What are the symptoms and treatment of hyperammonemia?

Symptoms and Treatment of Hyperammonemia

Prompt identification and treatment of hyperammonemia are imperative to optimize outcomes and avoid irreversible brain damage. 1

Symptoms of Hyperammonemia

Symptoms vary based on ammonia levels and patient age, progressing from mild to severe:

Early Symptoms

• Lethargy and somnolence 1
• Loss of appetite and vomiting 1
• Irritability 2

Progressive Symptoms (as ammonia levels rise)

• Hyperventilation resulting in respiratory alkalosis 1
• Hypotonia and ataxia 1, 3
• Disorientation 1
• Tremors 4
• Seizures 1, 4, 2

Severe Symptoms

• Cerebral edema 5
• Coma 1, 4
• Death if untreated 1, 4

Age-Specific Presentations

• Neonates: Often present within first few days of life after starting feeds 1
• Children/adolescents: May present with failure to thrive, persistent vomiting, developmental delay, or behavioral changes 2
• Adults: Can present with unexplained stupor or delirium 3

Treatment of Hyperammonemia

Initial Medical Management

1. Immediate stabilization measures:

   • Secure airway, breathing, and circulation 1
   • Monitor vital signs 1
   • Establish intravenous access 1
   • Intubate and ventilate if necessary 1
   • Start adequate rehydration with dextrose-containing fluid at high infusion rate 1

2. Diagnostic workup:

   • Accurate ammonia measurement from free-flowing venous or arterial blood sample collected in lithium heparin or EDTA tube and transported on ice 1
   • Sample must be processed within 15 minutes of collection 1
   • Laboratory testing to establish cause of hyperammonemia 1

Non-Kidney Replacement Therapy (NKRT)

1. Nutritional management:

   • Temporarily stop protein intake when hyperammonemia is identified 1
   • Monitor plasma ammonia levels every 3 hours 1
   • Initiate intravenous glucose (8-10 mg/kg/min) and lipids to prevent catabolism 6
   • Aim for caloric intake >80 kcal/kg/day 6
   • Reintroduce protein within 48 hours once ammonia levels return to 80-100 μmol/l (136-170 μg/dl) 1

2. Pharmacological therapy (generally indicated at serum ammonia levels >150 μmol/l): 1

   • Nitrogen scavengers:

     • Sodium benzoate 1
     • Sodium phenylacetate 1
     • Sodium phenylbutyrate 1
     • Glycerol phenylbutyrate 1

   • Dosing for nitrogen scavengers: 6

     • For patients 0-20 kg:
       • Loading dose: 250 mg/kg sodium phenylacetate and 250 mg/kg sodium benzoate over 90-120 minutes
       • Maintenance: Same dose over 24 hours
     • For patients >20 kg:
       • Loading dose: 5.5 g/m² sodium phenylacetate and 5.5 g/m² sodium benzoate over 90-120 minutes
       • Maintenance: Same dose over 24 hours

   • Arginine supplementation: 6

     • For CPS and OTC deficiency: 200 mg/kg
     • For ASS and ASL deficiency: 600 mg/kg

Kidney Replacement Therapy (KRT)

1. Indications for KRT: 1

   • Rapidly deteriorating neurological status, coma, or cerebral edema with blood ammonia level >150 μmol/l (256 μg/dl)
   • Moderate or severe encephalopathy
   • Blood ammonia levels >400 μmol/l (681 μg/dl) refractory to NKRT medical measures
   • Rapid rise in ammonia levels >300 μmol/l (511 μg/dl) within a few hours that cannot be controlled via NKRT

2. KRT modalities:

   • Continuous Kidney Replacement Therapy (CKRT):

     • First-line treatment when possible 1
     • High-dose continuous venovenous hemodialysis (CVVHD) is recommended 1
     • Results in fewer cardiovascular complications, less need for transfusions, and lower risk of rebound hyperammonemia compared to HD 1
     • Maintains hemodynamic stability 1

   • Hemodialysis (HD):

     • Most effective for rapidly reducing blood ammonia levels 2
     • Consider for patients with severe hyperammonemia or who are not responsive to nitrogen scavengers 6

   • Peritoneal Dialysis (PD):

     • Recommended when other KRT modalities are unavailable 1
     • Rigid peritoneal catheters are not recommended due to increased complications 1

Prognostic Factors

• Duration of hyperammonemic coma (>3 days is poor prognosis) 1
• Plasma ammonia levels (>1,000 μmol/l or 1,703 μg/dl is poor prognosis) 1
• Increased intracranial pressure 1
• Ammonia levels ≥600 μg/dL (360 μmol/L) cause significant brain damage 4

Monitoring During Treatment

• Plasma ammonia and glutamine levels 6
• Quantitative plasma amino acids 6
• Blood glucose levels 6
• Electrolytes 6
• Venous or arterial blood gases 6
• Liver function tests (AST, ALT) 6
• Neurological status and Glasgow Coma Scale 6
• Signs of cerebral edema 6

Common Pitfalls and Caveats

• Delayed recognition and treatment can lead to irreversible neurological damage 1, 7
• Ammonia samples must be properly collected and processed quickly to avoid false elevations 1
• Consider non-hepatic causes of hyperammonemia in patients with normal liver function 5, 3
• Protein restriction should not be prolonged beyond 48 hours to avoid catabolism 1
• Nitrogen scavengers will be dialyzed along with ammonia during KRT but can still be effective 1
• Monitor for hyperchloremic acidosis when administering high-dose arginine hydrochloride 6