What is the treatment for chronic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Treatment of Chronic SIADH

For chronic Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), fluid restriction of 1-1.5 L/day is the cornerstone of first-line treatment, with pharmacological options including tolvaptan reserved for cases that fail to respond to conservative measures. 1, 2

Initial Assessment and Classification

Treatment approach should be guided by:

• Severity of hyponatremia
• Presence and severity of symptoms
• Volume status (euvolemic in SIADH)
• Chronicity of the condition

Symptom-Based Treatment Algorithm

Asymptomatic or Mildly Symptomatic SIADH (Na 125-130 mmol/L):

1. Fluid restriction (1-1.5 L/day) 1, 2
2. High solute intake:
   • High protein diet
   • Salt tablets (NaCl 100 mEq PO TID) if no response to fluid restriction 1

Moderate Symptoms (nausea, vomiting, headache, Na <125 mmol/L):

1. Fluid restriction (<1 L/day)
2. Monitor serum sodium every 4-6 hours
3. Consider second-line therapies if inadequate response:
   • Oral urea (considered effective and safe) 3
   • Tolvaptan (if other measures fail) 4

Severe Symptoms (mental status changes, seizures):

1. Transfer to ICU
2. 3% hypertonic saline with careful monitoring:
   • Correct 6 mmol/L over 6 hours or until severe symptoms resolve
   • Total correction should not exceed 8 mmol/L/24h 1
3. Monitor sodium every 2 hours
4. Daily weights and strict I/O monitoring
5. Once stabilized, transition to treatment for mild symptoms 1

Evidence for First-Line Therapy

Fluid restriction is the mainstay of treatment for chronic SIADH, though evidence shows modest efficacy:

• A randomized controlled trial showed fluid restriction (1 L/day) increased sodium by a median of 4 mmol/L after 30 days compared to 1 mmol/L in untreated patients 5
• Only 61% of patients on fluid restriction achieved sodium ≥130 mmol/L after 3 days 5

Second-Line Therapies

When fluid restriction fails or is poorly tolerated:

Tolvaptan (Vasopressin Receptor Antagonist)

• Indication: Clinically significant euvolemic hyponatremia (Na <125 mmol/L or symptomatic) that has resisted fluid restriction 4
• Dosing: Start at 15 mg once daily, can increase to 30 mg after 24 hours, maximum 60 mg daily 4
• Important cautions:
  • Must be initiated in hospital with close sodium monitoring
  • Avoid correction >12 mEq/L/24h to prevent osmotic demyelination syndrome
  • Do not use for more than 30 days (risk of liver injury) 4
  • Contraindicated in hypovolemic hyponatremia 4

Urea

• Effective alternative to vaptans
• Dosage: 40g in 100-150 mL normal saline every 8 hours 1
• Less expensive than vaptans, with good safety profile 3

Other Options

• Demeclocycline (induces nephrogenic diabetes insipidus) 6, 7
• Loop diuretics with salt supplementation (not superior to fluid restriction alone) 8

Monitoring and Follow-up

• For mild-moderate cases: Check serum sodium daily initially, then every 2-3 days once stable
• For patients on tolvaptan: Monitor sodium at 0,6,24, and 48 hours after initiation 6
• If discontinuing tolvaptan after >5-6 days, taper dose or reinstitute fluid restriction to prevent hyponatremic relapse 6

Important Cautions

1. Avoid rapid correction: Do not exceed 8-10 mmol/L/24h to prevent osmotic demyelination syndrome 1, 2
2. Risk factors for osmotic demyelination: Malnutrition, alcoholism, advanced liver disease 4
3. Fluid restriction failure: Almost half of SIADH patients do not respond adequately to fluid restriction 3
4. Tolvaptan discontinuation: Monitor for hyponatremic relapse when stopping treatment 6

Treatment Duration

For chronic SIADH, treatment is typically long-term unless the underlying cause can be addressed. The optimal approach is to identify and treat the underlying cause whenever possible.