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CME

Patients with hypervolemic hyponatremia may have a

Key points history of liver and kidney failure, and the physical exam-
Hyponatremia is the most common electrolyte ination may reveal jugular venous distension, peripheral
imbalance in older adults. Causes in older adults edema, and pulmonary congestion.7,10,16 If the patient is not
include changes in the aging kidney, hormonal taking diuretics, the fractional excretion of sodium (FENa)
changes related to aging, medications, low dietary can be calculated; the result should be less than 1% if the
sodium intake, and idiopathic SIADH. patient has cardiac failure or cirrhosis, and greater than 1%
Acute severe hyponatremia can cause significant morbidity in patients with acute kidney injury or chronic kidney
and mortality, but too-rapid reversal of hyponatremia can
disease.7
cause serious neurologic issues or death.
Patients with euvolemic hyponatremia have total body
Hypotonic hyponatremia, the most common form,
sodium close to normal without extracellular fluid volume
occurs when patients have excess free water
abnormalities such as edema, ascites, pulmonary congestion,
relative to serum sodium levels.
or pleural effusion.7,10,16 With euvolemic hyponatremia,
Treatment includes IV administration of hypertonic
saline and treating underlying conditions, while clinicians must rule out hypothyroidism, hypopituitarism,
taking into account the patient’s volume status. pharmacologic stimulation of ADH (Table 1), severe emo-
tional and physical stress including psychosis, anesthesia, and
surgery before considering a diagnosis of SIADH. Laboratory
studies to evaluate SIADH include thyroid stimulating
Significant renal, cardiac, and hepatic dysfunction, com- hormone (TSH) and cortisol response to adre-nocorticotropic
mon in older adults, are the greatest risk factors for devel- hormone (ACTH).7
oping hyponatremia due to the nonosmotic release of Patients with SIADH generally have low urine output
antidiuretic hormone (ADH, also called vasopressin). 4 In (for example, 500 mL/24 hours) with a concomitant
fact, nonosmotic release of ADH is the cause in more than increase in urine sodium concentration.7 For a diagnosis of
95% of inpatients and long-term care residents diagnosed SIADH, the patient must be euvolemic, with a urine
with hyponatremia. In addition, various medications com- osmolality greater than 100 mOsm/kg and low serum
monly prescribed to older adults decrease the ability to osmolality.17 The patient also should be evaluated for
concentrate urine or can induce syndrome of inappropri-ate pulmonary, nervous system, vascular, and neoplastic con-
secretion of antidiuretic hormone (SIADH), ultimately ditions, which are responsible for more than 90% of cases
leading to drug-induced hyponatremia (Table 1).2,7,14 of SIADH.7,10
Older adults who are immobile also may have a con- Hyponatremia can present with varied tonicity:
comitant increase in total body water with lower serum • Hypertonic hyponatremia occurs when another osmole,
sodium. Some of the many other causes include postop- such as glucose, draws water into the intravascular space,
erative complications, acute illness, hypocortisolism, and diluting the serum sodium content. This type of hypona-
hypothyroidism.2,15 tremia can occur in patients with hyperglycemia and after
mannitol or contrast media administration.4,8,10,18
TABLE 1. Drugs that can induce hyponatremia2,7,18 • Isotonic hyponatremia, also known as pseudohypona-
tremia, is a rare finding often resulting from
Drugs or drug classes in italics may induce SIADH.
hyperlipidemia or hyperproteinemia causing an artificially
• Acetaminophen• Morphine and opioid derivatives low serum sodium due to a dilutional effect. 4,10,18 In such
• Amiloride • Nicotine cases the plasma may be isotonic or hypertonic to the
• Amiodarone • NSAIDs intracellular fluid, but neither results in intracellular fluid
• Antidepressants • Proton pump inhibitors
shifts and will not result in adverse reactions.4
• Antiepileptics • Prostaglandin-synthesis
• Antipsychotics inhibitors
• Hypotonic hyponatremia is the most common of the
• Barbiturates • Phenothiazines
hyponatremias, occurring when the patient has excess free
• Bromocriptine • Theophylline water relative to serum sodium levels. 3,18 Common causes
• Carbamazepine • Thiazides of hypotonic hyponatremia are listed in Table 2.
• Chlorpropamide • Tolbutamide Hypotonic hyponatremia can be further subdivided based
• Ciprofloxacin • Tricyclic antidepressants on the patient’s volume level, and many causes of hypo-
• Clofibrate • Trimethoprim-sulfamethoxazole natremia can be categorized by volume status.
• Cyclophosphamide • Venlafaxine Euvolemic hyponatremia is most common due to the
• Desmopressin • Vincristine abundance of disease states presenting with concomitant
• Indapamide • Vinblastine SIADH.3,5 This type of hypotonic hyponatremia is charac-
• IV Immunoglobulin terized by an increase in total body water with no concurrent
• Loop diuretics
change to serum sodium levels. SIADH, the most common
• Lorcainide
cause of hyponatremia, is more common in older adults. 17

24 www.JAAPA.com Volume 27 • Number 4 • April 2014

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 Managing hyponatremia in adults
Hypervolemic hyponatremia results when both total
body water and sodium retention are increased with over- TABLE 2. Causes of hypotonic hyponatremia3,10,14,15,21
all water retention exceeding sodium retention. Euvolemic—SIADH, diabetes insipidus, CNS disorders,
Hypovolemic hyponatremia is defined as sodium loss drug induced, adrenal insufficiency, pulmonary diseases,
that far surpasses water loss in spite of both water and hypothyroidism, primary polydipsia, beer potomania, very
sodium levels decreasing.3,10,18-20 low protein diet

PATHOPHYSIOLOGY AND RISK FACTORS Hypervolemic—heart failure, nephrotic syndrome, renal

failure, Cushing syndrome, saline infusions
The principal mechanisms of water and sodium homeo-
stasis in the body are controlled by hypothalamic osmo- Hypovolemic—GI losses such as from vomiting, diarrhea,
receptors, which regulate the secretion of ADH and or GI suction; renal losses from diuretic therapy, cerebral
perception of thirst.2,5,21 When osmoreceptors sense slight salt wasting, or mineralocorticoid deficiency; third-spacing
increases in plasma tonicity, ADH is released from the from burns, bowel obstruction, or pancreatitis; sweating
posterior pituitary, causing increased
kidney tubule permeability, increased
water reabsorption, and formation
of more concentrated urine.2
In older adults, osmoreceptors
are hypersensitive compared with
younger adults, as shown by hyper-
tonic fluid administration and water
deprivation tests.5 The same phenom-
enon can be observed by administer-
ing metoclopramide to stimulate
vasopressin, resulting in significantly
higher ADH release in older adults.5
Hypersensitivity of these mechanisms
along with increased time to excrete
excess water predispose older adults
to hyponatremia.5
Structural changes in the aging kid-
ney also can contribute to the devel-
opment of hyponatremia. These
changes include glomerular sclerosis
of the superficial cortex, tubular
atrophy, interstitial fibrosis, and
hyalinosis of the arterioles. This
leads to functional declines including
decreases in glomerular filtration rate
(GFR), creatinine clearance, renal
plasma flow, and the ability to dilute
and concentrate filtrate.2,22 Normally,
older adults are able to compensate
for these changes and sustain a nor-
mal balance of electrolytes. However,
© NUCLEUS MEDICAL ART, INC / PHOTOTAKE

illness or injury may potentiate loss

of electrolyte homeostasis and lead
to dysnatremias and volume dys-
regulation.2
Hormonal changes with aging
result in decreased renin and renin
activity, decreased aldosterone, and
may contribute to heightened excre-
tion of sodium into the urine, espe-
cially in patients with hypovolemia.2 FIGURE 1. Severe acute hyponatremia and the brain

JAAPA Journal of the American Academy of Physician Assistants www.JAAPA.com 25

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CME
Natural age-related changes also occur in atrial natriuretic
hormone secretion and the renin-angiotensin-aldosterone
system (RAAS). These changes alter homeostatic
regulation of fluid balance and may lead to hyponatremia.5
Risk factors for hyponatremia in older adults include
administration of hypotonic fl uid, low dietary sodium intake,
low-sodium enteral nutrition formulas for primary nutrition,
previous brain injury, age, and idiopathic SIADH. Whites and
Hispanics appear to be at higher risk than African Americans. 5
Thiazide diuretics and selective sero-tonin reuptake inhibitors
are more likely to cause hypo-natremia in older adults than in
younger adults.2 Clinicians must take steps to avoid promoting
hyponatremia in older adults because of these structural and
functional altera-tions, comorbid conditions, and medications
that can lead to fluid and sodium dysregulation.
CLINICAL PRESENTATION
Patients may present with varying signs and symptoms,
including headache, muscle weakness, nausea, vomiting,
lethargy, disorientation, depressed reflexes, or seizures. 1
The severity depends on many factors, including the dura-
tion of the condition, serum sodium levels, and the acute or
chronic nature of onset.23,24
The symptoms of mild-to-moderate hyponatremia—
lethargy, weakness, irritability, nausea, abdominal pain,
confusion, and tachypnea—also may be characteristic of
hypothyroidism, hypoglycemia, viral or psychiatric illness,
and various other electrolyte imbalances. Patients with
more severe hyponatremia may present with a head injury
resulting from a fall or seizure. Head injury secondary to a
fall also may be characteristic of nonhyponatremia-related
seizures, stroke, polysubstance abuse, and cardiac
emergencies.10
Acute hypotonic hyponatremia This electrolyte
imbal-ance arises in less than 48 hours. 24 Common
symptoms include mental status changes (confusion,
lethargy, and irritability), anorexia, and nausea.7 The rapid
change in sodium levels may cause cerebral edema and
intracranial hypertension (Figure 1), which can quickly
progress to brainstem herniation, seizure, coma, and
respiratory arrest.9,24 In very severe cases (serum sodium
less than 125 mEq/L), patients may suffer permanent
neurologic damage, coma, or death. 1 Cerebral edema, if
present, is visible on CT and MRI. Acute hyponatremia is a
medical emergency and must be corrected promptly to
avoid irreversible consequences. 25 Within a few hours of
onset, brain volume begins adaptation via excretion of
intracel-lular and extracellular solutes to stimulate water
loss and decrease brain swelling.24 Within 2 days,
intracranial pressure can essentially stabilize. Although
brain adapta-tion helps reduce symptoms of hyponatremia,
it also greatly increases the patient’s risk for osmotic
demyelin-ation.9 Prompt and appropriate treatment is
essential to prevent further neurologic damage.
26 www.JAAPA.com
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Chronic hyponatremia This type of hyponatremia
has a gradual onset (over more than 48 hours), and occurs
when the brain volume is able to adapt with concomitant fl
uid loss; brain volume is near-normal in spite of the signifi
cant decrease in serum sodium levels. 23,24 Modest
symptoms were thought to be the only manifestation of
chronic hyponatremia.16 However, recent insight into older
adults has revealed that manifestations of chronic
hyponatremia may include gait instability leading to
increased falls and fractures, as well as attention difficul-
ties.15,16,23,24,26-28 Osteoporosis has also been linked to
chronic hyponatremia because patients with chronic
hyponatremia mobilize bone matrix sodium stores at an
increased rate and also have heightened osteoclast
activity.15,16,23,24 Chronic hyponatremia can lead to
increased osteoporosis and fractures and increased patient
morbidity and mortality.15,23,24
MORTALITY
Hospitalized patients with hyponatremia have a 50%
greater risk of death than normonatremic patients; older
adults with hyponatremia have a doubled risk of death
compared with normonatremic older adults.2,29-31 Studies
evaluating mortality in patients with various severities of
hyponatremia found an overall increase in mortality
regard-less of degree of severity, and increased mortality
especially in patients with multiple underlying
illnesses.2,29-31 Hypo-natremia is also a marker in heart,
liver, and kidney disease or injury, as well as brain tumors,
brain hemorrhages, and malignancy. 31 Waikar and Chawla
found that underlying illness contributed more to mortality
than the severity of hyponatremia; Whelan adjusted for
such factors and still found hyponatremia independently
and significantly asso-ciated with mortality.30-32
DIAGNOSIS
Obtain a thorough history and physical examination,
assessing the patient’s medications, neurologic state, and
extracellular fluid volume status. These objective methods
may add insight into volume status to help better classify
the suspected hyponatremia. For exam-ple, patients with
hypovolemic hyponatremia may present with vomiting,
diarrhea, diuretic use, hypergly-cemia with glucosuria,
increased thirst, weight loss, orthostatic hypotension,
tachycardia, dry mucous mem-branes, decreased skin
turgor, and decreased capillary refi ll.10,16
To differentiate GI and renal losses, calculate the patient’s
FENa, the ratio between sodium excreted via urine and the
amount of sodium filtered and reabsorbed by the kid-ney. The
calculation is based on the concentrations of sodium and
creatinine in the blood and urine. 33 The values needed are
serum sodium (PNa), urine sodium (UNa), serum creatinine
(PCr), and urine creatinine (U Cr), and the formula is FENa =
((UNa x PCr)/(PNa x UCr) x 100.34
Volume 27 • Number 4 • April 2014

TABLE 3. Diagnostic studies and laboratory tests
useful in diagnosing hyponatremia 9,12,35,36,42,43
• Urine osmolality can help clinicians differentiate
between impaired excretion of water versus normal
but excessive water excretion as in polydipsia.
• Serum osmolality measures the body’s electrolyte-
water balance and can differentiate between true and
pseudo-hyponatremia.
• Urinary sodium concentration can help differentiate
hypovolemic hyponatremia from hyponatremia
secondary to SIADH.
• CBC count with differential, basic metabolic panel,
and renal and liver function tests can help identify
comorbidi-ties and their potential causes.
• TSH and cortisol response to ACTH can evaluate
for SIADH as a potential cause of hyponatremia.
• Serum uric acid and urea concentrations can
identify hypouricemia associated with SIADH.
• A brain CT or MRI and chest radiographs may reveal
cerebral edema, demyelination, pulmonary congestion as
a potential cause of SIADH, or cerebral salt wasting.
In patients with GI losses from vomiting and diarrhea,
the FENa should be within normal limits and less than 1%.
In patients with renal losses, such as from diuretics,
glucosuria, and bicarbonaturia, the FENa will be greater
than 1%.7 Clinical presentation should always be taken into
account when examining FENa.
Patients with hyponatremia should undergo a full labo-
ratory workup to identify potential causes of the disorder,
differentiate between types of hyponatremia, and inves-
tigate other comorbidities. Urine osmolality, serum osmo-
lality, and urine sodium concentrations are the three
cornerstone tests that help to differentiate between causes
of the electrolyte disorder (Table 3).35,36
Confi rmed normal or elevated serum osmolality sug-
gests the presence of another osmole, aside from sodium,
that draws water out of the cells and into the intravas-cular
space. Most commonly, low serum osmolality is found on
laboratory analysis, and in that case, the next step is
urinalysis, to determine urine osmolality and whether the
patient’s renal function is intact. Maximally dilute urine
(less than 100 mOsm/L) indicates normal kidney function
and may suggest primary polydipsia or low solute intake;
excessively concentrated urine (more than 200 mOsm/L)
indicates some impairment of renal fi ltration or dilution as
in SIADH or cerebral salt wast-ing (urinary sodium
concentrations greater than 40 mEq/L).16,37 These
diagnostic tests will guide later treat-ment because
management is based on the apparent cause of
hyponatremia.
Evidence of osmotic demyelination is not usually vis-ible
on CT or MRI until 6 to 10 days after clinical
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Managing hyponatremia in adults
TABLE 4. Initial
treatment of hyponatremia
based on patient volume status4,12,44
Euvolemic
• Restrict fluids
• Prescribe loop diuretics and saline infusions to
replace urinary sodium losses
• Prescribe demeclocycline and vasopressin
receptor antagonists
• Enhance solute intake if patient has poor
nutritional status
• Discontinue medications associated with SIADH
• Treat underlying conditions associated with SIADH
• Treat endocrinopathies (for example, hypothyroidism)
Hypervolemic
• Restrict fluids and sodium
• Prescribe loop diuretics
• Treat underlying conditions
Hypovolemic
• Prescribe IV isotonic saline
• Discontinue diuretics
• Replace mineralocorticoid deficiencies.
symptoms appear.7,25 Uric acid generally rises with volume
depletion and is low in SIADH. 3 Arterial sodium can be
measured with a blood gas device to rule out suspected
pseudohyponatremia.4 To aid in determining the cause of
hyponatremia, assess serum osmolality as promptly as
possible.
TREATMENT
Management depends on the patient’s clinical presentation
(including volume status and severity of symptoms) and
the cause of the electrolyte imbalance. 4,10,19 Because hypo-
natremia is potentially fatal, prompt intervention is impor-
tant. The appropriate rate of correction depends on whether
the patient has acute or chronic hyponatremia.4,7,12 Next,
assess the patient’s volume status to determine the appro-
priate correction strategy (Table 4).4,7
Acute hyponatremia Acute onset of symptomatic
hypo-natremia can be a medical emergency leading to
cerebral edema, brain herniation, and cardiopulmonary
arrest, and requires rapid correction with 3% hypertonic
saline.7 If the patient is hypervolemic because of heart
failure or underlying cardiovascular disease, also
administer a loop diuretic to avoid volume overload. 4,7,10
Closely monitor patients receiving hypertonic saline for
extracellular volume status, neurologic symptoms, and
serum sodium trends to avoid rapid overcorrection.4,7
Once the patient’s severe signs and symptoms have
resolved, discontinue 3% hypertonic saline, reassess
www.JAAPA.com 27
CME
volume status, and tailor treatment based on the patient’s
volume status and cause of the hyponatremia (Table 4).4
Chronic hyponatremia Patients with chronic hypona-
tremia are unlikely to present with serious signs and
symptoms. If they do, carefully tailor sodium correction to
reverse serious signs and symptoms only and avoid
overcorrection.4 Too-rapid correction of chronic hypo-
natremia with hypertonic saline can cause excessive loss of
intracellular water, cell shrinkage, and osmotic demy-
elination syndrome (damage to the myelin sheaths cover-
ing axons of the brainstem, which can lead to permanent
neurologic damage).1,4,7 Patients with osmotic demyelin-
ation syndrome may show improved mental status initially,
accompanied by neurologic declines, paresis, fl accid
paralysis, dysarthria, dysphagia, hypotension, and pos-sible
death.4 Patients who are malnourished; abuse alco-hol;
have hypokalemia, burns, or advanced liver disease; and
older women on thiazide diuretics have much lower
thresholds for osmotic demyelination and should be cor-
rected much more slowly.3,4,7
Patients with chronic hyponatremia who do not display
serious signs and symptoms do not need immediate treat-
ment to correct serum sodium, but may be mildly symp-
tomatic, putting them at increased risk for falls and devel-
opment of osteoporosis.4,15,27 Fluid restriction is the treat-
ment of choice; instruct patients not to take in more fluid
than they excrete in urine and insensible losses.3,4,13,38
Water excretion can be calculated from solute intake and
urine osmolarity.4
Other chronically hyponatremic patients have shown
asymptomatic sodium levels as low as 115 to 120 mEq/L
due to cerebral adaptation. In such cases, consider revers-
ible causes of excess water (such as continuous
maintenance fluid infusions or excess oral fluid intake) and
eliminate them when possible.4
If the timing of hyponatremia development is unknown,
clinicians should assume the hyponatremia is chronic and
should apply conservative measures, avoiding too-rapid
correction to prevent osmotic demyelination. 4,9 Patients
presenting with severe neurologic signs and symptoms
require immediate increases in serum sodium, whether
hyponatremia is acute or chronic.4,20 When the patient’s
neurologic symptoms improve, treatment can be adjusted
depending on how long the hyponatremia is thought to
have been present. In nonemergent cases, initial treatment
should be based on volume status (Table 4).4,12
RATE OF CORRECTION
A patient’s serum sodium level should be increased by no
more than 10 to 12 mmol/L in the first 24 hours and then
by no more than 18 mmol/L in the first 48 hours of ther-
apy.3,4,7,12 Rates of correction should be even lower in
patients with chronic hyponatremia and signs or symptoms
of cerebral edema. Terminating fluids before the serum
sodium has increased 10 to 12 mmol/L in the first 24 hours
28 www.JAAPA.com
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is also important because the sodium level can continue to
rise after fluids have been discontinued.4
As emphasized previously, great care must be taken to
avoid overcorrection. If overcorrection results, discontinue
all sodium-containing therapies and immediately admin-
ister IV D5W.10 Although more research is needed about
using desmopressin to manage sodium overcorrection, this
drug may be given for prevention and reversal of serum
sodium overcorrection.4,39 Desmopressin decreases sodium
by 2 to 9 mmol/L without serious adverse reactions and
can be given alone or with D5W.
EMERGING THERAPIES:
VASOPRESSIN ANTAGONISTS
Vasopressin antagonists are fairly new drugs that inhibit
the V1A, V1B, or V2 subtypes of vasopressin receptors and
block ADH action.40 Vasopressin antagonists are indicated
for use in patients with severe hyponatremia (serum
sodium less than 125 mEq/L) or in those with less severe
hyponatremia who are symptomatic and ineffec-tively
treated with fl uid restriction.41 Based on recent studies,
therapy with vasopressin antagonists appears promising;
however, further recommendations are neces-sary to
ensure that they can be used safely to correct
hyponatremia.3,4,7,38,40 Concerns about vasopressin antag-
onists include their high cost, the adverse reaction of
increased thirst, and whether they can be used safely in
patients with cirrhosis-related ascites.4,7,40
Because of the limited experience in using vasopressin
antagonists to treat signs and symptoms of cerebral edema
in patients with hyponatremia, 3% hypertonic saline
remains the gold standard for treatment.
CONCLUSION
Hyponatremia is a complex condition that demands a
systematic approach to diagnosis and management. 23 In
older adults, hyponatremia is one of the most com-mon
electrolyte imbalances and is associated with increased
mortality.11 Careful attention to common causes, clinical
presentation, laboratory diagnosis, and appropriate
treatment will help practitioners safely reverse this
potentially life-threatening condition. The primary
treatment for hyponatremia is to identify and correct
underlying causes and, if necessary, correct sodium
imbalances slowly to lessen the chance of neurologic
disease. Vasopressin antagonists have emerged as
promising new treatments that may improve outcomes. 29
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Successful completion is defined as a cumulative score of at least 70%
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Volume 27 • Number 4 • April 2014

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