What is the treatment for Syndrome of Inappropriate Antidiuretic Hormone (SIADH)?

Treatment of SIADH

For mild to moderate SIADH, fluid restriction to 1 L/day is the cornerstone of treatment, while severe symptomatic cases require immediate 3% hypertonic saline with a target correction of 6 mmol/L over 6 hours, never exceeding 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome. 1, 2, 3

Diagnostic Confirmation Before Treatment

Before initiating treatment, confirm SIADH diagnosis with the following criteria 2, 3:

• Hyponatremia with serum sodium <135 mmol/L (treatment typically warranted when <131 mmol/L) 1
• Hypoosmolality with plasma osmolality <275 mOsm/kg 2, 3
• Inappropriately concentrated urine with osmolality >500 mOsm/kg 2, 3
• Elevated urine sodium >20-40 mEq/L despite hyponatremia 2, 3
• Euvolemic state on physical examination (no edema, no orthostatic hypotension, normal skin turgor, moist mucous membranes) 1
• Normal thyroid and adrenal function (normal TSH, cortisol) 1

Critical pitfall: Distinguish SIADH from cerebral salt wasting (CSW), particularly in neurosurgical patients, as they require opposite treatments—SIADH needs fluid restriction while CSW requires volume and sodium replacement 1, 2, 3

Treatment Algorithm Based on Symptom Severity

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

Immediate management 1, 2, 3:

• Transfer to ICU for continuous monitoring 2
• Administer 3% hypertonic saline immediately 1, 2, 3
• Target correction: 6 mmol/L over first 6 hours or until severe symptoms resolve 1, 2, 3
• Maximum correction: Never exceed 8 mmol/L in 24 hours 1, 2, 3, 4
• Monitor serum sodium every 2 hours during initial correction phase 1, 2

High-risk patients (malnutrition, alcoholism, advanced liver disease) require even slower correction at 4-6 mmol/L per day 1, 2, 3, 4

Mild to Moderate Symptomatic or Asymptomatic SIADH

First-line treatment: Fluid restriction 1, 2, 3:

• Restrict fluids to 1 L/day (or 1000-1500 mL/day) 1, 2, 3
• This achieves correction rate averaging 1.0 mEq/L/day 3
• Monitor serum sodium every 4 hours initially, then daily 2
• Patients can continue fluid intake in response to thirst during first 24 hours 4
• Avoid overly strict fluid restriction during first 24 hours to prevent too rapid correction 4

If fluid restriction fails after 24-48 hours, add oral sodium supplementation 1:

• Sodium chloride 100 mEq orally three times daily 1

Second-Line Pharmacological Options

When fluid restriction is ineffective or poorly tolerated 1, 2, 3:

Vasopressin Receptor Antagonists (Vaptans)

Tolvaptan is FDA-approved for clinically significant euvolemic/hypervolemic hyponatremia 4:

• Starting dose: 15 mg once daily without regard to meals 4
• Titration: Increase to 30 mg after at least 24 hours, maximum 60 mg daily as needed 4
• Duration: Do not exceed 30 days to minimize hepatotoxicity risk 4
• Monitoring: Check serum sodium at 0,6,24, and 48 hours after initiation 5
• Efficacy: Increases serum sodium by 3.0 mEq/L/day on average 2

Critical safety considerations for tolvaptan 4:

• Must initiate and re-initiate in hospital setting with close sodium monitoring 4
• Avoid fluid restriction during first 24 hours of therapy 4
• Side effects include thirst, polydipsia, and urinary frequency 5
• Contraindicated with strong CYP3A inhibitors 4

Alternative Pharmacological Agents

Urea (0.25-0.50 g/kg/day) 3:

• Highly effective for chronic SIADH management 3
• Induces osmotic water drive 3
• Well-tolerated long-term, though distaste is common (54% of patients) 3
• Particularly useful when urine osmolality <400 mOsm/kgH2O at baseline 6

Demeclocycline 1, 2, 3:

• Induces nephrogenic diabetes insipidus, reducing kidney's response to ADH 2, 3
• Second-line option when fluid restriction ineffective 1, 2
• Long history of use in persistent SIADH 3

Loop diuretics, lithium are less commonly used with limited supporting data 1, 7

Correction Rate Guidelines and Osmotic Demyelination Prevention

Absolute maximum correction rates 1, 2, 3, 4:

• Standard patients: Maximum 8 mmol/L in 24 hours 1, 2, 3
• High-risk patients (advanced liver disease, alcoholism, malnutrition, severe hyponatremia): Maximum 4-6 mmol/L per day 1, 2, 3, 4
• FDA warning: Correction >12 mEq/L/24 hours can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, seizures, coma, and death 4

If overcorrection occurs 1:

• Immediately discontinue current fluids and switch to D5W 1
• Consider administering desmopressin to slow or reverse rapid rise 1

Special Populations and Considerations

Neurosurgical Patients

Avoid fluid restriction in subarachnoid hemorrhage patients at risk for vasospasm 1, 2, 3:

• Fluid restriction worsens outcomes in this population 1, 2
• Consider fludrocortisone or hydrocortisone instead 1, 2, 3

Cancer Patients with Paraneoplastic SIADH

Treatment of underlying malignancy is essential 2:

• SIADH affects 1-5% of lung cancer patients, particularly small cell lung cancer 1
• Hyponatremia usually improves after successful cancer treatment 2
• Continue symptomatic management while treating malignancy 2

Drug-Induced SIADH

Discontinue offending medications immediately 2:

• Common culprits: SSRIs, carbamazepine, chlorpropamide, cyclophosphamide, vincristine 2, 7
• Implement fluid restriction while medication is cleared 2

Monitoring During Treatment

Acute phase monitoring 1, 2:

• Severe symptoms: Check serum sodium every 2 hours 1, 2
• Mild symptoms: Check every 4 hours initially, then daily 2
• Monitor for signs of osmotic demyelination syndrome (dysarthria, dysphagia, oculomotor dysfunction, quadriparesis) typically occurring 2-7 days after rapid correction 1

Chronic management monitoring 1:

• Check sodium every 24-48 hours initially 1
• Adjust frequency based on response and stability 1

Treatment Discontinuation and Follow-up

Upon discontinuation of therapy 4:

• Resume fluid restriction 4
• Monitor for hyponatremic relapse 5
• May need to taper vaptan dose or restrict fluid intake 5
• Reevaluate 7 days after stopping treatment 4

Common Pitfalls to Avoid

• Never use fluid restriction in cerebral salt wasting—this worsens outcomes 1, 2, 3
• Never correct chronic hyponatremia faster than 8 mmol/L in 24 hours—this causes osmotic demyelination syndrome 1, 2, 3
• Never ignore mild hyponatremia (130-135 mmol/L)—it increases fall risk and mortality 1
• Inadequate monitoring during active correction leads to overcorrection complications 1, 2
• Failing to identify and treat underlying cause results in treatment failure 1, 2
• Using tolvaptan beyond 30 days increases hepatotoxicity risk 4