What are the causes and treatments of hyponatremia (low sodium levels)?

From the Guidelines

Hyponatremia treatment should prioritize careful sodium correction, with a goal of increasing serum sodium by 4-6 mEq/L in the first 24 hours, not to exceed 8 mEq/L per 24-hour period, to prevent osmotic demyelination syndrome, as recommended by the American Association for the Study of Liver Diseases in 2021 1. The causes of hyponatremia can be diverse, including cirrhosis, heart failure, adrenal insufficiency, and certain medications. Treatment depends on the severity, symptoms, and underlying cause of the condition.

Treatment Approaches

• For mild asymptomatic hyponatremia, fluid restriction to 800-1000 mL/day is often sufficient, as stated in the guidance by the American Association for the Study of Liver Diseases in 2021 1.
• In cases of moderate to severe symptomatic hyponatremia, especially with neurological symptoms, 3% hypertonic saline may be administered intravenously, with the goal of increasing serum sodium by 4-6 mEq/L in the first 24 hours, as recommended by the guidelines on the management of ascites in cirrhosis in 2021 1.
• Vasopressin receptor antagonists like tolvaptan may be used for SIADH-related hyponatremia, but their use should be cautious and limited to a short term (≤30 days), as advised by the American Association for the Study of Liver Diseases in 2021 1.

Key Considerations

• Underlying causes such as medications, heart failure, or adrenal insufficiency must be addressed simultaneously with hyponatremia treatment.
• Regular monitoring of serum sodium levels (every 2-4 hours initially in severe cases) is essential to guide therapy, as rapid correction can cause permanent neurological damage, while inadequate treatment of severe hyponatremia can lead to seizures, coma, or death.
• The use of hypertonic saline is reserved for short-term treatment of patients with symptomatic or severe hyponatremia or those with imminent liver transplant, as recommended by the American Association for the Study of Liver Diseases in 2021 1.

From the FDA Drug Label

In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone [SIADH] and others) were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal.

The causes of hyponatremia mentioned in the study include:

• Heart failure
• Liver cirrhosis
• Syndrome of inappropriate antidiuretic hormone (SIADH)
• Other underlying causes

The treatment of hyponatremia mentioned in the study is:

• Tolvaptan, a medication that can be taken orally at an initial dose of 15 mg once daily, with possible increases to 30 mg once daily and then to 60 mg once daily
• Fluid restriction, which may be avoided if possible during the first 24 hours of therapy to avoid overly rapid correction of serum sodium 2

From the Research

Causes of Hyponatremia

• Hyponatremia is defined by a serum sodium level of less than 135 mEq/L and most commonly results from water retention 3
• It can occur through any mechanism that produces a relative excess of body water to body sodium 4
• The condition primarily results from the combination of impaired free water excretion due to elevated vasopressin levels in conjunction with a source of free water intake 5
• Increased vasopressin secretion due to nonosmotic stimuli leads to decreased electrolyte-free water excretion with resulting water retention and hyponatremia 6

Symptoms of Hyponatremia

• Symptoms and signs of hyponatremia range from mild and nonspecific (such as weakness or nausea) to severe and life-threatening (such as seizures or coma) 3
• Symptom severity depends on the rapidity of development, duration, and severity of hyponatremia 3
• Mild chronic hyponatremia is associated with cognitive impairment, gait disturbances, and increased rates of falls and fractures 3
• Hyponatremic encephalopathy is the most serious complication of hyponatremia, and can result in permanent neurologic impairment or death if left untreated 5

Treatments of Hyponatremia

• For most patients, the approach to managing hyponatremia should consist of treating the underlying cause 3
• Urea and vaptans can be effective treatments for the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure, but have adverse effects 3
• Severely symptomatic hyponatremia (with signs of somnolence, obtundation, coma, seizures, or cardiorespiratory distress) is a medical emergency and should be treated with bolus hypertonic saline 3, 5, 7
• The preferred therapy for hyponatremic encephalopathy is a 100-ml bolus of 3 % sodium chloride (513 mEq/L) administered in repeated doses until symptoms reverse, with the goal of increasing the serum sodium 5-6 mEq/L 5
• Vasopressin receptor antagonists, urea, and loop diuretics can be used to increase renal free water excretion, but received different recommendations in different guidelines 7

Diagnosis of Hyponatremia

• The initial step in diagnosing hyponatremia is to differentiate hypotonic from nonhypotonic hyponatremia 7
• Hypotonic hyponatremia is further differentiated on the basis of urine osmolality, urine sodium level, and volume status 7
• Recently identified parameters, including fractional uric acid excretion and plasma copeptin concentration, may further improve the diagnostic approach 7
• Clinicians should categorize patients according to their fluid volume status (hypovolemic hyponatremia, euvolemic hyponatremia, or hypervolemic hyponatremia) 3