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

From the Guidelines

Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) should primarily focus on addressing the underlying cause while managing hyponatremia, with the most recent and highest quality study suggesting the use of vasopressin receptor antagonists like tolvaptan as an effective option for increasing free water excretion 1. For mild to moderate SIADH, fluid restriction to 800-1000 mL/day is the first-line approach. In more severe cases or when fluid restriction is ineffective, pharmacological options include:

• Oral salt tablets (1-2 g three times daily)
• Urea (15-60 g/day divided into 2-3 doses)
• Vasopressin receptor antagonists like tolvaptan (starting at 15 mg once daily, titrated up to 60 mg if needed) Loop diuretics such as furosemide (20-40 mg daily) may be used in conjunction with salt supplementation. For acute, severe hyponatremia with neurological symptoms, 3% hypertonic saline (100-150 mL over 10-20 minutes, repeatable) may be necessary, aiming for a sodium correction rate not exceeding 8-10 mEq/L in 24 hours to prevent osmotic demyelination syndrome 1. Throughout treatment, frequent monitoring of serum sodium levels, fluid status, and neurological signs is essential, as highlighted in the study published in the Journal of Hepatology in 2018 1. The treatment approach works by either restricting water intake, increasing solute load, or directly antagonizing ADH effects at the kidney, all aimed at normalizing serum sodium concentration, which is crucial for preventing complications such as seizures, coma, and death, as noted in the study published in Chest in 2013 1. It is also important to consider the pathophysiology of hypervolemic hyponatremia and the role of vaptans in encouraging the excretion of solute-free water, as discussed in the study published in Clinical and Molecular Hepatology in 2018 1.

From the FDA Drug Label

Tolvaptan tablets are indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Tolvaptan is used to treat SIADH. The usual starting dose for tolvaptan tablets is 15 mg administered once daily without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium.

• Key points:
  • Initiate and re-initiate in a hospital and monitor serum sodium.
  • Avoid too rapid correction of hyponatremia.
  • Do not administer tolvaptan tablets for more than 30 days to minimize the risk of liver injury.
  • During initiation and titration, frequently monitor for changes in serum electrolytes and volume.
  • Patients receiving tolvaptan tablets should be advised that they can continue ingestion of fluid in response to thirst. 2

From the Research

Treatment Options for SIADH

• Fluid restriction is a commonly used treatment for SIADH, as it helps to increase serum sodium levels 3, 4, 5.
• Hypertonic saline can also be used to treat SIADH, especially in cases where fluid restriction is not effective 3.
• Vasopressin receptor antagonists, such as vaptans, have been introduced as a specific and direct therapy for SIADH 3, 6, 7.
• Demeclocycline is sometimes used to treat SIADH, but its efficacy is based solely on laboratory endpoints and it has adverse effects shared by all tetracyclines 7.
• Urea can also be used as a therapeutic modality for SIADH 3.

Efficacy and Safety of Treatment Options

• The efficacy of fluid restriction in treating SIADH has been demonstrated in a prospective randomized controlled trial, which showed a modest early rise in plasma sodium concentration 4.
• Vaptans have been shown to be effective in correcting hyponatremia in patients with SIADH, but their use is limited by dose-dependent side effects and high cost 3, 6, 7.
• The use of tolvaptan, a vasopressin V2 receptor antagonist, has been reported to be effective in treating SIADH, but its efficacy and safety profile are not well established 6, 7.
• Intermittent lower dose of tolvaptan combined with fluid restriction may be an effective choice for patients with chronic SIADH 6.

Management of SIADH

• The treatment of SIADH should aim to cure symptoms, and the choice of treatment should be individualized based on the patient's condition 3.
• It is important to limit the daily increase of serum sodium to less than 8-10 mmol/liter to prevent osmotic demyelination 3.
• The serum sodium level should be monitored closely during treatment, especially in the first 24 hours of vaptan therapy 3.
• Discontinuation of vaptan therapy should be monitored to prevent hyponatremic relapse, and it may be necessary to taper the vaptan dose or restrict fluid intake or both 3.