Case Presentation: A 37 y/o woman presents to the ED with altered mental status. The vital signs are within normal limits. The history is provided by a friend who states that the patient was normal 2 hours ago when they were together. When she returned home, she found the patient in this state next to an empty bottle of acetaminophen (APAP) and 5 empty beer cans. A recent loss in the family has led to some depression in the last few weeks. A battery of labs are sent off including a ‘tox panel’ consisting of serum EtOH, salicylate, and APAP levels. The presumed time of ingestion is 2 hours prior to presentation.

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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.

Figure 1. Blue foot

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.

Background

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.

Mechanism

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.

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

Diagnosis

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

Treatment

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.

Figure 3. Methylene blue antidote

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.

Pearls

• 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.