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Methemoglobinemia, Pediatric

Basics

Description

- Toxic methemoglobinemia - Dietary or environmental chemicals: chlorates, chromates, copper sulfate fungicides, naphthalene, nitrates, and nitrites - Industrial chemicals: aniline and other nitrogenated organic compounds - Drugs: amyl nitrite, benzocaine, dapsone, lidocaine, metoclopramide, nitric oxide, nitroprusside, phenazopyridine, prilocaine, many others - Methemoglobinemia is a common iatrogenic complication of drug therapy.

  • Methemoglobin is dysfunctional hemoglobin in which the deoxygenated heme moiety has been oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state.
  • Methemoglobinemia is an undue accumulation of methemoglobin within the blood.

Epidemiology

  • Toxic methemoglobinemia, resulting from exposure to oxidant chemicals or drugs, is the most common cause of methemoglobinemia among children older than 6 months of age.
  • Enteritis-associated methemoglobinemia is the most common cause among children younger than 6 months of age:As many as 2/3 of infants with severe diarrhea have methemoglobinemia.

Pathophysiology

  • Hemoglobin in the allosteric configuration of methemoglobin cannot carry oxygen.
  • Methemoglobin increases the oxygen affinity of normal heme moieties in the blood and results in impaired oxygen delivery to tissues.
  • NADH-dependent cytochrome b5 methemoglobin reductase is the major source of physiologic reduction of methemoglobin.
  • A normally dormant NADPH-dependent methemoglobin reductase is the site of action for antidotal methylene blue therapy.

Etiology

  • Toxic methemoglobinemiaDietary or environmental chemicals: chlorates, chromates, copper sulfate fungicides, naphthalene, nitrates, and nitritesIndustrial chemicals: aniline and other nitrogenated organic compoundsDrugs: amyl nitrite, benzocaine, dapsone, lidocaine, metoclopramide, nitric oxide, nitroprusside, phenazopyridine, prilocaine, many othersMethemoglobinemia is a common iatrogenic complication of drug therapy.
  • Enteritis-associated methemoglobinemia is multifactorial in origin:Intestinal nitrate and nitric oxide promotes methemoglobin formation.Innate enzymatic methemoglobin reduction systems may be underdeveloped during infancy.Acidemia further inhibits enzymatic methemoglobin reduction systems.Methemoglobinemia is also reported with nitrite-producing bacterial infections of the intestines or urinary tract.
  • Congenital methemoglobinemia (rare)Hemoglobin M: Heterozygotes for autosomal dominant hemoglobin M will exhibit lifelong cyanosis.NADH-dependent methemoglobin reductase deficiency: Homozygotes for this autosomal recessive enzyme will have lifelong cyanosis; heterozygotes may have increased susceptibility to oxidative hemoglobin injury.

Commonly Associated Conditions

  • Heinz body hemolytic anemiaOxidant stress on the globin protein may cause hemolysis.
  • SulfhemoglobinemiaOxidant stress on the hemoglobin porphyrin ring may cause sulfhemoglobinemia.

Diagnosis

History

  • Age of onsetNew onset of cyanosis in children older than 6 months of age is unlikely to be due to congenital or enteritis-associated methemoglobinemia.
  • Source of waterWell water may be contaminated with nitrates.
  • Drug or chemical exposureMay suggest a source of toxic methemoglobinemia
  • DiarrheaMay suggest enteritis-associated methemoglobinemia

Physical Exam

  • CyanosisCyanosis becomes apparent in the presence of 1.5 g/dL of methemoglobin (in contrast to 4 " 5 g/dL of deoxyhemoglobin).
  • Heart murmurMay suggest right-to-left intracardiac shunting rather than methemoglobinemia
  • Abnormal lung auscultation:May suggest cyanosis due to pulmonary disorder
  • Signs and symptomsMalaiseFatigueDyspneaTachycardiaCyanosis

Diagnostic Tests & Interpretation

Lab

  • Oxygen saturationOxygen saturation measured by pulse oximetry is artificially low, but oxygen saturation calculated from arterial blood gas is normal (a "saturation gap " ).
  • Co-oximetryMultiple-wavelength co-oximetry is the standard for quantifying methemoglobin in the blood.
  • Hemoglobin quantitationThe percent methemoglobin concentration must be considered in relation to the total hemoglobin.Anemia may suggest concurrent hemolysis.
  • Serum bicarbonateMetabolic acidosis is relatively mild in cases of <40% toxic methemoglobinemia.Metabolic acidosis is typically profound in cases of enteritis-associated methemoglobinemia.
  • Glucose-6-phosphate dehydrogenase (G6PD) assayG6PD deficiency does not predispose to methemoglobinemia and should not be routinely ordered.
  • Hemoglobin electrophoresisHemoglobin M is rare and does not respond to therapy.This test should not be routinely ordered.

Diagnostic Procedures/Other

  • Pulse oximetry may be inaccurate in the setting of methemoglobinemia or methylene blue therapy.
  • Blood may have a "chocolate brown " appearance despite exposure to air.

Differential Diagnosis

  • Environmental hypoxia
  • Cardiovascular disease
  • Pulmonary disease
  • Sulfhemoglobinemia
  • Factitious skin discoloration

Treatment

Medication

  • Consider administration of 1% methylene blue.Dose: 1 " 2 mg/kg IV over 5 minutes, repeated as necessary (caution above 4 " 7 mg/kg total)Indications: signs of tissue hypoxia, CNS depression, >30% methemoglobinemiaContraindications (relative): known, severe G6PD deficiency
  • Methylene blue therapy may be ineffective ifPatient is G6PD deficient.Ongoing drug or chemical absorption or biotransformation leads to continuing methemoglobin formation.Sulfhemoglobin is present.Hemoglobin M is present.High doses of methylene blue add to, rather than ameliorate, the oxidant stress.

Additional Therapies

General Measures

  • Acquired methemoglobinemiaAdminister 100% oxygen.Decontaminate or remove from toxic source of oxidative stress.Alleviate enteritis with IV fluids or elemental formulas.Treat identified bacterial infections.Exchange transfusion is a consideration of last resort.
  • Congenital methemoglobinemiaNo beneficial therapy exists for hemoglobin M.Oral methylene blue or ascorbic acid may provide alternative reduction pathways for patients with NADH-dependent reductase deficiencies.

Ongoing Care

Follow-up Recommendations

  • Toxic methemoglobinemiaConsider consultation with a medical toxicologist.May require environmental investigation
  • Enteritis-associated methemoglobinemiaCareful formula rechallenge warranted if possibility exists for milk protein allergy or other dietary intolerance
  • Congenital methemoglobinemiaConsider consultation with a hematologist.

Prognosis

  • Toxic methemoglobinemiaFull recovery with recognition, removal of oxidant stress, and appropriate therapy
  • Enteritis-associated methemoglobinemiaMethemoglobinemia may be prolonged and relapsing until enteritis healed.
  • Congenital methemoglobinemiaLifelong cyanosis expected

Complications

  • >10% methemoglobinemia
  • >30% methemoglobinemiaMalaise, fatigue, dyspnea, tachycardia
  • >50% methemoglobinemiaSomnolence, tissue ischemia
  • 60% methemoglobinemia

Additional Reading

  • Canning J, Levine M. Case files of the medical toxicology fellowship at Banner Good Samaritan Medical Center in Phoenix, AZ: methemoglobinemia following dapsone exposure. J Med Toxicol. 2011;7(2):139 " 146. [View Abstract]
  • Osterhoudt KC. Methemoglobinemia. In: Erickson TB, Ahrens WR, Aks SE, eds. Pediatric Toxicology. New York: McGraw Hill; 2005:492 " 500.
  • Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South Med J. 2011;104(11):757 " 761. [View Abstract]

Codes

ICD09

ICD10

  • D74.9 Methemoglobinemia, unspecified
  • D74.8 Other methemoglobinemias
  • D74.0 Congenital methemoglobinemia

SNOMED

  • 38959009 Methemoglobinemia (disorder)
  • 191390009 Drug-induced methemoglobinemia
  • 267550008 Congenital methemoglobinemia (disorder)

FAQ

  • Q: Can methemoglobinemia be diagnosed by the color of the blood?
  • A: The "chocolate brown " blood of methemoglobinemia is most easily noted when compared to "control " blood on a white filter paper background. In contrast to deoxygenated blood from patients with cardiopulmonary disease, methemoglobin-darkened blood does not redden on exposure to room air.
  • Q: Is methemoglobin responsible for the profound metabolic acidosis often found in diarrheal infants?
  • A: Benzocaine-induced methemoglobinemia rarely causes acidosis in infants. In contrast, infants with enteritis-associated methemoglobinemia often have a profound acidemia with a relatively narrow anion gap. Acidosis should be considered a contributing or coexisting factor, rather than a result, of methemoglobinemia among infants with diarrhea.