What are the causes and treatment options for hypervolemic hyponatremia (low sodium levels in the blood with excess fluid volume)?

From the Guidelines

Hypervolemic hyponatremia should be managed with fluid restriction to 1–1.5 L/day in patients who are clinically hypervolaemic with severe hyponatraemia (serum sodium <125 mmol/day). The management of hypervolemic hyponatremia involves addressing the underlying cause while carefully managing fluid and sodium balance.

• The primary approach involves fluid restriction, along with sodium restriction.
• Diuretic therapy is often necessary, with loop diuretics like furosemide being the preferred option, as seen in the management of ascites in cirrhosis 1.
• In severe cases, 3% hypertonic saline may be administered intravenously with close monitoring to avoid rapid correction.
• The underlying condition causing fluid retention—typically heart failure, cirrhosis, or kidney disease—must be treated simultaneously, as guided by the 2013 ACCF/AHA guideline for the management of heart failure 1.
• Careful monitoring of serum sodium levels is essential, as correction should not exceed 8 mEq/L in 24 hours to prevent osmotic demyelination syndrome.
• It is also crucial to monitor patients initiating diuretics for adverse events, as almost half of those with adverse events require diuretic discontinuation or dose reduction 1.

In terms of specific treatment,

• fluid restriction to 1–1.5 L/day should be reserved for those who are clinically hypervolaemic with severe hyponatraemia (serum sodium <125 mmol/day) 1.
• Hypertonic sodium chloride (3%) administration should be reserved for those who are severely symptomatic with acute hyponatraemia, with slow correction of serum sodium 1. This approach works by gradually removing excess fluid while maintaining appropriate sodium levels, allowing the body to restore proper osmotic balance.

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 primary endpoint for these studies was the average daily AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium less than 135 mEq/L. Compared to placebo, tolvaptan caused a statistically greater increase in serum sodium ( p <0. 0001) during both periods in both studies

Tolvaptan is effective in treating hypervolemic hyponatremia.

• The studies showed a statistically significant increase in serum sodium levels in patients with hypervolemic hyponatremia treated with tolvaptan compared to placebo.
• The effect of tolvaptan was seen across all disease etiology subsets, including heart failure, liver cirrhosis, and SIADH.
• Tolvaptan reduced the need for fluid restriction in patients with hypervolemic hyponatremia 2.

From the Research

Definition and Classification 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 be classified into three types based on fluid volume status: hypovolemic hyponatremia, euvolemic hyponatremia, and hypervolemic hyponatremia 3, 4.

Hypervolemic Hyponatremia

• Hypervolemic hyponatremia is the most common type of hyponatremia in patients with advanced cirrhosis and develops as a consequence of an impairment in the renal capacity to eliminate solute-free water 5.
• It is associated with increased morbidity and mortality in patients with cirrhosis, and it has also been associated with increased complications after liver transplantation 5.
• The key mechanism leading to solute-free water retention is a non-osmotic hypersecretion of vasopressin (AVP), secondary to a reduction in effective arterial blood pressure existing in patients with advanced cirrhosis 5.

Treatment of Hypervolemic Hyponatremia

• The management of hypervolemic hyponatremia in cirrhosis is based on fluid restriction 5.
• Vaptans, oral selective vasopressin V2-receptor antagonists, and particularly tolvaptan, have been investigated as a pharmacological approach for the management of hypervolemic hyponatremia in cirrhosis 6, 5.
• Tolvaptan is effective for the correction of hyponatremia but has not been associated with significant improvements in mortality in patients with heart failure compared with placebo 6.
• Hypervolemic hyponatremia responds well to fluid restriction and diuretics 4.
• Arginine vasopressin receptor antagonists provide a new treatment option for patients with disorders of water metabolism, including hypervolemic hyponatremia 7.