What is the recommended dose of L-ornithine L-aspartate (LOLA) and sodium benzoate for managing hyperammonemia in Acute Liver Failure (ALF)?

Recommended Dosing of L-ornithine L-aspartate (LOLA) and Sodium Benzoate for Hyperammonemia in Acute Liver Failure

For patients with acute liver failure (ALF) and hyperammonemia, intravenous LOLA should be administered at a dose of 30 g daily as a continuous infusion, while there is insufficient evidence to make a specific recommendation for sodium benzoate dosing in ALF.

Evidence for LOLA Dosing in Acute Liver Failure

Intravenous LOLA Administration

• The most recent high-quality evidence supports using LOLA at 30 g daily as a continuous intravenous infusion for 3-5 days 1
• This dosing regimen has been consistently used across clinical trials:
  • In a 2022 double-blind randomized controlled trial, LOLA was administered as a continuous intravenous infusion at 30 g over 24 hours for 5 days 1
  • A 2009 randomized controlled trial also used 30 g daily for 3 days 2

Efficacy of LOLA in ALF vs. ACLF

• Current guidelines note insufficient evidence to make a firm recommendation on LOLA use specifically for ALF patients with hyperammonemia 3
• However, LOLA is suggested for use in acute-on-chronic liver failure (ACLF) patients with overt hepatic encephalopathy (conditional recommendation, very low quality evidence) 3
• The 2022 study showed that combining LOLA with lactulose and rifaximin was more effective than lactulose and rifaximin alone for severe hepatic encephalopathy, with:
  • Higher rates of improvement in encephalopathy grade (92.5% vs. 66%, p<0.001)
  • Shorter time to recovery (2.70 ± 0.46 vs. 3.00 ± 0.87 days, p=0.03)
  • Lower 28-day mortality (16.4% vs. 41.8%, p=0.001) 1

Mechanism of Action

• LOLA works as a substrate for the urea cycle and stimulates enzymatic activity in residual hepatocytes, leading to increased urea excretion 3
• It reduces ammonia levels by enhancing both hepatic ammonia disposal and peripheral metabolism 2

Sodium Benzoate for Hyperammonemia in ALF

• There is a notable lack of evidence in the provided guidelines regarding specific dosing recommendations for sodium benzoate in ALF
• None of the current guidelines mention sodium benzoate dosing for hyperammonemia in ALF 3

Important Clinical Considerations

Monitoring and Supportive Care

• Regular monitoring of ammonia levels is essential during treatment
• Target serum sodium levels between 140-145 mmol/L, as hyponatremia correlates with increased intracranial pressure 3
• Monitor blood glucose at least every 2 hours, as hypoglycemia is a common complication of severe ALF 3
• Correct electrolyte disturbances, particularly phosphate abnormalities 3

Important Caveats

• The 2009 study found that LOLA did not significantly lower ammonia levels or improve survival in ALF compared to placebo 2, but more recent evidence shows benefit 1
• The use of osmotic laxatives (lactulose) or non-absorbable antibiotics (rifaximin) alone to lower ammonia levels is not recommended in ALF 3
• Oral LOLA (18 g daily in divided doses) has shown efficacy in chronic hepatic encephalopathy 4, but intravenous administration is preferred in acute settings

Treatment Algorithm for Hyperammonemia in ALF

1. Initiate intravenous LOLA at 30 g/day as a continuous infusion
2. Continue for 3-5 days while monitoring ammonia levels
3. Consider combination therapy with lactulose and rifaximin for severe hepatic encephalopathy
4. Monitor for and treat complications including electrolyte disturbances, hypoglycemia, and increased intracranial pressure
5. Consider early transfer to a liver transplantation center, as liver support devices should not delay such transfer 3