What are the diagnosis and treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Diagnosis and Treatment of SIADH

Diagnostic Criteria

SIADH is diagnosed when a patient presents with euvolemic hypoosmolar hyponatremia (serum sodium <134-135 mEq/L, plasma osmolality <275 mOsm/kg) accompanied by inappropriately concentrated urine (>500 mOsm/kg) and elevated urinary sodium (>20 mEq/L), after excluding hypothyroidism, adrenal insufficiency, diuretic use, and volume depletion. 1, 2

Essential Laboratory Findings

• Serum sodium <134-135 mEq/L with corresponding plasma osmolality <275 mOsm/kg 1, 2
• Urine osmolality >500 mOsm/kg (inappropriately concentrated relative to low serum osmolality) 1, 2
• Urine sodium >20-40 mEq/L despite hyponatremia 1, 3
• Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 4, 2
• Low blood urea nitrogen is typical in SIADH, though less specific in elderly patients 3

Critical Volume Status Assessment

Confirming euvolemia is essential to distinguish SIADH from cerebral salt wasting (hypovolemic) or heart failure/cirrhosis (hypervolemic). 4, 1, 2

• Euvolemic patients show no edema, no orthostatic hypotension, normal skin turgor, and moist mucous membranes 4
• Central venous pressure of 6-10 cm H₂O supports SIADH (versus <6 cm H₂O in cerebral salt wasting) 2
• Physical examination alone has poor accuracy (sensitivity 41%, specificity 80%), so laboratory parameters are crucial 4

Exclusion Criteria

Before diagnosing SIADH, you must rule out:

• Hypothyroidism (check TSH) 4, 1
• Adrenal insufficiency (check morning cortisol) 1, 3
• Diuretic use (especially thiazides) 3, 5
• Volume depletion (urine sodium <30 mEq/L suggests hypovolemia, not SIADH) 4

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Treatment Algorithm

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

Administer 3% hypertonic saline immediately with a target correction of 6 mEq/L over the first 6 hours or until severe symptoms resolve, but never exceed 8 mEq/L total correction in 24 hours. 4, 1, 6

• Transfer to ICU for continuous monitoring 1
• Check serum sodium every 2 hours during initial correction 4, 1
• Bolus 100 mL of 3% saline over 10 minutes, repeatable up to 3 times at 10-minute intervals until symptoms improve 4
• Maximum correction: 8 mEq/L in 24 hours to prevent osmotic demyelination syndrome 4, 1, 6
• High-risk patients (alcoholism, malnutrition, advanced liver disease) require even slower correction at 4-6 mEq/L per day 4, 1, 6

For Mild Symptoms or Asymptomatic Patients

Fluid restriction to 1 L/day is the cornerstone of SIADH treatment for patients without severe symptoms. 4, 1, 5

• Restrict fluids to 1 L/day as first-line therapy 4, 1
• Avoid fluid restriction during the first 24 hours if using tolvaptan to prevent overly rapid correction 6
• Add oral sodium chloride 100 mEq three times daily if no response to fluid restriction alone 4
• Monitor serum sodium every 24 hours initially, then adjust frequency based on response 4

Pharmacological Options for Refractory Cases

Tolvaptan (vasopressin V2 receptor antagonist) is FDA-approved for clinically significant euvolemic hyponatremia (serum sodium <125 mEq/L or symptomatic hyponatremia resistant to fluid restriction). 6

• Starting dose: 15 mg once daily, titrate to 30 mg after 24 hours, maximum 60 mg daily 6
• Must initiate in hospital with close serum sodium monitoring 6
• Limit use to 30 days maximum to minimize hepatotoxicity risk 6
• Contraindicated with strong CYP3A inhibitors (ketoconazole, clarithromycin, ritonavir) 6
• Tolvaptan increased serum sodium by 3.7 mEq/L at Day 4 and 4.6 mEq/L at Day 30 versus placebo 6

Alternative agents for chronic SIADH:

• Demeclocycline (induces nephrogenic diabetes insipidus) 4, 1
• Urea (15-30 g twice daily) is effective and well-tolerated 4, 5
• Loop diuretics with salt supplementation 4, 2

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Critical Safety Considerations

Preventing Osmotic Demyelination Syndrome

Overly rapid correction (>8 mEq/L in 24 hours, or >12 mEq/L in 48 hours) causes osmotic demyelination syndrome, manifesting as dysarthria, dysphagia, lethargy, quadriparesis, seizures, coma, or death. 4, 1, 6

• Standard correction limit: 8 mEq/L per 24 hours for most patients 4, 1, 6
• High-risk patients require 4-6 mEq/L per day: those with alcoholism, malnutrition, advanced liver disease, or baseline sodium <120 mEq/L 4, 1, 6
• If overcorrection occurs, immediately give desmopressin and D5W to relower sodium 4, 5
• **Acute hyponatremia (<48 hours)** can be corrected more rapidly without ODS risk, but chronic hyponatremia (>48 hours) requires slow correction 4

Common Diagnostic Pitfalls

• Do not use 0.9% normal saline in SIADH – it acts as hypotonic fluid in these patients and can paradoxically worsen hyponatremia 5
• Distinguish SIADH from cerebral salt wasting in neurosurgical patients – CSW requires volume replacement, not fluid restriction 4, 1, 2
• Measuring plasma ADH levels is not routinely recommended and has limited diagnostic value 4, 2
• Do not ignore mild hyponatremia (130-135 mEq/L) – it increases fall risk (21% vs 5%) and mortality (60-fold increase) 4

Underlying Cause Identification

Always identify and treat the underlying cause of SIADH, as this is the definitive therapy. 1, 7

Common causes include:

• Malignancy (especially small cell lung cancer: 15% incidence) 7
• CNS disorders (meningitis, hemorrhage, trauma) 1, 8
• Pulmonary diseases (pneumonia, tuberculosis) 1, 9
• Medications (SSRIs, carbamazepine, vincristine, cyclophosphamide, cisplatin) 4, 7
• Postoperative state with hypotonic fluid administration 8, 9

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Monitoring During Treatment

• Severe symptoms: check sodium every 2 hours during initial correction 4, 1
• After symptom resolution: check every 4 hours 4
• Stable patients: daily sodium checks until target reached 4
• Watch for osmotic demyelination signs 2-7 days post-correction: dysarthria, dysphagia, oculomotor dysfunction, quadriparesis 4

Upon discontinuation of therapy, resume fluid restriction and monitor for sodium decline. 6