Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Chapter: Syndrome of Inappropriate Antidiuretic Hormone Secretion
McMaster Section Editor(s): Victor M. Montori, Juan P. Brito
Section Editor(s) in Interna Szczeklika: Barbara Jarząb, Ewa Płaczkiewicz-Jankowska
McMaster Author(s): René Rodríguez-Gutiérrez, Juan P. Brito
Author(s) in Interna Szczeklika: Jolanta Kunert‐Radek, Ewa Płaczkiewicz-Jankowska
Additional Information

Definition, Etiology, PathogenesisTop

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is caused by excessive blood levels of antidiuretic hormone (ADH) in relation to the osmolality of plasma in patients with clinical euvolemia. The excess of ADH causes water retention with normal sodium excretion, which results in euvolemic hyponatremia, plasma hypo-osmolality (<280 mOsm/kg), urine hyperosmolality (≥100 mOsm/kg), and urine sodium concentration usually >40 mmol/L.

Causes: Central nervous system pathology (trauma, tumor, surgery, inflammation, psychosis), pulmonary diseases (pneumonia, tuberculosis, pleural empyema, asthma), cancer (lung, renal, gastrointestinal, prostate, thymoma, carcinoid), right ventricular failure, human immunodeficiency virus infection, surgery, drugs (analgesic, psychotropic, diuretic, cytotoxic), and substance abuse.

The pathogenesis of SIADH is complex. For instance, cancers may cause ectopic secretion of ADH, while in nonneoplastic conditions, such as pulmonary diseases, the secretion of ADH is stimulated by hypoxia. This results in concentrated urine, reduced urine volumes, water retention, and transitory extracellular volume expansion with a consequent increase in urinary sodium excretion.

Clinical Features and Natural HistoryTop

The two most important determinants of the clinical presentation of SIADH are the severity and the rapidness with which hyponatremia develops. Signs and symptoms may include headache, apathy, fatigue, nausea, vomiting, muscle cramps, altered mental status, and in severe cases, coma, seizures, and respiratory arrest, which may be fatal (with the serum sodium level usually around 100 mmol/L or less). If hyponatremia develops rapidly, life-threatening signs and symptoms of cerebral edema may occur even with sodium levels of 120 mmol/L. Despite high ADH levels, neither peripheral edema nor arterial hypertension is observed (the “vasopressin escape” phenomenon, in which blood volume is normal and fluids are evenly distributed between body compartments).

DiagnosisTop

Determine the serum sodium level, urinary sodium excretion, urine osmolality, and plasma osmolality. Exclude renal failure, adrenal insufficiency, and hypothyroidism by measuring serum creatinine, morning cortisol, and thyroid-stimulating hormone (TSH) levels. Once these etiologies and related drugs have been ruled out, perform diagnostic tests to identify an organic cause of SIADH.

Diagnostic Criteria

Hyponatremia (<135 mmol/L), low plasma osmolality (<280 mOsm/kg), and urinary sodium excretion >40 mmol/L along with a normal sodium intake and normal renal, adrenal, and thyroid function test results. The diagnosis of SIADH is established in the context of euvolemia (neither hypovolemia nor hypervolemia can be present).

Differential Diagnosis

Chronic hypovolemia caused by thiazide diuretics, diarrhea or vomiting (SIADH is suggested by elevated urinary sodium excretion in the absence of features of dehydration), acute or chronic renal failure, hypopituitarism, adrenal insufficiency, hypothyroidism, pseudohyponatremia (apparently low serum sodium levels in patients with severe hyperlipidemia or hyperproteinemia).

TreatmentTop

Use the same general treatment principles as in patients with hypotonic hyponatremia, particularly in terms of the rate of hyponatremia correction.

Drugs used in SIADH: Table 4.3-3.

1. Whenever possible, eliminate or treat the underlying disease causing SIADH.

2. Fluid restriction is the mainstay of therapy, with a suggested goal intake of 500 to 1000 mL/d, including liquid in foods. The fluid intake should be 500 mL less than the daily urine output. The restriction may not yield satisfactory results in patients with high urine osmolality (>500 mmol/kg H2O), combined urine sodium and potassium levels exceeding serum sodium levels, daily urine output <1500 mL, or in the setting of a serum sodium increase <2 mmol/L/d after a 48-hour restriction of fluid intake (<1 L/d).

3. In mild to severe hyponatremia where fluid restriction has proven to be ineffective or in a patient who is unable/unwilling to comply, increase oral sodium intake (3-9 g/d), administer a low-dose loop diuretic (furosemide 20-40 mg/d), or consider oral urea 0.25-0.5 g/kg of body weight/d. Note that an excessively rapid increase in the serum sodium concentration (>8-10 mmol/L in a 24-hour period) may cause osmotic demyelination syndrome (see Hyponatremia).

4. In severe, life-threatening hyponatremia (altered mental status, seizures, or coma) in which serum sodium levels usually fall <120 mmol/L in <48 hours, the administration of hypertonic saline (3% saline) is warranted until neurologic symptoms are reverted.

5. Vasopressin V2-receptor and V1a/2-receptor antagonists (tolvaptan, conivaptan) are not used routinely in treatment of SIADH-associated hyponatremia except in severe unresponsive hyponatremia (intravenous conivaptan). This is in accordance with the current European guidelines; however, some experts consider SIADH with coexisting hyponatremia to be an indication for the use of the antagonists.

TablesTop

Table 4.3-3. Selected drugs associated with syndrome of inappropriate antidiuretic hormone secretion

Drug class

Drug

Anticonvulsants

– Carbamazepine

– Oxcarbazepine

– Valproic acid

Antineoplastics

– Vincristine

– Vinblastine

– Cyclophosphamide

– Ifosfamide

– Melphalan

– Cisplatin

Antidiabetics

– Chlorpropamide

– Tolbutamide

Psychotropics

– Sertraline

– Fluoxetine

– Amitriptyline

– Haloperidol

Others

– Vasopressin/desmopressin

– Ciprofloxacin

– Bromocriptine

– Imatinib

– Methotrexate

– Amiodarone

– Ecstasy (3,4-methylenedioxymethamphetamine)

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