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The Pathophysiology of Sodium Depletion in Man
•
The Pathophysiology of Sodium Depletion in Man HARVEY R. BUTCHER, JR., M.D., F.A.C.S.*
Bodily deficits of sodium salts in man produce many of the , physiological changes common to shock. The weakness, apathy, hypotension, oliguria and azotemia incident to negative sodium loads in the body frequently accompany periods of severe diarrhea or vomiting, extensive injury and large burns. Such illnesses or injury obviously are accompanied by derangements in metabolism other than simple sodium depletion. The presence of blood loss, water intoxication, sepsis, potassium deficits and so forth have not permitted those caring for these ill persons to define quantitatively the relationship between specific deficits of exchangeable body sodium alone and the biologic responses resulting from them. Recently, however, the quantitative relations of these responses to unit deficits of rapidly exchangeable sodium salts have been defined in part by the experiments of Grayson, White and Moyer." Their conclusions have been confirmed and extended by the collection of additional data from volunteers subjected to stepwise sodium depletion in a similar way.
METHODS
Deficits of sodium salts were induced in seven lean, fasting men by constantly removing duodenal fluid from them through a metal-tipped duodenal tube, the position of which was confirmed radiographically. During the period of depletion 10 ml./kg. of body weight of 5 per cent glucose in water was given each subject daily as replacement for the net losses of water insensibly and through the urine. The time required to produce the desired losses of sodium salts was four to five days. The experiments were terminated by repleting them with intravenous infusions of lactated Ringer's solution in quantities sufficient to replace the accumulated deficits of sodium in four to six hours. Five of the volunteers were
* Professor of Surgery, Washington University School of Medicine; Department of Surgery J Barnes Hospital, St. Louis, Missouri
345
346
HARVEY
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BUTCHER, JR.
alcoholic men who had been in the hospital for psychiatric therapy for more than two months. Two persons were nonalcoholic; one had schizophrenia, the other an inguinal hernia. All subjects appeared healthy and felt well. No physical or chemical evidence of liver disease existed. The experiments were begun by 12 hours of fasting. The duodenal tube was positioned in the second part of the duodenum and a steady small suction applied to it by a mechanical pump. Simultaneously a Foley catheter was inserted and urine collections begun. When signs of illness, such as orthostatic hypotension or profound weakness occurred or when the estimated sodium deficit reached six to eight mEq.jkg. body weight, the duodenal tube was removed and Hartmann's solution was infused intravenously until the cumulative deficits of sodium were replaced. The intravenous infusion of sufficient Hartmann's solution was completed in four to six hours. After 24 hours of further observation the urinary catheter was removed and eating and drinking permitted.
OBSERVATIONS The observations made during the periods of depletion and during and after repletion are shown in Table 1. The data from these experiments are presented in Figures 2 to 6 and Tables 2 to 8. Changes in Oxygen Consumption The elevations of minute oxygen consumption associated with sodium depletion in chronic alcoholic men not having drunk alcohol for several months are shown in Table 2. Only one alcoholic subject (R.J.) failed to have a higher rate of oxygen consumption after sodium depletion than he had before it. The elevated oxygen consumption in these persons was associated with agitation, an inability to sleep and a tendency to mild delirium. Similarly, an agitated behavior was observed in the schizophrenic man who also had an elevated oxygen consumption during sodium depletion. The increased minute oxygen consumptions of alcoholic human beings reported by Grayson, White and Moyer were of similar magnitude. They also showed that nonalcoholic men subjected to sodium depletion exhibited a nearly direct relationship between minute oxygen consumption and the amount of rapidly exchangeable sodium salts remaining in the body. In other words, as sodium depletion increased the minute oxygen consumption decreased in normal persons. For every milliequivalent of sodium deficit per kilogram of body weight there was a reduction of minute oxygen consumption of 5 to 15 ml. per minute (Fig. 1).1 The normal person's response to sodium depletion also differs from the response of the alcoholic in other ways. A decrease in spontaneous motor activity, apathy and slow but rational communicative responses are manifest by the sodium depleted normal person while the alcoholic man depleted of sodium salts displays
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347
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
Table 1.
Observations Made and Methods Used FREQUENCY OF
OBSERVATIONS
METHOD
OBSERVATION
Basal oxygen consumption
, Daily
q12h q4h q4h q4h q4h q4h q4h q4h q4h
Collin's respirometer (two 8-min. periods) Capillary method 10,000 G. for 5 min. Schales and Schales Spectrophotometry (Weichselbaum-Varney) Weichselbaum Van Slyke Spectrophotometry (Weichselbaum-Varney) Rosenthal Weichselbaum-Varney Schales and Schales Kjeldahl (Van Slyke and Peters) Beckman Beckman Weichselbaum-Varney Weichselbaum-Varney Schales and Schales
q4h q4h q4h q12h
Riva-Rocci apparatus Maximum thermometer Questioning and observation Silk scale, sensitivity 50 gm.
Hematocrit q12h Serum chloride. . . . . . . . . . . . . . . . . . .. q 12h Serum sodium , q12h Serum albumin and globulin Serum bicarbonate Serum potassium
,
q12h , q12h q12h
Serum urea nitrogen , Urinary sodium , Urinary chloride. . . . . . . . . . . . . . . . .. Urinary nitrogen , Urine pH* , Duodenal pH* . . . . . . . . . . . . . . . . . . .. Sodium in duodenal fluid , Potassium in duodenal fluid , Chloride in duodenal fluid , Blood p.re~sure while recumbent and sitting , . . . . . . . . . . . . . . . . . . .. Oral temperature Mental responsivity. . . . . . . . . . . . . .. Weight * On pooled 4-hour specimens.
Table 2.
0 xygen Consumptions Associated with Sodium Depletion and Repletion BEFORE SODIUM
AFTER SODIUM
AFTER LV. REPLETION
DEPLETION
DEPLETION
OF SODIUM SALTS
(ml.yrnin.)
(ml.y'min.)
(ml.yrnin.)
1. Chronic alcoholic men R.J. 127 J.S. l83 B.T. 72 I.P. 131 G.W. 56 -Mean 94
110 158 104 200 112 -137
103 94 80 138 62 -94
2. Normal man (hernia) C.L. 94
91
83
169
150
3. Man ill of schizophrenia R.G. 141
348
HARVEY
R.
BUTCHER, JR.
175
165
155
• Pot!s \ \
\ \ \ \
\ \ \
......
"
.
......
//
,,
,
Harmon
/
/
" ,
' ......./
,/
/
/
"
105 Penn
Hill
95
--Normals - --- Alcoholics
85
-8
-7
-6
- 5
-4
- 3
-2
-I
LOAD No mEq/K. B wo
Figure 1. Oxygen consumptions of 5 normal persons and 5 chronic alcoholics during transduodenal depletions of sodium salts.
increased spontaneous motor activity, agitation, irrational responses and mild delirium. Although we do not know the basic causes for the hypometabolism incident to acute deficits of sodium salts in normal persons and the hypermetabolism accompanying such deficits in chronic alcoholics, it would appear that the differences in spontaneous motor activity and in the affect of normal and alcoholic persons subjected to depletion of sodium salts are at least in part responsible. The ability of acute deficits of sodium salts in the body to produce agitational symptomatic psychosis in the chronic alcoholic and contrariwise apathy, somnambulance and hyporeflexia in normal persons suggest that the mental responses induced by acute sodium deficits may be exceedingly
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349
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
varied in different illnesses and under the influence of different drugs. Obviously, however, the chronic alcoholic who develops acute symptomatic psychosis postoperatively may have as the precipitating cause an acute deficit of exchangeable sodium salts.
Changes in Urine Both in these experiments and those reported by Grayson, White and Moyer, the volumes of urine fell below 20 ml./hr. before the depletions of sodium salts were completed. However, there appeared to be no regular relationship between the severity of the oliguria and the magnitude of the sodium deficit. In other words, the rate of excretion of urine could not be used to predict the extent of sodium deficit. Stokes et al.? have shown that renal water and solute excretion are reduced by reductions in the exchangeable sodium mass of the body but their investigations showed no proportionality between unit deficits of sodium and the magnitudes of these changes. All subjects depleted of sodium salts had a fall in the concentrations of sodium in the urine during depletion (Fig. 2). However, concentrations of sodium in the urine below 25 mEq./L. did not develop until after more than 4 mlsq.Na"/kg. had been lost in five of the experiments. Indeed, in CONCENTRATION
SODIUM ION IN URINE mEq/Liters
160 140 oR.G.
• 8.7:_ eR.J.
120
AJ.S. 6G:~
100
.I.R cC.L.
80 60 40 20
-8
-7
-6
-5
-4
-3
-2
-I
SODIUM LOAD mEq/Kg BODY WT.
Figure 2. The individual concentrations of sodium in the urine accompanying negative corporeal sodium loading in 7 persons are shown. Obviously, the concentration of urinary sodium is no indicator of the magnitude of sodium deficit.
350
HARVEY
CONCENTRATION
BUN
IN SERUM ASSOCIATED
R.
BUTCHER, JR.
WITH
Nat DEPLETION
«sr
mg/IOOml.
o R.G. /
0R.J. .I.F! cC.L. AJ.S. AG.~
/
60
/ / /
After No+ Repletion
~
/
50
/ / /
/
40
/
/ /
A
/
;' ;'
."
~'//
30
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,;"
~~"
--; ~~ "/
----
f~~-- -- --- - - ---.... ~ .0--.J""~""--
t -9
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-----
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-7
20
I
-6
-5
-4
-3
-2
I -I
SODIUM LO AD m Eq / Kg BODY WT. Figure 3. This graph shows the blood urea nitrogen concentrations in 7 persons subjected to transduodenal depletions of sodium salts.
one (R.G.) the concentration of sodium in the urine remained above 25 mEq.jL. despite a deficit of 7.75 mliq.Nat /kg. body weight. In other words, although a low concentration of urinary sodium may be indicative of a serious negative sodium load in the body, such may, in fact, also exist when concentrations of sodium in the urine are 40 or 50 mEq.jL. Obviously, the concentration of sodium in the urine is a poor sign of an acute deficit of sodium salts in the body. The renal conservation of sodium during acute enteral depletion of sodium salts is slow and variable, so much so that sodium concentrations above 25 mEq.jL. or even 50 mEq.jL. in the urine may exist despite oliguria and prerenal nitrogen retention incident to deficits of extracellular fluid. On the other hand, if the sodium concentration in the urine of a vomiting person ill of intestinal obstruction or peritonitis is found to be below 15 or 20 mEq.jL., it is very likely that a dangerous depletion of sodium salts exists in the body. The fact that acute sodium deficits may be sufficient to endanger life, cause oliguria and azotemia, and yet be associated with sodium concentrations in the urine of 50 mEq.jL. or higher means that the physician cannot depend upon the concentration of urinary sodium to differentiate azotemia caused by renal insufficiency from azotemia caused by acute sodium deficiency. AIJpersons depleted offi or moremlilq.Na/kg. body weight of sodium sho~ed- rises in their blood urea nitrogen. concentrations (Fig. 3). The
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351
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
magnitude of rise in blood urea nitrogen concentration tended to be the greater the lower the sodium concentration in the urine (Compare Fig. 2 with Fig. 3).
Changes in Duodenal Fluid The duodenal fluids removed during sodium depletion showed variable changes in the concentrations of hydrogen ion, sodium, chloride and potassium (Table 3). The hydrogen ion concentration increased in three subjects as sodium concentrations decreased, but changed little in the others. Clearly, in some persons at least a part of the cations replacing sodium in the duodenal fluid during enteral sodium depletion are hydrogen ions. How the duodenum performs such substitution is unknown. However, the fact that acidity of duodenal fluid may be associated with sodium depletion in some persons suggests that sodium deficit may be one cause of the duodenal ulceration seen after burns or other trauma.
Changes in Plasma Changes in hematocrits during sodium depletion in each of the experiments are shown in Figure 4. A mean rise in hematocrit of approximately 1.4 occurred with each milliequivalent of Naf lost per kilogram of body weight. This linear relationship reflected a mean decrease in original CHANGE IN HEMATOCRITS DURING SODIUM
DEPLETION
Mean Rise net. I. 4/mEq Na 1'Losl/Kg
oR.G .
• '.P.
eS.T. AJ.S. oCL. A 6:1«
0RJ.
I
I
-8
-7
-6
-5
-4
-3
-2
-I SODIUM LOAD mEq /Kg BODY WT.
140
0
Figure 4. The hematocrits associated with corporeal sodium deficits in 7 individuals rose as the negative sodium load increased.
~
01
~
Table 3.
Hydrogen Ion, Sodium, Potassium and Chloride Concentrations in Duodenal Fluid During Depletion (mEq./L.) N a + CONCENTRATION
pH
C.L. R.J. I.P. G.W.
K+
CONCENTRATION DEFICIT
CASE
B.T. J.S. R.G.
01 CONCENTRATION
Initial
At Maximal Depletion
8.0 6.0 6.5 7.0 6.4 7.0 5.5
4.5 4.0 6.5 7.0 6.8 7.5 5.0
Initial At Maximal Depletion
98 96 161 86 53 86 82
63 86 105 103 114 125 66
Initial At Maximal Depletion
103 114 108 108 58 85 98
96 121 65 125 114 104 80
Initial
At Maximal Depletion
Na+ (mEq./kg.)
10.5 31.2 9.2 8.0 4.0 8.8 13.2
7.7 7.0 3.5 7.4 7.2 8.0 8.0
6.10 6.08 7.75 5.38 5.11 3.84 5.58
0::
~ ~
< t:t.1
~
~ td
c::8 C
II: t:t.1
Jtl ~
:0
t-3 tIl
l;9
~ 103 tIl
o
"'d
tIl ~
Table 4.
Relationships oj Hematocrits, Plasma Volumes oj Blood Samples and Serum Sodium Concentrations to Duodenal Depletions . oj Sodium Salts (Man)
[J). to-o4
o
S ~ ~
HEMATOCRIT* CASE
HI
DECREASE IN PLASMA
H2
(% of original sample)
52 54 50 48 55.5 52 56
24.5 33.0 30.6 11.4 31.7 24.5 24.5
NET LOSS OF SODIUM
(mEq.)
LOSS OF SODIUM
CHANGE IN VOL. OF PLASMA IN A LITER OF PATIENT'S BLOOD
(mEq./kg.)
(ml./mEq. N a lost/kg.)
5.11 6.08 6.06 3.84 5.58 5.38 7.75
26 30 30 16 31 25 16 25 5.97
DECREASE IN PLASMA
(% of original/ mEq.Na lost/kg.)
PLASMA EXTINCTION
CHANGE IN SERUM SODIUM
(mEq.Na/ kg.)
(Na+/mEq.N a/lost/kg.)
20.8 18.5 19.6 33.6 17.6 21.7 31.2 23.3 5.95
+0.2 -1.6 -1.6 -0.1 +0.2 -1.5 .0 -0.63
o
~
00
o
t:::l
~
tJ
R.J. J.S.
B.T. I.P. G.W. C.L. R.G.
45 44 41 45 46 45 49
495 410 385 301 358 364 542
Mean t 0.05Sx
4.8 5.4 5.1 3.0 5.7 4.6 3.2 4.5
l;9
"'d t'4
l;9
103
o Z ~
Z
~
>
Z
* HI-Original predepletional hematocrit; H 2-Hematocrit at maximal sodium depletion.
~
01
~
354
HARVEY
R.
BUTCHER, JR.
plasma volume of 4.5 per cent per milliequivalent of sodium lost per kilogram (Table 4). If one assumes that the relation of the rise in the hematocrits to increasing deficits of sodium salts remains linear during depletions exceeding those studied, the mEq.Na/kg. deficit of sodium needed to reduce plasma volume to zero may be calculated (column labeled plasma extinction in Table 4). The mean deficit of sodium salts at which plasma would no longer exist in these seven experiments (23.3 mEq.Na/kg.) did not differ significantly from the plasma extinction calculated by Grayson et al.' (25.7 mEq.Na/kg.). These values indicate that it is the extracellular and extraosseous sodium which sustains plasma volume. (The normal range of total body sodium is 40 to 44 mEq./kg.; extraosseous extracellular sodium amounts to 22 to 28 mEq./kg.) Repletions of the sodium deficits in these experiments were accompanied by a fall in hematocrits to levels usually slightly below the original ones (Table 5). The mean increase in plasma volume 'associated with repletion was 7.9 per cent of the original plasma volume per milliequivalents of Nat gained per kilogram, a value exceeding the mean decrease (4.5 per cent) associated with sodium depletion. The rapid rate of repletion in these persons may be responsible for this. In the repletional phase of the experiments of Grayson, White and Moyer the mean increase in plasma volume was calculated as 4.9 per cent of the original per each milliequivalent of sodium gained per kilogram. The time taken for restitution of the sodium deficits in their experiments was 12 hours rather than four to six hours. The serum concentrations of potassium, sodium, chloride and bicarbonate did not change significantly during sodium depletion and repletion (Tables 6 and 7). The volume djstributions, 'of sodium salts administered for repletion approximated the calculated extracellular fluid volume (Table 7). Obviously, the concentration of sodium or chloride in the serum is no measure of the corporal content of rapidly exchangeable sodium salts. Plasma protein concentrations uniformly become elevated during sodium depletion. The mean rise in plasma protein concentration was 0.38 gm./100 ml.yrulsq.Na" lost/kg. (Fig. 5). The mean per cent decrease in the original plasma volume calculated from the change in plasma protein concentration was 4.8 per cent for each milliequivalent of sodium lost per kilogram (Table -8). This value did not differ significantly from the percentage decrease in original plasma volume calculated from changes in hematocrit (4.5 per cent, Table 3). The maintenance of the linear relationship between hematocrit and increasing deficits of sodium salts in the body even when the deficits are maximal but still compatible with life indicate that the plasma protein concentration is not a highly important determinant of the plasma volume. Should plasma ,protein concentration be a primary factor in the maintenance of plasma. volume its rising concentration during sodium depletion should result in a decrease in the rate of change in the hematocrit as the deficit of sodium increases. However, within the limits of corporal sodium
~
::t trj
~
> ~ ~
o
.-c
::0
Table 5.
Relationships of Hematocrits, Plasma Volumes of Blood Samples and Serum Sodium Concentrations to Repletions of Sodium Salts (Man)
~
t»
2) t'4
o o
~
HEMA'rOCRIT* CASE
H2
Ha
INCREASE IN PLASMA YOLo
(% of original sample)
GAIN OF
CHANGE IN YOLo OF PLASMA IN A LITER
OF SODIUM
SODIUM
OF A PERSON'S BLOOD
(mEq.)
(% of original
(mEq./kg.)
(ml./mEq.Na/kg. gain)
mEq.Na gained /kg.)
NET GAIN
INCREASE IN PLASMA
o
PLASMA EXTINCTION
CHANGE IN SERUM
W
(mEq.Na/ kg.)
(Na+/mEq. Na/lost/fg·)
c:l
"%J
o
t:t
l-4
~
tj
R.J. J.S., B.T. I.P. G.W. C.L. R.G.
52 54 50 48 55.5 52 56
44 40 39 41 43 46 41
·28.4 61.0 39.2 29.1 44.6 20.5 62.8
323 ' 375 352 268 323 289 521
3.34 5.55 5.55 3.44 5.05 4.25 7.45 Mean t 0.05Sx
47 51 41 47 48 27 43 43 7.4
8.50 9.18 7·06 8.46 8.83 4.83 8.43 7.90
trj
11.8 10.9 14.2 11.8 11.3 20.8 11.9 13.2 3.3
+1.2 + .6 -0.2 +2.3 +0.3 .0 + .2 +0.63
.-c
t'4 tr:1 ~
2) Z
Z ~
> Z
* H 2- Hematocrit at maximal sodium depletion; H a- Hematocrit at end of repletion.
~
01 01
~
01
~
1-3 ~
tr:j
Table 7.
Volume Distributions
of Sodium Salts Given for Repletion *
~
> 8 ~
CASE
TIME AFTER REPLETION COMPLETE
(hrs.)
ORIGINAL WEIGHT
mlsq.Na" DISTRIBUTED IN MORE ( +) OR LESS ( -
SERUM SODIUM CONCENTRATION
(mEq./L.)
(kg.) NIt
NET GAIN IN
Na+(mEq.)
NET GAIN IN WATER
WEIGHT GAIN
(L.)
(kg.)
N2t
EXTRACELLULAR FLUID VOLUME
(liters) (20% Bw)
0
"'d
)
EXTRACELLULAR FLUID CALCULATED BY
~
to<
00
1-1
0
~
0
~
Wt.Gain (mI.)
Net H 20 Gain
to<
0
r.r;j
(ml.)
00 0 t::;
0 12 0 12 0 12 0 10 12 0 0 12 1.5 13.5
R.J. J.S.
B.T. I.P. G.W. C.L.
R.G.
96.9
142
67.6
131
63.5
134
78.31
138
64.1
138.1
68.1
131
69.9
133.7
146 141 134 134 133 135 149 146 139.5
324 225 375 290 352 332 275 268 323
2,360 1,810 2,750 2,212 2,902 2,557 1,750 1,482 1,080
131 139 135.2 139.5
289 270 521 460
1,780 1,421 3,900 3,450
* (mlilq.Na t distributed in more or less volume than estimated ECF)
=
3.20
-
3.70 2.50 -
1.94 .80 1.20
-
3.3
19.4 19.4 13.5 13.5 12.7 12.7 15.7 15.7 12.8 13.6 13.6 14.0 14.0
-210t
-
-234t
-
- 14
-
-125 +195 +
-
4
- 62
1-1
- 88 - 12 - 25 - 39 - 23 - 22 -140 - 61 +156 + -
(net gain Na") - (N, X net gain H 20) - ECF volume (N 2
~
a= t:l t.%j "'d
~ 8
1-1
0
Z 1-1
z
~
z>
56 24 21 82 -
Nt)
(20% Bw). [ N, = Na" concentration at maximal depletion; N 2 = Na + concentration after repletion of Na" salts. t Oral water intake suspected. ~ ~ ~
358
HARVEY
CHANGE
R.
BUTCHER, JR.
CONCENTRATION PER mEq Na+ LOST I KQ
IN PLASMA PROTEIN
1.6 ~ A
Mean Change ppe = 038mg/KJOml/m£qNo'" Lost/Kg
'"
A 0
A
•
0
- -- - - - - - -
-
-
0
e
0
A
0
e
•
• ••
(I)
o • •
.e
e
•
• • o
•
- - - - - - - - - - --e-A- - - - - - - -
•
1.2 ~ ~
0
0.8
.•
• ------10.4 ~'1
------ ---------- --- --A
0
0.8 ~
•
•
AJ.S. A G.t¥.
-6
-4
-5
<:
-,
• I.P. oC.L.
-7
~
f')
•
oR.G. eR.S.
o
0.4 ~ <:
A
.S.T.
~
-3
-2
~ ~
1.2 ~ r-
o
-I
SODIUM LOAD mEq/KQ BODY WEIGHT
Figure 5. The changes in plasma protein concentrations of 7 persons depleted of sodium salts, though somewhat erratic, were higher the greater the deficit of sodium.
Table 8.
Relationships of Plasma Proteins and Plasma Volumes to Duodenal Depletions of Sodium Salts (Man)
PLASMA PROTEIN CONCENTRATION CASE
(gm./100 ml.)
DECREASE IN PLASMA
PP 1
PP 2
(% of original sample) *
6.8 7.5 7.6 6.4 5.9 4.0 7.5
8.7 9.8 8.8 10.2 9.6 5.2 10.5
22 23 14 37 38 23, 29
R.J. C.L. R.G. J.B. B.T. I.P.
G.W.
DECREASE NET
IN PLASMA
PLASMA
LOSS OF
(% of
EXTINCTION
SODIUM
(mEq./kg.)
5.11 5.38 7.75 6.08 6.06 3.84 5.58 Mean
* (PP2
PP1 ) X 100 = % change in plasma volume. PP2 PP1 = plasma protein before depletion. PP2 = plasma protein after depletion. -
original/ mEq.Na lost./kg.)
(mEq.Na lost/kg.)
4.3 4.3 1.8 6.1 6.3 6.0 5.1 4.8
23.3 23,.3 55'.5 16.4 15.9 16.7 19.6 24.4
359
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN PL ASMA VOLUME DURING
No DEPLETION
CALCULAT ED FROM:
•\ \
AND REPL ETION
HEMATOCRIT • PLASMA PROTEIN A 1/3 / DILUTION 0 .
\
\ \
\A
\\ \ \ \\ \\ \
\
\\ \\ \\ \\ '\
\'./. /
o
/ /
/ /
/ /
/
/
o
t
/
Repletion of Sod ium Solts
-7
-6
-4
-5
-3
Na+ DEFICIT mEq/Kg
-2
o
Figure 6. Plasma volumes associated with sodium depletion and repletion were calculated both from changes in hematocrit and plasma protein and from changes in blood volume determinations made by the 1131 dilutional technique. The latter method failed to show an increase in plasma volume after repletion of sodium salts.
deficit studied there was no such departure from the linearity of this relationship between sodium deficit and hematocrit. Plasma volumes were determined in one subject (G.W.) before and during sodium depletion and after repletion by the 1131-tagged serum albumin dilutional technique. The fall in plasma volume measured in this way during depletion was similar to the fall as calculated from changes in hematocrit and in plasma protein concentration. However, after repletion of the sodium salts the plasma volume as measured by 1131 remained quite low (Fig. 6). The inaccuracy of the iodinated serum albumin dilutional technique for measuring blood volumes is attributable to changes in plasma protein concentration.' When the protein concentrations of the blood are low, the blood volumes measured with 1131 are low.
Cardiovascular Responses Changes in pulse rate, systolic and diastolic blood pressures occurred regularly after sufficiently large depletions of sodium salts had developed. These changes as well as the magnitude and times of onset of orthostatic hypotension during the periods of depletion varied greatly. For example, tachycardia above 85 or 90 per minute occurred in nearly all subjects, but the size of the sodium deficit could not be related to the magnitude of pulse rate acceleration. In some persons peripheral resistance appeared to increase (diastolic blood pressure rose) in others to decrease (diastolic blood pressure fell). Pulse pressures decreased in some persons but increased in
360
Table 9.
HARVEY
FACTORS
DEFICITS OF SODIUM SALTS
Viscosity
BUTCHER, JR.
A Correlation of Some Factors Associated with the Cardiovascular Effects ~f Sodium Deficit and Hemorrhage DURING INCREASING
FUNCTION
R.
Hematocrit Plasma protein concentration
Increases steadily Increases steadily
DURING PROGRESSIVE HEMORRHAGE
Decreases, if anything Does not change or decrease
----- -----------)----------,1-----------
Capillary Functional volume dis- Does not change or intribution of water creasesv" exchange (deuterium) surface* Rate of capillary ex- Increases'> change of water (deuteriurn) Oligemia Oxygen consumption
Decreases" Decreases"
Increases (plasma defi- Increases (red cell and cit only) plasma defieitsj] Decreases in normal Decreases in normal perpersons and animals sons and animals Increases in chronic Unknown in alcoholics alcoholics
* The volume of distribution of deuterium decreases about 50 per cent after controlled hemorrhage sufficient to reduce the blood pressure to 75 mm. Hg systolic for 90 minutes." This means that some parts of the circulation (capillary bed) are closed and no blood flows through those areas for as long as the animal lives before dying of shock. Such does not take place during sodium deficit shock. t Red cell deficit is relatively greater than the plasma deficit because more or less hemodilution takes place rather quickly.
others. Obviously, cardiovascular responses were so variable as to make them useless as a clinical measure of unit sodium deficit. Very large and dangerous deficits may be unaccompanied by significant changes in blood pressures or pulse rates. Even orthostatic hypotension occurs first over such a wide range of sodium deficit as to be practically useless as a quantitative diagnostic sign of these deficits. The oligemia. of .sodium. depletion differs from that associated with hemorrhage (where orthostatic hypotension is a reasonable good measure of a significant degree of blood volume reduction) in the following important ways: 1. Hematocrit, plasma protein concentration and blood viscosity increase during sodium depletion; they remain the same or decrease during hemorrhage. 2. Peripheral vasoconstriction does not occur excepting with profound acute hypotension in sodium depletion. 3. The capillary beds in all parts of the body remain open during sodium depletion as indicated by a normal volume distribution of deuterium,"- 3 such is not the case in hemorrhagic shock' (Table 9). The fact that the body's exchangeable sodium salts are a primary,
361
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
determinant of plasma volume is most likely responsible for the efficacy of sodium-containing solutions intravenously in the treatment of those forms of shock not associated with massive loss of red blood cells. The next question is: Does the sodium mass of the body play any part in the etiology of the shock accompanying hemorrhage? Actually, the temporary loss of sodium incident to the removal of blood in the production of the Wigger's type of controlled experimental hemorrhagic shock in the dog is 5 to 6 mEq. of sodium per kilogram of body weight. Still more sodium salts apparently are "lost" or become no longer rapidly exchangeable for reasons yet unknown. A reduction in the sodium distributional space of approximately 40 per cent occurs during controlled canine hemorrhagic shock; this functional sodium space remains low if only the shed blood is used to treat the shock. 6 However, when sodium-containing solutions are also given in sufficient volume the functional sodium space is reconstituted. Is this important? It appears to be because the use of sodium-containing solutions' as well as blood in the treatment of controlled canine hemorrhagic shock of the Wigger's type has reduced the mortality of the experimental preparation from 50-70 per cent to 20-30 per cent (Table 10).1, 6,8 The use of plasma instead of lactated Ringer's solution (in volumes 20 to 25 per cent of the volumes of lactated Ringer's solution used) did not reconstitute the sodium distributional space nor did it reduce significantly the mortality of the experiment." The loss of plasma proteins appears to be of little significance in the production and treatment of hemorrhagic shock. The observation that a combination of buffered saline solution plus sufficient blood to maintain adequate oxygen transport will prevent the death of most dogs subjected to so-called irreversible shock supports the concept that the primary determinants of an adequate circulating blood volume are the red blood cell mass and the rapidly exchangeable sodium salts of the body. In other words, hemorrhagic shock may well prove to be as efficaciously treated with buffered saline solutions such as lactated Ringer's solution plus preserved red blood cells as with anything else. Colloidal solutions other than blood appear to have little if any place in the therapy of hemorrhagic shock (Table 10). Table 10.
Survivalfrom Controlled Hemorrhagic Shock in the Dog After Treatment
METHOD OF TREATMENT
Shed blood only Lactated Ringer's solution*
NUMBER OF DOGS
24 27 pH 8.5 pH6.5 Lactated Ringer's solution and blood .. 13 Dextran in saline (N aCI) 9 7% starch in lactated Ringer's solution .. 7 * Volume used
=
NUMBER DYING
NUMBER LIVING
PROPORTION LIVING
12 10
12 10
.50 .50 .14 .85 .22
6
1
2
11
7 7
o
2
plasma volume plus 4 X RBC volume removed.
.00
362
HARVEY
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BUTCHER, JR.
SUMMARY The changes accompanying acute corporeal deficits of rapidly exchangeable sodium salts in normal and alcoholic men are as follows: 1. Oxygen consumption during the production of deficits of sodium between 4 and 8 milliequivalents of sodium per kilogram is decreased in normal persons and increased in chronic alcoholics (Fig. 1, Table 2). The oxygen consumptions of these persons return to predepletional levels with the restitution of the sodium deficits with lactated Ringer's solution. 2. Sodium depletion produced apathy and somnolence in normal persons; similar deficits of sodium cause alcoholics to become agitated, restless and occasionally irrational. 3. The concentrations of sodium, potassium, chloride and bicarbonate ions in the plasma do not change significantly during sodium depletion by duodenal aspiration if the insensible losses of water from the body are replaced with 10 ml. of 5 per cent glucose in water per kilogram of body weight daily (Table 6). 4. The ionic concentrations of the duodenal fluid aspirated during the production of sodium depletion changed variably. In three persons the concentration of sodium fell as the magnitude of sodium depletion increased, while the hydrogen ion concentration increased (Table 3). 5. Sodium concentrations in the urine, though usually falling during progressive sodium depletion, are so random and variable that they cannot be depended upon as indicators of the existence or degree of sodium deficit (Fig. 2). 6. Similarly the variability of the changes in pulse rate, rate of urine flow and blood pressure was sufficiently great to eliminate them as quantitative indicators of sodium deficits. 7. The hematocrit rises linearly as the degree of corporal sodium deficit increases (Fig. 4). This relationship remains constant despite increasing concentrations of plasma proteins. It would appear that the rapidly exchangeable sodium content of the body is more important than the plasma proteins are in the maintenance of plasma volume. The plasma volume is reduced 4 to 5 per cent with each milliequivalent of sodium lost per kilogram of body weight. 8. The rapidly exchangeable sodium mass of the body is functionally important in the etiology and treatment of chronic hemorrhagic shock. Indeed, buffered saline solutions and blood as treatment for controlled hemorrhagic shock in dogs have produced higher survival rates than anything else.
REFERENCES 1. Dillon, John: Personal communication. 2. Fogelman, M. J. and Wilson, B. J.: Internal water exchange rates in burns and other forms of trauma. S. Forum 4: 473, 1953.
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
363
3. Fogelman, M. J. and Wilson, B. J.: Blood extracellular fluid and total body water relationships in the early stages of severe burns. S. Forum 5: 762, 1954. 4. Fogelman, M. J., Montgomery, O. B. and Moyer, C. A.: Water exchange rates after hemorrhage. Am. J. Physiol. 169: 94, 1952. 5. Grayson, T. L., White, J. E. and Moyer, C. A.: Oxygen consumption; concentrations of inorganic ions in urine, serum and duodenal fluid; hematocrits; urinary excretions; pulse rates and blood pressure during duodenal depletions of sodium salts in normal and alcoholic man. Ann. Surge 158: 840-858, 1963. 6. Shires, T., CoIn, D. and Carrico, J.: Fluid therapy in hemorrhagic shock. Arch. Surge 88: 688-693, 1964. 7. Stokes, J. M., Bernard, H. R. and Balfour, J.: Effects of experimental electrolyte depletion upon renal water and solute excretion. Arch. Surge 85: 540-548, 1962. 8. Wolfman, E. F., Neill, S. A., Heaps, D. K. and Zuidema, G. D.: Donor blood and isotonic salt solution: Effect on survival after hemorrhagic shock and operation. Arch. Surge 86: 869-873, 1963. 4960 Audubon Avenue St. Louis, Missouri 63110
The Pathophysiology of Sodium Depletion in Man HARVEY R. BUTCHER, JR., M.D., F.A.C.S.*
Bodily deficits of sodium salts in man produce many of the , physiological changes common to shock. The weakness, apathy, hypotension, oliguria and azotemia incident to negative sodium loads in the body frequently accompany periods of severe diarrhea or vomiting, extensive injury and large burns. Such illnesses or injury obviously are accompanied by derangements in metabolism other than simple sodium depletion. The presence of blood loss, water intoxication, sepsis, potassium deficits and so forth have not permitted those caring for these ill persons to define quantitatively the relationship between specific deficits of exchangeable body sodium alone and the biologic responses resulting from them. Recently, however, the quantitative relations of these responses to unit deficits of rapidly exchangeable sodium salts have been defined in part by the experiments of Grayson, White and Moyer." Their conclusions have been confirmed and extended by the collection of additional data from volunteers subjected to stepwise sodium depletion in a similar way.
METHODS
Deficits of sodium salts were induced in seven lean, fasting men by constantly removing duodenal fluid from them through a metal-tipped duodenal tube, the position of which was confirmed radiographically. During the period of depletion 10 ml./kg. of body weight of 5 per cent glucose in water was given each subject daily as replacement for the net losses of water insensibly and through the urine. The time required to produce the desired losses of sodium salts was four to five days. The experiments were terminated by repleting them with intravenous infusions of lactated Ringer's solution in quantities sufficient to replace the accumulated deficits of sodium in four to six hours. Five of the volunteers were
* Professor of Surgery, Washington University School of Medicine; Department of Surgery J Barnes Hospital, St. Louis, Missouri
345
346
HARVEY
R.
BUTCHER, JR.
alcoholic men who had been in the hospital for psychiatric therapy for more than two months. Two persons were nonalcoholic; one had schizophrenia, the other an inguinal hernia. All subjects appeared healthy and felt well. No physical or chemical evidence of liver disease existed. The experiments were begun by 12 hours of fasting. The duodenal tube was positioned in the second part of the duodenum and a steady small suction applied to it by a mechanical pump. Simultaneously a Foley catheter was inserted and urine collections begun. When signs of illness, such as orthostatic hypotension or profound weakness occurred or when the estimated sodium deficit reached six to eight mEq.jkg. body weight, the duodenal tube was removed and Hartmann's solution was infused intravenously until the cumulative deficits of sodium were replaced. The intravenous infusion of sufficient Hartmann's solution was completed in four to six hours. After 24 hours of further observation the urinary catheter was removed and eating and drinking permitted.
OBSERVATIONS The observations made during the periods of depletion and during and after repletion are shown in Table 1. The data from these experiments are presented in Figures 2 to 6 and Tables 2 to 8. Changes in Oxygen Consumption The elevations of minute oxygen consumption associated with sodium depletion in chronic alcoholic men not having drunk alcohol for several months are shown in Table 2. Only one alcoholic subject (R.J.) failed to have a higher rate of oxygen consumption after sodium depletion than he had before it. The elevated oxygen consumption in these persons was associated with agitation, an inability to sleep and a tendency to mild delirium. Similarly, an agitated behavior was observed in the schizophrenic man who also had an elevated oxygen consumption during sodium depletion. The increased minute oxygen consumptions of alcoholic human beings reported by Grayson, White and Moyer were of similar magnitude. They also showed that nonalcoholic men subjected to sodium depletion exhibited a nearly direct relationship between minute oxygen consumption and the amount of rapidly exchangeable sodium salts remaining in the body. In other words, as sodium depletion increased the minute oxygen consumption decreased in normal persons. For every milliequivalent of sodium deficit per kilogram of body weight there was a reduction of minute oxygen consumption of 5 to 15 ml. per minute (Fig. 1).1 The normal person's response to sodium depletion also differs from the response of the alcoholic in other ways. A decrease in spontaneous motor activity, apathy and slow but rational communicative responses are manifest by the sodium depleted normal person while the alcoholic man depleted of sodium salts displays
<
347
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
Table 1.
Observations Made and Methods Used FREQUENCY OF
OBSERVATIONS
METHOD
OBSERVATION
Basal oxygen consumption
, Daily
q12h q4h q4h q4h q4h q4h q4h q4h q4h
Collin's respirometer (two 8-min. periods) Capillary method 10,000 G. for 5 min. Schales and Schales Spectrophotometry (Weichselbaum-Varney) Weichselbaum Van Slyke Spectrophotometry (Weichselbaum-Varney) Rosenthal Weichselbaum-Varney Schales and Schales Kjeldahl (Van Slyke and Peters) Beckman Beckman Weichselbaum-Varney Weichselbaum-Varney Schales and Schales
q4h q4h q4h q12h
Riva-Rocci apparatus Maximum thermometer Questioning and observation Silk scale, sensitivity 50 gm.
Hematocrit q12h Serum chloride. . . . . . . . . . . . . . . . . . .. q 12h Serum sodium , q12h Serum albumin and globulin Serum bicarbonate Serum potassium
,
q12h , q12h q12h
Serum urea nitrogen , Urinary sodium , Urinary chloride. . . . . . . . . . . . . . . . .. Urinary nitrogen , Urine pH* , Duodenal pH* . . . . . . . . . . . . . . . . . . .. Sodium in duodenal fluid , Potassium in duodenal fluid , Chloride in duodenal fluid , Blood p.re~sure while recumbent and sitting , . . . . . . . . . . . . . . . . . . .. Oral temperature Mental responsivity. . . . . . . . . . . . . .. Weight * On pooled 4-hour specimens.
Table 2.
0 xygen Consumptions Associated with Sodium Depletion and Repletion BEFORE SODIUM
AFTER SODIUM
AFTER LV. REPLETION
DEPLETION
DEPLETION
OF SODIUM SALTS
(ml.yrnin.)
(ml.y'min.)
(ml.yrnin.)
1. Chronic alcoholic men R.J. 127 J.S. l83 B.T. 72 I.P. 131 G.W. 56 -Mean 94
110 158 104 200 112 -137
103 94 80 138 62 -94
2. Normal man (hernia) C.L. 94
91
83
169
150
3. Man ill of schizophrenia R.G. 141
348
HARVEY
R.
BUTCHER, JR.
175
165
155
• Pot!s \ \
\ \ \ \
\ \ \
......
"
.
......
//
,,
,
Harmon
/
/
" ,
' ......./
,/
/
/
"
105 Penn
Hill
95
--Normals - --- Alcoholics
85
-8
-7
-6
- 5
-4
- 3
-2
-I
LOAD No mEq/K. B wo
Figure 1. Oxygen consumptions of 5 normal persons and 5 chronic alcoholics during transduodenal depletions of sodium salts.
increased spontaneous motor activity, agitation, irrational responses and mild delirium. Although we do not know the basic causes for the hypometabolism incident to acute deficits of sodium salts in normal persons and the hypermetabolism accompanying such deficits in chronic alcoholics, it would appear that the differences in spontaneous motor activity and in the affect of normal and alcoholic persons subjected to depletion of sodium salts are at least in part responsible. The ability of acute deficits of sodium salts in the body to produce agitational symptomatic psychosis in the chronic alcoholic and contrariwise apathy, somnambulance and hyporeflexia in normal persons suggest that the mental responses induced by acute sodium deficits may be exceedingly
q
349
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
varied in different illnesses and under the influence of different drugs. Obviously, however, the chronic alcoholic who develops acute symptomatic psychosis postoperatively may have as the precipitating cause an acute deficit of exchangeable sodium salts.
Changes in Urine Both in these experiments and those reported by Grayson, White and Moyer, the volumes of urine fell below 20 ml./hr. before the depletions of sodium salts were completed. However, there appeared to be no regular relationship between the severity of the oliguria and the magnitude of the sodium deficit. In other words, the rate of excretion of urine could not be used to predict the extent of sodium deficit. Stokes et al.? have shown that renal water and solute excretion are reduced by reductions in the exchangeable sodium mass of the body but their investigations showed no proportionality between unit deficits of sodium and the magnitudes of these changes. All subjects depleted of sodium salts had a fall in the concentrations of sodium in the urine during depletion (Fig. 2). However, concentrations of sodium in the urine below 25 mEq./L. did not develop until after more than 4 mlsq.Na"/kg. had been lost in five of the experiments. Indeed, in CONCENTRATION
SODIUM ION IN URINE mEq/Liters
160 140 oR.G.
• 8.7:_ eR.J.
120
AJ.S. 6G:~
100
.I.R cC.L.
80 60 40 20
-8
-7
-6
-5
-4
-3
-2
-I
SODIUM LOAD mEq/Kg BODY WT.
Figure 2. The individual concentrations of sodium in the urine accompanying negative corporeal sodium loading in 7 persons are shown. Obviously, the concentration of urinary sodium is no indicator of the magnitude of sodium deficit.
350
HARVEY
CONCENTRATION
BUN
IN SERUM ASSOCIATED
R.
BUTCHER, JR.
WITH
Nat DEPLETION
«sr
mg/IOOml.
o R.G. /
0R.J. .I.F! cC.L. AJ.S. AG.~
/
60
/ / /
After No+ Repletion
~
/
50
/ / /
/
40
/
/ /
A
/
;' ;'
."
~'//
30
~;,;"
,;"
~~"
--; ~~ "/
----
f~~-- -- --- - - ---.... ~ .0--.J""~""--
t -9
I
-8
-----
I
-7
20
I
-6
-5
-4
-3
-2
I -I
SODIUM LO AD m Eq / Kg BODY WT. Figure 3. This graph shows the blood urea nitrogen concentrations in 7 persons subjected to transduodenal depletions of sodium salts.
one (R.G.) the concentration of sodium in the urine remained above 25 mEq.jL. despite a deficit of 7.75 mliq.Nat /kg. body weight. In other words, although a low concentration of urinary sodium may be indicative of a serious negative sodium load in the body, such may, in fact, also exist when concentrations of sodium in the urine are 40 or 50 mEq.jL. Obviously, the concentration of sodium in the urine is a poor sign of an acute deficit of sodium salts in the body. The renal conservation of sodium during acute enteral depletion of sodium salts is slow and variable, so much so that sodium concentrations above 25 mEq.jL. or even 50 mEq.jL. in the urine may exist despite oliguria and prerenal nitrogen retention incident to deficits of extracellular fluid. On the other hand, if the sodium concentration in the urine of a vomiting person ill of intestinal obstruction or peritonitis is found to be below 15 or 20 mEq.jL., it is very likely that a dangerous depletion of sodium salts exists in the body. The fact that acute sodium deficits may be sufficient to endanger life, cause oliguria and azotemia, and yet be associated with sodium concentrations in the urine of 50 mEq.jL. or higher means that the physician cannot depend upon the concentration of urinary sodium to differentiate azotemia caused by renal insufficiency from azotemia caused by acute sodium deficiency. AIJpersons depleted offi or moremlilq.Na/kg. body weight of sodium sho~ed- rises in their blood urea nitrogen. concentrations (Fig. 3). The
<
351
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
magnitude of rise in blood urea nitrogen concentration tended to be the greater the lower the sodium concentration in the urine (Compare Fig. 2 with Fig. 3).
Changes in Duodenal Fluid The duodenal fluids removed during sodium depletion showed variable changes in the concentrations of hydrogen ion, sodium, chloride and potassium (Table 3). The hydrogen ion concentration increased in three subjects as sodium concentrations decreased, but changed little in the others. Clearly, in some persons at least a part of the cations replacing sodium in the duodenal fluid during enteral sodium depletion are hydrogen ions. How the duodenum performs such substitution is unknown. However, the fact that acidity of duodenal fluid may be associated with sodium depletion in some persons suggests that sodium deficit may be one cause of the duodenal ulceration seen after burns or other trauma.
Changes in Plasma Changes in hematocrits during sodium depletion in each of the experiments are shown in Figure 4. A mean rise in hematocrit of approximately 1.4 occurred with each milliequivalent of Naf lost per kilogram of body weight. This linear relationship reflected a mean decrease in original CHANGE IN HEMATOCRITS DURING SODIUM
DEPLETION
Mean Rise net. I. 4/mEq Na 1'Losl/Kg
oR.G .
• '.P.
eS.T. AJ.S. oCL. A 6:1«
0RJ.
I
I
-8
-7
-6
-5
-4
-3
-2
-I SODIUM LOAD mEq /Kg BODY WT.
140
0
Figure 4. The hematocrits associated with corporeal sodium deficits in 7 individuals rose as the negative sodium load increased.
~
01
~
Table 3.
Hydrogen Ion, Sodium, Potassium and Chloride Concentrations in Duodenal Fluid During Depletion (mEq./L.) N a + CONCENTRATION
pH
C.L. R.J. I.P. G.W.
K+
CONCENTRATION DEFICIT
CASE
B.T. J.S. R.G.
01 CONCENTRATION
Initial
At Maximal Depletion
8.0 6.0 6.5 7.0 6.4 7.0 5.5
4.5 4.0 6.5 7.0 6.8 7.5 5.0
Initial At Maximal Depletion
98 96 161 86 53 86 82
63 86 105 103 114 125 66
Initial At Maximal Depletion
103 114 108 108 58 85 98
96 121 65 125 114 104 80
Initial
At Maximal Depletion
Na+ (mEq./kg.)
10.5 31.2 9.2 8.0 4.0 8.8 13.2
7.7 7.0 3.5 7.4 7.2 8.0 8.0
6.10 6.08 7.75 5.38 5.11 3.84 5.58
0::
~ ~
< t:t.1
~
~ td
c::8 C
II: t:t.1
Jtl ~
:0
t-3 tIl
l;9
~ 103 tIl
o
"'d
tIl ~
Table 4.
Relationships oj Hematocrits, Plasma Volumes oj Blood Samples and Serum Sodium Concentrations to Duodenal Depletions . oj Sodium Salts (Man)
[J). to-o4
o
S ~ ~
HEMATOCRIT* CASE
HI
DECREASE IN PLASMA
H2
(% of original sample)
52 54 50 48 55.5 52 56
24.5 33.0 30.6 11.4 31.7 24.5 24.5
NET LOSS OF SODIUM
(mEq.)
LOSS OF SODIUM
CHANGE IN VOL. OF PLASMA IN A LITER OF PATIENT'S BLOOD
(mEq./kg.)
(ml./mEq. N a lost/kg.)
5.11 6.08 6.06 3.84 5.58 5.38 7.75
26 30 30 16 31 25 16 25 5.97
DECREASE IN PLASMA
(% of original/ mEq.Na lost/kg.)
PLASMA EXTINCTION
CHANGE IN SERUM SODIUM
(mEq.Na/ kg.)
(Na+/mEq.N a/lost/kg.)
20.8 18.5 19.6 33.6 17.6 21.7 31.2 23.3 5.95
+0.2 -1.6 -1.6 -0.1 +0.2 -1.5 .0 -0.63
o
~
00
o
t:::l
~
tJ
R.J. J.S.
B.T. I.P. G.W. C.L. R.G.
45 44 41 45 46 45 49
495 410 385 301 358 364 542
Mean t 0.05Sx
4.8 5.4 5.1 3.0 5.7 4.6 3.2 4.5
l;9
"'d t'4
l;9
103
o Z ~
Z
~
>
Z
* HI-Original predepletional hematocrit; H 2-Hematocrit at maximal sodium depletion.
~
01
~
354
HARVEY
R.
BUTCHER, JR.
plasma volume of 4.5 per cent per milliequivalent of sodium lost per kilogram (Table 4). If one assumes that the relation of the rise in the hematocrits to increasing deficits of sodium salts remains linear during depletions exceeding those studied, the mEq.Na/kg. deficit of sodium needed to reduce plasma volume to zero may be calculated (column labeled plasma extinction in Table 4). The mean deficit of sodium salts at which plasma would no longer exist in these seven experiments (23.3 mEq.Na/kg.) did not differ significantly from the plasma extinction calculated by Grayson et al.' (25.7 mEq.Na/kg.). These values indicate that it is the extracellular and extraosseous sodium which sustains plasma volume. (The normal range of total body sodium is 40 to 44 mEq./kg.; extraosseous extracellular sodium amounts to 22 to 28 mEq./kg.) Repletions of the sodium deficits in these experiments were accompanied by a fall in hematocrits to levels usually slightly below the original ones (Table 5). The mean increase in plasma volume 'associated with repletion was 7.9 per cent of the original plasma volume per milliequivalents of Nat gained per kilogram, a value exceeding the mean decrease (4.5 per cent) associated with sodium depletion. The rapid rate of repletion in these persons may be responsible for this. In the repletional phase of the experiments of Grayson, White and Moyer the mean increase in plasma volume was calculated as 4.9 per cent of the original per each milliequivalent of sodium gained per kilogram. The time taken for restitution of the sodium deficits in their experiments was 12 hours rather than four to six hours. The serum concentrations of potassium, sodium, chloride and bicarbonate did not change significantly during sodium depletion and repletion (Tables 6 and 7). The volume djstributions, 'of sodium salts administered for repletion approximated the calculated extracellular fluid volume (Table 7). Obviously, the concentration of sodium or chloride in the serum is no measure of the corporal content of rapidly exchangeable sodium salts. Plasma protein concentrations uniformly become elevated during sodium depletion. The mean rise in plasma protein concentration was 0.38 gm./100 ml.yrulsq.Na" lost/kg. (Fig. 5). The mean per cent decrease in the original plasma volume calculated from the change in plasma protein concentration was 4.8 per cent for each milliequivalent of sodium lost per kilogram (Table -8). This value did not differ significantly from the percentage decrease in original plasma volume calculated from changes in hematocrit (4.5 per cent, Table 3). The maintenance of the linear relationship between hematocrit and increasing deficits of sodium salts in the body even when the deficits are maximal but still compatible with life indicate that the plasma protein concentration is not a highly important determinant of the plasma volume. Should plasma ,protein concentration be a primary factor in the maintenance of plasma. volume its rising concentration during sodium depletion should result in a decrease in the rate of change in the hematocrit as the deficit of sodium increases. However, within the limits of corporal sodium
~
::t trj
~
> ~ ~
o
.-c
::0
Table 5.
Relationships of Hematocrits, Plasma Volumes of Blood Samples and Serum Sodium Concentrations to Repletions of Sodium Salts (Man)
~
t»
2) t'4
o o
~
HEMA'rOCRIT* CASE
H2
Ha
INCREASE IN PLASMA YOLo
(% of original sample)
GAIN OF
CHANGE IN YOLo OF PLASMA IN A LITER
OF SODIUM
SODIUM
OF A PERSON'S BLOOD
(mEq.)
(% of original
(mEq./kg.)
(ml./mEq.Na/kg. gain)
mEq.Na gained /kg.)
NET GAIN
INCREASE IN PLASMA
o
PLASMA EXTINCTION
CHANGE IN SERUM
W
(mEq.Na/ kg.)
(Na+/mEq. Na/lost/fg·)
c:l
"%J
o
t:t
l-4
~
tj
R.J. J.S., B.T. I.P. G.W. C.L. R.G.
52 54 50 48 55.5 52 56
44 40 39 41 43 46 41
·28.4 61.0 39.2 29.1 44.6 20.5 62.8
323 ' 375 352 268 323 289 521
3.34 5.55 5.55 3.44 5.05 4.25 7.45 Mean t 0.05Sx
47 51 41 47 48 27 43 43 7.4
8.50 9.18 7·06 8.46 8.83 4.83 8.43 7.90
trj
11.8 10.9 14.2 11.8 11.3 20.8 11.9 13.2 3.3
+1.2 + .6 -0.2 +2.3 +0.3 .0 + .2 +0.63
.-c
t'4 tr:1 ~
2) Z
Z ~
> Z
* H 2- Hematocrit at maximal sodium depletion; H a- Hematocrit at end of repletion.
~
01 01
~
01
~
1-3 ~
tr:j
Table 7.
Volume Distributions
of Sodium Salts Given for Repletion *
~
> 8 ~
CASE
TIME AFTER REPLETION COMPLETE
(hrs.)
ORIGINAL WEIGHT
mlsq.Na" DISTRIBUTED IN MORE ( +) OR LESS ( -
SERUM SODIUM CONCENTRATION
(mEq./L.)
(kg.) NIt
NET GAIN IN
Na+(mEq.)
NET GAIN IN WATER
WEIGHT GAIN
(L.)
(kg.)
N2t
EXTRACELLULAR FLUID VOLUME
(liters) (20% Bw)
0
"'d
)
EXTRACELLULAR FLUID CALCULATED BY
~
to<
00
1-1
0
~
0
~
Wt.Gain (mI.)
Net H 20 Gain
to<
0
r.r;j
(ml.)
00 0 t::;
0 12 0 12 0 12 0 10 12 0 0 12 1.5 13.5
R.J. J.S.
B.T. I.P. G.W. C.L.
R.G.
96.9
142
67.6
131
63.5
134
78.31
138
64.1
138.1
68.1
131
69.9
133.7
146 141 134 134 133 135 149 146 139.5
324 225 375 290 352 332 275 268 323
2,360 1,810 2,750 2,212 2,902 2,557 1,750 1,482 1,080
131 139 135.2 139.5
289 270 521 460
1,780 1,421 3,900 3,450
* (mlilq.Na t distributed in more or less volume than estimated ECF)
=
3.20
-
3.70 2.50 -
1.94 .80 1.20
-
3.3
19.4 19.4 13.5 13.5 12.7 12.7 15.7 15.7 12.8 13.6 13.6 14.0 14.0
-210t
-
-234t
-
- 14
-
-125 +195 +
-
4
- 62
1-1
- 88 - 12 - 25 - 39 - 23 - 22 -140 - 61 +156 + -
(net gain Na") - (N, X net gain H 20) - ECF volume (N 2
~
a= t:l t.%j "'d
~ 8
1-1
0
Z 1-1
z
~
z>
56 24 21 82 -
Nt)
(20% Bw). [ N, = Na" concentration at maximal depletion; N 2 = Na + concentration after repletion of Na" salts. t Oral water intake suspected. ~ ~ ~
358
HARVEY
CHANGE
R.
BUTCHER, JR.
CONCENTRATION PER mEq Na+ LOST I KQ
IN PLASMA PROTEIN
1.6 ~ A
Mean Change ppe = 038mg/KJOml/m£qNo'" Lost/Kg
'"
A 0
A
•
0
- -- - - - - - -
-
-
0
e
0
A
0
e
•
• ••
(I)
o • •
.e
e
•
• • o
•
- - - - - - - - - - --e-A- - - - - - - -
•
1.2 ~ ~
0
0.8
.•
• ------10.4 ~'1
------ ---------- --- --A
0
0.8 ~
•
•
AJ.S. A G.t¥.
-6
-4
-5
<:
-,
• I.P. oC.L.
-7
~
f')
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o
0.4 ~ <:
A
.S.T.
~
-3
-2
~ ~
1.2 ~ r-
o
-I
SODIUM LOAD mEq/KQ BODY WEIGHT
Figure 5. The changes in plasma protein concentrations of 7 persons depleted of sodium salts, though somewhat erratic, were higher the greater the deficit of sodium.
Table 8.
Relationships of Plasma Proteins and Plasma Volumes to Duodenal Depletions of Sodium Salts (Man)
PLASMA PROTEIN CONCENTRATION CASE
(gm./100 ml.)
DECREASE IN PLASMA
PP 1
PP 2
(% of original sample) *
6.8 7.5 7.6 6.4 5.9 4.0 7.5
8.7 9.8 8.8 10.2 9.6 5.2 10.5
22 23 14 37 38 23, 29
R.J. C.L. R.G. J.B. B.T. I.P.
G.W.
DECREASE NET
IN PLASMA
PLASMA
LOSS OF
(% of
EXTINCTION
SODIUM
(mEq./kg.)
5.11 5.38 7.75 6.08 6.06 3.84 5.58 Mean
* (PP2
PP1 ) X 100 = % change in plasma volume. PP2 PP1 = plasma protein before depletion. PP2 = plasma protein after depletion. -
original/ mEq.Na lost./kg.)
(mEq.Na lost/kg.)
4.3 4.3 1.8 6.1 6.3 6.0 5.1 4.8
23.3 23,.3 55'.5 16.4 15.9 16.7 19.6 24.4
359
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN PL ASMA VOLUME DURING
No DEPLETION
CALCULAT ED FROM:
•\ \
AND REPL ETION
HEMATOCRIT • PLASMA PROTEIN A 1/3 / DILUTION 0 .
\
\ \
\A
\\ \ \ \\ \\ \
\
\\ \\ \\ \\ '\
\'./. /
o
/ /
/ /
/ /
/
/
o
t
/
Repletion of Sod ium Solts
-7
-6
-4
-5
-3
Na+ DEFICIT mEq/Kg
-2
o
Figure 6. Plasma volumes associated with sodium depletion and repletion were calculated both from changes in hematocrit and plasma protein and from changes in blood volume determinations made by the 1131 dilutional technique. The latter method failed to show an increase in plasma volume after repletion of sodium salts.
deficit studied there was no such departure from the linearity of this relationship between sodium deficit and hematocrit. Plasma volumes were determined in one subject (G.W.) before and during sodium depletion and after repletion by the 1131-tagged serum albumin dilutional technique. The fall in plasma volume measured in this way during depletion was similar to the fall as calculated from changes in hematocrit and in plasma protein concentration. However, after repletion of the sodium salts the plasma volume as measured by 1131 remained quite low (Fig. 6). The inaccuracy of the iodinated serum albumin dilutional technique for measuring blood volumes is attributable to changes in plasma protein concentration.' When the protein concentrations of the blood are low, the blood volumes measured with 1131 are low.
Cardiovascular Responses Changes in pulse rate, systolic and diastolic blood pressures occurred regularly after sufficiently large depletions of sodium salts had developed. These changes as well as the magnitude and times of onset of orthostatic hypotension during the periods of depletion varied greatly. For example, tachycardia above 85 or 90 per minute occurred in nearly all subjects, but the size of the sodium deficit could not be related to the magnitude of pulse rate acceleration. In some persons peripheral resistance appeared to increase (diastolic blood pressure rose) in others to decrease (diastolic blood pressure fell). Pulse pressures decreased in some persons but increased in
360
Table 9.
HARVEY
FACTORS
DEFICITS OF SODIUM SALTS
Viscosity
BUTCHER, JR.
A Correlation of Some Factors Associated with the Cardiovascular Effects ~f Sodium Deficit and Hemorrhage DURING INCREASING
FUNCTION
R.
Hematocrit Plasma protein concentration
Increases steadily Increases steadily
DURING PROGRESSIVE HEMORRHAGE
Decreases, if anything Does not change or decrease
----- -----------)----------,1-----------
Capillary Functional volume dis- Does not change or intribution of water creasesv" exchange (deuterium) surface* Rate of capillary ex- Increases'> change of water (deuteriurn) Oligemia Oxygen consumption
Decreases" Decreases"
Increases (plasma defi- Increases (red cell and cit only) plasma defieitsj] Decreases in normal Decreases in normal perpersons and animals sons and animals Increases in chronic Unknown in alcoholics alcoholics
* The volume of distribution of deuterium decreases about 50 per cent after controlled hemorrhage sufficient to reduce the blood pressure to 75 mm. Hg systolic for 90 minutes." This means that some parts of the circulation (capillary bed) are closed and no blood flows through those areas for as long as the animal lives before dying of shock. Such does not take place during sodium deficit shock. t Red cell deficit is relatively greater than the plasma deficit because more or less hemodilution takes place rather quickly.
others. Obviously, cardiovascular responses were so variable as to make them useless as a clinical measure of unit sodium deficit. Very large and dangerous deficits may be unaccompanied by significant changes in blood pressures or pulse rates. Even orthostatic hypotension occurs first over such a wide range of sodium deficit as to be practically useless as a quantitative diagnostic sign of these deficits. The oligemia. of .sodium. depletion differs from that associated with hemorrhage (where orthostatic hypotension is a reasonable good measure of a significant degree of blood volume reduction) in the following important ways: 1. Hematocrit, plasma protein concentration and blood viscosity increase during sodium depletion; they remain the same or decrease during hemorrhage. 2. Peripheral vasoconstriction does not occur excepting with profound acute hypotension in sodium depletion. 3. The capillary beds in all parts of the body remain open during sodium depletion as indicated by a normal volume distribution of deuterium,"- 3 such is not the case in hemorrhagic shock' (Table 9). The fact that the body's exchangeable sodium salts are a primary,
361
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
determinant of plasma volume is most likely responsible for the efficacy of sodium-containing solutions intravenously in the treatment of those forms of shock not associated with massive loss of red blood cells. The next question is: Does the sodium mass of the body play any part in the etiology of the shock accompanying hemorrhage? Actually, the temporary loss of sodium incident to the removal of blood in the production of the Wigger's type of controlled experimental hemorrhagic shock in the dog is 5 to 6 mEq. of sodium per kilogram of body weight. Still more sodium salts apparently are "lost" or become no longer rapidly exchangeable for reasons yet unknown. A reduction in the sodium distributional space of approximately 40 per cent occurs during controlled canine hemorrhagic shock; this functional sodium space remains low if only the shed blood is used to treat the shock. 6 However, when sodium-containing solutions are also given in sufficient volume the functional sodium space is reconstituted. Is this important? It appears to be because the use of sodium-containing solutions' as well as blood in the treatment of controlled canine hemorrhagic shock of the Wigger's type has reduced the mortality of the experimental preparation from 50-70 per cent to 20-30 per cent (Table 10).1, 6,8 The use of plasma instead of lactated Ringer's solution (in volumes 20 to 25 per cent of the volumes of lactated Ringer's solution used) did not reconstitute the sodium distributional space nor did it reduce significantly the mortality of the experiment." The loss of plasma proteins appears to be of little significance in the production and treatment of hemorrhagic shock. The observation that a combination of buffered saline solution plus sufficient blood to maintain adequate oxygen transport will prevent the death of most dogs subjected to so-called irreversible shock supports the concept that the primary determinants of an adequate circulating blood volume are the red blood cell mass and the rapidly exchangeable sodium salts of the body. In other words, hemorrhagic shock may well prove to be as efficaciously treated with buffered saline solutions such as lactated Ringer's solution plus preserved red blood cells as with anything else. Colloidal solutions other than blood appear to have little if any place in the therapy of hemorrhagic shock (Table 10). Table 10.
Survivalfrom Controlled Hemorrhagic Shock in the Dog After Treatment
METHOD OF TREATMENT
Shed blood only Lactated Ringer's solution*
NUMBER OF DOGS
24 27 pH 8.5 pH6.5 Lactated Ringer's solution and blood .. 13 Dextran in saline (N aCI) 9 7% starch in lactated Ringer's solution .. 7 * Volume used
=
NUMBER DYING
NUMBER LIVING
PROPORTION LIVING
12 10
12 10
.50 .50 .14 .85 .22
6
1
2
11
7 7
o
2
plasma volume plus 4 X RBC volume removed.
.00
362
HARVEY
R.
BUTCHER, JR.
SUMMARY The changes accompanying acute corporeal deficits of rapidly exchangeable sodium salts in normal and alcoholic men are as follows: 1. Oxygen consumption during the production of deficits of sodium between 4 and 8 milliequivalents of sodium per kilogram is decreased in normal persons and increased in chronic alcoholics (Fig. 1, Table 2). The oxygen consumptions of these persons return to predepletional levels with the restitution of the sodium deficits with lactated Ringer's solution. 2. Sodium depletion produced apathy and somnolence in normal persons; similar deficits of sodium cause alcoholics to become agitated, restless and occasionally irrational. 3. The concentrations of sodium, potassium, chloride and bicarbonate ions in the plasma do not change significantly during sodium depletion by duodenal aspiration if the insensible losses of water from the body are replaced with 10 ml. of 5 per cent glucose in water per kilogram of body weight daily (Table 6). 4. The ionic concentrations of the duodenal fluid aspirated during the production of sodium depletion changed variably. In three persons the concentration of sodium fell as the magnitude of sodium depletion increased, while the hydrogen ion concentration increased (Table 3). 5. Sodium concentrations in the urine, though usually falling during progressive sodium depletion, are so random and variable that they cannot be depended upon as indicators of the existence or degree of sodium deficit (Fig. 2). 6. Similarly the variability of the changes in pulse rate, rate of urine flow and blood pressure was sufficiently great to eliminate them as quantitative indicators of sodium deficits. 7. The hematocrit rises linearly as the degree of corporal sodium deficit increases (Fig. 4). This relationship remains constant despite increasing concentrations of plasma proteins. It would appear that the rapidly exchangeable sodium content of the body is more important than the plasma proteins are in the maintenance of plasma volume. The plasma volume is reduced 4 to 5 per cent with each milliequivalent of sodium lost per kilogram of body weight. 8. The rapidly exchangeable sodium mass of the body is functionally important in the etiology and treatment of chronic hemorrhagic shock. Indeed, buffered saline solutions and blood as treatment for controlled hemorrhagic shock in dogs have produced higher survival rates than anything else.
REFERENCES 1. Dillon, John: Personal communication. 2. Fogelman, M. J. and Wilson, B. J.: Internal water exchange rates in burns and other forms of trauma. S. Forum 4: 473, 1953.
THE PATHOPHYSIOLOGY OF SODIUM DEPLETION IN MAN
363
3. Fogelman, M. J. and Wilson, B. J.: Blood extracellular fluid and total body water relationships in the early stages of severe burns. S. Forum 5: 762, 1954. 4. Fogelman, M. J., Montgomery, O. B. and Moyer, C. A.: Water exchange rates after hemorrhage. Am. J. Physiol. 169: 94, 1952. 5. Grayson, T. L., White, J. E. and Moyer, C. A.: Oxygen consumption; concentrations of inorganic ions in urine, serum and duodenal fluid; hematocrits; urinary excretions; pulse rates and blood pressure during duodenal depletions of sodium salts in normal and alcoholic man. Ann. Surge 158: 840-858, 1963. 6. Shires, T., CoIn, D. and Carrico, J.: Fluid therapy in hemorrhagic shock. Arch. Surge 88: 688-693, 1964. 7. Stokes, J. M., Bernard, H. R. and Balfour, J.: Effects of experimental electrolyte depletion upon renal water and solute excretion. Arch. Surge 85: 540-548, 1962. 8. Wolfman, E. F., Neill, S. A., Heaps, D. K. and Zuidema, G. D.: Donor blood and isotonic salt solution: Effect on survival after hemorrhagic shock and operation. Arch. Surge 86: 869-873, 1963. 4960 Audubon Avenue St. Louis, Missouri 63110