PRACTICE ESSENSIALS

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.
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:

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:

Confusion, disorientation, delirium

Generalized muscle weakness, myoclonus, tremor, asterixis,
hyporeflexia, ataxia, dysarthria, Cheyne-Stokes respiration, pathologic
reflexes
Generalized seizures, coma

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[1] :

Hyponatremia with corresponding hypo-osmolality

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:

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 patients volume should be assessed clinically to help rule out the
presence of hypovolemia.
Imaging studies that may be considered include the following:

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)

Management
Treatment of SIADH and the rapidity of correction of hyponatremia depend
on the following:

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:

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:

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:

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:

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

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 hypoosmolality 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 AVPs 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.[2] 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. [2] V2
receptors are also found in vascular endothelial cells and stimulate the
release of von Willebrand factor.[2]
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.

Patophysiology
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.[3]
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.[3]

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:

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-Barr 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:

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:

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
Pulmonary abscess
Pulmonary fibrosis
Sarcoidosis
Tuberculosis
Viral pneumonia

Drugs that stimulate AVP release are as follows:

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:

Clofibrate
Griseofulvin
Hypoglycemic agents Metformin, phenformin, tolbutamide
Oxytocin (large doses)
Prostaglandin synthetase inhibitors (inhibit renal PGE 2 synthesis)
Indomethacin, aspirin, nonsteroidal anti-inflammatory drugs
Theophylline
Triiodothyronine
Vasopressin analogs (eg, AVP, DDAVP)

Drugs with an uncertain mechanism are as follows:

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. [4] 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:

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. [5] 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%. [6, 7,
8, 9]
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.[6]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.[9]Men appear to be more likely to develop mild or moderate, but
not severe, hyponatremia.[9] Low body weight is also a risk factor for
hyponatremia. Women appear to be more prone to drug-induced
hyponatremia and to exercise-induced hyponatremia (marathon runners),
although this may be an association with low body weight rather than sex.
[2]

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:

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.[10]
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. [11] The risk is
increased in persons with hepatic failure, potassium depletion, large
burns, and malnutrition.[12]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+.[13]
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.[8] When the Na+ concentration drops below 105
mEq/L, life-threatening complications are much more likely to occur.[12]
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. [14] 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.