The Genesis of Hyponatremia Associated with
Marked Overhydration and Water Intoxication
By JAMES M. STORMONT, M.D.,
AND
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nurses and physicians throughout the day and
night provided an accurate record of symptomatology. t
Following suitable adjustment on a constant diet,
a control period of 3 days was begun, which was
followed by a treatment period during which 1
or 2 units of Pitressin were injected twice daily.
In several instances, overhydration was reduced
with infusion of 10 to 12.5 per cent mannitol,
and Pitressin was continued. A control period
after Pitressin was utilized whenever possible. In
some studies other drugs were administered
throughout both control and Pitressin periods
to minimize symptomatology. This included atropine in studies 4 and 5, paraldehyde in study 1,
Gelusil in studies 7 and 8, and either chloral
hydrate or Nembutal to all.
Sodium and potassium were analyzed on an
internal-standard flame photometer. Chloride was
analyzed with automatic titration5 with a Cotlove
chloridimeter,5 and nitrogen was analyzed by the
macro-Kjeldahl method. Osmolality was analyzed
by freezing-point depression, and calcium was
determined by an established method.6 Potassium
balance was corrected for nitrogen balance (2.7
mEq. K/Gm./N). An insensible loss of 5 mEq./day
for sodium, potassium, and chloride was assumed
although no visible sweat was noted.
Changes in chloride space were calculated by
standard methods.2 An initial chloride space of
20 per cent body weight was assumed. Changes
in total body water were calculated with the Newburgh modifications7 of Laveties formula for fat
balance.8 Previous studies have indicated a close
correlation between changes in body water determined by this method and the deuterium dilution
method.9' 10 Initial total body water was assumed
to be 60 per cent of body weight. With use of the
observed serum sodium concentration, sodium and
T HE PRESENCE of severe hyponatremia,
not associated with salt depletion, is now
well known in a wide variety of disease states.
In nearly all situations in which it has been
studied, low serum sodium concentrations have
been accompanied by an increase in body
water and thus the term "dilutional hyponatremia" has been used. In spite of the wellknown dilutional factor, certain studies have
indicated changes of serum cation not accounted for by fluid and electrolyte balances.'14 The hyponatremia in these states may
be due not only to dilution but also to an internal reduction of osmotic activity. The present study was designed to evaluate the role
of overhydration in the latter process. We
have used daily injections of Pitressin Tannate in Oil* to induce overhydration and
marked hyponatremia while maintaining strict
balance conditions. This approach has allowed further study of the mechanism involved in the genesis of severe hyponatremia,
water intoxication, and the diuretic escape
from Pitressin.
Methods
Thirteen balance studies were conducted in 10
patients hospitalized on the metabolism ward of
the Strong Memorial Hospital (table 1). Each
patient was in a separate, temperature-controlled
room. A constant diet was administered and this
was analyzed twice during each study. Constituents
of each diet are recorded in table 1. All excreta
were collected quantitatively and stool collections
were separated into periods with carmine markers.
Data were collected for water, sodium, potassium,
chloride, and nitrogen balance. The patients were
weighed at the end of each 24-hour period and a
fasting blood sample was obtained without exposure to air. Close observation by specially trained
tFor the purposes of graphic representation, symptoms of water intoxication were graded as follows:
Grade I, mild (lethargy, drowsiness, malaise, fatigue,
nervousness, bloated feeling, weakness, headaches).
Grade II, moderate (anorexia, epigastric "hunger
pains," nausea, frequent stools, abdominal cramps,
tightness of the chest, minimal vomiting). Grade
III, severe (haggard appearance, diarrhea, delirium,
marked nausea with vomiting). Severe coma or
convulsions were not observed. There was no marked
change in blood pressure in any subject.
From the Department of Medicine, University
of Rochester School of Medicine and Dentistry,
Rochester, New York.
Aided by grant H1969 from the U. S. Public
Health Service.
*Parke, Davis & Company, Detroit, Michigan.
Circulation, Volume XXIV, August 1961
CHRISTINE WATERHOUSE, M.D.
191
STORMONT, WATERHOUSE
192
Table 1
Clinical Data and Dietary Intake
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Study
Patient
1
A.G.
2
I.F.
3
4
5
M.S.
D.C.
D.C.
6
O.H.
7a
F.F.
7b
F.F.
8a
A.F.
8b
A.F.
9
10
I.C.
S.M.
11
T.C.
Age, sex, diagnosis
Group I
63, M, chronic alcoholism
and recent pneumonia
46, F, chronic alcoholism
and recent pneumonia
47, F, chronic alcoholism
50, F, fractured hip
50, F, fractured hip
Group II
54, M, chronic alcoholism,
gout, coin lesion-lung
54, M, reformed alcoholic,
cirrhosis, emphysema
54, M, reformed alcoholic,
cirrhosis, emphysema
40, F, obesity, bilateral
pulmonary hilar adenopathy
40, F, obesity, bilateral
pulmonary hilar adenopathy
Group III
54, M, chronic bronchiectasis
30, M, chronic alcoholism and
recent pneumonia
35, M, chronic alcoholism and
recent pneumonia
potassium balance, and calculated total body water,
values were estimated for total body osmotically
active cation, change in osmotically active cation
unaccounted for by electrolyte balance, and
changes in serum sodium concentration predicted
by water and electrolyte balance.* Isotonicity
*Body cation concentration was assumed to be
the serum sodium concentration corrected for Donnan
and protein factors plus 10 mEq./L. Total body
fluid osmotically active cation (TBC) was calculated
as the product of calculated total body water (TBW)
and cation concentration. The change in osmotically
active cation unaccounted for by balance (AuOAC)
was calculated as follows: AuOAC=TBC2-TBC1b(Na+K), where b(Na+K)=the sum of sodium and
potassium balance and TBC1 and TBCM=the total
body cation at the beginning and end of a period.
Predicted serum cation concentration at the end
of a period was calculated as follows: [TBC1+
b (Na+K) ] /TBW2. The change in serum sodium
concentration unaccounted for by balance=Observed
ANa-Predicted ANa=AuNa. Per cent change in
serum sodium concentration unaccounted for by
balance = %AuNa = ObservedANa-predictedANa
X100/observedANa. The absolute value for observed ANa was used as divisor. (See appendix for
sample calculations.)
Initial
weight
Kg.
Daily intake
Na (mEq.) K (mEq.) N (Gm.) H20 (liters) Calories
59
20
83
12.4
3.2
2570
53
47
68
9.3
2.2
1390
56
77
74
86
95
16
90
87
126
8.2
11.5
11.5
2.0
1.9
1.6
1800
1860
1860
64
187
110
17.0
2.8
3220
57
11
61
7.3
1.9
1370
59
11
61
7.3
2.5
1370
121
16
48
6.8
1.9
715
121
16
48
6.8
2.6
715
45
73
77
102
90
112
8.8
17.5
2.6
3.3
2020
2770
78
177
97
16.4
2.2
2115
among body fluid compartments was assumed.12 13
The use of serum sodium as an arbitrary point
for calculating cation balance has been of value
in evaluating osmotic changes, and errors inherent
in this method have been discussed.1' 10, 13 Furthermore, a linear relation has been demonstrated
between corrected serum sodium concentration and
serum osmolality (corrected for blood urea nitrogen and blood sugar).14 In our studies, there was
a close relationship between serum sodium and
serum osmolality. When total fall in sodium concentration was contrasted with total fall in serum
osmolality divided by two, a discrepancy of 2
mEq./L. or less was noted in all but one instance,
in which the difference was 4 mEq./L.
Renal concentrating ability was estimated by the
U/P osmolar ratio determined on 24-hour urine
specimens, and by net solute-free water reabsorption (TCH2O = Cosm - V). TCH2O was determined
following infusions of 10 to 12.5 per cent mannitol
at a rate of 10 to 20 ml. per minute. No catheter
was used. Subjects were fasting and received distilled water 20 ml./Kg. by mouth 1 hour prior
to the infusion except as noted in table 4. After
urine flow greater than 5 ml. per minute was
established with mannitol, aqueous Pitressin, 100
mU, was administered through the intravenous
tubing and 100 mU were added to the infusion,
Circulation, Volume XXIV, August 1961
HYPONATREMIA
which ran 30 to 45 minutes (i.e., 1 to 2 mU/Kg.
/hour). TCH20 was determined from plasma and
urine samples obtained during the infusions and
corrected to 1.73M.2 body surface area.
193
L 1,
589
Wt
55,7
Agm
12 CL SPACE L.
,1
55 j
/
10
i_-
54
Results
Clinical and Balance Data
The studies have been divided into three
groups based on the response to Pitressin:
Group I, marked fluid retention with severe
water intoxication; group II, initial antidiuresis, with escape from Pitressin effect; and
group III, minimal fluid retention (tables
1 and 2).
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Group I
Balance data were obtained in five studies
on four patients (table 2 and figs. 1 and 2).
Studies 4 and 5 on subject D.C. were carried
out as a continuous balance experiment. After
9 days of Pitressin administration on a 95mEq. sodium diet (study 4), the sodium intake was reduced to 16 mEq./day and Pitressin was stopped. Following equilibration on
this intake, Pitressin was again administered
for 17 days (study 5).
A prompt antidiuretic effect occurred in
all studies with urine volumes 27 to 48 per
cent of the control values and osmotic U/P
ratios of 2.5 to 4.1. Fluid retention occurred
at a rate of 0.4 to 2 liters a day and mild
symptoms of water intoxication began on the
second to the fourth days. A slight escape
from Pitressin antidiuresis was evident after
the third or fourth day with increasing sodium and chloride excretion, urine volumes
58 to 79 per cent of control values and osmotic
U/P ratios of 2.1 to 3.8 (table 2). As progressive overhydration and hyponatremia
continued, symptoms became marked and
potassium excretion increased without a corresponding fall in sodium excretion. Severe
water intoxication developed in all instances,
forcing discontinuation of Pitressin after 6
to 12 days.
There are several points of interest in the
balance data of these patients. 1. The Pitressin-induced loss of 359 mEq. of sodium and
90 mEq. of potassium during study 4 (subject
D.C.) did not affect the development of a
Circulation, Volume XXIV, August 1961
+
*00
XL U OAC
a
nEQ/doy
-
1A
I00
-
-150
40
13 0 S£ RU
t
120
-
NA
mEOIL
20
BALANCE
mEoldoa,
K
m
Q
- 50
'
NAA
e
-50-
a
FLU/D INrTAE LBoy
UR9INE VOLUME
L
doy
1
"800 -
3
0
I
2
400 URINE
CONCENTrArToV
-200
2
3 4 5
6
7 8 9 10 PI
DX rs
2 13 14
Figure 1
Balance study 3 (M.S.) showvinig rapid development
of severe water intoxication with marked caution
losses unaccounted for by balance. (*) Denotes
emesis which was analyzed and included in data.
Balance data are graphically represented by plotting intake downward from zero line. The bars
then represent output and the area above the
zero line indicates negative balance.
typical, although delayed, response to Pitressin during study 5 with further electrolyte
loss. 2. Mannitol-induced diuresis in study 5
(fig. 2) rapidly corrected the overhydration
from Pitressin. The patient was munch improved symptomatically by this procedure.
The prompt return of marked antidiuresis
with Pitressin is also clearly seen. 3. Although
the increase in urinary potassium was marked
in some patients of this group, the total potassium loss was never exeessive (the cumulative
potassium balance varied from 0 to -90 mEq.).
In most instances the potassium loss began
before the patient's intake of food was limited
by severe nausea or anorexia.
Group II
In this group there were five studies ill
three patients (table 2 and figs. 3 and 4).
Studies 7a and 7b were a continuous experiment and are shown together in figure 3. The
only change in the experimental design of
these two studies was an increased fluid intake
STORMONT, WATERHOUSE
194
BODrY Wt Kg9
CL. SPACE L
_----
SYMProMs
Au OAC
SERUM NA
mEo/L.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
BALANCE
U
* K
E*
S.
mEo /day
FL U/V IN7AKE L /doa
URINE CWCENTRA TICW
-_mOsm/L.
URINE VOLUME L /day
.
.
.
.
.
.
.
.
.
.
.
s
~ ~ ~
.'
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
DA YS
Figure 2
Balance study .5 (D.C.) showing the gradual delelopment of severe wiuater intoxication
inb a moderately salt depleted subject. (M) denotes hypertonic muannitol infusion which,
was follo wed by loss of overhydration, gain in cation unaccounted for by balance
(zAlOA C), and ieluprovenelenit in symlptomls. On day 3.5, the sodium balance was -212 nmlEq.
in study 7b. Studies 8a and 8b were also
earried out continuously on the same patient
(A.F., fig. 4), and agaiii the major change in
the two studies was increased fluid intsake.
The antidiuretie respoiise was less inarked
than in group I with urine volumes 44 to 63
per cent of control (table 2). Overhydration
occurred iniitially l)ut fluid retention rapidly
became less marked or absent. The escape
from Pitressin antidiuresis was more pronounced than in group I, with urine volumes
85 to 87 per cent of control and osmnotic
U/P ratios 2.0 or less. Loss of sodium and
chloride occurred at a rate similar to group
I. Potassium loss was less marked than in
group I and in some instances was inversely
related to sodium loss (fig. 4). Symptoms of
water intoxication were less prominent than
in group I.
With increased fluid intake (studies 7b
and 8b, figs. 3 and 4) and continuous Pitressin administration, fluid retention again became marked and peripheral edema occurred.
(Both subjects had a history of peripheral
edema.) Intermittent diuresis with urine
volumes in excess of control and osmotic U/P
ratios equal to or less than 1.0 limited continued gaini in total body water. This diuresis
was not associated with an increase in urinary sodium and chloride. Total cumulative
Circulation, Volume XXIV, August 1961
HYPONATREMIA
195
Table 2
Fluid and Electrolyte Changes
Gain in total body water
Group I
Days on
Pitressin
Urine volume*
ConMini- Maxitrol
mum
mum
Liters/day
U mOsm
P
Maximum Minimum
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Study 1
7
2.4
0.7
1.3
2
7
1.8
0.6
0.9
3
6
1.7
0.6
1.1
4
9
1.7
0.7
0.9
5
12
1.2
0.6
1.0
Group II
6
7
2.1
1.3
1.8
7
7a
1.3
0.5
1.1
b
10
1.2
2.0
t
8
8a
1.0
0.6
0.9
t
14
b
1.0
1.8
Group III
8
9
2.2
1.7
2.8
9
2.3
1.8
2.5
10
8
1.4
1.2
2.0
11
*Figures represent mean values for 3-day periods.
Continuous study-no control.
tOver-all maximum gain for studies a and b.
2.5
3.0
4.1
3.6
2.4
2.1
3.8
2.8
2.8
2.7
1.4
2.5
1.4
2.0
1.0
0.4
1.2
0.8
1.4
2.0
2.9
0.7
1.0
1.0
gain in body water was similar in groups
I and II (table 2).
A good antidiuretic response to Pitressin
was again observed following mannitolinduced diuresis in study 8b (fig. 4).
Group III
Three patients. There was a minimal antidiuretic effect with more rapid increase in
urine volume, and osmotic U/P ratios of 1.0
or less (table 2). Overhydration and hyponatremia were less than in groups I and II.
Sodium and chloride losses were less marked
and usually inversely related to potassium
losses.
Changes in Electrolyte Concentration and
Distribution
Serum sodium concentration fell to the
range of 100 to 113 mEq./L. in group I after
6 to 12 days of Pitressin administration and
increasing overhydration (figs. 1 and 2 and
table 3). In group II, with similar degrees
of overhydration, serum sodium remained
above 115 mEq./L. (figs. 3 and 4 and table
3). There was a rough correlation between
serum sodium concentration and degree of
Circulation, Volume XXIV, August
1961
MaxiMaxi- mum Mean
mum
rate
rate
Liters L./day* L./day
Mean balance
Na
K
mEq./day rnEq./day
8.3
5.5
3.2
2.5
5.1
2.0
1.3
1.1
0.4
0.6
0.9
0.8
0.4
0.2
0.4
-28
-27
-59
-44
- 8
0
- 2
- 3
-10
- 4
5.9
4.9$
1.0
0.7
0.6
0.5
0.5
0.8
0.4
0.1
0.4
0.2
-51
-14
-20
- 9
+
-
-14
1
3
4
7
+ 3
0.4
0.3
0.6
0.1
0.2
0.1
-13
+14
- 8
- 2
- 3
- 5
6.1:
1.7
2.0
2.1
symptomatology. Mild. symptoms were seen
with serum sodium concentration in the range
of 120 to 130 mEq./L. Moderate symptoms
were associated with serum sodium concentrations of 114 to 120 mEq./L., and severe
symptoms occurred in all subjects with serum
sodium concentrations below 114 mEq./L.
Serum potassium concentrations varied less
than 1 mEq./L. throughout and there was no
consistent change in blood urea nitrogen or
hematocrit even with marked sodium losses.
Serum carbon dioxide content fell slightly
from control values of 26 to 32 mM/L. to
values of 22 to 24 mM/L. during severe hyponatremia.
Changes in serum sodium concentration,
which could not be accounted for by cation
and fluid balance (A uNa), occurred in all
studies (table 3). Although variable changes
in A uNa occurred with the development
of mild to moderate hyponatremia, greater
than 50 per cent of the fall in serum sodium
concentration was unaccounted for at the
lower serum sodium concentrations (table 3
and fig. 5). Changes in total body fluid os-
196
STORMONT, WATERHOUSE
Table 3
Changes in Serum Sodium Concentration Not Accounted for by Balance
Study Days*
1
4
3
2
4
3
4
2
6
3
5t
7
2
3
4t
2
5
7
3
4
4
4
4
5
3
3
3
4
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
5
6
7
8
9
10
(A)
Final
serum Na
mEq./L.
Observed
change
mEq.
(B)
Predicted
change
mEq.
AuNa
Difference
(A)-(B)
mEq.
114
108
117
100
126
111
121
113
132
128
122
112
134
121
117
127
118
133
125
117
128
-20.7
- 5.4
-20.4
-17.5
-15.1
-15.5
-17.9
- 8.2
+19.2
- 7.0
- 5.7
-10.2
+17.6
-23.6
- 43
-11.8
-- 9.1
- 7.3
- 8.3
- 7.4
-14.7
+ 7.3
- 4.9
+ 4.5
-25.6
0
-18.5
- 8.5
-16.5
- 3.9
-12.2
- 2.6
+ 7.5
-10.2
- 3.8
- 5.1
+ 9.8
-21.4
- 4.8
-12.5
- 8.3
-12.4
-10.5
- 7.4
-11.1
+ 5.6
- 6.0
+ 1.6
+ 4.9
- 5.4
- 1.9
- 9.0
+ 1.4
-11.6
- 5.7
- 5.6
+11.7
+ 3.2
- 1.9
- 5.1
+ 7.8
- 2.2
+ 0.5
+ 0.7
- 0.8
+ 5.1
+ 2.2
0
- 3.6
+ 1.7
+ 1.1
+ 2.9
11
136
133
137
138
% AuNa
(A)-(B)
(A)
X 100
per cent
+ 24
-100
- 9
- 53
+ 7
- 75
- 32
- 68
+ 61
+ 46
- 33
- 50
+ 44
- 9
+ 10
+ 6
- 9
+ 70
+ 26
0
- 24
+ 23
+ 22
+ 64
Symptomst
2+
3+
1+
3+
1+
3+
1+
3+
0
1+
1+
3+
0
0
2-f
1+
2+
0
1+
2+
1+
0
0
0
*Data represent sequential periods of Pitressin administration except for studies 7 to 11
where data represent only periods in which the observed change in serum sodium was at
least 1 mEq./day, and for recovery periods (t) where Pitressin was not given.
tSee footnote page 191.
motically active cation
were
directly related
to A uNa and reflect the same mechanism.
Maximal A uOAC losses (greater than 80
mEq./day in studies 1-5) also occurred with
severe hyponatremia and water intoxication
(figs. 1-4). During recovery from severe hyponatremia, induced either by intravenous
mannitol administration or by discontinuance
of Pitressin, a gain in cation unaccounted
for by balance (both A uNa and A uOAC)
was observed (figs. 1-5 and table 3).
Additional data taken from the reports of
others4' 15, 16 fall in the same range as data
from this study (fig. 5). When this data are
represented as a per cent of the observed fall
in serum sodium,* a good correlation is evident (fig. 5). A curve fitted to the data in
figure 5 by the method of least squares, has a
formula of Y = 0.26X + 123.1 if Y = final
serum sodium concentration and X = %o A
serum sodium unaccounted for by balance.
Correlation coefficient is 0.90 with a p value
of less than 0.01. In all subjects with severe
symptoms, over 50 per cent of the fall in
serum sodium was unaccounted for by balance and serum sodium concentrations were
below 114 mEq./L., regardless of the rate of
change of observed serum sodium concentra*See footnote page 192.
Circulation. Volume XXIV, August 1961
HYPONATREMIA
197
,
'
A R.R.M.
'
- ---w--
'
1
14
Por
We/gmM
CL SPACE
58
..-_.k |-v
*
~~~~~~~~~~~~~~~~~~~~~10
56
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
MUMCE -50,
into/day
TAKME
mE6/eet
Lidey
i.
12
w
|~~~~~~~~~~~~~~~~~EOL
.1 10
40SRMSDU
0
3
I
7.. .......URINE
.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..
a
0
.~ ~ ~ ~i
COACENTARAJON/
400
2.I.'.
200
2 3 4 5 6 7 8 9 10 II 12'13 14 15 16 17 18 19 20'2122'23'24'25
26
DAYS
Figure 3
Balance study 7 (F.F.) showing prolonged overhydration with intermittent episodes
of hypotonic diuresis, and failure to develop severe water intoxication even with increased
fluid intake, (M) denotes hypertonic mannitol infusion. Period 7a includes days 4 to
10, while 7b includes days 11 to 20.
tion, the rate of fluid retention or the total
gain in total body water (figs. 1, 2, and 5
table 3).
Renal Response to Pitressin
Progressive overhydration in groups II and
III was limited by intermittent periods of isotonic or hypotonic diuresis. This increase in
urine volume occurred spontaneously in response to Pitressin-induced overhydration,
and was not associated with increased total
solute excretion (fig. 6), calcium excretion or
potassium loss (tables 2 and 4). In addition,
there was no correlation with variations in
fluid, nitrogen, sodium, or potassium intake
(table 1). This diuresis began in group III
Circulation, Volume XXIV, Auguat
1961
subjects as early as 2 days following the start
of daily Pitressin injections, at a time when
there had been no marked gain in total body
water (table 2).
Studies of renal function during infusion
of hypertonic mannitol and Pitressin revealed
a correlation between increase in total body
water and maximum ability to concentrate
the urine in the presence of an osmotic load
(table 4). Following spontaneous diuresis
with loss of overhydration (studies 9 and
11) the response to hypertonic mannitol and
Pitressin more closely approximated the normal response (table 4 and fig. 7). A marked
diuretic effect and weight loss of 1 to 3 Kg.
198
STORMONT, WATERHOUSE
BODY Wt K9g
#
114
|\
',
112
A U OA
mEo/d
23
,5 _
+50
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
450-
;
-
140
SERUM /N4
120
BALANCE
U
NA
an
miEo/diy
K
0.
FLUID INTAKE L/Oo
UR/F/E VOL UME L/do,
O-
o1
2
tj|08
3
2 3
4 5
6 7
rL7 LJ1 f ~ ~ ~ ~ ~CONVCENRAM
~ ~URINE /OV
200e~L3A'2'3U
29'30'31 '32 33'34
8 9 10 11 12 13 14 IS 16 17 18 19 202 122 23 24'25 2627 28
35
DAYS
Figure 4
Balance study 8 (A.F.) showing priolonged orerhydration in subject recei iing a lowii,calorie diet with escape from antidiuretic effect and failure to develop symptoms of
severe water intoxication. (M) denotes hypertonic mannitol infusion. Period 8a includes
days 4 to 11, and 8b includes days 12 to 25.
in 24 hours was observed following mannitol infusion in those patients with overhydration and decreased TdH20, in spite of
continued daily Pitressin administration. This
defect in renal concentration during osmotic
loading could not be directly correlated with
the spontaneous low solute diuresis which
limited overhydration in groups II and III.
Estimation of one aspect of adrenal function through measurement of urine hydroxysteroid excretion revealed a consistent difference between group I subjects in whom
antidiuresis was maintained, as contrasted
with groups II and III subjects in whom
antidiuresis was less muarked and of limited
duration. In groups 11 and III a fall in 24hour urine total hydroxycortiicoid excretion
occurred during the first 3 to 5 days of Pitressin administration followed by rapid return to control values at 7 to 9 days. In
group I, the fall ill corticoid excretion was
more pronounced and the return to normal
less rapid (fig. 8).
Discussion
Hyponatremia associated with alterations
in total body osmotically active cation unaccounted for by balance has been postulated
in certain disease states.1-4, 17-19 Our studies
demonstrate a marked decrease ill osmotically
active cation, which was unaccounted for by
balance and ail observed fall ill serumn sodium
concentration greater thail predicted. This
was induced by severe overhydration and was
Circulation, Volume XXIV, August 1961
HYPONATREMIA
199
,
/40-
x
x
xX
.'
10
I>cc
00
/30-
A
Serum
.
'..
Sodium /20 -
0
MEQ/L.
Cd
A
//0-
o o
00
0
inn;Tlu
-0
-i. 5
b0
-5
+5/
+/b
._,
- Predicted A)
A[No](Observed AMEQ/L
++
0
S
/40 -
x
x
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
e
/30
Serum
Sodium
MEO/L /20
to m
c
Co
P..i
0
P4~
o
0
zbD
COD
lool
t
-/00
-50
%A [Na]
0 LO 1
d A CQ
'50
0
+100
(Observed A -Predicted A,)
Obs. A
Figure 5
Derived data from all balance studies (0) showing
changes in serum sodium concentration unaccounted
for by fluid and electrolyte balance as related to
final serum sodium concentration (table 3). Data
from the literature are included as follows: A (16),
X (4), and 0 (15). The lower graph depicts this
data as a per cent of observed change, and a
curve fitted to this data has a formula Y=0.26
X +123.1.
OF URINE VOLUME rO SOLUrE EXCRETON
RELArION
DURING P/TRESS/N ADtINISrRAriONv
35
*
25
Gr.
G'
G' il
a
a
'7
0
00
a
/00
o
200
300
SqS
4-O~
:
p.,4C4-4
TJo /
0
0
O
l O
*1
0
0o
*
* **
*
*
/0
a
a
XI
000
0
IS
05
CH
Q)
3'.
0
0
4.
O'
S
0
0
0
a
0
10
ce
o
e
5
a
a
0)
Volume
L1/24hs.
'04 0,-
cc
0
20
Urine
0
0
3.t
a
30
P
3.:
-0
,, 1.4
cl
11
V
0/2
*3'.
*
400
500
600
700
800
90
00
0/
*0!;
N
n
Solute Excretion
0/
,o-6<
Figure 6
Solution excretion and urine volume for subjects
in groups I, II, and III.
Circulation, Volume XXIV, August 1961
4-*'
0
CA.p4
CII>
+'
+co
200
STORMONT, WATERHOUSE
No. I
CONv TROL
No.I1
|
| MANNITOL|
30
IRTMSIN I
l
l
l
n/in.
No. 8
P/ITRESS/N DAILY
Aorked Over H/ydrotion
| MANN ITOL
PITES8IN
AS~~~~~~~
l
1
$
pl
20.
I5
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
C140
MANNITOL
|PITRE5SI1
25-
Cosm ml rin
Urine Volume
P/rRESS/N DAILY
After Spontaneous Diuresis
nJ
POM'°
EY°
10
rIME /N MINUTES
Figure 7
Clearance studies during infusion of hypertonic mannitol and aquous Pitressin in patients
A.F., (no. 8) and T.C. (no. 11). Water load was given orally 1 hour prior to mannitol
infusion.
not associated with
active disease state. It
was readily reversible, either by discontinuation of Pitressin and allowing water diuresis
to occur, or by inducing osmotic diuresis with
intravenous hypertonic mannitol in the presence of continuing Pitressin administration.
Correction of overhydration was associated
with a gain of osmotically active cation unaccounted for by balance, a rise in serum
sodium concentration greater than predicted,
and a loss of symptomatology within 24 to 72
hours. Unaccountable cation changes were
most evident at serum sodium concentrations
below 114 mEq./L. In this range, over 50
per cent of the fall in serum sodium concentration was unaccounted for by fluid and
cation balance, and severe symptoms of water
intoxication were noted. At higher serum
sodium concentrations, the unaccounted for
changes in cation were less prominent, and
daily variations were evident with cation gains
often balancing cation losses.
While certain studies lend support to the
an
hypothesis that cellular hypotonicity may be
a factor in the development of hyponatreia~l-4 17-19 other studies have failed to show
a loss of cation other than that unaccounted
for by balance.'1520-22 The present study suggests that such losses may become evident
only with severe degrees of fluid retention.
Previous attempts to demonstrate unaccounted
for loss of cation resulting from overhydration in man, have dealt with serum sodium
concentrations in the range of 118 to 130
mEq./L., a range where undetected cation loss
was minimal or variable in our studies. There
are certain difficulties in applying data from
azotemic or hyperglycemic dogs to the clinical
situation; nevertheless, data of Wynn15 reveal
values that fall close to the values obtained in
our data (fig. 5).
Loss of cation unaccounted for by balance
may represent either an undetected external
loss or an internal alteration in metabolism
resulting in loss of osmotic activity. Our
studies would not detect losses from the body
Circulation, Volume XXIV, August 1961
201
HYPONATREMIA
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
of hydrogen, magnesium, or amino acids that
are capable of acting as cations (lysine, arginine). Although we cannot exclude an undetected cation loss of this type, the rapid
gain in unaccounted for cation with correction
of overhydration would suggest that this was
not a major factor. Reversible reduction of
osmotic activity could be accomplished by
cation binding in mucopolysaccharides, proteins, weak acids, or bone, and this would
not necessitate an osmotic gradient between
cells and extracellular fluid. The observation14 that serum sodium concentration is proportional to the sum of exchangeable sodium
and potassium divided by total body water
even at low serum sodium concentrations, as
well as other studies,"1 12 suggests that there
is no sustained osmotic gradient between cells
and extracellular fluid. Our data suggest that
with severe overhydration, isotonicity is maintained not only by fluid shifts, but also by
reduction in total number of active cellular
osmols. This mechanism could act as a homeostatic compensation tending to maintain cell
volume.
Severe symptoms of water intoxication occurred in all studies in group I, and were
associated with marked overhydration, negative sodium and potassium balance, and a
fall in serum sodium concentration below
114 mEq./L. The failure to develop severe
symptoms in group II during an equivalent
degree of Pitressin-induced overhydration
(table 2) was correlated with (1) intermittent episodes of increased urine volume without increased total solute output (figs. 3, 4,
and 6) so that maximum gain in total body
water was accomplished more slowly, and
only after an increased fluid intake; (2) less
fall in serum sodium with relatively close
agreement of predicted and observed values
(table 3 and fig. 5); and (3) less fall in total
urine hydroxycorticoid excretion with more
rapid return to or beyond control levels
(fig. 8).
These studies indicate that certain patients
receiving daily Pitressin injection may develop a failure to form concentrated urine.
This is manifest both in response to simple
Circulation, Volume XXIV, Auguet
1961
24 He
TOrAL URINE CORTICOID EXCRETION
/000
s0
..
,e of Contro/ 60
....
. ..
.....
40
Gr
Gr
Gr.
20
*
22
Severe Woter Intoxicotion
12
/0
8
Doys of Pitressin Administration
4
1
Ill
6
14
Figure 8
Urine hydroxycorticoid excretion indicating more
pronounced fall in three studies of group I relative to three studies of group II and one of group
III.
overhydration (continuous water load) or
to intravenous mannitol (osmotic load). The
spontaneous development of isotonic (or even
hypotonic) urine was not directly correlated
with either the degree or duration of overhydration. These data confirm in part earlier
observations in animals23 24 and man.16 25, 26
Decreased permeability of the renal tubular
cells to water may be responsible for this spontaneous escape from Pitressin effect.'6 In contrast, the inability to concentrate maximally
during an osmotic load appeared to be related
to the degree of overhydration and was corrected following dehydration. Previous studies
have demonstrated that overhydration may
affect renal concentrating ability.27-29 This
correlation with changes in body water and
the lack of correlation with the spontaneous
diuresis suggests that decreased solute concentration in the renal medullary interstitial fluid
may be an etiologic factor. Osmotic mechanisms in urine concentration and dilution
have been recently reviewed30 and will not be
further discussed here.
Escape from Pitressin-induced antidiuresis
associated with prolonged overhydration may
act as a self-regulatory mechanism during abnormal states to limit excessive fluid retention and consequent water intoxication. It
is possible that the concentration defect observed in certain patients with cirrhosis3'
STORMONT, WATERHOUSE
202
and other states associated with overhydration and hyponatremia3 may be related to a
similar phenomenon.
The present data would suggest that certain
clinical states associated with fluid retention,
severe hyponatremia, and water intoxication
be benefited by fluid restriction, osmotic
or steroid therapy. Unfortunately
one or all of these measures may be contraindicated in overhydration associated with severe renal, cardiac, infectious, or brain dis-
may
diuresis,
ease.
Summary
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Prolonged overhydration and hyponatremia
have been produced in 10 patients with use
of Pitressin Tannate in Oil. Balance studies
have shown that in patients who developed
moderate hyponatremia, the drop in serum
sodium could be explained by water retention.
In patients who developed severe water intoxication, the very low levels of serum sodium (100-114 mEq./L.) could not be entirely
accounted for by changes in salt and water
balance.
Certain patients failed to develop severe
water intoxication although an equivalent
degree of overhydration was achieved. In these
subjects, further overhydration was limited
by intermittent episodes of low solute diuresis.
This diuretic escape from Pitressin effect has
been evaluated by measurement of U/P osmolar ratio on 24-hour urine specimens as well as
TdH2O during hypertonic mannitol infusion.
Defects in both aspects of renal concentration
were observed, although they were not necessarily coexistent.
Appendix
Sample Calculations
Study 2: Control 3 days, Pitressin 7 days, control
4 days.
Balance Data-Days 8 and 9
1. I. L.=insensible weight loss=weight in-weight
out-Abody weight=5590-3480 ( 340)=2450
or 1225 Gm. q.d.
2. Fb=fat burned=I. L.-(2.18C + 12.26 UN)=
3.93
1225-(2.18 X 149 + 12.26 X 8.0)=204 Gm.
3.93
q.d.
3. ABF=Abody fat=fat in
-
fat burned
=
61-204= -143 Gm. q.d.= -286 Gm./2 days.
ABP=Abody protein=6.25X0.08 = -.5 q.d.=
-1 Gm./2 days.
4. ATBW=Atotal body water=Abody weight
ABF
-
ABP= -340-(-286)-(-1)=
-53 ml.= -0.05L.
5. TBW1=total body water, initial=36.97.
TBW2=total body water, final=36.92.
6. Initial serum sodium=117.2, corrected=119.7=
[Na]1
Final serum sodium=107.6, corrected=109.9=
[Na]2
+ K) =balance of sodium + potassium
(corrected) = -172 mEq.
8. TBC,=total body cation, initial=TBWi X
([Na]1 + 10)
TBC1=36.97 X 129.7=4795 mEq.
7. 1) (Na
9.
TBC2=final TBC=26.92 X
AuOAC=TBC2 - TBC1
119.9 = 4427 mEq.
-
b(Na + K)=
-196 mEq. or 98 mEq. q.d.
10. [Na] pr=predicted serum sodium concentration
=
[cation]pr
TBW2)
-
-
10=(TBC, + b(Na + K)/
10= 4795 + (-172)
36.92
-
10=115.2
mEq.
11.
12.
A[Na]pr=119.7 - 115.2= -4.5 mEq/L.
A [Na] b=observed change in serum sodium
concentration=119.7 - 109.9=9.8 mEq.
:.% AuNa=
-9.8 - (-4.5) A [Na]ob - A[Na]pr
A [Na]ob
9.8
54% = per cent of change in serum sodium
concentration unaccounted for by balance.
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The Genesis of Hyponatremia Associated with Marked Overhydration and
Water Intoxication
JAMES M. STORMONT and CHRISTINE WATERHOUSE
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Circulation. 1961;24:191-203
doi: 10.1161/01.CIR.24.2.191
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
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Copyright © 1961 American Heart Association, Inc. All rights reserved.
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