What are the causes of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)?

Causes of SIADH

SIADH has three major non-pharmacological etiologic categories—malignancies, central nervous system disorders, and pulmonary diseases—plus a critical fourth category of drug-induced causes that must always be considered. 1

Malignant Causes

• Small cell lung cancer is the most common malignant cause of SIADH, occurring in approximately 15% of small cell lung cancer patients, making it the single most important malignancy to consider. 1
• Non-small cell lung cancer causes SIADH in only 0.7% of cases, representing a much lower risk than small cell histology. 2
• Head and neck cancers cause SIADH in 3% of patients (47 cases out of 1,696 patients in larger series). 2, 3
• A broad spectrum of other malignancies has been reported including primary brain tumors, hematologic malignancies, intrathoracic non-pulmonary cancers, gastrointestinal cancers, gynecological cancers, breast and prostatic cancer, and sarcomas, though these are documented primarily in case reports. 2

Central Nervous System Disorders

• CNS pathology represents a major category through disruption of hypothalamic-pituitary function, including subarachnoid hemorrhage as a particularly important cause. 1
• CNS infections and space-occupying lesions, including abscesses, cause SIADH through disruption of normal hypothalamic-pituitary function and ADH regulation. 4
• Various disorders involving the central nervous system can trigger inappropriate ADH secretion. 5

Critical Pitfall to Avoid

• In neurosurgical patients, you must distinguish SIADH from cerebral salt wasting (CSW), as they require opposite treatments—SIADH requires fluid restriction while CSW requires volume repletion. 1, 4

Pulmonary Disorders

• Intrathoracic non-malignant conditions cause SIADH through nonosmotic stimulation of AVP release. 1
• Pneumonia and other pulmonary infections are well-established causes of SIADH. 1
• Positive pressure ventilation can trigger SIADH. 2

Drug-Induced SIADH

This is an extremely important and often preventable category:

Chemotherapeutic Agents

• Cisplatin, vinca alkaloids (vincristine, vinblastine), cyclophosphamide, and melphalan are established causes. 6, 2, 7

Psychotropic Medications

• SSRIs and SNRIs are major culprits, particularly in older adults, through stimulation of inappropriate ADH release despite low serum osmolality. 6
• Carbamazepine and oxcarbazepine have moderate to high level evidence for causing SIADH. 6
• Certain antipsychotics are associated with SIADH risk. 6
• Tramadol was added to the list of SIADH-inducing drugs in the 2019 AGS Beers Criteria update. 6

Other Medications

• NSAIDs and opioids can induce SIADH. 6
• Chlorpropamide is a recognized cause. 6, 7
• Thiazide diuretics are a major cause of hyponatremia in older adults and should be avoided in patients with a history of diuretic-associated hyponatremia. 6
• Loop diuretics (furosemide, bumetanide, torsemide) can cause hyponatremia, though the incidence is lower than with thiazides. 6

High-Risk Drug Combinations

• The combination of thiazide diuretics with SSRIs or other SIADH-inducing medications substantially increases risk. 6
• Concurrent use of multiple CNS agents (antidepressants, antipsychotics, benzodiazepines, antiepileptics, opioids) compounds SIADH risk. 6

Post-Operative and Iatrogenic Causes

• Hospital-acquired hyponatremia from hypotonic IV fluids affects 15-30% of hospitalized patients and is entirely preventable by using isotonic maintenance fluids. 1
• Surgery itself can trigger SIADH. 5

Conditions with Decreased Left Atrial Pressure

• Conditions that decrease left atrial pressure can trigger nonosmotic ADH release. 2

Clinical Context for Reversibility

• For cancer patients with SIADH, treating the underlying malignancy is the optimal therapy, as hyponatremia usually improves after successful treatment of the underlying cause. 1, 2
• Hyponatremia typically develops within 2 weeks after starting thiazide therapy but can occur at any time during treatment. 6
• Drug-induced SIADH requires immediate discontinuation of the offending medication if symptomatic hyponatremia is present. 6