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Syndrome of Inappropriate ADH Secretion (SIADH)

By

James L. Lewis III

, MD, Brookwood Baptist Health and Saint Vincent’s Ascension Health, Birmingham

Last full review/revision Apr 2020| Content last modified Apr 2020
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The syndrome of inappropriate ADH (vasopressin) secretion is defined as less than maximally dilute urine in the presence of serum hypo-osmolality, in patients with normal adrenal, thyroid, renal, hepatic, and cardiac function who do not have hypotension, volume depletion, or other physiologic causes of vasopressin secretion. SIADH is associated with myriad disorders. Hyponatremia is the result, and symptoms are those of hyponatremia. Diagnosis is by measurement of serum and urine osmolality and electrolytes. Treatment is with water restriction, sometimes with oral or intravenous sodium chloride, and rarely with vasopressin receptor antagonist drugs such as conivaptan or tolvaptan.

Pathophysiology of SIADH

Vasopressin is a hormone produced by the posterior pituitary to help control fluid homeostasis. The hormone increases water reabsorption in the distal nephron, producing a concentrated urine and diluted plasma. Vasopressin release is stimulated by any of the following:

  • Increased plasma osmolality

  • Decreased blood volume

  • Decreased blood pressure

  • Stress

  • Certain drugs

Low plasma osmolality inhibits vasopressin secretion, allowing the kidneys to produce dilute urine. 

Vasopressin release is inappropriate in the presence of normal or low plasma osmolality and normal or high blood volume and blood pressure. In such cases, the water inappropriately retained by the kidneys ultimately causes euvolemic (dilutional) hyponatremia Euvolemic hyponatremia Hyponatremia is decrease in serum sodium concentration 136 mEq/L ( 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, liver... read more , in which total body sodium and thus extracellular fluid (ECF) volume are normal or near normal; however, total body water is increased.

Etiology of SIADH

Vasopressin release can be enhanced by a number of central nervous system disorders. In addition, ectopic vasopressin may be produced by certain cancers or pulmonary disorders (eg, tuberculosis, pneumonia).

In some patients, vasopressin release is appropriately suppressed but at a lower-than-normal plasma osmolality (reset osmostat).

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Drugs and SIADH

Many drugs cause fluid retention which can result in dilutional hyponatremia.

Some drugs trigger vasopressin release and/or potentiate the renal effect of endogenous vasopressin; some have a direct vasopressin-like effect on the kidneys (eg, oxytocin, desmopressin). There is some debate as to whether drug causes of euvolemic hyponatremia that do not directly involve vasopressin or its receptors should be considered SIADH, but most authorities include drugs as causes.

Many drugs have been linked to SIADH, but members of five drug classes are most often implicated: analgesics (particularly opioids and nonsteroidal anti-inflammatory drugs), antiseizure drugs (particularly carbamazepine), antidepressants (particularly certain selective serotonin reuptake inhibitors, venlafaxine), antipsychotic drugs, and cytotoxic drugs (particularly cyclophosphamide and vincristine). Not all drugs in each class seem equally causative (1 Etiology reference The syndrome of inappropriate ADH (vasopressin) secretion is defined as less than maximally dilute urine in the presence of serum hypo-osmolality, in patients with normal adrenal, thyroid, renal... read more ).

Etiology reference

Symptoms and Signs of SIADH

Symptoms of SIADH are those of hyponatremia, which mainly involve central nervous system dysfunction and generally occur when the effective plasma osmolality falls to < 240 mOsm/kg (< 240 mmol/kg). Symptoms can be subtle and consist mainly of changes in mental status, including altered personality, lethargy, and confusion. As the serum sodium falls to < 115 mEq/L (< 115 mmol/L), stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and death can result.

Diagnosis of SIADH

  • Serum and urine osmolality and electrolyte measurements showing inappropriately high urine osmolality compared to serum osmolality

  • Normal adrenal,thyroid,renal, cardiac and hepatic function

SIADH is suspected in patients who have hyponatremia and are euvolemic (ie, neither hyper- nor hypovolemic on physical examination).

Laboratory tests should include serum and urine osmolality and electrolytes. Euvolemic patients should also have thyroid and adrenal function tested. Hypo-osmolality in euvolemic patients should cause excretion of a large volume of dilute urine (eg, osmolality < 100 mOsm/kg [<100 mmol/kg]) and specific gravity < 1.003). Serum sodium concentration and serum osmolality that are low and urine osmolality that is inappropriately high (120 to 150 mmol/L [120 to 150 mOsm/kg])) with respect to the low serum osmolality suggest volume overload, volume contraction, or SIADH. Volume overload Volume Overload Volume overload generally refers to expansion of the extracellular fluid (ECF) volume. ECF volume expansion typically occurs in heart failure, kidney failure, nephrotic syndrome, and cirrhosis... read more and volume contraction Volume Depletion Volume depletion, or extracellular fluid (ECF) volume contraction, occurs as a result of loss of total body sodium. Causes include vomiting, excessive sweating, diarrhea, burns, diuretic use... read more are differentiated clinically.

When neither volume overload or volume contraction appears likely, SIADH is considered. Patients with SIADH are usually euvolemic or slightly hypervolemic. BUN (blood urea nitrogen) and creatinine values are normal, and serum uric acid is generally low. Urine sodium concentration is usually > 30 mEq/L (30 mmol/L), and fractional excretion of sodium is > 1% (for calculation, see Evaluation of the Renal Patient Other urine tests In patients with renal disorders, symptoms and signs may be nonspecific, absent until the disorder is severe, or both. Findings can be local (eg, reflecting kidney inflammation or mass), result... read more Other urine tests ).

Diagnosis of etiology should be pursued based on symptoms and signs. Because potentially causative drugs are relatively commonly used, other etiologies must also be considered even when patients are taking such a drug. In general, a chest x-ray should be done. Central nervous system (CNS) imaging can be reserved for patients in whom a brain disorder is clinically suspected or no other cause for SIADH can be found.

Treatment of SIADH

  • Treatment of cause

  • Fluid restriction

  • Sometimes a vasopressin receptor antagonist

  • Sometimes hypertonic saline

When SIADH is present, severe water restriction (eg, 250 to 500 mL/24 hours) is generally required. Additionally, a loop diuretic may be combined with IV 0.9% saline as in hypervolemic hyponatremia. Lasting correction depends on successful treatment of the cause, particularly treating infection and stopping any drug cause. When the underlying disorder is not correctable, as in metastatic cancer, and patients find severe water restriction unacceptable, demeclocycline 300 to 600 mg orally every 12 hours may be helpful by inducing a concentrating defect in the kidneys. However, demeclocycline is not widely used due to the possibility of drug-induced acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more .

IV conivaptan, a selective vasopressin receptor antagonist Selective receptor antagonists Hyponatremia is decrease in serum sodium concentration 136 mEq/L ( 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, liver... read more , causes effective water diuresis without significant loss of electrolytes in the urine and can be used in hospitalized patients for treatment of resistant hyponatremia. Oral tolvaptan is another vasopressin receptor antagonist with similar action to conivaptan. Tolvaptan use is limited to less than 30 days due to the potential for liver toxicity and it should not be used in patients with liver or kidney disease

Key Points

  • Patients with SIADH are euvolemic and have low serum osmolality but inappropriately high urine osmolality.

  • Despite the name, not all patients with SIADH have excessive vasopressin.

  • Causes include central nervous system disorders, lung disorders (particularly infections), certain cancers (particularly lung cancer) and certain drugs.

  • Water restriction and treatment of cause may be adequate.

  • Some patients will also require a vasopressin receptor antagonist or hypertonic saline.

Drugs Mentioned In This Article

Drug Name Select Trade
CYTOXAN (LYOPHILIZED)
No US brand name
TEGRETOL
DDAVP, STIMATE
EFFEXOR XR
MARQIBO KIT
VASOSTRICT
VAPRISOL
SAMSCA
PITOCIN
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