Some Effects of Digoxin upon the Heart and Circulation in Man Digoxin in Combined (Left and Right) Ventricular Failure By M. IRENE1 FERRER, M.D. RICHARD J. CONROY,* M.D.. AND REfJANE M. HARVEY, M.D. HEMODYNA\tXMIC studies of the effects of cardiac glycosides o01 the failing human lieart have beeni numerous aiid have shown one consistent alteration following admiinistration of the drug, nanmely, a rise in cardiac out- put.1-13 Alterations in lesser circulation pres- suires have niot always beecnl homogeneous. h-1owever, they are more or less predictable in failure of olnlv one ventriele. When only the left venitricle fails and a sinlus iiechanism is l)resent, a decrease in the elevated pulmonary adtery pressures occurs after the adininistra- t-ioii of Digoxin and the normal right ventric- ular diastolic pressure shows no change.5 14 In isolated right ventricular failure with this lhythm the elevated right ventricular diastol- ic. pressure falls and pulmoniary artery sys- tolic pressure tends to rise rather than to decline.7 i- 16 In the preseniee of combined ventricular failure, the behavior of these pres- suires has been variable.4 6, 8, 9, 11, 12, 17 The reasons for this lack of uniformity may well l)e due to the presenee of a niumber of physio- logie variables, which are complications of the state of failure but which iionetheless may ini- fluienee the response of the eirculation to (1rugs. Prom the Department of Medicinie, Columbia UUni- versity, College of Physicians and Surgeons and the Cardiopulmonary Laboratory of the First Medical and Chest Services (Columbia University Division), B3ellevue Hospital, N.Y. Supported by a granit from the Life Insuran-ce Medical Researeh Fund, and by a research grant (PIIS Grant H 2001 (C4)) from the Nationial Heart Tinstitute, National Instituites of Healthl IJ.S. Ptublic Thealth Service. *National Heart TInstituite Trai-nee of the Natioinal Institutes of Health. 372 It is the purpose of this investigation to examine the various factors influencing the response of combined left and right ventric- ular failure to Digoxin. Because mechanical factors sueh as valvular or pericardial lesions miiay of themselves alter pressure patterns, pa- tients with such lesions were excluded fronm this presentation. It also seemed wise to group patienits accordinig to basic cardiac rhythm, since it is known that the atrial ar- rhythmias influenee the hemodynamnic picture to some extent.12 Materials and Methods Thirteen patients with hypertensive and/or ar- teriosclerotic heart disease were studied with use of the teclinic of cardiac catheterization. The methods utilized in this laboratory to measure blood pres- sures, cardiac output (by the Fick principle), and blood volume have been published previously.5' 8 The stroke volume was calculated by dividing the cardiac output by the ventricular rate. The pulse pressure was determined by the difference between lie average systolic and average diastolic pressures, which were measured over 2 respiratory cycles in patients with sinus rhythm and 2 or nmore conmplete cycles in those with atrial fibrillation in order to sample at least 10 consecutive beats. It is recog- nized that in atrial fibrillation the values for stroke volume and pulse pressure are approximate. The (letailed protocol and the criteria used for evaluat- ing significant change following the drug are the .same as in previous reports.5 7 Although several determinations of pressures were imade in the con- trol period, only one representative value is giveni il tables 1, 2, and 3. Following administration of the drug, pressure measurements were miade every ) to 15 minutes; however, for the sake of brevity, only the values nearest in time to the deteriinai- tion of caidiae output appear in the tables. All patients had clinical evidence of miiarked pul- nonary and periphert l congestion and were (lassi- fled as IV-D at the time of study according to the ;rcGla'i<Vn, Volume XXI, March 1960 by guest on March 17, 2018 http://circ.ahajournals.org/ Downloaded from
Transcript
Some Effects of Digoxin upon the Heart andCirculation in Man
Digoxin in Combined (Left and Right) Ventricular Failure
By M. IRENE1FERRER, M.D. RICHARD J. CONROY,* M.D..AND REfJANE M. HARVEY, M.D.
HEMODYNA\tXMIC studies of the effects ofcardiac glycosides o01 the failing human
lieart have beeninumerous aiid have shown oneconsistent alteration following admiinistrationof the drug, nanmely, a rise in cardiac out-put.1-13 Alterations in lesser circulation pres-suires have niot always beecnl homogeneous.h-1owever, they are more or less predictable infailure of olnlv one ventriele. When only theleft venitricle fails and a sinlus iiechanism isl)resent, a decrease in the elevated pulmonaryadtery pressures occurs after the adininistra-t-ioii of Digoxin and the normal right ventric-ular diastolic pressure shows no change.5 14 Inisolated right ventricular failure with thislhythm the elevated right ventricular diastol-
ic. pressure falls and pulmoniary artery sys-tolic pressure tends to rise rather than todecline.7 i- 16 In the preseniee of combinedventricular failure, the behavior of these pres-suires has been variable.4 6, 8, 9, 11, 12, 17 Thereasons for this lack of uniformity may welll)e due to the presenee of a niumber of physio-logie variables, which are complications of thestate of failure but which iionetheless may ini-fluienee the response of the eirculation to(1rugs.
Prom the Department of Medicinie, Columbia UUni-versity, College of Physicians and Surgeons and theCardiopulmonary Laboratory of the First Medicaland Chest Services (Columbia University Division),B3ellevue Hospital, N.Y.
Supported by a granit from the Life Insuran-ceMedical Researeh Fund, and by a research grant(PIIS Grant H 2001 (C4)) from the Nationial HeartTinstitute, National Instituites of Healthl IJ.S. PtublicThealth Service.
*National Heart TInstituite Trai-nee of the NatioinalInstitutes of Health.
372
It is the purpose of this investigation toexamine the various factors influencing theresponse of combined left and right ventric-ular failure to Digoxin. Because mechanicalfactors sueh as valvular or pericardial lesionsmiiay of themselves alter pressure patterns, pa-tients with such lesions were excluded fronmthis presentation. It also seemed wise togroup patienits accordinig to basic cardiacrhythm, since it is known that the atrial ar-rhythmias influenee the hemodynamnic pictureto some extent.12
Materials and MethodsThirteen patients with hypertensive and/or ar-
teriosclerotic heart disease were studied with use ofthe teclinic of cardiac catheterization. The methodsutilized in this laboratory to measure blood pres-sures, cardiac output (by the Fick principle), andblood volume have been published previously.5' 8The stroke volume was calculated by dividing thecardiac output by the ventricular rate. The pulsepressure was determined by the difference betweenlie average systolic and average diastolic pressures,which were measured over 2 respiratory cycles inpatients with sinus rhythm and 2 or nmore conmpletecycles in those with atrial fibrillation in order tosample at least 10 consecutive beats. It is recog-nized that in atrial fibrillation the values for strokevolume and pulse pressure are approximate. The(letailed protocol and the criteria used for evaluat-ing significant change following the drug are the.same as in previous reports.5 7 Although severaldeterminations of pressures were imade in the con-trol period, only one representative value is giveniil tables 1, 2, and 3. Following administration ofthe drug, pressure measurements were miade every) to 15 minutes; however, for the sake of brevity,only the values nearest in time to the deteriinai-tion of caidiae output appear in the tables.
All patients had clinical evidence of miiarked pul-nonary and periphert l congestion and were (lassi-fled as IV-D at the time of study according to the
criteria of the New York Heart Association. Thepatients are grouped in tables 1 and 2 accordingto the presence of sinus rhythm or atrial fibrilla-tion. Details of diagnoses can be found in thesetables as can the dosage of Digoxin administered.Of those with sinus rhythmi, 1 (no. 625) had hadsymptoms of failure for 3 years and was the mzostdisabled of this group. The duration of complaintswas much shorter in the 4 others in table 1, rangingfrom 1 to 6 months. Two (nos. 417 and 625) hadlhad infrequent miercurial diuretics but none of the5 had ever received digitalis bodies. One mnan(no. 519) had needed 3 thoracenteses on the leftbut had reaccumulated pleural fluid before hiscatheterization. In the group with atrial fibrilla-tion, 3 (nos. 588, 682, and 794) had had previousepisodes of failure for which they had been digi-talized. They had discontinued the medication,hlowever, 6 weeks, 4 months, and 5 months, re-spectively, before the study. Symuptoms of failurerecurred almost immiiiiediately in 1 man (no. 682).In the other 2 (Inos. 588 and 794) as well as inthe remuaining 5 who were never digitalized, thesymptoms had been present for less than 1 mlonthprior to admission to the hospital. Two subjects(nos. 453 and 794) had received 1 or 2 doses ofmercurial diuretics and in 5 (nos. 453, 806, 544,794 and 940) thoracenteses were required to allevi-ate severe orthopnea but chest fluid was presentat the timie of study, as indicated in table 2.
It is of interest that in the group of patientswith sinus rhythm the symnptoms of left ventricularfailure preceded those of peripheral congestioni )Xya considerable period of time, while those inli-viduals with atrial fibrillationi complained of symp-toms of right ventricular failure very shortly a;-fterthose of left-sided failure had appeared.
ResultsPatients with Combined Left and Right VentricularFailure and Sinus Rhythm
Prior to administration of Digoxin the car-diac output in 4 of the 5 patients (table 1)was lower than normal and there was mod-erate to severe pulmonary hypertension witha wide pulse pressure and an elevated riglutventricular diastolic pressure. Total bloodvolume was increased in all 5 subjects. Thleplasma volume was lnormal onily in the 1 pa.-tient (no. 417) who had had repeated diuret-ics. The ventilation was also elevated in all5 but the oxygen uptake was within miormnlalimits. Mild to moderate arterial blood oxy-geni unsaturatioii (93 to 85 per eniit) occurredin 3 subjects.Circulation, Volume XXI, March 1960
CARDIACINDEX a 3 00o -
IL/min./m, BSA) fSTROKEVOLUME A V
(ml) 00 0
VENTRICULAR 60RATE
(bects per 120 -minute) 80 r .
PULMONARY 6ARTERYAND
so
RIGHTVENTRICULAR '0\PRESSURES
(mm. Hg)3
B A B A B A 8 A B A 8 A.5 .625 .453 8 06 .544 .682
Figure 1He XRBodynamic responses to the acute (iodm iiistra(i-tion of Digoxin in patients with left and rightventricular failure. The symbols are identified asfollows: the square indicates the cardiac index;the triangle, the stroke volyme; the target dot. theventricular rate; the solid circles, the systolic a.ddiastolie pulmonary artery pressures; the openicircles, the right ventricular end-diastolic p-res-sures; and the cross, the pulmonary artery meanpressures. B represents values before and A valuesafter Digoxin. Patients 519 and 625 were in sinusrhythm and the remaining 4 were in atrial fibril-lation.
After Digoxin was given (via the catheter)the cardiac output rose in all patients (9 to94 per cent) as did the stroke output. Theheart rate fell in all, although hardly in a
striking fashion (from 3 to 15 beats per min-ute). The changes in systemic arterial pres-sures were not great although there wvas a
tendeney to an increase in the systolic levelwith little or lno fluctuation in diastolie orniean pressure. The right ventricular diastoliepressure declined in all 5 patients.
In 3 of the 4 patients in whom measure-iients of pulmonary arterial pressures were
available, the systolic, diastolic, meani andpulse pressures decreased (as exemplified byno. 519 in figure 1) while in the fourth (ino.625) the signifieammt chaniges were a fall in di-astolic amid a rise in puilmonary artery pulsepressuire (fig. 1). In this fourth case a secoiid
study was made 19 days after the first, atwhich time he was iio longer considered eliii-ically to be in failure. The seconid catheteriza-tion (table 1) revealed a cardiac outplut whichwas higher thani the final post-Digoxini valuein the first study, a striking decrease ini allpulmonarv artery pressures, a further drol)in right ventricular diastolic pressure, and nochange in the large blood volume. None of thesubjects in this group with sinius rhythm hadany change in venitilationl after Digoxin.Patients with Combined Left and Right VentricularFailure and Atrial Fibrillation
The level of blood flow in these 8 individ-uals was markedly reduced (table 2) with acardiac index of less thani 2.0 liters in everyinstanee. In each there was elevationi of alllesser circulation pressures but the level ofpulmoniary hypertelnsion was (quite differenitfrom that of the grou) with sinus rhythmn;the systolic anid pulse pressures were muehlower. Tricuspid insufficieney was presenit iniall 8 patienits as judged from the right atrialpressure curves. Total blood volume was uni-versally increased and the onily subject witha normal plasma volume (lno. 453) had hadseveral doses of merelurial diuretics. In thisgroup too, venitilation was increased but theoxygen uptake was within normal limits. Mildarterial oxygen unsaturation (92 to 93 percent) occurred in 3 subjects.After administrationi of Digoxin the cardiac
output iniereased, 13 to 73 per cent, and theventricular rate deelinied to a greater extentthan in the group with sinus rhythm. Therewere also large inereases in stroke volume.The changes in systemic arterial pressureswere the same as in the group with siinusrhythm. The right ven-tricular diastolic pres-sure fell in the 7 instaniees in which it waasmeasured.The alterations in the pulmoniary arterial
pressures produced bv the drug in these 8subjects can be divided inito 2 types. In thefirst, as seen in 3 patients (nos. 453, 806, and544), the diastolic pressure fell after Digoxinbut the systolic response was variable, falling(no. 453), remnaininig the same (no. 806), anidCirculation, Volume XXI, March 1960
rising (no. 544) (fig. 1). In all, the pulsepressure rose. In the seconid type, as occurredin 5 patients (and as is exemplified by no. 682in fig. 1) there were minior pressure changesin the pulmonary artery systolic and dias-tolic pressures but the pulse pressures in-creased in 4 of the 5 durinig the periodobserved. In the fifth (no. 794) the pulsepressure remained unehanged. Venitilation didnot alter after Digoxini in anyv of these pa-tients.
Fortuniately, it was possible to restudy 4 ofthese 8 patients (nos. a44, 588, 682, anid 794)when elilnieal evidences of congestive failurebad disappeared. All lesser circuit pressureswere lower at this later date even thoughblood flows were approximiiately in the samerange as on the first study (table 2). Thel)lood volumes were also considerably loweralthough not one was niormial. The ventilationiremained unchanged at the time of the secondevaluationi, despite the improvemnents in the('ireillation.
DiscussionHemodynamic Considerations
As was expected, the inotropic eflect of the'lug was expressed by a rise in cardiac out-put in all 13 subjects. Heart rate decreasedill all and contributed to the accompanyingincrease in stroke volume. The average in-crease in stroke outpuit in the patients withatrial fibrillation was 77 per cent as comparedto 46 per cent in those with sinus rhythm. Theeff-ect on ventricular rate was mnueh greater(an average deeline of 28 beats per minute)in those with atrial fibrillationl thani in thosewith sinus rhythm (8 beats per minute).Ileart rate, however, and output did not al-ways vary in a consistent manner, as therewere large increases in blood flow with onlvsmiiall changes ini rate (iio. 519, table 1) an-dlarge falls in rate with less impressive risesin output (nio. 453, table 2). There was nofixed relationship in time betweeni changes inventricular rate and cardiac output. In somepatients (nos. 544 and 940. table 2) there wasa progressive fall in the heart rate anid a con-it)inniing rise ill output, while in others the veni-
l ise in cardiac output (nos. 433, 388, and 682,flable 2), and in still others the ventriculariate fell at first anid then becanie relativelystabl.e although the cardiac output continuedto rise (iio. 519, table 1; lios. 806, 588, 437,and 794, table 2). Furthermore, the changeill ventricular rate, both in terms of magni-tiide and timing, gave no indication of altera-ti.ons in lesser eirculation pressure.
The same dichotomy between heart rate andthe other hemodynamic effects of the drug can
be shown in 2 other subjects (table 3) wholiad a rise in ventricular rate but nieverthelesshlad iniereases in cardiac oultput aind decreasesiti lesser circuit pressures, the latter 2 altera-tions speaking for a contilnued ni-yocardialeffect of Digoxin. Both subjects had pneu-ri-onia (no. 492 raii a temperature of 100.2°p).r. during study) which was probably re-
sponsible for the elevated oxygen uptake.Nevertheless the respiratory quotienits re-
intained normal and stable during the obser-vation period. In olie (nio. 492) sinustatchyeardia imiereased at the seventeenth mili-ute, and in the other atrial flutter with 2:1and 3 :1 AV response began at the thirty-fourth miiiute after Digoxin. Despite theirrore rapid veiitricular rate the cardiac out-put rose and lesser circuit pressures continuedto decline.
F'urther evidence of imuproved venltricularfVinction following Digoxiii can be found inthe uniiform decrease in right ventricular end-(.iastolie pressure; presumably the increase insystolic ejectioli resulting in a decrease in(liastolic right ventricular volume. Betteremptying of the left ventriele can be inferredfrom the drop in the pulmonary artery di-astolic pressure in the 7 patients in whom itoccurred, since in the abseniee of vascular dis-ease or demionstrated vasoniotoricity the levelof this pressure is primarily regulated byevents in the left heart. In these patients theleft ventricle must have ejected more bloodth.an was offered to it by the right and there-fore as a consequenee of a temporary hetero-dyilanmism of the 2 ventricles, there was a
Circulation, Volume XXI, March 1960
redluction in pulmonary blood volume. In aof the 8 patients with atrial fibrillation the1iulmionary arterial diastolic pressure did notfall significantly (-1 to -4 mm. Hg) ; none-Ilh.eless one must assume that left ventricularlunction was imiproved, since this ventriclewas able to accept froin the right ventricle itsaldditional output anid deliver this additionialvolume to the aorta. It- did so, eveni though itcould not signifieantly reduce its owIi diastolicpressure as evideneed by the lack of changeii. pulmonary artery diastolic pressure. Hencethere was probably no change in pulmoiaryblood volume. The fact that the pulmonaryartery diastolic pressure remained elevatedand unchanged could be explained by onie ofthese 2) mechaniisms-either the left ventric-ul-ar diastolic volume had not been reducedand henee the diastolic pressure remainedelevated, or, there was a change in left ven-tricular myocardial tonie, so that, despite afall in diastolic volume, diastolic pressure re-meained unchanged. The lack of change inpulmonary artery diastolic pressure cannot beascribed to pulmlonarv vascular disease, sincea seconid catheterization in 3 of these 5 re-vealed a later drop to virtually lnormal levels(table 2).A further word should be said concerning
the differenee in responise of the pulmonaryartery diastolic pressure. It could not be re-lated to the level of total blood or plasma vol-umes, as these were equally large in those whodid or did not have a fall in this pressure(tables 1 anid 2). The dosage of Digoxin givenwas also similar in the 2 groups. The etiologicfactor of the heart disease and age of the pa-tient also appear not to be different. It is in-teresting however that 3 of the 5 patientswithout this pressure change had had a pre-vious bout of cardiac fiilure. In all 8 patientswith atrial fibrillation the clinical story sug-gested the onset of symptoms of right heartfailure aluost as soon as left, in contradistine-tion to patients with sinus rhythm where left-sided symptoms antedated those of right bysome time. This time differenice could be in-terpreted as indicating a more or less simul-
Figure 2Relationship between pulmonary artery diastolicand pulmnonary artery pulse pressures when strokerfiolumne is ojier 30 kml. The correlation coefficient ishighly significant (r = 0.505, p < 0.01).
taneous failure of both ventrieles in atrialfibrillatioln, with both equally involved, whilein the subject with sinus rhythm there was
more involvemelnt of the left venltriele. In. thelatter after Digoxin, one could say that theinotropic effect of the drug would be greaterin the more involved ventriele and heniee itwould empty more completely. This reason-
ing could also apply to the first 3 patientswith atrial fibrillation in table 2. In the 5patients who did not have a fall in pulmonaryartery diastolic pressure, emptying was thesame for both ventrieles durilg the acutestudy of Digoxin. Henee there was no imme-diate change in pulmonary blood volunme.Later, there was a reductionl in pulmonarvblood volume and a fall in pulmoonary arterypressures. This may have occurred either be-cause heterodynamism appeared. with the leftventricle becoming capable of emptyinog more
than the right, or, with a fall in total bloodvolume (due to diuresis) the right ventriclenio loniger ejected as muieh into the lungs, theleft could still discharge this amioulnt butcould then add more of its own diastolic vol-ume to its stroke volumne and thus reduee thepulmonary blood volume.The behavior of the pulmoniary artery pulse
pressure was variable. This is not surprising,sinee pulmonary artery pulse pressure reflectsnot only stroke volume but also the state of
disteiisibilitv of the pulmoniary vascular tree.This latter is governed by the level of pulmo-nary blood volunme anld the intrinsic charac-teristics of the vessels themselves. The nornmalpulmoniary vascular bed is so distensible- that:r.elatively large changes i: flow have verylittle effect oni pressure. However ocee thesystem becomes distended, either bv aii i-crease in pulmonary blood volume or a ehanigein the characteristics of the vasculature. tlhen.changes in volurne or flow will producechanges in pressure. Thus onie inight expectthat the greater the stroke volume or thegreater the degree of pulmionaryv congestion.the higher will he the pulse )ressure.
Since more thaii onie physiologic variable isoperating to affect. pulse pressure under these('ondition.s, their relative inifluence imust be ex-am imied. Direct miieasuremenit of pulnmonaryy1)lood0 volumiie aind estimates of the character-isticds of the vaseulature are not Yet availablehut onie can get ani indirect. estimate of thedegree of pulmuoinary conigestioni fromn the pul-iionlarv arterv diastolic press-ire, pr-ovidledtlhere are no mnajor alterationis in the charac-teristies of the pulmlronaryv vaseulature. Sincenii the patients iii this stuidy one would not ex-peet such1 alterations, onle can assume that thediastolic pressure is largely determined by thepulnionary blood volume. Stroke volumle isprobably estiimated fairly accurately.Thus in order to clarify this particular
l)roblemn a study of the initerrelatiotnships ofpulmonmary artery pulse pressure, diastolicpressuire, and stroke voluime was nmade.Since the 13 pattienits presented in this reportwould comip:rise a rather small group, thestudy was enlarged to include 67 observationsin 39 patients with degenerative heart diseaseand pulmiioniary congestion. These data weresecured both at rest and durinig exercise an(d:include the patients found in tables 1 and 2before digitalizationi. It was found that, inlgeneral, as the pulmnonary artery diastolicpressure rises or falls, so does the pulmonaryartery pulse pressure, as long as the strokevolume is over 30 ml. (fig. 2). The correlation(coefficieiit is highlv sigllificallt (m. 0.050p < 0.01). Below this critical level of stroke
ti/f r eitfi/ l b /si (,/iliif/t ttre tlelintitefi i cross barit
the 2 areas of' stroikt rt)luitttt fdjs(toss,,efd ii ti/ete.
V ottf ti//t ji llSe fies 1/ire rises //it/I n fdi
is 00 to 70
It t /is iS t t ilh i s
"0 vit/ it tl fcr
o ot fol l io t is du s
t tttt r re ih s
volu mec, s1 i11o /correlation a nld p1ll,',5(
of the l.evel of dliastoilie l)tessluFe. unil.ess the
latter. is over 30 mnlt. JIgo (fig. 3). rrhe ill
fluecue of st.roke votlmne o1i l)mlse pressure, is,
tIot (1s defined atethe level- of pmtl
moiiary blood. volumie, mtay also aff'e/t thec re-
latiotiship. As already stztte(l, if the stroke
volumeic is less,- tlatn 30 nitl., 110n) l)ttsc ipressur'eremains low uinless -vetv hig.h level- of di-
astolie P)1 DCssliPe is 0)e oe vol-
time exceeds 3() tol., 8is it r.ises so does lie
p)u118 pressure (fig. 4). If1 th,ie at-
tlery diastol-ie, is olilly~ slightly elevated (f/ot
example, betweett 10 atld 15 inmi. 11g as
sliow ni on- fig.. 4), tIl' volitnie
aI s alle..1 ,r ill1 )11180m tIla the
stroke volmnle wouldlL/115 at a hnfigher level
a rter P reSssure (O n cesee t hie ni (fig. 5) thati 1111i st r.o volinle allId(-liastolie are 11o)1h lse I)1/s-sure will 1)b all/ wvliell hoth
so will. heO the I)1i180 Ljooked at
thit )oillt of view of efle/'t ol sing-le
variable. the highei r tIl-- diastolie.
Ili gIlle the pul1s d8 the lo wve
1I toe we r. the pulse
Circua/tion, 1)t1i//ttt/ XAI, Mari/i 1960
PAPI.
1H
Figure 4
(/11ptin l/iIdttr/~ IMst prt ssorc hl f /the crtclbars). Th?e sbstHibnts cat los ct ti/f
clocs the j)iiNts f/Sssure, r7sf is riole /ittt fJ/7/s
b/gnCd1tt ti//It if, tilt ditti trstr s ti/I//iskqitfiei d 4 10 tt It5 in t. 11/7 u~si//f I
ovf shadedt tir/I) ti/o st ol/0//t/f }irffl/cf S i
i/SI//t c/i//st t/t ti ilf itet it e o! lts h jtso('tq25 tti Ha- tiIt. li ts setnit itt oti/ftt/r sit iteti
lIt'lc finial Iorisit t111/ )051/ l il
deli1Cate balanee 01 1-11/'elet of tlles/ 2 vat ia
bios, and ill all p)lo1ba1ility oil wIX bll o111/ is I lIeiiioreaboml
T~he vaMiitsilpliott alt/Tv l)11Is/l)1t'551l' '801 aft/r Diotoxiii c811 l/low be eluici-dated bv eoli1Ttg~webch of till abloxe aCi-A&Ses,1 Pre1lliltg11 5s 1.11' /1teiiclat ion10(.ad2ut8st to the illottoj.)ie' otftttltediiiAll1 of the patieiits withi sinuis H, vi lIlt ichad a
laroQe p11isc 1)r0881110 (table 4) before1( l igoxi.TIn 2 (tnos. 5l19 an1( 625) . despite Iib ott blot o atthe eritical level lot str-oke( voltl1nl, 29 atnl :30in]. respectiv/'ly, thecre w~as, a v/t-v hligh1 pl)l1io)nayartery /iat)f1 )/511 l/ Itt ch
001nd mnr rC/ pcrlsc snc(odctcIly tire vetial rs). The uprshadedretnlc at/c01te010 rti,het'c 1)011 stroI e olncand (lire.-
tolic pre.snare aire laruje and in whir-h jirles/11S (is also lnrt,c rchile 1110 1011cr rc ctc#tile
eloses OIl 1r(1 ill 11hich oP3cllc r smara/.
somen p)uliionany 1m)1((( volume decreased. Th'irfouth )Ptlclt(no1. (125) w ho 110(1 a m-uch
smallr fal iii iastoi~' ;ressire itlite iresuit that this prsue(11( not leraebelow30 iuui o.JI,rs)l(d to a r-ise inl s,trokce vol-1hiltc (wh-11ich then mIoved hiun above the e"ritien,illevel of 80 mil,.) wiha r.ise iii 1)1115 pr.essure.Sinee pulmonavyx pr-essures later fell mnark-edlly, (setalble 1, iio. (625, seceod su>)thejinereasedi plIlse prsueafter l)igoxin e.anuothe aserilbed to 1pulmiioiitti.rv vaseular. disease huitwas, r.elated to a lrePul1monary. 1)100( vol-unine thiat later beeanIie iran.~.is,loeate..CI
Thle S aiet with atrial fibrllWation hadmu11ch smllr l)lllonary artery pullse pres--soMres iefr the uirug. thanl d idtos withisinus r.hyllthm. T1i1e smnall puilse pesrswerel)robal)ly primarily related to thec smuall strokevolume w ihwas cosdeal lss, thian 80nil. inall- but I- in.dividuial (nio. 794, table 4)
111in this one exception it xvas 88 itil. Bfrtire glloid.te low stoevolume, by -virtueof' its moilt igeal to disen te p 111100-naryree,olrscreclthe evidenlce (If pulmonary.111.
stroke volumec PA,,, jrnl11ornnA r C rter pulse pr-essure.
s'ure. 'lTherefom' oile can sa-that it oceurreniwXhenl b)lIoL x Ilood voluime 110(1 not
liigdor had dcardoinly slightly. When--s,tr~oke( volume did trot inraestrikingilly, lessthan;ii 501 per cent (nios. 458., and 7794 in table-F) th1ere was little or nio effec"(t omi l)ulse pres-sine.oInone individucal (nio. 458) thie 48 per
rent. rise iii) stoevlm a ounterbal,anced LX a fall (If 10 mm11. Jig inl pulmouaryartery (liast oliT9rcs r.'ire othier patient
no1.. 794) lid irot hiave iothl dlistention of the.,puIrtoimarv vascular bed (as 'indha.tA~ by thereaieylow level of dias.,tolic, pressure, 106
11---h) .Under strucirusacs sincesroevolume was ared above the citical
neV(,1lto begimi withl and iuse ounly tdsl (35JIP ent) and (litIpil)essure did Itot fallsioiicatlvmon would nlot, e'xpec't ae chanlge
ill the(" pnllsc 1pre5s c.(
Clinical Considerations
Seerlclnical. imnplicatioirs, tha,"t bear 1111011evaluatiolt of thle effects ofSlsuch a ding-- at timebdie am be nicrived fr-ont thi1s, study. Fir-st,
hle amoni(11t ol l)igoxinl givenl iirti.ravcnloosly toa pcatient :ni cogs iveailure. nediot he the
so-called "digitalizing" or "full*' dose (1.5mg.) in order to elicit marked hemodynamicchanges toward normal. Ten of the 13 sub-jects received less than this dose (0.75 to 1.25ing.), and 2 of these had reached normal lessercirculation pressures at the end of the periodof observation (inos. 616 and 417). The ear-
liest moment at which any effect of the drugwas noted (change in heart rate, pressures or
output), w,vas a minutes after the completionof the injection of drug (the administrationof the drug itself took a minutes). All pa-
tients had had some effect from the medica-tion by 30 minutes. It is interesting that the2 cardiotonic effects of the drug that were
measured in this study (a rise in cardiac out-put alnd a fall in lesser eirculatioln diastolicpressures) did not necessarily occur simulta-neously, i.e., one could appear before theother (nos. 919, 417, and 453). In one subject(no. 919) the right ventricular diastolic pres-
sure fell somewhat before the pulmonary ar-
tery pressures declined and this effect was
patent 10 miniutes after Digoxin, before any
obvious rise occurred in cardiac output. Fiur-thermore, stroke volume had increased onlyslightly (3 inl.) and heart rate fallen only 6;beats. Thus it appears that improvement iniventricular funetioni evoked by Digoxin is a
complex and initerdigitating series of mech-anisms and the fundamental and earliestevent is still unknown and is not uniformlyexpressed in any one hemodynamic alterationi.
These observations render somewhat tenu-ous the present clinical immethod of judgingdigitalization in which the cardiotonic effectof the drug is timed and assumed to occur al-most solely in relation to the response of theventricular rate ;18 the implication being thatif rate is niot affected the myocardial effecthas not occurred. This reasoning would beparticularly erroneous in patients with sinlusrhythm. This concept of the secondary posi-tion held by change in rate has recently beentreeniphasized by McMichaell9 on the basis ofstudies made in his laboratory.20 Althoughchanges in rate miav evetntually appear follow-ing this drug, it is now clear that the con-
tractile myocardial effects may precede theni
Circulation, Volume XXI, March 1960
by somy-e time. Thlus one should beware of in-creasing the amounit of glycoside early in itsadministration if the rate response is negligi-ble.Another clinical sign that has been much
used to determine the so-called digitalis effectis alteration of S-T and T waves and Q-T in-terval of the electrocardiogram. These varia-bles were examilned in relation to themyoeardial effect of the drug in 12 of the 13patients: the one (no. 623) with left bundle-branch block was exeluided. In 11 the stand-ard leads were followed and in the twelfthonly lead V1 was monitored after the drug.There were no S-T shifts in any patient; in11 of 12 there were nio signiificant alterationsin the T waves but in one subject (no. 417)T2 became upright from an isoelectric con-tour. The Q-T interval was not always meas-urable due to low voltage T waves but in 7 of9 subjects where this was feasible, there wasno change and in 2 the interval shortened. Itis obvious therefore that electrocardiographicsigns are lnot constantly indicative of the he-modynamie results of this drug and that thewell known S-T, T, and Q-T changes may notappear early in the period after Digoxin.
The bedside diagnosis of congestive (rightand left) heart failure usually depends uponcertaini objective signs in addition to thesymptoms of dyspnea, orthopnea, and fatigue.A mid or protodiastolic gallop, pulsus alter-nans, cardiomegaly, hyperventilation, pulmo-nary rales, hepatomegaly, peripheral venouscongestion, edema, and cy anosis are alsosearehed for. Following the hemodynamicevidences of marked improvement in cardiacfunction, the patielnts were reexamined at theend of the study period anid before returningto their ward, in order to correlate the speedwith whielh these objective signs would mirrorthe improved circulatory status. The galloprhythm, when preseit, almost always subsidedby the ell(l of the study; pulsus alternanswould often disappear, occasionally from oneeirculation, say the lesser, before the other,as previously reported.21 The other signs forthe most part remained unaltered at the com-pletion of the observation period. Hence it
is apparenit that rales, hepatoniegaly, anidedema are slower to disappear thani the pres-sure abnormnalities that mav be related totheir productioni. The lungs, liver, and sub-cutaneous tissues are therefore depots thatnay remiain as passive pools of congestion andgive up this state rather slowly. This fact mayexplain some of the elinical paradoxes onesees, e.g., where the peripheral venous pres-sure may be normiial or the patient free ofdcyspnea and yet hepatom-zegaly, edemia and(rales are found. The sequence of old and re-cent events must be considered ini such even-tualities anid the assumption iiade of previousventricular failure and slow resolution of thecongestive phenomena. OIn the other hand,following Digoxin there was always ani earlysubjective improvenmen.t in dyspnea and or-thopnea although hyperventilationi persisted,an observation also made by Eichna et al.9Therefore the persistence of hyperventilationat an unchanged level does niot represent abarrier to the relief of some of the dyspnea.Furthernmore, the hyperventilation did inotdiminish in those patients with a decrease inipulmuonary artery pressures eveni if thesereached nornial levels, tending to show thatthis ventilatory response is miot closely linkedwith pressure elevations in the lung vessels.It is also worth noting here that there is nioelevation in basal metabolic rate in these pa-tieiits with congestive failure and pulmo-narycongestion.The slow disappearance of some of the ob-
jective evideniees of congestive failure despiteindicatiolns of the cardiotonic effects of theglycoside anld resolution of much if not all ofthe pressure abnormalities, has considerablebearing upoii the elinieal problem of intrave-nous administration of this medication in aiiemergency situation. It has been the practiceof some to 'redigitalize'? a patient orally theiorning or day after an intravenous dose hasbeen giveni, particularly if some of the above-imentioIned signls are unialtered. From the ob-servationis just cited it can be seen that thisoral exhibitioii would theni in many instancesbe directed at a circulation and a myoeardiuni
iadically differenit froim wvhat they had beenbefore the intravenous (lose. There is no in-formationi to suggest that in 12 to 24 lhoursthe eirculation has returniecl to the state inwhich it was found prior to the first admini-istration anid that a se( oind large or "digital-zing ldose is nieeded.
Summary and ConclusionsThe acuite effects of initravenous Digoxiin
were studied, with use of the cardiac catheter-izationi technic, in 13 patients with hyperten-sive or arterioselerotic heart disease incombined (left and right) ventricular failuire.Two patienits who ill additioni had broneho-pienmiiolmia were also included to demonstratethe dichotomy between the iniotropic effects ofthe drug and changes in heart rate.
Digoxin produced a rise in cardiac outputanid a fall in right ventricular end-diastolicpressure in every case.The readjustments of the pulmonary arte-
rial pressures after the drug were analyzedand it becam[ne apparetll that the interrelationt-ship between stroke volume and the degree olpulmonary congestion was the basic variableregulating the several different responsesfoutnd after Digoxini.
Several elinieal amid hemodynamic consider-ations bearing upon the whole concept of a'digitalizing" dosage, the relationship be-tween hemodynamic and electrocardiographicalterations of the drug, the inadvisability ofusing the effect upon ventricular rate as a re-liable guide to its cardiotonie behavior, anidthe disappearance time of the clinieal signs ofcongestive heart failure in relation to theearly lhemodynamic improvemients were alldliscussed.
SummariL in InterlinguaLe effectos acute del adminiistration intraveniose de
Digoxina esseva studiate per mnedio del teclinica decatheterismo cardliac in 13 patientes con morbo cardiachypertensive o arteriosclerotic in disfallimento ven-tricular combinate (sinistre e dextere). Duo pa-tientes, qui habeva brolnlcio-pneumionia additional,esseva etiam studiate pro demoinstrar le dichotonliainter le effectos iniotropic del droga e alterationes inle frequentia del corde.
Digoxina produceva uIII augmiieinto del rendimento
cardiac e un reduction del tension termino-diastolicdextero-ventricular in omne le casos.Le re-adjustamento del tenision pulmono-arterial
post le droga esseva analysate, e il deveniva appa-rente que le relation inter le volumine per pulso e legrado del congesti.on pulmonar esseva le variabilefundamental que regulava le plure differente respon-sas observate post le uso de Digoxina.Es etiam discutite plure punctos clinic e hemody-
namic de interesse ab le puncto de vista del coneeptogeneral do un dosage ''digitalisante,'' le relationinter le alterationes hemodynamic e electrocardio-graphic producite per le droga, le riscos inherente inle uso del effecto del droga super le frequentia ven-tricular como criterio de su action cardiotonic, e letempore del disparition del signos clinic de conges-tive disfallimento cardiacin relation con le precocemelioration hemodynamic.
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Circulation, Volume XXI, March 1960
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is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.21.3.372
1960;21:372-385Circulation.
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