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Effects of lanatoside C on cardiovascular hemodynamics
Clinical
Study
Effects of Lanatoside
C on Cardiovascular
Hemodynamics Acute Digitalizing
Doses in Subjects
with Normal
Hearts and with Heart Disease Without Failure* DAVID T.
DRESDALE, M.D., YUSUP ZIYA YUCEOGLU, M.D., F.A.G.c.,~ ROBERT J. MICII~I.O~~,11.~. MARTIN SCHULTZ, M.D., and MAURICE LUNGER, ~I.D.$ Brooklyn,
S
New York
the use of foxglove in dropsy by Withering,’ digitalis glycosides have been used widely in the treatment of heart failure and their effects have been subject to extensive clinical, experimental, and physiologic investigation. Numerous studies utilizing the technique of right heart catheterization have established some of the effects of cardiac glycosides on cardiovascular hemodynamics in patients with heart failure.2--8 However, a survey of the literature reveals only few studies5-7,g-12 with limited numbers of patients with normal hearts or patients with heart disease without heart failure. In these studies it was found that cardiac glycosides in normal individuals either decreased the cardiac output7 zg
heart disease without evidence of heart failure. Patients with heart disease but not in failure are frequently considered for prophylactic digitalization prior to major surgery or other types of unIf no deleterious effects on the carusual stress. diovascular hemodynamics are demonstrated, such therapy might well be justified. This report presents the early effects of lanatoside C on the cardiovascular hemodynamics in 11 patients studied by the technique of right heart catheterization. To establish criteria for the determination of significant changes in cardiac output that could be attributed to the drug, 100 right heart catheterizations in which two cardiac output determinations were done within 9 to 91 minutes (average 36 minutes) lvithout any drug administration were analyzed.‘” On the basis of this study the ranges of allowable spontaneous variations under “steady state” conditions were determined.
INCE
MATERIALS
AND
METHODS
Seven subjects without heart disease and four with heart disease but not in heart failure were studied Four of the seven subjects without (Tables I and II). heart disease were males and three were females.
* From the Cardio-Pulmonary Laboratory, Department of Medicine, Maimonides Hospital of Brooklyn. and the Department of Medicine, State University of New York, College of Medicine at New York City. t Part of this work was done during tenure of Research Fellowship of the New York Heart Association. f Postdoctoral Fellow, National Heart Institute, U. S. Public Health Service. This investigation was supported in part by a research grant from the National Heart Institute of the National Institutes of Health, United States Public Health Service.
88
THEAMERICANJOURNALOF
CARDIOLOGY
Dresdale,
Yuceoglu,
Michtom,
In the other Their ages ranged from 25 to 58 years. group there tvere two males and two females, their ages ranging from 49 to 63 years. All had normal The electrocardiograms lvere within sinus rhythm. normal limits except one (case 11) which had some In the group wilh heart nonspecific T \vave changes. disease cardiac enlargement w-as absent or slight on x-ray examination. The patirnts were studied in the resting state after fasting for at least twelve hours. They were hospitalized at least three days before the study was done. They all received phenobarbital 0.06 Gm and Nembutal 0.1 (+rn the evening before any observations were made. None had received cardiac glycosides in the past. The ph>.siologic data were obtained by utilizing the The blood technique of right heart catheterization. oxygen content and capacity were determined by the method of Van Slyke and Neil1.14 The expired air was collected in a Tissot spirometer and analyzed in the Scholander gas analyzer.15 The cardiac outputs were determined by the direct Fick principle. Pressures wcrc recorded using Sanborn electromanometers and a direct-writing Sanborn Poly-Yiso rehlean pressures were determined by planicorder. metric measurement of the electrically integrated pressure tracings using one or more complete respiraThe point of zero reference for measuretory cycles ment of cellrral pressures was 5 cm below the angle of Louis with the patient in the supine position. Total pulmonar) artery and total peripheral arterial resistances \verc calculated according to the following formula:‘“,‘;
Control measurements were made after the catheter and the venous and indwelling arterial needles were inserted and the patient was quiet for at least fifteen minutes. Two control cardiac outputs were taken in three patients and one control cardiac output in the Lanatoside C, 1.2 to 1.6 others (Tables III and IV). mg (as noted in Tables III and IV), was injected slowly through the catheter into the pulmonary artery Cardiac outputs were then over a two-minute period. obtained from 40 to 121 minutes later. Multiple pressure measurements were recorded throughout the study. QT, intervals were measured in six cases before and after lanatoside C injection (Table V). The criteria for interpretation of the results are based on a study in our laboratory of the “steady state.” using the direct Fick principle.13 According to this analysis. any change in cardiac output within the range of plus or minus 15 per cent should not rightfully be attributed to drug effect. Changes within this range can be due to the inherent experimental error- of the technique. J’XY,
1959
Schultz,
and
Lunger RESULTS
Heart Rate: In the two groups of patients, there was no significant change in the heart rate. In 4 out of 11 cases a decrease up to 4 beats per The remainder of the paminure eras noted. tients shoM-ed an increase up to 9 Ijeats per minute. QT, intervals in the six cases measured showed a decrease, indicating digitalis effcsct electrocardiographically (see Table V). Oxygen Conszim~tion: Control oxygen consumptions (see Tables III and IV) \\-ere normal as compared to the generally accepted figure of 138 f 14 cc/min/‘sq. M BSA except for cases 1 and 4 whose values were slightly- hut not significantll- above normal. Oxygen consumption calculated at different time intervals following digitalis administration did not show any significant changes from control le\~rls. The greatest change Ivas 16 cc. Cardiac Outjut: The 7 patients bvith normal hearts had changes in cardiac indices from control level follo\ving digitalization ranging from + 13 to - 13 per cent (see Table I and Fig. 1 j. In the second group, the patients with heart disease without evidence of heart failure, the change from control levels ranged from - 11 to + 13 per On the basis of cent (see Table II and Fig. 1). analyses of preiious experiences in our department,‘” differences of the order cited ahove are within the limits of expected variation (Fig. 1). * ‘~WJ patients without heart disease and one patient with heart disease without heart failure (cases 6, 7, and 10) had two control cardiac outThese cases demput determinations (Fig. 2).* onstrate the value of at least two control cardiac output determinations in this t)-pe of study-. Control cardiac indices and cardiac indices at different time intervals following digitalization If the control are shown in Tables III and 11’. cardiac indices of higher value are considered, two (cases 6 and 10) show significant fall and one (case 7) shows insignificant fall after digitalization (see Fig. 2). However, when cardiac indices with lower values are considered, this imIn case 6, 97 minpression is not corroborated. utes after digitalization there was a fall in cardiac index of 19 per cent from the second control level. If the first control cardiac index is taken, then thert is only a negligible change of In case 10, the fall in cardiac in3.5 per cent. dices from initial control level (cardiac index with higher value) was also significant (-24 prr cent) follo\ving digitalization. Howe\,er: if *See page 95.
:
zr
2
data
M.; F, age 57: carcinoma of the breast with metastases; no heart disease
M.
3
.I. C.; M, age 28; diabetes mellitus no heart disease
F.; F, age 44; multiple sclrrosis, argyria; no heart disease
hi.
2
5
F. I>.;
M, age 5X; G-I disease undiagnosed; no heart disease
Clinical
1
CkiSC
;
hlcasurcn~uts
97 83 94 35 91 87 93 99 79
132/62* 145/67 154/72 142/69 153/65 137162 137/70” 139/75 118/61
Control 20” 29 43 80 95 tr.01
146 26 37 54 90
Control
17u 73 80
Cor1
3Ob 58 88 103
70 78 75 74 73 67 72
83
121/68 100/55d 107/68 104/63 103/63 97/61 103/50 96/60
72
116/57 -
-
21/8 -
80 82 80 89
110/61” 110,‘64 113/62 124/70 128/72 127/77
Control
55”
11 12
20,‘5 23/7 22/6 18/8 18/8 -
13 14 16 14 14 14 14
-
15
-
10 -._. -
18/3 20/5 -
8 7 0
.-
14 15 15
~___ 25/s 25/8 25/8
102 104 108
S/D
141/7Y 138/75 155/75
‘lime (min)
hl
Heart
M
Without
S/D
Patients
Pulmonary artery pressure (mm Ha)
in Seven
Brachial or femoral artery pressure (mm Hg)
of tlrc Circulation
During
17/2 2Oi2.5 1812 20/2 18/3 t8/4 16/2
-
21/3.5 25/4.0 -
32/‘5 31/5 26/l 32/~21/l 26/-22/l
19/l 24/2 --/3
21/4 2013 -
24/-p
.-_
Right ventricular pressure (mm Hg ), S/D ‘_
IJisrasc
Digitalization
(mm
1
2.7
-.
-
~-
_
‘1
4.7 4.8 4.4 5 0 5 0 4.3 4.6
8.6 7.9 7.8 6.9 6.9 7.6 6.6
4.4 4.4 4.4
5.6
2
-
HE), M_
4
____
(mm
1 -.._
2
2 2
4
3
-.
MU
Ha),
Kight Peripheral auricular venous press urc press urc
.%cutc
5,08
5.27
8.64
I-
8.92
. ..-
4.44
5.71
5.13 _ -,_. -
4.60
4.48 -
4.91
7 .07 7.31
C:arcli;~c output (I,/min)
Studies
.3
61.7
-.
88.0
123,5
131 ,o
67
77.2
-_
75.3
63.8
65.8
71.2 I--
110.5 114.0
(cc)
vdumc
Strukc
105 97
60
70
68 6K
66
74
68
72
68
69
64 GO
Heart ratr (beats/ min) ----~
-~
Dresdale,
Yuceoglu,
Michtom.
Schultz,
and
Lunger
the other control cardiac index is considered in comparison with those determined after digitalization, the change was then only -4 per cent. Cast 7 also demonstrates the same kind of mariations Ijut to a lesser degree. Apparent changes in cardiac indices in cases 6 and 10 arise from significant differences in the Figure 2 shows tb’(J control cardiac indices. that there never was a continuous trend in an!. direction. These figures fall outside the range of “normal variations” previously determined in This indicates patients in the “steady state.“13 that during determination of at least one of these control cardiac outputs, the patient’s state \vas changing in spite of the absence of any significant change in oxygen consumption or heart rate. Therefore, if two control cardiac output determinations Ivere not obtained, a change in cardiac output due to a change in state might falsel>- have lien attributed to the effect of digitalis. Right Heart and Pulmonary Artcry Pressures: Right ventricular end-diastolic and mean right auricular pressures were within the accepted normal values, except in case 6. In cases 3 and 6 end-diastolic pressures in the right ventricle fell 4 mm Hg in each without significant change in Right auricular pressures, in 5 cardiac output. of the 6 patients in whom multiple mean measurements were obtained (cases 2, 6, 7, 8, and 11 ), fell 1 to 3 mm Hg, and in the other there jcas no change. Peripheral venous pressures were measured in 7 cases and did not show any change following lanatoside C. Three of these showed a slight fall in right auricular pressure. There cvere no significant changes in right ventricular systolic and.‘or pulmonary artery pressures after drug administration except in case 3. where there was a slight fall in ri~ght ventricular systolic pressure. Systemic and Pulmonary Arterial Pressure and Systemic and pulmonary arterial Resistance: pressure and resistance varied slightly, hut in no consistent fashion. These variations were veil within the expected range.” Arteriouenous Oxygen D#erence: No significant change was observed in the arteriovenous oxygen differences after digitalization in any patient, although in 10 of the II cases there \\-asa tendenc\for a minimal Arterial \I
JULY, 1959
increase.
Oxygen
Saturation..
.4rterial
oxy)gen
saturation remained fairly constant folloving digitalis administration. This condition in-
I. K.; F, age 62; .4SHD, LV hypertrophy, myocardial damage, NSR, no CHF; old hypertension ; emphysema; bronchial asthma; recent bronchopneumonia; diabetes mellitus
11
C.
18” 31 42 48 82 104 117 120 CHF = Rheumatic
D Minutes
-__-
Control
lSb 47 52 58 97
Control
ASHD = Arteriosclerotic heart disease. NSR = Normal sinus rhythm. RHD =
u Minutes after 1.6 mg lanatosidc
H. S.; F, age 56; ASHD, NSR, myocardial damage, no CHF
10
13” 25 40 48 64 72 85 94 108 121 88 100 82 92 92 91 93 86 92 76 78
126/68 143/78 119/58 128/72 137/U” 132/64 136/67 132/64 132/67 110/57 125/57
II
91 96 94 95
143/60 148,‘68 150/68 1X/68
-
Congestive heart heart disease.
failure.
C.
-.
LV
32/12 35/14 33/16 36/14 32/l 2 35/13 32/l 5 32/15
18/5
-
19/-
20/22/9 22/7
42/22 47/27 43/22
43/23 41/-
44/25 43/23 46/23 43/22
31/9 33/8
S/D
(mm
= Left
ventricle.
artery. MI
31/2 33/4 32/5.5 33/3 31/3.5 33/0.5 36/6 32/0.5 30/2 32/2.5
20/4.5 21/3.5 18/2.5 2014 18/l. 5 21/4 20/3 18/2
11 12 12 11 11 11 11 11 20 23 23 23 21 23 22 25
43/l 44/o 43/2 45/o 44/2 44/l
45/2 44/2 43/1.5 4712 45j1.5
Right ventricular pressure imm Hg), S/D
0 5
-
1.5
1
-
2
-
4 1
=
Mitral
artery. insufficiency.
5.9 5.7 6.2 5.7 4.9 6.2 4.8 4.7 5.7 57
8.8 7.7 5.2 4.8 4.8 4.9 3.8 3.5 3.7 3.2 3.2 3.2 3.7 -
-
Studies
MS
6.71
6.30 -
6.41 --
4.82 -
5 39
6.33 5.04 -
6.92 -
6.90 -
6 71 -
=
Mitral
stenosis.
10.7
70.7
77.3
58.1
64 1
77.2 71.9
70.7
70.5
70.7
68.8
-
6.46
91.0 84.5
6.0 5.32
_
Cardiac output (L/min)
Acute Digitalization
Right Peripheral auricular venous pressure pressure (mm Hg), (mm Hg), M M
During
” Femoral
-
Failure
29 29 31 36 30
32 31 31 31
35
17 19
M
’ Brachial
Hg)
Pulmonary artery pressure
after 1.2 mg lanatosidc
95
155/65
93 85
33 92 88
134/73 130/72 125/72 -
135/66” 120/69 -
92 97 87
125/70” 130/77 127/68 -
Control
J. R.; M, age49; RHD, NSR, MS & MI ; recurrent hemoptyses ; no CHF
116 112
9
M-
H,K)
S/D
(mm
167/8Sc 167/80
(min)
Control 53a
data
TABLE with Heart Disease but Not in Heart
Brachial or femoral artery pressure
in Four Patients
E. S.; M, age 63; ? polycythemia; ASHD, NSR
Clinical
Time
of the Circulation
8
Case
Measurements
95
89
-
90 83
83
84
82 82 77
98
98
95
108 94
66 63
Dresdale,
Yuceoglu,
Michtom,
Schultz,
TABLE Physiologic
Data Concerning
Cardiac
Oxygen consumption (cc/ min/sq M RSA)
Cardiac index (L ‘min/ sq M BSA)
A-V
mygen difference (\“I
93
Lunger
III
Output in Seven Patients Digitalization Studies
Respiratory quotient
and
Without
.Irterial
Cardiac index
G,Iltent Iv01 $1
(SC change)
5;)
Heart
Disease During
blood
Calculated resistance .‘dvnes ser cm-s1
“xveen
Capacity (““1 c;)
Acutr
lY
Saturation (‘7)
Pcriphera1
TOT31 pulmonary ,rtCry
-
1 .36
1 .68
1.80 1 45 1 .62
1.78
a hlinutes
0.72 0.76
4.16 4.30
4.3 4.4
+
3.4
17.6 l-.6
19.0 18.9
92.5 93.1
1175 1183
CO” W”l 581’ 103
130 I19 135
0.75 0.79 0.82
3.61 3.29 3.38
3.6 3.6 4.0
8.8 -64
1.5.6 15.6 15.6
16.0 16.0 16.0
97.5 97.5 97.5
1305 1590 1685
Control 43u 95
119 129 II9
0.74 0.79 0.73
3.05 3.40 2.65
3.9 3.8 4.5
+11.5 -13.1
14.3 14.3 1s 9
15.4 15.4 -
92.7 92.7 -
1295 1330 1555
Control 8011
178 173
1.01 0.81
4.96 4.67
3.6 3.7
-
IF.6 I- 9
19.4 18.5
95.8 96.8
890 770
Control 901’
149 152
0.82 0.83
3.64 4.12
4.1 3.7
t13.2
15.4 14.3
16.2 15.2
95.0 94.1
1062 963
COotKJl Cootr01 490 97
122 129 134 129
0.75 0.72 0.76 0.75
3.70 4.30 3.73 3.57
3.3 3.0 3.4 3.6
17.6 -
92.0 -
+:.2c 3.5
16.2 15.5 15.4 15.4
16.1 16.1
95.7 95.7
1440 1205 1255 1343
240 207 213 707
Con:rol Conrrol 920 123
151 143 152 143
0.73 0.69 0.58 0.64
4.56 4.07 4.23 4.22
3.3 3.5 3.6 3.4
+ +
19.3 19.2 19.0 I8 8
19.6 19.6 19.5 19.5
98.3 98.0 97.0 96.3
949 1080 1083 1llU
-. -
after 1.6 mg lanatoside
C.
b Minutes
after 1.2 mg lanatoside
TABLE Physiologic
Data Concrrning
Cardiac
Oqgen c”Ils”ElDtion (cc’/ min/sq M BSA)
ChX
8
1 58 2.11
9
1 :a2
10
11
1.65
a Minutes
-
5.8
-
_ 3.9(1 3.7
C Using
C.
Rcsvir-
1 atOT-y quotient
Cardiac index II./min/ sq M BS.4)
A-V oxygen differt:nce (vol ‘;;>I
Cardiac index (% change)
167 169
0.70 0.73
3.80 3.37
4.4 5.0
-11.3
COIW”1 40a X5 121
144 146 160 157
0.80 0.85 0.80 0.74
3.06 3.18 3.27 3.28
4.7 1.6
-t
Contlol Control 520 97
12; 127 130 131
0.70 0.71 0.73 0.73
3.91 3 11 3.33 2.98
3 .2 4. 1 3.9 ‘1 4
Control 4w 120
Iii 183 191
after 1.6 mg Ianaloside
C.
first wntrol.
0.7s 0.74 0.75
b Minutes
3.89 3.82 4.07
DISCUSSIOK with heart disease none evidence of heart failure.
3.9
+ -
7.lC 4.2 -
4.5 i.8 4.7
after 1.2 mg lanatoqide
d Using second
170 I64
126 130 -
control.
IV
C0lltr01 S?a
Among the cases showed hemodynamic 1959
-
Output in Four Patients with Heart Acute Digitalization Studies
eludes the one patient (case 11) who had arterial oxygen unsaturation due to chronic pulmonary disease.
IlJLY.
-
179 189
1.8 +13.3
C.
Disease but Not in Heart Failure During
Arterial Conwnt (t-01 %)
blood Capacity (vol r;)
oxygen Satoradon (4;))
Kesisrance (dynes see cm -6) __~-Total pulmoPeriphnary era1 artery
19 3 19 1
20.2 20.2
‘95.7 94.6
154s 1685
227 286
14 3 14.2 14 5 14.1
14.8 14.8 14.8 14.8
96 6 95.9 98.0 95.2
1200 1110 1020 1065
396 350 336 347
14.6 14.6 143 14.4
15.0 14.6
47.3 98.6
1162 1445 1365 1295
152 190 163 182
18.5
86.0 86.0
1060 1155 1123
287 192 -
15.7 15.1 15.
C L-?ing second
)
18.5
control.
There was only one case (case 9) with a moderate degree of pulmonary hypertension, and two cases (cases 8 and 11) with slight elevation of pulmonary artery pressure. Case 9 had rheumatic heart disease with mitral stenosis and mitral insufTicienc)-; cases 8 and 11 had pulmonary emphysema. Case 11 had some arterial
Effects TABLE The Average
QT,
Interval
of Lanatoside
C in Nonfailing artery,
V
Before and After Cedilanid
1 l-27
19 mm Hg:
Hearts 4-l 9 mm Hg, mean prcssurr right
ventricle
8 to
14-31.5:‘---0.5-+7
mm Hg ; and right auricle mean
- 2 to + 5 mm
Hg Effect Control 66(’ 88
0.412 0 335 0.334
Control Control 60b 80 105
0.453 0 437 0.349 0 418 0.331
Control Control 23a 61 80
0 436 0.440 0 387 0.353 0.332
Control Control 49* 97
0.417 0.418 0.405 0 394
Control Control 3Sb
0 363 0.344 0.342
Control Control 17” 35
0.460 0 420 0.312 0 276
ca Minutes after 1.2 mg after 1.6 mg lanatoside C.
lanatoside
C.
b Minutes
blood oxygen unsaturation. Normal right ventricular end-diastolic pressure, normal control cardiac output without any increase after digitalization, and absence of any significant change in the pulmonary artery pressure following digitalis administration in these patients would be hemodynamically inconsistent with congestive heart failure. In three (cases 3, 6, and 7) of the group of subjects without heart disease, pulmonary artery or right ventricular systolic pressures were close to abnormal levels. Case 7 was a 25-year-old man who did not have any clinical evidence of lung or heart disease. The control right ventricular systolic pressures ranged between 28 and 32 mm Hg. In case 6, right ventricular end-diastolic and mean right auricular pressures were minimally above usually observed normal average However, these are within the normal values. ranges reported by some investigators.18-21 Normal pressures in the right heart chambers and the pulmonary artery as reported by Fowler et al.,2”based on their own findings and a review of those of other authors, were : for the pulmonar)
Pressures:
on Right Right
I’entricular
or Pulmonary
ventricular
systolic,
or
Artery pul-
monary artery systolic, diastolic and mean pressures were not affected by digitalis in the tlvo groups of cases with the exception of case 3. The cause for the slight fall in the right ventricular systolic pressure in this case is not apparent. This patient did not have clinical evideilcc of heart disease. Since “pulmonary wedge” pressure was not measured, a decreased left ventricular reserve cannot be excluded. However, if this were due to left heart failure one would perhaps expect an increase in cardiac output after digitalization. In this instance there was a slight fall in cardiac output. The slight fall in pressure therefore ma)- have been related to the decrease in cardiac output. b-feet on L’enous Pressure: In 7 of the casts reporied here in which successive peripheral venous pressure measurements were obtained, there were no significant decreases following digitalization. Dock and TainteP and Katz rt al.S4 showed that in dogs digitalis produced a fall in cardiac output due to its peripheral action. They found pooling of the blood in the viscera caused by constriction of hepatic veins. This action of digitalis has not been observed in .4 number of years ago Rytand’j rcman. ported a fall in venous pressure in 8 normal suI)jects maximal at 24 to 32 hours after oral diyDirect venous puncture using the italization. Moritz-Tabora technique was employed. HOXVever, the fall was only 1.96 cm salincl, and its significance therefore questionable. Steu.art and Cob@ did not find any significant change in venous pressure in normal individuals bv a method similar to Rytand’s. In man, Harvc) and her associatesLo postulated that “either there is no peripheral venous action of the drug, or that if there is such an effect, it is too small to be detected, is obscured by rapid refles \renous adjustments or does not influence central or right heart filling pressures.“ Right Auricular Pressure and Right Ventricular EndTendency of the right \‘enDiastolic Pressure: tricular end-diastolic pressure to fall in two cases (cases 3 and 6) and the slight decrease in mean right auricular pressure in 5 of 6 cases in which it was measured may have been an effect of digitalis, though this cannot be stated with cerTHE
AMERICAN
JOURXAL
OF CARDIOLOGY
Dresdale,
Yuceoglu,
Michtorn,
VARIATIONS
‘STEADY
95
Schultz? and Lunger
WITH
STATE’
HEART DISEASE WITHOUT HEART FAILURE
TYO COWTRM. c 0 Y,THO”T DR”O
,, CHANGE IN
0 I
Frc.
1.
CARDIAC
OUTPUT
43-60
CARDIAC
OUTPUT
BO-l2Omn
Effect of lanatoside
ml” AFTER AFTER
C: on cardiac
LANATOSIDE
C
LANATOSIMC
output.
E:,
I
\ ‘\
2
3oJ
\
\ ___---______----
\
l
-20Y. -42%
I 2.5 BASED
ON HIGHER
CONTROL
A H.M. 1.6mg 0 6.R 1.61119 l Ii R. 12mG
C 0
I
6
Ii
3b
6
CONTROLS FIG. 2. higher
taint)-.
Changes in cardiac of two control cardiac
2.0
MINUTES
40
$0
AFTER
LANATOSIDE
output after lanatoside indices. A Case 6;
The changes in the pressures were small and the changes in the end-diastolic pressure occurred in only 2 of 8 patients in which it was obtained. In normal dogs intravenous infusion of cardiac glycosides has been shown to increase the contractile force of the right ventricle.” This might account for better emptying and. ]UI.Y. 1959
8'0
160
Ii0
I40
C INJECTION
C in three patients, calculated 0 case 7; n case 10.
from
therefore, a decrease in right ventricular enddiastolic pressure. A decrease in right auricular pressure was observed by McMichael and Sharpey-SchaferY following intravenous digoxin in three normal subjects studied by the technique of right heart catheterization. Cardiac output was also considered to have fallen. The fall in
Effects
of Lanatoside
C in Nonfailing
Hearts
right auricular pressure in these patients as well as in those with heart failure following digoxin led them to an impression that “the major benefits of digoxin treatment result from a peripheral action on venous pressure and not from any tonic However, or stimulating action on the heart.“9 this was not confirmed later by Ahmed et al.,5 in the same kind of study with another cardiac glycoside, ouahain, nor by other investigators with the administration of digoxin4 .F aloor Cedilanid.‘? EJect on Cardiac Rate: Cardiac glycosides in subjects with normal hearts and patients with heart disease without heart failure may produce slight slowing in the heart rate or there may be 829 In the present study no change. 5.6,9 .rr 712>26,28 lanatoside C did not cause a significant change in the heart rate. Changes in Cardiac Outfiut: Burwell et a1.28 in 1928 gave digitalis leaf orally in four normal subjects and made daily observations of cardiac output using a modification of the carbon dioxide method.30 They found a decrease in cardiac output with a tendency to return toward normal when toxic levels were reached. Stewart and Cohn2’j in 1932, using the acetylene method of Grollman,31 studied the effects of a single dose of oral digitalis (0.8 to 1.0 Gm) in normal individuals. A decrease in cardiac output and diminution of the heart size were described. The maximum effects were observed Experi4 to 24 hours after digitalis was given. ments in dogs have also shown a decrease in cardiac output following intravenous digitalization.‘3,3”-35 This decrease may be due to hepatic vein constriction which has not been demonstrated to occur in man. It is difficult to compare the indirect methods of cardiac output determinations with those done by direct methIn addition the methods of digitalization ods. and the times of observations were also different. In acute studies in man with intravenous cardiac glycosides using the technique of right heart catheterization in subjects with normal hearts or diseased hearts which are not in failure, the cardiac outputs have been reported to decrease or McMichael and Sharshow no change.5-7~g-13 pey-Schafer9 in three, Harvey et ~1.‘~ in two, and Bing et a1.7 in seven subjects with normal hearts
idence of heart disease and in three patients with car pulmonale vvithout heart failure did not find any significant change in cardiac output after cardiac glycoside administration. In 12 patients with enlarged hearts who had no evidence of heart failure, Harvey et a1.r” reported a decrease in cardiac output in five, increase in one, and no change in six cases. Lagerlijf and \Yerkii,” in a series of seven patients with compensated heart disease, found no change in cardiac output following lanatoside C administration. Interpretation of Cardiac Output Changes: In none of the 11 cases reported here was there a significant change in cardiac output following acute digitalization. The changes noted following digitalis administration were closely similar both in magnitude and distribution to the changes occurring in 71 cardiac catheterizations in patients not receiving medication who had two control resting cardiac output determinations under “steady state” conditions.r3 The true mean deviation for the control group and the group in the glycoside study was approximately zero. The average change in the glycoside group was 6.7 per cent compared to 5.7 per cent in the overall control study. Since 10 of the 11 cases had cardiac indices above 3.5 L/min/sq M BSA, controls with cardiac indices over 3.5 L/min/sq M BSA are used here for comparison. The average variation in the 11 cases was 6.6 per cent. Three (23 per cent) had changes in cardiac output greater than 10 per cent but less Twenty per cent of the conthan 15 per cent. trols showed the same variations. The greatest variation in this study was 13 per cent and in the control study it was 15.7 per cent. The decrease in cardiac output after digitalis administration reported in the literature in subjects with normal hearts and patients with heart disease not in failure comes mostly perhaps from the lack of criteria to determine both the “steady state” and the significance of the changes observed. If our control study group is used for most of the cases reported in the comparison, literature would show no significant change. Some variations in cardiac outputs after lanatoside C administration were shown in the presented data. As demonstrated in the cases with
reported a decrease in cardiac output following However, administration of cardiac glycosides.
two control
Ahmed et al.5 in nine individuals with normal hearts and Ferrer et ~1.~ in two cases with slight
levels after digitalization depended upon which control was used as the base line to measure the
degree
variation,
of pulmonary
hypertension
without
ev-
Fig.
2),
the
cardiac
output
percentage
If only THE
one
AMERICAN
determinations
changes
from
control
output
JOURNAL
OF
(see
control
deter-
CARDIOLOGY
Dresdale,
Yuceog-lu,
Michtom,
Schultz,
and
97
Lunger
mination had been available, an error could easily have been made in interpretation in these
cases there were changes
cases. The oxygen consumption andior the heart rate alone would not have been of help in these cases, since they were fairly constant. A decrease in A-V oxygen difference may be the only hemodynamic manifestation of anxiety.“” On the basis of statistical analysis of two successive cardiac output determinations in 20 control patients not receiving medication, Harve) and her associates4 found that the cardiac outputs did not chanp-e more than =!=I9per cent. Any change more than this value was considered In a report from the same laborasigiificant. tory Cathcart rt ~1.~~’in a series of 100 catheterizations M.ith two control determinations, found that 83 per cent varied less than 10 per cent, while 17 per cent of the cases showed greater deviations. In two cases there was a variation of greater than 15 per cent in cardiac outputs. In our series of 71 catheterizations, 80.3 per cent varied less than 10 per cent; only 2 or 2.8 per cent varied slightly more than 15 per cent. On the basis of the foregoing, 4 out of 5 cases reported to show- a decreased cardiac output following digoxin by Harvey et al.‘” Mould not be considered significant. In two of their cases they found a decrease of 32 per cent and 21 per cent. In one of these cases the drop of 32 per cent was calculated 46 minutes after digitalis. In the same case, 20 minutes after digitalis the fall \vas 12 per cent, and 69 minutes later, at which time theoretically the more significant change should have occurred, there was only a decrease of 13 per cent. One normal subject had a fall of 18 per cent in cardiac output 20 minutes after digoxin; however, 75 minutes later the decrease xvas only 1.2 per cent. McMichael and iharpey-Schafer” reported a fall in cardiac output in three normal subjects following digoxin. In two instances, according to our criteria, the decrease would be considered Ahmed et a1.5 later studied the efsignificant. fect of ouabain in nine normal sub.jects and could not find any significant change in cardiac output following administration of the drug. Two of these patients had changes in cardiac output greater than 15 per cent but in divergent directions. In both reports there are no data avail-
Since strophanthus is not known to cause such changes in oxygen consumption, these variations indicate changes in state in those patients during the stud!.. Control cardiac indices in two other patients are far above the range considered to be basal. The narrow A-V oxygen difference suggests in these cases a state of anxiety. Observations in the cases reported here and those cases reviewed in the literature, using our control group [or comparison, strongly suggest that acute digitalization in patients with normal hearts and diseased nonfailing hearts does not produce a significant change in cardiac output. This suggests that lanatoside C tither has no action on nonfailing hearts, or this action is not detectable I)), the methods used. The duration Ohser\,ation of the study may also be a factor. may not have been long enough to oljtain the Hoxscver, at optimum effect of the drug used. least some effects should be expected during this period of ol,ser\fation if this is considered in light of the results obtained in patients w.ith heart failure.gP” Unless the nonfailing myocardium responds at a different time, a one- to t\vo-hour folio\%.-up after acute digitalization would seem to I,e suficient to observe any changes w-hich may occur. Changrs in Systemic Blood Pressure: Sex-era1 authors”.6~“‘-1” ha\,e found either no change or some increase in svstemic arterial blood pressure after acute digitalization in the types of patients under IHarvey fd al.“’ postulated a \.asocondiscussion. strictor effect ofdigoxin on the arteriolar I)ed on the basis of’ no change or an increase in mean systemic pressure M hen there was no change or a fall in cardiacoutput. It is not unusual forcompensatar! vasoconstriction to occur in the presrnce of a fall in cardiac output. In the cases reported here, there was no significant change in cardiac output and in most instances the \.ariations in systemic pressure following lanatoside C: iver-e In aniobserved prior to drug administration. mals, toxic doses of digitalis have tIcen clcmonstrared to cause a rise in i)lood pressure secondarb- to vasoconstriction.3’ This apparcntlbresults from a direct effect on the smooth muscles and partly
from a central
able
Ho\ve\.cr,
this \vas not found
regarding
ox)-gen
consumption
and
A-\
difference.
italir.ing
Decrease
in cardiac
was reported patients
from control
bvith
output
after
strophanthus
by Ring and his associates7 normal
hearts.
In
in seven
tL1.o of these
(.‘linirnl presented, (and
in oxygen consumption levels of +SO cc and - 133 cc.
vasomotor
stimulation.
wh(sn avcraqc
dig-
doses \\-c-re used.
Szgnifkanct~ of it has bren
presumal,l\
Results: sho\rn
I he other
Frown thr that
cardiac
data
lanatoside
C
qlycosicles
as
98
Effects
of Lanatoside
well) in therapeutic doses does not seem to have any acute measurable deleterious effects on the hemodynamics of the cardiovascular system in subjects with normal hearts or cardiac patients not in heart failure. The problem of whether prophylactic digitalization is useful in patients with heart disease but not in heart failure is, however, not solved by this study. Nevertheless, it is felt that these patients can be digitalized without fear of decreasing cardiac output or producing unfavorable changes in blood pressure.
C in Nonfailing
4.
5.
6.
SUMMARY
(1) The effect of acute digitalizing doses of lanatoside C on cardiovascular hemodynamics has been studied by the technique of right heart catheterization in 7 subjects with normal hearts and 4 patients with heart disease without clinical or hemodynamic evidence of heart failure. (2) Lanatoside C in full therapeutic doses caused no significant changes in cardiac output, heart rate, systemic venous, right ventricular The systolic, and pulmonary artery pressures. systemic arterial pressures and resistances similarly were not appreciably affected. In 2 of 8 cases, there was a slight fall in the right ventricular end-diastolic pressure and in 5 of 6 cases there was a slight fall in right auricular pressure. (3) Interpretations of the presented data Difwere made on the basis of control studies. ficulties in interpreting the changes in cardiac output in this type of study are emphasized. (4) It would seem from this study that digitalis given prophylactically- to patients with heart disease but not in failure would not have any deleterious effect on cardiovascular hemodynamics.
The authors wish to express their appreciation to Dr. Max Michael, Jr., for reviewing this paper and for his valuable suggestions. REFERENCES 1. WITHERING, W.: An Account of the Foxglove and Some of Its Medical Uses; with Practical Remarks on Dropsy and Other Diseases. M. Swinney, Birmingham, England, 1785. 2. STEAD, E. A., WARREN, J. V., and BRANNON, E. S.: Effect of lanatoside C on the circulation of patients with congestive failure; a study using catheterization of the right side of the heart. Arch. Int. Med. 81: 282, 1948. 3. BLOOMFIELD, R. A., RAPOPORT, B., MILNOR, J. P., LONG, W. K., MEBANE, J. G., and ELLIS, L. B.: The effects of the cardiac glycosides upon the dynamics of the circulation in congestive heart
7.
8.
3.
10.
11.
12.
13.
14.
15.
16.
Hearts
failure: 1. Ouabain. ./. C/in. I~~~Ps~.27: 588, 1348. HARVEY, R. M., FERRER, M. I., CATHCARL., R. T., RICHARDS, D. W., .JR., and COURNAND, A.: Some effects of digoxin upon the heart and circulation in man; digoxin in left ventricular failure. llm. .I. Med. 7: 439, 1949. AHMED, S., BAYLISS, R. I. S., BRISCOE, W. A., and MCMICHAF.L, J. : The action of ouabain (Gstrophanthin) on the circulation in man, and a comparison with digoxin. Clin. SC. 9 : 1, 1950. FERRER, M. I., HARVEY, R. M., CATHCART, R. ‘I’., WEBSTER, C. A., RICHARDS, D. W., JR., and COURNAND,A. : Some effects of digoxin upon the heart and circulation in man; digoxin in chronic car pulmonale. Circulation 1 : 161, 1950. BING, R. J., MARAIS.~, F. M., DAMMANN, J. F., DRAPER, A., HEIMBECIXR, R., D.~I.EY, R., GERARD, R., and CALAZEI.. P.: ICffect of strophanthus on coronary blood flow and cardiac oxygen consumption of normal and failing human hearts. Cirrulntion 2: 513, 1750. EICHNA, I.. W., FARBER, S. J., BERGER, A. R., EARL, D. I’., KAIIER,B., PELLEGRINO, E., ALBERT, K. E., ALEX.ANDER, J. D., T~URE, H., andYou~owIRTH, S.: Cardiovascular dynamics, blood volumes, renal functions and electrolyte excretions in the same patients during congestive heart failure and after recovery of cardiac compensation. Circulation 7: 674, 1953. MCMICHAEI , d. and SHARPEY-SCHAFER, E. P.: The action of intravenous digoxin in man. Quart.J. .Vfed.13: 123, 1944. HARVEY, R. M., FERRER, M. I., CATHCART, R. T., and ALXXANIXR, J. K.: Some effects of digoxin on the heart and circulation in man; digoxin in enlarged hearts not in clinical congestive failure. Circulatio~z 4: 366, 1951. LACERL~~F, H. and WERK~, L.: Stud& on the circulation in man; the effect of Cedilanid (lanatoside C) on cardiac output and blood pressure in the pulmonary circulation in patients with compensated and decompensated heart disease. Acta cnrdiol. 4: 1, 1949. HARMANCT, N., OZCAN, R., BASSIPAHI, M., and P.ARI..A, N.: The mechanisms of digitalis (Cedilanid) action on the human heart. Istanbul Contrib. Clin. SC. 1 : 67, 1951. DRESDALT’, D. T., LCNGER, M., and Yuc~ocru, Y. Z.: ‘l’he “steady state” and the direct Fick principlr: Study of 100 cardiac catheterizations. To be published. VAN SLYRE. D. D. and NEILL, J. M.: The determination of gases in blood and other solutions bv vacuum rxtractton and manometric mrasurrment. .1. Biol. Chrm. 61: 524, 1924. SCIIOL,ANDER,P. F.: Analyzer for accurate estimation of respiratory gases in one-half cubic ccntimeter samples. J. Biol. Chem. 167: 235, 1947. COURNAN~, A., RILEY, R. I,., BRADLEY, S. E., BREED. E. S., NOBLE, R. P . LAUSON, H. D.,
GREGEKSEN, M. I., and RICIIARDS, D. W., JR.: Studies of the circulation in clinical shock. Sqrry 13 : 964, 1943. 17. APERIA, A. : Hemodynamical studies. Sknndinnv.
Arch. Physiol. Suppl. 16, 1940. ‘THE AMERICANJOURNAL OF CARUIOLOCY
Dresdale,
Yuceoglu,
Michtom,
18. I.AG~KI.KF. H. and WERK~, L. : Studies on the circuldtion in man: II. Xormal values for cardiac output and pressure in the right auricle, right ventricle, and pttlmonary artery. ‘lctrr pfIyJiol. Jim/lln/2l’.16: 75, 1748. 19. B~ooz~er.n. R. ;1., L.AUSOX, H. D., C:OURN.~ND, 3.: BRFLU. F,. S., and ~CIIAKDS, D. hr., JR. : Recordin? of right heart pressures in normal subjects and in patients with chronic pulmonary disease and various types of cardio-circulatory disease. J. (“Iin. /wr.!t. 75: 639, 1’146. 20. BOKDI N. CT.: Fundamental and clinical aspects of pul~nonaryhypertension. .lZ/n,1~~0/0 .l/rd. 31 : 12 I (1.1948. 21, Iksr~- K, I... Dow. J. W., H,AYNES, I:. \t’., WHITTENB~R(:~:R. J. L... FERRIS, B. G., GOOUALE, W. T., and HEILEMS, II. K.: Studies of the pulmonary circulation in man at rest: normal variations and interrelations bctwren increased pulmonary blood flow, elevated pulmonary arterial prrssure. and high pulmonar! “capillary” prcssurrs. J. C/in. Zn7,r.,l. 29: 602, 1950. 22. Fowi_rr<, N. O., WESTCOTT, R. JX., and SCOTT. R. (1.: Normal pressure in the right heart and .4m. Heart J. 46: 265, 1953. pulmonary artery. 23. DOCK, W. and ‘PAINTER, 51. I,.: ‘l’hc circulatory changes after full therapeutic doses of digitalis, with a critical discussion of views on cardiac outZ. Clin. z7,wst.8: 407, 1729. put. 24. KATZ, 1,. N., RODRARD, S., FRIEND, hf., and ROTIXRM.~N, L%‘.: The effect of digitalis on the anrsthctizrd dog: I. Action on the splanchnic bed. .Z. Pfwmmd. &? Eqvr. 7.hrmp. 62: 1, 1938.
D. A. : ‘T,‘le effect of digitalis on the venous pressure of normal individuals. .Z. CZ:lin. Ime:/. 12: 847,1933. 26. STEWART~ H. J. and COHN, A. E.: Studies on the effect of the action of digitalis on the output of blood from the heart. Z. Clin. Zm~st. 11 : 917, 1932. 27. WALTON, R. P., LEARY, J. S., and .JONES, H. P.: Comparative increase in ventricular contractile force produced by several cardiac glycosides. J. Z%ormacoZ. &g Eqer. Thewj. 98: 346, 1950.
25.
KYTAND,
JULY, 1959
Schultz,
:lnd Lunger
28. BURL\-t t-1, (: S.. NEIolIBORs, I).. and Rtcxh. 1:. M.: The cfl’cct of digitalis upon the output of the heart in normal man. ./. (,‘lrn. ZENITH.5: 125. 1028. 29. Yu. P. N. G., I.ovrJo~, F. \I:., .JK., Hur.i~rs~. B., HI~\.EI.I., M. AI., Joos, H. .\., ‘J.ENNE\.. S. hf.. HARO~~IT.~IA\-, I_. Xl., and I:\,sNs, H. it.: Cardiorespiratory changes during cxcrcisc bcforr and after intravenous digosin in normal sltbjrrts. :lni. .Z. .\I. .S<. 224: 146, 1952. 30. FIEI n. H., .JK., BOOK, .1. V., (+II ni A. 1:. l’., and l~r11RoP. F. I,.: The r&c of the circulation of the blood m normal restinq indi\-iduals. .Z. Ciin. Zmw. 1 : 6i, 1024. 31. GROI.I.MAN, ‘1. : The determination of tlx, cardiac output of inan by the use of acctylenc. .In/. .J. f’hpd. 88: 432, 1929. 32. HARRISON, ‘I R. and LEON.ARD, B. Lb’. : ‘I’hc effect of digitalis on the cardiac output of dogs and its bearing on the action of the drug in heart disease. .f. Clin. Znwst. 3: 1, 192661927. 33. COHN, :1. C. and STEM.ART, H. .J.: The relation between cardiac size and cardiac output per minute following the administration of digitalis in normal clogs. J. C/in. Znwrt. 6: 53, 1928. 34. SHA~LF, 0. IV., FERNSON. T. B.. SABISTOS, D. C., .JR.. and (;REC;G, D. C.: ‘l‘he hcmodynamic rcsponsr to lanatosidr C of dogs with experimental aortir-caval listulas. .Z. C/i,/. Zrl, r~l. 30: 335. 195:. 35. COTTEN. hf. D. and STOPP, P. E.: Action of digitalis on the nonfailing heart of the dog. .1/r/. ./. Phy.tiu/.192 : 114, 1958. 36. HICKAM, J. B., CARGILL. 1%‘. H.. and Got op.&, :1.: Cardiovascular reactions to emotional stimuli. effect on the cardiac output, artrriovrnous oxygen diffcrrncc. .irtrrial pressure, and peripheral rcsistancc. ./. Q1n. znw.rt. 27 : 290. 1948. 37. CAT~I~:.~KT. R. T., FIELD, W.. and RICIIARDS, I). W., JR. : Comparison of cardiac output detcrmined by the ballistocardioqraph (Nickerson apparatus) and the direct Fick method. .J. C/in. Z,imt. 32: 5. 1953. 38. GOODMAN, I,. S. and GIIMAN, A.: The Z’furmrrmfo,p~d f70,, r of Thm+rri.r. cd. 2. h?Iacmillan New York. 1955.
Study
Effects of Lanatoside
C on Cardiovascular
Hemodynamics Acute Digitalizing
Doses in Subjects
with Normal
Hearts and with Heart Disease Without Failure* DAVID T.
DRESDALE, M.D., YUSUP ZIYA YUCEOGLU, M.D., F.A.G.c.,~ ROBERT J. MICII~I.O~~,11.~. MARTIN SCHULTZ, M.D., and MAURICE LUNGER, ~I.D.$ Brooklyn,
S
New York
the use of foxglove in dropsy by Withering,’ digitalis glycosides have been used widely in the treatment of heart failure and their effects have been subject to extensive clinical, experimental, and physiologic investigation. Numerous studies utilizing the technique of right heart catheterization have established some of the effects of cardiac glycosides on cardiovascular hemodynamics in patients with heart failure.2--8 However, a survey of the literature reveals only few studies5-7,g-12 with limited numbers of patients with normal hearts or patients with heart disease without heart failure. In these studies it was found that cardiac glycosides in normal individuals either decreased the cardiac output7 zg
heart disease without evidence of heart failure. Patients with heart disease but not in failure are frequently considered for prophylactic digitalization prior to major surgery or other types of unIf no deleterious effects on the carusual stress. diovascular hemodynamics are demonstrated, such therapy might well be justified. This report presents the early effects of lanatoside C on the cardiovascular hemodynamics in 11 patients studied by the technique of right heart catheterization. To establish criteria for the determination of significant changes in cardiac output that could be attributed to the drug, 100 right heart catheterizations in which two cardiac output determinations were done within 9 to 91 minutes (average 36 minutes) lvithout any drug administration were analyzed.‘” On the basis of this study the ranges of allowable spontaneous variations under “steady state” conditions were determined.
INCE
MATERIALS
AND
METHODS
Seven subjects without heart disease and four with heart disease but not in heart failure were studied Four of the seven subjects without (Tables I and II). heart disease were males and three were females.
* From the Cardio-Pulmonary Laboratory, Department of Medicine, Maimonides Hospital of Brooklyn. and the Department of Medicine, State University of New York, College of Medicine at New York City. t Part of this work was done during tenure of Research Fellowship of the New York Heart Association. f Postdoctoral Fellow, National Heart Institute, U. S. Public Health Service. This investigation was supported in part by a research grant from the National Heart Institute of the National Institutes of Health, United States Public Health Service.
88
THEAMERICANJOURNALOF
CARDIOLOGY
Dresdale,
Yuceoglu,
Michtom,
In the other Their ages ranged from 25 to 58 years. group there tvere two males and two females, their ages ranging from 49 to 63 years. All had normal The electrocardiograms lvere within sinus rhythm. normal limits except one (case 11) which had some In the group wilh heart nonspecific T \vave changes. disease cardiac enlargement w-as absent or slight on x-ray examination. The patirnts were studied in the resting state after fasting for at least twelve hours. They were hospitalized at least three days before the study was done. They all received phenobarbital 0.06 Gm and Nembutal 0.1 (+rn the evening before any observations were made. None had received cardiac glycosides in the past. The ph>.siologic data were obtained by utilizing the The blood technique of right heart catheterization. oxygen content and capacity were determined by the method of Van Slyke and Neil1.14 The expired air was collected in a Tissot spirometer and analyzed in the Scholander gas analyzer.15 The cardiac outputs were determined by the direct Fick principle. Pressures wcrc recorded using Sanborn electromanometers and a direct-writing Sanborn Poly-Yiso rehlean pressures were determined by planicorder. metric measurement of the electrically integrated pressure tracings using one or more complete respiraThe point of zero reference for measuretory cycles ment of cellrral pressures was 5 cm below the angle of Louis with the patient in the supine position. Total pulmonar) artery and total peripheral arterial resistances \verc calculated according to the following formula:‘“,‘;
Control measurements were made after the catheter and the venous and indwelling arterial needles were inserted and the patient was quiet for at least fifteen minutes. Two control cardiac outputs were taken in three patients and one control cardiac output in the Lanatoside C, 1.2 to 1.6 others (Tables III and IV). mg (as noted in Tables III and IV), was injected slowly through the catheter into the pulmonary artery Cardiac outputs were then over a two-minute period. obtained from 40 to 121 minutes later. Multiple pressure measurements were recorded throughout the study. QT, intervals were measured in six cases before and after lanatoside C injection (Table V). The criteria for interpretation of the results are based on a study in our laboratory of the “steady state.” using the direct Fick principle.13 According to this analysis. any change in cardiac output within the range of plus or minus 15 per cent should not rightfully be attributed to drug effect. Changes within this range can be due to the inherent experimental error- of the technique. J’XY,
1959
Schultz,
and
Lunger RESULTS
Heart Rate: In the two groups of patients, there was no significant change in the heart rate. In 4 out of 11 cases a decrease up to 4 beats per The remainder of the paminure eras noted. tients shoM-ed an increase up to 9 Ijeats per minute. QT, intervals in the six cases measured showed a decrease, indicating digitalis effcsct electrocardiographically (see Table V). Oxygen Conszim~tion: Control oxygen consumptions (see Tables III and IV) \\-ere normal as compared to the generally accepted figure of 138 f 14 cc/min/‘sq. M BSA except for cases 1 and 4 whose values were slightly- hut not significantll- above normal. Oxygen consumption calculated at different time intervals following digitalis administration did not show any significant changes from control le\~rls. The greatest change Ivas 16 cc. Cardiac Outjut: The 7 patients bvith normal hearts had changes in cardiac indices from control level follo\ving digitalization ranging from + 13 to - 13 per cent (see Table I and Fig. 1 j. In the second group, the patients with heart disease without evidence of heart failure, the change from control levels ranged from - 11 to + 13 per On the basis of cent (see Table II and Fig. 1). analyses of preiious experiences in our department,‘” differences of the order cited ahove are within the limits of expected variation (Fig. 1). * ‘~WJ patients without heart disease and one patient with heart disease without heart failure (cases 6, 7, and 10) had two control cardiac outThese cases demput determinations (Fig. 2).* onstrate the value of at least two control cardiac output determinations in this t)-pe of study-. Control cardiac indices and cardiac indices at different time intervals following digitalization If the control are shown in Tables III and 11’. cardiac indices of higher value are considered, two (cases 6 and 10) show significant fall and one (case 7) shows insignificant fall after digitalization (see Fig. 2). However, when cardiac indices with lower values are considered, this imIn case 6, 97 minpression is not corroborated. utes after digitalization there was a fall in cardiac index of 19 per cent from the second control level. If the first control cardiac index is taken, then thert is only a negligible change of In case 10, the fall in cardiac in3.5 per cent. dices from initial control level (cardiac index with higher value) was also significant (-24 prr cent) follo\ving digitalization. Howe\,er: if *See page 95.
:
zr
2
data
M.; F, age 57: carcinoma of the breast with metastases; no heart disease
M.
3
.I. C.; M, age 28; diabetes mellitus no heart disease
F.; F, age 44; multiple sclrrosis, argyria; no heart disease
hi.
2
5
F. I>.;
M, age 5X; G-I disease undiagnosed; no heart disease
Clinical
1
CkiSC
;
hlcasurcn~uts
97 83 94 35 91 87 93 99 79
132/62* 145/67 154/72 142/69 153/65 137162 137/70” 139/75 118/61
Control 20” 29 43 80 95 tr.01
146 26 37 54 90
Control
17u 73 80
Cor1
3Ob 58 88 103
70 78 75 74 73 67 72
83
121/68 100/55d 107/68 104/63 103/63 97/61 103/50 96/60
72
116/57 -
-
21/8 -
80 82 80 89
110/61” 110,‘64 113/62 124/70 128/72 127/77
Control
55”
11 12
20,‘5 23/7 22/6 18/8 18/8 -
13 14 16 14 14 14 14
-
15
-
10 -._. -
18/3 20/5 -
8 7 0
.-
14 15 15
~___ 25/s 25/8 25/8
102 104 108
S/D
141/7Y 138/75 155/75
‘lime (min)
hl
Heart
M
Without
S/D
Patients
Pulmonary artery pressure (mm Ha)
in Seven
Brachial or femoral artery pressure (mm Hg)
of tlrc Circulation
During
17/2 2Oi2.5 1812 20/2 18/3 t8/4 16/2
-
21/3.5 25/4.0 -
32/‘5 31/5 26/l 32/~21/l 26/-22/l
19/l 24/2 --/3
21/4 2013 -
24/-p
.-_
Right ventricular pressure (mm Hg ), S/D ‘_
IJisrasc
Digitalization
(mm
1
2.7
-.
-
~-
_
‘1
4.7 4.8 4.4 5 0 5 0 4.3 4.6
8.6 7.9 7.8 6.9 6.9 7.6 6.6
4.4 4.4 4.4
5.6
2
-
HE), M_
4
____
(mm
1 -.._
2
2 2
4
3
-.
MU
Ha),
Kight Peripheral auricular venous press urc press urc
.%cutc
5,08
5.27
8.64
I-
8.92
. ..-
4.44
5.71
5.13 _ -,_. -
4.60
4.48 -
4.91
7 .07 7.31
C:arcli;~c output (I,/min)
Studies
.3
61.7
-.
88.0
123,5
131 ,o
67
77.2
-_
75.3
63.8
65.8
71.2 I--
110.5 114.0
(cc)
vdumc
Strukc
105 97
60
70
68 6K
66
74
68
72
68
69
64 GO
Heart ratr (beats/ min) ----~
-~
Dresdale,
Yuceoglu,
Michtom.
Schultz,
and
Lunger
the other control cardiac index is considered in comparison with those determined after digitalization, the change was then only -4 per cent. Cast 7 also demonstrates the same kind of mariations Ijut to a lesser degree. Apparent changes in cardiac indices in cases 6 and 10 arise from significant differences in the Figure 2 shows tb’(J control cardiac indices. that there never was a continuous trend in an!. direction. These figures fall outside the range of “normal variations” previously determined in This indicates patients in the “steady state.“13 that during determination of at least one of these control cardiac outputs, the patient’s state \vas changing in spite of the absence of any significant change in oxygen consumption or heart rate. Therefore, if two control cardiac output determinations Ivere not obtained, a change in cardiac output due to a change in state might falsel>- have lien attributed to the effect of digitalis. Right Heart and Pulmonary Artcry Pressures: Right ventricular end-diastolic and mean right auricular pressures were within the accepted normal values, except in case 6. In cases 3 and 6 end-diastolic pressures in the right ventricle fell 4 mm Hg in each without significant change in Right auricular pressures, in 5 cardiac output. of the 6 patients in whom multiple mean measurements were obtained (cases 2, 6, 7, 8, and 11 ), fell 1 to 3 mm Hg, and in the other there jcas no change. Peripheral venous pressures were measured in 7 cases and did not show any change following lanatoside C. Three of these showed a slight fall in right auricular pressure. There cvere no significant changes in right ventricular systolic and.‘or pulmonary artery pressures after drug administration except in case 3. where there was a slight fall in ri~ght ventricular systolic pressure. Systemic and Pulmonary Arterial Pressure and Systemic and pulmonary arterial Resistance: pressure and resistance varied slightly, hut in no consistent fashion. These variations were veil within the expected range.” Arteriouenous Oxygen D#erence: No significant change was observed in the arteriovenous oxygen differences after digitalization in any patient, although in 10 of the II cases there \\-asa tendenc\for a minimal Arterial \I
JULY, 1959
increase.
Oxygen
Saturation..
.4rterial
oxy)gen
saturation remained fairly constant folloving digitalis administration. This condition in-
I. K.; F, age 62; .4SHD, LV hypertrophy, myocardial damage, NSR, no CHF; old hypertension ; emphysema; bronchial asthma; recent bronchopneumonia; diabetes mellitus
11
C.
18” 31 42 48 82 104 117 120 CHF = Rheumatic
D Minutes
-__-
Control
lSb 47 52 58 97
Control
ASHD = Arteriosclerotic heart disease. NSR = Normal sinus rhythm. RHD =
u Minutes after 1.6 mg lanatosidc
H. S.; F, age 56; ASHD, NSR, myocardial damage, no CHF
10
13” 25 40 48 64 72 85 94 108 121 88 100 82 92 92 91 93 86 92 76 78
126/68 143/78 119/58 128/72 137/U” 132/64 136/67 132/64 132/67 110/57 125/57
II
91 96 94 95
143/60 148,‘68 150/68 1X/68
-
Congestive heart heart disease.
failure.
C.
-.
LV
32/12 35/14 33/16 36/14 32/l 2 35/13 32/l 5 32/15
18/5
-
19/-
20/22/9 22/7
42/22 47/27 43/22
43/23 41/-
44/25 43/23 46/23 43/22
31/9 33/8
S/D
(mm
= Left
ventricle.
artery. MI
31/2 33/4 32/5.5 33/3 31/3.5 33/0.5 36/6 32/0.5 30/2 32/2.5
20/4.5 21/3.5 18/2.5 2014 18/l. 5 21/4 20/3 18/2
11 12 12 11 11 11 11 11 20 23 23 23 21 23 22 25
43/l 44/o 43/2 45/o 44/2 44/l
45/2 44/2 43/1.5 4712 45j1.5
Right ventricular pressure imm Hg), S/D
0 5
-
1.5
1
-
2
-
4 1
=
Mitral
artery. insufficiency.
5.9 5.7 6.2 5.7 4.9 6.2 4.8 4.7 5.7 57
8.8 7.7 5.2 4.8 4.8 4.9 3.8 3.5 3.7 3.2 3.2 3.2 3.7 -
-
Studies
MS
6.71
6.30 -
6.41 --
4.82 -
5 39
6.33 5.04 -
6.92 -
6.90 -
6 71 -
=
Mitral
stenosis.
10.7
70.7
77.3
58.1
64 1
77.2 71.9
70.7
70.5
70.7
68.8
-
6.46
91.0 84.5
6.0 5.32
_
Cardiac output (L/min)
Acute Digitalization
Right Peripheral auricular venous pressure pressure (mm Hg), (mm Hg), M M
During
” Femoral
-
Failure
29 29 31 36 30
32 31 31 31
35
17 19
M
’ Brachial
Hg)
Pulmonary artery pressure
after 1.2 mg lanatosidc
95
155/65
93 85
33 92 88
134/73 130/72 125/72 -
135/66” 120/69 -
92 97 87
125/70” 130/77 127/68 -
Control
J. R.; M, age49; RHD, NSR, MS & MI ; recurrent hemoptyses ; no CHF
116 112
9
M-
H,K)
S/D
(mm
167/8Sc 167/80
(min)
Control 53a
data
TABLE with Heart Disease but Not in Heart
Brachial or femoral artery pressure
in Four Patients
E. S.; M, age 63; ? polycythemia; ASHD, NSR
Clinical
Time
of the Circulation
8
Case
Measurements
95
89
-
90 83
83
84
82 82 77
98
98
95
108 94
66 63
Dresdale,
Yuceoglu,
Michtom,
Schultz,
TABLE Physiologic
Data Concerning
Cardiac
Oxygen consumption (cc/ min/sq M RSA)
Cardiac index (L ‘min/ sq M BSA)
A-V
mygen difference (\“I
93
Lunger
III
Output in Seven Patients Digitalization Studies
Respiratory quotient
and
Without
.Irterial
Cardiac index
G,Iltent Iv01 $1
(SC change)
5;)
Heart
Disease During
blood
Calculated resistance .‘dvnes ser cm-s1
“xveen
Capacity (““1 c;)
Acutr
lY
Saturation (‘7)
Pcriphera1
TOT31 pulmonary ,rtCry
-
1 .36
1 .68
1.80 1 45 1 .62
1.78
a hlinutes
0.72 0.76
4.16 4.30
4.3 4.4
+
3.4
17.6 l-.6
19.0 18.9
92.5 93.1
1175 1183
CO” W”l 581’ 103
130 I19 135
0.75 0.79 0.82
3.61 3.29 3.38
3.6 3.6 4.0
8.8 -64
1.5.6 15.6 15.6
16.0 16.0 16.0
97.5 97.5 97.5
1305 1590 1685
Control 43u 95
119 129 II9
0.74 0.79 0.73
3.05 3.40 2.65
3.9 3.8 4.5
+11.5 -13.1
14.3 14.3 1s 9
15.4 15.4 -
92.7 92.7 -
1295 1330 1555
Control 8011
178 173
1.01 0.81
4.96 4.67
3.6 3.7
-
IF.6 I- 9
19.4 18.5
95.8 96.8
890 770
Control 901’
149 152
0.82 0.83
3.64 4.12
4.1 3.7
t13.2
15.4 14.3
16.2 15.2
95.0 94.1
1062 963
COotKJl Cootr01 490 97
122 129 134 129
0.75 0.72 0.76 0.75
3.70 4.30 3.73 3.57
3.3 3.0 3.4 3.6
17.6 -
92.0 -
+:.2c 3.5
16.2 15.5 15.4 15.4
16.1 16.1
95.7 95.7
1440 1205 1255 1343
240 207 213 707
Con:rol Conrrol 920 123
151 143 152 143
0.73 0.69 0.58 0.64
4.56 4.07 4.23 4.22
3.3 3.5 3.6 3.4
+ +
19.3 19.2 19.0 I8 8
19.6 19.6 19.5 19.5
98.3 98.0 97.0 96.3
949 1080 1083 1llU
-. -
after 1.6 mg lanatoside
C.
b Minutes
after 1.2 mg lanatoside
TABLE Physiologic
Data Concrrning
Cardiac
Oqgen c”Ils”ElDtion (cc’/ min/sq M BSA)
ChX
8
1 58 2.11
9
1 :a2
10
11
1.65
a Minutes
-
5.8
-
_ 3.9(1 3.7
C Using
C.
Rcsvir-
1 atOT-y quotient
Cardiac index II./min/ sq M BS.4)
A-V oxygen differt:nce (vol ‘;;>I
Cardiac index (% change)
167 169
0.70 0.73
3.80 3.37
4.4 5.0
-11.3
COIW”1 40a X5 121
144 146 160 157
0.80 0.85 0.80 0.74
3.06 3.18 3.27 3.28
4.7 1.6
-t
Contlol Control 520 97
12; 127 130 131
0.70 0.71 0.73 0.73
3.91 3 11 3.33 2.98
3 .2 4. 1 3.9 ‘1 4
Control 4w 120
Iii 183 191
after 1.6 mg Ianaloside
C.
first wntrol.
0.7s 0.74 0.75
b Minutes
3.89 3.82 4.07
DISCUSSIOK with heart disease none evidence of heart failure.
3.9
+ -
7.lC 4.2 -
4.5 i.8 4.7
after 1.2 mg lanatoqide
d Using second
170 I64
126 130 -
control.
IV
C0lltr01 S?a
Among the cases showed hemodynamic 1959
-
Output in Four Patients with Heart Acute Digitalization Studies
eludes the one patient (case 11) who had arterial oxygen unsaturation due to chronic pulmonary disease.
IlJLY.
-
179 189
1.8 +13.3
C.
Disease but Not in Heart Failure During
Arterial Conwnt (t-01 %)
blood Capacity (vol r;)
oxygen Satoradon (4;))
Kesisrance (dynes see cm -6) __~-Total pulmoPeriphnary era1 artery
19 3 19 1
20.2 20.2
‘95.7 94.6
154s 1685
227 286
14 3 14.2 14 5 14.1
14.8 14.8 14.8 14.8
96 6 95.9 98.0 95.2
1200 1110 1020 1065
396 350 336 347
14.6 14.6 143 14.4
15.0 14.6
47.3 98.6
1162 1445 1365 1295
152 190 163 182
18.5
86.0 86.0
1060 1155 1123
287 192 -
15.7 15.1 15.
C L-?ing second
)
18.5
control.
There was only one case (case 9) with a moderate degree of pulmonary hypertension, and two cases (cases 8 and 11) with slight elevation of pulmonary artery pressure. Case 9 had rheumatic heart disease with mitral stenosis and mitral insufTicienc)-; cases 8 and 11 had pulmonary emphysema. Case 11 had some arterial
Effects TABLE The Average
QT,
Interval
of Lanatoside
C in Nonfailing artery,
V
Before and After Cedilanid
1 l-27
19 mm Hg:
Hearts 4-l 9 mm Hg, mean prcssurr right
ventricle
8 to
14-31.5:‘---0.5-+7
mm Hg ; and right auricle mean
- 2 to + 5 mm
Hg Effect Control 66(’ 88
0.412 0 335 0.334
Control Control 60b 80 105
0.453 0 437 0.349 0 418 0.331
Control Control 23a 61 80
0 436 0.440 0 387 0.353 0.332
Control Control 49* 97
0.417 0.418 0.405 0 394
Control Control 3Sb
0 363 0.344 0.342
Control Control 17” 35
0.460 0 420 0.312 0 276
ca Minutes after 1.2 mg after 1.6 mg lanatoside C.
lanatoside
C.
b Minutes
blood oxygen unsaturation. Normal right ventricular end-diastolic pressure, normal control cardiac output without any increase after digitalization, and absence of any significant change in the pulmonary artery pressure following digitalis administration in these patients would be hemodynamically inconsistent with congestive heart failure. In three (cases 3, 6, and 7) of the group of subjects without heart disease, pulmonary artery or right ventricular systolic pressures were close to abnormal levels. Case 7 was a 25-year-old man who did not have any clinical evidence of lung or heart disease. The control right ventricular systolic pressures ranged between 28 and 32 mm Hg. In case 6, right ventricular end-diastolic and mean right auricular pressures were minimally above usually observed normal average However, these are within the normal values. ranges reported by some investigators.18-21 Normal pressures in the right heart chambers and the pulmonary artery as reported by Fowler et al.,2”based on their own findings and a review of those of other authors, were : for the pulmonar)
Pressures:
on Right Right
I’entricular
or Pulmonary
ventricular
systolic,
or
Artery pul-
monary artery systolic, diastolic and mean pressures were not affected by digitalis in the tlvo groups of cases with the exception of case 3. The cause for the slight fall in the right ventricular systolic pressure in this case is not apparent. This patient did not have clinical evideilcc of heart disease. Since “pulmonary wedge” pressure was not measured, a decreased left ventricular reserve cannot be excluded. However, if this were due to left heart failure one would perhaps expect an increase in cardiac output after digitalization. In this instance there was a slight fall in cardiac output. The slight fall in pressure therefore ma)- have been related to the decrease in cardiac output. b-feet on L’enous Pressure: In 7 of the casts reporied here in which successive peripheral venous pressure measurements were obtained, there were no significant decreases following digitalization. Dock and TainteP and Katz rt al.S4 showed that in dogs digitalis produced a fall in cardiac output due to its peripheral action. They found pooling of the blood in the viscera caused by constriction of hepatic veins. This action of digitalis has not been observed in .4 number of years ago Rytand’j rcman. ported a fall in venous pressure in 8 normal suI)jects maximal at 24 to 32 hours after oral diyDirect venous puncture using the italization. Moritz-Tabora technique was employed. HOXVever, the fall was only 1.96 cm salincl, and its significance therefore questionable. Steu.art and Cob@ did not find any significant change in venous pressure in normal individuals bv a method similar to Rytand’s. In man, Harvc) and her associatesLo postulated that “either there is no peripheral venous action of the drug, or that if there is such an effect, it is too small to be detected, is obscured by rapid refles \renous adjustments or does not influence central or right heart filling pressures.“ Right Auricular Pressure and Right Ventricular EndTendency of the right \‘enDiastolic Pressure: tricular end-diastolic pressure to fall in two cases (cases 3 and 6) and the slight decrease in mean right auricular pressure in 5 of 6 cases in which it was measured may have been an effect of digitalis, though this cannot be stated with cerTHE
AMERICAN
JOURXAL
OF CARDIOLOGY
Dresdale,
Yuceoglu,
Michtorn,
VARIATIONS
‘STEADY
95
Schultz? and Lunger
WITH
STATE’
HEART DISEASE WITHOUT HEART FAILURE
TYO COWTRM. c 0 Y,THO”T DR”O
,, CHANGE IN
0 I
Frc.
1.
CARDIAC
OUTPUT
43-60
CARDIAC
OUTPUT
BO-l2Omn
Effect of lanatoside
ml” AFTER AFTER
C: on cardiac
LANATOSIDE
C
LANATOSIMC
output.
E:,
I
\ ‘\
2
3oJ
\
\ ___---______----
\
l
-20Y. -42%
I 2.5 BASED
ON HIGHER
CONTROL
A H.M. 1.6mg 0 6.R 1.61119 l Ii R. 12mG
C 0
I
6
Ii
3b
6
CONTROLS FIG. 2. higher
taint)-.
Changes in cardiac of two control cardiac
2.0
MINUTES
40
$0
AFTER
LANATOSIDE
output after lanatoside indices. A Case 6;
The changes in the pressures were small and the changes in the end-diastolic pressure occurred in only 2 of 8 patients in which it was obtained. In normal dogs intravenous infusion of cardiac glycosides has been shown to increase the contractile force of the right ventricle.” This might account for better emptying and. ]UI.Y. 1959
8'0
160
Ii0
I40
C INJECTION
C in three patients, calculated 0 case 7; n case 10.
from
therefore, a decrease in right ventricular enddiastolic pressure. A decrease in right auricular pressure was observed by McMichael and Sharpey-SchaferY following intravenous digoxin in three normal subjects studied by the technique of right heart catheterization. Cardiac output was also considered to have fallen. The fall in
Effects
of Lanatoside
C in Nonfailing
Hearts
right auricular pressure in these patients as well as in those with heart failure following digoxin led them to an impression that “the major benefits of digoxin treatment result from a peripheral action on venous pressure and not from any tonic However, or stimulating action on the heart.“9 this was not confirmed later by Ahmed et al.,5 in the same kind of study with another cardiac glycoside, ouahain, nor by other investigators with the administration of digoxin4 .F aloor Cedilanid.‘? EJect on Cardiac Rate: Cardiac glycosides in subjects with normal hearts and patients with heart disease without heart failure may produce slight slowing in the heart rate or there may be 829 In the present study no change. 5.6,9 .rr 712>26,28 lanatoside C did not cause a significant change in the heart rate. Changes in Cardiac Outfiut: Burwell et a1.28 in 1928 gave digitalis leaf orally in four normal subjects and made daily observations of cardiac output using a modification of the carbon dioxide method.30 They found a decrease in cardiac output with a tendency to return toward normal when toxic levels were reached. Stewart and Cohn2’j in 1932, using the acetylene method of Grollman,31 studied the effects of a single dose of oral digitalis (0.8 to 1.0 Gm) in normal individuals. A decrease in cardiac output and diminution of the heart size were described. The maximum effects were observed Experi4 to 24 hours after digitalis was given. ments in dogs have also shown a decrease in cardiac output following intravenous digitalization.‘3,3”-35 This decrease may be due to hepatic vein constriction which has not been demonstrated to occur in man. It is difficult to compare the indirect methods of cardiac output determinations with those done by direct methIn addition the methods of digitalization ods. and the times of observations were also different. In acute studies in man with intravenous cardiac glycosides using the technique of right heart catheterization in subjects with normal hearts or diseased hearts which are not in failure, the cardiac outputs have been reported to decrease or McMichael and Sharshow no change.5-7~g-13 pey-Schafer9 in three, Harvey et ~1.‘~ in two, and Bing et a1.7 in seven subjects with normal hearts
idence of heart disease and in three patients with car pulmonale vvithout heart failure did not find any significant change in cardiac output after cardiac glycoside administration. In 12 patients with enlarged hearts who had no evidence of heart failure, Harvey et a1.r” reported a decrease in cardiac output in five, increase in one, and no change in six cases. Lagerlijf and \Yerkii,” in a series of seven patients with compensated heart disease, found no change in cardiac output following lanatoside C administration. Interpretation of Cardiac Output Changes: In none of the 11 cases reported here was there a significant change in cardiac output following acute digitalization. The changes noted following digitalis administration were closely similar both in magnitude and distribution to the changes occurring in 71 cardiac catheterizations in patients not receiving medication who had two control resting cardiac output determinations under “steady state” conditions.r3 The true mean deviation for the control group and the group in the glycoside study was approximately zero. The average change in the glycoside group was 6.7 per cent compared to 5.7 per cent in the overall control study. Since 10 of the 11 cases had cardiac indices above 3.5 L/min/sq M BSA, controls with cardiac indices over 3.5 L/min/sq M BSA are used here for comparison. The average variation in the 11 cases was 6.6 per cent. Three (23 per cent) had changes in cardiac output greater than 10 per cent but less Twenty per cent of the conthan 15 per cent. trols showed the same variations. The greatest variation in this study was 13 per cent and in the control study it was 15.7 per cent. The decrease in cardiac output after digitalis administration reported in the literature in subjects with normal hearts and patients with heart disease not in failure comes mostly perhaps from the lack of criteria to determine both the “steady state” and the significance of the changes observed. If our control study group is used for most of the cases reported in the comparison, literature would show no significant change. Some variations in cardiac outputs after lanatoside C administration were shown in the presented data. As demonstrated in the cases with
reported a decrease in cardiac output following However, administration of cardiac glycosides.
two control
Ahmed et al.5 in nine individuals with normal hearts and Ferrer et ~1.~ in two cases with slight
levels after digitalization depended upon which control was used as the base line to measure the
degree
variation,
of pulmonary
hypertension
without
ev-
Fig.
2),
the
cardiac
output
percentage
If only THE
one
AMERICAN
determinations
changes
from
control
output
JOURNAL
OF
(see
control
deter-
CARDIOLOGY
Dresdale,
Yuceog-lu,
Michtom,
Schultz,
and
97
Lunger
mination had been available, an error could easily have been made in interpretation in these
cases there were changes
cases. The oxygen consumption andior the heart rate alone would not have been of help in these cases, since they were fairly constant. A decrease in A-V oxygen difference may be the only hemodynamic manifestation of anxiety.“” On the basis of statistical analysis of two successive cardiac output determinations in 20 control patients not receiving medication, Harve) and her associates4 found that the cardiac outputs did not chanp-e more than =!=I9per cent. Any change more than this value was considered In a report from the same laborasigiificant. tory Cathcart rt ~1.~~’in a series of 100 catheterizations M.ith two control determinations, found that 83 per cent varied less than 10 per cent, while 17 per cent of the cases showed greater deviations. In two cases there was a variation of greater than 15 per cent in cardiac outputs. In our series of 71 catheterizations, 80.3 per cent varied less than 10 per cent; only 2 or 2.8 per cent varied slightly more than 15 per cent. On the basis of the foregoing, 4 out of 5 cases reported to show- a decreased cardiac output following digoxin by Harvey et al.‘” Mould not be considered significant. In two of their cases they found a decrease of 32 per cent and 21 per cent. In one of these cases the drop of 32 per cent was calculated 46 minutes after digitalis. In the same case, 20 minutes after digitalis the fall \vas 12 per cent, and 69 minutes later, at which time theoretically the more significant change should have occurred, there was only a decrease of 13 per cent. One normal subject had a fall of 18 per cent in cardiac output 20 minutes after digoxin; however, 75 minutes later the decrease xvas only 1.2 per cent. McMichael and iharpey-Schafer” reported a fall in cardiac output in three normal subjects following digoxin. In two instances, according to our criteria, the decrease would be considered Ahmed et a1.5 later studied the efsignificant. fect of ouabain in nine normal sub.jects and could not find any significant change in cardiac output following administration of the drug. Two of these patients had changes in cardiac output greater than 15 per cent but in divergent directions. In both reports there are no data avail-
Since strophanthus is not known to cause such changes in oxygen consumption, these variations indicate changes in state in those patients during the stud!.. Control cardiac indices in two other patients are far above the range considered to be basal. The narrow A-V oxygen difference suggests in these cases a state of anxiety. Observations in the cases reported here and those cases reviewed in the literature, using our control group [or comparison, strongly suggest that acute digitalization in patients with normal hearts and diseased nonfailing hearts does not produce a significant change in cardiac output. This suggests that lanatoside C tither has no action on nonfailing hearts, or this action is not detectable I)), the methods used. The duration Ohser\,ation of the study may also be a factor. may not have been long enough to oljtain the Hoxscver, at optimum effect of the drug used. least some effects should be expected during this period of ol,ser\fation if this is considered in light of the results obtained in patients w.ith heart failure.gP” Unless the nonfailing myocardium responds at a different time, a one- to t\vo-hour folio\%.-up after acute digitalization would seem to I,e suficient to observe any changes w-hich may occur. Changrs in Systemic Blood Pressure: Sex-era1 authors”.6~“‘-1” ha\,e found either no change or some increase in svstemic arterial blood pressure after acute digitalization in the types of patients under IHarvey fd al.“’ postulated a \.asocondiscussion. strictor effect ofdigoxin on the arteriolar I)ed on the basis of’ no change or an increase in mean systemic pressure M hen there was no change or a fall in cardiacoutput. It is not unusual forcompensatar! vasoconstriction to occur in the presrnce of a fall in cardiac output. In the cases reported here, there was no significant change in cardiac output and in most instances the \.ariations in systemic pressure following lanatoside C: iver-e In aniobserved prior to drug administration. mals, toxic doses of digitalis have tIcen clcmonstrared to cause a rise in i)lood pressure secondarb- to vasoconstriction.3’ This apparcntlbresults from a direct effect on the smooth muscles and partly
from a central
able
Ho\ve\.cr,
this \vas not found
regarding
ox)-gen
consumption
and
A-\
difference.
italir.ing
Decrease
in cardiac
was reported patients
from control
bvith
output
after
strophanthus
by Ring and his associates7 normal
hearts.
In
in seven
tL1.o of these
(.‘linirnl presented, (and
in oxygen consumption levels of +SO cc and - 133 cc.
vasomotor
stimulation.
wh(sn avcraqc
dig-
doses \\-c-re used.
Szgnifkanct~ of it has bren
presumal,l\
Results: sho\rn
I he other
Frown thr that
cardiac
data
lanatoside
C
qlycosicles
as
98
Effects
of Lanatoside
well) in therapeutic doses does not seem to have any acute measurable deleterious effects on the hemodynamics of the cardiovascular system in subjects with normal hearts or cardiac patients not in heart failure. The problem of whether prophylactic digitalization is useful in patients with heart disease but not in heart failure is, however, not solved by this study. Nevertheless, it is felt that these patients can be digitalized without fear of decreasing cardiac output or producing unfavorable changes in blood pressure.
C in Nonfailing
4.
5.
6.
SUMMARY
(1) The effect of acute digitalizing doses of lanatoside C on cardiovascular hemodynamics has been studied by the technique of right heart catheterization in 7 subjects with normal hearts and 4 patients with heart disease without clinical or hemodynamic evidence of heart failure. (2) Lanatoside C in full therapeutic doses caused no significant changes in cardiac output, heart rate, systemic venous, right ventricular The systolic, and pulmonary artery pressures. systemic arterial pressures and resistances similarly were not appreciably affected. In 2 of 8 cases, there was a slight fall in the right ventricular end-diastolic pressure and in 5 of 6 cases there was a slight fall in right auricular pressure. (3) Interpretations of the presented data Difwere made on the basis of control studies. ficulties in interpreting the changes in cardiac output in this type of study are emphasized. (4) It would seem from this study that digitalis given prophylactically- to patients with heart disease but not in failure would not have any deleterious effect on cardiovascular hemodynamics.
The authors wish to express their appreciation to Dr. Max Michael, Jr., for reviewing this paper and for his valuable suggestions. REFERENCES 1. WITHERING, W.: An Account of the Foxglove and Some of Its Medical Uses; with Practical Remarks on Dropsy and Other Diseases. M. Swinney, Birmingham, England, 1785. 2. STEAD, E. A., WARREN, J. V., and BRANNON, E. S.: Effect of lanatoside C on the circulation of patients with congestive failure; a study using catheterization of the right side of the heart. Arch. Int. Med. 81: 282, 1948. 3. BLOOMFIELD, R. A., RAPOPORT, B., MILNOR, J. P., LONG, W. K., MEBANE, J. G., and ELLIS, L. B.: The effects of the cardiac glycosides upon the dynamics of the circulation in congestive heart
7.
8.
3.
10.
11.
12.
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