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Treatment of ingestion of diphenhydramine
Volume 92 Number 1
Editorial correspondence
16 7
animal model for drug evaluation is illustrated by this study, since it appears that a metabolite, presumably benzoic acid, and not benzyl alcohol itself, is responsible for the observed displacement. Some caution must be applied in translating Gunn rat data to newborn infants since (1) metabolism and clearance of drugs may be different than in human beings, (2) the binding affinity of rat albumin for bilirubin is lower than that of human serum albumin, and (3) the interaction of competing ligands with serum albumin of different species may vary. Although metabolism of benzoate is retarded in both newborn rats 2 and human beings, 3 the significance of benzoate administration with respect to bilirubin displacement in man has recently been questioned. 4 Unfortunately, most binding tests currently available are inappropriate for evaluating bilirubin displacement by weak competitors in vivo, either because the tests are insensitive to small changes in unbound bilirubin or because the serum is diluted before testing. Serum dilution enhances dissociation of weaker bound competitors and minimizes their effect? Until this problem is satisfactorily resolved clinicians should use multiple dose preparations containing either methyl paraben or benzyl alcohol with great caution, and pharmaceutical companies should either alter their formulations of multi-dose pediatric preparations or label their products with an appropriate warning. Physicians should be aware that sick infants may receive great quantities of potentially harmful preservatives from repeated flushes of umbilical artery catheters after blood sampling. This hazard may be substantial when water or saline obtained from multi-dose vials is used for volume expansion in sick jaundiced infants. Richard P. Wennberg, M.D. Sacramento Medical Center Department of Pediatrics 4301 X St. Sacramento, CA 95817
intoxication in a 13-month-old boy. Symptoms were muscle tremor, motor seizures, apnea, mydriasis, hyperpyrexia, and complete left bundle branch block. Therapy suggested by the authors consisted of aggressive symptomatic and supportive care (gastric lavage, diphenylhydantoin, antipyresis, and assisted ventilation). We want to recall attention to another drug for therapy. Diphenhydramine hydrochloride is one of the drugs capable of producing anticholinergic poisoning with central and peripheral symptoms like anxiety, disorientation, tremor, motor seizures, tachycardia, hyperpyrexia, and mydriasis; severe poisoning may even produce coma and death. 2, 3 Anticholinesterases may antagonize the anticholinergic syndrome. Whereas neostigmine and pyridostigmine (both quaternary amines) are only capable of diminishing the peripheral anticholinergic actions, physostigmine (a tertiary amine), can antagonize the central anticholinergie actions too? Physostigmine is given as physostigmine salicylate (Antilirium, O'Neal, Jones & Feldman Inc., St. Louis Mo.) in a pediatric dosage of 0.5 mg intravenously, slowly, to avoid chofinergic side effects. (Atropine should be available.) If the anticholinergic syndrome persists, the same dosage may be repeated up to 2 mg. Because of the quick metabolism ofphysostigmine, readministration of the same dosage may be necessary after one hour? In our experience, physostigmine salicylate is of great value in the therapy of central and peripheral actions in anticholinergic poisoning in childhood2 Dr. M. Borkenstein Dr. M. Haidvogl University of Graz Childrens Hospital A-8036 Graz, Austria
REFERENCES
REFERENCES
I.
2. 3. 4.
5.
Ballowitz L, Hanefeld F, and Schmid H: The influence of various aminoglycoside preparations on bilirubin/albumin binding, J Perinat Med 4:168, 1976. Brandt IK: The development of the hippuric acid-synthe9sizing system in the rat, Dev Biol 10:202, 1964. Vest MF: The development of conjugation mechanisms and drug toxicity in the newborn, Biol Neonate 8:258, 1965. Nathenson G, Cohen MI, and McNamara H: The effect of Na benzoate on serum bilirubin of the Gunn rat, J PEmATR 86:799, 1975. Jacobsen J, and Wennberg RP: Determination of unbound biliruNn in the serum of newborns, Clin Chem 20:783, 1974.
Treatment of ingestion of diphenhydramine To the Editor: In the June, 1977, issue of THE JOURNAL OF PEDIATRICS, Hestand and Teske ~ described diphenhydramine hydrochloride
1. Hestand HE, and Teske DW: Diphenhydramine hydrochloride intoxication, J PEDIATR, 90:1017, 1977. 2. Rumack BH: Anticholinergic poisoning: treatment with physostigmine, Pediatrics 52:449, 1973. 3. Wyngaarden JB, and Seevers MH: The toxic effects of antihistaminic drugs, JAMA 145:277, 1951. 4. Borkenstein M, and Haidvogl M: Physostigmintherapie einer Dimenhydrinatvergiftung im Kindesalter, Paediatr Paedol (in press).
Rep y To the Editor: We appreciate Drs. Borkenstein and Haidvogl's comments on our paper. If a child presents with a history of an ingestion of a drug or chemical that is capable of producing an anticholinergic response, we agree that physostigmine salicylate therapy is indicated. However, in our hospital, the vast majority of ingestion patients present without knowledge of the ingested compound. Because of the known contraindications to physostigmine therapy, we prefer on all of our ingestion patients to employ aggressive symptomatic and supportive care until the toxicology
Editorial correspondence
16 7
animal model for drug evaluation is illustrated by this study, since it appears that a metabolite, presumably benzoic acid, and not benzyl alcohol itself, is responsible for the observed displacement. Some caution must be applied in translating Gunn rat data to newborn infants since (1) metabolism and clearance of drugs may be different than in human beings, (2) the binding affinity of rat albumin for bilirubin is lower than that of human serum albumin, and (3) the interaction of competing ligands with serum albumin of different species may vary. Although metabolism of benzoate is retarded in both newborn rats 2 and human beings, 3 the significance of benzoate administration with respect to bilirubin displacement in man has recently been questioned. 4 Unfortunately, most binding tests currently available are inappropriate for evaluating bilirubin displacement by weak competitors in vivo, either because the tests are insensitive to small changes in unbound bilirubin or because the serum is diluted before testing. Serum dilution enhances dissociation of weaker bound competitors and minimizes their effect? Until this problem is satisfactorily resolved clinicians should use multiple dose preparations containing either methyl paraben or benzyl alcohol with great caution, and pharmaceutical companies should either alter their formulations of multi-dose pediatric preparations or label their products with an appropriate warning. Physicians should be aware that sick infants may receive great quantities of potentially harmful preservatives from repeated flushes of umbilical artery catheters after blood sampling. This hazard may be substantial when water or saline obtained from multi-dose vials is used for volume expansion in sick jaundiced infants. Richard P. Wennberg, M.D. Sacramento Medical Center Department of Pediatrics 4301 X St. Sacramento, CA 95817
intoxication in a 13-month-old boy. Symptoms were muscle tremor, motor seizures, apnea, mydriasis, hyperpyrexia, and complete left bundle branch block. Therapy suggested by the authors consisted of aggressive symptomatic and supportive care (gastric lavage, diphenylhydantoin, antipyresis, and assisted ventilation). We want to recall attention to another drug for therapy. Diphenhydramine hydrochloride is one of the drugs capable of producing anticholinergic poisoning with central and peripheral symptoms like anxiety, disorientation, tremor, motor seizures, tachycardia, hyperpyrexia, and mydriasis; severe poisoning may even produce coma and death. 2, 3 Anticholinesterases may antagonize the anticholinergic syndrome. Whereas neostigmine and pyridostigmine (both quaternary amines) are only capable of diminishing the peripheral anticholinergic actions, physostigmine (a tertiary amine), can antagonize the central anticholinergie actions too? Physostigmine is given as physostigmine salicylate (Antilirium, O'Neal, Jones & Feldman Inc., St. Louis Mo.) in a pediatric dosage of 0.5 mg intravenously, slowly, to avoid chofinergic side effects. (Atropine should be available.) If the anticholinergic syndrome persists, the same dosage may be repeated up to 2 mg. Because of the quick metabolism ofphysostigmine, readministration of the same dosage may be necessary after one hour? In our experience, physostigmine salicylate is of great value in the therapy of central and peripheral actions in anticholinergic poisoning in childhood2 Dr. M. Borkenstein Dr. M. Haidvogl University of Graz Childrens Hospital A-8036 Graz, Austria
REFERENCES
REFERENCES
I.
2. 3. 4.
5.
Ballowitz L, Hanefeld F, and Schmid H: The influence of various aminoglycoside preparations on bilirubin/albumin binding, J Perinat Med 4:168, 1976. Brandt IK: The development of the hippuric acid-synthe9sizing system in the rat, Dev Biol 10:202, 1964. Vest MF: The development of conjugation mechanisms and drug toxicity in the newborn, Biol Neonate 8:258, 1965. Nathenson G, Cohen MI, and McNamara H: The effect of Na benzoate on serum bilirubin of the Gunn rat, J PEmATR 86:799, 1975. Jacobsen J, and Wennberg RP: Determination of unbound biliruNn in the serum of newborns, Clin Chem 20:783, 1974.
Treatment of ingestion of diphenhydramine To the Editor: In the June, 1977, issue of THE JOURNAL OF PEDIATRICS, Hestand and Teske ~ described diphenhydramine hydrochloride
1. Hestand HE, and Teske DW: Diphenhydramine hydrochloride intoxication, J PEDIATR, 90:1017, 1977. 2. Rumack BH: Anticholinergic poisoning: treatment with physostigmine, Pediatrics 52:449, 1973. 3. Wyngaarden JB, and Seevers MH: The toxic effects of antihistaminic drugs, JAMA 145:277, 1951. 4. Borkenstein M, and Haidvogl M: Physostigmintherapie einer Dimenhydrinatvergiftung im Kindesalter, Paediatr Paedol (in press).
Rep y To the Editor: We appreciate Drs. Borkenstein and Haidvogl's comments on our paper. If a child presents with a history of an ingestion of a drug or chemical that is capable of producing an anticholinergic response, we agree that physostigmine salicylate therapy is indicated. However, in our hospital, the vast majority of ingestion patients present without knowledge of the ingested compound. Because of the known contraindications to physostigmine therapy, we prefer on all of our ingestion patients to employ aggressive symptomatic and supportive care until the toxicology