Hyponatremia Review: Causes, Diagnosis and Treatment

Hyponatremia: A Review
Mary Ansley Buffington, MD, JD1
and Kenneth Abreo, MD1
Abstract
Hyponatremiaisthemostfrequentlyoccurringelectrolyteabnormalityandcanleadtolife-threateningcomplications.Thisdisordermay
bepresent onadmissiontotheintensivecaresettingor developduringhospitalizationasaresultoftreatment or multiplecomorbidities.
Patients with acute hyponatremia or symptomatic chronic hyponatremia will likely require treatment in the intensive care unit (ICU).
Immediate treatment with hypertonic saline is needed to reduce the risk of permanent neurologic injury. Chronic hyponatremia should
be corrected at a rate sufficient to reduce symptoms but not at an excessive rate that would create a risk of osmotic injury. Determi-
nation of the etiology of chronic hyponatremia requires analysis of serum osmolality, volume status, and urine osmolality and sodium
level. Correct diagnosis points to the appropriate treatment and helps identify risk factors for accelerated correction of the serum
sodium level. Management in the ICU facilitates frequent laboratory draws and allows close monitoring of the patient’s mentation as
well as quantification of urine output. Overly aggressive correction of serum sodium levels can result in neurological injury caused
byosmoticdemyelination.Therapeuticmeasurestolowertheserumsodiumlevelshouldbeundertakeniftherateincreasestoorapidly.
Keywords
hyponatremia, osmotic demyelination syndrome, syndrome of inappropriate antidiuretic hormone, vasopressin receptor
antagonist
Introduction
Hyponatremia is the most common electrolyte abnormality in
hospitalized patients and is frequently encountered in the inten-
sive care setting. Treatment varies significantly according to
the timing of onset and etiology of the disorder. Inadequate
or improper treatment may lead to brain edema or demyelina-
tion with life-threatening consequences. Hyponatremia is the
excess of total body water relative to extracellular sodium. A
simplified version of the Edelman equation demonstrates the
relationship in Equation 1:
½Nas ¼
½Nae þ ½Ke
TBW
:
The serum sodium level is determined by the relationship of
total body exchangeable sodium and potassium with total body
water. Hyponatremia develops due to primary sodium deficit,
primary potassium deficit, primary water excess, or a combina-
tion of these conditions.1
Notably, increases in sodium or potas-
sium will increase the serum sodium level. Diagnosis requires
recognition of sometimes subtle neurological symptoms, evalua-
tion of volume status, and analysis of serum and urine sodium
levels and osmolality. Appropriate treatment rendered in a
timely manner can result in complete recovery in many cases.
Incidence and Mortality
Analysis of hyponatremia in the National Health and Nutrition
Examination Survey (NHANES; 1999-2004) cohort showed
the prevalence in the general US population to be 1.72%.2
Hyponatremia is common in hospitalized patients, occurring
in 30% to 40% of patients with a serum sodium of
135 mEq/L.3
DeVita et al found that approximately 25% to
30% of patients admitted to an intensive care unit (ICU) had
hyponatremia defined as serum sodium 134 mEq/L.4
A retro-
spective review of a database of patients admitted to 151,486
ICUs showed that hyponatremia, defined as serum sodium
135 mEq/L, was noted in 17.7%.5
Of the total sample,
13.8% had borderline hyponatremia (serum sodium 130-135
mEq/L), 2.7% had mild hyponatremia (serum sodium
125-129 mEq/L), and 1.2% had severe hyponatremia (serum
sodium 125 mEq/L). The adjusted odds ratio for risk of
mortality in these patients was 1.32 (confidence interval [CI]
1.25-1.39), 1.89 (CI 1.71-2.09), and 1.81 (CI 1.56-2.10),
respectively, compared to patients admitted with a serum
sodium in the normal range. Similarly, a point prevalence study
involving 1265 ICUs in 76 countries showed that 12.9%
1
LSU Health Shreveport School of Medicine, Nephrology Section of Department
of Internal Medicine, Shreveport, LA, USA.
Received March 19, 2014, and in revised form October 23, 2014.
Accepted for publication October 24, 2014.
Corresponding Author:
Mary Ansley Buffington, Louisiana State University Health Sciences, 1501 Kings
Highway, Shreveport, LA 71130, USA.
Email: mbuffi@lsuhsc.edu
Journal of Intensive Care Medicine
1-14
ª The Author(s) 2015
Reprints and permission:
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of 13,276 patients had hyponatremia.6
When the degree of
hyponatremia is stratified, the prevalence was 10.2% with mild
hyponatremia (SNa 130-134), 1.9% with moderate hyponatre-
mia (SNa 125-129), and 0.76% with severe hyponatremia (SNa
125). The adjusted odds ratio for hospital mortality compared
to patients with a normal serum sodium in the cohort were 1.27
(CI 1.08-1.49), 1.76 (CI 1.27-2.43), and 2.11 (CI 1.28-3.46) in
the sub-groups, respectively. Hyponatremia that develops after
admission to the ICU can increase mortality.7
Although hyponatremia is associated with an increased risk
of mortality, the presence of serious comorbidities makes it dif-
ficult to calculate the risk attributable only to the electrolyte
abnormality and not coexisting illnesses. This is highlighted
by variable mortality findings according to severity of hypona-
tremia. Waikar et al conducted a prospective cohort study eval-
uating hyponatremia in 98,411 patients who had been
hospitalized for at least 48 hours.8
Although the odds ratio for
in-hospital mortality with serum sodium 135 mEq/L was
1.47 (95% CI 1.33-1.62), there was a trend toward lower mortal-
ity for patients with a serum sodium of 120 mEq/L compared to
that for serum sodium of 120 to 125 mEq/L. This trend toward
lower mortality as the serum sodium falls is illustrated more
definitively in a retrospective study of hospitalized patients with
severe hyponatremia, where the mortality of patients with a
serum sodium of 120 to 124 mEq/L was 11.2% compared to a
mortality of 6.8% of patients with serum sodium 115 mEq/
L.9
Other studies have shown increasing mortality in severe
hyponatremia. More research is needed to determine whether
hyponatremia per se is an independent cause of mortality.10
Pathophysiology
Water diffuses freely across the cell membrane; thus, the osmol-
ality of the intracellular and extracellular fluid is the same. In
hyponatremia, decreased osmolality in the extracellular com-
partment creates an osmotic gradient relative to the intracellular
environment and causes water influx into cells with a corre-
sponding increase in size. The resulting edema occurring in the
brain can be life threatening. In response, a compensatory pro-
cess begins to reduce intracellular and interstitial edema. Brain
volume regulation occurs via decreases in the interstitial concen-
tration of Naþ
and intracellular content of electrolytes (Kþ
and
Cl
) and organic solutes, such as inositol, taurine, creatine, and
glutamine.11
The loss of osmolytes causes a decrease in brain
water content. Electrolytes are extruded rapidly in response to
increased volume. Organic osmolytes are extruded over the
course of 24 to 72 hours. Brain edema occurs when the inflow
of water exceeds the compensatory mechanism.12
As hyponatremia is corrected, the adaptive process reverses,
and the brain must reaccumulate the electrolytes and organic
solutes. This reaccumulation is slower and less efficient. Correc-
tion of hyponatremia causes increased osmolality in the extracel-
lular compartment with resulting movement of water from the
intracellular to extracellular compartments. Restoration of intra-
cellular stores of organic osmolytes occurs over several days;
thus, rapid correction of hyponatremia can lead to effective
dehydration of brain cells and resulting demyelination. An
increase in osmolality that exceeds the capacity to reaccumulate
these solutes can lead to pontine and extrapontine demyelination
that causes neurological sequelae. Initially, the patient may
improve due to correction of the electrolyte disturbance but sub-
sequently deteriorate as the demyelination progresses.
Arginine vasopressin (AVP) is the primary regulator of
plasma osmolality and total body water. It is synthesized in the
supraoptic nucleus and paraventricular nucleus of the hypotha-
lamus and stored in the posterior pituitary.13
Release of AVP is
stimulated by an increase in plasma osmolality, decrease in
blood pressure or blood volume, nausea, emesis, pain, stress,
hypoxia, and fear.14
In the kidney, AVP acts on the V2 vaso-
pressin receptors (V2Rs) on the basolateral membrane of
epithelial cells in the collecting duct. Activation of the V2R sti-
mulates adenylate cyclase resulting in increased intracellular
cyclic adenosine monophosphate. This causes movement of
vesicles containing aquaporin 2 channels to the apical mem-
brane and thus increases water reabsorption. Osmotic stimula-
tion of AVP release occurs at approximately 285 mOsm/kg
with AVP levels being very low or nondetectable at lower
osmolality in normal physiology.15
At a plasma osmolality of
290 to 295 mOsm/kg, urine is maximally concentrated; thus,
further increases in plasma osmolality or the AVP level will not
cause increased renal response. However, plasma osmolality of
295 mOsm/kg stimulates osmoreceptors for thirst in the
hypothalamus and leads to the intake of water, which lowers
plasma osmolality.16
Reabsorption of free water and the intake
of water in response to thirst lead to a return of plasma osmol-
ality to the normal range. AVP levels and free water reabsorp-
tion then decrease.
The optimum excretion of free water by the kidneys requires
maximum suppression of AVP and adequate solute intake;
thus, the amount of solute available for excretion is one deter-
minant of the amount of water that can be excreted.17-19
The
following formula illustrates the relationship of solute excre-
tion and urine concentration on the volume of urine excreted:
Urine Volume ¼
Daily Solute Excretion ðmmol=dÞ
Urinary Solute Concentration ðmmol=LÞ
:
A normal participant has a daily solute excretion of
800 mmol/d and a maximal urinary diluting capacity of
60 mmol/L; hence, the maximum urine volume would be
13.3 L. If reduced solute intake reduces the solute available for
water clearance to 300 mmol/d, despite unchanged diluting
capacity, the urine volume would drop to 5 L/d.
Clinical Features
The symptoms of acute hypotonic hyponatremia, present for
less than 48 hours, are attributable to edema of brain cells.
Symptoms in mild hyponatremia are nausea, vomiting, and
headache.20
As sodium levels decrease, symptoms include
altered mental status, seizures, obtundation, coma, and death.21
The clinical manifestations of chronic hyponatremia, or
hyponatremia, that exists for at least 48 hours, are disorientation,
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lethargy, dysarthria, gait disturbances, and rarely seizure.22
Mild
chronic hyponatremia can be asymptomatic due to osmotic
adaptation that reduces edema in brain cells over time; however,
gait and attention impairments along with an increased incidence
of falls may be subtle manifestations.23
Correction of chronic
hyponatremia can lead to osmotic demyelination syndrome
(ODS). This occurs most commonly with severe hyponatremia
(serum sodium 120 mEq/L) when serum sodium has been cor-
rected too quickly.24
Symptoms attributable to ODS manifest
24 to 48 hours after correction. Those symptoms are quadri-
plegia, pseudobulbar palsy, coma, seizures, and death.22
Hypoxia may play a role in the development of hyponatremic
encephalopathy and may also impair the brain volume regula-
tory adaptation.25
Diagnostic Approach
Hyponatremia is typically categorized as hypertonic, isotonic,
or hypotonic (Figure 1). Initial evaluation of a patient with
hyponatremia should include a plasma osmolality to distin-
guish among these entities because treatment of each differs
considerably. Careful history and physical examination should
determine the time of onset of hyponatremia and the onset of
symptoms. Further analysis of urine osmolality and sodium
concentration will give clues to the etiology of the hyponatre-
mia, which can then guide treatment.
Nonhypotonic Hyponatremia
There are 2 types of nonhypotonic hyponatremia, pseudohypo-
natremia and hypertonic hyponatremia. Pseudohyponatremia is
hyponatremia occurring at an isotonic osmolality. The compo-
sition of plasma is usually 93% water and 7% lipids and pro-
tein. Electrolytes are routinely measured by indirect
potentiometry, wherein the sample is diluted and measurement
assumes that water constitutes 93% of plasma volume. Expan-
sion of the lipid or protein portion decreases the water portion
in comparison; thus, measured serum sodium would be at an
artifactually lower level than if measured directly within the
water portion of plasma volume. This inaccurate sodium level
is termed pseudohyponatremia. Measurement of serum osmol-
ality would be within the normal range. However, measure-
ment of the sodium activity directly within the water phase
without dilution of the sample shows it to be within the normal
range. Measuring the sodium activity via direct potentiometry
using a blood gas analyzer yields an accurate result.26
Multiple
myeloma or macroglobulinemia can cause expansion of the
plasma protein composition. Case reports have identified
lipoprotein-X, an abnormal lipoprotein seen in cholestatic jaun-
dice and lecithin cholesterol acyl transferase deficiency, as a
cause of pseudohyponatremia.27
Treatment of the underlying
protein-related disorder may lead to an increased serum sodium
concentration.
Hypertonic hyponatremia occurs when plasma contains an
osmotically active substance such as mannitol or excess glu-
cose. Urea and alcohols such as ethanol and methanol are inef-
fective osmoles because they freely cross the cell membrane
and therefore do not induce a concentration gradient that causes
movement of water. As such, a normal or elevated plasma
osmolality does not rule out hypotonic hyponatremia in the set-
ting of a high blood alcohol level or azotemia. Mannitol and
glucose in hyperglycemia do not cross freely into the cell; thus,
there is a concentration gradient that translocates or draws
water out of the cells. This increase in the water phase of
plasma causes the concentration of sodium to appear reduced.
For each 100 mg/dL of glucose above normal, the serum
sodium should be corrected by 2.4 mEq/L.28
Measurement of
osmolality would show a hypertonic state.
Administration of intravenous immune globulin (IVIG) can
cause both pseudohyponatremia and hypertonic hyponatremia.
Administration of IVIG can cause pseudohyponatremia by
increasing the protein concentration of plasma and sucrose
added as a carrier in commercial IVIG preparations causes
hypertonic hyponatremia.29
Additionally, a large amount of
sterile water delivered with the infusion can cause hypotonic
hyponatremia.
Hypotonic Hyponatremia
When hypotonic hyponatremia is present, urine osmolality
should be measured to determine whether the urine is maxi-
mally dilute with a urine osmolality 100 mOsm/L (Figure
2). If so, antidiuretic hormone (ADH) is not a factor in causing
the hyponatremia. Causes of this type of hyponatremia are from
either excess fluid intake and/or low solute intake as in psycho-
genic polydipsia and beer potomania. In psychogenic polydip-
sia, the patient drinks an amount of water that exceeds the
capacity of the kidney to excrete, despite suppression of ADH
with an intact ability to dilute the urine.30
Typically, the
amount of intake required to cause this kind of hyponatremia
is upward of 1 L/h. Hyponatremia associated with beer potoma-
nia and malnutrition results from a combination of poor solute
intake and relatively excessive fluid intake.
Isotonic or hypotonic irrigation solutions used during trans-
urethral prostatectomy and hysterectomy can also cause hypo-
tonic hyponatremia.31
These nonelectrolyte solutions contain
sorbitol, mannitol, or glycine. Absorption of large volumes of
the irrigation solution causes an initial iso- or hypo-osmolar
hyponatremia, which is followed by water movement into the
Figure 1. Initial evaluation of hyponatremia.
Buffington and Abreo 3
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Figure
2.
Evaluation
of
hypotonic
hyponatremia.
4
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cells as the compound gets excreted or metabolized. If the
solute is cleared faster than free water, hypo-osmolality will
develop. Sorbitol is metabolized by the liver with some renal
excretion, mannitol is excreted in the urine, and glycine is
metabolized in the liver to urea and ammonia. Patients can
develop neurologic symptoms from hypo-osmolality, ammonia
toxicity, and transient visual symptoms from glycine toxicity.
It should be kept in mind that a patient with hypovolemic
hyponatremia who has received treatment with normal saline
may also have a low urine osmolality (100 mOsm/L) when
hypovolemia is corrected causing suppression of ADH and
excretion of free water.
To evaluate other causes of hypotonic hyponatremia, it is
helpful to determine volume status of the patient to decide if
he or she has hypovolemic, hypervolemic, or euvolemic hypo-
natremia. Also, urine sodium is helpful in further distinguish-
ing between renal and nonrenal causes of hyponatremia.
Hypovolemic Hyponatremia
In hypovolemic hyponatremia, the patient may have signs of
volume depletion such as decreased skin turgor, dry mucous
membranes, orthostatic hypotension, and tachycardia. How-
ever, detecting hypovolemia in patients with hyponatremia can
be difficult in the absence of obvious signs.32
The patient has a
deficit in serum sodium and total body water but has lost rela-
tively more sodium. These sodium deficits can be due to renal
or extrarenal losses. A urine sodium concentration 30 mEq/L
would be consistent with renal losses of sodium and water,
which can occur with diuretic use, mineralocorticoid defi-
ciency, salt-wasting nephropathy, and cerebral salt wasting
(CSW). A urine sodium 30 mEq/L indicates a nonrenal loss
from vomiting, diarrhea, pancreatitis, or burn injury.32
Hypovolemia is a nonosmotic stimulus for AVP release;
however, the volume- and pressure-related stimuli for AVP
secretion do not act independent of the osmotically mediated
stimulus. In hypovolemia, the osmotic threshold at which AVP
is released shifts to the left, such that AVP is released at a lower
plasma osmolality. The magnitude of the shift depends on the
degree of volume depletion or hypotension. The shift of the
osmotic threshold causes concentration of the urine and conser-
vation of free water in order to correct the volume depletion.
The threshold for stimulation of thirst also shifts to the left;
thus, there is the drive for water intake at a lower plasma
osmolality.16
The AVP-mediated conservation of free water
combined with thirst-related intake of water causes an increase
in volume. However, the decreasing plasma osmolality in that
setting can lead to hyponatremia.
Extrarenal volume depletion can result from vomiting,
diarrhea, and third spacing of fluids due to trauma, pancreati-
tis, or burns. The urine sodium would be 30 mEq/L. How-
ever, in patients with hypovolemia having metabolic
alkalosis, the urine sodium may be misleadingly high and in
this setting the low urine chloride should be used to diagnose
hypovolemia. Thiazide exposure has been associated with
an almost 5 times higher risk of hyponatremia than
nonexposure.33
Factors associated with the occurrence of
thiazide-induced hyponatremia are older age, lower body
mass, and lower serum potassium level.34
Thiazides block the
sodium chloride cotransporter of the distal convoluted tubule,
which is an important mechanism of urinary dilution. They
also cause volume depletion that stimulates AVP release and
leads to retention of free water.35
Potassium depletion can
cause a shift of sodium into cells to restore osmotic equili-
brium.36
Also, increased water intake in the setting of
elevated AVP provoked by diuretic use can be a factor in
causing hyponatremia.37
Finally, studies have shown that
thiazides increase water absorption in the collecting duct by
upregulation of aquaporin 2.38
Mineralocorticoid deficiency due to primary adrenal insuffi-
ciency will cause decreased levels of aldosterone, cortisol, and
adrenal androgens.39
This results in sodium loss, hyperkalemia,
metabolic acidosis, and volume depletion that can lead to hypo-
natremia. The urine sodium will be 30 mEq/L, despite volume
depletion due to an inability to reabsorb sodium. The AVP lev-
els are elevated due to nonosmotic stimulus likely mediated by
baroreceptor response to volume depletion.40
Cerebral salt wasting syndrome is the renal loss of sodium
that leads to hypovolemia and hyponatremia in the setting of
intracranial injury or disease. In one retrospective review of
patients in a neuroscience center, CSW syndrome occurred in
4.8% of patients with hyponatremia compared to 62% with syn-
drome of inappropriate secretion of antidiuretic hormone
(SIADH).41
The clinical findings are similar to those in
SIADH; however, in SIADH the patient is euvolemic rather
than volume depleted. Thus, careful attention to the onset of
hyponatremia, including the urine sodium excretion and vol-
ume status, is important in distinguishing the two. In CSW syn-
drome, the negative sodium balance must accompany the
development of hyponatremia. Serum sodium should be
increased by giving hypertonic saline because evaluation of
volume status can be inaccurate in patients with hyponatremia
and SIADH occurs much more frequently than CSW syn-
drome. Also, giving a trial of normal saline to a patient with
SIADH and intracranial injury risks lowering serum sodium
and increasing cerebral edema.42
The exact pathophysiologic
mechanism of CSW syndrome is unknown, but natriuretic fac-
tors have been associated with its development.43,44
Euvolemic Hyponatremia
Euvolemic hyponatremia occurs with an increased amount of
total body water with normal or reduced total body sodium.
The cause can be iatrogenic with administration of hypotonic
fluids without careful monitoring of serum sodium levels.
Administration of hypotonic fluid following elective surgery
resulted in the acute onset of hyponatremia with resulting neu-
rological damage in 15 otherwise healthy women.45
The SIADH, also termed the syndrome of inappropriate
antidiuresis, is the most common electrolyte disorder in hospi-
talized patients.46,47
This disorder was first recognized by
Schwartz in 1957.48
Diagnostic criteria were articulated by
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Bartter and Schwartz in 1967.49
There is an excess of total body
water relative to a normal amount of total body sodium. Diag-
nosis requires hyponatremia with hypo-osmolality of the serum
and extracellular fluid. The excretion of sodium in the urine is
intact with urine sodium concentrations 40 mEq/L with nor-
mal salt and water intake. The urine is not maximally dilute but
is inappropriately concentrated with an osmolality greater than
that appropriate considering the plasma hypotonicity. In
SIADH, the patient is euvolemic with normal renal, adrenal,
thyroid, cardiac, and liver function.50
A low serum BUN and
uric acid occur in SIADH. A uric acid of 4 mg/dL or less was
characteristic of SIADH, while a uric acid of more than 5 mg/dL
occurred in non-SIADH hyponatremia.51
The fractional excre-
tion of uric acid can be used to differentiate patients with SIADH
who are on diuretics from patients with hypovolemia.52
SIADH occurs when an excess of AVP is present with con-
tinued intake of water. A number of conditions cause an
increase in AVP, including pulmonary disease, neoplasm, cen-
tral nervous system injury or disease (Table 1). Drugs can cause
SIADH either through the stimulation of AVP release or
through enhancement of its effect on the kidney (Table 2).
Hyponatremia can result in a downward resetting of the osmol-
ality at which AVP is released or reset osmostat. Secretion of
AVP occurs at a hypotonic osmolality rather than at the physio-
logic level of 285 mOsm/kg.53
Some patients with SIADH have an appropriately sup-
pressed AVP level. This could be explained by a gain of func-
tion mutation in the gene for the V2 receptor that causes
constitutive activation. Mutations have been identified in case
reports, and this condition is referred to as the nephrogenic syn-
drome of inappropriate antidiuresis.54
Glucocorticoid deficiency from hypopituitarism, hypothala-
mic dysfunction, Sheehan syndrome, tumors, or empty sella
causes a euvolemic hyponatremia similar to that seen in
SIADH. Glucocorticoids are tonic inhibitors of the secretion
of AVP.55
Without that modulating influence, AVP is
inappropriately secreted.56
However, the sodium reabsorption
via the RAAS pathway is intact so that there is not the volume
depletion as seen in hyponatremia from a mineralocorticoid
deficiency. Additionally, glucocorticoid deficiency causes
decreased cardiac output and hypotension that are nonosmotic
stimulators of AVP secretion.57
Patients will also have low
serum BUN and uric acid with higher urine sodium concentra-
tions similar to patients with SIADH. A morning cortisol level
should be decreased in a patient with glucocorticoid deficiency,
but if results are equivocal, a cosyntropin test can be performed
to determine whether the adrenal gland is able to release gluco-
corticoid in response.
The mechanisms by which hypothyroidism causes hypona-
tremia may be an inability to suppress AVP and a decreased
excretion of free water due to decreased glomerular filtration
rate (GFR). Some reports have shown that hyponatremia in
hypothyroidism is independent of AVP secretion.58
A
decreased GFR in hypothyroidism results in decreased
excretion of water simply because less fluid is delivered to the
diluting segment. Hyponatremia associated with acute
hypothyroidism does not occur frequently. Hammami et al pro-
spectively evaluated 212 patients with thyroid cancer who
underwent induction of hypothyroidism in preparation for
radioiodine treatment of thyroid cancer.59
Mild hyponatremia
(serum sodium of 130 mEq/L or more) occurred in 8.5% and
moderate hyponatremia (serum sodium of 120 mEq/L or more)
occurred in 1.9% of hypothyroid patients. Although hyponatre-
mia has been reported in patients with myxedema having ele-
vated AVP levels, the stimulation for AVP secretion could
have been nonosmotic and related to sequelae of hypothyroid-
ism such as nausea, decreased cardiac output, and hypotension.
Exercise-associated hyponatremia (EAH) is the occurrence
of hyponatremia during or up to 24 hours after prolonged phys-
ical activity resulting in a plasma sodium concentration below
the normal reference range, usually 135 mEq/L.20
Early signs
Table 1. Causes of SIADH.
Pulmonary disease Pneumonia
Tuberculosis
Abscess
Asthma
Aspergillosis
Malignancy Lung
Gastrointestinal
Genitourinary
Lymphoma
CNS disease Hemorrhage
Hematoma
Infection
Tumors
Drugs AVP analogues
Stimulate AVP release
Potentiate AVP activity
Abbreviations: AVP, arginine vasopressin; SIADH, syndrome of inappropriate
secretion of antidiuretic hormone.
Table 2. Drugs that Cause SIADH.
Stimulate AVP release Chlorpropamide
Clofibrate
Carbamazepine
Vincristine
Selective serotonin reuptake inhibitors
3,4-Methylenedioxy-N-methamphetamine
(MDMA)
Ifosfamide
Antipsychotics
Narcotics
Potentiate action of
AVP
Chlorpropamide
NSAIDs
Cyclophosphamide
AVP analogues Desmopressin
Oxytocin
Vasopressin
Abbreviations: AVP, arginine vasopressin; NSAIDs, nonsteroidal anti-
inflammatory drugs; SIADH, syndrome of inappropriate secretion of antidiure-
tic hormone.
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of EAH are nausea, vomiting, and headache. As the hyponatre-
mia worsens, edema of the brain can produce neurological
symptoms such as altered mental status, seizures, obtundation,
coma, and death. The etiology is a dilutional hyponatremia
caused by consumption of fluids in excess of fluid losses. Other
factors are loss of sodium in sweat, inappropriate AVP stimu-
lation with impaired renal diluting ability, and the inability to
mobilize nonosmotically active sodium stores.60
Risk factors
for EAH include excessive fluid drinking during exercise,
weight gain during exercise, low body weight, and female gen-
der. Inexperience running marathons associated with slower
pace and longer race times were also factors. For asymptomatic
athletes, treatment of EAH is fluid restriction but those with
symptoms of hyponatremic encephalopathy should receive
intravenous hypertonic saline.61
Hypervolemic Hyponatremia
Patients with hypervolemic hyponatremia will have signs
of volume overload, such as peripheral edema, pulmonary
edema, or pleural effusion. This condition involves an excess
of water and an excess of sodium. Hypervolemic hyponatre-
mia occurs in congestive heart failure, cirrhosis, nephrotic
syndrome, and renal failure. Hemodynamic changes occur-
ring in these conditions cause systemic arterial underfilling,62
which is caused by decreased cardiac output in congestive
heart failure or by decreased intravascular volume due to
decreased oncotic pressure in nephrotic syndrome.51
Systemic
arterial underfilling can also be caused by peripheral arterial
vasodilation as seen in cirrhosis, sepsis, pregnancy, or high-
output heart failure.
In response to arterial underfilling, baroreceptors in the car-
otid body and aortic arch sense a decreased mean arterial pres-
sure resulting in decreased glossopharyngeal and vagal tone.63
This leads to beta-adrenergic stimulation and nonosmotic
release of AVP. Baroreceptors in the juxtaglomerular cells of
the kidney stimulate the secretion of renin and production of
angiotensin II and aldosterone.62
Neurohumoral activation of
the sympathetic nervous system and renin angiotensin aldoster-
one system cause vasoconstriction and increased vascular resis-
tance. Aldosterone causes increased sodium reabsorption and
AVP causes water reabsorption. Cardiac output increases in the
setting of cirrhosis or sepsis as an additional compensatory
mechanism. These responses work to restore effective arterial
blood volume and perfusion; however, persistent activation
of neurohumoral responses leads to edema and impaired water
metabolism.
Treatment of Acute Hyponatremia
Acute hyponatremia develops over the course of 24 to 48 hours
and most often results from psychogenic polydipsia, EAH, and
‘‘ecstasy’’ or methylenedioxy-N-methamphetamine use.30
Also, patients treated with hypotonic IV fluids postoperatively
can have acute-onset hyponatremia.45
Rapidly developing
hyponatremia causes brain edema and the risk of transtentorial
herniation (TTH) is the most concerning issue. Death or pro-
found neurologic injury has been reported when acute hypona-
tremia was not corrected immediately.64
Acute hyponatremia
can be corrected more rapidly than chronic hyponatremia
because the process of extrusion of organic osmolytes of the
brain volume regulatory response has not taken full effect. If
there is any question about the time of onset of hyponatremia,
then it should be treated as though it were chronic.
Hypertonic saline is the mainstay of treatment for sympto-
matic hyponatremia because raising serum sodium reduces
brain edema. A retrospective study of 63 patients receiving
hypertonic saline for TTH showed that an increase in the serum
sodium level of 5 mEq/L was an independent predictor of
reversal of TTH.65
The increase in serum sodium concentration
of 5 mEq/L effectively reduced intracranial pressure by 50%.
An initial 4 to 6 mEq/L increase in serum sodium concentration
will decrease brain edema resulting in resolution of symptoms
in patients with hyponatremia.66
There are varied recommen-
dations for achieving this increase in serum sodium. A recent
consensus guideline on treatment of EAH recommended that
athletes with symptomatic hyponatremia should receive an
infusion of 100 mL of 3% NaCl that can be repeated every
10 minutes for a total of 3 doses as needed until symptoms
resolve.20
This infusion can be given through peripheral intra-
venous access. Oral salt loading following exercise does not
significantly increase serum sodium concentration.67
Experts
have agreed with this therapeutic approach in the management
of acute symptomatic hyponatremia in general66,68
; however,
caution to avoid overcorrection in smaller sized patients should
be exercised.69
When symptoms of acute hyponatremia are less
severe, an infusion of 3% NaCl at a rate of 1 to 2 mL/kg/h
should be started.47
The goal should be to increase the serum
sodium up to 2 mEq/L/h. Replacement of potassium will also
cause an increase in sodium, and the potassium concentration
should be considered when calculating your projected rate of
correction. Furosemide 20 mg should be given intravenously
to increase excretion of dilute urine. The serum sodium level
should be checked every 2 hours and the rate of the infusion
adjusted accordingly to achieve correction. The rate of correc-
tion can be reduced when symptoms improve.
For psychogenic polydipsia, the symptomatic patient must
be treated with hypertonic saline as mentioned earlier. Water
diuresis will ensue in the absence of renal failure and the hypo-
natremia will correct. Risk factors for neurologic complications
of correction are alcoholism, malnourishment, and nonacute
hyponatremia. In those patients, the hyponatremia should be
corrected at a slower rate once the risk of brain edema has been
overcome.30
Treatment of asymptomatic acute hyponatremia
depends on the etiology. In asymptomatic EAH, fluid restric-
tion is appropriate and correction will occur as the athlete
excretes free water.
Treatment of Chronic Hyponatremia
Patients with chronic hyponatremia evidencing neurologic
changes should be treated with hypertonic saline (3% NaCl)
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until symptoms resolve because those symptoms can rapidly
worsen. Failure to promptly give IV NaCl for chronic hypona-
tremic encephalopathy in postmenopausal women resulted in a
high rate of permanent neurological debilitation or death.25
As
mentioned earlier, 100 mL of 3% NaCl should be given, then
repeated every 10 minutes for 2 additional doses if needed.
When neurologic symptoms resolve, a long-term strategy to
correct the serum sodium level must be formulated based on the
etiology of the hyponatremia.
Rapid increases in the serum sodium level while correcting
chronic hyponatremia can lead to brain injury from ODS. In
chronic hyponatremia, neurologic sequelae from correction has
been well documented at rates of correction above 12 mEq/L
over the first 24 hours and 18 mEq/L over the first
48 hours.22,30,70,71
However, one study showed neurological
sequelae in 6 patients corrected at a rate of 10 mEq/L/24
h.72
Additionally, one patient with neurological sequelae cor-
rected at an average rate of 5 mEq/L/d; however, this was an
average rate of correction over 4 days because a follow-up serum
sodium level was not available until the fourth day. Conversely,
the serum sodium should not be corrected too slowly. Postmeno-
pausal women with chronic hyponatremic encephalopathy had
poor outcomes with serum sodium correction of 4 mEq/L over
the first 24 hours.25
The recommendation for the minimum goal
of correction of chronic hyponatremia is 4 to 8 mmol/L per day
with a maximum limit of 10 to 12 mEq/L for the first 24 hours
and 18 mEq/L over the first 48 hours.68
The goal is reduced in
those patients with high risk of developing ODS.
Risk factors for developing ODS are chronic hyponatre-
mia with serum sodium level of 105 mEq/L or lower, hypo-
kalemia, alcoholism, malnutrition, and advanced liver
disease (Table 3).24,73,74
One review of 74 cases of ODS
where both serum sodium and serum potassium were mea-
sured noted that hypokalemia was present in 89% of cases.75
The serum sodium should be corrected at a lower rate in
patients with these risk factors, with a recent consensus rec-
ommendation that the serum sodium should be corrected at
a minimum of 4 to 6mmol/L per day with a maximum limit
of 8 mmol/L/d.68
After the initial NaCl infusion to address neurological symp-
toms, an infusion of NaCl may be needed to attain the desired
serum sodium level. Intravenous administration of potassium
chloride (KCl) will increase the serum sodium level; thus, a
patient with hypokalemia and hyponatremia can be treated with
KCl alone or in combination with saline.
We agree with a recently published expert consensus
opinion that recommends starting 3% NaCl at an initial hourly
infusion rate equal to body weight in kilograms multiplied
by the desired hourly rate of increase in serum sodium in
mmol/L/h.68
As an example given in these guidelines, a
70-kg man needing an increase in serum sodium of 0.5
mmol/L/h would have an initial infusion of 35 mL/h of 3%
NaCl. Regardless of the formula used to determine the initial
rate of correction, frequent testing of serum sodium is neces-
sary so that the rate of infusion can be adjusted.
Hypovolemic hyponatremia can be treated by volume reple-
tion with normal saline. The serum sodium should be checked
every 4 to 6 hours to make sure correction of the serum sodium
level is not increasing too rapidly. Diuretics should be stopped.
Correction of the hyponatremia in a study of 25 patients
occurred over the course of 3 to 10 days after withdrawing the
medication.36
Administration of potassium supplementation
causes a shift of sodium from intracellular to extracellular
space and will increase the serum sodium level. This increase
should be factored into the rate of correction. As volume status
is corrected with normal saline administration, the impetus for
AVP secretion diminishes and the patient will begin to excrete
more dilute urine. The rate of correction of hyponatremia will
increase and an over correction may occur.
Acute symptomatic hyponatremia due to heart failure should
be treated by infusion of hypertonic saline until neurologic
symptoms resolve; however, saline should be administered with
caution to minimize the risk of pulmonary edema. Chronic hypo-
natremia due to cardiac failure is treated by fluid restriction to
less than 1000 mL/d to reduce fluid overload. Loop diuretics
decrease urine osmolality and increase water excretion. One
small study showed that the infusion of hypertonic saline along
with high-dose furosemide resulted in fewer readmissions to the
hospital and improved mortality.76
Treatment with vasopressin
receptor blockers is discussed subsequently.
SIADH is usually a chronic process in which hyponatremia
develops over days rather than hours. Patients with neurologi-
cal symptoms should receive hypertonic saline until symptoms
resolve, increasing the serum sodium by 4 to 6 mEq/L within a
few hours. Because patients with SIADH are usually euvole-
mic, aldosterone is suppressed and sodium is excreted in the
urine. Because AVP is inappropriately secreted, water excre-
tion is reduced at a relatively fixed urine osmolality rather than
being determined by changes in water intake or volume status.
With urine osmolality being relatively fixed, changes in solute
excretion will determine the water volume. For a given urinary
concentration of sodium and potassium with a fixed urine
osmolality, electrolyte-free water excretion depends on the
excretion of solute.17,19
The parenteral and oral fluid intake
should be restricted and serum sodium should be measured fre-
quently to monitor the rate of recovery. The degree of fluid
restriction needed to cause an increase in serum sodium can
be determined by calculating urine/plasma electrolyte (U/P)
ratio using spot urine values for sodium and potassium.18,47
The U/P ratio is a simplification of the formula for
electrolyte-free water clearance (Equation 3):
Table 3. Risk Factors for Osmotic Demyelination Syndrome.
Chronic hyponatremia
Serum [Na] 105 mEq/L
Hypokalemia
Alcoholism
Malnutrition
Liver cirrhosis
Abbreviation: ODS, osmotic demyelination syndrome.
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U
P
Ratio ¼
Na
½ uþ ½Ku
½Nas
:
The U/P ratio is the ratio of urine electrolytes to plasma
electrolytes; [Na]u is urine sodium concentration; [K]u is urine
potassium concentration; and [Na]s is serum sodium concentra-
tion. When the urine sodium and potassium is greater than
serum sodium (U/P ratio 1), electrolyte-free water excretion
is negative and fluid restriction alone is not likely to increase
serum sodium. Water consumed will be conserved rather than
excreted. Fluid intake in excess of insensible losses (typically
about 700-800 mL/d) will be conserved rather than excreted
and will cause a decrease in serum sodium. Thus, in that
instance, fluid restriction should be less than 500 mL/d. This
is a process referred to as desalination of fluid intake. One
study demonstrated the desalination of isotonic IV fluid in
22 women who underwent surgery then developed hyponatre-
mia after receiving normal saline or Ringer lactate solution.77
The patients were not volume depleted; thus, the aldosterone-
mediated excretion of sodium was intact. However, nonosmo-
tic stimuli for AVP such as nausea, pain, and stress caused
retention of electrolyte-free water.
Hypertonic fluid with electrolyte concentrations greater
than that lost in the urine should be administered in order to
increase serum sodium. For a U/P ratio 1, with plasma sodium
concentration more than urine sodium plus potassium, some
electrolyte-free water is excreted (Table 4). Fluid restriction
should be 1 L/d. If needed, an infusion of hypertonic fluid can
be administered to slowly correct the sodium to a level at which
neurologic sequelae are not likely to occur.
Drugs known to cause SIADH should be discontinued.
Treatment of underlying infection or malignancy will lead to
increased serum sodium over the long term. Nausea and post-
operative pain can lead to transient increases in AVP, which
will decrease when the nausea and pain are controlled. Long-
term treatment for hyponatremia may not be necessary when
the cause is attenuated or reversed.
As mentioned earlier, oral solute administration will
increase the excretion of solute and increase the amount of
water accompanying that solute. Sodium chloride tablets at
3 g given 3 times a day will increase the solute load and lead
to increased water excretion over the long term. Urea is the
end product of protein catabolism and can increase urinary
solute excretion and enhance solute diuresis. Doses of 30 g
daily are given but are not well tolerated in patients. An Food
and Drug Administration (FDA)-approved formulation of
urea is not available in the United States; however, it is
prescribed in Europe and has even been used to treat hypona-
tremia in the intensive care setting.78,79
Urea also promotes
sodium retention and can act as an osmolyte that is protective
against ODS.80
It may be necessary to initiate long-term treatment for hypo-
natremia in the ICU. Demeclocycline, a tetracycline antibiotic,
is used to treat SIADH by decreasing osmolality of the urine.
Kortenoeven et al found that demeclocycline downregulated
the aquaporin 2 channel and decreased adenylate cyclase activ-
ity in mouse cortical collecting duct cells.81
A dose of 300 to
600 mg taken orally twice daily is a long-term treatment of
SIADH; however, the medication is very expensive. Renal
function should be monitored because nephrotoxicity is com-
mon, particularly in cirrhotics.82
Treatment of Hyponatremia with
Vasopressin Receptor Antagonists
Vaptans are vasopressin (ADH) receptor blockers. Vasopressin
receptors are of 3 types, namely, V1a located predominantly on
blood vessels cause vasoconstriction, V1b in the pituitary
release adrenocorticotropin (ACTH), and V2 on the basolateral
membrane of the chief cells of the collecting duct increase
synthesis and insertion of aquaporin 2 water channels on the
apical membrane results in water reabsorption. Vaptans block
ADH binding to the V2 receptor and induce an electrolyte-
free diuresis (aquaresis). In patients with hyponatremia, the
serum sodium increases as a result of aquaresis (acquired
nephrogenic diabetes insipidus). Theoretically, vaptans should
be excellent agents for the treatment of hyponatremia in criti-
cally ill patients.
Vaptans that specifically block the V2 receptor are tolvap-
tan, moxavaptan, lixivaptan, and satavaptan. Conivaptan is a
nonspecific receptor blocker in that it also blocks both the
V2 and the V1a receptors. Tolvaptan and conivaptan are avail-
able for clinical use in the United States. Moxavaptan has been
approved for the treatment of SIADH in Japan. Lixivaptan has
not been released for clinical use in the United States and sata-
vaptan has been withdrawn from further development. Coni-
vaptan is only available as an intravenous drug, which may
be of advantage in the treatment of critically ill patients. The
oral preparation has not been marketed because it is a potent
inhibitor of the cytochrome P450 3A4 system and prolonged
use would cause many drug–drug interactions.
The role of vaptans in the treatment of hyponatremic criti-
cally ill patients is unclear.83
All the randomized controlled
trials with vaptans were done in asymptomatic patients with
mild chronic hyponatremia (average serum sodium 130 mEq/
L). Patients with symptomatic severe chronic hyponatremia
were not selected for these trials because of ethical concerns
that the patients in the placebo arm would be harmed. There are
no randomized controlled trials comparing treatment with
vaptans to administration of hypertonic saline for the treat-
ment of chronic hyponatremia. There are also no studies
evaluating the efficacy of vaptans in the treatment of acute
hyponatremia. There is clearly no role for vaptans in the
Table 4. Fluid Restriction based on U/P Electrolyte Ratio.
U/P Ratio Fluid Restriction
1 500 mL/d
*1 500-700 mL/d
1 1000 mL/d
Abbreviation: U/P ratio, ratio of urine electrolytes to plasma electrolytes.
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treatment of acute hyponatremia and symptomatic hyponatre-
mia where hypertonic saline is the unequivocal choice. There
may be occasions where the vaptans could be used cautiously for
euvolemic and hypervolemic hyponatremic critically ill patients,
especially if there are concerns that hypertonic saline may either
correct hyponatremia too quickly or may induce volume over-
load. Since conivaptan and tolvaptan are approved for use in the
United States, only these agents will be discussed.
The safety and efficacy of intravenous conivaptan was
shown in a randomized placebo-controlled trial in hospitalized
asymptomatic patients with euvolemic and hypervolemic
hyponatremia (serum sodium 115 to 130 mEq/L).84
Intrave-
nous conivaptan at a bolus dose of 20 mg followed by a contin-
uous infusion of either 40 or 80 mg/d for 4 days significantly
raised the serum sodium concentration 6.3 mEq/L and 9.4
mEq/L in the 40 mg/d and 80 mg/d study arms, respectively,
compared to 0.8 mEq/L in the placebo arm. In another retro-
spective study in a neurosurgical ICU, conivaptan was used
together with hypertonic saline (1.25%-2%) in 19 patients
who had a serum sodium 135 mEq/L. Conivaptan was well
tolerated with no episodes of hypotension, despite increased
urine volume. Since the new guidelines for the correction of
severe hyponatremia recommend a change in serum sodium
10 mEq/L in the first 24 hours, there is clearly a danger of
overcorrection with conivaptan.85
In one study, conivaptan cor-
rected hyponatremia too fast in 50% of patients who required
stopping, interrupting, or reversing treatment. There is a theo-
retical danger of worsening hypotension in patients with cirrho-
sis from blockade of the V1a receptor on the splanchnic blood
vessels and thereby worsening the prerenal state and inducing
the hepatorenal syndrome.86
The efficacy and safety of tolvaptan was shown in ambula-
tory (mean sodium 129 mEq/L) patients with hyponatremia
having SIADH, heart failure, and cirrhosis in 2 combined
placebo-controlled randomized trials called study of ascending
levels of tolvaptan in hyponatremia (SALT-I and SALT-
II).87,88
Tolvaptan at an oral dose of 15 mg daily with increases
to 30 and 60 mg daily based on the serum sodium concentra-
tion, significantly increased the serum sodium concentration
at day 4 (134 vs 130) and at day 30 (136 vs 131) when com-
pared to placebo. Of the 448 patients enrolled in SALT-I and
SALT-II trials, only 4 patients (1.8%) had correction of serum
sodium level 0.5 mEq/L/h in the first 24 hours of the study.89
There were no osmotic demyelination events. However, if the
more stringent guidelines were applied to this study, more
patients would have overcorrection with tolvaptan. The effi-
cacy and safety of tolvaptan was also shown in the Efficacy
of Vasopressin antagonism in hEart failuRE: outcome Study
with Tolvaptan (EVEREST) trial in which tolvaptan was given
to 2072 patients hospitalized for decompensated heart failure.90
Although hyponatremia was not an inclusion criteria, there was
a significant increase in the serum sodium levels in patients
who had hyponatremia and received tolvaptan with no adverse
effects. Two postmarketing reports of osmotic demyelination
have been filed when tolvaptan was used with hypertonic saline
to correct hyponatremia.91
The FDA has issued a warning not
to use tolvaptan in patients with liver injury and has also lim-
ited the length of use to 30 days, after the Tolvaptan Efficacy
and Safety in Management of Autosomal Dominant Polycystic
Kidney Disease and its Outcomes (TEMPO) trial in which tol-
vaptan used to prevent progressive renal failure in patients with
polycystic kidney disease showed a 2.5-fold increase in liver
enzymes compared to placebo.88
The dose used in this trial was
significantly higher (60-120 mg/d, average 90 mg/d) when
compared to the doses used in the hyponatremia trials (maxi-
mum 60 mg/d).89
In summary, the role of vaptans in the treatment of hypona-
tremia remains unclear. They should not be used in patients
with symptomatic hyponatremia, patients with hypovolemic
hyponatremia, and in patients with liver injury. Studies have
shown that they are not as effective in cirrhosis probably
because glomerular filtrate is absorbed proximally or that V2
receptors remain activated by another mechanism.92-94
They
also induce a successful aquaresis in patients with congestive
heart failure but do not show any benefit on survival.90,95
Vap-
tans are most effective in SIADH and some experts recommend
using a smaller starting dose of 7.5 mg (half tablet).68
Vaptans
should not be used together with hypertonic saline, since the
danger of overcorrection is more likely to occur. To avoid over-
correction with vaptans, the experts recommend not to restrict
oral fluid in the first 24 to 48 hours of treatment and to check
serum sodium and urine osmolality frequently. If there is over-
correction, the vaptan should be stopped and intravenous D5W
should be administered as desmopressin (DDAVP) will not
work since the V2 receptor is blocked.
Overly Rapid Correction of Hyponatremia
Some etiologies of hyponatremia predispose to a more rapid
correction of hyponatremia once the underlying cause is
addressed (Table 5). These patients should have serum sodium
monitored frequently to allow adjustment of the rate of correc-
tion. Secretion of AVP can be temporary; thus, when the cause
of AVP secretion is reversed, an excretion of electrolyte-free
water begins and causes rapid increase in serum sodium. Such
reversible causes of AVP secretion are hypovolemia, nausea,
and pain. Rapid correction of hyponatremia is more likely in
hypovolemic hyponatremia because AVP secretion decreases
when intravascular volume is repleted.96
The ensuing excretion
of electrolyte-free water causes the serum sodium level to
increase more rapidly. In secondary adrenal failure due to
hypopituitarism, a rapid correction of hyponatremia will result
after cortisol treatment and a resulting decrease in AVP release.
Increased excretion of free water will occur in beer potomania
Table 5. Risk Factors for Rapid Correction of Hyponatremia.
Hypovolemia
Glucocorticoid deficiency
Beer potomania
Polydipsia
Desmopressin discontinuation
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or ‘‘tea and toast’’ hyponatremia caused by malnutrition after
solute intake is increased. Also the discontinuation of DDAVP
will result in a rapid increase in serum sodium. Patients with
polydipsia typically are not volume depleted and thus AVP is
not a factor in causing hyponatremia. The serum sodium will
rapidly increase after water intake is restricted due to a sponta-
neous water diuresis.30
When the rise in serum sodium level approaches the goal for
that time period, infusions to raise the sodium level should be
stopped. When a patient begins excreting maximally dilute
urine and risks exceeding the goal of therapy, measures should
be taken to prevent further increase. Desmopressin 2 to 4 mg
intravenously or 10 mg intranasally has been shown to stop the
water diuresis.97
An infusion of D5W can be given to lower the
serum sodium if an overcorrection has occurred. In patients at
risk of rapid correction of hyponatremia, DDAVP can be given
along with an infusion of 3% NaCl to have a controlled correc-
tion of the serum sodium level.98
DDAVP will not likely
reverse the diuresis caused by vaptans; thus, excessive urinary
losses should be replaced with D5W.
The prognosis of ODS reported in recent literature is better
than once thought. A retrospective observational study following
36 ICU patients for 1 year diagnosed with ODS showed that 31%
(11 patients) died but 56% (14 patients) survived with good func-
tionality.99
Of 11 patients who had care withdrawn, 5 improved
clinically and 4 of those survived with good functionality. Case
reports indicate that relowering serum sodium when symptoms
of ODS initially occur can reverse neurological deficits.100-102
Conclusion
Hyponatremia is frequently encountered in hospitalized
patients. Delayed treatment or overaggressive correction can
cause life-threatening complications. Accurate evaluation of
the patient to determine the etiology of hyponatremia points
to the appropriate treatment. The causes of severe neurological
morbidity have been elucidated over the years and most
patients can recover without residual morbidity.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
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