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2016

Benzocaine-Induced Methemoglobinemia: A Case Report

Keith Veltri Touro College of Pharmacy, [email protected]

Ellen Rudnick

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Recommended Citation Veltri, K., & Rudnick, E. (2016). -induced methemoglobinemia: A case report. P & T, 41(3), 180-183, 191.

This Article is brought to you for free and open access by the Touro College of Pharmacy (New York) at Touro Scholar. It has been accepted for inclusion in Touro College of Pharmacy (New York) Publications and Research by an authorized administrator of Touro Scholar. For more information, please contact [email protected]. Pharmacovigilance Forum

Benzocaine-Induced Methemoglobinemia: A Case Report Keith T. veltri, PharmD; and ellen rudnick, mS, BPharm

INTRODUCTION Welcome to the Pharmacovigilance Forum, many of these approvals involved complex bio- Local are classifi ed by where we report on interesting adverse drug logic agents. Yet all pharmaceuticals carry a risk their chemical structures, with the two reactions (ADRs), including drug-induced disease. of ADRs, whether they are new and improved, major categories being esters and amides ADRs are a leading cause of morbidity and mortal- generic agents, older brand products, complex (Table 1). The agent of choice depends ity. The Institute of Medicine has estimated that biologics, or biosimilars. Publishing ADR cases is on the method of administration, the 44,000 to 98,000 deaths a great way to educate others about little-known length of time for which the affected areas occur annually from medi- reactions, unique patient management of a require local anesthesia, and potential cal errors, with 7,000 due reaction, or interesting presentations of known adverse effects. to ADRs. Studies suggest reactions to a drug or drug class. Esters include benzocaine (Cepacol, that 6.7% of hospitalized Each Pharmacovigilance Forum will discuss Reckitt Benckiser; Dermoplast, Prestige patients have a serious noteworthy topics related to ADRs in the clini- Brands Holdings; Chloraseptic, Prestige ADR; about 0.5% die as a cal realm. Every medication has the potential to Brands Holdings; HurriCaine, Beutlich consequence. ADRs are a cause disease, but clinicians are often slow to Pharmaceuticals; Lanacane, Reckitt signifi cant, preventable public health problem recognize drug therapy as an etiological factor. Benckiser; Orabase, Colgate-Palmolive that we can help mitigate through education. I encourage anyone with a potentially interest- Company; Orajel, Church & Dwight; and Drug approvals in the U.S. continue to grow. ing case to contact me, to publish ADRs here Zilactin, Blairex Laboratories); chloropro- In 2015, the Food and Drug Administration (FDA) or elsewhere, and to report ADRs to the FDA caine (Nesacaine, APP Pharmaceuticals); approved 45 novel drugs—up from an average MedWatch program. (Novocaine, Colgate-Palmolive of about 28 per year from 2006 through 2014. —Michele B. Kaufman Company); and .1 This is a signifi cant increase, especially since Amides include (Mar- caine, Hospira; Sensorcaine, AstraZen- eca); dibucaine (Nupercainal, Nucere monly used of these agents include lido- ceuticals; Itch-X, B. F. Ascher & Company; Pharma); (Chirocaine, caine/ (Emla, Akorn, Inc.) and Pramegel, Pharmaderm; Pramosone, Purdue Pharma); (Dilocaine, benzocaine/tetracaine/butamben (Ceta- Sebela Pharmaceuticals; Prax, Ferndale Shire; Solarcaine, Bayer; Lidoderm, caine, Cetylite Industries).1 Laboratories; and Tronolane, Abbott Endo Pharmaceuticals; and Xylocaine, Amides have largely replaced the Laboratories) is a local that Fresenius Kabi USA); (Car- esters because they produce fewer does not belong to either the amide or bocaine, Cooke-Waite; Isocaine, Novo- adverse effects and generally have a lon- ester class.1 col Pharmaceutical; Polocaine, Novocol ger duration of action.1 Local anesthesia can be achieved by Pharmaceutical); prilocaine (Citanest, Pramoxine (Analpram, Sebela Pharma- various methods, including topical admin- Dentsply Pharmaceutical); and ropiva- istration, infi ltration, fi eld block, nerve caine (Naropin, Fresenius Kabi).1 Table 1 General Anesthetic Agents1 block, and intravenous regional injection. Some combination products contain Esters The method by which a both amides and esters; the most com- is administered aids its effectiveness • Benzocaine by delivering the agent directly to the • Dr. Veltri is Associate Professor at Touro area that is causing or will cause pain. • Procaine College of Pharmacy, New York, New York. This decreases systemic absorption and • Tetracaine His clinical practice site is Montefi ore Medi- related toxic effects. Systemic absorption cal Center in Bronx, New York, as a Clinical Amides could produce toxic effects on both the cardiovascular and nervous systems.1 Pharmacy Manager for Family Medicine. • Bupivacaine Recently, topical anesthetics have been Ms. Rudnick is Director of Pharmacy Opera- • Dibucaine reported to cause methemoglobinemia, tions, Department of Pharmacy, Montefi ore • Levobupivacaine an elevated fraction of methemoglobin (an Medical Center, The University Hospital for • Lidocaine unstable type of hemoglobin within eryth- Albert Einstein College of Medicine. Michele • Mepivacaine rocytes). The popularity of benzocaine as B. Kaufman, PharmD, CGP, RPh, editor of this • Prilocaine column, is a freelance medical writer living • in New York City and a Pharmacist in the Disclosure: The authors report no commer- New-York–Presbyterian Lower Manhattan Miscellaneous cial or fi nancial relationships in regard to this Hospital Pharmacy Department. • Pramoxine article.

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a has diminished as a oxygen saturation in the blood. However, agent that compromises the physiologi- result of increasing concerns regarding the measurement of PO2 is not affected by cal cellular defenses of red blood cells. its potential to induce this hematological the presence of methemoglobin, and as a The disorder can also be hereditary. It is disorder. Numerous case reports have result, pulse oximetry readings that are associated with the production of abnor- been published.2–17 As of 2009, a review inconsistent with oxygen saturation are mal hemoglobin, which usually presents of 242 published cases implicated ben- suggestive of methemoglobin.4,5 as cyanosis at birth or as a secondary zocaine in 66% of methemoglobinemia A pulse oximeter is a noninvasive feature of NADH reductase deficiency.5,12 related to local anesthesia, while lidocaine device attached to the finger, earlobe, Exogenous agents that pose a risk for accounted for only about 5% of cases.13 or nose that emits two separate wave- methemoglobinemia are listed in Table 2. lengths of light, red (660 nm) and infrared PATHOPHYSIOLOGY (940 nm). A co-oximeter is used to meas- Table 2 Selected Agents Associated Hemoglobin is composed of four ure the absorbance of oxyhemoglobin and With Methemoglobinemia5–7, 9, 11 heme groups: deoxyhemoglobin, oxy- deoxyhemoglobin circulating throughout High Risk hemoglobin, carboxyhemoglobin, and the capillaries. It reflects the amount of methemoglobin. Each group contains oxygen in the blood, expressed as a per- • Benzocaine • Nitroglycerin an iron atom capable of binding oxygen. centage, measuring light absorbance at • Chloroquine • Nitric oxide This binding, however, can occur only four different wavelengths, correlating to • Ciprofloxacin • Phenazopyridine if the iron is in the reduced state (Fe+2). the absorption characteristics off all four • Dapsone • Phenelzine The removal of an electron from reduced heme groups.18 Carboxyhemoglobin­ has • Flutamide • Phenobarbital iron—oxidizing it from Fe+2 to Fe+3—pro- an almost identical absorption spectrum • Isosorbide • Prilocaine duces methemoglobin. In addition, the (660 nm) to that of oxyhemoglobin.18 dinitrate • Primaquine production of a ferric (Fe+3) heme group Methemoglobin absorbs light at both • Metoclopramide • Quinine sulfate interferes with oxygen unloading by the wavelengths (660 nm and 940 nm) that • Naphthalene • Sulfonamides other ferrous (Fe+2) heme groups on the standard oximeters emit.18 Therefore, a • Nitrofurantoin • Trimethoprim hemoglobin molecule. Red blood cells are definitive diagnosis should be confirmed Moderate Risk continuously under stress by oxidative by co-oximetry in patients who present processes and undergo numerous struc- with cyanosis of an uncertain cause. • Acetaminophen • Fentanyl tural changes that result in the formation A “filter paper test” provides a rapid • Aspirin • Lidocaine of methemoglobin. The development of bedside method for diagnosing methe- • Bupivacaine • Mepivacaine methemoglobin is regulated by various moglobin. In patients with this disorder, • • Nitrous oxide enzymatic processes, which include the arterial blood, when drawn and placed on Low Risk major pathway nicotinamide adenine the filter paper, is often chocolate brown • Benzodiazepines • Phenothiazines dinucleotide methemoglobin reductase or black and does not change color when • Ibuprofen • Propofol 4,5,9 and the minor pathway nicotinamide ade- exposed to oxygen. • Inhalational • Succinylcholine nine dinucleotide phosphate (NADPH) The clinical manifestations of methemo- anesthetics • Thiopental 2,4,7,9 methemoglobin reductase. A small globinemia directly correlate with the level • Meperidine amount of methemoglobin is reduced via of measured methemoglobin. Symptoms nonenzymatic pathways, such as by ascor- can be worse in those at age extremes bic acid, reduced glutathione, riboflavin, (e.g., very young or very old) or with mul- PRINCIPLES OF TREATMENT and cysteine.5 During these major and tiple comorbidities. Elderly and pediatric AND REPLACEMENT minor processes, iron is in the ferrous patients, as well as hypoxic patients, are The topical anesthetics benzocaine form (Fe+2) and combines with oxygen for more prone to the formation of methemo- 20% (HurriCaine spray) and lidocaine transportation to the tissues.2,4,7–9 globin. Neonates express low levels of func- are readily available in most emergency Because methemoglobin prevents oxy- tional NADPH methemoglobin reductase, departments and are commonly used gen transport to cells, patients present- and this enzyme becomes less efficient to anesthetize a patient’s airway before ing with methemoglobinemia become in the elderly.17 A normal methemoglobin elective endotracheal intubations or endo- cyanotic despite an adequate respira- level is less than 1% to 3% of the fraction scopic procedures.14 Both agents have tory status. Increased oxygenation has of hemoglobin in healthy individuals. been reported to cause methemoglobin- no effect on either the cyanotic state or When the methemoglobin level indicated emia. A recent review of the literature oxygen saturation. Pulse oximetry will through arterial co-oximetry is 15% to 20%, indicated that methemoglobinemia was most likely be inaccurate, and readings patients are usually cyanotic, but they may reported more frequently with spray ben- will be inconsistent with the patient’s be asymptomatic. When methemoglobin zocaine used during dental or endoscopic increasing cyanosis.5 Oxygen saturation levels reach 20% to 50%, the patient may procedures (such as for transesophageal measured by pulse oximetry is typically experience headache and lightheadedness, echocardiography).14 The potentially fatal in the range of 80% to 85% regardless of weakness, chest discomfort, palpitations, effects of benzocaine may be due to a the severity of methemoglobinemia.4 Rou- and dyspnea. Death can occur when met- toxic metabolite, an N-hydroxy derivative tine analysis of arterial blood gas is used hemoglobin levels exceed 70%.2,5–7,10 that has an aniline group incorporated to determine the partial pressure of oxy- Methemoglobinemia usually results into its structure.6,14 This compound has gen (PO2), which is then used to calculate from exposure to an external oxidizing oxidizing properties.

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From November 1997 through March Case Report if the methemoglobin level remained above 2002, 132 cases of methemoglobinemia The following report describes a patient 20%. The patient ultimately received two associated with benzocaine administra- with benzocaine-induced methemoglobin- doses of 70 mg in two hours before there tion were reported to the FDA. In 123 emia who was seen at our hospital. was an initial decline in the methemoglo- of these cases (93%), the product was A 46-year-old woman with a medical his- bin level (Figure 1). The patient became less a spray; in two cases, the product was tory of hypertension, anemia, depression, cyanotic, and her oxygenation improved a benzocaine-containing lozenge; and and morbid obesity (which persisted after a (Table 3). Hematology further recommended in one case, it was a gel.14 These per- gastric bypass in 2003) presented on April 3, that the medical team continue trending the centages may not accurately represent 2013, for laparoscopic fi stula repair and revi- patient’s methemoglobin levels over the next actual occurrence rates because cases sion of her 2003 gastric bypass. She felt 24 hours. This was advised because of the were likely underreported. For example, well at discharge, but soon afterward she potential for a rebound e ect, which could patients with mild methemoglobinemia experienced chest pain that “felt as though occur secondary to the presence of the circu- may be asymptomatic or may present an elephant was sitting on her chest.” She lating oxidant. Repeat methylene blue doses with only mild symptoms, which may presented to the emergency department were not recommended unless the patient’s not be recognized as potential cases on April 12. An upper gastrointestinal series methemoglobin level exceeded 20%. of drug-induced methemoglobinemia. and computed tomogra- Differences in absorption and metabo- phy revealed free air in Figure 1 Level of Methemoglobin Before lism may explain the variability of ben- the upper abdomen and a and After Methylene Blue Treatment zocaine-induced methemoglobinemia in large extraluminal contrast these individuals.6,14 collection posterior to the 50 Mild methemoglobinemia can be gastric pouch, with free treated with supplemental oxygen to air bubbles in the upper 40 maximize the oxygen-carrying capacity quadrant. She decompen- 38.8 Methylene blue 1 mg/kg of the remaining normal hemoglobin after sated, and a nasogastric removal of the causative agent. These (NG) tube was temporarily cases generally do not require specifi c placed. After removal of 30 treatment.4,5 Symptomatic patients with the NG tube, benzocaine methemoglobinemia presenting with 20% topical oral spray 20.4 methemoglobin levels exceeding 20% to (HurriCaine) was ordered, 20 30% should receive methylene blue, which with nursing instructions acts as a cofactor for the enzyme NADPH to apply one spray to the Methemoglobin level (%) methemoglobin reductase. Electrons are 10 back of the throat. The 7.1 transferred from NADPH to methylene order also included instruc- 2.2 blue, which leads to a reduction of the tions to repeat the spray heme iron to deoxyhemoglobin.9 Methy- every six hours for pain 0 lene blue should be administered at an relief. The following day, 0 1 2 3 4 5 6 7 8 9 10 11 12 initial intravenous dose of 1 mg/kg to the nurse accidentally left Hours after methylene blue administration 2 mg/kg over fi ve minutes.4,5,9 If there is the HurriCaine spray canis- no response, a repeat 1-mg/kg dose may ter at the patient’s bedside, be administered after 30 to 60 minutes.5,9 and the patient subsequently overdosed as DISCUSSION The adverse effects of methylene blue the result of continuous excessive admin- Numerous case reports have described include bluish skin discoloration (which istration of the anesthetic over the next methemoglobinemia after gastrointesti- can complicate the assessment of cyano- four days. nal endoscopy, endotracheal intubation, sis), hemolysis, gastrointestinal distress, On the morning of April 17, the patient bronchoscopic NG tube placement, and bladder irritation, and rebound methe- was found to be cyanotic and “blue.” The other inpatient procedures that involve moglobinemia, particularly with doses patient stated that she felt short of breath, prescription topical anesthetics. How- that exceed 7 mg/kg.4,5,9 Methylene blue dizzy, and fatigued. She was immediately ever, many over-the-counter (OTC) topi- should not be administered to patients placed on 2 L of oxygen via nasal cannula. cal anesthetic gels, throat lozenges, or with glucose-6-phosphate dehydrogenase Later that morning, she desaturated to 83% sprays can cause methemoglobinemia. (G6PD) defi ciency or with congenital and was placed on 100% fraction of inspired The easy access to OTC benzocaine prod- abnormal hemoglobin or NADH reduc- oxygen (Fi02). An arterial blood gas (ABG) ucts, such as Cepacol anesthetic troches tase defi ciency. Low levels of NADPH are was ordered “stat.” The ABG showed a (Reckitt Benckiser) and Sucrets maxi- present in these patients, and as a result, methemoglobin level of 38.8%. mum-strength lozenges (Prestige Brands methylene blue will be ineffective and will At this point, the medical team con- Holdings), may lead clinicians to believe ultimately cause hemolysis. Exchange tacted the hematology service regarding that these products are free from adverse transfusions should be considered in therapeutic management for this patient. effects, including methemoglobinemia. these individuals.4,5,7,9 The hematology service recommended Methemoglobinemia often occurs immediate treatment with methylene blue when the doses of benzocaine spray (or 1 mg/kg, with a repeat dose one hour later other local anesthetic agents) exceed

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Table 3 Arterial Blood Gases and Co-Oximetry Values caine spray ordered for “sore throat.” Our staff has been educated on contacting the Normal Time of Time after Administration of Methylene Blue prescriber to recommend an alternative Values Diagnosis 3 hours 5 hours 10 hours agent, such as benzocaine troches or loz- enges, or phenol 0.5% spray (Chloraseptic, Arterial blood gas Prestige Brands Holdings), which can be pH 7.350–7.450 7.490 7.398 7.434 7.404 administered to both adults and pediatric patients over the age of 2 years. PCO2 (mm Hg) 35.0–45.0 31.7 43.1 38.8 46.0 PO (mm Hg) 80–100 180.0 57.3 71.5 139.0 2 CONCLUSION

HCO3 (mmol/L) 22.0–28.0 23.9 26.0 25.6 28.1 Methemoglobinemia is a persistent SaO 94–100 96.3 88.2 92.9 97.8 and significant clinical condition that can 2 result from the use of topical anesthetics, Arterial co-oximetry among other causes. Although it is treat- able, its detection has been complicated by O2Hb 60–90 59.6 69.9 85.7 94.3 a general lack of awareness in the medical Carboxy Hb < 9.1 0.0 0.4 0.7 1.4 community and by the limited availability MetHb < 1.6 38.8 20.4 7.1 2.2 of standard co-oximetry for an accurate Deoxy Hb (%) < 2 2.3 9.3 6.5 2.2 diagnosis in the inpatient setting. Clini- cians should be on the alert for this poten- FiO2 (%) 4L NC 6L NC 4L NC 80% tially serious disorder if patients show an

Carboxy Hb = carboxyhemoglobin; deoxy Hb = deoxyhemoglobin; FiO2 = fraction of inspired oxygen; inconsistency between the oxygen satura- Hb = hemoglobin; HCO3 = plasma bicarbonate; metHb = methemoglobin; NC = nasal canula; tion of arterial blood and the saturation O2Hb = oxyhemoglobin; PCO2 = partial pressure of carbon dioxide; PO2 = partial pressure of oxygen; calculated from partial pressure of oxy- SaO = arterial saturation of oxygen. 2 gen. In addition, methylene blue should be readily available in facilities where topical Table 4 Minimizing the Risk of Methemoglobinemia anesthetics are administered. When Using Topical Anesthetics21 • Affix labels to topical anesthetic spray bottles warning staff of the danger of excessive REPORTING ADVERSE patient use. DRUG REACTIONS All ADRs should be reported to Med- • Identify risk factors while obtaining the patient’s medical history. Watch at 1-888-INFO-FDA, 1-888-463- • Document the amount of drug administered, including measuring and recording the 6332, or online. The FDA 3500 Volun- number of sprays applied. The use of a reference chart with maximum recommended tary Adverse Event Report Form can be doses of anesthetics may be helpful. accessed easily online for reporting ADRs • Supplemental oxygen and methylene blue should be kept handy whenever topical at www.fda.gov/Safety/Medwatch/How- anesthetics are used. ToReport/ucm085568.htm. • Use delivery devices that provide more precision in drug administration, such as atomizers The FDA is interested in serious reports (many are available). that include any of the following patient • Stock only one topical anesthetic product to reduce dosing confusion. Lidocaine may be outcomes: death; life-threatening condi- safer than benzocaine. tion; initial hospitalization; prolonged hos- pitalization; disability or permanent dam- the manufacturers’ recommendations. 60 mg of the anesthetic in one second. age; congenital anomalies or birth defects; Clinicians have long pointed out that Adverse events related to topical anes- and other serious conditions for which ambiguous package instructions for thetics usually involve the use of multiple medical or surgical intervention is needed use of the spray canisters of benzocaine sprays or of sprays lasting longer than the to prevent one of the aforementioned out- products can be easily misinterpreted recommended duration.3,11,20 Table 4 lists comes. The FDA is also interested in any and can lead to potential overdoses. Pack- several strategies to reduce the risk of unlabeled ADRs for new drugs. age instructions commonly suggest that methemoglobinemia when using topical the user should “activate the spray with anesthetics.21 REFERENCES the forefinger for approximately one sec- After discussing the potential for met- 1. Katzung BG, Masters SB, Trevor AJ, eds. ond. Maximum anesthesia is produced in hemoglobinemia in patients treated with Basic and Clinical Pharmacology, 12th ed., one minute.” 19 This direction could easily topical anesthetics, our pharmacy depart- New York, New York: McGraw-Hill; 2012. 2. Sachdeva R, Pugeda JG, Meizlish JL, et al. be misinterpreted to mean that a continu- ment decided to remove the HurriCaine Benzocaine-induced methemoglobinemia. ous spray of up to one minute is permitted spray canister from the formulary and Texas Heart Institute J 2003;30:308–310. and even desirable for maximum anesthe- replace it with unit-dose nonspray benzo- 3. Paparella S. Topical anesthetic sprays sia.19 OTC benzocaine formulations may caine (HurriCaine One), thus making it directly associated with a serious, sometimes fatal adverse drug reaction: contain up to 20% benzocaine, and sprays easier to control the amount of drug being methemoglobinemia. J Emerg Nurs containing benzocaine deliver 45 mg to administered. We continue to see benzo- 2005;31:468–469. continued on page 191

Vol. 41 No. 3 • March 2016 • P&T® 183 Pharmacovigilance Forum continued from page 183 4. Bayard M, Farrow J, Tudiver F. Acute methemoglobinemia after endoscopy. J Am Board Family Pract 2003;17:227–229. 5. Chung NY, Batra R, Itzkevitch M, et al. Severe methemoglobinemia linked to gel-type topical benzocaine use: a case report. J Emerg Med 2010;38:601–606. 6. Bittmann S, Kruger C. Benzocaine-induced methemoglobinemia: a case study. Br J Nurs 2010;19:S42–S44. 7. Kern K, Langevin P. Methemoglobinemia after topical administra- tion with lidocaine and benzocaine for a difficult intubation. J Clin Anesth 2000;12:167–172. 8. Hahn IH, Hoffman RS, Nelson LS. Emla-induced methemoglo- binemia and systemic topical anesthetic toxicity. J Emerg Med 2004;26:85–88. 9. Abu-Laban RB, Zed PJ, Purssell RA, et al. Severe methemoglo- binemia from a topical anesthetic spray: case report, discussion, and qualitative systematic review. Can J Emerg Med 2001;3:51–56. 10. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiol- ogy, pharmacology, and clinical management. Ann Emerg Med 1999;34:646–656. 11. Orr TM, Orr Dl. Methemoglobinemia secondary to over-the- counter Anbesol. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:e7–e11. 12. Bong CL, Hilliard J, Seefelder C. Severe methemoglobinemia from topical benzocaine 7.5% (Baby Oragel) use for teething pain in a toddler. Clin Pediatr 2009;48:209–211. 13. Guay J. Methemoglobinemia related to local anesthetics: a sum- mary of 242 episodes. Anesth Analg 2009;108(3):837–845. 14. Vallurupalli S, Manchanda S. Risk of acquired methemoglobinemia with different topical anesthetics during endoscopic procedures. Local Reg Anesth 2011;4:25–28. 15. Suchard J, Rudkin S. Poison control center management of ben- zocaine exposures. Cal J Emerg Med 2004;5:55–59. 16. Hersh EV, Ciancio SG, Kuperstein AS, et al. An evaluation of 10 percent and 20 percent benzocaine gels in patients with acute toothaches: efficacy, tolerability, and compliance with label dose administration directions. J Am Dent Assoc 2013;144:517–526. 17. Gupta PM, Lala DS, Asura EL. Benzocaine-induced methemoglo- binemia. South Med J 2000;93:83–86. 18. Hasan A. Handbook of Blood Gas/Acid-Base Interpretation, 2nd ed. New York, New York: McGraw-Hill; 2013. 19. Pasternack AS. A puzzling case of methemoglobinemia in the intensive care unit. Hosp Physician 2004;38:30–32. 20. Benzocaine-containing topical sprays and methemoglobinemia. Institute for Safe Medication Practices (ISMP) Safety Alert. Octo- ber 3, 2002. Available at: www.ismp.org/newsletters/acutecare/ articles/20021003.asp. Accessed December 29, 2015. 21. Golembiewski J, Meyer T. Use of topical anesthetics to support intubation. Pharm Pract News 2015 (August):56–58. n

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