What are the treatment guidelines for Syndrome of Inappropriate Antidiuretic Hormone (SIADH)?

Treatment Guidelines for SIADH

Diagnostic Confirmation

Before initiating treatment, confirm SIADH diagnosis with hyponatremia (serum sodium <134 mEq/L), hypoosmolality (plasma osmolality <275 mosm/kg), inappropriately high urine osmolality (>500 mosm/kg), and inappropriately high urinary sodium (>20 mEq/L) in the absence of hypothyroidism, adrenal insufficiency, or volume depletion. 1

• Assess extracellular fluid volume status to distinguish SIADH (euvolemic) from cerebral salt wasting (hypovolemic), as treatment approaches differ fundamentally 1
• Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH 1

Treatment Algorithm Based on Severity

Severe Symptomatic Hyponatremia (Seizures, Coma, Altered Mental Status)

Transfer immediately to ICU and administer 3% hypertonic saline with a goal to correct 6 mmol/L over 6 hours or until severe symptoms resolve. 1

• Monitor serum sodium every 2 hours initially 1
• Total correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 2
• For high-risk patients (malnutrition, alcoholism, advanced liver disease), limit correction to 4-6 mmol/L per day 1, 2
• The FDA warns that too rapid correction (>12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, seizures, coma, and death 3

Mild Symptomatic or Asymptomatic Hyponatremia (Sodium <120 mEq/L)

Implement fluid restriction to 1 L/day as first-line treatment. 1, 2

• Avoid fluid restriction during the first 24 hours if using pharmacologic therapy to prevent overly rapid correction 1
• If no response to fluid restriction, add oral sodium chloride 100 mEq three times daily 2
• Monitor serum sodium every 4 hours initially, then daily 2

Pharmacological Treatment Options

Second-Line Therapies

Demeclocycline can be considered for chronic SIADH when fluid restriction is ineffective or poorly tolerated. 1

• Other options include urea, lithium, and loop diuretics, though these are less commonly used 1
• Urea is considered very effective and safe in recent literature 1

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan is FDA-approved for clinically significant euvolemic hyponatremia (serum sodium <125 mEq/L or symptomatic hyponatremia resistant to fluid restriction). 3

• Starting dose: 15 mg once daily, can be titrated to 30 mg after 24 hours, maximum 60 mg daily 1, 3
• Must be initiated and re-initiated only in a hospital where serum sodium can be monitored closely 3
• Do not administer for more than 30 days to minimize risk of liver injury 3
• In clinical trials, tolvaptan increased serum sodium by 3.0 mEq/L/day compared to placebo 1
• Avoid fluid restriction during first 24 hours of tolvaptan therapy; patients can continue fluid intake in response to thirst 3

Critical Safety Considerations

Prevention of Osmotic Demyelination Syndrome

Never exceed 8 mmol/L correction in 24 hours for chronic hyponatremia (>48 hours duration). 1, 2

• For high-risk patients (advanced liver disease, alcoholism, malnutrition, severe hyponatremia), limit to 4-6 mmol/L per day 1, 2
• If overcorrection occurs, immediately discontinue current fluids, switch to D5W, and consider desmopressin 2
• Watch for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 2

Monitoring Requirements

• Severe symptoms: Check serum sodium every 2 hours during initial correction 1
• Mild symptoms: Check every 4 hours after resolution of severe symptoms 2
• With tolvaptan: Monitor at 0,6,24, and 48 hours of treatment 4

Treatment of Underlying Cause

Always identify and treat the underlying cause of SIADH. 1

• Discontinue offending medications (carbamazepine, SSRIs, chlorpropamide, cyclophosphamide, vincristine, cisplatin, vinca alkaloids) 1
• In SCLC patients with paraneoplastic SIADH, treatment of underlying malignancy is important alongside hyponatremia management 1
• Hyponatremia usually improves after successful treatment of the underlying cause 1

Special Populations

Neurosurgical Patients

Distinguish SIADH from cerebral salt wasting (CSW), as fluid restriction in CSW can worsen outcomes. 1, 2

• In subarachnoid hemorrhage patients at risk for vasospasm, avoid fluid restriction 1
• Fludrocortisone may be considered for hyponatremia in these patients 1

Cirrhotic Patients

• Use tolvaptan with extreme caution due to higher risk of gastrointestinal bleeding (10% vs 2% placebo) 2
• Consider albumin infusion alongside fluid restriction 2

Common Pitfalls to Avoid

• Overly rapid correction leading to osmotic demyelination syndrome 1
• Inadequate monitoring during active correction 1
• Using fluid restriction in cerebral salt wasting instead of SIADH 1
• Failing to recognize and treat the underlying cause 1
• Ignoring mild hyponatremia (130-135 mmol/L), which increases fall risk and mortality 2