What causes and how is isotonic euvolemic hyponatremia, specifically due to Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion, managed?

From the Guidelines

Isotonic euvolemic hyponatremia due to SIADH is primarily caused by the excessive secretion of antidiuretic hormone (ADH), leading to water retention and dilutional hyponatremia, and is managed through fluid restriction, pharmacological interventions, and addressing underlying causes, with vasopressin receptor antagonists such as tolvaptan being a key treatment option, as supported by the most recent and highest quality study 1.

Causes of Isotonic Euvolemic Hyponatremia

The causes of isotonic euvolemic hyponatremia, specifically due to SIADH, include:

• Excessive secretion of ADH, leading to water retention and dilutional hyponatremia
• Malignancy, such as small cell lung cancer (SCLC), which can produce ADH
• CNS disorders, such as stroke or traumatic brain injury, which can disrupt normal ADH regulation
• Pulmonary disease, such as pneumonia or chronic obstructive pulmonary disease (COPD), which can stimulate ADH release
• Medications, such as selective serotonin reuptake inhibitors (SSRIs) or antipsychotics, which can increase ADH secretion

Management of Isotonic Euvolemic Hyponatremia

The management of isotonic euvolemic hyponatremia due to SIADH involves:

• Fluid restriction to create a negative water balance
• Pharmacological interventions, such as:

• Vasopressin receptor antagonists, such as tolvaptan, which can help increase serum sodium levels
• Urea, which can be used as an alternative osmotic agent

• Addressing underlying causes, such as treating malignancy or CNS disorders
• Regular monitoring of serum sodium, urine osmolality, and volume status throughout treatment

Key Treatment Options

• Tolvaptan: a vasopressin receptor antagonist that can help increase serum sodium levels, starting at 15 mg daily and titrating up to 60 mg if needed, as supported by the most recent and highest quality study 1
• Fluid restriction: restricting fluid intake to 800-1000 mL/day to create a negative water balance
• Urea: using urea as an alternative osmotic agent, 30 g daily mixed in water or juice

Important Considerations

• Regular monitoring of serum sodium, urine osmolality, and volume status is essential throughout treatment
• Avoiding rapid correction of serum sodium levels to prevent osmotic demyelination syndrome
• Identifying and treating underlying causes of SIADH, such as malignancy or CNS disorders, as supported by the study 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)

• Causes of isotonic euvolemic hyponatremia include Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion.
• The management of isotonic euvolemic hyponatremia due to SIADH involves the use of tolvaptan, a vasopressin receptor antagonist, which can help increase serum sodium levels.
• Tolvaptan should be initiated and re-initiated in a hospital setting, with close monitoring of serum sodium levels to avoid too rapid correction of hyponatremia, which can cause osmotic demyelination syndrome.
• The usual starting dose of tolvaptan is 15 mg once daily, which can be increased to 30 mg and then 60 mg once daily as needed to achieve the desired level of serum sodium 2.

From the Research

Causes of Isotonic Euvolemic Hyponatremia

• Isotonic euvolemic hyponatremia is frequently encountered in hospitalized patients and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause in most patients 3.
• SIADH is defined by euvolemic hyponatremia due to an inappropriate retention of free water under the effect of antidiuretic hormone 4.
• The etiologies of SIADH are classified into four main groups: tumors, drugs, diseases of the central nervous system, and lung diseases 4.
• Psychotropic medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antipsychotics, carbamazepine, and oxcarbazepine, have a moderate to high level of evidence demonstrating their association with SIADH 5.
• Antipsychotic-induced hyponatremia is a rare but clinically important adverse reaction to treatment with antipsychotic drugs 6.

Diagnosis of SIADH

• Diagnosis of SIADH involves a precise evaluation of volemia and the elimination of differential diagnoses 4.
• Patients should be screened for thiazide use and adrenal or thyroid dysfunction should be ruled out before making a diagnosis of SIADH 3.
• Clinical mimics of SIADH, such as cerebral salt wasting and reset osmostat, should be considered in some patients 3.
• Decreased serum osmolality, inappropriately elevated urine osmolality (>100 mosmol/L), and elevated urine sodium (Na) levels are characteristic of SIADH 3.

Management of SIADH

• Fluid restriction is the recommended first-line treatment for mild or moderate hyponatremia 4.
• Free water restriction combined with increased solute intake (e.g., urea) is the most effective therapy to treat patients with SIADH 3.
• Hypertonic (3%) saline should be used in patients with significant neurologic symptoms, and maximal correction of serum Na level should be limited to <8 mEq over 24 hours to prevent osmotic demyelination syndrome (ODS) 3.
• Simultaneous administration of parenteral desmopressin is one of the best ways to prevent overly rapid Na correction in high-risk patients 3.
• Evaluation for avoidance of medications that cause hyponatremia is particularly important, and substitution with medication that is less likely to cause SIADH should be considered when appropriate 5.