Lingua Medica
Language Guiding Therapy: The Case of Dehydration versus
Volume Depletion
P atients presenting with orthostatic hypotension
and normal plasma sodium concentrations are
frequently admitted to the hospital with a diagnosis
of dehydration. If they are fortunate, they receive
fluids containing sodium chloride instead of free
water to correct obvious extracellular fluid volume
depletion. Confusing this diagnosis highlights the
growing and pernicious habit of using the terms
dehydration and volume depletion interchangeably at
the bedside when the two describe clearly different
disturbances.
The heuristic value of describing discrete body
fluid spaces affected by disorders of salt and water is
a well-established bedside strategy (1-5). It sprang
from an early curiosity about the best treatment for
fatal diarrhea (6) and seizures (7) and from classic
experiments that formulated the volume behavior
and osmolarity of cells (8, 9). Adapting this infor-
mation from cells to humans in the late 1930s re-
quired more conceptual thinking about the special
role of vascular volume in the control of body fluids
(2, 10). The wartime assessment of potential fluid
losses encountered by shipwrecked aviators and sail-
ors in the early 1940s further enhanced our under-
standing of salt and water metabolism (11-13), as
did "the emerging role of cardiac performance (14, 15).
With the advent of radioactive tracers (16, 17),
medical language in the latter part of the 20th cen-
tury began to discriminate more carefully between
dehydration associated with hypertonicity, a principal
loss of body water from the intracellular and inter-
stitial compartments, and extracellular fluid volume
depletion, a fluid deficiency that clinically affects the
vascular tree (3, 5, 18). The proper use of the terms
dehydration and volume depletion informs communi-
cation and should improve patient care.
The Language of Salt and Water in
Body Fluid Spaces
At steady state, the hydration or water content
of body fluids represents a physiologic balance
achieved by the ingestion of water and its further
distribution, evaporation, and clearance by the kid-
neys and gut (19, 20). Total body water disperses in
848 ©1997 American College of Physicians
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a well-defined pattern (8, 21, 22) across several
elastic or "virtual" spaces (1, 3, 5, 22). Approxi-
mately 66% of water is confined by solute to the
intracellular compartment, whereas 33% is found in
the extracellular space. Only 25% of this extracel-
lular fluid, or 8% of total body water, resides within
the vasculature (1, 4, 17), and eventually all spaces
achieve identical osmolarity (23).
The concept of osmotic pressure derives from the
fundamental gas laws of physical chemistry (2, 24).
Water moves down a concentration gradient gener-
ated by the osmotic properties of solutes bound by
a semipermeable membrane to achieve equilibrium
(2). Simple osmosis of water across virtual body
compartments is further amended by the Gibbs-
Donnan effect of charge-bearing proteins (2) and, in
blood vessels, by the hydrostatic attributes of Star-
ling forces (10, 25). Although measured osmolarity
reflects all particles per volume of water, not all
osmols influence transmembrane water flow (5).
The power to move water across cell membranes
is a property of "effective" osmols (2, 26, 27). To-
nicity describes the volume behavior of such cells in
solution and is modulated by the number of effec-
tive osmols, or osmotically active particles, that are
restricted to one side of the cell membrane because
of permeability characteristics, transmembrane pumps,
or both (28). Most effective osmols are extracellular
sodium, chloride, and bicarbonate or intracellular po-
tassium, chloride, and phosphate. Less abundant effec-
tive osmols are sugars, lipids, and proteins. Solutes
such as urea or alcohol, however, freely move across
cell membranes and are therefore ineffective osmols
unable to effect transmembrane water flow (26).
Acutely, effective osmols in the intracellular space
(particularly potassium salts) are relatively fixed,
and thus the major influence on the location of
water in this space is the effective osmolarity of the
extracellular compartment (3, 26). When water is
lost from the skin, gut, or kidneys, the hypertonicity
created in the extracellular space is directly trans-
ferred to the larger intracellular space (5). Worsen-
ing hypertonicity therefore has its biggest impact on
the size of the intracellular compartment and, to a
lesser extent, on interstitial spaces. To dehydrate is
to lose this intracellular water and stimulate thirst.
 The physiologic concept of dehydration, at first
glance, might subsume the definition of volume de-
pletion. This erroneous assumption, made by inves-
tigators early in this century (26, 29), was corrected
by physiologists in the era after World War II (3,
18, 30) but today has insidiously resurfaced because
volume depletion has become a shorthand for extra-
cellular fluid volume depletion, and the first two
words of the latter phrase make all the difference.
The volume of the extracellular fluid space is
principally regulated by the ingestion and excretion
of sodium salts (31). Sodium is largely confined to
extracellular fluid because cell membrane pumps
operate to actively exclude it from the intracellular
compartment (28, 32). Thus, the addition of sodium
leads to a specific gain of effective osmols in extra-
cellular spaces. If sodium is added isotonically to
the extracellular compartment, no shift of water
from the intracellular space will ensue and the vol-
ume increase of the extracellular space will equal
the volume of isotonic infusate. If hypotonic or
hypertonic sodium is added to the extracellular
space, the volume of the intracellular space changes
accordingly (26, 29).
Changes in extracellular volume can therefore be
dissociated from changes in intracellular volume (5,
21, 33). For example, a patient who bleeds will have
a rapid decline in vascular volume but, in the ab-
sence of tissue injury or change in extracellular to-
nicity, will not have redistribution of water from
intracellular spaces (3, 34). Such a person will have
a deficit of body water equal to the proportionately
small water content of the lost blood. This can be
illustrated quantitatively by considering the fate of
an administrated infusate of 5% dextrose compared
with an equal volume of fluid given as 0.9% saline
(Table). Both infusates provide equal amounts of
water, but their effect on plasma volume is vastly
different.
Assessment of Body Fluid Spaces in
Designing Effective Therapies
Dehydration
To best assess the state of hydration, one needs
to ascertain the concentration of a marker sub-
stance whose content is constant and whose distri-
bution is uniform throughout all virtual fluid spaces.
Of course, surrogate markers were devised because
no such natural substance exists (16). Because so-
dium is the most abundant extracellular solute and
its concentration (p[Na + ]) influences water move-
ment across cells, p[Na + ] may be used as a surro-
gate at the bedside to gauge the relation between
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Table. Effect of a 1-L Infusion of W a t e r or 0.9% Saline on
Virtual Body Fluid Spaces
Variable* 5% Dextrose 0.9% Saline
Sodium content, mEq 0 154
Water content, mL 1000 1000
Change in extracellular fluid space, mL 333 1000
Change in intracellular fluid space, mL 667 0
Change in osmolarity, % decrease 2.5 0
Change in plasma volume, mL 83 250
* Change in body salt and water after a 1-L infusion of 5% dextrose (5% glucose in
water; 0 mEq/L of Na+) or 0.9% saline (NaCI, 154 mEq/L) into a 70-kg person.
Calculations are based on achievement of equilibrium without urinary losses of the
infusate. Although both solutions are isotonic (approximately 300 mOsm of H20 per
kg), infusing 5% dextrose is tantamount to providing pure (or free) water because of
the rapid insulin-dependent metabolism of glucose.
water and effective osmols in all body fluids (5).
Although anions and large molecules contribute to
the property of tonicity, some intracellular anions
are complex moieties that are not easy to formulate
in simple terms; therefore, it is more convenient
to estimate effective osmols in a representational
shorthand that consists of cations. Formula [1] pro-
vides a conceptual framework with which to pre-
dict relative water deficit or excess determining
tonicity (30):
CM
+ +
TBNa Q TBK TBNa
+
+ TBK+
[1]p[Na+] =
" TBH 2 0 TBH 2 0
TBNa +
TBK +
=
ECHp° iCH2Oatequilibrium
r
where TBNa + is total body sodium, TBK + is total
body potassium, TBH 2 0 is total body water, CM is
cell membrane, E C H 2 0 is extracellular water, and
ICH 2 0 is intracellular water. In this formula, extra-
cellular total body sodium and intracellular total
body potassium represent the principal effective os-
mols that partition total body water (0.6 L/kg of
body weight in adult men and 0.5 L/kg in adult
women) across cell membranes at equilibrium (21,
23, 27, 35).
The signs and symptoms of acute dehydration are
thirst and, progressively, confusion, coma, and re-
spiratory paralysis (28). These complications may be
mitigated if hypertonicity develops over time and if
the brain and other tissues are allowed to adapt by
generating new intracellular solutes (previously
called idiogenic osmols) to minimize shrinkage (33,
36). These new solutes include sodium chloride,
amino acids, myoinositol, and methylamines (37, 38).
Isolated water deficits are corrected by water re-
placement and can be estimated (30), over and
above any isotonic change in extracellular volume,
by using formula [5] (for the derivation of formula
849
 [5], see Appendix):
[Present p[Nal
Water Deficit = Present TBH20 X
[Normal p[Na+]
The presentation of dehydration is well illus-
trated by the case of an elderly 70-kg woman with
bipolar disorder and angina who was receiving lith-
ium therapy and was admitted after a positive stress
test result. Her blood pressure was 128/85 mm Hg,
and her heart rate was 82 beats/min. Evaluation was
unremarkable except for thirst and a p[Na + ] of 150
mEq/L. Without orthostasis or evidence of de-
creased tissue perfusion, the patient was given a
diagnosis of hypertonicity brought on by acute water
deprivation superimposed on lithium-induced neph-
rogenic diabetes insipidus. She required intravenous
water expansion with 5% dextrose before cardiac
catheterization because the dye load and ensuing
osmotic diuresis would have worsened the hyperto-
nicity by producing urine with lower concentrations
of sodium and potassium than are found in body
fluids (39).
Assuming the expected restoration of p[Na + ] to
140 mEq/L, the patient's free water deficit was cal-
culated by using formula [5], as follows:
(0.5 L/kg X 70 kg) X [(150 mEq/L -r- 140 mEq/L) -1]
= 35 L X 0.07 = 2.5 L
In addition, any urine output during treatment
should be replaced in the same ratio of solute (so-
dium plus potassium) to water. If the patient's con-
dition had actually been mislabeled as extracellular
fluid volume depletion and 0.9% saline (154 mEq of
Na + /L) had been administered instead of 5% dex-
trose, p[Na + ] would have increased to
[(0.5 L/kg x 70 kg x 0.33) X 150 mEq/L
+ (154 mEq/L X 2.5 L)] - [(0.5 L/kg X 70 kg
X 0.33) + 2.5 L] = 151 mEq/L
leaving the tonicity slightly worse and possibly ex-
panding the extracellular fluid volume beyond the
tolerance of her cardiac function. The choice of
fluid in this case is dictated by the correct diagnosis
of dehydration.
Volume Depletion
Extracellular fluid volume depletion is precipi-
tated by blood loss, a net reduction in total body
sodium content, or both. Patients with this condition
are often light-headed and orthostatic as a result of
reduced effective circulatory blood volume (38, 39).
The steady-state content of extracellular sodium
regulating volume is modulated by the kidneys in
response to a variety of sensing and effector mech-
anisms (40-50), which lead to neurohormonal and
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intrarenal hemodynamic changes that control uri-
nary sodium. There are no normal values for uri-
1
nary sodium or potassium excretion because these
- 1
urinary solutes tend to equal dietary intake at a
steady state termed euvolemia (51, 52). When extra-
cellular volume is depleted by 10% to 15%, renal
hypoperfusion may lead to oliguria with intense
conservation of sodium and water (31, 44).
Renal sodium handling is modulated by the state
of the extracellular fluid volume or, more concep-
tually, the fullness of the circulation (9). If the cir-
culation is too full, the renal reabsorption of sodium
rapidly decreases to restore the initial circulatory set
point. If the fullness of the circulation, particularly
the arterial circulation (53), is sensed to be reduced,
then renal conservation of sodium and water is en-
hanced. Sodium and not pure water retention is
most crucial for the repair of circulatory volume
because retention of water without sodium chloride
will have a marginal effect on the size of the intra-
vascular volume (Table 1).
This is illustrated by the case of a middle-aged
man admitted to the hospital for extensive watery
diarrhea after returning from Mexico. He had been
self-treating at home with juices until nausea set in.
On examination, he was weak with postural hypo-
tension, a p[Na + ] of 137 mEq/L, and a p[K + ] of 3.7
mEq/L. His weight had decreased from 70 to 66 kg,
and his bladder was empty except for a small
amount of urine with an osmolarity of 670 mOsm/L,
a Na + concentration of 5 mEq/L, and a K + con-
centration of 60 mEq/L. Stool electrolyte studies
revealed a Na + concentration of 103 mEq/L and a
K + concentration of 35 mEq/L.
This patient's diarrhea and self-ministrations had
produced near-isotonic losses of solute with extra-
cellular fluid volume depletion. The patient was
treated with antibiotics for Vibrio cholerae and was
given fluids to restore extracellular volume. A loss
of 4 L of isotonic fluids was replaced with 0.9%
saline to improve tissue perfusion. The resultant
p[Na + ] was as follows:
[(0.6 L/kg X 66 kg X 0.33) X 137 mEq/L
+ (154 mEq/L X 4 L)] - [(0.6 L/kg X 66 kg
X 0.33) + 4 L] = 141 mEq/L.
Administration of oral fluids was restarted shortly
thereafter.
Dehydration and Volume Depletion
Fluid homeostasis normally operates to preserve
tissue perfusion first and tonicity second (54, 55).
Orthostatic decreases in blood pressure that are not
due to neurologic disorders, deconditioning, or sep-
sis almost always imply sodium deficits. Further-
more, it is very difficult to develop severe extracel-
 hilar fluid volume depletion during a pure state of
dehydration because, although water deficits are
shared proportionally by all compartments, 92% of
the water losses are intracellular and interstitial and,
unless massive, do not significantly modulate vol-
ume receptors. The vascular compartment in this
case is also reduced, but the increase in oncotic
pressure from concentrated plasma proteins further
protects the small 8% reduction in circulatory vol-
ume (30). To realize extracellular volume depletion
equal to that achieved by a loss of 1 L of blood
would require the loss of approximately 12 L of
pure water across the total body water. Of course,
dehydration and volume depletion can occur to-
gether. Because each is treated differently and at a
different rate (slow for dehydration and rapid for
volume depletion), it is essential to recognize their
separate characteristics in correcting complex fluid
and electrolyte disturbances.
For example, a 70-year-old woman with diabetes
was admitted to the hospital from a nursing home
for change in mental status. Her caregiver had been
withholding insulin because she had stopped eating.
On examination, she was comatose and weighed 50
kg. She had a palpable blood pressure of 80 mm Hg
while supine, a body temperature of 38.3 °C, poor
skin turgor, dry mucous membranes, and foul-smell-
ing urine. She had a p[Na + ] of 175 mEq/L, a p[K + ]
of 3.8 mEq/L, a p [ C l ] of 139 mEq/L, a p[HC0 3 ~]
of 23 mEq/L, a urea nitrogen concentration of 65
mg/dL, a creatinine concentration of 2.8 mg/dL, and
a glucose concentration of 1260 mg/dL.
The patient was given a diagnosis of hyperosmo-
lar, hyperglycemic, nonketotic diabetic coma (56).
She had had substantial loss of total body sodium
from glucose-induced osmotic diuresis, which had
led to circulatory compromise (39). In addition, her
water deficits and hypertonicity had been aggra-
vated by an inability to drink fluids to correct on-
going hypotonic losses. Her hypotension demanded
immediate volume resuscitation and treatment for
presumed sepsis.
The patient's tonicity on admission was estimated
to be at least 420 mOsm/L, of which 70 mOsm/L
was attributable to her elevated blood glucose con-
centration. Hypertonicity of this magnitude is life-
threatening and may be associated with early brain
cell shrinkage followed by a complex reequilibration
(36, 56, 57). The patient's water deficits were far
worse than her p[Na + ] of 175 mEq suggested be-
cause for every 100 mg/dL increase in the plasma
glucose concentration, there is a reduction in
p[Na + ] of 1.6 mEq/L, caused by the redistribution
of intracellular water to the extracellular fluid (58).
If her glucose concentration were not increased, the
p[Na + ] would correct to the following:
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{[(1260 mg/dL - 100 mg/dL) - 100] X 1.6}
+ 175 mEq = 193 mEq/L.
This blood glucose level should be decreased
with insulin, but this should not be done so quickly
that extracellular fluid volume is reduced before
some saline has been administered.
The fluid management strategy was staged to first
restore blood pressure. If hypotension was due prin-
cipally to fluid losses and not septicemia, the patient
would need an initial infusion of 0.9% saline to
increase extracellular volume. Although the magni-
tude of the patient's volume deficit cannot be pre-
dicted with great precision, it is at least 10% to 15%
of body weight:
(0.5 L/kg x 0.33) x [(50 kg x 0.15) + 50 kg]
- (0.5 L/kg X 50 kg x 0.33) = 1.25 L.
Bedside examination and reassessment of on-
going fluid and solute losses is the best guide to
how much additional saline the patient should be
given once this first estimate is reached. Saline here
will also gradually decrease tonicity because its os-
molarity is hypotonic to the patient's current state,
and volume expansion will promote glycosuria. Po-
tassium is added to the replacement fluid after
urine output is restored and before too much glu-
cose and potassium are driven back into cells with
insulin.
In the second stage of fluid therapy, the patient
needs to have her water deficit corrected gradually
according to formula [5]:
(0.5 L/kg X 50 kg) X [(193 mEq/L + 140 mEq/L) - 1]
= 25 L X 0.38 = 9.5 L.
The rate for this correction is usually factored
empirically against the duration of hypertonicity, in
recognition of the fact that the patient's brain can
swell when dehydration is corrected too rapidly (33,
36, 57, 59).
Summary
Indiscriminate use of the terms dehydration and
volume depletion, so carefully crafted by our prede-
cessors, risks confusion and therapeutic errors.
These two conditions should be distinguished at the
bedside and in how we speak to one another. De-
hydration largely refers to intracellular water deficits
stemming from hypertonicity and a disturbance in
water metabolism. The diagnosis of dehydration
cannot be established without laboratory analysis of
p[Na + ] or calculation of serum tonicity. In contrast,
volume depletion describes the net loss of total body
 sodium and a reduction in intravascular volume and Grant Support: In part by grant DK-07006 from the National
Institutes of Health and by the DCI RED fund. Drs. Mange,
is best termed extracellular fluid volume depletion. Matsuura, Cizman, and Soto are first-year renal fellows in the
The diagnosis of this condition relies principally on Renal-Electrolyte and Hypertension Division.
history, careful physical examination, and adjunctive
data from laboratory studies. Requests for Reprints: Eric G. Neilson, MD, Renal-Electrolyte
and Hypertension Division, 700 Clinical Research Building, Uni-
The pathophysiology of both dehydration and ex- versity of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA
tracellular fluid volume depletion must be under- 19104-6144.
stood if these conditions are to be recognized and
Current Author Addresses: Drs. Mange, Matsuura, Cizman, Soto,
appropriately treated when they occur separately or Ziyadeh, Goldfarb, and Neilson: Renal-Electrolyte and Hyper-
together. There is no inclusive therapy for all situ- tension Division, 700 Clinical Research Building, University of
ations. For example, indiscriminate treatment with Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104-6144.
0.45% saline cannot be recommended when these Ann Intern Med. 1997;127:848-853.
conditions coexist because extracellular fluid volume
depletion is often treated rapidly with 0.9% saline
and dehydration is often treated more slowly with References
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