Methemoglobinemia-causes and management

Methemoglobin contains iron in the ferric state (Fe3+) rather than the reduced ferrous form (Fe2+) found in hemoglobin. This structural change causes an alteration in the blood’s ability to bind oxygen.

Methemoglobin is generated by oxidation of the heme iron moieties to the ferric state, causing a characteristic bluish-brown muddy colour resembling cyanosis. Methemoglobin has such high oxygen affinity that virtually no oxygen is delivered. Methemoglobinemia often causes symptoms of cerebral ischemia at levels >15%; levels >60% are usually lethal.

Causes

• Congenital methemoglobinemia arises from globin mutations that stabilize iron in the ferric state (e.g., HbM Iwata [α87His→Tyr] or from mutations that impair the enzymes that reduce methemoglobin to hemoglobin (e.g., methemoglobin reductase, NADP diaphorase).
• Acquired methemoglobinemia is caused by toxins that oxidize heme iron, notably nitrate and nitrite-containing compounds, including drugs commonly used in cardiology and anesthesiology.
  Trimethoprim
  Sulfonamides
  Dapsone
  Primaquine
  Tefnoquine
  Benzocaine/Lidocaine
  Rasburicase
  inhaled Nitric oxide (iNO)
  cyanide antidote kits

Diagnosis

• Methemoglobin should be suspected in patients with hypoxic symptoms who appear cyanotic but have a Pao2 sufficiently high that hemoglobin should be fully saturated with oxygen.
• A history of nitrite or other oxidant ingestions may not always be available; some exposures may be inapparent to the patient, and others may result from suicide attempts.
• The characteristic muddy appearance of freshly drawn blood can be a critical clue.
• The best diagnostic test is methemoglobin assay, which is usually available on an emergency basis.

Formation of methemoglobin leads to an overall reduced ability of the red blood cell to release oxygen to tissues, with the associated oxygen–hemoglobin dissociation curve therefore shifted to the left.

Treatment modalities for methemoglobinemia include the following:

1. Methylene blue – This is the primary emergency treatment for documented symptomatic methemoglobinemia.

• Intravenous injection of 1 mg/kg of methylene blue is effective emergency therapy.
• Milder cases and follow-up of severe cases can be treated orally with methylene blue (60 mg three to four times each day)

Methylene blue restores the iron in hemoglobin to its normal (reduced) oxygen-carrying state. This is achieved by providing an artificial electron acceptor for NADPH methemoglobin reductase. The NADPH is generated via the hexose monophosphate shunt.

• Contraindicated in G6PD deficiency and ineffective with haemoglobin M

2) Exchange transfusion – This can be considered for patients who do not respond to methylene blue or G6PD-deficient individuals who are severely symptomatic

3) Hyperbaric oxygen treatment – This is another option when methylene blue therapy is ineffective or contraindicated

Also, vitamin C can occasionally reduce cyanosis associated with chronic methemoglobinemia but has no role in treatment of acute acquired methemoglobinemia.