What is the initial management of non-hepatic hyperammonemia?

Initial Management of Non-Hepatic Hyperammonemia

Immediately discontinue all protein intake and begin aggressive caloric support with IV dextrose and lipids while simultaneously initiating nitrogen-scavenging agents—do not delay treatment to wait for diagnostic workup. 1, 2

Immediate Stabilization (Within Minutes)

Airway and Circulation

• Secure airway, breathing, and circulation—intubate if neurological status is deteriorating or Glasgow Coma Scale is declining 2, 3
• Assess for signs of encephalopathy, seizures, or coma, as coma duration and peak ammonia levels directly correlate with irreversible neurological damage and death 2

Stop Nitrogen Load

• Discontinue all oral feeds immediately to halt nitrogen load and prevent further ammonia production 1, 2
• This is critical because continued protein intake will worsen hyperammonemia through ongoing nitrogen metabolism 3

Aggressive Caloric Support (Within First Hour)

Prevent Catabolism

• Provide ≥100 kcal/kg/day through IV dextrose and lipids to prevent protein catabolism, which paradoxically worsens hyperammonemia 1, 2
• Maintain glucose infusion rate at 8-10 mg/kg/min 1, 2
• Start IV lipids at 0.5 g/kg/day, titrating up to 3 g/kg/day for additional non-protein calories 1, 2

Critical pitfall: Prolonged protein restriction beyond 48 hours without adequate caloric support will trigger endogenous protein breakdown, driving further ammonia production 1

Pharmacological Therapy

Nitrogen-Scavenging Agents

Initiate nitrogen scavengers immediately without waiting for specific diagnosis 1, 2, 4:

For patients <20 kg:

• IV sodium benzoate and sodium phenylacetate: 250 mg/kg each, given over 90-120 minutes as loading dose, then same dose as maintenance over 24 hours 1, 4
• Maximum sodium benzoate dose is 12 g daily (high-dose benzoate can be toxic and lethal within 1 hour) 1

For patients >20 kg:

• IV sodium benzoate and sodium phenylacetate: 5.5 g/m² each, given over 90-120 minutes as loading dose, then same dose as maintenance over 24 hours 1, 4

Urea Cycle Intermediates

Dosing depends on suspected enzyme deficiency 1, 4:

L-arginine hydrochloride:

• For OTC and CPS deficiencies: <20 kg: 200 mg/kg; >20 kg: 4 g/m² 1
• For ASS and ASL deficiencies: <20 kg: 600 mg/kg; >20 kg: 12 g/m² 1
• Given over 90 minutes as bolus, then as maintenance over 24 hours 1

L-carnitine:

• 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg/day 1, 2
• Essential for organic acidemias but not required for urea cycle disorders 1

Important caveat: Do not administer repeat loading doses of phenylacetate due to prolonged plasma levels and risk of neurotoxicity 4

Kidney Replacement Therapy Decision Algorithm

Indications for Dialysis

Consider hemodialysis or CKRT when 1, 2, 5:

• Ammonia levels exceed 300-400 μmol/L (513-680 μg/dL) despite medical therapy 1, 2
• Moderate to severe encephalopathy or seizures present 1
• Rapidly deteriorating neurological status regardless of ammonia level 2, 3

Modality Selection

• Hemodialysis is most effective: 95-96% ammonia filtration fraction with 50% reduction within 1-2 hours 2, 6, 5
• CKRT (specifically high-dose CVVHD) is preferred for hemodynamically unstable patients 2, 6
• Peritoneal dialysis is significantly less effective than HD or CKRT and should only be used when extracorporeal therapies are unavailable 1, 2

Key point: Nitrogen scavengers remain effective during dialysis and should be continued concurrently despite being dialyzed 2, 6

Monitoring Protocol

Ammonia and Metabolic Parameters

• Check plasma ammonia levels every 3-4 hours until normalized 2, 3, 6
• Monitor electrolytes closely, especially potassium (can decrease with treatment) 4
• Perform frequent blood pH and pCO₂ measurements to detect hyperventilation and metabolic acidosis (salicylate-like toxicity from phenylacetate) 4

Neurological Assessment

• Assess neurological status regularly using Glasgow Coma Scale 4
• Monitor for signs of cerebral edema via CT/MRI or fundoscopic examination 4
• Watch for symptoms of acute neurotoxicity from phenylacetate 4

Sample Collection Pitfall

Ammonia samples must be collected from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid false elevations 3, 6

Protein Reintroduction

Gradually reintroduce protein within 48 hours once ammonia decreases to 80-100 μmol/L 1, 3:

• Start at 0.25 g/kg/day 1, 3
• Increase gradually up to 1.5 g/kg/day as tolerated 1, 3
• If stabilization takes longer than 48 hours without protein supply, protein catabolism will drive further ammonia production 1

Diagnostic Workup (Concurrent with Treatment)

Conduct investigations immediately without delaying treatment 1:

• Plasma amino acids (quantitative) to identify specific urea cycle defects or organic acidemias 4, 7
• Urine organic acids for organic acidemias 7
• Plasma glutamine levels 4
• Consider urea cycle disorders, organic acidemias (propionic, methylmalonic, isovaleric acidemia), fatty acid oxidation defects, medications, and transient hyperammonemia of the newborn 2, 7, 8