What is the treatment for hyperammonia in neonates?

Treatment of Hyperammonia in Neonates

Immediate Initial Management

Stop all protein intake immediately and initiate aggressive caloric support with intravenous glucose and lipids to prevent catabolism, which drives further ammonia production. 1, 2, 3

• Discontinue all oral feeds to halt nitrogen load and prevent further ammonia generation 1, 2, 3
• Provide ≥100 kcal/kg/day through intravenous dextrose and lipids to prevent protein breakdown 1, 2, 3
• Maintain glucose infusion rate at 8-10 mg/kg/min to prevent catabolism 1, 2, 3
• Start IV lipids at 0.5 g/kg/day, titrating up to 3 g/kg/day for additional caloric support 1, 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 1, 2, 3

Pharmacological Therapy

Nitrogen-Scavenging Agents

• Administer intravenous sodium benzoate and sodium phenylacetate at the following dosages 1, 2, 4:
  • For body weight <20 kg: 250 mg/kg of each agent
  • For body weight >20 kg: 5.5 g/m² of each agent
• Infuse as a bolus over 90 minutes to 6 hours, followed by continuous maintenance infusion of the same dose over 24 hours 4
• Continue nitrogen scavengers even during dialysis—they remain effective despite being partially dialyzed 2, 3

Urea Cycle Intermediates

• Administer intravenous L-arginine hydrochloride based on the specific urea cycle disorder 1, 2:
  • For OTC and CPS deficiencies: 200 mg/kg (body weight <20 kg) or 4 g/m² (body weight >20 kg)
  • For ASS and ASL deficiencies: 600 mg/kg (body weight <20 kg) or 12 g/m² (body weight >20 kg)

L-Carnitine (For Organic Acidemias Only)

• Administer L-carnitine for organic acidemias (propionic acidemia, methylmalonic acidemia, isovaleric acidemia): 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg/day 1, 2, 3, 5
• L-carnitine is NOT indicated for urea cycle disorders 2

Kidney Replacement Therapy (KRT)

Indications for Urgent KRT

Initiate KRT immediately in the following situations 6, 1, 2, 3:

• Ammonia levels >300-400 μmol/L (511-681 μg/dl) despite medical therapy
• Rapidly deteriorating neurological status, coma, or cerebral edema with ammonia >150 μmol/L (256 μg/dl)
• Moderate to severe encephalopathy (lethargy, hypotonia, weak suck, absent reflexes, stupor, or coma)
• Rapid rise in ammonia to >300 μmol/L within a few hours uncontrolled by medical therapy

First-Line KRT Modality

High-dose continuous venovenous hemodialysis (CVVHD) is the first-line treatment for neonatal hyperammonemia when available. 6, 1, 2

• Use blood flow rate (Qb) of 30-50 ml/min with dialysate flow rate (Qd)/Qb ratio >1.5 6, 1
• For extremely high ammonia levels >1,000 μmol/L (1,703 μg/dl), initiate high-dose CKRT with dialysate flow rates of 8,000 mL/h/1.73 m² (approximately 5,000 mL/h absolute) 6, 7, 8
• CVVHD provides greater ammonia clearance than CVVH and maintains hemodynamic stability better than intermittent HD 6
• Warm the dialysate to maintain hemodynamic stability in neonates 6

Alternative KRT Modality: Intermittent Hemodialysis

• Intermittent HD achieves 50% reduction in ammonia within 1-3 hours with 95-96% filtration fraction 1, 2, 3
• HD is more effective than CKRT for rapid ammonia reduction but carries risk of post-dialytic ammonia rebound 1, 7
• Consider HD for patients requiring the most rapid ammonia clearance who are hemodynamically stable 1

Hybrid/Sequential Therapy Strategy

For hemodynamically unstable neonates or to prevent ammonia rebound, use a biphasic strategy combining HD followed by CKRT, or high-dose CKRT followed by standard-dose CKRT. 1, 7, 8

• Start with high-dose CVVHD (dialysate flow 5,000-8,000 mL/h/1.73 m²) to rapidly decrease ammonia to <400 μmol/L within 2-3 hours 7, 8
• Step down to standard-dose CKRT (dialysate flow 500-1,000 mL/h or 4,000 mL/h/1.73 m²) when ammonia is <200 μmol/L on two consecutive hourly measurements to prevent rebound 6, 7
• CKRT with ECMO support may be considered for low-birth-weight neonates with severe hypotension, though this increases risk of cerebrovascular events 6

Peritoneal Dialysis

• Peritoneal dialysis is significantly less effective than HD or CKRT and should not be used as first-line therapy 2, 3

Monitoring During Treatment

• Check plasma ammonia levels every 3-4 hours until normalized 1, 2, 3
• Assess neurological status regularly for signs of encephalopathy (lethargy, hypotonia, seizures, coma) 1, 2
• Monitor electrolytes closely, especially during CKRT, to prevent complications 1, 2, 3
• If ammonia fails to fall below 150 μmol/L or by >40% within 4-8 hours after starting pharmacological therapy, hemodialysis is recommended 4

Critical Pitfalls and Caveats

• The duration of hyperammonemic coma prior to dialysis is the most important prognostic factor—not the rate of ammonia clearance 6, 1, 2
• Delayed recognition and treatment leads to irreversible neurological damage, including seizures, permanent disability, and death 1, 2, 3
• Ammonia samples must be collected from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid falsely elevated results 1, 2, 3
• Do not prolong protein restriction beyond 48 hours—this causes catabolism and worsens hyperammonemia 2, 3
• Therapeutic hypothermia combined with KRT may be considered as each 1°C decrease in body temperature reduces basal metabolic rate by 8%, slowing ammonia production 6, 2