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emesis or gastric iavage at varying times following the administration. In studies by Arnold and colleagues, ipecac removed 45% and 30%, respectively, of a known amount of sodium salicylate when it was given immediately or 1 hour following the drug administration. 35 Gastric lavage removed 38% and 10% of the sodium salicylate marker at similar times. In a study similarly performed by Abdallah and Tye, ipecac syrup removed 60%, 40%, and 20%, immediately, 30 minutes, and 60 minutes, respectively, following the administration of a barium sulfate marker.36 Gastric lavage removed 45%, 26%, and 8% of the marker at similar times. Finally, Corby and coworkers, in an animal study, demonstrated the ability of gastric lavage to remove 29% and ipecac 19% following the administration of barium sulfate.37 Boxer and associates treated one half of a group of children who had ingested aspirin in overdose with ipecac followed by gastric lavage while the other half was treated with gastric lavage followed by ipecac.38 Ipecac removed more of the ingested substance in both groups, irrespective of the order of the decontamination procedures. In a second study in overdosed children presenting to the emergency room, Corby and associates demonstrated that ipecac removed approximately 28% of a magnesium hydroxide marker 15 minutes following administration.3g Thus, by the late 1960s and based on these studies, ipecac appeared to have an advantage over gastric lavage and appeared to remove 30% to 40% of an ingested product when ipecac was administered 30 minutes to 1 hour following an overdose. Based on these studies, the American Academy of Pediatrics pursued a vigorous campaign to place ipecac in homes with children and educate parents and physicians in its correct use. Ipecac became the treatment of choice for childhood poisoning in the home setting and in the alert patient in the hospital setting.
Ipecac Versus Gastric Lavage- Later Studies The studies by Corby and coworkers showed large interpatient variance both in volume of emesis and in recovery of the marker substance.37 This variability, as well as the belief that the animal studies favored ipecac-induced emesis over gastric lavage because only a relatively small gastric tube was able to be passed in animals, led to subsequent tracer studies in the human overdose setting. Tandberg and associates, using vitamin B12 as a tracer given to overdosed adults once they presented to the emergency room, demonstrated that gastric lavage removed 45% of the tracer substance while ipecac removed only 28%.40 In a similarly designed study using thiamine as a tracer in the overdose setting, Auerbach and colleagues demonstrated a superiority of gastric lavage over ipecac4’ At first glance, these data appeared to reverse former teaching. Litovitz, however, suggested that methodologic biases might explain the results showing a superiority of lavage.42 She noted that the investigators in the first study administered over 1,000 mL of tap water with ipecac, increasing the likelihood of gastric emptying and making the marker substance less available for subsequent removal. In contrast, 250 mL of fluid was utilized with each lavage exchange. Second, the subjects in the lavage group were placed in a left lateral decubitus position with the head of the bed lowered, thereby minimizing a loss of gastric contents into the small bowel. Third, the relative timing of ipecac versus gastric lavage introduced a lo-minute advantage to the lavage group. Finally, additional holes were placed in the gastric tube, enhancing its removal ca-
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care for their own children, leaving them at high risk for neglect and other psychosocial trauma. More and more children in such circumstances are being placed under the supervision of the state in an already overburdened foster care program. There is case report evidence now that cocaine can be transmitted in breast milk to breast-feeding babies6 children can also become intoxicated by the passive inhalation of “crack” smoke.7 There is anecodotal evidence that some pediatric intoxications have resulted from accidental ingestion of cocaine casually left in their environment’-” or from inadvertent ingestion when cocaine dust was applied topically to relieve nipple pain before breast-feeding.” Cocaine has been intentionally given to children-another agent implicated as an instrument of “chemical child abuse.“12 Unlike other substances of abuse, adolescents may initiate experimentation with crack or other forms of cocaine anytime during the teenage years or early 20s. Use of cocaine by adolescents has been linked to increased rates of motor vehicle fatalities,13 depression and suicidal thinking,14 sexually transmitted diseases,15 and delinquent behavior among these troubled youth.16 For all ages, then, cocaine intoxication represents only the most obvious sign of a disheartening array of medical, psychosocial, and family problems that are as complex as they are intractable.
Fetal Effects Maternal cocaine use in the third trimester has been associated with an increased incidence of abruptio placentae.17 There is also clear evidence that some infants born with neurologic deficits have suffered in utero cerebral hemorrhage and/or infarction, presumably due to cocaine’s hypertension-inducing effects.‘8* ” Cocaine use during pregnancy has also been linked to fetal growth retardation and microcephaly, perhaps due to cocaine’s appetite-suppressant actions affecting the adequacy of the mother’s diet or its vasoconstrictive properties reducing placental blood flow and nutrition to the fetus.‘, 20-23 An abstinence syndrome in the infant has been characterized by lethargy, poor feeding, and transient electroencephalographic (EEG) changes (bursts of sharp waves and spikes), which generally resolve over a period of days to weeks.24 There are some preliminary investigations suggesting that many cocaine-exposed neonates have increased state disorganization and depressed interactive behavioral scores on the Brazelton Neonatal Behavioral Assessment Scale.25 Longitudinal studies are currently underway to assess longer-term neurodevelopment and cognitive effects attributable to fetal cocaine exposure. Whether cocaine’s vasoconstrictive properties are responsible for specific teratogenic syndromes in humans remains controversial. Murine animal models have demonstrated increased rates of fetal resorption, skeletal defects, and ophthalmic deformities in mice whose mothers were exposed to cocaine.26 Many studies in humans are confounded by a lack of verification of maternal cocaine use, the presence of multiple substances abused during pregnancy, and inadequate controls. 27 However, an association between fetal exposure to cocaine and cerebral, cardiac, skeletal, renal, and/or ophthalmic abnormalities is suspected. Dominquez and colleagues2’ reported on ten infants with a history of exposure to cocaine who were born with cerebral and ophthalmic abnormalities, thought to be related to vascular disruption during fetal life. In one prospective study of 50 infants of cocaine-using mothers by Chasnoff and associates, 7 were found to have hypospadias and/or hydronephrosis on renal ultrasound, as opposed to none among the infants born to polydrug (but not cocaine)-abusing women2’ In a large case-control study, Chavez and, coworkers found a greater
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emesis or gastric iavage at varying times following the administration. In studies by Arnold and colleagues, ipecac removed 45% and 30%, respectively, of a known amount of sodium salicylate when it was given immediately or 1 hour following the drug administration. 35 Gastric lavage removed 38% and 10% of the sodium salicylate marker at similar times. In a study similarly performed by Abdallah and Tye, ipecac syrup removed 60%, 40%, and 20%, immediately, 30 minutes, and 60 minutes, respectively, following the administration of a barium sulfate marker.36 Gastric lavage removed 45%, 26%, and 8% of the marker at similar times. Finally, Corby and coworkers, in an animal study, demonstrated the ability of gastric lavage to remove 29% and ipecac 19% following the administration of barium sulfate.37 Boxer and associates treated one half of a group of children who had ingested aspirin in overdose with ipecac followed by gastric lavage while the other half was treated with gastric lavage followed by ipecac.38 Ipecac removed more of the ingested substance in both groups, irrespective of the order of the decontamination procedures. In a second study in overdosed children presenting to the emergency room, Corby and associates demonstrated that ipecac removed approximately 28% of a magnesium hydroxide marker 15 minutes following administration.3g Thus, by the late 1960s and based on these studies, ipecac appeared to have an advantage over gastric lavage and appeared to remove 30% to 40% of an ingested product when ipecac was administered 30 minutes to 1 hour following an overdose. Based on these studies, the American Academy of Pediatrics pursued a vigorous campaign to place ipecac in homes with children and educate parents and physicians in its correct use. Ipecac became the treatment of choice for childhood poisoning in the home setting and in the alert patient in the hospital setting.
Ipecac Versus Gastric Lavage- Later Studies The studies by Corby and coworkers showed large interpatient variance both in volume of emesis and in recovery of the marker substance.37 This variability, as well as the belief that the animal studies favored ipecac-induced emesis over gastric lavage because only a relatively small gastric tube was able to be passed in animals, led to subsequent tracer studies in the human overdose setting. Tandberg and associates, using vitamin B12 as a tracer given to overdosed adults once they presented to the emergency room, demonstrated that gastric lavage removed 45% of the tracer substance while ipecac removed only 28%.40 In a similarly designed study using thiamine as a tracer in the overdose setting, Auerbach and colleagues demonstrated a superiority of gastric lavage over ipecac4’ At first glance, these data appeared to reverse former teaching. Litovitz, however, suggested that methodologic biases might explain the results showing a superiority of lavage.42 She noted that the investigators in the first study administered over 1,000 mL of tap water with ipecac, increasing the likelihood of gastric emptying and making the marker substance less available for subsequent removal. In contrast, 250 mL of fluid was utilized with each lavage exchange. Second, the subjects in the lavage group were placed in a left lateral decubitus position with the head of the bed lowered, thereby minimizing a loss of gastric contents into the small bowel. Third, the relative timing of ipecac versus gastric lavage introduced a lo-minute advantage to the lavage group. Finally, additional holes were placed in the gastric tube, enhancing its removal ca-
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emesis or gastric iavage at varying times following the administration. In studies by Arnold and colleagues, ipecac removed 45% and 30%, respectively, of a known amount of sodium salicylate when it was given immediately or 1 hour following the drug administration. 35 Gastric lavage removed 38% and 10% of the sodium salicylate marker at similar times. In a study similarly performed by Abdallah and Tye, ipecac syrup removed 60%, 40%, and 20%, immediately, 30 minutes, and 60 minutes, respectively, following the administration of a barium sulfate marker.36 Gastric lavage removed 45%, 26%, and 8% of the marker at similar times. Finally, Corby and coworkers, in an animal study, demonstrated the ability of gastric lavage to remove 29% and ipecac 19% following the administration of barium sulfate.37 Boxer and associates treated one half of a group of children who had ingested aspirin in overdose with ipecac followed by gastric lavage while the other half was treated with gastric lavage followed by ipecac.38 Ipecac removed more of the ingested substance in both groups, irrespective of the order of the decontamination procedures. In a second study in overdosed children presenting to the emergency room, Corby and associates demonstrated that ipecac removed approximately 28% of a magnesium hydroxide marker 15 minutes following administration.3g Thus, by the late 1960s and based on these studies, ipecac appeared to have an advantage over gastric lavage and appeared to remove 30% to 40% of an ingested product when ipecac was administered 30 minutes to 1 hour following an overdose. Based on these studies, the American Academy of Pediatrics pursued a vigorous campaign to place ipecac in homes with children and educate parents and physicians in its correct use. Ipecac became the treatment of choice for childhood poisoning in the home setting and in the alert patient in the hospital setting.
Ipecac Versus Gastric Lavage- Later Studies The studies by Corby and coworkers showed large interpatient variance both in volume of emesis and in recovery of the marker substance.37 This variability, as well as the belief that the animal studies favored ipecac-induced emesis over gastric lavage because only a relatively small gastric tube was able to be passed in animals, led to subsequent tracer studies in the human overdose setting. Tandberg and associates, using vitamin B12 as a tracer given to overdosed adults once they presented to the emergency room, demonstrated that gastric lavage removed 45% of the tracer substance while ipecac removed only 28%.40 In a similarly designed study using thiamine as a tracer in the overdose setting, Auerbach and colleagues demonstrated a superiority of gastric lavage over ipecac4’ At first glance, these data appeared to reverse former teaching. Litovitz, however, suggested that methodologic biases might explain the results showing a superiority of lavage.42 She noted that the investigators in the first study administered over 1,000 mL of tap water with ipecac, increasing the likelihood of gastric emptying and making the marker substance less available for subsequent removal. In contrast, 250 mL of fluid was utilized with each lavage exchange. Second, the subjects in the lavage group were placed in a left lateral decubitus position with the head of the bed lowered, thereby minimizing a loss of gastric contents into the small bowel. Third, the relative timing of ipecac versus gastric lavage introduced a lo-minute advantage to the lavage group. Finally, additional holes were placed in the gastric tube, enhancing its removal ca-
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pabilities. All of these factors appeared to offer advantages to lavage in the experimental setting that would be difficult to accomplish in the overdose setting. These reservations notwithstanding, the long-held view of the superiority of ipecac over lavage was placed in question.
Activated Charcoal Versus Ipecac or Gastric Lavage in Volunteers The late 1970s and early 1980s witnessed a remarkable outpouring of both in vitro and in vivo studies involving activated charcoal. Studies by Neuvonen and colleagues elucidated the physical and chemical properties of activated charcoal, the differences in efficacy based on brand and formulation, the effect of the charcoal-to-drug ratio and stomach contents on adsorption, and the reversibility of adsorption.431 44 Studies by Berg and associates45 in the volunteer setting, the results of which were subsequently confirmed by Pond and others46v47 in the overdose setting, demonstrated the ability of gastrointestinal dialysis to enhance the removal of ingested products from the blood via the gastrointestinal tract. In simultaneously performed studies of activated charcoal as the initial means of gastrointestinal decontamination, Neuvonen and coworkers showed the superiority of single-dose activated charcoal over ipecac or lavage, using therapeutic doses of acetaminophen, tetracycline, and aminophylline in the volunteer setting. 48 In these studies, activated charcoal prevented 50% to 75% of the administered drug from being absorbed. Curtis and colleagues, in a similarly designed study in volunteers, using percent urinary salicylate recovery as the outcome parameter, also showed the superiority of activated charcoal in preventing approximately 50% absorption of the administered salicylate, as contrasted with 30% for ipecac.4g The limitation associated with studying drugs administered in therapeutic doses was overcome when Tenenbein and coworkers, using ampicillin (a relatively nontoxic substance) in overdose, showed that activated charcoal prevented 57%, ipecac 38%, and lavage 32% of the administered ampicillin from being absorbed.50 This evidence was compelling in its consistent demonstration of the advantage of activated charcoal over ‘ipecac and lavage, with the result that the physicians in the emergency room setting have increasingly selected activated charcoal as the primary means of gastrointestinal decontamination, expecting a 50% reduction in drug absorption when accomplished within an hour of the ingestion.
Efficacy of Ipecac or Lavage Plus Charcoal Versus Charcoal Alone in the Overdose Setting In the mid 1980s Rumack, in an editorial in Pediatrics, and Vail and colleagues, in the British Medical Journal, questioned the value of gastric emptying in the pediatric setting.51~ 52 In most of the previous studies, the outcome parameters were pharmacokinetic in nature, including peak serum level, area under the (blood) curve, or percentage recovery of the ingested substance in the urine. More recent studies utilized different outcome parameters, including length of stay in the emergency room or intensive care setting, percentage of patients admitted to the hospital, length of ventilator time, and length of hospitalization. In an overdose population presenting to the emergency room in whom ipecac followed by activated charcoal was contrasted with activated charcoal
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alone (thereby studying the efficacy of ipecac as a method of intervention), Kulig and colleagues found no difference in the percentage of patients admitted to the hospital or subsequently deteriorating clinically.53 In the same study in patients presenting in an obtunded state and treated with gastric lavage and charcoal versus activated charcoal alone (thereby studying the efficacy of gastric lavage as a method of intervention), gastric lavage when performed within 1 hour after the ingestion resulted in a more satisfactory outcome, as assessed by subsequent clinical deterioration or hospital admission (P i .05). Albertson and coworkers undertook a study similar in design to that of Kulig’s study in which overdosed patients were treated with either ipecac followed by activated charcoal or activated charcoal alone.54 The ipecac-treated group spent a longer time in the emergency room and had a higher rate of aspiration pneumonia. The rates of hospitalization and the length of hospital stay were similar. In a prospective study of 808 consecutive overdoses by Merigian and associates, symptomatic patients were treated with either emesis or lavage followed by charcoal while the alternative group received charcoal alone:55 The outcomes assessed included length of time in the emergency room or intensive care unit, intubation time, incidence of intensive care unit admission, and complication rates. The investigators found no benefit of gastric emptying as compared with charcoal alone in symptomatic patients. Further, gastric lavage resulted in a higher incidence of aspiration pneumonia and intensive care admission when compared with the group treated with charcoal alone (although aspiration might result from aggressive use of prophylactic intubation rather than the lavage procedure). These studies suggested that gastrointestinal intervention involving either ipecac or gastric lavage resulted in a higher rate of complication, without clear evidence of clinical efficacy. Only for symptomatic patients in the Kulig study was gastric lavage shown to be effective and only if it was instituted within 1 hour. Olson, in an accompanying editorial, suggested that sufficient evidence now exists to be able to recommend charcoal alone without gastric lavage or ipecac-induced emesis in the hospital setting.56 Because the current studies failed to include pharmacokinetic data as an outcome parameter, failed to quantitate clinical assessment prior to and following the intervention, and failed to include a sufficiently large number of seriously or potentially lethal overdoses, further studies are needed to address these limitations.
Observation Alone for “Minimally Symptomatic” Patients Foulke and colleagues, in a group of “minimally symptomatic” patients presenting to the emergency room, compared ipecac to no intervention.57 The ipecactreated group stayed in the emergency room for a longer period of time and had a higher complication rate than did the group of patients in whom no intervention was instituted. Merigian and associates also studied “minimally symptomatic” patients treated with either charcoal or observation alone, using the outcome parameters previously noted, and found no benefit of charcoal over no treatment.55 These results thus went one step further to suggest that in the asymptomatic or “minimally symptomatic” patient presenting to the emergency room, neither ipecac nor charcoal was superior to observation alone. Clearly, however, these are very preliminary studies requiring confirmation in larger populations of overdosed patients.
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Implications
Where does this information leave the pediatrician? 1. In the symptomatic but alert child with a minor ingestion presenting to the emergency room, activated charcoal alone (for drugs adsorbed by activated charcoal) by mouth appears to be sufficient for gastrointestinal decontamination. 2. For the obtunded or comatose child with a potentially serious overdose, lavage followed by activated charcoal via an orogastric or nasogastric tube should be used within 1 to 2 hours after ingestion (or longer in the case of sustained-release drugs, gastric concretions, or delayed gastric emptying). Repetitive dosing of activated charcoal should be used when indicated by the substance ingested. 3. For the asymptomatic child with a minimal amount ingested in the emergency room setting, there is now initial information to suggest that relatively little is gained by any removal procedure. Clearly, careful assessment for a sufficiently long period of time, however, is absolutely necessary. The asymptomatic patient presenting early may in fact have ingested a very large overdose of a toxic substance or may not be forthcoming with a reliable history.56 In these instances, charcoal should be used. 4. For the overdosed patient in the home setting, compliance with the use of charcoal remains problematic. No study .has compared ipecac-induced emesis to observation alone in the home setting, and until that study is carried out, ipecac, as recommended by poison centers or pediatricians, is the logical approach.
Advances in the Use of DMSA for Lead Poisoning The recent Food and Drug Administration (FDA) approval of the oral chelator 2,3-dimercaptosuccinic acid (DMSA) represents an important advance in medical toxicology. Because it appears at a time when concern about exposure to environmental toxins, particularly heavy metals, is growing, it appears that DMSA will be the answer to a much-needed oral treatment for many heavy-metal intoxications in patients of all ages.
identification
and History
DMSA is an oral congener of the chelator dimercaprol (British antilewisite, BAL). 58* 5g BAL was created during World War I as a treatment for exposure to the arsenical gas lewisite. It was quickly found to be an effective chelator of other heavy metals, including lead and mercury. For many years after its creation, BAL was considered a “universal antidote” for heavy-metal intoxications6’ BAL assumed importance in the treatment of childhood lead intoxication when it was found to be a necessary adjunct to (CaNa,edetate tetraacedic acid [EDTA]) in reducing the mortality of severe lead poisoning.5g*61 However, BAL had many undesirable properties, including a lack of stability in water (which required its parenteral administration in a peanut-oil vehicle) and a rate of adverse reactions as high as 50%.58* 5g DMSA was first synthesized in 1954. Its potential role as a heavy-metal chelator was first reported in 1965 but largely ignored.62l 63 Renewed interest in this agent appeared in the 1970s leading to several important studies of its safety and efficacy. Much of this research interest was directed to its role in the treat-
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ment of lead intoxication. Because gathering data proved DMSA to be safe and effective for plumbism, it became the first oral chelator approved for childhood plumbism in 1991.
Pharmacology DMSA is a dithiol derivative of succinic acid (the sulfur groups are responsible for its unpleasant, mercaptan odor). Sulfur is one of the several atoms that are able to act as ligands with polyvalent minerals, creating a stable covalent bond (usually in a heterocyclic configuration).58l 6o Available data indicate that DMSA is rapidly but incompletely absorbed. While pharmacokinetic information is incomplete, DMSA appears to have a small volume of distribution (~1 Ukg) and has an elimination half-life of approximately 48 hours. Studies with radiolabeled drug suggest primary renal elimination of the drug metabolites, with an additional portion excreted fecally. Only 10% of the drug is excreted in the unchanged form.62Z 64
Uses and Indications DMSA comes closest to providing all the properties desired of a chelator: (1) It can be administered orally, therefore, in an outpatient setting (convenient). (2) Its efficacy is broad enough for it to be effective for many types of heavy-metal intoxications. (3) Its specificity is narrow enough that it enhances the elimination of toxic heavy metals, with minimal chelation of essential minerals zinc, calcium, and copper. (3) The metal-DMSA complex is rapidly eliminated in the urine. (4) Based on existing data, it is safe and has a prolonged effect.63 DMSA, like BAL, has in vitro and in vivo efficacy with a number of heavy metals, including lead, arsenic, mercury, antimony, bismuth, cobalt, gold, and nickel. However, because controlled studies of its efficacy have only been performed with lead, its sole indication for use is plumbism (although there are several case series on the successful treatment of arsenic and mercury poisoning with DMSA).63* 65 The approval of DMSA for the treatment of childhood lead intoxication comes at a time of increasing concern about lead and a decrease in the tolerable levels of lead in children. Because compelling data have demonstrated the risk of biochemical and neurodevelopmental injury when blood lead levels exceed 10 pg/mL, there has been a redefinition of lead poisoning and a trend toward “zero tolerance” with childhood lead exposure. By current estimates, more than 15% of children less than 6 years old have a significant lead burden (as many as 50% of children in selected urban areas). Chelation therapy for lead intoxication has historically been unsatisfying, with available treatments (BAL, CaNa,EDTA, o-penicillamine) having a narrow therapeutic index and a significant rate of adverse effects. While DMSA has been heralded as the best treatment for plumbism, many lead specialists have argued the inappropriateness of widespread pharmacologic treatment of these children; instead they emphasize the importance of efforts to reduce the amount of lead in the environment.66-68 DMSA has an impressive record of efficacy in treating lead intoxication. In a controlled study of lead-poisoned children, Graziano and colleagues demonstrated that DMSA administered orally for 5 days will reduce blood lead levels by as much as 78%. This rate compared with a mean 47% reduction in blood lead level after a conventional 5day course of CaNa2EDTA.61-63v 6g These lead reductions are associated with prompt normalization of the biochemical indicators of plumbism, for example, delta-aminolevulinic acid dehydratase activity.
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Unlike EDTA, which appears to chelate lead from intracellular water only, DMSA appears capable of acting in both intracellular and extracellular spaces.62 A 5-day course of DMSA is consistently followed by a significant rebound in blood lead levels, the result of a redistribution of lead from bone and soft tissues.” The recommended dosing schedule is therefore to administer.DMSA for 14 additional days after the initial 5-day course. Multiple courses may be necessary, depending on the goals of treatmentm
Contraindications and Adverse Effects Under present guidelines, DMSA is contraindicated in patients with known hypersensitivity, and in children with preexisting renal or hepatic disease (although it has been used successfully in children with renal failure).64 Even though BAL is relatively contraindicated in children with glucose-6-phosphate dehydrogenase deficiency, because of its oxidizing potential, DMSA has been used in such children without untoward effects5*, 64 While DMSA has a broad safety profile, adverse drug reactions (ADRs) have been reported. Children appear to have a lower rate of ADRs than adults. Adverse effects are primarily gastrointestinal, where a rate of 12% has been reported, consisting primarily of gastrointestinal upset. Dermatologic eruptions have been reported at a rate of 3%. Liver function abnormalities, which are reported in up to 10% of adults, have been seen in 4% of children.64* 6g DMSA possesses no evidence of mutagenicity. However, in animal models, both fetotoxicity and teratogenicity have been observed. It is unknown whether DMSA crosses the placenta. Given these data, DMSA has been placed in pregnancy category C, indicating that animal studies have demonstrated adverse fetal effects but controlled data in pregnant women do not exist. The extent of the transmission of DMSA via breast milk is unknown.63, 64
lmplica tions Under current manufacturer’s recommendations, DMSA is indicated for blood lead levels higher than 45 mg/dL. Dosing consists of a 5-day course of 30 mg/ kg/day, given three times a day, followed immediately by a 14-day course of 20 mg/kg/day, given twice daily. Retreatment is advised if lead levels remain above 45 mg/dL; DMSA is not approved for use in children with blood lead levels less than this. As experience expands, DMSA will likely be approved for children with lower blood levels and for other poisons, for example, arsenic intoxication. DMSA has the potential to replace other heavy-metal antagonists in current use, not only for the treatment of lead intoxication but also for the treatment of poisoning by other metals. Appearing when the tolerance for lead in children is being lowered, the availability of such a safe oral therapy is exciting and is certain to open a new chapter in the treatment of lead and other heavy-metal intoxications.
References 1. Zuckerman B. Frank DA, Hingson R, et al: Effects of maternal marijuana and cocaine use on fetal growth. A/ Engl J Med 1989; 320:762-768. 2. Kharasch SJ, Glotzer D, Vinci R, et al: Unsuspected cocaine exposure in young children. Am J Dis Child 1991; 145204-206. 3. Shannon M, Lacouture PG, Roa J, et al: Cocaine exposure among children seen at a pediatric hospital. Pediatrics 1989; 83:337-342. 4. Johnson LD, O’Malley PM, Bachman GG: National Trends in Drug Use and Related Substances
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5. 6. 7. 8. 9. 10. 11, 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
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among High School Senior Students, National Institute on Drug Abuse publication No. (ADM) 19-1813. Rockville, MD, Department of Health and Human Services, 1991. Dimies JD, Darr CD, Saulys AJ: Cocaine toxicity in toddlers. Am J Dis Child 1990; 144:743-744. Chasnoff IJ, Lewis DE, Squires L: Cocaine intoxication in a breast-fed infant. Pediatrics 1987; 80:836-838. Bateman DA, Heagarty MC: Passive freebase cocaine (‘crack’) inhalation by infants and toddlers, Am J Dis Child 1989; 143:25-27. Dimies JD, Darr CD, Saulys AJ: Cocaine toxicity in toddlers. Am J Dis Child 1990; 144:743-744. Rivkin M, Gilmore HE: Generalized seizures in an infant due to environmentally-acquired cocaine. Pediatrics 1989; 84: 11 OO- 1101. Garland JS, Smith DS, Rice TB, et al: Accidental cocaine intoxication in a nine-month-old infant: Presentation and treatment. Pediatr Emefg Cafe 1989; 5:245-247. Chaney NE, Franke J, Wadlington WB: Cocaine convulsions in a breast feeding infant. J Pediatr 1988; 112:134-135. Kharasch S, Vinci R, Reece R: Esophagitis, epiglottitis, and cocaine alkaloid (“crack”): “Accidental” poisoning or child abuse? Pediatrics 1990; 86: 117- 1 l-8. Williams AF, Peat MA, Crouch DJ, et al: Drugs in fatally injured young adult male drivers. Public Health Rep 1985; 100:19-25. Crumley FE: Substance abuse and adolescent suicidal behavior. JAMA 1990; 263:3051-3056. Fullilove RE, Fullilove MT, Bowser BP, et al: Risk of sexually-transmitted disease among black adolescent crack users in Oakland and San Francisco, California. JAMA 1990; 263:851-855. Estroff TW, Schwartz RH, Hoffmann NG: Adolescent cocaine abuse. C/in Pediafr 1989; 28:550-555. Acker D, Sachs BP, Tracey KJ, et al: Abruptio placenta associated with cocaine use. Am J Obstet Gynecol 1983; 146:220221. Mellott JM, Kaltenbach KA, Finnegan LP: Cocaine and pregnancy: Developmental effects at birth (abstract). Pediatf Res 1989; 2573. Chasnoff IJ, Bussey ME, Savich A, et al: Perinatal cerebral infarction and maternal cocaine use. J Pediatf 1986; 108:456-459. Fulroth R, Phillips 8, Durand DJ: Perinatal outcome of infants exposed to cocaine and/or heroin in utero. Am J Dis Child 1989; 143:905-910. Bingo1 N, Fuchs M, Diaz V, et al: Teratogenicity of cocaine in humans. J Pediatr 1987; 110:93-96. MacGregor SN, Keith LG, Chasnoff IJ, et al: Cocaine use during pregnancy: Adverse perinatal outcome. Am J Obstet Gynecol 1987; 157:686-690. Oro AS, Dixon SD: Perinatal cocaine and methamphetamine exposure: Maternal and neonatal correlates. J Pediatf 1987; 111571-578. Doberczak TM, Shanzer S, Senie RT, et al: Neonatal neurologic and electroencephalographic effects of intrauterine cocaine exposure. J Pediatf 1988; 113:354-358. Chasqoff IJ, Burns WJ, Schnoll SH, et al: Cocaine use in pregnancy. A! Engl J Med 1985; 313:666-669. Mahalik MP, Gautieri RF, Mann DE: Teratogenic potential of cocaine hydrochloride in CF.1 mice. J Phafmacol Sci 1980; 69:703-706. Koren G, Shear H, Graham K, et al: Bias against the null hypothesis: The reproductive hazards of cocaine. Lancet 1989; 1: 1440- 1441, Dominquez R, Aguirre Vila-Coro A, Slopis JM, et al: Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs. Am J Dis Child 1991; 145688-695. Chasnoff IJ, Chisum GM, Kaplan WE: Maternal cocaine use and genitourinary tract malformations Teratology 1988; 37:201-204. Chavez GF, Mulinare J, Corder0 JF: Maternal cocaine use during early pregnancy as a risk factor for congenital urogenital anomalies. JAMA 1989; 262:795798. Telsey AM, Merrit TA, Dixon SD: Cocaine exposure in a term infant-necrotizing enterocolitis as a complication. C/in Pediatf 1988; 27:547-550. Miller BM, Rosario PG, Prakash K, et al: Neonatal intestinal perforation: The ‘crack’ connection. Am J Gastfoentefol 1990; 85:767768. Wiener MD, Putman CE: Pain in the chest in a user of cocaine. JAMA 1987; 258:2087-2088. Farrar HC, Kearns GL: Cocaine: Clinical pharmacology and toxicology. J Pediatf 1989; 115:665-675. Arnold FJ Jr, Hodges JB Jr, Barta RA, et al: Evaluation of the efficacy of lavage and induced emesis in treatment of salicylate poisoning. Pediatrics 1959; 23:286-310. Abdallah AH, Tye A: A comparison of the efficacy of emetic drugs and stomach lavage. Am J Dis Child 1967; 113:571-574. Corby DG, Lisciandro RC, Lehman RH, et al: The efficacy of methods used to evacuate the stomach after acute ingestions. Pediatrics 1967; 40:871-874.
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38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.
55. 56. 57. 58.
59. 60.
61. 62. 63. 64. 65. 66. 67. 68. 69.
Boxer L, Anderson FP, Rowe DS: Comparison of ipecac-induced emesis with gastric lavage in the treatment of acute salicylate ingestion. J fed&r 1969; 74:800-803. Corby DG, Decker WJ, Moran MJ, et al: Clinical comparison of pharmacologic emetics in children. Pediatrics 1968; 42:361-364. Tandberg D, Diven BG, McLeod JW: Ipecac-induced emesis versus gastric lavage: A controlled study in normal adults. Am J Emerg Med 1986; 4:205-209. Auerbach PS, Osterloh J. Braun 0, et al: Efficacy of gastric emptying: Gastric lavage versus emesis induced with ipecac. Ann Emerg Med 1986; 15:692-698. Litovitz TL: Emesis versus lavage for poisoning victims. Am J Emerg Med 1986; 4:294-295. Neuvonen PJ: Clinical pharmacokinetics of oral activated charcoal in acute intoxications. C/in Pharmacokinet 1982; 7:465-489. Park GD, Spector R, Goldberg MJ, et al: Expanded role of charcoal therapy in the poisoned and overdosed patient. Arch Intern Med 1986; 146:969-973. Berg MJ, Berlinger WG, Goldberg MJ. et al: Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med 1982; 251:642-644. Pond SM, Olson KR. Osterloh JD, et al: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 1984; 251:3104-3108. Pond SM: Role of repeated oral doses of activated charcoal in clinical toxicology. Med Toxicol Adverse Drug Exp 1986; 1:3- 11. Neuvonen PJ, Vartianen, Tokola 0: Comparison of activated charcoal and ipecac syrup in prevention of drug absorption. Eur J C/in Pharmacol 1983; 24:557-562. Curtis RA, Barone J, Giacona N: Efficacy of ipecac and activated charcoal/cathartic prevention of salicylate absorption in a simulated overdose. Arch,/ntem Med 1984; 144:48-52. Tenenbein M, Cohen S, Sitar DS: Efficacy of ipecac-induced emesis, orogastric lavage, and activated charcoal for acute drug overdose. Ann Emerg Med 1987; 16:838-841. Rumack BH: Ipecac use in the home. Pediatrics 1985; 75:1148. Vale JA, Meredith TJ, Proudfoot AT: Syrup of ipecacuanha: Is it really useful? i3r Med J 1986: 293: 1321- 1322. Kulig K, Bar-Or D, Cantriil SV, et al: Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 1985; 14:562-567. Albertson TE, Derlet RW, Foulke GE, et al: Superiority of activated charcoal alone compared with ipecac and activated charcoal in the treatment of acute toxic ingestions. Ann Emerg Med 1989; 18:101-104. Merigian KS, Woodard M, Hedges JR, et al: Prospective evaluation of gastric emptying in the self-poisoned patient. Am J Emerg Med 1990; 8:479-483. Olson KR: Is gut emptying all washed up? (editorial). Am J Emerg Med 1990; 8:560-561. Foulke GE, Albertson TE. Derlet RW: Use of ipecac increases emergency department stays and patient complication rates. Ann Emerg Med 1988; 17:402. Klaassen CD: Heavy metals and heavy-metal antagonists, in Gilman AG, Rail TW, Nies AS, Taylor P (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, ed 8. New York, Pergamon Press, 1990, pp 1592- 1614. Chisolm JJ Jr: The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatr 1968; 73:i -38. Goyer RA: Toxic effects of metals, in Klaassen CD, Amdur MO, Doull J (eds): Casarett and Doull’s Toxicology-The Basic Science of Poisons, ed 3. New York, Macmillan Publishing Co, 1986, pp 582-635. Graziano JH, Lolacono NJ, Meyer P: Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations. J Pediah 1988; 113:751-757. Graziano JH, Sins ES, Lolacono N, et al: 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. C/in Pharmacol Ther 1985; 37:431-438. Grazrano FH: Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal poisonrng. Med Toxicol Adverse Drug Exp 1986; 1 :155- 162. McNeil Consumer Products Company. Data on file. Evansville, Indiana, 1991. Freidheim E, Corvi C: Meso-dimercaptosuccinic acid, a chelating agent for the treatment of mercury poisoning. J Pharm Pharmacol 1975; 27:624-626. Piomelli S: Use of penicillamine in children with small lead burdens (letter). N Engl J Med 1990; 322: 1888. Graziano JH: Use of penicillamine in children with small lead burdens (letter). N Engl J Med 1990; 322:1888. . Shannon MW, Graef J: Use of penicillamine in children with small lead burdens (letter), N Engl J Med 1990; 322:1888. Graziano JH, Leong JK, Friedheim E: 2,3-Dimercaptosuccinic acid: A new agent for the treatment of lead poisoning. J Pharmacol Exp Ther 1978; 206:696-700.
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emesis or gastric iavage at varying times following the administration. In studies by Arnold and colleagues, ipecac removed 45% and 30%, respectively, of a known amount of sodium salicylate when it was given immediately or 1 hour following the drug administration. 35 Gastric lavage removed 38% and 10% of the sodium salicylate marker at similar times. In a study similarly performed by Abdallah and Tye, ipecac syrup removed 60%, 40%, and 20%, immediately, 30 minutes, and 60 minutes, respectively, following the administration of a barium sulfate marker.36 Gastric lavage removed 45%, 26%, and 8% of the marker at similar times. Finally, Corby and coworkers, in an animal study, demonstrated the ability of gastric lavage to remove 29% and ipecac 19% following the administration of barium sulfate.37 Boxer and associates treated one half of a group of children who had ingested aspirin in overdose with ipecac followed by gastric lavage while the other half was treated with gastric lavage followed by ipecac.38 Ipecac removed more of the ingested substance in both groups, irrespective of the order of the decontamination procedures. In a second study in overdosed children presenting to the emergency room, Corby and associates demonstrated that ipecac removed approximately 28% of a magnesium hydroxide marker 15 minutes following administration.3g Thus, by the late 1960s and based on these studies, ipecac appeared to have an advantage over gastric lavage and appeared to remove 30% to 40% of an ingested product when ipecac was administered 30 minutes to 1 hour following an overdose. Based on these studies, the American Academy of Pediatrics pursued a vigorous campaign to place ipecac in homes with children and educate parents and physicians in its correct use. Ipecac became the treatment of choice for childhood poisoning in the home setting and in the alert patient in the hospital setting.
Ipecac Versus Gastric Lavage- Later Studies The studies by Corby and coworkers showed large interpatient variance both in volume of emesis and in recovery of the marker substance.37 This variability, as well as the belief that the animal studies favored ipecac-induced emesis over gastric lavage because only a relatively small gastric tube was able to be passed in animals, led to subsequent tracer studies in the human overdose setting. Tandberg and associates, using vitamin B12 as a tracer given to overdosed adults once they presented to the emergency room, demonstrated that gastric lavage removed 45% of the tracer substance while ipecac removed only 28%.40 In a similarly designed study using thiamine as a tracer in the overdose setting, Auerbach and colleagues demonstrated a superiority of gastric lavage over ipecac4’ At first glance, these data appeared to reverse former teaching. Litovitz, however, suggested that methodologic biases might explain the results showing a superiority of lavage.42 She noted that the investigators in the first study administered over 1,000 mL of tap water with ipecac, increasing the likelihood of gastric emptying and making the marker substance less available for subsequent removal. In contrast, 250 mL of fluid was utilized with each lavage exchange. Second, the subjects in the lavage group were placed in a left lateral decubitus position with the head of the bed lowered, thereby minimizing a loss of gastric contents into the small bowel. Third, the relative timing of ipecac versus gastric lavage introduced a lo-minute advantage to the lavage group. Finally, additional holes were placed in the gastric tube, enhancing its removal ca-
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care for their own children, leaving them at high risk for neglect and other psychosocial trauma. More and more children in such circumstances are being placed under the supervision of the state in an already overburdened foster care program. There is case report evidence now that cocaine can be transmitted in breast milk to breast-feeding babies6 children can also become intoxicated by the passive inhalation of “crack” smoke.7 There is anecodotal evidence that some pediatric intoxications have resulted from accidental ingestion of cocaine casually left in their environment’-” or from inadvertent ingestion when cocaine dust was applied topically to relieve nipple pain before breast-feeding.” Cocaine has been intentionally given to children-another agent implicated as an instrument of “chemical child abuse.“12 Unlike other substances of abuse, adolescents may initiate experimentation with crack or other forms of cocaine anytime during the teenage years or early 20s. Use of cocaine by adolescents has been linked to increased rates of motor vehicle fatalities,13 depression and suicidal thinking,14 sexually transmitted diseases,15 and delinquent behavior among these troubled youth.16 For all ages, then, cocaine intoxication represents only the most obvious sign of a disheartening array of medical, psychosocial, and family problems that are as complex as they are intractable.
Fetal Effects Maternal cocaine use in the third trimester has been associated with an increased incidence of abruptio placentae.17 There is also clear evidence that some infants born with neurologic deficits have suffered in utero cerebral hemorrhage and/or infarction, presumably due to cocaine’s hypertension-inducing effects.‘8* ” Cocaine use during pregnancy has also been linked to fetal growth retardation and microcephaly, perhaps due to cocaine’s appetite-suppressant actions affecting the adequacy of the mother’s diet or its vasoconstrictive properties reducing placental blood flow and nutrition to the fetus.‘, 20-23 An abstinence syndrome in the infant has been characterized by lethargy, poor feeding, and transient electroencephalographic (EEG) changes (bursts of sharp waves and spikes), which generally resolve over a period of days to weeks.24 There are some preliminary investigations suggesting that many cocaine-exposed neonates have increased state disorganization and depressed interactive behavioral scores on the Brazelton Neonatal Behavioral Assessment Scale.25 Longitudinal studies are currently underway to assess longer-term neurodevelopment and cognitive effects attributable to fetal cocaine exposure. Whether cocaine’s vasoconstrictive properties are responsible for specific teratogenic syndromes in humans remains controversial. Murine animal models have demonstrated increased rates of fetal resorption, skeletal defects, and ophthalmic deformities in mice whose mothers were exposed to cocaine.26 Many studies in humans are confounded by a lack of verification of maternal cocaine use, the presence of multiple substances abused during pregnancy, and inadequate controls. 27 However, an association between fetal exposure to cocaine and cerebral, cardiac, skeletal, renal, and/or ophthalmic abnormalities is suspected. Dominquez and colleagues2’ reported on ten infants with a history of exposure to cocaine who were born with cerebral and ophthalmic abnormalities, thought to be related to vascular disruption during fetal life. In one prospective study of 50 infants of cocaine-using mothers by Chasnoff and associates, 7 were found to have hypospadias and/or hydronephrosis on renal ultrasound, as opposed to none among the infants born to polydrug (but not cocaine)-abusing women2’ In a large case-control study, Chavez and, coworkers found a greater
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emesis or gastric iavage at varying times following the administration. In studies by Arnold and colleagues, ipecac removed 45% and 30%, respectively, of a known amount of sodium salicylate when it was given immediately or 1 hour following the drug administration. 35 Gastric lavage removed 38% and 10% of the sodium salicylate marker at similar times. In a study similarly performed by Abdallah and Tye, ipecac syrup removed 60%, 40%, and 20%, immediately, 30 minutes, and 60 minutes, respectively, following the administration of a barium sulfate marker.36 Gastric lavage removed 45%, 26%, and 8% of the marker at similar times. Finally, Corby and coworkers, in an animal study, demonstrated the ability of gastric lavage to remove 29% and ipecac 19% following the administration of barium sulfate.37 Boxer and associates treated one half of a group of children who had ingested aspirin in overdose with ipecac followed by gastric lavage while the other half was treated with gastric lavage followed by ipecac.38 Ipecac removed more of the ingested substance in both groups, irrespective of the order of the decontamination procedures. In a second study in overdosed children presenting to the emergency room, Corby and associates demonstrated that ipecac removed approximately 28% of a magnesium hydroxide marker 15 minutes following administration.3g Thus, by the late 1960s and based on these studies, ipecac appeared to have an advantage over gastric lavage and appeared to remove 30% to 40% of an ingested product when ipecac was administered 30 minutes to 1 hour following an overdose. Based on these studies, the American Academy of Pediatrics pursued a vigorous campaign to place ipecac in homes with children and educate parents and physicians in its correct use. Ipecac became the treatment of choice for childhood poisoning in the home setting and in the alert patient in the hospital setting.
Ipecac Versus Gastric Lavage- Later Studies The studies by Corby and coworkers showed large interpatient variance both in volume of emesis and in recovery of the marker substance.37 This variability, as well as the belief that the animal studies favored ipecac-induced emesis over gastric lavage because only a relatively small gastric tube was able to be passed in animals, led to subsequent tracer studies in the human overdose setting. Tandberg and associates, using vitamin B12 as a tracer given to overdosed adults once they presented to the emergency room, demonstrated that gastric lavage removed 45% of the tracer substance while ipecac removed only 28%.40 In a similarly designed study using thiamine as a tracer in the overdose setting, Auerbach and colleagues demonstrated a superiority of gastric lavage over ipecac4’ At first glance, these data appeared to reverse former teaching. Litovitz, however, suggested that methodologic biases might explain the results showing a superiority of lavage.42 She noted that the investigators in the first study administered over 1,000 mL of tap water with ipecac, increasing the likelihood of gastric emptying and making the marker substance less available for subsequent removal. In contrast, 250 mL of fluid was utilized with each lavage exchange. Second, the subjects in the lavage group were placed in a left lateral decubitus position with the head of the bed lowered, thereby minimizing a loss of gastric contents into the small bowel. Third, the relative timing of ipecac versus gastric lavage introduced a lo-minute advantage to the lavage group. Finally, additional holes were placed in the gastric tube, enhancing its removal ca-
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emesis or gastric iavage at varying times following the administration. In studies by Arnold and colleagues, ipecac removed 45% and 30%, respectively, of a known amount of sodium salicylate when it was given immediately or 1 hour following the drug administration. 35 Gastric lavage removed 38% and 10% of the sodium salicylate marker at similar times. In a study similarly performed by Abdallah and Tye, ipecac syrup removed 60%, 40%, and 20%, immediately, 30 minutes, and 60 minutes, respectively, following the administration of a barium sulfate marker.36 Gastric lavage removed 45%, 26%, and 8% of the marker at similar times. Finally, Corby and coworkers, in an animal study, demonstrated the ability of gastric lavage to remove 29% and ipecac 19% following the administration of barium sulfate.37 Boxer and associates treated one half of a group of children who had ingested aspirin in overdose with ipecac followed by gastric lavage while the other half was treated with gastric lavage followed by ipecac.38 Ipecac removed more of the ingested substance in both groups, irrespective of the order of the decontamination procedures. In a second study in overdosed children presenting to the emergency room, Corby and associates demonstrated that ipecac removed approximately 28% of a magnesium hydroxide marker 15 minutes following administration.3g Thus, by the late 1960s and based on these studies, ipecac appeared to have an advantage over gastric lavage and appeared to remove 30% to 40% of an ingested product when ipecac was administered 30 minutes to 1 hour following an overdose. Based on these studies, the American Academy of Pediatrics pursued a vigorous campaign to place ipecac in homes with children and educate parents and physicians in its correct use. Ipecac became the treatment of choice for childhood poisoning in the home setting and in the alert patient in the hospital setting.
Ipecac Versus Gastric Lavage- Later Studies The studies by Corby and coworkers showed large interpatient variance both in volume of emesis and in recovery of the marker substance.37 This variability, as well as the belief that the animal studies favored ipecac-induced emesis over gastric lavage because only a relatively small gastric tube was able to be passed in animals, led to subsequent tracer studies in the human overdose setting. Tandberg and associates, using vitamin B12 as a tracer given to overdosed adults once they presented to the emergency room, demonstrated that gastric lavage removed 45% of the tracer substance while ipecac removed only 28%.40 In a similarly designed study using thiamine as a tracer in the overdose setting, Auerbach and colleagues demonstrated a superiority of gastric lavage over ipecac4’ At first glance, these data appeared to reverse former teaching. Litovitz, however, suggested that methodologic biases might explain the results showing a superiority of lavage.42 She noted that the investigators in the first study administered over 1,000 mL of tap water with ipecac, increasing the likelihood of gastric emptying and making the marker substance less available for subsequent removal. In contrast, 250 mL of fluid was utilized with each lavage exchange. Second, the subjects in the lavage group were placed in a left lateral decubitus position with the head of the bed lowered, thereby minimizing a loss of gastric contents into the small bowel. Third, the relative timing of ipecac versus gastric lavage introduced a lo-minute advantage to the lavage group. Finally, additional holes were placed in the gastric tube, enhancing its removal ca-
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pabilities. All of these factors appeared to offer advantages to lavage in the experimental setting that would be difficult to accomplish in the overdose setting. These reservations notwithstanding, the long-held view of the superiority of ipecac over lavage was placed in question.
Activated Charcoal Versus Ipecac or Gastric Lavage in Volunteers The late 1970s and early 1980s witnessed a remarkable outpouring of both in vitro and in vivo studies involving activated charcoal. Studies by Neuvonen and colleagues elucidated the physical and chemical properties of activated charcoal, the differences in efficacy based on brand and formulation, the effect of the charcoal-to-drug ratio and stomach contents on adsorption, and the reversibility of adsorption.431 44 Studies by Berg and associates45 in the volunteer setting, the results of which were subsequently confirmed by Pond and others46v47 in the overdose setting, demonstrated the ability of gastrointestinal dialysis to enhance the removal of ingested products from the blood via the gastrointestinal tract. In simultaneously performed studies of activated charcoal as the initial means of gastrointestinal decontamination, Neuvonen and coworkers showed the superiority of single-dose activated charcoal over ipecac or lavage, using therapeutic doses of acetaminophen, tetracycline, and aminophylline in the volunteer setting. 48 In these studies, activated charcoal prevented 50% to 75% of the administered drug from being absorbed. Curtis and colleagues, in a similarly designed study in volunteers, using percent urinary salicylate recovery as the outcome parameter, also showed the superiority of activated charcoal in preventing approximately 50% absorption of the administered salicylate, as contrasted with 30% for ipecac.4g The limitation associated with studying drugs administered in therapeutic doses was overcome when Tenenbein and coworkers, using ampicillin (a relatively nontoxic substance) in overdose, showed that activated charcoal prevented 57%, ipecac 38%, and lavage 32% of the administered ampicillin from being absorbed.50 This evidence was compelling in its consistent demonstration of the advantage of activated charcoal over ‘ipecac and lavage, with the result that the physicians in the emergency room setting have increasingly selected activated charcoal as the primary means of gastrointestinal decontamination, expecting a 50% reduction in drug absorption when accomplished within an hour of the ingestion.
Efficacy of Ipecac or Lavage Plus Charcoal Versus Charcoal Alone in the Overdose Setting In the mid 1980s Rumack, in an editorial in Pediatrics, and Vail and colleagues, in the British Medical Journal, questioned the value of gastric emptying in the pediatric setting.51~ 52 In most of the previous studies, the outcome parameters were pharmacokinetic in nature, including peak serum level, area under the (blood) curve, or percentage recovery of the ingested substance in the urine. More recent studies utilized different outcome parameters, including length of stay in the emergency room or intensive care setting, percentage of patients admitted to the hospital, length of ventilator time, and length of hospitalization. In an overdose population presenting to the emergency room in whom ipecac followed by activated charcoal was contrasted with activated charcoal
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alone (thereby studying the efficacy of ipecac as a method of intervention), Kulig and colleagues found no difference in the percentage of patients admitted to the hospital or subsequently deteriorating clinically.53 In the same study in patients presenting in an obtunded state and treated with gastric lavage and charcoal versus activated charcoal alone (thereby studying the efficacy of gastric lavage as a method of intervention), gastric lavage when performed within 1 hour after the ingestion resulted in a more satisfactory outcome, as assessed by subsequent clinical deterioration or hospital admission (P i .05). Albertson and coworkers undertook a study similar in design to that of Kulig’s study in which overdosed patients were treated with either ipecac followed by activated charcoal or activated charcoal alone.54 The ipecac-treated group spent a longer time in the emergency room and had a higher rate of aspiration pneumonia. The rates of hospitalization and the length of hospital stay were similar. In a prospective study of 808 consecutive overdoses by Merigian and associates, symptomatic patients were treated with either emesis or lavage followed by charcoal while the alternative group received charcoal alone:55 The outcomes assessed included length of time in the emergency room or intensive care unit, intubation time, incidence of intensive care unit admission, and complication rates. The investigators found no benefit of gastric emptying as compared with charcoal alone in symptomatic patients. Further, gastric lavage resulted in a higher incidence of aspiration pneumonia and intensive care admission when compared with the group treated with charcoal alone (although aspiration might result from aggressive use of prophylactic intubation rather than the lavage procedure). These studies suggested that gastrointestinal intervention involving either ipecac or gastric lavage resulted in a higher rate of complication, without clear evidence of clinical efficacy. Only for symptomatic patients in the Kulig study was gastric lavage shown to be effective and only if it was instituted within 1 hour. Olson, in an accompanying editorial, suggested that sufficient evidence now exists to be able to recommend charcoal alone without gastric lavage or ipecac-induced emesis in the hospital setting.56 Because the current studies failed to include pharmacokinetic data as an outcome parameter, failed to quantitate clinical assessment prior to and following the intervention, and failed to include a sufficiently large number of seriously or potentially lethal overdoses, further studies are needed to address these limitations.
Observation Alone for “Minimally Symptomatic” Patients Foulke and colleagues, in a group of “minimally symptomatic” patients presenting to the emergency room, compared ipecac to no intervention.57 The ipecactreated group stayed in the emergency room for a longer period of time and had a higher complication rate than did the group of patients in whom no intervention was instituted. Merigian and associates also studied “minimally symptomatic” patients treated with either charcoal or observation alone, using the outcome parameters previously noted, and found no benefit of charcoal over no treatment.55 These results thus went one step further to suggest that in the asymptomatic or “minimally symptomatic” patient presenting to the emergency room, neither ipecac nor charcoal was superior to observation alone. Clearly, however, these are very preliminary studies requiring confirmation in larger populations of overdosed patients.
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Implications
Where does this information leave the pediatrician? 1. In the symptomatic but alert child with a minor ingestion presenting to the emergency room, activated charcoal alone (for drugs adsorbed by activated charcoal) by mouth appears to be sufficient for gastrointestinal decontamination. 2. For the obtunded or comatose child with a potentially serious overdose, lavage followed by activated charcoal via an orogastric or nasogastric tube should be used within 1 to 2 hours after ingestion (or longer in the case of sustained-release drugs, gastric concretions, or delayed gastric emptying). Repetitive dosing of activated charcoal should be used when indicated by the substance ingested. 3. For the asymptomatic child with a minimal amount ingested in the emergency room setting, there is now initial information to suggest that relatively little is gained by any removal procedure. Clearly, careful assessment for a sufficiently long period of time, however, is absolutely necessary. The asymptomatic patient presenting early may in fact have ingested a very large overdose of a toxic substance or may not be forthcoming with a reliable history.56 In these instances, charcoal should be used. 4. For the overdosed patient in the home setting, compliance with the use of charcoal remains problematic. No study .has compared ipecac-induced emesis to observation alone in the home setting, and until that study is carried out, ipecac, as recommended by poison centers or pediatricians, is the logical approach.
Advances in the Use of DMSA for Lead Poisoning The recent Food and Drug Administration (FDA) approval of the oral chelator 2,3-dimercaptosuccinic acid (DMSA) represents an important advance in medical toxicology. Because it appears at a time when concern about exposure to environmental toxins, particularly heavy metals, is growing, it appears that DMSA will be the answer to a much-needed oral treatment for many heavy-metal intoxications in patients of all ages.
identification
and History
DMSA is an oral congener of the chelator dimercaprol (British antilewisite, BAL). 58* 5g BAL was created during World War I as a treatment for exposure to the arsenical gas lewisite. It was quickly found to be an effective chelator of other heavy metals, including lead and mercury. For many years after its creation, BAL was considered a “universal antidote” for heavy-metal intoxications6’ BAL assumed importance in the treatment of childhood lead intoxication when it was found to be a necessary adjunct to (CaNa,edetate tetraacedic acid [EDTA]) in reducing the mortality of severe lead poisoning.5g*61 However, BAL had many undesirable properties, including a lack of stability in water (which required its parenteral administration in a peanut-oil vehicle) and a rate of adverse reactions as high as 50%.58* 5g DMSA was first synthesized in 1954. Its potential role as a heavy-metal chelator was first reported in 1965 but largely ignored.62l 63 Renewed interest in this agent appeared in the 1970s leading to several important studies of its safety and efficacy. Much of this research interest was directed to its role in the treat-
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ment of lead intoxication. Because gathering data proved DMSA to be safe and effective for plumbism, it became the first oral chelator approved for childhood plumbism in 1991.
Pharmacology DMSA is a dithiol derivative of succinic acid (the sulfur groups are responsible for its unpleasant, mercaptan odor). Sulfur is one of the several atoms that are able to act as ligands with polyvalent minerals, creating a stable covalent bond (usually in a heterocyclic configuration).58l 6o Available data indicate that DMSA is rapidly but incompletely absorbed. While pharmacokinetic information is incomplete, DMSA appears to have a small volume of distribution (~1 Ukg) and has an elimination half-life of approximately 48 hours. Studies with radiolabeled drug suggest primary renal elimination of the drug metabolites, with an additional portion excreted fecally. Only 10% of the drug is excreted in the unchanged form.62Z 64
Uses and Indications DMSA comes closest to providing all the properties desired of a chelator: (1) It can be administered orally, therefore, in an outpatient setting (convenient). (2) Its efficacy is broad enough for it to be effective for many types of heavy-metal intoxications. (3) Its specificity is narrow enough that it enhances the elimination of toxic heavy metals, with minimal chelation of essential minerals zinc, calcium, and copper. (3) The metal-DMSA complex is rapidly eliminated in the urine. (4) Based on existing data, it is safe and has a prolonged effect.63 DMSA, like BAL, has in vitro and in vivo efficacy with a number of heavy metals, including lead, arsenic, mercury, antimony, bismuth, cobalt, gold, and nickel. However, because controlled studies of its efficacy have only been performed with lead, its sole indication for use is plumbism (although there are several case series on the successful treatment of arsenic and mercury poisoning with DMSA).63* 65 The approval of DMSA for the treatment of childhood lead intoxication comes at a time of increasing concern about lead and a decrease in the tolerable levels of lead in children. Because compelling data have demonstrated the risk of biochemical and neurodevelopmental injury when blood lead levels exceed 10 pg/mL, there has been a redefinition of lead poisoning and a trend toward “zero tolerance” with childhood lead exposure. By current estimates, more than 15% of children less than 6 years old have a significant lead burden (as many as 50% of children in selected urban areas). Chelation therapy for lead intoxication has historically been unsatisfying, with available treatments (BAL, CaNa,EDTA, o-penicillamine) having a narrow therapeutic index and a significant rate of adverse effects. While DMSA has been heralded as the best treatment for plumbism, many lead specialists have argued the inappropriateness of widespread pharmacologic treatment of these children; instead they emphasize the importance of efforts to reduce the amount of lead in the environment.66-68 DMSA has an impressive record of efficacy in treating lead intoxication. In a controlled study of lead-poisoned children, Graziano and colleagues demonstrated that DMSA administered orally for 5 days will reduce blood lead levels by as much as 78%. This rate compared with a mean 47% reduction in blood lead level after a conventional 5day course of CaNa2EDTA.61-63v 6g These lead reductions are associated with prompt normalization of the biochemical indicators of plumbism, for example, delta-aminolevulinic acid dehydratase activity.
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Unlike EDTA, which appears to chelate lead from intracellular water only, DMSA appears capable of acting in both intracellular and extracellular spaces.62 A 5-day course of DMSA is consistently followed by a significant rebound in blood lead levels, the result of a redistribution of lead from bone and soft tissues.” The recommended dosing schedule is therefore to administer.DMSA for 14 additional days after the initial 5-day course. Multiple courses may be necessary, depending on the goals of treatmentm
Contraindications and Adverse Effects Under present guidelines, DMSA is contraindicated in patients with known hypersensitivity, and in children with preexisting renal or hepatic disease (although it has been used successfully in children with renal failure).64 Even though BAL is relatively contraindicated in children with glucose-6-phosphate dehydrogenase deficiency, because of its oxidizing potential, DMSA has been used in such children without untoward effects5*, 64 While DMSA has a broad safety profile, adverse drug reactions (ADRs) have been reported. Children appear to have a lower rate of ADRs than adults. Adverse effects are primarily gastrointestinal, where a rate of 12% has been reported, consisting primarily of gastrointestinal upset. Dermatologic eruptions have been reported at a rate of 3%. Liver function abnormalities, which are reported in up to 10% of adults, have been seen in 4% of children.64* 6g DMSA possesses no evidence of mutagenicity. However, in animal models, both fetotoxicity and teratogenicity have been observed. It is unknown whether DMSA crosses the placenta. Given these data, DMSA has been placed in pregnancy category C, indicating that animal studies have demonstrated adverse fetal effects but controlled data in pregnant women do not exist. The extent of the transmission of DMSA via breast milk is unknown.63, 64
lmplica tions Under current manufacturer’s recommendations, DMSA is indicated for blood lead levels higher than 45 mg/dL. Dosing consists of a 5-day course of 30 mg/ kg/day, given three times a day, followed immediately by a 14-day course of 20 mg/kg/day, given twice daily. Retreatment is advised if lead levels remain above 45 mg/dL; DMSA is not approved for use in children with blood lead levels less than this. As experience expands, DMSA will likely be approved for children with lower blood levels and for other poisons, for example, arsenic intoxication. DMSA has the potential to replace other heavy-metal antagonists in current use, not only for the treatment of lead intoxication but also for the treatment of poisoning by other metals. Appearing when the tolerance for lead in children is being lowered, the availability of such a safe oral therapy is exciting and is certain to open a new chapter in the treatment of lead and other heavy-metal intoxications.
References 1. Zuckerman B. Frank DA, Hingson R, et al: Effects of maternal marijuana and cocaine use on fetal growth. A/ Engl J Med 1989; 320:762-768. 2. Kharasch SJ, Glotzer D, Vinci R, et al: Unsuspected cocaine exposure in young children. Am J Dis Child 1991; 145204-206. 3. Shannon M, Lacouture PG, Roa J, et al: Cocaine exposure among children seen at a pediatric hospital. Pediatrics 1989; 83:337-342. 4. Johnson LD, O’Malley PM, Bachman GG: National Trends in Drug Use and Related Substances
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5. 6. 7. 8. 9. 10. 11, 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.
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