Methemoglobinemia Secondary to Topical ...

Methemoglobinemia Secondary to Topical Benzocaine Use in a Lung Transplant Patient Aimée C LeClaire, Timothy W Mullett, M Salik Jahania, and Jeremy D Flynn

OBJECTIVE:

To report a case of methemoglobinemia secondary to the administration of topical benzocaine spray in an anemic patient who had previously undergone a lung transplant.

CASE SUMMARY: A 40-year-old white man with a past medical history significant for lung transplant acutely decompensated following oropharyngeal administration of topical benzocaine spray. Subsequent blood analysis revealed a methemoglobin concentration of 51.2%. Following the administration of a single dose of methylene blue 2 mg/kg intravenously, the patient’s respiratory status dramatically improved and stabilized. DISCUSSION:

Methemoglobinemia is a rare but potentially fatal condition that may be either acquired or congenital; however, the disorder is most commonly acquired secondary to exposure to oxidizing chemicals, which are often routinely prescribed medications, including benzocaine. Benzocaine can react with hemoglobin to form methemoglobin at a rate that exceeds reduction capabilities, which may result in oxygenation difficulty and respiratory distress. In severe or symptomatic methemoglobinemia, the treatment of choice is methylene blue.

CONCLUSIONS:

Application of the Naranjo probability scale established a highly probable relationship between topical benzocaine spray and methemoglobinemia and associated respiratory compromise. The risks of palliative use of topical benzocaine in patients with preexisting disorders that compromise oxygen delivery may outweigh any benefit. In our patient, anemia and lung disease increased his risk for clinically significant adverse respiratory events secondary to deficiencies or interferences in oxygen delivery. Topical benzocaine should be administered with caution and careful monitoring in such patient populations.

KEY WORDS: benzocaine, lung transplant, methemoglobinemia, methylene blue.

Ann Pharmacother 2005;39:373-6. Published Online, 11 Jan 2005, www.theannals.com, DOI 10.1345/aph.1E315

ethemoglobinemia is a rare but potentially fatal condition that may be either acquired or congenital; however, the disorder is most commonly acquired secondary to ingestion of or dermal exposure to a number of commonly prescribed medications that have oxidizing effects (Table 1).1-3 Methemoglobin is produced when ferrous iron (divalent) is oxidized to ferric iron (trivalent) within the hemoglobin molecule.1,2,4-9 Oxygen and carbon dioxide transportation are altered by the oxidation reaction, and in severe methemoglobinemia, tissue hypoxia occurs. Patients with preexisting disease states impairing oxygenation and limiting functional reserve are particularly at risk for adverse

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events associated with tissue hypoxia.1 The induction of methemoglobinemia by topical benzocaine administration in patients undergoing endoscopic procedures, as well as teething infants, has been reported.2,5-8,10-13 We describe a case of severe methemoglobinemia leading to respiratory compromise in a lung transplant patient following the elective, topical administration of benzocaine. To our knowledge, as of December 27, 2004, this is the first reported case of clinically significant methemoglobinemia in the highly susceptible population of lung transplant recipients. Case Report A 40-year-old white male with a past medical history significant for a single lung transplant was admitted to the hospital for respiratory distress

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requiring intubation. The patient’s hospital course was complicated by pneumonia and failure to wean from the mechanical ventilator. The patient was extubated on hospital day 22; however, he required reintubation on day 24. On day 31, the patient acutely decompensated, with a respiratory rate of 25 breaths/min and pulse oximetry O2 saturation (SpO2) of 86%. At the time of the event, his ventilator settings were 40% fractional concentration of inspired oxygen (FiO2), 10 cm H2O pressure-support ventilation, rate of 8 breaths/min, 550 mL tidal volume, and 5 cm H2O positive-end expiratory pressure. Approximately one hour prior to the acute desaturation, the patient was breathing 12 times/min with an SpO2 of 96%. Routine arterial blood gas measurement was obtained at that time. The baseline arterial blood gas parameters were pH 7.31, pCO2 45 mm Hg, pO2 116 mm Hg, O2 saturation 99%, serum bicarbonate 27 mEq/L, and base deficit 3.7 mEq/L. Hemoglobin and hematocrit values were 10 g/dL and 29.8%, respectively. Following the initial onset of dyspnea, the SpO2 decreased to as low as 80%, and the patient was noted to have a cyanotic pallor. In response, the FiO2 was increased to 100%, and a second arterial blood gas measurement was performed, showing pH 7.27, pCO2 47 mm Hg, pO2 267 mm Hg, SaO2 100%, serum bicarbonate 15 mEq/L, and base deficit 11.3 mEq/L. Due to the brownish color of the arterial blood sample, a methemoglobin level was measured by co-oximetry simultaneously with the blood gas. The methemoglobin level was 51.2%. Because of significant respiratory compromise and the diagnosis of methemoglobinemia, the patient promptly received methylene blue 84 mg (2 mg/kg) in 50 mL of NaCl 0.9% intravenously over 10 minutes. One hour following the infusion of the methylene blue, a second methemoglobin level was measured at 13.9%. At this time, the patient’s respiratory rate was 15 breaths/min with an SpO2 of 93%; administration of additional methylene blue was considered unnecessary. A third and final methemoglobin concentration of 10% was obtained approximately 5 hours after the single infusion of methylene blue. The patient’s respiratory status remained stable at 17 breaths/min and SpO2 90%. An initial review of the patient’s medication administration record did not reveal any likely drug-related causes of methemoglobinemia. Further review of medications recently administered identified topical benzocaine 20% spray as a potential causative agent. For throat discomfort and irritation secondary to the endotracheal tube, the patient received 2–3 sprays of topical benzocaine 20% to his oropharynx. Since topical benzocaine spray is a component of the intubation kits in the intensive care units, the spray was readily available for use without being prescribed. Because administration of the aerosol was not documented, identification of the cause for methemoglobinemia was delayed. Furthermore, the exact amount of topical benzocaine administered to the patient cannot be quantified. The patient’s oxygenation and respiratory status began to improve almost immediately following the infusion of methylene blue. Due to his continued failure to wean from the mechanical ventilator, the patient subsequently underwent a tracheostomy and was discharged after a total of 57 days.

Discussion Benzocaine is the topical anesthetic most frequently linked to methemoglobinemia.2 Methemoglobinemia is a

Table 1. Medications Associated with Methemoglobinemia1-3 Amyl nitrate Benzocaine Chloroquine Dapsone Lidocaine Menthol Methylene blue Metoclopramide Nitric oxide

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Nitrofurantoin Nitroglycerin Nitroprusside Phenazopyridine Phenytoin Prilocaine Primaquine Sulfonamides

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rare but potentially fatal condition that is estimated to occur in one of every 7000 patients who receive a topical anesthetic.13 Like other topical anesthetics, benzocaine is a direct oxidizing agent, reacting with hemoglobin to form methemoglobin at a rate that exceeds reduction capabilities.11,14 When methemoglobin is produced, the ability of the hemoglobin molecule to effectively transport oxygen and carbon dioxide is altered. Normally, the blood methemoglobin concentration is 20%, the patient may experience symptoms attributed to tissue hypoxia including anxiety, fatigue, dyspnea, dizziness, tachycardia, headache, and syncope.2,3,7,10 A methemoglobin concentration >50% is associated with significant dyspnea, metabolic acidosis, arrhythmias, and lethargy, which may progress to seizures, coma, and death. In severe or symptomatic methemoglobinemia, the treatment of choice is methylene blue 1–2 mg/kg given intravenously over 3–10 minutes.1-5,8,10,12,14 Methylene blue is rapidly converted to the reducing agent, leukomethylene blue, which restores functional hemoglobin by returning iron to the divalent state.1,4 The antidote may be given as the 1% solution or diluted in NaCl 0.9%.4 A methemoglobin level >30% warrants methylene blue therapy; however, for patients with concurrent conditions compromising oxygen delivery, including anemia, lung disease, or heart disease, administration of methylene blue is recommended at a methemoglobin concentration as low as 10%.1,2,4,7 If the methemoglobin concentration is >50%, methylene blue 2 mg/kg should be given initially.4 Following administration of methylene blue, the methemoglobin level should be significantly reduced within an hour.1 A second dose of methylene blue 1 mg/kg may be given an hour after the initial dose if the clinical signs and symptoms of methemoglobinemia have not begun to resolve.1,2,4 Cumulative doses of methylene blue >7 mg/kg have been associated with induction or worsening of methemoglobinemia because the parent compound, an oxidizing agent, is present in disproportionately greater amounts than the reducing agent.1,7 Adverse events reported with methylene blue include nausea, vomiting, dyspnea, diaphoresis, and paresthesias, as well as blue discoloration of the urine, feces, skin, and mucous membranes. Risk factors for development of methemoglobinemia are not clearly defined; however, underlying cardiac or respiratory diseases may worsen the symptoms associated with methemoglobinemia.9 For a variety of reasons, lung transplant recipients are at a potentially greater risk of suffering clinically significant adverse events secondary to methemoglobinemia following exposure to a drug with oxidizing properties. After lung transplantation, patients often have a limited functional reserve as oxygen delivery may continue to be compromised, thus rendering the lung trans-


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Methemoglobinemia Secondary to Topical Benzocaine

plant recipient more susceptible to conditions or medications that may alter oxygenation. In addition, lung transplant recipients receive several drugs, which often include multiple oxidizing agents. For instance, these patients frequently receive sulfonamide antibiotics for Pneumocystis jirovedi prophylaxis following the transplant. In sulfonamide-allergic patients, dapsone is typically given for P. jirovedi prophylaxis. Sulfonamides and dapsone are both associated with methemoglobinemia. The same patient may require administration of topical anesthetics for intubation or minor procedures. In our patient, profound signs and symptoms of methemoglobinemia manifested following oropharyngeal administration of topical benzocaine 20% spray. Because pulse oximetry and arterial blood gas analysis do not accurately measure or reflect the true methemoglobin concentration, the patient was likely symptomatic earlier than detected. Furthermore, identification of benzocaine as the causative agent for the methemoglobinemia was delayed in our patient because the administration of the topical benzocaine was not documented in his medication administration record. Within an hour of the intravenous administration of a single dose of methylene blue 2 mg/kg, the patient’s respiratory status dramatically improved and stabilized. Application of the Naranjo probability scale established a highly probable relationship between topical benzocaine spray and methemoglobinemia and associated respiratory compromise.15 Conclusions Our case emphasizes the potentially greater susceptibility for the development of methemoglobinemia in patients with concomitant conditions that alter oxygen delivery, specifically anemia and lung disease in our patient. The risks of palliative use of topical benzocaine in patients with preexisting disorders that compromise oxygen delivery may outweigh any benefit. Medical, nursing, respiratory, and pharmacy personnel should be made aware of the potential adverse reaction to topical benzocaine. Likewise, accurate documentation of the administration or application of any drugs must be continually reiterated to all healthcare personnel through regular educational opportunities. Only after thorough consideration of the risks and benefits in at-risk populations, such as lung transplant recipients, should topical benzocaine be administered for palliative purposes. Use of topical benzocaine should proceed with caution and careful monitoring. Aimée C LeClaire PharmD, Critical Care Specialty Pharmacy Resident, Chief Pharmacy Resident, Pharmacy Services, University of Kentucky Chandler Medical Center, Lexington, KY Timothy W Mullett MD, Director, Lung Transplant Program; Associate Professor, Division of Cardiothoracic Surgery, University of Kentucky Chandler Medical Center, Lexington M Salik Jahania MD, Assistant Professor, Division of Cardiothoracic Surgery, University of Kentucky Chandler Medical Center Jeremy D Flynn PharmD, Clinical Pharmacy Specialist, Surgical Critical Care, Pharmacy Services, University of Kentucky Chandler Medical Center; Assistant Professor, Pharmacy, College of Pharmacy, University of Kentucky

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Reprints: Dr. Flynn, College of Pharmacy, University of Kentucky, 800 Rose St., Rm. C-117, Lexington, KY 40536-0293, fax 859/3232048, [email protected]

References 1. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med 1999;34:64656. 2. Khan NA, Kruse JA. Methemoglobinemia induced by topical anesthesia: a case report and review. Am J Med Sci 1999;318:415-8. 3. Coleman MD, Coleman NA. Drug-induced methemoglobinemia. Drug Saf 1996;14:394-405. 4. Bradberry SM. Occupational methemoglobinemia. Toxicol Rev 2003; 22:13-27. 5. Cooper HA. Methemoglobinemia caused by benzocaine topical spray. South Med J 1997;90:946-8. 6. Rinehart RS, Norman D. Suspected methemoglobinemia following awake intubation: one possible effect of benzocaine topical anesthesia— a case report. AANA J 2003;71:117-8. 7. Guerriero SE. Methemoglobinemia caused by topical benzocaine. Pharmacotherapy 1997;17:1038-40. 8. Wurdeman RL, Mohiuddin SY, Holmberg MJ, Shalaby A. Benzocaineinduced methemoglobinemia during an outpatient procedure. Pharmacotherapy 2000;20:735-8. 9. Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med 2004;164:1192-6. 10. Gupta PM, Lala DS, Arsura EL. Benzocaine-induced methemoglobinemia. South Med J 2000;93:83-6. 11. Gentile DA. Severe methemoglobinemia induced by a topical teething preparation. Pediatr Emerg Care 1987;3:176-8. 12. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. Ann Pharmacother 1994;28:643-9. 13. Douglas WW, Fairbanks VF. Methemoglobinemia induced by a topical anesthetic spray (Cetacaine). Chest 1977;71:587-91. 14. Clifton J, Leikin JB. Methylene blue. Am J Ther 2003;10:289-91. 15. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.

EXTRACTO OBJETIVO: Informar sobre un caso de metahemoglobinemia secundaria a la administración de benzocaina tópica en aerosol en un paciente anémico con transplante de pulmón. RESUMEN: Un hombre caucásico de 40 años con historial médico pasado significativo para un transplante de pulmón secundario a deficiencia de alfa-1-antitripsina se descompensó agudamente luego de la administración orofaringeal de benzocaina tópica en aerosol. Un análisis de sangre reveló una concentración de metahemoglobina de 51.2%. Luego de administrar una sola dosis de azul de metileno 2 mg/kg por la vía endovenosa, el estado respiratorio del paciente mejoró marcadamente y el paciente se estabilizó. DISCUSIÓN: La metahemoglobinemia es una condición rara pero potencialmente fatal que puede ser adquirida o congénita. Sin embargo, esta condición es comúnmente adquirida secundaria a la exposición de agentes químicos oxidantes que son recetados rutinariamente, incluyendo benzocaina. Benzocaina puede reaccionar con hemoglobina para formar metahemoglobina a una velocidad que excede la capacidad para reducirla. Esto puede resultar en una oxigenación inadecuada y dificultad respiratoria. En metahemoglobinemia severa o sintomática, el tratamiento de elección es azul de metileno. CONCLUSIONES: La utilización de la escala de probabilidad de Naranjo estableció una asociación altamente probable entre benzocaina tópica en aerosol, metahemoglobinemia, y la descompensación respiratoria asociada. El riesgo del uso paliativo de benzocaina tópica en pacientes con desórdenes preexistentes que comprometen el suplido de oxígeno


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podría invalidar su beneficio. En este paciente, el diagnóstico de anemia y enfermedad pulmonar aumentan el riesgo de un evento adverso respiratorio clínicamente significativo secundario a deficiencias o interferencias en el suplido de oxígeno. La benzocaina tópica se debe administrar con precaución y debe ser monitoreada cuidadosamente en estas poblaciones. Annette Perez RÉSUMÉ OBJECTIF: Rapporter un cas de méthémoglobinémie secondaire à la vaporisation de benzocaïne topique chez un patient anémique transplanté pulmonaire. RÉSUMÉ DU CAS: La condition d’un homme caucasien de 40 ans avec une histoire médicale de transplantation pulmonaire suite à une déficience en α-1 antitrypsine s’est rapidement détériorée suite à l’administration oropharyngée de vaporisation topique de benzocaïne. Une analyse de sang a révélé une concentration de méthémoglobine de 51.2%. Suite à l’administration d’une dose unique intraveineuse de 2 mg/kg de bleu de methylène, la condition respiratoire du patient s’est grandement améliorée.

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DISCUSSION: La méthémoglobinémie est une condition rare et potentiellement fatale de nature acquise ou congénitale. La majorité des cas sont secondaires à l’exposition de produits chimiques oxydants prescrits de routine tels la benzocaïne. Celle-ci peut réagir avec l’hémoglobine pour former la méthémoglobine à une vitesse qui excède la capacité de réduction, résultant en des difficultés d’oxygénation et de détresse respiratoire. Dans les cas sévères ou symptômatiques, le traitement de choix est le bleu de méthylène. CONCLUSIONS: Selon l’échelle de Naranjo, une forte probabilité a été attribuée à la vaporisation topique de benzocaïne et à la méthémoglobinémie associée à la décompensation respiratoire. Les risques d’utilisation de la benzocaïne à des fins palliatives chez des patients ayant un désordre respiratoire peuvent dépasser les bénéfices associées. Chez notre patient, les diagnostics d’anémie et de maladie pulmonaire augmentent le risque d’effets respiratoires indésirables compromettant la livraison d’oxygène. La benzocaïne topique devrait être administrée avec précaution et un monitoring serré sera nécessaire chez cette population de patients.


Marc M Perreault

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