What are the diagnostic criteria and treatment options for Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Diagnosis of SIADH

Essential Diagnostic Criteria

SIADH is diagnosed when five cardinal criteria are met: hypotonic hyponatremia (serum sodium <135 mEq/L), inappropriately elevated urine osmolality (>100-500 mOsm/kg), urine sodium >20-40 mEq/L, euvolemic state (absence of edema or volume depletion), and normal thyroid, adrenal, and renal function. 1, 2, 3

Laboratory Findings Required for Diagnosis

• Serum sodium <135 mEq/L with plasma osmolality <275 mOsm/kg 1
• Urine osmolality inappropriately elevated (>100 mOsm/kg, typically >500 mOsm/kg) in the presence of low plasma osmolality 1, 2, 3
• Urine sodium concentration >20-40 mEq/L (typically >30 mEq/L), reflecting continued sodium excretion despite hyponatremia 1, 3, 4
• Fractional excretion of sodium >0.5% in approximately 70% of cases 3
• Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH, though this may include cerebral salt wasting patients 5, 1
• Low blood urea nitrogen (BUN) is typical, though less specific in elderly patients 3

Critical Exclusions Before Diagnosis

• Rule out hypothyroidism with thyroid-stimulating hormone (TSH) 5, 1
• Rule out adrenal insufficiency with cortisol levels 5, 2
• Exclude thiazide diuretic use, as this is a common mimic 4
• Confirm absence of hypovolemia (no orthostatic hypotension, dry mucous membranes, poor skin turgor) and hypervolemia (no edema, ascites, jugular venous distention) 5, 1, 2

Volume Status Assessment

Euvolemia is the hallmark of SIADH and must be confirmed clinically. 1, 2 Look for:

• No peripheral edema 1
• No orthostatic hypotension 1
• Normal skin turgor and moist mucous membranes 1
• Absence of signs of volume depletion or overload 5, 2

In neurosurgical patients, distinguishing SIADH from cerebral salt wasting (CSW) is critical, as CSW presents with hypovolemia (hypotension, tachycardia, dry mucous membranes) despite similar laboratory findings. 5, 1

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Treatment Algorithm Based on Symptom Severity

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

For patients with severe neurological symptoms, immediately transfer to ICU and administer 3% hypertonic saline with a goal to correct 6 mEq/L over 6 hours or until symptoms resolve. 5, 1

• Administer 3% hypertonic saline as 100 mL boluses over 10 minutes, which can be repeated up to three times at 10-minute intervals 5
• Monitor serum sodium every 2 hours during initial correction 5, 1
• Total correction must not exceed 8 mEq/L in 24 hours to prevent osmotic demyelination syndrome 5, 1, 6
• Avoid fluid restriction during the first 24 hours to prevent overly rapid correction 5, 6

Mild to Moderate Symptomatic or Asymptomatic SIADH

Fluid restriction to 1 L/day is the cornerstone of treatment for mild to moderate SIADH. 5, 1, 4

• Restrict fluid intake to <1 L/day (1000 mL/day) as first-line therapy 5, 1, 4
• If no response to fluid restriction, add oral sodium chloride 100 mEq three times daily 5
• Monitor serum sodium every 4 hours initially, then daily 5

Second-Line Pharmacological Options

If fluid restriction fails or is poorly tolerated:

• Demeclocycline can be considered for chronic SIADH when fluid restriction is ineffective 1, 7
• Urea is effective and can be combined with fluid restriction 5, 8
• Tolvaptan (vasopressin V2 receptor antagonist) starting at 15 mg once daily, titrated to 30-60 mg based on response 5, 6
  • Tolvaptan must be initiated in hospital with close sodium monitoring 6
  • Do not use tolvaptan for more than 30 days due to hepatotoxicity risk 6
  • Avoid in patients taking strong CYP3A inhibitors 6
• Loop diuretics, lithium, and fludrocortisone have limited evidence but may be considered 5, 1

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Correction Rate Guidelines and Prevention of Osmotic Demyelination

The maximum correction rate is 8 mEq/L in 24 hours for all patients. 5, 1, 6, 4

• For high-risk patients (advanced liver disease, alcoholism, malnutrition, severe hyponatremia), limit correction to 4-6 mEq/L per day 5, 1
• Correction rates >12 mEq/L in 24 hours can cause osmotic demyelination syndrome, resulting in dysarthria, dysphagia, quadriparesis, seizures, coma, or death 5, 6
• If overcorrection occurs, immediately administer desmopressin or D5W to relower sodium 5, 4
• Watch for osmotic demyelination symptoms 2-7 days after rapid correction 5

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Common Etiologies to Investigate

• Malignancy (especially small cell lung cancer, which causes SIADH in 1-5% of cases) 5, 1, 2
• CNS disorders (meningitis, encephalitis, head trauma, subarachnoid hemorrhage) 5, 1, 2
• Pulmonary diseases (pneumonia, tuberculosis) 1, 2
• Medications: chlorpropamide, carbamazepine, SSRIs, vincristine, cyclophosphamide, cisplatin 1, 7, 2
• Post-operative state with hypotonic fluid administration 5, 2

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Critical Pitfalls to Avoid

• Do not use 0.9% normal saline in SIADH, as it acts as a hypotonic solution and can worsen hyponatremia 4
• Do not ignore mild hyponatremia (130-135 mEq/L), as it increases fall risk (21% vs 5%) and mortality 5
• Do not use fluid restriction in cerebral salt wasting, as this worsens outcomes 5, 1
• Do not fail to reassess volume status, as misdiagnosis leads to inappropriate treatment 5, 4
• Do not correct chronic hyponatremia rapidly (>1 mEq/L/hour) 5
• Inadequate monitoring during active correction is a common cause of osmotic demyelination 5, 1