A Prospective Evaluation of Benzocaine-Associated Methemoglobinemia in Human Beings

TOXICOLOGY/ORIGINAL

CONTRIBUTION

A Prospective Evaluation of BenzocaineAssociated Methemoglobinemia in Human Beings From the Department ~Emergency Medicine,* and Gastrocnteroh)~ Service/Department of Medicine, Madgan Army Medical Center, Tacoma, Washington. Received[or publication November I5, 199.3. Revision received February23, 1994-. Accepted jor pablication March 4, 1994. Copyright 9 by ~hcAmerican (T(~IIegc ol F_mel',gen~(yPhysicians,

Andrew T Guertler, MO, FACEP*

Study objective: This study determined the frequency and

William A Pearce, MD, PhDt

severity of benzocaine-associatedmethemoglobinemia in routine clinical use. Design: Prospective, crossover, convenience study. .Setting: Gastroenterologyclinic at a US Army medical center functioning as a community hospital and tertiary referral center.

Participants: Healthy adult volunteers and patient volunteers undergoing an upper gastrointestinal endoscopic procedure. Interventions: Baseline methemoglobin levels were measured. Subjects then received a 2-second spray of benzocaine to the oropharynx. Venous blood for methemoglobin analysis was collected 20, 40, and 60 minutes after benzocaine dosing and analyzed using a co-oximeter. Results: A statistically significant (P<.05) increase in methemoglobin level between baseline (0.8+0.2%) and 20-, 40-, and 60-minute measurements (0.9_+0.2%)was identified using oneway analysis of variance followed by Fisher's protected leastsquares difference. Conclusion: A 2-second spray of 20% benzocaineapplied to the oropharynx of human beings induces a statistically significant, but clinically insignificant, increase in methemoglobin levels. [Guertler AT, PearceWA: A prospective evaluation of benzocaine-associated methemoglobinemia in human beings. Ann EmergMed October 1994;24:626-630.]

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INTRODUCTION

Benzocaine is an ester-class local anesthetic used primarily to obtain topical anesthesia of mucous membranes and skin. There are more than 25 different benzocaine-containing products available in over-the-counter preparations. These me&cations include throat lozenges, teething gels, sprays for dermal or pharyngeal anesthesia, and rectal suppositories, with benzocaine concentrations of 2 to 20 mg/dL, t Fourteen additional benzocaine preparations are available by prescription. 2 Physicians and ancillary personnel use benzocaine to produce nasopharyngeal and oropharyngeal anesthesia prior to endoscopy, laryngoscopy, bronchoscopy, endotracheal intubation, and orogastric lavage. Benzocaine is known to induce methemoglobinemia in cats,3 5 dogs,5,6 sheep,r,8 and several other laboratory animal species, 5 as well as human beings. 9q6 Methemoglobinemia becomes clinically important when it causes hypoxemia. Methemogtobin (MHb) results when the ferrous (Fe 2+) heme iron is oxidized to the ferric (Fe 3+) state. MHb does not carry oxygen and may increase the affinity for oxygen of the remaining ferrous heme irons, lr Both the diminished oxygen-carrying capacity and increased oxygen affinity may result in decreased tissue oxygen delivery. In healthy individuals, MHb levels of 35% or more cause headache, weakness, and breathlessness. ~8 Smaller MHb elevations may cause serious effects in patients with underlying medical illnesses. Diseases that may be exacerbated by decreased oxygen-carrying capacity include atherosclerotic vascular disease, restrictive or obstructive pulmonary disease, anemia, sepsis, toxic exposures, and trauma. Patients frequently are administered benzocaine prior to invasive procedures. Many have underlying illnesses that can be exacerbated by hypoxemia. Because of concerns generated by numerous case reports implicating benzocaine as a cause of methemoglobinemia, some authors recommend avoiding this topical anesthetic. 19 Prospective studies of the extent and frequency of benzocaine-associated methemoglobinemia have not been performed in human beings. This study was conducted to determine the frequency of clinically important benzocaine-associated methemoglobinemia in human beings given clinical doses of a benzocaine-containing topical anesthetic. MATERIALS AND METHODS

This study was approved by our institutional review board. Ninety-one adult patient volunteers and healthy

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volunteers were enrolled. Healthy volunteers were recruited from health care workers in the emergency department. Patient volunteers were recruited from patients presenting to the gastroenterology clinic at Madigan Army Medical Center to undergo an endoscopic procedure. No patient had an acute illness, such as sepsis, that might predispose to hemoglobin oxidation. All subjects signed an informed consent form. Subjects were excluded if they had a known allergy to benzocaine, midazolam, or meperidine, or if a second local anesthetic was used in addition to benzocaine. Subjects had an IV catheter with saline lock placed in an upper extremity vein, and a baseline blood sample for MHb analysis was obtained. Patients were premedicated using a combination of IV midazolam hydrochloride and meperidine hydrochloride titrated to an endpoint of satisfactory sedation. Healthy volunteers received no IV medication. Subjects then received a single, 2-second (determined by counting one-thousand-one, one-thousand-two) dose of 20% benzocaine applied to the oropharynx. Blood for MHb analysis was obtained at 20, 40, and 60 minutes after benzocaine dosing. After first discarding 5 mL of blood, 1 mL of blood was collected anaerobically in a lithium heparin blood gas syringe (Marquest Medical Products, Inc, Englewood, Colorado). Blood samples were placed immediately on ice, and MHb levels were determined by one investigator on a single instrument within 20 minutes. MHb levels were measured with an OSM-3 CO-Oximeter | (Radiometer America, Westlake, Ohio) using the extinction coefficients for human blood and appropriate blanks and controls. This instrument reports MHb levels to the nearest tenth of a percent. Data analysis used analysis of variance for repeatedmeasures and post-hoe testing with Fisher's protected least-squares difference. Significance was designated as P<.05. RESULTS

Ninety-one subjects entered the study, 80 patient volunteers and 11 healthy volunteers. All subjects completed the study. Fifty-seven subjects were male, and ages ranged from 20 to 81 years (median, 52 years). Seventy-three volunteers were Caucasian, nine were black, six were Hispanic, and one each was Japanese, Eskimo, and Arab. Two subjects had known G-6-PD deficiency. None reported a history of methemoglobinemia. Thirty-three subjects used no prescription medications; 58 used one or more. Although the subjects were on more

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than 65 different prescription medications collectively, only three medication classes (nitrates, quinine, and oral hypoglycemics) had been reported to cause methemoglobinemia. One person had been using an over-the-counter, benzocaine-based local anesthetic but had not used this medication for more than 1 month. Patient volunteers received 2 to 9 mg of midazolam (3.7+1.3 mg) and 25 to 270 mg of meperidine (57+34 mg). The procedures performed included 51 esophagogastroduodenoscopies, 16 esophagogastroduodenoscopies with subsequent colonoscopy, 12 endoscopic retrograde cholangiopancreatoscopies, and one endoscopic ultrasound. No procedures were performed on the 11 healthy volunteers. Methemoglobin levels were 0.8+0.2%, 0.9+0.2%, 0.9+0.2%, and 0.9+0.2% at baseline, 20 minutes, 40 minutes, and 60 minutes, respectively a statistically significant increase. There were no differences in MHb levels at any time interval between the patient volunteers and healthy volunteers. One patient had a baseline MHb level of 20% that reached 2.5% at 60 minutes. This patient was taking no medications prior to the study and had no known enzyme deficiencies. No further studies were done to determine the cause of this mild methemoglobinemia. There was no difference in baseline MHb levels in the two

subjects with known G-6-PD deficiency compared with the other subjects. DISCUSSION

MHb cannot carry oxygen and can cause tissue hypoxia and death. In the treatment of critically ill or potentially critically ill patients, formation of MHb can cause deterioration due to tissue hypoxia. Benzocaine-based anesthetics are used frequently during evaluation and treatment of critically ill patients and may cause methemoglobinemia in animals and human beings. ~-d6 Benzocaine induces MHb levels in many species. Two of seven cats receiving 14% benzocaine to the larynx developed MHb levels of 20% or more. The remaining cats had levels of 1.9% to 6.1%. 3 Some sheep developed MHb levels of more than 16% after benzocaine application to the nares, while other phenotypically similar sheep developed levels of less than 2.8%.r,~ Nonhuman primates have developed elevated MHb levels following a 2-second intranasal spray of 14% benzocaine. 5,2o In contrast, reports of benzocaine-associated methemoglobinemia in human beings have been limited to numerous case reports. These reports include all age groups and both sexes. Levels as high as 72% have been

Figure. Chemical struaures of MHb forming agents,

H2N ---~[

)z ~--

H2N--~ - IIC--CH2CH3

C -- 0 -- CHzCH 3

II

0

O

Benzocaine

Paraaminopropiophenone

H O H N ~

H2N'~~

IC--OH O Paraaminebenzoiacid c

'••NH Aniline

628

2

i -- CHzCH3

Para-hydroxyarninopropiophenone

~

NHOH

Phenylhydmxy[amine

NO Nitrosobenzene

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Guertler & Pearce

reported following mucous membrane, dermal, or intestinal benzocaine exposure. One author has proposed specific guidelines and Food and Drug Administration inquiries concerning the use of this drug. 19 Our study indicated that benzocaine-associated methemoglobinemia in adult human beings occurs infrequently We found no clinically significant increase in MHb levels in 91 subjects who received clinical doses of 20% benzocaine. These findings support the anecdotal experience of Adriani and Zepernick, 21 who reported one case of methemoglobinemia (no level provided) in an estimated more than 120,000 patients exposed to 20~ benzocaine ointment used to lubricate endotracheal tubes and catheters. It is likely that most human beings are not susceptible to benzocaine-associated methemoglobinemia following typical doses. There may be a small population of people who metabolize benzocaine through a different pathway, producing a toxic metabolite that oxidizes hemoglobin. Benzocaine is hydrolyzed by serum pseudocholinesterase to ethanol and para-aminobenzoic acid; the latter is metabolized further to aminohippuric acid. However, the toxic effects of benzocaine may result from a different metabolic pathway It has been postulated that benzocaine is metabolized to aniline, which then is transformed into phenylhydroxylamine and nitrosobenzene, both of which are MHb-forming compounds. 22 Animal data indicate that metabolic differences are the basis for benzocaine-associated methemoglobinemia. Eight phenotypically similar ewes demonstrated two distinct groups when given intranasal benzocaine. The first group, "responders," produced MHb levels of 16.3% to 26.4% after a 2-second intranasal exposure to 14% benzocane. The second group, "nonresponders," developed peak MHb levels of 1.6% to 2.7% after similar benzocaine exposure. Each group then was challenged with a known indirect methemoglobin former, para-aminopropiophenone (PAPP). The hemoglobin-oxidizing metabolite of PAPP is an N-hydroxylated derivative, parahydroxyaminopropiophenone. 23 The responders again developed significantly elevated MHb levels (16.7% to 23.0%) after receiving 0.6 mg/kg IV PAPE while the nonresponders developed MHb levels of 2.8% to 5.2%. 7 Benzocaine and PAPP differ only by the presence of an oxygen molecule in an ester bond in benzocaine (Figure). The structural similarities between these two drugs and the similar MHb response by sheep suggest that benzocaine is ultimately metabolized by responders to an N-hydroxy derivative (perhaps phenylhyroxylamine), which then oxidizes hemoglobin. Variation in N-hydroxy-

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lation activity could explain different MHb responses to these drugs in sheep. Differences in benzocaine metabolism as an explanation of the variability seen in benzocaine-associated methemoglobinemia is supported by other animal studiesP,5,8, 2o Most species studied have at least two different response groups, those that develop MHb after benzocaine exposure and those that develop little or no MHb. Some species appear to have an intermediate response group.3,5,2o The amount of benzocaine used is typical of our usual clinical dose. The manufacturer of the spray used recommends half-second dosing that may be repeated. The manufacturer of another topical anesthetic spray that contains 14% benzocaine recommends a dose of 2 seconds. A 2-second spray is consistent with practice in the ED and gastroenterology clinic at our institution. It is unlikely that a subject developed delayed methemoglobinemia and that our findings resulted from failure to sample for more than 60 minutes. Animal studies consistently show that peak MHb levels occur within 15 to 45 minutes of benzocaine application to mucous membranes. 5,7,s The slight increase in MHb is not likely to be due to either meperidine or midazolam. Review of the literature revealed no evidence implicating these medications as MHb-inducing agents. The findings of this study apply only to the adult population without G-6-PD deficiency. It is possible that pediatric patients may be more susceptible to benzocaineassociated methemoglobinemia due to different or immature metabolic pathways. Also, a larger G-6-PD-deficient study population may have demonstrated clinically significant MHb levels following benzocaine exposure. It is probable that benzocaine-associated methemoglobinemia affects a small population and that the power of this study was not adequate to capture any of these subjects. Doses of benzocaine higher than those recommended by the manufacturers were not used; therefore, we can make no comment as to whether overdosing may have caused any of the cases of significant methemoglobinemia reported in the literature. CONOLUSION

In adult human beings, a 2-second oropharyngeal dose of 20% benzocaine produced a statistically significant, but clinically insignificant, increase in MHb. Benzocaine is a safe topical anesthetic when administered correctly to adults, but users should be aware that some patients may develop clinically significant methemoglobinemia.

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Controlled studies of the association between benzocaine and methemoglobinemia in the pediatric population are warranted.

The authors thank Mr Troy Patience for his assistance with the statistical analysis and Dr Jan Vanderlinde for assistance with sample collection. The authors also thank Drs Scott Syverud and G Randall Bond for their reviews and comments during manuscript preparation. Reprint no. 47/1/58684

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Address for reprints: Andrew T Guertler, MD

2. Physician's Desk Reference, ed 45. Oradell, New Jersey, Medical Economics Co, 1991.

Division of Emergency Medicine

3. Krake AC, Arendt TD, feachout DJ, et al: Cetacaine-inducedmethemoglobinemia in domestic cats. J Am Anim HospAssoc 1985;21:527-534.

University of Virginia Health Sciences Center

4. Wilkie BA, Kirby R: Methemoglobinemia associated with dermal application of benzocaine cream in a cat. JAm Vet MedAssoc 1988;192:85-86. 5. Davis JA, Greenfield RE, Brewer TG: Benzocaine-inducedmethemoglobinemia attributed to topical application of the anesthetic in several laboratory-animal species. Am J Vet Res 1993;51:1322-1326.

PO Box 523-21 Charlottesville, Virginia 22901 804-924-8485 Fax 804-924-2877

6. Harvey JW, SameckJH, 8urgard FJ: Benzocaine-inducedmethemoglobinemia in dogs. JAm Vet Med Assoc1979;175:1171 1175. 7. Guertler AT, Lagutchik MS, Martin DG: Topical anesthetic-induced methemoglobinemia in sheep: A comparison of benzocaineand lidocaine. FundamAppl Toxico11992;18:294-298. 8. Lagutchik MS, Mundie TG, Martin DG: Methemoglobinemia induced by a benzocaine-based topically administered anesthetic in eight sheep. JAm VetMedAssoc 1992;201:1407-1410 9. Douglas WW, FairbanksVF: Methemoglobinemia induced by a topical anesthetic spray (Cetacaine| Chest 1977;71:587-591. 10 Townes PL, Geertsman MA, White MR: Benzocaine-inducedmethemoglobinemia. Am J Dis Child 1977;13t :697-698. 11. O'DonohueWJ, Moss LM, Angelillo VA: Acute methemoglobinemia induced by topical benzocaineand lidocaine. Arch Intern Med 1980;140:1508-1509. 12. SandzaJG, Roberts BW, Shaw BC, et al: Symptomatic methemoglobinemia with a commonly used topical anesthetic, Cetacaine| Ann ThoracSurg 1980;30:187-190. 13. Olson ML, McEvoy GK: Methemoglobinemia induced by local anesthetics, Am J Hosp Pharm 1981;38:89-93. 14 Gosselin RE, Smith RP, Hodge HC: Cl#rical Toxicologyof Dommercial Products, ed 5. Baltimore, Williams and Wilkins, 1984, p 11-397. 15. Seibert RW, Seibert JJ: Infantile methemoglobinemia induced by a topical anesthetic, Cetacaine| Laryngoscope 1984;94:816-817. 16. FerraroL, Zeichner S, Greenblott G, et ah Cetacaine-inducedacute methemoglobinemia. Anesthesiology 1988;69:614 615. 17. Darling RC, Roughton FJW: The effects of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol 1942;137:56-68. 18. Goldfrank LR, Price D, Kirstein BH: Nitroglycerin (methemoglobinemia),in Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank's Toxicologic Emergencies, ed 3. Norwalk, Connecticut, Appleton Century-Crofts, 1986, p 321. 19. SeveringhausJW, Xu E, Spellman MJ: 8enzocaine and methemoglobin: Recommended actions. Anesthesiology 1991;74:385-386. 20. Martin DG, Woodard C, Gold M, et al: Methemoglobin and suifhemoglobin formation due to benzocaineand lidocaine in macaques. Proceedingsof the 1993 Medical Defense Bioscience Review, vol 2. Aberdeen Proving Grounds, Maryland, US Army Medical Researchand Development Command, 1993, p 939-949. 21. Adriani J, Zepernick R: Clinical effectiveness of drugs used for topical anesthesia. JAMA 1964;188:93-98. 22. Liebelt EL, Shannon MW: Small doses, big problems: A selected review of highly toxic common medications. Ped Emerg Care 1993;9:292-297. 23. Graffe W, Kiese M, RauscherE: The formation in-vivo of p hydroxyaminopropiophenonefrom p-aminopropiophenoneand its action in-vivo and in-vitro. Arch Exp Pathol Pharmakol 1964;249:168-175.

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