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A large number of chemical agents are capable of oxidizing ferrous hemoglobin to its ferric state (methemoglobin), a form that cannot carry oxygen. Drugs and chemicals known to cause methemoglobinemia include benzocaine (a local anesthetic found in some topical anesthetic sprays and a variety of nonprescription products), aniline, propanil (an herbicide), nitrites, nitrogen oxide gases, nitrobenzene, dapsone, phenazopyridine (Pyridium), and many others. Dapsone has a long elimination half-life and may produce prolonged or recurrent methemoglobinemia. Amyl nitrite and isobutyl nitrite (“poppers”) are inhaled as sexual stimulants but can result in methemoglobinemia.


Methemoglobinemia reduces oxygen-carrying capacity and may cause dizziness, nausea, headache, dyspnea, confusion, seizures, and coma. The severity of symptoms depends on the percentage of hemoglobin oxidized to methemoglobin; severe poisoning is usually present when methemoglobin fractions are greater than 40–50%. Even at low levels (15–20%), victims appear cyanotic because of the “chocolate brown” color of methemoglobin, but they have normal PO2 results on arterial blood gas determinations. Conventional pulse oximetry gives inaccurate oxygen saturation measurements; the reading is often between 85% and 90%. Severe metabolic acidosis may be present. Hemolysis may occur, especially in patients susceptible to oxidant stress (ie, those with glucose-6-phosphate dehydrogenase deficiency).


A. Emergency and Supportive Measures

Administer high-flow oxygen. If the causative agent was recently ingested, administer activated charcoal. Repeat-dose activated charcoal may enhance dapsone elimination.

B. Specific Treatment

Methylene blue enhances the conversion of methemoglobin to hemoglobin by increasing the activity of the enzyme methemoglobin reductase. For symptomatic patients, administer 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) intravenously. The dose may be repeated once in 15–20 minutes if necessary. Patients with hereditary methemoglobin reductase deficiency or glucose-6-phosphate dehydrogenase deficiency may not respond to methylene blue treatment. In severe cases where methylene blue is not available or is not effective, exchange blood transfusion may be necessary.

Cefalu  JN  et al. Methemoglobinemia in the operating room and intensive care unit: early recognition, pathophysiology, and management. Adv Ther. 2020;37:1714.
[PubMed: 32193811]  
Siendones  E  et al. Cellular and molecular mechanisms of recessive hereditary methaemoglobinaemia type II. J Clin Med. 2018;7:E341.
[PubMed: 30309019]  

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