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AMBULATORY TREATMENT OF LEAD POISONING: REPORT OF 1,155 CASES Henrietta K. Sachs, M.D., Lorry A. Blanksma, Ph.D., Edward F. Murray, M.D., and Morgan J. O'Coimell, M.D From the Lead Poisoning Clinic, Chicago Board of Health ABSTRACT. Subjects with lead concentrations greater than 50 jxg per 100 ml whole blood were referred to a municipal lead poisoning clinic for evaluation. Chelating agents were administered when two blood lead levels were more than 50 fig, or calcium disodium edetate (EDTA) provocative test yielded over 1,000 fig/l of lead in ie urine in the succeeding 8 hours. Therapy was on an ambu latory basis. Patients with moderate encephalop athy were hospitalized. Intramuscular EDTA, oral penicillamine, or the two drugs in sequence were given to 582 patients in 1967 and to 573 patients in 1968. Clinical evidence of lead intoxication was present in 103 or 8.9$ of the 1,155 patients. Sev eral drug reactions to penicillamine were observed, but none to EDTA, and mortality dropped due to early detection and detoxification of subclinical Cases of lead poisoning. Pediatrics, 46:389, 1970, LEAD POISONING, AMBULATORY TREATMENT OF LEAD POISONING, EDTA IN TREATMENT OF LEAD POISONING, PENICILLAMINE IN SUBCLINICAL LEAD POISONING. t n October 1966, the Chicago Board of X Health initiated an extensive case-find ing program to detect incipient lead poison ing in an estimated 150,000 children at risk in high incidence neighborhoods.1 The test used was blood lead determination by atomic absorption spectroscopy. A special ized clinic was opened January 1, 1967 for the evaluation and treatment of all subjects found to have elevated blood lead values. The undertaking burgeoned far beyond what was anticipated. Nearly 4,000 children with lead values of 50 p.g per 100 ml of whole blood were detected during the first % years of the program and referred to the clinic for evaluation. Approximately 85% responded. An additional 1,500 children un der 5 years of age were admitted to the clinic for lead values between 40 and 49 fjt.g/100 ml. Satellite cases, physician refer rals, and a pica-free group with severe iron deficiency anemia, hematocrits ranging from 12% to 25% as discovered by the screening test, comprised another 200 patients. The structure of the clinic, guide lines used in case selection and treatment, and the results obtained are presented here., THE LEAD POISONING CLINIC The clinic occupies a wing in the Munici pal Contagious Disease Hospital. It is staffed by a pediatrician, two registered nurses, one licensed practical nurse, an aide, a clerk, and an x-ray technician. Dur ing the summer the staff is augmented by a second physician and practical nurse. The clinic is open Monday through Friday from 8:00 a m. to 4:00 p .m. Clinic appointments are made by the head nurse, who reaches die parent by tele phone whenever possible, by letter, through home visit by the neighborhood Urban Progress Center representative (UPC "rep*'), or the district health nurse. All val ues over 80 p.g are considered urgent and the parent is contacted immediately to de termine whether the child has symptomatic lead poisoning. When a parent is unable or refuses to bring the child to the clinic, she usually gives permission to the UPC "rep" (Received September 11,1969; accepted for publication April 23,1970,) Supported in part by Children and Youth Project 601, Children's Bureau, Social and Rehabilitation Service, U.S. Department of Health, Education and Welfare. M.J.O'C. was Commissioner of Health, City of Chicago. ADDRESS FOR REPRINTS: (H.K.S.) 182 La Pier Street, Glencoe, Illinois 60022. 389 -396 390 LEAD POISONING TABLE I Dir e c t io n s f o r Th e r a p y Blood Lead Values Disposition 60 /t*g or more in two samples 50 to 60 /tg in two samples 40 to 50 fig in two samples if no longer exposed to lead hazard if exposure continues and EDTA provocative test is negative EDTA provocative test is positive Intramuscular EDTA Oral penicillamine Discharge Retest every 8 months Oral penicillamine to escort the child to the clinic for evalua tion and treatment. Even if successive ini tial appointments were broken, eventually 90$ of the children with lead values over 60 [xg were brought to the clinic. History, physical examination, and labo ratory studies are completed at the initial visit. Five milliliters of venous blood are again submitted to the City Clinical Labora tory where lead content, hematocrit, G6PD, and hemoglobin electrophoresis are deter mined routinely on every sample. Urine is examined for sugar, protein, and cells. Urin alysis is repeated at every visit while the pa tient is receiving chelating agents. Roent genograms are taken of the abdomen and wrists, and the wet films are interpreted to the parents. If lead values are between 40 and 60 {Ag, a provocative test is performed with cal cium disodium edetate (EDTA) based on the therapeutic dose of 50 mg/kg. A frac tion of all urine excreted in the succeeding 8 hours is analyzed for lead content. Values over 1,000 p.g/1 are considered abnormal/ Mothers are provided with perineal bags for children not toilet trained to assist in collection of specimens. The aide instructs in proper application of perineal bags. All patients are treated on an ambulatory basis, including those with mild encepha lopathy. Sick children have 24 hour access to the clinic physician by using a tele phone. Patient observation varies from a mini mum of 3 months to several years. The child is discharged when blood lead has fallen below 50 jAg on two consecutive occa sions at an interval of at least 1 month, and when his environmental hazard has been corrected. If his blood lead does not drop at any one visit as anticipated, he is recalled for an x-ray of the abdomen to check for radiopacities suggestive of recent lead in gestion. INDICATIONS FOR THERAPy An empirical concept of asymptomatic lead intoxication was evolved during the initial months of the clinics operation. In creased exposure was assigned a value of 40 jAg, and intoxication was given a value of 50 jAg. Directions for therapy were estab lished (Table I). Date 5-11 5-16 (1-5 7-11 8-8 9-10 10-28 TABLE II ' Tr e a t me n t or Le a d Po is o n in g w it h Pe n ic il l a min e {Ca s e 1) Blood Lead i}ig/100 ml) 67 58 Hematocrit (%) 28 27 64 32 57 37 39 39 40 38 32 Comments Treatment screening value x-ray: abdomen negative inetaphyses 2 mm lines recalled for chelate therapy landlord repaired apartment bottle feedings discontinued iron 15 mg t.i.d. PNC 125 mg b.i.d. for 28 days PNC 125 mg b.i.d. for 28 days PNC 125 mg b.i.d. for 28 days PNC 125 mg b.i.d. for 28 days discharged DUP050058566 tfjM Date 6-15 6-19 6-20 7-8 7-5 7-17 7-30 8-22 10-8 11-8 ARTICLES TABLE III Tr e at me n t o p Le a d Po is o n in g w it h EDTA (Ca s e 2} 391 Blood Lead (jig/100 ml) 115 130 158 80 24 34 48 46 Hematocrit <%) Comments 29 screening value x-ray: abdomen filled with particles 3 mm line at metaphyses urine: 5,450/tg/l x-ray : many opacities in intestine landlord repaired apartment pica has ceased 33 failed subsequent appointments Treatment EDTA for 5 days fleet enema iron 15 mg t.i.d. EDTA for 5 days fleet enema EDTA continued EDTA for 5 days THERAPEUTIC REGIME Two chelating agents are employed, EDTA and penicillamine. Selection of the drug depends on the initial lead concentra tion. The drugs are not used concurrently. EDTA is given in 5-day courses, 50 mg/ kg, administered once daily. It is injected into the anterior thigh muscles, with 1 ml of 1% procaine added to the syringe. Urine is collected for 8 hours after each injection, and a 2 oz aliquot is submitted the follow ing morning for lead analysis. Blood lead is determined the day treatment is initiated and again 1 week after the fifth injection. The 5-day course is repeated until levels drop to 60 to 70 p.g/100 ml. Blood is tested every clinic visit, with the exception of the second through fifth day of a course of EDTA. PNC is given orally in 4-week courses. The dose is 125 mg, two Or three times daily, averaging 20 to 25 mg/kg. One-half the contents of a 250 mg capsule is offered in a palatable medium, such as juice, "pop," or TABLE IV Tr e a t me n t o f Le a d Po is o n in g w it h EDTA Fo l l o w ed b y Pe n ic il l a min e (Ca s e 3) Date 6-25 6-28 6-29 7-11 7-12 7-25 9-i 10-10 12-13 Blood Lead (fjtg/100 nit) 140 94 69 64 40 27 24 Hematocrit (%) Comments Treatment Value obtained at referring hospital 27 x-ray: several particles in abdomen bottle feedings discontinued 1 mm line at metaphyses iron 15 mg t.i.d.. fleet enema EDTA for 5 days urine: 17,600 jug/1 EDTA for 5 days urine: 12,800 jtg/1 37 apartment repaired PNC 125 mg b.i.d. for 28 days PNC 125 mg b.i.d. for 28 days PNC 125 mg b.i.d. for 28 days 85 discharged ''Wrmmw. DUP050058567 LEAD POISONING TABLE V In it ia l Bl o o d Le a d Le v e l s o p Pa t ie n t s Tr e at e d in 1967 a s Co mp ar ed t o 1968 to 30 mg elemental iron three times daily, elimination of bottle feedings, and decrease , in milk to 1 pint daily. Year 40-69 jig 70-99 fig 100-219 fig Total 1967 1968 Total 210 883 593 292 165 457 80 582 25 573 105 1155 jelly. Blood is tested for lead after 4 weeks and the drug continued until the level re mains below 50 [ag for two consecutive months. When prolonged treatment is re quired, PNG is given for 3-month periods, followed by a medication-free interval of 1 month. Patients with high initial lead levels who receive EDTA may be transferred to PNG when lead values drop to 60 to 70 [Ag range. Dtmercaprol (BAL) is used only in pa tients requiring hospitalization for enceph alopathy. It is given as intramuscular injec tions, 2.5 mg/kg every 4 hours for 5 days and is used concurrently with EDTA, 75 mg/kg, given in divided doses over 24 hours. If opacities suggestive of lead are noted in the intestine on x-ray, the parent is given instructions to administer an enema packet (provided by the clinic) to the patient at home, EDTA is not withheld pending evac uation of the paint or plaster. Iron deficiency anemia is frequently en countered and is almost invariably associ ated with prolongation of bottle feedings beyond infancy. It is treated with oral iron concentrates, 0.6 Or 1.2 ml, equivalent to 15 CASE HISTORIES Because of lack of guide lines for use of PNC in children with lead intoxication, an empirical method was devised, as illustrated by Case 1. This was an anemic but otherwise asymptomatic 17month-old girl with a history of plaster ingestion. She drank five 8 oz bottles of milk daily. Labora tory findings and treatment are given in Table II. Delay in initiating deleading therapy was due to the mother's failure to keep earlier appointments. Case 2 represents treatment with EDTA alone (Table III). This was a 27-month-old girl who continued to eat plaster from the walls for 2 weeks after the initial visit, when the apartment was re paired by the landlord. She remained asympto matic even during the period of rising blood lead. Pica ceased a month after treatment began when the child learned to relate the painful injections to putting objects into her mouth. EDTA followed by PNC for several months was die therapeutic approach utilized for most patients with initial lead concentrations above 70 fig, Case 3 was- an 18-month-old boy referred from another hospital with a blood lead value of 140 fig. His twin sister's history paralleled his, although her lead concentration was only 86 jig, Both children ate crumbling plaster from the walls. They were "poor eaters," but drank six, 8 oz bottles of milk daily. Symptoms of lead poisoning were absent. Laboratory data and treatment are summarized in Table IV. RESULTS Comparison of Blood Lead Levels of Patients Treated in 1967 and 1968 The marked decline of lead values over 50 ptg in the screened population, from 8,5% in 1967 to 3.88 in 1968, was reflected TABLE VI Cl in ic a l Fin d in g s in 1,155 Pa t ie n t s Ja n u a r y 1,1967, t o De c emb e r 31,1968 Data 1967 1968 Total Percentage for 2 years Patients treated Pica for paint, piaster Metaphyseal lines Opaque material in gastrointestinal tract Urine lead 1,000 /ug/1 Symptoms of lead poisoning 582 458 459 205 258 71 573 1,155 100.0 443 901 78,0 494 953 82.5 202 407 35.2 297 555 48,0 32 103 8.9 \ DUP050058568 ARTICLES 393 in the lead values of patients treated with chelates (Table V). Comparison of blood val ues for the 2 years shows 372 (64%) of the patients had 70 j/g or more in 1967, in con trast to 190 ( 33%) in 1968, although the number treated was roughly the same in both years. In the range of greatest hazard-- between 100 and 220 (ig>-there were 80 pa tients (14%) in 1967 compared to 25 ( 4%) in 1968. Beginning August 1, 1967, more em phasis was placed on treating children with values between 50 and 60 y.g, thus account ing for the increase in this area in 1968. Seasonal Variation in Blood head Levels During the period of this study, 676 (58.5% ) of the patients were treated in the 4 months from June through September, and 479 (41,5%) were treated in the re maining 8 months of both years. There were 83 patients in the "off-season" in 1967 with lead values from 80 to 220 fig and 24 in 1968 with a range of 80 to 130 jig in the same period. The etiology of seasonal varia tion in blood lead levels remains obscure* Clinical Findings in 1,155 Patients Although blood lead values were lower in 1968 than in the previous year, there was a remarkable similarity in the number of children with pica and clinical findings in both years (Table VI). Pica was observed in 78% of the patients who had eaten paint, plaster, or putty. Radiopaque parti cles in the intestine, presenting a transitory clue to pica, were seen in 35% of the pa tients, as well as in many children whose tests were below the level requisite for che late therapy. Metaphyseal lines at the wrist and proxi mal femur, graded according to width in millimeters, were present in 82.5%; how ever, width of the line could not be corre lated with symptoms, elevation of blood lead, or reported period of ingestion. Lines less than 1 mm were considered as negative; those of I mm in association with other findings as positive; lines of 2 mm were con- 50-59 60-69 70-79 80-89 90-99100409 H0-U9 120429 130-09 V40-W9 150-09 160210 BLOOD LEAD LEVELS Oifl/lOOiwt BLOOD) Fig . I. Number of children observed to eat paint or plaster correlated with file number demonstrating abdominal radiopacities, at blood levels ranging from 50* ag to 210 fig. 394 tEAD POISONING TABLE VII Ma n if e s t a t io n s o f Le a d To x ic it y Ob s e r v e d in 108 Pa t ie n t s Symptom Instances blood lead than the one obtained in the screening study. Manifestations of Load Toxicity in 103 Patients Fatigue Stupor Ataxia Gastrointestinal Vomiting Irritability Drowsiness Total Symptoms of lead intoxication were en 2 countered in 103 (8.9%) of the 1,155 9 treated children (Table VII). There were 12 two manifestations of equal importance in 28 21 of those children. Drowsiness and vomit 83 ing was the most frequent combination. 88 124 Convulsions occurred in three of the screened patients whose lead values were over 200 (ig. They were hospitalized di rectly by the clinic pediatrician on being sidered as definite evidence of lead inges advised of the excessively high lead values. tion. These children were not seen at the clinic. Urine specimens containing at least 1,000 p.g/1 of lead were submitted by 555 of the 608 patients who received EDTA. Data on Urine lead for patients receiving PNC are not presented here because the number of dependable 24-hour collections was inade quate for meaningful evaluation. History of Pico Compared to Abdominal Opacities on X-ray Age Distribution Seventy-two percent of the patients were almost equally divided between i- and 2year-olds. Sixteen percent were 3-year-olds and 7.8% were 4-year-olds. An older sibling of 5 or 6 years occasionally followed the ex*" ample-of a younger one in picking plaster off the wall. Persistence of pica for paint and plaster was not observed in children Ingestion of paint or plaster was ob served in 78% of all patients, the incidence rising from 65% in the 50 to 59 -pig group to nearly 100% over llOjrg (Fig. 1). Like wise, radiographic evidence of ingestion older than 5% years, although several chil dren between age 5 and 7 had a residual lead burden from previous ingestion high enough to warrant chelate therapy (Table VIII). was noted at die initial visit of 17% in the 50 to 59 [i.g range, rising to 60% to 100% in 10 p.g increments over 110 jig. The presence of particles in the gut on the day of evalua tion was generally associated with a higher Humber of Patients Treated with Each Chelate Regime Each patient was treated by one of three chelate regimes: PNC, EDTA, or both used in sequence (Table IX). PNC was used as the sole chelating drug in 47% of the patients, TABLE VIII Ag e Dis t r ibu t io n o f 1,155 Pa t ien t s all of whom had a lead content under 70 {xg. EDTA alone was used in 13% of the pa tients. In 39% therapy was initiated with EDTA then continued with PNC after the Age (yr) im 1968 Total Percentage blood lead had decreased to the 60 to 70 fxg Under 1 i 1 2 0.2 range. 1 2 192 15 217 12 409 427 35.4 36.9 Complications Dye to Use of Chelates 3 102 83 185 16.0 There were no significant complications 4 48 42 90 7.8 from the use of EDTA. Drowsiness was 5 17 13 30 2.6 noted occasionally in the afternoon follow 6 and older 7 5 12 1.1 ing the initial one or two injections. This .'.^3 DUP050058570 W: ate ' 2 k' -A'i*' ARTICLES 395 condition apparently was not related to concentration of blood lead. Transient he maturia appearing in one specimen only was observed in six patients. No infections occurred at injection sites. A tender, non suppurative nodule developed in one child but disappeared in a few days. Reactions to penicillamine were few but tended to be more serious than to EDTA. Several patients experienced vomiting or diarrhea, although not simultaneously, but nearly all were able to resume the drug af ter a few days* interruption. About 0.5% developed pruritic urticaria. In two pa tients, the eruptions resembled erythema multiforme and erythema annulare and were accompanied by high fever. A third child had generalized angioedema without proteinuria. All children with dermatologic complications responded well to oral antihistaminics and withdrawal of the drug. Most PNC complications occurred in the first week or two of medication. However, one child entered another hospital with a 2week history of progressive edema after taking PNC for 3 months. Proteinuria was present and a diagnosis of nephrosis, possi bly due to PNG, was considered. She had a spontaneous diuresis shortly after entering the hospital and was discharged without a renal biopsy. Although chelation therapy was not with held while the gut was emptied of radio paque material, no aggravation of symptoms or increase in blood lead was noted. Febrile illness was not observed to produce an in crease in blood lead or to precipitate acute encephalopathy. Venous samples were obtained more than 20 times in some patients during the course of treatment, but no instance of thrombo phlebitis was encountered. Complications Due to Asymptomatic Lead Poisoning The effect of lead in producing mental retardation in asymptomatic patients has yet to be thoroughly evaluated. Delay in the appearance of speech beyond the third birthday and behavior problems were pres- TABLE IX Nu mb er o f Pa t ien t s Tr e at e d w it h Ea c h Ciie l a t e Re g ime Ckdate 1967 Penicillamine EDTA EDTA--Penicillamine 252 112 218 582 196S 295 42 236 573 Total 547 154 454 1,155 Percentage 47.4 13.3 30.3 100.0 ent in about \5% of the patients studied; however, some of these children were slow to achieve early developmental objectives before the onset of pica. No gross neurolog ical defects or nonfebrfle seizures devel oped in any patients up to the time of dis charge from the clinic. Several parents of seemingly "asymptomatic" patients re ported improvement in behavior and lan guage ability after a course of therapy. This indicates the difficulty in recognizing dete rioration in a chronic disease such as lead poisoning. Recurrence Recurrent ingestion, as established by history obtained from the mother, by repeat x-rays of the abdomen, and by secondary rises in blood lead levels, was observed in 3% of our patients. None developed symp toms of intoxication before treatment was reinstituted. CONCLUSION In die 6 years from I960 through 1965, during which time some screening for lead poisoning was carried out in the citys in fant welfare clinics utilizing coproporphyrinuria for case detection, 1,081 cases were reported with HO deaths.8 In 1966, when public health and volunteer workers canvassed the high-risk neighborhoods to aid in securing urine specimens,4 recorded cases rose to 320, with seven deaths.5 Fol lowing the introduction of blood lead test ing as the screening method late in 1966, there were 1,336 cases reported in the 2year period 1967 and 1968, with 17 deaths. The impact of the program became quite evident in 1969 when reported cases DUP050058571 LEAD POISONING REFERENCES 1. Blanksma, L., Sachs, H. K., Murray, E. F., and O'Connell, M. J.: Incidence of high blood lead levels in Chicago children. Ped iat r ic s , 44:661, 1969. 2. Whitaker, J. A., Austin, W., and Nelson, J, D.; Early detection of lead poisoning. Pe d iat r ic s , 29:384, 1962. 3. Christian, J. P., Celewycz, A. S., and Andelman, S. H.: Three year study of lead poisoning in Chicago. Amer. J. Public Health, 54:1241, 1964. Greengard, J., Zollar, L., and Sharifi, M.: Medi cal progress in the prevention of childhood lead intoxication. Illinois Med. J., 133:615, 1968* 5. Chicago Board of Health: Unpublished data. DUP050058572 V-*