What is the treatment for hyperammonemia?

Hyperammonemia Treatment

Immediate Initial Management

Stop all protein intake immediately and provide aggressive caloric support with intravenous glucose (8-10 mg/kg/min) and lipids (0.5-3 g/kg daily) to prevent catabolism, while simultaneously initiating nitrogen-scavenging agents and preparing for kidney replacement therapy if ammonia levels exceed 300-400 μmol/L or if encephalopathy is present. 1, 2, 3

Nutritional Management (First Priority)

• Discontinue all oral feeds to eliminate nitrogen load and prevent further ammonia production 1, 3
• Provide ≥100 kcal/kg daily through intravenous routes to prevent protein catabolism 1, 2, 3
• Maintain glucose infusion at 8-10 mg/kg/min to prevent endogenous protein breakdown 1, 2, 3
• Administer intravenous lipids starting at 0.5 g/kg daily, escalating up to 3 g/kg daily for adequate caloric support 1, 2, 3
• Reintroduce protein gradually within 48 hours (increase by 0.25 g/kg daily up to 1.5 g/kg daily) to avoid prolonged catabolism 1, 2, 3

Pharmacological Therapy

Nitrogen-Scavenging Agents (Mandatory)

Administer intravenous sodium benzoate and sodium phenylacetate immediately as both loading dose and continuous infusion: 1, 2, 3

• For patients <20 kg: 250 mg/kg of each agent 1, 2, 3
• For patients >20 kg: 5.5 g/m² of each agent 1, 2, 3
• Administration: Give as bolus over 90-120 minutes, followed by maintenance infusion over 24 hours 2
• Important note: These agents will be partially removed by dialysis but remain effective when used concurrently with kidney replacement therapy 2, 3

L-Arginine Hydrochloride (Disorder-Specific)

Dosing depends on the specific urea cycle disorder: 1, 2, 3

• For OTC and CPS deficiencies:

  • <20 kg: 200 mg/kg 1, 3

  • 20 kg: 4 g/m² 1, 3

• For ASS and ASL deficiencies:

  • <20 kg: 600 mg/kg 1, 3

  • 20 kg: 12 g/m² 1, 3

L-Carnitine (Only for Organic Acidemias)

• Loading dose: 50 mg/kg over 90 minutes 2, 3
• Maintenance: 100-300 mg/kg daily 2, 3
• Critical caveat: L-carnitine is NOT indicated for urea cycle disorders—only for organic acidemias 3

Kidney Replacement Therapy (KRT)

Indications for Immediate KRT

Initiate KRT urgently when: 1, 2, 3

• Ammonia levels >300-400 μmol/L despite medical therapy 1, 2, 3
• Rapidly deteriorating neurological status or coma 1, 2, 3
• Moderate to severe encephalopathy at any ammonia level 1, 2
• Ammonia levels >1,000 μmol/L regardless of clinical status 2

KRT Modality Selection

High-dose continuous venovenous hemodialysis (CVVHD) is the first-line modality: 1, 2, 3

• Blood flow rate (Qb): 30-50 mL/min 1, 2, 3
• Dialysate flow rate (Qd): Maintain Qd/Qb ratio >1.5 1, 2, 3
• Advantages: Maintains hemodynamic stability, particularly critical in neonates and unstable patients 1, 2
• Warm the dialysate to maintain hemodynamic stability 2

Intermittent hemodialysis (HD) is the alternative for rapid clearance: 1, 2

• Efficacy: Achieves 50% ammonia reduction within 1-3 hours 1, 2
• Advantage: More rapid ammonia clearance than CVVHD (75% reduction in 3-4 hours) 2, 3
• Disadvantage: Risk of post-dialytic ammonia rebound 3
• Consider for: Patients requiring the most rapid ammonia clearance 1

Hybrid/sequential therapy (HD followed by CVVHD): 1

• Indication: Hemodynamically unstable neonates requiring both rapid clearance and prevention of rebound 1

KRT Duration

• Continue until: Ammonia <200 μmol/L on at least two consecutive hourly measurements 2

Monitoring Protocol

Ammonia Monitoring

• Check plasma ammonia levels every 3-4 hours until normalized 1, 2, 3
• Sample collection is critical: Use free-flowing venous or arterial blood, transport on ice, and process within 15 minutes to avoid false elevations 1, 2, 3

Clinical Monitoring

• Assess neurological status regularly using Glasgow Coma Scale for signs of encephalopathy 2, 3
• Monitor electrolytes closely, especially during CKRT, to prevent complications 1, 2, 3

Critical Pitfalls and Caveats

Time-Dependent Neurological Damage

The duration of hyperammonemic coma before dialysis initiation is the most important prognostic factor—NOT the rate of ammonia clearance. 1, 3 Delayed recognition and treatment lead to irreversible neurological damage, seizures, coma, and death. 1, 3 Treat hyperammonemia as a life-threatening emergency requiring immediate intervention. 1, 4

Protein Restriction Duration

• Do not prolong protein restriction beyond 48 hours as this causes catabolism and paradoxically worsens hyperammonemia 2, 3
• Reintroduce protein when ammonia returns to 80-100 μmol/L 2

Sample Collection Errors

• Improper ammonia sample handling causes false elevations: Samples must be from free-flowing blood, transported on ice, and processed within 15 minutes 1, 2, 3

Hemodynamic Considerations

• For severe hemodynamic instability: Consider CKRT with ECMO support for rapid ammonia clearance while maintaining circulatory support 3
• Therapeutic hypothermia may be considered as adjunct therapy (each 1°C decrease reduces basal metabolic rate by 8%, slowing ammonia production) 3