Download Print - Circulation

Studies
on
Digitalis
VI. Reduction of the Oxygen Debt after Exercise with Digoxin
in Cardiac Patients without Heart Failure
By RICHARD
KAHLER, M.D., RONALD H. THOMPSON, PH.D., ELSWORTH R.
BUSKIRK, PH.D., ROBERT L. FRYE, M.D., AND EUGENE BRAUNWALD, M.D.
L.
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
T IS undisputed that the administration
of digitalis to patients with many forms
of congestive heart failure results in an improvement in both the clinical state and in
the abnormal circulatory dynamics that are
characteristic of heart failure.'-6 The effects
of digitalis in subjects without heart failure
are less well defined. Although some glycosides augment the contractile force of non-
oxygen debt during exertion. The development of an oxygen debt is characteristic of
congestive failure.'8' 19 It was therefore
thought that accurate measurement of the
oxygen debt after exercise might provide an
appropriate means of evaluating the effects
of cardiac glycosides on the adequacy of cir-
culatory function.
Description of Patients
failing hearts of patients with heart disease,7
and increase the rate of intraventricular pressure development in intact normal subjects,8
these drugs have not been shown to elevate
the cardiac output at rest and during exercise in normal subjects or in patients with
heart disease without failure.9-15 When administered acutely to patients with "latent"
heart failure, an improvement of circulatory
dynamics occurs in some individuals, but not
in all.16 In view of the conflicting interpretations of these observations, the role of digitalis in the treatment of patients with heart
disease but without heart failure is not clear.
Accordingly, the present investigation was
designed to assess the effects of digitalis on
the response of the cardiovascular system to
the stress of muscular exercise in patients with
heart disease and cardiac enlargement without
clinical evidence of congestive heart failure.
One of the fundamental functions of the
cardiovascular system is delivery of oxygen
for metabolism in tissues at rest and during
activity. The inability of the cardiovascular
system to perform this function adequately
results in the accumulation of excess lactate,17
and the development of an abnormally high
The three patients chosen as the subjects for
this study all had inactive rheumatic valvular
disease, cardiomegaly, and a history of cardiac
decompensation some months or years previously,
but had none of the clinical signs of congestive heart failure at the time of study. These three
patients were selected because they were capable
of performing light physical activities without
cardiac symptoms in the absence of digitalis
therapy. They did not complain of orthopnea or
paroxysmal nocturnal dyspnea. Detailed and repeated physical -examinations during the course of
the investigation failed to disclose rales at the
lung bases at rest or during exercise; the patients
were free from edema, had normal levels of systemic venous pressure, and did not have clinical
evidence of hepatic enlargement.
C.A. (no. 02-57-64) is a 54-year-old man with
rheumatic mitral regurgitation and stenosis. Easy
fatigability, exertional dyspnea, and peripheral
edema had developed 5 years prior to study and
he had been maintained on digitalis, a diuretic
regimen, and a low-sodium diet for several years.
Physical examination indicated the presence of
rheumatic mitral regurgitation and stenosis. The
electrocardiogram showed atrial fibrillation, left
axis deviation, and left bundle-branch block. Chest
x-ray and fluoroscopy revealed enlargement of the
left atrium and left ventricle. The patient was
maintained on a diet containing 1 Gm. of sodium
daily and he received 1 Gm. of chlorothiazide daily
throughout the study. He was studied on 10 occasions on nine separate days during three periods
(fig. 1). During the first period he was maintained
on a daily dose of 0.25 mg. of digoxin. The glycoside was replaced by a placebo during the second
period. He was then redigitalized with 4.75 mg.
From the Cardiology Branch, National Heart Institute and the Metabolic Diseases Branch, National
Institute of Arthritis and Metabolic Diseases, Bethes-
da, Maryland.
Circulation, Volume XXVII, March
1963
397
: 3-8INIA I I IRL ErI Al.,
,8e'}S
70
BODY
WEIGHT
kg.
68
66
VENOUS
PRESSURE 150
mmH20
50
DIGOXIN
mg
1.0
5
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
0
1000
SODIUM
I NTAKE 500
mg
25
30
April /960
10
5
May /960
15
Figure 1
patient C.A. daring the period of studi. The
of
pressure
Body weight and venous
vertical arrows indicate the days on wvhich the exercise studies ivere, carried o't. Thie
patient had been main tained on digoxini (0.25 tMg. doilu) for-' 3 Jircrs prior to /he
first study period.
of digoxin given over a 6-day period anid durling,
the third period of the study lie wais maintained
on 0.50 mg. of digoxin dailvy
P.F (no. 02-28-79) is a 38-vear-old iiian iin
whom a heart mnurmutr was detected in 1949 anld
who developed exertional dvspnea and paroxysmalc:11
nocturnal dyspuean in 1957. On phvsical examiniation lie was eonsidered to liave rheumatic mnitral
reonroitation. He had slight cardiae enlarfgemennt
with left ventricular predominaiaee on roentgenogr11a,phic examiniation. The electrocardiog-raiii showed
niormnal siinus rhy\-thm and left e-01-trieular hypertrophy and strain. However. eoi nbmi ned riglht and
left heart eatheterizations in Fehruarv- 1959 dlemon-4rated that intracafrdie priezssirVs and the cardiac
index were within. nornial liniits. -le was imaitained on a diet containing SOO 0iig. of sodiu tl a ad
he receiv ed 50 lug, of hvdrochlorothiazide dailv
throughout the study during which the oxyg en debt
was mneasured. Two determinations of oxygen
(lebt wer-e mnade wlhile lhe received 0.50 rtwig. of
digoxin. and three studies were carried out after
this drug had been diseontinued ancd a placebo
haIdl l)eel mhbstituted. TIn addition. to- his. usal
activities the patient walked 3 mtiles (tcailv without
symptoms throughouLt the period of study.
S.AT. (o. 03-54- 72). a 19-yeat o-ld girl kniowinl
to have rheumnatic heart disease sinee 1949, developed signs and sym3ptoins of congestive heart
failure for the first time during a recurrencee of
acute rheumiatic fever in 1957. Shle was maintained
on digitalis and a low--sodiumit diet and had no
sy wptoiis except for occatsional pAplitations durin,
strenuous exertionm. Onl exa inimati on she was coii
sidered to hasve the itlir'lIiiurs of miiitral regurgitatiion anid stenosis aili aortic regrirgitation. The
ejlec.ton idoi<gran3li showed siiiuiUe rli.vthni anid firstdegree atrioventrivular block, left atrial enlargement, auth left ventricular lbypertrophy. She
received a diet conftaifnin-g 500 nig. of sodiunii dailv
througlhout the study. The postexercise ox> geii
debt was deteruiiined oni fidye occtasions, wbile she
received nno medictation. Sh-ie was then digitalized
with 2..50 nig. of dig,oxini du-lilgll a 4S-hiour period,
received 0.50 wig. oni the third day and 0.25 iig.
as daily mtnaintenance thereafter. Eight studies were
carried out while she was receiving this dose (fig.
(irc ulation, bsolni5XXII, MarchJ
399
STUDIES ON DIGITALIS
44
BODY
WEIGHT 42
kg.
40
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Venous 150
Pressure
mm H20 50
1.25
1.00
DIGOXIN .75
.50
mg.
.25
SODIUM
INTAKE 400
26
November 196/
21
44
1
6
II
December /96/
Figure 2
Body weight of patient S.M. during the period of study. The vertical arrows indicate
the specific days on which the exercise studies were carried out. On several of these
datys more than one oxygen debt after exercise was measured (table 1).
The exercise studies were carried out on a motordriven treadmill at speeds of 2.1 to 2.5 miles per
hour and at grades of 0 to 7.5 per cent. All
patients had undergone extensive training on the
treadmill several times weekly for 4 to 6 weeks
prior to the study. Thus, they were thoroughly
familiar with the procedure so that alterations in
their performnance during the period of investigation could not be attributed to further training
during the study. The specific conditions under
which each patient was studied are presented in
detail in table 1. The exercise was carried out in
a Mfetabolic Chamber, which is an air-conditioned
Circulation, Volume XXVII, March 1963
room maintained at constant temperature and
humidity. The open-circuit method of indirect
calorimetry was employed for measurement of
oxygen consumption ( °2 ) . The technic and
instrumentation employed have been described in
detail elsewhere (fig. 3).20 Briefly, the subject's
head is enclosed by a light vinyl plastic hood
suspended from the ceiling. A relatively large volume of fresh air enters the hood through an
imperfect seal about the shoulders. Air is continuously drawn from the hood through appropriate
tubing at a constant rate approximating 10 times
the subject's respiratory minute volume during
4KAIHIlER ET AL,
400
Table 1
,Summnary of Oxygen Debts after E.rercise
Pre-exercise
Exercise conditions
Pt.
B.S.A. M.- Digoxin
C.A.
1.88
+
I_
Date
M.P.H.
4/26/60
4/ 29
5/5
2.1
5/6
5 1fl0
5/17
5,119
-f
(.8. #1I
5f6'/60
1.96
5)/]Q,
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
p
F.X-x
2-3
-
2.327
**
+
21 :1
12/
12 7
11/28
496
433
768
733
14
10
190
10'
210
10'
184
4105
7'40"
7,8"
245
222)
4386
3305
1,009
661
20
10'
2940
1.1
40
3882
3055
427
10'
1'
.336
11
340
13,010
16,338
1,301
2,124
10
10'
10,
3329
17,185
2,406
7"35,'
'10"
41"f
400
330
11,481
13,672
1,837
2.461
14
16
195
1941
893
2.5
2.5
41"
1 62
2090
836
4'41"
"
4'41
4'4t1 "
4 41
170
.3
2102
2026
1791
883
851
210
0
2.1
0
2.1.
2.1
2,1
2.
0
At.-
_.
0
2.1
2.},1
0
10
i .3
7.5D%<c
I
.0
2.5
I
.0
.1 .5
2.5
i..)
168
188
27
20
ils
413
15
594
698
17
17
11 1)
1s
46
40
42
788
42
44
35
+
12/5
2.5
2.5
1 5*
'L95
.
2.
15I
1 5'
173
+
12/ 7
2065
3830
3743
4800
5717
3554
4818
195
4466
402
9
1804
1817
433
418
260
25 2
24
23
+
12o/8
11/21
2.5
3
4'4 1 "
10'
190
-.
3
102
180
15'
15'
160
2.5
-D
_
11/22
C.8. #2
1.40
182
176
258
21 2
2'35
0
.
11/21
-4-
lo,
10'
0'
1'
excess
V02 %0
10'
-,
2.1.
11/22/61.
1.34
ml./min.
10'
0
2.
25
S.M.
excess Vo2
Dur.
Min. /Sec.
02 debt
Total
02 debt
ml.
3543
4330
2844
3665
3590
2753
3494
2.1
2/1161
2/8
Grade
Total
excess V02
ml.
12/1191 61
12/19
12/19
12/19
)
.0
.t
2.5
2,5
2.5:
5
i5
2.5)
4'41
4'41
195
"
"
15
2.)
200
221
202
185
3250
3600
766
20
14
624
13
686
462
530
12
13
11
8
I
*Body weight was 112.64 Kg. on 2/1, 110.27 Kg. on 2/8, anld 109.27 Kg. on 2/10.
C.S. #1 weighed 71.4 Kg., C(.S. #2 weighed 45.4 Kg.
Pt., patient; B.S.A., bod(y surface area in MV.2; C.S., control stubject; +, study doae while patient was receiving
digoxin; -, no digoxin; V 02, oxygen Consumption; patienit earried external weiglht totaling 14.7,2 Kg. dulring the
study designatecd with *
*
The total flow rate of air is continuously
monitored and aliquots of the stream are directed
to a modified Beckman F3 paramagnetic oxygen
analyzer, located outside the chamber. The analyzer functions with an operational sensitivity of
about ±0.02 per cent oxygen on thje seale range
used. It is calibrated and standardized with gases
of knoxwn oxygen concentrations. The output of the
gas analyzer was recorded on a Leeds-Northtup
recorder at intervals of 3 seconds. The response
of the svstena to a known square wave change
exercise.
of gas concentration in the hood was determined
and utilized in the calculation of the oxygen
(lebt following exercise (fig. 4). The total excess
.'02 resulting fronit exercise was calculated as the
of the excess oxy,gen above control levels con-
sum
sumed during the actual exercise period and the
oxygen debt (fig. 4).
All subjects were studied in the postabsorptive
state and were weighed every morning after voiding. A minimum period of 20 minutes with the
patient sitting on a chair placed on the treadmill
Circulation, Volime XXVII,
.Mlarch
1960
401
STUDIES ON DIGITALIS
CHAMBER
GAS VOLUME
METER
l
GAS ANALYZERSj
REC.A
RIAMLI
CORRECTION
CALIBRATION
4TS\CEL
__
_
\DATA HANDLI NG
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
|SYSTEM
__
PAPER TAPE
COMPUTOR
Figure 3
Block diagram of instrumentation
in
Metaboli c Chamber.
in the Metabolic Chamber was allowed for stabilization prior to the measurement of Vo2 before
exercise, which was also made with the patient
in the sitting position. When a stable V before
exercise was achieved, the subject was asked
to stand and start walking. The transition from
sitting to walking or vice versa took 15 seconds
or less. Immediately following the exercise the
patient returned to the sitting position and the
oxygen debt was recorded. An investigator wearing
a separate hood continuously observed the subject
in the Metabolic Chamber during the exercise
periods. Two subjects, each with a normal cardiovascular system and of body builds and weights
comparable to two of the patients, were exercised
under identical conditions to those employed for
the patients. The resultant oxygen debts of control
subject no. 1 were compared with those of patient
C.A., while the debts of subject no. 2 were
pared with those of patient S.M.
Results
02
com-
The dietary sodium intake, body weight,
admninistradebt measurements were carried out in patients C.A.
and S.M. are illustrated in figures 1 and 2.
Patient P.F. 's body weight on the days of
study is shown in table 1. No notable changes
occurred in the patients' subjective condivenous pressure, periods of drug
tion, and days on which oxygein
Circulation, Volume XXVII, March 1963
tions, body weights, or venous pressures when
digoxin was discontinued or restarted.
During the first period of study, while patient C.A. was receiving digoxin, the oxygen
debts following two 10-minute walks were
496 ml. and 433 ml., respectively. During these
two studies the oxygen debts averaged 12 per
cent of the total excess Vo2 resulting from
exercise. During the second period, while receiving the placebo, the resting vTo tended to
be higher than during the prior period when
on digoxin. The oxygen debts rose to 768 ml.,
733 ml., and 718 ml., representing, on the
average, 22.3 per cent of the total excess Vo2
resulting from exercise. When digoxin was
reinstituted, resting VO2 fell and the oxygen
debts fell to 413 ml., 594 ml., and 698 ml.,
with the oxygen debts averaging 16.3 per cent
of the total excess Vo2 resulting from exercise.
In addition, the oxygen debt following a
shorter (7 min. 40 see.) walk equaled 1,009
ml. when the patient was not receiving digoxin, and declined to 661 ml. after the glycoside was reinstituted. Control subject no. 1
developed oxygen debts of 427 and 336 ml.
respectively during two 10-minute walks and
40()C-
IK\ LFE2V E rl' A' L.
402A
1000
F-
0
Potient C.A
r
D'goor'n
* No Digoxin
900
A Control
su
bjecI!/1
800
700 F-
0
STOP
EXERCISE
START
EXERCISE
600 1-
Figure 4
(}
ni / ?'fan
Jse t7Hlly ( 'Itn;fr
1 f11
ll//l I) n
to1(111 Vo in )(patient S.M. Du ri nl till pre U ei
period, 102 eqiltl.l('(l .19,- mil.z
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
. Th(, ofz.set (n114
the 1. nitexe
C1r(-is( afre in(ldaated
b)lii - U eli -al (ifll, iii s/ i pp/I tf'tall/I ?lU iH
1 ' /c
Sod11 1hle (f'coi'S, oJ1U/eli,
(e1aborc
l bifl.i, Coni.i 1(t4l
PM
(-710R'11i Of] tlii0?':llit f(.1 l( 'i.e 1)wo'to)1d. 7?i e
ilst ifn1,(e }ltif lZy Hs rej i)'siblc m't, th P 'r ttee n io 1,
?t
I f (.
pO1ti(i / 0) 111/
h Ii i f U r
( is
tI
(ofl.stilfoll
Th
02
DEBT 500 Fml.
n
(i/Ud
HJIreIl Is Me f/
1.
I
400 F-
AL
300-
Tb1
t(iib'ff .:,
.~ In.
{ , Isf .S1110///
t J tJ J Unf
i(
}X,.*XtiH s 15; H
Sell t(f4 b1) 1/ic.;i' ,,of the 541j)JlWe 1 / 111/ ((1 ,1/(01,
2
200
2.J
0
7f
Ilis oxyg1en del)ts av-eraged 101
A) er Hiolit if
tlle total excess Vo, resulting fr1m1 (xereise
Jtable 1, fig. 5K
Patient P.F. was exereised oni a sigo-le oc(casion for 10 minutes while reeeiving digoxini
ani-d developed ali oxygell debt of 1301 itil.
this value represented 10 per lient of the total
eXCess Vo2 resulting fromii exercise. After discontinuation of this nmedication, thie oxygo_en
debt for the sauie exercise rose to 2,124 ani(d
9,406 mnl. o11 two oeeTasions, wx itli tlhe debts
averagino, 13.5 per eent of tlhe total excessxx o,
ressulting from exereise. lIn additionl. the oxYg-Yen debt following a shorter period of exercise (7 min. 35 sec.i" equaled 1.837 ml. during
digoxin adminiistration and rose to 2,461 ml.
after the glycoside was discontiniued (table
1, fig. 6).
Patienit S.A1 was exereised for 15 minmtes
on two oceasions while not receivino dioyoxini
and developed oxygen debts of 624 ml. aid(
686 mul. respectively , with these debts represeimting. on] thle average, 12.5 per cent o-f til
total excess V02 resulting froml exercise. During digoxin administration the restinog st02
values were comparable to those obtained
100 r
II
2. / mph
0 %grode
1O minss
CONDI 77ONS OF EXERCISE
0
Figure 5
Oxigei debts iOl pati( at C(1 flien onf or off
diqyoxin, an-?d in control subjectfn. 1, ztchose fweight
012(, bod1! build resemlble(d thaoc of patielit C.A.
The co0fltiitlOlfS eh
0
xerc
e
i(
i.
riod0
re
ai-IdiNated
Hep
at tile bo0tftonl (f tlef f/ure.
lurillng thle preiolls period, auiel tIfie oxygen
debts after exercise deelilled to) 4-62 il., 5830
11m., and 402 mul. During these tlhree studies the
oxygen debts averaged 11.0 per cent of the
total excess Vo,2 resulting front:l exereise. The
normal subject developed debts of 260 mnl.
and 252 nil. with tile oxvyen debts averaging
i-a per cellt of the total eXcess Vo2 resIlting
fromn. exercise. Tit addition, patient S.M. was
exercised botlh witIl and witloUit digoxin allmillistration under three oth-er conditions (table 1. . Under eaeTi condition the oxyrgen
debts after exercise were alwax s lower duringc
dgio-xin adinimstration (tab-le L fi. 7)1
Discussion
The oxygen debt measured following the
Circltatfion, VolwOie XVI
XX
Mardb 196f
403
STUDIES ON DIGITALTIS
1000 r
Potient P X
2400
O
O Digoxin
* No Digoxin
2800
PotienI S M.
900 H
0
8001-
subject 02
0
0
S
0
2000
0
700 e
0
02
0
DEBT 1600
600 K
ml
0
0
02
1200 K
DEBT 500
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
1
t
2.5 mph
7.5 %grode
/O m ins
2.5
7.5
7 *400 H
CON1DITIONS OF EXERCISE
0
0
400[K
300 K
f I ~t
0
Figure 6
Oxygen debts in p,atient P.F. when on or off
digoxin. The conditions of each exercise period are
indicated at the bottom of the figure.
completion of exercise represents the summation of instantaneous oxygen deficits accumulated during the entire exercise period. Measurement of this variable is a sensitive technic
for assessing the adequacy of the circulatory
system, especially when au individual can be
employed as his own control. If the delivery
of oxygen is only slightly impaired by an inability of the cardiac output to rise adequately
during exercise, the circulatory deficit may be
difficult or impossible to detect by the measurement of cardiac output alone, but a measurable oxygen debt may accumulate. For
example, an increase from 300 to 600 ml. of
the oxygen debt incurred during two 10-minute periods of identical exercise represents a
rise of 100 per cent and nmay easily be detected by the methods employed in this study.
If it is assumed that the cardiac output is
constant during the entire exercise period, the
higher oxygen debt would be associated with
an oxygen delivery which is only 30 ml. per
minute lower during the study in which the
oxygen debt was greater. If an arterio-mixed
Circulation, Volume XXVII, March 1963
0
-
ml.
800 H
Digoxin
A Control
0
0
0
Digoxin
* No
0
200K
2.55
5
100
r
4I'I
It
2.5
5
'41"
2.5
3
/0'
2.5 mph
2.5 %grode
JS'
CONDITIONS OF EXERCISE
0'
Figure 7
Oxygen debts in patient S.M. when on or off
digoxin. Four levels of exercise were employed
and these are indicated at the bottom of the figure.
The triangles present data obtained from control
subject no. 2 whose weight and body build reseemb led those of patient C. A.
venous oxygen difference during exercise of
12 vol. per cent is assumed, the difference
in cardiac outputs during the two periods
would be only 250 ml. per minute, a value
that is impossible or extremely difficult to
measure reliably by the best technics available to the clinical investigator. It was with
these considerations in mind that the measurement of the oxygen debt after exercise rather
than the more usual approach of measuring
cardiac output at rest and during exertion
was selected for studying the effects of digitalis.
In 1931, Harrison, Calhoun, and Turley2'
studied the effects of digitalis in a group of
K AIILER EP l Al.
404
c!ardiae patients with exertiomal dyspnea,
some of whoml also had paroxysmal niocturnal
dyspnea. These investigators observed that
concomitant with the patients symllptomlatic
im.provement, the ratio of venitilationi to vital
durinig exercapacity ve(itilatiomi inldex
tiont dimriniished. Nylin2 not-ed that the Vo2
itueasured several m:inlutes after exer(eise dedlinied followinrg
patienit
digitalization
in
a
singole
ithli heart disease and exertional
dysplnea.
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Although the patients utilized in the prescut studies had previously experienlced congestive heart failure aiid although some
dimiinutioin int cardiac reserve persisted, they
wvere. compensated in the abseiice of digitalis
therapy and wvere able to performi their norntial everyday activities xvithout sym-ptomns.
Indeed, patient P.F. walked 11/½ miles twice
dlailv without diseomnfort while the studies
were beinog clarried out. The administration
withldrawal of digitalis in these patien-ts
did not result in anyy apparenit subjective
changes or alterationis of weight?. venous pressure, or of cardiac size, as determined by chest
or
roenitgenograms.
On
the basis of these obser-
vationis and r-neasurem:leilts there was no evidenee that the effects of digitalis adminlistration wecre benieficial. However, detailed and
repeated nieasureinents of the absolute oxygen
debt after exercise always revealed lower valuies while the patients were receiving digoxini,
although there was comisiderable variationi
individual studies. There was also
conisiderable variationi in the total exeess Yo
resultinig fromn idenitieal exercise periods in
each patient, but the adninistrationi of digoxin did not appear to affeet this -variable.
The ehanges in the oxygemi debt Avere therefore accomiipanied by declines in the ratio of
the oxygen debt to the total excess VoY- resultinrg froml exercise. However, in. spite of the
Ireduction of the oxygeni debt during digoxin-i
administration, it was apparenit that in two
of time three patients studied, tIme debts did
niot decline to the levels observed in subjects
with niormnal cardiovascular systems (figs. a
aId 7) These reductionis of thel oxygen debts
after exercise withouit coneoinutant chamiges ini
among
the total oxygen eost of exercise are consistenit
with the hypothesis that in these three patients digitalis in-iproved the (leliverv of OXygen to the systemnie vascular bed during exertion, anid thus permitted the oxygen delivery
to mneet the oxygen requiremlents ill a mriore
satisfactory fashioin. These observationis suggest strongly tlhat. in the tl-hree patients studied, the digitalis glyeoside resulted in signiifi(alit improvementt of over all circulatory
func(tionl in spite of the absenee of any appareilt elinical benefits. Firomii a therapeutic
poinlt of view it therefore appears that at least
some patients x it1l enlargedlhearts without
leart failure are beniefited bv digitalis adniiiiiistration,
Summary
TThree patienits with aecqtlired vatlvular hieart
disease anid cardiac enlargemienat who were
able to perforn-i lnormal every day activ ity
without diffieulty in the absenee of digitalis
therapy were exercised while receiving a
plaeebo anid againi while receivinlg digffoxin
Digoxin administrationi did n:ot produce, a
signifieant chanrge in body weight or in the
subjective condition of the inidividuals. Varying degrees of exercise wvere performiied on1 a
treadmnill in a Metabolic Chamrlber anid oxygen
consumption was miieasured coiitinuouslv before, during, aind after the period of exercise,
utilizing a contirnuous gas flow paramiagnetie
oxvgen analyzer. The oxygen debt that developed durinig digoxini adminiistrationi was coilpared to that observed durinig placebo admimilistration.
In all patielnts the oxygeie debt was slmaller
durinog the period of digoxin adminiistrationi,
although the external work performled was
identical. In the first patient, following a 7minute walk, the oxygen debt wvas 33 per cent
muore and followinig a 10-miiiniute walk it averaged 40 per cenit more while inot receivinlg di(goxin than wlihen receiving this drug. In tlIe
seconid subject the oxygen debt following a
-muilute walk was 34 per cent more and following ai 10-iniriute walk it averaged 74 per
cenat more wheni he was not receiving digoxin
than vwheni receivinig this drug. In the third
subject the oxygen debts were 46 per cent
and 41 per cenit greater following 10- anid 15Circulation. Volunui;XXVII, NiMarch
1963
STFUDIES ON DIGITALIS
iinute walks respectively, whleni she was niot
receiviniog digoxin.
The accumnulationi of a smiialler oxygen debt
following exercise while these subjects were
receiving digoxin indicates that the functional
status of their circulatory system was improved by the drug. It would appear that
digitalis administration is beneflcial to at
least some patients who have cardiac disease
and enlarged hearts and some decrease in cardiae reserve without signs or symptoms of
heart failure.
References
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
1. MCMICHAEL, J., AND SHARPEY SCHAFER, E. P.:
The action of intravenous digoxin in man.
Quart. J. Med. 12: 1"23, 1944.
2. BLOOMFIELD, R. A., RAPOPORT, B., MILNOS, J. P.,
LONG, W. K., 'MEBANE, J. G., AND ELLIS, L. B.:
Effects of cardiac glycosides upon dynamics
of circulation in congestive heart failure;
ouabain. J. Clin. Invest. 27: 588, 1948.
3. LAGERL6F, H., AND WERKO, L.: Studies on eirculationi in man; the effect of Cedilanid (laniatoside C) on cardiac output and blood pressure
in the pulmonary circulation in patients with
compensated and decompensated heart disease.
Acta cardiol. (Brux.) 4: 1, 1949.
4. AHMED, S., BAYLISS, R. I. S., BRISCOE, W. A.,
AND MCMICHAEL, J.: Action of ouabain
(g-strophanthin) on circulation in man, and
comparison with digoxin. Clin. Se. 9: 1, 1950.
5. BING, R. J., MARAIST, F. M., DAMMANN, J. F.,
JR., DRAPER, A., JR., HEI-MBECKER, R. DALEY,
R., GERARD, R., AND CALAZEL, P.: Effect of
strophanthus on coronary blood flow and cardiac oxygen consumption of normal and failing
human hearts. Circulation 2: 513, 1950.
6. FERRER, M. I., HARVEY, R. M., CATHCART, R. T.,
WEBSTER, C. A., RICHARDS, D. W., JR., AND
COURNAND, A.: SoIme effects of digoxin upon
the heart and eirculation in man; digoxin in
cor pulmonale. Circulation 1: 161, 1950.
7. BRAUNWALD, E., BLOODWELL, R. D., GOLDBERG,
L. I., AND MORROW, A. G.: Studies on digitalis.
IV. Observations in man on the effects of
digitalis preparations on the contractility of
the non-failiing heart aind on total vascular
resistance. J. Clin. Invest. 40: 52, 1961.
8. MASON, D. T., AND BRAUNWALD, E.: Inotropic
effects of a digitalis glycoside on nion-failinig
lhearts studied in intact human subjects. Clini.
Res. 10: 176, 1962.
9. BURWELL, C. S., NEIGHBORS, DEW., AND REGENS,
E. M.: The effect of digitalis upon the output
of the heart in niormal man. J. Clin. Invest.
5: 125, 1927.
Circulation, Volume XXVII, March 196,3
405
10. STEWART, H. J., AND COHN, A. E.: Studies on
the effect of the action of digitalis on the
output of blood from the heart. III. Part I.
The effect on the output in normal human
hearts. Part 2. The effect on the output of
hearts in heart failure with congestion in
human beings. J. Clin. Invest. 11: 917, 1932.
11. HARVEY, R. M., FERRER, M. I., CATHCART, R. T.,
AND ALEX \NDER, J. K.: Somle effects of digoxin
oni the heart and circulation in man; digoxin
in enlarged hearts not in clinical congestive
failure. Circulation 4: 366, 1951.
12. SELZER, A., HULTGREN, H. N., EBNOTHER, C. L.,
BRADLEY, R.. W., AND STONE, A. O.: Effect of
digoxin on the circulation in normal man.
Brit. Heart J. 21: 335, 1959.
13. DRESDALE, D. T., YUCEOGLU, Y. Z., MICHTON,
R. J., SCHULTZ, M., AND LUNGER, M.: Effects
of lanatoside C on cardiovascular hemodynamies; acute digitalization doses in subjects
with normal hearts and with heart disease
without failure. Am. J. Cardiol. 4: 88, 1959.
14. WILLIAMIS, M. H., JR., ZOHMAN, L. R., AND
RATNER, A. C.: Hemiio(lyiiaaniie effects of cardiac glycosides on normal human subjects
during rest anid exercise. J. Appl. Ph-ysiol. 13:
417, 1958.
15. GOODYER, A. V. N., CHETRICK, A., AND HUvos,
A.: The effect of laniatoside C on the response
of the human cardiac output to walking exercise. Yale J. Biol. & Med. 32: 265, 1959.
16. SELZER, A., AND MALMIBORG, R. O.: Hemodynamic
effects of digoxin in latent cardiac failure.
Circulation 25: 695, 1962.
17. HUCKABEE, W.. E.: Relationships of pyruvate
and lactate during anaerobic metabolism. II.
Exercise and formation of 02 -debt. J. Clini.
Invest. 37: 955, 1958.
18. MEAKINS, J., AND LONG, C. N. H.: Oxygen consumption, oxygen debt, and lactic acid in
circulatory failure. J. Clin. Invest. 4: 273, 1927.
19. HARRISON, T. R., AND PILCHER, C.: Studies on
congestive heart failure. II. The respiratory
exchange during and after exercise. J. Clin.
Invest. 8: 291, 1930.
20. BUSKIRK, lE. R., THOMPSON, R. H., MOORE, R.,
AND WHEDON, G. D.: Human Energy Expenditure studies in the National Institute of
Arthritis and Metabolie Diseases Metabolic
Chamber. Am. J. Clin. Nutrition 8: 602, 1960.
2 1. HARRISON, T. R., CALHOUN, J. A., AND TURLEY,
F. C.: Congestive heart failure. XI. The effect
of digitalis on the dyspnea and on the ventilation of ambulatory patients with regular cardiac rhythm. Arch. Int. Med. 48: 1203, 1931.
22. NYLIN, G.: L 'influence de la digitale sur la
dette relative d 'oxygene dans 1 'insuffisance
cardiaque latenite a rhythme eardiaque normal.
Arch. mal. coeur 32: 1010, 1939.
Studies on Digitalis: VI. Reduction of the Oxygen Debt after Exercise with
Digoxin in Cardiac Patients without Heart Failure
RICHARD L. KAHLER, RONALD H. THOMPSON, ELSWORTH R. BUSKIRK,
ROBERT L. FRYE and EUGENE BRAUNWALD
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Circulation. 1963;27:397-405
doi: 10.1161/01.CIR.27.3.397
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1963 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://circ.ahajournals.org/content/27/3/397
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles
originally published in Circulation can be obtained via RightsLink, a service of the Copyright
Clearance Center, not the Editorial Office. Once the online version of the published article for
which permission is being requested is located, click Request Permissions in the middle column of
the Web page under Services. Further information about this process is available in the Permissions
and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/