Tox Time: Methemoglobinemia

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January 16, 2018 by jtreb

Connie Benge is a 33 yo F /w a history of depression brought in by EMS for altered mental status. Per her husband, she started complaining of a headache and some shortness of breath earlier today. Later, she began acting differently and “not herself” and this prompted her husband to call 911. She recently returned from a trip to Africa with her husband. ABC intact, GCS 12 (E3, V5, M5), dexi 130. Vitals notable for tachypnea to 35 and satting 85% despite nonrebreather.  

What: Methemoglobinemia. Patients will present with a variety of symptoms depending on the level of methemoglobinemia, ranging from asymptomatic, mild cyanosis, anxiety, headache, tachycardia, chest pain, depressed mental status, arrhythmias, seizures, and coma. Can think about as follows:

-10% MetHb –> cyanosis

-20-50% MetHb –> dizziness, fatigue, headache, shortness of breath

-50-70% MetHb –> myocardial ischemia, lethargy, stupor, seizures

->70% MetHb –> death


Who: Congenital or Acquired

-Congenital (rare) –> NADH cytochrome b5 reductase deficiency, hemoglobin M disease, cytochrome b5 deficiency

-Acquired (more common and the focus of this post)–> Usually from exposure to an oxidizing agent/medication such as:

-Anesthetics (particularly benzocaine, but also prilocaine, lidocaine)

-Antimalarial medications




-Nitrates (nitroprusside, nitroglycerin, nitrous oxide)




How:  Short answer: Hemoglobin becomes modified to a form that cannot carry oxygen

Less short answer: An iron moiety in hemoglobin loses an electron and goes from ferric (Fe3+) to ferrous Fe2+) state due to the oxidative effects of the toxin/drug/medication. This makes the hemoglobin unable to carry oxygen or carbon dioxide. Methemoglobinemia reduces the oxygen-carrying capacity of the blood (and ultimately leads to hypoxia) in two ways:

1) Methemoglobin cannot carry oxygen

2) Methemoglobin causes a left shift on the oxyhemoglobin dissociation curve. Regular hemoglobin will be binding oxygen with increased affinity and will have reduced ability to release oxygen to tissues.

In those with NADH reductase deficiency, they are unable to reduce Fe3+ to Fe2+


Clues:-Peripheral or generalized cyanosis

-Oxygen saturation hovering around 85% despite supplemental O2

-Normal PaO2 (dissolved oxygen content still the same)

-“Chocolate brown” color of blood


Management: As always, ABCs first. Co-oximetry will detect methemoglobin (along with levels of oxyhemoglobin and carboxyhemoglobin)–usually it is performed on an arterial blood sample, but fingertip co-oximetry devices exist. Baseline methemoglobin level is approximately 1% of total hemoglobin. Be sure to rule out other causes of altered mental status as appropriate and address symptom specific complaints as well (ie, if chest pain, ekg/trop etc).

Initial treatment involves:

1) Discontinue offending agent

2) High flow oxygen –> Even if you are not raising levels above 90%,, it is important to help saturate the available hemoglobin with oxygen

3) Methylene blue –> The classic antidote. The methylene blue acts as a cofactor that facilitates NADPH methemoglobin reductase –> methylene blue gets reduced to leukomethylene blue –> donates an electron to ferric iron –> ferrous state –> hemoglobin back to normal!

                -1-2mg/kg over 5 minutes, repeat dose if no effect; improvement can be seen within 20-30minutes.

                -Be aware—methylene blue is contraindicated (and ineffective) in G6PD deficiency. It can precipitate a hemolytic anemia.

4) Other modalities include exchange transfusion, hyperbaric O2, and ascorbic acid



Hoffman RS, Nelson LS, Howland MA, Lewin NA, Flomenbaum NE, and Goldrank LR. “Methemoglobin Inducers” and “Methylene Blue.”  Goldfrank’s Manual of Toxicologic Emergencies. McGraw Hill, 2007. 977-987. Print.

Prchal JT. Clinical features, diagnosis, and treatment of methemoglobinemia. UpToDate 2017. Accessed at




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