Distribution of Body Fluids in Congestive
Heart Failure
1V. Exchanges in Patients, Refractory to Mercurial
Diuretics, Treated with Sodium and Potassium
The
BY J.
H.
ELKINTON,
M.D.,
It. D. SQUIRES,
M.D., AND
L. W. BLUEMLE, JR., M.D.
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The clinical couise w-as obser1ved and balance studies were conducted in a series of patients with
congestive heart failure who had hvponatiemia and who had become iefractory' to me'cuiial diuretics. The data obtained during control periods and during treatment with hylpertonic sodium solutions suggest that, in addition to sodium depletion, some disturbance is present in the mechanisms
which regulate the water balance of the body. The administration of potassium (lid not appear to
effect a diuresis.
IN THE previous paper' data were presented on the exchanges of water and
electrolytes in patients with congestive
heart failure during loss of their edema by
diuresis. In the present communication similar
studies are set forth of edematous patients who
had become refractory to mercurial diuretics.
In the first paper of this series2 the possible
effects of certain changes in body fluid distribution on circulatory and renal function were
discussed. Reductioni of cardiac output, rate of
glomerular filtration, and renal insufficiency
are known to be regular effects of depletion of
sodium ion,3 4 and the administration of sodium to salt-depleted subjects has been shown
to restore the effectiveness of mercurial diuretics.5 6 Sodium depletion as a result of excessive administration of mercurial diuretics
has been described by many observers7-12 and
has been termed by Schroeder "the low-salt
syndrome." Since hyponatremia is a common
finding in edematous cardiacs who have received mercurials,13 it seemed pertinent to inquire whether loss of sodium in relation to water
was the principal factor in the refractoriness
of these patients to various diuretic measures.
Disturbances in the distribution of potassium
have also been implicated in congestive heart
failure. Newman and co-workers14 and
others,'5-17 as well as ourselves,1 had shown that
potassium may be retained inl excess of nitrogen
(luring the diuresis of the edema fluid. Fox
and associates"8 have claimed that the administration of potassium to hyponatremic cardiacs,
along with sodium, is a factor in the initiation
of diuresis. For this reason the effect of potassium therapy in such patients requires study.
The purpose of this investigation was to determine in a group of hyponatremic mercurialfast edematous cardiacs (1) whether the hyponatremia could be attributed to retention of
water, to loss of sodium, or to both, (2) whether
the raising of the extracellular concentration of
sodium by the administration of hypertonic
solutions of sodium would promote the onset
of diuresis, and (3) whether the administration of potassium played a critical role in the
diuresis of the edema fluid.
From the Chemical Section of the Department of
Medicine, and the Hospital of the University of
Pennsylvania, Philadelphia, Pa.
Laboratory facilities and personnel were aided by
a grant from the National Heart Institute, United
States Public Health Service, and by the C. M\ahlon
Kline Fund of the Department of Medicine.
During the study, J. R. E. was an Established Investigator of the American Heart Association.
EXPERIMENTAL METHODS AND PROCEDURE
Thirteen patients with peiipheial edema due to
heart disease were the subjects of study. All of these
patients had become r'efractory to mercurial diuretics during sustained administration of the drug;
most of them were hvponatremic. Nine of the patients were given hypertonic solutions of sodium
during which time water was restricted; three were
58
Circulation, Volume 1, January, 1952
59
J. R. ELKINTON, R. D. SQUIRES AND L. W. BLUEMLE, JR.
given hypertonic sodium solutions and potassium;
and two were given, on three occasions, potassium
solutions only.
The clinical response in terms of sense of wellbeing, thirst, and diuresis were observed; the changes
in components of the body fluids were calculated
Patient:
Therapy
F. N.
Arterioscler.
Heart
were treated with hypertonic sodium solutions
are tabulated in table 1 and illustrated in
figures 1 to 6. All of the patients were still
edematous despite intensive mercurial therapy
immediately prior to the period of study. At
Disease
c
congestive failure:
KHP04 p.O.
Mercurial
(H 9)
[Low
NO
3%
g1
Digitoxin
Edema - pulmonary
peripheral
conc.
Serum
7.5-
4+
2+
1
z+
-I
1
30 -
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
BUN 20-
K
x_ -X
5.5- m9.%
1V
0-0
Na
3.5-_
meq. per liter
125
Discharged
edema- free
Daily balance of:
Sodium
l
+400mre q.
+ 200
intake -
-
-output
4o
Potassium
.200 L
+
meq.
Weight
68
66]
Kg.
6462
Total f luid
Intake
Output urine M
4-
2
n
FIIF
J[i¶iI
-
Doy of
study
0
5
10
15
20
FIG. 1. Patient F. N.. Clinical course. Successful response to mercurial diuretic occurred following
the administration of hypertonic sodium solution. This took place after recovery from acute left
ventricular failure due to potassium cardiotoxicity induced by potassium therapy.
from data obtained by the balance technic. The
details of procedure, the calculation of results, and
the chemical methods were the same as those detailed in the previous paper.'
RESULTS
The results are presented in tables 1 to 3B
and in figures 1 to 6.
Clinical Course. The diagnosis and clinical
course of the 11 hyponatremic patients who
least six of the 11 patients were hypotensive
and eight were azotemic. All of the patients
were weak and anorexic, one was cold and
sweating, and four were mentally confused or
comatose. One of these, R. S., who had the
lowest serum level of sodium in the group, had
a severe paralytic ileus simulating intestinal
obstruction or mesenteric thrombosis. During
treatment with hypertonic sodium solutions
60
BODY FLUIDS IN CONGESTIVE HEART FAILURE
A.
.
cl4
0.
.4Q)d
4) ~ ~
4~~~44.44)
~~~
0
0
0
'-
C~
~
~~~~~
~~ 000
0
0
0
--)
IC
0
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c
0
0
02
02
>4
~
0
0
$44
4~
c
c
.
4))~~~~~~~~~~~~~~~~4
0
0
1
.4.
4)4
C)
'4
44J
-
4)
cm
ce4J
'4
- 0
~~~~~~~~~~~~~~~~~~~~~~~
'4
4)4
10
to
4)4) 0 0 c~ ~ ~
0
c~~
_W
ce
0
c~ c~~ 02
4.4)~~z
0+
0.)
4) M
0-4)
M~~~~4).
+)
-H +H
i
*s
To
0
cl
424242
03
)
42
)
4)
)
Ic4) Ct-
to
C)
C).
CO
~~~4) + ± (~~~~~~~~~~~~~~~~4.. ++ +0
~~
~~Cdi
~ c
ce
bO
H
-
m0
ce
b2
Cd
h-
ce
C
0
L.4CL.
.44
00
00
c
00
00
m 00~~~~~~~~~~0
j
P4
.
4-;
Iz
61
J. R. ELKINTON, R. D. SQUIRES AND L. W. BLUEMLE, JR.
seven of the patients developed moderate to
extreme thirst; in six of these this symptom appeared while the serum concentration of sodium was still below the range of normal values.
Mainly because of this symptom, water restricPatient: J. F.
Theropy:
increase in urine flow during the period of administration of sodium, and in only five was
there some degree of diuresis immediately after
the sodium therapy (in four of these when
mercurial diuretics were again instituted). In
49 e W, Rheumatic valvular heart dis. E AF and congestive failure
B
Milk
Low No Diet
E
.
LA
1ol1
HQ I
19
mE__ Exin
2+
Edema - periph.
Serum conc.:
tsi BUN
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
K
m
To-
,.-__it. _X 20
I0 1451
f
_ /1
O
3.s L
I35
Na
meq. per
Dot
ox
40
301
,,,
___x___
-X.X.
_-
5.
o-
1
l.
01BO
\_
0
--- 0o
l
liter
125-
**
Daily balonce of:
Sodium
+200
n-1
intoke-
+ 100
output
0
meq.
Potassium
24 hr. endogenous
croatinine clearance
cc. per min.
+100
a_
01I-
100
Soil
liters
0
Intake
Output - urine U
Total fluid
Day
of
study
.._nn
. Ln
3
2i
IL
n
0
26
30
p
35
40
45
FIG. 2. Patient J. F. Clinical course. The serum sodium concentration continued to fall on days
37 and 38 despite a slightly positive sodium balance, indicating a primary retention of water. Following sodium therapy the serum concentration was partially restored but no diuresis occurred, even
when mercury was given (day 44).
tion and sodium administration were carried to
the point of complete restoration of the serum
sodium to within the normal range in only four
of the patients.
The therapeutic results of this treatment in
terms of diuresis were inconstant. In only three
of the patients was there a slight or moderate
F. N., of the two patients who completely
eliminated their edema, the diuresis appeared
to be delayed by the deleterious effect of the
potassium therapy (fig. 1). In the other of these
two patients, H. W., the diuresis of water with
very little salt continued after the administration of hypertonic sodium chloride (and before
one,
BODY FLUIDS IN CONGESTIVE HEART FAILURE
62
mercurials has an extremely poor prognosis
under present therapy. In patient G. C., potassium was given alone or in conijunc(.tioni with
that of mercury) to the point where the edema
was removed and the serum sodium concentration restored to high normal levels (fig. 3).
Myocardial infarction with congestive failure.
H. W., 47 0r,
Patient:
Therapy:
Diitoxin
Low No
diet
.j1
1
80
80%
Kx
mg.%
Serum
0.9% i.v.
2+-1
Edema - peripheral
x-
NoCI
ENC
g
0.9
5.0 %
,9
0.9
BUN
DDigitOlis
A,
-
\
/
/
x
60O
/
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
7.5
x-- x
40-
K
0-0
s
--X
5.5.-
20_
3.5j3-
1,
Na
-*
meq. per Alter
120
66
80 110
S8 80
,1
+200:
output
Intake
98
70
100
78
BP:
Daily balance of:
Sodium
0
meq.
0]
Potaossiumn
24 hr. endogen.
100
creotinine
so50
cleoaronce
-100o
......L
cc. per mle.
Total f luid4Intake
Output- urine
Day of study
0
E
M~r ~
0
H~
?
5
10
[~~
15
20
FIG. 3. Patient H. W. Clinical course. During the oliguric phase when the fluid intake was increased (days 8 to 11) the patient was hypotensive, the serum sodium level fell, and azotemia rapidly
developed. On day 12 severe limitation of water intake plus hypertonic sodium therapy resulted in
a rise in serum sodium concentration to 129 mEq. per liter and a moderate increase in urinary output. On days 13 to 15 when water intake was moderately restricted but no hypertonic salt was given,
the patient excreted a large volume of water with very little salt, resulting in the loss of edema and a
restoration of the serum sodium concentration to high normal levels. This readjustment occurred
without the retention of potassium. Subsequently the blood urea nitrogen returned to normal levels.
The fact that death occurred within a week
in six of the patients indicates, at most, that
the sodium therapy as administered was not
only ineffectual but may have been harmful, or
at least, that the patient with chronic congestive failure who has become refractory to
sodium during three different admissions (fig.
6), each time raising the serum level to abnormally high values. Only on the third admission can the potassium therapy possibly be
interpreted to have accelerated the loss of
edema. On the other admissions of this patient
J. R. ELKINTON, R. D. SQUIRES AND L. W. BLUENMLE, Jll.
no diuresis was associated with the administration of this iolI. This was likewise true in the
other two patients, G. B. and J. B., who retained large amounts of administered potassium (figs. 4 and 5A, tables 2B and 3B).
Patient:
Therapy:
G.B.
heart
Rheumatic
balance was zero or positive; that is, the concentration decrement was due to retention of
water rather than to loss of sodium. When
sodium ion was administered to the hyponatremic patients, the serum or extracellular conwith
disease
chronic congestive
K Acet.|
Mercuriol
Con cAlb
| NoC3
LNH4CI 1 Na Acet
Edema - periph.
Blood urea N
Serum conc.:
Albumin gm %
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
K
failure.
|K Acet.|
ConcAlb|
°
63
2+
3.0]
2.0]-,-
Na
4.5
° 3.5
0--me
-
2.5
mneq. per i.
Daily balance of
Chloride
meq
o
_
L
c
+200
+100
Sodium
meq.
s
10
lo
-200
-
100 ]
Potassium
meq.
Endoa:g. creatinine
clearance
Weight
Kg
01
Output
Doy of study
n nnn1
n
nin n n n
n
74
Total flui.d
Intake and
a
+50
cc/min- olnnn
2
I IIi
liters
0
L L L h i
I
5
10
15
20
FIG. 4. Patient G. 13. Clinical course. Despite the restoration of serum sodium concentration to
normal levels on two occasions (days 6 to 7 and 18 to 20), the administration of concentrated albumin,
and the administration of potassium, the patient failed to have a diuresis. The two relapses of the
serum sodium concentration to hyponatremic levels without a negative sodium balance (days 8 to
11 and 20 to 24) suggest lprimary retention of water.
Sodiutm and WVater Exchanges. In 12 of the
15 studies the initial serum sodium concentratiolls were abnormally low (table 3 and fig. 5).
In six of seven periods in hyponatremic patienits, when neither mercurials
nor
hypertonic
sodium solutions were being given, the serum
sodium concentrationi was observed to fall to
still lower levels at a time when the sodium
centration rose, and the chloride space expanded. However, in one patient, F. N., the
total water of the body was demonstrated not
to increase (table 3B), and in two other patients, H. W. and R. S., whose urinary output
increased, the intake-output data suggest that
during hypertoniic sodium therapy their total
body water was actually diminished (table 2A).
BODY FLUIDS IN CONGESTIVE HEART FAILURE
64
phase in a majority of the patients receiving
hypertonic sodium therapy. But in three of the
five patients in which changes in volume of the
intracellular fluid was estimated, the fluid com-
Following the sodium therapy two patients,
F. N. and J. L., when given mercurials, excreted their edema fluid, presumably both water
and salt (fig. 1). Patient H. W. likewise had a
40 d' W
Patient: J.B.,
Therapy:
,
W_ low
vo
C.
Edema
Serum conc.:
5.5
A9
NO diet
No
-
NH4C1
HQ
disease e congestive failure
Digitalis
Milk
free milk AL.
KCl, p.o.
4
r&
heart
V.
A
1
A
sc:11E.
HQ
-"A
4
2+
145.
_
Na
4.5s
K
Chr. rheumatic
W.
0-0 3.5_
135-
*
2.5 -
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
1251
40*
C02
35
-a-
25
~~~~~~
~
~
-
A\
-
AQ_0>ts,0/° \
105_
30
mM/1.
~~ ~
aA
meq./1.
1004
Cl
95-
Daily
90
balance of
+ 200 +
100]
O0.
Chloride
meq. - 00
Sodium
meq.
+200 -
+ 1001
Potassium
.1
0-_
a 9
rdrdrdrdr-
meq.
641
Weight
kg.
Total f luid
intake
62
60
liters
0
urinary output U
2
-
1
5
0
Doy of study
-5
0
A
a
f
9
5
5
10
1
9
Is
FIG. 5A. Patient J. B. Clinical course. The patient's metabolic alkalosis (elevated serum carbon
dioxide) is shown to respond to the administration of ammonium chloride (days 1 to 5 and 14 to 15)
and to be reinduced by mercurial diuretics (days 16 to 19). A rise in serum carbon dioxide was not
prevented by the administration of potassium chloride nor was a diuresis initiated (days 6 to 13).
diuresis following hypertonic sodium therapy
but excreted water greatly in excess of salt,
further concentrating his total level of electrolyte (tables 2A and 2B, fig. 3).
Expansion of the extracellular phase must
have been at the expense of the intracellular
partment was expanded rather than contracted
(tables 2B and 3B), indicating that changes in
intracellular as well as extracellular osmolarity
were conditioning the distribution of water
under these circumstances.
Potassium Exchanges. The serum potassium
J. R. ELKINTON, R. D. SQUIRES AND L. W. BLUEMLE, JR.
weight, respectively, during the periods of potassium therapy (table 3B). In patient G. B.
during the entire period of study of 21 days,
during which time she was on a basic milk
concentration was normal or elevated during
the course of observation in 12 of the 15 studies; in only one patient, G. B., did the level
fall to below 3.0 mEq. per liter (table 2B,
Patient: J. B., oe 40
Therapy:
W, Chr. rheumatic heart disease
Edema
c
congestive
failure
Digitalis
e
E_ Low No diet
E:
65
K
He
NH4CI
MBaa NO - fret milk EaF_
paPo.
.
1w
ilku
KC'a
A
MRI,¢
V&
He
'12
4+2+-
Serum
conc.
-~
~~,-41:5^_^
40.2
35]
AdaAA
\
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
A Ad
30}_
mM/I
25
5
100-
Cl
-
W-W
A,,
A
4LEA-
2W
-
95.
901
meq./i.
Cumulative change in
Extracellular
.400.
+2 -
H20
(d E)
o
liters
400
No
o -_
--
-2I
meq.
Intracellular
+400K
H20
(AlI) 0j-2 _
liters
0-
Na40X 0
.1
meq. _
Weight
kg
0-
^-A 8
64
62
60
Total fluid
liters
0
Intake
Urinary output a
Day
of
study
2ji
-5
I 1
nI
0
5
10
15
FIG. 5B. Patient J. B. Calculated changes in body fluid components. Intracellular sodium was
not diminished and intracellular potassium was not increased when ammonium chloride was given
and the serum carbon dioxide fell (days 1 to 5 and 14 to 15). Such exchanges did take place during
potassium chloride therapy but the serum carbon dioxide content rose. Thus no recognized relationship appeared to occur between the extracellular alkalosis and exchanges of intracellular
cations. Nor did any diuresis occur when potassium was retained in the cellular phase.
fig. 3). Potassium was retained in the intracellular phase on all six occasions of its administration. In patients G. B. and J. B. the increase in
intracellular potassium in excess of nitrogen
amounted to 7.3 and 7.7 mEq. per Kg. of body
diet, the total retention of potassium in excess
of nitrogen was 1015 mEq., or 13.5 mEq. per
Kg. The calculated changes in intracellular
sodium did not bear a reciprocal relation to
those of intracellular potassium during many
66
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i
z
I
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F
BODY FLUIDS IN CONGESTIVE HEART FAILURE
C -
n :°
O | IsI
_XI IO IO
00
00
N
~2Cd
m
10COCOm
0
C)010
._
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+
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4
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b'>
ce f
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z cc
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o~o~~
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cc a)
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Oj
I
_ I
I
__
I__s
a)a)
r-
Ia) a> c
V eC
m
Y
CC
-
*
V~
-
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CO*
o'
._CO
._
C Y
.-
CO
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_O
02-
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I__ I__ ____
1
_
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--- _
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COCOC
N
C
N
I__
000
Cl
67
J. R. ELKINTON, R. D. SQUIRES AND L. W. BLUEMLE, JR.
a discrepancy between water shifts and cation
transfers, was in the negative direction in most
of the 19 periods of the six studies in which it
could be calculated (tables 2B and 3B).
of the periods of observation. During three of
the five periods of potassium therapy and uptake by the cellular phase, when the final
carbon dioxide content of serum was measured,
I
Serum
failure
Low-Na diet
Digitoxin
XuII
NH4CI
-HI
912 - 10/9/1949
with congestive
heart disease
46 ? W, Chronic rheumatic
-- ~ 1
G.C.,
IH
Ij
gms.
3
4 gins.
conc.
js5.4
K
5.9
Weight
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
kg.
45.
Edema ~w
Edema
2+
3
0
Day of study
5
Serum con c.
K
No
Weight
eg.
Edema
6.5
135
15
10
Low-Na diet
1
20
|
Digitozish
I
2/2-23/1950
mHe
Serum conc.
6.1
K
123
Na
Weight
5101
Day of study
10 ems.
1 1e
5
0o
m
Edema
S
4.8
2 +j
Day of study
kg.
diet5 g
Low-N o
I
I
NH GI
12/6-31/1949
20
is
t0
5
4
5
5
4 gms.
MKC
4.8
131
5 gms.
7.0
130
5.6
126
41
2+]
0
5
10
15
20
FIG. 6. Patient G. C. Clinical course. The temporal relationship of a few doses of potassium salts
to the degree of edema and the changes in body weight are shown for three different admissions. On
each admission potassium was retained in amounts sufficient to raise the serum concentration of
the ion to supranormal levels. Only during admission III, and following sodium therapy for hyponatremia, did the administration of potassium coincide with an acceleration of the loss of weight
and of edema fluid.
the serum bicarbonate concentration rose to
abnormally high levels, rather than fell.
Osmotically Active Base. Change in osmotically active base, a calculated value indicating
Changes in this value were in the positive
direction in only six of the periods, in four of
which hypertonic sodium solution was being
given, and in one when potassium was ad-
68
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ministered. These positive values were not associated with diuresis. Total change in osmotically active base for each of six studies
amounted to 28 to 125 per cent of the total
external transfers of sodium plus potassium.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
DISCUSSION
The observations in these patients have not
been complete enough to yield definitive data
on the problems outlined in the introduction.
Obviously, the lack of measurements of general
and renal hemodynamics and of regional differences in fluid distribution prevents accurate
assessment of the effect of changes inl the systemic circulation on the loss of edema. Nevertheless, these studies do permit a few conclusions to be draw inl respect to this type of
patient, and the findings demonstrate that the
problem is not a simple one.
The response of some of the patients to hypertoniic solutions of sodium indicates that sodium depletion is sometimes a factor in the
oliguria of hyponiatremic cardiac patients. The
presence of hypotension and the symptoms of
weakness and occasional ileus support this interpretation. Sodium depletion is not ruled out by
the failure of a maj ority of these patients to
have a diuresis following such therapy in their
particular instance; other factors must be involved as well. The facts that the serum sodium
concentration continues to fall when the sodium is not being lost, that during sodium administration thirst appears long before the
serum sodium reaches normal, and that after
therapy the serum sodium concentration fre(tuently returns to its previous low level,
strongly suggest that some process is operative
in these patients which requires the maintenawice of a lower thaiw normal total conicenitrationi of electrolytes. In the previous study1
it was showni that during diuresis of edema fluid
intracellular water was lost, and that intracellular base wN-as being inactivated. As was pointed
out inl the dis(ussion of this problem in the
first paper2 such a process might result inl intracellular dehydration ill the presence of a low
concentration of electrolyte (or hyponatremia),
an initrancellular abnormality that might through
humoral mechanisms inhibit the excretion of
water and salt. Since no measurements were
7-1
made either of the absolute volume of the intracellular fluid compartment, or of antidiuretic
hormone production, these particular studies
neither confirm nor deny this hypothesis.
The hyponatremia that occurs in other states
of sodium depletion, such as in gastrointestinal
fluid loss, sweating, or adrenocortical insufficiency, usually appears after the initial stages of
the conditions. Where the fluid lost is isotonic
(as in succus entericus) or hypotonic (as in sweat)
the onset of hyponatremia is dependent upon
the acquisition of salt-free water. Peters'9 has
interpreted the fall in total electrolyte concentration to indicate that under such stress the
volume of body fluids is more zealously guarded
than composition. While such an interpretation
is possible in these cases, not only is the mechanism of such a teleologic homeostasis quite
unknown, but the recurrence of hypoiiatremia
following sodium therapy is strongly against
such an interpretation. It seems reasonable,
therefore, to seek some explanation such as
intrinsic change inl intracellular osmolarity.
The role that mercury has played in these
cases is somewhat obscure. It is entirely possible that the development of resistance to the
diuretic action of mercurial preparations was
quite unrelated to the drug and was due to
other factors of central, peripheral, and renal
circulatory failure. Oni the other hand, the occurrence of hyponatremia seemed to be more
common in cardiac patients who had received
mercury than inl those who had not,13 and the
patients reported in this paper had certainly
had intense mercury therapy (table 1). MXlercury appears to be a poison to certain cytologic
enzyme systems, including those responsible
for electrolyte transport in the cells of the renal
tubule.20 It is not inc nceivable that it may effect intracellular processes inl other tissues as
well.
Potassium therapy was hardly given a fair
trial; it was tried in too fexs cases in large
enough amounts. When it was given, it was
retained in cells in excess of nitrogen. Retention of this fraction of the ion in amounts of
7.3 and 7.7 mEq. per Kg. of body weight is
comparable to the retention in other types of
postassium deficiency.2' But even in patient
G. B., inl whom the total retention of 13.5
72
BODY FLUIDS IN CONGESTIVE HEART FAILURE
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mEq. per Kg. was equivalent to that of severe
cases of infant diarrhea,22 diabetic acidosis,23
or metabolic alkalosis due to starvation or
ACTH therapy,24 the retention of potassium
produced no diuresis.
The metabolic alkalosis which was present
in these patients did not appear to be related
to abnormalities of potassium or sodium content of the intracellular phase, as reported in
other conditions.24 25 In patient J. B. the extracellular bicarbonate concentration fell when
ammonium chloride was given and rose when
mercury was given, without significant change
in cellular sodium or potassium (fig. 5). This
fits in with the evidence in the previous studies'3 that the metabolic alkalosis found in some
of these edematous cardiac patients is caused
by the relatively high rate of excretion of
chloride in respect to sodium during diuresis,
rather than to a response to primary carbonic
acid retention or to intracellular cation abnormalities.
Schwartz and Wallace have reported"7 that
when sodium moved into the intracellular phase
during mercurial diuresis the patients became
refractory to the drug. When ammonium chloride was administered, the sodium left the cells
as potassium was taken up, and the patients
again responded to mercury. Exchanges of intracellular sodium did not appear to play such
a critical role in the cases reported here. In
patient G. B. the administration of ammonium
chloride led to some loss of cellular sodium but
no diuresis (although mercury was not given
immediately) (table 2B). In patient J. B. the
administration of potassium resulted in loss
of intracellular sodium but did not prevent a
rise in serum bicarbonate concentration, nor
did it lead to a diuresis immediately or subsequently when ammonium chloride and mercurials were given (fig. 5B). Miller'6 has stated
that sodium as well as potassium regularly
enters cells during diuresis and interprets this
to mean that these ions leave this phase during
the development of edema. He suggests that
primary water retention has occurred with
movement of sodium from cells to the diluted
extracellular fluid. Our studies confirm the development of intracellular potassium deficiency,
but we interpret our data to indicate that
changes in osmolarity of solutes within the cell
are quantitatively more important than transfers of sodium across the cell boundary.
The practical therapeutics of the hyponatremic cardiac patient refractory to mercurial
diuretics remain to be clarified. Certainly some
of these patients need sodium ion in hypertonic
solution. Such patients are those with severe
hyponatremia, with azotemia, and with evidence of peripheral vascular collapse: weakness,
cold sweating, and hypotension. When these
findings are present the authors believe that
such therapy should be tried. It is impossible,
however, at the present time, to predict whether
such therapy will be successful. We do not know
enough concerning the other factors involved.
The factor of time, or speed of therapy, is probably very important. Patient R. S. may well
have been lost because the sodium was administered too rapidly. Patient H. W. was
given hypertonic sodium solution with much
greater restraint (less sodium over a longer
period of time); the immediate effect on his
renal function was much better than in patient R. S. Perhaps rehydration of cells which
must result from Schemm's treatment26 plays
an important part in the initiation of diuresis.
A great deal more observation is needed to work
out the precise therapeutic indications of this
syndrome.
SUMMARY AND CONCLUSIONS
Fifteen balance studies were carried out in 13
edematous cardiac patients, most of whom were
hyponatremic, and all of whom had become
refractory to mercurial diuretics. The majority
were given hypertonic sodium solution, some
received potassium, and a few were given both
ions.
During control periods in six patients the
serum sodium concentration fell to even lower
levels when the patient was in sodium equilibrium or was retaining sodium.
The administration of hypertonic sodium
solution resulted in some degree of diuresis in
only five of 11 patients; in only two was the
edema completely eliminated. Most of the patients developed thirst while still hyponatremic.
The administration of potassium, with or
without sodium, to a few of the patients was
J. R. ELKINTON, R. D. SQUIRES AND L. W. BLUEMLE, JR.
not associated with
diuresis, although potassium was retained in the cellular phase.
It is concluded that while systemic sodium
depletion may be present, may be depressing
the circulation, and may be treated successfully with hypertonic sodium solution, other
factors are involved in this syndrome leading
to retention of water rather than to loss of
salt. Alteration in intracellular osmolarity may
be one of these. Only when these factors are
understood will the precise indications for therapy of this syndrome be known.
any
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ACKNOWLEDGMENTS
The help of the laboratory and clinical staffs of
the Hospital is gratefully acknowledged.
REFERENCES
SQUIRES, R. D., CROSLEY, A. P., JR., AND ELKINTON, J. R.: The distribution of body fluids in
congestive heart failure. III. Exchanges in patients during diuresis. Circulation 4: 868, 1951.
2 ELKINTON, J. R., AND SQUIRES, R. D.: The distribution of body fluids in congestive heart
failure. I. Theoretic considerations. Circulation
4: 679, 1951.
3 MCCANCE, R. A., AND WIDDOWSON, E. M.: The
secretion of urine in man during experimental
salt deficiency. J. Physiol. 91: 222, 1937.
4ELKINTON, J. R., DANOWSKI, T. S., AND WINKLER,
A. W.: Hemodynamic changes in salt depletion
and in dehydration. J. Clin. Investigation 25:
120, 1946.
5 EVANS, W. A., JR.: The effect of changes in salt
and water metabolism upon salyrgan diuresis
(with special reference to the effect of permanent
bile fistula). Medical Papers Dedicated to Henry
Asbury Christian. Baltimore, Waverly Press,
1936. P. 204.
4GOLDRING, W.: Edema in congestive failure. Effectiveness of diuretics as a guide to prognosis.
Arch. Int. Med. 44: 465, 1929.
7 POLL, D., AND STERN, J. E.: Untoward effects of
diuresis with special reference to mercurial diuretics. Arch. Int. Med. 58: 1086, 1936.
8KLINGHOFFER, K. A.: Dehydration from diuretics.
New Internat. Clinics, s. 4. 1: 221, 1941.
9 MAcGuIRE, W. B., Jo,.: Risk of uremia due to sodium depletion. J. A. M. A. 137: 1377, 1948.
10 WESTON, R. E., AND ESCHER, D. J. W.: An analysis of the unresponsiveness to mercurial diuretics observed in certain patients with severe
chronic congestive failure. J. Clin. Investigation
27: 561, 1948.
11 SOLOFF, L. A., AND ZATUCHNI, J.: Syndrome of
salt depletion. J. A. M. A. 139: 1136, 1949.
12
SCHROEDER, H. A.: Renal failure associated with
1
73
low extracellular sodium chloride. The low salt
syndrome. J. A. M. A. 141: 117, 1949.
13SQUIRES, R. D., SINGER, R. B., MOFFITT, G. R.,
JR., AND ELKINTON, J. R.: The distribution of
body fluids in congestive heart failure. IL. Abnormalities in serum electrolyte concentration
and in acid-base equilibrium. Circulation 4:
697, 1951.
14 NEWMAN, E. V.: Functions of the kidney and
metabolic changes in cardiac failure. Am. J.
Med. 7: 490, 1949.
15 ISERI, L. T., BOYLE, A. J., Rosow, W. A., GRIFFIN,
R., AND ENGSTROM, F.: Metabolic studies during treatment of severe congestive heart failure with 50 milligram sodium diet. J. Clin.
Investigation 29: 825, 1950.
16 MILLER, G. E.: Electrolyte exchange between
body fluid compartments during recovery from
congestive heart failure. J. Clin. Investigation
29: 835, 1950.
17 SCHWARTZ, W. B., AND WALLACE, W. M.: Observations on electrolyte balance during mercurial diuresis in congestive heart failure. J.
Clin. Investigation 29: 844, 1950.
"8Fox, C. L., JR., FRIEDBURG, C. K., AND WHITE,
A. G.: Electrolyte abnormalities in chronic
congestive heart failure: effects of administration of potassium and sodium salts. J. Clin.
Investigation 28: 781, 1949.
19 PETERS, J. P.: Water balance in health and in
disease. In G. Duncan, ed.: Diseases of Metabolism. Philadelphia, W. B. Saunders, 1947. Ch.
VI, pp. 271-346.
20 RAY, C. T., AND BURCH, G. E.: Progress of medical
sciences. The mercurial diuretics. Am. J. M.
Sc. 217: 96, 1949.
21 TARAIL, R., AND ELKINTON, J. R.: Potassium deficiency and the role of the kidney in its production. J. Clin. Investigation 28: 99, 1949.
22 DARROW, D. C.: The retention of electrolyte during recovery from severe dehydration due to
diarrhea. J. Pediat. 28: 515, 1946.
23 DANOWSKI, T. S., PETERS, J. H., RATHBUN, J. C.
QUASHNOCK, J. M., AND GREENMAN, L.: Studies in diabetic acidosis and coma, with particular emphasis on the retention of administered potassium. J. Clin. Investigation 28: 1,
1949.
24 ELKINTON, J. R., SQUIRES, R. D., AND CROSLEY,
A. P., JR.: Intracellular cation exchanges in
metabolic alkalosis. J. Clin. Investigation 30:
369, 1951.
25 DARROW, D. C., SCHWARTZ, R., IANNUCCI, J. F.
AND COVILLE, F.: The relation of serum bicarbonate concentration to muscle composition.
J. Clin. Investigation 27: 198, 1948.
26 SCHEMM, F. R.: A high fluid intake in the management of edema, especially cardiac edema. II.
Clinical observations and data. Ann. Int. Med.
21: 937, 1944.
The Distribution of Body Fluids in Congestive Heart Failure: IV. Exchanges in Patients,
Refractory to Mercurial Diuretics, Treated with Sodium and Potassium
J. R. ELKINTON, R. D. SQUIRES and L. W. BLUEMLE, JR.
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Circulation. 1952;5:58-73
doi: 10.1161/01.CIR.5.1.58
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1952 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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