From the FDA Drug Label
The efficacy of Sodium Phenylacetate and Sodium Benzoate Injection in improving patient survival of acute hyperammonemic episodes was demonstrated in an analysis of 316 patients (1,045 episodes of hospitalization) treated between 1981 and 2003. On admission to the hospital, patients with hyperammonemia and a suspected or confirmed urea cycle disorder (UCD) diagnosis were treated with a bolus dose of 0.25 g/kg (or 5.5 g/m 2) sodium phenylacetate + 0.25 g/kg (or 5. 5 g/m 2) sodium benzoate over a period of 90 minutes to 6 hours, depending on the specific UCD. Infusions also contained arginine; the dose of arginine depended on the specific UCD. After completion of the bolus dose, maintenance infusions of the same dose over 24 hours were continued until the patient was no longer hyperammonemic or oral therapy could be tolerated.
The algorithm for emergency treatment of hyperammonemia in adults in the UK is as follows:
- Bolus dose: 0.25 g/kg (or 5.5 g/m 2) sodium phenylacetate + 0.25 g/kg (or 5.5 g/m 2) sodium benzoate over 90 minutes to 6 hours
- Arginine dose: depends on the specific urea cycle disorder (UCD)
- Maintenance infusion: same dose as bolus over 24 hours until patient is no longer hyperammonemic or oral therapy can be tolerated
- Monitoring: plasma ammonia levels, blood chemistry profiles, blood pH, and pCO2
- Hemodialysis: recommended if plasma ammonia levels fail to fall below 150 µmol/L or by more than 40% within 4 to 8 hours after receiving Sodium Phenylacetate and Sodium Benzoate Injection 1
From the Research
The emergency treatment of hyperammonemia in adults in the UK involves a multi-step approach to rapidly reduce ammonia levels, with the most recent guidelines recommending initiation of hemodialysis when ammonia levels are >150-200 µmol/L 2.
Algorithm for Emergency Treatment
The algorithm for emergency treatment of hyperammonemia in adults in the UK is as follows:
- Initial management: stop protein intake, provide adequate caloric support with glucose (10% dextrose at 2-3 L/day)
- Administer nitrogen-scavenging medications: sodium benzoate and sodium phenylacetate, typically given as a combined formulation at a loading dose of 10 g each over 90-120 minutes, followed by a maintenance infusion of 10 g each over 24 hours 3
- L-arginine is also administered at 6 g over 90 minutes, then 6 g every 24 hours to support the urea cycle
- If ammonia levels remain critically high (>200 μmol/L), hemodialysis should be initiated promptly 2
- Lactulose (25-30 mL every 2-4 hours) is given to reduce intestinal ammonia production and absorption
- Neomycin or rifaximin may be added to decrease gut bacterial ammonia production
Key Considerations
- Fluid management, correction of electrolyte imbalances, and treatment of precipitating factors (such as infection, gastrointestinal bleeding, or medication effects) are essential components of care
- The efficacy and safety of i.v. sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders is well known, with a retrospective multicentre study showing that i.v. sodium benzoate associated with an emergency regimen is an effective and safe treatment for acute episodes of UCD 4
- The pathophysiology of hyperammonaemia and non-cirrhotic causes should be considered, with a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases 5
Prioritization of Morbidity, Mortality, and Quality of Life
The treatment approach prioritizes morbidity, mortality, and quality of life, with the goal of rapidly reducing ammonia levels to prevent cerebral edema and irreversible neurological damage, and to minimize the risk of mortality and long-term neurological sequelae.