Hyponatremia

Jessica Reid-Adam
Pediatrics in Review 2013;34;417
DOI: 10.1542/pir.34-9-417

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in brief

In Brief
Hyponatremia
Jessica Reid-Adam, MD
Mount Sinai School of Medicine
New York, NY

Author Disclosure
Drs Adam and Reid-Adam have
disclosed no financial relationships
relevant to this article. This
commentary does not contain
discussion of unapproved/investigative
use of a commercial product/device.

Rose BD, Post TW. Clinical Physiology of

Acid-Base and Electrolyte Disorders.
5th ed. New York, NY: McGraw Hill;
2001:696745
Moritz ML, Ayus JC. Disorders of water
metabolism in children: hyponatremia
and hypernatremia. Pediatr Rev. 2002;
23(11):371379
Freda BJ, Davidson MB, Hall PM.
Evaluation of hyponatremia: a little
physiology goes a long way. Cleve Clin
J Med. 2004;71(8):639650

Hyponatremia is one of the most commonly encountered electrolyte disorders among both adults and children.
Although childhood cases can occur
in the ambulatory setting, most occur
among inpatients, with the condition
affecting approximately 25% of hospitalized children. Defined as a plasma sodium concentration less than 135 mEq/L
(135 mmol/L), hyponatremia can result
from either a deficit of sodium or an excess of free water.
Plasma sodium concentration is the
largest determinant of plasma osmolality; therefore, disturbances in sodium
concentration are associated most often with disturbances in plasma osmolality. Normally, the body is able to keep

plasma osmolality tightly controlled,

with values ranging from 280 to 295
mOsm/kg. Homeostatic regulation is
achieved through 2 important mechanisms: the thirst mechanism, which is
activated in response to a salt load
(and thus an increase in plasma osmolality), and the upregulation or downregulation of arginine vasopressin (also
known as antidiuretic hormone [ADH])
secretion.
The effect of ADH on plasma osmolality depends on intact kidney function,
which is required for appropriate retention or excretion of free water. ADH binds
to vasopressin receptors in the cortical
collecting duct, which in turn results in
the insertion of aquaporin channels and
leads to increased free water reabsorption and decreased plasma osmolality.
When plasma osmolality decreases below
280 mOsm/kg, ADH secretion is diminished; concomitantly, the presence of
aquaporin decreases, which results in
the creation of more dilute urine through
inhibition of water reabsorption.
The serum sodium concentration
sometimes can be decreased with a normal or even increased plasma osmolality.
For example, factitious hyponatremia
can be caused by severe hyperlipidemia
or hyperproteinemia. Depending on laboratory technique, the serum sodium
concentration may falsely appear to be
low (a laboratory artifact) because of
the relative increases in lipids or proteins
within the plasma compartment. However, measurement of the plasma osmolality will reveal a normal value. Although
hyperlipidemia or hyperproteinemia might
occupy an increased percentage of the
overall plasma volume, the sodium concentration in the physiologically pertinent
compartment (the aqueous part of the
plasma) is normal.

Hypertonic hyponatremia results from

the presence of some osmotically active
solute, such as excessive plasma glucose, which causes water to move from
the intracellular to extracellular space
and thus dilute the sodium in the extracellular compartment. Although hypertonic hyponatremia sometimes is
considered false, the sodium measurement is in fact accurate. A key clinical
point, however, is that the sodium level
will increase as the hyperglycemia or
other elevated solute concentration is
reduced, as when insulin therapy lowers
the glucose level.
In the evaluation of a patient with
hyponatremia, assessment of clinical
status, and especially neurologic status,
is of the utmost importance and will
help to guide therapy when correcting
the hyponatremia. Hyponatremia and
decreased extracellular osmolality, combined with relatively preserved intracellular osmolality, lead to water entry into
cells and subsequent cell swelling. Cells
of the central nervous system are at particular risk because of limited physical
space for swelling, and the resulting cerebral edema can manifest with symptoms that range from mild to severe
encephalopathy. With mild hyponatremia, patients may appear anxious or agitated; these neurologic symptoms may
worsen to include headaches, nausea
and vomiting, ataxia, and disorientation
and eventually may include seizures, coma, and death. The rate of decrease in
the plasma sodium concentration and
chronicity of the hyponatremia are critical both in determining severity of
symptoms and in planning correction
of the hyponatremia.
With laboratory confirmation of hyponatremia, plasma osmolality should
be measured to identify an associated
Pediatrics in Review Vol.34 No.9 September 2013 417

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in brief

hypo-osmolality: hyponatremia in the

context of low osmolality can be classified further based on the patients volume status and by sodium and water
balance. Hypovolemic hyponatremia is
generated by the net loss of sodium
in excess of the net loss of free water.
Body fluids generally are hypotonic or
isotonic and rarely are hypertonic; consequently, hypovolemic hyponatremia
occurs in situations in which loss of
body fluid, although hypo- or isotonic,
is followed by replacement with fluid
that is hypotonic relative to the fluid
loss. Replacement of gastrointestinal
losses (most commonly diarrhea) with
hypotonic fluids is a common cause of
hypovolemic hyponatremia in children.
Despite hyponatremia, increased
ADH release is maintained in response
to ongoing hypovolemia; elevated ADH
results in retention of free water and
potentiation of the hypo-osmolar state.
As long as hypovolemia is present, hyponatremia is exacerbated by therapy
with hypotonic fluids. Other conditions
that can present with hypovolemic hyponatremia include salt loss through
excessive sweating, as might occur in
patients with cystic fibrosis, and renal
losses, as might occur with salt-losing
nephropathies or mineralocorticoid deficiency. Diuretic therapy can produce
hyponatremia, particularly in patients
taking thiazide diuretics, when solute
loss (sodium and potassium) is in excess
of free water loss. Excess water intake
often contributes to the hyponatremia
seen in this patient population.
Because intact renal function is the
central requirement for correction of
hyponatremia, measurement of the
urine sodium concentration often is
helpful. In the setting of ongoing hyponatremia, a urinary sodium level greater
than 20 mEq/L (20 mmol/L) in the presence of hypovolemia is suggestive of renal losses, which can result from renal
disease, such as renal tubular acidosis,
or tubular defects in salt reabsorption,
as is the case in Bartter syndrome or

with diuretic use. High urinary sodium

levels also can be seen with mineralocorticoid deficiency, in which a low aldosterone level causes loss of sodium in
the distal tubule. In contrast, a urine sodium concentration less than 20 mEq/L
(20 mmol/L) in the setting of hypovolemia is indicative of appropriate sodium
handling by the kidney and therefore
suggests extrarenal losses.
Euvolemic hyponatremia, in which
there is little sodium loss and a gain
of free water, most often results from
the syndrome of inappropriate diuretic
hormone (SIADH) secretion. Osmolality
is the main determinant of ADH secretion. However, ADH can be secreted in
response to stimuli other than increases
in plasma osmolality. For example, various central nervous system disorders,
including infections and neoplasms,
can result in increased production of
ADH. In addition, other types of neoplasms and pulmonary diseases, such
as pneumonia, bronchiolitis, and tuberculosis, have been associated with increased ADH secretion.
SIADH has been studied extensively
in postoperative patients, and inappropriate hypothalamic production of ADH
has been linked to postoperative pain
and nausea. Hypovolemia also is a stimulus for ADH secretion, and in the hypovolemic state, as described previously,
ADH continues to be secreted despite
a normal or even decreased plasma osmolality. In addition, various drugs can
cause increased production of ADH, including neuropsychiatric drugs, such as
haloperidol, thioridazine, and selective
serotonin reuptake inhibitors, and chemotherapeutics, such as cyclophosphamide and vincristine.
In the setting of SIADH, the urine sodium concentration usually is greater
than 20 mEq/L (20 mmol/L). Measurement of urine osmolality also may be
useful in establishing an inappropriately
concentrated urine (>100 mOsm/kg),
which indicates an inability to excrete
free water appropriately in the setting

of hypo-osmolality. In contrast, urine

osmolality less than 100 mOsm/kg
may indicate an appropriate response
to hypo-osmolality by the kidney, but
maintenance of plasma hypo-osmolality
with a low urine osmolality suggests excess free water intake, as can occur with
psychogenic polydipsia, with water intoxication in infants caused by longterm inappropriate dilution of formula,
or with excessive administration of hypotonic fluids in hospitalized patients.
A reset osmostat, in which the threshold
for ADH release is lowered, can also be
a cause of hypo-osmolality in the setting
of low urine osmolality. Affected patients have a stable hyponatremia with
an appropriate ADH response if osmolality decreases below the individual
threshold.
Recently, 2 clinical syndromes have
been described that are relevant to pediatric practice, especially in the emergency department. The first is the
phenomenon of exercise-induced hyponatremia, in which prolonged activity
and concomitant hydration, as during
marathon running, results in a net
loss of sodium compared with water.
Although uncommon in most casual
activities, children participating in prolonged athletic activity should be cautioned to avoid both dehydration and
excessive hydration. The second syndrome is associated with the recent
trend in MDMA (3,4-methylenedioxyN-methylamphetamine, also known as
Ecstasy) use among adolescents. Hyponatremia from MDMA intoxication occurs
both as a result of excessive fluid intake
and through MDMA-induced SIADH.
In hypervolemic hyponatremia, the
net balance of both sodium and water
is positive, but there is greater gain of
free water relative to sodium. This situation may occur in conditions associated
with edema or ascites, such as nephrotic
syndrome, congestive heart failure, liver
cirrhosis, or advanced acute or chronic
renal failure. In these cases, ADH release
is increased in response to a decreased

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in brief

effective circulating volume, leading to

water retention and increased thirst.
The positive free water balance induced
by ADH exceeds that of sodium intake.
This dilutional hyponatremia, in which
the total body sodium is actually elevated, is important to distinguish from
hyponatremia that results from a depletion of total body sodium, which occurs
in hypovolemic hyponatremia.
Despite excess total body sodium,
the decreased effective circulation
volume causes the kidney (with intact
renal tubular function) to retain sodium. Therefore, the urine sodium concentration in these cases should be
less than 20 mEq/L (20 mmol/L). In
contrast, a urine sodium level greater
than 20 mEq/L (20 mmol/L) in the setting of hypervolemic hyponatremia is
suggestive of renal dysfunction or renal failure.
In the evaluation of a patient with
hyponatremia, estimation of daily sodium intake can aid in guiding therapy
in both outpatient and inpatient settings. A careful diet history should be
taken, with special focus on the nature
and amount of daily fluid ingestion in
contrast with the types and quantity
of solid foods. One important example
is assessing how infant formula is prepared by the caregiver because the improper mixing of formula can lead to
hyponatremia.
In the hospital setting, attention
should be paid to the type and amount
of parenteral fluids the patient is receiving and the length of time the child
has been receiving intravenous fluids.
Several studies have pointed to the
common use of hypotonic fluids as
a large contributing factor to the high
incidence of hyponatremia among

hospitalized children, who already are

likely to have elevated SIADH levels.
In addition, children are at higher risk
than adults for developing symptomatic
hyponatremia because they have a
higher brain-to-intracranial volume ratio. Although the brain reaches adult
size by age 6 years, the skull is not fully
grown until age 16 years.
Most cases of hypovolemic hyponatremia respond to isotonic fluid replacement. Water restriction is indicated in
most cases of euvolemic and hypervolemic hyponatremia. Limiting the intake of
sodium also is indicated in cases of hypervolemic hyponatremia, in which the
total body sodium level is elevated.
The use of 3% hypertonic saline should
be reserved for symptomatic hyponatremia, specifically, hyponatremia accompanied by neurologic symptoms,
such as headache, nausea and vomiting, behavioral changes, or seizures.
With hypertonic saline administration,
electrolytes should be monitored at
least every 2 hours to avoid overcorrection. Although there is debate about
how rapidly to correct hyponatremia,
a reasonable consensus is that the sodium correction should be limited to
10 to 12 mEq/L (10-12 mmol/L) during
the first 24 hours. There is little dispute
that the rate of correction for the first
3 to 5 mEq/L (3-5 mmol/L) must be
rapid if the hyponatremic patient is
showing seizure activity, lethargy, or
other signs of neurologic compromise.
After any such initially rapid correction, especially with improvement of
neurologic symptoms, caution generally is warranted to avoid further correction at a rate of greater than 4 to 5
mEq/L (4-5 mmol/L) during any 12hour period.

Hyponatremia remains a common

disorder in children, with potentially
important consequences if not corrected. Heightened awareness of this
problem can facilitate diagnosis and
treatment, reducing the morbidity
that can ensue from this electrolyte
imbalance.
Comment: In a commentary published in Pediatrics (2011;128:980-983),
Moritz and Ayus reviewed the extensive
literature on hospital-acquired hyponatremia among children. As they, and
Dr Reid-Adam in her In Brief, point
out, hyponatremia is epidemic in our
hospitals, affecting approximately 25%
of patients. Contributing factors are
(1) that children sick enough to be hospitalized have a multitude of risk factors for increased ADH production,
leading to dilutional free water retention, and (2) that our long-established
choice for intravenous maintenance
therapy has been hypotonic fluids. We
generally have little control over the
first factor (yes, we can reduce pain
and try to minimize stress), but certainly we can control the second. The
conclusion of the commentary is that
there can no longer be any justification
for the routine administration of hypotonic fluids in hospitalized children.
This simple maneuver of using
isotonic fluids when parenteral fluids
are indicated would greatly reduce the
incidence of hospital-acquired hyponatremia and virtually eliminate all cases
of hospital-acquired hyponatremic
encephalopathy. The evidence makes
the argument.
Henry M. Adam, MD
Editor, In Brief

Pediatrics in Review Vol.34 No.9 September 2013 419

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Hyponatremia
Jessica Reid-Adam
Pediatrics in Review 2013;34;417
DOI: 10.1542/pir.34-9-417

Updated Information &

Services

including high resolution figures, can be found at:

http://pedsinreview.aappublications.org/content/34/9/417

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