H y p o n a t re m i a

Jaspinder Sra,

MD*,

Allen B. Repp,

MD, MS, FHM

KEYWORDS

Hyponatremia
Osmotic demyelination
Antidiuretic hormone

Total body water

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Hyponatremia is most commonly caused by abnormality in water handling by

the kidney as opposed to a true sodium deficit; that is, renal water excretion
is insufficient to offset water intake.
2. Hyponatremia is common and is associated with increased length of stay and
mortality in inpatients.
3. The symptoms of hyponatremia are nonspecific and highly variable in severity.
4. Sodium is usually the major determinant of serum osmolality, therefore most
cases of hyponatremia are hypotonic.
5. Assessment of volume status is key to the evaluation of hypotonic
hyponatremia.
6. When possible, urine osmolality and urine sodium levels should be obtained
before therapy. Thyroid-stimulating hormone and cortisol levels should be
routinely obtained in the workup of euvolemic hyponatremia.
7. Acute, symptomatic hyponatremia should be treated promptly, and the
response to treatment monitored closely.
8. Rapid correction of hyponatremia can cause severe neurologic sequelae
caused by osmotic demyelination.

DEFINITION

1. What is hyponatremia?
Hyponatremia is defined as a serum sodium concentration less than 135 mEq/L. In the
past, high serum lipid or serum protein levels could result in erroneously low serum
Department of Medicine, Division of Primary Care Internal Medicine, University of Vermont
College of Medicine, Fletcher Allen Health Care, 111 Colchester Avenue, Burlington, VT
05401, USA
* Corresponding author.
E-mail address: jaspindersra@gmail.com
Hosp Med Clin 1 (2012) e199e208
doi:10.1016/j.ehmc.2012.03.007
2211-5943/12/$ see front matter 2012 Elsevier Inc. All rights reserved.

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sodium results (pseudohyponatremia). This artifactual phenomenon has been largely

eliminated by the use of sodium electrode methodology in almost all laboratories in the
United States.
2. How is hyponatremia classified?
Hyponatremia can be classified in multiple ways. The first step in classification is
measurement of serum osmolality (Table 1). Hyponatremia with high serum osmolality
(hypertonic hyponatremia) usually represents osmotic shifts attributable to hyperglycemia or marked azotemia. Hyponatremia in the setting of normal serum osmolality
(isotonic hyponatremia) may occur with systemic absorption of isosmotic nonelectrolyte irrigation solution used during surgery, such as mannitol irrigation solution during
transurethral resection of the prostate. Hyponatremia with low serum osmolality
(hypotonic hyponatremia) is often regarded as true hyponatremia.
Unless hyperglycemia, azotemia, or unmeasured osmotic agents (eg, mannitol) are
present, serum sodium is the major determinant of serum osmolality (Sosm), as shown
by the equation:



Sosm 5 2  serum Na1 1serum glucose=181BUN=2:8
where BUN is blood urea nitrogen. Therefore, most cases of hyponatremia are associated with low serum osmolality.
Hypotonic hyponatremia may be further subdivided based on the volume status of
the patient into 3 categories: hypervolemic, euvolemic, and hypovolemic. These
Table 1
Classification of hyponatremia by serum osmolality and causes
Low Osmolality

Normal Osmolality

High Osmolality

Decreased effective arterial

blood volume
True volume depletion
(vomiting, diarrhea,
diuretic, bleeding)
Decreased effective
circulation volume
(heart failure, cirrhosis)

Nonelectrolyte irrigation
solutions
Glycine
Sorbitol (TURP, hysterectomy,
laparoscopic surgery)

Marked hyperglycemia
Serum sodium decreases 1.6
mEq/L for every increase of
100 mg/dL in glucose

SIADH

Pseudohyponatremia
Largely eliminated by
modern laboratory assays

Advanced renal failure

with extremely high BUN

Hormonal changes
Adrenal Insufficiency
Hypothyroidism
hCG during pregnancy
(mild osmotic resetting)
Exercise induced
Renal failure
Primary polydipsia
Low dietary solute intake
Abbreviations: BUN, blood urea nitrogen; hCG, human chorionic gonadotropin; SIADH, syndrome
of inappropriate antidiuretic hormone hypersecretion; TURP, transurethral resection of the
prostate.
Data from Refs.811

Hyponatremia

distinctions are particularly important because each of these clinical situations is associated with specific disease states and respond to different therapies (Table 2).
3. What is the pathophysiology of hyponatremia?
To understand the pathophysiology of hyponatremia, one must understand how the
body maintains serum osmolality and effective arterial blood volume (EABV). Although
these 2 processes are closely related, they are regulated by distinct physiologic
pathways.
EABV is primarily controlled by carotid and aortic baroreceptors, which regulate
blood pressure through changes in vascular tone, and the juxtaglomerular apparatus
in the kidney, which regulates the renin-angiotensin-aldosterone system (RAAS). Activation of the RAAS causes vasoconstriction through the effects of angiotensin on
vascular smooth muscles and sodium retention through the actions of aldosterone.
Serum osmolality is maintained by regulation of the intake and excretion of free
water. The former is controlled by the thirst mechanism and the latter by the actions
of antidiuretic hormone (ADH) on the kidney, which is the primary hormone responsible for maintaining osmolality. ADH is secreted by the posterior pituitary and acts
on the V2 receptors in the renal collecting tubules to increase free water reabsorption.
Under normal physiologic conditions, ADH secretion is tightly controlled by changes in
serum osmolality: below a Sosm of approximately 280 mOsm/kg, ADH is completely
suppressed; above that value, ADH secretion increases rapidly. Thus, when the Sosm
is low, ADH secretion is low, and the kidney excretes maximally dilute urine (50100
mOsm/kg). Conversely, when the Sosm increases, ADH secretion increases proportionally, which causes the kidney to make concentrated urine and resorb free water,

Table 2
Classification of hypotonic hyponatremia by volume status
Volume Status TBS/TBW Urine Na <20 mEq/L
Hypovolemic

YY/Y

Euvolemic

4/[

Hypervolemic

[/[[

GI losses (vomiting,
diarrhea)
Insensible losses
(pancreatitis,
burns, sweating )

Urine Na >20 mEq/L

Comments

Often associated
Diuretics
hyperuricemia
Mineralocorticoid
due to shared
deficiency
activation of
Osmotic diuresis
proximal tubular
Ketonuria
Na/Cl transport
Cerebral salt wasting
and uric acid
transport
Hypothyroidism
Glucocorticoid
deficiency
Pain, stress
SIADH
Drugs

CHF, decreased
Acute or chronic
cardiac output
renal failure
Cirrhosis, arteriolar Concomitant
vasodilatation
diuretic therapy
Nephrotic syndrome

ADH is an ACTH
secretagogue

In CHF, degree of
hyponatremia has
prognostic value

Abbreviations: ACTH, corticotropin; ADH, antidiuretic hormone; CHF, congestive heart failure; GI,
gastrointestinal; TBS, total body salt; TBW, total body water.
Data from Refs.811

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thereby returning free water to the circulation. With maximal ADH secretion the urine
can be concentrated up to 900 to 1200 mOsm/kg.
Although normally insensitive to changes in EABV, ADH secretion will occur when
there is a marked decrease in EABV, as may occur with blood loss, dehydration, or
advanced cirrhosis or heart failure. This process explains why ADH may be secreted
in hypovolemic states, even when the Sosm is below normal. In these settings the
RAAS system is also activated, and through the effects of aldosterone the kidney is
sodium avid, which manifests as urine sodium concentration generally less than 40
mEq/L. Hypovolemic hyponatremia is typically transient as volume repletion leads
to suppression of ADH and the RAAS.
In euvolemic hyponatremia, ADH secretion is triggered by processes unrelated to
Sosm or EABV. This secretion may occur in response to many stimuli including
pain, nausea, pulmonary infections, or medications. ADH may also be ectopically
produced by several malignancies such as small-cell lung cancer. Similar effects
may be observed in hypothyroidism and adrenal insufficiency. In the setting of euvolemia aldosterone levels are low, and the urine sodium concentration is generally
greater than 40 mEq/L.
Paradoxically, most hypervolemic states, such as heart failure, cirrhosis, and the
nephrotic syndrome, are characterized by total body volume overload accompanied
by low EABV. As in hypovolemic hyponatremia, low EABV triggers both ADH secretion
and the RAAS. This process results in water and sodium retention, with retention of
water greater than that of salt. Therefore, urine sodium is usually less than 20 mEq/L
unless there is concomitant diuretic therapy or impairment in renal function. Because
the underlying disease states are chronic, the stimulus for ADH secretion and RAAS
activation is persistent.
EPIDEMIOLOGY

1. What is the frequency and significance of hyponatremia in hospitalized patients?

Hyponatremia is the most common electrolyte abnormality in hospitalized patients. It is reported that 28% of patients have hyponatremia at the time of admission, and approximately 14% of inpatients acquire hyponatremia during their
hospitalization.1
Inpatients with hyponatremia have substantially increased length of stay. For
example, patients admitted with heart failure who had a serum sodium concentration
of less than 135 mEq/L had an average hospital length of stay 3 to 5 days longer than
their normonatremic counterparts.2 In addition, patients with hyponatremia have
a significantly increased risk of death during hospitalization, and at 1 year and 5 years
following admission.3
HISTORY AND EXAMINATION

1. What are the signs and symptoms of hyponatremia?

The clinical signs and symptoms of hyponatremia depend on many factors, including
the rate and extent of the decrease in serum sodium concentration.
Acute hyponatremia results in cerebral edema, which is responsible for producing
most of the signs and symptoms. The body adapts to these changes by the movement
of major intracellular ions (eg, chloride, potassium) out of brain cells, followed more
slowly by the movement of organic osmolytes (creatinine, glutamate).4 Cerebral

Hyponatremia

edema and symptoms develop when these compensatory mechanisms are overcome
by a rapid decrease in osmolality. Early symptoms include malaise, headache,
nausea, and vomiting. Seizures, brainstem herniation, respiratory arrest, coma, and
death can occur: acute symptomatic hyponatremia is a medical emergency.
In chronic hyponatremia, symptoms are usually lacking in patients with sodium
levels of more than 125 mEq/L, but when present, may include subtle defects in
gait and cognition that improve with correction of hyponatremia.5 Once serum sodium
falls below 125 mEq/L, neurologic symptoms become more likely and may include
fatigue, gait abnormalities, memory impairment, vomiting, nausea, confusion, and
(rarely) seizures.
2. What are the key elements of the clinical history that should be evaluated in patients
with hyponatremia?
A careful review of recent events, medical history, medication changes, and social and
psychiatric history is essential in ascertaining the cause of hyponatremia. Table 3
details key historical elements in hyponatremia.
Table 3
Key historical elements in hyponatremia
Category

Element

Current hospitalization

Recent surgery/trauma/pain
IVF (administration of hypotonic fluids)
Irrigation with glycine (TURP, laparoscopy)

Medical history

Current pregnancy
Recent vomiting, diarrhea
Diabetes mellitus, hyperglycemia
Heart failure, edema, dyspnea
Pulmonary disease or symptoms
Renal disease
Cirrhosis
Hypothyroidism
Adrenal insufficiency
Central nervous system disease or insult

Medicines

Medication changes
Diuretics
ACE inhibitors
Medications associated with SIADH (see Box 1)

Social history

Alcohol (beer potomania)

Illicit drugs (especially Ecstasy)
Strenuous exercise
Dietary history

Psychiatric history

Psychogenic polydipsia (often seen in schizophrenia)

Abbreviations: ACE, angiotensin-converting enzyme; IVF, in vitro fertilization.

3. What signs, symptoms, and laboratory data are most accurate in assessing volume
status in a patient with hyponatremia?
Although assessment of volume status is key to the classification of hyponatremia,
there is no single sign or laboratory result that reliably indicates volume status. Much
of the literature in assessing volume status stems from evaluation of patients with dyspnea or suspected heart failure. In this population, the presence of dyspnea on exertion,

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rales on lung examination, and elevated brain natriuretic peptide are highly sensitive but
not specific for hypervolemia, whereas paroxysmal nocturnal dyspnea, systolic hypotension, jugular venous distention, third or fourth heart sounds, and the presence of
ascites are more specific but not as senstive.6,7 Although peripheral edema suggests
hypervolemia and argues against hypovolemic hyponatremia, its sensitivity and specificity for volume overload are not exceptionally high (see Table 2).7

DIAGNOSIS

1. What are the key steps in the diagnosis of hyponatremia?

Take a careful history (refer to Question #3 in History & Physical) with special
attention to prescribed and over-the-counter medications

Perform a detailed physical examination including an accurate assessment of
patients volume status

Check basic laboratory tests
 Complete blood count, electrolytes, blood urea nitrogen, creatinine, serum
glucose
 Serum osmolality
 Urinalysis
 Urine sodium and urine osmolality; note that these have limited utility in the
setting of recent diuretic use
 Thyroid-stimulating hormone, morning cortisol levels for euvolemic hypotonic
hyponatremia

Consider additional imaging studies in the proper clinical scenario
 Screening chest radiograph or computed tomography scan if difficulty in assessing volume status on examination, or if respiratory symptoms such as
cough or dyspnea are present.

MANAGEMENT

1. When should treatment be initiated and why?

Treatment should be initiated immediately for patients with symptomatic hyponatremia or serum sodium less than 120 mEq/L.9,12 On the other hand, chronic, mild to
moderate hyponatremia may be asymptomatic, and the potential benefits should be
weighed carefully against the risks before treatment is initiated in this situation.
2. What are the nonpharmacologic approaches to treatment?
Multiple nonpharmacologic interventions are used to treat specific causes of
hyponatremia:

Discontinuation of offending medications (hypovolemic hyponatremia, syndrome
of inappropriate antidiuretic hormone hypersecretion [SIADH]) (Box 1)

Fluid restriction to less than 1.25 L/d (mild to moderate SIADH and most hypervolemic hyponatremic states)

Large-volume paracentesis (cirrhosis)

Eliminating low solute intake (low dietary solute intake, SIADH)

Behavior modification (psychogenic polydipsia).

Hyponatremia

Box 1
Common inpatient medications associated with syndrome of inappropriate antidiuretic
hormone hypersecretion
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Carbamazepine
Opiates
Nonsteroidal anti-inflammatory medications
Haloperidol
Nicotine
Data from Refs.811

3. What are the conventional pharmacologic strategies?

Several factors influence the approach to the treatment of patients with hypotonic
hyponatremia: (1) volume status; (2) acute versus chronic onset; (3) presence and
severity of symptoms; and (4) underlying etiology.
For patients with hypovolemic hyponatremia, volume replacement is the first
step in treatment. Based on acuity and severity, one of the following agents may be
used:

Normal saline: typically used to treat hypovolemic hyponatremia with serum
sodium concentration greater than 120 mEq/L

Hypertonic (3%) saline: typically used to treat severe, acute hyponatremia to
bring serum sodium concentration up to 120 mEq/L range, after which 3% saline
may be replaced by normal saline.
The sodium requirement and initial appropriate infusion rate can be accurately estimated for most patients1,12:

Value
Sodium deficit

Equation
(total body water)  (desired serum sodium  actual serum
sodium)

Initial rate of infusion (mL/h)

Sodium deficit  1000/Infusate sodium concentration

(mEq/L)  Time (hours)

Total body water 5 0.5 weight (kg) for women, and 0.6 weight (kg) for men

Common Intravenous Fluids

3% saline

Sodium Concentration (mEq/L)

513

0.9% saline (normal saline)

154

Lactate Ringer

130

0.45% saline (one-half normal saline)

77

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When moderate to severe hyponatremia is actively corrected with intravenous fluids,

multiple daily serum sodium measurements should be performed to confirm appropriate
rate of correction. Most experts recommend that the rate of correction should be aligned
with the rate of the development of hyponatremia; that is, acute symptomatic hyponatremia should be corrected more rapidly than chronic, less symptomatic hyponatremia.
Regardless of the cause and acuteness of the hyoponatremia, it is generally recommended that serum sodium levels be corrected no more than 12 mEq/L in the first 24 hours and
no more than 18 mEq/L in the first 48 hours, to minimize the risk of osmotic demyelination
syndrome (ODS).12 Certain patients, such as those with hypokalemia, malnutrition, alcoholism, or advanced liver disease, are at higher risk for ODS. A slower rate of correction is
recommended in such patients.
Other pharmacologic agents may be used to treat specific causes of hyponatremia:

Diuretics, along with fluid and sodium restriction, are used in the treatment of hypervolemic hyponatremia

Loop diuretics may be helpful in patients with SIADH because they interfere with
the concentration gradient that is maintained by the countercurrent multiplier;
this in turn minimizes the effects of ADH on the collecting ducts, resulting in
the excretion of more dilute urine.

Demeclocycline impedes the effect of ADH on the collecting tubule and may be
used to treat refractory SIADH

Medical therapy for specific underlying endocrinopathies such as hypothyroidism or hypoadrenalism is essential.
4. How do vasopressin antagonists (vaptans) work, and what patients are candidates
for their use in the inpatient setting?
The vaptans (the orally available tolvaptan, and conivaptan for intravenous use) are
a newer class of drugs that act as V2 receptor antagonists. Vaptans compete with
ADH on the collecting duct, thereby increasing water excretion and serum sodium
concentrations. Tolvaptan is approved for treating clinically significant hypervolemic
and euvolemic hyponatremia, defined as serum sodium of less than 125 mEq/L or
hyponatremia that is symptomatic and is resistant to fluid restriction. Tolvaptan has
been associated with more rapid improvement in serum sodium concentration,
short-term improvement in edema and dyspnea, and reduced length of stay in
patients with hyponatremia and heart failure.2,13 However, tolvaptan has not been
demonstrated to reduce rehospitalization, mortality, or long-term morbidity in this
patient population.2,13 Moreover, continued outpatient therapy is costly, and hyponatremia will recur with cessation unless the underlying cause has been reversed.
5. What are indications for admission to the intensive care unit?
Although institutional practices may vary, admission to the intensive care unit is
usually warranted in several scenarios:

Acute hyponatremia with hypoxia

Seizures or depressed sensorium due to hyponatremia

Patient with severe hyponatremia undergoing treatment with hypertonic saline
and requiring close neurologic monitoring.
9. What are the complications of overly rapid correction of hyponatremia?
Overly rapid correction of hyponatremia is believed to result in shrinkage of brain cells
and a disruption in the blood-brain barrier, exposing brain cells to damage by immune

Hyponatremia

mediators. It is postulated that these insults are the basis for ODS. As hyponatremia is
reversed, patients may initially improve, but over the next few days they develop
progressive neurologic deficits, from dysphagia, dysarthria, and diplopia to paraparesis, quadriparesis, or even locked-in syndrome. The lesions in ODS typically affect the
pons (historically ODS was known as central pontine myelinolysis) but other regions
can also be affected, notably the thalamus, cerebellum, and the putamen.14
ODS is best prevented by slow correction of chronic hyponatremia, no more than 12
mEq/L within the first 24 hours and less than 18 mEq/L within the first 48 hours. Once
ODS has set in, relowering of the serum sodium concentration may prevent or reduce
further loss of neurologic function.14
GUIDELINES AND STATEMENTS

Verbalis JG, Goldsmith SR, Greenberg A, et al. Hyponatremia treatment guidelines

2007: Expert panel recommendations. Am J Med 2007;120(11A):S121.
Rozen-Zvi B, Yahav D, Gheorghiade M, et al. Vasopressin receptor antagonists for
the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis
2010;56(2):32537.
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tolvaptan treatment on length of hospitalization in patients with heart failure. Am J
Health Syst Pharm 2011;68(4):32833.
3. Waikar SS, Mount DB, Curhan G. Mortality after hospitalization with mild,
moderate, and severe hyponatremia. Am J Med 2009;122(9):857.
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nervous system. J Am Soc Nephrol 1992;3(1):12.
5. Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia is
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13. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in
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339(6):5617.