THE CASE A 65-year-old African American woman presented with a chief complaint of dyspnea after walking half a block. She had a history of chronic obstructive pulmonary disease (COPD), anemia, spontaneous pneumothorax, and 40 pack-years of smoking. In the emergency department, the patient was found to have a recurrent spontaneous pneumothorax on a chest radiograph, and a chest CT scan demonstrated 30% right-sided pneumothorax. She was initially treated with chest tube insertion but continued to have an air leak 7 days later, which required therapeutic video-assisted thoracoscopy (VATS). Her medications included aspirin and albuterol inhaler as needed. Six days after the VATS, hemoptysis developed. Before undergoing bronchoscopy, the patient was consciously sedated with 2 mg of midazolam, and local anesthetic was applied to her oropharynx with four 1-second sprays of benzocaine (consisting of 14% benzocaine, 2% butamben, and 2% tetracaine hydrochloride in a polyethylene glycol base). In addition, 10 mL of 2% lidocaine gel was applied to the patient's nasal cavity to facilitate the introduction of the bronchoscope. During bronchoscopy, she was given endotracheal lidocaine multiple times to minimize the cough reflex. The airways were patent, and a small ulceration was noticed at the carinal bifurcation. The patient maintained an oxygen saturation of 94% on 2 L of oxygen via nasal cannula throughout the procedure. Twenty minutes after termination of the procedure, the patient became lethargic and her oxygen saturation dropped to 80%. Her blood pressure was 100/50 mm Hg and heart rate was 80 beats per minute. No cyanosis was found on physical examination, and minimal wheezing was noted on lung examination, which excluded pneumothorax. A non-rebreather mask was placed, and flumazenil was given to reverse the sedation. Despite these steps, her level of consciousness deteriorated to stupor. Endotracheal intubation was performed for possible hypoventilation coma (CO2 narcosis) and an arterial blood gas (ABG) sample was taken. ABG analysis demonstrated chocolate-colored blood, with a pH of 7.41, PCO2 of 40 mm Hg, PO2 of 480 mm Hg (on 100% fraction of inspired oxygen [FiO2]), and oxygen saturation of 99%. Co-oximetry revealed a methemoglobin (metHb) level of 77% (normal, 0.4% to 1.5%). The patient was given 1 mg/kg of methylene blue and 2 mg of ascorbic acid intravenously. Two units of packed red blood cells was transfused in expectation of hemolysis over the next 24 to 48 hours. ABG analysis repeated 1 hour later revealed a metHb level of 40%; a second dose of methylene blue was given. Another hour later, the metHb level had dropped to 7%. The patient showed clinical improvement, with return of her mental status to baseline. She was extubated the same day and discharged home the following day. DISCUSSION In a literature search, we identified 102 case reports of adults with benzocaine-related methemoglobinemia. Benzocaine-induced methemoglobinemia has been a well-documented illness that is simple to cure but can be life-threatening if not recognized. As the use of "scope" procedures becomes more commonplace, early recognition of hypoxemia resulting from methemoglobinemia is critical. As in our case, sedation for the procedure can complicate the clinical picture. Because of this, suspicion must be high and immediate diagnosis is warranted. Etiology and pathophysiology Methemoglobin results from the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+) in the hemoglobin molecule. At any given time, approximately 1% of total hemoglobin is in the form of metHb. Several enzyme systems in red blood cells continuously reduce metHb to hemoglobin. The most important enzyme system is the cytochrome b5 metHb reductase system, which converts 99% of metHb to hemoglobin. Ascorbic acid and glutathione, which are cellular antioxidants without enzyme activity, contribute slightly to the overall reduction of metHb to hemoglobin. Unlike hemoglobin, metHb cannot carry either oxygen or carbon dioxide. Because of this, an increased level of metHb can cause cyanosis, impaired aerobic respiration, metabolic acidosis, and death.1 The cause of methemoglobinemia can be genetic or acquired. In congenital diseases, patients typically present shortly after birth with cyanosis and hypoxemia. These patients can have a deficiency (autosomal recessive inheritance) either in cytochrome b5 reductase or cytochrome b5. Acquired methemoglobinemia can result from exposure to toxins or dietary agents that cause the reduction of hemoglobin to methemoglobin (Table 1). In the case of benzocaine-induced methemoglobinemia, benzocaine acts as an indirect oxidizer, which reduces O2 to O22 (a free radical), which then oxidizes hemoglobin to metHb. Diagnosis The initial suspicion of methemoglobinemia is crucial. It should be a consideration in patients who become hypoxemic while receiving oxygen supplementation and remain refractory to an increase in FiO2 with previous exposure to benzocaine. The patient may have a change in mental status, especially lethargy and possibly stupor. In addition, cyanosis is an important physical finding. At increasing concentrations of methemoglobin, symptoms become progressively worse (Table 2). As metHb levels increase, pulse oximetry readings become an unreliable assessment of oxygen saturation. The pulse oximeter measures the absorbance of light at 660 nm and 940 nm.1 Oxyhemoglobin and deoxyhemoglobin absorb light at these wavelengths. The pulse oximeter determines oxygen saturation based on the ratio of absorption at these wavelengths, with a ratio of 0.43 (660 nm/940 nm) corresponding to 100% saturation. It assumes that other forms of hemoglobin are present in low quantities.2 Methemoglobin absorbs light equally at both wavelengths. At metHb levels greater than 30% to 35%, pulse oximetry readings stabilize around 82% to 84%, regardless of the actual amounts of oxyhemoglobin or deoxyhemoglobin in the blood.1 An ABG sample should be obtained as soon as possible. A chocolate-brown color of the blood drawn is pathognomonic for methemoglobinemia, especially if the color does not change over time with exposure to air. However, the ABG analysis may show a falsely normal arterial oxygen tension because it measures the amount of dissolved oxygen rather than the oxygen that is actually bound to hemoglobin. The oxygen satu- ration is then calculated using the standard oxygen-hemoglobin curve, under the assumption that normal hemoglobin is present.2 Because of this, ABG values can be confusing. Thus, if methemoglobinemia is suspected, co-oximetry must be specifically requested because most hospitals do not routinely perform this. Unlike conventional pulse oximetry, co-oximetry measures light absorbance at 4 wavelengths corresponding to the absorbance characteristics of oxy- hemoglobin, deoxyhemoglobin, carboxyhemoglobin, and hemoglobin. Methemoglobin is characterized by a peak absorption at 630 nm. Co-oximetry values revealing increased levels of metHb confirm the diagnosis of methemoglobinemia and should prompt immediate initiation of therapy. Treatment Patients with metHb levels greater than 30% or methemoglobinemia with hypoxia should be treated with methylene blue, 1 to 2 mg/kg in a 1% solution intravenously over 5 minutes.2,3 The level of metHb in the blood should be rechecked within 30 to 60 minutes of administration of methylene blue to monitor response to therapy.2 Additional doses can be given if levels fail to decrease adequately, with a maximum dose of 7 mg/kg. Consideration should also be given to supportive care. Patients should be given supplemental oxygen (at 100% FiO2), and the airway should be secured. Blood samples should be checked for evidence of hemolysis and anemia--adverse effects of methylene blue--and the possibility of blood transfusion should be considered. An ECG should be obtained to exclude hypoxemia-related myocardial ischemia, especially in patients with preexisting anemia or cardiovascular disease. Other adverse effects of treatment can include precordial pain, dyspnea, restlessness, apprehension, tremor, and a transient blue color to the skin and urine.3 The use of methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because they may have insufficient nicotinamide adenine dinucleotide phosphate, making methylene blue therapy ineffective, and because they are more prone to suffer from methylene blue- related hemolysis.2 Benzocaine-induced methemoglobinemia Our patient's case of methemoglobinemia was unique in several aspects. Early recognition of her condition was clouded for 2 reasons: First, discerning cyanosis was difficult because of her race. The naturally occurring dark skin pigment in African Americans masks any cyanosis that may be present. Second, assessment of her mental status was complicated by sedation. We considered recurrent pneumothorax in our initial differential. However, the patient had stable vital signs and bilateral breath sounds, which eliminated pneumothorax. Her persistent desaturation, despite reversal of sedation and supplemental oxygen at 100% FiO2, led us to continue searching for the cause of her hypoxia. On diagnosing the methemoglobinemia, we were surprised by her relatively mild presentation. With a metHb level of 77%, she exhibited stupor and hypoxia but maintained otherwise stable vital signs. According to the literature, a metHb level greater than 70% is lethal. However, our literature review identified 5 other patients with metHb levels greater than 70%, all of whom survived. Our patient had several risk factors that predisposed her to methemoglobinemia. Her history of both COPD and anemia placed her at higher risk for hypoxemia with increasing levels of metHb in her blood. Also, she had previously been exposed to benzocaine when undergoing therapeutic VATS. Other case reports have cited previous sensitization to pharyngeal anesthetics without adverse reaction and the development of methemoglobinemia with subsequent exposures.4-7 The true incidence of methemoglobinemia related to benzocaine is unknown. Several case reports and studies have identified the number of cases at single institutions. One case report identified 1 incident of methemoglobinemia in 7000 bronchoscopies.8 Another report found 2 cases in more than 1000 endoscopies performed at one institution.9 There is no reliable count of the number of adverse events involving benzocaine-related methemoglobinemia because reporting to the FDA Adverse Events Reporting Systems or even to the manufacturers of products containing benzocaine is voluntary.10 In fact, the FDA estimates that only about 10% of adverse events are reported. However, in the cases reported, benzocaine applied to mucosal tissues in the spray form was the most frequent cause of methemoglobinemia. The results of our review of case reports is shown in Table 3. Careful assessment of the risk factors for benzocaine-induced methemoglobinemia can aid in early diagnosis. Although drug-related exposure is the greatest risk factor, other important physiological, local, and genetic factors have been identified (Table 4).5 One well-known, although rare, risk factor for acquired methemoglobinemia is G6PD deficiency. However, screening for this disease before procedures is not a general practice.10 Case reports have also shown that anemia may play a role in acquired methemoglobinemia. In 2004, Ash-Bernal and associates11 identified 138 cases of acquired methemoglobinemia in 2 tertiary care hospitals. They found that 94% of the patients were anemic (hemoglobin level less than 12 g/dL in women and less than 14 g/dL in men).11 In cases of methemoglobinemia in the presence of anemia, the risk of hypoxia and ischemia is high. Aggressive medical management is necessary, especially in the presence of cardiovascular disease. Reexposure also may increase the risk of methemoglobinemia, although no clinical studies have proved this to date. These considerations are especially important in the setting of bronchoscopy. Hypoxemia can be encountered at any point during the procedure, from premedication to the recovery period. Causes of the hypoxemia can be systematically eliminated. An excessive dose of benzocaine spray or loss of integrity of the mucosal surface can predispose the patient to methemoglobinemia. Moreover, the use of sedatives for the procedure can mask early signs methemoglobinemia.12 However, if the hypoxemia is refractory to oxygen therapy, methemoglobinemia must be included in the differential. Ash-Bernal and associates11 found that 20% benzocaine spray caused the most severely elevated levels of metHb. Precautions Since benzocaine spray as an anesthetic is currently the standard practice in premedication for bronchoscopies, several precautions should be taken. First, the need for benzocaine spray for anesthesia must be determined. Second, if benzocaine is needed, the dosage must be considered carefully. Currently, there is a lack of standardization in the amount of benzocaine administered for bronchoscopy and in the method of delivery. Guidelines for 20% benzocaine spray specify 2 sprays lasting a total of 1 second. Although this 1-second spray is designed to deliver 60 mg of benzocaine,13 the actual duration of a spray and the dose can be difficult to estimate. A study of factors affecting dose delivery showed that current methods of application cannot deliver a consistent amount of the drug.14 Spraying time cannot be measured accurately, and positioning of the canister can alter delivery of the drug.14 In one study, benzocaine doses of 15 to 20 mg/kg were considered to be sufficient to cause significant metHb formation.13 The authors of this study offered suggestions to improve the safety of benzocaine spray, including use of a mucosal atomizing device to deliver a predetermined dose and use of preparations with less than 20% benzocaine. Another author suggested using 4% lidocaine (5 mL) in a nebulizer face mask to quantify and limit the amount of anesthetic delivered to a patient before performing a procedure.15 Regardless of how the physician chooses to deliver benzocaine as a topical anesthetic, precautions should be taken to prevent methemoglobinemia and to be prepared for the possibility that it may occur during the procedure. Ascorbic acid, which can slightly reduce metHb levels and is used in treatment of methemoglobinemia, may be helpful as a preventive measure, although no clinical studies have demonstrated this. In addition, the patient should be informed of the risk of methemoglobinemia. Informed consent forms or verbal explanations of risks for the procedure should specifically mention methemoglobinemia. Severinghaus and associates16 recommended to product suppliers that "all products containing benzocaine over 8% should carry suitable warning of the probability that methemoglobinemia will occur in proportion to dosage. Labels should provide information on the possible need for methylene blue treatment and the recommended dosage." With this consideration in mind, we suggest that methylene blue be available in emergency kits at any location where benzocaine may be used as a topical anesthetic. An informal survey of our institution's practicing pulmonologists revealed that all of them use benzocaine spray as their choice of topical anesthetic. However, none were aware of the presence of methylene blue in the vicinity of the bronchoscopy suite. While being prepared to treat immediately is a critical step in the management of methemoglobinemia, being equipped to handle its occurrence is just as important. This includes being able to recognize the signs and symptoms of methemoglobinemia as well as knowing how to diagnose it. References: 1. Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med . 1999; 34:646-656. 2. Sharma VK, Haber AD. Acquired methemoglobinemia: a case report of benzocaine-induced methemoglobinemia and a review of the literature. Clin Pulm Med . 2002;9:1. 3. Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine . 14th ed. New York: McGraw-Hill; 1998: 2538. 4. Basra SK, Vives MJ, Reilly MC, et al. Methemoglobinemia after fiberoptic intubation in a patient with an unstable cervical fracture: a case report. J Spinal Disord Tech .2006;19: 302-304. 5. Novaro GM, Aronow HD, Militello MA, et al. Benzocaine-induced methemoglobinemia: experience from a high-volume transesophageal echocardiography laboratory. J Am Soc Echocardiogr. 2003;16:170-175. 6. Udeh C, Bittikofer J, Sim-Ping ST. Severe methemoglobinemia on reexposure to benzocaine. J Clin Anesth. 2001;13:128-130. 7. Nguyen ST, Cabrales RE, Bashour CA, et al. Benzocaine-induced methemoglobinemia. Anesth Analg. 2000;90:369-671. 8. Douglas WW, Fairbanks VF. Methemoglobinemia induced by a topical anesthetic stray (cetacaine). Chest. 1977;71:587-591. 9. Srikanth MS, Kahlstrom R, Oh KH, et al. Topical benzocaine (Hurricaine) induced methemoglobinemia during endoscopic procedures in gastric bypass patients. Obes Surg .2005;15:584-590. 10. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med . 1991;324: 169-174. 11. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). 2004;83:265-273. 12. Gorman SR, Beamis JF. Complications of flexible bronchoscopy. Clin Pulm Med. 2005; 12:177-183. 13. Wilburn-Goo D, Lloyd LM. When patients become cyanotic: acquired methemoglobinemia. J Am Dent Assoc. 1999;130:826-831. 14. Khorasani A, Candido KD, Ghaleb AH, et al. Canister tip orientation and residual volume have significant impact on the dose of benzocaine delivered by Hurricaine® spray. Anesth Analg. 2001;92:379-383. 15. Wong DH, Wilson SE. Avoiding topical anesthesia-induced methemoglobinemia. Obes Surg. 2005;15:1088. 16. Severinghaus JW, Xu F-D, Spellman MJ Jr. Benzocaine and methemoglobinemia: recommended actions. Anesthesiology . 1991; 74:385-387.
