Hyperammonemia

The child with altered mental status certainly grabs our attention (rightfully so) and we have discussed several related topics. We often consider the infectious concerns (ex, Encephalitis, Meningitis, Sepsis) and traumatic etiologies (ex, head injury, hemorrhagic shock). We are always very vigilant for possible Hypoglycemia! Unquestionable, toxicologic issues also leap to our minds (ex, Loperamide Overdose, Ethanol Ingestion, Huffing Hydrocarbons, Iron toxicity, and Carbon Monoxide Poisoning), but let us not overlook the potential for that “poison” coming from the patient’s own body (ex, Inborn Errors of Metabolism). Let us take a minute to digest a morsel on the management of Hyperammonemia:

Hyperammonemia: Basics

  • Hyperammonemia is defined as: [Savy, 2018]
    • Plasma level > 80 micromol/L for newborns to 1 month of age;
    • Plasma level > 55 micromol/L for children > 1 month of age
  • Ammonia Metabolism (in brief – cuz I ain’t that smart) [Savy, 2018]
    • Ammonia is derived from:
      • Break down of proteins
      • Amino acid metabolism
      • Gut bacteria production
    • Ammonia is mostly (~90%) converted to urea via the urea cycle in hepatocytes.
    • ~10% is combined with glutamate to make glutamine.
      • Glutamine can be excreted in the urine.
      • Glutamine can be used as an energy source.
    • Ammonia is not water soluble.
      • Increased production or decreased elimination leads to excess ammonia.
      • Excess ammonia will accumulate in the brain and lead to dysfunction.
  • Can lead to severe morbidity and mortality. [Savy, 2018]
    • Can cause irreversible damage to the developing brain!
    • Severe neurologic impairment
    • Cerebral edema
    • Can lead to death.
      • Levels >200 micromol/L have been found to be associated with increased mortality. [Ozanne, 2012]
      • There is still debate over what levels confer prognostic utility.

Hyperammonemia: Presentation

  • Acute events often triggered by protein catabolic states: [Savy, 2018]
    • Prolonged fasting
    • Fever
    • Infections
    • GI Bleeding
    • Dehydration
    • High Protein Intake
    • Anesthesia
    • Surgery
  • Symptoms include: [Savy, 2018]
    • Nausea, vomiting, anorexia, abdominal pain
    • Headaches, ataxia, behavioral changes, hypotonia, dysarthria
    • Seizures
    • Altered mental status [Galal, 2010]
    • Cerebral hypoventilation
    • Signs of Liver failure
    • Signs of Multi-organ failure
    • Neonates may have “sepsis-like” presentation

Hyperammonemia: Evaluation

  • Check the Ammonia level! [Savy, 2018]
    • Seems simple… but obtaining a reliable ammonia level is challenging too. [Galal, 2010]
      • Capillary samples should NOT be used.
      • Hemolysis can lead to false elevations.
      • Delayed transport to lab can lead to false readings.
    • Collect sample without a tourniquet from free flowing source and transport rapidly to lab on ice!
    • If results are elevated, good idea to repeat the lab,…
      • but if abnormal and hyperammonemia could explain the scenario, don’t delay treatment.
      • Pay attention to your “pre-test” probability!
      • Mild elevations are not uncommon, but very high levels should not be dismissed as lab error initially. [Galal, 2010]
  • Ask yourself why? [Savy, 2018]
    • Numerous conditions can lead to hyperammonemia.
    • Primary Liver Failure / Injury
      • Viral infections (ex, HSV, enteroviruses)
      • Metabolic (ex, Galactosemia, Tyrosinemia, Reye’s Syndrome, Fatty Acid Oxidation Disorders)
      • Toxic (ex, Acetaminophen, Valproate, Carbamazepine, Topiramate, Chemotherapies)
      • Vascular disease
      • Autoimmune Disease
    • Urea Cycle Defects
      • ~23% of acute hyperammonemia in critically ill children.
      • Ornithine transcarbamylase (OTC) Deficiency is the most common inherited defect of the urea cycle.
    • Organic Acidurias
    • Fatty Acid Oxidation defects
  • Work up based on suspicion for underlying etiology… but some basic, reasonable tests would be:
    • Fingerstick glucose (you should have already gotten this)
    • Electrolytes and Blood Gas (anion gap?)
    • Urinalysis
    • Liver enzymes, fractionated bilirubin, coagulation studies
    • EXTRA Blood and Urine for EXTRA tests:
      • Plasma amino acids
      • Urine organic acids
      • Acylcarnitine profile
      • Carnitine (free and esterified) levels

Hyperammonemia: Management

  • Primary goals are to:
    • Protect the brain!
      • Head of bed at 30 degrees.
      • Head midline to allow adequate venous flow.
    • Lower ammonia plasma level
  • Some basic guidelines: [Savy, 2018]
    • Stop protein intake!
    • Give glucose… +/- insulin to prevent catabolism
    • Give L-Carnitine
      • An essential element in fatty acid oxidation.
      • Can be given in undiagnosed hyperammonemia!
      • 100 – 200 mg/kg/Day divided TID efficacious. [Glatstein, 2019]
    • L-Arginine and L-Citrulline
      • Can help promote nitrogen excretion through the urea cycle.
      • Cannot give Arginine in cases of Arginase deficiency (which we most likely won’t know in undifferentiated cases).
    • Nitrogen scavengers are useful for those with inborn errors of metabolism.
      • Sodium benzoate
      • Sodium phenylacetate
      • Sodiume phenylbutyrate
    • Lactulose?
      • Efficacy is not clear.
      • It is not useful for inherited metabolic conditions.
    • Dialysis
      • If initial level is > 500 micromol/L.
      • If level continues to rise after 4 hours of therapy.

Moral of the Morsel

  • It isn’t always just “CT / LP” for change in mental status. Think about a broad Ddx with the challenging presentation of altered mental status.
  • Got Hyperammonemia? If the patient with altered mental status does not clearly have a reason for it, check an ammonia level!
  • Prioritize the lab run! Get the sample rapidly to the lab to attain most accurate results.
  • Forget the Lactulose and give L-Carnitine! It is super cool when simple vitamins can save the day!
  • Call in the troops! Toxicology? Genetics? Nephrology? Intensivist? Pharmacists? Yup. Everyone.

References

Glatstein M1,2,3, Bonifacio Rino P4, de Pinho S4, Scolnik D5, Pivko-Levi D1, Hoyte C2,3. Levocarnitine for the Treatment of Valproic Acid-Induced Hyperammonemic Encephalopathy in Children: The Experience of a Large, Tertiary Care Pediatric Hospital and a Poison Center. Am J Ther. 2019 May/Jun;26(3):e344-e349. PMID: 29232283. [PubMed] [Read by QxMD]
Brossier D1,2,3,4, Goyer I1,5, Ziani L1, Marquis C1,5, Mitchell G2,6, Ozanne B7, Jouvet P1,2. Influence of implementing a protocol for an intravenously administered ammonia scavenger on the management of acute hyperammonemia in a pediatric intensive care unit. J Inherit Metab Dis. 2019 Jan;42(1):77-85. PMID: 29872971. [PubMed] [Read by QxMD]
Savy N1, Brossier D2, Brunel-Guitton C1, Ducharme-Crevier L1, Du Pont-Thibodeau G1, Jouvet P1. Acute pediatric hyperammonemia: current diagnosis and management strategies. Hepat Med. 2018 Sep 12;10:105-115. PMID: 30254497. [PubMed] [Read by QxMD]
Ozanne B1, Nelson J, Cousineau J, Lambert M, Phan V, Mitchell G, Alvarez F, Ducruet T, Jouvet P. Threshold for toxicity from hyperammonemia in critically ill children. J Hepatol. 2012 Jan;56(1):123-8. PMID: 21703182. [PubMed] [Read by QxMD]
Häberle J1. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011 Jan;170(1):21-34. PMID: 21165747. [PubMed] [Read by QxMD]
Galal NM1, Fouad HM, Saied A, Dabnon M. Hyperammonemia in the pediatric emergency care setting. Pediatr Emerg Care. 2010 Dec;26(12):888-91. PMID: 21088638. [PubMed] [Read by QxMD]

Sean M. Fox

I enjoy taking care of patients and I finding it endlessly rewarding to help train others to do the same. I trained at the Combined Emergency Medicine and Pediatrics residency program at University of Maryland, where I had the tremendous fortune of learning from world renowned educators and clinicians. Now I have the unbelievable honor of working with an unbelievably gifted group of practitioners at Carolinas Medical Center. I strive every day to inspire my residents as much as they inspire me.

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