What are the diagnosis and management strategies for a patient with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)?

Diagnosis and Management of SIADH

Diagnostic Criteria

SIADH is diagnosed when five cardinal criteria are simultaneously met: hypotonic hyponatremia (serum sodium <134 mEq/L), plasma osmolality <275 mosm/kg, inappropriately concentrated urine (osmolality >500 mosm/kg), urinary sodium >20 mEq/L, and clinical euvolemia in the absence of hypothyroidism, adrenal insufficiency, or volume depletion. 1, 2, 3

Essential Laboratory Findings

• Serum sodium <134-135 mEq/L with simultaneous plasma osmolality <275 mosm/kg 3
• Urine osmolality >500 mosm/kg despite low plasma osmolality (inappropriately concentrated urine) 1, 2, 3
• Urine sodium concentration >20 mEq/L, indicating continued natriuresis 1, 2, 3
• Normal thyroid, adrenal, and renal function must be confirmed to exclude other causes 3

Critical Volume Status Assessment

Volume status assessment is paramount—SIADH patients are euvolemic, not hypovolemic or hypervolemic. 3 Look for:

• Absence of orthostatic hypotension or tachycardia (rules out hypovolemia) 3
• No peripheral edema, ascites, or jugular venous distention (rules out hypervolemia) 3
• In neurosurgical patients, use central venous pressure (CVP) when available: SIADH shows CVP 6-10 cm H₂O versus cerebral salt wasting (CSW) with CVP <6 cm H₂O 1, 3
• Serum uric acid <4 mg/dL has 73-100% positive predictive value for SIADH 1

Common Etiologies to Identify

• Malignancy: Small cell lung cancer is the most common malignant cause (1-5% of cases) 3
• CNS disorders: Meningitis, subarachnoid hemorrhage, head trauma, space-occupying lesions 3
• Pulmonary diseases: Pneumonia, other pneumopathies 4
• Medications: SSRIs, carbamazepine, oxcarbazepine, cyclophosphamide, vincristine, cisplatin, NSAIDs, opioids 1, 3

---

Management Algorithm Based on Severity

Severe Symptomatic Hyponatremia (Na <120 mEq/L with neurological symptoms)

For severe symptomatic hyponatremia, transfer to ICU immediately and administer 3% hypertonic saline with a target correction of 6 mmol/L over 6 hours or until severe symptoms resolve. 1, 2

• Monitor serum sodium every 2 hours initially 1
• Severe symptoms include: seizures, coma, altered mental status, respiratory distress 2
• Critical safety rule: Total correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 1, 2, 5
• In high-risk patients (malnutrition, alcoholism, advanced liver disease), use more cautious correction rates of 4-6 mmol/L per day 1

Mild to Moderate Symptomatic or Asymptomatic Hyponatremia (Na 120-130 mEq/L)

Fluid restriction to 1 L/day is the first-line treatment for mild to moderate SIADH. 1, 2

• Avoid fluid restriction during the first 24 hours if using tolvaptan to prevent overly rapid correction 5
• Discontinue offending medications immediately (SSRIs, carbamazepine, NSAIDs, etc.) 1, 2
• Treat underlying cause (malignancy, infection, CNS disorder) as definitive therapy 1, 2

---

Pharmacological Treatment Options

Tolvaptan (Vasopressin Receptor Antagonist)

Tolvaptan is FDA-approved for clinically significant euvolemic hyponatremia (Na <125 mEq/L or symptomatic) and must be initiated in a hospital setting with close sodium monitoring. 5

Dosing regimen:

• Start at 15 mg once daily 5
• Increase to 30 mg after at least 24 hours, then to maximum 60 mg daily as needed 5
• Check serum sodium at 0,6,24, and 48 hours after initiation 1
• Do not use for more than 30 days due to hepatotoxicity risk 5
• Avoid fluid restriction during first 24 hours of tolvaptan therapy; patients can drink to thirst 5

Efficacy data:

• Tolvaptan increases serum sodium by 3.7 mEq/L at Day 4 and 4.6 mEq/L at Day 30 versus placebo 5
• In patients with Na <125 mEq/L, correction was 5.3 mEq/L at Day 4 and 5.7 mEq/L at Day 30 5

Contraindications:

• Anuria, hypovolemic hyponatremia, inability to sense thirst 5
• Concurrent use with strong CYP3A inhibitors (ketoconazole, clarithromycin, ritonavir) 5

Demeclocycline (Second-Line)

Demeclocycline is recommended as second-line treatment for chronic SIADH when fluid restriction is ineffective or poorly tolerated. 1, 2

• Mechanism: Induces nephrogenic diabetes insipidus, reducing kidney's response to ADH 1
• Use in patients who do not respond to fluid restriction 1, 2

Other Options

• Oral salt supplementation can be used as adjunctive therapy 1
• Urea is considered very effective and safe in recent literature 1
• Loop diuretics with hypertonic saline for acute symptomatic cases 6

---

Special Clinical Scenarios

Neurosurgical Patients with Subarachnoid Hemorrhage

In patients with subarachnoid hemorrhage at risk for vasospasm, fluid restriction should be avoided as it worsens outcomes. 1, 2

• Consider fludrocortisone in these specific neurosurgical patients 1
• Hyponatremia in SAH is associated with higher rates of cerebral ischemia and worse 3-month outcomes 1

Cancer-Related SIADH

Treatment of the underlying malignancy is the definitive treatment for paraneoplastic SIADH. 1, 2

• Small cell lung cancer is the most common cause 1, 3
• Hyponatremia usually improves after successful cancer treatment 1
• Chemotherapy agents (cisplatin, vincristine) can worsen hyponatremia 1

---

Critical Pitfalls to Avoid

Osmotic Demyelination Syndrome

Never correct serum sodium faster than 8 mmol/L in 24 hours; overly rapid correction causes osmotic demyelination syndrome with dysarthria, dysphagia, quadriparesis, seizures, coma, and death. 1, 2, 5

• In high-risk patients (alcoholism, malnutrition, advanced liver disease), limit correction to 4-6 mmol/L per day 1, 5
• Monitor sodium every 2 hours during active correction 1

Misdiagnosis: SIADH versus Cerebral Salt Wasting

Confusing SIADH with cerebral salt wasting leads to dangerous treatment errors—SIADH requires fluid restriction while CSW requires volume and sodium replacement. 1, 3

• Use CVP to differentiate: SIADH (CVP 6-10 cm H₂O) versus CSW (CVP <6 cm H₂O) 1, 3
• Physical examination alone has poor accuracy for volume assessment 3

Medication-Induced SIADH

Failing to identify and discontinue offending medications is a common error. 1, 2

• High-risk medications: SSRIs, carbamazepine, oxcarbazepine, NSAIDs, tramadol, thiazide diuretics, cyclophosphamide, vincristine 1, 3
• Combination of thiazide diuretics with SSRIs substantially increases risk 1
• Hyponatremia typically develops within 2 weeks of starting thiazides but can occur anytime 1

Inappropriate Fluid Administration

Discontinue hypotonic fluids (D5W) immediately in SIADH patients, as they worsen hyponatremia by providing free water that cannot be excreted. 1

• Post-operative hypotonic fluid infusion remains a common iatrogenic cause 7