Contemporary Surgery

CASE REPORT

Methemoglobinemia Induced by Topical Benzocaine Spray for Feeding Tube Placement

YASAMAN MOHADJER, MD; OMAR DANNER, MD; SELWYN M. VICKERS, MD Drs Mohadjer and Danner are from the Department of Surgery, and Dr Vickers is from the Section of Gastrointestinal Surgery at the University of Alabama School of Medicine, Birmingham. Correspondence Yasaman Mohadjer, MD; 4496 #3A Maryland Avenue, St. Louis, MO 63108; telephone (314) 276-0550; fax (314) 371-0295 (e-mail: mohadjery@yahoo.com).

abstract Feeding tube placement is commonly facilitated with topical anesthetic sprays such as benzocaine. However, topical anesthetic sprays have been increasingly linked to the rare development of methemoglobinemia, which, if not recognized in a timely matter, can be fatal. Because the signs and symptoms of methemoglobinemia can often be nebulous and nonspecific, physicians need to be aware of this potential complication any time a benzocaine anesthetic is used. We report a case of methemoglobinemia occurring after routine placement of a narrow-lumen feeding tube in a surgical patient.

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Methemoglobinemia is a rare form of central cyanosis that can soon be fatal if not recognized and treated rapidly. As of the year 2000, only 58 cases of idiosyncratic benzocaine-induced methemoglobinemia have 1 been reported. Many of these reported cases occurred in relation to upper gastrointestinal (UGI) endoscopy. Cases of benzocaine-related methemoglobinemia due to bronchoscopy and trans 7 esophageal echocardiography also have been noted. Benzocaine-induced methemoglobinemia associated with the placement of feeding tubes has not been widely reported.
2- 4 5 ,6

Case Report
An otherwise healthy, 44-year-old Caucasian female was admitted to the surgical intensive care unit (SICU) 10 days after a Whipple procedure for pancreatic cystadenoma. While on the general surgical floor, the patient developed bacteremia and increasing pulmonary compromise. On admission to the SICU, the patients temperature was 38.0 degrees Celsius (38.0C; 100.4F ), with a heart rate of 105115 beats per minute (BPM) and a mean arterial pressure (MAP) of 60100 mm Hg. The patient was maintained on 40% fraction of inspired oxygen (FIO2) via open face mask; pulse oximetry values were within the range of 3 94%98%. The patient had a white blood count of 29,000/mm and a hematocrit concentration of 29%. Results of an arterial blood gas (ABG) sample returned these values: pH, 7.45; arterial partial pressure of carbon dioxide (PaCO2), 27 mm Hg; arterial partial pressure of oxygen (PaO2), 102 mm Hg; and bicarbonate (HCO3), 20.8 mEq/L. Based on isolated culture results, the patient was subsequently treated with vancomycin, gentamicin, piperacillin sodium and tazobactam sodium, and fluconazole and was maintained on bowel rest with total parental nutrition (TPN) until bowel function returned. As bowel function returned (as measured by bowel sounds and movements), placement of a feeding tube was initiated. At this time, the patients pulmonary status had been stable on FIO 2 of 40% via nasal

cannula. Analysis of an ABG sample revealed these values: pH, 7.48; PaCO2, 27 mm Hg; and PaO2, 123 mm Hg. Oxygen saturation measured 97.2% by pulse oximetry.

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Hemoglobin concentration was 9.5% and hematocrit, 28%. Prior to feeding tube placement, the patient was administered two pharyngeal sprays of Hurricaine, a 20% benzocaine topical anesthetic spray. A 10F Dobhoff feeding tube (Biosearch Medical Products, Inc, Somerville, NJ ) was placed under fluoroscopy. The tube traversed the gastrojejunostomy anastomosis and was visualized descending down the jejunal limb. Proper positioning was verified by x-ray. Initially, the patient tolerated the procedure well. Within 45 minutes, however, she became significantly pale with associated peripheral cyanosis. The patient did not, however, show any other signs of distress, respiratory or otherwise. Blood pressure and heart rate remained stable. Within an hour of the procedure, the patients pulse oximetry showed an oxygen saturation of 49%, with ABG results of pH, 7.44; PaCO2, 39 mm Hg; and PaO2, 174 mm Hg. Oxygen saturation was measured at 68.0% on FIO2 of 60%. Methemoglobin level was 36% (reference range, 0.6% 1%). Her hemoglobin and hematocrit readings remained stable. The patient, now extremely cyanotic but still without clinical respiratory distress, was placed on a 100% oxygen supply via a non-rebreather face mask. Results of a repeat ABG 1.5 hours after Dobhoff feeding tube placement included: pH, 7.49, PaCO2, 34 mm Hg; PaO2, 242 mm Hg; HCO3; 25.5 mEq/L; with measured O2 saturation of 62.7%. The patient was administered 1 mg/kg of methylene blue intravenously over 5 minutes along with 2 units of packed red blood cells. The next ABG result (FIO2, 60%) 5 hours later showed significant improvement: pH, 7.49; PaCO2, 36 mm Hg; PaO2, 131 mm Hg; HCO3, 26.9 mEq/L; measured O2saturation was 94.9%. Methemoglobin levels were within normal range. Hemoglobin concentration increased to 10.2% with a hematocrit concentration of 30%. Clinically, the patients cyanosis resolved. The rest of the patients SICU course was uneventful. The patient continued to improve and was subsequently transferred to the general surgical floor 8 days later.

Discussion
Methemoglobinemia is a rare condition characterized by oxidation of iron within the hemoglobin molecule from the ferrous (Fe++) to the ferric (Fe+++) state. This event significantly diminishes the oxygen-carrying capacity of the red blood cell and can rapidly lead to central and peripheral cyanosis, metabolic acidosis due to inability of the cells to carry out aerobic metabolism, and eventually coma and death if left untreated. Although methemoglobin is continuously produced within erythrocytes, multiple enzyme systemsprimarily NADH-methemoglobin reductase function to maintain methemoglobin at very low levels, usually <1%2%. The leading cause of methemoglobinemia is drug toxicity caused by an oxidizing toxin. The agents most frequently associated with methemoglobinemia are aniline, benzocaine, dapsone, 8 pyridium, nitrites, nitrates, and naphthalene. In most cases, the drug becomes toxic only after it has been metabolized by the cytochrome P-450SCC system in the liver, producing free oxygen radicals. These oxidative species can then lead to oxidation of the ferrous to the ferric form of hemoglobin iron. However, because not all individuals metabolize these drugs the same way, only certain individuals are susceptible to having a methemoglobinemia reaction. Methemoglobinemia also can occur idiopathically with metabolic acidosis in children who are fed well water containing nitrates, and with genetic deficiencies of methemoglobin reductase.

The leading cause of methemoglobinemia is drug toxity caused by an oxidizing toxin.

Elevated methemoglobin levels cause significant changes in pulse oximetry and oxygen saturation as

measured by a blood gas machine, leading to clinical changes and metabolic failure. A patient with methemoglobinemia will not appear to be in respiratory distress, but will be cyanotic on physical exam. O Oxygen saturation by pulse oximetry shows a low SP 2 due to a small difference in light absorption by methemoglobin and hemoglobin. Some authors state that this small difference allows the oximetry machine to detect only mild oxygen desaturation, of no less than 85%, even in the face of severe 8 O methemoglobinemia. However, in the case presented above, as well as in others, much lower SP 2levels 6 have been noted.

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Arterial blood gas should be analyzed. In methemoglobinemia, blood appears chocolate brown in color, as opposed to the dark red/purple blood seen with deoxygenation. Even in severe cases, the partial pressure of oxygen will remain elevated on ABG scores, because PO2 is a calculated value based on pH, PCO2, and the oxygenhemoglobin dissociation curve. When abnormal hemoglobin is present and unable to carry oxygen, there is a falsely elevated oxygen level. Finally, in severe cases, pH will be low secondary to tissue hypoxia, anaerobic metabolism, and lactate production. Methemoglobin is definitively measured by co-oximetry, which measures light absorbance at four different wavelengths, allowing direct detection of 6 ,8 methemoglobin, carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin. Methemoglobinemia becomes clinically significant when rates of methemoglobin production exceed rates of reduction. However, identification of methemoglobin in a patient can be difficult, because early clinical symptoms are vague and nonspecific. As stated above, the patient usually shows no clinical signs of respiratory distress, and may be asymptomatic early on. When symptoms do occur, they are related to tissue hypoxia caused by decreased oxygen supply. Cyanosis begins at levels of 10%25%, but may even become apparent at methemoglobin levels of 2.5% in anemics. At 30% 40%, patients commonly complain of headache, fatigue, dizziness, dyspnea, and may be tachycardic. At increasing levels of 60% 70%, the patient may have arrythmias, seizures, lethargy, and may become comatose. At methemoglobin 8-10 levels >70%, death occurs. Severe methemoglobinemia is a medical emergency, and when identified, should promote a rapid response by house staff. Methemoglobinemia should be considered and diagnosed when oxygen saturation levels measured by pulse oximetry fall significantly and remain unresponsive to increased oxygen administration. The offending agent should be identified and discontinued. The patient should be given supplemental oxygen with a high flow rate. Treatment should begin with intravenous methylene blue at 12 mg/kg as a 1% solution over 510 minutes. Dose should be repeated within 60 minutes for inadequate response, marked by sustained elevation in methemoglobin levels. However, it should be noted that excessive methylene blue can actually promote increased methemoglobin levels. Response to therapy is best monitored by analysis of repeated ABG samples. In severe cases, exchange blood 6 ,7 transfusion may be necessary.

Methemoglobinemia becomes clinically significant when rates of methemoglobin production exceed rates of reduction.
Methylene blue is a cofactor that significantly increases the amount, and thus the role, of reduced nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase to promote the reduction of methemoglobin to hemoglobin. However, in individuals with NADPH reductase or glucose-6phosphate dehydrogenase deficiencies, methylene blue will not be useful. Exchange blood transfusion 6 ,8 may also be necessary in these cases.

Conclusion
This patientpreviously stable from a respiratory standpoint on an FIO2 of 40%was administered benzocaine spray to ease tolerance of feeding tube placement. Subsequently, the patients oxygen

saturation as measured by pulse oximetry fell rapidly and severely without response to increased oxygen administration. Arterial blood gas showed normal partial pressure of oxygen. However, co-oximetry detected high levels of methemoglobin. The patient responded to and recovered with intravenous methylene blue. After an extensive literature search, it became clear that benzocaine had previously been associated with methemoglobinemia in other procedures, although it had never been reported in association with Dobhoff tube placement. Because the patient had no other clinical predisposition, it was clear that benzocaine had also caused methemoglobinemia in this case. A Dobhoff tube is a widely used and ideal method for enteric feeding. Because of transpyloric placement, the narrow-lumen Dobhoff tube is an ideal feeding tube that allows minimal risk for aspiration of stomach contents, and for these reasons, is widely employed. Passing such a tube through the nares and pharynx can be quite uncomfortable for patients. There are many methods of increasing tolerance for this procedure. Due to ease of administration, 14% and 20% benzocaine topical sprays have been widely employed in Dobhoff tube placement, upper gastrointestinal endoscopy, transesophageal echocardiography, and bronchoscopy with rare complications.

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While generally very well tolerated, safe, and effective, rare methemoglobinemia reactions do occur secondary to oxidation of hemoglobin by a benzocaine metabolite.
A widely reported study showed that benzocaine topical anesthetic sprays improved patient tolerance and increased success of the procedure in a randomized double-blind study of 256 patients undergoing 11 unsedated upper endoscopy. Benzocaine sprays are frequently used in patients prior to any procedure requiring the passing of a tube through the pharynx. Although benzocaine use is not necessary for successful placement of a Dobhoff tube, it has been our experience that it greatly enhances patient cooperation and comfort. While generally very well tolerated, safe, and effective, rare methemoglobinemia reactions do occur secondary to oxidation of hemoglobin by a benzocaine metabolite. Patients with mucosal breakdown also have been shown to have higher rates of methemoglobinemia due to increased 6 absorption. Feeding tube placement is a common procedure in an inpatient hospital setting, and often is preceded by application of benzocaine anesthetic sprays. While the benefits of these sprays are numerous and side effects are rare, the physician should take care to limit the dosage and be acutely aware of potential complication. It is important for the physician to recognize the risk of methemoglobinemia and to be available to react in a timely and efficient manner to prevent fatality. REFERENCES 1. 2. Bernstein BM. Cyanosis following use of anesthesia (ethylaminobenzoate). Gastroenterology. 1950;17:123124 Gunaratnam NT, VazquezSequeiros E, Gostout CJ, Alexander GL.Methemoglobinemia related to topical benzocaine use: Is it time to reconsider the empiric use of topical anesthesia before sedated EGD? Gastroenterol Endosc. 2000;52:692693. 3. 4. Collins JF. Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy. Gastroenterology. 1990;98:211213. Brown CM, Levy SA, Susann PW. Methemoglobinemia: life-threatening complications of endoscopy premedication. Am J Gastroenterol. 1994;89:11081109. 5. Nguyen ST, Cabrales RE, Bashour CA , et al. Benzocaine-induced methemoglobinemia. Anesth Analg. 2000;90:369.

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10. Donovan JW. Nitrates, nitrites, and other sources of methemoglobinemia. In: Haddad LM, Winchester JF, eds. Clinical Management of Drug Overdose.Philadelphia: WB Saunders; 1990;14191431. 11. Campo R, Brullet E, Montserrat A , et al. Topical pharyngeal anesthesia improves tolerance of upper gastrointestinal endoscopy: a randomized doubleblind study. Endoscopy. 1995;27:659664.