Clinical and Cardiodynamic Effects of Adrenocortical Steroids in Congestive Heart Failure
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Clinical and Cardiodynamic Effects of Adrenocortical
Steroids in Congestive Heart Failure
By MURRAY A. GREENE, AI.D., ARTHUR GORDON, AI.D., AND
ADOLPH J. BOLTAX, AI.D.
T HE TENDENCY of adrenocortical ste- A steady clinical state of at least 5 to 7 days' dura-
roids and corticotrophin (ACTH) to tion was required as a control period prior to
promote salt and water retention, resulting physiologic testing. This state was maintained by
the usual therapy for congestive heart failure and
in an inereased extracellular fluid volume, has included a standard lowv-salt diet (less than 2 to 3
been established by many investigators.1-' Gm. of sodium ehloride daily). Mercurial diuretics
Studies have also demonstrated the impor- were not given during this control period although
tance of excessive activity of the adrenal cor- most patients had received this therapy during the
tex in the pathogenesis of fluid retention and course of their previous illness.
edema formation in various disease states, During the control period, routine clinical ob-
servations were made and pertinent laboratory data
including heart failure.6 In contrast, so- obtained. Radioiodine uptakes by the thyroid
dium and water diuresis and an improved re- gland were measured in order to evaluate the pos-
sponse to mercurial diuretics, accompanied by sibility that depression of thyroid function by
clinical improvement, were reported in some steroids may secondarily affect clinical states and
patients with congestive heart failure during cardiodynaiies. Phenolsulfonphthalein excretions
and urea clearances were measured as gross indices
or following the administration of cortico- of renal function. Fluid balances were evaluated
steroids and ACTH.12-19 The need to eluci- according to daily fasting weights, daily urine out-
date the problem of the effects of these agents puts, and frequent determinations of serum and
in heart failure and the role of adrenal corti- urine electrolytes.
coids in the formation of edema are the basis Physiologic studies of cardiovascular hemody-
for the present study of the effects of corti- namics by the standard technic of right heart
catheterization were then performed (tables 2A
costeroids upon the clinical status, electrolyte and 2B). The patients were in the resting recum-
balances, and cardiovascular dynamics in a bent positions and were not given premedication.
group of subjects having heart disease of Duplicate measurements of cardiac output (direct
varied etiologies and congestive failure of Fick) were made. Pressures were obtained with the
varying severity. use of Statham strain-gage transducers (P23A)
and recorded on a multichannel oscillographic pho-
Materials and Methods tographic recorder. Mean pressures were obtained
Nine patients, 4 female and 5 male, with con- by electrical integration of the pressure pulses.
gestive heart failure are the subjects of this study Since flow and pressure miieasuremiients did not vary
(table 1). Ages ranged from 17 to 65 vears. The significantly during single studies, olnly average
patients are further classified according to etiology, values are tabulated. Total pulmonary vascular,
functional capacity (New York Heart Associa- pulmonary "arteriolar," and total peripheral arte-
tion), and clinical status in table 1. Varied etiolo- rial resistances were calculated according to stand-
gies and mild to severe degrees of heart failure ard formulas (Poiseuille). Resistance is expressed
are represented. as dynes see. ci.-5 by the use of conversion fac-
The patients were hospitalized throughout the tors.: Total plasma volumiies were determined by
study and were semi-aimbulatory or restricted to the I131-labeled human serum albumin method
bed rest according to their functional capacities. and converted to total blood volumes by the use
of peripheral hematocrit values. Predicted plasma
From the Department of MIedicine, The Bronx volumes for either sex were based on the studies
Hospital, New York, N. Y. of Samet et al.20 These values are essentially simi-
Supported in part by a grant from The John lar to those reported by other investigators. Pul-
Polachek Foundation for Medical Research and in
part by a grant (H-4344) from the National Insti- *1,332 = conversion factor fronm mmn. Hg to clynes
tutes of Health, U. S. Public Health Service. cm.4
Circulation, Volume XXI, May 1960 661
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015662 GREENE, GORDON, BOLTAX
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Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015STEROIDS IN CONGESTIVE FAILURE 663
monary vital capacities and maximum breathing analyzed. In each of these studies at least 2 con-
capacities were obtained the day prior to cathe- trol "resting" cardiac output deternminations (direct
terization with the modified Benedict-Roth spirom- Fick), multiple pressure measurements, and resist-
eter. ance calculations were performed at intervals of
After the control clinical and physiologic studies 22 to 143 nminutes (average 41 minutes), while the
were completed, adrenocortical steroids were ad- patients' states were considered to be constant.
ministered for 13 to 16 days (table 1). Six pa- Chance or expected variations in terms of 95 per
tients received prednisone and 3 received triameino- cent confidence limits (2 standard deviations from
lone." These agents were selected because of their the mean variation) were established on this basis
diminished tendency to cause soduim and water for the various measures of cardiovascular hemo-
retention, edema, and potassium depletion as com- dynamics. A wide range of abnormalities in cardio-
pared to other agents.21-25 None of the other usual dynamics was present in this control group, as
contraindications to steroid therapy was present. would be expected in any series of patients with
Clinical status, routine laboratory data, and fluid heart disease and congestive failure. It was there-
balances were evaluated throughout the phase of fore thought that greater reliability in an evalua-
steroid therapy. Radioiodine uptakes by the thy- tion of the results would exist if these confidence
roid gland were measured prior to repeat cardiac limits were expressed in terms of percentage varia-
catheterization. The previously stabilized cardiac tions rather than changes in absolute values. Two
regimen was continued during this period. Mer- exceptions are pulmonary "wedge" and right ven-
curial diuretics were given whenever warranted by tricular end-diastolic pressures. These parameters
the development of appreciable aggravation of elin- are expressed in terms of absolute changes because
ical heart failure. Supplementary potassium ther- only mininmal variations usually occur during a
apy was not given. ''resting" state and because small variations in
Right heart catheterization and blood volume their usually low num-lerical values frequently re-
determinations were then performed on the last sult in inordinately high percentage changes.
day of steroid administration; vital capacities and Changes in cardiovascular dynamics in the pres-
maximum breathing capacities were determined on ent series of 9 patients who received steroids were
the day prior to catheterization (tables 2A and then evaluated in terms of statistical significance
2B). at the 5-per cent level. Changes that are consid-
Clinical status and fluid balances were observed ered to be statistically significant are appropriately
in some patients for several days following steroid indicated in tables 2A and 2B. It is appreciated
withdrawal. that appraisals of the 2 sets of data in these sub-
Changes in cardiovascular hemodynamics as a jects may not be strictly comiiparable with those of
result of drug administration were evaluated in the control group because of the differences in time
terms of statistical probabilities. In order to de- intervals. The possibility of greater variations in
termine whether these changes may have been due "resting" states may exist when studies are sep-
to chance variation, or due to the action of an arated by greater time intervals. This factor does
introduced variable (steroids in this study), 29 not appear to represent a major difficulty, how-
consecutive right heart catheterizations in this lab- ever, since miietabolic states could be studied and
oratory in adults with varied types of heart disease compared on the basis of oxygen consumptions
and with varying degrees of conlgestive failure were and respiratory quotients.
**The authors wish to thank The Squibb Institute Results
for Medical Researeh, New Jersey, for their supply Three types of responses to steroid adminis-
of triameinolone, (Kenaeort ®). tration occurred in this series of patients:
*S. Tinie periods are denoted in this column. I, control observation period prior to initial
physiologic studies; II, during the period of steroid administration (maximal changes and
their time of occurrence are indicated); III, immediately prior to the repeat physiologic
studies.
tDyspilea. Severe if at rest, moderate if during mild effort, and slight if only during
moderate effort.
+Edema. Marked if involving more than lower extremities (presacral, abdominal wall),
slight, if involving ankles.
AI, aortic insufficiency; AS, aortic stenosis; CHF, congestive heart failure; CP, cor pul-
monale; E, emphysema; HHD, hypertensive heart disease; IMH, idiopathic myocardial hyper-
trophy; MI, mitral insufficiency; MS, mitral stenosis; PF, pulmonary fibrosis; RHD, rheu-
inatic heart disease.
Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015664 G(REENE G(RD()N, BOL'TAX
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Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015666 GREENE, GORDON, BOLTAX
Increases in congestive heart failure (5 pa- few statistically significant changes in cardio-
tients), no significant changes in clinical states dynamics occurred (tables 2A and 2B). This
(3 patients), and improvement in clinical lack of change could be attributed to the ap-
state and in cardiodynamics (1 patient). preciable neutralization of the clinically ob-
Increases in Congestive Heart Failure vious detrimental effects of steroids by mer-
curial therapy, which was administered until
Clinical heart failure increased in severity
in 5 (cases 1 to 5) of the 9 patients during clinical improvement was obtained.
steroid therapy (table 1). In 4 of these pa- Total plasma volumes were elevated ini-
tients (cases 1 to 4) slight to mnoderate reduc- tially in all 5 patients, but they did not change
tions in daily urine volumes occurred concomi- much after steroid therapy. Slight falls in
tant with increases in weight, indicating posi- plasma volumes in 3 patients may well have
tive fluid balances. Laboratory data suggest- resulted froni mercurial diuretics used to com-
ed worsening of hepatic function (increased bat congestive failure. No significant changes
bromsulfalein retention) and renal function in vital capacities and maximum breathing
(increased blood urea nitrogen and decreased capacities occurred as a result of steroid ad-
urea clearance) in some patients of this group. ministration. In 3 patients (cases 1 to 3) in
All initially had normal 24-hour radioiodine whom fluid balances were measured for sev-
uptakes (thyroid); no changes occurred dur- eral days following steroid withdrawal, no
ing steroid therapy. Parenteral mercurial significant changes occurred in weights, urine
diuretics were given to 4 patients (cases 2 to volumes, and urinary excretions of elec-
5) because it was considered hazardous to per- trolytes.
muit the deteriorated clinical conditions to per- No Significant Changes in Clinical States
sist. Responses to this therapy were poor. In 3 patients (cases 6 to 8) no changes in
Hyponatremia and hypochloremia existed clinical heart failure occurred during steroicd
in 2 patients in the control period, slight in administration (table 1). A weight loss of 5
one (case 1) and marked in the other (case 3). pounds was noted in 1 patient (case 8). Mark-
During steroid therapy slight depression of ed anorexia and diminished food intake as
serum sodium occurred in 2 patients (cases well as a decline in urine output and in uiin-
1 and 4) and of serum chloride in 2 (cases I ary sodium and chloride exeretions suggested
and 3). In all 5 patients daily urine sodium that this weight loss was due to a decrease
and chloride exeretions were markedly de- in tissue mass rather than to a diuretic re-
pressed in the control period. During steroid sponse. No changes occurred in laboratory
therapy excretion of these ions did not change data or in 24-hour radioiodine uptake by the
or decreased slightly in 4 patients, whereas thyroid gland. In 2 patients (cases 6 and 7)
ani increase occurred in 1 (case 2). control 24-hour urine sodium and chloride
At the time of the second physiologic exeretiolis were within normal limits; in the
studies, 1 patient (case 1) who did not re- other patient excretions of these ions were
ceive mercurials had a weight gain of 6 dimninished. Moderate reductions in daily so-
pounds and considerable increase in heart dium and chloride excretions occurred in
failure, and another (case 2) was somewhat these 3 patients during steroid administration.
improved by mercurial therapy but was still No significant changes in cardiodynamics
worse than his control state as well as 2 occurred as a result of corticosteroid adminis-
pounds heavier. The others had resumed their tration except for a decrease in right ventricu-
control clinical states after mercurial therapy lar end-diastolic pressure and pulnionary
although 2 (cases 3 and 5) were 2 and 4 "arteriolar'" resistanee in 1 patielnt (case 7)
pounds lighter. (tables 2A and 2B).
In 1 patient (case 3) the second catheteri- Total plasma volumes were elevated initial-
zation was unsuccessful. In the others very ly in all 3 patients. In 2 (eases 6 and 7)
Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015STEROIDS IN CONGESTIVE FAILURE 667
slight to moderate decreases occurred during Discussion
steroid therapy; in 1 (case 8) a moderate The effects of ACTH and adrenal cortical
increase occurred. steroids upon renal and cardiovascular sys-
No significant changes in vital capacities tems in man and experimental animals have
and maximum breathing capacities occurred been far from uniform, so that generaliza-
as a result of steroid therapy. In 2 patients tion about the specific activities of these hor-
(cases 6 and 8) in whom fluid balances were inones is most difficult. The tendency of these
studied for several days following steroid hormones to promote salt and water retention
withdrawal, no changes occurred in body and, consequently, an increase in extracellu-
weights, urine volumes, and urine electrolyte lar fluid volume has been observed by many
excretions. investigators.1-5, 26 Corticoids that have prom-
Improvement in Clinical State and in Cardiody- inent actions of this type include desoxy-
namics corticosterone, cortisone, hydrocortisone, and
In the patient (case 9) with pulmonary aldosterone. Newer synthetic derivatives
fibrosis and emphysema and cor pulmonale have distinctly less tendency to cause salt
as the basic disease, there was an improve- and water retention although positive fluid
ment in dyspnea during steroid therapy (table balance has been observed, especially with
1). However, a weight gain of 4 to 5 pounds higher dosages.2' 25 In contrast, some studies
and a slight decrease in daily urine output demonstrate that these hormones may possess
occurred concomitantly. There were no diuretic properties. Davis and Howell27 ob-
changes in routine laboratory data or in radio- served that both ACTH and cortisone pro-
iodine uptake by the thyroid gland. A slight duced an initial loss of salt and water in the
fall in serum chloride occurred. intact dog. Other authors have reported
Improvement in cardiodynamics resulted natriuresis and chloruresis during the ad-
ministration of ACTH in man28 and in the
from administration of corticoids (tables 2A rat.29 Gaunt, Birnie, and Eversole30 cited
and 2B). There were a significant increase
in cardiac output and lowered pulmonary experimental data indicating that cortical
artery systolic and mean pressures and right
hormones may produce diuresis in animals
ventricular end-diastolic pressure. Although with normal water balance, in overhydrated
these changes in pressures may have been due ones, and even in mildly dehydrated ones.
to corresponding changes in intrathoracie In view of this diversity of steroid actions,
pressure (which was not measured), the simi- it is not difficult to understand the uncer-
larity of pulmonary "wedge" pressures in tainties regarding clinical applicabilities of
both studies suggests that the decreases in these hormones in patients with diseases char-
pulmoonary artery and right ventricular pres- acterized by positive fluid balanees, particu-
sures were due to decreases in effective intra- larly congestive heart failure. This difficulty
vascular pressures. Pulmonary vascular and is further compounded by studies that have
pulmonary "arteriolar" resistances also de- demnonstrated increased activity of endogenous
creased significantly. Qxygen consumption salt-retaining adrenal cortical hormone, aldo-
was higher during the second study and may sterone, in these diseases.7 31-33 In
T gen-
have indicated some change in metabolic state. eral corticoids have been used with caution
Nevertheless, the data indicate improvement in these conditions because of their tendeney
in dynamics. Total plasma volume increased to promote salt and water retention. Vari-
slightly with steroid therapy. Minimal, if ous investigators, however, have reported fav-
any, improvement in vital capacity and maxi- orable results following the administration of
mum breathing capacity occurred. these hormones to patients with congestive
No changes in fluid balance occurred fol- heart failure.12-19 Results, however, were not
lowing steroid withdrawal. uniform in all studies. Some patients had
Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015668 GREENE, GORDON, BOLTAX
cliniical and hemodynamic deterioration prob- improved durinig steroid therapy. This was
ably due to renal retentioni of salt an-d water.12 the only subject who had pulmonary fibrosis
In another study'8 a small number of pa- and emphysema with cor pulmionale. This
tients demonstrated decreased urinary sodiuim patienlt had imnprovement in cardiodylnamicis
excretion, inerease in weight, and possibly despite a positive fluid balanee. It wouLld
inerease in dyspnea. be difficult in this case to define the primary
The present study was undertaken to eluci- mode of action of the steroid frolm the limit-
date the effects of adrenal cortieoids in conl- ed amount of data available concerniing pri-
gestive heart failure. In the 5 of the 9 pa- marv pulmoinary functions. Possibilities in-
tients in this series subjective anid objective elude improvemieint in pulmonary iniflamma-
clinical manifestations and laboratory data tion, bronelhomotor tone, anid vascular resis-
indicated positive fluid balalnces with increas- tance, causilng a decline in right heart work
ed fluid accumulationi anid inereased cardiac load and, conisequently, improvement in right
deeompensation during the phase of steroid heart function. Other workers have described
therapy. Respolnses to mnercurial diuretics favorable clinical results and improvenments
were poor. Heightened responsiveness dur- in pulmaonarv function following corticoster-
ing steroid therapy was lnot observed in any oid therapy in patients with chronic pul-
patient in this study. An evaluation of muonarv disease.34 This ease is of initerest
cardiodynamic changes is more difficult be- in that clinical an-d hemodyniamie improve-
cause of the effects of additional diuretie mnent occurred onlv in that patient who did
measures given to 4 patients during steroid not have uncomitplicated heart failure. Fac-
therapy. These agents were givenl because of tors were probably presenit that are kniowln to
the development of precarious clinical condi- be favorably affected by corticosteroids, e.g.,
tions. It is therefore not surprising that 11o iniflammnatioin, and so forth. It is also prob-
significant changes in cardiodynamics and able that the additional fluid retained was
some decreases in plasma volunmes were noted distributed throughout the body compart-
in those patients given miiercurial diuretics menets and any7 inierease in fluid that miight
until clinical improvement occurred. In 1 pa- have occurred in the right heart was nmore
tient (case 2) who was clinically worse and than compensated bv the favorable primary
had an inerease in plasma volume (in spite of effect on the cardiopulmonary systeuis.
2 mercurial injections) at the time of the It is difficult to delineate those factors that
second cardiac catheterizationi significant in- may favor fluid retention during steroid
creases occurred in pulmoonary artery anId therapy in some patients anid not in others.
right ventricular end-diastolic pressures. The patienits whose heart failure inereased
In 3 of the remaining 4 patients no changes were those who gelnerally seemed to haave
in cliniical status occurred durinig steroid greater degrees of decompensation character-
therapy. Somue diminution in urinary sodium ized bv severe subjective maniifestations, co'n-
and chloride excretions occurred in these pa- siderable fluid accumnulationi, alnd marked de-
tients although the depressioln present in the pressionis in sodium. anid chloride exeretions.
first group was nlot observed. One patient Comparisoln of cardiovascular dyianmics be-
(case 8) had a reduction in circulating volumne tween the first 2 groups reveals much overlap-
and a deeline in right venitricular elnd-diastolic ping in many of the mneasurements. However.
pressure. A minimal inerease in daily urin- the generally higher pulmonary "wedge" and
arv volunme in this patient would not appear right ventricular enid-diastolie pressures and
to account completely for the diminution in total plasma volumes in those patients worsen-
eirculatilng volume although it could have con- ed by steroids suggest that deteriorationi is
tributed to it. Another possibility may be more likely to be produced in those patients
that of internal fluid shifts. who already have conisiderable fluid accumula-
In 1 patienlt (case 9') eliuiical symptoms tion. The addition of agents that can retaini
Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015STEROIDS IN CONGESTIVE FAILURE 669
salt and water simply increases the severity cifically antagonize endogenous fluid-retaining
of the existing positive fluid balance. factors may prove fruitful in patients with
It is difficult to explain the differences in congestive heart failure. The prominent role
results in the present study from those re- of endogenous adrenocortical hormones (espe-
ported by others, 12-19 in which diuresis and cially aldosterone) in retaining fluid and in
clinical improvement were noted in many pa- promoting formation of edema in patients
tients with congestive heart failure. Evalua- with heart failure has recently been empha-
tion of the effects of prolonged administration sized. Drugs that may antagonize these hor-
of various drugs in heart failure may be haz- mones would be most important.38
ardous in view of the spontaneous variations
Summary
that may occur in this state. Strict selection
of patient miaterial is also important. Sub- This study is concerned with the effects of
jects who are in a steady clinical state are best adrenocortical steroids in patients with con-
studied; those who have had acute deteriora- gestive heart failure.
tion in cardiac funetion prior to drug admin- Nine adults with heart failure were studied
istration may not be satisfactory subjects for during a steady clinical state (5 to 7 days),
this way suggest variable extralneous adverse during administration for 13 to 16 days of
factors which by their presence or remittanee prednisome (6 patients) or triameinolone (3
may influence results. Concomitant therapy patients) and in some subjects following ster-
that nmay be detrimental to subjects with heart oid withdrawal. Daily determinations of
failure should be avoided. One group of in- fluid balances were made. Standard right
vestigators maintainied high levels of water heart catheterizations and inieasurements of
intake before anid during steroid administra- blood volumes were performed prior to and
tion.'5-1' Leiter35 has reviewed data which in- at the terminiation of therapy.
dicate that subjects with congestive failure Three types of responses to steroids oc-
may retain water excessively (resembling the curred. In 5 patients increases in subjective
effects of excessive antidiuretic hormone), and objective manifestations of heart failure
leading to a worseninig of elinical status. Ster- and increased fluid retention occurred. Four
oids may have prevented overhydration in of them developed precarious clinical condi-
these patientsl'5 16 as it does in water intoxi- tions during steroid therapy, requiring mer-
cation aiid as an anitagonist to antidiuretic curial diuretics, but with poor results. In
hormone30' 36, 37 and niav niot have affected general, cardiodynamie status at the termin-
any of the originally existing abnormal eardi-
ation of steroid therapy correlated well with
clinical status. In 3 patients the clinical
ovascular-renal hemodvnaniies.
status did not change. Some depression in
Patients were selected for the presenit study urinary sodium and chloride excretions were
who were in a steady clinieal state and who noted during therapy. Cardiodynamics were
had heart disease of varied etiologies and of unaltered, except for an unexplained decrease
varying severity and no other condition that in right ventricular end-diastolic pressure in
could be favorably affected bv steroids, espe- 1 patient. In 1 patient elinical and cardio-
cially infectious diseases and overt inflanmma- dynlamic state improved, despite positive fluid
tory processes. The one exception was the balance. This was the only subject with
patient with pulmuonary fibrosis and emphy- primary lung disease (emphysema) and cor
sema. The results in this patient demonstrate pulmonale.
the need for care in patient selection. The These studies suggest that corticosteroids
phase of drug adminiistration was restricted are generally detrimental in uncomplicated
to 13 to 16 days to miinimize the possibility of congestive heart failure. Greater deteriora-
spontaneous change in disease states. tion appeared in subjects having the more
Further work with agents that more spe- severe degrees of decompensation, suggesting
Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015670 GREENE, GORDON, BOLTAX
that exogenous fluid-retaininig influences were References
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congestive heart failure. Cireulation 12: 1047,
Acknowledgment 1955.
The authors wish to express their appreciation to 2. ZIFF, M., SIMSON, J., AND BUNIM, J. J.: Effect
Miss Olga Gallego and Mrs. Josephine Damsky for of ACTH on water distribution in man as
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Circulation, Volume XXI, May 1960
Downloaded from http://circ.ahajournals.org/ by guest on November 4, 2015Clinical and Cardiodynamic Effects of Adrenocortical: Steroids in Congestive
Heart Failure
MURRAY A. GREENE, ARTHUR GORDON and ADOLPH J. BOLTAX
Circulation. 1960;21:661-671
doi: 10.1161/01.CIR.21.5.661
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