Methemoglobin is produced as a result of normal oxidant stress and comprises approximately 3% of a person's total hemoglobin.
2 Two primary adaptive mechanisms can restrict this value to less than 1%: the cytochrome b5-MetHb reductase pathway and the NADPH-MetHb reductase pathway.
2 The cytochrome b5-MetHb reductase pathway is responsible for 95% to 99% of the reductive activity that converts Fe
3+ to Fe
2+ and essentially restores normal hemoglobin functioning. It uses nicotinamide adenine dinucleotide (NADH) as a major cofactor. This pathway is capable of operating at a conversion rate of up to 15% per hour. The NADPH-MetHb reductase pathway accounts for up to 5% of the reductive activity that converts Fe
3+ to Fe
2+. The production of NADPH relies on the availability of G6PD and is provided by the hexose monophosphate shunt.
2 This pathway can be induced with the administration of methylene blue.
10 Ascorbic acid and glutathione account for small amounts of reducing activity.
3 N-acetylcysteine and riboflavin have been studied as well, with conflicting results.
11
Two forms of methemoglobinemia exist: hereditary and acquired. The hereditary form is associated with a deficiency of intrinsic cytochrome b5-MetHb reductase or with the presence of congenital hemoglobin M, a form of hemoglobin unable to bind oxygen.
7 Acquired forms of methemoglobinemia are much more common
6 and are a result of exposure to a long list of common oxidants (
Figure), most notably nitrates, chlorates, aniline compounds, benzocaine, and dapsone.
Benzocaine, prilocaine, and dapsone are among the most commonly studied oxidants. Prilocaine, a common anesthetic in dental procedures, appears to be the most potent topical anesthetic to cause methemoglobinemia.
12 Sambrook et al
13 looked at 221 adverse reactions to dental local anesthetics and found that prilocaine was used in 59% of all cases and in all 6 cases of methemoglobinemia. In a separate study
14 of 242 cases of methemoglobinemia, 60.7% of cases were associated with dental procedures. Currently, few systemic reports of methemoglobinemia in a hospital setting exist. One such report
15 details dapsone being the cause of 42% of methemoglobinemia cases, whereas another report
16 implicated benzocaine in 82% of cases. In the perioperative period, most methemoglobinemia cases manifest as a result of local anesthetic use, most commonly topical benzocaine used for laryngoscopy, bronchoscopy, or upper gastrointestinal endoscopic procedures.
9,17 A class of recreational drugs, often referred to as poppers, have also been implicated in methemoglobinemia, as they contain the ingredient methyl nitrite (used to manage cyanide toxicity) and carry a high abuse potential.
18 Although the exact prevalence of methemoglobinemia is unknown, these compounds are well-documented causes of the disorder.