What is the management approach for hyperammonemia (elevated ammonia level) unresponsive to lactulose (beta-galactoside fructose)?

From the Guidelines

When elevated ammonia levels do not respond to lactulose, adding rifaximin 550 mg twice daily is the most effective next step, as it has been shown to be an effective add-on therapy to lactulose for prevention of overt hepatic encephalopathy (OHE) recurrence 1. This approach is based on the 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver 1. Before adding rifaximin, ensure the lactulose dose is optimized, typically 25-30 mL every 6 hours, titrated to achieve 2-3 soft bowel movements daily. Some key points to consider in managing elevated ammonia levels not responding to lactulose include:

• Evaluating and addressing precipitating factors such as GI bleeding, infection, dehydration, electrolyte abnormalities, or medication non-compliance.
• Protein restriction to 0.8-1.0 g/kg/day may be beneficial temporarily.
• Other treatment options, though less preferred due to side effects or lower efficacy, include neomycin 500 mg four times daily and metronidazole 250 mg three times daily 1.
• For persistent hyperammonemia, consider L-ornithine L-aspartate (LOLA) or branched-chain amino acids as alternative or additional agents 1. The goal of treatment is to reduce ammonia production in the gut and enhance its clearance, thereby mitigating ammonia toxicity that results from bacterial metabolism of nitrogenous compounds in the intestine and impaired hepatic clearance in liver disease.

From the FDA Drug Label

Sodium phenylbutyrate tablets are indicated as adjunctive therapy in the chronic management of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS) Any episode of acute hyperammonemia should be treated as a life-threatening emergency Sodium phenylbutyrate tablets may be required lifelong unless orthotopic liver transplantation is elected.

Elevated ammonia levels not responding to lactulose may be managed with sodium phenylbutyrate as an adjunctive therapy in patients with urea cycle disorders.

• The treatment should be initiated immediately to improve survival.
• Sodium phenylbutyrate must be combined with dietary protein restriction and, in some cases, essential amino acid supplementation.
• The goal of treatment is to prevent hyperammonemic encephalopathy and reduce the risk of mental deterioration. 2

From the Research

Elevated Ammonia Level Not Responding to Lactulose

• Elevated ammonia levels can be a serious condition, particularly in patients with liver disease, and require prompt treatment 3, 4.
• Lactulose is a commonly used treatment for hyperammonemia, but its effectiveness can vary depending on the individual patient and the underlying cause of the condition 5, 6.
• In some cases, lactulose may not be effective in reducing ammonia levels, and alternative treatments may be necessary 3, 7.
• The use of L-ornithine L-aspartate (LOLA) has been shown to be effective in reducing ammonia levels and improving mental status in patients with hepatic encephalopathy 3.
• Intravascular resuscitation may also be beneficial in patients with dehydration-associated pseudo-hyperammonemia 5.
• The management of hyperammonemia should be individualized and based on the underlying cause of the condition, as well as the patient's overall health status 4, 6.

Alternative Treatments

• L-ornithine L-aspartate (LOLA) may be a useful alternative to lactulose in patients with hepatic encephalopathy 3.
• Intravascular resuscitation may be beneficial in patients with dehydration-associated pseudo-hyperammonemia 5.
• Other treatments, such as rifaximin, may also be effective in reducing ammonia levels and improving symptoms 4.
• The use of molecular adsorbent recirculating system (MARS) has been shown to be effective in patients with severe hepatic encephalopathy, although its mechanism of action is not fully understood 4.

Clinical Management

• The management of hyperammonemia should be based on the underlying cause of the condition, as well as the patient's overall health status 4, 6.
• Ammonia levels do not always guide clinical management, and treatment should be individualized based on the patient's symptoms and response to therapy 6.
• The use of lactulose may not always be effective, and alternative treatments should be considered in patients who do not respond to lactulose 7.