What is the recommended treatment for Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) given elevated vasopressin (antidiuretic hormone) levels?

Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Vasopressin receptor antagonists (vaptans) are the most effective targeted pharmacological treatment for SIADH, with tolvaptan being the first-line medication for patients with moderate to severe SIADH who don't respond to fluid restriction.

Diagnostic Criteria for SIADH

Before initiating treatment, confirm SIADH diagnosis with:

• Hyponatremia (serum sodium <134 mEq/L)
• Plasma hypoosmolality (<275 mOsm/kg)
• Inappropriately high urine osmolality (>500 mOsm/kg)
• Elevated urinary sodium concentration (>20 mEq/L)
• Clinical euvolemia (no edema or signs of dehydration)
• Normal adrenal and thyroid function 1

Treatment Algorithm Based on Severity

1. Mild to Moderate SIADH (Na 125-134 mEq/L)

• First-line: Fluid restriction (1,000-1,500 mL/day) and adequate oral salt intake 1
• Second-line (if fluid restriction fails after 24-48 hours):
  • Tolvaptan 15 mg once daily, titrated as needed to 30 mg, then maximum 60 mg daily 2

2. Severe SIADH (Na <125 mEq/L)

• For symptomatic patients (confusion, seizures, coma):

  • Hypertonic (3%) saline infusion for rapid initial correction 1
  • Target correction rate: 6-8 mEq/L in first 24 hours, not exceeding 10-12 mEq/L/24h to avoid osmotic demyelination syndrome 2

• For asymptomatic patients:

  • Start tolvaptan 15 mg once daily 2
  • Monitor serum sodium closely (initially every 4-6 hours)
  • Titrate dose as needed (maximum 60 mg daily)

Important Considerations with Tolvaptan

1. Initiation setting: Must be initiated in a hospital setting where serum sodium can be closely monitored 2

2. Monitoring: Frequent monitoring of serum sodium and neurologic status, especially during initiation and dose titration 2

3. Duration limitation: Limit treatment to 30 days to minimize risk of liver injury 2

4. Contraindications:

   • Patients unable to sense or respond to thirst
   • Hypovolemic hyponatremia
   • Concomitant use of strong CYP3A inhibitors
   • Anuria
   • Underlying liver disease 2

5. Avoid fluid restriction during the first 24 hours of tolvaptan therapy to prevent overly rapid correction of serum sodium 2

Alternative Treatments

If tolvaptan is contraindicated or unavailable:

1. Urea: Effective for rapid correction of symptomatic hyponatremia in SIADH 1

   • Dosing: 30g orally 2-3 times over 24 hours or 80g as a 30% solution infused over 6 hours 3
   • Works by inducing osmotic diuresis and promoting sodium retention 4

2. Demeclocycline: Can be used to induce negative free-water balance if fluid restriction is not tolerated 1, 5

3. Conivaptan: Alternative vasopressin receptor antagonist, requires hospital monitoring due to risk of rapid sodium correction 6

Pitfalls and Caveats

1. Avoid too rapid correction of serum sodium (>12 mEq/L/24 hours) which can cause osmotic demyelination syndrome, resulting in serious neurological sequelae 2

2. Higher risk patients for osmotic demyelination include those with:

   • Severe malnutrition
   • Alcoholism
   • Advanced liver disease 2

3. Avoid concomitant use of tolvaptan with:

   • Hypertonic saline (increases risk of too rapid correction) 2
   • Moderate to strong CYP3A inhibitors 2

4. Monitor for hepatotoxicity: Discontinue tolvaptan if symptoms of liver injury develop (fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice) 2

5. Watch for dehydration and hypovolemia, especially in patients receiving diuretics or those who are fluid restricted 2

Post-Treatment Monitoring

After discontinuing tolvaptan:

• Resume fluid restriction
• Monitor serum sodium levels for rebound hyponatremia
• Provide supportive care with careful management of fluid balance and electrolytes 1, 2