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

From the Guidelines

Hyponatremia treatment should prioritize correcting serum sodium levels at a rate of 4-6 mEq/L per 24-hour period, not to exceed 8 mEq/L per 24-hour period, to minimize the risk of osmotic demyelination syndrome, as recommended by the American Association for the Study of Liver Diseases in 2021 1. The causes of hyponatremia can be attributed to an imbalance of water and sodium in the body, often resulting from excess water retention or sodium loss, which disrupts cellular osmotic pressure and can lead to neurological symptoms if severe or rapidly developing.

Treatment Approaches

• For mild cases (sodium 130-134 mEq/L), fluid restriction to 1-1.5 liters daily is often sufficient, with monitoring and water restriction being the primary management strategy for mild hyponatremia in cirrhosis without symptoms 1.
• For moderate to severe symptomatic hyponatremia, 3% hypertonic saline may be administered intravenously at 1-2 mL/kg/hr, with the goal of increasing sodium by 4-6 mEq/L in the first 24 hours to prevent cerebral edema, while avoiding correction faster than 8-10 mEq/L/day to prevent osmotic demyelination syndrome, as guided by both 1 and 1.
• Vasopressin receptor antagonists like tolvaptan (starting at 15 mg daily) may be used for SIADH-induced hyponatremia, but their use should be cautious and limited to a short term (≤30 days) 1.
• Patients with hypovolemic hyponatremia require isotonic fluid replacement with normal saline, while loop diuretics like furosemide (20-40 mg IV or oral) may help in hypervolemic states.

Monitoring and Correction

Ongoing monitoring of serum sodium every 4-6 hours during correction is essential to ensure that the correction rate does not exceed safe limits, thereby minimizing the risk of complications such as osmotic demyelination syndrome. The use of hypertonic saline is reserved for short-term treatment of patients with symptomatic or severe hyponatremia or those with imminent liver transplant, emphasizing the need for careful patient selection and monitoring 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

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

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 to reverse hyponatremic encephalopathy 3, 5
• 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
• Urea can be used to correct hyponatremia and has been shown to minimize brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline 6

Considerations for Treatment

• The ideal magnitude of correction is also controversial, as both inadequate therapy and overly aggressive therapy can result in neurologic injury 5
• Overly rapid correction of chronic hyponatremia may cause osmotic demyelination, a rare but severe neurological condition, which can result in parkinsonism, quadriparesis, or even death 3, 7
• The therapeutic strategy that should guide optimal treatment of hyponatremia requires attention to the patient's volume status, the presence or absence of symptoms, duration of hypo-osmolality, and the presence or absence of risk factors for the development of neurologic complication 4