Document omdod7e2zYDnGRpr412qNKEoX

594 / Chisolm tion of abnormal exposure provides an index of the period of time a patient will require careful medical supervision after exposure ends. Serial blood and urine lead determinations together with urine coproporphyrin (UCP) arid S-aminoIevulinic acid (ALA) measure ments provide the best index of soft tissue lead toxicity (3,11). Al though measurements of S-aminolevulinic acid dehydratase (ALAD) activity in vitro in hemolysatcs of blood and free erythrocyte protoporphyrin in peripheral blood can probably provide comparable information; they are not, at this writing, as well standardized as the other measurements. Administration of chelating agents rapidly reduces the lead content of soft tissues. The most severe clinical manifestation of intoxication is acute encephalopathy, which is more frequent in children than in adults, carries a significant mortality and results in severe permanent brain damage in at least 25 per cent of survivors. Since one of the main goals of therapy is to prevent injury to the central nervous system, it is axiomatic that treatment must be started before classic signs of increased intracranial pressure make the diagnosis of encephalop athy obvious. Accurate lead analyses may be difficult to obtain but are essential to proper treatment. Blood samples must be collected into lead-free equipment 'and analyzed bv a laboratory experienced in lead deter minations. Bisks with respect to the acute adverse effects of increased lead absorption may be estimated in terms of current blood lead concentrations as follows: a) >40 p.g Pb/100 g whole blood indicates undue lead exposure; b) 50-79 jug Pb/100 g indicates excessive absorp tion, is associated, in most instances, with metabolic evidence of im paired heme synthesis and may, in some instances, be associated with mild symptoms compatible with lead poisoning. Such cases require careful medical supervision and should be considered possible cases of plumbism, especially in anemic patients. Blood lead concentrations of more than SO p.g Pb/100 g whole blood indicate risks which in children are unacceptable; virtually all cases of severe acute lead poisoning, including those with, apute encephalopathy, are associated with blood lead concentrations of 100 fig Pb/100 g whole blood or greater. At blood lead concentrations of more than 80 fig Pb/100 g whole blood, symptoms may be absent, but onset of severe acute illness isunpredictable: CHILDHOOD LEAD INTOXICATION Lead poisoning in childhood should be approached, as a chronic disease because of the long-term high-dose type of exposure to which N 27045 DUP040007472 596 / Chisolm Table 1. Environmental Exposure of Young Children to Lead in Urban Housing Children with Residence No. of .children Abnormal urine* Phjnbhin No. % No. % Old housing New housing protect 801 .105 216 27 3-- 33 0 4.7 D * Concentration of both lead and coproporphyrin increased [Prom Origgs et at UO}] same household so that all preschool children should be tested for pltunbisni wherever an index case is found. Prospective screening programs are currently in operation in Chicago and New York. Recently, cases of severe lead poisoning have been traced to the con tamination of juices (and other acidic beverages) stored in improperly lead-glazed earthenware vessels. Prompt Diagnosis An indirect epidemiologic approach is essential for prompt clinical diagnosis since a history of pica often is not elicited at the first clinic visit. We ask the following questions: a) Does the child live in or visit a house built prior to World War II? (A list of high-risk addresses should be posted in all pediatric clinics to aid physicians table 2, Uncommon Nan-industrial Types of Potentially Hazardous Environmental Lead Exposure Children Adult: Children and adults Toys and child furniture (beware of items repainted by relatives] Lead toys and baubles* Lead nipple shields bootleg -whiskey Ceramic and pottery glazing in home 'Home battery manufacturing Lead dust in shooting gallery (attendant at risk) Artist's paint pigments jhand- mixing) Improperly lead-glazed dishware,and cookware Soft well-water conveyed in lead pipes Ashes and fumes .of painted wood and battery casings used for fuel in ..stoves .and fireplaces * [Plastic beads, necklaces and jewelry coated with lead fa simulate a pearl appearance, .are sources, often unnoticed,--Ed.] \ D UP040007473 598 / Chisolm Table .3. Laborato-y Determingtions Required for Diagnosis of lead Intoxication in Children tetf Technical factors Interpretation EMERGENCY TESTS FOR RAPID PRESUMPTIVE DIAGNOSIS Qualitative urinary $ee Appendix p for Intense orange-red fluorescence {-j--f--f~ or coproporphyrin procedure; peroxide- 4--often associated with blood lead (UCP) fast 12) free ether required- > 100 jsg Pb/100 g whole blood and, test urine within 10 -therefore, is indication for immediate min < afiter voiding hospitalization and chelation therapy in symptomatic children even if all other pre sumptive tests negative-test may give misleading negative result! initially in moribund patients and severely iron-de pleted children not regenerating heme-- moribund patients usually have glycosuria and other urine: abnormalities X-rays Flat plate of Use KUB technique; look Abdominal fiat plate positive for radiopaque abdomen carefully in rectosig^ material in approx. 50% of symptomatic moid area for-radio young children; rarely positive in adults paque Rees when rest of intestine appears negative PA views .of wrists Must be differentiated Interpret bone films with respect to child's age: and knees -from growth arrest a) <2 yrs "lead Tines'* frequently .absent lines: "lead tines" at in symptomatic cases metqphyse* qrebroad b) 2-5 yr: "lead lines" usually present {>2 mm] continuous and may show "Seasonal banding" bands of increased c) >5 yrs "lead lines" rarely prominent. density# whereas Width of "lead lines" reflect duration of in growth arrest tines ap creased load absorption but is unrelated to pear as multiple nar symptoms row discrete tines; study films under bright tight Hemoglobin# hematocrit, reticulocyte count, smear for morphology (basophilic stippled cell count) Basophilic stippled cell count requires specialized technique not usually available in general hospital laboratories Hb Usually <10 g; findings os in untreated irpn deficiency states except reticulocytes often Increased; basophitic stippled ceil .counts in peripheral blood of .children too variable to bo helpful but basophilic stippling of normoblasts in bone marrow .smears uniformly increased ( >5Q%] in plumbism in children .and adults-hematocrit required for interpretation of blood lead since 90% of lead in whole blood is attached to red blood cell surface, correct blood lead data for very low hematocrits 600 / Chisolm case The rate of intravenous infusion is adjusted hourly until that rate is found which will maintain the rate of urine flow within basal metabolic limits {0.35 to 0.5 ml urine secreted/calorie metabolized/24 hr). This is equivalent to a daily urine output of 350 to 500 ml/sq m/24 hr. Children with encephalopathy behave as though their secretion of antidiuretic hormone is inappropriate; the above technique is essen tial to avoid excessive fluid administration which can further increase cerebral edema. All oral intake is prohibited until the child is greatly improved. Body temperature is maintained at normal but not hypothermic levels by using a cooled oxygen tent, supplemented by cooling blankets when necessaiy. Oxygen is administered. For the quick control of seizures, Valium is effective. In patients with acute encephalopathy, control can be maintained thereafter dur ing the first few days of treatment with repeated doses of paraldehyde. Barbiturates and diphenylhydantoin are better reserved for long-term anticonvulsant use. During the acute phase, one should not await frank seizures. Better control can be achieved if doses of paraldehyde are given whenever there is a significant increase in muscle tone or muscle twitching. Administration of paraldehyde should overlap the institution, of long-term anticonvulsant therapy with barbiturates in order to prevent seizures from recurring during the early convalescent phase. Barbiturates should be avoided during the first few days be cause severely depressEin( amounts are often needed' and even then may be ineffectual. Chelation Therapy After uririe flow is established, which should require 2 to 3 hours at most, chelation therapy is started with .2,3-dimercaptopropanoI (BAL) and edathamil calcium disodium {CaEDTA, calcium disodium versenate) in combination according to the dosage schedule shown in Table 4. This combination is used in all symptomatic patients. In cases of acute encephalopathy, the usual'5-day course may be extended to 7 days if great clinical improvement has not occurred by the fourth day. In symptomatic patients without encephalopathy, who show a quick and dramatic clinical response, and in those asymptomatic patients with whole blood lead concentrations in the range of 100-200 p.g Pb/lOOj g, BAL may be discontinued after 2 to 3 days and the dosage I,cjf CaEDTA may be reduced to 50 mg/kg/day, in divided doses, its either two 6-botir intravenous irtfu- 602 / Chisolm Table 5. Choice of Chelating Agents Based on Symptomatology and Blood Lead Concentration OM/cqf presentation Chelating agent* Comment A. CHILDREN 1. Ail symptomatic cases . BAl-CaEDTA (IM) :a. Acute encephalopathy BAL-CoEDTA (IM) b. Intoxication without encephalopathy BAl-CaffiTA(IM) 2. Asymptomatic cases .a. Bipod lead >100 pg Pb/IQGg whole blood <100pgl*b/)00g whole blood BAl-CaEDTA (IM) CaEDTA pnly (IM) Any symptoms in children call for at least one 5-day course First course 5^7 days; give second 5-day course if blood lead > 80 pg Pb/TOQ g whole blood 14-2.1 days after first course; transfer patient to convalescent hospital far .3*-.6 mo course of ora! D-p.ehiciildmine First .course,5 days only; indication for secand co.urse.sGme os above; .follow with oral penicillamine {3--5 mo) if .blood lead >60 pg Pb/1.00 g whole blood and long bane X-rays show prominent '`lead lines*' Choice far first course indicated by blood lead; follow with oral p-penicillamine as above (section lb) .3. Long-term followup care .a> Intercurrent Infection, demineralizing dis orders b. Recurrent ingestion c. long-term chelation B. ADULTS I. Symptomatic cases a* Acute encephalopathy b Abdominal syndromes (muscle pain, weak ness, colic) (continued) CaEDTA only (IM) BAl-CaEDTA (IM) or CaEDTA only (IM) D-Penitittamine* (oral) BAl-CaEDTA (IM) BAL-CaEDTA (IM) CaEDTA only (IV) Oive ;3-day course whenever ..significant increase in U.C.P and/or ALA occurs even ifinc increase in blood lead occurs Choice same as for asymptomatic cases above {.section 2a) Do not use any chelating agent.orally if risk of residual.lead in bowel Use oral penicillamine under conditions preclud ing risk of hazardous environmental lead exposure for followup after initial therapy with parenteral BAL-.CaEDTA or CaEDTA only Same as for children Course of 3--5 days followed by oral P- penicillamine until urine lead <500 pg Pb/24 hr or 2 mo, whichever is less Use if pgtienf intolerant of BAL Do not infuse total daily dose in less than 6 hr 604 / Chisolm enhances the absorption of lead from the gut; on the contrary, there is evidence, in animals, that BAL enhances the excretion of lead through the intestinal tract. Neurosurgical operations for the relief of increased intracranial pressure are contraindicated. There is no decisive evidence concerning the effectiveness of steroids in com batting cerebral edema in lead encephalopathy. In view of evidence in animals which shows that steroids enhance the renal toxicity of CaEDTA, these compounds are not used by the author. Repeated doses of mannitol appear safest and most efficacious for the relief of persistent cerebral edema, as indicated by persistent deep unconsciousness. Asymptomatic Children Asymptomatic children should be separated from their environ mental lead sources promptly. Usually this entails brief hospitalization for diagnostic study, preliminary evaluation of environmental lead sources, and protection of the child until temporary safe residence is found. The laboratory tests in Table 3 are performed and chelation therapy is given according to the doses in Table 4 and the indications in Table 5. If the UGP test gives a 3-4-f- result we do not await the results of blood lead analysis but begin BAL-CaEDTA immediately. This policy is based upon past clinical experience; the condition of yopng children with plumbism can deteriorate precipitously even in the hospital It is safer to start chelation therapy promptly and then stop if blood lead determinations later prove the initial diagnosis in eiTor. Recently we have been using penicillamine on an investigational basis; it has been administered orally for periods of 1-6 months to 32 children without serious side-effects. The treatment is started in the hospital and completed in a convalescent home or inspected leadfree temporary foster home. It is possible with this drug to maintain blood lead concentration within the normal range during early convalescence. Precautions "with Chelating Agents The main toxic effects of BAL are nausea and vomiting which can be avoided if oral intake is withheld. Due to the formation of a toxic BAL-iron complex medicinal iron may not be given concurrently. CaEDTA is not metabolized in the body; virtually all of this com- DUP040007477 600 / Chisolm procedures used by the Baltimore City Health Department for detec tion (12) and eradication (14) of hazardous lead sources in the home are published elsewhere. The family is evaluated with respect to the need for psychiatric consultation to assist in bringing the child's pica under control. If the home is too deteriorated to permit adequate repair, the family is assisted by the medical social worker to find new safe housing. Modern public housing areas are preferred. In no instance should affected children be allowed to remain in die home while the necessary repair work is in progress. The procedures necessary to find a safe location for the child often require several weeks. During this time it is our policy to transfer the patient to a convalescent home. Children recovering from acute encephalopathy usually exhibit severe behavioral abnormalities during the first 3 to 6 months of con valescence. It is our practice to transfer all such patients to a con valescent children's home and to administer oral penicillamine during this period. These institutions usually have an active child life pro gram which can be most beneficial in terminating the child's pica and in revealing new areas of interest to him. Careful follow-up is continued after the child returns home. We encourage enrollment in a nursery school or 'Head Start" program to provide continued stimulation for the child. Many of the mothers of children with plumbism show multiple maternal inadequacies and require constant support. During the first year after acute intoxication intercurrent infections may be associated with biochemical evidences of increased soft tissue lead toxicity (increased UCP and ALA) (3) requiring chelation therapy (Table 5). Long-term administration of penicillamine on an outpatient basis cannot be recommended at present. Serial blood leads should be obtained at bimonthly intervals or more frequently as indicated. Values in excess 60 /ig Pb/100 g whole bldod during convalescence call for repeat courses of CaEDTA or penicillamine in the hospital. Values >100 fig Pb/100 g whole blood alnios't certainly indicate recurrent lead ingestion which calls for review of the psychodynamic aspects of the case and recheck of environmental lead sources. The families at greatest risk move with the greatest frequency. This close surveillance should be main tained until blood lead returns to and remains within the normal range (15-40 fig Pb/100 g whole blood). Phenobarbital and/or diphenylhvdantcin (Dilantin) are adequate for the control of seizures that follow lead encephalopathy. Recurrence of seizures - without re current lead ingestion is usually indicative of a lapse m anticonvulsant medication. Both seizures and behavioral disturbances tend to abate 608 / Chisolm Table 6. laboratory Tests Used in Industrial Medicine to Monitor Occupational Exposure to Inorganic lead .lead workers Genera/ Increased Dangerous population absorption absorpt/on Test (nonexposed) (worker healthy) (may bo symptomatic) Blood lead (fig Pb/.lOO g whole blood) Urine lea.d| 0*9 Pb/liter) Hemoglobin (g/1Q0 ml whole blood) Urine coproporphyrin* {^g/literj Qualitative testf Urine*} S-aminolevulmic acid (mg/Gter) <40 <80 >13 <250 0 to <4 55-80 <150 >13 <500 +++ <13 >80 >200 <13 >800 ++++ >19 * Based oh analysis of overnight urine {first morning voiding), but same data applicable to 24-hour urine collections which are preferable. f technique of Benson and Chisolm described in this article (2) % Method .of Mauzeralf and Qrarrick [J Biol Chen; 219:4.35, 1956); subtract 2 mg/liter from each ALA value if method of Uraf.a and Oranick (J Biol Chem 238:811, 1963} used. in UCP so that values <800 /xg UCP/24 hr cannot be considered diagnostic of plumbism (11), Table 7 shows pyrrole excretion patterns in diseases sometimes confused with plumbism. The combination of increased ALA and UCP is specific for. pliimhrsm (11), Findings Table 7. Patterns of Increased Pyrrole Excretion in Urine of Acute Symptomatic Patients* Pyrroles Disease ALA PBGf UUP UCP lead intoxication Acute intermittent porphyria Acute hepatitis (toxic and infectious types) Acute alcoholism -b++ d--i--1--h 0 0 o ++++ 0 0 + to ++++ 0 i +++ 4- to 4-4-4" + to +++ 4 to 4--b4 * 0 := Normal; -f- to |--f- = degree of increase; ALA == 5-aminolevulinic add; PEG = porphobilinogen; UUP = urine uroporphyrin; UCP = urine co'proporphyrin f Qualitative WaIson-Sdiwartz test for PBG . DUP040007479 610 / Chisolm from ail industrial operations. As .control procedures improve it is likely tliat acceptable limits of "safe" occupational exposure {Table 6) will be lowered (16). The presence of chronic renal, bone of other metabolic diseases are indications for terminating further occu pational exposure to lead. Upon termination of exposure, medical followup should be continued in all patients for a period of time equivalent to twice the duration of abnormal exposure. Chelating agents should not be administered orally in the presence of continued, hazardous exposure. Oral EDTA increases the absorption of lead from the intestine. Comparable data for penicillamine are not available. Intoxication Due to Organic Lead Compounds Intoxication due to tetraethyl lead and tetramethyl lead presents a special problem (15). Exposure is limited entirely to the manu facture, transport, and handling of these compounds in the petroleum industry up to the point where the concentrated material is mixed into gasoline as an antiknock additive. Cleaning and repairing of tanks used for storage of leaded gasoline may also be hazardous. The number of workers at risk is limited. Illness begins acutely with insomnia, wild and terrifying dreams, emotional instability and hyper activity, and may progress to frank toxic psychosis. The hematologic abnormalities of inorganic lead poisoning are not found. Urinary lead excretion is very elevated but blood lead is only slightly high. No specific therapy is available. Chelating agents are not used. Heavy and prolonged sedation with short-acting barbiturates in hospital provide the most effective therapy available. Fluid and electrolyte balance must be carefully maintained and may be difficult due to the patient's hyperactivity. Convalescence may be prolonged and punctuated by recurrence of irrational behavior. The disease carries a mortality rate of approximately 20 per cent. References 1. AMA Co u n c il o n Dr u g s ; Copper chelating agent, penicillamine {Cuprimine). JAMA 189:158,1964 2. Ben s o n PF, Ch is o l m JJ Jr : A reliable qualitative urine copro porphyria test for lead intoxication in young children. J Pediat 56:759, I960 3. Ch is o l m JJ Jr : Disturbances in the biosynthesis of heme in lead intoxication. J Pediat 64:174, 1964 4. Idem: The iase of chelating agents in the treatment of aeute and chronic lead intoxication in childhood. J Pediat 73:1, I960 DUP04Q007480 Lead Poisoning / 611 5. Co f f in R, Ph il l ip s JL, St apes WI, Spec t c r S: Treatment of lead encephalopathy in children. J Pediat 69:198, ,1966 6. Emmer s o n BT: Chronic lead nephropathy: the diagnostic use of calcium EDTA and the association with gout. Australian Aim Med 12:310, 1963 . 7. Fo r e man H, Fin n ec an C, Lu s h bau g h CC: Nephrotoxic hazard from uncontrolled edathamil calcium-disodium therapy. JAMA 160:1042, 1956 8. Fo r eman H: Toxic side effects of ethylenediaminetetraacetic acid. J Chron Dis 16:319, 1963 9. Go l d ber g A, Smit h JA, Lo c h iiead AC: Treatment of lead-poisoning with oral penicillamine. Brit Med J 1:1270, 1963 10. Gr ig g s RC, Su n s h in e I, Ne w il l VA, Ne w t o n BW, Bu c h a n an S, Ras c ii CA: Environmental factors in childhood lead poisoning JAMA 187:703, 1964 11. Haeg er -Ar o n s en B: Studies on urinary excretion of aminolevulinic acid and other heme precursors in lead workers and lead-intoxicated rabbits. Scand J Clin Lab Invest 12:Suppl 47:1, I960 12. Kapl an E, Sh au l l RS: Determination of lead in paint scrapings as an aid in the control of lead paint poisoning in young children. Amer j Public Health 51:64, 196 L 13. Keh o e R4.: Metabolism of lead in man in health and disease {The Harben Lectures, 1960). J Roy Inst Public Health 24:81, 101, 129, 177, 1961 *" ` 14. Sc h u c k eh GW, Va il EH, Ke l l ey EB, Ka pl a n E:: Prevention of lead paint poisoning among Baltimore children. Public Health Rep (Wash) 80:969, 1965 15. Sy mpo s iu m o n Lead . Arch Environ Health 8:199-354, 1964 16. Sel an d er S, Cr amer K: Interrelationships between lead in blood, lead in urine, and ALA in urine during lead work. Brit J Indust Med 27:28, 1970