PEDIATRIC PHARMACOLOGY AND THERAPEUTICS
Need for the lead mobilization test in children with lead poisoning Morri E. M a r k o w i t z , MD, a n d John F. Rosen, MD From the Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
We evaluated the recommendation of the Centers for Disease Control, that children with moderate lead poisoning undergo the lead mobilization test (I.MT) to determine the need for a full course of chelation treatment. Current criteria for selection for this test include a blood Pb concentration (bPb) between 25 and 55 ~g/dl and an erythrocyte protoporphyrin level >35 ~g/dl. To determine whether the eligibility criteria could be refined to a smaller group of patients, we c o m p a r e d bPb determinations obtained on the d a y of the LMT in 198 children with moderate Pb poisoning to the results of the LMT. We found that children with bPb -40 ~g/dl were likely to excrete sufficient Pb to indicate the need for a full course of chelation. We conclude that the LMT is indicated for children with bPbs between 25 and 40 /~g/dl. Children with bPb between 40 and 55/~g/dl may receive chelation thera p y without having an LMT, if the performance of the LMT is not practical. Patients with levels -55 gg/dl are considered at need for immediate therapy to reduce the body burden of Pb. 2 This is carried out most efficaciously by the administration of one or more chelating agents in the hospital. Children with bPb --35 ~tg/dl, describes the vast majority of children with elevated bPb entering Pb treatment programs nationally. For this group of children the CDC has recommended that the evaluation include the lead mobilization test (also called the Pb or calcium disodium ethylenediamine tetraacetate provocative test) to determine which children will respond to a course of chelation
bPb CaNa2EDTA EP LMT uPbr
Blood lead concentration Calcium disodium ethylenediamine tetraacetate Erythrocyte protoporphyrin Lead mobilization (provocative) test Urine Iead/CaNa2EDTA dose ratio
therapy with an enhanced Pb diuresis. 1 This test consists of the administration of a dose of CaNa2EDTA, the current drug of choice for the treatment of moderate Pb poisoning, followed by the timed collection of urine for urinary Pb determination. Criteria to establish whether Pb diuresis
305
306
Markowitz and Rosen
induced by the drug has been sufficient to warrant a full course of chelation therapy have been established.i, 3 However, few medical centers are equipped to perform this test in either its 24-hour in-hospital or 8-hour outpatient form. Instead, practitioners may elect to measure blood Pb and EP concentrations over time or to empirically admit the patient to the hospital for chelation therapy on the basis of the blood values. As a result, children with moderate Pb poisoning may not be receiving optimal therapy. To determine whether selection criteria for LMT eligibility and hence chelation treatment could be simplified, we analyzed the relationship between bPb and LMT results in 198 children with moderate Pb poisoning. Our goal was to help primary care providers narrow the need for the LMT to the fewest children and provide more timely chelation therapy to patients in need. METHODS Children aged 1 to 7 years were referred to the Montefiore Medical Center Pediatric Metabolism Clinics if screening tests performed by primary providers showed bPb and EP concentrations of 25 to 55, and ___35~g/dl, respectively. This study is part of a multidisciplinary longitudinal evaluation of the effects of treatment intervention on children with moderate Pb poisoning. Selection criteria for the study included age of 1 to 7 years, absence of overt clinical symptoms, and (except among the first 20 patients enrolled) no previous treatment for Pb poisoning. The population was drawn from the Bronx and Westchester counties of New York State. Informed consent was obtained from a parent. In addition to the LMT, an extensive evaluation of the child was performed, including biochemical, electrophysiologic, bone Pb measurements by L-line x-ray fluorescence, and neurobehavioral measurements, in addition to a home environmental evaluation to ascertain the source of the Pb. Analyses of the data from this population generated a hypothesis that children with bPb >40 #g/dl were likely to have positive LMT results, indicating the need for full courses of chelation therapy. This was tested by analyzing LMT results in a second group of 20 children, concurrently referred to the metabolism clinic for the evaluation of Pb poisoning and comparable to the first group except that they were not enrolled in the longitudinal study and that their bPb ranged from 40 to 54 t~g/dt. The LMT was performed in the outpatient clinic under the direct supervision of two nurse practitioners, one of us (M.E.M.), and a clinic nurse. A standard 8-hour protocol was followed) This consisted first of obtaining a repeated blood sample for bPb and EP determination, followed by the administration of a 500 m g / m 2 dose of CaNa2EDTA~
The Journal of Pediatrics August 1991
mixed 1:1 by volume with 1% procaine and given intramuscularly. This in turn marked the beginning of an 8-hour urine collection. Urine was collected in acid-washed Pb-free polyethylene containers. Whenever practical, the older children were asked to void before receiving the medication; younger children had urine collection bags applied immediately after receiving their injection. Fluid intake was encouraged during the first 4 hours of the test. Blood and urine Pb levels were measured by graphite furnace atomic absorption spectrophotometry on a VarianTechtron instrument by methods published previously) The laboratory participates in proficiency testing programs carried out by the CDC and by New York City's department of health. The confidence limits of the methods as determined by an analysis of variance of duplicate measurements were 1.0 #g/dl and 5.0 #g/vol for blood and urine Pb, respectively. Erythrocyte protoporphyrin concentration was assayed fluorometrically by the ethyl acetate-acetic acid extraction method) Previously published criteria were used to determine a positive LMT result, indicating the need for chelation treatment. These were as follows: (1) a ratio of urinary Pb content divided by the dose of CaNa2EDTA ___0.60 for children less than 3 years of age and >__0.70 for children more than 3 years, or (2) an absolute urinary Pb excretion of >__200 #g per 8 hours. 1"3 The former criterion was recommended by the CDC1; the latter criterion reflects the historic development of the LMT. 3 RESULTS The average lag time between referral and performance of the LMT was between 1 and 2 weeks. Children did not complete the LMT if urine was lost or if a repeated bPb value performed between the time of referral and the day of the LMT was outside the 25 to 55 ~zg/dl range. Of the 190 children eligible for study at referral, 178 successfully completed the LMT. Their average age was 36 months. Of these 178 Pb-poisoned children, 112 were less than 3 years of age; 62 were African-American, 103 were Hispanic, and 13 were of other racial or ethnic background. Of the 20 children in the second group, all had complete urine collections. Their average age was 44 months (range 23 to 102 months); 10 were African-American, 8 were Hispanic, and 2 were of other racial origin. The range of bPb obtained on the day of the LMT in the 178 children was 13 to 60 #g/dl, the range ofuPb r was 0.03 to 1.70 ~zgper milligram CaNa2EDTA, and the range of the total urinary Pb excretion per 8 hours was 4 to 608 #g/vol. The correlation between bPb and uPb r was 0.64 (p _0.70i"
+ LMT result
Dose ratio >_0.60~
+ LMT result
Absolute excretion criterionw
+ LMT result
C o m b i n e d criteria]I
+ LMT result
+ LMT result
bPb (#g/dl)
n
n
%
n
n
%
n
n
%
n
n
%
n
n
%
55 Total (mean)
20 33 21 21 7 3 4 3 II2
0 5 5 14 5 3 4 2 38
0 15 24 67 71 100 100 67 (34)
5 20 21 5 8 6 1
0 4 13 4 8 6 1
0 20 62 80 100 100 100
5 20 21 5 8 6 1
0 8 14 5 8 6 1
0 40 67 100 100 I00 100
(55)
66
42
(64)
4 21 36 58 73 89 I00 33 (38)
l 13 20 19 13 9 5 2 82
4 24 48 73 87 100 100 66
36
I 11 15 15 11 8 5 1 67
25 53 42 26 15 9 5 3
66
25 53 42 26 15 9 5 3 178
178
(46)
n. Number of children. *Positive LMT result uPb~ >0.60. tPositive I "tiT result = uPbr >--0.70. :~P0sitive LMT result = uPbr >-0.60. w LMT result = absolute urinary Pb excretion >__200~zg/8 hr. ]]Positive LMT result = urinary Pb ratio >---0.6or 0.7, or absolute urinary Pb excretion >_200 ,zg/8 hr. =
in the older group of children is lowered to match that used in the younger children, 0.60, then agreement on L M T results between the two criteria reaches 98%. The results in the group of 32 children with bPb -->40 tzg/dl were compared with those in the second group of 20 children (Table II). When both L M T criteria were used, results of 17 & t h e 20 L M T results were positive (85 -+ 16%, at the 95% confidence limit). All three negative L M T s results occurred in the younger children. Because both groups of children had comparable L M T results, the data were combined and yielded 88 _+ 9% positive L M T results when bPb was >_40 ~g/dl. The EP levels, on average, did not contribute to the predictability of L M T results in the children with bPb ->40 ug/dl. In the initial group of 32 children the mean EP of both LMT-negative and LMT-positive children was 159 #g/dl. In the second group of children the mean EP was 154 # g / d l in the LMT-negative group and 148 ~,g/dl in the LMT-positive children. DISCUSSION The subjects in this study are representative of the majority of Pb-poisoned children in terms of age, social class, race, and geographic location. 5 Distinguishing the subgroup likely to benefit from treatment is the purpose of the LMT. This test identifies children who have a mobilizable and
T a b l e II. Results of lead mobilization test in group 2 Age Criterion
--36 mo
uPb >--200 ~*g/8 hr uPb ratio >-0.6 or 0.7
5/9 6/9
Both criteria
6/9
1 i/11 9/11 (ratio 0.7) 11 / 11 (ratio 0.6) 11/11
uPb, Urinary Pb excretion. hence potentially more toxic Pb burden. 68 Initially it was structured as a 24-hour procedure entailing two injections of C a N a 2 E D T A and a 24-hour urine collection, This proved to be unwieldy in the pediatric population because of the difficulty in successfully completing any timed urine collection in small children. To improve the rate of successful completion of the test, we and others developed shortened 6- to 8-hour versions that allowed it to be performed in an outpatient department. 3, 9, to This shortened test reduced the cost and improved the likelihood of obtaining complete urine collections. In our previous efforts to develop an 8-hour L M T , we performed 83 24-hour tests and obtained complete urine collections in only 38. 3 In the current study our success rate was well over 90%. Even in this modified testing form, dedicated personnel are necessary for complete urine collections. Unfortunately,
Volume 119 Number 2
few medical centers or physician's offices have the necessary personnel to offer the LMT. Instead, providers are likely either to refer patients to Pb treatment centers, to treat empirically, or to follow the patients clinically while intervening environmentally to eradicate the Pb source. The latter two approaches may result in either overtreatment (i.e., chelation of children who do not have a Pb diuresis induced by medication) or in delay of treatment and hence ongoing exposure to potentially toxic amounts of Pb. A second, more theoretic concern has been raised about the safety of the LMT.11 Data from a study of rats indicated the potential for tissue redistribution of Pb after single intraperitoneal injections of CaNa2EDTA, resulting in transient increases in Pb content of the CNS. 4 This finding is consistent with historic observations in children with severe Pb encephalopathy, treated with CaNa2EDTA alone, whose neurologic function deteriorated at the initiation of treatment.~2 However, no data that we are aware of support any evidence of CNS damage by a single dose of CaNa2EDTA in children with moderate Pb poisoning. Even in the study by Cory-Schlecta, a~ completion of treatment with CaNa2EDTA did not result in a net increase in CNS Pb. Moreover, the half-life of CaNazEDTA differs considerably in rats from that in human beings, making extrapolation of studies performed in that species to human beings problematic.a3, 14 In any case, children with substantial amounts of mobilizable Pb, as determined by LMT, are immediately admitted for complete chelation courses, thereby reducing soft-tissue Pb by the completion of a full course of therapy. The LMT is efficacious but not widely available, so we attempted to address the issue of who most needs this test. Our data demonstrate that children, especially those more than 36 months of age, are very likely to have a positive LMT result if their blood Pb concentrations are >_40 #g/ dl. Both our study groups yielded comparable data on LMT outcomes when bPbs were >-40 #g/dl: 29 of 32 and 17 of 20 patients had positive results. On the other hand, at any age, if blood Pb is
Need for the lead mobilization test in children with lead poisoning Morri E. M a r k o w i t z , MD, a n d John F. Rosen, MD From the Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
We evaluated the recommendation of the Centers for Disease Control, that children with moderate lead poisoning undergo the lead mobilization test (I.MT) to determine the need for a full course of chelation treatment. Current criteria for selection for this test include a blood Pb concentration (bPb) between 25 and 55 ~g/dl and an erythrocyte protoporphyrin level >35 ~g/dl. To determine whether the eligibility criteria could be refined to a smaller group of patients, we c o m p a r e d bPb determinations obtained on the d a y of the LMT in 198 children with moderate Pb poisoning to the results of the LMT. We found that children with bPb -40 ~g/dl were likely to excrete sufficient Pb to indicate the need for a full course of chelation. We conclude that the LMT is indicated for children with bPbs between 25 and 40 /~g/dl. Children with bPb between 40 and 55/~g/dl may receive chelation thera p y without having an LMT, if the performance of the LMT is not practical. Patients with levels -55 gg/dl are considered at need for immediate therapy to reduce the body burden of Pb. 2 This is carried out most efficaciously by the administration of one or more chelating agents in the hospital. Children with bPb --35 ~tg/dl, describes the vast majority of children with elevated bPb entering Pb treatment programs nationally. For this group of children the CDC has recommended that the evaluation include the lead mobilization test (also called the Pb or calcium disodium ethylenediamine tetraacetate provocative test) to determine which children will respond to a course of chelation
bPb CaNa2EDTA EP LMT uPbr
Blood lead concentration Calcium disodium ethylenediamine tetraacetate Erythrocyte protoporphyrin Lead mobilization (provocative) test Urine Iead/CaNa2EDTA dose ratio
therapy with an enhanced Pb diuresis. 1 This test consists of the administration of a dose of CaNa2EDTA, the current drug of choice for the treatment of moderate Pb poisoning, followed by the timed collection of urine for urinary Pb determination. Criteria to establish whether Pb diuresis
305
306
Markowitz and Rosen
induced by the drug has been sufficient to warrant a full course of chelation therapy have been established.i, 3 However, few medical centers are equipped to perform this test in either its 24-hour in-hospital or 8-hour outpatient form. Instead, practitioners may elect to measure blood Pb and EP concentrations over time or to empirically admit the patient to the hospital for chelation therapy on the basis of the blood values. As a result, children with moderate Pb poisoning may not be receiving optimal therapy. To determine whether selection criteria for LMT eligibility and hence chelation treatment could be simplified, we analyzed the relationship between bPb and LMT results in 198 children with moderate Pb poisoning. Our goal was to help primary care providers narrow the need for the LMT to the fewest children and provide more timely chelation therapy to patients in need. METHODS Children aged 1 to 7 years were referred to the Montefiore Medical Center Pediatric Metabolism Clinics if screening tests performed by primary providers showed bPb and EP concentrations of 25 to 55, and ___35~g/dl, respectively. This study is part of a multidisciplinary longitudinal evaluation of the effects of treatment intervention on children with moderate Pb poisoning. Selection criteria for the study included age of 1 to 7 years, absence of overt clinical symptoms, and (except among the first 20 patients enrolled) no previous treatment for Pb poisoning. The population was drawn from the Bronx and Westchester counties of New York State. Informed consent was obtained from a parent. In addition to the LMT, an extensive evaluation of the child was performed, including biochemical, electrophysiologic, bone Pb measurements by L-line x-ray fluorescence, and neurobehavioral measurements, in addition to a home environmental evaluation to ascertain the source of the Pb. Analyses of the data from this population generated a hypothesis that children with bPb >40 #g/dl were likely to have positive LMT results, indicating the need for full courses of chelation therapy. This was tested by analyzing LMT results in a second group of 20 children, concurrently referred to the metabolism clinic for the evaluation of Pb poisoning and comparable to the first group except that they were not enrolled in the longitudinal study and that their bPb ranged from 40 to 54 t~g/dt. The LMT was performed in the outpatient clinic under the direct supervision of two nurse practitioners, one of us (M.E.M.), and a clinic nurse. A standard 8-hour protocol was followed) This consisted first of obtaining a repeated blood sample for bPb and EP determination, followed by the administration of a 500 m g / m 2 dose of CaNa2EDTA~
The Journal of Pediatrics August 1991
mixed 1:1 by volume with 1% procaine and given intramuscularly. This in turn marked the beginning of an 8-hour urine collection. Urine was collected in acid-washed Pb-free polyethylene containers. Whenever practical, the older children were asked to void before receiving the medication; younger children had urine collection bags applied immediately after receiving their injection. Fluid intake was encouraged during the first 4 hours of the test. Blood and urine Pb levels were measured by graphite furnace atomic absorption spectrophotometry on a VarianTechtron instrument by methods published previously) The laboratory participates in proficiency testing programs carried out by the CDC and by New York City's department of health. The confidence limits of the methods as determined by an analysis of variance of duplicate measurements were 1.0 #g/dl and 5.0 #g/vol for blood and urine Pb, respectively. Erythrocyte protoporphyrin concentration was assayed fluorometrically by the ethyl acetate-acetic acid extraction method) Previously published criteria were used to determine a positive LMT result, indicating the need for chelation treatment. These were as follows: (1) a ratio of urinary Pb content divided by the dose of CaNa2EDTA ___0.60 for children less than 3 years of age and >__0.70 for children more than 3 years, or (2) an absolute urinary Pb excretion of >__200 #g per 8 hours. 1"3 The former criterion was recommended by the CDC1; the latter criterion reflects the historic development of the LMT. 3 RESULTS The average lag time between referral and performance of the LMT was between 1 and 2 weeks. Children did not complete the LMT if urine was lost or if a repeated bPb value performed between the time of referral and the day of the LMT was outside the 25 to 55 ~zg/dl range. Of the 190 children eligible for study at referral, 178 successfully completed the LMT. Their average age was 36 months. Of these 178 Pb-poisoned children, 112 were less than 3 years of age; 62 were African-American, 103 were Hispanic, and 13 were of other racial or ethnic background. Of the 20 children in the second group, all had complete urine collections. Their average age was 44 months (range 23 to 102 months); 10 were African-American, 8 were Hispanic, and 2 were of other racial origin. The range of bPb obtained on the day of the LMT in the 178 children was 13 to 60 #g/dl, the range ofuPb r was 0.03 to 1.70 ~zgper milligram CaNa2EDTA, and the range of the total urinary Pb excretion per 8 hours was 4 to 608 #g/vol. The correlation between bPb and uPb r was 0.64 (p _0.70i"
+ LMT result
Dose ratio >_0.60~
+ LMT result
Absolute excretion criterionw
+ LMT result
C o m b i n e d criteria]I
+ LMT result
+ LMT result
bPb (#g/dl)
n
n
%
n
n
%
n
n
%
n
n
%
n
n
%
55 Total (mean)
20 33 21 21 7 3 4 3 II2
0 5 5 14 5 3 4 2 38
0 15 24 67 71 100 100 67 (34)
5 20 21 5 8 6 1
0 4 13 4 8 6 1
0 20 62 80 100 100 100
5 20 21 5 8 6 1
0 8 14 5 8 6 1
0 40 67 100 100 I00 100
(55)
66
42
(64)
4 21 36 58 73 89 I00 33 (38)
l 13 20 19 13 9 5 2 82
4 24 48 73 87 100 100 66
36
I 11 15 15 11 8 5 1 67
25 53 42 26 15 9 5 3
66
25 53 42 26 15 9 5 3 178
178
(46)
n. Number of children. *Positive LMT result uPb~ >0.60. tPositive I "tiT result = uPbr >--0.70. :~P0sitive LMT result = uPbr >-0.60. w LMT result = absolute urinary Pb excretion >__200~zg/8 hr. ]]Positive LMT result = urinary Pb ratio >---0.6or 0.7, or absolute urinary Pb excretion >_200 ,zg/8 hr. =
in the older group of children is lowered to match that used in the younger children, 0.60, then agreement on L M T results between the two criteria reaches 98%. The results in the group of 32 children with bPb -->40 tzg/dl were compared with those in the second group of 20 children (Table II). When both L M T criteria were used, results of 17 & t h e 20 L M T results were positive (85 -+ 16%, at the 95% confidence limit). All three negative L M T s results occurred in the younger children. Because both groups of children had comparable L M T results, the data were combined and yielded 88 _+ 9% positive L M T results when bPb was >_40 ~g/dl. The EP levels, on average, did not contribute to the predictability of L M T results in the children with bPb ->40 ug/dl. In the initial group of 32 children the mean EP of both LMT-negative and LMT-positive children was 159 #g/dl. In the second group of children the mean EP was 154 # g / d l in the LMT-negative group and 148 ~,g/dl in the LMT-positive children. DISCUSSION The subjects in this study are representative of the majority of Pb-poisoned children in terms of age, social class, race, and geographic location. 5 Distinguishing the subgroup likely to benefit from treatment is the purpose of the LMT. This test identifies children who have a mobilizable and
T a b l e II. Results of lead mobilization test in group 2 Age Criterion
--36 mo
uPb >--200 ~*g/8 hr uPb ratio >-0.6 or 0.7
5/9 6/9
Both criteria
6/9
1 i/11 9/11 (ratio 0.7) 11 / 11 (ratio 0.6) 11/11
uPb, Urinary Pb excretion. hence potentially more toxic Pb burden. 68 Initially it was structured as a 24-hour procedure entailing two injections of C a N a 2 E D T A and a 24-hour urine collection, This proved to be unwieldy in the pediatric population because of the difficulty in successfully completing any timed urine collection in small children. To improve the rate of successful completion of the test, we and others developed shortened 6- to 8-hour versions that allowed it to be performed in an outpatient department. 3, 9, to This shortened test reduced the cost and improved the likelihood of obtaining complete urine collections. In our previous efforts to develop an 8-hour L M T , we performed 83 24-hour tests and obtained complete urine collections in only 38. 3 In the current study our success rate was well over 90%. Even in this modified testing form, dedicated personnel are necessary for complete urine collections. Unfortunately,
Volume 119 Number 2
few medical centers or physician's offices have the necessary personnel to offer the LMT. Instead, providers are likely either to refer patients to Pb treatment centers, to treat empirically, or to follow the patients clinically while intervening environmentally to eradicate the Pb source. The latter two approaches may result in either overtreatment (i.e., chelation of children who do not have a Pb diuresis induced by medication) or in delay of treatment and hence ongoing exposure to potentially toxic amounts of Pb. A second, more theoretic concern has been raised about the safety of the LMT.11 Data from a study of rats indicated the potential for tissue redistribution of Pb after single intraperitoneal injections of CaNa2EDTA, resulting in transient increases in Pb content of the CNS. 4 This finding is consistent with historic observations in children with severe Pb encephalopathy, treated with CaNa2EDTA alone, whose neurologic function deteriorated at the initiation of treatment.~2 However, no data that we are aware of support any evidence of CNS damage by a single dose of CaNa2EDTA in children with moderate Pb poisoning. Even in the study by Cory-Schlecta, a~ completion of treatment with CaNa2EDTA did not result in a net increase in CNS Pb. Moreover, the half-life of CaNazEDTA differs considerably in rats from that in human beings, making extrapolation of studies performed in that species to human beings problematic.a3, 14 In any case, children with substantial amounts of mobilizable Pb, as determined by LMT, are immediately admitted for complete chelation courses, thereby reducing soft-tissue Pb by the completion of a full course of therapy. The LMT is efficacious but not widely available, so we attempted to address the issue of who most needs this test. Our data demonstrate that children, especially those more than 36 months of age, are very likely to have a positive LMT result if their blood Pb concentrations are >_40 #g/ dl. Both our study groups yielded comparable data on LMT outcomes when bPbs were >-40 #g/dl: 29 of 32 and 17 of 20 patients had positive results. On the other hand, at any age, if blood Pb is
