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The relationship of urinary potassium excretion to dietary sodium content in cardiac patients receiving oral diuretics∗
The
Relationship
Excretion Cardiac
of Urinary
to Dietary Patients
IRWIN S. ESKWITH,
M.D.,
F.A.c.c.,
Sodium
Receiving
Content
Oral
in
Diuretics*
JOHN J. LAWRENCE, M.D. and THOMAS MCLOUGHLIN, M.D.t Bridgeport,
Connecticut
the related drug, chlorphthalidone (HygrotorP). It was believed that this would be of interest because of the known increase in digitalis toxicity It was also believed when potassium loss occurs. that such a study might clarify the relationship, if any, of sodium intake to potassium loss.
INTRODUCTION of the chlorothiazide group of diuretics has relieved many patients of the necessity for frequent injections of parenterally active diuretics. Along with this advantage, however, the chlorothiazide preparations have been found to exert, at times, a The great rather marked kaliuretic effect.’ majority of patients using chlorothiazide aiso take digitalis. Since it is well known that digitalis and potassium are antagonistic in their actions upon the myocardium,2 potassium loss increases the possibilities for digitalis intoxication. There have been reports in the literature that sodium is potassium sparing.3 Other reports state that the primary cause of this potassium loss appears to be an alteration in renal tubular function and it does not depend solely upon sodium intake or upon the frequency of chlorothiazide dosage.4 Talbot et a1.5 have stated that hypokalemiaper se does not necessarily result in maximal conservation of potassium by the kidneys. On the other hand, depletion of cellular sodium stores usually does lead to conservation of this ion by the kidneys. Talbot has also stated that the body is unable to conserve cellular potassium stores when deprived of potassium unless the sodium intake is also restricted sharply. Fuchs et al.6 have stated conversely that potassium excretion appeared to be spared to some degree during a study on increasing sodium intake in the diet. The purpose of this study was to determine whether, in the presence of varying amounts of salt in the diet, potassium loss in the urine could be altered in patients taking chlorothiazide or
T
Potassium
HE
MATERIALS AND METHODS The patients selected for this study were hospitalized patients with cardiac disease on the medical wards of St. Vincent’s Hospital. All were studied during a 10 day period. The patients were divided into two groups. Group 7 was composed of eleven patients. Six of these had been in congestive heart failure prior to the start of the experiment and had been receiving one of two oral diuretics up to the time the study began. Five were in minimal heart failure and showed no gross peripheral edema. All were semiambulatory except for two patients (Cases 10 and ll), who had suffered recent myocardial infarctions. Six patients in the group received (Hygroton) daily 100 mg. of chlorphthalidone and five received 500 mg. of chlorothiazide (Diuril%) daily. Both drugs were administered for the full study period of 10 days. During the first 5 days of study, the patients were maintained on a diet which contained 10 gm. of sodium chloride. To this were added 5 gm. of salt in the form of tablets, for a total daily sodium chloride intake of 15 gm. or 660 mEq. During the second 5 days, the salt content of the diet was reduced to 0.5 gm. daily or 22 mEq. The initial diet contained approximately 5 gm. or 128 mEq. of potassium and the low salt diet somewhat less, approximately 70 In two patients it was necessary to deviate mEq. somewhat from this regimen. A thoracentesis was performed in one patient (Case 5) because of a persistent left pleural effusion. In another (Case 7), it was necessary to discontinue the diuretic and add
* From the Department of Medicine, St. Vincent’s Hospital, Bridgeport, Connecticut. Aid for this study was furnished by the Geigy Chemical Company, Merck Sharp and Dohme Research Laboratories, and the Connecticut Chapter of the American Heart Association. t Prrsent address, Danbury, Connecticut. 194
THE AMERICANJOURNAL
OF CARDIOLOGY
Potassium
Excretion,
Sodium
Intake
and
Oral
195
Diuretics
TABLE I 24 Hour Urine Volumes and Electrolytes
Group 1.
(mEq./L.)
0.5 gm. NaCl Diet
15 gm. NaCl Diet
-
-
2 3 4 5 6 7 8 9 IO 11 Mean valuer
Sodium
Potassium
59.4 113.0 121.6 253.0 251.0 32.0 286 0 376 0 117.0 209.6 182.0 181.2
40.0 74.9 61.8 115.0 51.0 164.2 101.3 72.0 59.0 85.0 92.0 83.3
2:480 2,330 3,810 1.630 1,265 2,690 2,550 980 2,172 2.900 2.116
Chloride
Volume (cc.)
84.9 134.5 115.4 264.0 231 .O 87.8 261 .O 366.5 136.6 174.3 180.0 185.6
1,290 2,450 2,030 3,810 3,740 1,435 2,285 1,535 1,004 2,460 2,060 2,203
Sodium
Potassium
Chloride
Diuretic
43.2 140.5 52.4 156.0 512.5 60.6 123.0 50.1 94.0 107.0 65.0 127.7
36.2 63.5 82.8 131 .o 76.9 86.4 84.0 61.3 52.0 68.0 81 .O 74.8
84.9 105.0 86.3 125.0 309.0 80.1 103.8 71.9 32.5 109.2 66.0 127.8
Chlorphthalidone Chlorphthalidone Chlorphthalidone Chlorpthalidone Chlorpthalidone Chlorpthalidone Chlorothiazide Chlorothiazide Chlorothiazide Chlorothiazide Chlorothiazide
-
potassium supplements to the regimen because of clinical and laboratory evidence of hypokalemia. Group 2 consisted of four patients. Two were maintained on a low salt diet for 10 days and given one of the diuretics in the above mentioned dosage for The remaining two patients the second 5 days. received the high sodium chloride diet for 10 days with a similar addition of a diuretic during the last half of their observation period. In addition, daily serum electrolyte studies were performed on seven patients in group 1. Twentyfour hour urine specimens were collected on the wards and sent to the chemical laboratory where total urine volume was measured. The sodium and potassium content of the urine was determined with Chlothe Baird-Atomic flame spectrophotometer. rides were determined by the method of Schales and &hales. Six patients in group 1 received chlorphthalidone and five chlorothiazide. In group 2 the diuretics were .equally distributed.
Table
I shoM-s the mean
volumes
and
chloride 5-day
excretion
urine
values
volume.
for the entire equal
It
to patient
mean
intake. on
the
The 15 gm.
FEBRUARY 1962
urine
sodium
and
patients
may
be
is marked
intake. first mEq.
The 5 days on the
observed
mean was
83.3
0.5
gm.
It was thought paper
excretion
mEq. NaCl
This
sured for each patient.
for the to
to include
in the four quantities
The daily variation
1=---+-----*-+---c____---_
150
fell
74.8
diet.
inconvenient
the variations
160
potassium
in this
meain uri-
___d
L
in each that
from
variation
in
of these substances and in the The mean value for the latter, as a whole,
dietary
an 87 cc. increase
of 24 hour
there
group
on both
values
potassium,
for the eleven
period.
patient the
urinary
182.1 mEq. per 24 hours. This fell to 120.9 on the low salt diet, a value not unexpected in view of the known tendency of urinary sodium to vary directly with the amount ingested. The chloride pattern followed the sodium pattern quite closely, falling from 181.2 mEq. on the high salt intake to 127.0 mEq. on the low salt
400
RESULTS
-
regimens,
is approximately there
being
on the 0.5 gm. sodium
mean
sodium
sodium
excretion
chloride
diet,
only
chloride
was higher averaging
FIG. 1. Case 7 (Group 1). sodium and chloride. C.T. explanation in text.
Excretory pattern of water, = chlorothiazide. Further
196
Eskwith, Lawrence
I
POTASSIUM
SODIUM
%
I 1000 900
-
.
-
600
-
700
-
600
.
%
I
+ 100
I I
+ 75
I I
-
.
400-
.
0 0.
300
-*
.
200
1 1
25 .
.
l o-**
.
.
.
I ’ I I I I
.
. -*
.
-
25
-
50
.
l
l* l*
2 1
+
t
0
le
100
55
1 . t
I 500
+
POTASSIUM
t
I I
-
and McLaughlin
I
FIG. 2. Percentage variations in sodium and potassium excretions in each patient of Group 1 during the entire 10 day period.
nary volume and sodium chloride content were quite marked although in each patient, with one exception (Case 6) potassium excretion remained relatively constant. Figure 1 is a graphic exposition of these data in a typical patient in the It can be seen that the potassium curve series. is relatively flat while abrupt peaks and valleys typify the patterns of urine volume and sodium chloride content. It is also clear that in this patient the salt content of the urine varied more with urine volume than it actually did with salt intake. Figure 2 demonstrates the maximal variations percentagewise in sodium and potassium excretion during a IO-day period in each patient. This was calculated by finding the lowest and the highest excretion of sodium and potassium during the 1 O-day period. The former was subtracted from the latter and the difference recorded as a percentage increase over the lowest amount excreted. The daily sodium content of the urine in these patients varied from 100 to 1,000 per cent. The horizontal line, which represents the mean, shows an average variation of 430 per cent for the group as a whole so far as sodium excretion is concerned. On the other hand, the variation in potassium excretion during the lo-day period was much less marked, with most of the dots clustered closely about the mean of 120 per
FIG. 3. Difference in mean potassium excretion for each 5 day period in each patient of Group 1. If mean potassium excretion was greater on the high NaCl diet, the difference is charted as positive; if less, as negative.
cent. Only one patient (Case 6) deviated markedly from this, showing a variation in his potassium excretion of 400 per cent. Figure 3 is a graphic presentation of the difference in mean potassium excretion in each 5-day period. Actually, the same data are tabulated in Table I. If potassium excretion was higher on the 15 gm. sodium chloride diet, the percentage is shown as positive. Conversely, a lesser excretion on this diet is recorded as negative. The mean excretion of +16.5 per cent reveals a slightly greater mean potassium excretion on the high salt diet. However, eliminating the rather atypical Case 6 lowers this to +9 per cent, a figure which is not believed to be significant. One patient (Case 5) showed a moderate diuresis throughout the first 4 days of the study. On the fifth day a left thoracentesis was performed which yielded 650 cc. of fluid. Following this, a rather
spectacular diuresis occurred resulting in a 5,000 cc. urinary output (Fig. 4). Concomitantly, sodium and chloride excretion increased, although potassium excretion was unchanged. This case illustrates quite well at least one of the benefits that may accrue to the patient with cardiac disease from a timely thoracentesis. Figure 4 not only illustrates
the diuresis and natriuresis but vividly confirms the marked constancy of potassium excretion. Another patient (Case 6) has already been alluded to. Figure 5 illustrates the constantly high potassium excretion which was present from the start of THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Potassium
Excretion,
Sodium
Intake
and Oral
o---o ---K 130
Diuretics
197
Na Cl
--6-e “c----_
--A----o
115 160 140
-
h-
120 110 100 soIO5o600
-
600
-
400
-
200
o-
6000
-
5000
k
w
f
i
;
t \
4000 3000
=
2
$
2000
IO00
1
1
---t’-‘-I I
I 2
I 3
I 4
I 5
I 6
I 7
I 6
I 9
I IO
DAYS FIG. 4.
pattern.
5. The effect of a thoracentesis (indicated Note constancy of potassium excretion.
Case
the experiment. It also reveals the rather low serum potassium which was also initially present. On the eighth day this fell to a dangerously low level of 1.5 The patient had marked weakness, almEq. per L. though he did not show electrocardiographic changes. The diuretic was discontinued and the serum levels, with the aid of potassium supplements, climbed to On the ninth and tenth day, the safer levels. urinary potassium content showed a marked fall. This was the only patient who showed this peculiar pattern. Interestingly, serum sodium and chloride levels were also rather low throughout the test period. The patient showed no gross evidence of blood urea nitrogen on two renal dysfunction ; FEBRUARY
1962
occasions was tained neither GROUP
by arrow) on urinary
13 mg. protein
per cent and the urine nor formed elements.
con-
2
Table II summarizes the results obtained in patients maintained on one of the two diets for 10 days. During the second 5 days they received one of the two oral diuretics. Two patients in group 2 received the low salt diet. As was expected the sodium chloride content of the urine was low during the first 5 days. When the diuretic was given, a moderate (66 per cent) increase in mean urinary output resulted, but
Eskwith,
198
La\vrencc
and
McLaughlin
-
No
---K
Cl
165.H----‘__
*
*e-L---
_---
I
I
I
I
I
I
I
I
I
I
I
2
3
4
5
6
7
8
9
IO
DAYS FIG. 5. Case 6. Urinary and serum electrolyte patterns. Note low serum levels of all electrolytes and high levels of urinary potassium. Chlorphthalidone (C.P.) was discontinued on the eighth day and supplementary potassium administered orally.
there were marked increases in sodium and chloride excretion (600 and 420 per cent, respectively). Potassium excretion also increased, but to a lesser extent, namely 145 per cent. Figure 6 depicts this change in one patient (Case 13). The two members of group 2B, ingesting the higher salt diet, showed urinary outputs that compared favorably with the first two members of this group. The salt diet during the first 5 days was higher than that for the patients in group 2A. However, when the two patients in group 2B were given the diuretic, the urine volume increased only 22 per cent, although the absolute amount was somewhat greater than
Sodium the average for the first two subjects. increased only 19 per cent, chloride 28 per cent and potassium increased more than either of the first two substances, i.e., increasing 51 per cent. Table III gives the range between the highest and lowest serum electrolyte concentrations recorded, as determined for each of the seven patients in group 1, and the calculated mean variations. These were 12.0 mEq. for sodium, 11.7 mEq. for chloride and 2.1 mEq. for potassium. Fortunately, only one patient (Case 6) had signs of hypokalemia. In several other patients, scattered readings as low as 3.5 mEq. per L. were obtained. These seemed to be sporadic, did not THE
AMERICAN
JOURNA”
OF
CARDIOLOGY
Potassium
Excretion,
Sodium
Intake
and Oral
199
Diuretics
TABLE II Group 2. Without
24 Hour Urine Volumes
and Electrolytes
(mEq./L.) With Diuretic
Diuretic
(A) 0.5 gm. NaCl Diet
12
1,475
13
a77
Mean Per cent increase on diuretic
1,173
27
36
29.2
1,962
81
10.5
36.5
20.5
1,766
191.6
81.9
186.5
19.3
36.3
24.9
1,864 66
136.0 600
90.5 145
129.8 420
(B) 75 gm. N&l 14
2,760
15
888
Mean Per cent increase on diuretic
form
1,824
diet
208.6
3,355
273.5
125.0
305.1
43.0
49.0
39.0
1,310
77.0
77.0
84.6
105.0
79.0
123.8
2,332 22
125.3 19
101 .o 28
/
/ pattern,
or the duration
and
I were
not related
of the experiment.
COMMENTS
e-0
e
NO
---Cl -K IJOc--+---4---__
Y Km -
--c--L--__
I
Chlorothiazide Chlorphthalidone
Diet
109.0
The choice of a lo-day study for each patient divided into two equal phases seemed desirable
5
73
266.0
..
a continuous
to either
109
I
Chlorothiazide Chlorphthalidone
194.8 51
I
I
I
for several reasons. The cooperation of the patient is often inversely proportional to the length of time required for an experiment. This period not only assured adequate cooperation, but similar observations are applicable to the nursing and laboratory staffs. This relatively short interval of surveillance did possess the disadvantage of not permitting observation of long-term trends which would have been particularly advantageous in the second group of patients. Two diuretics were used to broaden the study. It is not believed that any significant TABLE III Electrolyte
Variations
Case No. 1
FIG. 6. Case 13. Note upward surge of urinary volume and electrolytes when chlorothiazide (C.T.) was administered. Low urinary salt levels prior to diuresis are striking. FEBRUARY 1962
2 3 4 5 6 7
Mean
-I
in Serum (mEq./L.)
-
-
Sodium
Chloride
Potassium
7.0 13.0 10.0 18.0 10.0 8.0 18.0 12.0
8.7 6.0 12.6 9.0 19.0 3.7 23.0 11.7
2.0 0.8 2.8 2.6 3.2
-
1.9 1.4 2.1
-
200 difference
Eskwith,
Lawrence
exists in the action of the various thiazide and phthalidone preparations. The relationship, if any, of sodium content of the diet and sodium excretion to that of urinary potassium content has been the subject of several recent papers. As was mentioned earlier, Lown3 believes that salt restriction may actually aggravate potassium loss. Berliner et al.* suggest that potassium and hydrogen compete for various cations to permit sodium reabsorption by the renal tubule, the so-called exchange hypothesis. Such competition, between hydrogen and potassium, seems somewhat unequal for the latter. The available supply of hydrogen ion would appear to be much greater than that of potassium because of the small amount of potassium normally found in serum as opposed to the readiness with which carbonic anhydrase can furnish available hydrogen ions. Lesser and his colleagues* have stated that potassium loss may be accentuated in patients given mercurial diuretics when they have been maintained on a low salt diet. Anderson and Larraghg found little change in potassium excretion in human subjects or dogs when sodium was restricted. In potassium depleted subjects, or those unable to have ingested an adequate amount of potassium for a period of time, both Talbot5 and RandalllO and their co-workers state that sodium restriction is necessary to conserve body stores of potassium. However, their subjects were mainly patients who underwent surgery and who were unable to ingest food, circumstances not often encountered in patients with cardiac disease. Factors Affecting Urinary Potassium Excretion: Body mechanisms determining the urinary content of potassium are poorly understood. It has been known that conservation mechanisms for this mineral are less efficient than those for Dietary restriction of the latter, for sodium. example, may result in urinary sodium falling to minimal levels,” an observation readily apparent in one patient (Case 13) of group 2 (Fig. 6). However, such near complete reabsorption of potassium does not occur, and potassium excretion will continue at a fairly steady state for sometime after the substance has been withdrawn from the diet. When one deals with patients with cardiac disease who may have some physiologic renal disturbance and adds to their regimen a diuretic, the situation becomes somewhat more complex. The kaliuretic effect of the chlorothiazide group of diuretics has been well documented.12J3
and McLaughlin However, this loss may not be particularly serious unless rather large doses are administered to the patient.14rn The kaliuretic effect of these substances may also be dependent upon the state of the patient at the time administration has begun. The patients in group 1 for example, had either received diuretics up to the time of the experiment or else had been in early congestive heart failure with minimal edema. The previous diet of this latter group had not featured sodium restriction. Once in the experiment, they initially received a rather high salt diet. In each case, the patient’s potassium excretion remained relatively constant even when the change was made to a lower content of salt, with the outstanding exception of one patient (Case 6). This patient showed a marked kaliuresis while on a Iow salt diet, and also failed to maintain his serum electrolytes at a satisfactorily high level. Apart from this patient, alternation in diet while the diuretic was continued had little effect on potassium excretion. The slight increase in the mean excretion, as expressed in Figure 5, on the high salt diet is really due to one patient (Case 6). Also, although the absolute amount of potassium excreted on the high salt diet was somewhat higher, the percentage of potassium excreted in relation to intake was actually somewhat higher on the low salt regimen. We believe, therefore, that when potassium intake is adequate, changing the salt content of the diet does not alter potassium excretion at all. Since even our low salt diet contains adequate potassium, approximately 3,000 mg. (about 70 mEq.), fear of excessive potassium loss due to renal tubular mechanisms seems unwarranted. Factors Affecting Sodium Chloride Excretion: Sodium and chloride patterns paralleled each other and as might be expected, showed a marked fall on the low salt diet. This seems somewhat contradictory to the hypothesis that restricting dietary sodium and permitting adequate fluid will result in a rapidly developing negative sodium balance. Considering that aldosterone secretion is inversely proportional to the amount of sodium ingested, it might well be that sodium restriction actually favors sodium retention. It is also clear that ingestion of large amounts of salt did not inhibit diuresis, the mean urinary volumes being equal in both phases of group 1. In group 2 the mean urinary excretion was THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Potassium
Excretion,
Sodium
lower in the patients adhering to a low salt diet with no diuretic than in those adhering to a high salt diet with no diuretic. Our figures show that in general, sodium chloride and water excretion were directly proportional. The changes in the urine in one patient (Case 5), for example, vividly illustrate this. Figure 4 depicts a marked diuresis and natriuresis following thoracentesis. This figure also illustrates the independence of potassium output. Low Salt Diet and Potassium Excretion: The second group of patients presented a marked contrast to the first. The first two patients of group 2 (Cases 12 and 13) were placed on a diet containing 0.5 gm. of NaCl for 10 days. During the last half, one of the two diuretics was administered. This resulted not only in a marked diuresis but a pronounced increase in the excretion of sodium chloride, and to a lesser extent, of potassium. It is probable that this effect represented a summation of the effects of increased endogenous aldosterone excretion and the administration of the diuretic. Figure 6 (Case 13) demonstrates these changes. On the other hand, the addition of a diuretic to the two patients (Cases 14 and 15) on a high salt diet enhanced the excretion of the three substances only moderately above the prediuretic levels. Urinary volume in both groups in each phase was approximately equal. Although the number of patients in each of these subgroups is small, it would appear that the previously low salt diet favors increased potassium excretion at the start of a diuretic regimen. It is probable, however, that after this initial outpouring of electrolytes, excretion of these substances gradually diminishes and descends to a lower plateau, corresponding to the behavior of the eleven patients in group 1. This lessening of the kaliuretic effect of chlorothiazide and related diuretics as time goes by has been suggested by others.*6 Serum Electrolyte Levels: The relative constancy of serum sodium and chloride levels was quite different from the variability of urinary excretion. It is clear that serum sodium and chloride levels represent a staunch homeostatic mechanism, not easily disturbed. Because of this, it is believed that determination of these levels gives scant indication of sodium chloride balance or body salt content. Daily serum electrolyte determinations, therefore, were discontinued after having been performed on the first seven patients of group 1. Serum potassium, as Table III reveals, showed variations that FEBRUARY
1962
Intake
and
Oral
Diuretics
201
were of sufficient magnitude to present a potential hazard to the patient. Fortunately, with one exception, the occasional low levels encountered did not persist. Interestingly, no level was found above 5.5 mEq. per L. in any patient. It is suggested that in patients receiving diuretics of any kind, occasional serum potassium levels be obtained, and if found to be abnormal, repeated. This would seem particularly important at the start of therapy. The marked diuresis that occurred in one patient (Case 5) following thoracentesis demonstrates another good reason for timely thoracentesis in decompensated patients with cardiac disease. The bizarre electrolyte pattern, both in the serum and urine, shown in Figure 5, is not readily explicable. There is no evidence on the basis of the clinical investigation of the patient that the kidney was at fault during the period of study.
SUMMARYAND CONCLUSIONS In eleven patients who had been previously given chlorothiazide or chlorphthalidone and who were in minimal heart failure, changes in salt content of the diet did not affect the potassium content of the urine. In each patient except one, this seemed to maintain itself at a fairly steady rate. It is believed that all of the mechanisms responsible for the potassium levels in the urine are not known at present. However, there would seem to be no danger in giving rather large amounts of salt to patients ingesting diets containing potassium. When patients have not received previous diuretics, the administration of these drugs results in increased content of sodium, chloride and potassium in the urine. This is particularly marked in patients who had previously received a low (0.5 gm.) salt diet. It is assumed that this marked kaliuresis falls and levels off as medication is continued. There was no evidence that a high salt diet interfered with diuresis. Actually, urine volume seemed altered in this study chiefly by the administration of the diuretic rather than the diet, and in general urine sodium chloride varied directly with urine volume. Marked reduction in dietary sodium resulted in prompt and equally severe restriction of sodium excretion. This latter reduction was not reversed until a diuretic was administered. It was not believed, therefore, that the average low sodium diet results by itself in a rapidly effective net sodium balance. It is further
Eskwith, Lawrence
202
hypothesized that such sodium dietary restriction leads to increased aldosterone production, augmenting sodium retention. Finally, serum sodium and chloride levels give no indication of sodium balance and are of limited value. On the other hand, serum potassium studies are of considerable importance. The low serum level of this anion makes minor variations relatively important. It is suggested, therefore, that patients receiving diuretics, i.e., mercurial as well as thiazide, should have occasional serum potassium determinations. ACKNO\YLEDGMENTS
Our special thanks are due to Mrs. Mary Jean Steere, technician in the chemistry laboratory, for her untiring interest and work in behalf of this experiment, and to Miss Lourdes Santos. head dietitian, for her careful attention to the diets of the patients used in this study. Our thanks are also due to Dr. Franklin Epstein, Associate Professor of Medicine, Yale University, for his careful review of, and helpful COINSments concerning this paper. REFERENCES Review of the thiazides. In: Hyper1. FUCHS, M. tension, p. 534. Edited by Moyer, J. Philadelphia, 1959. W. B. Saunders Co. 2. ENSELBERG, C. D., SIMMONS, H. C. and MURITZ, A. A. Effects of potassium upon the heart with special reference to possibility of treatment of Am. Heart J., toxic arrhythmias due to digitalis. 39: 713, 1950. 3. LOWN, B. Potassium and digitalis, In: Digitalis, A Symposium, pp. 167-186. Edited by Dimond, E. Springfield, Ill., 1957. Charles C Thomas. 4. BERLINER, R. W., KENNEDY, T. J., JR. and ORLOFP, J. Relationship bctwcen acidification of urine
and McLaughlin
5.
6.
7.
8.
9.
IO.
11. 12.
and potassium metabolism: effect of carbonic anhydrase inhibition on potassium excretion. Am. J. Med.. 11: 274, 1951. TALBOT, .4. B:, RITCH~E, R. H. and CRAWKIRD, J. D. Metabolic Homeostasis: A Syllabus for Those Concerned with the Care of Patients. Cambridge, Mass., 1959. Harvard University Press. FUCHS, hl., NEWMAN, B. E. and SNYDER, D. Effect of variable salt intake on the electrolyte response to diuretics. In: Edema, A Symposium, pp. 192~195. Edited by Moyer, J. H. and Fuchs, M. Philadelphia, 1960. W. B. Saunders Co. &HALES, 0. and SCMLES, S. S. A simple and accurate method for determination of chloride in biological fluids. J. Biol. Chern., 140: 879, 1941. LESSER. G. T.. DUNNIXG. hl. F.. EPSTEIN. F. H. and BEYER, IS. %. Merc&ial diwesis in’edematous patients. Circulation, 5: 85, 1952. ANDERSON, H. M. and LARRAGH, .J. H. Renal excretion of potassium in normal and sodium depleted dogs. J. C/in. huest., 37: 323, 1958. RANDALL, H. T., HABIF, D. V., LOCKM~OOD, J. S. and WRRNER, S. C. Potassium deficiency in Stcrgey, 26: 341, 1949. surgical patients. STATLAND, H. Fluid and Electrolytes in Practice, p. 32. Philadelphia, 1954. J. B. Lippincott Co. SLATER, J. H. D. and NABARRO, .I. D. N. Clinical experience with chlorothiazide. Imcrt, 1 : 224
1958. 13. SCHREINER? G. E. and BLOOUER, H. i\. Effect of chlorothiazide on edema of cirrhosis nephrosis, congestive heart failure, and chronic renal insufficiency. I\‘PW England J. 12/led., 257: 1016, 1957. 14. FORD, R. V. Limitations and potential and actual side effects of thiazide derivatives. In: Edema, Mechanisms and Management, pp. 289-298. Edited by Moyer, J. H. and Fuchs, M. Philadelphia, 1960. W. B. Saunders Co. 15. GROSS~~AN, I. Electrolyte abnormalities associated with mercurial, thiazide and carbonic anhydrase In reference 14, pp. -inhibiting diuretics. 292-298. 16. FORD, R., MOYER, I. and SPURR, C. Clinical and and laboratory observation on chlorothiazide (Diuril). Arch. Znt. Med., 100: 582, 1957.
THE AMERICAN JOURNAL OF CARDIOLOGY
Relationship
Excretion Cardiac
of Urinary
to Dietary Patients
IRWIN S. ESKWITH,
M.D.,
F.A.c.c.,
Sodium
Receiving
Content
Oral
in
Diuretics*
JOHN J. LAWRENCE, M.D. and THOMAS MCLOUGHLIN, M.D.t Bridgeport,
Connecticut
the related drug, chlorphthalidone (HygrotorP). It was believed that this would be of interest because of the known increase in digitalis toxicity It was also believed when potassium loss occurs. that such a study might clarify the relationship, if any, of sodium intake to potassium loss.
INTRODUCTION of the chlorothiazide group of diuretics has relieved many patients of the necessity for frequent injections of parenterally active diuretics. Along with this advantage, however, the chlorothiazide preparations have been found to exert, at times, a The great rather marked kaliuretic effect.’ majority of patients using chlorothiazide aiso take digitalis. Since it is well known that digitalis and potassium are antagonistic in their actions upon the myocardium,2 potassium loss increases the possibilities for digitalis intoxication. There have been reports in the literature that sodium is potassium sparing.3 Other reports state that the primary cause of this potassium loss appears to be an alteration in renal tubular function and it does not depend solely upon sodium intake or upon the frequency of chlorothiazide dosage.4 Talbot et a1.5 have stated that hypokalemiaper se does not necessarily result in maximal conservation of potassium by the kidneys. On the other hand, depletion of cellular sodium stores usually does lead to conservation of this ion by the kidneys. Talbot has also stated that the body is unable to conserve cellular potassium stores when deprived of potassium unless the sodium intake is also restricted sharply. Fuchs et al.6 have stated conversely that potassium excretion appeared to be spared to some degree during a study on increasing sodium intake in the diet. The purpose of this study was to determine whether, in the presence of varying amounts of salt in the diet, potassium loss in the urine could be altered in patients taking chlorothiazide or
T
Potassium
HE
MATERIALS AND METHODS The patients selected for this study were hospitalized patients with cardiac disease on the medical wards of St. Vincent’s Hospital. All were studied during a 10 day period. The patients were divided into two groups. Group 7 was composed of eleven patients. Six of these had been in congestive heart failure prior to the start of the experiment and had been receiving one of two oral diuretics up to the time the study began. Five were in minimal heart failure and showed no gross peripheral edema. All were semiambulatory except for two patients (Cases 10 and ll), who had suffered recent myocardial infarctions. Six patients in the group received (Hygroton) daily 100 mg. of chlorphthalidone and five received 500 mg. of chlorothiazide (Diuril%) daily. Both drugs were administered for the full study period of 10 days. During the first 5 days of study, the patients were maintained on a diet which contained 10 gm. of sodium chloride. To this were added 5 gm. of salt in the form of tablets, for a total daily sodium chloride intake of 15 gm. or 660 mEq. During the second 5 days, the salt content of the diet was reduced to 0.5 gm. daily or 22 mEq. The initial diet contained approximately 5 gm. or 128 mEq. of potassium and the low salt diet somewhat less, approximately 70 In two patients it was necessary to deviate mEq. somewhat from this regimen. A thoracentesis was performed in one patient (Case 5) because of a persistent left pleural effusion. In another (Case 7), it was necessary to discontinue the diuretic and add
* From the Department of Medicine, St. Vincent’s Hospital, Bridgeport, Connecticut. Aid for this study was furnished by the Geigy Chemical Company, Merck Sharp and Dohme Research Laboratories, and the Connecticut Chapter of the American Heart Association. t Prrsent address, Danbury, Connecticut. 194
THE AMERICANJOURNAL
OF CARDIOLOGY
Potassium
Excretion,
Sodium
Intake
and
Oral
195
Diuretics
TABLE I 24 Hour Urine Volumes and Electrolytes
Group 1.
(mEq./L.)
0.5 gm. NaCl Diet
15 gm. NaCl Diet
-
-
2 3 4 5 6 7 8 9 IO 11 Mean valuer
Sodium
Potassium
59.4 113.0 121.6 253.0 251.0 32.0 286 0 376 0 117.0 209.6 182.0 181.2
40.0 74.9 61.8 115.0 51.0 164.2 101.3 72.0 59.0 85.0 92.0 83.3
2:480 2,330 3,810 1.630 1,265 2,690 2,550 980 2,172 2.900 2.116
Chloride
Volume (cc.)
84.9 134.5 115.4 264.0 231 .O 87.8 261 .O 366.5 136.6 174.3 180.0 185.6
1,290 2,450 2,030 3,810 3,740 1,435 2,285 1,535 1,004 2,460 2,060 2,203
Sodium
Potassium
Chloride
Diuretic
43.2 140.5 52.4 156.0 512.5 60.6 123.0 50.1 94.0 107.0 65.0 127.7
36.2 63.5 82.8 131 .o 76.9 86.4 84.0 61.3 52.0 68.0 81 .O 74.8
84.9 105.0 86.3 125.0 309.0 80.1 103.8 71.9 32.5 109.2 66.0 127.8
Chlorphthalidone Chlorphthalidone Chlorphthalidone Chlorpthalidone Chlorpthalidone Chlorpthalidone Chlorothiazide Chlorothiazide Chlorothiazide Chlorothiazide Chlorothiazide
-
potassium supplements to the regimen because of clinical and laboratory evidence of hypokalemia. Group 2 consisted of four patients. Two were maintained on a low salt diet for 10 days and given one of the diuretics in the above mentioned dosage for The remaining two patients the second 5 days. received the high sodium chloride diet for 10 days with a similar addition of a diuretic during the last half of their observation period. In addition, daily serum electrolyte studies were performed on seven patients in group 1. Twentyfour hour urine specimens were collected on the wards and sent to the chemical laboratory where total urine volume was measured. The sodium and potassium content of the urine was determined with Chlothe Baird-Atomic flame spectrophotometer. rides were determined by the method of Schales and &hales. Six patients in group 1 received chlorphthalidone and five chlorothiazide. In group 2 the diuretics were .equally distributed.
Table
I shoM-s the mean
volumes
and
chloride 5-day
excretion
urine
values
volume.
for the entire equal
It
to patient
mean
intake. on
the
The 15 gm.
FEBRUARY 1962
urine
sodium
and
patients
may
be
is marked
intake. first mEq.
The 5 days on the
observed
mean was
83.3
0.5
gm.
It was thought paper
excretion
mEq. NaCl
This
sured for each patient.
for the to
to include
in the four quantities
The daily variation
1=---+-----*-+---c____---_
150
fell
74.8
diet.
inconvenient
the variations
160
potassium
in this
meain uri-
___d
L
in each that
from
variation
in
of these substances and in the The mean value for the latter, as a whole,
dietary
an 87 cc. increase
of 24 hour
there
group
on both
values
potassium,
for the eleven
period.
patient the
urinary
182.1 mEq. per 24 hours. This fell to 120.9 on the low salt diet, a value not unexpected in view of the known tendency of urinary sodium to vary directly with the amount ingested. The chloride pattern followed the sodium pattern quite closely, falling from 181.2 mEq. on the high salt intake to 127.0 mEq. on the low salt
400
RESULTS
-
regimens,
is approximately there
being
on the 0.5 gm. sodium
mean
sodium
sodium
excretion
chloride
diet,
only
chloride
was higher averaging
FIG. 1. Case 7 (Group 1). sodium and chloride. C.T. explanation in text.
Excretory pattern of water, = chlorothiazide. Further
196
Eskwith, Lawrence
I
POTASSIUM
SODIUM
%
I 1000 900
-
.
-
600
-
700
-
600
.
%
I
+ 100
I I
+ 75
I I
-
.
400-
.
0 0.
300
-*
.
200
1 1
25 .
.
l o-**
.
.
.
I ’ I I I I
.
. -*
.
-
25
-
50
.
l
l* l*
2 1
+
t
0
le
100
55
1 . t
I 500
+
POTASSIUM
t
I I
-
and McLaughlin
I
FIG. 2. Percentage variations in sodium and potassium excretions in each patient of Group 1 during the entire 10 day period.
nary volume and sodium chloride content were quite marked although in each patient, with one exception (Case 6) potassium excretion remained relatively constant. Figure 1 is a graphic exposition of these data in a typical patient in the It can be seen that the potassium curve series. is relatively flat while abrupt peaks and valleys typify the patterns of urine volume and sodium chloride content. It is also clear that in this patient the salt content of the urine varied more with urine volume than it actually did with salt intake. Figure 2 demonstrates the maximal variations percentagewise in sodium and potassium excretion during a IO-day period in each patient. This was calculated by finding the lowest and the highest excretion of sodium and potassium during the 1 O-day period. The former was subtracted from the latter and the difference recorded as a percentage increase over the lowest amount excreted. The daily sodium content of the urine in these patients varied from 100 to 1,000 per cent. The horizontal line, which represents the mean, shows an average variation of 430 per cent for the group as a whole so far as sodium excretion is concerned. On the other hand, the variation in potassium excretion during the lo-day period was much less marked, with most of the dots clustered closely about the mean of 120 per
FIG. 3. Difference in mean potassium excretion for each 5 day period in each patient of Group 1. If mean potassium excretion was greater on the high NaCl diet, the difference is charted as positive; if less, as negative.
cent. Only one patient (Case 6) deviated markedly from this, showing a variation in his potassium excretion of 400 per cent. Figure 3 is a graphic presentation of the difference in mean potassium excretion in each 5-day period. Actually, the same data are tabulated in Table I. If potassium excretion was higher on the 15 gm. sodium chloride diet, the percentage is shown as positive. Conversely, a lesser excretion on this diet is recorded as negative. The mean excretion of +16.5 per cent reveals a slightly greater mean potassium excretion on the high salt diet. However, eliminating the rather atypical Case 6 lowers this to +9 per cent, a figure which is not believed to be significant. One patient (Case 5) showed a moderate diuresis throughout the first 4 days of the study. On the fifth day a left thoracentesis was performed which yielded 650 cc. of fluid. Following this, a rather
spectacular diuresis occurred resulting in a 5,000 cc. urinary output (Fig. 4). Concomitantly, sodium and chloride excretion increased, although potassium excretion was unchanged. This case illustrates quite well at least one of the benefits that may accrue to the patient with cardiac disease from a timely thoracentesis. Figure 4 not only illustrates
the diuresis and natriuresis but vividly confirms the marked constancy of potassium excretion. Another patient (Case 6) has already been alluded to. Figure 5 illustrates the constantly high potassium excretion which was present from the start of THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Potassium
Excretion,
Sodium
Intake
and Oral
o---o ---K 130
Diuretics
197
Na Cl
--6-e “c----_
--A----o
115 160 140
-
h-
120 110 100 soIO5o600
-
600
-
400
-
200
o-
6000
-
5000
k
w
f
i
;
t \
4000 3000
=
2
$
2000
IO00
1
1
---t’-‘-I I
I 2
I 3
I 4
I 5
I 6
I 7
I 6
I 9
I IO
DAYS FIG. 4.
pattern.
5. The effect of a thoracentesis (indicated Note constancy of potassium excretion.
Case
the experiment. It also reveals the rather low serum potassium which was also initially present. On the eighth day this fell to a dangerously low level of 1.5 The patient had marked weakness, almEq. per L. though he did not show electrocardiographic changes. The diuretic was discontinued and the serum levels, with the aid of potassium supplements, climbed to On the ninth and tenth day, the safer levels. urinary potassium content showed a marked fall. This was the only patient who showed this peculiar pattern. Interestingly, serum sodium and chloride levels were also rather low throughout the test period. The patient showed no gross evidence of blood urea nitrogen on two renal dysfunction ; FEBRUARY
1962
occasions was tained neither GROUP
by arrow) on urinary
13 mg. protein
per cent and the urine nor formed elements.
con-
2
Table II summarizes the results obtained in patients maintained on one of the two diets for 10 days. During the second 5 days they received one of the two oral diuretics. Two patients in group 2 received the low salt diet. As was expected the sodium chloride content of the urine was low during the first 5 days. When the diuretic was given, a moderate (66 per cent) increase in mean urinary output resulted, but
Eskwith,
198
La\vrencc
and
McLaughlin
-
No
---K
Cl
165.H----‘__
*
*e-L---
_---
I
I
I
I
I
I
I
I
I
I
I
2
3
4
5
6
7
8
9
IO
DAYS FIG. 5. Case 6. Urinary and serum electrolyte patterns. Note low serum levels of all electrolytes and high levels of urinary potassium. Chlorphthalidone (C.P.) was discontinued on the eighth day and supplementary potassium administered orally.
there were marked increases in sodium and chloride excretion (600 and 420 per cent, respectively). Potassium excretion also increased, but to a lesser extent, namely 145 per cent. Figure 6 depicts this change in one patient (Case 13). The two members of group 2B, ingesting the higher salt diet, showed urinary outputs that compared favorably with the first two members of this group. The salt diet during the first 5 days was higher than that for the patients in group 2A. However, when the two patients in group 2B were given the diuretic, the urine volume increased only 22 per cent, although the absolute amount was somewhat greater than
Sodium the average for the first two subjects. increased only 19 per cent, chloride 28 per cent and potassium increased more than either of the first two substances, i.e., increasing 51 per cent. Table III gives the range between the highest and lowest serum electrolyte concentrations recorded, as determined for each of the seven patients in group 1, and the calculated mean variations. These were 12.0 mEq. for sodium, 11.7 mEq. for chloride and 2.1 mEq. for potassium. Fortunately, only one patient (Case 6) had signs of hypokalemia. In several other patients, scattered readings as low as 3.5 mEq. per L. were obtained. These seemed to be sporadic, did not THE
AMERICAN
JOURNA”
OF
CARDIOLOGY
Potassium
Excretion,
Sodium
Intake
and Oral
199
Diuretics
TABLE II Group 2. Without
24 Hour Urine Volumes
and Electrolytes
(mEq./L.) With Diuretic
Diuretic
(A) 0.5 gm. NaCl Diet
12
1,475
13
a77
Mean Per cent increase on diuretic
1,173
27
36
29.2
1,962
81
10.5
36.5
20.5
1,766
191.6
81.9
186.5
19.3
36.3
24.9
1,864 66
136.0 600
90.5 145
129.8 420
(B) 75 gm. N&l 14
2,760
15
888
Mean Per cent increase on diuretic
form
1,824
diet
208.6
3,355
273.5
125.0
305.1
43.0
49.0
39.0
1,310
77.0
77.0
84.6
105.0
79.0
123.8
2,332 22
125.3 19
101 .o 28
/
/ pattern,
or the duration
and
I were
not related
of the experiment.
COMMENTS
e-0
e
NO
---Cl -K IJOc--+---4---__
Y Km -
--c--L--__
I
Chlorothiazide Chlorphthalidone
Diet
109.0
The choice of a lo-day study for each patient divided into two equal phases seemed desirable
5
73
266.0
..
a continuous
to either
109
I
Chlorothiazide Chlorphthalidone
194.8 51
I
I
I
for several reasons. The cooperation of the patient is often inversely proportional to the length of time required for an experiment. This period not only assured adequate cooperation, but similar observations are applicable to the nursing and laboratory staffs. This relatively short interval of surveillance did possess the disadvantage of not permitting observation of long-term trends which would have been particularly advantageous in the second group of patients. Two diuretics were used to broaden the study. It is not believed that any significant TABLE III Electrolyte
Variations
Case No. 1
FIG. 6. Case 13. Note upward surge of urinary volume and electrolytes when chlorothiazide (C.T.) was administered. Low urinary salt levels prior to diuresis are striking. FEBRUARY 1962
2 3 4 5 6 7
Mean
-I
in Serum (mEq./L.)
-
-
Sodium
Chloride
Potassium
7.0 13.0 10.0 18.0 10.0 8.0 18.0 12.0
8.7 6.0 12.6 9.0 19.0 3.7 23.0 11.7
2.0 0.8 2.8 2.6 3.2
-
1.9 1.4 2.1
-
200 difference
Eskwith,
Lawrence
exists in the action of the various thiazide and phthalidone preparations. The relationship, if any, of sodium content of the diet and sodium excretion to that of urinary potassium content has been the subject of several recent papers. As was mentioned earlier, Lown3 believes that salt restriction may actually aggravate potassium loss. Berliner et al.* suggest that potassium and hydrogen compete for various cations to permit sodium reabsorption by the renal tubule, the so-called exchange hypothesis. Such competition, between hydrogen and potassium, seems somewhat unequal for the latter. The available supply of hydrogen ion would appear to be much greater than that of potassium because of the small amount of potassium normally found in serum as opposed to the readiness with which carbonic anhydrase can furnish available hydrogen ions. Lesser and his colleagues* have stated that potassium loss may be accentuated in patients given mercurial diuretics when they have been maintained on a low salt diet. Anderson and Larraghg found little change in potassium excretion in human subjects or dogs when sodium was restricted. In potassium depleted subjects, or those unable to have ingested an adequate amount of potassium for a period of time, both Talbot5 and RandalllO and their co-workers state that sodium restriction is necessary to conserve body stores of potassium. However, their subjects were mainly patients who underwent surgery and who were unable to ingest food, circumstances not often encountered in patients with cardiac disease. Factors Affecting Urinary Potassium Excretion: Body mechanisms determining the urinary content of potassium are poorly understood. It has been known that conservation mechanisms for this mineral are less efficient than those for Dietary restriction of the latter, for sodium. example, may result in urinary sodium falling to minimal levels,” an observation readily apparent in one patient (Case 13) of group 2 (Fig. 6). However, such near complete reabsorption of potassium does not occur, and potassium excretion will continue at a fairly steady state for sometime after the substance has been withdrawn from the diet. When one deals with patients with cardiac disease who may have some physiologic renal disturbance and adds to their regimen a diuretic, the situation becomes somewhat more complex. The kaliuretic effect of the chlorothiazide group of diuretics has been well documented.12J3
and McLaughlin However, this loss may not be particularly serious unless rather large doses are administered to the patient.14rn The kaliuretic effect of these substances may also be dependent upon the state of the patient at the time administration has begun. The patients in group 1 for example, had either received diuretics up to the time of the experiment or else had been in early congestive heart failure with minimal edema. The previous diet of this latter group had not featured sodium restriction. Once in the experiment, they initially received a rather high salt diet. In each case, the patient’s potassium excretion remained relatively constant even when the change was made to a lower content of salt, with the outstanding exception of one patient (Case 6). This patient showed a marked kaliuresis while on a Iow salt diet, and also failed to maintain his serum electrolytes at a satisfactorily high level. Apart from this patient, alternation in diet while the diuretic was continued had little effect on potassium excretion. The slight increase in the mean excretion, as expressed in Figure 5, on the high salt diet is really due to one patient (Case 6). Also, although the absolute amount of potassium excreted on the high salt diet was somewhat higher, the percentage of potassium excreted in relation to intake was actually somewhat higher on the low salt regimen. We believe, therefore, that when potassium intake is adequate, changing the salt content of the diet does not alter potassium excretion at all. Since even our low salt diet contains adequate potassium, approximately 3,000 mg. (about 70 mEq.), fear of excessive potassium loss due to renal tubular mechanisms seems unwarranted. Factors Affecting Sodium Chloride Excretion: Sodium and chloride patterns paralleled each other and as might be expected, showed a marked fall on the low salt diet. This seems somewhat contradictory to the hypothesis that restricting dietary sodium and permitting adequate fluid will result in a rapidly developing negative sodium balance. Considering that aldosterone secretion is inversely proportional to the amount of sodium ingested, it might well be that sodium restriction actually favors sodium retention. It is also clear that ingestion of large amounts of salt did not inhibit diuresis, the mean urinary volumes being equal in both phases of group 1. In group 2 the mean urinary excretion was THE
AMERICAN
JOURNAL
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CARDIOLOGY
Potassium
Excretion,
Sodium
lower in the patients adhering to a low salt diet with no diuretic than in those adhering to a high salt diet with no diuretic. Our figures show that in general, sodium chloride and water excretion were directly proportional. The changes in the urine in one patient (Case 5), for example, vividly illustrate this. Figure 4 depicts a marked diuresis and natriuresis following thoracentesis. This figure also illustrates the independence of potassium output. Low Salt Diet and Potassium Excretion: The second group of patients presented a marked contrast to the first. The first two patients of group 2 (Cases 12 and 13) were placed on a diet containing 0.5 gm. of NaCl for 10 days. During the last half, one of the two diuretics was administered. This resulted not only in a marked diuresis but a pronounced increase in the excretion of sodium chloride, and to a lesser extent, of potassium. It is probable that this effect represented a summation of the effects of increased endogenous aldosterone excretion and the administration of the diuretic. Figure 6 (Case 13) demonstrates these changes. On the other hand, the addition of a diuretic to the two patients (Cases 14 and 15) on a high salt diet enhanced the excretion of the three substances only moderately above the prediuretic levels. Urinary volume in both groups in each phase was approximately equal. Although the number of patients in each of these subgroups is small, it would appear that the previously low salt diet favors increased potassium excretion at the start of a diuretic regimen. It is probable, however, that after this initial outpouring of electrolytes, excretion of these substances gradually diminishes and descends to a lower plateau, corresponding to the behavior of the eleven patients in group 1. This lessening of the kaliuretic effect of chlorothiazide and related diuretics as time goes by has been suggested by others.*6 Serum Electrolyte Levels: The relative constancy of serum sodium and chloride levels was quite different from the variability of urinary excretion. It is clear that serum sodium and chloride levels represent a staunch homeostatic mechanism, not easily disturbed. Because of this, it is believed that determination of these levels gives scant indication of sodium chloride balance or body salt content. Daily serum electrolyte determinations, therefore, were discontinued after having been performed on the first seven patients of group 1. Serum potassium, as Table III reveals, showed variations that FEBRUARY
1962
Intake
and
Oral
Diuretics
201
were of sufficient magnitude to present a potential hazard to the patient. Fortunately, with one exception, the occasional low levels encountered did not persist. Interestingly, no level was found above 5.5 mEq. per L. in any patient. It is suggested that in patients receiving diuretics of any kind, occasional serum potassium levels be obtained, and if found to be abnormal, repeated. This would seem particularly important at the start of therapy. The marked diuresis that occurred in one patient (Case 5) following thoracentesis demonstrates another good reason for timely thoracentesis in decompensated patients with cardiac disease. The bizarre electrolyte pattern, both in the serum and urine, shown in Figure 5, is not readily explicable. There is no evidence on the basis of the clinical investigation of the patient that the kidney was at fault during the period of study.
SUMMARYAND CONCLUSIONS In eleven patients who had been previously given chlorothiazide or chlorphthalidone and who were in minimal heart failure, changes in salt content of the diet did not affect the potassium content of the urine. In each patient except one, this seemed to maintain itself at a fairly steady rate. It is believed that all of the mechanisms responsible for the potassium levels in the urine are not known at present. However, there would seem to be no danger in giving rather large amounts of salt to patients ingesting diets containing potassium. When patients have not received previous diuretics, the administration of these drugs results in increased content of sodium, chloride and potassium in the urine. This is particularly marked in patients who had previously received a low (0.5 gm.) salt diet. It is assumed that this marked kaliuresis falls and levels off as medication is continued. There was no evidence that a high salt diet interfered with diuresis. Actually, urine volume seemed altered in this study chiefly by the administration of the diuretic rather than the diet, and in general urine sodium chloride varied directly with urine volume. Marked reduction in dietary sodium resulted in prompt and equally severe restriction of sodium excretion. This latter reduction was not reversed until a diuretic was administered. It was not believed, therefore, that the average low sodium diet results by itself in a rapidly effective net sodium balance. It is further
Eskwith, Lawrence
202
hypothesized that such sodium dietary restriction leads to increased aldosterone production, augmenting sodium retention. Finally, serum sodium and chloride levels give no indication of sodium balance and are of limited value. On the other hand, serum potassium studies are of considerable importance. The low serum level of this anion makes minor variations relatively important. It is suggested, therefore, that patients receiving diuretics, i.e., mercurial as well as thiazide, should have occasional serum potassium determinations. ACKNO\YLEDGMENTS
Our special thanks are due to Mrs. Mary Jean Steere, technician in the chemistry laboratory, for her untiring interest and work in behalf of this experiment, and to Miss Lourdes Santos. head dietitian, for her careful attention to the diets of the patients used in this study. Our thanks are also due to Dr. Franklin Epstein, Associate Professor of Medicine, Yale University, for his careful review of, and helpful COINSments concerning this paper. REFERENCES Review of the thiazides. In: Hyper1. FUCHS, M. tension, p. 534. Edited by Moyer, J. Philadelphia, 1959. W. B. Saunders Co. 2. ENSELBERG, C. D., SIMMONS, H. C. and MURITZ, A. A. Effects of potassium upon the heart with special reference to possibility of treatment of Am. Heart J., toxic arrhythmias due to digitalis. 39: 713, 1950. 3. LOWN, B. Potassium and digitalis, In: Digitalis, A Symposium, pp. 167-186. Edited by Dimond, E. Springfield, Ill., 1957. Charles C Thomas. 4. BERLINER, R. W., KENNEDY, T. J., JR. and ORLOFP, J. Relationship bctwcen acidification of urine
and McLaughlin
5.
6.
7.
8.
9.
IO.
11. 12.
and potassium metabolism: effect of carbonic anhydrase inhibition on potassium excretion. Am. J. Med.. 11: 274, 1951. TALBOT, .4. B:, RITCH~E, R. H. and CRAWKIRD, J. D. Metabolic Homeostasis: A Syllabus for Those Concerned with the Care of Patients. Cambridge, Mass., 1959. Harvard University Press. FUCHS, hl., NEWMAN, B. E. and SNYDER, D. Effect of variable salt intake on the electrolyte response to diuretics. In: Edema, A Symposium, pp. 192~195. Edited by Moyer, J. H. and Fuchs, M. Philadelphia, 1960. W. B. Saunders Co. &HALES, 0. and SCMLES, S. S. A simple and accurate method for determination of chloride in biological fluids. J. Biol. Chern., 140: 879, 1941. LESSER. G. T.. DUNNIXG. hl. F.. EPSTEIN. F. H. and BEYER, IS. %. Merc&ial diwesis in’edematous patients. Circulation, 5: 85, 1952. ANDERSON, H. M. and LARRAGH, .J. H. Renal excretion of potassium in normal and sodium depleted dogs. J. C/in. huest., 37: 323, 1958. RANDALL, H. T., HABIF, D. V., LOCKM~OOD, J. S. and WRRNER, S. C. Potassium deficiency in Stcrgey, 26: 341, 1949. surgical patients. STATLAND, H. Fluid and Electrolytes in Practice, p. 32. Philadelphia, 1954. J. B. Lippincott Co. SLATER, J. H. D. and NABARRO, .I. D. N. Clinical experience with chlorothiazide. Imcrt, 1 : 224
1958. 13. SCHREINER? G. E. and BLOOUER, H. i\. Effect of chlorothiazide on edema of cirrhosis nephrosis, congestive heart failure, and chronic renal insufficiency. I\‘PW England J. 12/led., 257: 1016, 1957. 14. FORD, R. V. Limitations and potential and actual side effects of thiazide derivatives. In: Edema, Mechanisms and Management, pp. 289-298. Edited by Moyer, J. H. and Fuchs, M. Philadelphia, 1960. W. B. Saunders Co. 15. GROSS~~AN, I. Electrolyte abnormalities associated with mercurial, thiazide and carbonic anhydrase In reference 14, pp. -inhibiting diuretics. 292-298. 16. FORD, R., MOYER, I. and SPURR, C. Clinical and and laboratory observation on chlorothiazide (Diuril). Arch. Znt. Med., 100: 582, 1957.
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