At what ammonia level should treatment be initiated?

Treatment Thresholds for Hyperammonemia

Initiate nitrogen-scavenging agents (sodium benzoate and sodium phenylacetate) at ammonia levels >150 μmol/L (255 μg/dl), and strongly consider kidney replacement therapy at levels >300-400 μmol/L, particularly with neurological deterioration. 1, 2

Treatment Algorithm Based on Ammonia Level

Mild Elevation (Upper Limit of Normal to 150 μmol/L)

• Stop all protein intake immediately and initiate intravenous glucose (8-10 mg/kg/min) plus lipids (0.5-3 g/kg/daily) to prevent catabolism 1
• Target caloric intake ≥100 kcal/kg daily to prevent endogenous protein breakdown 1, 2
• Monitor ammonia levels every 3 hours 1, 3
• This conservative approach is generally adequate for mild elevations without pharmacological intervention 1

Moderate Elevation (>150 μmol/L)

• Begin nitrogen-scavenging therapy immediately with intravenous sodium benzoate and sodium phenylacetate 1, 2
  • For patients <20 kg: 250 mg/kg of each agent given over 90-120 minutes as bolus, then maintenance over 24 hours 1, 4
  • For patients >20 kg: 5.5 g/m² of each agent 1
• Add L-arginine hydrochloride: 200-600 mg/kg for patients <20 kg (dose depends on specific urea cycle disorder) 1, 4
• Add L-carnitine if organic acidemia suspected: 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg daily 1, 4
• Continue conservative measures (protein restriction, IV glucose/lipids) 1, 3

Severe Elevation (>300-400 μmol/L or Rapid Rise)

• Initiate continuous kidney replacement therapy (CKRT), preferably continuous venovenous hemodialysis (CVVHD) 2, 4
• CVVHD is superior to peritoneal dialysis in maintaining hemodynamic stability, particularly in neonates and infants 2
• Continue nitrogen scavengers concurrently (they will be dialyzed but remain effective) 2, 3
• Target blood flow rate 30-50 ml/min with dialysate flow rate/blood flow rate >1.5 2
• Continue CKRT until ammonia <200 μmol/L on two consecutive hourly measurements 2

Critical Elevation (>400 μmol/L with Neurological Deterioration)

• Hemodialysis is urgently indicated as it reduces ammonia by 75% within 3-4 hours 4, 5
• Intermittent hemodialysis removes ammonia more rapidly than CKRT but may be less hemodynamically stable 1, 2
• Secure airway immediately if decreased consciousness or apnea present 4
• If hemodialysis unavailable, use peritoneal dialysis as alternative, though less effective 1

Life-Threatening Elevation (>1,000 μmol/L)

• High-dose CKRT or intermittent hemodialysis is mandatory 2
• This level carries adverse prognosis with risk of irreversible brain damage 1
• Duration of hyperammonemic coma >3 days and levels >1,000 μmol/L are associated with poor neurological outcomes 1

Critical Monitoring Requirements

• Collect ammonia samples from free-flowing venous or arterial blood (never from IV line), transport on ice, and process within 15 minutes to avoid falsely elevated results 1, 4, 3
• Check plasma ammonia every 3-4 hours until normalized 2, 4, 3
• Assess neurological status continuously using Glasgow Coma Scale 4
• Monitor for cerebral edema in patients with altered mental status 4

Protein Reintroduction

• Reintroduce protein within 48 hours maximum once ammonia decreases to 80-100 μmol/L to prevent catabolism 1, 3
• Start at 0.25 g/kg/daily and gradually increase up to 1.5 g/kg/daily 1, 3
• Prolonged protein restriction beyond 48 hours drives protein catabolism and paradoxically increases ammonia production 1

Common Pitfalls to Avoid

• Do not use lactulose for urea cycle disorders or non-hepatic hyperammonemia - it is ineffective and delays definitive treatment 4
• Do not delay dialysis while waiting for medical management alone at levels >400 μmol/L with neurological symptoms 4
• Do not continue protein intake during acute crisis, but equally important, do not extend restriction beyond 48 hours 1, 4
• Do not rely on ammonia levels alone - clinical deterioration with rapidly rising levels (>300 μmol/L within hours) warrants aggressive intervention even if absolute threshold not yet reached 1
• Hemodialysis is specifically recommended if ammonia fails to fall below 150 μmol/L or by >40% within 4-8 hours after initiating nitrogen scavengers 5