Basics
Description
- 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 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.
- 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 anemia
- Oxidant stress on the globin protein may cause hemolysis.
- Sulfhemoglobinemia
- Oxidant stress on the hemoglobin porphyrin ring may cause sulfhemoglobinemia.
Diagnosis
History
- Age of onset
- New onset of cyanosis in children older than 6 months of age is unlikely to be due to congenital or enteritis-associated methemoglobinemia.
- Source of water
- Well water may be contaminated with nitrates.
- Drug or chemical exposure
- May suggest a source of toxic methemoglobinemia
- Diarrhea
- May suggest enteritis-associated methemoglobinemia
Physical Exam
- Cyanosis
- Cyanosis becomes apparent in the presence of 1.5 g/dL of methemoglobin (in contrast to 4 " 5 g/dL of deoxyhemoglobin).
- Heart murmur
- May suggest right-to-left intracardiac shunting rather than methemoglobinemia
- Abnormal lung auscultation:
- May suggest cyanosis due to pulmonary disorder
- Signs and symptoms
- Malaise
- Fatigue
- Dyspnea
- Tachycardia
- Cyanosis
Diagnostic Tests & Interpretation
Lab
- Oxygen saturation
- Oxygen saturation measured by pulse oximetry is artificially low, but oxygen saturation calculated from arterial blood gas is normal (a "saturation gap " ).
- Co-oximetry
- Multiple-wavelength co-oximetry is the standard for quantifying methemoglobin in the blood.
- Hemoglobin quantitation
- The percent methemoglobin concentration must be considered in relation to the total hemoglobin.
- Anemia may suggest concurrent hemolysis.
- Serum bicarbonate
- Metabolic 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) assay
- G6PD deficiency does not predispose to methemoglobinemia and should not be routinely ordered.
- Hemoglobin electrophoresis
- Hemoglobin 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% methemoglobinemia
- Contraindications (relative): known, severe G6PD deficiency
- Methylene blue therapy may be ineffective if
- Patient 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 methemoglobinemia
- Administer 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 methemoglobinemia
- No 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 methemoglobinemia
- Consider consultation with a medical toxicologist.
- May require environmental investigation
- Enteritis-associated methemoglobinemia
- Careful formula rechallenge warranted if possibility exists for milk protein allergy or other dietary intolerance
- Congenital methemoglobinemia
- Consider consultation with a hematologist.
Prognosis
- Toxic methemoglobinemia
- Full recovery with recognition, removal of oxidant stress, and appropriate therapy
- Enteritis-associated methemoglobinemia
- Methemoglobinemia may be prolonged and relapsing until enteritis healed.
- Congenital methemoglobinemia
- Lifelong cyanosis expected
Complications
- >10% methemoglobinemia
- >30% methemoglobinemia
- Malaise, fatigue, dyspnea, tachycardia
- >50% methemoglobinemia
- Somnolence, 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.