Local anesthetic reactions and methemoglobinemia
Question:
6/24/2019
A patient was referred to me for evaluation of the risk of receiving local anesthetic. Her history is that she had several dental extractions and for several days was applying benzocaine topically several times daily. She developed methemoglobinemia which resolved with stopping the benzocaine. I would expect single use of lidocaine to be relatively safe but have no data to back that up.
Answer:
Methemoglobin is the result of the oxidation of ferrous ion (Fe+2) of hemoglobin to the ferric ion (Fe+3). Methemoglobin is incapable of binding and transporting oxygen. Benzocaine induced methemoglobinemia was first described by BM Bernstein in 1950 (1). The occurrence of drug induced methemoglobinemia is rare but potentially fatal. In addition to benzocaine, other oxidant substances may cause. These include amyl nitrate, aniline dyes, bismuth subnitrate, cetacaine (combination of 14% benzocaine, 2% tetracaine, 2% butamden), dapsone, lidocaine, nitroglycerin, p-aminosalicylic acid, phenytoin, prilocaine, primaquine, pyridine, silver nitrate, and sulfonamides. Aniline derivates (C6H5NH2), such as lidocaine, prilocaine and nitrates, are the most common methemoglobin-inducing drugs. Hereditary causes, including hemoglobinopathies and NADH/NADPH dependent enzyme deficiencies, are even rarer than the drug induced cases.
Methemoglobin reductase (cytochrome b5 reductase) deficiency is autosomal recessive and is more common in Athabascan Alaskans, Navajo Indians and Yakutsk natives of Siberia (2). Predisposing factors include ‘excessive doses’ of culprit agents and age extremes, with infants and older adults at greater risk. Risk is also increased if more than one agent associated with methemoglobinemia is used coincidently (3). The effect of medications on methemoglobinemia is metabolic and not immunologic. The treatment for drug related methemoglobinemia is 1-2mg/kg of methylene blue, although the treatment may be less effective in subjects with a glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Lidocaine-induced methemoglobinemia has occurred with both injected and topical lidocaine (4,5,6).
There is no specific test for local anesthetics to cause methemoglobinemia. It is dose dependent so I would feel safe in a patient with a history of benzocaine methemoglobinemia in the subject receiving less than 100-200 mg of a local anesthetic injection such as lidocaine. I would avoid topical anesthetics, particularly benzocaine, and also not use concomitant medications that increase risk as described above.
1. Bernstein BM. Cyanosis following use of anesthesia (ethylaminobenzoate). Rev Gastroenterol 1950;17:123-4.
2. Udeh, Chiedozie, John Bittikofer, and ST John Sum-Ping. "Severe methemoglobinemia on reexposure to benzocaine." Journal of clinical anesthesia 13.2 (2001): 128-130.
3. Jakobson, B., and A. Nilsson. "Methemoglobinemia associated with a prilocaine‐lidocaine cream and trimethoprim‐sulphamethoxazole. A case report." Acta Anaesthesiologica Scandinavica 29.4 (1985): 453-455.
4. Deas TC. Severe methemoglobinemia following dental extraction under lidocaine anesthesisa. Anesthesiology 1956;17:204.
5. Burne D, Doughty A. Methemoglobinemia following lignocaine. Lancet 1964; 2:971.
6. O’Donohue WJ Jr, Moss LM, Angelillo VA. Acute methemoglobinemia induced by topical benzocaine and lidocaine. Arch Int Med 1980;140:150
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI