THE EFFECTS OF THE CARDIAC GLYCOSIDES UPON THEDYNAMICS OF THE CIRCULATION IN CONGESTIVE HEARTFAILURE. I. OUABAIN

Richard A. Bloomfield, … , Laurence B. Ellis, M. Rita Lavin

J Clin Invest. 1948;27(5):588-599. https://doi.org/10.1172/JCI102004.

Research Article

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THE EFFECTS OF THE CARDIAC GLYCOSIDESUPONTHEDYNAMICS OF THE CIRCULATION IN CONGESTIVE

HEARTFAILURE. I. OUABAIN1, 2

BY RICHARD A. BLOOMFIELD, BERNARDRAPOPORT, J. PERVIS MILNOR,WALTERK. LONG,3 J. GILMER MEBANE, AND LAURENCEB. ELLIS

WITH THE TECHNICAL ASSISTANCE OF M. RITA LAVIN

(From the Thorndike Memorial Laboratory, Second and Fourth Medical Services [Harvard],Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston)

(Received for publication December 22, 1947)

INTRODUCTION

While the clinical recognition, and even quanti-tative appraisal of congestive heart failure is a

matter of routine in the practice of medicine, no

precise definition of this state has been formulatedwhich is equally satisfactory to clinicians, physi-ologists and pathologists. There seems little doubtthat among the many aspects of the circulationwhich may be affected when cardiac function isabnormal, no single abnormality is always themajor or primary factor, nor need any single one

invariably be present. This is true for changes incardiac output, blood volume, sodium retention,diastolic heart volume, mechanical efficiency of theheart, peripheral venous pressure, intracardiacpressures, and peripheral vasomotor reactions. Itis nevertheless true that clinically the diagnosis ofheart failure is made by the detection of signs andsymptoms referable to abnormal increases in thevolume of blood in various parts of the circula-tion-and the assumption is made that these in-creases are the result of aberration in cardiacfunction.

Equally a matter of routine in clinical medicineis the administration of a cardiac glycoside, eitherin a relatively pure state or more often as digitalisleaf, in the justified expectancy that it will serve

to help dispel and prevent recurrence of conges-tive heart failure. Yet, in spite of a voluminousliterature upon the subject, there is still great di-versity of opinion as to the site and mode of ac-

tion of these drugs upon the circulation, especiallyin human beings, and as to differences among theindividual drugs in these actions.

1 The expenses of this investigation were supported bya grant from the Life Insurance Medical Research Fund.

2Read at the Meeting of the American Society forClinical Investigation, Atlantic City, May 5, 1947.

8 Post-graduate Research Fellow, Life Insurance Medi-cal Research Fund.

The object of the present study is twofold: first,by the application of certain newer techniques, togain further insight into the action of variouscardiac glycosides in patients with congestiveheart failure; second, to gain information as tocausal relationships between the various circula-tory abnormalities, from a study of the emergenceof patients from congestive failure.

Thirteen patients with heart disease, with and withoutclinical evidence of congestive failure, were chosen whohad not received any cardiac glycoside within three weeks.The one exception to this was Patient No. 12, who wasgiven 0.6 mg. of ouabain 12 hours before the controlobservations reported. Most of them were studied within12 to 24 hours after admission to the hospital. Therapyhad consisted of rest, sedation and occasionally oxygen.Patients were studied fasting, and wherever compatiblewith their comfort, in the recumbent position. While cir-cumstances were often not conducive to a truly basalstate, a preliminary oxygen consumption was done underconditions of quiet, for purposes of comparison with laterdeterminations. Catheterization of the right heart wasperformed with a single-lumen catheter, using the methodof Cournand and Ranges (1-3), and the catheter wasguided into the right ventricle or pulmonary artery underfluoroscopic visualization.4 In one case, auricular cathe-terization only was possible. An inlying needle wasplaced in one femoral artery, and in nine patients in aperipheral arm vein. Electrocardiographic leads were at-tached in all cases. The catheter was kept patent by aslow, continuous drip of a 5 per cent solution of glucosein distilled water, to 1500 cc. of which 5 mg. of heparinwas added. Cardiac outputs were done by the directFick method. Mixed venous blood samples were takenfrom the right ventricle except in Patient No. 7 wherean auricular sample was used; blood oxygen contentswere measured by the Van Slyke technique. Oxygenconsumption during the blood sampling was determinedgraphically on a metabolism machine, using two- to four-minute breathing periods as the basis for computing theminute uptake. Intracardiac, femoral arterial and periph-eral venous pressures were optically recorded through

4Assistance in fluoroscopic visualization was given bythe X-ray Department (Dr. Max Ritvo, Director),

EFFECTS OF OUABAIN ON 'CIRCULATION IN HEART FAILURE

Hamilton manometers. The zero level for pressures inthe peripheral vein and lesser circuit was taken as 5 cnLbelow the angle of Louis. Femoral systolic and diastolicpressures were obtained by averaging the measured valuesof a representative sequence of beats in one or morerespiratory cycles. Right ventricular systolic and pul-monary arterial systolic and diastolic pressures weresimilarly averaged. Femoral mean, pulmonary mean,right auricular and peripheral venous pressures were-measured by planimetric integration. The diastolic pres-sure in the right ventricle was measured at the momentof onset of the systolic rise, since this figure was held tobe most representative of the filling pressure at whichsystole began (4), and hence of the tension within theventricular myocardium at its beginning of contraction.Pulse pressures in the femoral and pulmonary arterieswere measured as the difference between the systolic anddiastolic values. The right ventricular pulse pressurewas measured as the difference between the systolic andthe end-diastolic pressures. The peripheral arterial re-sistance was computed in accordance with the formula:

* R = Pm(mean pressure in mm. Hg) X 1332C.O. (cardiac output in cc./sec.)

Sterile solutions of ouabain were injected through thecatheter over a period of one to two minutes in doses of0.25 to 0.75 mg.

In nine patients, a cardiac output was done before giv-ing ouabain, and at the end of the observation period,which varied from about 40 to about 160 minutes. Inone patient studied early in the series, before it wasrealized how quickly significant data could be obtained,both outputs were done after the administration of oua-bain. In three patients (Nos. 11, 12, 13), in addition toa control, serial cardiac outputs were done after they hadreceived the drug, at the times noted on the charts. Ineach instance pressures were recorded as close to thetime of the outputs as possible and at varying intervalsbetween.

CASE MATERIAL

Thirteen patients were studied. The diagnoses andclinical state of compensation are listed below.

(a) In clinical congestive failure-10Arteriosclerotic heart disease 4Hypertensive heart disease 3Hypertensive and arteriosclerotic heart disease 2Cor pulmonale 1

Lo" I t ILIi______FIG. 1. THREE PATIENTS WITH HYPERTENSIVE HEART DISEASE IN CLINICAL HEART FAILURE, WITH

INCREASE IN CARDIAC OUTPUTSAFTER OUA3AIN

589

BLOOMFIELD, RAPOPORT, MILNOR, LONG, MEBANE, AND ELLIS

(b) Not clearly in clinical congestive failure-3Arteriosclerotic heart disease 1

Rheumatic heart disease with mitral stenosis 1Heart disease of unknown etiology,, ? beriberi 1

Four of the patients in Group (a) and two of those inGroup (b) had auricular fibrillation.

RESULTS

Cardiac output. An increase in cardiac out-put was noted in ten patients, including nine ofthose in obvious congestive failure. A decreasein output was observed in two patients, neither ofwhom was in clinical failure. No significantchange took place in one patient who was in heartfailure.

Pressure changes. Significant pressure changes

following ouabain were noted within one to eightminutes in ten of the 12 studies in which controldata were obtained prior to the drug's adminis-tration. One exception was Patient No. 7 who re-ceived the small dose of 0.25 mg. At five minuteshis pressures were unchanged; the next observa-tions were made at 35 minutes. The other ex-

ception was Patient No. 10 whose first post-ouabain measurements were not made until 27minutes, at which time changes were present. InPatient No. 8 the first measurements were made46 minutes after ouabain was given; at the timeof the next observation-27 minutes later-thechanges shown on his chart were found.

The multiplicity of changes which had occurredby the end of the experimental period made it ap-

CASENUMBER 4 5 6DIAGNOSIS ASUD too"*" J£1$0 %, -

160~~~~~~~160 on

FEMORAL ARTERY 120 1c X20

PULMONARYARTERY 60 _ . 8060~~~~~~6

By = 1 1 = - C = _ 106060#l

4040

6~~~~~~~~~~~~~~~6RIGHT VENTRICLE 60

40

40~~~~~~~~~~~~~~~40~~~~~~~~42~~~~~~~~~~~~~~~~~2A 2

PERIPHERAL VEIN 20 20

HEART RATE 60 ItO 0d s

CARDIAC OUTPUT (Limb) 3.05 44 1394 31 2.55CARDIAC INDEX (L~mbAmIft 1.96 2.91 1.08 1.66 0.92 t5STROK VOLUME 1....) 34 54 19 35 53

PERIPOI RESIST. (do" gm~ gu) 2 46 3621214040

FIG. 2. THREE PATIENTS WITH -ARTERIOSCLEROTIC HEARTDISEASE IN CLINICAL HEARTFAILURE, WITHIN4CREASE IN CARDIAC OUTPUTSAFTER OUJABAIN

In Case No. S during periods of 'bigeminy the pressures of ectopic beats are charted separately andconnected to the pressures of normal beats by vertical broken lines. In Case No. 6 the discrepancy be-tween pulmonary arterial and right ventricular systolic pressures was due to oscillatory artefacts whichrendered inexact the measurement of the point of maximum pressure.

590

EFFECTS OF OUABAIN ON CIRCULATION IN HEART FAILURE

CASE NUMBER 7

DIAGNOSIS HHD 8 ASHD

_1 801 *+-coin =5mg.ISO~~~~~~~~~'

FEMORAL 140ARTERY, -

RIGHT 20 _.AURICLE m.

Mm.

HEART RATE rhythm

CARDIAC OUTPUT 6.00 7.67CL/mis.)

CARDIAC INDEX 2.72 148(L/mlm/s*m).

STROKE VOLUME 68 86( a.e.).

PERIPH. RESIST. 1612 1394(dp"e cem see.)

tml

MINUTES 30 60

FIG. 3. PATIENT WITH HYPERTENSIVE AND ARTERIOSCLEROTICHEART DISEASE IN CLINICAL HEART FAILURE, WITH INCREASE INCARDIAC OUTPUTAFTER OUABAIN

parent that the site and mode of action of ouabaincould only be seen from the actual sequence inwhich such changes developed. For purposes ofclarity the complete data from each' case are showngraphically.

A. Early changes.I. In the course of a rising cardiac output.(a) Patients in clinical congestive failure: A

striking uniformity of response can be seen inthe nine patients who were in failure (Nos. 1-7;11, 12). All initially showed elevations of pres-sure in the right heart and pressure pulse contoursof a type previously reported as found in rightheart failure (4). In every instance followingouabain, femoral arterial systolic pressurespromptly rose as did the mean and pulse pres-sures; this occurred, however, considerably later

in Patient No. 7 who received the smallest dose.In the eight on whom records were taken, rightventricular systolic and pulse pressures also in-creased (Nos. 1-6; 11, 12). In Patient No. 6technical difficulty made impossible the measure-ment of femoral mean pressure at the time theother earliest changes were seen; at the time ofthe next observations, the femoral mean pressurewas found to have risen markedly. In the threeinstances in which it was possible also to measurepulmonary arterial pressures both systolic andpulse pressures were similarly increased (Nos. 4-6; Figure 8). While ventricular diastolic pres-sures varied in degree of response, a significantdrop was noted only in the ventricular diastolicpressure of Patient No. 6; here, too, however, theincreased pulse pressure was accompanied by anincreased systolic pressure. In the seven caseswith recorded peripheral venous pressures no sig-

591

BLOOMFIELD, RAPOPORT, MILNOR, LONG, MEBANE, AND ELLIS

nificant change was seen up to the time at whichthese other phenomena had become apparent (Nos.2-6; 11, 12). In the two patients lacking periph-eral venous pressure data, the auricular pressure

was unchanged in one (No. 7), while the ventric-ular diastolic pressure actually rose slightly in theother (No. 1). At the time that pressure changesalready were manifest, the heart rate had not al-tered in five patients (Nos. 3-5; 7, 12) ; in two,the rate had risen by four beats per minute (Nos.1, 6), and one of these had auricular fibrillation.The other two patients with auricular fibrillationexhibited a decline in ventricular rate from 114 to97 in the first six minutes in Patient No. 2, andfrom 140 to 130 in three minutes in Patient No. 11.

(b) Patients not in clinical congestive failure:In the one patient not clearly in heart failure inwhom the cardiac output rose (No. 8), the onlysignificant change was a decline of 5 mm. Hg inthe initially normal ventricular systolic pressure.

II. In the course of a falling cardiac output.

Patient No. 10 showed a small diminution infemoral systolic and diastolic pressures, with a

slight decrease in the pulse pressure; the rightventricular pulse pressure widened by 4 mm., as

a result of a slight rise in the systolic and a slightfall in the diastolic pressures. The fall in outputwas due almost wholly to a drop in heart rate, as

CASE NO. 8DIAGNOSIS AS HD

16 cuoboin O.5 mo

FEMORALARTERY 120syst. ..-meon......diost. 808

m Hg.

40RIGHTVENTRICLE

20

mm Hg.

20PERIPHERAL

VEINmm. Hg.

14 auricular fbnilationHEART RATE 12

CAIRDIAC OUTPUT 5.04 6.10

CA$RDIAC IINDEX 3.10 3.80ILlmninlhs~LJ

STROKEVOLUME 37 46(C C.)

PERIPH. RESIST. 1775 I 89(dynles owm560C.) fIMINUTES 30 60 90 120 ¢0

FIG. 4. PATIENT WITH ARTERIOSCLEROTIC HEART DISEASE NOTIN CLINICAL HEART FAILURE, WITH INCREASE IN CARDIAC OUT-PUT AFTER OUABAIN

592

EFFECTS OF OUABAIN ON CIRCULATION IN HEART FAILURE

PATIENTS NOT IN CL.INICAL. HEART FATI.URE, \W ITH DECREASE IN CARDIAC OUTIPUTSAFTER OUABAIN

seen by the stroke volume which changed by only1 cc., from 49 to 48.

The second patient whose output fell (No. 9)showed a definite early increase in femoral sys-

tolic and diastolic pressures, with a moderate in-crease in the pulse pressure; the right ventricularpulse pressure rose 4 mm., as a result chiefly ofthe fall in diastolic pressure. At this time hisheart rate had decreased by 13 beats per minute.

In neither case was the peripheral venous pres-

sure measured.

III. In the absence of a change in cardiacoultptu t.

In Patient NTo. 13 the changes in cardiac outputwere of an order so small that no action of oua-bain can be held accountable for them. Five min-

utes after the drug was given the femoral systolic.diastolic and mean pressures had all risen to the

same degree., with no resulting alteration in pulsepressure. At ten minutes these values showeda decline toward control levels. During this in-terval the ventricular systolic and diastolic, andperipheral venous pressures, as well as the heartrate, were essentially unaltered.

B. Later changes.

As seen in the figures there was considerablevariation in the degree to which the early changesdescribed were maintained over the remainder ofthe experiments.

Of the nine patients in congestive failure show-ing rises in cardiac output, seven maintained a

femoral systolic pressure increase (Nos. 1, 2, 4,

6, 7, 11, 12), while two returned to approximatelycontrol levels (Nos. 3. 5). Three maintainedtheir early diastolic arterial pressure rise (Nos.5-7). Only one, however, failed to keep an in-

GASE NUMBER 9 10DIAGNOSIS RHD E MS Unknown Etiology I? Bribeti

.--ouoboin o.s mg, 4.-ouoboin 0.5 mg.

FEMORAL |20ARTERY ~

syst. *.. tso ..

60 40diost.

mm. mm. Hg.

60RIGHT VENTRICLE

40

2020

0mnL Hg mm.

10o sinus rhythm so _ uricular fibrillation

HEART RATE 8 06060 401

CARDIAC OUTPUT 5.13 4.37 3.60 2.90

CARDIAC INDEX 2.93 2.49 2.04 1.64

STROKE, VOLUME 60 49 48

PERIPH. RSIST. 1433 I6 1798 1970

coItra -c690tre_MINUTES 30 60 90 1 810 30 60 90 120

Fi([. 5. Two

593

BLOOMFIELD, RAPOPORT, MILNOR, LONG. MEBANE, AND ELLIS

creased arterial pulse pressure (No. 5). Five ofthe eight patients with ventricular pressure recordsmaintained their early systolic increase (Nos. 1; 4-

6; 12); only four showed a significant fall in dia-stolic pressure (Nos. 2, 3, 6, 1 1 ) ; all but two(Nos. 3, 11) maintained a widened ventricularpulse pressure. Only two of the pulmonary arterystudies were followed throughout the experiment(Nos. 5, 6). In both the initial increase in pulsepressure was present to the end; in one the earlyslight diastolic pressure rise was followed by a fallto the control value. The peripheral venous pres-

sure fell in five cases (Nos. 2, 3, 6, 11, 12). Infour also, there was a decline in heart rate by theconclusion of the observations (Nos. 1, 2, 6, 11).No change occurred in the auricular pressure inPatient No. 7.

In the patient not clinically in heart failure(No. 8), but whose cardiac output rose, no

further important change was noted in any ofthe subsequent measurements.

The patient with mitral stenosis and a fall incardiac output (No. 9) showed a return to therange of his control values except for a continueddecline of ventricular diastolic pressure. Theother patient whose cardiac output dropped (No.10) showed no significant further changes afterthe early ones described, except a continuing mod-erate fall in heart rate. In the patient (No. 13)whose cardiac output showed little variation therewas a gradual return of femoral pressures totheir control level. The other data showed no

appreciable variation throughout the experiment.

DISCUSSION

Numerous articles have been published on thephysiological and pharmacological effects of oua-

bain (6-9) as well as of the other cardiac glyco-

CASE NUMBERl 12

DIAGNOSIS HHD ond ASHD COR PULMONALE

#ouoboin 0.5 mg. ouaboin 0.5 mg.

FEMORAL ARTERY MD ~ ---. 220

syst..-. -

mean---1 180 /%

diast.- *..140 ,.

00

RIGHT VENTRICLE -.-6----_--

1qd41t1'"''"a-'-40

20

40

PERIPHERAL VEIN 2t._

14 auiicular fibrillation - -fbilo160

HEART RATE 120 14

CARDIAC OUTPUTILMSm 3I .O 4.7 4.6 6.62 1196 12.25CARDIAC INDEXAm.%m) 2.3 3.7 3.6 3.4 3.58 6.46 663STROKE VOLUMEIce.) 22 38 40 40 41 74 ofPERIPHERAL LESISTAN 3194 2302 2397 2106 1450 917 682

(am-m$m1*.) ...ONR152'@O~mMINUTES 10 20 30 40 50 0 20 30 40 50

FIG. 6. Two PATIENTS IN CLINICAL HEARTFAILURESerial determinations show increases in cardiac outputs after ouabain.

594

EFFECTS OF OUABAIN ON CIRCULATION IN HEART FAILURE

CASE NUMBER 13

DIAGNOSIS ASHD

4.-ouoboin 0.5mg.FEMORAL ARTERY

mean .......diast.- 80--*

60

50 _._-. ._*.

40RIGHT VENTRICLE 30

2

1 -

10

PERIPHERAL VEINm

normal sinus100

HEART RATE 80

CARDIAC OUTPUT 4.27 4.12 4.39 4.72

CARDIAC INDEX 2.47 238 2.54 2.72

STROKE VOLUME 48.5 467 467 51.8

PERIPH. RESIST. 1385 1602 1409 1312

MINUTES control 0 20 30 40 5o 60 70

FIG. 7. PATIENT WITH ARTERIOSCLEROTIC HEART DISEASE INCLINICAL HEART FAILURE

Serial determinations show no definite effect of ouabain oncardiac output.

sides. Summaries have been recently publishedby Freedberg and Zoll (10) as well as in themonograph by Movitt (11). In general it isbelieved that ouabain has an action on the circu-lation that is qualitatively similar to that of thedigitalis glycosides and that the chief quantitativedifferences in its behavior are its rapidity ofaction, its rapid elimination, and its failure otabsorption by the gastro-intestinal tract. It isthe opinion (12) of some physiologists and clini-cians, especially of the European and Latin Ameri-can schools, that ouabain also differs from digitalisin having relatively less effect on the sinus nodeand junctional tissues but a more effective actionon the cardiac musculature itself.

The pattern of early response in the nine pa-tients in heart failure who exhibited a rise incardiac output was so consistent that an identicaleffect of ouabain is suggested in them all. Theirresting cardiac outputs were below normal, asshown by cardiac indices varying from 0.92 to2.72 L/mmin./sq. m.. with the exception of Pa-tient No. 12 whose higher figure is consistentwith his diagnosis of cor pulmonale (13. 14).5As seen from the data, the stroke vvoltume rose ineach instance under the influence of ouabain.That a decrease in filling, and hence a decreasein diastolic stretch "from behind," from the pe-

5 The average normal cardiac index is considered to be3.12 + .40 L/min./sq. m. (3. 15).

595

BLOOMFIELD, RAPOPORT, MILNOR, LONG, MEBANE, AND ELLIS

ripheral venous pressure head, did not account forthis stroke volume change seems established bythe fact that the peripheral venous pressure hadnot decreased at the time of the first demonstratedincrease in cardiac output in four of the sevensubjects in which it was measured. In the twopatients in whom this phenomenon was not stud-ied, an equally valid index to ventricular fillingwas seen in the unchanged auricular pressure ofPatient No. 7, and in the ventricular diastolicpressure of patient No. 1. In the three patientsin whom the venous pressure had decreased atthe time of the post-ouabain cardiac output deter-mination, no change in this measurement had oc-curred earlier at a time when other marked circu-

:4ASE - CAYS

180-140_100_

F

latory effects were already evident in vascularpressure changes.

An effect on stroke volume and cardiac outputthrough an action of ouabain on the ventricularrate seems poorly borne out by the lack of corre-lated change in seven instances; in Patient No.11 where the rate had fallen at the time of thefirst measured rise in output it is noteworthy thatthe subsequent decline in rate was of the sameorder, but with a slight drop in output and nochange in stroke volume. The only other mecha-nism, therefore, that can plausibly explain the in-creased stroke volume, is an increase in the vigorof ventricular systole as a result of the directaction of ouabain upon the contractility of the

F F

80-

bo-

ONTROL 0- 40-ao0-

Q0PA

220._80.-

140._0060-_

F

RV

F

Pv

F

100_

80_60 -

0 40..MINUTLESS 20oAFTER

.:1.625mg. QUABAIN PA RV PV

FIG. 8. TRACINGS OF CASE No. 4

The upper group shows control observations: simultaneous femoral arterial (F)and pulmonary arterial (PA) pressures; femoral arterial (F) and right ventricular(RV) pressures; and femoral arterial (F) and peripheral venous (PV) pressures.A simultaneous electrocardiogram is recorded in the lower part of each series. Thepressure scales are in mm. of mercury, one for the femoral artery, one for the rightheart and venous pressures. The two latter were done with the same manometer andfrom the same zero. The lower group shows corresponding tracings eight minutesafter ouabain with the changes in pressures readily seen.

596

'I-, \., '.I-

EFFECTS OF OUABAIN ON CIRCULATION IN HEART FAILURE

myocardium. The early pulse pressure changesare consistent with such a mechanism, and wouldindicate that it occurs very promptly after injec-tion of ouabain. While changes in the peripheralresistance at this time, at both pulmonary andsystemic arterioles, cannot be wholly excluded inthose patients lacking early output studies afterouabain, the observed pressure changes are pre-cisely what would be expected in the presence ofa rapid and significant increase in cardiac output.In Patient No. 11 an increase in stroke volumeand decrease in peripheral resistance were demon-strable within three minutes after the adminis-tration of ouabain at a time when the heart ratehad fallen only from 140 to 130, and the increasein stroke volume was maintained at two furtherobservations. In Patient No. 12, in whom theheart rate did not change, the increase in cardiacoutput and decrease in peripheral resistance ob-served at 19 minutes after giving ouabain weremaintained at 45 minutes. The predominant roleof the systolic component in the pulse pressureincrease speaks, furthermore, chiefly for a strokevolume change, rather than for a change in periph-eral resistance. Moreover, were the pressure risesdue mainly to an increase in peripheral resistance,one would expect not only a more uniform find-ing of increased diastolic pressure, but also, inthese already decompensated hearts, still furtherevidence of failure in the form of an increasingvenous pressure and a decreasing cardiac output.The variability of the later findings, in which insome instances a return of pressures toward thecontrol level occurred, does not argue against suchan interpretation, in view of the likelihood thatultimately such other factors must come into playas changes in blood volume, heart rate, blood vis-cosity, etc. It is of interest, and indeed in keep-ing with the proposed explanation, that in everycase in this group, regardless of the absolutevalues of the final measured pressures, the periph-eral resistance was below its initial figure.

In Patient No. 8, who was not clearly in heartfailure, the output increased between 32 and 110minutes after ouabain administration. It is pos-sible that earlier changes occurred, which tookplace before the observations were made. Thepatient was of particular interest for his unchang-ing ventricular rate of 133, in the presence ofauricular fibrillation. While his initial right ven-

tricular systolic pressure was normal, the periph-eral venous pressure -was in the upper normalrange, and the normal gradient between the venousand ventricular diastolic pressures did not exist-a finding which, as Richards et al. (16, 17) havepointed out, may have the same significance inearly right heart failure as a heightened venouspressure. In view, then, of his unaltered ven-tricular rate, and unaltered venous pressure, it isreasonable to suppose that the decline in ventricu-lar pressures, chiefly systolic, resulted from thetransfer of blood from the pulmonary field to thesystemic side; and that there was prompt adjust-ment to this increased systemic arterial input bya lowering of the peripheral resistance. Thiswould account for the absence in this case of thesystemic arterial pressure rise seen in the patientswith congestive heart failure, in whom later pe-ripheral resistance fall seems to come only afteradequate improvement of arterial filling.

The two patients whose cardiac outputs de-creased (Nos. 9, 10) were not in heart failureby the usual criteria. Patient No. 10, however,had previously been in failure on several occa-sions, with heart disease of uncertain etiology.At the time of the present study, both right ven-tricular systolic and diastolic pressures wereslightly elevated; the cardiac index was definitelylow. The decline of his ventricular rate from 73to 60, while not striking, actually represents astroke volume change only from 49 to 48 cc., sothat the decline in cardiac output must here beascribed almost wholly to the fall in rate, with afailure of ouabain in this case to affect ventricularsystole. The slight drop in systemic pressureswould be compatible with this decrease in arterialinflow from the left heart.

Patient No. 9 was suffering from rheumaticheart disease with mitral stenosis, not clinically inheart failure; he was able to work as a long-shoreman until admission for study. His onlysymptom was cough. It will be seen that hiscardiac index was also in the lower normal region,and that his ventricular diastolic pressure of 16mm. Hg was of the order seen in right heartfailure. While there was some fall in heart ratebetween the two outputs, the rates at the time ofblood sampling were 81 and 84, respectively. Thestroke volume decreased from 60 cc. to 52 cc.The early rise in systemic pressures was not sus-

597

BLOOMFIELD, RAPOPORT, MILNOR, LONG, MEBANE, AND ELLIS

tained, final values being essentially the same ashis controls. There was, however, a progressivefall in ventricular diastolic pressure to 8 mm. Inview of the nearly 20 per cent increase in periph-eral arteriolar resistance, the decline in ventricu-lar filling pressure may simply have representeda diminution of the venous return, as a conse-quence of decreased arteriolar outflow. The lesionin this instance was not comparable to those pres-ent in the other cases, and the action of ouabain,particularly upon a presumably normal left ven-tricle, was likewise not comparable. Furtherstudies on the effects of ouabain in mitral stenosisare now in progress.

In Patient No. 13, who was in heart failure,the slight variation in all pressures except thosein the femoral artery at five minutes after ouabainwas consistent with the fact that there was butsmall variation in the cardiac output and strokevolume. The equal and brief rise in femoral sys-tolic, diastolic and mean pressures five minutesafter the drug was given suggests a transitoryvasopressor response in this instance. However,the failure to obtain a closer time correspondencebetween the taking of control pressures and out-put on the one hand, and the follow-up pressuresand outputs on the other, leaves interpretationof this early systemic response at best uncertain.This was the only patient in the series in whom,at the end of the observation period, no cleareffect of ouabain upon the circulation was ap-parent.

The present study confirms in human beingswith congestive heart failure the physiologicaleffects of ouabain described in experimental ani-mals as well as those reported in patients by lessexact clinical measurements. Ouabain acts di-rectly on the failing heart by increasing its strokeoutput, and this action may and usually doesprecede cardiac slowing or any decrease in periph-eral venous or right ventricular filling pressure.The latter effects usually do take place, but later.Our results with ouabain are at variance withthose reported by McMichael and Sharpey-Shafer6 (18) with digoxin, in that they ascribed

6 It should be pointed out that McMichael and Sharpey-Shafer imply peripheral venous pressure alterations, al-though measuring only central (auricular) pressures.Hemodynamically the two may not be regarded assynonymous.

the improvement in cardiac output to a fall inright auricular pressure, and in our cases evidencefor an improvement in cardiac output precededany fall in venous pressure. Further studies arenow in progress in this laboratory with digoxin aswell as other digitalis glycosides.

SUMMARY

1. The intracardiac administration of ouabain indoses of 0.25 to 0.75 mg. to patients in clinicalcongestive heart failure, suffering from non-valvu-lar types of heart disease, is usually followed bya rise in cardiac output, as seen in nine out often patients in heart failure in the present study.

2. Effects on the circulation may be notedwithin one to eight minutes, and are characterizedby an increase in the systemic systolic and pulsepressures and in the right ventricular systolic andpulse pressures. There is a less marked and lessuniform early change in the diastolic pressures inthese two systems. Where measured, increasesin the pulmonary arterial systolic and pulse pres-sures have also been seen.

3. There is a variability in the later pressurefindings, at the end of one to two hours, whichmay be accounted for by the additional play ofother factors such as changes in blood volume andperipheral arteriolar resistance.

4. While there may ultimately be seen evidenceof diminished filling pressure in the right ventri-cle, measurement of the peripheral venous, auricu-lar or ventricular diastolic pressure shows thesevalues to be essentially unchanged at the time ofthe other pressure rises.

5. The increase in cardiac output is due to anincrease in stroke volume.

6. The increased stroke volume can best beexplained by a direct action of ouabain upon thecontractility of the myocardium.

7. The systemic and right heart pressure changesdescribed are consistent with such an explanation,although vasopressor effects of the drug are notentirely excluded.

8. In three patients the cardiac output wasunchanged or fell after ouabain administration.Two of these patients were not in clinical heartfailure.

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EFFECTS OF OUABAIN ON CIRCULATION IN HEART FAILURE

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