be manifested in this type of case whensigns of serious heart failure develop, such as oedema,cyanosis, and breathlessness, while the cardiac rate is notincreased. Here, also, my experience has been that nobenefit has followed the use of digitalis.

MODE OF ACTION ÒF DIGITALIS.We have now got thus far that digitalis would appear tc

act through the vagus on certain parts of the supra-ventri cut attissues. We have seen that this action may be on the sino-auricular node, or on some abnormal focus of impulse pro.duction in the auricular tissues, or on the junctional tissues.It has been established and accepted that this action isshown more frequently and more effectively in the case ojcardiac disease resulting from rheumatic inflammation-thaiis to say, the other great class of cardiac disease, that dueto various forms of degeneration, does not respond so well.It is not known, and it has not been suggested, that th<

vagus nerve is itself affected or in any way altered byrheumatic infection. The conclusion to which one is led ia,therefore, that the cardiac tissues, those on which the vagusacts, are in themselves altered in some way so as to berendered more sensitive to the action of the vagus. Rapidityof cardiac action means over-action in the stimulus-producingcentre. Depression or moderation of over-action seems tobe the great function of the vagus. One cannot depend onbringing into play this vagal action by means of digitalis inall cases of rapidly acting hearts, but there are some inwhich this action may be confidently expected, and they areespecially those in which the heart has been affected byrheumatic inflammation. In connexion with vagal actionthere is also to be taken into account the fact that an over-

acting centre tends to become exhausted and an over-

stimulated conducting tissue tends to lose in conductingpower. Thus the sino-auricular node may be so far preparedfor an increase of vagal depression by its previous over-action, and the auriculo-ventricular bundle may be similarlyprepared by over-stimulation from auricular impulses, as inthe case of auricu!ar fibrillation.

It would appear, further, that in the case of a rapidlyacting heart which we desire to slow the problem is, will thevagns under digitalis stimulation be able to moderate theimpulse-producing centre, or will the latter prove too powerfuland maintain its rate ? Under many conditions, as is wellknown, digitalis has no effect in slowing the heart, and herewe may assume that the over-acting centre is too excitable.On the other hand, under other conditions the vagus cancontrol the over-acting centre and check the disturbedaction. When the vagus fails to check the rapid productionof impulses to contraction at their centre, it has still auseful function left-namely, to prevent the disturbancereaching the ventricle through the induction of partialheart-block by diminishing the excitability of the conductingfibres. This protective method of heart-block is of extremevalue in maintaining efficient ventricular action in manycases. One point about this action of digitalis may bereferred to. It is an imitation of Nature’s way of maintain-ing efficient cardiac (ventricular) contractions in similar con-ditions of distress. The natural means of preventingexcessive ventricular rate and consequent ventricular exhaus-tion is by stopping a certain number of the impulsesdescending from above at the junctional tissues-a partialheart-block. This may or may not be sufficient. If it isnot, by means of digitalis we can supplement the blockingaction already existing and increase it to the extent.

necessary to relieve the ventricular distress.. If these views as to the action of digitalis are correct itwould appear that the slowing effect on the left ventricle-from which we have traced all the benefit derived fromdigitalis-is accomplished without any action on theventricular muscle. Further, it would appear that digitalis,the great cardiac " tonic," has no action whatever in,medicinal doses on the cardiac tissues; it neither weakens:them nor tones them up, but acts only on the vagus nerve.by increasing its inhibitory functions. It does not seemnecessary to assume any effect other than that of a slowerrate, and the beneficial rest to the heart which follows.

Effect of Compression of Vagu8 Nerve.By compression of the - vagus nerve in man evidence

is gained which supports the view that the actionof digitalis is on the vagus and not on the heart muscle.Ritchie found that by digital compression of the vagus hecould slow the whole heart, the normal rhythm being main-tained, and the action being on the sino-auricular node. Hecould obtain no evidence of a direct action on the othertissues in the auricle, and in no instance has he observedauricular fibrillation to be checked or arrested by vagus com-pression. He failed to find any direct effect on theventricles by vagal stimulation. Ritchie states that althoughin animals the conduction of stimuli to the ventricles

through the junctional tissues may be impaired by vagalstimulation, in healthy human hearts he failed to obtain anydepression of the conductivity of the auriculo-ventricularbundle unless there was some antecedent impairment of itsfunction. In many cases of auricular flutter compression ofone or other vagus was found to induce well-marked blockingof stimuli to the ventricles. Whenever the ventricular ratewas slowed, the slowing was always the result of the actionof the vagus off the supra-ventricular tissues. In cases of

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B complete hea-rt-blbck the rate, rhythm, and strength of theventricular beats were found to be uninfluenced by vagalstimulation.We have already- considered the clinical effects of digitalison cardiac action. Now if we compare the results of vagal stimulation by digital’ compression there is a strikingsimilarity in the effects produced. In both cases the resultsare primarily inhibitory -and not augmentory of cardiac func-’ tibns. In both cases there may be a local action on thesino-auricular node, the aurioulo-ventrioular node, or the’ auHculo-ventricular bundle, but never direotly on the ven-‘$ricles themselves. In the one case mechanical stimulation

produces effects which are temporary and cannot be long- ’s&uuml;stained ; in the other, digitalis produces identical effects’which can be regulated and indefinitely prolonged. Stillsome would ask us to believe that as the vagus picks out

certain areas and certain functions of the heart in the’exercise of its physiological r61e, so digitalis picks out thesame areas and the same functions in the exercise of its I’ therapeutic r&le.,

OBSERVATIONS ON DIRECT ACTION OF DIGITALIS.. We have seen the typical class of case in which digitaiis’:!s useful-namely, the rheumatic heart with a rapid rate or

With a rapid and irregular rate, and signs of left ventricularfailure. This class will comprise some 90 per cent. of the

B caMs in which we can state before treatment that digitalis’will do good, and the way in which it will do good, and thegood which it will do. Regarding how many drugs can the’ same statement be made ? 1 We are not tied down to thisclassof case, because in a sense the investigation into theaction of digitalis is only in its infancy-certainly it is very

far from being completed, But we have reached this con-I6lus!*on, that it is foolish to give digitalis solely because ofcardiac weakness orof cardiac dilatation or of valvular disease,,.irrespective of the special conditions present. It is equallyt foolish to refrain from giving digitalis because of someSupposed action on the contractility or relaxation of the left Iventricle, or because of the presence of some lesion supposed Ito militate against the use of digitalis such as aortic

t incompetenoe or mitral obstruction.’ Physiologists somewhat vaguely, and pharmacologistsmore precisely, have dealt with -the action of the vagus and

of digitalis on the contractile power of the left ventricle.. In this connexion one law must be kept in mind-namely,. th’at ’the cardiac muscle, when -it contracts, contracts withi atl the power which it possesses at the time. Gaskell putsdigitalis into the class, of substances which act in the

z’ d’irectiow of bringing about a tonic contraction of the leftventricle, as opposed to the muscarin class which brings

’ about an atonic condition of that muscle.’ Onshny has concluded from his experiments with largedoses that digitalis strengthens the contractions and oftenlessens the relaxation of the heart by direct action. on the- cardiac muscle. Anything that Cushny writes about digitalismust be received with respect, but when he enters thecMcioal field we are at least entitled to offer criticism. The

clinical problem he set himself to decide was whether thetherapeutic effects of digitalis are.to be attributed to stimu-lation of the inhibitory action of the vagus or to its directaction on the cardiac muscle. The method he employed

wats -to paralyse the vagus by means of atropine before and, after the use of digitalis. If a heart slowed by means ofdigitalis did not show,an increase of rate under atropine he,’c@ncluded that the slowing was due to a direct action of. digitalis, on the heart muscle, the vagus having been thrown,’out of action by the atropine. From a considerable numberc3f clinical tests he drew the following conclusions :-I (1) The members of the, digitalis group slow the putaem certain number of cases in which the rhythm is given by’the normal pacemaker, and as a general rule this slowingmaybe removed by atropine, and is therefore inhibitory. Inother oases, however, the sinus slowing and block are un

, changed by atropine, and then arise from the direct actionof digitalis on the conducting fi’bres from the pacemaker to

’ the auricle, and from the auricle to the ventricle.’

(2) In auricular fibrillation digitalis slows the heart from’ some direct action on the heart and not from stimulation ofthe inhibitory mechanism, for atropine does not restore tt2e- original rate of the released heart. The reduction in rateHl3>Y be due to a direct depression of the conduction or of the

. excitability of tiw heart muscle by digitalis. But it issuggested that these functions are reduced indirectlythrough the fmproved nutrition of the heart fmm tbr,augmented 1."’B’ cr of contraction of the heart muscle,

(3) The inhibitory stimulation induced by digitalis, there-fore, does not play any part in the beneficial action of thedrug, which is to be ascribed to its direct action on thecardiac. muscle solely.

It is surprising to learn that in cases of auricular fibrilla.tion, where the slowing of the ventricular rate pnder digitalisis so striking, the vagus does not come into play at all andan entirely different process is at work. I question whetherthis conclusion is justified by the clinical tests employed.The atropine test was employed when the vagus was fullydigital ised-that is to say, when the vagus centre was beingstrongly and continuously stimulated. To paralyse the

vagus, therefore, one required not an ordinary physiologicaldose of atropine, but a dose proportional to the degree ofvagus stimulation by the digitalis. One may put a normalindividual to sleep with 20 grains of bromide of potassium,but such a dose will do little to quiet an alcoholic subjectsuffering from delirium tremens. In order to make histests conclusive Cushnyought to have greatly increased hisdose of atropine. Not that I advise this continuation of histests, because in all probability the patient would die fromatropine poisoning before the vagus escaped from the grip ofdigitalis. The results which Cushny obtained are exactlythose which one would expect in auricular fibrillation withthe vagus fully digitalised, if one believed that the slowingof the heart was through the vagal action. Mackenzie,dealing with the same type of case as Cushny, differs as tothe clinical facts and the conclusions to be drawn from them.He says :-So far as our observations go the action of atropine in

increasing the rate when it has slowed, seems to indicatethat digitalis acts through the vagus nerve, both in theslowing which occurs in auricular fibrillation, and in partialheart-block.But the clinical conclusions of these two authorities may

be satisfactorily reconciled if we assume that the larger theamount of digitalis taken the bigger will the dose of atropinerequire to be in order to throw the vagus out of action.Mackenzie was dealing with small doses of digitalis andCushny with large ones.Oonsideration of Cus7iny’s Oonolusions from Clinical Side.,On the clinical side also one must take exception to the

haziness of Cushny’s conclusions as to the direct action ofdigitalis on the heart, after he considered that he hadeliminated the vagal factor. " The reduction in rate may bedue to a direct depression of the conduction or of theexcitability of the heart muscle by digitalis." It certainlywou!d be curious if digitalis imitated exactly the well-knownfunctions of the vagus described in this sentence. " But itis suggested that these functions are reduced indirectlythrough the improved nutrition of the heart from the

augmented power of contraction of the heart muscle." Thatis to say, that with a cardiac (ventricular) rate say of 150 theheart is so toned up by digitalis that the rate is slowed. Butwe find clinically that we cannot strengthen the cardiac con-tracti )ns until the rate has been slowed do Nn. We get noevidence of stronger contractions, and the patieat gets norelief from the symptoms, and the physical signs of cardiacfailure do not alter until after slowing has taken place.

Is it not a commonplace of medicine that with a rapidcardiac action we cannot have a strong pulse ? Take thecase of a healthy young man with a rapid pulse under someform of excitement, and we find it small and weak. When

: the excitement has passed off and the heart rate has slowed,.

we find the pulse stronger and fuller. Does any cliniciandoubt that the cardiac action was weaker when the rate wasrapid and that it was stronger when the rate had slowed andbecause the rate had slowed ? Has experience not shown

, that the faster the cardiac rate the weaker are the contrac-, tions ? Can we imagine digitalis producing in a rapidly: acting heart the same powerful contractions which we knowwill foll w from the mere slowing of the rate ? This sagges-

tion of Cushny’s would appear to be merely a revival of. theold pharmacological view, which was accepted therapeuti-oally, that there must be some direct action of digitalis on

t the cardiac muscle. The acceptance of this view, withoutE any proof, as to its accuracy when the drug was used in} medicinal doses, led to the great misuse of digitalis in thepast.

Accepting the all-or-nothing " action of the ventricle in, contraoting, we must take the other fact that if the

ventricular rate is increased the contractions are weakenedbecause the resting-time is diminished. Rest and relaxation

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of the muscle are essential if the ventricle is to evolve itsfull power of contraction. Contraction, relaxation, andrest are the three elements in the normal ventricular action.

Physiologists have taught that the tonicity of the ventricleis increased by digitalis and that the contractile power isincreased, using large doses for the experimental proofs. Ifthe tonic contraction of the ventricle is increased it followsthat the relaxation is diminished pari passu, for a tonic con-traction in the physiological sense means a prolonged con-traction without relaxation. If the relaxation is diminishedthe complete filling of the ventricle cannot be effected. Ifthe ventricle is not filled the efficiency of a ventricularcontraction in carrying on the circulation must necessarilybe impaired.

It is difficult to see how these results of poisonous dosesof digitalis in physiological experiments can be made use ofin cardiac therapeutics. The well-known experiment of

bringing a frog’s heart to a standstill in tonic contractionof the left ventricle has no bearing on our therapeuticdosage, for anything of this nature would be singularlyinappropriate in an attempt to help a struggling ventricle.If physiologists say that the contraction of the ventricle isincreased by digitalis through the vagus there is this furtherdifficulty. The physiological action of the vagus is inhibitory;its recognised effect under digitalis is to inhibit cardiacfunctions-for example, inhibition of rate, inhibition ofconductivity, inhibition of excitability, &c. So that if itshould under the same conditions increase the contractilityof the ventricles, there would be a change in the normalfunction of the vagus which can only be described as

puzzling. Gaskell, however, definitely states that the" stair-case phenomenon " which arises after an experimental stand-still of the whole heart through vagal stimulation is due toexhaustion of contractility. He points out that the vagusstimulation depresses all the functions and their restorationis gradual, the restoration of contractility being shown by agradual increase in the strength of the beat-the staircasephenomenon.

Conclusions as to Different Actions of Digitalis.Cushny’s conclusions as to the action of digitalis in cases

with a normal rhythm of the heart are also difficult tofollow, and for this reason. He finds that in some casesthis action is inhibitory and through the vagus, while inothers there is a direct action of digitalis on the conductingfibres from the sino-auricular node to the end of the.auriculo-ventricular bundle. So that in the same class ofcase we have two entirely different actions of digitalis, theone on the nerve and the other on the muscle. This is adifficult doctrine to accept, but it does not complete theexposition of the action of digitalis. In the fibrillatingcases, that is, those with an abnormal rhythm, these explana-tions are dropped, and he suggests a third-namely, "anaugmented power of contraction of the heart muscle."From these statements one gathers that in Cushny’s clinicalexperience digitalis may stimulate the vagus directly, or maydepress the conductivity of the heart directly, or mayincrease the contractility of the heart directly. The path ofclinical medicine is not made smooth by such varied anduncertain action on the part of digitalis. Surely if we canexplain our therapeutic results by one line of action, clearlyaimed at and clearly manifested in clinical work, we shallprefer it. The line of action is that digitalis acts on thesupra-ventricular tissues through the vagus nerve, and bychecking impulse production or impulse conduction slowsthe rate of the ventricles.

It would appear that nature has not supplied any naturalpaths by which the ventricles can be stimulated directly ’toincreased contraction. In the field of experimental medi-cine Ritchie and others have failed to produce a directeffect on the ventricular contraction by stimulating thevagus. The effects of stimulation of the accelerator nervesof the heart by experiment or by drugs have not shown anydefinite action on the ventricles. Is it not possible that thenatural powers are the best defenders of ventricular actionand that our efforts to aid it by direct stimulation are

wasted ? 1 If we consider the condition of a patient suffer-ing from paroxysmal tachycardia, the heart having beenpreviously healthy, we may find marked signs and symptomsof cardiac failure. On the occurrence of spontaneous cegm-tion of an attack there is a rapid disappearance of all thesigns of cardiac distress. Is it any use giving drugs toincrease the cardiac (ventricular) contractions ? The heart

has been beating at a rate of about 200 per minute. It isimpossible for the contractions to be powerful at that rate ; ’

*

the only question is, Will they be sufficient to carry on the ‘

circulation ? When the pulse-rate drops to 80 the wholescene changes, and by the mere slowing of the rate the cardiac’(ventricular) contractions at once becomes stronger and an’efficient circulation is established. If given a sufficiency ofrest and relaxation the ventricle is quite capable of doing allthat is required in the way of contraction. A similar state of affairs is seen in cases of auricular fibrillation, as alreadyreferred to, when the cessation of an attack is quicklyfollowed by the return of the heart to the status quo ante. The ventricle needs no stimulation to bring out its contractile’power when rest and relaxation are afforded. So whendigitalis is used in the case of auricular fibrillation and the,same relief of symptoms follows the slowing of the’ventricular rate, it seems superfluous to bring in as a,pharmacological explanation an assumed action of digitalis’on the contractile powers of the ventricles. ’

’

Clinical Experience in Support of Digitalis Acting Beneficallyby Slowing of the Heart.

If digitalis has any therapeutic action on the wall of theleft ventricle it ought to be capable of clinical demonstra-tion. The typical case for this pnrpose is not uncommon- namely, one in which there i8 a failure of the left ventricle ’with a normal rate and rhythm of the heart, and withdefinite signs present, for example, oedema, oliguria, andbreathlessness. A record of a series of cases of this type,;with details as to the benefits which followed from theuse of digitalis, would go far to settle the question as to the,’direct action of digitalis on the ventricles. But I do no,tfind such cases to be common amongst published records and hI cannot supply any from my own experience. ,

Recently the electrocardiograph has been employed totest the effect of digitalis on the cardiac records and certainchanges have been discovered in the ventricular peaks,notably in the T wave. Further, under full doses of digitalis.a ventricular extra-systole sometimes occurs. It is scarcely’convincing to assume from these facts that digitalis acts directly on the ventricular wall. As bearing on the subjectof the action of digitalis on the wall of the ventricle thereis this fact to be remembered. When the cardiac rate hasbeen much reduced by digitalis, say to 40 ventricular beatsper minute, as the result of full doses, we sometimes find thatthe ventricle "escapes." Ventricular escape means that the .

ventricle starts its own independent rhythm and contractswhen the pauses between the normal beats are very pro-longed. This shows that the ventricle itself has been so’little affected by digitalis as compared to other parts of the heart that its idio-rhythm emerges unaffected and unimpairedwhenever an opportunity presents itself. We have little’evidence of the other functions of the ventricle being affecteddirectly by digitalis, and we can state definitely that theidio-ventricular rhythm is not affected at all.

’

The other great cardiac tonic is- rest. Why does restrelieve the weakened or failing heart ? 2 There is no questionhere of a direct tonic action on the cardiac muscle. such as’has been claimed for digitalis. There is no positive actionof any kind on the cardiac muscle. But there is a negativeone in the diminution or cessation of the rapid cardiac actionwhich follows from physical exertion and mental excitement,In other words, rest leads ’to a slowing of the cardiac rate kand from this slowing follow those benefits which havealready been described as the result of digitalis therapy. So far as we are entitled to dogmatise from clinical experience,we may say that all the ascertained benefits derived fromdigitalis and from rest in rapidly acting and failing hearts.are to be traced to one and the same result-namely, theslowing of the heart-rate, - This slowing may be brought’about in different ways and ’by various means, but it is the .best cardiac tonic we possess.

NEED OF FURTHER INVESTIGATION.While digitalis gives its most striking results in cases of

very rapid and grossly irregular cardiac action, further

investigation is required as to its-value in less severe casesand before signs of definite cardiac failure have manifestedthemselves. There is a large class of sufferers from cardiacinsufficiency-that is to say, the reserve power of the hearthas gone and the resporrse to anything save mild exertion isvery limited. Take the case of mitral stenosis where theabove conditions are present, but where the pulse-rate is still’

482

normal or slow. I do not anticipate any benefit from digitalisin such a case.In others, however, we find the pulse-rate persistently

rapid and much increased on exertion. It is extremelyprobable that this increase of rate has a definite result inthe way of producing over-action and weakening of the leftventricle, as well as of the right. In several cases of thisnature I have given digitalis in order to prevent weakeningof the heart and to postpone, as far as possible, the onset ofcardiac failure. It has seemed to me that distinct benefithas followed in these cases from the slowing of the heartinduced by digitalis. The action was always on the sino-auricular node, so that the normal rhythm was preserved,and the patients had always had rheumatic infection, so thatthe heart may have been in a sense prepared for digitalis.As a preventive of cardiac failure, the usefulness of digi-talis in slowing the heart under these special conditionsmight be further tested. -

CONCLUSION.I have now dealt, very imperfectly as I know, with some

additions to our knowledge of heart disease, and somechanges in our views regarding it. As an observer I cannotreproduce to you the results exactly as they are but only asthey appear to me to be. Looking backwards we recallwith gratitude the light thrown on the subject of heartdisease by eminent clinicians in the past. Advance inclioical medicine and by clinical methods has not cameto a standstill, Looking forwards we see one of the bestguarantees of future progress in the existence of a band ofBritish workers who are devoting themselves enthusiasticallyto the further elucidation of the problems of heart disease.Miy I add that this Oollege desires to extend to them all thesupport and encouragement in its power.

Literatitre.Balfour. G. W. : Clinical Lectures on Diseases of the Heart and Aorta.

1898; The Senile Heart. 1894.Barr. Sir James: Paroxysmal Tachvcardia. Brit. Meri. Jour., 1904, ii.Broadbent, Sir W. H. : Heart Disease, 1897.B-nnton. Sir Louder: Therapeutics of the Circulation. 1914.Cohn. Fitter, and Jamieson: Influence of Digitalis on the T Wave of

the Human Electro-Oardiogram, Jour. Experimental Medicine,1915, xxi.

Coombs, Carey: Rheumatic Myocarditis, Quart. Jour. Med., 1908.October.

Oushny. Marris, and Silberberg: On Digitalis. Heart, 1912-13. iv., 33.Oushny, A. R. Pharm acology and Therapeutics. 1915.Dixon, W. E.: The Selective Action of Drugs on Nerve-endings,

Proc. Roy. Soc. of Med., 1912. vi., No. 1 (Therap. and Pharm.Section); The Digitalis Preparations Employed in Medicine,Quart. Jour. Med., 19 2, January.

Dunn, C. A : Cardiac Disease in Childhood, Am. Jour. Dis. of Child.,1913, vi.

Eggleston, Cary : The Durability of Digitalis Action, Jour. Am. Med.Assoc., 1912, lix.

Fleming. G. B.: Triple Rhythm due to Extra-systoles, Quart. Jour.Med., 1912. April.

Gaskell, W. H.: The Contraction of Cardiac Muscle, Schiifer’sPhysiology, 1900.

Hume and Clegg: A Study of the Heart in Diphtheria, Quart. Jour.Med.. 1914., October.

Kemp. C. G.: Acute Articular Itheumatism, Quart. Jour. Med.,1914. April.

Lewis, Thomas: Clinical Disorders of the Heart-beat, 1912; ClinicalElectro-cariliography. 1913; The Mechanism of the Heart-beat,1911; Paroxysmal Dyspncea ifi Cardio-renal Patients, Brit. Med.Jour., 1913, ii. ; Auricular Flutter, Heart, 1912, iv.. No. 2; ThePathologv of Heart Function, THE LANCET, 1914. ii., 882.

Lewis and Silberberg: The Origin of Premature Contractions, Quart.Jour. Med., 1912, April. ’

Mackenzie, Sir -Tamea: Diseases of the Heart, 1913; Principles ofDiagnosis and Treatment in Heart Affections, 1916: DigitalisHeart, 1911, ii., No. 4 ; The Soldier’s Heart. Brit. Med. Jour.,1916, i.

Naish. A. E.: Conduction in the Auricles, Quart. Jour. Med., 1914,October.

Parkinson and Rowlands: Strychnine in Heart Failure, Quart. Jour.MId., 1913, vii., No. 25.

Parkinson, John : The Cardiac Disabilities of Soldiers on ActiveSe’vi.-e. THE LANCET, 1916, ii.

Powell. Sir R Douglas: Treatment in Diseases and Disorders of theHeart.1899.

Price. F. W.: Digitalis and the Blood Pressure in Man, Brit. Med.Jour.. 1912, ii.

Ritchie, W, T.: Auricular Flutter, 1914; The Action of the Vagus onthe Human Heart, Quart. Jour. Med., 1912, October.

Rudolf, R. D.: The Use of Digitalis in Practice, Canada Lancet,March, 1914; The Irritable Heart of Soldiers. Canad. Med. Assoc.Jour., 1916, September.

Starling and Markwalder: The Constancy of the Systolic Output underVarying Conditfons, Jour. of Physiol.. 1914, xlviii.. No. 4.

Starling and Patterson : The Mechanical Factors which Determine theOutput of the Ventricles, Jour. of. Physiol., 1914. xlviii.. No. 5.

Starling, Patterson, and Piper: The Regulation of the Heart-beat.Jour. of Phvsiol., 1914, xlviii.. No. 6.

Stevens. H. W.: Electrocardiographic Studies of Patients underDigitalis Treatment, Boston Med. and Surg. Jour., 1916. i.

Wiggers, O. J. : The Circulation in Health and Disease, 1915.Windle. J. Davenport : Prognostic Value of Pulsus Alternans In

Myocardial and Arterial Disease, Quart. Jour. Med,, 1913, July.

FURTHER EXPERIENCES WITH

EMETINE BISMUTH IODIDE IN AM&OElig;BIC

DYSENTERY, AM&OElig;BIC HEPATITIS,AND GENERAL AM&OElig;BIASIS.

BY GEORGE C. LOW, M.A. ST. AND., M.D. EDIN.,ASSISTANT PHYSICIAN AND LECTURER, LONDON SCHOOL OF TROPICAL

MEDICINE.

(Report to the Medical Research Committee.)

IN THE LANCET of August 19th, 1916, Dobell and myselfbriefly described three cases of infection by Entam&oelig;ba histo-lytica treated by emetine bismuth iodide. Two of these havesince been followed up accurately, one W. (No. 3) by Dobell,the other C. (No. 2) by myself. Neither of these has evershown E. histolytica cysts again and C. has had no furtherclinical signs of dysentery. Dietetic errors and cold anddamp have, it is true, produced a certain amount of abdo-minal discomfort and slight pain, but, after extensive ulcera-tion of the bowel, one could not expect otherwise. Withthese symptoms no blood or mucus appeared in the stoolsand, as stated above, no parasites were found. Coincidentwith the disappearance of the dysenteric symptoms thepatient improved in general condition and gained weight.Both these cases, I think, may be considered as complete andpermanent cures. Tables I and II. show at a glance thedetailed examinations of the stools.The value of the double iodide of emetine and bismuth, by

the mouth, in the treatment of histolytica carriers is now

fully recognised; it remained to be seen, however, whetherthe drug would be equally efficacious in cases where liverinvolvement had also taken place. In the following seriesof cases to be described three cases of amoebic hepatitisfigure and, as will be seen later, very good results have alsobeen obtained. In addition an example of the somewhatrare condition "general amoebiasis " is included. By thisterm is meant a febrile state without dysenteric and manifestliver symptoms, yet responding quickly to treatment byemetine. E. histolytica cysts may be found only with greatdifficulty. but if sufficient numbers of faecal examinations aremade they should eventually be demonstrable.

Method of administration.-To begin with, keratin-coatedtabloids and stearettes were tried and appeared to act satis-factorily. In one instance, however, suspecting that thedrug was not being absorbed, the stools were carefullyexamined and three stearettes were recovered quite un-changed. The uncertainty of such an occurrence taking placein other cases decided one therefore to employ the drug inall the other patients as the loose powder in an ordinarygelatin capsule, similarly to the first cases treated by Dobelland myself. The dosage in all the series has been 3 grainsnightly for 12 consecutive nights, as originally recommendedby Dale.A certain amount of sickness occurred in some of these,

but this was never of sufficient importance to interfere withthe continuation of the treatment, and the same may besaid of the diarrhoea which is sometimes met with: Toprevent sickness the precautions that were of use in theipecacuanha days may be employed, the drug, however, inthis instance being given on a full and not on an emptystomach. During the course the patient is better keptstrictly in bed, the diet being arranged in accordance withthe acuteness or chronicity of the symptoms. For mostcases a light diet consisting of milk. white meat, and whitefish will be found most suitable. At 10 P.M. a small mealshould be given, arrowroot, sago, tapioca, or cornflour witha little milk, for example and then immediately after thisthe capsule is taken. Five to ten minutes later someboiling water should be sipped, and this should be repeatedif any sign of nausea or sickness occur throughout thenight. For the first few nights, until one sees how thepatient is to tolerate the drug, the pillows should beremoved so as to keep the head low, no movement shouldbe allowed, and if saliva accumulates in the mouth it muston no account be swallowed, but should be expectorated orremoved by cotton swabs. If after all these precautions thepatient is still sick a mustard leaf may be applied to theepigastrium on subsequent evenings, or 10 to 20 minims oftinct. opii may be given half an hour before the administra-tion of the emetine. Such precautions will greatly mitigate,if not entirely prevent, sickness.The occurrence of this symptom is a very variable one;

sometimes the first doses produce it and then a tolerance isestablished, while in other cases it appears towards the endof the course or irregularly throughout it. Three to fourhours after taking the capsule is the usual time for the sick-ness to appear; there may be one emesis and then no more,