What is the appropriate diagnosis and treatment for a patient with hyperammonemia and lactic acidosis, potentially due to an underlying condition such as liver disease, sepsis, or a mitochondrial disorder?

Diagnostic and Treatment Approach for Hyperammonemia with Lactic Acidosis

When confronted with combined hyperammonemia and lactic acidosis, immediately initiate ammonia-lowering therapy while simultaneously investigating the underlying etiology—this dual presentation suggests either acute liver failure, sepsis, mitochondrial disease, or an inborn error of metabolism, each requiring distinct management strategies. 1

Immediate Diagnostic Workup

Confirm and Quantify the Metabolic Derangements

• Obtain properly collected ammonia levels from free-flowing venous or arterial blood, processed immediately on ice to avoid false elevations—a normal ammonia level essentially excludes hepatic encephalopathy as the primary diagnosis 2
• Measure lactate and pyruvate levels to assess for mitochondrial dysfunction, as elevated lactate-to-pyruvate ratios suggest primary mitochondrial disorders 1, 3
• Assess neurological status using West Haven criteria or Glasgow Coma Scale—Grade 3-4 encephalopathy or GCS <8 indicates severe injury requiring ICU admission 2

Identify the Underlying Etiology

For liver-related causes:

• Check complete metabolic panel, liver function tests, PT/INR, and total bilirubin—acute liver failure typically shows marked PT prolongation before other hepatic abnormalities, while chronic liver disease may show minimal changes 2, 4
• Investigate precipitating factors: gastrointestinal bleeding (endoscopy, CBC, stool blood test), infection (blood cultures, urinalysis, diagnostic paracentesis if ascites present), dehydration, constipation, and nephrotoxic medications 2

For metabolic disorders:

• Obtain plasma amino acid profile to identify patterns suggestive of urea cycle disorders—this is critical in neonates or patients without known liver disease 1, 5
• Measure urine organic acids to detect organic acidemias and 3-methylglutaconic aciduria (seen in MEGDHEL syndrome) 1, 5
• Check plasma acylcarnitine profile for fatty acid oxidation disorders 1
• Consider genetic testing for SERAC1 mutations if hyperammonemia occurs with liver synthesis dysfunction but without transaminase elevation or cholestasis—this presentation is pathognomonic for MEGDHEL syndrome 5

Brain Imaging Considerations

• Perform CT or MRI only for differential diagnosis in first episodes of encephalopathy, focal neurological signs, seizures, or failure to respond to empiric therapy 2
• Routine imaging in recurrent, non-focal presentations similar to prior episodes is not warranted 2
• A normal ammonia level in a comatose patient mandates brain imaging to exclude structural lesions, particularly in patients with alcohol use disorder who have 5-fold increased risk of intracerebral hemorrhage 2

Immediate Therapeutic Interventions

Metabolic Stabilization (Initiate Simultaneously with Diagnostic Workup)

Stop all protein intake immediately and provide IV glucose at 8-10 mg/kg/min plus IV lipids starting at 0.5 g/kg daily (up to 3 g/kg daily) to prevent catabolism and achieve ≥100 kcal/kg daily caloric intake 1, 6

Ammonia-Lowering Therapy Based on Etiology

For liver disease (cirrhosis or acute-on-chronic liver failure):

• Administer lactulose 30-45 mL every 1-2 hours orally or via nasogastric tube until achieving 2-3 soft stools daily 2
• For Grade 3-4 encephalopathy or inability to take oral medications, give lactulose enema (300 mL lactulose in 700 mL water) retained for at least 30 minutes, repeated 3-4 times daily 2
• Polyethylene glycol is an alternative if ileus or abdominal distention is present 2
• Rifaximin's role in acute settings remains unclear—it is not recommended as monotherapy in acute liver failure 2

Critical caveat: Lactulose has not demonstrated benefit in acute liver failure and should not delay more definitive therapies 2. A 2022 study showed lactulose provided no outcome benefit for hyperammonemia in ICU patients without chronic liver disease, and paradoxically increased hospital length of stay in moderate hyperammonemia (60-99 μmol/L) 7.

For suspected metabolic disorders or acute liver failure:

• Initiate IV sodium benzoate immediately: 250 mg/kg IV over 90 minutes as loading dose for patients <20 kg, or 5.5 g/m² IV over 90 minutes for patients >20 kg, followed by same dose as continuous maintenance over 24 hours 1, 6
• Sodium phenylacetate dosing mirrors sodium benzoate 6

Kidney Replacement Therapy Decision Algorithm

Initiate dialysis when:

• Ammonia >400 μmol/L refractory to medical therapy 2
• Ammonia >300 μmol/L with rapid rise within hours 2, 1, 6
• Ammonia >150 μmol/L with rapidly deteriorating neurological status, coma, or cerebral edema 2
• Moderate or severe encephalopathy present (lethargy, decreased activity, hypotonia, weak suck, or worse) 2

Modality selection:

• High-dose continuous venovenous hemodialysis (CVVHD) is first-line when available with blood flow rate 30-50 mL/min and dialysate flow rate/Qb ratio >1.5 2, 6
• Use warmed dialysate to maintain hemodynamic stability 2
• Intermittent hemodialysis achieves most rapid ammonia clearance (50% reduction in 1-3 hours) for rapidly deteriorating patients 6
• Step down to lower-intensity CKRT when ammonia <200 μmol/L on two consecutive hourly measurements 2

The duration of hyperammonemic coma before dialysis initiation is the most important prognostic factor—not the rate of ammonia clearance 2

Lactic Acidosis Management

For Mitochondrial Disease

• No controlled studies exist for acute metabolic crisis management in mitochondrial disorders—treatment is supportive 3
• Provide buffering with sodium bicarbonate for severe acidosis, though this has ethical limitations without addressing the underlying cause 3
• Avoid prolonged fasting and maintain adequate caloric intake to prevent further metabolic decompensation 3

For Liver-Related Lactic Acidosis

• Identify and treat precipitating events: sepsis (empiric antibiotics) and gastrointestinal hemorrhage (endoscopic intervention, vasoactive drugs) are most common 2, 4
• In acute hepatic failure with hypoglycemia, glucose administration alone can rapidly lower lactate levels 4
• Prognosis is poor in chronic liver disease with lactic acidosis (no long-term survivors in one series), but better in acute liver failure (43% survival) 4

Monitoring During Treatment

• Check ammonia levels every 2-4 hours initially until trending downward 1, 6
• Monitor neurological status continuously 1
• Check electrolytes (especially sodium and potassium), blood glucose, and acid-base status every 3-4 hours 1, 6
• Watch for rebound hyperammonemia after dialysis discontinuation—nitrogen-scavenging agents may prevent this 2

Protein Reintroduction

Gradually reintroduce protein at 0.25 g/kg daily once ammonia decreases below 200 μmol/L on two consecutive hourly measurements, increasing incrementally to 1.5 g/kg daily over 48 hours 6

Special Considerations

Plasma Exchange for Acute Liver Failure

Consider plasma exchange when available for critically ill acute liver failure patients with hyperammonemia >150 μmol/L, as this modality addresses both ammonia removal and coagulopathy 2

Invasive ICP Monitoring

Do not routinely use invasive ICP monitoring in acute liver failure with advanced encephalopathy—the risk-benefit ratio does not support this intervention 2