Question 1

List the causes and outline your management of a patient with methaemoglobinaemia.

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College Answer

Methaemoglobin = altered state of haemoglobin where ferrous ions (Fe2+) of haem are oxidised to the ferric state (Fe3+), which are unable to bind oxygen. Usual level < 1.5%. Results in appearance of cyanosis despite normal arterial PaO2.

Causes of methaemoglobinaemia: congenital (eg. cytochrome b5 reductase deficiency, haemoglobin M disease), acquired (commonest cause overall; due to exposure to any of a number of toxins/drugs eg. aniline dyes, benzene derivatives, chloroquine, dapsone, plilocaine, metoclopramide, nitrites [including nitroglycerin and nitric oxide], sulphonamides).

Management: includes confirmation of diagnosis (co-oximetry ± specific assay), and history of exposures (including toxins and drugs). Congenital cases usually need no more than avoidance of precipitants. Acquired cases need cessation of exposure to precipitants, but in severe cases may require additional specific treatment. Methylene blue (1-2 mg/kg over 5 minutes, may need to be repeated) provides an artificial electron acceptor to facilitate reduction of MetHb via the NADPH-dependent pathway. Response to methylene blue cannot be followed by co-oximetry (detects methylene blue as MetHb).

Alternative agent (eg. ascorbic acid) may be given if methylene blue is contraindicated (eg. G6PD deficiency). Rarely, severe cases (eg. MetHb > 50%) may require exchange transfusion or hyperbaric oxygen.


Methaemoglobin is what happens when the Fe2+ of iron is oxidised into Fe3+. The vast majority of the time it is drug-related. Question 29 from the second paper of 2012 presents a dapsone-related case. Very occasionally, some unlucky person is born with a congenital methaemoglobinaemia.  A list of causes of methaemoglobinaemia is offered below.

Physiological normality

  • Normal rate of autooxidation: 0.5-3% of total Hb per day

Direct Oxidants of Haemoglobin

  • Methylene blue
  • Nitrites
    • Sodium or potassium nitrite
    • Amyl nitrite
    • Nitric oxide
  • Nitrates
    • GTN
    • Nitroprusside
  • Antimalarial quinones
    • Pentaquine
    • Primaquine (maybe)
    • Chloroquine (big maybe)

Congential metabolic defects

  • Cytochome b5 deficiency
  • Cytochrome b5 reductase 3 deficiency
  • Haemoglobin M disease

Indirect Oxidants of Haemoglobin

  • Aromatic hydrocarbons
    • Aniline
    • Naphthalene
    • Nitrobenzene
  • Sulfonamides
    • Trimethoprim / sulfomethoxazole (Bactrim)
    • Dapsone
  • Random antibotics
    • Nitrofurantoin
  • Local anaesthetics
    • Benzocaine
    • Prilocaine

Management of methaemoglobinaemia consist of trying to reduce Fe3+ back to Fe2+.

Glucose infusion

  • Whichever reducing agent is used, glucose will be required for the generation of NADPH by the hexose monophosphate shunt.

Methylene blue

  • 1-2mg/kg over 5 minutes
  • By cycling through its two states (methylene blue and leucomethyene blue) this molecule burns through glucose to reduce Fe3+ to Fe2+ by donating electrons to the ferric iron.
  • This reaction requires G6PD.
  • In the absence of G6PD, haemolysis will develop;
  • thus, G6PD-deficient patients will require an alternative reducing agent.

Alternative reducing agents:

  • Ascorbic acid, 200mg/k: activity seems to rely on the presence of glutathione
  • N-acetylcysteine (well, it seems to work in vitro)

Blood transfusion

  • If one is unable to conver the affected haemoglobin, one needs to supplement with more fresh haemoglobin. An exchange transfusion is possible (i.e. replace all the red cells) if the causative agent has been convincingly cleared from the body; however this is an inelegant solution.

Supportive management

  • It is tiresome and ridiculous to write "supportive management" for all these "how would you manage" questions. Surely, the college does not believe that the candidates who fail to mention FASTHUG in writing would willfully withhold supportive management from their patients? No Mr Jones, I will not offer you nasogastric feeds, and you can sort out your own thromboprophylaxis. 


Wright, Robert O., William J. Lewander, and Alan D. Woolf. "Methemoglobinemia: etiology, pharmacology, and clinical management."Annals of emergency medicine 34.5 (1999): 646-656.


Modarai, B., et al. "Methylene blue: a treatment for severe methaemoglobinaemia secondary to misuse of amyl nitrite." Emergency Medicine Journal 19.3 (2002): 270-270.


Deeny, James, Eric T. Murdock, and John J. Rogan. "Familial Idiopathic Methaemoglobinaemia: Treatment with Ascorbic Acid." British medical journal1.4301 (1943): 721.


Ward, Kristina E., and Michelle W. McCarthy. "Dapsone-induced methemoglobinemia." Annals of Pharmacotherapy 32.5 (1998): 549-553.


Wright, Robert O., William J. Lewander, and Alan D. Woolf. "Methemoglobinemia: etiology, pharmacology, and clinical management."Annals of emergency medicine 34.5 (1999): 646-656.