Preventing Lead Poisoning in Young Children: Chapter 7

• Table of Contents
• Chapter 1. Introduction
• Chapter 2. Background
• Chapter 3. Sources and Pathways of Lead Exposure
• Chapter 4. The Role of the Pediatric Health-Care Provider
• Chapter 5. The Role of State and Local Public Agencies
• Chapter 6. Screening
• Chapter 7. Diagnostic Evaluation and Medical Management of Children with Blood Lead Levels > or = to 20 µg/dL
  • Summary
  • Symptoms of Lead Poisoning
  • Evaluation of the Child with a Blood Lead Level > or = to 20 µg/dL
  • Pharmacology of Chelating Agents
  • Treatment Guidelines for Children with Blood Lead Levels > or = to 20 µg/dL
  • Post-chelation Followup
  • Research Areas and Future Trends in the Management of Childhood Lead Poisoning
  • References
• Chapter 8. Management of Lead Hazards in the Environment of the Individual Child
• Chapter 9. Management of Lead Hazards in the Community
• Appendix I. Capillary Sampling Protocol
• Appendix II. Summary for the Pediatric Health-Care Provider
• Tables
• Figures

Chapter 7. Diagnostic Evaluation and Medical Management of Children with Blood Lead Levels > or = to 20 µg/dL

Summary

Children with blood lead levels between 10 µg/dL and 19 µg/dL and their siblings need followup and repeat screening as described in previous Chapters. They do not, however, need medical evaluation as described in this Chapter.

The cornerstones of clinical management are careful clinical and laboratory surveillance of the child, medical treatment when indicated, and eradication of controllable sources of environmental lead. The most important factor in case management is to reduce the child's exposure to lead.

All children with confirmed venous blood lead levels > or = to 20 µg/dL require medical evaluation. The urgency of further medical evaluation depends on the blood lead level and whether symptoms are present.

The decision to institute medical management should virtually always be made on the basis of a venous blood lead measurement. No other screening test can be considered diagnostic. If the first evaluation was made on capillary blood, a confirmatory venous blood lead level must be done. Even if the first diagnostic measurement was on venous blood, it is preferable to retest before starting chelation therapy. For children with blood lead levels > or = to 70 µg/dL or clinical symptoms of lead poisoning, chelation should not be postponed while awaiting results of the repeat test.

Symptoms of Lead Poisoning

Symptoms of lead poisoning in a child with an elevated blood lead level constitute a medical emergency, and the child should be hospitalized. Symptoms, which can mimic several other pediatric disorders, must be looked for so they are not missed (Piomelli et al.,1984).

Acute lead encephalopathy is characterized by some or all of these symptoms: coma, seizures, bizarre behavior, ataxia, apathy, incoordination, vomiting, alteration in the state of consciousness, and subtle loss of recently acquired skills. Any one or a mixture of these symptoms, associated with an elevated blood lead level, is an acute medical emergency. Lead encephalopathy is almost always associated with a blood lead level exceeding 100 µg/dL, although, occasionally, it has been reported at blood lead levels as low as 70 µg/dL. Even when identified and promptly treated, severe and permanent brain damage may result in 70%-80% of children with lead encephalopathy (Perlstein and Attala, 1966). Children with symptomatic lead poisoning with or without encephalopathy represent an acute medical emergency. The possibility of lead encephaliopathy should be considered in the differential diagnosis of children presenting with coma and convulsions of unknown etiology.

Except for coma and seizures, symptomatic lead poisoning without encephalopathy is characterized by symptoms similar to those of lead encephalopathy. Symptomatic lead poisoning without encephalopathy is characterized by one or a combination of these symptoms: decrease in play activity, lethargy, anorexia, sporadic vomiting, intermittent abdominal pain, and constipation. These symptoms are usually associated with a blood lead levels of at least 70 µg/dL, although occasionally cases have been associated with levels as low as 50 µg/dL. If the blood lead level is below 50 µg/dL, other causes of the symptoms should be sought. Since acute lead encephalopathy may develop in any symptomatic child, treatment and supportive measures must be started immediately on an emergency basis.

Evaluation of the Child with a Blood Lead Level > or = to 20 µg/dL

History and Physical Examination

A child with a blood lead level > or = to 20 µg/dL should have a pediatric evaluation, whether or not symptoms are present.

Special attention should be given to:

1. A detailed history, including the presence or absence of clinical symptoms, child's mouthing activities, the existence of pica, nutritional status (especially iron and calcium intake), dietary habits, family history of lead poisoning, potential sources of lead exposure (including exposure due to home renovation), and previous blood lead measurements.
2. Detailed environmental and occupational histories of adults in the household or other places the child spends a lot of time.
3. The physical examination, with particular attention to the neurologic examination and psychosocial and language development. A neurobehavioral assessment may be useful in children receiving chelation therapy both at the time of diagnosis and as the child approaches school age. Findings of language delay or other problems can prompt referral to appropriate programs.
4. Evaluation of iron status using measurement of iron and total iron binding capacity or of ferritin.

Iron Status and Special Tests

1. Tests for Iron Deficiency
   Because iron deficiency can enhance lead absorption and toxicity and often coexists with it, all children with blood lead levels > or = to 20 µg/dL should be tested for iron deficiency. Measurements of hemoglobin, hematocrit, and reticulocyte are not adequately sensitive, and erythrocyte Protoporphyrin (EP) is not specific enough to diagnose iron deficiency (although EP can be used to screen for iron deficiency).

   Serum iron and iron binding capacity (transferrin saturation) and ferritin are the most sensitive indicators of iron status. An abnormally low ratio of serum iron to iron binding capacity (transferrin saturation) of 0.2 is consistent with iron deficiency. The serum ferritin level, however, is the most definitive and accurate indication of overall iron status, although it is an acute phase reactant and may be falsely elevated in sick children; a value < or = to 12 µg/dL indicates iron deficiency. Although all iron deficient children should receive treatment for this condition, the treatment should not be started until after chelation is completed in children receiving dimercaprol (BAL).

2. EP Level
   An elevated EP level indicates impairment of the heme biosynthetic pathway. EP levels are sensitive screening tests for iron deficiency, and iron status should be assessed in any child with an elevated EP level (that is, > or = to 35 µg/dL when standardized using 241 L cm-1 mmol-1, > or = to 28 µg/dL when standardized using 297 L cm-1 mmol-1, or > or = to 70 µmol/mol when measured in µmol/mol units).

   Because EP levels take about 2 weeks to increase, EP levels may provide an indication of the duration of lead exposure (Chisolm, 1982; Chisolm, personal communication). Similarly, monitoring the EP level after medical and environmental interventions for poisoned children may be useful. If exposure to lead has ceased, EP values elevated because of lead poisoning decline slowly over several weeks or months (Piomelli et al., 1984). A progressive decline in EP concentrations indicates that combined medical and environmental case management is proceeding efficaciously.

3. Edetate Disodium Calcium (CaNa₂EDTA) Provocative Chelation Test
   The mobilization test is used to determine whether a child with an initial confirmatory blood lead level of 25 to 44 µg/dL will respond to chelation therapy with a brisk lead diuresis (Piomelli et al., 1984; Markowitz and Rosen, 1991). Because of the cost and staff time needed for quantitative urine collection, this test is used only in selected medical centers where large numbers of lead-poisoned children are treated. Children whose blood lead levels are > or = to 45 µg/dL should not receive a provocative chelation test; they should be referred for appropriate chelation therapy immediately.

   The outcome of the provocative chelation test is determined not by a decrease in the blood lead level but by the amount of lead excreted per dose of CaNa₂EDTA given. This ratio correlates well with blood lead levels. In one study, almost all children with blood lead levels 45 µg/dL had positive provocative tests, 76% of the children with blood lead levels 35 to 44 µg/dL had positive test results, and 35% of the children with blood lead levels 25 to 34 µg/dL had positive test results (Markowitz and Rosen, 1991). This test should not be done until the child is iron replete, since iron status may affect the outcome of the test (Markowitz et al., 1990).

   Conducting a CaNa₂EDTA Provocative Chelation test. First, a repeated baseline blood lead level must be obtained. The patient is asked to empty the bladder, and then CaNa₂EDTA is administered at a dose of 500 mg/m² in 5% dextrose infused over 1 hour. (A somewhat painful but practical alternative is to administer intramuscularly the same dose mixed with procaine so that the final concentration of procaine is 0.5%.) All urine must be collected with lead-free equipment over the next 8 hours. (An 8 hour mobilization test has been shown to be as reliable as a 24-hour mobilization test (Markowitz and Rosen, 1984).) An 8-hour test can be accomplished on an out-patient basis, but the patient should not leave the clinic during this test.) In the laboratory, the urine volume should be carefully measured and stored at 20°C until the lead concentration is measured. Extreme care must be taken to ensure that lead-free equipment is used.

   The use of lead-free apparatus for urine collection is mandatory. Special lead-free collection apparatus must be used if valid test results are to be obtained. The laboratory that will perform the analysis should supply the proper collection apparatus. Preferably, urine should be voided directly into polyethylene or polypropylene bottles that have been cleaned by the usual procedures, then washed in nitric acid, and thoroughly rinsed with deionized, distilled water. For children who are not toilet trained, plastic pediatric urine collectors can be used. Urine collected in this manner should be transferred directly to the urine collection bottles.

   Interpretation of a CaNa₂EDTA Provocative Chelation Test. To obtain the total lead excretion in micrograms, the concentration of lead in the urine (in micrograms per milliliter) is multiplied by the total urinary volume (in milliliters). The total urinary excretion of lead (micrograms) is divided by the amount of CaNa₂EDTA given (milligrams) to obtain the lead excretion ratio:

    

   Lead excreted (µg)
   
   __________________
   CaNa ₂EDTA given (mg)
   

   An 8-hour CaNa₂EDTA chelation provocative test is considered positive if the lead excretion ratio is > 0.6 (Markowitz and Rosen, 1991). Some clinicians use a cutoff of 0.5 for the lead excretion ratio (Weinberger et al., 1987). Children with blood lead levels 25 to 44 µg/dL and positive chelation test results should undergo a 5-day course of chelation.

   Regardless of age, all children with elevated blood lead values and negative provocative chelation results should have blood lead levels measured monthly. If the elevation in blood lead values persists, the CaNa₂EDTA provocative test can be repeated every 1 to 3 months and interpreted according to the above guidelines.

4. Radiologic Examination of the Abdomen
   Radiologic examination of the abdomen (flat plate) may show radiopaque foreign material if the material has been ingested during the preceding 24 to 36 hours. Neither negative nor positive x-ray results are diagnostic or definitive. A flat plate of the abdomen may, however, provide information about the source of lead if paint chips or other lead objects are found.

5. Radiologic Examination of the Long Bones
   X-rays of the long bones are unreliable for diagnosing acute lead poisoning, and they should not be obtained on a routine basis. They may provide some indication of whether lead poisoning has occurred in the past or has been ongoing for a length of time, and this may occasionally be important. Lines of increased density in the metaphyseal plate of the distal femur, proximal tibia, and fibula may be caused by lead which has disrupted the metabolism of bone matrix. Although these lines are sometimes called lead lines, they are areas of increased mineralization or calcification and not x-ray shadows of deposited lead.

   The following tests are NOT indicated for the diagnosis or clinical management of lead poisoning:

   1. Microscopic Examination of Red Cells for Basophilic Stippling
      Since basophilic stippling is not always found in severe lead poisoning and is insensitive to lesser degrees of lead poisoning, it is not useful in diagnosis.

   2. Tests of Hair and Fingerprints for Lead Levels
      The levels of lead in hair or fingernails do not correlate well with blood lead levels, except in extreme cases of symptomatic lead poisoning; therefore, these tests are not useful in diagnosis. Children should never receive chelating agents on the basis of analyses of lead levels in hair or fingernails.

Pharmacology of Chelating Agents

Table 7-1 Several drugs are used in the treatment of lead poisoning. These drugs, capable of binding or chelating lead, deplete the soft and hard (skeletal) tissues of lead and thus reduce its acute toxicity (Chisolm, 1968; Markowitz and Rosen, 1984; Piomelli et al., 1984; Rosen et al., in press). All drugs have potential side effects and must be used with caution (Piomelli et al., 1984). The basic pharmacologic characteristics of the various drugs are described below.

BAL

Mechanism of action. Two molecules of dimercaprol (BAL) combine with one atom of heavy metal to form a stable complex. BAL enhances fecal and urinary excretion of lead and diffuses well into erythrocytes. Because it is predominantly excreted in bile, BAL can be administered in the presence of renal impairment (Chisolm, 1968).

Route of administration and dosage. BAL is available only in peanut oil for intramuscular administration. It is usually given every 4 hours, although it may be given every 8 hours; dosages are discussed in Treatment Guidelines for Children with Blood Lead Levels > or = to 20 µg/dL.

Precautions and toxicity. For patients with glucose-6-phosphate dehydrogenase deficiency (G-6-PD), some clinicians recommend that BAL should be used only in life-threatening situations because it may induce hemolysis. Medicinal iron should never be administered during BAL therapy, because the combination of iron and BAL has been implicated in serious reactions. If iron deficiency coexists, it should not be treated until after BAL therapy has been completed. In cases of extreme anemia, blood transfusions are preferable.

Between 30% and 50% of patients who receive BAL will experience side effects. Mild febrile reactions and transient elevations of hepatic transaminase may be observed. Other minor adverse effects include, in order of frequency, nausea and occasional vomiting, headache, mild conjunctivitis, lacrimation, rhinorrhea, and salivation. Most side effects are transient and rapidly subside as the drug is metabolized and excreted. Intravenous hydration coupled with restricting oral intake can circumvent, in large part, gastrointestinal distress.

BAL should not be used for children who are allergic to peanuts or peanut products.

CaNa₂EDTA

Only CaNa₂EDTA can be used for treating children with lead poisoning. Na₂EDTA (disodium edetate) should never be used for treating children with lead poisoning because it will induce tetany and possibly fatal hypocalcaemia.

Mechanism of action. CaNa₂EDTA increases urinary lead excretion twentyfold to fiftyfold. CaNa₂EDTA removes lead from the extra cellular compartment only, because it does not enter cells (Osterloh and Becker, 1986).

Route of administration and dosage. The preferred route for administration of CaNa₂EDTA is intravenous. CaNa₂EDTA must be diluted to a concentration of <0.5% either in dextrose and water or in 0.9% saline solution. It can be given as a continuous infusion or it can be given in two divided doses a day through a heparin lock over 30 to 60 minutes. CaNa₂EDTA causes extreme pain when administered intramuscularly; therefore, when given by this route, it should be mixed with procaine so that the final concentration of procaine is 0.5%. CaNa₂EDTA should never be given orally because it enhances absorption of lead from the gastrointestinal tract.

Dosages vary by situation and are detailed in Treatment Guidelines for Children with Blood Lead Levels > or = 20 µg/dL. Individual courses should be limited to 5 days and repeated courses should be given at a minimum of 2- to 5-day intervals. Particularly when CaNa₂EDTA is given on an outpatient basis, some clinicians use sequential 3-day courses of treatment.

Precautions and toxicity. During chelation therapy with CaNa₂EDTA, urine output, urine sediment, blood urea nitrogen (BUN), serum creatinine, and hepatocellular enzyme levels must be carefully monitored. The appearance of protein and formed elements in urinary sediment, and rising BUN and serum creatinine values reflect impending renal failure—the serious toxicity associated with inappropriately excessive or prolonged administration of CaNa₂EDTA. Liver transaminases may increase by the fifth day of therapy, but return to pretreatment levels within a week after treatment has ended.

When CaNa₂EDTA is used alone without concomitant BAL therapy, it may aggravate symptoms in patients with very high blood lead levels. Therefore, it should be used in conjunction with BAL when the blood lead level is > or = to 70 µg/dL or overt clinical symptoms of lead poisoning are present. In such cases, the first dose of BAL should always precede the first dose of CaNa₂EDTA by at least 4 hours.

The kidney is the principal site of potential toxicity. Renal toxicity is dose related, reversible, and rarely (if ever) occurs at doses <1500 mg/m² when the patient is adequately hydrated. CaNa₂EDTA must never be given in the absence of an adequate urine flow (Piomelli et al., 1984).

D-penicillamine

The Food and Drug Administration (FDA) has approved D-penicillamine for the treatment of Wilson's disease, cystinuria, and severe, active rheumatoid arthritis. Although not approved for this use, it is used in some centers for treating lead poisoning. Until the recent approval of succimer, it was the only commercially available oral chelating agent. It can be given over a long period (weeks to months). D-penicillamine has been used mainly for children with blood lead levels < 45 µg/dL.

Mechanism of action. D-penicillamine enhances urinary excretion of lead, although not as effectively as CaNa₂EDTA. Its specific mechanism and site of action are not well understood.

Route of administration and dosage. D-penicillamine is administered orally. It is available in capsules or tablets (125 mg and 250 mg). These capsules can be opened and suspended in liquid, if necessary. The usual dose is 25 to 35 mg/kg/day in divided doses. Side effects can be minimized, to an extent, by starting with a small dose and increasing it gradually, monitoring all the time for side effects. For example, 25% of the desired final dose could be given in week 1, 50% in week 2, and the full dose by week 3.

Precautions and toxicity. Toxic side effects (albeit minor in most cases) occur in as many as 33% of patients given the drug (Shannon et al., 1988). The main side effects of D-penicillamine are reactions resembling those of penicillin sensitivity, including rashes, leukopenia, thrombocytopenia, hematuria, proteinuria, hepatocellular enzyme elevations, and eosinophilia. Anorexia, nausea, and vomiting are infrequent. Of most concern, however, are isolated reports of nephrotoxicity, possibly from hypersensitivity reactions. For these reasons, patients should be carefully and frequently monitored for clinically obvious side effects, and frequent blood counts, urinalyses, and renal function tests should be performed. In particular, blood counts and urinalyses should be done on day 1, day 14, day 28, and monthly thereafter. If the absolute neutrophil count falls to < 1500/µg/dL, the count should be rechecked immediately, and treatment should be stopped if it falls to < 1200/µg/dL. D-penicillamine should not be given on an outpatient basis if exposure to lead is continuing or the physician has doubts about compliance with the therapeutic regimen.

D-penicillamine should not be administered to patients with known penicillin allergy.

Succimer

The FDA approved succimer in January, 1991 for treating children with blood lead levels > 45 µg/dL. Succimer appears to be an effective oral chelating agent. Its selectivity for lead is high, whereas its ability to chelate essential trace metals is low. Although its use to date has been limited, succimer appears to have promising potential, and a broader range of clinical research studies in children are being undertaken.

Succimer is chemically similar to BAL but is more water soluble, has a high therapeutic index. and is absorbed from the gastrointestinal tract (Aposhian and Aposhian, 1990). It is effective when given orally and produces a lead diuresis comparable to that produced by CaNa₂EDTA (Chisolm, 1990). This diuresis lowers blood lead levels and reverses the biochemical toxicity of lead, as indicated by normalization of circulating aminolevulinic acid dehydrase levels (Graziano et al., 1988). Succimer is not indicated for prophylaxis of lead poisoning in a lead-containing environment. As with all chelating agents, succimer should only be given to children who reside in environments free of lead during and after treatment.

Mechanism of action. Succimer appears to be more specific for lead than the most commonly used chelating agent, CaNa₂EDTA; the urinary loss of essential trace elements (for example, zinc) appears to be considerably less with succimer than with CaNa₂EDTA (Aposhian and Aposhian, 1990). The site of lead chelation by succimer is not known.

Route of administration and dosage. Succimer is administered orally. It is available in 100 mg capsules. The recommended initial dose is 350 mg/m² (10 mg/kg) every 8 hours for 5 days, followed by 350 mg/m² (10 mg/kg) every 12 hours for 14 days. A course of treatment, therefore, lasts 19 days. If more courses are needed, a minimum of 2 weeks between courses is preferred, unless blood lead levels indicate the need for immediate retreatment. These doses may be modified as more experience is gained in using succimer.

Patients who have received therapeutic courses of CaNa₂EDTA with or without BAL may use succimer for subsequent treatment after an interval of 4 weeks. Data on the concomitant use of succimer and CaNa₂EDTA with or without BAL are not available, and such use is not recommended.

If young children cannot swallow capsules, succimer can be administered by separating the capsule and sprinkling the medicated beads on a small amount of soft food or by putting them on a spoon and following with a fruit drink. Data are not available on how stable succimer is when it is suspended in soft foods for prolonged periods of time; succimer should be mixed with soft foods immediately before being given to the child.

Precautions and toxicity. To date, toxicity due to succimer (transient elevations in hepatic enzyme activities) appears to be minimal (Graziano et al., 1988). The most common adverse effects reported in clinical trials in children and adults were primarily gastrointestinal and included nausea, vomiting, diarrhea, and appetite loss. Rashes, some necessitating discontinuation of therapy, have been reported for about 4% of patients. Though succimer holds considerable promise for the outpatient management of lead poisoning, clinical experience with succimer is limited. Consequently, the full spectrum and incidence of adverse reactions, including the possibility of hypersensitivity or idiosyncratic reactions, have not been determined.

If succimer is used, the following precautions must be taken:

1. Monitor for side effects (especially effects on liver transaminase), the rapidity of the initial decrease in blood lead levels, and the course of the rebound in blood lead levels once treatment has ended.
2. Succimer, like other chelators, is not a substitute for effective and rapid environmental interventions. Use succimer as part of an integrated environmental and medical approach to treating patients with lead poisoning.
3. Do not give succimer (or any other chelating agent) in situations where high dose lead sources are available to the child. In rats, gastrointestinal absorption of lead and whole body lead retention were reduced by a single oral dose of succimer (Kapoor et al., 1989). The potential for enhancing human lead absorption from the gastrointestinal tract during the use of succimer is under study.
4. Children with blood lead levels >45 µg/dL who are being treated with succimer, should, if possible, be hospitalized until their blood lead levels fall below 45 µg/dL and the lead hazards in their homes are abated or alternative lead hazard-free housing has been identified.
5. Children with blood lead levels > or = to 70 µg/dL should be immediately hospitalized. The decision to treat such children with succimer instead of CaNa₂EDTA and BAL should be made with the understanding that experience with using succimer in children with these blood lead levels is limited.

Treatment Guidelines for Children with Blood Lead Levels > or = to 20 µg/dL

The single most important factor in managing of childhood lead poisoning is reducing the child's exposure to lead; some children, however, will benefit from chelation therapy. One approach for pharmacologic treatment of children with lead poisoning follows. It is a general guide and is not the only pharmacologic regimen that can be used to treat poisoned children.

Medical Management of Symptomatic Lead Poisoning (with or without Encephalopathy)

General Management. Children with symptomatic lead poisoning (with or without encephalopathy) must be treated only at a pediatric center that has an intensive care unit. They should be managed by a multidisciplinary team that includes, as needed, critical care, toxicology, neurology, and neurosurgery. The child's neurological status and fluid balance must be carefully monitored.

The symptoms associated with lead poisoning (with or without lead encephalopathy) are described in Symptoms of Lead Poisoning. One or more of those symptoms associated with an elevated blood lead level constitutes an acute medical emergency. Because chelation regimens are the same for cases of symptomatic lead poisoning (with and without encephalopathy), guidelines for clinical management have been included in a single section.

Chelation Therapy. Although succimer has been approved for chelation of children with blood lead levels > 45 µg/dL, experience in treating symptomatic children is limited. Therefore, the treatment regimen discussed here uses CaNa₂EDTA and BAL. Chelation with succimer is discussed in Succimer.

Start treatment with a dose of 75 mg/m² BAL only, given by deep intramuscular injection; administer BAL at a dose of 450 mg/m²/day in divided doses of 75 mg/m² every 4 hours. Once this dose is given and an adequate urine flow is established, administer CaNa₂EDTA at a dose of 1,500 mg/m²/day. Give CaNa₂EDTA as a continuous intravenous infusion in dextrose and water or in a 0.9% saline solution. The concentration of CaNa₂EDTA should not exceed 0.5% in the parenteral fluid. (When treating a child with encephalopathy, the physician may choose to give CaNa₂EDTA intramuscularly to reduce the amount of fluid administered.) Treat with combined BAL-CaNa₂EDTA therapy for a total of 5 days. During treatment, monitor renal and hepatic function and serum electrolyte levels daily (Piomelli et al., 1984).

A second course of chelation therapy with CaNa₂EDTA alone (at blood lead levels 45-69 µg/dL) or combined with BAL (at blood lead levels 70 µg/dL), may be required once there is a rebound in the blood lead level after chelation. Wait at least 2 days before giving a second course of chelation. A third course is required only if the blood lead concentration rebounds to a value > 45 µg/dL within 48 hours after the second course of treatment. Unless there are unusual and compelling clinical reasons, wait at least 5 to 7 days before beginning a third course of CaNa₂EDTA (Piomelli et al., 1984).

Medical Management of Asymptomatic Lead Poisoning

Clinical management of asymptomatic lead-poisoned children with blood lead levels high enough to require chelation is similar to that of symptomatic children. Focus on reducing the child's exposure to lead and decreasing the child's body burden of lead.

Although succimer has been approved for chelation of children with blood lead levels > 45 µg/dL, experience with this drug is limited. Therefore, the treatment regimen discussed here uses CaNa₂EDTA and BAL.

Blood lead level > or = to 70 µg/dL. Children with blood lead levels > or = to 70 µg/dL (with or without symptoms) represent an acute medical emergency. If the blood lead level is > or = to 70 µg/dL, give both BAL and CaNa₂EDTA in the same doses and using the guidelines as for treatment of symptomatic lead poisoning (discussed in Treatment Guidelines for Children with Blood Lead Levels > or = to 20 µg/dL. ). A second course of chelation therapy with CaNa₂EDTA alone may be required if the blood lead concentration rebounds to a value > or = to 45 µg/dL within 5 to 7 days after treatment. In general allow at least 5 to 7 days before beginning a second course of CaNa₂EDTA. Some practitioners give a second course of chelation after a 3-day rest period if the immediate post-treatment blood lead level is >35 µg/dL (J. Chisolm, personal communication).

Blood lead level 45 to 69 µg/dL. If the blood lead value is between 45 and 69 µg/dL, chelation treatment should be limited to CaNa₂EDTA only. CaNa₂EDTA is given for 5 days at a dose of 1,000 mg/m²/ day intravenously by continuous infusion or in divided doses, as described under the heading CaNa₂EDTA. During treatment, evaluate renal and hepatic function and serum electrolyte levels regularly. Do not continue CaNa₂EDTA treatment for more than 5 days (Piomelli et al., 1984).

A second course of chelation therapy with CaNa₂EDTA alone may be required if the blood lead level rebounds to 45 µg/dL within 7 to 14 days after treatment. Allow 5 to 7 days before beginning a second course of CaNa₂EDTA.

Blood lead level 25 to 44 µg/dL. For this blood lead range, the effectiveness of chelation therapy in decreasing the adverse effects of lead on children's intelligence has not been shown. Treatment regimens vary from clinic to clinic. Some practitioners treat children with lead levels in this range pharmacologicly. (Although it is not approved for this use, some use D-penicillamine for children in this blood lead range.) The minimum medical management for children with these blood lead levels is to decrease the children's exposure to all sources of lead, to correct any iron deficiency and maintain an adequate calcium intake, and to test frequently to ensure that the child's blood lead levels are decreasing. Many experienced practitioners decide whether to use chelation therapy on the basis of the results of carefully performed CaNa₂EDTA mobilization tests (See Edetate Disodium Calcium (CaNa₂EDTA) Provocative Chelation Test).

Blood lead level 20 to 24 µg/dL. Only very minimal data exists about chelating children with blood lead levels below 25 µg/dL, and such children should not be chelated except in the context of approved clinical trials. A child with a confirmed blood lead level of 20 to 24 µg/dL will require individual case management by a pediatric health-care provider. The child should have an evaluation with special attention to nutritional and iron status. The parents should be taught about: 1) the causes and effects of lead poisoning, 2) the need for more routine blood lead testing, 3) possible sources of lead intake and how to reduce them, 4) the importance of adequate nutrition and of foods high in iron and calcium, and 5) resources for further information. (This is described in more detail in Chapter 4.) Sequential measurements of blood lead levels along with review of the child's clinical status should be done at least every 3 months. Iron deficiency should be treated promptly. Children with blood lead levels in this range should be referred for environmental investigation and management. Identifying and eradicating all sources of excessive lead exposure is the most important intervention for decreasing blood lead levels (Chapter 8).

Post-chelation Followup

At the end of each treatment cycle, the blood lead concentration usually declines to <25 µg/dL. Within a few days, however, reequilibration among body lead compartments takes place and may result in a rebound; thus, the blood lead level must be rechecked 7 to 21 days after treatment to determine whether retreatment is necessary (Piomelli et al., 1984; Chisolm et al., 1985).

Children who undergo chelation treatment require long-term followup preferably from pediatric health-care providers, nutritionists, environmental specialists, and community out-reach workers. Community outreach workers provide a critical bridge between hospital-based or clinic-based (outpatient) medical care, health advocacy education, and environmental remediation outside the hospital. Children should never be discharged from the hospital until they can go to a lead-free environment (CDC, 1985; Piomelli et al., 1984). Lead-free safe housing (with friends, relatives, or in designated transitional housing), in which a treated child can live during the entire abatement process through the post-abatement clean-up, must be arranged. With appropriately carried-out public health measures, complete and safe abatement should be achieved during the treatment period (CDC, 1985).

Once a child is discharged to a safe environment, frequent followup is mandatory. In general, depending on the initial blood lead value, most children who require chelation therapy must be followed closely for at least one year or more. All children undergoing chelation treatment should be seen every other week for 6-8 weeks, then once a month for 4-6 months. A child treated with BAL and CaNa₂EDTA should be followed more closely: weekly for 4 to 6 weeks, then monthly for 12 months.

At each clinic visit, housing information should be updated. If history suggests that exposure is increasing or if blood lead levels are rising, the dwelling must be reinspected to evaluate the possibility of new sources of environmental lead, inadequate abatement, or unsound structures in buildings (for example, poor plumbing with leaks) that cause further chipping or breakdown of a previously repaired dwelling (Piomelli et al., 1984).

Research Areas and Future Trends in the Management of Childhood Lead Poisoning

Bone Lead Measurements Using Xray Fluorescence (XRF)

According to published data, L-line and the K-line XRF techniques permit non-invasive assessment of skeletal lead stores. These bone stores reflect the lead burden accumulated over an individual's life. In contrast, blood lead values reflect recent lead exposure and absorption during the past 1 to 3 months and provide limited information about lead toxicokinetics over time (Rabinowitz et al., 1977). Evaluations using the L-line methodology in children have shown that blood lead levels underestimate the body burden of lead in lead-poisoned children (Rosen et al., in press); and sequential measurements of lead in lead-poisoned children by the L-line technique have shown decreases in bone lead after CaNa₂EDTA treatment or environmental intervention (Rosen et al., in press). K-line techniques have been used mainly to measure bone lead levels in workers. Quantitation of bone lead content of children takes about 16 minutes.

At present, XRF equipment is available only in a few centers in the United States and Europe.

Efficacy of Chelating Agents

The benefits of chelation therapy in symptomatic lead-poisoned children are well known (Chisolm, 1968). Prompt intervention with chelating agents prevents progression to symptomatic disease and normalizes biochemical indices of lead toxicity. However, the efficacy of chelating agents in reversing or modifying the adverse neurobehavioral effects at all blood lead levels in apparently asymptomatic children needs to be carefully assessed. Better understanding of this issue is critical in deciding the end-point of medical treatment. It is also essential in defining when chelation should be used.

Succimer

Data are needed on the tissue sites of lead chelated by succimer, the adverse effects of succimer, the effect of succimer on absorption of lead from the gastrointestinal tract, and the effectiveness of different dose regimens of succimer. Assuming that no new significant adverse effects are noted after succimer is used more widely, the efficacy and appropriate use of succimer for treating lead-poisoned children with blood lead levels below 45 µg/dL needs to be established.

Toxicity of CaNa₂EDTA

Results of one animal study suggest that CaNa₂EDTA may transiently increase brain lead levels (Cory-Slechta et al., 1987). The redistribution of lead during chelation needs further study.

References

Aposhian HV, Aposhian MM. Meso-2,3-dimercaptosuccinic acid: chemical, pharmacologic and toxicological properties of an orally effective metal chelating agent. Ann Rev Pharmacol Toxicol 1990; 30:279-306.

CDC (Centers for Disease Control). 1985. Preventing lead poisoning in young children: A statement by the Centers for Disease Control. Atlanta: CDC, 1985; CDC report no. 99-2230.

Chisolm JJ Jr. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatr 1968:73:1-38.

Chisolm JJ Jr. Management of increased lead absorption - illustrative cases. In: Chisolm JJ Jr, O'Hara DM, editors. Lead absorption in children: management, clinical, environmental aspects. Baltimore: Urban and Schwarzenberg, 1982:171-88.

Chisolm JJ Jr, Mellits ED, Quaskey SA. The relationship between the level of lead absorption in children and the age, type, and condition of housing. Environ Res 1985;38:31-45.

Chisolm JJ Jr. Evaluation of the potential role of chelating therapy in the treatment of low to moderate lead exposures. Environ Health Perspect 1990;89:67-74.

Cory-Slechta DA, Weiss B, Cox C. Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Ther 1987;243:804-13.

Graziano JH, LoIacono NJ, Meyer P. Dose-response study of oral 2, 3-dimercaptosuccinic acid in children with elevated blood lead concentrations. J Pediatr 1988:113:751-7.

Kapoor SC, Wielopolski L, Graziano JH, LoIacono NJ. Influence of 2,3-dimercaptosuccinic acid on gastrointestinal lead absorption and whole-body lead retention. Toxic Appl Pharmacol 1989;97:525-9.

Markowitz ME, Rosen JF. Assessment of lead stores in children: validation of an 8-hour CaNa₂EDTA provocative test. J Pediatr 1984;104:337-2.

Markowitz ME, Rosen JF, Bijur PE. Effects of iron deficiency on lead excretion in children with moderate lead intoxication. J Pediatr 1990;116:360-4.

Markowitz ME, Rosen JF. Need for the lead mobilization test in children with lead poisoning. J Pediatr 1991;119:305-10.

Osterloh J, Becker CE. Pharmacokinetics of CaNa₂EDTA and chelation of lead in renal failure. Clin Pharm Ther 1986;40:686-93.

Perlstein MA, Attala R. Neurologic sequelae of plumbism in children. Clin Pediatr 1966;5:292-8.

Piomelli S, Corash L, Corash MB, Seaman C, Mushak P, Glover B, Padgett R. Blood lead concentrations in a remote Himalayan population. Science 1980;210:1135-7.

Piomelli S, Rosen JF, Chisolm JJ Jr, Graef JW. Management of childhood lead poisoning. J Pediatr 1984;105:523-32.

Rabinowitz MB, Wetherill GW, Kopple JD. Magnitude of lead intake from respiration by normal man. J Lab Clin Med 1977;90:238-48.

Rosen JF, Markowitz ME, Bijur PE, Jenks ST, Wielopolski L, Kalef- Ezra JA, Slatkin DN. L-line x-ray fluorescence of cortical bone lead compared with the CaNa₂EDTA-treated lead-toxic children. Environ Health Perspect (in press).

Shannon M, Graef J, Lovejoy FH Jr. Efficacy and toxicity of D-penicillamine in low-level lead poisoning. J Pediatr 1988;112:799-804.

Weinberger HL, Post EM, Schneider T, Helu B, Friedman J. An analysis of 248 initial mobilization tests performed on an ambulatory basis. Am J Dis Child 1987;141:1266-70.