Methaemoglobinaemia
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Direct answer
Methaemoglobinaemia is a state in which haemoglobin iron is oxidised to the ferric form, so the blood cannot carry oxygen normally and looks chocolate-brown. Its classic clue is a low pulse oximetry reading with a normal PaO2 that does not improve with oxygen. Causes include drugs such as dapsone, nitrates and local anaesthetics, plus congenital NADH cytochrome b5 reductase deficiency, and methylene blue is the antidote for symptomatic cases.
What you must remember
- Mechanism: haemoglobin iron is oxidised from the ferrous to the ferric state, which cannot bind oxygen effectively.
- Blood colour: chocolate-brown blood that does not turn bright red on exposure to air or oxygen.
- Oximetry gap: SpO2 tends to plateau near 85 per cent, while PaO2 on blood gas remains normal.
- Drug causes: dapsone, nitrates and nitroprusside, prilocaine, benzocaine, sulfonamides and primaquine.
- Congenital causes: NADH cytochrome b5 reductase deficiency is the commonest, and haemoglobin M variants are the other main cause.
- Antidote: intravenous methylene blue, usually 1 to 2 mg per kg over five minutes, reduces methaemoglobin back to haemoglobin.
- Cautions: G6PD deficiency predisposes to haemolysis after methylene blue, and serotonergic drugs raise the risk of serotonin syndrome.
Recognising and reversing methaemoglobinaemia
A 35-year-old man on dapsone for leprosy develops cyanosis and breathlessness, with a pulse oximetry reading of 84 per cent that does not rise with oxygen. His arterial PaO2 is normal, and the mismatch is the key diagnostic clue.
- Suspect from the mismatch: a low SpO2 with a normal PaO2 and cyanosis unresponsive to oxygen points to methaemoglobin rather than lung disease.
- Confirm with co-oximetry: a co-oximeter measures methaemoglobin directly, because standard blood gas calculations do not reliably report it.
- Withdraw the trigger: stop dapsone, the nitrate, the local anaesthetic or the other suspected agent, and avoid re-exposure.
- Consider G6PD status: check it where possible, because methylene blue is generally avoided in known G6PD deficiency; in a life-threatening case, seek senior toxicology advice rather than withholding all treatment.
- Give methylene blue: intravenous methylene blue, usually 1 to 2 mg per kg over five minutes, reverses the defect within minutes to hours, and the dose is not repeated without reassessment.
- Use alternatives when needed: oral or intravenous ascorbic acid is a weaker option, often used where methylene blue is unsuitable, and exchange transfusion is reserved for refractory cases.
Where the exam tries to catch you
Methaemoglobinaemia questions reward recognition of the mismatch between the oximeter and the blood gas.
- Trap: giving more oxygen for cyanosis with a low SpO2 and normal PaO2 Correct: oxygen delivery is not the problem, since the defect lies in the haemoglobin, so the treatment is methylene blue.
- Trap: assuming a normal PaO2 excludes hypoxaemia Correct: the arterial oxygen tension is normal, but oxygen content is reduced, which the low SpO2 reflects.
- Trap: giving methylene blue to a patient on an SSRI without thinking Correct: methylene blue inhibits MAO and can precipitate serotonin syndrome, so the risk is weighed first.
- Trap: expecting methylene blue to work for haemoglobin M variants Correct: HbM variants do not respond to methylene blue, because the reductase pathway is not the cause.
Frequently asked questions
What is the classic clue that points to methaemoglobinaemia?
The classic clue is cyanosis with a pulse oximetry reading near 85 per cent that does not improve with oxygen, while the PaO2 is normal. Chocolate-brown blood that does not redden on exposure to air is another characteristic finding. A gap between SpO2 and PaO2 should prompt co-oximetry.
Which drugs most commonly cause methaemoglobinaemia?
Dapsone, nitrates and nitroprusside, prilocaine, benzocaine, sulfonamides and primaquine are classic causes of drug-induced methaemoglobinaemia. Dapsone is particularly important in India because it forms part of leprosy treatment. The condition usually resolves once the causative drug is withdrawn.
What is the treatment for methaemoglobinaemia?
Intravenous methylene blue, usually given at 1 to 2 mg per kg over five minutes, is the antidote for symptomatic methaemoglobinaemia. It restores haemoglobin's ability to carry oxygen by reducing the ferric iron. The trigger must also be removed, and serotonergic drugs are reviewed before methylene blue is given.
Why does methylene blue carry a risk in G6PD deficiency?
Methylene blue can itself oxidise haemoglobin and cause oxidative stress within red cells. In G6PD deficiency, red cells have less NADPH to protect against that stress, so haemolysis can follow. Methylene blue is therefore generally avoided in known deficiency, where ascorbic acid or exchange transfusion is considered instead.
What is the commonest congenital cause of methaemoglobinaemia?
NADH cytochrome b5 reductase deficiency is the commonest congenital cause, inherited in an autosomal recessive pattern. It causes lifelong mild cyanosis without systemic illness. Haemoglobin M variants also cause the condition, but they are inherited in an autosomal dominant pattern and do not respond to methylene blue.