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

From the Guidelines

SIADH should be managed with fluid restriction and hypertonic saline in severe cases to prevent life-threatening manifestations and improve patient outcomes. The management of SIADH is based on expert opinion, as there are no evidence-based guidelines available 1. According to the American College of Chest Physicians evidence-based clinical practice guidelines, approximately 10% to 45% of small cell lung cancer (SCLC) and 1% of other lung cancer cases produce arginine vasopressin, leading to SIADH 1.

Key Characteristics of SIADH

• 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

Diagnosis and Management

Diagnosis of SIADH requires a clinical assessment of intravascular volume status and biochemical measurements in blood and urine 1. The accuracy of a diagnostic algorithm for SIADH can approach 95% by assessing the effective arterial blood volume with the fractional excretion of urate 1. Management includes 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 1. Hypertonic 3% saline IV is given in life-threatening or acute symptomatic and severe (< 120 mEq/L) hyponatremia 1.

Pharmacologic Options

Pharmacologic options for managing SIADH include demeclocycline, lithium, and vasopressin 2 receptor antagonists (conivaptan, lixivaptan, tolvaptan, and satavaptan) to correct hyponatremia 1. It is essential to monitor serum sodium levels and adjust treatment accordingly to prevent rapid correction and osmotic demyelination syndrome. Regular monitoring of serum sodium, osmolality, and volume status is crucial throughout treatment.

Importance of Early Detection and Management

Early detection and appropriate management of SIADH can prevent severe hyponatremia, which can lead to seizures, coma, and death 1. Hyponatremia in patients with SCLC is associated with shortened survival, emphasizing the need for prompt and effective management 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. The drug label states that tolvaptan tablets are indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with SIADH 2.

• Key points:
  • Tolvaptan is used to treat SIADH.
  • The treatment should be initiated and re-initiated in a hospital where serum sodium can be monitored closely.
  • The dose of tolvaptan can be increased at 24-hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) is reached 2.
  • Tolvaptan has been shown to cause a statistically greater increase in serum sodium compared to placebo in patients with SIADH 2.

From the Research

Definition and Diagnosis of SIADH

• The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a condition where the body produces an excessive amount of antidiuretic hormone (ADH), leading to water retention and hyponatremia 3, 4.
• SIADH is the most frequent underlying disorder causing hyponatremia, which is the most common electrolyte disturbance encountered in clinical practice 4.
• The diagnosis of SIADH involves ascertaining the euvolemic state of extracellular fluid volume, both clinically and by laboratory measurements 3.

Treatment Options for SIADH

• Treatment options for SIADH include fluid restriction, hypertonic saline, urea, demeclocycline, and vasopressin receptor antagonists (vaptans) 3, 4, 5.
• Vaptans, such as tolvaptan, are a specific and direct therapy for SIADH, which can correct hyponatremia comfortably and within a short time without the need for fluid restriction 3, 5.
• Conivaptan, an intravenous vasopressin-receptor antagonist, is also used to treat hyponatremia secondary to SIADH, especially in refractory cases 6.

Efficacy and Safety of Tolvaptan

• Tolvaptan has been shown to be effective in correcting mild or moderate hyponatremia in patients with SIADH 5, 7.
• Long-term low-dose tolvaptan has been found to be safe and effective in treating SIADH, with no cases of overcorrection or osmotic demyelination syndrome reported 7.
• The use of tolvaptan is associated with mild side effects, such as thirst and pollakiuria 3, 7.

Clinical Considerations

• It is essential to limit the daily increase of serum sodium to less than 8-10 mmol/liter to prevent osmotic demyelination 3.
• The serum sodium level should be monitored closely during treatment with vaptans, especially during the first 24 hours 3.
• Discontinuation of vaptan therapy should be done cautiously to prevent hyponatremic relapse 3.