Methemoglobinemia: Not the Usual Blue Man With Low SpO2

On a Friday night shift, an ambulance brings you a 52 year-old man who had an episode of syncope at a local club. EMS found him confused and hypoxic with poor skin color. The patient was placed on oxygen via face mask en route to your ED without clinical improvement.  On exam, you note a blue discoloration of his extremities, and his chest x-ray and ECG are unremarkable. You draw blood, which appears very dark, and an ABG demonstrates pH 7.39, PCO2 41, and PO2 176.

Blue foot

Figure 1. Blue foot

dark arterial blood

Figure 2. Dark arterial blood

You suspect that your patient has methemoglobinemia, so you order a methemoglobin level which comes back at 37%. The patient receives antidotal therapy, and, on further interviewing, ultimately explains that he had been using amyl nitrate “poppers” at the club prior to arrival.


Hemoglobin is a protein tetramer, with each subunit consisting of an iron-containing heme group. Normally, the iron in heme exists in a reduced state as ferrous iron (Fe 2+). Methemoglobinemia occurs when some proportion of this ferrous iron is oxidized to produce ferric iron (Fe 3+). 1 This oxidation renders the effected heme groups unable to carry oxygen. Even though not every heme group  is oxidized, every heme group in the same hemoglobin tetramer is affected by so-called cooperative binding: oxidized heme molecules induce conformational changes in hemoglobin which increase the un-oxidized heme’s affinity for oxygen. As a result, the oxygen–hemoglobin dissociation curve shifts to the left, and oxygen is less readily released to tissues.

Methemoglobinemia is essentially a functional anemia with normal cardiopulmonary function. Because the cardiovascular system must still circulate these inactivated hemoglobin containing red blood cells, a methemoglobin level of 34% has more effects than if the patient had lost 34% of their blood. The resulting cellular hypoxia leads to a range of end organ dysfunction and clinical signs: gray discoloration, dyspnea, fatigue, acidosis, dysrhythmia, seizure, coma, and ultimately death. Co-morbid anemia as well as cardiopulmonary disease will exacerbate symptoms.


Methemoglobinemia is not always the result of exogenous substances. Normal oxidative metabolism results in a small amount of endogenously produced methemoglobin (usually < 1%). This process is kept in check by NADH methemoglobin reductase, which uses NADH to reduce methemoglobin back to hemoglobin. Genetic deficiencies in this enzyme, as well as alterations in hemoglobin, can lead to congenital methemoglobinemia. 2,3 Infants under 4 months of age are also at increased risk of methemoglobinemia due to immature activity levels of this enzyme. When oxidative stress overwhelms the NADH reduction pathway, methemoglobin levels rise and patients turn blue.

Many agents have been associated with methemoglobinemia.

Aniline dyes Nitrates, Nitrites Sulfa drugs
Benzocaine, Lidocaine Phenazopyridine Trinitrotoluene
Dapsone Prilocaine  Quinones

Additionally, extremes of age, anemia, diarrhea, hospitalization, malnutrition, renal failure, and sepsis are predisposing factors.


Methemoglobinemia should be suspected in patients with low pulse oximetry who do not respond to supplemental oxygen. Low SpO2 readings occur because pulse oximeters utilize light absorption at 660 and 940 nm to calculate the ratio of oxy-hemoglobin to deoxy-hemoglobin in blood. Methemoglobin absorbs light at both of those wavelengths, thus the presence of these additional hemoglobin species makes SpO2 calculation inaccurate. 4 Arterial blood gas measurement of PO2 is not affected by methemoglobin, resulting in a normal (and often elevated due to supplemental oxygen) calculated SaO2. Whenever there is dissociation between the PO2 and the SpO2, a hemoglobinopathy should be suspected. Additionally, arterial blood has been described as “chocolate brown” with degree of color change correlating to methemoglobin level. 5


Asymptomatic patients with low levels of methemoglobinemia (10% or less) may be managed conservatively by removing oxidizing drugs and arranging follow up. 1 In patients with dapsone-associated methemoglobinemia, administration of cimetidine has been associated with reduced methemoglobin levels. 6 Symptomatic patients or patients with elevated levels of methemoglobin (25% or more) usually require antidotal treatment with methylene blue.

Methylene blue is reduced by NADPH reductase to leukomethylene blue in RBCs, which subsequently reduces methemoglobin to hemoglobin. In this way, though stores of NADH are exhausted, NADPH functions as a reducing agent. Dosing is 1-2 mg/kg of methylene blue administered intravenously over 5 minutes. Though an initial drop in pulse oximeter reading (due to the blue color of the antidote) is expected, cyanosis and methemoglobinemia should improve over the following hour.

Methylene blue antidote

Figure 3. Methylene blue antidote

Intravenous administration of methylene blue

Figure 3. Intravenous administration of methylene blue

While conflicting data exist, many consider G6PD-deficiency (and resulting low levels of NADPH) to be a relative contraindication to methylene blue therapy; treatment failures and hemolysis have been reported in patients with G6PD-deficiency who received high doses of methylene blue. 7  Where methylene blue is not available or contra-indicated, ascorbic acid 0.5 g IV every six hours has been described, but clinical relevance remains uncertain. 8 If treatment fails, consider decontamination to remove remaining oxidant drugs, repeat administration of methylene blue, exchange transfusion, and/or hyperbaric oxygen therapy.


  • Be aware of medications that can lead to methemoglobinemia, especially nitrates/nitrities, local anesthetics, dapsone, phenazopyridine, and aniline dyes.
  • Consider hemoglobinopathy when SpO2 doesn’t improve with supplemental oxygen and when the SpO2 doesn’t correlate with SaO2.
  • In patients with symptoms or elevated levels of methemoglobinemia, consider antidotal therapy with methylene blue 1-2 mg/kg intravenously.
  • Consider consultation with poison control and/or medical toxicology.


Hoffman R, Howland M Ann, Lewin N, Nelson L, Goldfrank L. Goldfrank’s Toxicologic Emergencies, Tenth Edition. McGraw-Hill Education / Medical; 2014.
Hall A, Kulig K, Rumack B. Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. Med Toxicol. 1986;1(4):253-260. [PubMed]
James SD. Fugates of Kentucky: Skin Bluer than Lake Louise. ABC News. Accessed February 22, 2012. [Source]
Barker S, Tremper K, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70(1):112-117. [PubMed]
Shihana F, Dissanayake D, Buckley N, Dawson A. A simple quantitative bedside test to determine methemoglobin. Ann Emerg Med. 2010;55(2):184-189. [PubMed]
Barclay J, Ziemba S, Ibrahim R. Dapsone-induced methemoglobinemia: a primer for clinicians. Ann Pharmacother. 2011;45(9):1103-1115. [PubMed]
Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf. 2010;33(9):713-726. [PubMed]
Rino P, Scolnik D, Fustiñana A, Mitelpunkt A, Glatstein M. Ascorbic acid for the treatment of methemoglobinemia: the experience of a large tertiary care pediatric hospital. Am J Ther. 2014;21(4):240-243. [PubMed]

Future of ALiEM: Need YOUR input

The 2014 year has been amazing. As 2015 approaches, the ALiEM team has gotten quite reflective and thankful for the past amazing 12 months. We can track many things through Google Analytics, but there’s nothing like hearing from our readership directly to help us shape the upcoming 12 months. There are many innovative plans in the works, and your input would be incredibly helpful to help us tailor our priorities to what YOU want. We are a volunteer organization, made up of passionate, early-adopting educators, who are asking for nothing more than YOUR valuable input. Please donate 1 minute of your time to fill out this quick survey. Once you submit your feedback, you can see what everyone else said. The beautiful infographic results page by Google Forms is worth seeing too. Thanks!

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