1. Matthew C Miller MD*, Michael T Gaslin MD*, Kathleen Herb MD, DMD**, and David Rosen MD*. Thomas Jefferson University Hospital, Philadelphia, PA *Department of Otolaryngology-Head and Neck Surgery **Department of Oral-Maxillofacial Surgery Abstract Introduction: Although local anesthetics are usually well tolerated, otolaryngologists need to be aware of the sometimes serious adverse events they can cause. The benzocaine containing sprays Hurricaine and Cetacaine are occasionally associated with the onset of life-threatening methemoglobinemia. The specific treatment for this condition is methylene blue. Methods and Measures: We describe a case report of a 48 year old female who developed a methemoglobin level of 41% after receiving topical benzocaine to her oropharynx. We discuss the case in light of the current literature. Results: After exposure to benzocaine, the patient developed severe cyanosis refractory to supplemental oxygen. Methemoglobinemia was suspected based on the recent exposure to benzocaine and the deeply cyanotic “chocolate” colored blood in the arterial blood gas specimen. After confirming the diagnosis with co-oximetry, the patient was treated with methylene blue. Her methemoglobin levels returned to normal within several hours. Conclusions: Otolaryngologists who use local anesthesia should be aware of the rare but serious complication of methemoglobinemia. Early diagnosis with co-oximetry and subsequent treatment with methylene blue can avoid a potentially life threatening situation. Methemoglobin Case Report A 48 year-old female was admitted to the Oral and Maxillofacial Surgery Service with one day history of pain and swelling of the left face and neck. Radiographic studies confirmed the presence of fluid collections in the peritonsillar and submandibular spaces. Given that the patient had significant trismus, plans were made for awake fiberoptic intubation by the anesthesia team followed by incision and drainage of the collections. The anesthesia team utilized a topical anesthetic consisting of 3 mL of nebulized 4% lidocaine solution and two brief sprays of 14% benzocaine (Cetacaine®) spray. Oral intubation proved difficult given the degree of trismus, and the otolaryngology team was consulted for trans-nasal intubation. Following successful endotracheal intubation, the incision and drainage procedure proceeded without further incident. On post-operative day 3, the patient had continued trismus and pain. Repeat CT scan revealed persistent fluid collections and the decision was made to return to the operating room for repeat drainage. The anesthesia team utilized a topical anesthetic consisting of 3 mL of nebulized 4% lidocaine solution and two brief sprays of 14% benzocaine (Cetacaine®) spray. Oral intubation proved difficult given the degree of trismus, and the otolaryngology team was consulted for trans-nasal intubation. Following successful endotracheal intubation, the incision and drainage procedure proceeded without further incident. On post-operative day 3, the patient had continued trismus and pain. Repeat CT scan revealed persistent fluid collections and the decision was made to return to the operating room for repeat drainage. The Otolaryngology team was again asked to perform awake fiberoptic intubation through the nose. The patient was pre-treated with 2-3 mL of 2% viscous lidocaine applied topically via nasal trumpet, 3 mL of 4% lidocaine solution via nebulizer, and 2 applications of 20% benzocaine (Hurricaine®) spray. She was then transferred to the operating room where she was noted to be cyanotic and mildly lethargic, though communicative and in no apparent distress. She denied dyspnea or chest pain. She was not tachypneic. Vital signs at the time were as follows: Pulse: 88, BP: 160/80, Oxygen Saturation: 90% on room air. A face mask with 100% oxygen was placed and the patient’s oxygen saturation remained in the range of 88 to 91%. The patient was urgently intubated trans-nasally over a flexible bronchoscope without difficulty. The endotracheal tube was secured, its position confirmed bronchoscopically, and the FIO 2 was set at 100%. Oxygen saturation remained unchanged. EKG and chest x-ray were unremarkable. An arterial sample taken for blood gas analysis appeared dark blue to brown in color. ABG was as follows: pH: 7.42 pCO 2 : 40 mmHg pO 2 : 261 SpO 2 : 100% Co-oximetry was then performed and revealed a Methemoglobin level of 41%. With confirmation of the diagnosis of methemoglobinemia, the patient was administered 70 mg of methylene blue by IV push. Oxygen saturation improved to 98% on 100% FIO 2 over the next several minutes. MetHgb levels fell initially to 11.6% and then serially to 0.8%. The patient’s abscesses were then satisfactorily drained. On postoperative day #2, she was extubated and she had an uncomplicated postoperative course. Methemoglobin is a form of hemoglobin characterized by the presence of iron in the ferric (Fe 3+ ) as opposed to the normally occurring ferrous (Fe 2+ ) state. In the ferric state, iron cannot share an electron with solublized oxygen and thus cannot participate in its carriage. This may occur as a result of innate errors in globin structure or synthesis, deficiencies in the naturally occurring methemoglobin reductase system, or, more commonly, as a result of exposures to oxidizing agents. The presence of oxidized heme moieties can also induce a conformational change in the four-globulin superstructure of hemoglobin, thereby increasing the overall affinity for oxygen. The net result is a leftward shift of the oxygen-hemoglobin dissociation curve. Bound oxygen is thus held more tightly and is unavailable for exchange at and use at the cellular level. Symptoms vary as the ratio of methemoglobin to hemoglobin A increases. Below 15-20%, patients are generally asymptomatic and acyanotic. Progressive respiratory distress, cardiac abnormalities, and neurological deterioration ensue with high mortality rates once methemoglobin levels surpass 70%. 13 Early recognition and treatment with reducing agents is essential to maintaining aerobic cellular respiration, and preventing permanent neurologic damage and death. Symptoms vary as the ratio of methemoglobin to hemoglobin A increases. Below 15-20%, patients are generally asymptomatic and acyanotic. Progressive respiratory distress, cardiac abnormalities, and neurological deterioration ensue with high mortality rates once methemoglobin levels surpass 70%. 13 Early recognition and treatment with reducing agents is essential to maintaining aerobic cellular respiration, and preventing permanent neurologic damage and death. 48 year-old female with methemoglobinemia status-post fiberoptic trans-nasal intubation Topical Anesthetics as Inciting Agents Topical anesthetic agents are frequently implicated in the development of methemoglobinemia. These substances are frequently utilized in otolaryngology during awake fiberoptic intubation and bronchoscopy. Topically applied Benzocaine (as in Hurricaine® or Cetacaine®) spray is poorly water soluble and is minimally absorbed through intact skin and mucosal surfaces, even at high doses. 14 Thus it is postulated that Benzocaine induced methemoglobinemia necessitates that the drug be delivered to a mucosal surface that has been previously broken. In addition, the dose of benzocaine delivered to a surface is highly operator dependent. It follows that the inconsistency in dose of topical lidocaine and benzocaine delivered and absorbed during fiberoptic intubation makes it difficult to predict which patients may be at risk for development of methemoglobinemia. However, factors such as advanced age, sepsis, acidosis, and malnutrition are known to potentiate the effects of oxidizing agents in the development of methemoglobinemia. 1,3,4 Diagnosis and Management Furthermore, arterial blood gases (ABGs) of patients with methemoglobinemia may have normal PaO 2 and SaO 2. However, the samples most often exhibit a characteristic “chocolate brown” color. Given the inherent limitations of standard blood gas analysis and pulse oximetry in methemoglobinemia, a technique known as co-oximetry should be employed. Co-oximetry allows for the confirmation of methemoglobinemia. Co-oximeters measure the absorbance of light at four different wavelengths – corresponding to oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin. Differential absorbances correlate with the relative concentrations of each heme moiety. As such, the MetHgb burden can be quantitated prior to and during treatment. 7 Goals of treatment should be the removal or discontinuation of the offending agent, support and monitoring of the airway, breathing, and circulation, and maintenance of high arterial PO 2. Symptomatic patients and asymptomatic patients with MetHgb levels greater than 30% or with poor baseline oxygen carriage and delivery should receive reducing agents. 13 The agent of choice for methemoglobinemia is intravenous methylene blue (1-2 mg per kg push over five minutes). 1 This generally results in a significant reduction of the MetHgb level over then next 15 to 60 minutes. If repeat co-oximetry fails to demonstrate a reduction of MetHgb levels, methylene blue administration may be repeated to a maximum dose of 7 mg per kg. 13 Methylene blue should not be used in patients with Glucose-6-Phosphate dehydrogenase deficiency as it may induce hemolytic anemia. Ascorbic acid and N-acetylcysteine are direct reducing agents which may be alternatively be utilized in these circumstances. In severe or refractory cases, exchange transfusion or hemodialysis may be required. 1,3,4,8,13,14 Repeat Exposure to Topical Anesthetics This patient was exposed to topical benzocaine and lidocaine on two separate occasions over a 72 hour period and subsequently developed methemoglobinemia. Interestingly, she did not develop methemoglobinemia until the second exposure. One possible explanation for this phenomenon is that the patient had a sub-clinical methemoglobinemia in the three day interim between surgical procedures. Repeat exposure may have increased MetHgb levels above symptomatic thresholds. However, this seems unlikely given that multiple half lives (55 minutes) had passed between exposures. There was no exposure to any additional known precipitants of methemoglobinemia in that interim. A second and more plausible explanation may be that the effective dose of oxidizing agents was increased during the second intubation. And though the volumes of benzocaine delivered were comparable, the concentration utilized was 14% at the initial surgery and 20% at re- intubation. Furthermore, a more liberal use of lidocaine was employed during the second intubation – as a 2% oral swish and swallow, a viscous 2% solution lubricating the nasal cavity, and as 3 mL of a 4% nebulized solution. That the anesthetics were being presented to a recently instrumented and traumatized mucosal surface only served to increase the effective dose delivered to the systemic circulation. It is our contention that methemoglobinemia was an idiosyncratic response that developed consequent to the use of multiple potential oxidizing agents at high doses and in the presence of mucosal injury, malnutrition, and possibly hepatic insufficiency due to chronic alcoholism. That the patient had been exposed to the offending agents previously seems to have no bearing on the subsequent development of methemoglobinemia in this case. Table I: Methemoglobin Levels with Associated Signs and Symptoms 1 % MethemoglobinSymptoms < 10None 10-20Cyanosis 20-30 Anxiety, Lightheadedness, Headache, Tachycardia 30-50 Fatigue, Confusion, Dizziness, Tachypnea 50-70 Seizures, Coma, Arrhythmias, Acidosis > 70Death Since it is difficult to predict which patients are at risk for the development of methemoglobinemia, prompt recognition and treatment are imperative. In the setting of the difficult intubation, dyspnea, cyanosis, and decreased oxygen saturation by pulse oximetry should prompt immediate evaluation of the airway and the addition of supplemental oxygen. Auscultation of the chest, measurement of airway pressures and volumes, end-tidal CO2 determination, flexible bronchoscopy, and chest x-ray should be employed to rule-out malpositioning of the endotracheal tube and structural pulmonary disorders. Oxygen saturation by pulse oximetry and blood gas calculation may be falsely reassuring in the presence of significant and dangerous levels of methemoglobin. Standard pulse oximeters measure light absorbance at two wavelengths: 660 and 940 nm. Methemoglobin also absorbs light at these wavelengths. This limits the accuracy of pulse oximeters such that even in the presence of nearly 100% MetHgb, SPO 2 will be reported as approximately 85% 1,7,12 Oxygen saturation by pulse oximetry and blood gas calculation may be falsely reassuring in the presence of significant and dangerous levels of methemoglobin. Standard pulse oximeters measure light absorbance at two wavelengths: 660 and 940 nm. Methemoglobin also absorbs light at these wavelengths. This limits the accuracy of pulse oximeters such that even in the presence of nearly 100% MetHgb, SPO 2 will be reported as approximately 85% 1,7,12 Conclusions Otolaryngologists frequently perform diagnostic and therapeutic endoscopy of the upper aerodigestive tract. Respect for patient discomfort warrants use of topical anesthetic agents during these procedures. These medications may induce a potentially fatal methemoglobinemia and more judicious dosing must be exercised in patients with recent instrumentation or trauma to the target area. In the post-exposure period, cyanosis in conjunction with low SpO2, chocolate brown blood, and an oxygen saturation gap should arouse the suspicion of methemoglobinemia. Co-oximetry should be ordered with prompt respiratory support and infusion of methylene blue (or other reducing agents) once the diagnosis is confirmed. 1. Wright RO, Lewander WJ, and Woolf AD. Methemoglobinemia: Etiology, Pharmacology, and Clinical Management. Ann. 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