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Severe MethemoglobinemiaFrom Topical Benzocaine 7.5%

(Baby Orajel) Use for TeethingPain in a Toddler

Choon L. Bong, MBChB, FRCA, Jessica Hilliard, BA,and Christian Seefelder, MD

Introduction

Topical benzocaine products are widely available overthe counter for use in children, commonly for thetreatment of oral or teething pain. Most of thereported cases of acquired methemoglobinemia(MHb) linked to topical benzocaine involve its useduring dental and endoscopic procedures,1,2 includ-ing transesophageal echocardiography.2 We report acase of acquired MHb in a toddler with a complexmedical history who received small amounts oftopical benzocaine 7.5% (Baby Orajel) for teethingpain in the postoperative period. She eventually

developed severe cyanosis and hypoxemia requiringresuscitation following administration of the fourthdose in a 24-hour period. There was initial delay inthe diagnosis and management of the conditionbecause other causes for postoperative desaturationand oxygen requirement were pursued. Once diag-nosed, she responded promptly to the administrationof intravenous methylene blue.

Patient Presentation

The patient was a 15-month-old, 6.8 kg female childwith VACTERL association and a complex medicalhistory. She had undergone tracheoesophageal fistula

repair as a neonate and subsequently aortopexy, fundoplication, and gastrostomy. She continued to suffer

from residual tracheomalacia, persistent gastroesophageal reflux, recurrent aspiration, reactive airwaydisease, and failure to thrive. On this occasion, sheunderwent direct laryngoscopy and rigid bronchoscopy to rule out a recurrent tracheoesophageafistula. She received inhalational anesthesia withsevoflurane and 1 mL of lidocaine 1% topically to her

vocal cords. The intraoperative course was uneventfubut because of her previous postoperative respiratorydifficulty, she was brought to the ICU for weaningand extubation.

She was extubated to high-flow nasal cannula 6hours after arrival to the ICU. Soon after extubationshe was fussing and crying. Her mother attributed thisto teething pain and obtained some Baby Oraje(benzocaine 7.5%, Del Pharmaceuticals, Inc) fromthe local pharmacy and applied a pea-sized amountopically to the patients gum, according to the recommended dosage. Shortly thereafter, the patienhad an episode of unexplained desaturation, whichwas attributed to atelectasis. This resolved afteseveral hours of increased oxygen supplement. Two

similar episodes of desaturation happened overnightwhich were followed by gradual improvement overseveral hours of increased oxygen supplementationby face mask. The mother (a biochemist) noticedthe temporal association of the episodes with theapplication of Baby Orajel, but she was reassured bythe medical staff that this was an unlikely cause forthe patients acute desaturation because it waswithin the recommended dose.

The following day, the patient was transferred tothe ward. When she became fussy again, the motheapplied a further dose of Baby Orajel to the patient

Clinical Pediatric

Volume 48 Number 2

March 2009 209-21

2009 Sage Publication

10.1177/000992280832449

http://clp.sagepub.com

hosted a

http://online.sagepub.com

From the Childrens Hospital, Harvard Medical School (CLB,CS) and Smiths College (JH), Boston, Massachusetts.

Funding was from departmental sources only. There are no con-flicts of interest.

Address correspondence to: Choon L. Bong, Department ofAnesthesiology, Perioperative and Pain Medicine, ChildrensHospital, 300 Longwood Avenue, Boston, MA 02115; e-mail:clbong1@gmail.com.

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gum. Minutes later, the patient developed profoundcyanosis accompanied by tachycardia up to 180beats per minute. The patients oxygen saturationwas unrecordable by pulse oximetry despite beingawake with seemingly adequate respirations. Shewas placed on 100% oxygen via a nonrebreathingmask. Again, the mother suggested an associationwith Baby Orajel. CO oximetry of an arterial blood

sample showed a methemoglobin (MetHb) level of42.5% (Table 1). Methylene blue 1 mg/kg was admi-nistered intravenously; the patients SpO2 promptlyimproved to 100%, and the tachycardia resolvedwithin minutes. Baby Oragel was discontinued, andthe patient had no further cyanotic episodes duringher inpatient stay.

Discussion

Methemoglobinemia occurs when iron atoms inhemoglobin molecules are oxidized from theirnormal ferrous (Fe2+) to a nonfunctional ferric(Fe3+) state, resulting in reduced oxygen delivery atthe tissue level.3 MetHb is normally present inhuman blood at levels less than 1% to 2%, and MHboccurs when levels exceed this. Cyanosis is observedwhen MetHb levels reach 5% to 15%. Headaches, diz-ziness, weakness, dyspnea, and tachycardia occur atlevels of 30% to 40%. As levels increase to 55% to60%, lethargy, confusion, stupor, seizures, and coma

may result, and levels greater than 70% cause lethacirculatory collapse.4

The pathognomonic feature of MHb is unexplained cyanosis and decreased SpO2 despiteadequate ventilation and increased FiO2. Pulse oximetry is unreliable, often showing SpO2 approaching

85%. Arterial blood gases typically show normavalues for paO2 and oxygen saturation, but CO oximetry results reveal increases in MetHb and decrease inoxyhemoglobin levels. Immediate primary treatmenof MHb is administration of methylene blue 1 to 2mg/kg intravenously over a 5- to 10-minute periodrepeatable in 1 hour, to a maximum of 7 mg/kg. Moststudies recommend this treatment when patientsbecome symptomatic and/or reach MetHb levels o30%.4

MetHb is rapidly reduced back to hemoglobin

primarily by the enzyme NADH-diaphorase. Analternate hemoglobin reducing system is nicotinamide adenine dinucleotide phosphate (NADPH)which requires glucose-6-phosphate dehydrogenase(G6PD). Methylene blue donates electrons toNADPH and, therefore, is ineffective for patientwith hemoglobin M, NADPH deficiencies, and/oG6PD deficiencies. These patients may requirehyperbaric oxygen, charcoal, exchange blood transfusions, and/or hemodialysis.3

There are 3 etiological categories of MHb: (1) an

autosomal dominant trait that causes production oabnormal hemoglobin, usually presenting as cyanosisat birth; (2) an autosomal recessive trait resulting indecreased activity of MetHb reductase, typicallyresulting in subclinical MHb; and most commonly(3) introduction of an external oxidizing agentwhich overwhelms the reducing capacity of redblood cells. Benzocaine, a commonly used estelocal anesthetic, has been associated with cases oflife-threatening MHb.

From November 1997 through March 2002, there

were 132 cases of MHb associated with benzocaineadministration reported to the US Food and DrugAdministration. In 123 cases (93.2%), the producwas a spray; in 2 cases, a benzocaine-containinglozenge; and in 1 case a gel.5 Most of these casesoccur in the setting of medical or dental proceduresTo date, we are not aware of any reports of MHbfrom topical benzocainegel administration forteethingpain in a toddler.

The risk factors for the development of MetHbwith benzocaine have not been clearly defined

Table 1. Arterial Blood Gases and CO Oximetry Values

Time ofDiagnosis

Two Hours AfterAdministration

of MethyleneBlue

Arterial blood gaspH 7.401 7.435pCO2 (mm Hg) 29.0 (L) 32.4 (L)pO2 (mm Hg) 132.0 (H) 156.0 (H)HCO3 (mmol/L) 18 (L) 21 (L)SaO2 (%) 98 98

Arterial co-oximetryO2 Hb (%) 57.1 (L) 97O2 Sat (%) 98 (f) 98 (f)MetHb (%) 42.5 (H) 0.9Deoxy-Hb (%)

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Certain risk factors that were suggested include her-editary lack of MetHb reductase, extremes of age(because most cases occurred in infants or elderlypeople),6 breaks in the mucosal barrier, concomitantuse of other oxidative agents, and in particular, anexcessive dose of benzocaine.7 In addition, underlying

cardiac or respiratory conditions may exacerbate thesymptoms of MetHb.

It remains unclear why our patient developedtoxicity if the administered dose was within the rec-ommended range of 4 applications in a 24-hourperiod. It is possible that because of the patientssmall size and the poor dose definition of gels from atube, an overall larger dose may have been adminis-tered. Other contributing factors may be interactionwith other drugs administered perioperatively(although the patient was not on any medication

known to interact with benzocaine or any obviousoxidizing agents) or an inborn error of metabolismfor benzocaine. In this case, the adverse reactionoccurred during the perioperative period when thepatient happened to be monitored in the ICU. Eventhen, the many differential diagnoses for acute cyano-sis and other confounding factors led to a delay inrecognition of the condition. The patients mothersinput regarding the temporal association of desatura-tion episodes with the benzocaine application wascrucial in establishing the diagnosis and initiating

the appropriate treatment. Under any other circum-stance, it is likely that the diagnosis would havebeen further delayed.

In summary, we report a case of life-threateningMHb following perioperative application of theseemingly innocuous over-the-counter benzocainegel for teething pain. With its short half-life and

minimal systemic absorption, benzocaine is perceivedto be a relatively benign product. It is likely that itsadverse reactions are underreported.5 However, it isimportant for clinicians to be aware that benzocainegel, even in small quantities, administered by wellmeaning caregivers, may cause rare but potentially

fatal MHb. Prompt recognition and treatment arerequired to ensure a successful clinical outcome.

References

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