What is the treatment for hyperammonemia?

Treatment of Hyperammonemia

High-dose continuous venovenous hemodialysis (CVVHD) is the first-line treatment for severe hyperammonemia when available, combined with immediate cessation of protein intake, aggressive caloric support, and nitrogen-scavenging agents. 1, 2

Immediate Stabilization (Within Minutes)

Stop all protein intake immediately to halt nitrogen load and prevent further ammonia production 3, 4. This is the single most critical initial step.

• Secure airway, breathing, and circulation—intubate if neurological status is deteriorating 4
• Begin aggressive caloric support within the first hour to prevent catabolism, which worsens hyperammonemia 4

Caloric Support Protocol (Start Immediately)

Provide ≥100 kcal/kg/day (some guidelines recommend ≥80 kcal/kg/day minimum) through IV dextrose and lipids 2, 3, 5:

• Glucose infusion rate: 8-10 mg/kg/min to prevent protein breakdown 2, 3, 4
• IV lipids: Start at 0.5 g/kg/day, titrate up to 3 g/kg/day for additional calories 2, 3
• Reintroduce protein within 48 hours (starting at 0.25 g/kg/day, increasing to 1.5 g/kg/day) once ammonia decreases—prolonged protein restriction causes catabolism 2, 3, 4

Critical pitfall: Protein restriction should not be prolonged beyond 48 hours to avoid catabolism 3

Pharmacological Therapy (Start Concurrently)

Nitrogen-Scavenging Agents

Administer sodium phenylacetate and sodium benzoate as soon as hyperammonemia is diagnosed 5:

Dosing (weight-based for <20 kg, BSA-based for ≥20 kg):

• Sodium phenylacetate: 250 mg/kg for <20 kg OR 5.5 g/m² for ≥20 kg 2, 3, 5
• Sodium benzoate: 250 mg/kg for <20 kg OR 5.5 g/m² for ≥20 kg 2, 3, 5

Administration: Loading dose over 90-120 minutes, followed by maintenance infusion over 24 hours 5. Do not repeat loading doses due to prolonged plasma levels 5. Must be diluted in D10W and administered via central line only—peripheral administration causes burns 5.

Important: Nitrogen scavengers remain effective during dialysis and should be continued concurrently despite being dialyzed 3, 4

L-Arginine Hydrochloride

Essential component for urea cycle disorders 5:

• OTC and CPS deficiencies: 200 mg/kg for <20 kg OR 4 g/m² for ≥20 kg 2, 3
• ASS and ASL deficiencies: 600 mg/kg for <20 kg OR 12 g/m² for ≥20 kg 2, 3

Monitor for hyperchloremic acidosis and administer bicarbonate as needed 5

L-Carnitine

For organic acidemias: 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg/day 3, 4

Kidney Replacement Therapy (KRT) Decision Algorithm

Indications for Urgent KRT Initiation:

Initiate KRT immediately if ANY of the following:

• Ammonia >300-400 μmol/L despite medical therapy 2, 3, 4
• Rapidly deteriorating neurological status or coma 1, 3
• Cerebral edema 1
• Ammonia >300 μmol/L with rapid rise within hours 1
• Persistently high ammonia >400 μmol/L refractory to medical measures 1, 3

KRT Modality Selection:

First-line: High-dose CVVHD (if vascular access can be obtained and patient is hemodynamically unstable) 1, 2:

• Blood flow rate (Qb): 30-50 mL/min 2
• Dialysis fluid flow rate (Qd)/Qb ratio: >1.5 2
• Use warmed dialysate in neonates for hemodynamic stability 1
• Fewer cardiovascular complications, less rebound hyperammonemia, reduced risk of aggravating intracranial pressure 1

Alternative: Intermittent hemodialysis (HD) (if rapid ammonia clearance is priority and patient is hemodynamically stable) 2, 3:

• Most effective for rapid reduction: 95-96% ammonia filtration fraction 3, 4
• 50% reduction in ammonia within 1-3 hours 2, 6
• Risk of post-dialytic ammonia rebound 1

Hybrid/Sequential therapy: Combine HD followed by CKRT to achieve rapid reduction while controlling rebound—recommended for hemodynamically unstable neonates 2, 7

Last resort: Peritoneal dialysis (PD) (only if HD/CKRT unavailable) 1, 4:

• Significantly less effective than HD or CKRT 4
• Avoid rigid peritoneal catheters due to increased complications 1

Advanced Considerations:

• CKRT with ECMO support may be considered for severe hemodynamic instability 3
• Therapeutic hypothermia combined with KRT may slow ammonia production (each 1°C decrease reduces basal metabolic rate by 8%) 3

Monitoring Protocol

Plasma ammonia levels: Check every 3-4 hours until normalized 2, 3, 4

Hemodialysis should be considered if ammonia fails to fall below 150 μmol/L or by >40% within 4-8 hours after starting nitrogen scavengers 5

Additional monitoring:

• Neurological status, Glasgow Coma Scale 5
• Electrolytes (especially during CKRT) 2, 3
• Blood glucose, venous/arterial blood gases, AST/ALT 5
• Glutamine, quantitative plasma amino acids 5
• CT/MRI for cerebral edema 5

Critical Pitfalls to Avoid

Delayed treatment is the most important prognostic factor—the duration of hyperammonemic coma prior to dialysis determines survival, not the rate of ammonia clearance 1, 3. Coma duration and ammonia peak levels directly correlate with irreversible neurological damage and death 4

Ammonia sample collection: Must be from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid false elevations 2, 3, 4

Antiemetic administration may be needed during nitrogen scavenger infusion to control nausea/vomiting 5

Terminate oral sodium phenylbutyrate prior to IV nitrogen scavenger infusion 5