Elevated blood ammonia levels occur early in the neonatal period. Infants are typically healthy in the first one or two days. As the ammonia levels rise, the baby begins to exhibit symptoms such as lethargy, irritability, poor feeding, and vomiting. So, how should elevated blood ammonia in children be treated?
What is elevated blood ammonia?
Elevated blood ammonia is a metabolic disorder characterized by high levels of ammonia in the blood. When increased ammonia enters the brain, it can cause neurological and metabolic disturbances in infants.
Causes of elevated blood ammonia
In the urea cycle, there are several enzymes and cofactors that act as catalysts for the occurring reactions. When one or more of these enzymes are missing or have reduced activity, certain reactions in the cycle do not take place, leading to the accumulation of ammonia. The causes of elevated blood ammonia include:
Deficiency of N-acetylglutamate synthase (NAGS): The lack of this enzyme results in a deficiency of N-acetylglutamate, which is an activator of carbamoyl phosphate synthetase.
Deficiency of carbamoyl phosphate synthetase I (CPS I): In the presence of N-acetylglutamate, ammonia ions combine with bicarbonate to form carbamoyl phosphate. This reaction occurs in the liver mitochondria. Elevated ammonia in this case develops as early as the first day of life, and infants can experience life-threatening conditions during the neonatal period.
Deficiency of Ornithine transcarbamoylase (OTC): OTC is also found in the liver mitochondria. In its presence, ornithine combines with carbamoyl phosphate to form citrulline, which is then transported out of the mitochondria. In the absence of the enzyme, accumulated carbamoyl phosphate enters the cytosol and participates in pyrimidine synthesis with the presence of CPS II. This is the most common urea cycle disorder, with an incidence rate of approximately 1 in 14,000 individuals.
Deficiency of argininosuccinic synthetase (AS): Citrulline combines with aspartate to form argininosuccinic acid. AS deficiency leads to citrullinemia, which typically manifests between 24 and 72 hours of life.
Deficiency of argininosuccinic lyase (AL): This enzyme cleaves argininosuccinic acid to produce fumarate and arginine. Its deficiency results in argininosuccinic aciduria, the second most common urea cycle disorder. Symptoms may appear in the neonatal period or later.
Deficiency of arginase: This enzyme participates in the final step of the urea cycle, breaking down arginine into urea and ornithine. Its deficiency leads to argininemia, the least common urea cycle disorder. Blood urea elevation is not severe, but it can cause neurotoxicity. Patients with this disorder may exhibit progressive spasticity or quadriplegia, intellectual impairment, recurrent vomiting, delayed development, and seizures.
Inherited Organic Acid Metabolism Disorders Causing Elevated Blood Ammonia in Infants:
These disorders are typically associated with ketosis and metabolic decompensation, leading to increased blood ammonia levels and, in some cases, an increased risk of urea cycle disorders. The mechanism behind elevated blood ammonia in these cases is the accumulation of CoA derivatives of organic acids, which inhibits the formation of N-acetylglutamate, an activator of carbamoyl phosphate synthetase in the liver.
Disorders in this group include: Methylmalonic acidemia, Multiple carboxylase deficiency, Beta-ketothiolase deficiency…
Defects in Fatty Acid Oxidation Causing Elevated Blood Ammonia:
Deficiency of Acyl CoA dehydrogenase: Deficiency of medium-chain or long-chain acyl CoA dehydrogenase leads to a defective beta-oxidation process of fatty acids. Patients experience severe hypoglycemia. Some patients with secondary hyperammonemia may have liver dysfunction.
Deficiency of Systemic Carnitine: Carnitine is essential for the transport of long-chain fatty acids into the mitochondria. Its deficiency results in hypoglycemia without ketosis, increased liver transaminases, and elevated ammonia levels. Patients may experience muscle weakness, cardiomyopathy, hepatomegaly, and developmental delay.
Defects in Dibasic Amino Acid Transport:
Lysinuric protein intolerance (LPI): This disorder is characterized by a defect in the transport across the membrane of cationic amino acids lysine, arginine, and ornithine. The mechanism leading to elevated blood ammonia is the deficiency of ornithine and arginine.
Transient Neonatal Hyperammonemia:
This disorder is observed in premature infants. Symptoms appear on the first or second day of life before the introduction of any protein into the infant’s body. These infants experience seizures, decreased consciousness, fixed pupils, and absent pupillary reflex. The mechanism may involve delayed completion of urea cycle function.
Inherited Lactic Acidemia:
These disorders are characterized by increased lactate levels (10-20 mmol/L), elevated lactate/pyruvate ratio, metabolic acidosis, and ketosis. Inherited lactic acidemia disorders include deficiencies of pyruvate dehydrogenase, pyruvate carboxylase, and mitochondrial disorders.
Elevated blood ammonia has been observed in newborns with severe birth asphyxia. High ammonia levels are found within the first 24 hours of life. Increased ammonia is often accompanied by elevated serum glutamic oxaloacetic transaminase (SGOT).
Reye syndrome is a disorder that can cause elevated blood ammonia and commonly occurs after viral infections. Patients with Reye syndrome exhibit symptoms and signs of brain and liver dysfunction, including vomiting, altered consciousness, seizures, cerebral edema, and absence of jaundice.
Furthermore, treatment with valproate is associated with increased blood ammonia. It is commonly seen in patients undergoing combined therapy for epilepsy. The mechanism involves reducing the production of acetyl CoA in the liver, leading to decreased N-acetylglutamate, an activator of carbamoyl phosphate synthetase. Valproate can also cause carnitine deficiency, resulting in impaired fatty acid oxidation and subsequent inhibition of the urea cycle.
Acute elevation of blood ammonia has been reported following high-dose chemotherapy with 5-fluorouracil, leading to high mortality rates. In a study using concurrent carbonic anhydrase inhibitors with or without valproic acid, it was identified as a risk factor for elevated blood ammonia. Additionally, in infants receiving valproic acid, concurrent use of phenytoin or phenobarbital increases the risk of hyperammonemia. Other significant risk factors include female gender, symptomatic epilepsy, and concurrent use of acetazolamide, topiramate, or zonisamide.
Herpes infection: Elevated blood ammonia is associated with herpes simplex virus-induced pneumonia in newborns. The increased ammonia concentration is a result of protein catabolism due to prolonged oxygen deprivation.
Symptoms of elevated blood ammonia
Elevated blood ammonia typically manifests early in the neonatal period. Infants are usually healthy in the first one or two days. As ammonia levels rise, the baby begins to exhibit symptoms of lethargy, irritability, poor feeding, and vomiting. These symptoms correlate with ammonia levels 2-3 times higher than normal. Subsequently, the infant may experience decreased ventilation, mumbling, and coma.
Late-onset hyperammonemia is often due to urea cycle disorders and may present later in life. The clinical presentation of urea cycle disorders varies depending on age-related physiological and biochemical differences. Older children have greater energy reserves than newborns, allowing them to compensate during stressful periods.
Children with elevated blood ammonia may also have an unsteady gait, intellectual impairment, and functional disorders. The intermittent nature of these symptoms is attributable to periodic increases in ammonia concentration. Additionally, due to the impairment of the urea cycle, children may experience seizures and recurrent Reye syndrome.
Severe hyperammonemia can result in coma in children.
Treatment of elevated blood ammonia in children
The objective is to correct biochemical abnormalities and ensure adequate nutrition. Treatment involves the use of compounds that increase the elimination of nitrogenous waste. These compounds convert nitrogen into other products outside of urea, which are then excreted, thereby reducing the load on the urea cycle.
Emergency treatment for children with hyperammonemia
The initial intravenous infusion required for the child is Glucose at a dose of 10mg/kg/minute or a corresponding dose of 10% solution at 12 ml/kg/hour. Additionally, appropriate electrolyte supplementation should be administered to the child.
Treatment for elevated blood ammonia within 2 hours involves the use of the following substances:
L-arginine hydrochloride at a dose of 360 mg/kg, equivalent to 2 ml/kg of a 1M solution. Na-benzoate at a dose of 250 mg/kg. Intravenous Na-phenylacetate at a dose of 250 mg/kg. Alternatively, it can be replaced with oral Na-phenylbutyrate at a dose of 250 mg/kg. L-Carnitine at a dose of 100 mg/kg, with a reduced dose if there is suspicion of a fatty acid oxidation disorder. Consider using intravenous Ondansetron at a dose of 0.15 mg/kg if the child is not comatose. L-arginine HCl, Na-benzoate, and Carnitine should be diluted with 5% Glucose solution and administered at regular intervals using different infusion sets. Monitor the child’s glucose levels, supplement if there is hyperglycemia, and re-evaluate the blood ammonia concentration after 2 hours.
If the NH3 concentration exceeds 500 µmol/l, extracorporeal detoxification should be initiated immediately. If possible, use hemodialysis as continuous venovenous hemofiltration is often ineffective, and blood transfusion should be avoided as it would increase protein and ammonia levels.
Consider using Carbamyl glutamate at an initial dose of 100-200 mg/kg, followed by the same dose divided into 3 to 4 doses per day. Consider using it if biochemical testing suggests a deficiency of CPS I or NAGS or in cases where specialized biochemical testing cannot be performed within a few hours.
Treatment for maintaining elevated blood ammonia:
Sustained infusion for more than 24 hours is necessary if the child is determined to have a deficiency in the urea cycle or an organic acidemia:
- Arginine hydrochloride at a dose ranging from 180 to 360 mg/kg to maintain a blood Arginine concentration of 80-150 µmol/l. If the child has elevated blood Arginine or cannot metabolize protein-derived Lysine, the infusion should be discontinued.
- Na-benzoate at a dose of 250 mg/kg, which can be increased to 500 mg/kg if the deficiency in the urea cycle is accurately known. During the infusion, the serum drug levels should be monitored. Oral Na-phenylbutyrate can be used at a daily dose of 250-500 mg/kg divided into 3 doses.
- Consider using Carnitine at a daily dose of 100 mg/kg.
- Administer glucose at a dose of 10-20 g/kg. If the child has blood glucose levels above 150 mg/dl or glucosuria, supplement with insulin at a dose of 0.1-1 IU/kg per hour.
- After resolving the long-chain fatty acid disorder, use Intralipid at a dose of 0.5-1 g/kg.
- Additionally, during this process, ensure adequate fluid and electrolyte supplementation and use antiemetic medication such as Ondansetron when necessary.
- If the term-born child is comatose within 36 hours before initiating specific therapy, there will be fewer neurological complications and better cognitive development.
We hope this article helps you better understand the treatment of elevated blood ammonia in children for timely intervention.
Johnny Jacks was born in 1985 in Texas, USA. He is the founder of Good Health Plan and is passionate about helping people improve their health and physical well-being. With over a decade of experience working in the healthcare industry, he currently works at Goodheathplan.com – a blog that shares knowledge on beauty and health.