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There are several caveats about the management of patients with lead poisoning. First, the most important aspect of treatment is removal from further exposure to lead. Unfortunately, effective implementation of this therapy is often beyond the control of the clinician but rather depends on a complex interplay of public health, social, and political actions. Currently, the ability to control exposure is generally more applicable to adults with occupational exposures than to children exposed to residential hazards. Second, in children for whom some residual lead exposure potentially continues, optimization of nutritional status is vital in order to minimize absorption. Finally, pharmacologic therapy with chelators, although a mainstay of therapy for symptomatic patients, is an inexact science, with numerous unanswered questions despite almost 50 years of clinical use.2,4,85 The rationale for chelation therapy of lead poisoned patients is that chelators complex with lead, forming a chelate that is excreted in urine, feces, or both. Chelation therapy increases lead excretion, reduces blood concentrations, and reverses hematologic markers of toxicity during therapy. Reports from the 1950s found symptomatic improvement in adults chelated for lead colic.174 The institution of effective combination chelation treatment of childhood lead encephalopathy in the 1960s contributed to the dramatic decline in mortality and morbidity of that devastating degree of plumbism.34 However, the same era saw major advances in pediatric critical care in general and medical management of increased ICP in particular. The situation of chelation therapy for asymptomatic patients with mildly to moderately increased body burdens of lead is even less clear, and many questions regarding efficacy and safety remain.32,60,85,124 To date, long-term reduction of target tissue lead content or reversal of toxicity is not demonstrated in human trials.42,102,138
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All patients with significantly elevated BLLs warrant identification of the lead exposure source, and specific environmental and medical interventions, or both (Table 96–7). In adults, this usually involves worksite changes.41,86,144 The risk of occupational lead exposure correlates with several factors that contribute to the occurrence of respirable lead fumes or dust particles in the worksite atmosphere.144 First, there are hazards inherent in the work process itself, including high temperatures; significant aerosol, dust, or fume production; and a less mechanized workplace (with resulting greater “hands-on” employee exposure). Second, the adequacy of dust elimination, such as local and general ventilation, is critical. The third category is that of worksite and personal hygiene, including proper use of protective clothes and equipment, and thorough housekeeping. Remedial actions might include improvements in ventilation, modification of personal hygiene habits, and optimal use of respiratory apparatus. It is vital to prohibit smoking, eating, and drinking in a lead exposed work area. Work clothes should be changed after each shift and should not be lockered together with street clothes.
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In patients with plumbism caused by retained bullets, surgical removal of this lead source should be considered.28,94,107Table 96–7 also summarizes several specific educational guidelines that may be offered to parents of lead-exposed children.3,14,22 Overarching principles include home lead paint abatement (done preferably by professionals, with the family out of the home), home dust reduction techniques, decreasing soil lead exposure, and nutritional evaluation and counseling. Patients manifesting iron deficiency should be treated, and for others, a diet sufficient in trace nutrients, particularly iron and calcium (which may decrease lead absorption) and vitamin C (which may enhance renal lead excretion) is likely of value.3 Clinicians who have primary responsibility for children with elevated BLLs should refer to the exhaustive monograph developed by the CDC, which details such pediatric case management.22
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Occasionally, children may require urgent GI decontamination to reduce ongoing acute lead exposure. Patients with large burdens of lead paint chips may benefit from prompt institution of whole-bowel irrigation (WBI) (Fig. 94–6) (Antidotes in Depth: A2). The presence of ingested lead foreign bodies is a unique situation that requires careful individualization of management. Several case reports document rapid absorption, with significantly elevated BLLs measured within 24 hours of ingestion in some cases. Such patients warrant baseline BLL determination and frequent repeat BLLs, with consideration for prompt endoscopic removal, particularly with gastric location and increasing BLLs.106,112,172 Proton pump inhibitor and prokinetic therapy are recommended for gastric foreign bodies in an effort to decrease gastric acidity, retention time, and resultant lead dissolution.51 WBI may be an adjunct for more distally located foreign bodies but has not been uniformly successful. Endoscopic or surgical removal may be indicated with delayed passage of foreign bodies, inability to tolerate WBI due to intestinal obstruction, or rapid elevations in BLL soon after foreign body ingestion.51,112,172 The issue of concomitant chelation therapy in patients with significant GI lead burdens is addressed in the following section.
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The indications for and specifics of chelation therapy are determined by the age of the patient, the BLL, and clinical symptomatology (Table 96–8). Three chelators are currently recommended as drugs of choice for the treatment of lead poisoning: BAL (Antidotes in Depth: A25) and CaNa2EDTA (Antidotes in Depth: A27) are used parenterally for more severe cases, and succimer (Antidotes in Depth: A26) is available for oral therapy. A fourth drug, d-penicillamine, has been used orally for patients with mild to moderate excess lead burdens. Unfortunately, d-penicillamine has a toxicity profile that includes life-threatening hematologic disorders and reversible, but serious, dermatologic and kidney effects; consequently, since 1991, its role in lead poisoning treatment at most centers has been largely replaced by succimer. Currently, the American Academy of Pediatrics recommends d-penicillamine use only when unacceptable adverse reactions to both succimer and CaNa2EDTA occur, and it remains important to continue chelation.2,3
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Chelation is not a panacea for lead poisoning. It is a relatively inefficient process, with a typical course of therapy decreasing body content of metal by only 1% to 2%.85,111 Furthermore, there is little evidence that chelators have significant access to critical sites in target organs, particularly in the brain.37 Assumptions that reducing BLL will improve subtle neurocognitive dysfunction or other subclinical organ toxicity are appealing theoretically but unproven.42,138
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Lead encephalopathy is an acute life-threatening emergency and should be treated under the guidance of a multidisciplinary team in the intensive care unit of a hospital experienced in the management of critically ill children. Encephalopathy requires treatment by combination parenteral chelation therapy with maximum-dose BAL and CaNa2EDTA along with meticulous supportive care.2,22,34 Such combination therapy has a dramatic effect on decreasing BLL—to 50% or less of baseline within 15 hours and to 75% to 80% of baseline by 48 to 72 hours. It is far superior to monotherapy with CaNa2EDTA in this regard.34
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Chelation is instituted with 450 mg/m2/d (or 25 mg/kg/d) of intramuscular (IM) BAL in six divided doses.2,22 The second dose of BAL is given 4 hours later followed immediately by IV CaNa2EDTA, in maximum concentration of 0.5% solution, at 1500 mg/m2/d (or 50 mg/kg/d) as a continuous infusion or in divided-dose infusions over several hours.2,22,125 The delay in initiating CaNa2EDTA infusion is based on past observations of clinical deterioration in encephalopathic patients treated with CaNa2EDTA alone.2,34 Therapy is typically continued with both agents for 5 days, although in milder cases with prompt resolution of encephalopathy and decrease of BLL to below 50 μg/dL, BAL may be discontinued after 3 days, with continuation of CaNa2EDTA alone for 2 more days.
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The presence of radiopaque material in the GI tract on radiography has raised concern that parenteral chelation might enhance absorption of residual gut lead. This issue is not settled fully,32,78 but most experts advocate initiation of parenteral chelation without delay in seriously symptomatic patients. It seems reasonable to simultaneously attempt whole bowel irrigation with a polyethylene glycol preparation.2 One case report described the successful use of chelation therapy begun with parenteral BAL and CaNa2EDTA and then enteral succimer (initiated after 3 days of WBI) for a child with lead encephalopathy and an extraordinarily high BLL of 550 µg/dL.57 This issue applies as well to ingested lead foreign bodies, as noted above.106,112,172 Generally, oral fluids, feedings, and medications are withheld for at least the first several days. Careful provision of adequate IV fluids optimizes kidney function while avoiding overhydration and the risk of exacerbating cerebral edema. The occurrence of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may be associated with lead encephalopathy,34,163 so urine volume, specific gravity, and serum electrolytes should be closely monitored, especially as fluids are gradually liberalized with clinical improvement (Chap. 19). In the context of lead encephalopathy, this approach would need to be tempered by the requirement for maintaining good urine output to optimize chelation efficacy.
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Seizure control is usually accomplished with benzodiazepines. Ongoing anticonvulsant therapy is typically continued with phenytoin or phenobarbital. Rarely, continuous infusions of midazolam or high-dose pentobarbital therapy may be necessary.178
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Modern approaches to the management of cerebral edema and increased ICP have not been critically evaluated in the context of lead encephalopathy. Lumbar puncture should probably be avoided if lead encephalopathy is highly suspected and acute infectious processes are not. Of note, repeated lumbar puncture was used as an adjunct to the treatment of lead encephalopathy associated with increased ICP in the 1950s but was complicated by proximate death when signs of impending herniation were present.35 It seems reasonable that measures such as prevention of hypoxia and hypercarbia with tracheal intubation and controlled ventilation, seizure treatment and prophylaxis, maintenance of adequate cerebral perfusion pressure, mild hyperventilation with PCO2 of 30 to 35 mm Hg, and neutral head positioning with elevation of the head of the bed to 30 degrees might have a salutary effect at minimal risk of increased iatrogenic morbidity.2,162 Mannitol administration may prove beneficial in deteriorating patients and has been particularly suggested as an adjunctive therapy when cerebral edema is complicated by SIADH or impaired kidney function.34 Whether more aggressive measures, such as acute hyperventilation for impending herniation, ICP monitoring, drainage of ventricular cerebrospinal fluid, decompressive craniectomy, induced hypothermia, or barbiturate coma would decrease mortality or morbidity further is unknown.
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For children with milder effects or who are asymptomatic with BLL greater than 70 μg/dL, chelation with a two-drug regimen similar to that used for encephalopathy is recommended. It is likely that this group of patients will require only 2 to 3 days of BAL in addition to 5 days of CaNa2EDTA. Some authors have suggested that asymptomatic patients in this group, particularly those with BLLs below 100 μg/dL, might also be adequately treated with CaNa2EDTA alone,181 succimer plus CaNa2EDTA, or even succimer alone, most recently a large cohort of 1193 Nigerian children with moderate to severe lead poisoning were managed with succimer alone. Although data concerning long term efficacy is still emerging, this appears to be a safe alternative if circumstances preclude standard two drug chelation.164a Intensive care monitoring may be prudent for such patients as well, at least during the initiation of chelation therapy.111
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Chelation therapy is widely recommended for asymptomatic children with BLLs between 45 and 70 μg/dL.2,4,22,111 Children without overt symptoms may be treated with succimer alone, which has documented efficacy in lowering BLLs and short-term safety since its approval by the Food and Drug Administration in 1991.63,91 Succimer is initiated at 30 mg/kg/d (or 1050 mg/m2/d) orally in three divided doses; this is continued for 5 days and then decreased to 20 mg/kg/d (or 700 mg/m2/d) in two divided doses for 14 additional days.2,62 The original data establishing this empiric dosing regimen were based on body surface area rather than weight.62 For younger children, the alternative dosing by body weight results in suboptimal dosing.136 Although the ability to chelate children orally with succimer makes it tempting to prescribe routinely for outpatient therapy and some animal evidence suggests succimer does not enhance enteral lead absorption,80 clinical reports suggest that children must be protected from continued lead exposure during succimer chelation.31,33 Home abatement and reinspection should be accomplished before initiation of ambulatory succimer therapy; if this is not feasible, hospitalization is still warranted. Alternative regimens (for rare patients with succimer intolerance or allergy or because of parental noncompliance) include parenteral chelation with CaNa2EDTA at 25 mg/kg/d for 5 days.2
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After initial chelation therapy, decisions to repeat treatment are based on clinical symptoms and follow-up BLLs. Patients with encephalopathy or any severe symptoms or with an initial BLL above 100 μg/dL often require repeated courses of treatment. It is suggested that at least 2 days elapse before restarting chelation. The precise regimen and dosing of chelating agents are determined by ongoing symptomatology and the repeat BLLs (Table 96–8). A third course of chelation should rarely be necessary sooner than 5 to 7 days after the second course ends.125 For patients with milder degrees of plumbism (eg, asymptomatic, initial BLL <70 μg/dL), it is reasonable to allow 10 to 14 days of reequilibration before restarting treatment.2
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The management of asymptomatic children with BLLs of 20 to 44 μg/dL is controversial.31,100,110,166 The National Institutes of Health–sponsored Treatment of Lead-exposed Children (TLC) trial found only modest efficacy of succimer in reducing BLL. Furthermore, at 3 years postenrollment, no benefit was noted in treated patients on measures of cognition, neuropsychiatric function, or behavior.138 This large study enrolled 780 children in a multicenter, randomized, placebo-controlled, double-blind trial, but it still has been criticized, particularly for using a single chelator and having failed to lower BLL significantly over time between treated and control groups.151 Of note, small but statistically significant decrements in growth velocity were noted in the treatment group, which might reflect trace mineral depletion.124 Since its initial publication, the primary findings of the TLC trial on lack of cognitive improvement were confirmed in a 7 year follow-up study.42 In addition,a reanalysis of the original data found that decreasing blood concentrations did correlate with improved cognitive scores over the initial 36 month trial period (~4 IQ points for each 10 μg/dL decrease in BLL), but only in the placebo group.96 Nevertheless, there may still be potential indications for occasional chelation treatment in this group, including BLLs at the higher end of the range (eg, 35–44 μg/dL), especially if BLLs remain the same or increase over several months after rigorous environmental controls are instituted, in younger children (eg, younger than 2 years), in children with evidence of biochemical toxicity (an elevated erythrocyte protoporphyrin concentration, after iron supplementation, if necessary), or any hint of subtle symptoms. Currently, the CDC19 and the American Academy of Pediatrics2,3 recommend aggressive environmental and nutritional interventions with close monitoring of blood lead concentrations, without routine chelation therapy, for such children.
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BLLs of 5 to 19 μg/dL are defined by the CDC as representing excessive exposure to lead but not requiring chelation therapy. Close monitoring (for the 5–14 μg/dL range) and careful environmental investigation and interventions as necessary (particularly for the 15–19 μg/dL range) are appropriate and sufficient.2,3,22 The educational approaches outlined earlier should be included in the case management of all children with even modestly elevated lead levels (Table 96–7).
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General Considerations.
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The first principle in the treatment of adults with lead poisoning is that chelation therapy may not substitute for adherence to OSHA lead standards at the worksite and should never be given prophylactically.41,82 In addition to the guidelines for decreasing lead exposure noted earlier, chelation therapy is indicated for adults with significant symptoms (encephalopathy, abdominal colic, severe arthralgias, or myalgias), evidence of target organ damage (neuropathy or nephropathy), and possibly in asymptomatic workers with markedly elevated BLLs or evidence of biochemical toxicity.86,134,144,150Table 96–8 outlines suggested chelation therapy regimens for adults. For encephalopathic adult patients, our practice is to recommend combined BAL and CaNa2EDTA therapy, just as for children, although some clinicians suggest that adults with severe lead poisoning may be successfully treated with CaNa2EDTA alone in doses of 2 to 4 g/d by continuous IV infusion.84 Recent reports support the use of succimer in adult patients with mild to moderate plumbism after environmental and occupational remedies have been instituted.92,128 Chelation therapy should also be considered in the perioperative period for patients undergoing surgical removal of retained bullets or débridement of adjacent lead-contaminated tissue.94,107,148Treatment of patients with acute TEL toxicity is largely supportive, with sedation as necessary. For patients seen soon after a large-volume ingestion, nasogastric suction, with airway protection as needed, may be warranted. In general, chelation therapy for TEL toxicity is associated with enhanced lead excretion12 but has not been found to be clinically efficacious.144,164,180 However, for symptomatic, especially encephalopathic patients with very elevated BLLs (in whom there may be a significant component of metabolically derived inorganic lead toxicity), we recommend chelation therapy.
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Pregnancy, Neonatal, and Lactation Issues.
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An area of particular concern in the management of adult plumbism involves decisions regarding therapy during pregnancy. As noted previously, lead freely passes the placental barrier and accumulates in the fetus throughout gestation. Chelation therapy during early pregnancy poses theoretical problems of teratogenicity, particularly that caused by enhanced excretion of potentially vital trace elements, or translocation of lead from mother to fetus (Antidotes in Depth: A25, A26, and A27). Symptomatic pregnant women with elevated BLLs certainly warrant chelation therapy, regardless of these concerns. Additionally, of some reassurance regarding fetal health, a case series and 25 year literature review of lead poisoning during pregnancy found no reports of chelation-associated birth defects in the handful of published cases.152 It should be noted that despite decreases in maternal BLL with chelation therapy, newborn BLLs may be considerably higher and, in some cases, may approximate the pretreatment maternal BLL, implying limited efficacy for in utero fetal chelation. However, in these cases, the hemoglobin concentration of the newborn was generally much higher than that of the mother, and thus some of the maternal–neonatal difference in BLL may simply reflect this difference in hemoglobin concentration and hence total blood lead content. In general, there currently seems little support for routine chelation therapy in pregnant women who would not otherwise warrant treatment based on their own symptoms or degree of elevated BLL. Calcium carbonate supplementation may be considered because its use is associated with decreased bone resorption during pregnancy and thus possibly lessened fetal lead exposure.74
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Postnatally, infant BLLs may decline over time without chelation, but this occurs very slowly.141 In two reported neonates exposed to prenatal maternal chelation who were then monitored for 2 weeks postpartum, the BLL remained stable or increased until chelation therapy was instituted.123,165 In two additional cases of neonates whose mothers were not treated prepartum, BLLs also remained stable or increased for 17 days to 3 weeks.55,159 Thus, postpartum chelation therapy is warranted for neonates, depending on BLLs, as per the guidelines described above for older children. Exchange transfusion might be considered for neonates with extremely elevated BLLs.13 Succimer chelation therapy was used for one neonate with presumed organic lead exposure via maternal gasoline sniffing.129
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Lastly, the issue of allowing mothers with elevated BLLs to breastfeed their infants may arise. Breast milk from heavily exposed mothers may be a potential source of lead exposure and may require lead concentration analysis before breastfeeding can be safely recommended.7,48 One small case series found that breast milk from two women with BLLs of 34 and 29 μg/dL, respectively, had clinically insignificant lead content (<0.01 μg/mL).7 Breast milk analysis may be warranted in some cases, particularly with BLLs of 35 μg/dL or greater, before safely advising continued nursing. Despite these considerations, the majority of women without excessive lead exposure should still be encouraged to breastfeed. Of note, one study has found that a relatively simple intervention, calcium supplementation (1200 mg/d of elemental calcium as calcium carbonate), reduces breast milk lead content by 5% to 10%.47