From the Guidelines
Severe hyponatremia in cirrhotic patients should be managed with a combination of fluid restriction, hypertonic saline, and vasopressin receptor antagonists, with the goal of correcting serum sodium levels by 4-6 mEq/L per 24-hour period, as recommended by the American Association for the Study of Liver Diseases in 2021 1.
Management Approach
The management of severe hyponatremia in cirrhosis involves several key strategies:
- Fluid restriction to less than 1-1.5 liters per day for all patients with serum sodium below 130 mEq/L
- Hypertonic saline (3% NaCl) may be administered at 1-2 mL/kg/hour with close monitoring to avoid rapid correction for severe symptomatic hyponatremia (sodium <125 mEq/L with neurological symptoms)
- Vasopressin receptor antagonists, such as tolvaptan, can be used starting at 15 mg daily and titrated up to 60 mg if needed, though they require careful monitoring for overcorrection
- Albumin infusion (1 g/kg) may help improve effective circulating volume
- Diuretics should be temporarily discontinued if possible, as they exacerbate hyponatremia
Correction Goals
The goal of correction is to increase serum sodium levels by 4-6 mEq/L per 24-hour period, 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.
Underlying Causes
Addressing the underlying causes of hyponatremia is essential, including treating infections, stopping alcohol consumption, and optimizing nutrition.
Refractory Cases
For refractory cases, continuous renal replacement therapy may be considered. The use of vasopressin receptor antagonists, such as tolvaptan, has been shown to be effective in improving serum sodium concentration in patients with cirrhosis and hyponatremia, as reported in the 2010 European Association for the Study of the Liver (EASL) clinical practice guidelines 1. However, the most recent and highest quality study, the 2021 American Association for the Study of Liver Diseases (AASLD) practice guidance, recommends a more conservative approach to correction and emphasizes the importance of careful monitoring to avoid rapid correction and prevent osmotic demyelination syndrome 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 dose of tolvaptan could be increased at 24-hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) was reached
Gastrointestinal bleeding in patients with cirrhosis In patients with cirrhosis treated with tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients
Management of Severe Hyponatremia in Cirrhosis:
- Tolvaptan can be used to manage severe hyponatremia in patients with cirrhosis.
- The initial dose is 15 mg once daily, which can be increased to 30 mg once daily, then to 60 mg once daily, as needed and as tolerated.
- Key Considerations:
- Monitor serum sodium levels closely to avoid overly rapid correction.
- Avoid fluid restriction during the first 24 hours of therapy.
- Be aware of the potential risk of gastrointestinal bleeding in patients with cirrhosis.
- Hypernatremia is a potential adverse effect, and patients should be monitored to ensure serum sodium remains within normal limits 2.
From the Research
Management of Severe Hyponatremia in Cirrhosis
- Severe hyponatremia in patients with cirrhosis is a common complication that arises due to the impairment of the renal capacity to eliminate solute-free water, leading to a disproportionate retention of water compared to sodium 3.
- The main pathogenic factor responsible for hyponatremia in cirrhosis is non-osmotic hypersecretion of arginine vasopressin (AVP) or antidiuretic hormone, related to circulatory dysfunction 3, 4.
- Hyponatremia in cirrhosis is associated with increased morbidity and mortality, and it also impairs short-term survival after transplantation 3, 4, 5.
Treatment Approaches
- The current standard of care, which involves restricting fluids to 1-1.5 L/day, is rarely effective in managing hyponatremia in cirrhosis 3.
- Other approaches, such as albumin infusion and the use of vaptans (which act by specifically antagonizing the effects of AVP on the V2 receptors located in the kidney tubules), have been evaluated for their role in the management of hyponatremia 3, 4, 5.
- Vaptans have been shown to increase renal solute-free water excretion and improve hyponatremia in the short term, but their use in patients with end-stage liver disease is limited by hepatotoxic effects and high cost 3, 5.
- Midodrine and octreotide have also been used as a therapeutic approach to increase urinary electrolyte-free water clearance in the correction of cirrhosis-associated hyponatremia, with statistically significant increases in serum sodium concentration and urinary electrolyte-free water clearance observed 6.
- Treatment practices and effectiveness in cirrhotic patients with hyponatremia vary, with the most common initial treatments being isotonic saline, fluid restriction, and no specific therapy, and treatment success occurring in a significant proportion of patients treated with hypertonic saline and tolvaptan 7.
Outcomes and Prognosis
- Hyponatremia in cirrhosis carries a prognostic burden and correlates with the severity of cirrhosis, and it has also been implicated in the pathogenesis of hepatic encephalopathy 5.
- Relapse of hyponatremia after correction is associated with increased length of stay, highlighting the need for effective management strategies to prevent relapse and improve outcomes 7.