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Diphenoxylate poisoning in children
4 62
4. 5. 6.
7.
8.
Brief clinical and laboratory observations
antigens by single radial immunodiffusion, Immunochemistry 2: 235, 1965. Stiehm, E. R., and Fudenberg, H. H.: Serum levels of immune globulins in health and disease: A survey, Pediatrics 37: 715, 1966. Johansson, S. G. O., and Berg, T., Immunoglobulin levels in healthy children, Acta paediat, scandinav. 56: 572, 1967. Washburn, T. O.: A lor_gitudinal study of serum immunoglobulins in newborn premature infants, Bull. Johns Hopkins Hosp. 118: 40, 1966. Alford, C. A., Schaefer, J., Blankenship, W. J., Straumfjord, J. V., and Cassady, G.: A correlative immunologic, microbiologic, and clinical approach to the diagnosis of acute and chronic infections in newborn infants, New England J. Med. 277: 437, 1967. Stiehm, E. R., Ammann, A. J., and Cherry, J. D.: Elevated cord macroglobulins in the diagnosis of intrauterine infections, New England J. Med. 275: 971, 1966.
Dipbenoxylate poisoning in children M a r v i n E. A m e n t , C a p t a i n , U S A F ( M C ) SEATTLE., WASH.
DIPHENoXYLATE H Y D R 0 G H L Ois a n agent frequently used for control of diarrhea. T h e purpose of this p a p e r is to present 2 cases of diphenoxylate poisoning in children, to review the p h a r m a cology of the drug, a n d to discuss its clinical manifestations a n d treatment. RIDE
CASE REPORTS Case 1. At t2:00 P.~. a 2-year-old boy ingested 30 to 40 diphenoxylate with atropine tablets (Lomotil). Each tablet contained 2.5 mg. of diphenoxylate hydrochloride and 0.025 rag. From the Department of Medicine, University o[ Washington. Request for reprints: Marvin E. Ament, M.D. Department of Medicine, University o[ Washington, Seattle, Wash.98105.
The Journal of Pediatrics March I969
9. Lowell, A. B., and Malmquist, J.: Separation of the Wassermann reagins by cellulose column chromatography of serum, Aeta path. et microbiol, scandinav. 51: 187, 1961. 10. Kohler, P., Jr., and Farr, R. S.: Elevation of cord over maternal IgG immunoglobulin: Evidence for an active placental IgG transport, Nature 210: 1070, 1966. 11. Gitlln, D., Xumate, J., Uirusti, J., and Morales, C.: The selectivity of the human placenta in the transfer of plasma proteins from mother to fetus, J. Clin. Invest. 43: 1938, 1964. 12. van Furth, R,, Schmidt, H. R. E., and Hijmans, W.: The immunological development of the human fetus, J. Exper. Med. 122: 1173, 1965. 13. Osier, A. G., and Knipp, E. A.: Quantitative studies of lipid-soluble tissue antigens as exemplified by the Wasserman antigen-antibody system, J. Immunol. 78: 19, 1957.
of atropine sulfate. During the next 2 hours, he asked for and received 4 eight-ounce glasses of water. Two hours later a temperature of 39.8 ~ C. rectally was recorded. He was flushed, tachypneic, and lethargic. Twenty minutes later he was brought to the emergency room. His temperature had decreased to 38.2 ~ C., although aspirin had not been given. His blood pressure was 100/80, heart rate 180 per minute, respiratory rate 26 per minute, and weight 13.0 kilograms. He was no longer flushed but remained lethargic. The patient was admitted to the ward 150 minutes after ingestion. His respiratory rate was 16 per minute.and he had normal color. His temperature was 37.9 ~ C. Five minutes later his respirations decreased to zero and he became cyanotic. His heart rate remained at I00 to 110 per minute, and he became rigid. Endotracheal intubation was completed in 5 minutes and his respirations were supported with an Ambu bag. The contents of the stomach were aspirated. A liter of fluid and bits of undigested tablets were removed. An intravenous infusion of ~ isotonic saline in 5 per cent dextrose was started. Caffeine sodium benzoate, t5 milligrams per kilogram, was given intramuscularly twice without response. Although the patient responded to deep stimulation by opening hls eyes and crying, he made no attempts to breath spontaneously. At 6:50 P.y. the first dose of nalor-
Volume 74 Number 3
phine, 2.0 mg., was given intravenously. Within one minute he became restless and breathed spontaneously for 3 minutes. During the next 3 hours the patient was given a total of 24.0 mg. of nalorphine to sustain his respirations. After 9:45 p.M. he continued to breathe spontaneously and regularly. The endotracheal tube was removed the following morning. He received dexamethasone every 6 hours, starting at midnight, for laryngeal edema and was placed in a mist tent. He was discharged after an uneventful recovery on the fourth hospital day. Case 2. On the .morning of the day of admission, this 27-month-old girl was seen in the pediatric clinic because of a heat rash and upper respiratory infection. Her temperature in the clinic was 37.7 ~ C. rectally. No medications were prescribed for the respiratory infection. Instructions for skin care and a lotion were prescribed for the heat rash. At 1:00 P.M. she ate lunch and went to sleep. At 4:00 p.M. she awoke flushed, febrile (40 ~ C.), and lethargic. She was given 180 mg. of aspirin and put into bed. She awoke at 5:00 P.~. and staggered into the living room. Hospital course. Her temperature was 38.2 ~ C., respiratory rate 16 per minute, blood pressure 90/20, and heart rate 114 per minute. The pupils were constricted and did not react to light. Muscle tone was diminished, as were the reflexes. Her respirations ceased and she entered a tonic state. An airway was inserted and the trachea was intubated. Four c.c. of paraldehyde were administered intramuscularly. A lumbar puncture was done; the fluid contained one white blood cell per high power field, 0 red blood cells, protein 30 mg. per cent, and glucose 65 mg. per cent. Blood was obtained for glucose, calciUm, urea nitrogen and culture. The bladder was catheterized and the urine sent for analysis for barbiturates, salicylates and phenothiazines. A gastric lavage revealed fluid and white particles. By 7:00 p.~. she was still being manually resuscitated, but would open her eyes and cry when deeply stimulated. The parent initially denied that any medications were missing. When asked specifically about medications for diarrhea, she remembered that a prescription had been filled the day before. The vial was found to be empty; it had contained 40 tablets of diphenoxylate with atropine. The patient was given 5.0 mg. of nalorphine intravenously and in 60 seconds be-
Brief clinical and laboratory observations
463
gan to cough and breathe spontaneously. No further doses of nalorphine were necessary. The endotracheal tube was removed the following morning. Dexamethasone was administered every 6 hours for laryngeal edema and she was placed in a mist tent. She had an uneventful recovery. DISCUSSION T h e first phase of poisoning with tablets containing diphenoxylate hydrochloride and atropine sulfate is m a r k e d by the sudden appearance of a high unremitting fever with a generalized flushed appearance and tachypnea, which m a y last for 2 to 3 hours. This is caused by the overdosage of atropine. T h e patient m a y become lethargic and possibly comatose. Seizures m a y occur due to the high fever. O n physical examination, the reflexes are hypoactive and muscle tone is diminished. T h e pupils m a y become miotic and unresponsive to light. T h e second phase, which m a y last 30 minutes~ begins abruptly with a fall in t e m p e r a t u r e and the disappearance of the flush. T h e r e is progression of the central nervous system depression. I t is in this phase that the respirations suddenly slow, become shallow, and m a y cease. A m a j o r m o t o r seizure m a y occur secondary to hypoxia. T h e cardiac rate at first is maintained despite the hypoxia. I n caring for these patients, an endotracheal tube should be placed and followed by a gastric lavage. M a n y hours after ingestion it is still possible to remove partially digested tablets f r o m the stomach due to the decrease in gastrointestinal motility caused by the diphenoxylate and atropine. Is the etiology is not recognized, resuscitative measures must be carried out until the medication is detoxified and excreted. T h e patient should be catheterized and an intravenous infusion started; transient retention of urine m a y occur. Nalorphine should be administered intravenously in dosage sufficient to relieve the respiratory depression. T h e duration of action of diphenoxylate hydrochloride is m u c h longer than that of nalorphine. Respirations m a y improve but
464
Brief clinical and laboratory observations
then m a y be followed by respiratory depression. The patient must be observed closely and nalorphine readministered if this occurs.l, 2 Diphenoxylate hydrochloride, ethyl 1(3-cyano-3, 3 diphenylpropyl)-4 phenylisonipecotate HC1 is a synthetic constipating drug which is structurally related to alphaprodine, anilerdine and meperidine. It acts on the smooth muscle of the intestinal tract, in a manner similar to that of morphine, by inhibiting gastrointestinal motility. T h e drug has little or no analgesic action and is free of parasympatholytic activity. It is slightly soluble in water at room temperature and has no distinguishing taste. Numerous difficulties have been encountered with the chemical measurement of diphenoxylate and thus no data are available on the metabolism of the substance. Chronic toxicity studies with diphenoxylate, completed in 1960, have been unrevealing. Daily administration of the compound to rats in doses of 2, 10, or 40 rag. per kilogram for 6 months did not produce significant adverse effects in the animals. Histological examination of various organs at autopsy did not show abnormalities. In similar studies, dogs receiving an oral dose of 2, 8, or 32 mg. of diphenoxylate per kilogram of body weight, 6 days a week for 3 months, showed no adverse effects of the treatment. In a more recent study, diphenoxylate hydroehloride was administered to weanling rats in doses of 3, 8, or 32 mg. per kilogram of body weight per day for a period of 1 month. Gross visual observations and microscopic examinations of tissue sections did not reveal any compound-induced gross or histological alterations in the organs? Addiction to the drug does not occur when used at recommended dosage for long intervals. The side effects, which include nausea, vomiting, abdominal cramps, drowsiness, vertigo, pruritus, skin rashes, restlessness and insomnia, are relatively un-
The Journal of Pediatrics March 1969
common. Rare isolated side effects are numbness of the extremities, headache, blurring of vision, swelling of gums, euphoria, depression, and general malaise. 2' * In addition to these patients, 3 other instances 5-7 of diphenoxylate and atropine overdosage have been reported. In 2 of these, the dosage was 4 to 5 times the recommended one. In one of them, the patient developed respiratory difficulty and apneaJ The effect of the drug even at recommended dosage levels m a y be as long as 24 hours; paralytic ileus m a y result in certain casesJ
SUMMARY Two cases of diphenoxylate hydrochlorid e with atropine sulfate (Lomotil) poisoning in children are presented; both patients recovered following appropriate therapy. Early symptoms are due to atropinism; these are followed by progressive depression of the central nervous system which m a y require resuscitative measures and repeated administration of nalorphine. The pharmacology of diphenoxylate is reviewed.
REFERENCES 1. Goodman, L. A., and A. Gilman.: The pharmacological basis of therapeutics, ed. 5, New York, 1955, The Macmillan Company, pp. 274-278. 2. Van Derstappen, G., Vantroppen, G., and Vandenbrouche, J.: Long term clinical studies with Rl132, a new constipating agent, Gastroenterology 39: 725, I960. 3. Drill, V. A.: Personal communication, Director of Biological Research, G. D. Searle and Co., June, 1968. 4. Kasich, A. M.: Treatment of diarrhea in irritable colon including preliminary observations with a new anti-diarrheal agent, diphenyloxylate hydrochloride (Lomotil), Am. J. Gastroenterol. 35: 46, 1961. 5. Coplan, L. H., and Grand, M. J. H.: Antidiarrheal drug effect simulating intestinal obstruction, Am. J. Gastroenterol. 42: 540, 1964. 6. King, M. J., and Powell, J.: Coma associated with excessive dosage of an antidiarrheal drug, J. Am. Osteopath. A. 65: 181, 1965. 7. Canby, J. P.: Letters to the Journal, J. A. M. A. 192; 920~ 1965.
4. 5. 6.
7.
8.
Brief clinical and laboratory observations
antigens by single radial immunodiffusion, Immunochemistry 2: 235, 1965. Stiehm, E. R., and Fudenberg, H. H.: Serum levels of immune globulins in health and disease: A survey, Pediatrics 37: 715, 1966. Johansson, S. G. O., and Berg, T., Immunoglobulin levels in healthy children, Acta paediat, scandinav. 56: 572, 1967. Washburn, T. O.: A lor_gitudinal study of serum immunoglobulins in newborn premature infants, Bull. Johns Hopkins Hosp. 118: 40, 1966. Alford, C. A., Schaefer, J., Blankenship, W. J., Straumfjord, J. V., and Cassady, G.: A correlative immunologic, microbiologic, and clinical approach to the diagnosis of acute and chronic infections in newborn infants, New England J. Med. 277: 437, 1967. Stiehm, E. R., Ammann, A. J., and Cherry, J. D.: Elevated cord macroglobulins in the diagnosis of intrauterine infections, New England J. Med. 275: 971, 1966.
Dipbenoxylate poisoning in children M a r v i n E. A m e n t , C a p t a i n , U S A F ( M C ) SEATTLE., WASH.
DIPHENoXYLATE H Y D R 0 G H L Ois a n agent frequently used for control of diarrhea. T h e purpose of this p a p e r is to present 2 cases of diphenoxylate poisoning in children, to review the p h a r m a cology of the drug, a n d to discuss its clinical manifestations a n d treatment. RIDE
CASE REPORTS Case 1. At t2:00 P.~. a 2-year-old boy ingested 30 to 40 diphenoxylate with atropine tablets (Lomotil). Each tablet contained 2.5 mg. of diphenoxylate hydrochloride and 0.025 rag. From the Department of Medicine, University o[ Washington. Request for reprints: Marvin E. Ament, M.D. Department of Medicine, University o[ Washington, Seattle, Wash.98105.
The Journal of Pediatrics March I969
9. Lowell, A. B., and Malmquist, J.: Separation of the Wassermann reagins by cellulose column chromatography of serum, Aeta path. et microbiol, scandinav. 51: 187, 1961. 10. Kohler, P., Jr., and Farr, R. S.: Elevation of cord over maternal IgG immunoglobulin: Evidence for an active placental IgG transport, Nature 210: 1070, 1966. 11. Gitlln, D., Xumate, J., Uirusti, J., and Morales, C.: The selectivity of the human placenta in the transfer of plasma proteins from mother to fetus, J. Clin. Invest. 43: 1938, 1964. 12. van Furth, R,, Schmidt, H. R. E., and Hijmans, W.: The immunological development of the human fetus, J. Exper. Med. 122: 1173, 1965. 13. Osier, A. G., and Knipp, E. A.: Quantitative studies of lipid-soluble tissue antigens as exemplified by the Wasserman antigen-antibody system, J. Immunol. 78: 19, 1957.
of atropine sulfate. During the next 2 hours, he asked for and received 4 eight-ounce glasses of water. Two hours later a temperature of 39.8 ~ C. rectally was recorded. He was flushed, tachypneic, and lethargic. Twenty minutes later he was brought to the emergency room. His temperature had decreased to 38.2 ~ C., although aspirin had not been given. His blood pressure was 100/80, heart rate 180 per minute, respiratory rate 26 per minute, and weight 13.0 kilograms. He was no longer flushed but remained lethargic. The patient was admitted to the ward 150 minutes after ingestion. His respiratory rate was 16 per minute.and he had normal color. His temperature was 37.9 ~ C. Five minutes later his respirations decreased to zero and he became cyanotic. His heart rate remained at I00 to 110 per minute, and he became rigid. Endotracheal intubation was completed in 5 minutes and his respirations were supported with an Ambu bag. The contents of the stomach were aspirated. A liter of fluid and bits of undigested tablets were removed. An intravenous infusion of ~ isotonic saline in 5 per cent dextrose was started. Caffeine sodium benzoate, t5 milligrams per kilogram, was given intramuscularly twice without response. Although the patient responded to deep stimulation by opening hls eyes and crying, he made no attempts to breath spontaneously. At 6:50 P.y. the first dose of nalor-
Volume 74 Number 3
phine, 2.0 mg., was given intravenously. Within one minute he became restless and breathed spontaneously for 3 minutes. During the next 3 hours the patient was given a total of 24.0 mg. of nalorphine to sustain his respirations. After 9:45 p.M. he continued to breathe spontaneously and regularly. The endotracheal tube was removed the following morning. He received dexamethasone every 6 hours, starting at midnight, for laryngeal edema and was placed in a mist tent. He was discharged after an uneventful recovery on the fourth hospital day. Case 2. On the .morning of the day of admission, this 27-month-old girl was seen in the pediatric clinic because of a heat rash and upper respiratory infection. Her temperature in the clinic was 37.7 ~ C. rectally. No medications were prescribed for the respiratory infection. Instructions for skin care and a lotion were prescribed for the heat rash. At 1:00 P.M. she ate lunch and went to sleep. At 4:00 p.M. she awoke flushed, febrile (40 ~ C.), and lethargic. She was given 180 mg. of aspirin and put into bed. She awoke at 5:00 P.~. and staggered into the living room. Hospital course. Her temperature was 38.2 ~ C., respiratory rate 16 per minute, blood pressure 90/20, and heart rate 114 per minute. The pupils were constricted and did not react to light. Muscle tone was diminished, as were the reflexes. Her respirations ceased and she entered a tonic state. An airway was inserted and the trachea was intubated. Four c.c. of paraldehyde were administered intramuscularly. A lumbar puncture was done; the fluid contained one white blood cell per high power field, 0 red blood cells, protein 30 mg. per cent, and glucose 65 mg. per cent. Blood was obtained for glucose, calciUm, urea nitrogen and culture. The bladder was catheterized and the urine sent for analysis for barbiturates, salicylates and phenothiazines. A gastric lavage revealed fluid and white particles. By 7:00 p.~. she was still being manually resuscitated, but would open her eyes and cry when deeply stimulated. The parent initially denied that any medications were missing. When asked specifically about medications for diarrhea, she remembered that a prescription had been filled the day before. The vial was found to be empty; it had contained 40 tablets of diphenoxylate with atropine. The patient was given 5.0 mg. of nalorphine intravenously and in 60 seconds be-
Brief clinical and laboratory observations
463
gan to cough and breathe spontaneously. No further doses of nalorphine were necessary. The endotracheal tube was removed the following morning. Dexamethasone was administered every 6 hours for laryngeal edema and she was placed in a mist tent. She had an uneventful recovery. DISCUSSION T h e first phase of poisoning with tablets containing diphenoxylate hydrochloride and atropine sulfate is m a r k e d by the sudden appearance of a high unremitting fever with a generalized flushed appearance and tachypnea, which m a y last for 2 to 3 hours. This is caused by the overdosage of atropine. T h e patient m a y become lethargic and possibly comatose. Seizures m a y occur due to the high fever. O n physical examination, the reflexes are hypoactive and muscle tone is diminished. T h e pupils m a y become miotic and unresponsive to light. T h e second phase, which m a y last 30 minutes~ begins abruptly with a fall in t e m p e r a t u r e and the disappearance of the flush. T h e r e is progression of the central nervous system depression. I t is in this phase that the respirations suddenly slow, become shallow, and m a y cease. A m a j o r m o t o r seizure m a y occur secondary to hypoxia. T h e cardiac rate at first is maintained despite the hypoxia. I n caring for these patients, an endotracheal tube should be placed and followed by a gastric lavage. M a n y hours after ingestion it is still possible to remove partially digested tablets f r o m the stomach due to the decrease in gastrointestinal motility caused by the diphenoxylate and atropine. Is the etiology is not recognized, resuscitative measures must be carried out until the medication is detoxified and excreted. T h e patient should be catheterized and an intravenous infusion started; transient retention of urine m a y occur. Nalorphine should be administered intravenously in dosage sufficient to relieve the respiratory depression. T h e duration of action of diphenoxylate hydrochloride is m u c h longer than that of nalorphine. Respirations m a y improve but
464
Brief clinical and laboratory observations
then m a y be followed by respiratory depression. The patient must be observed closely and nalorphine readministered if this occurs.l, 2 Diphenoxylate hydrochloride, ethyl 1(3-cyano-3, 3 diphenylpropyl)-4 phenylisonipecotate HC1 is a synthetic constipating drug which is structurally related to alphaprodine, anilerdine and meperidine. It acts on the smooth muscle of the intestinal tract, in a manner similar to that of morphine, by inhibiting gastrointestinal motility. T h e drug has little or no analgesic action and is free of parasympatholytic activity. It is slightly soluble in water at room temperature and has no distinguishing taste. Numerous difficulties have been encountered with the chemical measurement of diphenoxylate and thus no data are available on the metabolism of the substance. Chronic toxicity studies with diphenoxylate, completed in 1960, have been unrevealing. Daily administration of the compound to rats in doses of 2, 10, or 40 rag. per kilogram for 6 months did not produce significant adverse effects in the animals. Histological examination of various organs at autopsy did not show abnormalities. In similar studies, dogs receiving an oral dose of 2, 8, or 32 mg. of diphenoxylate per kilogram of body weight, 6 days a week for 3 months, showed no adverse effects of the treatment. In a more recent study, diphenoxylate hydroehloride was administered to weanling rats in doses of 3, 8, or 32 mg. per kilogram of body weight per day for a period of 1 month. Gross visual observations and microscopic examinations of tissue sections did not reveal any compound-induced gross or histological alterations in the organs? Addiction to the drug does not occur when used at recommended dosage for long intervals. The side effects, which include nausea, vomiting, abdominal cramps, drowsiness, vertigo, pruritus, skin rashes, restlessness and insomnia, are relatively un-
The Journal of Pediatrics March 1969
common. Rare isolated side effects are numbness of the extremities, headache, blurring of vision, swelling of gums, euphoria, depression, and general malaise. 2' * In addition to these patients, 3 other instances 5-7 of diphenoxylate and atropine overdosage have been reported. In 2 of these, the dosage was 4 to 5 times the recommended one. In one of them, the patient developed respiratory difficulty and apneaJ The effect of the drug even at recommended dosage levels m a y be as long as 24 hours; paralytic ileus m a y result in certain casesJ
SUMMARY Two cases of diphenoxylate hydrochlorid e with atropine sulfate (Lomotil) poisoning in children are presented; both patients recovered following appropriate therapy. Early symptoms are due to atropinism; these are followed by progressive depression of the central nervous system which m a y require resuscitative measures and repeated administration of nalorphine. The pharmacology of diphenoxylate is reviewed.
REFERENCES 1. Goodman, L. A., and A. Gilman.: The pharmacological basis of therapeutics, ed. 5, New York, 1955, The Macmillan Company, pp. 274-278. 2. Van Derstappen, G., Vantroppen, G., and Vandenbrouche, J.: Long term clinical studies with Rl132, a new constipating agent, Gastroenterology 39: 725, I960. 3. Drill, V. A.: Personal communication, Director of Biological Research, G. D. Searle and Co., June, 1968. 4. Kasich, A. M.: Treatment of diarrhea in irritable colon including preliminary observations with a new anti-diarrheal agent, diphenyloxylate hydrochloride (Lomotil), Am. J. Gastroenterol. 35: 46, 1961. 5. Coplan, L. H., and Grand, M. J. H.: Antidiarrheal drug effect simulating intestinal obstruction, Am. J. Gastroenterol. 42: 540, 1964. 6. King, M. J., and Powell, J.: Coma associated with excessive dosage of an antidiarrheal drug, J. Am. Osteopath. A. 65: 181, 1965. 7. Canby, J. P.: Letters to the Journal, J. A. M. A. 192; 920~ 1965.