When to Order Serum Ammonia
Serum ammonia should be ordered in patients with altered mental status or encephalopathy when the diagnosis is uncertain, particularly to rule out hepatic encephalopathy in liver disease or to identify urea cycle disorders and other non-cirrhotic causes of hyperammonemia—but it should NOT be routinely ordered when the clinical diagnosis is already clear. 1
Primary Clinical Indications for Ordering Serum Ammonia
In Patients with Known Liver Disease
Order ammonia when altered mental status occurs for the first time in a patient with cirrhosis, as this helps differentiate hepatic encephalopathy from other causes of confusion such as alcohol withdrawal, structural brain injury, or medication effects. 1
Order ammonia when a patient with known hepatic encephalopathy fails to respond to standard therapy (lactulose or rifaximin), as a normal ammonia level should prompt investigation of alternative diagnoses including drug toxicity, infection, or intracranial pathology. 1
A normal ammonia level (≤35 μmol/L) has high negative predictive value and should lead you to reconsider the diagnosis of hepatic encephalopathy entirely, redirecting your workup toward other causes of altered mental status. 1
In Patients WITHOUT Known Liver Disease
Order ammonia urgently in any critically ill patient with unexplained encephalopathy, coma, or seizures, especially when accompanied by respiratory alkalosis, as this constellation suggests possible urea cycle disorder or other metabolic crisis requiring immediate intervention. 2, 3, 4
Order ammonia in patients with unexplained neurological symptoms plus any of these risk factors: malnutrition with recent protein refeeding, total parenteral nutrition, gastric bypass surgery, valproic acid use, high tumor burden, renal failure, or family history of metabolic disorders. 5
In neonates and young children with lethargy, poor feeding, vomiting, or hypotonia appearing within days of birth or after protein intake, ammonia measurement is essential to diagnose urea cycle disorders before irreversible brain damage occurs. 1, 3
When NOT to Order Serum Ammonia
Do NOT routinely order ammonia in patients with cirrhosis and typical recurrent hepatic encephalopathy when the clinical picture is consistent with prior episodes and there are clear precipitating factors (infection, GI bleeding, constipation). 1
Do NOT use serial ammonia levels to monitor response to hepatic encephalopathy treatment, as ammonia levels correlate poorly with clinical improvement and may remain elevated despite symptom resolution. 1
Do NOT order ammonia when the pretest probability of hepatic encephalopathy is very high or very low, as the result will not meaningfully change management in these scenarios. 6
Critical Thresholds and Interpretation
Defining Hyperammonemia
Normal ammonia is ≤35 μmol/L (≤60 μg/dL) in adults. 3
Hyperammonemia is defined as >100 μmol/L (170 μg/dL) in neonates or ≥50 μmol/L (85 μg/dL) in term infants, children, and adults. 3
Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes and warrant aggressive intervention. 3
Urgent Action Thresholds
Ammonia >300 μmol/L with moderate-to-severe encephalopathy or seizures requires immediate initiation of ammonia-scavenging therapy and preparation for urgent hemodialysis or continuous kidney replacement therapy. 1, 2, 7
Ammonia >150 μmol/L with rapidly deteriorating neurological status, coma, or cerebral edema warrants urgent consideration of kidney replacement therapy. 7
Common Pitfalls and How to Avoid Them
Collection and Processing Errors
Ammonia samples MUST be collected from free-flowing venous or arterial blood (no tourniquet stasis), placed immediately on ice in an EDTA tube, and processed within 15-60 minutes to avoid falsely elevated results. 2, 3
Hemolysis, prolonged tourniquet time, and delayed processing are the most common causes of spuriously elevated ammonia levels that lead to unnecessary interventions. 3, 8
Interpretation Pitfalls
Do not assume elevated ammonia always means hepatic encephalopathy—hyperammonemia occurs in 4.5% of critically ill patients without liver failure due to causes like valproic acid toxicity, urea cycle disorders, malignancy, or renal failure. 5
Do not delay treatment waiting for ammonia results when clinical suspicion for severe hyperammonemia is high (neonatal presentation, known urea cycle disorder, or acute liver failure with coma). 2, 7
Do not use ammonia levels alone to guide treatment intensity—the patient's evolving clinical status (level of consciousness, seizures, cerebral edema) should drive therapeutic decisions, not rigid numerical thresholds. 1, 2
Diagnostic Pitfalls
In patients with cirrhosis and altered mental status, always investigate precipitating factors (infection, GI bleeding, electrolyte disorders, medications) regardless of ammonia level, as these require specific treatment beyond ammonia-lowering therapy. 1
Consider urea cycle disorders in adults with recurrent unexplained encephalopathy, especially with history of protein intolerance, psychiatric symptoms, or migraine-like headaches—late-onset presentations can occur in adulthood. 3, 4
Respiratory alkalosis is a key early clue that distinguishes hyperammonemic encephalopathy from other causes and should prompt immediate ammonia measurement. 3