- Email: [email protected]
Topical Benzocaine-induced Methemoglobinemia in the Pediatric Population
Department
www.jpedhc.org
Pharmacology Continuing Education
Section Editors Teri Woo, MS, RN, CPNP University of Portland School of Nursing, Kaiser Permanente Portland, Oregon Elizabeth Farrington, PharmD, FCCP, BCPS, FCCM University of North Carolina School of Pharmacy and North Carolina Children’s Hospital Chapel Hill, North Carolina
Topical Benzocaineinduced Methemoglobinemia in the Pediatric Population CE
Tsz-Yin So, PharmD, & Elizabeth Farrington, PharmD, FCCP, BCPS, FCCM
OBJECTIVES After reading this manuscript, the reader should be able to: 1. Illustrate a case of topical benzocaine-induced methemoglobinemia in a child. 2. Identify potential adverse effects and warnings of topical benzocaine use. 3. Understand the physiology of hemoglobin and methemoglobin. 4. State the pathogenesis, risk factors, and signs and symptoms of benzocaine-induced methemoglobinemia. Tsz-Yin So is Pediatric Pharmacy Specialty Resident, University of North Carolina Hospitals, Chapel Hill, NC, and Clinical Instructor, University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC. Elizabeth Farrington is Pediatric Pharmacy Clinical Specialist, University of North Carolina Hospitals, Chapel Hill, NC, and Clinical Assistant Professor, University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC. Correspondence: Tsz-Yin So, PharmD, University of North Carolina Hospitals, Department of Pharmacy, CB 7600, 101 Manning Dr, Chapel Hill, NC 27514; e-mail: [email protected]; Jeremy.So@ mosescone.com. J Pediatr Health Care. (2008). 22, 335-339. 0891-5245/$34.00 Copyright Q 2008 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.pedhc.2008.08.008
Journal of Pediatric Health Care
5. List the treatment options available for benzocaine-induced methemoglobinemia.
ABSTRACT Topical benzocaine is an anesthetic agent that is often used before procedures and clinical tests, such as esophagoscopy, bronchoscopy, and endotracheal intubation. However, a potential deadly condition known as methemoglobinemia can occur with this agent. It causes the oxidation of hemoglobin to methemoglobinemia to occur more rapidly than the reduction of methemoglobin back to hemoglobin. Certain congenital and clinical conditions that affect oxygen delivery can increase the patient’s risk of having methemoglobinemia develop with the use of benzocaine. Topical benzocaine-induced methemoglobinemia can occur in the pediatric population. Prompt management with intravenous
methylene blue should be initiated for reversal. Key words: Pediatric, benzocaine, methemoglobinemia, methylene blue.
Topical benzocaine is an anesthetic agent that is often used at dental clinics and hospitals. Clinicians use this medication before procedures and clinical tests such as esophagoscopy, bronchoscopy, and endotracheal intubation (AbuLaban, Zed, Purssell, & Evans, 2001). It also can be used for pain associated with burns, insect bites, itching, or teething. It exhibits its anesthetic action by inhibiting the neuronal activities/conduction that November/December 2008
335
are initiated as a result of pain stimuli (Lexi-Comp, 2008). Benzocaine comes in different dosage forms ranging from gel to spray. Common topical sprays are Hurricane (benzocaine 20%) and Cetacaine (benzocaine 14% and tetracaine 2%) (Abu-Laban et al.). Topical benzocaine has good absorption through the mucous membrane. It is metabolized primarily in plasma via hydrolysis, yet it utilizes the cytochrome P450 hepatic system as a secondary route of metabolism. After metabolism, the metabolites are eliminated renally (Lexi-Comp, 2008). Topical benzocaine is contraindicated in patients who are allergic to the medication or those with a previous history of methemoglobinemia. Caution should be taken when topical benzocaine is administered to infants who are younger than 6 months or individuals with the following conditions: glucose6-phosphate dehydrogenase deficiency, nicotinamide adenine dinucleotide (NADH)–dependent methemoglobin reductase deficiency, and pyruvate kinase deficiency (Lexi-Comp). Common adverse effects associated with topical benzocaine include, but are not limited to, burning, redness, itching, rash, and irritation at the site of administration. The most serious adverse effect reported with topical benzocaine administration is methemoglobinemia (Lexi-Comp, 2008). CASE REPORT S.R. is a 17-year-old White male (36 kg) with a history of cystic fibrosis, severe obstructive lung impairment, and diabetes mellitus who presented to the hospital for double lung transplantation. Unfortunately, complications developed after his transplant, which included brain and spinal cord watershed infarcts, pressure ulcers, and pseudomonas meningitis. Left lower lobe empyema and consolidation also developed, for which he underwent left thoracotomy and removal 336
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of the left lower lobe. After this procedure, he experienced respiratory distress requiring intubation and mechanical ventilation. One day after intubation, his respiratory status deteriorated, and the patient underwent bronchoscopy to assess the etiology of his respiratory distress. The differentials were respiratory infection or pulmonary hemorrhage. At 6 AM, results of a venous blood gas report were as follows: pH, 7.39 (7.32-7.43); PaCO2, 55 mmHg (40-60); PaO2, 38 mmHg (30-55); bicarbonate, 30.5 mmol/L (22-27); and arterial oxygen saturation (SaO2), 69.5% (40%-85%). At approximately 1:30 PM, benzocaine 20%, 1 spray topically, was administered to the patient prior to bronchoscopy. His vital signs were stable with a temperature of 36.7 C, blood pressure of 109/64 mmHg, heart rate of 88 beats per minute, and respiratory rate of 20 breaths per minute. Approximately 20 minutes after the administration of topical benzocaine, he became cyanotic and dyspneic. Because of his clinical state at that time, a STAT arterial blood gas report was obtained at 2:05 PM. Of note, the patient’s blood sample appeared to be chocolate-brown in color. Results of the arterial blood gas report were as follows: pH, 7.36 (7.357.45); PaCO2, 54 mmHg (35-45); PaO2, 220 mmHg (80-110); bicarbonate, 28.2 mmol/L (22-27); and SaO2, 99% (94-100). The laboratory also revealed a methemoglobin level of greater than 20%. Because the patient was cyanotic, dyspneic, and had an elevated PaO2 level and an elevated methemoglobin level, he was given methylene blue, 2 mg/kg of the 1% solution intravenously over 5 minutes. Approximately 20 minutes after the administration of methylene blue, the patient’s cyanosis was resolved. At 3:45 PM, another arterial blood gas report was obtained, which revealed the following: pH, 7.36; PaCO2, 53 mmHg; PaO2, 287 mmHg; bicarbonate, 28.1 mmol/L;
and SaO2, 99.8%. His methemoglobin level at this time had reduced to 5.1%. To confirm the resolution of his methemoglobinemia, another arterial blood gas report was obtained at 10:55 PM. The analysis revealed the following: pH, 7.38; PaCO2, 53 mmHg; PaO2, 135 mmHg; bicarbonate, 29 mmol/L; SaO2, 98.7%; and a methemoglobin level of 2.4%. Six days after methemoglobinemia developed, the patient was extubated. He was discharged 1 month later following a cochlear implantation performed as a result of ototoxicity from the use of tobramycin for his cystic fibrosis. He is currently well after undergoing the lung transplantation. PHYSIOLOGY OF HEMOGLOBIN AND METHEMOGLOBIN Hemoglobin is a major component of red blood cells in humans. It is responsible for carrying oxygen to all organs in the body. Each hemoglobin molecule has four subunits, or heme groups (two a and two b subunits). Each heme group carries an iron atom, which has the capability of carrying oxygen. However, the iron atom can only carry oxygen if it is in its reduced form (Fe2+) (AbuLaban et al., 2001; Hegedus & Herb, 2005). Methemoglobin is produced from the removal of an electron from the iron atom (Fe2+ / Fe3+). Therefore, methemoglobin is incapable of carrying any oxygen. As a matter of fact, methemoglobinemia also interferes with the unloading of oxygen from the heme group, ‘‘causing the oxyhemoglobin curve to shift to the left’’ (Abu-Laban et al., 2001). It is normal for people to have some methemoglobin, but the normal methemoglobin concentration is usually less than 2%. Once the methemoglobin concentration rises above 20% (levels range from 19%-75% in various case reports), it can potentially be harmful or even fatal (Abu-Laban et al.). Journal of Pediatric Health Care
Under normal circumstance, methemoglobin can be converted back to hemoglobin at a rate of about 15%/hour by an enzyme known as NADH-dependent methemoglobin reductase (Abu-Laban et al., 2001; Darracq & Daubert, 2007; Wright, Lewander, & Woolf, 1999). As its name implies, the function of this reductase is dependent on the transfer of electron from the co-factor NADH. This mechanism of how methemoglobin is reduced to hemoglobin is vital to the decision to administer benzocaine to patients because patients with deficiencies in these co-factors or enzymes are at an increased risk of methemoglobinemia. Besides NADH-dependent methemoglobin reductase, other reducing agents of methemoglobin exist in humans, including ascorbic acid, glutathione, flavin, and tetrahydropterin (Wright et al.). BENZOCAINE-INDUCED METHEMOGLOBINEMIA Introduction, Epidemiology, and Etiology Although topical benzocaine can cause methemoglobinemia, not many health care professionals are aware of this potential adverse effect (Abu-Laban et al., 2001). Benzocaine-induced methemoglobinemia is seen not only with the spray dosage form but also has been reported with the gel form (Darracq & Daubert, 2007). Methemoglobinemia is rarely seen in the adult population; it is mostly reported in children, especially those who are younger than 6 months, because they have a small supply of NADH-dependent methemoglobin reductase in their body (AbuLaban et al.; Wright et al., 1999). As a matter of fact, infants and the elderly comprise more than 50% of reported cases of methemoglobinemia (Nguyen et al., 2000). There are two types of methemoglobinemia: acquired and congenital. Congenital methemoglobinemia can be caused by deficiency in certain enzymes that are inJournal of Pediatric Health Care
volved in the physiology of hemoglobin and methemoglobin production. Congenital conditions include glucose-6-phosphodiesterase deficiency, nicotinamide adenine dinucleotide phosphate (NADPH) dependent methemoglobin reductase deficiency, and NADH-dependent methemoglobin reductase deficiency (Abu-Laban et al., 2001; Birchem, 2005; Darracq & Daubert, 2007; Nguyen et al., 2000; Wright et al., 1999). Such deficiencies are quite rare, so the majority of reported cases of methemoglobinemia are due to acquired sources (Nguyen et al.). Acquired sources can be divided into three major categories: (a) diet; (b) toxins; and (c) drug-induced. Food that is high in nitrates can cause methemoglobinemia. These nitrates can be transformed chemically into nitrites by gastrointestinal flora. Nitrites are powerful oxidizers of hemoglobin. Toxins like aniline possess similar action on hemoglobin (Wright et al.). Lastly, methemoglobinemia can be induced by certain medications. There are two types of drug-induced methemoglobinemia: direct oxidizers and indirect oxidizers. Direct oxidizers are agents that can directly oxidize hemoglobin to methemoglobin, while indirect oxidizers are agents that indirectly induce the oxidization of hemoglobin to methemoglobin by reducing O2 and H2O to potent free radical of O2- and H2O2, respectively (Wright et al., 1999). The Box illustrates a list of potential medications that can induce methemoglobinemia. For the purpose of this article, we will focus on benzocaine-induced methemoglobinemia. Pathogenesis and Risk Factors of Benzocaineinduced Methemoglobinemia The pathogenesis of benzocaine-induced methemoglobinemia (BIM) is not totally understood. Some researchers believe
BOX. Examples of druginduced methemoglobinemia
Acetaminophen Benzocaine Dapsone Celecoxib Chloroquine Cyclophosphamide Ifosfamide Lidocaine Methanol Methylene blue (at high doses) Metoclopramide Nitrates Phenazopyridine Phenytoin Primaquine Prilocaine Riluzole TrimethoprimSulfamethoxazole
Data from Abu-Laban, Zed, Purssell, & Evans, 2001; Birchem, 2005; Dahshan & Donovan, 2006; Darracq & Daubert, 2007; Hegedus & Herb, 2005; Nguyen et al., 2000; Wright, Lewander, & Woolf, 1999.
that the benzocaine causes the oxidation of hemoglobin to methemoglobin to occur more rapidly than the reduction of methemoglobin back to hemoglobin (Nguyen et al., 2000). Other researchers believe that benzocaine is an indirect oxidizer. It is metabolized into a chemical known as phenylhydroxylamine, which in turn interacts with oxygen to produce a very powerful free radical O2-. This free radical can then oxidize hemoglobin into methemoglobin (Wright et al., 1999). Other risk factors exist to increase patients’ chance of developing BIM, including a high concentration (>20%) of benzocaine and re-exposure to benzocaine. In addition, any congenital abnormalities (e.g., M-hemoglobinopathies) (Abu-Laban et al., 2001; Nguyen et al., 2000) that interfere with the production of hemoglobin and November/December 2008
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medical conditions that affect oxygen delivery (e.g., anemia and pulmonary dysfunction) (Wright et al., 1999) can put patients at an increased risk of the development of methemoglobinemia. Patients who have severe metabolic acidosis also are at increased risk of BIM because the reduction of methemoglobin to hemoglobin is inhibited under an acidic environment (Wright et al., 1999). Thus, it is prudent to maintain a normal pH in patients who receive topical benzocaine. Signs and Symptoms The signs and symptoms of methemoglobinemia usually occurs 20 to 60 minutes (up to 2 hours) after the administration of benzocaine. Patients with BIM usually present with cyanosis that is refractory to oxygen supplementation. The cyanosis starts in the extremities, like the nail beds; however, central cyanosis can occur when a patient’s methemoglobin concentration reaches more than 15%. In patients with underlying anemia, however, cyanosis can appear at a methemoglobin level as low as 2.5% (AbuLaban et al., 2001; Nguyen et al., 2000; Wright et al., 1999). Like the case patient, patients with BIM also can present with chocolate-brown arterial blood, compared with the dark red blood seen in patients with deoxygenated blood. In fact, when clinicians expose the methemoglobin arterial blood to air, it will stay chocolatebrown, whereas when deoxygenated blood is exposed to air, it will turn into a normal red color (Wright et al., 1999). Other potential adverse effects of methemoglobinemia include dyspnea, weakness, and altered mental status. In patients with severe cases of methemoglobinemia (with a methemoglobin level of >50%), seizures and ultimately coma also can develop (Darracq & Daubert, 2007). In addition to physical findings, patients with methemoglobinemia also can have 338
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TABLE. Management options for benzocaine-induced methemoglobinemia Primary options
Secondary options
Discontinue benzocaine Avoid re-challenge of agent Methylene blue 1-2 mg/kg administered intravenously; may repeat 1 mg/kg 1 if symptoms persist after 20 minutes
Exchange transfusion Hemodialysis Hyperbaric oxygen administration
Data from Abu-Laban, Zed, Purssell, & Evans, 2001; Nguyen et al., 2000.
various laboratory abnormalities: a methemoglobin level greater than 20%, anemia, and an elevated PaO2 level (Abu-Laban et al., 2001). Patients with methemoglobinemia may present with a low SaO2 measured by co-oximeter, while others may present with either a low or high oxygen saturation on pulse oximeter. Pulse oximeters only measure two ultraviolet wavelengths: oxyhemoglobin (940 nm) and deoxyhemoglobin (660 nm). At a low level of methemoglobin (\20%), methemoglobin is detected mainly by the deoxyhemoglobin sensor of the pulse oximeter, causing falsely low oxygen saturation values. At high levels of methemoglobin (>70%), methemoglobinemia is only detected by the oxyhemoglobin sensor, causing falsely high oxygen saturation readings. Because of this problem, if methemoglobinemia is suspected, it is much more prudent to look at the saturation gap instead of the oxygen saturation on the pulse oximeter. An oxygen saturation gap is defined as the difference in the oxygen saturation obtained from a cooximeter and one from a pulse oximeter. This gap is usually greater than 5% in patients with methemoglobinemia. Unlike the pulse oximeter, a co-oximeter measures numerous ultraviolet wavelengths, and it can detect carboxyhemoglobin, oxyhemoglobin, deoxyhemoglobin, and hemoglobin. Thus, it is a more accurate method to assess the oxygen saturation status in patients with methemoglobinemia (Abu-Laban et al., 2001; Wright et al., 1999).
Regardless of which signs and symptoms the patients may present with, they must meet four major criteria before they can be diagnosed as having BIM: (a) chocolatebrown arterial blood, (b) central cyanosis, (c) elevated methemoglobin concentration, and (d) greater than 5% of oxygen saturation gap (Nguyen et al., 2000). Meeting these diagnostic criteria enables our case patient to fulfill the Naranjo Adverse Drug Reaction (ADR) probability scale, showing a probable causality between methemoglobinemia and topical benzocaine administration (Naranjo et al., 1981). Management When BIM develops, the most important intervention is to discontinue the use of the offending agent. In fact, clinicians should not re-challenge the patient, because case reports have described incidences of severe methemoglobinemia after re-challenge with benzocaine (Udeh, Bittikofer, & Sum-Ping, 2001). Lastly, prompt treatment of the patient is required, because methemoglobinemia can be lethal (Logan & Gordon, 2005) (Table). It is vital to maintain airway, oxygen, and hemodynamic support initially when patients present with methemoglobinemia (Nguyen et al., 2000). Some clinicians believe a fluid containing dextrose should be given to patients because the catabolism of glucose via glycolysis is a major source of NADH and NADPH, which are all important chemicals needed in the reduction Journal of Pediatric Health Care
of methemoglobin to hemoglobin (Wright et al., 1999). However, the treatment of choice for BIM is the administration of methylene blue.
change (‘‘blue’’) and gastrointestinal and bladder irritation (Abu-Laban et al., 2001). Because methylene blue also can turn the
When BIM develops, the most important intervention is to discontinue the use of the offending agent. Indications for methylene blue include a methemoglobin level 20% or lower in a symptomatic patient, greater than 30% in an asymptomatic patient, and 10% to 30% in a patient with concomitant diseases like lung disease, similar to the case patient (Wright et al.). The dose is 1 to 2 mg/kg or 0.1 to 0.2 mL/kg of the 1% solution given intravenously over 3 to 5 minutes. It is recommended that the line be flushed with 15 to 30 mL of normal saline solution after the administration of methylene blue. If the patient’s symptoms do not resolve within 20 minutes after administration, another 1 mg/kg intravenous dose of methylene blue can be given to the patient 30 to 60 minutes from the time of the initial dose (Abu-Laban et al., 2001). For methylene blue to work, patients must have an adequate amount of NADPH in their body. NADPH acts as an electron donor for NADPH-dependent methemoglobin reductase, which in turn reduces methylene blue to leukomethylene blue. Leukomethylene blue then donates its electron to methemoglobin, causing its reduction into hemoglobin (Abu-Laban et al., 2001; Nguyen et al., 2000). These electrons transfers start with the pentose-phosphate shunt via glucose-6-phosphate-dehydrogenase (G6PD). Thus, methylene blue is contraindicated in patients with G6PD deficiency. If methylene blue is administered to patients with G6PD deficiency, hemolysis may develop (Wright et al., 1999). Common adverse effects of methylene blue include skin color
Journal of Pediatric Health Care
patients ‘‘blue,’’ clinicians cannot merely look at the patient to determine the resolution of methemoglobinemia. They must obtain arterial blood gas and methemoglobin levels to confirm the efficacy of methylene blue. Methylene blue is an oxidizing agent, so if it is administered in doses greater than 7 mg/kg, it can cause methemoglobinemia (AbuLaban et al., 2001; Nguyen et al., 2000). However, one review article indicates that such cyanosis only occurs if the dose reaches 80 mg/ kg (Clifton & Leikin, 2003). If symptoms of methemoglobinemia do not resolve after the second dose of methylene blue, other nonpharmacological treatment options are available, including hyperbaric oxygen administration, exchange transfusion, or dialysis (Abu-Laban et al., 2001; Nguyen et al., 2000). A prompt decision is needed because prolonged methemoglobinemia can be lethal. Other differential diagnoses include sulfhemoglobinemia, G6PD deficiency, NADPH-dependent methemoglobin reductase deficiency, congenital heart disease, or hereditary methemoglobinemia. The latter, however, is rare (Abu-Laban et al.; Nguyen et al.; Wright et al., 1999). CONCLUSION Topical benzocaine is not a benign anesthetic; it can induce methemoglobinemia. It is vital for clinicians to be aware of this potential adverse effect. Patients who present with methemoglobinemia should
be treated promptly with intravenous methylene blue as the primary management option because methemoglobinemia can potentially be lethal if untreated.
REFERENCES Abu-Laban, R. B., Zed, P. J., Purssell, R. A., & Evans, K. G. (2001). Severe methemoglobinemia from topical anesthetic spray: Case report, discussion and qualitative systemic review. Canadian Journal of Emergency Medicine, 3, 51-56. Birchem, S. K. (2005). Benzocaine-induced methemoglobinemia during transesophageal echocardiography. Journal of the American Osteopathic Association, 105, 381-384. Clifton, J., & Leikin, J. B. (2003). Methylene blue. American Journal of Therapeutics, 10, 289-291. Dahshan, A., & Donovan, G. K. (2006). Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: A case report and review of the literature. Pediatrics, 117, e806-809. Darracq, M. A., & Daubert, G. P. (2007). A cyanotic toddler. Pediatric Emergency Care, 23, 195-199. Hegedus, F., & Herb, K. (2005). Benzocaine-induced methemoglobinemia. Anesthesia Progress, 52, 136-139. Lexi-Comp. (2008, January 12). Retrieved January 12, 2008, from http://online. lexi.com/crlsql/servlet/crlonline Logan, B. K., & Gordon, A. M. (2005). Death of an infant involving benzocaine. Journal of Forensic Science, 50, 14861488. Naranjo, C. A., Busto, U., Sellers, E. M., Sandor, P., Ruiz, I., Roberts, E. A., et al. (1981). A method to estimate the probability of adverse drug reactions. Clinical Pharmacology & Therapeutics, 30, 239245. Nguyen, S. T., Cabrales, R. E., Bashour, C. A., Rosenberger, T. E., Michener, J. A., Yared, J., et al. (2000). Benzocaine-induced methemoglobinemia. Anesthesia & Analgesia, 90, 369-371. Udeh, C., Bittikofer, J., & Sum-Ping, S. T. J. (2001). Severe methemoglobinemia on re-exposure to benzocaine. Journal of Clinical Anesthesia, 13, 128-130. Wright, R. O., Lewander, W. J., & Woolf, A. D. (1999). Methemoglobinemia: Etiology, pharmacology, and clinical management. Annals of Emergency Medicine, 34, 646-656.
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www.jpedhc.org
Pharmacology Continuing Education
Section Editors Teri Woo, MS, RN, CPNP University of Portland School of Nursing, Kaiser Permanente Portland, Oregon Elizabeth Farrington, PharmD, FCCP, BCPS, FCCM University of North Carolina School of Pharmacy and North Carolina Children’s Hospital Chapel Hill, North Carolina
Topical Benzocaineinduced Methemoglobinemia in the Pediatric Population CE
Tsz-Yin So, PharmD, & Elizabeth Farrington, PharmD, FCCP, BCPS, FCCM
OBJECTIVES After reading this manuscript, the reader should be able to: 1. Illustrate a case of topical benzocaine-induced methemoglobinemia in a child. 2. Identify potential adverse effects and warnings of topical benzocaine use. 3. Understand the physiology of hemoglobin and methemoglobin. 4. State the pathogenesis, risk factors, and signs and symptoms of benzocaine-induced methemoglobinemia. Tsz-Yin So is Pediatric Pharmacy Specialty Resident, University of North Carolina Hospitals, Chapel Hill, NC, and Clinical Instructor, University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC. Elizabeth Farrington is Pediatric Pharmacy Clinical Specialist, University of North Carolina Hospitals, Chapel Hill, NC, and Clinical Assistant Professor, University of North Carolina at Chapel Hill, School of Pharmacy, Chapel Hill, NC. Correspondence: Tsz-Yin So, PharmD, University of North Carolina Hospitals, Department of Pharmacy, CB 7600, 101 Manning Dr, Chapel Hill, NC 27514; e-mail: [email protected]; Jeremy.So@ mosescone.com. J Pediatr Health Care. (2008). 22, 335-339. 0891-5245/$34.00 Copyright Q 2008 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.pedhc.2008.08.008
Journal of Pediatric Health Care
5. List the treatment options available for benzocaine-induced methemoglobinemia.
ABSTRACT Topical benzocaine is an anesthetic agent that is often used before procedures and clinical tests, such as esophagoscopy, bronchoscopy, and endotracheal intubation. However, a potential deadly condition known as methemoglobinemia can occur with this agent. It causes the oxidation of hemoglobin to methemoglobinemia to occur more rapidly than the reduction of methemoglobin back to hemoglobin. Certain congenital and clinical conditions that affect oxygen delivery can increase the patient’s risk of having methemoglobinemia develop with the use of benzocaine. Topical benzocaine-induced methemoglobinemia can occur in the pediatric population. Prompt management with intravenous
methylene blue should be initiated for reversal. Key words: Pediatric, benzocaine, methemoglobinemia, methylene blue.
Topical benzocaine is an anesthetic agent that is often used at dental clinics and hospitals. Clinicians use this medication before procedures and clinical tests such as esophagoscopy, bronchoscopy, and endotracheal intubation (AbuLaban, Zed, Purssell, & Evans, 2001). It also can be used for pain associated with burns, insect bites, itching, or teething. It exhibits its anesthetic action by inhibiting the neuronal activities/conduction that November/December 2008
335
are initiated as a result of pain stimuli (Lexi-Comp, 2008). Benzocaine comes in different dosage forms ranging from gel to spray. Common topical sprays are Hurricane (benzocaine 20%) and Cetacaine (benzocaine 14% and tetracaine 2%) (Abu-Laban et al.). Topical benzocaine has good absorption through the mucous membrane. It is metabolized primarily in plasma via hydrolysis, yet it utilizes the cytochrome P450 hepatic system as a secondary route of metabolism. After metabolism, the metabolites are eliminated renally (Lexi-Comp, 2008). Topical benzocaine is contraindicated in patients who are allergic to the medication or those with a previous history of methemoglobinemia. Caution should be taken when topical benzocaine is administered to infants who are younger than 6 months or individuals with the following conditions: glucose6-phosphate dehydrogenase deficiency, nicotinamide adenine dinucleotide (NADH)–dependent methemoglobin reductase deficiency, and pyruvate kinase deficiency (Lexi-Comp). Common adverse effects associated with topical benzocaine include, but are not limited to, burning, redness, itching, rash, and irritation at the site of administration. The most serious adverse effect reported with topical benzocaine administration is methemoglobinemia (Lexi-Comp, 2008). CASE REPORT S.R. is a 17-year-old White male (36 kg) with a history of cystic fibrosis, severe obstructive lung impairment, and diabetes mellitus who presented to the hospital for double lung transplantation. Unfortunately, complications developed after his transplant, which included brain and spinal cord watershed infarcts, pressure ulcers, and pseudomonas meningitis. Left lower lobe empyema and consolidation also developed, for which he underwent left thoracotomy and removal 336
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of the left lower lobe. After this procedure, he experienced respiratory distress requiring intubation and mechanical ventilation. One day after intubation, his respiratory status deteriorated, and the patient underwent bronchoscopy to assess the etiology of his respiratory distress. The differentials were respiratory infection or pulmonary hemorrhage. At 6 AM, results of a venous blood gas report were as follows: pH, 7.39 (7.32-7.43); PaCO2, 55 mmHg (40-60); PaO2, 38 mmHg (30-55); bicarbonate, 30.5 mmol/L (22-27); and arterial oxygen saturation (SaO2), 69.5% (40%-85%). At approximately 1:30 PM, benzocaine 20%, 1 spray topically, was administered to the patient prior to bronchoscopy. His vital signs were stable with a temperature of 36.7 C, blood pressure of 109/64 mmHg, heart rate of 88 beats per minute, and respiratory rate of 20 breaths per minute. Approximately 20 minutes after the administration of topical benzocaine, he became cyanotic and dyspneic. Because of his clinical state at that time, a STAT arterial blood gas report was obtained at 2:05 PM. Of note, the patient’s blood sample appeared to be chocolate-brown in color. Results of the arterial blood gas report were as follows: pH, 7.36 (7.357.45); PaCO2, 54 mmHg (35-45); PaO2, 220 mmHg (80-110); bicarbonate, 28.2 mmol/L (22-27); and SaO2, 99% (94-100). The laboratory also revealed a methemoglobin level of greater than 20%. Because the patient was cyanotic, dyspneic, and had an elevated PaO2 level and an elevated methemoglobin level, he was given methylene blue, 2 mg/kg of the 1% solution intravenously over 5 minutes. Approximately 20 minutes after the administration of methylene blue, the patient’s cyanosis was resolved. At 3:45 PM, another arterial blood gas report was obtained, which revealed the following: pH, 7.36; PaCO2, 53 mmHg; PaO2, 287 mmHg; bicarbonate, 28.1 mmol/L;
and SaO2, 99.8%. His methemoglobin level at this time had reduced to 5.1%. To confirm the resolution of his methemoglobinemia, another arterial blood gas report was obtained at 10:55 PM. The analysis revealed the following: pH, 7.38; PaCO2, 53 mmHg; PaO2, 135 mmHg; bicarbonate, 29 mmol/L; SaO2, 98.7%; and a methemoglobin level of 2.4%. Six days after methemoglobinemia developed, the patient was extubated. He was discharged 1 month later following a cochlear implantation performed as a result of ototoxicity from the use of tobramycin for his cystic fibrosis. He is currently well after undergoing the lung transplantation. PHYSIOLOGY OF HEMOGLOBIN AND METHEMOGLOBIN Hemoglobin is a major component of red blood cells in humans. It is responsible for carrying oxygen to all organs in the body. Each hemoglobin molecule has four subunits, or heme groups (two a and two b subunits). Each heme group carries an iron atom, which has the capability of carrying oxygen. However, the iron atom can only carry oxygen if it is in its reduced form (Fe2+) (AbuLaban et al., 2001; Hegedus & Herb, 2005). Methemoglobin is produced from the removal of an electron from the iron atom (Fe2+ / Fe3+). Therefore, methemoglobin is incapable of carrying any oxygen. As a matter of fact, methemoglobinemia also interferes with the unloading of oxygen from the heme group, ‘‘causing the oxyhemoglobin curve to shift to the left’’ (Abu-Laban et al., 2001). It is normal for people to have some methemoglobin, but the normal methemoglobin concentration is usually less than 2%. Once the methemoglobin concentration rises above 20% (levels range from 19%-75% in various case reports), it can potentially be harmful or even fatal (Abu-Laban et al.). Journal of Pediatric Health Care
Under normal circumstance, methemoglobin can be converted back to hemoglobin at a rate of about 15%/hour by an enzyme known as NADH-dependent methemoglobin reductase (Abu-Laban et al., 2001; Darracq & Daubert, 2007; Wright, Lewander, & Woolf, 1999). As its name implies, the function of this reductase is dependent on the transfer of electron from the co-factor NADH. This mechanism of how methemoglobin is reduced to hemoglobin is vital to the decision to administer benzocaine to patients because patients with deficiencies in these co-factors or enzymes are at an increased risk of methemoglobinemia. Besides NADH-dependent methemoglobin reductase, other reducing agents of methemoglobin exist in humans, including ascorbic acid, glutathione, flavin, and tetrahydropterin (Wright et al.). BENZOCAINE-INDUCED METHEMOGLOBINEMIA Introduction, Epidemiology, and Etiology Although topical benzocaine can cause methemoglobinemia, not many health care professionals are aware of this potential adverse effect (Abu-Laban et al., 2001). Benzocaine-induced methemoglobinemia is seen not only with the spray dosage form but also has been reported with the gel form (Darracq & Daubert, 2007). Methemoglobinemia is rarely seen in the adult population; it is mostly reported in children, especially those who are younger than 6 months, because they have a small supply of NADH-dependent methemoglobin reductase in their body (AbuLaban et al.; Wright et al., 1999). As a matter of fact, infants and the elderly comprise more than 50% of reported cases of methemoglobinemia (Nguyen et al., 2000). There are two types of methemoglobinemia: acquired and congenital. Congenital methemoglobinemia can be caused by deficiency in certain enzymes that are inJournal of Pediatric Health Care
volved in the physiology of hemoglobin and methemoglobin production. Congenital conditions include glucose-6-phosphodiesterase deficiency, nicotinamide adenine dinucleotide phosphate (NADPH) dependent methemoglobin reductase deficiency, and NADH-dependent methemoglobin reductase deficiency (Abu-Laban et al., 2001; Birchem, 2005; Darracq & Daubert, 2007; Nguyen et al., 2000; Wright et al., 1999). Such deficiencies are quite rare, so the majority of reported cases of methemoglobinemia are due to acquired sources (Nguyen et al.). Acquired sources can be divided into three major categories: (a) diet; (b) toxins; and (c) drug-induced. Food that is high in nitrates can cause methemoglobinemia. These nitrates can be transformed chemically into nitrites by gastrointestinal flora. Nitrites are powerful oxidizers of hemoglobin. Toxins like aniline possess similar action on hemoglobin (Wright et al.). Lastly, methemoglobinemia can be induced by certain medications. There are two types of drug-induced methemoglobinemia: direct oxidizers and indirect oxidizers. Direct oxidizers are agents that can directly oxidize hemoglobin to methemoglobin, while indirect oxidizers are agents that indirectly induce the oxidization of hemoglobin to methemoglobin by reducing O2 and H2O to potent free radical of O2- and H2O2, respectively (Wright et al., 1999). The Box illustrates a list of potential medications that can induce methemoglobinemia. For the purpose of this article, we will focus on benzocaine-induced methemoglobinemia. Pathogenesis and Risk Factors of Benzocaineinduced Methemoglobinemia The pathogenesis of benzocaine-induced methemoglobinemia (BIM) is not totally understood. Some researchers believe
BOX. Examples of druginduced methemoglobinemia
Acetaminophen Benzocaine Dapsone Celecoxib Chloroquine Cyclophosphamide Ifosfamide Lidocaine Methanol Methylene blue (at high doses) Metoclopramide Nitrates Phenazopyridine Phenytoin Primaquine Prilocaine Riluzole TrimethoprimSulfamethoxazole
Data from Abu-Laban, Zed, Purssell, & Evans, 2001; Birchem, 2005; Dahshan & Donovan, 2006; Darracq & Daubert, 2007; Hegedus & Herb, 2005; Nguyen et al., 2000; Wright, Lewander, & Woolf, 1999.
that the benzocaine causes the oxidation of hemoglobin to methemoglobin to occur more rapidly than the reduction of methemoglobin back to hemoglobin (Nguyen et al., 2000). Other researchers believe that benzocaine is an indirect oxidizer. It is metabolized into a chemical known as phenylhydroxylamine, which in turn interacts with oxygen to produce a very powerful free radical O2-. This free radical can then oxidize hemoglobin into methemoglobin (Wright et al., 1999). Other risk factors exist to increase patients’ chance of developing BIM, including a high concentration (>20%) of benzocaine and re-exposure to benzocaine. In addition, any congenital abnormalities (e.g., M-hemoglobinopathies) (Abu-Laban et al., 2001; Nguyen et al., 2000) that interfere with the production of hemoglobin and November/December 2008
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medical conditions that affect oxygen delivery (e.g., anemia and pulmonary dysfunction) (Wright et al., 1999) can put patients at an increased risk of the development of methemoglobinemia. Patients who have severe metabolic acidosis also are at increased risk of BIM because the reduction of methemoglobin to hemoglobin is inhibited under an acidic environment (Wright et al., 1999). Thus, it is prudent to maintain a normal pH in patients who receive topical benzocaine. Signs and Symptoms The signs and symptoms of methemoglobinemia usually occurs 20 to 60 minutes (up to 2 hours) after the administration of benzocaine. Patients with BIM usually present with cyanosis that is refractory to oxygen supplementation. The cyanosis starts in the extremities, like the nail beds; however, central cyanosis can occur when a patient’s methemoglobin concentration reaches more than 15%. In patients with underlying anemia, however, cyanosis can appear at a methemoglobin level as low as 2.5% (AbuLaban et al., 2001; Nguyen et al., 2000; Wright et al., 1999). Like the case patient, patients with BIM also can present with chocolate-brown arterial blood, compared with the dark red blood seen in patients with deoxygenated blood. In fact, when clinicians expose the methemoglobin arterial blood to air, it will stay chocolatebrown, whereas when deoxygenated blood is exposed to air, it will turn into a normal red color (Wright et al., 1999). Other potential adverse effects of methemoglobinemia include dyspnea, weakness, and altered mental status. In patients with severe cases of methemoglobinemia (with a methemoglobin level of >50%), seizures and ultimately coma also can develop (Darracq & Daubert, 2007). In addition to physical findings, patients with methemoglobinemia also can have 338
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TABLE. Management options for benzocaine-induced methemoglobinemia Primary options
Secondary options
Discontinue benzocaine Avoid re-challenge of agent Methylene blue 1-2 mg/kg administered intravenously; may repeat 1 mg/kg 1 if symptoms persist after 20 minutes
Exchange transfusion Hemodialysis Hyperbaric oxygen administration
Data from Abu-Laban, Zed, Purssell, & Evans, 2001; Nguyen et al., 2000.
various laboratory abnormalities: a methemoglobin level greater than 20%, anemia, and an elevated PaO2 level (Abu-Laban et al., 2001). Patients with methemoglobinemia may present with a low SaO2 measured by co-oximeter, while others may present with either a low or high oxygen saturation on pulse oximeter. Pulse oximeters only measure two ultraviolet wavelengths: oxyhemoglobin (940 nm) and deoxyhemoglobin (660 nm). At a low level of methemoglobin (\20%), methemoglobin is detected mainly by the deoxyhemoglobin sensor of the pulse oximeter, causing falsely low oxygen saturation values. At high levels of methemoglobin (>70%), methemoglobinemia is only detected by the oxyhemoglobin sensor, causing falsely high oxygen saturation readings. Because of this problem, if methemoglobinemia is suspected, it is much more prudent to look at the saturation gap instead of the oxygen saturation on the pulse oximeter. An oxygen saturation gap is defined as the difference in the oxygen saturation obtained from a cooximeter and one from a pulse oximeter. This gap is usually greater than 5% in patients with methemoglobinemia. Unlike the pulse oximeter, a co-oximeter measures numerous ultraviolet wavelengths, and it can detect carboxyhemoglobin, oxyhemoglobin, deoxyhemoglobin, and hemoglobin. Thus, it is a more accurate method to assess the oxygen saturation status in patients with methemoglobinemia (Abu-Laban et al., 2001; Wright et al., 1999).
Regardless of which signs and symptoms the patients may present with, they must meet four major criteria before they can be diagnosed as having BIM: (a) chocolatebrown arterial blood, (b) central cyanosis, (c) elevated methemoglobin concentration, and (d) greater than 5% of oxygen saturation gap (Nguyen et al., 2000). Meeting these diagnostic criteria enables our case patient to fulfill the Naranjo Adverse Drug Reaction (ADR) probability scale, showing a probable causality between methemoglobinemia and topical benzocaine administration (Naranjo et al., 1981). Management When BIM develops, the most important intervention is to discontinue the use of the offending agent. In fact, clinicians should not re-challenge the patient, because case reports have described incidences of severe methemoglobinemia after re-challenge with benzocaine (Udeh, Bittikofer, & Sum-Ping, 2001). Lastly, prompt treatment of the patient is required, because methemoglobinemia can be lethal (Logan & Gordon, 2005) (Table). It is vital to maintain airway, oxygen, and hemodynamic support initially when patients present with methemoglobinemia (Nguyen et al., 2000). Some clinicians believe a fluid containing dextrose should be given to patients because the catabolism of glucose via glycolysis is a major source of NADH and NADPH, which are all important chemicals needed in the reduction Journal of Pediatric Health Care
of methemoglobin to hemoglobin (Wright et al., 1999). However, the treatment of choice for BIM is the administration of methylene blue.
change (‘‘blue’’) and gastrointestinal and bladder irritation (Abu-Laban et al., 2001). Because methylene blue also can turn the
When BIM develops, the most important intervention is to discontinue the use of the offending agent. Indications for methylene blue include a methemoglobin level 20% or lower in a symptomatic patient, greater than 30% in an asymptomatic patient, and 10% to 30% in a patient with concomitant diseases like lung disease, similar to the case patient (Wright et al.). The dose is 1 to 2 mg/kg or 0.1 to 0.2 mL/kg of the 1% solution given intravenously over 3 to 5 minutes. It is recommended that the line be flushed with 15 to 30 mL of normal saline solution after the administration of methylene blue. If the patient’s symptoms do not resolve within 20 minutes after administration, another 1 mg/kg intravenous dose of methylene blue can be given to the patient 30 to 60 minutes from the time of the initial dose (Abu-Laban et al., 2001). For methylene blue to work, patients must have an adequate amount of NADPH in their body. NADPH acts as an electron donor for NADPH-dependent methemoglobin reductase, which in turn reduces methylene blue to leukomethylene blue. Leukomethylene blue then donates its electron to methemoglobin, causing its reduction into hemoglobin (Abu-Laban et al., 2001; Nguyen et al., 2000). These electrons transfers start with the pentose-phosphate shunt via glucose-6-phosphate-dehydrogenase (G6PD). Thus, methylene blue is contraindicated in patients with G6PD deficiency. If methylene blue is administered to patients with G6PD deficiency, hemolysis may develop (Wright et al., 1999). Common adverse effects of methylene blue include skin color
Journal of Pediatric Health Care
patients ‘‘blue,’’ clinicians cannot merely look at the patient to determine the resolution of methemoglobinemia. They must obtain arterial blood gas and methemoglobin levels to confirm the efficacy of methylene blue. Methylene blue is an oxidizing agent, so if it is administered in doses greater than 7 mg/kg, it can cause methemoglobinemia (AbuLaban et al., 2001; Nguyen et al., 2000). However, one review article indicates that such cyanosis only occurs if the dose reaches 80 mg/ kg (Clifton & Leikin, 2003). If symptoms of methemoglobinemia do not resolve after the second dose of methylene blue, other nonpharmacological treatment options are available, including hyperbaric oxygen administration, exchange transfusion, or dialysis (Abu-Laban et al., 2001; Nguyen et al., 2000). A prompt decision is needed because prolonged methemoglobinemia can be lethal. Other differential diagnoses include sulfhemoglobinemia, G6PD deficiency, NADPH-dependent methemoglobin reductase deficiency, congenital heart disease, or hereditary methemoglobinemia. The latter, however, is rare (Abu-Laban et al.; Nguyen et al.; Wright et al., 1999). CONCLUSION Topical benzocaine is not a benign anesthetic; it can induce methemoglobinemia. It is vital for clinicians to be aware of this potential adverse effect. Patients who present with methemoglobinemia should
be treated promptly with intravenous methylene blue as the primary management option because methemoglobinemia can potentially be lethal if untreated.
REFERENCES Abu-Laban, R. B., Zed, P. J., Purssell, R. A., & Evans, K. G. (2001). Severe methemoglobinemia from topical anesthetic spray: Case report, discussion and qualitative systemic review. Canadian Journal of Emergency Medicine, 3, 51-56. Birchem, S. K. (2005). Benzocaine-induced methemoglobinemia during transesophageal echocardiography. Journal of the American Osteopathic Association, 105, 381-384. Clifton, J., & Leikin, J. B. (2003). Methylene blue. American Journal of Therapeutics, 10, 289-291. Dahshan, A., & Donovan, G. K. (2006). Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: A case report and review of the literature. Pediatrics, 117, e806-809. Darracq, M. A., & Daubert, G. P. (2007). A cyanotic toddler. Pediatric Emergency Care, 23, 195-199. Hegedus, F., & Herb, K. (2005). Benzocaine-induced methemoglobinemia. Anesthesia Progress, 52, 136-139. Lexi-Comp. (2008, January 12). Retrieved January 12, 2008, from http://online. lexi.com/crlsql/servlet/crlonline Logan, B. K., & Gordon, A. M. (2005). Death of an infant involving benzocaine. Journal of Forensic Science, 50, 14861488. Naranjo, C. A., Busto, U., Sellers, E. M., Sandor, P., Ruiz, I., Roberts, E. A., et al. (1981). A method to estimate the probability of adverse drug reactions. Clinical Pharmacology & Therapeutics, 30, 239245. Nguyen, S. T., Cabrales, R. E., Bashour, C. A., Rosenberger, T. E., Michener, J. A., Yared, J., et al. (2000). Benzocaine-induced methemoglobinemia. Anesthesia & Analgesia, 90, 369-371. Udeh, C., Bittikofer, J., & Sum-Ping, S. T. J. (2001). Severe methemoglobinemia on re-exposure to benzocaine. Journal of Clinical Anesthesia, 13, 128-130. Wright, R. O., Lewander, W. J., & Woolf, A. D. (1999). Methemoglobinemia: Etiology, pharmacology, and clinical management. Annals of Emergency Medicine, 34, 646-656.
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