Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published October 18, 2023


What therapies are used for the outpatient management of the syndrome of inappropriate antidiuresis?

Hyponatremia (serum sodium level, <135 mmol per liter) is the most common electrolyte abnormality and affects 35% of hospitalized patients. Read the NEJM Clinical Practice Article here.

Clinical Pearls

Q: What is “inappropriate” about the antidiuresis in the syndrome of inappropriate antidiuresis (SIAD)?

A: The serum sodium level approximates the ratio of osmotically active sodium and potassium content to total body water. Hyponatremia typically reflects water excess relative to these body cations, most commonly resulting from disorders impairing electrolyte-free water excretion by the kidneys (aquaresis). Impaired aquaresis largely depends on increased secretion of arginine vasopressin (AVP), the antidiuretic hormone, which activates the vasopressin 2 receptor in the collecting duct of the nephron, thus promoting water retention. In hyponatremia that is associated with hypovolemia and certain hypervolemic disorders (e.g., heart failure), water retention is driven by AVP release caused by reduced effective arterial blood volume. In contrast, in SIAD, a euvolemic disorder, AVP secretion occurs in the absence of osmotic and hemodynamic stimuli (and the antidiuresis is therefore deemed “inappropriate”).

Q: What are some of the conditions associated with SIAD?

A: The causes of SIAD are numerous. Major categories (and their relative frequencies) associated with SIAD included in the Hyponatremia Registry are cancer (24%), certain drugs (18%), pulmonary conditions (11%), and CNS disorders (9%). Additional causes are exercise, pain, stress, severe nausea, postoperative state, and, rarely, gain-of-function variants of the gene encoding the vasopressin 2 receptor (in nephrogenic SIAD). More than one cause is frequently present. Antidepressants are the most commonly implicated drugs, especially in underweight older women. No cause is identified in 17 to 60% of patients with SIAD, depending on the extent of the evaluation and patient age.

Morning Report Questions

Q: How is SIAD diagnosed?

A: The diagnosis of SIAD requires clinical confirmation of euvolemic hypotonic hyponatremia. Given the low sensitivity and specificity of a physical examination in assessing volume status, European guidelines prioritize measurement of urine osmolality and sodium. Urine studies showing natriuresis (sodium, >30 mmol per liter) and inappropriate concentration (osmolality, >100 mOsm per kilogram of water) are consistent with SIAD. However, diagnosing SIAD requires ruling out secondary adrenal insufficiency and severe hypothyroidism. In practice, requisite serum and urine tests for diagnosis are often omitted; the Hyponatremia Registry showed that those tests were completed in only 21% of patients in whom SIAD was diagnosed.

Q: What therapies are used for the outpatient management of SIAD?

A: Fewer than 5% of patients with hyponatremia have sufficiently severe symptoms to need emergency treatment. For the majority of patients, treatment focuses on addressing the underlying cause (or causes) and is typically administered on an outpatient basis; exceptions include treatment of patients who are hospitalized for management of an underlying cause of hyponatremia or whose serum sodium level is less than 120 mmol per liter. Several therapies are available for outpatient treatment of patients with SIAD. Fluid restriction, the first-line treatment, is inexpensive and safe but of limited efficacy. Other therapies involve increasing salt, urea, or protein intake, although data are lacking from randomized, blinded trials. Tolvaptan, which competitively inhibits the vasopressin 2 receptor in the collecting duct, is a highly effective therapeutic agent. More recent data support a potential role for empagliflozin, a sodium glucose cotransporter 2 inhibitor that promotes osmotic diuresis by means of glucosuria in the treatment of patients with SIAD.

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