AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Red blood cells contain 4 hemoglobin chains. Each hemoglobin molecule is composed of 4 polypeptide chains associated with 4 heme groups. The heme group contains an iron molecule in the reduced or ferrous form (Fe²⁺). In this form, iron can combine with oxygen, by sharing an electron, to form oxyhemoglobin. When oxyhemoglobin releases oxygen to the tissues, the iron molecule is restored to its original ferrous state. Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous form. When hemoglobin becomes oxidized, it is converted to the ferric state (Fe³⁺) or methemoglobin. Methemoglobin lacks the electron that is needed to form a bond with oxygen and, thus, is incapable of oxygen transport. Because red blood cells are continuously exposed to various oxidant stresses, blood normally contains approximately 1% methemoglobin levels.

This low level of methemoglobin is maintained by 2 important mechanisms. One protective mechanism against oxidizing agents is the hexose-monophosphate shunt pathway within the erythrocyte. Through this pathway, oxidizing agents are reduced by glutathione prior to the formation of methemoglobin. The second and more important mechanism against methemoglobin formation uses 2 enzyme systems, diaphorase I and diaphorase II. These 2 enzyme systems require nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), respectively to reduce methemoglobin to its original ferrous state. Diaphorase II quantitatively contributes only a small percentage of the red blood cells reducing capacity. However, diaphorase II can be pharmacologically activated by exogenous cofactors (ie, methylene blue) to 5 times its normal level of activity.

Pathophysiology

Oxidation of iron to the ferric state reduces the oxygen-carrying capacity of hemoglobin and produces a functional anemia. In addition, a ferric heme group affects nearby ferrous heme groups. Ferric heme groups impair the release of oxygen from nearby ferrous heme groups on the same hemoglobin tetramer. The result of methemoglobinemia is that oxygen delivery to tissues is impaired and the oxygen hemoglobin dissociation curve shifts to the left.

Organs with high oxygen demands (ie, CNS, cardiovascular system) usually are the first systems to manifest toxicity. Oxygenated blood is red, deoxygenated blood is blue, and blood-containing methemoglobin is a dark reddish brown color. This dark hue imparts clinical cyanosis when methemoglobin levels are at 1.5 g/dL (approximately 10-15% methemoglobin concentration); however, a level of 5 g/dL of deoxygenated blood is required for similar effects. Therefore, when methemoglobin levels are relatively low, cyanosis may be observed without cardiopulmonary symptoms.

Mortality/Morbidity

As methemoglobin levels increase, patients demonstrate evidence of cellular hypoxia. Death occurs when methemoglobin fractions approach 70%. Death can occur at lower levels in patients with significant comorbidities.

Age

• Children, especially those younger than 4 months, are particularly susceptible to methemoglobinemia.
• The primary erythrocyte protective mechanism against oxidative stress is the NADH system. In infants, this system has not fully matured, and the NADH methemoglobin reductase activity and concentrations are low.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Normal methemoglobin concentrations are 1% (range, 0-3%).
• At concentrations of 3-15%, a slight discoloration (eg, pale, gray, blue) of the skin may be present.
• At fractions of 15-20%, the patient may be relatively asymptomatic, but cyanosis is likely to be present.
• Signs and symptoms at fractions of 25-50% are as follows:
• • Headache
  • Dyspnea
  • Lightheadedness
  • Weakness
  • Confusion
  • Palpitations, chest pain
• Signs and symptoms at fractions of 50-70% are as follows:
• • Altered mental status
  • Delirium

Physical

• Discoloration of the skin and blood is the most striking physical finding.
• Cyanosis occurs with the formation of 1.5 g/dL of methemoglobin, as compared to 5 g/dL of deoxygenated hemoglobin.
• Seizures
• Coma
• Dysrhythmias (eg, bradyarrhythmia, ventricular dysrhythmia)
• Acidosis
• Cardiac or neurologic ischemia

Causes

• Compromised physiologic cellular defenses against oxidant stress occur in some patients, including the following:
• • Children younger than 4 months may have underdeveloped protective mechanisms. Infections, especially GI infections, may cause a buildup of systemic oxidants by an overgrowth of gut bacteria.
  • Congenital lack protective cellular capabilities includes those with the following:
    • Patients with NADH methemoglobin reductase (diaphorase I) deficiency may develop congenital methemoglobinemia.
    • Patients with hemoglobin M disease may have abnormal hemoglobin that is not amenable to reduction.
    • Patients with pyruvate kinase deficiency may have an impaired glycolytic pathway, which results in deficient NADH production.
    • Patients with G-6-PD deficiency may have impaired production of NADPH in the hexose-monophosphate shunt.
• Agents that inflict large oxidant stress on patients include the following:
• • Pharmaceutical agents include local anesthetic agents (eg, benzocaine, lidocaine, prilocaine), amyl nitrite, chloroquine, dapsone, nitrates, nitrites, nitroglycerin, nitroprusside, phenacetin, phenazopyridine, primaquine, quinones, and sulfonamides.
  • Environmental agents include the following:
  • • Aniline dyes
    • Aromatic amines
    • Arsine
    • Butyl nitrite
    • Chlorates
    • Chlorobenzene
    • Chromates
    • Combustion products
    • Dimethyltoluidine
    • Foods containing nitrates or nitrites (including well water)
    • Isobutyl nitrite
    • Naphthalene
    • Nitroaniline
    • Nitrobenzene
    • Nitrofurans
    • Nitrophenol
    • Nitrosobenzene
    • Resorcinol
    • Silver nitrate
    • Trinitrotoluene

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Carbon monoxide poisoning
Ergot alkaloid poisoning
Sulfhemoglobinemia
Skin contamination with blue dyes causing skin discoloration

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The diagnosis is confirmed by direct measurement of methemoglobin by a multiple wavelength co-oximeter.
• Arterial blood gas
• • Normal PaO₂ concentrations are usually found on analysis. Clinical cyanosis in the presence of normal arterial oxygen tensions is highly suggestive of methemoglobinemia.
  • Oxygen saturations usually are inaccurate because they are calculated by using measured PaO₂ and pH levels.
  • The measured oxygen saturation is low.
• Pulse oximetry
• • Pulse oximetry is inaccurate and unreliable in patients with high methemoglobin fractions. However, an abnormal value in an asymptomatic patient may suggest the presence of an elevated methemoglobin fraction.
  • Pulse oximetry of patients with low-level methemoglobinemia often reveals falsely low values for oxygen saturation, and it often reveals falsely high values in those with high-level methemoglobinemia.
  • Methemoglobin absorbs light at wavelengths that also absorb deoxyhemoglobin and oxyhemoglobin. Thus, methemoglobin interferes with the colorimetric testing that is used to obtain the percentage of oxyhemoglobin to deoxyhemoglobin.

Imaging Studies

• CT scanning of the head, when appropriate

Other Tests

• Adjunctive laboratory tests include determining lactate levels and serum electrolyte levels. These may be helpful in determining the degree of tissue hypoxia and end-organ dysfunction.
• Urine pregnancy tests should be performed in females of childbearing age.

TREATMENT

Section 6 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Prehospital Care

• Administration of supplemental oxygen
• Removal of the offending oxidizing agent

Emergency Department Care

• Clinical recognition is paramount, as patients may have only vague complaints.
• Treatment is determined by symptomatology.
• Healthy asymptomatic patients without evidence of end-organ damage may require only observation.
• Patients with coronary artery disease or anemia may require therapeutic intervention at lower methemoglobin levels (eg, 10%) than a typical patient would, especially if end-organ dysfunction (eg, cardiac ischemia) is present.
• Supplemental oxygen
• Methylene blue is the first-line antidotal agent. Hyperbaric oxygen therapy or packed RBC exchange transfusions are alternative therapies for patients who are not candidates for methylene blue.
• Dermal decontamination (eg, water rinse, soap scrub, water rinse again)
• GI decontamination (eg, gastric lavage, activated charcoal administration)
• Investigational agents and therapies (eg, vitamin C, an antioxidant, and N-acetylcysteine, a cellular antioxidant)

Consultations

An American Association of Poison Control Centers (AAPCC)-certified regional poison control center or a medical toxicologist should be consulted in life-threatening cases.

MEDICATION

Section 7 of 11  

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Methylene blue is the first-line antidotal therapy.

Methylene blue accelerates the enzymatic reduction of methemoglobin by NADPH-methemoglobin reductase and also reduces to leucomethylene blue that, in turn, reduces methemoglobin. The initial dose is 1-2 mg/kg IV over 5 min. Its effects should be seen in approximately 20 min to 1 h. Patients who are exposed may require repeated dosing, but high doses of methylene blue may actually induce a paradoxical methemoglobinemia.

Treatment failure may occur in patients with ongoing exposure, patients exposed to sulfhemoglobinemia, and patients who have deficient NADPH-methemoglobin reductase enzymatic pathways. Methylene blue should be avoided in patients with G-6-PD deficiency, if possible, because case reports and in vitro models suggest that this antidote may induce hemolysis in this patient population.

Hyperbaric oxygen and exchange transfusion should be considered for patients who are not candidates for methylene blue treatment or when methylene blue is ineffective.

Drug Category: Pharmacologic antidotes

Are used to pharmacologically counteract the condition. Cimetidine may be used in dapsone-induced methemoglobinemia.

Drug Category: Cytochrome P-450 inhibitors

Recommended only for patients with methemoglobinemia secondary to dapsone.

FOLLOW-UP

Section 8 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit all symptomatic patients with abnormal methemoglobin levels.
• Admit all patients who require methylene blue treatment to an intensive care unit.

Complications

• End-organ damage (eg, myocardial infarction, seizure)

Prognosis

• For minor cases of methemoglobinemia, the prognosis is very favorable.
• In severe cases, prognosis is determined by the degree of anoxic end-organ damage.

Patient Education

• Patients who develop methemoglobinemia from oxidant stress of pharmaceutical agents should be warned of other potent oxidant compounds.
• Patients who develop methemoglobinemia secondary to environmental exposure require a meticulous workup to prevent re-exposure of the offending agent. All workplace or household members should be evaluated.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• The major pitfall is the misdiagnosis or the lack of recognition of this syndrome. Since initial symptoms can be vague, it easily can be mistaken for a common "garden variety" adverse drug event.

Special Concerns

• Methylene blue may be ineffective, or even deleterious, in certain situations, including the following:
• • History of G-6-PD deficiency
  • Persistent absorption of offending oxidant toxin
  • Excessive methylene blue administration (ie, discolors skin and produces methemoglobinemia itself)
  • NADPH methemoglobin reductase (ie, diaphorase II) deficiencies
  • Presence of an abnormal hemoglobin (ie, hemoglobin M)
  • Presence of sulfhemoglobinemia

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70%; tube 3, a concentration of 20%; and tube 4, a normal concentration.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

• Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). Sep 2004;83(5):265-73. [Medline].
• Conkling PR. Brown blood: understanding methemoglobinemia. N C Med J. Mar 1986;47(3):109-11. [Medline].
• Ellenhorn MJ, Barceloux DG. Nitrates, nitrites, and methemoglobinemia. In: Medical Toxicology, Diagnosis and Treatment of Human Poisonings. 1988:844-851.
• Fitzsimons MG, Gaudette RR, Hurford WE. Critical rebound methemoglobinemia after methylene blue treatment: case report. Pharmacotherapy. Apr 2004;24(4):538-40. [Medline].
• Henretig FM, Gribetz B, Kearney T, Lacouture P, Lovejoy FH. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988;26(5-6):293-301. [Medline].
• Herman MI, Chyka PA, Butler AY, Rieger SE. Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med. Jan 1999;33(1):111-3. [Medline].
• Howland MA. Methylene blue. In: Goldfrank's Toxicologic Emergencies. 8^th ed. 2006:1746-1748.
• Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. Jun 14 2004;164(11):1192-6. [Medline].
• Price D. Methemoglobin inducers. In: Goldfrank's Toxicologic Emergencies. 8^th ed. 2006:1734-1745.
• Umbreit J. Methemoglobin--it's not just blue: a concise review. Am J Hematol. Feb 2007;82(2):134-44. [Medline].

Article Last Updated: Aug 7, 2007