ACMT methemoglobinemia hand blue

Exposure to which of the following could produce the pictured results?

  1. Carbon monoxide
  2. Lead paint
  3. Morphine
  4. Oral analgesic gel

oral analgesic gel can cause methemoglobinemia

4 – Oral analgesic gel

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 [3]:

  • Cyanosis
  • Chocolate brown color of arterial blood
  • Low O2 saturation (usually about 85%) on pulse oximetry that does not improve with supplemental oxygen.
  • Dyspnea
  • Headache
  • Syncope
  • Coma
  • Seizures

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%. [4]
  • 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?

  • Indications
    • Blood methemoglobin level > 30%
    • Lower methemoglobin levels with symptoms of poor oxygen delivery including [5]:
      • Altered mental status
      • Ischemic chest pain
      • Shortness of breath
      • Signs of hypoperfusion
  • Dosing
    • 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.

Bedside Pearls

  • Methemoglobinemia results from oxidation, or loss of an electron, of the iron atom in hemoglobin.
  • Methemoglobinemia can be induced by medications such as
    • Local anesthetics
    • Dapsone
    • Quinones
    • Sulfonamides
    • Phenazopyridine
    • Ntrites
  • 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.


  1. Curry S. Methemoglobinemia. Ann Emerg Med. 1982;11(4):214-221. doi:10.1016/s0196-0644(82)80502-7. PMID 7073040
  2. Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. 2004;164(11):1192-1196. doi:10.1001/archinte.164.11.1192. PMID 15197044
  3. Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth. 2014;28(4):1043-1047. doi:10.1053/j.jvca.2013.02.005. PMID 23953868
  4. Mack E. Focus on diagnosis: co-oximetry. Pediatr Rev. 2007;28(2):73-74. doi:10.1542/pir.28-2-73. PMID 17272524
  5. El-Husseini A, Azarov N. Is threshold for treatment of methemoglobinemia the same for all? A case report and literature review. Am J Emerg Med. 2010;28(6):748.e5-748.e10. doi:10.1016/j.ajem.2009.10.014. PMID 20637402
  6. Kearney TE, Manoguerra AS, Dunford JV Jr. Chemically induced methemoglobinemia from aniline poisoning. West J Med. 1984;140(2):282-286. PMID 6730477
  7. Howland M. Methylene Blue, in Goldfrank’s Toxicologic Emergencies, L. Nelson, et al., Editors. 2019, McGraw-Hill Education: New York. p. 1713-1715.
  8. Price D. Methemoglobin Inducers, in Goldfrank’s Toxicologic Emergencies, L. Nelson, et al., Editors. 2019, McGraw-Hill Education: New York. p. 1703-1712.
  9. Rosen PJ, Johnson C, McGehee WG, Beutler E. Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med. 1971;75(1):83-86. doi:10.7326/0003-4819-75-1-83. PMID 5091568
Rafael Lima, MD

Rafael Lima, MD

Medical Toxicology Fellow
Indiana University School of Medicine
Rafael Lima, MD

Latest posts by Rafael Lima, MD (see all)

Arthur Daigh, MD

Arthur Daigh, MD

Assistant Professor of Clinical Emergency Medicine
Indiana University School of Medicine
Arthur Daigh, MD

Latest posts by Arthur Daigh, MD (see all)