How to manage hyperammonemia while on valproic acid (Valproate)?

From the Guidelines

To manage hyperammonemia while on valproic acid, it is recommended to stop protein intake, administer i.v. glucose at an infusion rate of 8–10 mg/kg/min, and consider i.v. sodium benzoate or sodium phenylacetate as ammonia-scavenging agents, as outlined in the consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy 1. The management of hyperammonemia is crucial to prevent neurological impairment and cerebral edema.

• The use of i.v. sodium benzoate and sodium phenylacetate as ammonia-scavenging agents has been shown to be effective in reducing ammonia levels in patients with hyperammonemia 1.
• In addition to these measures, L-carnitine supplementation may also be considered to aid in ammonia removal, as valproic acid can deplete carnitine levels 1.
• Regular monitoring of ammonia levels is essential while on valproic acid, and in severe cases with symptoms like confusion, lethargy, or vomiting, immediate medical attention is necessary to prevent valproic acid-induced hyperammonemic encephalopathy 1.
• The choice of dialysis modality, such as intermittent HD, CKRT, or PD, should be made jointly by a team of healthcare professionals, taking into account the patient's diagnosis, overall condition, and response to nitrogen-scavenger therapy 1.
• It is also important to note that valproic acid can cause hyperammonemia by interfering with the urea cycle and depleting carnitine, which is necessary for proper metabolism 1.
• Therefore, consulting a healthcare provider about adding L-carnitine supplementation and reducing valproic acid dose or switching to an alternative medication if ammonia levels remain high is crucial.
• Increasing dietary protein restriction may help temporarily, but this should only be done under medical supervision 1.
• Overall, the management of hyperammonemia while on valproic acid requires a comprehensive approach that includes medical management, potential dialysis, and close monitoring of ammonia levels to prevent serious complications.

From the FDA Drug Label

In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Hyperammonemia should also be considered in patients who present with hypothermia. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders.

Management of Hyperammonemia:

• Measure ammonia level in patients with unexplained lethargy, vomiting, or changes in mental status
• Discontinue valproate therapy if ammonia is increased
• Initiate appropriate interventions for treatment of hyperammonemia
• Investigate for underlying urea cycle disorders 2, 2 Key Considerations:
• Hyperammonemia can occur despite normal liver function tests
• Asymptomatic elevations of ammonia require close monitoring of plasma ammonia levels
• Concomitant administration of topiramate and valproic acid may increase the risk of hyperammonemia with or without encephalopathy

From the Research

Management of Hyperammonemia

To manage hyperammonemia while on valproic acid (Valproate), several strategies can be employed:

• L-carnitine supplementation: Studies have shown that L-carnitine can be effective in reducing ammonia levels in patients with valproic acid-induced hyperammonemia 3, 4, 5.
• Carglumic acid treatment: In cases where patients have a genetic N-acetyl glutamate synthase (NAGS) deficiency, carglumic acid can be used to increase NAGS levels and enhance the conversion of ammonia to urea 6.
• Discontinuation of valproic acid: In some cases, discontinuing valproic acid may be necessary to resolve hyperammonemia 7.
• Monitoring of ammonia levels: While there is insufficient data to support routine monitoring of ammonia levels, it may be necessary in certain cases to guide management 7.

Treatment Options

Treatment options for valproic acid-induced hyperammonemia include:

• L-carnitine administration: L-carnitine can be administered orally or intravenously to reduce ammonia levels 3, 4, 5.
• Carglumic acid administration: Carglumic acid can be used to treat patients with NAGS deficiency 6.
• Intermittent haemodialysis: In severe cases of encephalopathy, intermittent haemodialysis may be considered 5.
• Lactulose and intravenous hydration: These treatments may also be used in conjunction with L-carnitine to reduce ammonia levels 3.

Duration of Treatment

The duration of treatment with L-carnitine may vary, but it is recommended to continue therapy for at least 72 hours, followed by an additional 24 hours of monitoring for symptom relapse and hyperammonaemia after discontinuation 5.