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