Prilocaine-Induced Methemoglobinemia -- Wisconsin, 1993

Methemoglobinemia is an uncommon disorder in which hemoglobin is not oxidized and not capable of binding oxygen. This condition may be associated with exposure to nitrate-contaminated drinking water, aniline dyes, and amide-containing medications. Ortho-toluidine, a metabolite of the anesthetic prilocaine, also can induce this condition (1). During March-August 1993, three Wisconsin women treated by the same oral surgeon developed methemoglobinemia after being injected with a prilocaine-based local anesthetic. The surgeon notified the Division of Health, Wisconsin Department of Health and Social Services, of these cases 1 week after the third case occurred. This report summarizes the case investigations. Case 1. A 22-year-old woman (body weight: 127 lbs {58 kg}) sought care at an emergency department (ED) for dizziness approximately 5 hours after her oral surgeon extracted four wisdom teeth. The oral surgeon had administered anesthetic of 560 mg prilocaine (4.4 mg per pound {9.7 mg/kg} of body weight) by local injection and 90 mg methohexital sodium, 10 mg diazepam, and 6 mg dexamethasone sodium phosphate by intravenous infusion. On examination in the ED, the patient was alert but reported slight dizziness. The emergency physician noted perioral and nailbed cyanosis. Her oral temperature was 99.1 F (37.3 C); pulse, 108/minute; respirations, 20/minute; and blood pressure, 130/90 mmHg. A sample of venous blood was described as brown and indicated a methemoglobin level of 27%. Methemoglobinemia was diagnosed, and treatment was initiated with oxygen; in addition, 100 mg methylene blue was administered intravenously over 5 minutes. Within 1 hour, the patient was discharged. She recovered fully. Case 2. A 33-year-old woman (body weight: 112 lbs {51 kg}) was transported by ambulance from her oral surgeon's office to an ED 4 hours after extraction of four wisdom teeth. Her symptoms included fatigue, cyanosis, and orthostatic hypotension with syncope. The oral surgeon had administered 560 mg prilocaine (5.0 mg per pound {11.0 mg/kg} of body weight) by local injection and 60 mg methohexital sodium, 10 mg diazepam, and 0.025 mg fentanyl intravenously. On examination in the ED, her oral temperature was 98.1 F (36.7 C); pulse, 66/minute; respirations, 12/minute; blood pressure, 122/88 mmHg; and peripheral oxygen saturation, 89%. A venous blood sample revealed a methemoglobin level of 28%. Methemoglobinemia was diagnosed, and she was administered oxygen through a nasal cannula and 100 mg methylene blue intravenously over 5 minutes. One hour after treatment, her methemoglobin level was 2%, and the patient was discharged. She recovered fully. Case 3. A 17-year-old female (body weight: 105 lbs {48 kg}) was transported by ambulance from her oral surgeon's office to an ED after she developed tachycardia, drowsiness, and shakiness while being prepared for extraction of four wisdom teeth. The oral surgeon had administered 480 mg prilocaine (4.6 mg per pound {10.1 mg/kg} of body weight) by local injection and 7.5 mg diazepam, 6 mg dexamethasone sodium phosphate, and 0.025 mg fentanyl intravenously. The patient had been taking an oral contraceptive and, 1 week earlier, her physician had begun treating her with amitriptyline for headaches. In addition, she had a history of exercise-induced asthma and allergies to amoxicillin and cefaclor. On examination in the ED, she was alert and oriented. Her oral temperature was 98.1 F (36.7 C); pulse, 110/minute; respirations, 20/minute; blood pressure, 120/92 mmHg; peripheral oxygen saturation, 89%; and methemoglobin level, 10.7%. Methemoglobinemia was diagnosed, and she was treated with oxygen through a nasal cannula and an intravenous infusion of normal saline. The patient was hospitalized overnight for observation and recovered fully.

Reported by: L Knobeloch, PhD, J Goldring, PhD, W LeMay, DDS, H Anderson, MD, Environmental Epidemiologist, Div of Health, Wisconsin Dept of Health and Social Svcs.

Editorial Note

Editorial Note: Prilocaine is a lidocaine homologue and the only secondary amine local anesthetic that remains in clinical use. Prilocaine is biotransformed by hepatic amidase to aminophenol metabolites (i.e., ortho-toluidine and N-propylalanine), which subsequently can oxidize hemoglobin to methemoglobin. Administration of prilocaine in doses exceeding 400 mg has been associated with methemoglobinemia in adults. Proportionately lower doses may cause this problem in children (1). Methemoglobin levels above 10% may result in clinical anoxia (2), and levels above 60% can cause stupor, coma, and death.

The findings in this report indicate that doses of prilocaine only slightly exceeding the recommended therapeutic dose have the potential to cause methemoglobinemia. The manufacturer's package insert for prilocaine recommends a therapeutic dose of 4 mg/lb * (8 mg/kg) for "normal healthy adults," with a maximum dose of 600 mg indicated for persons weighing 150 lbs (68 kg) or more. For persons weighing less than 150 lbs (68 kg), the maximum dose must be accurately adjusted for body weight to reduce the risk for adverse effects. The Food and Drug Administration (FDA) has investigated the incidents in this report and recommends that the manufacturer update the package insert for prilocaine to emphasize the importance of adjusting dosage for body weight, particularly for persons weighing less than 150 lbs (68 kg).

During January 1992-September 1993, FDA received nine reports of prilocaine-induced methemoglobinemia. However, methemoglobinemia may be underreported because 1) some persons may develop only mild symptoms that do not require medical care, 2) some cases may not be recognized as prilocaine-induced, and 3) only drug manufacturers are required by law to report these events.

Oral surgeons and other health practitioners should use accurate body weight information to calculate safe doses of prilocaine and should know that doses exceeding 4.0 mg per pound (8 mg/kg) of body weight pose a risk to healthy adults. The risk for adverse effects associated with prilocaine use is increased for infants, persons with underlying health problems (i.e., anemia or diseases affecting the respiratory or cardiovascular systems), persons with hereditary deficiencies of glucose-6-phosphate dehydrogenase and methemoglobin reductase, and persons taking other oxidant drugs (e.g., nitrite-containing medications, sulfonamides, antimalarials, or acetaminophen).

References

1. Astra Pharmaceutical Products, Inc. Brief summary of prescribing information: Citanest Plain{Registered} and Citanest{Registered} Forte {Package insert}. Westborough, Massachusetts: Astra Pharmaceutical Products, Inc, 1992.

2. National Academy of Sciences. The health effects of nitrate, nitrite, and N-nitroso compounds. Washington, DC: National Academy Press, 1981.

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