MHg has an impaired O2 binding capacity and is unable to carry O2 from the lungs to metabolically active tissue. Furthermore, the oxidation of one subunit of the hemoglobin tetramer to MHg prevents the remaining normal subunits from unloading their bound O2, causing an additional leftward shift in the O2 dissociation curve. In the case of ben-zocaine, a toxic metabolite N-hydroxy derivative is thought to be responsible for the oxidation of hemoglobin to MHg . Under normal physiological conditions, approximately 0.5% of total hemoglobin exists in the oxidized form of MHg . These low levels of MHg are predominantly maintained enzymatically by NADH-MHg reductase; which is a two-enzyme system involving both cytochrome^ and cytochrome^ reductase; the latter reduces methemoglobin back to its functional form (Figure 1). Another important enzyme involved in reducing MHg is NADPH-MHg reductase. The activity of this enzyme to reduce MHg is greatly increased by methylene blue (Figure 1) . Other agents, such as ascorbic acid and glutathione, can act indirectly in these pathways to reduce oxidative stress and may thus prevent further production of MHg.
Methemoglobinemia arises when the level of MHg rises above 5% (Figure 1). Individuals that are deficient in the amount of NADH-MHg reductase (autosomal recessive deficiencies in cytochrome-b5 or cytochrome^ reductase) have congenital methemoglobinemia.
Figure 1) Clinical decision-making algorithm for methemoglobinemia induced by the use of lidocaine- or benzocaine-containing topical anesthetics during endoscopy. Adapted from Abdallah and Shah . G6PD Glucose-6-phosphate dehydrogenase; IV Intravenous; MHg Methemoglobin; pts Patients