What is the treatment for hyperammonemia?

Treatment of Hyperammonemia

Immediately stop all protein intake, secure the airway with intubation if neurological status is deteriorating, and initiate aggressive caloric support with IV dextrose and lipids while preparing for hemodialysis or continuous kidney replacement therapy (CKRT) if ammonia levels exceed 300-400 μmol/L or if the patient shows signs of encephalopathy. 1, 2

Immediate Stabilization

Airway and hemodynamic management takes priority:

• Secure airway, breathing, and circulation—intubate immediately if consciousness is declining or coma is present 3, 1
• Establish IV access for fluid and medication administration 3
• Begin high-rate infusion of dextrose-containing fluids to prevent catabolism 4, 3

Stop all protein intake immediately to halt nitrogen load and prevent further ammonia production 1, 2. This is non-negotiable in acute hyperammonemia.

Aggressive Caloric Support Protocol

The cornerstone of preventing worsening hyperammonemia is avoiding catabolism, which releases more ammonia:

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

Critical pitfall: Protein restriction must not exceed 48 hours—reintroduce protein gradually (starting at 0.25 g/kg/day, increasing to 1.5 g/kg/day) once ammonia decreases to 80-100 μmol/L to avoid catabolism 4, 1, 2

Pharmacological Therapy

Nitrogen Scavengers

Administer nitrogen-scavenging agents when ammonia exceeds 150 μmol/L:

• Sodium benzoate: 250 mg/kg for body weight <20 kg; 5.5 g/m² for body weight ≥20 kg 2
• Sodium phenylacetate: 250 mg/kg for body weight <20 kg; 5.5 g/m² for body weight ≥20 kg 2

These agents provide alternative pathways for nitrogen excretion and remain effective even during dialysis 1, 2.

Urea Cycle Intermediates

L-arginine hydrochloride dosing depends on the specific urea cycle disorder:

• 200 mg/kg for ornithine transcarbamylase (OTC) and carbamoyl phosphate synthetase (CPS) deficiencies 2
• 600 mg/kg for argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) deficiencies 2

Additional Medications

• L-carnitine: 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg daily for organic acidemias 1, 2
• Lactulose may be considered in hepatic encephalopathy cases to reduce intestinal ammonia absorption, as it reduces blood ammonia by 25-50% 5

Kidney Replacement Therapy (KRT) Decision Algorithm

Initiate KRT immediately when:

• Ammonia levels >300-400 μmol/L despite medical therapy 4, 1, 2
• Rapidly deteriorating neurological status or coma regardless of ammonia level 4, 1
• Moderate to severe encephalopathy 2

KRT Modality Selection

High-dose continuous venovenous hemodialysis (CVVHD) is first-line when available:

• Blood flow rate of 30-50 mL/min with dialysis fluid flow rate/Qb ratio >1.5 2
• Provides continuous ammonia removal without rebound 2

Intermittent hemodialysis (HD) is the most effective for rapid ammonia reduction:

• Achieves 95-96% ammonia filtration fraction 1, 2
• Reduces ammonia by 50% within 1-3 hours 2
• Caution: Risk of post-dialytic ammonia rebound 2

CKRT is preferred for hemodynamically unstable patients:

• Can be combined with ECMO support if needed 4, 1
• Success rate of 60% in pediatric studies 4

Peritoneal dialysis is significantly less effective than HD or CKRT and should be avoided when other options are available 1.

Special KRT Considerations

• Therapeutic hypothermia combined with KRT may slow ammonia production (each 1°C decrease reduces basal metabolic rate by 8%) 2
• Nitrogen scavengers will be dialyzed during CKRT but remain effective when used concurrently 2

Monitoring Protocol

Ammonia levels must be checked every 3-4 hours until normalized 3, 1, 2. This frequent monitoring is essential to guide therapy adjustments.

Critical sampling technique to avoid false elevations:

• Collect from free-flowing venous or arterial blood (not from tourniquet-occluded sites) 4, 2
• Use lithium heparin or EDTA tube 4
• Transport on ice and process within 15 minutes 4, 3, 2

Additional monitoring:

• Assess neurological status regularly for signs of encephalopathy 3, 2
• Monitor electrolytes closely, especially during CKRT 3, 1, 2
• Track blood glucose levels continuously 3

Prognostic Factors and Critical Timing

The duration of hyperammonemic coma is the most important prognostic factor, not the rate of ammonia clearance 2. Two factors determine neurological damage:

• Duration of hyperammonemic coma: Coma lasting >3 days predicts poor neurological outcome 4
• Peak ammonia levels: Levels >1,000 μmol/L (1,703 μg/dl) are associated with severe brain damage 4

Delayed recognition and treatment leads to irreversible neurological damage, including seizures, coma, and death 2, 6. Prompt identification and treatment are imperative to optimize outcomes 4.

Investigation of Underlying Cause

While treating the hyperammonemia, investigate the etiology:

• Urea cycle disorders 1
• Organic acidemias 1
• Severe liver failure 1
• Medications 1
• Transient hyperammonemia of the newborn 4, 1
• Septic shock with urea-splitting bacteria 7