What is the diagnosis and treatment for Syndrome of Inappropriate Antidiuretic Hormone (SIADH)?

From the Guidelines

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) should be managed with fluid restriction as the first-line approach for mild cases, and 3% hypertonic saline for moderate to severe symptomatic hyponatremia, with careful monitoring to avoid rapid correction. The treatment of SIADH depends on the severity of symptoms and sodium levels. For mild cases with minimal symptoms, fluid restriction to less than 1 L/day is recommended 1.

Key Considerations

• For moderate to severe symptomatic hyponatremia (sodium <125 mEq/L), 3% hypertonic saline may be administered intravenously at 0.5-2 mL/kg/hour, with careful monitoring to avoid rapid correction (limit to 6-8 mEq/L in 24 hours to prevent osmotic demyelination syndrome) 1.
• Pharmacological options include oral salt tablets, loop diuretics like furosemide, and vasopressin receptor antagonists such as tolvaptan (starting at 15 mg daily) 1.
• The underlying cause of SIADH must be identified and treated, whether it's malignancy, medications, pulmonary disease, or CNS disorders.
• Regular monitoring of serum sodium, urine osmolality, and volume status is essential during treatment. Some key points to consider in the management of SIADH include:
• The use of vaptans, such as tolvaptan, which are selective antagonists of the V2-receptors of arginine-vasopressin, can enhance solute-free water excretion and improve serum sodium concentration 1.
• The safety of vaptans has only been established for short-term treatments lasting from one week to one month 1.
• Long-term use of vaptans may be associated with a higher all-cause mortality rate, mostly associated with known complications of cirrhosis 1. It is essential to note that SIADH occurs because excessive ADH causes the kidneys to reabsorb more water than normal, diluting the blood sodium concentration while producing concentrated urine despite low serum osmolality, creating a paradoxical situation where the body retains water inappropriately 1.

From the FDA Drug Label

Tolvaptan tablets are indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Tolvaptan is indicated for the treatment of SIADH, which is a condition characterized by excessive secretion of antidiuretic hormone (ADH) leading to hyponatremia. The drug works by blocking the action of ADH, thereby increasing serum sodium levels.

• Key points:
  • Tolvaptan is used to treat clinically significant hypervolemic and euvolemic hyponatremia, including SIADH.
  • The drug should be initiated and re-initiated in a hospital setting where serum sodium can be closely monitored.
  • The usual starting dose is 15 mg once daily, which can be increased to 30 mg and then 60 mg as needed to achieve the desired level of serum sodium.
  • Patients should be advised to resume fluid restriction after discontinuation of tolvaptan and should be monitored for changes in serum sodium and volume status 2.

From the Research

Definition and Diagnosis of SIADH

• The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a condition characterized by the excessive release of antidiuretic hormone (ADH), leading to water retention and hyponatremia 3.
• The diagnosis of SIADH involves ascertaining the euvolemic state of extracellular fluid volume, both clinically and by laboratory measurements 3.

Treatment Options for SIADH

• Therapeutic modalities for SIADH include nonspecific measures such as fluid restriction, hypertonic saline, urea, and demeclocycline 3.
• Vasopressin receptor antagonists, called vaptans, have been introduced as a specific and direct therapy for SIADH, offering advantages such as no need for fluid restriction and efficient correction of hyponatremia 3, 4.
• Fluid restriction is the recommended first-line treatment for SIADH, despite limited prospective data to support its efficacy 5.
• Tolvaptan, an oral vasopressin V2 receptor antagonist, has been shown to be effective in treating SIADH, but its use is limited by dose-dependent side effects and high cost 4, 6, 7.

Efficacy and Safety of Treatment Options

• Fluid restriction has been shown to induce a modest early rise in plasma sodium concentration, but its effectiveness is limited, and more than one-third of patients may fail to reach a plasma sodium concentration of ≥130 mmol/L after 3 days of treatment 5.
• Vaptans, such as tolvaptan, have been shown to be effective in correcting hyponatremia, but their use requires careful monitoring to prevent overly rapid correction and potential side effects such as thirst, polydipsia, and frequency of urination 3, 4.
• The efficacy of tolvaptan in improving symptoms of hyponatremia or correcting hyponatremia in SIADH patients has not been firmly established, and its adverse effect profile is poorly documented 7.

Management of SIADH

• The management of SIADH involves individualized treatment, taking into account the severity of symptoms, the underlying cause of SIADH, and the patient's overall clinical condition 3, 6.
• A regimen of intermittent lower dose of tolvaptan combined with fluid restriction may be an effective choice for patients with chronic SIADH 4.
• Close monitoring of serum sodium levels and careful adjustment of treatment are crucial to prevent overly rapid correction and potential complications such as osmotic demyelination 3.