Oral analgesic gel contains benzocaine, which is an oxidizing agent and a common cause of methemoglobinemia. The pictured cyanosis and classic “chocolate” blood are seen with this condition.
Methemoglobinemia is a disorder of hemoglobin in which the iron atom has been oxidized from the normal Fe2+ to Fe3+. The Fe3+ iron is unable to bind to oxygen, effectively resulting in anemia and impaired oxygen delivery. Methemoglobinemia can be congenital due to enzyme deficiency, or acquired from exposure to a potent oxidizing agent. A variety of xenobiotics can act as oxidizing agents, inducing methemoglobinemia. Common agents include local anesthetics, dapsone, quinones, sulfonamides, phenazopyridine, and nitrites [1, 2].
What are the symptoms of Methemoglobinemia?
All symptoms are the result of impaired oxygen delivery to tissues and resulting end-organ dysfunction.
Signs and symptoms can include :
Chocolate brown color of arterial blood
Low O2 saturation (usually about 85%) on pulse oximetry that does not improve with supplemental oxygen.
How can you diagnose methemoglobinemia?
Regular pulse oximeters work by measuring absorption of different wavelengths of light, and since methemoglobin absorbs light differently, pulse-oximetry readings will be falsely low, usually about 85%-88%. 
The most common confirmatory test for methemoglobinemia is co-oximetry (multiple-wavelength oximetry) and results are usually reported as a percentage of methemoglobin.
Some blood gas analyzers are also able to detect methemoglobin from arterial or venous samples.
The oxidative stress that causes methemoglobinemia can also cause hemolysis, therefore patients being evaluated for methemoglobinemia should also be evaluated for hemolytic anemia.
How do you treat methemoglobinemia?
The primary treatment of acquired methemoglobinemia is identifying the offending agent and avoiding further exposure.
Mild acquired methemoglobinemia is self-limited and does not require further treatment.
Methylene blue is the antidote of choice for patients with signs and symptoms of end-organ injury from methemoglobinemia. It can reduce the Fe3+ in methemoglobin back to Fe2+.
Exchange transfusion can be used in patients with severe methemoglobinemia.
Vitamin C (ascorbic acid) can reduce Fe3+, but because it takes 24-48 hours to take effect, it is of limited use in patients with severe methemoglobinemia.
What are the indications and dosage for methylene blue?
Blood methemoglobin level > 30%
Lower methemoglobin levels with symptoms of poor oxygen delivery including :
Altered mental status
Ischemic chest pain
Shortness of breath
Signs of hypoperfusion
1 to 2 mg/kg of body weight infused intravenously over 5 minutes, followed by a 15-30 mL flush of normal saline or LR to minimize pain [6-8]
May be repeated if cyanosis persists.
If cyanosis persists after 2 doses, consider the possibility of G6PD deficiency. Treatment for methemoglobinemia in G6PD deficiency may consist of ascorbic acid, exchange transfusion, and hyperbaric oxygen [7, 9].
Adverse Effects of Methylene Blue
Pain at infusion site
Blue discoloration of urine and serum
Interferes with pulse oximetry, resulting in falsely low readings after administration.
Interference with laboratory studies that use light absorption.
Can cause serotonin toxicity in combination with serotonergic medications.
Use with caution in patients with G6PD deficiency, as methylene blue is itself an oxidizing agent and can cause hemolytic anemia in high doses.
Methemoglobinemia results from oxidation, or loss of an electron, of the iron atom in hemoglobin.
Methemoglobinemia can be induced by medications such as
Symptoms include cyanosis, pulse oximetry reading in mid-80’s that does not improve with supplemental oxygen, shortness of breath, and altered mental status.
Methylene blue is the first-line treatment for severe methemoglobinemia.
This post has been peer-reviewed on behalf of ACMT by Drs. Rob Hendrickson, Bryan Judge, and Louise Kao.
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Rafael Lima, MD
Medical Toxicology Fellow
Indiana University School of Medicine