What is the treatment for elevated ammonia levels?

Treatment of Elevated Ammonia Levels

High-dose continuous kidney replacement therapy (CKRT), specifically continuous venovenous hemodialysis (CVVHD), is the recommended first-line treatment for severe hyperammonemia when medical management fails. 1

Initial Assessment and Non-Dialysis Management

When to Initiate Treatment

Treatment should be initiated immediately when elevated ammonia levels are detected, without delaying for further investigations 1. The decision to treat depends on both ammonia levels and clinical status:

• Mild elevation with minimal symptoms: Begin medical management
• Moderate to severe elevation (>300 μmol/L) or neurological symptoms: Aggressive intervention required

First-Line Medical Management

1. Discontinue protein intake 1

   • Stop all oral feeds
   • Provide adequate calories (≥100 kcal/kg daily) via intravenous glucose and lipids
   • Maintain glucose infusion rate of 8-10 mg/kg/min
   • Provide lipids (0.5 g/kg daily, up to 3 g/kg daily)

2. Nitrogen-scavenging agents 1, 2

   • Sodium benzoate:

     • Weight <20 kg: 250 mg/kg
     • Weight >20 kg: 5.5 g/m²
     • Maximum dose: 12 g daily (high doses can be lethal within 1 hour)
     • Administration: Give over 90 minutes as bolus then as maintenance over 24 hours

   • Sodium phenylacetate:

     • Weight <20 kg: 250 mg/kg
     • Weight >20 kg: 5.5 g/m²
     • Administration: Give over 90 minutes as bolus then as maintenance over 24 hours

3. L-arginine supplementation 1

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

4. Other supportive measures

   • L-carnitine: 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg daily (needed for organic acidemias, not for urea cycle disorders) 1
   • Vitamins (B12 1 mg, biotin 5-15 mg) 1
   • Lactulose: May be considered in hepatic encephalopathy, though evidence for its effectiveness is limited 1, 3

Kidney Replacement Therapy for Severe Hyperammonemia

Indications for Dialysis 1

CKRT should be initiated in patients with hyperammonemia in the following situations:

• Rapidly deteriorating neurological status, coma, or cerebral edema with blood ammonia level >150 μmol/L
• Moderate or severe encephalopathy
• Persistently high blood ammonia levels >400 μmol/L refractory to medical measures
• Rapid rise in blood ammonia levels to >300 μmol/L within a few hours that cannot be controlled via medical therapies

Preferred Dialysis Method

1. High-dose CVVHD is the recommended first-line treatment 1

   • Blood flow rate (Qb): 30-50 ml/min
   • Dialysate flow rate (Qd)/Qb ratio: >1.5
   • For blood ammonia >1,000 μmol/L, use high-dose CKRT

2. Hemodialysis is an alternative when CVVHD is not available 1, 2

   • Hemodialysis provides approximately ten times greater ammonia clearance than peritoneal dialysis or hemofiltration 2
   • Step-down to CKRT can follow when blood ammonia level is <200 μmol/L on at least two hourly measurements

3. Peritoneal dialysis is less effective and not recommended if other options are available 1

Practical Considerations for Dialysis

• Warming the dialysate helps maintain hemodynamic stability 1
• Monitor for rebound hyperammonemia after dialysis 1
• Continue nitrogen-scavenging agents during dialysis 1, 2
• Monitor potassium levels closely as excretion of phenylacetylglutamine and hippurate enhances urinary potassium loss 2

Special Considerations

Monitoring During Treatment

• Frequent monitoring of plasma ammonia levels 2
• Neurological status assessment 2
• Electrolyte monitoring, particularly potassium 2
• Blood pH and pCO₂ measurements 2

Potential Complications

• Extravasation of sodium phenylacetate and sodium benzoate can lead to skin necrosis 2
• Neurotoxicity related to phenylacetate (avoid repeat loading doses) 2
• Hyperventilation and metabolic acidosis 2
• Fluid overload in patients with heart failure or renal insufficiency 2

Transitioning to Oral Therapy

Once ammonia levels have been reduced to the normal range, transition to oral therapy 2:

• Oral sodium phenylbutyrate
• Dietary management
• Maintenance protein restrictions

Common Pitfalls and Caveats

1. Delayed treatment: The duration of hyperammonemic coma prior to starting dialysis is the most important prognostic factor 1

2. Relying solely on ammonia levels: Clinical status should be the primary determinant of whether to begin kidney replacement therapy 1, 3

3. Inadequate monitoring: Ongoing assessment of ammonia levels, neurological status, and laboratory parameters is crucial 2

4. Underestimating rebound hyperammonemia: Continue nitrogen-scavenging agents even after dialysis 1

5. Overuse of lactulose: While commonly used, evidence for lactulose in non-hepatic hyperammonemia is limited 4