Benzocaine-Induced Methemoglobinemia: Report of a Severe Reaction and Review of the Literature

Rodríguez, L. F.; Smolik, Lynn M.; Zbehlik, Alicia J.

doi:10.1177/106002809402800515

Cited by 92 publications

(31 citation statements)

References 13 publications

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“…Benzocaine spray has become an increasing problem, and spray directed to the mucosa can gain rapid entry to the blood and result in severe levels of methemoglobin. There are a wide variety of case reports [99], but no systematic study. In one review from a transesophageal echocardiology laboratory the incidence was estimated at 0.115% [100].…”

Section: Acquired Methemoglobinemiamentioning

confidence: 99%

Methemoglobin—It's not just blue: A concise review

Umbreit¹

2006

American J Hematol

334

280

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Hemoglobin has functions besides carrying oxygen to the tissues, and regulates vascular tone and inflammation via a redox couple with methemoglobin. Hemoglobin has iron in the reduced valance Fe(II) and methemoglobin has iron in the oxidized valance Fe (III), with a free energy capable of producing water from oxygen. In generating methemoglobin the couple functions as a nitrite reductase. The degree of oxidation of hemoglobin senses the oxygen level in the blood and uses its ability to produce nitric oxide from nitrite to control vascular tone, increasing blood flood when the proportion of oxygenated hemoglobin falls. Additional cardiovascular damage is produced by methemoglobin mediated oxidation of light density lipoproteins, accelerating arteriosclerosis. In addition, the release of heme from methemoglobin is an important factor in inflammation. These physiologic functions are paralleled by the well-described role in the oxidation of various drugs resulting in methemoglobinemia. Am. J. Hematol. 82:134-144, 2007. V V C 2006 Wiley-Liss, Inc.

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Section: Acquired Methemoglobinemiamentioning

confidence: 99%

Methemoglobin—It's not just blue: A concise review

Umbreit¹

2006

American J Hematol

334

280

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“…Cyanosis usually occurs when Met-Hb concentrations increase above 10% and is followed by anxiety, fatigue, and tachycardia when MetHb levels reach 20%-50% of total hemoglobin levels. When Met-Hb levels reach 50%-70% of total hemoglobin levels, coma, and death may occur (Rodriguez et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Prilocaine- and Lidocaine-Induced Methemoglobinemia Is Caused by Human Carboxylesterase-, CYP2E1-, and CYP3A4-Mediated Metabolic Activation

et al. 2013

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Prilocaine and lidocaine are classified as amide-type local anesthetics for which serious adverse effects include methemoglobinemia. Although the hydrolyzed metabolites of prilocaine (o-toluidine) and lidocaine (2,6-xylidine) have been suspected to induce methemoglobinemia, the metabolic enzymes that are involved remain uncharacterized. In the present study, we aimed to identify the human enzymes that are responsible for prilocaine-and lidocaine-induced methemoglobinemia. Our experiments revealed that prilocaine was hydrolyzed by recombinant human carboxylesterase (CES) 1A and CES2, whereas lidocaine was hydrolyzed by only human CES1A. When the parent compounds (prilocaine and lidocaine) were incubated with human liver microsomes (HLM), methemoglobin (MetHb) formation was lower than when the hydrolyzed metabolites were incubated with HLM. In addition, Met-Hb formation when prilocaine and o-toluidine were incubated with HLM was higher than that when lidocaine and 2,6-xylidine were incubated with HLM. Incubation with diisopropyl fluorophosphate and bis-(4-nitrophenyl) phosphate, which are general inhibitors of CES, significantly decreased Met-Hb formation when prilocaine and lidocaine were incubated with HLM. An anti-CYP3A4 antibody further decreased the residual formation of Met-Hb. Met-Hb formation after the incubation of o-toluidine and 2,6-xylidine with HLM was only markedly decreased by incubation with an anti-CYP2E1 antibody. o-Toluidine and 2,6-xylidine were further metabolized by CYP2E1 to 4-and 6-hydroxy-o-toluidine and 4-hydroxy-2,6-xylidine, respectively, and these metabolites were shown to more efficiently induce Met-Hb formation than the parent compounds. Collectively, we found that the metabolites produced by human CES-, CYP2E1-, and CYP3A4-mediated metabolism were involved in prilocaine-and lidocaineinduced methemoglobinemia.

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“…Patients who are heterozygous may have low normal enzyme levels and are particularly predisposed to methemoglobinemia upon exposure to oxidizing agents (12). The actual functional level of the enzyme or its efficiency also seems to be important, as most reported cases occur in children and the elderly (13). Physiologic factors such as sepsis, hypoxia, and malnutrition may also predispose to this complication (14).…”

Section: ) a Small Amount Of Methemoglobin Is Reduced Viamentioning

confidence: 98%

“…In the patient with anemia or cardiovascular disease, methylene blue may be indicated at lower levels due to greater risk of tissue hypoxia. Most cases resolve within 24 -72 h (13). Repeat methylene blue doses may be necessary after 1 h, but the total dose should not exceed 7 mg/kg because symptoms of toxicity can occur (18).…”

Section: ) a Small Amount Of Methemoglobin Is Reduced Viamentioning

confidence: 99%