Document QkreRox9nvovxodRJa1LDZpwE

. O lV T SiO N O F TH E XSEFA RTM EN T O F PU B L IC W ELFA R E Ba l t imor e Cit y Hospit a l s F r e d e r ic G. Hu bba r d DIRECTOR A 9 A O EASTERN AVENUE BALTIMORE 24, MARYLAND Ju ly 19, 1963 DEPARTM ENT O F PE D IA T R IC S R ob ert A . Kehoe, M.D. The K e tte rin g L ab o rato ry C ollege o f Medicine Eden Avenue C in c in n a ti 1 9 , Ohio . Dear D r. Kehoe: Thank you fo r you r l e t t e r o f J u ly 1 6 th . I a p p r e c ia te you r answ ers to th e q u e s tio n s t h a t I r a i s e d ". I am p a r t i c u l a r l y g la d t o know t h a t y o u r d a ta i n d i c a t e d e f i n i t e l y t h a t the lead co n cen tratio n in the b rain is sig n ific a n tly elevated in acu te lead encephalopathy. I c e rta in ly agree w ith you th a t the most im portant a s p e c t o f t h i s problem i s th e p r e v e n tiv e o n e . We hope t o tu r n t o t h i s problem when th e c u r r e n t s tu d ie s on tre a tm e n t a r e co m p leted . I am e n c lo s in g a copy o f my p ap er b e f o r e th e A m erican P e d i a t r i c S o c i e t y , May 1 9 6 3 , on th e combined u se o f EDTA and BAL. Perhap s ev en w ith o u t s l i d e s i t may g iv e you some id e a a s to o u r f i n d i n g s . I am a l s o e n c lo s in g a p e n c i l draw ing o f th e u rin e stre a m s p l i t e r t h a t we have employed f o r some s p e c i a l s t u d ie s i n th e p a s t . T h is d e v ic e w i l l work i f g r e a t c a r e i s ta k e n t o l e v e l i t e x a c t l y and i f th e two c a p i l l a r y siphon arms a r e v e r y c a r e f u l l y uiade by th e g l a s s b lo w e r. They sh o u ld be i d e n t i c a l in s iz e and sh ap e. Concerning q u estion #3 th a t I ra is e d , in reread in g your paper I cannot find th e e x a c t paragraph from which I gained the im pression th a t lead ab so rp tio n is a c c e le r a te d in th e lead in to x ic a te d p a tie n t. However, your response has c la r if ie d th is p o in t. JJC /esp THE USE OF EDATHAMIL CALCIUM DISODIUM (EDTA) AND 2 , 3-DIMERCAPTOPROPANOL (BAL) IN COMBINATION FOB THE TREiTA ENT OF ACUTE LEAD ENCEPHALOPATHY J . Julian Chisolm, J r ., M .D .* Department of Pediatrics, Baltimore C ity Hospitals Baltimore, Maryland Introduced by Harold . Harrison, M .D . Mr. Chairman, members of the American Pediatric Society and guests the present treatment of acute lead encephalopathy with edathamil calcium disodium is for from satisfactory. While no obvious clin ical complications arise from the use of EDTA in children without encephalopathy, we have observed children with acute encephalopathy whose impaired renal and central nervous system functions deteriorate further during the first 48 - 72 hours of EDTA administration. While such deterioration may reflect the natural progression of fulminant d ise a se , recent studies in animals suggest that EDTA may its e lf contribute to this deterioration. This report is addressed to two questions: 1) Does EDTA enhance the toxic effects of lead in children with severe plumbism? and 2} If so , can such toxic metabolic effects be reversed by the simultaneous administration of a thiol reagent such as 2 , 3-dimercaptopropanol or BAL? To investigate these questions 40 young children with acute plumbism, including 15 with encephalopathy, have been studied at the Baltimore City Hospitals and Harriet Lane Home. Biochemical parameters sensitive to the toxic effects of lead were measured serially during treatment. EDTA and BAL were given in a uni form manner as follows: Both were given intramuscularly a t 4 hour intervals for 5 days: BAL .in a dose of 4 mg/kg/dose and the calcium salt of EDTA in a dose of 12.5 m g /kg /d o se. One of the principal toxic actions of lead is inhibition of sulphydryl enzymes. Such an enzyme is d-aminolevUlinic acid dehydrase. This enzyme is widely dis tributed throughout the tissu e s and many studies show that it is exquisitely sensitive to the toxic effects of lead. Thus, changes in the concentration of its substrate, d-aminolevulinic acid , in body fluids can provide an index of lead* s toxic effect upon i t . MayT emphasize that d-aminolevulinic acid# a precursor of heme, is not -3 toxic and is n^ot w.nonww*n. to bear any' direct relation to the symptoms of plumbism. This system is chosen only as a model for study. SLIDE I PLEASE - The concentration of d -am ln oiev u lin ic acid in plasma was m easured in all 40 patients prior to treatm ent. Measurements were also mad in 10 healthy ch ild ren . The re su lts ore shown here. Reading from right to le f t , the values tend to rise w ith increasing severity of plumbism. In patients with mild encephalopathy - second column from your left - plasma d - aminolevulinic acid ranges between 0 .2 and i.4 |^/m l. This is 4 - 25 times greater than the mean normal value found in healthy children - as shown in the column at the far right. LIGHTS PLEASE. The studies w e re carrlad lx* 3 phases. . irst - -X7A <rione was admin istered to 10 patients ana the concentration of d-aminolevulinic acid in plasma was measured after the injection of each d ose. During the in itial 48 hours of EDTA therapy, plasma d-ALA concentration increased further if the pre-treatment concen tration was greater than 0 . 2 5 j^/tn1, but not if the pre-treatment concentration was less. 4 Next, BAL and EDTA were given alternately to 4 patients whose in itial plasma d-ALA. was 0 . 2 5 /--t -- '"1_!-- J.n order to determine - whether - ML might reverse the rise in plasma d-ALA observed following EDTA, SLIDE 2, PLEASE - This shows the result in two representative subjects of th is group. BAL was injected first - as designated by the arrow at point B. During the ensuing 4 hours - as indicated by the solid portions of each line - the elevated plasma d-ALA decreased toward normal, but when EDTA was injected at point E the plasma d-ALA increased - as shown by the dotted portion of each lin e . When BAL was again given the rise following EDTA was reversed. These findings indicate that EDTA can enhance, at le a st one of the toxic metabolic effects of lead , and that th is effect can be reversed by BAL. The tMrd phaSe o f th e study was carried out during th e summer of 1962 and includes 11 patients with acute lead intoxication. Four patients, 2 of whom had mild encephalopathy, were randomly allotted to treatment with EDTA alone. Five patients were randomly allotted to combined BAL and EDTA therapy. In addition 2 comatose patients were arbitrarily plsced in the combined therapy group, so that this group K? 0020228 - 5- $k and 3 symptomatic patients without encephalopathy. In th is group alone was given *A as the in itial dose,* beginning 4 hours later both BAL and EDTA were given simultaneously for the next five days. SLIDE 3, PLEASE - The most striking difference between the two groups was the much more rapid decrease in blood lead concentration in the combined therapy patients a s shown in this graph. In each patient blood lead content was measured at 8 , 24, 48, and 72 hours after the start of therapy. The values found at each time are plotted logarithmically on the ordinate as a percentage of the ore-treatment value. The dark circle s show the data for the EDTA patients; the open circles the data for the BAL-EDTA group. By 72 hours blood lead is reduced to 25% or le s s of th e in itial value in the combined therapy group, but, at this tim e, it is still approximately 50% of the initial concentration in the EDTA group. The difference between the two groups is sta tistica lly significant at the 1% level at 8, 24, and 48 hours and at the 0.1% level at 72 hours. NEXT SLIDE, PLEASE. This shows some of tire actual data from which the results on the previous s lide were calcu lated . It is quite clear that blood lead concentration decreases far more rapidly during the first 72 hours in the combined therapy group - as indicated by the solid lines - .' -6- ' than It does to the EDTA group - as indicated by the dotted lines, ' In these patients serial determinations were also made of d-Aminolevulinic acid in plasma and urine and of lead and amino acids in urine. NH2CT SLIDE, PLEASE This show sdata from 6 representative patients. The urine d-aminolevulinic acid output is plotted on the ordinate as the d-ALA/creatinine excretion ratio against time on the a b sc is sa . One can see that d-ALA excretion in itially increases in the EDTA patients - as indicated by the dotted lines - but that it decreases steadily from the start of therapy in the BAL-EDTA group. The excretion of d-ALA shown here,, mirrors well the changes in plasma d-ALA found in each of these patients. Simul taneously, urine amino acid excretion increased in 2 of the 4 EDTA treated patients; but no such increases were detected in the BAL-EDTA group. LIGHTS PLEASE. Urine lead measurements indicate that the more rapid decrease in blood lead concentration in patients treated with both BAL and EDTA is largely due to the higher initial urinary excretion of lead in this group. SLIDE PLEASE - In th is graph the daily urine lead outputs of 4 patients with severe encephalopathy are compared. The height of each bar indicates;the amount of lead excreted on each of the 5 days i / / /// -*' .' / j ? of therapy Two combined therapy patients are compared with 2 ca se s of severe /' ..................................... encephalopathy treated in prior years with EDTA alone. The left-hand member of each pair of bars is from the BAL-EDTA patients , the right-hand bsrh ard frdm the EDTA patients. Patients R .N . and M . G . who received BAL and EDTA excreted 18.6 mg and 15. 3 mg of lead during the first 24 hours. This is 27% and 39% respectively of their 5 day total lead outputs. Patients A.W. and C. R. who received EDTA only excreted 25% and 16% respectively of their 5 day totals during ttie first 24 hours. LIGHTS PLEASE. GIVE METHODS IF BELL HAS HOT RUNG. d-ALA - Mauzerall and Granick Pb - Bessman and Layne M - paper chromatography Although the number of patients studied is small the various parameters measured are consistent within each group so that the following conclusions seemed ju stified . Blood lead decreases much more rapidly when BAL and EDTA are given simultaneously than it does when EDTA is given alone. This difference is XiT 0020231 -8- ` part to the higher in itial rate of urine lead excretion, in addition, BAL may ameliorate some of the5toxic metabolic effects of lead in the tis s u e s , whereas, EDTA, if given alone, in itially enhances some of th ese toxic e ffe c ts. The data on amino acid excretion and d-aminolevulinic acid lev els in plasma and urine are in accord with this hypothesis. With respect to clinical comparisons - I can only say that deterioration of central nervous system function and renal function did not occur in the three sick e st patients who received BAL and EDTA simultaneously. On the basis of previous experience such deterioration might have been anticipated had these children received EDTA alone. These data suggest that the combination of BAL and EDTA is superior to EDTA alone, esp ecially in children with encephalopathy. For such patients supportive measures include: administration of parenteral fluids in amounts sufficient to meet basal needs, to replace d eficits and to provide for adequate urine How; withholding of oral fluids; maintenance of body temperature at normal but not hypothermic levels; control of convulsions with paraldehyde; and prevention of hypoxia . Finally, may I speculate that the combined use of metal binding agents such as EDTA and BAL - which have differing metabolic e ffe cts, - 9' differing toxicities and differing distributions in the tissu e s may be efficacious in other heavy metal poisonings . At le a st the data in lead poisoning suggest that this idea merits exploration. Thank you.