Methaemoglobinaemia

A condition in which haemoglobin iron is oxidised from the ferrous (Fe2+) to the ferric (Fe3+) state, forming methaemoglobin, which cannot bind oxygen and additionally left-shifts the oxygen dissociation curve of remaining normal haemoglobin, worsening tissue oxygen delivery beyond what the methaemoglobin fraction alone would predict.

Pathophysiology

Physiologically, a small fraction of haemoglobin is continuously oxidised and is normally reduced back to the ferrous state by NADH-dependent cytochrome b5 reductase (the major pathway, responsible for over 95% of reduction capacity) and, to a lesser extent, NADPH-methaemoglobin reductase (activated pharmacologically by methylene blue). Methaemoglobinaemia arises when oxidation overwhelms this reductive capacity.

Causes

• Congenital: cytochrome b5 reductase deficiency (autosomal recessive; type I affects red cells only, type II is generalised and causes severe neurological impairment), or haemoglobin M variants (structural haemoglobinopathies with abnormal heme pocket favouring the ferric state).
• Acquired (far more common): oxidising drugs and toxins --- dapsone, local anaesthetics (particularly benzocaine and prilocaine), nitrates/nitrites (including well water contamination and nitroglycerin), nitric oxide, sulfonamides, chloroquine/primaquine, phenazopyridine, aniline dyes, and rasburicase (contraindicated in G6PD deficiency for the same oxidant mechanism).
• Neonates are particularly susceptible given physiologically lower cytochrome b5 reductase activity and higher susceptibility to nitrate exposure (well water, some vegetables).

• Cyanosis that is disproportionate to the measured oxygen saturation and does not improve with supplemental oxygen --- this is the classical clinical clue.
• Chocolate-brown coloured blood, visible on drawing a sample, a striking and diagnostically useful bedside sign.
• Symptoms correlate with methaemoglobin fraction: under 10-15% typically asymptomatic beyond cyanosis; 15-20% mild symptoms (headache, mild dyspnoea); 20-50% significant symptoms (fatigue, dyspnoea, tachycardia, confusion, chest pain); over 50-70% severe (seizures, arrhythmia, metabolic acidosis, coma) and potentially fatal.
• Pulse oximetry is unreliable and characteristically reads in the mid-80s percent regardless of the true methaemoglobin fraction, because methaemoglobin absorbs light at both measured wavelengths similarly.

• Co-oximetry (arterial or venous blood gas analyser with multi-wavelength spectrophotometry) is the definitive test, directly measuring the methaemoglobin fraction --- standard two-wavelength pulse oximetry cannot make this diagnosis.
• The saturation gap: a measured (co-oximetry) oxygen saturation significantly lower than the calculated saturation from PaO2, or a pulse oximetry reading that plateaus around 85% despite high supplemental oxygen and a normal PaO2, is a strong clue even before co-oximetry results return.
• Identify the causative exposure with a careful drug and toxin history.
• Full blood count and film, glucose-6-phosphate dehydrogenase level (important before giving methylene blue, given the risk of precipitating haemolysis in deficient patients), and lactate/blood gas to assess tissue hypoxia and acidosis.
• Genetic testing for suspected congenital cytochrome b5 reductase deficiency or haemoglobin M in the absence of an identifiable acquired cause, particularly in a cyanotic neonate.

• Remove/stop the causative agent immediately.
• High-flow supplemental oxygen, which does not correct the methaemoglobin itself but supports oxygenation of remaining functional haemoglobin.
• Methylene blue 1-2 mg/kg intravenously over 5 minutes, the specific antidote, acting as an electron acceptor that accelerates the NADPH-methaemoglobin reductase pathway. Indicated for symptomatic patients or methaemoglobin level above roughly 20-30%. May be repeated after 30-60 minutes if response is inadequate, to a cumulative dose limit (typically 7 mg/kg) given risk of paradoxical methaemoglobinaemia/haemolysis at high doses.
• Methylene blue is ineffective (and potentially harmful, precipitating haemolysis without benefit) in G6PD deficiency, since it depends on NADPH generated via the pentose phosphate pathway; in G6PD-deficient patients, use ascorbic acid (vitamin C, high dose) as a weaker alternative, and consider exchange transfusion or hyperbaric oxygen for severe cases.
• Methylene blue is also ineffective in haemoglobin M disease and in cytochrome b5 reductase type II deficiency, where alternative supportive measures and, in select cases, exchange transfusion are used.
• Exchange transfusion or hyperbaric oxygen reserved for severe, life-threatening methaemoglobinaemia unresponsive to methylene blue, or where methylene blue is contraindicated.
• In congenital cytochrome b5 reductase deficiency (type I), chronic oral ascorbic acid or methylene blue can manage the cosmetic cyanosis; type II carries a poor neurological prognosis requiring supportive multidisciplinary care.
• Educate patients and families about avoiding known precipitating drugs, and counsel on well-water nitrate risk in infants in affected areas.