Severe Methemoglobinemia From Topical Benzocaine 7.

5% (Baby Orajel) Use for Teething Pain in a Toddler

Choon L. Bong, MBChB, FRCA, Jessica Hilliard, BA, and Christian Seefelder, MD
Introduction
Topical benzocaine products are widely available over the counter for use in children, commonly for the treatment of oral or teething pain. Most of the reported cases of acquired methemoglobinemia (MHb) linked to topical benzocaine involve its use during dental and endoscopic procedures,1,2 including transesophageal echocardiography.2 We report a case of acquired MHb in a toddler with a complex medical history who received small amounts of topical benzocaine 7.5% (Baby Orajel) for teething pain in the postoperative period. She eventually developed severe cyanosis and hypoxemia requiring resuscitation following administration of the fourth dose in a 24-hour period. There was initial delay in the diagnosis and management of the condition because other causes for postoperative desaturation and oxygen requirement were pursued. Once diagnosed, she responded promptly to the administration of intravenous methylene blue.

Clinical Pediatrics Volume 48 Number 2 March 2009 209-211 2009 Sage Publications 10.1177/0009922808324491 http://clp.sagepub.com hosted at http://online.sagepub.com

Patient Presentation
The patient was a 15-month-old, 6.8 kg female child with VACTERL association and a complex medical history. She had undergone tracheoesophageal stula
From the Childrens Hospital, Harvard Medical School (CLB, CS) and Smiths College (JH), Boston, Massachusetts. Funding was from departmental sources only. There are no conicts of interest. Address correspondence to: Choon L. Bong, Department of Anesthesiology, Perioperative and Pain Medicine, Childrens Hospital, 300 Longwood Avenue, Boston, MA 02115; e-mail: clbong1@gmail.com.

repair as a neonate and subsequently aortopexy, fundoplication, and gastrostomy. She continued to suffer from residual tracheomalacia, persistent gastroesophageal reux, recurrent aspiration, reactive airway disease, and failure to thrive. On this occasion, she underwent direct laryngoscopy and rigid bronchoscopy to rule out a recurrent tracheoesophageal stula. She received inhalational anesthesia with sevourane and 1 mL of lidocaine 1% topically to her vocal cords. The intraoperative course was uneventful but because of her previous postoperative respiratory difculty, she was brought to the ICU for weaning and extubation. She was extubated to high-ow nasal cannula 6 hours after arrival to the ICU. Soon after extubation, she was fussing and crying. Her mother attributed this to teething pain and obtained some Baby Orajel (benzocaine 7.5%, Del Pharmaceuticals, Inc) from the local pharmacy and applied a pea-sized amount topically to the patients gum, according to the recommended dosage. Shortly thereafter, the patient had an episode of unexplained desaturation, which was attributed to atelectasis. This resolved after several hours of increased oxygen supplement. Two similar episodes of desaturation happened overnight, which were followed by gradual improvement over several hours of increased oxygen supplementation by face mask. The mother (a biochemist) noticed the temporal association of the episodes with the application of Baby Orajel, but she was reassured by the medical staff that this was an unlikely cause for the patients acute desaturation because it was within the recommended dose. The following day, the patient was transferred to the ward. When she became fussy again, the mother applied a further dose of Baby Orajel to the patients
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Table 1.

Arterial Blood Gases and CO Oximetry Values

Two Hours After Administration of Methylene Blue

Time of Diagnosis Arterial blood gas pH pCO2 (mm Hg) pO2 (mm Hg) HCO3 (mmol/L) SaO2 (%) Arterial co-oximetry O2 Hb (%) O2 Sat (%) MetHb (%) Deoxy-Hb (%)

7.401 29.0 (L) 132.0 (H) 18 (L) 98 57.1 (L) 98 (f) 42.5 (H) <0.1

7.435 32.4 (L) 156.0 (H) 21 (L) 98 97 98 (f) 0.9 <0.1

Note: L = low value; H = high value; f = agged (ie, brought to the attention of the clinician); Sat = saturation; MetHb = methemoglobin.

gum. Minutes later, the patient developed profound cyanosis accompanied by tachycardia up to 180 beats per minute. The patients oxygen saturation was unrecordable by pulse oximetry despite being awake with seemingly adequate respirations. She was placed on 100% oxygen via a nonrebreathing mask. Again, the mother suggested an association with Baby Orajel. CO oximetry of an arterial blood sample showed a methemoglobin (MetHb) level of 42.5% (Table 1). Methylene blue 1 mg/kg was administered intravenously; the patients SpO2 promptly improved to 100%, and the tachycardia resolved within minutes. Baby Oragel was discontinued, and the patient had no further cyanotic episodes during her inpatient stay.

Discussion
Methemoglobinemia occurs when iron atoms in hemoglobin molecules are oxidized from their normal ferrous (Fe2+) to a nonfunctional ferric (Fe3+) state, resulting in reduced oxygen delivery at the tissue level.3 MetHb is normally present in human blood at levels less than 1% to 2%, and MHb occurs when levels exceed this. Cyanosis is observed when MetHb levels reach 5% to 15%. Headaches, dizziness, weakness, dyspnea, and tachycardia occur at levels of 30% to 40%. As levels increase to 55% to 60%, lethargy, confusion, stupor, seizures, and coma

may result, and levels greater than 70% cause lethal circulatory collapse.4 The pathognomonic feature of MHb is unexplained cyanosis and decreased SpO2 despite adequate ventilation and increased FiO2. Pulse oximetry is unreliable, often showing SpO2 approaching 85%. Arterial blood gases typically show normal values for paO2 and oxygen saturation, but CO oximetry results reveal increases in MetHb and decrease in oxyhemoglobin levels. Immediate primary treatment of MHb is administration of methylene blue 1 to 2 mg/kg intravenously over a 5- to 10-minute period repeatable in 1 hour, to a maximum of 7 mg/kg. Most studies recommend this treatment when patients become symptomatic and/or reach MetHb levels of 30%.4 MetHb is rapidly reduced back to hemoglobin primarily by the enzyme NADH-diaphorase. An alternate hemoglobin reducing system is nicotinamide adenine dinucleotide phosphate (NADPH), which requires glucose-6-phosphate dehydrogenase (G6PD). Methylene blue donates electrons to NADPH and, therefore, is ineffective for patients with hemoglobin M, NADPH deciencies, and/or G6PD deciencies. These patients may require hyperbaric oxygen, charcoal, exchange blood transfusions, and/or hemodialysis.3 There are 3 etiological categories of MHb: (1) an autosomal dominant trait that causes production of abnormal hemoglobin, usually presenting as cyanosis at birth; (2) an autosomal recessive trait resulting in decreased activity of MetHb reductase, typically resulting in subclinical MHb; and most commonly (3) introduction of an external oxidizing agent, which overwhelms the reducing capacity of red blood cells. Benzocaine, a commonly used ester local anesthetic, has been associated with cases of life-threatening MHb. From November 1997 through March 2002, there were 132 cases of MHb associated with benzocaine administration reported to the US Food and Drug Administration. In 123 cases (93.2%), the product was a spray; in 2 cases, a benzocaine-containing lozenge; and in 1 case a gel.5 Most of these cases occur in the setting of medical or dental procedures. To date, we are not aware of any reports of MHb from topical benzocaine gel administration for teething pain in a toddler. The risk factors for the development of MetHb with benzocaine have not been clearly dened.

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Certain risk factors that were suggested include hereditary lack of MetHb reductase, extremes of age (because most cases occurred in infants or elderly people),6 breaks in the mucosal barrier, concomitant use of other oxidative agents, and in particular, an excessive dose of benzocaine.7 In addition, underlying cardiac or respiratory conditions may exacerbate the symptoms of MetHb. It remains unclear why our patient developed toxicity if the administered dose was within the recommended range of 4 applications in a 24-hour period. It is possible that because of the patients small size and the poor dose denition of gels from a tube, an overall larger dose may have been administered. Other contributing factors may be interaction with other drugs administered perioperatively (although the patient was not on any medication known to interact with benzocaine or any obvious oxidizing agents) or an inborn error of metabolism for benzocaine. In this case, the adverse reaction occurred during the perioperative period when the patient happened to be monitored in the ICU. Even then, the many differential diagnoses for acute cyanosis and other confounding factors led to a delay in recognition of the condition. The patients mothers input regarding the temporal association of desaturation episodes with the benzocaine application was crucial in establishing the diagnosis and initiating the appropriate treatment. Under any other circumstance, it is likely that the diagnosis would have been further delayed. In summary, we report a case of life-threatening MHb following perioperative application of the seemingly innocuous over-the-counter benzocaine gel for teething pain. With its short half-life and

minimal systemic absorption, benzocaine is perceived to be a relatively benign product. It is likely that its adverse reactions are underreported.5 However, it is important for clinicians to be aware that benzocaine gel, even in small quantities, administered by wellmeaning caregivers, may cause rare but potentially fatal MHb. Prompt recognition and treatment are required to ensure a successful clinical outcome.

References
1. Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: a case report and review of the literature. Pediatrics. 2006;117:806-809. 2. Kane GC, Hoehn SM, Behrenbeck TR, Mulvagh SL. Benzocaine-induced methemoglobinemia based on the Mayo Clinic experience from 28 478 transesophageal echocardiograms: incidence, outcomes, and predisposing factors. Arch Intern Med. 2007;167:1977-1982. 3. Ludwig SC. Acute toxic methemoglobinemia following dental analgesia. Ann Emerg Med. 1981;10:265-266. 4. Hall DL, Moses MK, Weaver JM, et al. Dental anesthesia management of methemoglobinemia susceptible patients: a case report and review of literature. Anesth Prog. 2004; 51:24-27. 5. Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. 2004;164:1192-1196. 6. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaineinduced methemoglobinemia: report of a severe reaction and review of the literature. Ann Pharmacother. 1994;28: 643-649. 7. Wurdeman RL, Mohiuddin SM, Holmberg MJ, Shalaby A. Benzocaine-induced methemoglobinemia during an outpatient procedure. Pharmacotherapy. 2000;20:735-738.