A27: Antidotes in Depth

Edetate calcium disodium (CaNa₂EDTA) is a chelator that is primarily used for the management of severe lead poisoning (blood lead concentrations >70 mg/dL) in conjunction with dimercaprol (British anti-Lewisite {BAL}). Edetate calcium disodium has been replaced by succimer (2,3-dimercaptosuccinic acid) for the treatment of patients with lead concentrations between 45 and 70 µg/dL. Recently, in a clinical trial with much criticism, disodium EDTA (Na₂EDTA) (not approved by the US Food and Drug Administration {FDA} and extemporaneously compounded) was demonstrated to produce some reduction in adverse cardiovascular outcomes in patients with a history of myocardial infarction.^3,21,32,38 This preparation is not to be used for lead chelation due to the potential for life-threatening hypocalcemia.

Ehylenediaminetetraacetic acid (EDTA) was first discovered and synthesized in the 1930s. In the late 1940s, it was approved by the FDA as a food additive. Work on using CaNa₂EDTA for lead toxicity began in the 1950s. At the same time, investigation into the uses of EDTA for the reversal of cardiovascular disease began.

The CaNa₂EDTA mobilization test was once widely recommended as a diagnostic aid for assessing the potential benefits of chelation therapy.^35,36 Currently, it can only be considered obsolete.^14,18,21 Criticisms of the test include difficulties with administration of the antidote, unreliability as a predictor of total-body lead burden, expense, and the risk of worsening toxicity through redistribution of lead to either the kidney or the brain.¹⁸

Chemistry

Edetate calcium disodium is an ionic, water-soluble compound with a molecular weight of 374.27 (anhydrous) and a formula of C₁₀H₁₂CaNa₂O₈.

Mechanism of Action

Edetate calcium disodium belongs to the family of polyaminocarboxylic acids. Although it is capable of chelating many metals, its current use is almost exclusively in the management of lead poisoning. The term chelate has its origin in the Greek word chele, which means “claw,” implying an ability to tightly grasp the metal.⁴⁸ Implicit in chelation is the formation of a ring-structured complex. When CaNa₂EDTA chelates lead, the calcium is displaced and the lead takes its place, forming a stable ring compound.³⁰ Bone is the primary source of lead chelated by CaNa₂EDTA. Blood lead concentration drops due to urinary elimination; however, once chelation is stopped, redistribution to soft tissues, including the brain, and then, ultimately, the return of lead to bone occurs.¹¹ Zinc is also capable of displacing calcium and forming a stable chelate, whereas copper and mercury are not.¹¹

Edetate calcium disodium is a highly polar drug with a small volume of distribution (Vd) due to its polar nature and approximates that of the extracellular fluid compartment in normal individuals,^25,30 but the Vd is less in patients with renal dysfunction.³⁹ Edetate calcium disodium appears to penetrate erythrocytes poorly,^2,25 and less than 5% of CaNa₂EDTA gains access to the spinal fluid.^25,30 Oral administration of CaNa₂EDTA is not practical because of an oral bioavailability of less than 5%. The half-life is about 20 to 60 minutes.^6,25,30 Renal elimination approximates the glomerular filtration rate,³⁷ which correlates with creatinine clearance,⁹ resulting in the excretion of 50% of CaNa₂EDTA in the urine within 1 hour, and more than 95% within 24 hours.^25,30 Elimination is all kidney with no appreciable metabolism. When CaNa₂EDTA combines with lead, it forms a stable, soluble, nonionized compound subsequently excreted in the urine. Following CaNa₂EDTA administration, urinary lead excretion is increased 20- to 50-fold.^13,40

Animals

Animal studies demonstrate a decrease in tissue lead stores, including brain concentrations, when measurements are performed following CaNa₂EDTA therapy.²⁸ A rat study examining the effect of a single dose of CaNa₂EDTA on brain lead concentrations demonstrated a significant increase in brain lead concentrations,²¹ suggesting that CaNa₂EDTA may initially mobilize lead and facilitate redistribution to the brain. Additional doses enhance lead elimination, reduce blood lead concentrations, and subsequently reduce brain lead concentrations. The initial increase in brain lead may explain why some human case reports demonstrate worsening lead encephalopathy when CaNa₂EDTA is used without concomitant dimercaprol (BAL) chelation therapy.

Humans

Edetate calcium disodium is capable of reducing blood lead concentrations, enhancing renal excretion of lead, and reversing the effects of lead on hemoglobin synthesis.¹⁸ With chronic lead exposure, blood lead concentrations rebound considerably in the days to weeks following cessation of CaNa₂EDTA.^1,2,27 Although CaNa₂EDTA has been used clinically since the 1970s, no rigorous clinical studies have ever been performed to evaluate whether CaNa₂EDTA is capable of reversing the neurobehavioral effects of lead.^19,20 Chelators are incapable of dramatically decreasing the body burden of lead, because only several milligrams of lead are eliminated during chelation.^13,15,41 Children evaluated with blood lead concentrations of 25 to 50 µg/dL who were given CaNa₂EDTA for 5 days revealed very little difference in blood lead, bone lead, or erythrocyte protoporphyrin concentrations, when compared with pretreatment values.³³ A study in children demonstrated no additional benefits of CaNa₂EDTA on cognitive performance beyond that which was achieved by limiting further lead exposure and correcting an iron deficiency anemia.^40,42 A follow-up study in children with initial blood lead concentrations between 25 and 55 µg/dL also suggested an interaction between initial iron status, blood lead concentration, and an improvement in perceptual motor performance over a 6-month period. Both the correction of iron deficiency and a reduction in blood lead concentration (accomplished with limiting further exposure and or CaNa₂EDTA chelation) contributed to the improvement, emphasizing a critical need to correct iron-deficiency anemia as well as limit lead exposure.⁴³

The principal toxicity of CaNa₂EDTA is related to the metal chelates it forms. In mice, the intraperitoneal (IP) LD₅₀ values of various CaNa₂EDTA metal chelates are CaNa₂EDTA, 14.3 mmol/kg; lead EDTA, 3.1 mmol/kg; and mercury EDTA, 0.01 mmol/kg.

When CaNa₂EDTA is given to patients with lead poisoning, the resultant sites of major renal toxicity are the proximal convoluted tubule, the distal convoluted tubule, and the glomeruli, possibly caused by the release of lead in the kidneys during excretion.³⁰ Of the 130 children who received both dimercaprol and CaNa₂EDTA, 13% had biochemical evidence of nephrotoxicity, and 3% developed acute oliguric renal failure, which resolved over time; none needed hemodialysis.³⁶ Other studies failed to demonstrate any cases of renal failure in more than 1000 patient courses of therapy when CaNa₂EDTA was given in divided daily doses of 1000 mg/m² intravenously (IV) over 1 hour every 6 hours.³⁴ Because lead toxicity causes renal damage independent of chelation, it is important to monitor renal function closely during CaNa₂EDTA administration and to adjust the dose and schedule appropriately.^37,38 Nephrotoxicity may be minimized by limiting the total daily dose of CaNa₂EDTA to 1 g in children or to 2 g in adults, although higher doses may be needed to treat lead encephalopathy. Continuous infusion while maintaining good hydration increases efficacy and decreases toxicity.³⁷ Because the administration of disodium EDTA can lead to life-threatening hypocalcemia and death, CaNa₂EDTA is the preparation of choice for lead toxicity and hypocalcemia is no longer a clinical concern.^4,9 Other adverse clinical effects of CaNa₂EDTA, most of which are uncommon, include malaise, fatigue, thirst, chills, fever, myalgias, headache, anorexia, urinary frequency and urgency, sneezing, nasal congestion, lacrimation, glycosuria, anemia, transient hypotension, increased prothrombin time, and inverted T waves.^11,30 Various mucocutaneous lesions in two patients included cheilosis and sore throat, magenta tongue, and papular lesions over the face, trunk and extremities, attributed to zinc deficiency.⁷ Mild increases in alanine aminotransferase and aspartate aminotransferase, which are usually reversible, and decreases in alkaline phosphatase are frequently reported. Extravasation may result in the development of painful calcinosis at the injection site.^40,44 Depletion of endogenous metals, particularly zinc, and perhaps iron, and manganese, can result from chronic therapy.^12,47 An animal study suggests that gastrointestinal lead absorption may be enhanced by either IP or oral administration of CaNa₂EDTA²⁹; consequently, removal of lead from the environment should always remain the first strategy in the management of lead toxicity. In the event of exposure to a new lead source, decontamination of the gastrointestinal tract must complement chelation.³⁵

Although CaNa₂EDTA is FDA pregnancy category B, there are no adequate and well-controlled studies in pregnant women and a risk-to-benefit analysis must be made if its use is considered. It is not known whether CaNa₂EDTA is excreted in human milk, but Briggs considers breast-feeding a contraindication.⁸

In a model of lead poisoning in pregnant rats, fetal resorption decreased and the number of live fetuses increased when CaNa₂EDTA was used, although the placental concentrations of lead were increased.²³ Zinc concentrations were not affected. However, another study found that when CaNa₂EDTA was given to pregnant rats not poisoned with lead, increases in submucous clefts, cleft palate, adactyly/syndactyly, curly tail, and abnormal ribs and vertebrae resulted.¹⁰ These teratogenic effects occurred with doses of CaNa₂EDTA comparable to human doses and without causing noticeable changes in the mother except for weight gain. Use of zinc calcium EDTA and zinc EDTA preparations in pregnant rats caused no teratogenic effects at low doses, but resulted in the development of submucous cleft palates in 30% of the offspring receiving the higher dose of zinc calcium EDTA.¹⁰ Another study in rats with doses 25 to 40 times that used in humans revealed fetal malformations that were prevented by simultaneous zinc supplementation.¹¹

There has never been a clinical trial to identify the best dose of CaNa₂EDTA or how best to administer the dose. The most commonly recommended dose is determined by the patient's body surface area or weight (up to a maximum dose), the severity of the poisoning, and renal function (Chap. 96; Tables 96–8 and A27–1).^18,33,40 For patients with lead encephalopathy, the dose of CaNa₂EDTA is 1500 mg/m²/d, approximately 50 to 75 mg/kg/d, by continuous IV infusion, starting 4 hours after the first dose of dimercaprol and after an adequate urine flow is established.¹⁷ The dose in obese patients has not been studied. A maximum dose of 3 g is suggested. Simultaneous dimercaprol and CaNa₂EDTA therapy is administered for 5 days, followed by a rest period of at least 2 to 4 days, which permits lead redistribution. For adults with lead nephropathy, the following dosage regimen is recommended: 500 mg/m² every 24 hours for 5 days for patients with a serum creatinine of 2 to 3 mg/dL; every 48 hours for three doses for a serum creatinine of 3 to 4 mg/dL; and one dose for a serum creatinine concentration higher than 4 mg/dL.¹¹ Previous recommendations were to limit the daily dose to 50 mg/kg when CaNa₂EDTA is used in patients with renal dysfunction.^25,37,39 There is limited evidence to suggest that folic acid, pyridoxine, and thiamine increase the efficacy of CaNa₂EDTA⁴⁵; therefore, data are inadequate to recommend their routine administration. A blood lead concentration should be measured one hour after the CaNa₂EDTA infusion is discontinued in order to avoid falsely elevated blood lead concentration determinations.

In symptomatic children without manifestations of lead encephalopathy, the dose of CaNa₂EDTA is 1000 mg/m²/d, approximately 25 to 50 mg/kg/d, in addition to dimercaprol at 50 mg/m² every 4 hours. However, with the FDA approval of succimer, and the demonstrated ability to reduce brain lead concentrations in animals, succimer has essentially replaced CaNa₂EDTA as the chelator of choice in lead-poisoned children without encephalopathy and lead concentration less than 70 µg/dL.^15,27

Due to the pain associated with intramuscular (IM) administration, it is recommended that CaNa₂EDTA be administered at concentrations of approximately 0.5% by continuous IV infusion over 24 hours in 5% dextrose or 0.9% NaCl.¹⁸ The package insert recommends infusing the dose over 8 to 12 hours.¹¹ Higher concentrations may lead to thrombophlebitis. Edetate calcium disodium is incompatible with other solutions. Careful attention to total fluid requirements in children and patients who have or who are at risk for, lead encephalopathy is paramount.^30,40 Rapid IV infusions in patients with lead encephalopathy may increase intracranial pressure and cerebral edema. In children with acute lead encephalopathy, starting BAL 4 hours prior to CaNa₂EDTA appears to be more effective than starting CaNa₂EDTA prior to and simultaneously with BAL.^16,19 In addition, treating with two chelators also reduces the blood lead concentration significantly faster than CaNa₂EDTA alone, while maintaining a better molar ratio of chelator to lead.¹⁶

If CaNa₂EDTA is to be administered IM to avoid the use of an IV and fluid overload, then either procaine or lidocaine is added to the CaNa₂EDTA in a dose sufficient to produce a final concentration of 0.5% (5 mg/mL). This can be accomplished by mixing 1 mL of a 1% procaine or 1% lidocaine solution with each mL of chelator.^11,30 The procaine or lidocaine minimizes pain at the injection site.

The possible benefit of combining CaNa₂EDTA with succimer or 2,3-dimercapto-1-propane-sulfonic acid (DMPS) is under investigation in animals.^22,24,46 The combination of CaNa₂EDTA with succimer appears more potent than either individual chelator in promoting urine and fecal lead excretion, and decreasing blood and liver lead concentrations. However, this approach may increase zinc depletion.⁴⁶

A retrospective analysis compared the combination of BAL and CaNa₂EDTA with succimer and CaNa₂EDTA in children with blood lead concentrations of about 35 to 70 µg/dL (up to 90 µg/dL for the BAL group).⁵ Equivalent reductions in blood lead concentrations were demonstrated with fewer adverse events in the succimer group. One case report of a child with lead encephalopathy and an extremely high blood concentration of 550 µg/dL employed initially a combination of BAL and CaNa₂EDTA followed by succimer, but a rebound increase in the lead concentration resulted in the addition of CaNa₂EDTA.²⁶ More data are needed to confirm this approach.

Edetate calcium disodium is available as calcium disodium versenate in 5-mL ampules containing 200 mg of CaNa₂EDTA per mL (1 g per ampule).³⁰ Disodium edetate (sodium EDTA) should not be considered an alternative to CaNa₂EDTA because of the risk of life-threatening hypocalcemia associated with sodium EDTA use.

• Edetate calcium disodium reduces blood lead concentrations, enhances urinary lead excretion, and reverses lead-induced hematologic effects.

• Edetate calcium disodium remains the standard of care for patients with lead encephalopathy when used in conjunction with dimercaprol.

• The first dose of dimercaprol should precede the first dose of CaNa₂EDTA by 4 hours.

• Recommended doses and schedules should not be exceeded and should be reduced when the creatinine clearance is reduced.

• Patients should be well hydrated to achieve an adequate urine flow prior to and during CaNa₂EDTA therapy.

References