Paraneoplastic SIADH

Paraneoplastic syndrome of inappropriate antidiuretic hormone secretion (SIADH) is hyponatraemia caused by ectopic or excessive secretion of arginine vasopressin (antidiuretic hormone) from a tumour, or tumour related stimulation of its release, with euvolaemia and inappropriately concentrated urine. It is the commonest paraneoplastic endocrine syndrome and ranges from an incidental finding to a life threatening neurological emergency.

Hyponatraemia is present in 15% to 30% of patients with cancer, and SIADH accounts for most of it. It occurs in 10% to 15% of patients with small cell lung cancer. Other causes are other lung cancers, head and neck cancer, pancreatic and duodenal cancer, thymoma, lymphoma, and brain tumours or metastases. Drugs (vincristine, vinblastine, cyclophosphamide, cisplatin, vinorelbine, melphalan, opioids, carbamazepine and antidepressants) are frequent contributors.

Pathophysiology. Vasopressin from the tumour acts on renal V2 receptors, increasing water reabsorption in the collecting duct, which expands body water and dilutes serum sodium. Natriuresis from volume expansion maintains euvolaemia. The risk is cerebral oedema in acute hyponatraemia (under 48 hours), and osmotic demyelination if chronic hyponatraemia is corrected too quickly.

Prognosis. Hyponatraemia is an independent marker of poor outcome in cancer. It resolves in most patients when the tumour responds to treatment, and recurs with relapse.

• Mild to moderate (sodium 125 to 134 mmol/L): often asymptomatic, or with nausea, headache, fatigue, confusion, unsteady gait, falls and cognitive slowing.
• Severe (sodium under 125 mmol/L, or any level with a fast fall): vomiting, drowsiness, seizures, coma, respiratory arrest.
• No oedema, dehydration or hypotension (euvolaemia).

Red flags.

• Seizure, coma or vomiting with confusion.
• Sodium under 120 mmol/L, or a fall of over 10 mmol/L in 24 hours.

• Serum sodium with osmolality (under 275 mOsm/kg), urine osmolality (over 100 mOsm/kg, usually over 300), and urine sodium (over 30 mmol/L on a normal salt intake).
• Euvolaemia on examination and exclusion of other causes: normal thyroid function, morning cortisol (adrenal insufficiency), normal renal function, and no diuretic, hypovolaemia, heart failure or cirrhosis.
• Confirm true hyponatraemia (exclude hyperglycaemia and pseudohyponatraemia), review drugs, and check uric acid (low, under 240 micromol/L) and urea (low).
• Search for the cause: CT of the chest, abdomen and pelvis, brain imaging, and tissue diagnosis of the tumour.

Differential diagnosis.

• Adrenal insufficiency, hypothyroidism, and cerebral salt wasting
• Diuretic induced hyponatraemia and hypovolaemic hyponatraemia (vomiting, diarrhoea)
• Heart failure, cirrhosis and nephrotic syndrome
• Polydipsia, beer potomania and drug induced SIADH

Management depends on symptoms, speed of onset and the underlying cause. Correct no faster than 8 mmol/L in 24 hours (6 mmol/L in patients at high risk of osmotic demyelination).

Severe symptoms (seizure, coma, vomiting with confusion).

• Hypertonic saline:
  • Hypertonic sodium chloride 3% 150 mL IV over 20 minutes for severe symptoms (seizure, coma, vomiting with confusion), repeated once or twice if symptoms persist, aiming for a rise in sodium of 5 mmol/L in the first hour.
  • Maximum rise 10 mmol/L in the first 24 hours and 8 mmol/L in each following 24 hours.
  • Monitoring: sodium every 2 hours initially and then every 4 to 6 hours, urine output, neurological state.
  • Adjustment: stop once symptoms improve or the 5 mmol/L target is reached.
  • Treat overcorrection by lowering the sodium again with desmopressin and 5% dextrose under specialist supervision.
  • Use caution in alcoholism, malnutrition, hypokalaemia and liver disease (osmotic demyelination).
  • Avoid in heart failure.

Mild to moderate symptoms or chronic asymptomatic hyponatraemia.

• Treat the tumour and stop or change causative drugs (for example, switch from vinca alkaloids when possible).
• Fluid restriction to 500 to 1000 mL daily (to less than urine output plus insensible loss), effective when urine osmolality is under 500 mOsm/kg and the urine-to-serum electrolyte ratio is under 0.5.
• Urea:
  • Urea 15 g orally once daily, increased to 30 g once daily after 3 to 5 days if the sodium remains low.
  • Maximum 60 g daily.
  • Monitoring: sodium, urea and creatinine every 2 to 3 days at first, hydration status, nausea.
  • Adjustment: dissolve in orange juice or other flavouring to mask the taste.
  • Reduce in renal impairment and avoid in severe hepatic impairment.
  • Stop if sodium correction is too fast.
• Vasopressin receptor antagonist when restriction fails and hyponatraemia is symptomatic or persistent:
  • Tolvaptan 15 mg orally once daily, increased at intervals of at least 24 hours to 30 mg and then 60 mg daily in response to the sodium.
  • Maximum 60 mg daily.
  • Monitoring: sodium every 6 hours for the first 24 to 48 hours (start in hospital), liver tests, thirst and urine output.
  • Adjustment: do not restrict fluid in the first 24 hours.
  • Avoid strong CYP3A4 inhibitors.
  • Stop if sodium rises by over 12 mmol/L in 24 hours.
  • Limit use to 30 days because of the risk of liver injury.
  • Avoid in hypovolaemia and anuria.

Cancer treatment. Chemotherapy for small cell lung cancer usually normalises sodium within 1 to 3 weeks, and radiotherapy or surgery is used for other tumours.

Monitoring. Sodium every 2 to 4 hours when treating severe symptoms, every 6 to 12 hours when on tolvaptan, and daily to weekly once stable. Watch for overcorrection (aquaresis, rapid sodium rise), and for delayed neurological signs of osmotic demyelination 2 to 6 days after correction.

Referral and escalation.

• Emergency admission for sodium under 125 mmol/L with symptoms or a sodium under 120 mmol/L.
• Endocrine review for persistent hyponatraemia, and intensive care for seizures or coma.

Special groups.

• Older adults: slower correction, review of thiazides, antidepressants and antipsychotics.
• Liver disease or malnutrition: higher risk of osmotic demyelination, correct more slowly.
• Chemotherapy with cisplatin: avoid hypotonic IV fluids during hydration and monitor sodium.