What are the diagnosis and management options for Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

SIADH Diagnosis and Management

Diagnostic Criteria

SIADH is diagnosed when five cardinal features are present: hyponatremia (serum sodium <134 mEq/L), plasma hypoosmolality (<275 mosm/kg), inappropriately concentrated urine (>500 mosm/kg), elevated urinary sodium (>20 mEq/L), and absence of volume depletion, hypothyroidism, or adrenal insufficiency. 1

Essential Laboratory Workup

• Serum sodium <134 mEq/L with plasma osmolality <275 mosm/kg confirms hypotonic hyponatremia 1
• Urine osmolality >500 mosm/kg despite low plasma osmolality indicates inappropriate ADH activity 1
• Urine sodium >20 mEq/L reflects physiologic natriuresis from volume expansion 1
• Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 1, 2
• TSH and cortisol levels must be checked to exclude hypothyroidism and adrenal insufficiency 1

Volume Status Assessment

• Euvolemia is the hallmark of SIADH - look for absence of orthostatic hypotension, normal skin turgor, moist mucous membranes, and no peripheral edema 1, 3
• Physical examination alone has poor accuracy (sensitivity 41%, specificity 80%) for volume assessment 3
• Central venous pressure 6-10 cm H₂O supports SIADH, while CVP <6 cm H₂O suggests cerebral salt wasting 1

Critical Differential: SIADH vs Cerebral Salt Wasting

This distinction is crucial in neurosurgical patients because treatments are opposite 1, 3:

• SIADH: Euvolemic, CVP 6-10 cm H₂O, treat with fluid restriction 1
• Cerebral Salt Wasting: Hypovolemic, CVP <6 cm H₂O, orthostatic hypotension, dry mucous membranes, treat with volume replacement 1, 3

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Management Based on Symptom Severity

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

For severe symptoms, immediately administer 3% hypertonic saline with a target correction of 6 mmol/L over 6 hours or until symptoms resolve, never exceeding 8 mmol/L total correction in 24 hours. 1, 3

• Transfer to ICU for continuous monitoring 1
• Give 3% hypertonic saline as 100-150 mL IV boluses over 10 minutes, repeatable up to 3 times at 10-minute intervals 3, 4
• Monitor serum sodium every 2 hours during initial correction phase 1, 3
• Stop at 6 mmol/L increase in first 6 hours or when severe symptoms resolve 1, 3
• Maximum 8 mmol/L correction in 24 hours to prevent osmotic demyelination syndrome 1, 3, 5

High-risk patients (cirrhosis, alcoholism, malnutrition, advanced liver disease) require even slower correction at 4-6 mmol/L per day maximum. 1, 3

Mild-Moderate Symptomatic or Asymptomatic Hyponatremia (Na <120 mEq/L)

Fluid restriction to 1 L/day is the cornerstone of treatment for chronic SIADH. 1, 3, 6

• Restrict fluids to 1000 mL/day as first-line therapy 1, 3
• Add oral sodium chloride 100 mEq three times daily if no response to fluid restriction alone 1, 3
• Monitor serum sodium every 24 hours initially, then adjust frequency based on response 3
• Avoid fluid restriction in the first 24 hours when using vaptans to prevent overly rapid correction 5

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Pharmacological Treatment Options

Second-Line Therapies When Fluid Restriction Fails

Nearly half of SIADH patients do not respond adequately to fluid restriction alone, requiring second-line pharmacological intervention. 4

Demeclocycline

• Demeclocycline induces nephrogenic diabetes insipidus, reducing kidney response to ADH 1, 6
• Considered second-line treatment when fluid restriction is ineffective or poorly tolerated 1
• Long history of use in persistent SIADH cases 1

Urea

• Oral urea is considered very effective and safe for chronic SIADH management 1, 4
• Dose: 40 g in 100-150 mL normal saline every 8 hours for 1-2 days in neurosurgical patients 3
• Particularly valuable when distinguishing SIADH from cerebral salt wasting is difficult 3

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan is FDA-approved for clinically significant euvolemic hyponatremia and provides reliable, comfortable correction without fluid restriction. 5, 6

• Starting dose: 15 mg once daily, titrate to 30 mg after 24 hours, maximum 60 mg daily 1, 5
• Initiate and re-initiate only in hospital where serum sodium can be monitored closely 5
• Check serum sodium at 0,6,24, and 48 hours after starting treatment 6
• Avoid fluid restriction first 24 hours to prevent overly rapid correction 5
• Maximum treatment duration 30 days to minimize hepatotoxicity risk 5
• Efficacy: Increases serum sodium by 4.0 mEq/L at Day 4 and 6.2 mEq/L at Day 30 vs placebo 5
• Side effects: Thirst, polydipsia, frequent urination 6
• Contraindicated: Hypovolemic hyponatremia, inability to sense thirst, anuria, concurrent strong CYP3A inhibitors 5

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Special Considerations

Neurosurgical Patients with Subarachnoid Hemorrhage

Never use fluid restriction in SAH patients at risk for vasospasm - this worsens outcomes. 1, 3

• Fludrocortisone 0.1-0.2 mg daily may be considered to prevent vasospasm 1, 3
• Hydrocortisone may prevent natriuresis 1, 3
• Aggressive volume resuscitation can ameliorate cerebral ischemia risk 3

Cancer Patients with Paraneoplastic SIADH

Treatment of the underlying malignancy is crucial alongside hyponatremia management, as successful cancer treatment often resolves the paraneoplastic syndrome. 1

• SCLC causes SIADH in 1-5% of patients 1
• Hyponatremia usually improves after successful treatment of underlying malignancy 1

Medication-Induced SIADH

Discontinue offending medications immediately - common culprits include SSRIs, carbamazepine, chlorpropamide, cyclophosphamide, vincristine, cisplatin, NSAIDs, and opioids 1, 7

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Critical Safety Considerations

Preventing Osmotic Demyelination Syndrome

The single most important safety rule: Never exceed 8 mmol/L sodium correction in 24 hours. 1, 3, 5, 6

• Standard correction rate: 4-8 mmol/L per day, not exceeding 10-12 mmol/L in 24 hours 3
• High-risk patients: 4-6 mmol/L per day maximum, not exceeding 8 mmol/L in 24 hours 1, 3
• If overcorrection occurs: Immediately discontinue current fluids, switch to D5W, consider desmopressin 3
• ODS symptoms (dysarthria, dysphagia, quadriparesis) typically occur 2-7 days after rapid correction 1, 3, 5

Monitoring Requirements

• Severe symptoms: Check sodium every 2 hours initially 1, 3
• Mild symptoms: Check sodium every 4 hours after symptom resolution 3
• Chronic management: Daily sodium checks until stable 3

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Common Pitfalls to Avoid

• Using fluid restriction in cerebral salt wasting - this is SIADH treatment and worsens CSW outcomes 1, 3
• Inadequate monitoring during active correction - leads to overcorrection and ODS risk 1, 3
• Failing to identify and treat underlying cause - SIADH is a syndrome, not a diagnosis 1, 3
• Ignoring mild hyponatremia (130-135 mmol/L) - associated with falls, mortality, and neurocognitive problems 3
• Using hypotonic fluids - worsens hyponatremia by providing free water that cannot be excreted 1