APPROACHES TO THE STUDY OF EDEMA AND DEHYDRATION*
F . WILLIAM SUNDERMAN, M.D., P H . D .
From the William Pepper Laboratory of Clinical Medicine, University of Pennsylvania,
Philadelphia, Pa.
The presence of edema and dehydration can, as a rule, be determined by
physical examination. However, several common laboratory measurements are
frequently helpful as aid in understanding the condition in individual cases.
For example, measurements of serum protein and chloride concentrations may
exhibit disturbance when edema is minimal and may guide the therapy; determinations of the basal metabolic rate and the concentrations of serum cholesterol
are important in establishing the diagnosis of myxedema and in guiding its
treatment; estimations of blood urea and non-protein nitrogen, hemoglobin,
serum proteins, and electrolyte components are at times helpful in deciding upon
the type and quantity of replacement therapy required in dehydration. Several
other useful laboratory aids in the study of edema and dehydration that might be
mentioned include measurements of serum volume, extracellular fluid volume,
water balance, total and colloidal osmotic pressures, and electrophoretic study of
the serum proteins. While most of these methods are not yet adapted to
routine clinical use, they have, nevertheless, advanced our knowledge of the
pathogenesis of edema and dehydration.
Edema may be defined as excessive accumulation of fluids between the cells of
the body while dehydration is loss of fluid from the tissues. In both of these
conditions, the mechanisms regulating the normal distribution of the body fluids
have become disturbed. The movement of fluids within the body and the
exchange of fluids between the body and its environment are controlled by many
physicochemical reactions which regulate volume, composition, and distribution
of the body fluids.
The body fluids are composed of water and solutes. Any consideration of
their behavior under pathologic conditions presupposes a knowledge of their
normal behavior. Water constitutes about 70 per cent of the normal body
Weight, and it is convenient to partition it into two major fractions: (1) intracellular water which constitutes from 45 to 50 per cent of the body weight and forms
an essential component of protoplasm and (2) extracellular water which amounts
to about 25 per cent of the body weight. The extracellular water may be
subdivided into two parts: (1) the vascular fluids, representing about 5 per cent
and (2) the interstitial fluids, comprising about 20 per cent of the body weight.
The vascular fluids and interstitial fluids together constitute the extracellular
water. The opinion is usually held that in edema, the interstitial fluids are
increased and that in dehydration, they are decreased. However, there is
evidence that this is not necessarily always the case, as for example the dehydration accompanying diabetic ketcsis.
* Read at the Refresher Course sponsored by the American Society of Clinical Pathologists in Chicago on March 3, 1946. Received for publication, April 15, 1946.
353
354
F. WILLIAM SUNDERMAN
Methods for measuring these various body fluids are available, but for the most
part, are somewhat complicated and time-consuming, and may be adapted only
to selected cases. The serum volume may be measured by either of two methods:
(1) by the injection of a known amount of a vital dye into the circulation and
measuring its concentration after thorough mixing has occurred, or (2) by the
inhalation of a measured amount of carbon monoxide and determining the concentration of carbon monoxide hemoglobin in the whole blood. The volume
of whole blood may then be calculated and the percentage of serum may be
estimated from the hematocrit readings.
The extracellular fluids (i.e., the sum of the vascular and interstitial fluids) are
measured by methods that employ the introduction of substances to which most
cells appear to be impermeable and which are not oxidized or otherwise altered
in the body. Such substances include sucrose, thiocyanates, sulfates, and bromides.
Attempts have been made to determine the total amount of body fluids
directly, so that the fluids in the intracellular fraction might be calculated.
Certain chemicals, such as thiourea, appear to penetrate into cells, and to be
dissolved in all of the body water. It is only fair to state, however, that such
direct methods have not proved to be very satisfactory and are still in the experimental stage.
Although the direct measurement of the body fluids is uncertain, nevertheless,
it is possible to determine changes in the total fluids of the body by estimating the
water balance. The water balance represents the difference between the total
water intake and the total water output. The total water intake constitutes
(1) the beverage water, (2) the preformed water of food, and (3) the water of
oxidation of foods. Solid food usually contains more than 75 per cent of preformed water. The amount of water formed in the metabolism of food stuffs
amounts to about 300 grams per day. The total water output constitutes the
water in the urine, feces, and the insensible loss from the skin and lungs and
occasionally loss in sweat, milk, and through wounds., When an individual is
weighed on a precision scale and a correction is made for the total quantity of
food and beverages ingested and the total quantity of urine and feces excreted,
there is observed a steady insensible loss of weight amounting to about 900 grams
per day. The insensible loss of weight represents the water evaporated from the
skin and lungs plus the difference in weights of oxygen inhaled and of carbon
dioxide exhaled.
On the histogram (fig. 1) is indicated average intake of water and average
output of water when there is perfect water balance. If the water output is less
than the intake, the water balance is obviously positive; when it is greater, it is
negative.
It is apparent when the various components are considered, that water
balance cannot be estimated by the common clinical practice of comparing
the volume of urine with the quantity of fluid ingested. To do this would be to
disregard a large proportion of both the water intake and the water output.
Normally, the beverage intake and the urinary output may approximate each
355
EDEMA AND DEHYDRATION
other, but this need not necessarily happen. It is probable that the clinical
estimation of the water balance is most easily obtained by measurement of the
daily change in body weight.
"Water Balance
Average total OUTPUT
Gms.
Average total INTAKE
62795.
4
12.00
1300
Urine
Beverage
Teces
900
300
Preformed
water
of
Food
Insensible
loss
(Skin-flirngs)
Nater of
oxidation
WATER B A L A N C E - W A T E R ^
Crams of water
yielded
Fat
107-1
S t a r c h - - 55a
R.00
|NTflKE
_
900
M T E R ^ ^ ^
per 100 grn. of
foodstuff
P r o t e i n - -41-3
117-3
Alcohol-
FIG. 1. AVERAGE INTAKE OF WATER AND AVERAGE OUTPUT OF WATER WHEN THERE IS
PERFECT WATER BALANCE
In considering laboratory approaches to the study of edema and dehydration,
it is desirable to mention briefly some of the mechanisms regulating the transfer
of body fluids. Such transfers are governed in large part by certain inherent
356
F. WILLIAM SUNDEEMAN
tendencies of the organism, several of which might be emphasized: (1) Under
normal conditions, the body tends to keep the volume of the different body
fluids constant within narrow limits. (2) Under normal conditions, the body
tends to maintain the concentrations of the solutes in each fluid constant within
narrow limits. Although the components of the various fluids may differ strikingly from each other, nevertheless, the osmolar concentrations of solutes in each
fluid tend to remain constant. The maintenance of constant osmolar concentration is aided obviously by the free movement of water through the membranes.
(3) The body fluids tend to establish osmotic equilibrium, or, in other words, to
become isotonic with each other. This, obviously, tends to occur under all
conditions since water is freely movable through the body membranes. (4) An
additional mechanism regulating the interchange of fluid between the vascular
CAPILLARY
MEMBRANE
-Vascular
compartment—
-Interstitial
compartment-
=>
CAPILLARY
BLOOD PRESSURE
i
j
-fri
INTERSTITIAL
FLUID
PROTEINS
SERUM
PROTEINS
>= Force driving
-
fluid
••
FROM
INTO
TISSUE
TENSION.
capillaries)
J
F I G . 2. COLLOIDAL OSMOTIC P R E S S U R E AND HYDROSTATIC P R E S S U R E I N T H E INTERCHANGE OF
F L U I D S ACROSS T H E C A P I L L A R Y M E M B R A N E
and interstitial compartments is diagrammatically portrayed in figure 2, in
accordance with the Starling hypothesis. 8 The length of the arrow has no significance in this diagram. There is a constant interchange of water, electrolytes,
and non-electrolytes between the blood stream and the tissue spaces through the
capillary membranes. The capillary blood pressure tends to drive the fluid out
of the capillaries, whereas the serum proteins, which are unable to escape through
the capillary walls, tend to draw the fluids back into the capillaries. On the
other hand, the interstitial fluid proteins, which are normally of low concentration, tend to draw the fluids from the capillaries.* The pressure exerted by the
elastic subcutaneous tissues and designated on the figure as "tissue tension" is
* There are available no very accurate measurements of the protein concentration of
interstitial fluids. Stead and Warren 9 found t h a t fluid obtained from t h e subcutaneous
tissues of normal subjects by means of their needle puncture technique contained on the
average 0.24 grams of protein per 100 ml. These workers found t h a t increase of the venous
pressure in the leg t o 30 mm. of H g produced edema fluid containing from 0.4 t o 1.3 grams of
protein per 100 ml.
357
EDEMA AND DEHYDRATION
a factor of importance in driving fluid back into the capillaries. The forces
driving fluid from the capillaries are the capillary blood pressure and the interstitial fluid proteins; the forces driving fluid into the capillaries are the serum
proteins and the tissue tension. Under normal circumstances, a perfect balance
is maintained between the inflow and the outflow of fluid through the capillary
membrane. However, under pathologic conditions, such as edema and ascites,
transudation exceeds absorption.
Estimations of the sodium and potassium contents of the urine are also
employed as a means of estimating the proportions of water derived from the
extracellular and intracellular compartments. These estimations are calculated
on the approximation that the potassium is wholly within the cells and the
sodium without. This approximation is not entirely correct, for in the case of
sodium, for example, only about eighty per cent is contained in the extracellular
fluids.
descending
mdinq
F I G . 3. T H E ELECTROPHORETIC P A T T E R N O F N O R M A L PLASMA
(After Dole, J , Clin. Investigation, 2 3 : 708, 1944)
In recent years much emphasis has been placed upon changes in the serum
protein fractions occurring in edema and to some extent in dehydration. Mention should be made of the electrophoretic method as an important laboratory
development for such fractionations. With this method the different serum
proteins are caused to migrate in electrical fields and the refractometric analysis
from the stratification is determined photographically. The amount of the
protein fractions may be calculated from the areas produced by the photographed
patterns. In figure 3 is shown the normal plasma electrophoretic pattern.
The tall peaks represent the albumin fraction. The «i, a^, /?, <j>, and y peaks
denote the globulin components,—the <t> peak denoting fibrinogen. The spike,
the S and e peaks represent principally buffer salt gradients with which we are not
concerned.
It has been shown that no clear-cut division of the serum proteins is obtained
from their solubilities in ammonium or sodium sulfate. On the other hand, by
electrophoresis, it would appear that the proteins may be separated in pure form
and the various fractions identified with greater accuracy.
358
F. WILLIAM SUNDERMAN
I . TYPES OF EDEMA
With these various physiologic and physicochemical considerations which have
been presented as a background, it is possible to classify edema and dehydration
into several distinct types. In table I is given a list of various types of edema.
It should be emphasized that, in clinical conditions, there is usually more than one
cause or mechanism involved.
A. Edema owing to primary retention of water (so-called "water intoxication").
Primary retention of water may produce edema. When this occurs, the hypoproteinemia that ensues appears to be due to a dilution of the serum rather than
to actual loss of serum proteins from the circulation. In our considerations it
should be borne in mind that hyproproteinemia does not necessarily indicate a
loss of proteins from the serum. A decreased concentration of protein may be
TABLE 1
TYPES OF EDEMA
A. Primary retention of water
1. Water intoxication
B. Primary retention of salt
1. Endocrine disturbances
Administration of adrenal cortical and gonadal hormones; excessive insulin, etc.
C. Reduction of colloid osmotic pressure (hypoproteinemia)
1. Prehepatic
Faulty diet; obstructive lesions of gastro-intestinal tract; diarrhea
2. Hepatic
Cirrhosis; phosphorus poisoning
3. Posthepatic. Increased permeability
Burns; nephritis; toxins
D. Changes in capillary blood pressure
1. General. Cardiac edema
2. Local. Mechanical obstruction to veins
Cirrhosis, thrombosis, etc.
E. Blockage of lymphatic return of protein-containing tissue fluid
Elephantiasis; inflammatory edema, etc.
due to an increase in blood volume owing to retention of water and subsequent
dilution.
Too much water, like too little water, may be fatal. Water intoxication may
be produced in animals by the administration of excessive amounts of water
under certain restricted conditions and, indeed, fatalities have occurred in patients from injudicious administration of fluids. In experimental animals, in
which water intoxication has been produced, there is first produced diuresis and
later, for some unknown reason, oliguria and anuria; toward the end, these
animals die of convulsions from acute cerebral edema. Helwig, Schutz and
Curry 5 report death in a patient who had absorbed nine liters of tap water by
proctoclysis within a period of thirty hours. Explanation of the mechanism of
water intoxication is not wholly satisfactory, but the evidence, insofar as it is
EDEMA AND DEHYDRATION
359
available, suggests that there is an increased volume of extracellular fluids with
reduction in the total osmotic, as well as the colloidal osmotic pressure. No
adequate reason for the failure of the kidneys to eliminate the excessive water
has been established.
B. Edema owing to primary retention of salt. There can be little doubt that salt
retention is an important factor in the production of edema. Admmistration
of sodium chloride to a slightly edematous patient, we all know, usually aggravates the edema; moreover when the patient is placed on a salt-poor diet, the
edema disappears. The studies of many investigators suggest that the sodium
ion in this type of edema is more influential than the chloride ion in the production
of the edema. In this connection it might be mentioned that there is no rational
basis for the use of sodium lactate or malate in the treatment of nephritic patients.
Edema produced by a primary retention of salt is probably due largely to
disturbances in endocrine physiology, and certain endocrine glandular products
have been shown by balance studies to produce a retention of both salt and
water. Administration of desoxycorticosterone to normal or adrenalectomized
animals perhaps presents the most striking example of this type of retention.
Furthermore, when desoxycorticosterone acetate is given in therapeutic doses to
patients suffering from Addison's disease, generalized edema with salt and water
retention is commonly observed.
The gonadal hormones have also been shown by Thorn and Emerson11 and
others to predispose to excessive retentions of both salt and water as well as
diminution in the concentrations of serum proteins. For example, the normal
cyclical changes in the secretion of the sex hormones is believed to be a precipitating factor in the development of premenstrual edema.
Administration of excessive amounts of insulin may also lead to edema with
salt retention. Insulin itself produces a readjustment of the partition between
the vascular and extravasuclar compartments.
A type of edema which may masquerade as myxedema has been described by
Means and Lerman and their associates. 7,6 Such edema not infrequently is
qbserved in patients exhibiting tumors or cysts of the pituitary gland. It might
also be mentioned that the so-called "endocrine edema" observed in Cushing's
disease has been regarded as probably related to an overly-active pituitary. The
hydration observed in pituitary disease might perhaps be regarded as a defect in
water matabolism rather than of electrolyte metabolism.
C. Edema owing to reduction of protein or colloidal osmotic pressure (hypoproteinemia). The edema owing to hypoproteinemia may be classified into three
types.
1. Prehepatic edema. This is the type observed in nutritional or famine states
in which there is interference with the intake, digestion, or absorption of the
components for protein synthesis. This type of prehepatic hypoproteinemia is
observed following the prolonged ingestion of faulty low-protein diets, in malnutrition, with obstructive lesions in the gastro-intestinal tract, and in some
diarrheal conditions.
360
F. WILLIAM SUNDEBMAN
Deficient protein intake may also occur in the aged owing to anorexia. The
hypoproteinemia of the prehepatic type seems to be definitely related to an
inadequate supply of essential protein building materials from the gastrointestinal
tract, since it has been frequently shown that the provision of a high protein
diet causes the disappearance of the edema. This is the type in which the
administration of amino acids may be most helpful.
2. Hepatic edema. This type of edema results from the inability of the liver
to synthesize plasma proteins despite an adequate supply of precursor materials.
In the hepatic type the administration of amino acids would not be expected to
be of great usefulness. It should be stated that while the sites of formation of
all of the plasma proteins are not conclusively established, it is probable that the
liver is specifically concerned with the synthesis of fibrinogen and in all probability with that of albumin. Disease of the liver may thus be associated with
edema. Specifically, hypoproteinemia has been noted in association with
hepatitis, tuberculous and syphilitic involvement of the liver, yellow atrophy,
cirrhosis, and chloroform and phosphorus poisonings.
3. Post hepatic edema. This is the type in which there is adequate production
of serum proteins by the liver but, through increased capillary permeability,
there is an abnormally great loss of protein. This is the type of hypoproteinemia
observed after severe burns, after chronic suppurations, and in nephritis.
In the production of edema in chronic nephritis, there is little doubt that the
most responsible factor is the depletion of albumin. Epstein 2 appeared to be the
first to recognize the application of Starling's celebrated theory regarding the
significance of the osmotic effects of the plasma proteins in regulating the interchange of fluids between the blood and tissues. The first to compute the
osmotic effects of plasma proteins in the production of edema was apparently
Govaerts 4 . According to Govaerts, a one per cent solution of albumin exerts an
osmotic pressure of 5.5 mm. of mercury as compared to 1.44 mm. exerted by a one
per cent solution of globulin. It is generally conceded that edema commences
when the albumin concentration is less than 2.5 grams and the total protein less
than 5 grams per 100 cc. of serum. In nephritic patients when the total protein
concentration falls below 4 grams per 100 ml. of serum, the edema is usually
intractable to all forms of treatment.
Of especial interest in this connection is the observation that for some unknown
reason the critical level for edema formation seems to vary with the pathologic
condition. Thus, for patients suffering from nutritional edema, the critical
level appears to be nearer 3 grams per 100 ml. than 5 grams. Of further interest
is the observation of Farr and Van Slyke3 that in children with the nephrotic
syndrome, the critical level is lower than in adults. Thus, the critical level for
serum albumin for adults is approximately 2.5 grams per 100 ml., whereas in
children it is only half as much, i.e., 1.2 grams per 100 ml. of serum.
D. Edema owing to changes in capillary blood pressures. Changes in capillary
blood pressure may lead either to generalized or localized edema. Edema from
congestive cardiac failure may be generalized owing to increased venous pressure
and distension of the vessels in the capillary areas. However, it should be
emphasized that the edema from cardiac failure is a complex process and that
EDEMA AND DEHYDRATION
361
elevation of the capillary pressure is probably only one of the contributing
factors.
It might be pointed out in this connection that Warren and Stead12 hold the
view that the edema of chronic congestive failure develops because the kidneys
do not excrete salt and water in a normal manner. They believe that disturbed
renal function in cardiac patients is related to decreased cardiac output and not
to engorgement of the kidneys from increased venous pressure, since electrolyte
retention may occur before there is an elevated venous pressure.
Mechanical obstruction to the larger veins may produce localized types of
edema. Thus, blockage of the portal vein in cirrhosis of the liver may contribute to the formation of ascites. Similarly, venous thrombosis of the peripheral veins is one of the commonest causes of edema localized to the extremities.
E. Edema owing to blockage of lymphatic return. When the lymphatic channels
become blocked so that the interstitial proteins cannot be removed, localized
TABLE 2
TYPES OF DEHYDRATION
A. Primary loss of water
1. High environmental temperature
2. Fevers
3. Deprivation of water
4. Excessive loss of water.
Diabetes insipidus
B. Primary loss of salt
1. Endocrine disturbances
Adrenal cortical insufficiency
Diabetic coma
2. Vomiting and diarrhea
C. Secondary types
1. Excessive water intake when eliminated
2. Introduction hypertonic solutions when eliminated
edema may also occur. This is the type observed in localized inflammations and
also in elephantiasis. The edema which develops following the tight application
of a plaster cast is due to blockage of both the venous and lymphatic circulations.
II. TYPES OF DEHYDRATION
In table 2 are presented types of dehydration observed clinically which are, to
a degree, the opposite of the types observed in edema. It is noteworthy that the
symptoms in patients suffering from either one of the first two types of dehydration may differ remarkably. Thus, when the loss of water is disproportionate
to the loss of "salt, thirst is usually conspicuous; when the loss of salt is in proportion to the loss of water weakness, apathy, and anorexia are more conspicuous
than thirst.
A. Dehydration owing to primary loss of water. Primary loss of water may be
observed in individuals exposed to high environmental temperatures in which
there is an unusually large loss of water through the skin and lungs. High fevers
and the deprivation of water that is occasionally observed in mental patients
362
F. WILLIAM SUNDERMAN
when they refuse to drink may also lead to dehydration from a primary loss of
water. This type of dehydration also occurs in castaways. Individuals suffering
from diabetes insipidus excrete large volumes of urine of low specific gravity
and of low salt content. These indivduals seem to have lost their power to
increase the concentration of either sodium or chloride excreted in the urine even
when their water intake is restricted.
B. Dehydration owing to primary loss of salt. Of the endocrine disturbances
producing dehydration from a primary loss of salt, adrenal cortical insufficiency
and diabetic coma may be cited as striking examples.
We have at the present time under study at the Hospital of the University of
Pennsylvania a patient, suffering from anorexia nervosa, who weighs only 55
pounds. Her serum chlorides have remained for weeks at concentrations
between 50 and 65 mEq. per liter. In spite of this low concentration, she continues to excrete a small amount of chloride in her urine (250 to 500 mg. NaCl
per day). Usually only traces are to be found in the urine when the concentration of serum chlorides is below 80 or 85 mEq/L. Our patient is tremendously
dehydrated. We believe that her dehydration may be due primarily to a loss of
salt.
The dehydration resulting from excessive vomiting and diarrhea might also be
regarded as the result of a primary loss of salt.
C. Secondary types of dehydration. Although it may seem paradoxical, nevertheless, the excessive ingestion of water when the water is excreted may also
lead to dehydration. This water in its excretion tends to carry salt away with it
and, thus, further depletes the body reserves of base. Therefore, the ingestion of
water without salt by individuals verging on dehydration may deplete the extracellular fluids of base and thus, hasten the development of severe dehydration.
The introduction of hypertonic solutions, such as hypertonic glucose or saline,
intravenously may initiate the withdrawal of water from the extravascular
compartments and produce an increase in the serum volume. This increased
serum volume may lead to a diuresis so that there results an overall loss of water.
Dehydration in diabetic ketosis. The movement of body fluids has been
intensely studied in the dehydration accompanying diabetic ketosis and we
should, therefore, like to outline briefly the changes in the body fluid distribution
occurring with this type of dehydration. 10
In figure 4 is given our schematic representation of the fluid changes in the
body during the course of diabetic acidosis. The first column represents the
normal concentration of the electrolytes of the serum, the normal volume of
serum and the normal amount of water and electrolyte in the extravascular
spaces. During the development of diabetic acidosis, ketone acids increase in
excessive amounts. The increase in these acids displaces HCOF, which is
expired into the air as C0 2 . The kidneys tend to provide a normal electrolyte
pattern by excreting organic acids in the urine as free acids and in combination
with NH^. The production of NH^" soon becomes insufficient to combine with
the organic acids awaiting excretion and, as a consequence, fixed base is excreted
for the purpose. This loss of base necessitates the withdrawal of water if
363
EDEMA AND DEHYDRATION
isotonicity of the body fluids is to be maintained. Coincident with the withdrawal of base and water from the tissues, the serum volume increases as well as
the total amounts of base and chloride in the serum. Increasing concentrations
of glucose, urea and other non-electrolytes appearing in the serum, elevate the
total osmotic pressure of the serum. In partial compensation, the concentration
^ 1
SOfly.
-^t*-
^ICHT
k
-HCO,
°3l
m
CaMg-
tanmc
NORMAL
DIABETIC
i
DIABETIC
n
KET0515
CI
.orq Ac.
-Pr.
-P0 4 8S0 4
AFTER
TREATMENT
WITH INSULIN <? SALINE
F I G . 4. F L U I D C H A N G E S I N T H E BODY D U R I N G D I A B E T I C ACIDOSIS
of the electrolytes may be decreased, although the total amount of electrolytes
is increased.
Finally, as shown in the third column, the extravascular fluids become greatly
depleted and, with the continued demand for fixed base to combine with the
organic acids, chloride releases its base by the excretion of HC1 in the vomitus.
304
F. WILLIAM SUNDERMAN
The protoplasmic structure of the organism is unable to withstand further
strain, and unless therapy is instituted, death ensues. In the last column is
shown a return to the normal distribution after administration of insulin and
saline.
A most conspicuous feature in the development of diabetic dehydration is the
depletion of fixed base and water. Administration of saline solutions alone will
not alleviate this dehydration. However, the administratin of insulin together
with saline solutions results in transfer of water and electrolytes from the serum
to the extravascular fluids and is recognized as the only successful method of
combating the dehydration of diabetic ketosis. We feel that this action of
insulin in repartitioning the body fluids is an important action of insulin and
deserves greater emphasis.
In conclusion, the treatment of edema and dehydration resolves itself essentially into an attempt to attack the underlying disturbance. Consideration of the
varied factors involved will indicate the direction toward which therapy might
be approached. Thus, for example, restriction of sodium in the diet may be of
greater importance than restriction of water and vice versa. The treatment of
edema due to hypoproteinemia will obviously depend upon the causative factors
producing the lowered concentration of serum protein. Guidance in the type
and quantity of replacement therapy must not only depend upon the consideration of the mechanisms involved, but also upon the results of blood and urine
analyses. The value of serum protein, hemoglobin, and the various electrolytes
and non-electrolytes measurements in edematous and dehydrated patients is
emphasized.
REFERENCES
1. ADOLPH, EDWARD P . : T h e metabolism and distribution of water in body and tissues.
Physiol. R e v . , 1 3 : 336, 1933.
2. E P S T E I N , ALBERT A . : Concerning t h e causation of edema in chronic parenchymatous
nephritis: Method for i t s alleviation. Am. J . M . S c , 154: 638, 1917.
3. F A R R , L. E . , AND VAN SLYKE, D . D . : Relation between plasma protein level and edema
in nephrotic children. Am. J . Dis. Child., 57: 306, 1939.
4. GOVAERTS, P . : Motient albumines-globulines e t pression osmotique des proteines d u
serum. Compt. rend. Soc. de biol., 95: 724, 1926; Influence d u rapport albuminesglobulines sur la pression osmotique des proteines d u serum. Ibid., 9 3 : 441, 1925;
Recherches cliniques sur la pression osmotique des colloides d u serum. Ibid., 8 9 :
678, 1923.
5. H E L W I G , F . C , SCHULTZ, C. B . , AND C U R R Y , D . E . : W a t e r intoxication.
R e p o r t of a.
fatal human case with clinical, pathologic, and experimental studies. J . A. M . A.,
104: 1569, 1935.
6. LERMAN, J . , AND STEBBINS, H . D . : P i t u i t a r y type of myxedema. J . A. M . A., 119:
391, 1942.
7. M E A N S , J . H . , H E R T Z , S A U L , AND L E R M A N , J A C O B : T h e p i t u i t a r y t y p e of m y x e d e m a or
Simmond's disease masquerading as myxedema. T r . A. Am. Physicians, 55: 32
1940.
8. STABLING, E R N E S T H . : On t h e absorption of fluids from t h e connective tissue spaces.
J . Physiol., 19: 312, 1895-96.
9. STEAD, E U G E N E A., J R . , AND W A R R E N , JAMES V . : T h e protein content of t h e extracellu-
lar fluid in normal subjects. J . Clin. Investigation, 23:283,1944.
10. SUNDERMAN, F . W I L L I A M : T h e water and electrolyte distribution in diabetes mellitus.
Dehydration in diabetes. Am. J . M . S c , 205: 102, 1943.
11. T H O R N , G E O R G E W., AND E M E R S O N , K . , J R . : T h e r61e of gonadal and adrenal cortical
hormones in t h e production of edema. Ann. I n t . Med., 14: 757, 1940.
12. W A R R E N , JAMES V., AND STEAD, E . A., J R . : Fluid dynamics in chronic congestive heart
failure. Arch. I n t . Med., 7 3 : 138, 1944.