Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

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 excessive 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, hemorrhage, tumor, surgery, inflammation, meningitis), pulmonary diseases (pneumonia, tuberculosis, pleural empyema, asthma, chronic obstructive pulmonary disease [COPD], pneumothorax), cancer (lung, renal, gastrointestinal, prostate, pancreatic, sarcoma, thymoma, neuroendocrine, lymphoma), HIV infection, surgery, drugs (desmopressin, nonsteroidal anti-inflammatory drugs [NSAIDs], opioids, selective serotonin-reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], thiazide diuretics, cytotoxic agents), and substance abuse (ecstasy), severe nausea, and idiopathic causes (Table 1).

The pathogenesis of SIADH is complex. Serum osmolality is normally maintained between 280 and 295 mOsm/kg. In SIADH, plasma levels of ADH are inappropriately increased when secretion from the posterior pituitary should be suppressed. 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 2 most important determinants of the clinical presentation of SIADH are the severity and acuity or rapidness (<48 h) 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 ~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 serum sodium level, urinary sodium excretion, urine osmolality, and plasma osmolality. Exclude pseudohyponatremia (due to excess proteins or lipids; although lipids no longer have much of an effect in today’s laboratories) and hyperglycemia, renal failure, adrenal insufficiency, and hypothyroidism by measuring serum creatinine, morning cortisol, and thyroid-stimulating hormone (TSH) with or without free thyroxine (FT4) levels. Once these etiologies and related drugs have been excluded, perform diagnostic tests to identify an organic cause of SIADH.

Diagnostic Criteria

1. Hyponatremia (<135 mmol/L).

2. Decreased plasma osmolality (<275 mOsm/kg H2O).

3. Inappropriately high urinary concentration (>100 mOsm/kg H2O).

4. Elevated urinary sodium excretion with normal salt and water intake (>30-40 mmol/L).

5. Clinical euvolemia.

6. Excluded other causes of diagnostic hypo-osmolality, as above (adrenal insufficiency, hypothyroidism).

7. No recent use of thiazide diuretics.

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 (see Hyponatremia), particularly in terms of the rate of hyponatremia correction. Ineffective treatment may lead to cerebral edema, and rapid overcorrection of hyponatremia carries the risk of osmotic demyelination syndrome, a life-threatening complication causing central pontine and extrapontine myelinolysis. Although the numbers are mostly arbitrary, in all cases the maximum desired elevation in serum sodium during initial treatment is 10 mmol/L in the first 24 hours, and then up to 8 mmol/L per day until the concentration of 130 mmol/L is achieved, with frequent sodium monitoring.

1. Whenever possible, eliminate or treat the underlying disease causing SIADH. Stop medications known to cause SIADH if safe to do so (drugs associated with SIADH: Table 2).

2. Fluid restriction is the mainstay of therapy, with a suggested goal intake of 500 to 1000 mL per day, 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 mOsm/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 per day after a 48-hour restriction of fluid intake (<1 L/d).

3. In mild to moderate 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 per day. Avoid excessively rapid increase in serum sodium concentration (>10 mmol/L in a 24-hour period) (see Hyponatremia).

4. In severe, acute, life-threatening hyponatremia (altered mental status, seizures, or coma) in which serum sodium levels usually fall <120 to 125 mmol/L in <48 hours, the administration of hypertonic saline (IV 3% saline) is warranted until neurologic symptoms are reverted and a safe sodium level is reached. Sodium concentration should be monitored every 1 to 2 hours.

A simple way to administer hypertonic saline is to first choose a desired correction rate of sodium (ie, 1 mmol/L/h) and then multiply the weight in kilograms by the desired correction rate and infuse at that rate.

Another way to administer hypertonic saline is to give a 150-mL bolus over 20 minutes and check the serum sodium level after 20 minutes. This step can be repeated twice if sodium concentration does not increase by 5 mM in the first hour or there is no improvement in symptoms. Once the sodium level has increased by 5 mM in the first hour, hypertonic saline can be discontinued. If there is no improvement in symptoms after the 5-mM sodium increase in the first hour, aim for an increase of 1 mM/h using hypertonic saline (see Hyponatremia).

For both methods hypertonic saline should also be discontinued when the signs and/or symptoms have resolved or when sodium concentration increases by the total of 10 mM or reaches 130 mM (whichever is first).

If no improvement in symptoms is achieved with the abovementioned measures, look for other causes of symptoms other than hyponatremia.

5. Vasopressin V2-receptor and V1a/2-receptor antagonists (tolvaptan, conivaptan) lead to selective water diuresis. They are not used routinely in treatment of SIADH-associated hyponatremia except in severe unresponsive hyponatremia (intravenous conivaptan). Risks of oral tolvaptan include rapid overcorrection of hyponatremia, adverse effects (on the liver), and cost. 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