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Methemoglobinemia: diagnosis

Methemoglobin (MetHb) is altered state of hemoglobin (Hb) in which the ferrous (Fe2+) irons of heme are oxidized to the ferric (Fe3+) state. The ferric hemes of MetHb are UNABLE to bind oxygen (O2). Thus, oxygen dissociation curve is left-shifted, making it more difficult to release O2.

Methemoglobinemia types:

  • Congenital – diminished enzymatic reduction of MetHb back to functional Hb. Affected patients appear cyanotic but are generally asymptomatic.
  • Acquired – from specific drugs that cause oxidation of Hb to MetHb more rapidly than MetHb is reduced to Hb. Can be fatal.

Drugs causing MetHb:

  • local anesthetics: prilocaine (with lidocaine in EMLA cream. Large amount – 600 mg doses required for development of MetHb; prilocaine generates O-toluidine which oxidizes Hb)
  • lidocaine
  • benzocaine (Hurricane spray, Cetacaine – benzo- and tetracaine)
  • nitroglycerine, sodium nitroprusside
  • phenytoin
  • sulfonamides
  • metoclopramide

Normal concentration of MetHb – < 1% of total Hb ( autooxidation of Hb to MetHb occurs spontaneously at a slow rate, each day converting 0.5 to 3% of the available Hb to MetHb. This autooxidation, combined with the subsequent reduction of MetHb acts to maintain a steady-state level of MetHb).

When > 10% (or 1.5 g/dL absolute concentration of MetHb) – central cyanosis occurs.Peak levels – 4-8 hrs after administration of local anesthetic (i.e. prilocaine).

Symptoms:Cyanosis — a slate-blue color of the skin and mucous membranes, a finding that is due to the different absorbance spectrum of MetHb compared with oxyHb.

MetHb < 20%: asymptomatic or have headache, fatigue, dyspnea, and lethargy (cerebral ischemia)

MetHb > 20%: respiratory depression, altered consciousness, shock, seizures, and death may occur.

MetHb > 40% – life threatening.

Clues for methemoglobinemia:

  • Cyanosis and low SpO2 in the presence of a normal arterial PO2 by ABG
  • Presence of “chocolate, dark-red, brownish to blue “ colored arterial blood (color does not change with addition of O2) and brown urine


The diagnosis is confirmed by direct measurement of methemoglobin by amultiple wavelength co-oximeter. On a blood gas,normal PaO2 concentrationsare usually found on analysis.Clinical cyanosis in the presence of normal arterial oxygen tensions is highly suggestive of methemoglobinemia.Pulse oximetry is inaccurate and unreliable in patients with high methemoglobin fractions. However, an abnormal value in an asymptomatic patient may suggest the presence of an elevated methemoglobin fraction.


Methylene blueis the first line. It accelerates the enzymatic reduction of methemoglobin by NADPH-methemoglobin reductase and also reduces to leucomethylene blue that, in turn, reduces methemoglobin. This iscontraindicated in patients with G6PD deficiency(can cause hemolysis).Hyperbaric O2andexchange transfusions can also be utilized.

An asymptomatic patient with a MetHb level <20% – no therapy other than discontinuation of the offending agent.

Symptomatic patient (or MetHb level is >20%) – methylene blue (MB).MB – 1 to 2 mg/kg IV over 5 min (total dose should not exceed 7-8 mg/kg – MB can cause dyspnea, chest pain, hemolysis). MB provides an artificial electron transporter for the reduction of MetHb via the NADPH-dependent pathway. The response – rapid; the dose may be repeated in one hour if the level of MetHb is still high 1 hr after the initial infusion.Rebound methemoglobinemia may occur up to 18 hours after MB administration, due to prolonged absorption of lipophilic agents (benzocaine) from adipose tissue. It is reasonable to perform serial measurements of MetHb levels following treatment with MB. MB should not be administered to patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, since the reduction of MetHb by MB is dependent upon NADPH generated by G6PD (hemolysis). An alternative treatment for these patients – ascorbic acid (2mg/kg).

Blood transfusion or exchange transfusion may be helpful in patients who are in shock. Hyperbaric oxygen has been used with anecdotal success in severe cases.