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

Diagnostic Criteria for SIADH

SIADH is diagnosed when a patient presents with hyponatremia (serum sodium <134 mEq/L), plasma osmolality <275 mosm/kg, inappropriately high urine osmolality (>500 mosm/kg), and elevated urinary sodium (>20 mEq/L), in the absence of hypothyroidism, adrenal insufficiency, or volume depletion. 1

Essential Diagnostic Criteria

The diagnosis requires all of the following 1, 2, 3:

• Hypotonic hyponatremia: Serum sodium <134 mEq/L with plasma osmolality <275 mosm/kg 1
• Inappropriately concentrated urine: Urine osmolality >500 mosm/kg (or at minimum >100 mosm/kg) despite low serum osmolality 1, 3
• Elevated urine sodium: Urinary sodium concentration >20 mEq/L 1, 3
• Euvolemic state: No clinical signs of hypovolemia (orthostatic hypotension, dry mucous membranes, decreased skin turgor) or hypervolemia (peripheral edema, ascites, jugular venous distention) 1, 2
• Normal renal, thyroid, and adrenal function: Must exclude hypothyroidism and adrenal insufficiency before confirming SIADH 1, 3

Volume Status Assessment

Accurate determination of extracellular fluid volume is the critical factor distinguishing SIADH from other causes of hyponatremia, particularly cerebral salt wasting. 4, 2

• Euvolemia in SIADH is characterized by no edema, no orthostatic hypotension, normal skin turgor, and moist mucous membranes 1
• Central venous pressure in SIADH typically ranges from 6-10 cm H₂O, compared to <6 cm H₂O in cerebral salt wasting 1
• Physical examination alone has poor accuracy (sensitivity 41.1%, specificity 80%) and should be supplemented with laboratory findings 1

Additional Diagnostic Clues

• Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH 1, 4
• Urine osmolality >100 mOsm/kg indicates impaired water excretion 1
• The patient should have normal renal function, as SIADH diagnosis requires the kidneys to be capable of responding to ADH 2, 3

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Treatment of SIADH

Treatment Based on Symptom Severity

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

For severe symptomatic hyponatremia, immediately transfer to ICU and administer 3% hypertonic saline with a goal to correct 6 mmol/L over 6 hours or until severe symptoms resolve. 1, 4

• Administer 3% hypertonic saline as 100 mL boluses over 10 minutes, which can be repeated up to three times at 10-minute intervals until symptoms improve 1
• Monitor serum sodium every 2 hours initially during active correction 1, 4
• Total correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 4, 5
• After correcting 6 mmol/L in the first 6 hours, only 2 mmol/L additional correction is allowed in the next 18 hours 1

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

Fluid restriction to 1 L/day is the cornerstone of treatment for mild symptomatic or asymptomatic SIADH. 1, 4, 6

• Implement strict fluid restriction to 1000 mL/day 1, 4
• If no response to fluid restriction after 24-48 hours, add oral sodium chloride 100 mEq three times daily 1
• Monitor serum sodium every 24 hours initially, then adjust frequency based on response 1
• Avoid fluid restriction during the first 24 hours when initiating tolvaptan to prevent overly rapid correction 5

Pharmacological Treatment Options

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan is FDA-approved for clinically significant euvolemic hyponatremia and should be initiated in a hospital setting with close sodium monitoring. 5

• Starting dose: 15 mg once daily, can be titrated to 30 mg after 24 hours, maximum 60 mg daily 1, 5
• Tolvaptan increased serum sodium by 3.7 mEq/L at Day 4 and 4.6 mEq/L at Day 30 compared to placebo 5
• Do not administer for more than 30 days to minimize risk of liver injury 5
• Patients should be advised they can continue fluid ingestion in response to thirst 5
• Common side effects include thirst, polydipsia, and urinary frequency 7

Second-Line Pharmacological Options

• Demeclocycline can be considered as second-line treatment when fluid restriction is ineffective or poorly tolerated 1, 4
• Urea is considered very effective and safe in recent literature for chronic SIADH management 1
• Lithium and loop diuretics are less commonly used alternatives 1

Critical Safety Considerations

Osmotic Demyelination Syndrome Prevention

The maximum correction rate should never exceed 8 mmol/L in 24 hours, with even slower rates (4-6 mmol/L per day) required for high-risk patients. 1, 4, 5

• High-risk populations include those with advanced liver disease, alcoholism, severe malnutrition, or prior encephalopathy 1, 4
• Osmotic demyelination syndrome presents with dysarthria, dysphagia, oculomotor dysfunction, and quadriparesis, typically occurring 2-7 days after rapid correction 1
• If overcorrection occurs, immediately discontinue current fluids, switch to D5W, and consider desmopressin to relower sodium levels 1

Chronic vs. Acute Hyponatremia

• Acute hyponatremia (<48 hours) can be corrected more rapidly without risk of osmotic demyelination 1
• Chronic hyponatremia (>48 hours or unknown duration) requires slower correction at 0.5 mEq/L/hour maximum 8, 3
• When duration is unknown, assume chronic and use conservative correction rates 3

Common Pitfalls to Avoid

• Never use normal saline (0.9% NaCl) in SIADH, as it acts as a hypotonic solution relative to the patient's concentrated urine and can paradoxically worsen hyponatremia 1, 3
• Avoid overly rapid correction leading to osmotic demyelination syndrome 1
• Do not confuse SIADH with cerebral salt wasting—they require opposite treatments (fluid restriction vs. volume replacement) 1, 4, 2
• Never ignore mild hyponatremia (130-135 mmol/L) as clinically insignificant, as it increases fall risk and mortality 1
• Failing to recognize and treat the underlying cause of SIADH 1

Treatment of Underlying Cause

• Discontinue offending medications (SSRIs, carbamazepine, NSAIDs, opioids, chemotherapy agents including cisplatin and vinca alkaloids) 1
• Treat underlying malignancy in paraneoplastic SIADH, as successful cancer treatment often resolves the syndrome 1
• Address CNS disorders, pulmonary diseases, or postoperative states contributing to SIADH 1, 3