Download Effect of Hydralazine on Renal Failure in Patients with Congestive

RENAL RESPONSE TO HYDRALAZINE IN CHF/Pierpont et al.
vasodilator drugs on transcapillary fluid exchange in the renal
cortex. Am J Physiol 230: 1148, 1976
29. Krakoff LR, Guia DD, Vlachakis N, Stricker J, Goldstein M:
Effect of sodium balance on arterial blood pressure and renal
responses to prostaglandin A, in man. Cire Res 33: 539, 1973
30. Merrill AJ: Mechanisms of salt and water retention in heart
failure. Am J Med 6: 357, 1949
31. Earley LE, Schrier RW: Intrarenal control of sodium excretion
by hemodynamic and physical factors. In Handbook of
Physiology. Section 8: Renal Physiology, edited by Orloff T,
Berlinger RW. Washington, DC, American Physiological
323
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32. LeJemtel T, Hellman C, Elkayam U, Strom J, Blaufox MD,
Frishman W, Ribner H, Sonnenblick E: Hemodynamic and
renal response to oral hydralazine therapy in severe heart
failure. Circulation 56 (suppl III): 111-9, 1977
33. Birch AA, Boyce WH: Changing renal blood flow following
sodium nitroprusside in patients undergoing nephrolithotomy.
Anesth Analg 56: 102, 1977
34. Pagani M, Vatner SF, Braunwald E: Hemodynamic effects of
intravenous sodium nitroprusside in the conscious dog. Circulation 57: 144, 1978
Effect of Hydralazine on Renal Failure
in Patients with Congestive Heart Failure
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GORDON L. PIERPONT, M.D., PH.D., DAVID C. BROWN, M.D., JOSEPH A. FRANCIOSA, M.D.,
AND JAY N. COHN, M.D.
SUMMARY Hydralazine is known to improve cardiac function in patients with congestive heart failure
(CHF), but its effects on renal function in CHF are less clear. Sodium retention is known to occur with longterm use of hydralazine to treat hypertension; if this occurs in patients with CHF it could be deleterious.
Therefore, in a metabolic unit we studied renal effects of hydralazine in patients with stable class III or IV
CHF. In a single-blind study, the patients were given placebo twice daily for 3 days (period P-1), 100 mg of
oral hydralazine twice daily for 3 days (period P-H), and placebo for 3 more days (period P-2). The average
24-hour creatinine clearance was 69.7 ± 7.7 ml/min (mean i SEM) in P-1, increased to 76.3 i 9.0 ml/min
with hydralazine (p < 0.01) and fell again when hydralazine was stopped (P-2) to 68.5 i 7.8 ml/min
(p < 0.02). Though the slight improvement in sodium excretion was not statistically significant (60.2 ± 12.1
mEq in P-1, 64.5 ± 12.4 mEq in P-H, 52.3 ± 7.7 mEq in P-2), serum osmolality decreased from 288 ± 1.8
mosM in P-1 to 283 ± 1.9 mosM in P-H (p < 0.02) and rose to 286 ± 1.9 mosM in P-2 (NS). During the
three periods, serum sodium, chloride, potassium, carbon dioxide, blood urea nitrogen, creatinine and glucose
were unchanged, as were weight and urine volume. Systolic blood pressure was 109.6 ± 3.6 mm Hg in P-1,
110.1 ± 3.9 mm Hg in P-H (NS), and 114.2 ± 5.0 mm Hg in P-2 (p < 0.05). Diastolic blood pressure, heart
rate and respirations were unchanged. Thus, we found no evidence of sodium or water retention during
hydralazine administration in patients with CHF, and renal function was actually improved, as evidenced by
the increased creatinine clearance.
HYDRALAZINE improves left ventricular performance in patients with congestive heart failure (CHF)'
and may be effective for long-term oral therapy of
patients with chronic CHF.1 2 However, hydralazine
can lead to sodium and fluid retention when used to
treat hypertension,3-5 and sodium retention has been
reported during administration of hydralazine in a
patient with CHF.6 Such a response to hydralazine in
patients with CHF might limit the value of this drug
for long-term therapy or necessitate larger doses of
diuretics. The present study assesses the effects of
hydralazine on renal function and sodium balance in
patients with CHF.
From the Department of Medicine, Cardiovascular and Renal
Sections, University of Minnesota Hospitals, and Veterans Administration Medical Center, Minneapolis, Minnesota.
Address for correspondence: Gordon L. Pierpont, M.D.,
Veterans Administration Medical Center, Cardiovascular Section,
Minneapolis, Minnesota 55417.
Received March 9, 1979; revision accepted August 20, 1979.
Circulation 61, No. 2, 1980.
Methods
Nine male patients with New York Heart Association functional class III or IV heart failure (three class
IV and six class III) who were on conventional
therapy were studied. The patients were ages 47-64
years (average 59 years). Three of the patients had
primary myocardial disease and six had ischemic
heart disease. Exclusion criteria included: insulindependent diabetes mellitus, severe pulmonary disease
(Po2 < 50 mm Hg or Pco2 > 50 mm Hg), renal insufficiency (BUN > 40 mg/dl or creatinine > 2.0
mg/dl), abnormal serum electrolytes, angina requiring nitrate therapy, myocardial infarction within the
past 3 months, significant primary heart valve disease,
hypertension requiring nondiuretic antihypertensive
agents or heart failure due to restrictive heart disease.
After giving written informed consent, the patients
were admitted to a special diagnostic and treatment
unit (SDTU) of the Minneapolis Veterans Administration Medical Center for evaluation. All
patients were clinically stable with a steady body
weight when admitted to the SDTU. All patients were
324
CIRCULATION
VOL 61, No 2, FEBRUARY 1980
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receiving a constant dose of diuretics, and eight of nine
were taking digitalis at the time of admission. These
medications, as well as any other medication the
patient was taking regularly, were continued at a con-
TABLE 1. Clinical Data from the Three Study Periods
stant dose throughout the study period. One patient
had been receiving isosorbide dinitrate, which was
stopped more than 24 hours before entry into the
study.
On admission to the SDTU a dietary history was
taken by a nutritionist and a diet constructed to match
the usual sodium intake for each patient. Sodium and
fluid intake were kept constant for the duration of the
study and patients were allowed their normal level of
activity. Supine blood pressure, heart rate, respirations and temperature were monitored four times
daily, and the patients were weighed twice daily.
The study protocol consisted of three periods of 3
days each. The first period consisted of 3 days of
placebo administration (two tablets twice daily). This
was followed by 3 days of active hydralazine therapy,
100 mg (two tablets twice daily) and another 3-day
placebo period. The investigators, but not the patients,
knew when hydralazine was being given. Each morning blood was drawn for determination of serum urea
nitrogen, creatinine, glucose, sodium, chloride, total
CO2, potassium and osmolality. In the last five
patients studied, blood samples for plasma renin activity (PRA) were drawn on the third day of each
period in the early morning with the patient supine.
Urine was collected at 8-hour intervals throughout the
study and analyzed for creatinine, potassium, sodium
and osmolality. Creatinine clearances were calculated
for each of the three daily 8-hour urine collections
using the serum creatinine value obtained at the end of
the day.
All data were analyzed using the paired t test and
differences were considered statistically significant for
p values less than 0.05. The mean of all values obtained during each 3-day period were compared, and
analysis of the data was repeated by averaging the
values from the two placebo periods and comparing
them with the values from the hydralazine period.
Combining the placebo periods would tend to correct
for trends during the course of hospitalization that
might occur independent of hydralazine therapy. In
order to examine the data for possible changes within
each drug period, an additional analysis of the more
pertinent variables was performed using an analysis of
BP (mm Hg)
HR (beats/min)
variance.
Results
Table 1 shows the mean values during each period
for mean arterial pressure (calculated as the diastolic
pressure plus one-third of the pulse pressure), heart
rate, body weight, serum creatinine, serum sodium,
serum chloride, serum potassium and urine volume.
None of these parameters changes significantly during
hydralazine therapy when compared with each
placebo period or with the average of the two placebo
periods.
In addition to the data presented in table 1, there
P1
Study period
H
P2
84 -2.0
85 2.1
87 3.4
83 - 3.0
84 - 3.3
84 2.7
178 9.8 179- 9.8 177
10.1
Weight (lbs)
Creat (mg/ml)
1.4 0.15 1.4- 0.18 1.4 0.16
BUN (mg/dl)
24 - 4.7
25 - 3.9
25 4.0
Na+ (mEq/l)
141 - 1.0 139 :1.5 140
1.6
Cl- (mEq/l)
100
1.4
99
1.9
99
1.9
K+ (mEq/l)
4.3 0.1
4.3
0.1
4.2 +0.1
Urine vol (1/24 hr)
2.1 0.26 2.2 0.27 2.1 i0.27
Values are average - SEM. None of the changes were
statistically significant when compared from one period to
another.
Abbreviations: BP = mean blood pressure; HR = heart
rate; Creat = creatinine; BUN = blood urea nitrogen;
Na+ = serum sodium; Cl- = serum chloride; K+ = serum
potassium; P1 = first placebo period; P2 = second placebo
period; H = hydralazine.
were no significant changes in respiratory rate, serum
glucose, serum total CO2, creatinine excretion, sodium
balance or combined sodium plus potassium excretion. Potassium excretion did not change from the first
placebo period (102 ± 10.5 mEq/24 hours) to the
drug period (103 ± 11.8 mEq/24 hours), but the
decrease to 98 ± 11.1 mEq/24 hours in the second
placebo period was statistically significant (p < 0.05)
when compared with the active drug period. Because
of this decrease during the second placebo period,
potassium excretion was statistically higher (p < 0.05)
during hydralazine therapy compared with the
average of the two placebo periods.
The effect of hydralazine on creatinine clearance,
sodium excretion and serum osmolality are shown in
figure 1. The average of all values during each period
is shown for every patient, as well as the mean + SEM
for the whole group. Creatinine clearance increased
from an average of 69.7 i 7.7 ml/min during the
first placebo period to 76.3 ± 9.0 ml/min during
hydralazine therapy (p < 0.01). In no patient did
creatinine clearance fall during administration of
hydralazine. The creatinine clearance fell again during
the second placebo period to 68.5 ± 7.8 ml/min,
which was significantly lower than during hydralazine
(p < 0.02). This value was not significantly different
from the first placebo period. When compared with
the average of the two placebo periods, the increase in
creatinine clearance during hydralazine was significant (p < 0.01).
Sodium excretion increased from 60.2 ± 12.1 mEq/
24 hours during placebo to 64.5 ± 12.4 mEq/24
hours during hydralazine and decreased again to 52.3
± 7.7 mEq/24 hours after hydralazine was stopped.
These changes were not statistically significant when
the hydralazine response was compared with each
placebo period separately or with the pooled placebo
periods.
RENAL RESPONSE TO HYDRALAZINE IN CHF/Pierpont et al.
125
1251
100t
t 1001
325
295
E
'
E
NI
E
z
z
FIGURE 1. Individual values for creatinine
clearance, sodium excretion and serum osmolality are shown for the first placebo
period (PJ, for hydralazine administration
(H), and for the second placebo period (P2).
The solid lines connect the values for a given
patient, the dotted line represents the mean
for the group and the shaded area represents the standard error of the mean.
E 290
CJ
W
4
75
z
75
1
0
285
-J
c)
Z
z
W
50-
2 280
50-
(n
4
0
25-
C,)1
275
25270-
P1
H
P2
p1
H
P2
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Serum osmolality decreased during hydralazine in
measured.
288 ± 2.6
mosM to 283 2.7 mosM during hydralazine
(p < 0.02), and returned toward baseline during the
second placebo period (286 + 2.7 mosM). The change
in serum osmolality during hydralazine compared
with the average of the two placebo periods was
significant (p < 0.02).
Although neither sodium excretion nor mean
arterial blood pressure changed significantly during
administration of hydralazine in these nine patients, it
is of interest to examine the relationship of these two
variables in individual patients. Figure 2 shows the
changes in blood pressure and sodium excretion from
the combined placebo periods to hydralazine administration for each patient. Sodium excretion was
lower during hydralazine in only three of nine
patients. A decrease in mean arterial blood pressure
occurred during hydralazine in all three of these
patients. The largest decrease in sodium excretion occurred in the patients who had the largest decrease in
blood pressure. In the three patients whose mean
arterial blood pressure increased, sodium excretion
also increased. In no patient did the blood pressure increase and sodium excretion decrease, and three
patients had an increase in sodium excretion despite a
decrease in blood pressure.
Creatinine clearance and serum osmolality were
further analyzed using the analysis of variance for
single-factor experiments with repeated measures on
the same elements.7 This analysis also showed the increase in creatinine clearance during hydralazine to be
significant (p < 0.01), as well as the decrease in serum
osmolality (p < 0.005), with no differences between
the first and second placebo periods. Examination of
the data for changes within each period revealed no
significant differences from day o day in any period for
either creatinine clearance or serum osmolality. We
conclude that the patients were indeed stable during
the initial placebo periods, and that they returned to
control levels and stayed unchanged during the second placebo period, with no evidence of prolonged
seven of the eight patients in whom it was
The mean serum osmolality dropped from
P
H
P
1
~~~2
effect after cessation of hydralazine. Also, because
there was no significant change from day to day during hydralazine therapy, there is no evidence of
tolerance or cumulative effect over the 3-day hydralazine period.
PRA increased during hydralazine administration
in all five patients in whom it was measured. The
average PRA increased from 4.2
1.18 ng/ml/hr
during the first placebo period to 8.5 2.05 ng/ml/hr
during hydralazine (p < 0.02), and decreased slightly
to 7.6 ± 3.13 ng/ml/hr during the second placebo
period.
Discussion
Most studies of the renal effects of hydralazine were
performed in hypertensive patients in the early 1950s.
These studies were stimulated in part by Reubi's8 find-
A
*
NaoEXCRETION
(meq / 24 hrs)
0
0
0
-8
-6
-4
-2
8
MABP
(m m Hg)
A
0
0
-30
-40
FIGURE 2. The changes in sodium excretion (ANa+ excretion) and in the mean arterial blood pressure (AMABP)
from the combined placebo periods to hydralazine administration are plotted for each of the nine patients.
326
CIRCULATION
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ing of increased renal plasma flow with no change in
glomerular filtration rate when six patients with
hypertension and four normal subjects were given 10
mg of hydralazine subcutaneously. Similar results in
patients with hypertension were subsequently reported
by other investigators.9"'4
In other studies in hypertensive patients, the renal
hemodynamic responses to hydralazine were more
variable.'5-17 Falch et al.15 found no change in effective
renal plasma flow in 11 patients with hypertension, but
the dose of hydralazine was only 25 mg given orally,
twice a day. In six patients with essential hypertension, Gjorup and Hilden'6 observed a variable
response to intravenous hydralazine. They suggested
that if the decrease in blood pressure was not marked,
renal blood flow increased, whereas it decreased if
blood pressure dropped markedly. Our data suggest
that this might also be true in patients with CHF, as
sodium retention during hydralazine, if it occurred,
appeared to be associated with a fall in blood pressure.
Schroeder'8 found no change in urea clearance or excretion of phenyl red in 50 hypertensives treated with
50-120 mg of hydralazine for 10-30 days,
Despite the variability of some of these studies, the
evidence suggests an increase in renal blood flow with
little change in glomerular filtration rate as the usual
response of hypertensive patients given hydralazine. A
similar response is likely in normal subjects if the data
obtained by Moyer et al.19 in nonhypertensive dogs are
applicable to humans.
Because the pathophysiology of CHF differs
significantly from that of hypertension, we cannot
readily assume that the renal responses to hydralazine
would be the same in the two groups. In hypertension,
the renal homeostatic mechanisms are altered toward
increased salt excretion.20 In contrast, in CHF, the
kidneys tend to retain salt and water, at least partly
because of renal vasoconstriction.21 Thus, it might be
expected that a vasodilator could improve salt excretion in CHF if renal perfusion is enhanced without a
decrease in blood pressure.
Data on renal vascular effects of hydralazine in
patients with heart failure are scarce. Two studies-2' 23
have reported on the renal responses of patients with
mitral stenosis given hydralazine, but these patients
are not comparable to our study group. Judson et al.23
included five patients with "cardiac insufficiency" in
their series, but four of the five were also hypertensive.
Our study therefore represents one of the first
attempts to analyze the effects of hydralazine
systematically in nonhypertensive patients with CHF
due to left ventricular dysfunction. In an uncontrolled
study, Packer et al.24 noted a brisk diuresis in some of
their refractory heart failure patients placed on
maintenance hydralazine therapy, but no further
analysis of renal function is described. Preliminary
reports of improved renal blood flow with hydralazine
administration in heart failure patients have also been
presented by LeJemtel et al.,25 Mantle et al.26 and
Cogan et al.27 In the patients of Cogan et al.,27
glomerular filtration increased insignificantly.
Because we wanted to keep the study noninvasive
VOL 61, No 2, FEBRUARY 1980
and were reluctant to water-load class III or IV heart
failure patients, we did not measure para-aminohippurate or inulin clearance in our patients. Nonetheless, creatinine clearance increased, consistent with
a rise in glomerular filtration rate. Because hydralazine is known to increase cardiac output in patients
with CHE," 2 it is likely that the improved creatinine
clearance was accompanied by an increase in renal
blood flow. We can thus infer that in contrast to
patients with hypertension, glomerular filtration rate
and renal blood flow are increased by hydralazine in
patients with CHF. This response could in part be attributed to the fact that renal blood flow and
glomerular filtration rate are functionally reduced in
CHF, probably because of renal vasoconstriction,
which can then be relaxed as the cardiac output increases.
Although we did not measure PRA in all patients,
PRA did increase during the period of hydralazine administration in all five patients in whom it was
measured. An increase in PRA also occurs when
hydralazine is given to hypertensives, and has been
thought to be related to the decrease in blood pressure.
In this subgroup of five patients, renin increased even
though blood pressure did not fall significantly and the
control PRA tended to be elevated. In these five
patients, no relationship was apparent between the
change in mean blood pressure and change in PRA.
Curtis et al.28 and Gavras et al.29 noted a wide range of
values for resting PRA in heart failure patients receiving diuretics, with many patients having quite high
levels. They postulated a role of renin in maintaining
the abnormally high peripheral resistance observed in
heart failure and noted hemodynamic improvement
with inhibition of the renin-angiotensin system. These
observations suggest that activation of the reninangiotensin system may tend to counteract the
vasodilator effect of hydralazine in CHF, and could
also contribute to sustained renal vasoconstriction.
The combination of a converting enzyme inhibitor
with hydralazine might therefore be appropriate for
vasodilator therapy in heart failure. The rapidity of
onset of changes in PRA and the duration of effect
have not been studied, and our data are far too few to
help define the time course of changes in PRA.
In this study, neither weight loss nor diuresis occurred
during the 3-day hydralazine period, despite the effect
on creatinine clearance. Our patients were considered
stable and reasonably well compensated before entry
into the study. It is entirely possible that hydralazine
administration to patients with CHF and acute
volume overload would initiate or enhance diuresis.
However, because of the instability of patients with
volume overload during hospitalization, the present
study was limited to patients who were relatively free
of edema.
The decrease in serum osmolality that occurred
with hydralazine is probably related to changes in
serum sodium concentration. Increased sodium excretion or water retention or both could alter the serum
sodium concentration and the osmolality. As we noted
no increase in body weight or decrease in urine output,
RENAL RESPONSE TO HYDRALAZINE IN CHF/Pierpont et al.
Downloaded from http://circ.ahajournals.org/ by guest on April 30, 2017
the slight (but statistically insignificant) increase in
sodium excretion may be the major reason for the
decrease in osmolality.
The absence of a significant decrease in blood
pressure or increase in heart rate is consistent with
previous observations with hydralazine in heart
failure."' 2 The dose of hydralazine chosen has been
confirmed effective in increasing cardiac output, which
allows systemic vascular resistance to fall without
changing blood pressure significantly. Although we
did not measure central hemodynamics, it is
reasonable to presume that similar responses were attained in the patients in this study.
In summary, our data show improved renal function during hydralazine administration in patients
with CHF, as manifested by increased creatinine
clearance. Although an occasional patient may tend to
retain sodium in response to hydralazine, this apparently is confined to patients whose blood pressure
falls. Although our data suggest that sodium retention
is not likely to be an important factor in the majority
of patients, the patients in our study received
hydralazine only for a period of 3 days. Extrapolation
of these findings to chronic therapy must be made with
caution, and the efficacy of long-term hydralazine
therapy in CHF remains to be established by longterm, controlled clinical trials.
Acknowledgment
We gratefully acknowledge the technical assistance of Irene
LaSota and secretarial help of Margaret Chelmo.
10.
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Effect of hydralazine on renal failure in patients with congestive heart failure.
G L Pierpont, D C Brown, J A Franciosa and J N Cohn
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Circulation. 1980;61:323-327
doi: 10.1161/01.CIR.61.2.323
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1980 American Heart Association, Inc. All rights reserved.
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