ABSTRACT
SUMMARY:
Benzocaine induced Methemoglobinemia
Contents Bibliography:
Page:
Title:
4 Coleman, M. D. and N. A. Coleman (1996). "Drug-induced methaemoglobinaemia. Treatment issues." Drug Saf 14(6): 394-405.
5 Rodriguez, L. F., L. M. Smolik, et al. (1994). "Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature." Ann Pharmacother 28(5): 643-9.
Hall, A. H., K. W. Kulig, et al.
(1986). "Drug- and chemical-induced methaemoglobinaemia. Clinical features and
management." Med Toxicol 1(4): 253-60.
Methaemoglobin is haemoglobin with the iron oxidised to the ferric (Fe ) state from the normal (or reduced) ferrous (Fe++) state. Methaemoglobinaemia refers to the presence of greater than the normal physiological concentration of 1 to 2% methaemoglobin in erythrocytes. Methaemoglobin is incapable of transporting oxygen. It has an intense dark blue colour; thus, clinical cyanosis becomes apparent at a concentration of about 15%. The symptoms are manifestations of hypoxaemia with increasing concentrations of methaemoglobin. Concentrations in excess of 70% are rare, but are associated with a high incidence of mortality. Methaemoglobinaemia may be congenital but is most often acquired. Congenital methaemoglobinaemia is of two types. The first is haemoglobin M disease (several variants) which is due to the presence of amino acid substitutions in either the alpha or beta chains. The second type is due to a deficiency of the NADH-dependent methaemoglobin reductase enzyme. This deficiency has an autosomal dominant transmission, and both homozygous and heterozygous forms have been reported. The heterozygous form is not normally associated with clinical cyanosis, but such individuals are more susceptible to form methaemoglobin when exposed to inducing agents. A wide variety of chemicals including several drugs, e.g. the antimalarials chloroquine and primaquine, local anaesthetics such as lignocaine, benzocaine and prilocaine, glyceryl trinitrate, sulphonamides and phenacetin, have been reported to induce methaemoglobinaemia. An intense 'chocolate brown' coloured blood and central cyanosis unresponsive to the administration of 100% oxygen suggests the diagnosis. A simple bedside test using a drop of the patient's blood on filter paper helps to confirm the clinical suspicion. Methaemoglobin can be quantitated rapidly by a spectrophotometric method.
Coleman, M. D. and N. A. Coleman
(1996). "Drug-induced methaemoglobinaemia. Treatment issues." Drug Saf
14(6): 394-405.
In normal erythrocytes, small quantities of methaemoglobin are formed constantly and are continuously reduced, almost entirely by the reduced nicotine adenine dinucleotide (NADH) diaphorase system, rather than the reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system. Methaemoglobinaemias are usually the result of xenobiotics, either those that may directly oxidise haemoglobin or those that require metabolic activation to an oxidising species. The most clinically relevant direct methaemoglobin formers include local anaesthetics (such as benzocaine and, to a much lesser extent, prilocaine) as well as amyl nitrite and isobutyl nitrite, which have become drugs of abuse. Indirect, or metabolically activated, methaemoglobin formation by dapsone and primaquine may cause adverse reactions. The clinical consequences of methaemoglobinaemia are related to the blood level of methaemoglobin; dyspnoea, nausea and tachycardia occur at methaemoglobin levels of > or = 30%, while lethargy, stupor and deteriorating consciousness occur as methaemoglobin levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure and neurological depression, while levels of 70% are usually fatal. Cyanosis accompanied by a lack of responsiveness to 100% oxygen indicates a diagnosis of methaemoglobinaemia, which should be confirmed using a CO-oximeter. Pulse oximeters do not detect methaemoglobin and may give a misleading impression of patient oxygenation. Methaemoglobinaemia is treated with intravenous methylene blue (methyl- thioninium chloride; ;1 to 2 mg/kg of a 1% solution). If the patient does not respond, perhaps because of glucose-6-phosphate dehydrogenase (G6PD) deficiency or continued presence of toxin, admission to an intensive care unit and exchange transfusion may be required. Dapsone- mediated chronic methaemoglobin formation can be reduced by coadministration of cimetidine to aid patient tolerance. Increasing knowledge and awareness of drug-mediated acute methaemoglobinaemia among physicians should lead to prompt diagnosis and treatment of this potentially life-threatening condition.
Rodriguez, L. F., L. M. Smolik, et al.
(1994). "Benzocaine-induced methemoglobinemia: report of a severe reaction and
review of the literature." Ann Pharmacother 28(5):
643-9.
OBJECTIVE: To report a case of benzocaine-induced methemoglobinemia and present a review of the related literature. CASE REPORT: An 83-year- old man received benzocaine topical anesthesia 600 mg prior to intubation for resection of a thyroid adenoma. The patient became severely cyanotic after induction of anesthesia. After a negative workup for common causes of cyanosis. blood co-oximetry analysis revealed a methemoglobin concentration of 54.1 percent. Intravenous methylene blue reversed the methemoglobinemia, although delayed recurrence 20 h later necessitated readministration of intravenous methylene blue. The patient developed cardiovascular instability and severe neurologic depression requiring prolonged ventilatory support. DISCUSSION: Methemoglobinemia can result from exposure to a number of drugs including benzocaine. Cyanosis, neurological and cardiac dysfunction may result when methemoglobin concentrations exceed 30 percent. Clinical diagnosis is made on the presentation of cyanosis unresponsive to oxygen administration and a distinctive arterial blood brown color; laboratory confirmation is by cooximetry. Treatment of symptomatic methemoglobinemia is by intravenous methylene blue (1-2 mg/kg) administration. Fifty-four cases of benzocaine-induced methemoglobinemia have been reported in the literature. Intubation, endoscopy/bronchoscopy, and ingestion were the most common procedures in which benzocaine administration produced methemoglobinemia. Infants and the elderly were more likely to develop toxic methemoglobinemia after benzocaine exposure. Other risk factors included genetic reductase deficiencies, exposure to high doses of anesthetic, and presence of denuded skin and mucous membranes. CONCLUSIONS: Because of the potential for severe complications, methemoglobinemia should be corrected promptly in compromised patients and those with toxic benzocaine concentrations. The possibility of masking symptoms during general anesthesia carries special risk of use of this agent in the preanesthesia setting.
Wurdeman, R. L., S. M. Mohiuddin, et
al. (2000). "Benzocaine-induced methemoglobinemia during an outpatient
procedure." Pharmacotherapy 20(6): 735-8.
Outpatient transesophageal echocardiography was performed in a 69-year- old man with a history of aortic valve repair. During the procedure the patient became markedly cyanotic and hypotensive. Oxygen saturation measured by pulse oximetry decreased from 97% to the mid-80s. The man's condition continued to deteriorate. On transfer to a critical care unit, blood analysis by co-oximetry showed methemoglobin saturation of 67.8%. The patient's condition improved significantly after intravenous administration of methylene blue 1 mg/kg. With increasing numbers of outpatient procedures performed under topical anesthesia, measures should be in place to deal with a potential life-threatening adverse event such as methemoglobinemia.
Collins, J. F. (1990).
"Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy."
Gastroenterology 98(1): 211-3.
Topical 20% benzocaine (Hurricaine, Beutlich, Inc., Niles, Ill.) spray is frequently used for oral anesthesia before upper endoscopy. Side effects attributed to this agent are exceedingly rare. The author reports one of these rare complications, drug-induced methemoglobinemia, in a patient with methemoglobin reductase deficiency. The mechanisms for the development of methemoglobinemia and its treatment are reviewed.
Douglas, W. W. and V. F. Fairbanks
(1977). "Methemoglobinemia induced by a topical anesthetic spray (cetacaine)."
Chest 71(5): 587-91.
In two seriously ill patients, cyanosis developed shortly after a topical anesthetic spray (Cetacaine) was used. In both cases the presence of methemoglobinemia was suggested by a discrepancy between the arterial oxygen tension and the oxygen saturation of hemoglobin, as measured spectrophotometrically. The characteristic responses of the spectrophotometric oximeter to blood containing different concentrations of methemoglobin are described. Physicians administering this topical anesthetic spray (Cetacaine) should be aware of the possible development of methemoglobinemia.
Ferraro-Borgida, M. J., S. A. Mulhern,
et al. (1996). "Methemoglobinemia from perineal application of an anesthetic
cream." Ann Emerg Med 27(6): 785-8.
A 34-year-old woman presented with cyanosis and a methemoglobin level of 23.2% after perineal application of a topical anesthetic cream containing 20% benzocaine. Many commonly used products contain high levels of benzocaine, and their use can lead to life-threatening methemoglobin levels. This case reinforces the need for stricter guidelines for product use and warning labels to alert consumers to this potential side effect of topical benzocaine-containing products sold over the counter.
Khan, N. A. and J. A. Kruse (1999).
"Methemoglobinemia induced by topical anesthesia: a case report and review."
Am J Med Sci 318(6): 415-8.
Topical anesthetic drugs are widely used by clinicians during hospital and outpatient procedures and are also available to the public in a variety of over-the-counter preparations. Although generally safe, they may cause potentially life-threatening methemoglobinemia. We describe a patient who developed repeated episodes of severe methemoglobinemia after administration of topical Cetacaine spray (a proprietary mixture of benzocaine, tetracaine, and butamben) employed for pharyngeal anesthesia before endotracheal intubation, and briefly review the etiology and pathophysiology of this disorder. Cautious interpretation of oxyhemoglobin saturation values obtained by pulse oximetry or estimated from arterial blood gas analysis is crucial lest the diagnosis of severe methemoglobinemia and the resulting hypoxemia are overlooked. If necessary, the condition is usually readily corrected by intravenous administration of methylene blue.
Guertler, A. T., M. S. Lagutchik, et
al. (1992). "Topical anesthetic-induced methemoglobinemia in sheep: a comparison
of benzocaine and lidocaine." Fundam Appl Toxicol 18(2):
294-8.
Benzocaine induces methemoglobin (MHb) in several species, whereas lidocaine may increase MHb in cats and human. Elevated MHb (greater than 20%) in sheep after benzocaine exposure was recently recognized. MHb decreases blood oxygen-carrying capacity which can complicate interpretation of experimental data. Sheep are used in research which requires tracheal intubation and blood gas analysis. Since benzocaine and lidocaine are used to provide local anesthesia prior to intubation, we compared MHb production by sheep after exposure to these drugs. A dose-response relationship between benzocaine and MHb was investigated. Eight crossbred Dorset ewes were dosed intranasally with benzocaine for 2 sec or with 40 mg of lidocaine in a randomized crossover design. Sheep with elevated MHb after the 2-sec benzocaine dose were later dosed with benzocaine intranasally for 10 sec. MHb levels were measured periodically on a CO-Oximeter. A quantitative MHb response to an indirect MHb former, p-aminopropiophenone (PAPP), by each sheep was determined 15 min after PAPP (0.6 mg/kg iv). MHb levels remained at baseline (1-2%) after lidocaine exposure in all sheep, as well as in four sheep (nonresponders) after the 2-sec benzocaine dose. Four sheep (responders) demonstrated 16.5-26.4% MHb after the 2-sec benzocaine dose. The responders formed 38.2-50.5% MHb after the 10-sec benzocaine dose. All responders developed high MHb after PAPP, while nonresponders developed slightly elevated MHb after PAPP. An N-hydroxy metabolite of benzocaine is the likely active MHb-forming substance. Benzocaine should be replaced by lidocaine when local anesthesia of the nasal or oropharyngeal region in sheep is required.
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