What is the diagnosis and management of Syndrome of Inappropriate Antidiuretic Hormone (ADH) secretion?

From the Guidelines

The diagnosis of Syndrome of Inappropriate Antidiuretic Hormone (ADH) secretion (SIADH) should be suspected in patients with euvolemic hypoosmolar hyponatremia, characterized by low serum osmolality and inappropriately high urine osmolality, and managed with fluid restriction, hypertonic saline, and vasopressin 2 receptor antagonists as needed, with a focus on correcting hyponatremia while addressing the underlying cause, such as small cell lung cancer 1.

Diagnosis of SIADH

The diagnosis of SIADH is based on the following criteria:

• Hyponatremia (serum sodium < 134 mEq/L)
• Hypoosmolality (plasma osmolality < 275 mosm/kg)
• Inappropriately high urine osmolality (> 500 mosm/kg)
• Inappropriately high urinary sodium concentration (> 20 mEq/L)
• Absence of hypothyroidism or adrenal insufficiency or volume depletion Laboratory findings in SIADH include urine osmolality of > 300 mosm/kg, urinary sodium level of > 40 mEq/L, serum osmolality of < 275 mosm/kg, and serum uric acid concentration of < 4 mg/dL 1.

Management of SIADH

The management of SIADH involves:

• Free water restriction (< 1 L/d) as a first-line treatment for asymptomatic mild SIADH and as an adjunct to other therapy for severe cases
• Hypertonic 3% saline IV for life-threatening or acute symptomatic and severe (< 120 mEq/L) hyponatremia
• Demeclocycline, lithium, and vasopressin 2 receptor antagonists (conivaptan, lixivaptan, tolvaptan, and satavaptan) may also be used to correct hyponatremia It is essential to address the underlying cause of SIADH, such as small cell lung cancer, and to continue cancer treatment as part of the management plan 1.

Key Considerations

• The pathophysiology of SIADH involves inappropriate secretion of ADH (vasopressin) causing water retention at the collecting ducts, leading to dilutional hyponatremia despite normal total body sodium
• Recognizing SIADH in cancer patients, especially those receiving cisplatin, is crucial, and implementing appropriate sodium correction strategies while treating the underlying malignancy is essential
• The goal of treatment is to correct hyponatremia while avoiding osmotic demyelination syndrome, which can occur with rapid correction of sodium levels 1.

From the FDA Drug Label

In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone [SIADH] and others) were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal.

The diagnosis of Syndrome of Inappropriate Antidiuretic Hormone (ADH) secretion (SIADH) is based on the presence of euvolemic or hypervolemic hyponatremia. The management of SIADH involves the use of tolvaptan, a vasopressin receptor antagonist, to increase serum sodium levels.

• The initial dose of tolvaptan is 15 mg once daily, which can be increased to 30 mg once daily, then to 60 mg once daily, until either the maximum dose or normonatremia is reached.
• Fluid restriction should be avoided during the first 24 hours of therapy to prevent overly rapid correction of serum sodium.
• Tolvaptan has been shown to be effective in increasing serum sodium levels in patients with SIADH, with a statistically significant increase in serum sodium compared to placebo 2.

From the Research

Diagnosis of Syndrome of Inappropriate Antidiuretic Hormone (ADH) Secretion

• The diagnosis of SIADH is confirmed by demonstration of a high urine osmolality with a low plasma osmolality, in the absence of diuretic use 3.
• The five cardinal criteria for diagnosing SIADH include hypotonic hyponatraemia, natriuresis, urine osmolality in excess of plasma osmolality, absence of oedema and volume depletion, and normal renal and adrenal function 4.
• Appropriate laboratory tests to diagnose SIADH were obtained in <50% of patients, and success rates in correcting hyponatremia were significantly higher when such tests were obtained 5.

Management of SIADH

• Immediate treatment of the symptomatic patient with SIADH includes intravenous furosemide and 3% sodium chloride injection to produce a negative free-water balance 3.
• For chronic SIADH, the mainstay of therapy remains fluid restriction 3, 4.
• Algorithm 1 addresses acute correction of hyponatremia posing as a medical emergency, and is applicable to both severe euvolemic and hypovolemic hyponatremia, with the mainstay of this algorithm being the iv use of 3% hypertonic saline solution 6, 7.
• Algorithm 2 is directed to the therapy of SIADH-induced mild or moderate, non-acute hyponatremia, and addresses when and how to use fluid restriction, solute, furosemide, and tolvaptan to achieve eunatremia in patients with SIADH 6, 7.
• The most common monotherapy treatments for hyponatremia in SIADH were fluid restriction (48%), isotonic (27%) or hypertonic (6%) saline, and tolvaptan (13%) 5.
• Hypertonic saline and tolvaptan produced the greatest mean rate of [Na(+)] change compared with lower interquartile range rates of [Na(+)] change for isotonic saline and fluid restriction 5.