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Infantile methemoglobinemia due to benzocaine suppository
BRIEF
CLINICAL
LABORATORY
AND OBSERVATIONS
Infantile metbemoglobinemia due to benzocaine suppository James R. Hughes, M.D.* BOSTON~
1V~A S S .
~Present address, Assistant Professor, ]ohns Hopkin~ University Center 1o1" Medical Research and Training, All lndia Institute oJ Hygiene and Public Health, 110 Chittaranjan Avenue, Calcutta 12, India.
tion. She was also given a rectal suppository* because of a rectal fissure. Approximately 45 minutes after insertion of the suppository, the infant was noted to be cyanotic. She was seen again by the original physician and taken to a nearby hospital where she was found to be in no distress but to have oxygen-resistant cyanosis. An electrocardiogram was obtained, and she was transferred to the Children's Hospital Medical Center. On admission she was intensely cyanotic but in no distress; her vital signs were within normal limits. Aside from a Grade 1 systolic murmur along the left sternal border, the remainder of her physical examination was unremarkable. A blood sample was chocolate brown in color and did not change color with agitation. She was given 100 mg. ascorbic acid intravenously and 45 minutes later 0.4 ml. of 1 per cent methylene blue solution was administered by the same route. Within 30 minutes following the latter her color had markedly improved and was entirely normal the next morning. Analysis of her original blood sample revealed a methemoglobin content of 54 per cent. Subsequently she did not develop hemolytic anemia or other sequelae of her illness.
Articles submitted [or this section should not exceed l,O00 words and may contain 1 or 2 illustrations or tables. Bibliography should not exceed 7 re[erences.
* I n tile form of Rectal Medicone - Medicone Company, Ne~r York, N . Y.
T g E d r a m a t i c onset of cyanosis in a previously well infant brings initially to m i n d respiratory and cardiac catastrophes such as obstruction of the airway, p n e u m o t h o r a x , apnea, acute a r r h y t h m i a s , a n d cardiovascular colIapse. An infant or child, however, m a y also develop cyanosis a b r u p t l y from acquired m e t h e m o g l o b i n e m i a following exposure to any of a n u m b e r of toxic chemicals or drugs.
CASE REPORT A 4-week-old female infant (CHMC No. A56-36-73) was referred from another hospital because of cyanosis not relieved by oxygen. She had been well at a routine visit to her physician 6 hours earlier. At that time she was given her first live attenuated oral polio vaccine dose and her first diphtheria-pertussis-tetanus injecFrom the Department o[ Pediatrics, Harvard Medical School, and the Department o[ Medicine, Children's Hospital Medical Center.
797
HC
Suppository,
7 9 8 Brie[ clinical and laboratory observations
DISCUSSION The rectal suppository employed in this case was found to contain benzocaine, 2 gr.; hydrocortisone acetate, 10 rag.; oxyquinoline sulfate, ~ gr.; zinc oxide, menthol, balsam peru, and cocoa butter (vegetable and petroleum oii base, color added). Of these agents, benzocaine has recently been reported to produce acquired methemoglobinemia when administered to infants topically 1 or by suppository 2 and to an older Negro boy as the lubricant of an endotracheal tube? Quinones 4 have also been reported as precipitating agents, and the oxyquinoline sulfate could conceivably be implicated here. Other drugs which can induce methemoglobin formation are phenacetin, antipyrine, acetanilid, pyridium, paraaminosalicylic acid, resorcinol, and bismuth. Aniline dyes and "corning extracts" for corning beef are known offenders. The nitrates of well water may be converted to potentialIy dangerous nitrites after ingestion and this reduction may be enhanced by the presence of sporulating bacteria found in certain dried milk preparations2 An epidemic due to heat-decomposed hexachlorophene or 3-4-4' trichlorocarbanilide has been reported2 Presumably because of a transient deficiency of DPNH-dependent methemogIobin reductase, 4 small infants seem to be much more susceptible to these agents. Methemoglobinemia due to ingestion of nitrate is reported t o be 4 times as common in infants under 3.months of age (52 per cent) as in older infants 3 to 12 months of age (13 per cent) in an endemic area in Czechoslovakia. The diagnosis of methemoglobinemia should be considered whenever unexplained cyanosis is present. Although as little as 15 per cent methemoglobin will cause cyanosis, cardiovascular compensatory mechanisms are not called into play until the concentration reaches about 40 per cent. Levels of over 60 per cent may cause increasing symptoms of ataxia, prostration, and unconsciousness until death supervenes at a methemoglobin concentration of about 85 per cent.4 The typical chocolate brown appearance of methe-
April 1965
moglobin-containing blood which does not change color with agitation in air occurs because of the oxidation of ferrous ion to ferric ion in the hemoglobin molecule, the latter form being incapable of oxygen transport. Sulfhemoglobin, which shares this chocolate brown appearance with methemoglobin, can be differentiated spectrophotometrically. Identical findings to those noted in "acquired methemoglobinemia" may be seen in the three additional types of "congenital methemoglobinemia." Treatment of acquired methemoglobinemia is directed toward the removal of the precipitating agent and in reducing the ferric ion back to the ferrous form. Although ascorbic acid, 100 to 200 nag., parenterally is stated to be effective, a more rapid response is obtained with methylene blue, 1 to 2 mg. per kilogram of body weight intravenously. Caution in respect to the dose of methylene blue must be employed. The drug is provided in 1 c.c. and 10 c.c. ampules and infants do not usually require more than 1 c.c. Methylene blue in overdosage is quite toxic and may produce methemoglobinemia. Congenital forms of the disease may or may not respond to this treatment, and in vitro evidence 7 suggests that patients with glucose-6-phosphate dehydrogenase deficiency may not readily respond. Although the usual patient , once properly treated, recovers rapidly without complication, it is prudent to watch for signs of hemolysis for several days. Infantile methemoglobinemia due to chemical toxins and drugs can be avoided only by the education of physicians, pharmacists, and parents in the dangers of the multitude of offending agents with which the infant may come in contact. Awareness of the infant's peculiar susceptibility to this disease should lead to greater care especially in prescribing drugs. Some of the drugs mentioned (e.g., phenacetin) are common occupants of the family medicine cabinet where they constitute a potential hazard to children. The ready availability of benzocaine in nonprescription sundries like sunburn cream must also be viewed with concern..
Volume 66
Number 4
Benzocaine-containing suppositories are contraindicated in infancy a n d have for this reason been eliminated from the p h a r m a c y of this hospital. I am indebted to Lo~fis K. Diamond, M.D., and Robert J. Haggerty, M.D., of the Children's Hospital Medical Center, for their advice in the preparation of this manuscript. REFERENCES 1. Haggerty, R. J.: Hazards to health, "Blue baby due to methemoglobinemia," New England J. Med. 267: 1303, 1962. 2. Peterson, H. deC.: Acquired methemoglobinemia in an infant due to benzocaine suppository, New England J. Med. 263: 454, 1960.
Brie[ clinical and laboratory observations
799
3. Steinberg, J. B., and Zepernlck, R. G.: Methemoglobinemia during anesthesia, J. PEDIAT. 61: 885, 1962. 4. Smith, C. H.: Blood diseases of infancy and childhood, St. Louis, 1960, The C. V. Mosby Company, pp. 301-304. 5. Knotek, Z., and Schmidt, P.: Pathogenesis, incidence, and posibilities of preventing alimentary nitrate methemoglobinemia in infants, Pediatrics 34: 78, 1964. 6. Johnson, R. R., Navone, R., and Larson, E. L.: An unusual epidemic of methemoglobinemia, Pediatrics 31: 222, 1963. 7. Jaffe, E. R.: The reduction of methemoglobln in erythrocytes of a patient with congenital methemoglobinemia, subjects with erythrocyte glucose-6-phospbate dehydrogenase deficiency, and normal individuals, Blood 21: 561, 1963.
Cross-sensitivity to Dilantin (dipbenylbydantoin) and Celontin (metbmximide) Stanley Stein, M.D., and Richard C. Pembrook, M.D. BALTIMORE~ iVID.
V , t e I o u s severe allergic reactions to Dil a n t i n have been reported. 1-11' la P r o m i n e n t clinical manifestations have included a measles-like rash, posterior cervical l y m p h a d enopathy, pyrexia, hepatitis, eosinophilia, a n d atypical lymphocytes in the peripheral smear. W e have observed a p a t i e n t who d e m o n s t r a t e d a severe reaction to D i l a n t i n and, later, a similar reaction to Celontin. T h e case is reported in order to p o i n t u p the rare possibility of cross-sensitivity to these two drugs.
From the Department o[ Pediatrics, United States Public Health Service Hospital, Baltimore, Md.
CASE REPORT R. B., a 12-year-old Negro male, had been noted to be hyperactive since the age of 5. At the University of Maryland Hospital, a diagnosis was made of brain damage. Administration of Dilantin and Benadryl was started on July 1, t963, in an effort to relieve the hyperactivity. On July 18, 1963, the patient became pyrexic, and a morbilliform rash developed on his face and neck. This gradually spread to involve the rest of his body. Administration of the drugs was not discontinued. He did not receive medical attention at this time, because his mother thought he had measles. A few days later the rash cleared. The mother discontinued administration of the drugs at this time. Two days later the pyrexia and rash returned.
CLINICAL
LABORATORY
AND OBSERVATIONS
Infantile metbemoglobinemia due to benzocaine suppository James R. Hughes, M.D.* BOSTON~
1V~A S S .
~Present address, Assistant Professor, ]ohns Hopkin~ University Center 1o1" Medical Research and Training, All lndia Institute oJ Hygiene and Public Health, 110 Chittaranjan Avenue, Calcutta 12, India.
tion. She was also given a rectal suppository* because of a rectal fissure. Approximately 45 minutes after insertion of the suppository, the infant was noted to be cyanotic. She was seen again by the original physician and taken to a nearby hospital where she was found to be in no distress but to have oxygen-resistant cyanosis. An electrocardiogram was obtained, and she was transferred to the Children's Hospital Medical Center. On admission she was intensely cyanotic but in no distress; her vital signs were within normal limits. Aside from a Grade 1 systolic murmur along the left sternal border, the remainder of her physical examination was unremarkable. A blood sample was chocolate brown in color and did not change color with agitation. She was given 100 mg. ascorbic acid intravenously and 45 minutes later 0.4 ml. of 1 per cent methylene blue solution was administered by the same route. Within 30 minutes following the latter her color had markedly improved and was entirely normal the next morning. Analysis of her original blood sample revealed a methemoglobin content of 54 per cent. Subsequently she did not develop hemolytic anemia or other sequelae of her illness.
Articles submitted [or this section should not exceed l,O00 words and may contain 1 or 2 illustrations or tables. Bibliography should not exceed 7 re[erences.
* I n tile form of Rectal Medicone - Medicone Company, Ne~r York, N . Y.
T g E d r a m a t i c onset of cyanosis in a previously well infant brings initially to m i n d respiratory and cardiac catastrophes such as obstruction of the airway, p n e u m o t h o r a x , apnea, acute a r r h y t h m i a s , a n d cardiovascular colIapse. An infant or child, however, m a y also develop cyanosis a b r u p t l y from acquired m e t h e m o g l o b i n e m i a following exposure to any of a n u m b e r of toxic chemicals or drugs.
CASE REPORT A 4-week-old female infant (CHMC No. A56-36-73) was referred from another hospital because of cyanosis not relieved by oxygen. She had been well at a routine visit to her physician 6 hours earlier. At that time she was given her first live attenuated oral polio vaccine dose and her first diphtheria-pertussis-tetanus injecFrom the Department o[ Pediatrics, Harvard Medical School, and the Department o[ Medicine, Children's Hospital Medical Center.
797
HC
Suppository,
7 9 8 Brie[ clinical and laboratory observations
DISCUSSION The rectal suppository employed in this case was found to contain benzocaine, 2 gr.; hydrocortisone acetate, 10 rag.; oxyquinoline sulfate, ~ gr.; zinc oxide, menthol, balsam peru, and cocoa butter (vegetable and petroleum oii base, color added). Of these agents, benzocaine has recently been reported to produce acquired methemoglobinemia when administered to infants topically 1 or by suppository 2 and to an older Negro boy as the lubricant of an endotracheal tube? Quinones 4 have also been reported as precipitating agents, and the oxyquinoline sulfate could conceivably be implicated here. Other drugs which can induce methemoglobin formation are phenacetin, antipyrine, acetanilid, pyridium, paraaminosalicylic acid, resorcinol, and bismuth. Aniline dyes and "corning extracts" for corning beef are known offenders. The nitrates of well water may be converted to potentialIy dangerous nitrites after ingestion and this reduction may be enhanced by the presence of sporulating bacteria found in certain dried milk preparations2 An epidemic due to heat-decomposed hexachlorophene or 3-4-4' trichlorocarbanilide has been reported2 Presumably because of a transient deficiency of DPNH-dependent methemogIobin reductase, 4 small infants seem to be much more susceptible to these agents. Methemoglobinemia due to ingestion of nitrate is reported t o be 4 times as common in infants under 3.months of age (52 per cent) as in older infants 3 to 12 months of age (13 per cent) in an endemic area in Czechoslovakia. The diagnosis of methemoglobinemia should be considered whenever unexplained cyanosis is present. Although as little as 15 per cent methemoglobin will cause cyanosis, cardiovascular compensatory mechanisms are not called into play until the concentration reaches about 40 per cent. Levels of over 60 per cent may cause increasing symptoms of ataxia, prostration, and unconsciousness until death supervenes at a methemoglobin concentration of about 85 per cent.4 The typical chocolate brown appearance of methe-
April 1965
moglobin-containing blood which does not change color with agitation in air occurs because of the oxidation of ferrous ion to ferric ion in the hemoglobin molecule, the latter form being incapable of oxygen transport. Sulfhemoglobin, which shares this chocolate brown appearance with methemoglobin, can be differentiated spectrophotometrically. Identical findings to those noted in "acquired methemoglobinemia" may be seen in the three additional types of "congenital methemoglobinemia." Treatment of acquired methemoglobinemia is directed toward the removal of the precipitating agent and in reducing the ferric ion back to the ferrous form. Although ascorbic acid, 100 to 200 nag., parenterally is stated to be effective, a more rapid response is obtained with methylene blue, 1 to 2 mg. per kilogram of body weight intravenously. Caution in respect to the dose of methylene blue must be employed. The drug is provided in 1 c.c. and 10 c.c. ampules and infants do not usually require more than 1 c.c. Methylene blue in overdosage is quite toxic and may produce methemoglobinemia. Congenital forms of the disease may or may not respond to this treatment, and in vitro evidence 7 suggests that patients with glucose-6-phosphate dehydrogenase deficiency may not readily respond. Although the usual patient , once properly treated, recovers rapidly without complication, it is prudent to watch for signs of hemolysis for several days. Infantile methemoglobinemia due to chemical toxins and drugs can be avoided only by the education of physicians, pharmacists, and parents in the dangers of the multitude of offending agents with which the infant may come in contact. Awareness of the infant's peculiar susceptibility to this disease should lead to greater care especially in prescribing drugs. Some of the drugs mentioned (e.g., phenacetin) are common occupants of the family medicine cabinet where they constitute a potential hazard to children. The ready availability of benzocaine in nonprescription sundries like sunburn cream must also be viewed with concern..
Volume 66
Number 4
Benzocaine-containing suppositories are contraindicated in infancy a n d have for this reason been eliminated from the p h a r m a c y of this hospital. I am indebted to Lo~fis K. Diamond, M.D., and Robert J. Haggerty, M.D., of the Children's Hospital Medical Center, for their advice in the preparation of this manuscript. REFERENCES 1. Haggerty, R. J.: Hazards to health, "Blue baby due to methemoglobinemia," New England J. Med. 267: 1303, 1962. 2. Peterson, H. deC.: Acquired methemoglobinemia in an infant due to benzocaine suppository, New England J. Med. 263: 454, 1960.
Brie[ clinical and laboratory observations
799
3. Steinberg, J. B., and Zepernlck, R. G.: Methemoglobinemia during anesthesia, J. PEDIAT. 61: 885, 1962. 4. Smith, C. H.: Blood diseases of infancy and childhood, St. Louis, 1960, The C. V. Mosby Company, pp. 301-304. 5. Knotek, Z., and Schmidt, P.: Pathogenesis, incidence, and posibilities of preventing alimentary nitrate methemoglobinemia in infants, Pediatrics 34: 78, 1964. 6. Johnson, R. R., Navone, R., and Larson, E. L.: An unusual epidemic of methemoglobinemia, Pediatrics 31: 222, 1963. 7. Jaffe, E. R.: The reduction of methemoglobln in erythrocytes of a patient with congenital methemoglobinemia, subjects with erythrocyte glucose-6-phospbate dehydrogenase deficiency, and normal individuals, Blood 21: 561, 1963.
Cross-sensitivity to Dilantin (dipbenylbydantoin) and Celontin (metbmximide) Stanley Stein, M.D., and Richard C. Pembrook, M.D. BALTIMORE~ iVID.
V , t e I o u s severe allergic reactions to Dil a n t i n have been reported. 1-11' la P r o m i n e n t clinical manifestations have included a measles-like rash, posterior cervical l y m p h a d enopathy, pyrexia, hepatitis, eosinophilia, a n d atypical lymphocytes in the peripheral smear. W e have observed a p a t i e n t who d e m o n s t r a t e d a severe reaction to D i l a n t i n and, later, a similar reaction to Celontin. T h e case is reported in order to p o i n t u p the rare possibility of cross-sensitivity to these two drugs.
From the Department o[ Pediatrics, United States Public Health Service Hospital, Baltimore, Md.
CASE REPORT R. B., a 12-year-old Negro male, had been noted to be hyperactive since the age of 5. At the University of Maryland Hospital, a diagnosis was made of brain damage. Administration of Dilantin and Benadryl was started on July 1, t963, in an effort to relieve the hyperactivity. On July 18, 1963, the patient became pyrexic, and a morbilliform rash developed on his face and neck. This gradually spread to involve the rest of his body. Administration of the drugs was not discontinued. He did not receive medical attention at this time, because his mother thought he had measles. A few days later the rash cleared. The mother discontinued administration of the drugs at this time. Two days later the pyrexia and rash returned.