Benzocaine-Induced Methemoglobinemia

Pradeep M. Gupta, MD, Deepa S. Lala, MD, Edward L. Arsura, MD, Department of Internal Medicine, University of Virginia School of Medicine, and VA Medical Center, Salem, Va.

South Med J. 2000;93(1) 

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Methemoglobinemia refers to the presence of an elevated circulating fraction of methemoglobin within the erythrocytes. In this condition, iron in hemoglobin is oxidized from the ferrous to the ferric form. This compound is unable to bind and carry oxygen, resulting in functional anemia and impairing oxygen delivery to the tissues. In normal erythrocytes, methemoglobin is present at <1% to 2%. Methemoglobin is continuously formed in red blood cells and is readily reduced to deoxyhemoglobin by nicotinamide adenine dinucleotide-dependent methemoglobin reductase enzyme. This accounts for 95% of the reducing activity and is accelerated in the presence of an exogenous electron carrier, such as methylene blue. Glutathione and ascorbic acid also play minor roles in the direct reduction of methemoglobin, and these are slow-acting pathways.[1]

Methemoglobinemia may be either congenital or acquired, with the acquired form being more common. Acquired methemoglobinemia occurs when the rate of methemoglobin formation exceeds the rate of its reduction. In clinical practice, pharmacologic agents are the most frequent cause. The drugs most often implicated are nitrates, nitrites, inhaled nitric oxide, nitro-prusside, topical silver nitrate, silver sulfadiazine, dapsone, sulfonamides, antimalarials (chloroquine, primaquine), flutamide, metoclopramide, acetanilide, phenacetin, chlorates, and pyridium.[2] Recently, topical anesthetics such as prilocaine, lidocaine, cetacaine, and benzocaine have been reported to cause methemoglobinemia.[2,3,4,5,6] Individuals can also acquire this condition from self-medication with readily available over-the-counter products advertised as toothache relief and baby-teething gels, sting relief formulas, pain relief sprays, hemorrhoidal creams, and vaginal and rectal suppositories. These preparations contain benzocaine in concentrations varying from 5% to 20%. They provide symptomatic relief of anal and genital pruritus, skin rashes, dermatoses, and toothaches.

Elderly and pediatric populations (including full-term and low birth weight infants) and hypoxic patients are more sensitive to methemoglobin formation.[2,7] Neonates express low levels of functional nicotinamide adenine dinucleotide phosphate methemoglobin reductase, while the enzyme becomes less efficient in the elderly.

The symptoms and signs of methemoglobinemia generally correlate to the amount of abnormal hemoglobin present. Onset is usually within 20 to 60 minutes of drug administration. Normally, 5 g/dL of reduced hemoglobin (deoxyhemoglobin) produces cyanosis, and only 1.5 g/dL of methemoglobin produces noticeable cyanosis.[1] Methemoglobin decreases oxygen-carrying capacity and also shifts the oxyhemoglobin dissociation curve to the left, accentuating the potential for tissue hypoxia. Clinical symptoms and signs are lacking with methemoglobin levels of <10% in non-anemic individuals. Concentrations of 10% to 15% (>1.5 g/dL) produce visible cyanosis unresponsive to oxygen therapy, and blood may appear burgundy brown in color. Concentrations above 20% result in symptoms related to tissue hypoxia and include anxiety, fatigue, dyspnea, dizziness, tachycardia, headache, and syncope. As levels exceed 50%, oxygen delivery suffers and results in marked dyspnea, metabolic acidosis, dysrhythmia, and lethargy, progressing to stupor, coma, and convulsions. Death has been reported[1,8] from levels >70% and may be due to arrhythmia, circulatory failure, or neurologic compromise.

Diagnostic suspicion of methemoglobinemia is based on clinical findings. Generalized cyanosis is out of proportion to respiratory status and does not improve with oxygen therapy. Arterial blood drawn for blood sampling is chocolate brown and fails to change color when exposed to air or when a drop is dried on filter paper.

Pulse oximetry yields information based on the differential light absorption of oxyhemoglobin and reduced hemoglobin. Oxyhemoglobin absorbs more light at 940 nm, and reduced hemoglobin absorbs more light at 660 nm. Methemoglobin absorbs light equally at both the wavelengths, with pulse oximetry displaying a SpO2 of 85%. The higher the methemoglobin concentration, the closer the SpO2 value is to 85%. However, the actual percentage of the arterial oxyhemoglobin concentration can be either underestimated or overestimated in the SpO2 value.[9]

Arterial blood gas analysis is of limited value, because the PaO2 is generally unremarkable or inappropriately high. Cooximetry is the diagnostic test of choice because it provides the concentration of methemoglobin and oxyhemoglobin. Light absorption of methemoglobin differs from that of normal hemoglobin and is measured through multiple wavelength spectrophotometry (cooximetry). In routine ABG analysis, O2 saturation is calculated from oxygen tension (PO2) and pH. Cooximetry determines the true percent of saturation, which is much lower than calculated O2 saturation on ABG analysis in cases of methemoglobinemia.[1,7] Hyperlipidemia interferes with the light absorption and, in such cases, cooximetry yields falsely elevated fractions of methemoglobin.[1]

The half-life of methemoglobin is 55 minutes.[7] Removal of the offending agent is important in the asymptomatic or mildly symptomatic individual. Most cases resolve within 24 to 36 hours after the clearing of residual benzocaine.[1] General supportive measures are appropriate, especially if methemoglobin levels are <30%, since lower levels are tolerated well.[10] However, in more severe cases, intravenous methylene blue in a dose of 1 to 2 mg/kg body weight is the preferred treatment. Methylene blue acts as a reducing agent via the NADPH methemoglobin reductase pathway. It converts ferric iron back to the ferrous state and restores the oxygen-carrying capacity of hemoglobin. Cyanosis resolves within 15 to 30 minutes. Marked reduction in the methemoglobin concentration, usually by 50%, is seen within 30 to 60 minutes.[1,10] Methylene blue by itself has oxidizing properties at higher doses, with toxic effects appearing in doses >7 mg/kg.[1,3] Hyperbaric oxygen and exchange transfusion may be used, especially in patients with leukocyte G6PD deficiency who do not respond to methylene blue.[10]

Benzocaine is available in spray form, throat lozenges, and liquid and gel preparations. Benzocaine spray is prepared as a 14% to 20% concentration. As stated in the dosing instructions for topical benzocaine,[11] it should not be sprayed for more than 1 second, and spraying for more than 2 seconds is considered contraindicated. Average expulsion rate is 200 to 295 mg/sec.[3] Predisposing factors for benzocaine-induced methemoglobinemia are not known. No readily identifiable factor is evident. The toxic effects of benzocaine may be due to a toxic metabolite, N-hydroxy derivative that has an aniline group incorporated in its structure and possesses oxidizing properties. Differences in metabolism of benzocaine may explain the variability of benzocaine-induced methemoglobinemia.[8]

A previous case report[12] intimates excessive to the agent or more ready entry of benzocaine into the bloodstream due to mucosal damage as contributing factors. Absorption of benzocaine through broken skin, mucosa, and the gastrointestinal tract is believed to be the main route of systemic access. Rectal fissures, oropharyngeal abrasions and erosions, gastritis, eczematous skin, and respiratory mucosa have also been proposed as contributing to enhanced systemic absorption. Increased systemic exposure probably plays a central role. Benzocaine has been found to produce symptomatic cyanosis and methemoglobinemia at 15 mg/kg body weight in infants and at 150 to 300 mg in adults. Local anesthetics are rapidly absorbed into the circulation after topical application to denuded skin and mucous membranes, especially when the mucosa is inflamed or disrupted. Absorption is particularly rapid from the tracheobronchial tree, and blood concentrations are nearly the same as those after intravenous injections.

All of our patients had life-threatening methemoglobinemia shortly after 20% topical benzocaine spray to the mucous membrane. All patients received up to two sprays to the oropharynx. Unfortunately, the duration of each spray was not documented. The patients were given intravenous methylene blue and responded well to the treatment. In three of our four cases, the diagnosis was established by cooximetry; in the fourth case, the circumstantial evidence was supportive.

When topical anesthetics are applied to the mouth, nose, or throat, the patient should be cautioned to expectorate the excess solution of anesthetic to avoid excessive absorption. Topical application over inflamed or broken skin and mucous membranes should be avoided. The application should be restricted to one or two sprays, each spray not exceeding one second. More than two sprays should be given with extreme caution, and the patient should be watched closely for the development of methemoglobinemia. Unfortunately, there are no warnings of the possibility of this complication in the Physician's Desk Reference[13] or in the package insert.[14] Our facility now labels the canister with yellow stickers advising physicians about dosage, concentration, and toxic reactions of benzocaine, especially methemoglobinemia.


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