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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] :
The patients volume should be assessed clinically to help rule out the
presence of hypovolemia.
Imaging studies that may be considered include the following:
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
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
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
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
Acute bronchitis/bronchiolitis
Acute respiratory failure
Aspergillosis (cavitary lesions)
Asthma
Atelectasis
Bacterial pneumonia
Chronic obstructive lung disease
Cystic fibrosis
Emphysema
Empyema
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)
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)
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
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: