In a patient on valproic acid who develops new confusion, irritability, asterixis, or fatigue, what laboratory tests should be ordered and how should valproate‑induced hyperammonemia be managed?

Valproate-Induced Hyperammonemia: Laboratory Testing and Management

Immediate Laboratory Testing

In any patient on valproic acid who develops new confusion, irritability, asterixis, or fatigue, immediately measure serum ammonia levels—do not wait for liver function tests or valproate levels, as hyperammonemia can occur with normal results for both. 1

• Order a serum ammonia level as the first-line test when a patient on valproate presents with unexplained lethargy, vomiting, or changes in mental status 2, 1
• Ensure proper specimen handling: collect in EDTA tube, place immediately on ice, and transport to laboratory at +4°C within 60–90 minutes to avoid falsely elevated results 2
• Also obtain complete blood count and coagulation parameters (platelets, PT/INR, fibrinogen), as valproate causes dose-related thrombocytopenia and coagulation abnormalities 1
• Measure serum valproate level, though hyperammonemia occurs even with therapeutic levels 1, 3
• Check liver function tests (AST, ALT, bilirubin), recognizing that hyperammonemia frequently occurs despite normal hepatic function 1, 3

Diagnostic Thresholds

• Normal ammonia: ≤35 μmol/L (≤60 μg/dL) 2, 4
• Hyperammonemia defined as: ≥50 μmol/L (85 μg/dL) in adults 2, 4
• Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes 2, 4

---

Management Algorithm

Step 1: Symptomatic Hyperammonemia (Encephalopathy Present)

If the patient has altered mental status, confusion, or lethargy WITH elevated ammonia, discontinue valproate immediately. 1

• Stop valproic acid without delay—do not attempt dose reduction 1, 5, 3
• Initiate appropriate interventions for hyperammonemia treatment 1
• Consider L-carnitine supplementation (50–100 mg/kg/day IV divided every 6 hours, maximum 3 g/day), as valproate depletes carnitine and contributes to hyperammonemia 6
• Lactulose may be used to reduce ammonia absorption from the gut 7
• Investigate for underlying urea cycle disorders, particularly ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder 2, 5
• If ammonia >300 μmol/L with moderate-to-severe encephalopathy, prepare for urgent hemodialysis or continuous kidney replacement therapy 2

Step 2: Asymptomatic Hyperammonemia

If ammonia is elevated but the patient remains asymptomatic, institute close monitoring with repeat ammonia levels every 3 hours initially. 8, 2

• If elevation persists or worsens, discontinue valproate 1
• Some asymptomatic patients may be managed with carnitine and lactulose while continuing valproate at reduced doses, but this approach carries risk and requires intensive monitoring 7
• The safer approach is valproate discontinuation given the unpredictable progression to encephalopathy 1, 5

Step 3: Identify High-Risk Drug Interactions

Check for concomitant topiramate or phenytoin use, as both significantly increase the risk of valproate-induced hyperammonemia. 1, 6, 9

• Topiramate inhibits carbonic anhydrase, reducing bicarbonate availability for the urea cycle's first step, synergistically worsening valproate's ammonia-elevating effect 9
• Phenytoin co-administration independently increases odds of hyperammonemia (OR 6.4) 6
• Discontinue the interacting agent if clinically feasible 1, 9

Step 4: Screen for Underlying Urea Cycle Disorders

Any patient with valproate-induced hyperammonemia should undergo metabolic evaluation for urea cycle defects, even if previously asymptomatic. 1, 5

• Valproate can unmask partial enzyme deficiencies, particularly OTC deficiency (X-linked, affects males and carrier females) 2, 5
• Obtain plasma amino acids, urine orotic acid, and genetic testing for urea cycle enzymes 5
• Family screening is indicated if a urea cycle disorder is diagnosed 5

---

Critical Clinical Pitfalls to Avoid

• Do not rely on liver function tests or valproate levels to exclude hyperammonemia—both are frequently normal in valproate-induced hyperammonemic encephalopathy 1, 3
• Do not delay ammonia measurement in patients with altered mental status; check it within the first hours of presentation, not 48 hours later 5
• Do not continue valproate at full dose in symptomatic patients hoping symptoms will resolve—this risks irreversible neurologic injury 1, 5
• Do not assume chronic stable valproate therapy is safe—hyperammonemia can develop after years of treatment without dose changes 7
• Do not overlook hypothermia (core temperature <35°C), which can be a manifestation of hyperammonemia and should prompt immediate ammonia testing 1

---

Monitoring After Resolution

• Once ammonia normalizes and encephalopathy resolves, do not restart valproate if an alternative anticonvulsant or mood stabilizer is available 1, 5
• If valproate must be continued (rare), monitor ammonia levels monthly and educate the patient to report early symptoms immediately 1
• Ensure the patient and family understand the risk of recurrence and the need for urgent evaluation if confusion or lethargy develops 1