What are the triggers of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion?

Triggers of SIADH

SIADH is triggered by four major categories: malignancies (especially small cell lung cancer), CNS disorders (infections, hemorrhage, trauma), pulmonary diseases, and medications (particularly SSRIs, carbamazepine, chemotherapy agents, and NSAIDs). 1

Malignant Causes

• Small cell lung cancer (SCLC) is the most common malignant trigger, occurring in 15% of SCLC cases, making it far more prevalent than in other cancers 2
• Non-small cell lung cancer causes SIADH in only 0.7% of cases, demonstrating the unique association with SCLC 2
• Head and neck cancers trigger SIADH in 3% of patients 2
• Less common malignant triggers include primary brain tumors, hematologic malignancies, gastrointestinal cancers, gynecological cancers, breast and prostate cancer, and sarcomas 2
• SCLC cells directly produce vasopressin (ADH), causing paraneoplastic SIADH 3

Central Nervous System Disorders

• CNS infections, space-occupying lesions, subarachnoid hemorrhage, and head trauma disrupt hypothalamic-pituitary function and trigger inappropriate ADH release 1
• Meningitis is the most common CNS trigger in pediatric populations 4
• The mechanism involves direct disruption of normal osmoregulation pathways in the hypothalamus 1

Pulmonary Disorders

• Acute respiratory diseases are specifically associated with inappropriate ADH production and water retention 5
• Intrathoracic infections and positive pressure ventilation can trigger SIADH 2
• Any severe pulmonary process requiring oxygen therapy increases SIADH risk, particularly in children with concurrent gastroenteritis 5

Medication-Induced SIADH

High-risk medications include:

• SSRIs and SNRIs - among the most common drug triggers in clinical practice 3
• Carbamazepine and oxcarbazepine - have moderate to high level evidence for causing SIADH 3
• Chemotherapeutic agents: cisplatin, vinca alkaloids (vincristine, vinblastine), cyclophosphamide, and melphalan 3, 2
• NSAIDs and tramadol - tramadol was specifically added to high-risk lists in 2019 3
• Antipsychotics and opioids - particularly when combined with other CNS agents 3
• Chlorpropamide and other older agents 6

Critical Medication Pitfall

• Combining thiazide diuretics with SSRIs or other SIADH-inducing medications substantially increases risk 3
• Concurrent use of multiple CNS agents (antidepressants, antipsychotics, benzodiazepines, antiepileptics, opioids) compounds SIADH risk 3

Postoperative State

• Inappropriate infusion of hypotonic fluids in the postoperative period remains a common iatrogenic cause 7
• The postoperative state itself creates a non-osmotic stimulus for ADH release through pain, nausea, and stress 1

Non-Osmotic Stimuli

• Pain, nausea, and stress override normal osmotic regulation and cause AVP excess even when plasma osmolality is low 1
• These stimuli are particularly relevant in hospitalized patients and explain why SIADH develops despite physiologic signals that should suppress ADH 1

High-Risk Patient Populations

• Elderly patients have increased sensitivity to SIADH triggers due to age-related reduction in glomerular filtration rate 3
• Patients with malnutrition, alcoholism, or advanced liver disease require heightened vigilance 3
• Neurosurgical patients, particularly those with subarachnoid hemorrhage, have elevated risk 3

Mechanism of Trigger Action

All triggers share a common final pathway: persistent or elevated plasma AVP despite hyponatremia and low plasma osmolality, leading to water retention and physiologic natriuresis where fluid balance is maintained at the expense of plasma sodium 3, 1