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Pediatrics, Inborn Errors of Metabolism: Treatment & Medication
Updated: Mar 30, 2009
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Treatment
Prehospital Care
Establish adequate airway, breathing, and circulation.
Emergency Department Care
Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category (see Emergent treatment below). In any critically ill child, airway, breathing, and circulation must be established first. D10 normal saline should be used as bolus fluid unless the patient is hypoglycemic in which case, dextrose should instead be given as a bolus as detailed below. Consider antibiotics in any child who may be septic.Emergent treatment4
- Access and establish airway, breathing, circulation: Fluid boluses D10 normal saline, avoid lactated Ringer’s. If the patient is hypoglycemic and dextrose will be administered as a bolus (see Dextrose below), give normal saline without D10. Avoid hypotonic fluid load due to the risk of cerebral edema, particularly if hyperammonemia is present.
- Discontinue intake of offending agents; provide adequate glucose to prevent catabolism.
- NPO (especially no protein, galactose, or fructose)
- Dextrose for hypoglycemia, 0.25-1 g/kg (maximum 25 g), D10 neonates, D10 or D25 beyond neonatal period
- D10 to D15 with electrolytes - 8-12 mg/kg/min IV at 1-1.5 times maintenance to maintain serum glucose level at 120–170 mg/dL
- If necessary, treat hyperglycemia with insulin (0.2-0.3 U/kg/h).
- Correct metabolic acidosis (pH < 7.0-7.2) slowly, cautiously: Sodium bicarbonate: 0.25-0.5 mEq/kg/h (up to 1-2 mEq/kg/h) IV; if intractable acidosis, consider hemodialysis (peritoneal dialysis, hemofiltration, exchange transfusion much less effective).
- Eliminate toxic metabolites
- Hyperammonemia therapy
- If acute hyperammonemia associated with encephalopathy due to urea cycle defect, administer sodium phenylacetate and sodium benzoate (Ammonul) (Ucyclyd Pharma, 1-888-829-2593). If <20 kg, load 250 mg/kg (2.5 mL/kg) in 10% glucose via central line over 90-120 minutes, then 250 mg/kg/d (2.5 mL/kg/d) in 10% glucose via central line continuous infusion; if >20 kg, 5.5 g/m2 (55 mL/m2) over 90-120 minutes, then 5.5 g/m2/d (55 mL/m2/d) via central line; arginine 600 mg/kg (6 mL/kg) IV in 10% glucose over 90-120 minutes, then 600 mg/kg/d IV continuous infusion. Ammonul must be given by central line. Arginine HCl can be mixed with Ammonul; arginine HCl dose can be decreased to 200 mg/kg if known carbamyl phophate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency. L-carnitine conjugates with and inactivates sodium benzoate; therefore, this must not be given with Ammonul.
- If ammonia ≥ 500–600 mg/dL before Ammonul, or ≥ 300 mg/dL and rising after Ammonul, consider hemodialysis.
- Hyperammonemia therapy
- Administer cofactors if indicated.
- L-carnitine 25-50 mg/kg IV over 2-3 minutes or as infusion, followed by 25-50 mg/kg/d (maximum 3 g/d) for carnitine deficiency (This is controversial, as it can be harmful. Consult with IEM specialist. It cannot be given with Ammonul.)
- Pyridoxine (B6) 100 mg IV for possible pyridoxine-responsive IEM (seizures unresponsive to conventional anticonvulsants).
Goals of treatment
Goals of treatment for patients with an inborn error of metabolism (IEM) are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites. Even the apparently stable patient with mild symptoms may deteriorate rapidly with progression to death within hours. With appropriate therapy, patients may completely recover without sequelae.
Start empiric treatment for a potential inborn error of metabolism as soon as the diagnosis is considered. Treatment of patients with a known inborn error of metabolism should be disease and patient specific. Families may have treatment protocols with them developed by an IEM specialist. They may also have instructions for what resuscitation measures should be given if resuscitation is necessary. Protocols for acute illness are available on the New England Consortium of Metabolic Programs at Children's Hospital Boston.1
- Eliminate potentially harmful protein or sugars. All oral intake should be stopped for those with suspected IEM. Disease-specific offending agents should be eliminated for those with known IEM and those with positive newborn screening results.
- Treat hypoglycemia, prevent catabolism, and promote urinary excretion of toxic metabolites.
- Correct hypoglycemia, if present, by IV dextrose bolus, as D10 for neonates and D10 or D25 beyond the neonatal period, 0.25-0.1 g/kg/dose, not to exceed 25 g/dose, and followed by continuous IV administration of dextrose.
- For all patients in whom an IEM cannot be ruled out, give dextrose 10-15% IV at 1-1.5 maintenance (8-12 mg/kg/min) to keep glucose level at 120-170 mg/dL, which should prevent catabolism. High-volume maintenance fluid will also promote urinary excretion of some toxic metabolites.
- Add insulin, 0.2-0.3 IU/kg, as needed to maintain glucose level in the desired range.
- Add electrolytes at maintenance concentrations, with appropriate adjustments to correct electrolyte disturbances if present.
- Treat acute acidosis and electrolyte abnormalities. The pH and dose at which bicarbonate should be administered are controversial because data are lacking; pH <7.0-7.2, dose 0.25-0.5 mEq/kg/h up to 1-2 mEq/kg/h. When patients are symptomatic or severely hypokalemic, potassium acetate is a useful replacement fluid (1 mEq/kg/h). Rapid correction or overcorrection may have paradoxical effects on the CNS. For intractable acidosis, consider hemodialysis.
- Significant hyperammonemia is life threatening and must be treated immediately upon diagnosis.
- To reduce ammonia, sodium phenylacetate and sodium benzoate (Ammonul; Food and Drug Administration [FDA] approved for hyperammonemia due to urea cycle defects and neonatal hyperammonemic coma) can be administered to augment nitrogen excretion.
- Arginine is an essential amino acid in patients with urea cycle defects and should be administered unless the patient has arginase deficiency.
- For ammonia level greater than 500-600 mg/dL before Ammonul or greater than 300 mg/dL and rising after Ammonul, hemodialysis should likely be initiated.
- If hemodialysis is not readily available, peritoneal dialysis (<10% as effective as hemodialysis) or double volume exchange transfusion (even less effective) can be performed while arrangements are made to transport to a center where hemodialysis is possible, as long as this does not delay transfer.
- Two to 3 days of therapy is usually necessary.
- L-carnitine may be administered empirically in life-threatening situations associated with carnitine deficiency. Administration of L-carnitine to patients with secondary carnitine deficiency is controversial. Consultation with an IEM specialist is recommended.
- Pyridoxine should be given to neonates with seizures unresponsive to conventional anticonvulsants.
Consultations
Consider consultation with an IEM specialist.
Medication
Emergency medications for inborn errors of metabolism (IEMs) in infants and children include drugs to eliminate toxic metabolites and/or amino acids and enzyme cofactors to compensate for metabolic deficiencies. These and other drugs may be required to maintain and treat the underlying IEM. Some IEMs are treated with replacement enzymes that are FDA approved, designated as orphan drugs, or investigational.
Helpful Web sites for finding information on orphan drug designation include the following:
- National Organization for Rare Disorders (NORD) (lists more than 1000 rare diseases)
- United States FDA's Other Sources of Rare Disease/Orphan Product Information (list of Web sites that provide information on rare diseases and orphan drugs)
- United States FDA's List of Orphan Drug Designations and Approvals
Ammonium detoxicants
Treatment of hyperammonemia; enhances elimination of nitrogen. This drug is FDA approved for treatment of hyperammonemia due to urea cycle defects and is available only from a specialty wholesaler, Ucyclyd Pharma (888-829-2593). For more information, see Ammonul prescribing information.
Sodium phenylacetate and sodium benzoate (Ammonul)
Indicated for acute hyperammonemic and associated encephalopathy due to urea cycle defects. For ammonia levels >500-600 mcg/dL, hemodialysis is the preferred treatment; however, sodium phenylacetate and sodium benzoate should be considered if dialysis cannot be initiated immediately. Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul should be administered with arginine-HCL for carbamyl phophate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies and should not be given for arginase deficiency. Approved as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Preparation contains 100 mg/mL each of sodium phenylacetate and sodium benzoate and comes in 50-mL vials. Must dilute IV dose in at least 25 mL/kg of dextrose 10% up to 600 mL. Do not mix directly with other medications, but it may be piggybacked. Give in addition to daily fluid requirement but decrease maintenance fluid by volume of Ammonul given.
Adult
Loading: 55 mL (5.5 g)/m2 IV over 90-120 min via central line
Maintenance: 55 mL (5.5 g)/m2/d IV over 24 h via central line
Pediatric
<20 kg:
Loading: 2.5 mL (250 mg)/kg IV over 90-120 min via central line
Maintenance: 2.5 mL (250 mg)/kg/d IV over 24 h via central line
>20 kg: Administer as in adults
Penicillin may decrease effects; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate; carnitine conjugates and inactivates sodium benzoate
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Must be given via central line; closely monitor especially if hepatic or renal impairment; caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin-binding sites on albumin); because of sodium content, caution when giving to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance; may also cause hyperglycemia or hypokalemia; if needed, may be given with furosemide for edema, insulin to maintain euglycemia, or ondansetron 0.15 mg/kg during initial 15 min of priming infusion to offset GI effects; overdose may result in death; decrease volume of maintenance fluid by volume of Ammonul, arginine HCl administered
Amino acid
Essential amino acid used for certain urea cycle defects.
Arginine (R-Gene)
Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol of arginine when cleaved by arginase. Preparation is 10% arginine hydrochloride. Can be mixed with sodium phenylacetate and sodium benzoate. If administering separately, mix with sodium bicarbonate.
Adult
600 mg/kg (6 mL/kg) IV over 90-120 min followed by infusion of 600 mg/kg (6 mL/kg) IV over 24 h; bolus and maintenance doses can be reduced to 200 mg/kg (2 mL/kg) IV if known OTC or CPS deficiency; can be mixed with Ammonul
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause electrolyte disturbances; elevated potassium levels may occur, hyperchloremic acidosis which may require treatment with bicarbonate (caution in patients with hepatic or renal disease or anuria); flushing, nausea, and vomiting may occur if administered too quickly; dilute to avoid extravasation; decrease volume of maintenance fluid given by volume of Ammonul, arginine HCl administered
Enzyme cofactor
Enzyme cofactors are used to enhance the activity of cofactor-dependent enzymes.
Pyridoxine
Precursor of pyridoxal, which functions in the metabolism of proteins, carbohydrates, and fats. Also aids in the release of liver- and muscle-stored glycogen and in the synthesis of GABA (within the CNS) and heme. Involved in synthesis of GABA within the CNS. Indicated for seizures of unknown etiology unresponsive to conventional anticonvulsants and for seizures in patients with known pyridoxine-dependent IEM. Give undiluted or mix with other solutions. Incompatible with alkaline or oxidizing solutions and iron salts. Not to be mixed with sodium bicarbonate.
Adult
Up to 600 mg/d PO/IV/IM until seizures abate, then 50 mg/d
Pediatric
Not established
Suggested dosing: 100 mg/d IV/IM initial, then 2-10 mg/d IM or 10-100 mg/d PO
May cause 50% decrease in serum concentration of phenobarbital and phenytoin; may decrease levodopa levels; oral contraceptives may increase pyridoxine requirement
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
>200 mg/d may precipitate withdrawal effects when medication is discontinued; may cause flushing, warmth, paresthesia, and lethargy
Nutritional Supplement
This agent is used for the treatment of primary and secondary carnitine deficiency.
Levocarnitine (Carnitor)
An amino acid derivative, synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects that bioaccumulate acyl-CoA esters. Carnitine is indicated for most organic acidemias and is controversial for fatty acid oxidation defects.
Adult
25-50 mg/kg IV over 2-3 min; range 25-100 mg/kg/d IV, up to 3 g/kg/d has been reported
Pediatric
Administer as in adults
Increases INR (caution with anticoagulants)
Documented hypersensitivity; controversial if fatty acid oxidation defect
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor blood chemistries, plasma carnitine concentrations, vital signs, and overall clinical condition of the patient; nausea, vomiting, abdominal cramps, and diarrhea may occur; IV administration may cause hypertension, tachycardia, or, with end-stage renal disease, atrial fibrillation
More on Pediatrics, Inborn Errors of Metabolism |
| Overview: Pediatrics, Inborn Errors of Metabolism |
| Differential Diagnoses & Workup: Pediatrics, Inborn Errors of Metabolism |
 Treatment & Medication: Pediatrics, Inborn Errors of Metabolism |
| Follow-up: Pediatrics, Inborn Errors of Metabolism |
| Multimedia: Pediatrics, Inborn Errors of Metabolism |
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References
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Further Reading
Keywords
inborn errors of metabolism, metabolic disease, IEM, disorders of protein metabolism, disorders of carbohydrate metabolism, lysosomal storage disorders, fatty acid oxidation defects, amino acidopathy, organic acidopathy, urea cycle defects, mitochondrial disorders, peroxisomal disorders, disorders of energy production, multiple sclerosis, MS, migraines, stroke, metabolic disorders, congenital adrenal hyperplasia, biotinidase deficiency, maple syrup urine disease, homocystinuria, sickle cell disease, cystic fibrosis, hyperammonemia, newborn screen
