Download Syndrome of Inappropriate Antidiuretic Hormone

Syndrome of Inappropriate Antidiuretic
Hormone Secretion
Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FACP, FASN
From eMedicine.com Used with permission.
Updated Feb 25, 2013
The syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) is defined by the
hyponatremia and hypo-osmolality resulting from inappropriate, continued secretion or action of the
hormone despite normal or increased plasma volume, which results in impaired water excretion. The key
to understanding the pathophysiology, signs, symptoms, and treatment of SIADH is the awareness that
the hyponatremia is a result of an excess of water rather than a deficiency of sodium.
Essential update: Response to conivaptan of neurosurgical ICU patients with SIADH
A retrospective study involving 32 hyponatremic neurosurgical patients with SIADH examined the
natremic response to a single 20-mg bolus dose of conivaptan over a period of 48 hours.[1] From a
baseline of 129.8 ± 3.4 mEq/L, the serum sodium concentration increased to 133.1 ± 3.2 mEq/L by 6
hours after administration of conivaptan and to 134.2 ± 3.2 mEq/L by 24 hours, indicating a significant 24hour natremic response. Patients who failed to reach the primary end point (serum sodium increase ≥4
mEq/L over the first 24 hours) were treated with additional doses of conivaptan and other agents. On the
basis of these findings, the authors recommend a single 20-mg dose of conivaptan as the preferred initial
approach to treating patients in the neurosurgical intensive care unit who have SIADH, with the 24-hour
natremic response dictating whether additional conivaptan doses or other interventions are required. [1]
Signs and symptoms
Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms.
The history should take into account the following considerations:
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In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop of
serum sodium to the same value
Signs and symptoms of acute hyponatremia do not precisely correlate with the severity or the acuity of
the hyponatremia
Patients may have symptoms that suggest increased secretion of ADH, such as chronic pain, symptoms
from central nervous system or pulmonary tumors or head injury, or drug use
Sources of excessive fluid intake should be evaluated
The chronicity of the condition should be considered
After the identification of hyponatremia, the approach to the patient depends on the clinically assessed
volume status. Prominent physical findings may be seen only in severe or rapid-onset hyponatremia and
can include the following:
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Confusion, disorientation, delirium
Generalized muscle weakness, myoclonus, tremor, asterixis, hyporeflexia, ataxia, dysarthria, CheyneStokes respiration, pathologic reflexes
 Generalized seizures, coma
See Clinical Presentation for more detail.
Diagnosis
In the absence of a single laboratory test to confirm the diagnosis, SIADH is best defined by the classic
Bartter-Schwartz criteria, which can be summarized as follows [2] :
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Hyponatremia with corresponding hypo-osmolality
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Continued renal excretion of sodium
Urine less than maximally dilute
Absence of clinical evidence of volume depletion
Absence of other causes of hyponatremia
Correction of hyponatremia by fluid restriction
The following laboratory tests may be helpful in the diagnosis of SIADH:
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Serum sodium, potassium, chloride, and bicarbonate
Plasma osmolality
Serum creatinine
Blood urea nitrogen
Blood glucose
Urine osmolality
Serum uric acid
Serum cortisol
Thyroid-stimulating hormone
The patient’s volume should be assessed clinically to help rule out the presence of hypovolemia.
Imaging studies that may be considered include the following:
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Chest radiography (for detection of an underlying pulmonary cause of SIADH)
Computed tomography or magnetic resonance imaging of the head (for detection of cerebral edema
occurring as a complication of SIADH, for identification of a CNS disorder responsible for SIADH, or for
helping to rule out other potential causes of a change in neurologic status)
See Workup for more detail.
Management
Treatment of SIADH and the rapidity of correction of hyponatremia depend on the following:
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Degree of hyponatremia
Whether the patient is symptomatic
Whether the syndrome is acute (< 48 hours) or chronic
Urine osmolality and creatinine clearance
If the duration of hyponatremia is unknown and the patient is asymptomatic, it is reasonable to presume
chronic SIADH. Diagnosis and treatment of the underlying cause of SIADH are also important.
In an emergency setting, aggressive treatment of hyponatremia should always be weighed against the
risk of inducing central pontine myelinolysis (CMP). Such treatment is warranted as follows:
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Indicated in patients who have severe symptoms (eg, seizures, stupor, coma, and respiratory arrest),
regardless of the degree of hyponatremia
 Strongly considered for those who have moderate-to-severe hyponatremia with a documented duration
of less than 48 hours
The goal is to correct hyponatremia at a rate that does not cause neurologic complications, as follows:
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Raise serum sodium by 0.5-1 mEq/hr, and not more than 10-12 mEq in the first 24 hours
Aim at maximum serum sodium of 125-130 mEq/L
In an acute setting (< 48 hours since onset) where moderate symptoms are noted, treatment options for
hyponatremia include the following:
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3% hypertonic saline (513 mEq/L)
Loop diuretics with saline
Vasopressin-2 receptor antagonists (aquaretics, such as conivaptan)
Water restriction
In a chronic asymptomatic setting, the principal options are as follows:
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Fluid restriction
Vassopressin-2 receptor antagonists
If vasopressin-2 receptor antagonists are unavailable or if local experience with them is limited, other
agents to be considered include loop diuretics with increased salt intake, urea, mannitol, and
demeclocycline
See Treatment and Medication for more detail.
Background
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of
euvolemic hyponatremia in hospitalized patients. The syndrome is defined by the hyponatremia and
hypo-osmolality that results from inappropriate, continued secretion and/or action of antidiuretic hormone
(ADH) despite normal or increased plasma volume, which results in impaired water excretion. The
antidiuretic hormone (ADH) promotes the reabsorption of water from the tubular fluid in the collecting
duct, the hydro-osmotic effect, and it does not exert a significant effect on the rate of Na + reabsorption. A
second action of ADH is to cause arteriolar vasoconstriction and a rise in arterial blood pressure, the
pressor effect.
Physiology of ADH
Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure
to oxytocin. AVP is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei
of the anterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior
pituitary. Here, it is stored in secretory granules in association with a carrier protein, neurophysin, in the
terminal dilatations of secretory neurons that rest against blood vessels.
The major stimuli for AVP secretion are hyperosmolality and effective circulating volume depletion, which
are sensed by osmoreceptors and baroreceptors, respectively. Osmoreceptors are specialized cells in the
hypothalamus that perceive changes in the extracellular fluid (ECF) osmolality. Baroreceptors are located
in the carotid sinus, aortic arch, and left atrium; these receptors participate in the nonosmolar control of
AVP release by responding to a change in effective circulating volume.
Three known receptors bind AVP at the cell membrane of target tissues: V1a, V1b (also known as V3),
and V2; these mediate AVP’s various effects.
V1a receptor is the vascular smooth muscle cell receptor but is also found on a number of other cells,
such as hepatocytes, cardiac myocytes, platelets, brain, and testis. The V1a receptors signal by
activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates
vasoconstriction. V1b (V3) receptors are found predominantly in the anterior pituitary, where they
stimulate ACTH secretion.
V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine
monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly
on the basolateral membrane of the principal cells of the connecting tubule and collecting duct of the
distal nephron.[3] Activation of the V2 receptor results in insertion of the water channel aquaporin-2 in the
luminal membrane of the collecting duct, thus making it more permeable to water. Activation of the V2
receptors also increases urea and Na+chloride reabsorption by the ascending limb of loop of Henle, thus
increasing medullary tonicity and providing the osmotic gradient for maximal water absorption. [3] V2
receptors are also found in vascular endothelial cells and stimulate the release of von Willebrand factor.[3]
Normally, AVP secretion ceases when plasma osmolality falls below 275 mOsm/kg. This decrease
causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg.
When plasma osmolality rises, AVP is secreted, which results in an increase in water reabsorption and an
increase in urine osmolality to as much as 1400 mOsm/kg. An 8-10% reduction in circulating volume also
significantly increases AVP release. In most physiologic states, the volume receptors and osmoreceptors
act in concert to increase or decrease AVP release. However, a reduction in actual or effective circulating
volume is an overriding stimulus for secretion of AVP and takes precedence over extracellular osmolality
when osmolality is normal or reduced. Finally, AVP is also released in response to stressful stimuli, such
as pain or anxiety, and by various drugs. The released AVP is rapidly metabolized in the liver and kidneys
and has a half-life of 15-20 minutes.
Pathophysiology
The key to understanding the pathophysiology, signs, symptoms, and treatment of SIADH is the
awareness that the hyponatremia in this syndrome is a result of an excess of water and not a deficiency
of Na+.
SIADH consists of hyponatremia, inappropriately elevated urine osmolality (>100 mOsm/kg), and
decreased serum osmolality in a euvolemic patient. SIADH should be diagnosed when these findings
occur in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function; in the
absence of diuretic therapy; and in absence of other factors known to stimulate ADH secretion, such as
hypotension, severe pain, nausea, and stress.
In general, the plasma Na+ concentration is the primary osmotic determinant of AVP release. In persons
with SIADH, the nonphysiological secretion of AVP results in enhanced water reabsorption, leading to
dilutional hyponatremia. While a large fraction of this water is intracellular, the extracellular fraction
causes volume expansion. Volume receptors are activated and natriuretic peptides are secreted, which
causes natriuresis and some degree of accompanying potassium excretion (kaliuresis). Eventually, a
steady state is reached and the amount of Na+ excreted in the urine matches Na intake. Ingestion of
water is an essential prerequisite to the development of the syndrome; regardless of cause, hyponatremia
does not occur if water intake is severely restricted.
In addition to the inappropriate AVP secretion, persons with this syndrome may also have an
inappropriate thirst sensation, which leads to an intake of water that is in excess of free water excreted.
This increase in water ingested may contribute to the maintenance of hyponatremia.
Neurologic manifestations
Neurologic complications in SIADH occur as a result of the brain's response to changes in osmolality.
Hyponatremia and hypo-osmolality lead to acute edema of the brain cells. The rigid calvaria prevent
expansion of brain volume beyond a certain point, after which the brain cells must adapt to persistent
hypo-osmolality. However, a rapid increase in brain water content of more than 5-10% leads to severe
cerebral edema and herniation and is fatal.
In response to a decrease in osmolality, brain ECF fluid moves into the CSF. The brain cells then lose
potassium and intracellular organic osmolytes (amino acids, such as glutamate, glutamine, taurine,
polyhydric alcohol, myoinositol, methylamine, and creatinine). This occurs concurrently to prevent
excessive brain swelling.[4]
Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics.
Electrolytes rapidly reaccumulate in the brain ECF within 24 hours, resulting in a significant overshoot
above normal brain contents within the first 48 hours after correction. Organic osmolytes return to normal
brain content very slowly over 5-7 days. Electrolyte brain content returns to normal levels by the fifth day
after correction, when organic osmolytes return to normal.
Irreversible neurologic damage and death may occur when the rate of correction of Na+ exceeds 0.5
mEq/L/h for patients with severe hyponatremia. At this rate of correction, osmolytes that have been lost in
defense against brain edema during the development of hyponatremia cannot be restored as rapidly
when hyponatremia is rapidly corrected. The brain cells are thus subject to osmotic injury, a condition
termed osmotic demyelination. Certain factors such as hypokalemia, severe malnutrition, and advanced
liver disease predispose patients to this devastating complication. [4]
Etiology
SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic
source or by ectopic production. The causes of SIADH can be divided into 4 broad categories: nervous
system disorders, neoplasia, pulmonary diseases, and drug induced (which include those that [1]
stimulate AVP release, [2] potentiate effects of AVP action, or [3] have an uncertain mechanism).
Nervous system disorders are as follows:
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Acute psychosis
Acute intermittent porphyria
Brain abscess
Cavernous sinus thrombosis
Cerebellar and cerebral atrophy
Cerebrovascular accident
CNS lupus
Delirium tremens
Encephalitis (viral or bacterial)
Epilepsy
Guillain-Barré syndrome
Head trauma
Herpes zoster (chest wall)
Hydrocephalus
Hypoxic ischemic encephalopathy
Meningitis (viral, bacterial, tuberculous, and fungal)
Midfacial hypoplasia
Multiple sclerosis
Perinatal hypoxia
Rocky Mountain spotted fever
Schizophrenia
Shy-Drager syndrome
Subarachnoid hemorrhage
Subdural hematoma
Ventriculoatrial shunt obstruction
Wernicke encephalopathy
Neoplasia disorders are as follows:
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Pulmonary - Lung carcinoma and mesothelioma
Gastrointestinal - Carcinomas of the duodenum, pancreas, and colon
Genitourinary - Adrenocortical carcinoma; carcinomas of cervix, ureter/bladder, and prostate; and
ovarian tumors
 Other - Brain tumors, carcinoid tumors, Ewing sarcoma, leukemia, lymphoma, nasopharyngeal
carcinoma, neuroblastoma (olfactory), and thymoma
Pulmonary disorders are as follows:
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Acute bronchitis/bronchiolitis
Acute respiratory failure
Aspergillosis (cavitary lesions)
Asthma
Atelectasis
Bacterial pneumonia
Chronic obstructive lung disease
Cystic fibrosis
Emphysema
Empyema
Pneumonia (viral, bacterial [mycoplasmal], fungal)
Pneumothorax
Positive pressure ventilation
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Pulmonary abscess
Pulmonary fibrosis
Sarcoidosis
Tuberculosis
Viral pneumonia
Drugs that stimulate AVP release are as follows:
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Acetylcholine
Antineoplastic agents - Adenine arabinoside, cyclophosphamide, ifosfamide, vincristine, vinblastine
Barbiturates
Bromocriptine
Carbachol
Chlorpropamide
Clofibrate
Cyclopropane
Dibenzazepines (eg, carbamazepine, oxcarbazepine
Halothane
Haloperidol
Histamine
Isoproterenol
Lorcainide
Opiates e.g. Morphine
Nicotine (inhaled tobacco)
Nitrous oxide
Phenothiazines (eg, thioridazine)
Thiopental
MAOIs (eg, tranylcypromine)
Tricyclic antidepressants (eg, amitriptyline, desipramine)
Drugs that potentiate the effects of AVP action (primarily facilitates peripheral action of ADH) are as
follows:
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Clofibrate
Griseofulvin
Hypoglycemic agents – Metformin, phenformin, tolbutamide
Oxytocin (large doses)
Prostaglandin synthetase inhibitors (inhibit renal PGE2 synthesis) – Indomethacin, aspirin, nonsteroidal
anti-inflammatory drugs
 Theophylline
 Triiodothyronine
 Vasopressin analogs (eg, AVP, DDAVP)
Drugs with an uncertain mechanism are as follows:
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Antineoplastic agents – Cisplatin, melphalan, methotrexate, imatinib
Ciprofloxacin
Clomipramine
Ecstasy
Phenoxybenzamine
Na+ valproate
SSRIs (eg, sertraline, fluoxetine, paroxetine)
Thiothixene
The list of drugs that can induce SIADH is long. SIADH has been reported as an adverse effect of
multiple psychotropic medications.[5] Many chemotherapeutic drugs cause nausea, which is a powerful
stimulus of vasopressin secretion. SIADH is also a leading cause of hyponatremia in children following
chemotherapy or stem cell transplantation.
Miscellaneous causes are as follows:
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Exercise-induced hyponatremia
Giant cell arteritis
HIV infection - Hyponatremia has been reported in as many as 40% of adult patients with HIV infection.
Patients with acquired immunodeficiency syndrome (AIDS) can have many potential causes for
increased ADH secretion, including volume depletion and infection of the lungs and the CNS. [6] Although
one third of the hyponatremic patients with AIDS are clinically hypovolemic, the remaining hyponatremic
patients fulfill most of the criteria for SIADH.
Idiopathic
Epidemiology
Occurrence in the United States
Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. When
defined as plasma Na+ concentration of less than 135 mEq/L, the prevalence of hyponatremia in
hospitalized patients has been reported in different studies as being between 2.5% and 30%. [7, 8, 9, 10] In the
majority of cases, the hyponatremia was hospital acquired or aggravated by the hospitalization and may
be secondary to the administration of hypotonic intravenous (IV) fluids. [7] SIADH can also arise
postoperatively from stress, pain, and medications used. However, not all hospital-acquired hyponatremia
is SIADH and SIADH should be differentiated from the hyponatremia that occurs in patients with limited
capacity to excrete free water, such as in patients with chronic kidney disease.
Sex- and age-related demographics
Increasing age (>30 y) is a risk factor for hyponatremia in hospitalized patients. [10]Men appear to be more
likely to develop mild or moderate, but not severe, hyponatremia.[10] Low body weight is also a risk factor
for hyponatremia. Women appear to be more prone to drug-induced hyponatremia and to exerciseinduced hyponatremia (marathon runners), although this may be an association with low body weight
rather than sex.[3]
Prognosis
The prognosis of SIADH correlates with the underlying cause and to the effects of severe hyponatremia
and its overzealous correction. Rapid and complete recovery tends to be the rule with drug-induced
SIADH when the offending agent is withdrawn. Successful treatment of pulmonary or CNS infection also
can lead to correction of SIADH. However, patients who present with neurologic symptoms or have
severe hyponatremia even without symptoms may develop permanent neurologic impairment. Patients
whose serum Na+ is rapidly corrected, especially those who are asymptomatic, can also develop
permanent neurologic impairment from central pontine myelinolysis (CPM).
Complications
The following complications are noted in SIADH:
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Cerebral edema may be observed when plasma osmolality decreases faster than 10 mOsm/kg/h. This
can lead to cerebral herniation.
Noncardiogenic pulmonary edema may develop, especially in marathon runners. [11]
CPM is the feared complication of excessive, overly rapid correction of hyponatremia. Typical features
are disorders of upper motor neurons, including spastic quadriparesis and pseudobulbar palsy, as well
as mental disorders ranging from confusion to coma.[12] The risk is increased in persons with hepatic
failure, potassium depletion, large burns, and malnutrition.[13] Premenopausal patients undergoing
surgery, especially gynecologic or related procedures, and those with serum Na of less than 105 may
also have an increased risk. Once CPM occurs as a complication, there is no proven treatment.
Morbidity and mortality
Previously, mild hyponatremia was considered relatively asymptomatic. However, evidence suggests that
even mild hyponatremia can cause significant impairment, such as unsteady gait, and lead to frequent
falls. This effect may be greater in elderly persons, who are more sensitive to changes in serum Na+.[14]
The mortality of patients with hyponatremia (Na+ < 130 mEq/L) is increased 60-fold compared with that of
patients without documented hyponatremia, although this may be partly related to their comorbid
conditions rather than to the hyponatremia itself. Predictors for higher morbidity and mortality rates
include being hospitalized, acute onset, and severity of hyponatremia. [9] When the Na+concentration drops
below 105 mEq/L, life-threatening complications are much more likely to occur.[13]
In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for
hyponatremia in an inpatient setting had significantly higher mortality rates. [15] The etiology of
hyponatremia was a more important prognostic indicator than the level of absolute serum Na+ in the
patients. The outcome was least favorable in patients who were normonatremic at admission and became
hyponatremic during the course of their hospitalization.
History
Hyponatremia is usually detected by laboratory testing.
Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms.
In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop of
serum Na+ to the same value. Patients with moderate, chronic hyponatremia may have decreased
reaction times, cognitive slowing, and ataxia resulting in frequent falls. [14, 16]
Signs and symptoms of acute hyponatremia do not precisely correlate with the severity or the acuity of
the hyponatremia. Some patients with profound hyponatremia may be relatively asymptomatic. Anorexia,
nausea, and malaise are early symptoms and may be seen when the serum Na + level is less than 125
mEq/L. A further decrease in the serum Na+ level can lead to headache, muscle cramps, irritability,
drowsiness, confusion, weakness, seizures, and coma. These occur as osmotic fluid shifts result in
cerebral edema and increased intracranial pressure.
Important considerations related to the history are symptoms that reflect the cause of SIADH. Patients
may have symptoms that suggest increased secretion of ADH, such as chronic pain, symptoms from CNS
or pulmonary tumors (eg, hemoptysis, chronic headaches), or head injury, and drug use. It is important to
determine if the patient has had excessive fluid intake because of inappropriate thirst or psychogenic
polydipsia or because hypotonic fluids were administered in a healthcare setting. The history may also
give important information about the chronicity of the condition, which may, in turn, influence the rate of
correction of hyponatremia.
Physical Examination
After the identification of hyponatremia, the approach to the patient depends on the clinically assessed
volume status. In SIADH, the patient is typically euvolemic and normotensive. Peripheral and pulmonary
edema, dry mucous membranes, reduced skin turgor, and orthostatic hypotension are usually absent.
Edema in a hyponatremic patient warrants consideration of another hyponatremic state, such as
congestive heart failure (CHF) or cirrhosis, or chronic kidney disease.
Prominent physical examination findings may be seen only in severe or rapid-onset hyponatremia and
can include confusion, disorientation, delirium, generalized muscle weakness, myoclonus, tremor,
asterixis, hyporeflexia, ataxia, dysarthria, Cheyne-Stokes respiration, pathologic reflexes, generalized
seizures, and coma.
Diagnostic Considerations
The differential diagnoses of SIADH include other hyponatremic conditions, which can be divided into
those that cause impairment in urinary water excretion and those in which renal handling of water is
normal. All patients with hyponatremia should have a plasma osmolality measured to confirm hypoosmolality.
Conditions in which renal water handling is impaired include the following:
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Effective circulating volume depletion - GI losses (eg, diarrhea, vomiting), renal losses (eg, diuretic
therapy, adrenal insufficiency, primary renal salt wasting), skin losses, edematous disorders (congestive
heart failure, cirrhosis with portal hypertension, severe nephrotic syndrome)
Renal failure - Acute kidney injury (AKI) or chronic kidney disease (CKD)
Other states of ADH excess - Cortisol deficiency, hypothyroidism, exogenous ADH (eg, deamino-Darginine-vasopressin, vasopressin, oxytocin)
Decreased solute intake
Nephrogenic syndrome of inappropriate anti-diuresis (NSIAD)
Disorders with normal water excretion include the following:
Primary polydipsia
Reset osmostat
Cerebral salt wasting
Pseudohyponatremia
Extreme elevations in plasma lipids or proteins can increase the plasma volume and can reduce the
measured plasma Na+ concentration. Na+ is contained in the aqueous phase of plasma; the proteins and
lipids cause an increase in the nonaqueous phase of plasma, leading to an overall increase in plasma
volume without an actual decrease or dilution of Na+ in the aqueous phase. This was more of an issue in
the past in the United States, when the conventional method of measuring Na+ (ie, flame-emission
spectrophotometry) measured the aqueous and nonaqueous phases of plasma. The correction factors
are as follows:
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Plasma triglycerides (g/L) x 0.002 = mEq/L decrease in Na+
Plasma protein level - 8 (g/L) x 0.025 = mEq/L decrease in Na+
The newer method (using ion-specific Na+ electrodes) measures the Na+ in the aqueous phase only, thus
avoiding the error of pseudohyponatremia. Pseudohyponatremia should be suspected when the
measured plasma osmolality is normal in the presence of hyponatremia. Pseudohyponatremia may
continue to be a problem in parts of the world where flame photometry is still used to measure Na +.
Hyperglycemia
Elevated glucose levels decrease the measured serum Na+ levels by 1.6 mEq/L for every 100 mg/dL
increase in glucose. This results from the osmotic effect of glucose drawing water into the intravascular
space. Plasma osmolality is high in this situation. This is a form of transient hyponatremia that corrects
itself as hyperglycemia is reversed.[13] A similar form of hyponatremia can occur with any osmotically
active substance in plasma, such as mannitol or dextran.
Exercise-induced hyponatremia
Exercise-induced hyponatremia has been reported during prolonged exercise such as in marathon
runners and triathletes, usually in warmer climates, which can lead to severe hyponatremia associated
with neurological symptoms.[17] The syndrome appears to arise because of excessive water consumption
during the physical exercise coupled with loss of sodium chloride in sweat and nonosmotic stimulation of
AVP secretion (from stress, volume contraction, nausea, and NSAIDs). Some athletes with cerebral
edema also develop noncardiogenic pulmonary edema.[11]
Cerebral salt wasting
The term cerebral salt wasting (CSW) was introduced in the 1950s to describe an entity seen with certain
cerebral disorders that can impair the ability of the kidneys to conserve Na+, with resultant salt wasting
and polyuria. CSW is defined as the renal loss of Na+ with intracranial disease, which leads to
hyponatremia and a decrease in extracellular fluid volume.[18, 19] Vasopressin-resistant polyuria with
hyponatremia, particularly in the setting of cerebral injury or cerebral disease or when accompanied by
dehydration, should prompt consideration of CSW in the differential diagnosis. CSW must be
distinguished from SIADH because management of these 2 conditions differs significantly.
The differences and similarities in findings for CSW and SIADH are itemized as follows:
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Hyponatremia - Present in both CSW and SIADH
Urine Na - Increased in both CSW and SIADH
Volume - Reduced in CSW and normal or increased in SIADH
Salt wasting - Gross in CSW and self-limited in SIADH
Urine output - Polyuria in CSW and variable in SIADH
Hypouricemia - Occasionally in CSW and frequent in SIADH
Over the years, much debate has been focused on the existence of this entity. The evidence in favor of
CSW rests on the following points: (1) the presence of a negative salt balance, (2) the development of
volume contraction (by definition, patients with SIADH are euvolemic), and (3) the fact that patients with
CSW respond to salt and volume replacement rather than to fluid restriction.
Various mechanisms have been postulated, including the roles of natriuretic peptides and neural
regulatory mechanisms. Measurement of AVP or atrial natriuretic peptide levels is not helpful because
they have been known to vary even in persons with SIADH.
CSW is treated with Na+ replacement, which is diametrically opposite to that for SIADH.
Na+ administration in persons with CSW corrects the hyponatremia and the fluid loss; however, in patients
with SIADH, the effect is temporary. The mineralocorticoid fludrocortisone has been used as part of the
treatment of CSW.[19]
Adrenal insufficiency
Cortisol has a negative feedback effect on ADH and corticotropin-releasing hormone. The absence of
cortisol thus removes this inhibitory effect, increasing the release of ADH.
Renal disease
With declining renal function, patients have a decreasing ability to excrete free water and the more
advanced the reduction in GFR, the easier it is for patients to become hyponatremic with unrestricted fluid
intake. In patients on long-term dialysis with no urine output, fluid intake no greater than insensible losses
leads to a predictable fall in serum Na, which, however, is not sustained because of regular maintenance
dialysis.
Reset osmostat
Persons with this entity have a normal response to changes in osmolality, but their threshold for ADH
release is reduced. Therefore, they have a lower, but stable, plasma Na + concentration. Some individuals
probably carry a nonsynonymous polymorphism (P19S) in the transient receptor potential vanilloid 4
(TRPV4) channel, part of the osmoreceptor system, since this mutation has been shown to be associated
with hyponatremia.[20]
The reset osmostat has been observed in pregnant women. Increased human chorionic gonadotropin
levels have been implicated to play a role in this condition. The serum Na + concentration falls by
approximately 5 mEq/L in the first 2 months of pregnancy and remains stable until after delivery, when it
returns to normal levels. Recognizing this entity is important because it does not require treatment.
Psychogenic polydipsia
This condition is characterized by an increase in water intake attributed to a defect in the thirst
mechanism. In some patients, the osmotic threshold for thirst is reset below the reset for release of ADH.
This disorder is mostly observed in patients with psychosis.
Water excretion is normal in these patients, and water restriction corrects the hyponatremia. In a patient
on a normal diet and an average solute (protein and salts) intake, a substantial amount of water must be
imbibed for hyponatremia to develop. Consider an individual who has 700 mOsm (primarily consisting of
urea, Na+, potassium, and chloride) to excrete per day. Ordinarily, this person can vary his or her urine
osmolality between 50 and 1400 mOsm/L and thus can excrete the osmotic load in a minimum of 500 mL
and a maximum of 14 L. As long as his or her fluid intake is between these extremes, he or she adjusts
urine osmolality to excrete the load. To become hyponatremic, such an individual must drink more than
14 L/d.
Decreased solute intake
This disorder is observed in persons who drink hyponatremic fluids without adequate food intake. The
condition is described in individuals who drink beer (beer potomania) and thrive on little else and thus
have substantially reduced protein and salt intake. The daily solute intake directly influences the osmotic
load to be excreted. With poor nutritional intake, the osmotic load may be as little as 200 mOsm; in this
situation, it can be excreted in a maximum of 4 L. Ingestion of a larger quantity of solute-free fluids
without other avenues for water loss can result in the development of hyponatremia.
Diuretics and hyponatremia
Diuretics can cause mild-to-severe hyponatremia. Thiazide diuretics cause hyponatremia more often than
loop diuretics. This is related to the different sites of action of these agents.
Loop diuretics act in the medullary thick ascending limb and prevent Na+ absorption in the medullary thick
ascending limb. This interferes with the concentrating ability by diminishing medullary osmolality. The
Na+ can be reabsorbed once it reaches the distal tubule and the collecting duct.
The thiazide diuretics prevent Na+ absorption in the distal tubule and do not interfere with the medullary
concentrating ability or the effect of ADH. However, the distal tubule is the diluting segment of the
nephron, and diminished Na+ absorption here increases urine osmolality and prevents the excretion of
hypotonic urine. In patients who are susceptible to this effect, hyponatremia is usually observed within 2
weeks. After that, a new steady state is reached and further changes in serum Na+ only occur with an
added stimulus such as vomiting and diarrhea.
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)
This is a rare X-linked recessive genetic disease secondary to gain of function mutations in the V2
receptor, resulting in a spontaneously active receptor and unregulated water reabsorption. The laboratory
features are identical to those of SIADH, with euvolemic hyponatremia, plasma hypo-osmolality, and
increased urinary osmolality. The disease is likely to present in early infancy, although so far only 2
patients have been described with this disorder.[21] If AVP levels are measured, they are predicted to be
low.
Hypervolemic hyponatremia
Other conditions to consider in the differential diagnosis of hyponatremia are those that are associated
with hypervolemia in which the baroreceptors perceive reduced effective circulating volume and stimulate
AVP secretion. These conditions include congestive heart failure, cirrhosis, and nephrotic syndrome.
These should be evident on clinical examination because of the presence of peripheral edema with
elevated jugular venous pressure, pulmonary rales, ascites, or stigmata of advanced liver disease.
Differential Diagnoses

Acute Renal Failure








Addison Disease
Adrenal Crisis in Emergency Medicine
Chronic Renal Failure
Diabetic Ketoacidosis
Hyponatremia
Hypothyroidism and Myxedema Coma in Emergency Medicine
Pediatric Diabetic Ketoacidosis
Waldenstrom Hypergammaglobulinemia
Approach Considerations
In the absence of a single laboratory test to confirm the diagnosis, SIADH is best defined by the classic
criteria introduced by Bartter and Schwartz in 1967, which remain valid today. They can be summarized
as follows[2] :




Hyponatremia with corresponding hypoosmolality
Continued renal excretion of Na+
Urine less than maximally dilute
Absence of clinical evidence of volume depletion - Normal skin turgor, blood pressure within the
reference range
 Absence of other causes of hyponatremia - Adrenal insufficiency (mineralocorticoid deficiency,
glucocorticoid deficiency), hypothyroidism, cardiac failure, pituitary insufficiency, renal disease with salt
wastage, hepatic disease, drugs that impair renal water excretion
 Correction of hyponatremia by fluid restriction
Hyponatremia (ie, serum Na+ < 135 mmol/L) with concomitant hypo-osmolality (serum osmolality < 280
mOsm/kg) and high urine osmolality is the hallmark of SIADH. However, these findings only indicate that
ADH is present and acting on the distal nephron; it does not indicate if the ADH secretion is
“inappropriate.” A good clinical examination is required to confirm that the hyponatremia is not the result
of decreased effective intravascular volume from volume depletion or from states of volume excess such
as congestive heart failure and cirrhosis for which the secretion of ADH is “appropriate.”
In SIADH, serum osmolality is generally lower than urine osmolality. In the setting of serum hypoosmolality, ADH secretion is usually suppressed to allow the excess water to be excreted, thus moving
the plasma osmolality toward normal. If ADH secretion is shut down completely, urine should have an
osmolality of less than 100 mOsm. Therefore, urine osmolality of more than 100 mOsm in the context of
plasma hypo-osmolality is sufficient to confirm ADH excess. Inappropriate water retention causes the
dilutional hyponatremia.
Urine Na+ concentration in persons with SIADH is usually more than 40 mEq/L because, in SIADH,
Na+ handling is not abnormal and the urine Na+ concentration reflects Na+ intake, which is generally more
than 40 mEq/d (usually 50-100 mEq/d). However, the urine Na+ concentration in persons with SIADH can
be modulated by dietary Na+ intake. Thus, on a low-Na+ diet, patients with SIADH may have a urine
Na+ level of less than 40 mEq/L.
Laboratory Tests
Order the following tests to help in the diagnosis of SIADH:







Serum Na+, potassium, chloride, and bicarbonate
Plasma osmolality
Serum creatinine
Blood urea nitrogen
Blood glucose
Urine osmolality
Serum uric acid


Serum cortisol
Thyroid-stimulating hormone
Serum osmolality
In persons with SIADH, the hyponatremia is associated with measured serum hypo-osmolality.
Serum Na
Hyponatremia (ie, serum Na+ < 135 mmol/L) is a defining feature of SIADH.
Serum bicarbonate
Serum bicarbonate remains within the reference range despite hypotonic expansion of body fluids in
SIADH. This is postulated to be due to the movement of hydrogen ions into the cells and to increased
hydrogen ion excretion by the renal tubules, both of which avert a dilutional fall in the serum bicarbonate
concentration.
Serum potassium
Serum potassium concentration generally remains unchanged. Movement of potassium from the
intracellular space to the extracellular space prevents dilutional hypokalemia. As hydrogen ions move
intracellularly, they are exchanged for potassium in order to maintain electroneutrality.
If both hypokalemia and metabolic alkalosis are present, consider diuretic therapy or vomiting as the
cause of hyponatremia. If hyperkalemia and metabolic acidosis coexist with hyponatremia, consider
adrenal insufficiency and volume depletion leading to AKI.
Anion gap
The anion gap is reduced in SIADH secondary to equal dilution of serum Na+ and chloride, with
unaffected bicarbonate (HCO3-). The anion gap is further decreased because the volume expansion
probably reduces the tubular reabsorption of unmeasured anions, such as sulfate, phosphate, and urate.
Urinary Na excretion
In SIADH, urinary loss of Na+ continues despite significant hyponatremia. In these patients, as in healthy
patients, urinary Na+ excretion is a reflection of Na+ intake and, therefore, usually is greater than 20
mmol/L. However, in the setting of Na+restriction in patients with SIADH or in patients with volume
depletion due to extrarenal losses, the urinary Na+ concentration may be very low.
Urinary osmolality
Patients with hyponatremia should turn off ADH and have a urine that is maximally dilute (ie, 50-100
mOsm/kg); however, in patients with SIADH, the urinary osmolality is usually submaximally dilute (ie,
>100 mOsm/kg). One of the more common errors in recognizing SIADH is the failure to realize that the
urine’s osmolality must be only inappropriately elevated and not necessarily greater than the
corresponding serum osmolality.
BUN levels
Blood urea nitrogen (BUN) levels are unusually low, usually below 10 mg/dL. A low BUN level in SIADH
occurs secondary to volume expansion because urea is distributed in total body water.
Hypouricemia
Hypouricemia (uric acid < 4 mg/dL) is frequently observed in patients with SIADH during the period of
hyponatremia. An increase in fractional uric acid excretion (usually >9%) occurs as a result of volume
expansion and a decrease in distal tubular reabsorption. In contrast, the serum uric acid is usually
increased in hypovolemia. A decrease in serum uric acid concentration has been suggested as a
screening procedure in patients with hyponatremia secondary to SIADH. However, hypouricemia lacks
sensitivity and specificity for making the diagnosis of SIADH.
Glomerular filtration rate
The glomerular filtration rate (GFR) is increased as a result of extracellular water expansion induced by
water retention.
ADH
The use of radioimmunoassay for ADH may provide supportive evidence for the diagnosis of SIADH.
However, the values are not usually available quickly enough to assist in clinical decision making.
Moreover, although the plasma ADH is typically elevated, this determination is not as important for the
diagnosis of SIADH.
Volume Assessment
Hypovolemia
The patient should be assessed clinically to help rule out the presence of hypovolemia. Clues from the
physical examination include hypotension with or without orthostasis, dry mucosae, cold peripheries,
reduced skin turgor, and low central venous pressures (if central venous pressure or pulmonary capillary
wedge pressure measurements are available).
In persons with hypovolemic hyponatremia, the urinary Na+ concentration is usually less than 20 mEq/L
and the fractional excretion of Na+ is low. Thus, if the urinary Na+ concentration is less than 25 mEq/L,
volume depletion from extrarenal volume loss should be excluded.
Volume depletion causes an appropriate (nonosmotic) secretion of ADH and leads to hyponatremia if
hypotonic fluid is used to replace isotonic fluid losses. Typically, a volume-depleted person responds to
thirst induced by volume depletion by drinking free water. Replacing isotonic losses (lost from the
extracellular compartment) with water or hypotonic fluids makes a patient hyponatremic.
Hypovolemia can also be associated with a urine Na+ concentration more than 25 mEq/L if the source of
volume loss is the kidney. Thus, diuretic use, mineralocorticoid deficiency, and salt-losing nephropathies
can lead to hyponatremia with a high urine Na+ concentration.
Hypervolemia
The presence of peripheral edema with elevated jugular venous pressure, pulmonary rales, or ascites
indicates increased volume, such as in heart failure or cirrhosis (with other signs of liver failure).
Euvolemia
In euvolemic states, before attributing the hyponatremia to SIADH, renal disease and endocrine disorders
such thyroid, pituitary, and adrenal insufficiency should be excluded.
Imaging Studies
Chest radiographs
Chest radiographs may reveal an underlying pulmonary cause of SIADH.
CT or MRI scans
Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the head may be
appropriate in selected cases. The study may show evidence of cerebral edema (eg, narrowing of the
ventricles), a complication of SIADH, or may identify a CNS disorder responsible for SIADH (eg, brain
tumor). CT scanning or MRI can also help rule out other potential causes of a change in neurologic
status.
Approach Considerations
The treatment of SIADH and the rapidity of correction of hyponatremia depend on the degree of
hyponatremia, on whether the patient is symptomatic, and on whether it is acute (< 48 h) or chronic. The
urine osmolality and creatinine clearance also must be considered when choosing the type of therapy. If
no history is available to determine the duration of hyponatremia and if the patient is asymptomatic, it is
reasonable to presume the condition is chronic. Diagnosis and treatment of the underlying cause of
SIADH is also important.
Extreme hyponatremia and an inappropriate approach to its treatment can both have disastrous
consequences; consultation with a nephrologist should be sought early in difficult cases. Correcting
hyponatremia too rapidly may result in central pontine myelinolysis (CPM) with permanent neurologic
deficits. It is important to remember that even severe hyponatremia can correct rapidly with just fluid
restriction if that hyponatremia is associated with absent ADH secretion (eg, psychogenic polydipsia).
Emergent Care
Aggressive treatment of hyponatremia should always be weighed against the risk of inducing CMP. CMP
is a rare but serious complication and can develop one to several days after aggressive treatment of
hyponatremia. Aggressive management of hyponatremia is indicated in patients with severe symptoms
such as seizures, stupor, coma, and respiratory arrest, regardless of the degree of hyponatremia.
Emergent treatment should also be strongly considered for those with moderate-to-severe hyponatremia
with a documented duration of less than 48 hours.
The goal is to correct hyponatremia at a rate that does not cause neurologic complications. The objective
is to raise serum Na+ levels by 0.5-1 mEq/h, and not more than 10-12 mEq in the first 24 hours, to bring
the Na+ value to a maximum level of 125 -130 mEq/L. Administration of 3% hypertonic saline should be
restricted to these emergent circumstances, and both neurological symptoms and serum Na + should be
monitored frequently to achieve the desired target and to prevent overcorrection.
Other authors have recommended a rate of initial correction of 1-2 mEq/L/h in severely symptomatic
patients until symptoms resolve (or for the first 3-4 h). However, total correction in the first 24 hours must
not exceed 10-12 mEq. CMP has been reported in cases in which the initial correction exceeded 12 mEq
and even in cases in which the correction was 9-10 mEq/24 h. This has led some authors to recommend
a lower target of 8 mEq in 24 hours. In the special situation of exercise-induced hyponatremia with
neurological symptoms, some authors recommend an immediate bolus of 100 mL of 3% hypertonic saline
repeated every 10 minutes until symptoms resolve.[17]
Formulas for the dose and rate of hypertonic saline have been proposed based on a Na + deficit to
calculate the rate of administration of hypertonic fluids.[13]However, they have not been prospectively
studied. Despite the correct use of these formulas, hyponatremia is often corrected too rapidly. Therefore,
these formulas should serve only as guidelines. Patients still require frequent retesting of their serum
Na+ concentration.[15]
The approximate Na+ deficit can be estimated by using the following formula (0.5 L/kg for females):

Na+ Deficit (mEq) = (Desired Na+ - Measured Na+) x 0.6 L/kg x Weight (kg)
Three-percent hypertonic saline has 513 mEq/L each of Na+ and Cl- and has an osmolality of 1026
mOsm/L. The volume of hypertonic saline needed to correct that deficit can be calculated as follows:

Volume of 3% Saline = (Na+ Deficit)/513 mEq/L Na+
Assuming a rate of correction of chronic hyponatremia of 0.5 mEq/L per hour, the amount of time needed
to correct a given degree of hyponatremia is as follows:

Time Needed for Correction = (Desired Na+ - Measured Na+)/0.5 mEq/L per hour
The rate of infusion of hypertonic saline is as follows:

Rate = (Volume of 3% Saline)/(Time Needed for Correction)
Furosemide increases excretion of free water and has been used along with hypertonic saline in severe
cases to limit treatment-induced volume expansion. The diuresis induced by furosemide has a urine
solute concentration roughly equivalent to half-normal saline; thus, excretion of free water occurs.
Electrolyte free water intake can be restricted. Combining furosemide with hypertonic saline and water
restriction may lead to a faster rate of correction of serum Na and requires that serum Na + osmolality and
urine osmolality be checked frequently to monitor the change in serum Na + values and to prevent
overcorrection. Attention should also be paid to the prevention of severe hypokalemia in conjunction with
treatment of hyponatremia.
Acute Setting
In the acute setting (ie, < 48 h since onset) with moderate symptoms such as confusion, delirium,
disorientation, nausea, and vomiting, treatment options for the hyponatremia include 3% hypertonic saline
(513 mEq/L), loop diuretics with saline, vasopressin-2 receptor antagonists (aquaretics), and water
restriction.
Depending on the rate of development of hyponatremia, the approach to correction varies. If an acute
onset and moderate neurologic symptoms have occurred, the use of hypertonic saline may be warranted
(discussed under Emergent Care). If symptoms are less severe (headache, irritability, inability to
concentrate, altered mood) or absent, then vasopressin-2 receptor antagonists (aquaretics) or water
restriction are both options. The patient's serum Na+ level and clinical status must be monitored often to
determine the need for continued aggressive therapy.
Water restriction
The degree of water restriction depends on the prior water intake, the expected ongoing fluid losses, and
the degree of hyponatremia. Water restriction to about 500-1500 mL/d (or even lower in some cases) is
usually prescribed. Although easier to maintain in the hospital setting, this becomes difficult for patients to
follow in an outpatient setting.
One of the functions of the kidneys is to excrete solutes in varying amounts of water. In persons with
SIADH, urine osmolality is fixed at a certain value; for the kidneys to eliminate an "X" amount of solutes, a
certain volume of water must be excreted. If water intake is lowered below total obligatory fluid losses
(insensible losses plus volume of urine required to excrete the osmolar load), then serum osmolality rises
because a net loss of water occurs. The insensible losses of relatively hypotonic fluids also contribute to
net water loss. The key is sufficient restriction of water intake so that the excretion of free water from all
sources is in excess of that taken in.
For example, consider a patient who has a net solute load of 900 mOsm/kg/day that must be excreted,
and, because of SIADH, his or her urine osmolality is fixed at 600 mOsm/kg. This patient then excretes
the solute load in 1.5 L of urine. On the other hand, if the urine osmolarity is fixed at 300 mOsm/kg, then 3
L of urine is required to excrete the same osmolar load. When water intake is restricted, the body
mobilizes the free water already present to excrete this load. Thus, if urine output (plus insensible losses)
exceeds water intake, a net water loss occurs and the serum Na+ level returns towards normal.
Vasopressin receptor antagonists
Inhibition of the AVP V2 receptor reduces the number of aquaporin-2 water channels in the renal
collecting duct and decreases the water permeability of the collecting duct. Collectively, agents that
competitively block ADH action and increase water excretion are called aquaretics, and they are useful in
the treatment of the hyponatremia in SIADH. The term "vaptan" has been coined to officially name all the
members of this new class of drugs.[3]
There are 2 aquaretics that are currently approved by the US Food and Drug Administration (FDA).
Conivaptan is a parenteral nonpeptide dual AVP V1a- and V2-receptor antagonist, which is approved for
use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia. The drug is given
as a 20-mg loading dose followed by a continuous infusion or as intermittent boluses, but it should not be
used for more than 4 days. The pivotal studies in euvolemic hyponatremia showed that compared with
fluid restriction alone, conivaptan together with a 2 L fluid restriction over 4 days increased serum Na by 6
mEq/L, with a median increase of 4 mEq/L by 23 hours.[22]
Tolvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients for
hypervolemia and euvolemic hyponatremia.[23, 24] The drug is started at 15 mg once daily and titrated up to
60 mg daily as required, and it is best to avoid fluid restriction during the dose-finding phase. In the pivotal
studies, which included patients with CHF, cirrhosis, and SIADH, tolvaptan compared with fluid restriction
alone increased serum Na by 8 mEq/L over 30 days, although with withdrawal of the drug, serum Na + falls
back to that seen in the placebo group.[25]
This is a useful drug to consider in a patient in whom serum Na+ does not rise by 2 mEq in the first 24 hrs
after a 1000-mL fluid restriction. Once the drug is initiated, the patient can be discharged in 24-48 hours if
neurological symptoms have resolved or the patient was asymptomatic at presentation. If the underlying
cause of SIADH has resolved, the drug can be withdrawn after 2-4 weeks, while carefully monitoring
serum Na+ daily for the next 5 days. If the serum Na+ falls again and if is less than 125 for more than 48
hours, the patient may need to be admitted again before reinitiating tolvaptan. Tolvaptan can also be
considered for long-term therapy of chronic hyponatremia.[26]
The vaptans can have a profound effect on serum Na and they should be used by physicians
experienced in the management of hyponatremia. These drugs should be avoided in hypovolemic
hyponatremia. The vaptans are more likely to be effective compared with fluid restriction alone in patients
in whom the sum of urinary potassium and Na+ concentration is greater than the plasma concentration.
They offer the benefit of prompt correction of serum Na+, producing water excretion without electrolyte
excretion and eliminating the need for fluid restriction. The primary risk of using these drugs is an
excessively rapid rate of correction of serum Na.
Furosemide
Furosemide and other loop diuretics can be used to increase the excretion of free water. Excess water
that must be removed to correct the hyponatremia can be calculated using total body water (TBW). TBW
equals body weight in kg multiplied by 0.6, assuming that the total body solute or water has not changed.
The diuresis induced by furosemide has a urine solute concentration roughly equivalent to half-normal
saline; thus, excretion of free water occurs. The excreted Na+ is replaced with 3% hypertonic saline or
with normal saline (NaCl 154 mEq/L), thus avoiding a net Na+ loss while effecting a loss of free water.
Other sources of free water intake should be restricted as well. If the measured sum of urinary potassium
and Na+ with furosemide is greater than the plasma Na, then hypertonic saline rather than normal saline
should be used to replace excreted Na. Serum Na+ and osmolality and urine osmolality should be
checked frequently to monitor the change in serum Na+ and the rate of correction.
Chronic Setting
In the chronic asymptomatic setting, the principal options are fluid restriction and V2 receptor antagonists
(see Acute Setting). If V2 receptor antagonists are not available or if local experience with these agents is
very limited, other therapeutic modalities include chronic loop diuretics with increased salt intake, urea,
mannitol, and demeclocycline.
Urea
Urea is a solute that must be excreted by the kidneys. Because urine osmolality is fixed in persons with
SIADH, the obligatory urine volume can be increased by increasing the osmotic or solute load. Increased
urinary loss of water decreases free water retention. This therapy can be used in chronic and acute
settings if the urine osmolality is low and can increase the serum Na + by up to 5 mEq/L/day. Urea is a
relatively nontoxic compound and, as opposed to sodium chloride treatment, does not cause edema or
increase body weight.
Urea can be administered on a long-term basis (0.5 g/kg body weight) without major adverse effects.
Urea is available as a powder, which is dissolved in water and taken orally during or after meals. To avoid
gastric upset, it can be taken with an antacid. Urea can also be used continuously in patients with
cerebral hemorrhage via a gastric tube or intravenously to prevent a rapid fall in intracranial pressure.
Urea should be used with great care in patients with serum creatinine of 2 mg/dL or more, BUN 80 mg/dL
or more, or bilirubin of 2 mg/dL or more, to avoid progressive azotemia, hyperammonemia, and hepatic
encephalopathy. Hypernatremia and dehydration may occur if the patient does not have free access to
water.
Medication Summary
Vasopressin receptor antagonists inhibit the V2 receptor, reducing the number of aquaporin-2 water
channels in the renal collecting duct and decreasing the water permeability of the collecting duct.
The use of a combination of a loop diuretic (eg, furosemide) and the replacement of urine output with a
solution that contains a higher Na+ concentration (ie, 3% sodium chloride solution) can be dramatically
successful in some patients. Concomitant use of furosemide increases free water excretion relative to
Na+excretion by the kidneys, thus correcting fluid expansion induced by hypertonic sodium chloride
solution.
Vasopressin-Related
Class Summary
The potential benefits of these drugs include the predictability of their effect, rapid onset of action, and
limited urinary electrolyte excretion. Conivaptan and tolvaptan are currently the only vasopressin receptor
antagonists that are commercially available in the United States and FDA-approved for the treatment of
euvolemic hyponatremia in hospitalized patients. These medications should be initiated in a closely
monitored setting to prevent rapid correction of serum Na+, which can result in central pontine
myelinolysis (CMP).[27]
Conivaptan (Vaprisol)
Conivaptan is a parenteral nonselective vasopressin receptor antagonist used for the treatment of
euvolemic hyponatremia in hospitalized patients. Conivaptan increases urine output of mostly free water,
with little electrolyte loss. It is indicated for hospitalized patients with more severe euvolemic or
hypervolemic hyponatremia.
Tolvaptan (Samsca)
Tolvaptan is an oral selective vasopressin V2-receptor antagonist. It is indicated for hypervolemic and
euvolemic hyponatremia (ie, serum Na level < 125 mEq/L) or less marked hyponatremia that is
symptomatic and has resisted correction with fluid restriction. It is used for hyponatremia associated with
CHF, liver cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Initiate or reinitiate the drug in a hospital environment only since there may be overly rapid correction of
the hyponatremia. However, it increases thirst (potentially limiting its effects) and is expensive.
Diuretics, Loop
Class Summary
These agents are often used in the treatment of hypervolemic hyponatremia. In patients with syndrome of
inappropriate antidiuretic hormone secretion (SIADH) with euvolemic hyponatremia, diuretics are usually
used in conjunction with normal saline to replenish the Na+ excreted with the diuresis.
Furosemide (Lasix)
Furosemide increases excretion of water by interfering with the Na+-K+-Cl- (Na-K-2Cl) transporter; that,
in turn, results in inhibition of Na+ and Cl- reabsorption in the ascending loop of Henle. Na+ is reabsorbed
more distally and the excreted urine is hypo-osmolar in relation to serum.
Diuretics, Osmotic Agents
Class Summary
These agents induce diuresis by elevating the osmolarity of the glomerular filtrate, thereby hindering the
tubular reabsorption of water. The overall effect is an increase in free water excretion by the kidneys.
Concomitantly, Na+ and Cl-excretion also increase, but to a lesser extent than water excretion.
Urea
Urea is used for the treatment of SIADH refractory to or in patients noncompliant with other therapies or
when other therapies are not available. Urea is known to promote diuresis. It decreases brain edema,
restores medullary tonicity, and induces Na+ retention. Isosmotic concentration of dextrose or invert
sugar is coadministered with urea to prevent hemolysis produced by pure solutions of urea.
Mannitol (Osmitrol)
Mannitol promotes a rapid free-water diuresis by elevating the osmolarity of the glomerular filtrate,
thereby hindering the tubular reabsorption of water. Concomitantly, Na+ and Cl- excretion also increase
but to a lesser extent than water excretion. It is typically used intravenously, as a 15-20% solution.
Tetracyclines
Class Summary
Demeclocycline is an older tetracycline. One of its adverse effects is nephrogenic diabetes insipidus and
polyuria, which can correct the excess of water seen in SIADH. It is no longer available in most countries
and may be nephrotoxic in patients with liver failure.
Demeclocycline
Demeclocycline is a tetracycline derivative that induces diabetes insipidus by impairing the generation
and action of cAMP, thus interfering with the action of AVP on the collecting duct. The drug's onset of
action may be delayed by over a week; thus, it is not indicated for the emergency management of
symptomatic hyponatremia.