11

Water Balance Paul G. Schmitz

Chapter Objectives

The student will discuss the role of water imbalance in the dysnatremias.
The student will discuss the mechanism responsible for the symptoms of hyponatremia
and the importance of rate of versus absolute decline in serum sodium concentration.
The student will construct an algorithm depicting the causes of the dysnatremias based
on volume status, urine sodium concentration, and urine osmolality.
The student will list of the major causes of SIADH and diabetes insipidus.
The student will discuss the pathophysiology and prevention of the osmotic demyelina-
tion syndrome.
The student will discuss the mechanisms and differential diagnosis of polyuria.
Introduction
Water imbalance is required to produce
changes in the Na+ concentration. Con-
versely, disorders of Na+ balance produce
changes in total body volume.
However, there are several common clini-
cal settings, in which both water and Na+
disorders coexist. For example, hypona-
tremia and volume expansion coexist in pa-
tients with congestive heart failure. Aware-
ness of this clinical reality is essential to
minimize confusion as one analyzes an
electrolyte problem.
The distinction between water and Na+ bal-
ance can be further appreciated by recall-
ing the body systems that defend against
changes in volume versus concentration.
The systems are specific and independ-
ent as outlined below.
The Defense of Concentration. Changes
in plasma osmolality alter the secretion of
ADH. ADH increases the water permeabil-
218
ity of the collecting duct. Unabated this
will eventually lower the Na+ concentration.
Unabated water loss will raise the Na+ con-
centration. Not surprisingly, hyponatremia
and hypernatremia are frequently accompa-
nied by changes in the blood level of ADH.

The Defense of Volume. Changes in

plasma volume elicits a complex neurohu-
moral response that alters renal Na+ trans-
port. Water will follow Na+ movement
(via passive diffusion) in an isosmotic
fashion. Therefore, Na+ transport per se
does not directly alter the concentration
of Na+. However, the attendant gain or loss
of water will expand or contract the total
body volume, respectively. Volume disor-
ders are virtually synonymous with altered
Na+ transport.

Clinical Example. Primary hyperaldosteronism is a

clinical condition characterized by an autonomous
increase in circulating aldosterone. Aldosterone pro-
motes Na+ reabsorption in the collecting duct via
ENaC. Clinically, these patients develop volume ex-
pansion and hypertension, but do not develop hy-
pernatremia.

219
Hyponatremia
The plasma Na+ concentration in hospital-
ized patients is ~8 mEq/l less than that re-
ported in the outpatient setting. It has a fre-
quency of 5-30% depending on the popu-
lation studied (e.g., it is particularly preva-
lent among the elderly and nursing home
patient).
Laboratory Evaluation
Definitive diagnosis of hyponatremia re-
quires laboratory determination of the se-
rum Na+ concentration. However, a falsely
low serum Na+ concentration is observed
in two clinical scenarios:
1. Hypertonic hyponatremia
2. Pseudohyponatremia
Hypertonic hyponatremia is caused by an
increase in the plasma glucose concentra-
tion. The rise in glucose concentration in-
creases the plasma osmolality, which pro-
motes passive diffusion of water from the
cellular compartment to the extracellular
compartment. The gain in extracellular wa-
ter lowers the concentration of Na+. Impor-
tantly, the plasma osmolality is increased,
not decreased in this type of hyponatre-
mia.
True hyponatremia induces cell swelling,
not shrinkage, because water moves into
the cellular compartment. The effects of hy-
perglycemia on the serum Na+ concentra-
tion are fairly predictable. Thus, a 100 mg/
dl increase in glucose typically lowers the
sodium concentration by 1.5-2.0 mEq/l.
Pseudohyponatremia is caused by an in-
crease in the concentration of proteins or
lipids (Figure 11.1). The decrease in
plasma Na+ concentration occurs when
dilution-based methodologies are em-
ployed to measure the Na+ concentration.
Since the Na+ concentration in the
aqueous-phase remains unchanged, the
osmolality is normal in pseudohyponatre-
mia.
Symptoms of Hyponatremia
The principle manifestations of hyponatre-
mia are due to altered cell volume. In par-
ticular, the inelastic cranium is associated
with a rise in intracerebral pressure when
brain cells swell beyond ~5%. Intracranial
220
 Figure 11.1 Pseudohyponatremia
Laboratory measurement of the Na+ concentration using flame-photometry. A normal plasma sam-
ple (left) is comprised of an aqueous-phase (93%) and a solid-phase (7%, mostly proteins and lip-
ids). The aqueous-phase is isolated via ultracentrifugation (middle column) and diluted with a stan-
dard amount of diluent to achieve a standardized sample volume (right). The Na+ concentration in
the reconstituted sample is measured using an autoanalyzer. When the solid-phase compounds in-
crease (e.g., severe hyperlipidemia), the amount of diluent added must necessarily increase to
achieve a standard sample volume. Accordingly, the measured Na+ concentration decreases, al-
though, the Na+ concentration in the aqueous-phase is unaffected. This underestimation of Na+ con-
centration can be avoided by measurement of osmolality using freezing point depression.

pressure rises exponentially with as little
as a 10% decrease in the plasma osmolal-
ity (Figure 11.2). Therefore, the cardinal
clinical manifestations of hyponatremia are
the result of CNS swelling. These symp-
toms include:
✴ Nausea and vomiting
✴ Behavioral changes
Brain cells are endowed with intrinsic os-
motic regulatory systems that regulate cell
volume. Cellular adaptation occurs acutely
(within 24 hours), but several days are re-
quired to achieve near-normal cell volume.
In the complete absence of adaptation,
life-threatening cerebral edema may occur
with as little as a 5-10% decrease in osmo-
lality.

✴ Decreased level of consciousness ad- Acute adaptation is secondary to extrusion

vancing to coma of intracellular Na+ and water. It is effec-
tive, albeit limited. Chronic adaptation de-
✴ Seizures

221

Figure 11.2 CNS Effects of Hyponatremia
Without cellular adaptation, the brain swells
considerably (panel A to B) producing cere-
bral edema. Fortunately, brain cells adapt
quickly to hyponatremia. Within hours, the
cells begin to extrude electrolytes and water,
which minimizes the swelling (panel B to C).
Within several days, the brain volume returns
to near normal (panel C to D), even with
marked decreases in the serum Na+ concen-
tration, as organic osmolytes are extruded
from the cell.
pends on the cell extrusion of organic com-
pounds known as osmolytes. Chronic ad-
aptation can completely normalize in-
tracerebral pressure. Therefore, the rate of
decrease in serum Na+ concentration is a
far more important factor governing symp-
toms than the absolute decline.
Clinical Implication. Even extreme decreases in the
serum Na+ concentration (<100 mEq/L) may be toler-
ated if the rate of decrease is slow. In addition,
these patients should not have their serum Na+ cor-
rected quickly because de-adaptation requires sev-
eral days. If the Na+ concentration is corrected rap-
idly, the myelin of axons and neurons may be irre-
versibly injured. This phenomenon is referred to as
the osmotic demyelination syndrome.
Pathophysiology
An increase in water input relative to water
output is a prerequisite for the develop-
ment of hyponatremia.
Water Input > Water Output 
Understanding the factors that regulate wa-
ter input and output underlies the physiol-
ogic classification of hyponatremia.
The maximal urine flow rate is quite impres-
sive under normal circumstances and pro-
vides an extraordinary buffer against the
development of hyponatremia from water
input alone. The maximal flow rate can be
calculated from knowledge of 2 variables:
222
✴ Maximum urine dilution (50 mOsm/l in
normal humans)

✴ The daily solute excretion (600

mOsm/day, which is comprised of Na+,
K+, Cl–, and urea).

A simple calculation yields a maximum

urine volume of 12 liters/day:

600 mOsm solute per day
50 mOsm solute in each liter of urine

Therefore, water intake must be prodigious

to generate hyponatremia without a con-
comitant defect in urine dilution or solute
load.

Clinical Implication. It is possible to dramatically

limit free water output by restricting solute intake.
Although relatively uncommon, such a phenomenon
has been described in the elderly and the alcoholic
in whom solute intake can be less than 100 mOsm/
day. Such a low output translates into a maximum
of 1-2 liters of urine output per day.
Figure 11.3 depicts the steps involved in
renal generation of free water. The majority
of hyponatremic states are characterized
by an increase in circulating ADH. The pre-
vailing level of ADH reflects the effects of
multiple factors that may stimulate or in-
hibit secretion (see Table 10.1). However,
when the stimulus for ADH secretion is un-
known the clinical condition is referred to
Figure 11.3 Free Water Generation
In step 1 Na+ and water are reabsorbed in
the proximal tubule. Conditions that increase
proximal tubular fluid reabsorption reduce
the maximal renal generation of free water
(low cardiac output states such as CHF). In
step 2 the urine undergoes dilution in the me-
dullary thick ascending limb. Loop diuretics
interfere with maximal urinary dilution by in-
hibiting NKCC2. In step 3, water is either ex-
creted (suppressed ADH) or conserved (in-
creased ADH). Step 3 is the most important
step in renal handling of water.
as the syndrome of inappropriate ADH se-
cretion (SIADH). In summary:
✴ Water input must exceed water output
for hyponatremia to develop.

223
✴ Recognition of the factors that influ- Low ECV
ence water balance is essential to for- Four clinical syndromes account for the
mulate a logical differential diagnosis.
vast majority of these conditions (Figure -.
✴ Water drinking alone is unlikely to pro- -):
duce hyponatremia.
✴ Volume Contraction
✴ ADH plays a prominent role in water out-
put, and is, therefore, frequently impli- ✴ Cardiac failure
cated in the pathophysiology of hypona-
tremia. ✴ Nephrotic syndrome

Physiological Classification ✴ Cirrhosis.

We employ a simple 2 category classifica-
The total body volume may be increased
tion scheme based on the effective circulat-
or decreased depending on the underlying
ing volume (ECV) to reflect the underlying
pathophysiology. Regardless, since renal
pathophysiology:
perfusion is reduced the kidney will con-
1. Conditions associated with a low ECV serve Na+ (Urine Na+ <10 mEq/l)

2. Conditions associated with a normal Normal ECV

ECV The prototypical syndrome in this category

The distinction between total body vol- is SIADH. The total body volume is virtually
normal (euvolemia) in these patients (Fig-
ume and ECV is subtle, yet pivotal in
ure 11.5). Since the volume status and
this scheme. The total body volume re-
ECV are normal, the urine Na+ concentra-
flects the combined volume of all major
tion is typically >20 mEq/l. Therefore, the
body fluid compartments (intravascular, in-
urine Na+ concentration is helpful in differ-
terstitial, and intracellular). In contrast, the
entiating SIADH from conditions with a low
ECV reflects the arterial volume, and im-
ECV.
plies perfusion to vital organs. It is possible
to develop volume expansion yet manifest
The Vasopressin Antagonists
a low ECV. For example, cardiac failure is Recently, V2R antagonists have emerged
accompanied by total volume expansion as a new approach to the management of
(i.e., edema) but is accompanied by a low
ECV.

224
 Figure 11.4 Pathophysiology of Hyponatremia in Low ECV Conditions
These four conditions account for nearly 75% of all hyponatremias. Each condition is characterized
by a low ECV and increased Na+ reabsorption in the proximal tubule. In addition, ADH secretion is
increased because of baroreceptor activation. Both effects impair free water excretion. Since cardiac
failure, nephrosis, and cirrhosis are characterized by Na+ retention, edema formation is also very
common in these settings. Volume contracted states yield a similar pathophysiology, although, the
physical exam reveals decreased volume, not edema. The urine Na+ is typically <10 mEq/L in these
conditions. The urine osmolality >300 mOsm because of the increase in circulating ADH. The low
ECV also stimulates water intake via ANG II. Therefore, water intake increases in tandem with a fall
in water output. ECV, effective circulating volume.

hyponatremia. These agents competitively
inhibit binding of ADH with V2R.
Evolving Research. Three vasopressin receptors
have been characterized over the past decade. V2R
mediates the effects of ADH on water permeability.
V1R is comprised of 2 receptor subtypes, V1Ra and
V1Rb. V1Ra is expressed on vascular smooth mus-
cle cells (vasoconstriction), platelets (aggregation),
hepatocytes (glycogenolysis), and the myometrium
(uterine contractions). V1Rb is widely expressed in
the brain, although, it’s exact role remains incom-
pletely understood.

225
Conivaptan was the first agent approved
for use in the United States in 2006. Coni-
vaptan is a non-selective vasopressin an-
tagonist (inhibiting V2R and V1Ra) only ap-
proved for use in SIADH. Conivaptan may
reduce blood pressure because of its ef-
fect on V1Ra. It is contraindicated in pa-
tients with heart failure and cirrhosis. Sev-
eral newer agents with greater receptor se-
lectivity have emerged. For example, tolva-
patan is V2R-specific and is approved for
use in SIADH as well as hyponatremia as-
sociated with CHF and cirrhosis. Tolvaptan
is available as an oral formulation.
Clinical Diagnostic Approach
The clinicians approach to hyponatremia is
weighted heavily on the volume assess-
ment. This appraoch works well at the bed-
side, since assessment of volume status is

Figure 11.5 Etiology of SIADH

SIADH accounts for about 20% of the hyponatremias. Three mechanisms are responsible for
these conditions: 1) increased hypothalamic/pituitary synthesis of ADH, 2) ectopic synthesis of
ADH, and 3) potentiation of the action of ADH. The most common causes are listed in the colored
bubbles. Cancers, brain lesions, pulmonary disease, and drugs are commonly implicated.

226
straightforward and convenient. The clini-
cal history and urine chemistries (Uosm and
UNa+) aid the clinician in refining the diagno-
sis.
The clinician should first establish that the
hyponatremia is not due to hyperglycemia
or pseudohyponatremia. If in doubt, meas-
uring the plasma osmolality via freezing-
point depression will discriminate pseudo-
hyponatremia and hyperglycemic hypona-
tremia from hypoosmolar hyponatremia
(Figure -.-).
There are several causes of hyponatremia
that are generally less common but should
be also be considered:
✴ Psychogenic water drinking has been
described in young women receiving
psychotropic agents. These individuals
often exhibit impaired maximal urine di-
lution as well. The mechanism of in-
creased thirst is not well understood, al-
though the anticholinergic effect of psy-
chotropic drugs is often implicated.
✴ Patients with adrenal insufficiency or hy-
pothyroidism can exhibit hyponatremia.
Increased sensitivity to the action of
ADH is thought to underlie the water re-
tention in these conditions. Correction
of the endocrine disturbance cures the
hyponatremia.
✴ Chronic administration of thiazide diuret-
ics is a common cause of hyponatremia
in the elderly. The thiazide diuretics pro-
mote volume contraction, which in-
creases ADH. Since the loop diuretics
interfere with urine concentration via
blockade of NKCC2 they are less com-
monly associated with hyponatremia.
✴ Decreased intake of solute (electrolytes)
or protein (which is metabolized to urea)
can markedly impair water excretion (as
noted above). This is common in the eld-
erly or the alcoholic. Since the circulat-
ing level of ADH is not increased in
these patients, the urine osmolality is
usually <100-150 mOsm/L.
General Treatment
Treating the underlying disturbance is al-
ways the optimal approach. Additionally,
water restriction and judicious use of a va-
sopressin antagonist may prove useful.
Water restriction is difficult to enforce in pa-
tients with heart failure, nephrotic syn-
drome, or cirrhosis, since the disease state
is characterized by a marked increase in
circulating ANG II, which is a potent stimu-
lus of thirst.
Life-threatening (acute) hyponatremia, usu-
ally accompanied by coma, seizures, leth-
227
 Figure 11.6 Clinical Approach to Hyponatremia
With the notable exception of two conditions (psychogenic polydipsia and low solute intake), all are
associated with an increase in ADH and, therefore, urine osmolality >300 mOsm/l. Two endocrine
disorders (adrenal insufficiency, hypothyroidism) must be considered, as they are treated with spe-
cific hormonal therapy. Note that the clinical volume assessment is a useful early step in the evalua-
tion of hyponatremia.

argy and confusion, requires a more ag-
gressive initial strategy. Typically a modest
(5-7 mEq/L) increase in serum Na+ is ade-
quate to prevent permanent neurologic se-
quelae. Careful intravenous administration
of hypertonic saline (3-5% saline) is used
to quickly raise the serum Na+ concentra-
tion.
Loop diuretics have also been employed in
this setting. Acutely, loop diuretics in-
crease water excretion because of their po-
tent diuretic properties. However admini-
stration of a loop diuretic must be moni-
tored carefully, since the simultaneous loss
of volume can produce dehydration.

228
Clinical Paradox. Paradoxically, chronic daily ad-
ministration of diuretics is implicated in the develop-
ment of hyponatremia. Since these patients are
mildly volume contracted, the circulating level of
ADH and ANG II is increased, which increases water
retention and thirst, respectively.

Osmotic Demyelination Syndrome

It is vital to avoid rapid or over correction
of the serum Na+ concentration, because
aggressive correction has been associated
with myelin injury. This condition was origi-
nally coined “central pontine myelinolysis”
because the pattern of myelin injury was
confined to the central pons (Figure 11.7).
The classic clinical features included quad-
riparesis and pseudobulbar palsies.
Recent evidence indicates that the lesions
also involve extrapontine areas. Thus, the
more general term osmotic demyelination
syndrome (ODS) has been adopted.
ODS was first described in alcohol abuse,
but more recent studies have documented
this type of injury in many other disorders,
including liver transplantation, malnutrition,
and AIDS. Post-mortem studies indicate
that the majority of cases are clinically as-
ymptomatic; therefore, the exact incidence
is difficult to ascertain. The onset of symp-
toms is usually delayed, typically requiring
24-48 hours to manifest. Therefore, pa-
Figure 11.7 Osmotic Injury
Magnetic resonance image at the level of
the central pons in a patient with osmotic de-
myelination. The T2-weighted image reveals
hyperintense (white) areas in the central
pons (arrows). These lesions reflect in-
creased water content in the area.
tients inadvertently subjected to rapid cor-
rection must be monitored carefully.
Unfortunately, the treatment of sympto-
matic ODS is ineffective, although sponta-
neous recovery has been reported in a
small number of cases. Recent studies sug-
gest that lowering the serum Na+ with wa-
ter should be considered in patients in
whom the serum Na+ has increased rap-
idly. Based on observational studies in pa-
tients and animal studies, a prudent ap-

229
proach to the correction of hyponatremia
is outlined below:

✴ Manage asymptomatic patients conser-

vatively.

✴ A 5-7 mEq/L increase in plasma Na+

concentration should reverse cerebral
edema.

✴ The correction rate should not exceed

0.5-1.0 mEq/hour.

✴ The absolute correction should not ex-

ceed 10-12 mEq/day.

The above guidelines should be adhered

to strictly in high-risk groups including, the
alcoholic, liver transplant recipients, or
those with previous CNS disease.

230
Hypernatremia

The pathophysiology of hypernatremia is

conceptually analogous to hyponatremia,
since the prerequisite for developing this
disorder is an imbalance in water homeo-
stasis.

Water Input < Water Output

Impaired thirst plays a critical role in the

pathogenesis of these disorders. The
regulation of thirst is complex, and in-
volves osmotic, hormonal, and neural input
(Figure 11.8).

Clinical Pearl. The importance of thirst is exempli-

fied in patients with diabetes insipidus (DI). These
individuals are ADH deficient or resistant to its ac-
tion, however they rarely develop hypernatremia.
They compensate for water losses by simply drink-
ing more water. Indeed, patients with DI typically pre-
sent with polyuria and polydipsia, not hypernatre-
mia.
Altered thirst is particularly common in pa-
tients with preexisting brain injury, demen-
tia, mental impairment, or in early life (in-
fancy).
Figure 11.8 Thirst Centers
Schematic depiction of the neural circuitry in-
volved in regulating thirst. Neural signals ema-
nating from hormonal (ANG II; atrial natriu-
retic peptide, ANP), hemodynamic (carotid
and aortic baroreceptors, BR), and osmotic
signals converge in various regions of the lam-
ina terminalis (LT). The signals are proc-
essed in the hypothalamus and cortex then
elicit a change in thirst. SFO, subfornical or-
gan; MnPO, median preoptic nucleus; OV, or-
ganum vasculosum.

231
Differential Diagnosis
Hypernatremia is classified into 3 major
groups based on the urine osmolality (Fig-
ure 11.9).

✴ Impaired Thirst

✴ Diabetes Insipidus

✴ Osmotic Diuresis

Occasionally, the urine osmolality falls

within a grey-zone (150-800 mOsm/l). This
is seen with partial variants of diabetes in-
sipidus, or the elderly, in whom, maximal
urine concentration and dilution are re-
duced.
Diabetes Insipidus
Although the mechanism responsible for
diabetes insipidus is relatively straightfor-
ward (ADH deficiency or resistance), the eti-
ology is diverse (Figure 11.10). CNS condi-
tions, such as trauma, infection, or tumors,
Figure 11.9 Etiology of Hypernatremia
A urine osmolality >800 mOsm indicates that
impaired thirst is responsible for hypernatre-
mia. A urine osmolality of <150 mOsm impli-
cates renal water loss, most likely diabetes
insipidus. A urine osmolality that is repeat-
edly ~300 mOsm/l suggests the presence of
an osmotic agent (usually glucose or urea).
Partial variants of diabetes insipidus and im-
paired countercurrent multiplication (CC) in-
terfere with water conservation. The urine os-
molality reflects the partial nature of these de-
fects.

are common causes of central diabetes in-

sipidus (CDI). Conversely, certain drugs,
electrolyte disturbances, or tubular injury
are responsible for the nephrogenic vari-
ants of diabetes insipidus (NDI).
Lithium as a Prototype. NDI has been described in
>40% of patients receiving Lithium for bipolar affec-
tive disorder. Lithium interferes with the expression
of AQP-2 in the collecting duct. Some, but not all,
resolve after discontinuing the drug.
Polyuria
Since patients with diabetes insipidus ex-
hibit polyuria more commonly than hyper-
natremia, the clinical evaluation of polyuria
is relevant. A urine output in excess of 2.5
L/day is the generally accepted definition
of polyuria. Urine flow is governed by sol-
ute (NaCl, urea, glucose or, rarely, drugs)
and water excretion.

232
 Figure 11.10 Features and Etiology of Diabetes Insipidus
Clinical features and major causes of central and nephrogenic diabetes insipidus. CDI manifests as
a decrease in circulating ADH. These individuals should respond to exogenous vasopressin. NDI is
associated with resistance to the action of ADH and, therefore, the circulating levels are usually in-
creased. The most common causes are listed for both disorders.

Clinically, it is useful to classify polyuria Serum Na+

( )
Water Deficit = Current TBW × −1
into 3 categories based on the composi- 140

tion of the urine (Figure 11.11).

Management of Hypernatremia
Treating the underlying disorder is the opti-
mal approach. Since many of these indi-
viduals are not drinking enough water, one
need simply provide sufficient water to re-
place the deficit. Calculation of the water
deficit provides a useful starting point for
replacement fluids:
In addition, ongoing losses of water must
be accounted for by measuring urine out-
put and estimating insensible losses.
Aqueous vasopressin (administered na-
sally or via the subcutaneous route) is use-
ful in patients with central diabetes insip-
idus, while the chronic administration of thi-
azide diuretics reduce free water excretion
in patients with nephrogenic diabetes insip-
idus.

233
 Figure 11.11 Evaluation of Polyuria
A urine output that exceeds 2.5 L/day is the typical threshold for diagnosing polyuria. The subse-
quent evaluation is directed toward establishing the mechanism of increased urine flow. A water
diuresis is characterized by dilute urine (typically <150 mOsm). Excessive water intake (aka psy-
chogenic polydipsia or diabetes insipidus) account for the majority of these cases. Solutes that can
mediate an increase in urine flow include, electrolytes, glucose, urea, and exogenous mannitol. Dif-
ferentiation of the salt-wasting variants from other osmotic agents requires both a calculation and
measurement of the urine osmolality. If the calculated osmolality is significantly less than the
measured osmolality, an osmotic agent should be suspected.

At the bench. Thiazide diuretics appear to exert Rapidly lowering the Na+ concentration
their effects via 2 mechanisms: 1) Mild volume con-
may precipitate cerebral edema as water
traction promotes increased water reabsorption in
the proximal tubule, thereby, decreasing water excre-
redistributes into the cellular compartment.
tion. 2) Recent studies demonstrate that thiazide diu- This can be avoided if the serum Na+ con-
retics increase expression of AQP-2 in the collecting centration is reduced gradually. Hence, the
duct.

234
following guidelines should be employed in
treatment of patients with hypernatremia:

✴ First restore volume contraction with

normal saline before initiating therapy
with dilute solutions. Correction of the
volume status is essential to prevent
cardiovascular collapse.

✴ Correct the water deficit at a rate not to

exceed 12 mEq/day or 0.5 mEq/hr (to
prevent life-threatening cerebral edema
with dilute saline solutions).

✴ Replace ongoing water and electrolyte

losses (urine, sweat) with an intrave-
nous solution of comparable tonicity.
This is particularly important when the
urine output or insensible losses are
high.

235
Suggested Readings

1. Sterns RH. Disorders of plasma sodium

- causes, consequences, and correction.
N Engl J Med. 2015;372(1):55-65.

2. Danziger J, Zeidel ML. Osmotic Homeo-

stasis. Clinical Journal of the American
Society of Nephrology.
2015;10(5):852-862.

3. Knepper MA, Kwon T-H, Nielsen S. Mo-

lecular Physiology of Water Balance.
The New England journal of medicine.
2015;372(14):1349-1358.

236
Key Points

Hyponatremia and hypernatremia are Hypernatremia is almost always secon-

caused by water imbalance, not so- dary to impaired or abnormal thirst, al-
dium imbalance. though excessive water loss in the
urine may predispose the individual to
The symptoms of hyponatremia are sec- hypernatremia.
ondary to cerebral swelling and include
lethargy, confusion, seizures, and Diabetes insipidus is associated with
coma. polyuria and polydipsia, but is usually
not characterized by hypernatremia (un-
The rate of decrease in the serum so- less thirst is impaired or access to wa-
dium concentration is a superior predic- ter is limited).
tor of the severity of symptoms, com-
pared to the absolute decrease in so- Hypernatremia must be corrected over
dium concentration. 48-72 hours to prevent the develop-
ment of cerebral edema.
Hyponatremia is usually secondary to
one of five clinical syndromes: conges-
tive heart failure, nephrotic syndrome,
cirrhosis, volume contraction, and SI-
ADH. All of these conditions elicit an in-
crease in circulating ADH. The underly-
ing cause of each of these conditions is
diverse.

Rapid correction of hyponatremia may

induce osmotic demyelination in the
brain. This syndrome is complicated by
permanent neurologic sequela that oc-
curs 24-48 hours after correction.

237