WORKUP	Section 5 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab Studies:

• Whole blood lead level: This is the most sensitive and specific test in the evaluation of lead toxicity. In children, levels greater than 10 mcg/dL are considered to be significant and require intervention. Levels greater than 70 mcg/dL are associated with encephalopathy. In adults, levels as low as 20 mcg/dL are associated with headache, irritability, and difficulty performing fine tasks. Levels of 60-80 mcg/dL are associated with anemia, renal insufficiency, abdominal colic, and constipation. Levels greater than 80 mcg/dL require immediate hospitalization and chelation therapy because they commonly are associated with overt serious toxicity. In adults, encephalopathy is associated with levels greater than 100 mcg/dL.

• Erythrocyte protoporphyrin: Because lead inhibits the conversion of delta-aminolevulinic acid dehydrase and ferrochelatase, delta-aminolevulinic acid cannot be converted to porphobilinogen, and iron is not incorporated into protoporphyrin. Hence, erythrocyte protoporphyrin is elevated to levels greater than 35 mcg/dL, a finding that also is common in iron deficiency anemia.

• Complete blood count: The peripheral smear may show evidence of hemolysis, normochromic or hypochromic microcytic anemia (due to iron deficiency and decreased hemoglobin synthesis), and basophilic stippling of the RBCs. Basophilic stippling is the result of aggregation of ribosomes in the RBCs and accumulation of byproducts of ribonucleic acid degradation. It is not specific to lead toxicity and may occur in a number of other different conditions such as arsenic poisoning, thalassemia, and sideroblastic anemia.

• Reticulocyte count: The reticulocyte count may be elevated because of increased RBC destruction and reduced heme synthesis.

• Electrolytes: Electrolyte abnormalities may elucidate the differential diagnosis. Serial electrolyte tests are indicated for patients with persistent severe vomiting and diarrhea and for patients with encephalopathy. Sodium abnormalities may herald the development of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or diabetes insipidus.

• Renal function tests: Renal function tests may reveal an elevated BUN and creatinine secondary to lead nephropathy. Uric acid levels may be elevated, even in the absence of gout.

• Urinalysis: Aminoaciduria, glycosuria, and phosphaturia may relate to a reversible Fanconilike effect on the renal tubule. Low molecular weight proteinuria may precede creatinine elevations. An elevated urine specific gravity in a setting of decreased urine output heralds the SIADH. An increase in dilute urine output heralds diabetes insipidus.

• Other tests: Liver transaminases may be elevated in acute lead poisoning. The bilirubin and alkaline phosphatase levels may remain within the reference range.

• Pancreatic function tests: These tests may reveal pancreatitis.

• Thyroid function tests: These tests may reveal hypothyroidism, which is common in chronic lead exposure.

Imaging Studies:

• Abdominal radiographs: Abdominal radiographs may show radiopaque spicules for as many as 36 hours following an ingestion of lead paint chips or folk remedies. The presence of lead spicules on the abdominal radiograph of a symptomatic patient is an ominous finding and represents an indication for whole bowel irrigation. The absence of lead spicules does not rule out lead toxicity.

• Bone radiographs: Imaging studies of the long bones of children may show areas of dense calcification at the distal metaphyseal plate, referred to as lead lines. Lead lines are observed most commonly in children aged 2-5 years and represent areas of bone remodeling failure, rather than lead deposition. The presence of lead lines signifies a heavy lead exposure, lasting at least 1-2 months. The width and density of the bands represent the duration of exposure, and the number of lead lines increases with repeated exposures.

• Brain imaging studies: Perform brain imaging studies in all comatose patients and in patients with abnormal neurologic examination results in order to elucidate the differential diagnosis.

Other Tests:

• Several tests, based on the inhibition of lead on some enzymatic steps in heme synthesis, were used in the past when lead levels were difficult to obtain. The use of these biomarkers of lead toxicity is no longer recommended because the whole blood lead level became the criterion standard test.

• Erythrocyte delta-aminolevulinic acid dehydratase levels, which show a 50% reduction with lead levels as low as 15 mcg/dL, cannot differentiate between different levels of toxicity.

• Erythrocyte protoporphyrin (EP) levels increase with an increasing lead level. The EP level has been used as an indirect measure of lead toxicity; however, it is not specific for lead because it also may be elevated in patients with iron deficiency. Furthermore, EP has low sensitivity for blood lead levels below 30 mcg/dL. The EP may be useful in determining whether the exposure was acute or remote because elevations of EP usually lag 2-6 weeks behind blood lead level elevations. An elevated whole blood lead level with an EP level within the reference range is an indication of a recent acute overdose.

• The calcium-sodium-edetic acid (Ca-Na₂-EDTA) challenge/provocative test originally was developed to evaluate the size of the chelatable lead burden, was found to be technically difficult, and proved to be unsafe because it resulted in redistribution of lead into the brain.

• Urinary lead excretion, which reflects the plasma lead concentration rather than whole blood lead concentration, is not a true reflection of blood lead levels because plasma lead fluctuates more rapidly than blood lead levels.

Procedures:

• Endotracheal intubation

• Gastric lavage

• Intracerebral pressure (ICP) monitor with ventricular drainage

	TREATMENT	Section 6 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical Care: Intensive care monitoring is indicated for patients with suspected lead encephalopathy. Consider intensive care monitoring during the initial phase of intravenous chelation.

• The care of all patients admitted to the ICU begins with meticulous attention to the airway and breathing and adequate support of circulation. Endotracheal intubation is indicated for the protection of the airway and the provision of adequate oxygenation.

• Correct hypovolemia with crystalloid solution and blood (when indicated). Once the circulatory volume is reestablished and renal function is optimized, balance fluid infusions with fluid restriction to prevent further brain edema. Daily fluid requirements are based on calculated maintenance fluids and the cc per cc replacement of ongoing fluid losses.

• Maintain urine output at 0.5–1 cc/kg/h. Urine output may be augmented by the intravenous infusion of mannitol. Mannitol is administered in a dose of 1-2 g/kg of a 20% solution and a rate of 1 cc/min.

• Convulsions and status epilepticus are treated in a conventional manner with benzodiazepines and other anticonvulsants, including phenobarbital and phenytoin. Patients with lead encephalopathy may require high doses of anticonvulsants for seizure control. Persistent status epilepticus may require neuromuscular blockade with EEG monitoring.

• Manage a brain edema in consultation with a neurosurgery service because patients may require an ICP monitor and removal of ventricular fluid for the management of ICP. Cerebral edema may be managed in a conventional manner with complete bed rest, sedation, and neuromuscular blockade; elevation of the head of the bed; fluid restriction; hyperventilation (maintain PCO₂ at 25-30 mm Hg); and mannitol and/or other diuretics such as furosemide. Barbiturates may be used empirically for the prevention of seizures, which may exacerbate the brain edema. The value of steroids in lead encephalopathy has not been demonstrated.

• Decontamination: The most important aspect of therapy for lead toxicity is removal of the patient from the source of exposure and optimization of the nutritional status of the patient. Optimization of the stores of calcium, copper, and zinc in the body reduces lead absorption from the gastrointestinal tract. Perform decontamination in all patients with recent lead ingestion because even a small paint chip or ceramic glaze may contain large concentrations of lead and should be considered in all patients with abdominal radiopacities.
  • Decontamination may be accomplished with gastric lavage if the ingestion is recent or with whole bowel irrigation, using a polyethylene glycol solution, when the presentation is remote, with visible abdominal radiopacities.

  • Whole bowel irrigation is performed with polyethylene glycol solution at a rate of 100-500 cc/h in children and 500-2000 cc/h in adults until the abdominal x-ray is clear.

• Chelation: Chelation therapy is indicated as soon as the diagnosis of severe lead toxicity is considered. Do not delay chelation therapy until a definitive blood lead level is obtained. Chelation functions by binding with lead and forming a water-soluble complex that may be excreted in urine. The efficacy of treatment may be monitored by postchelation decreases in blood lead concentrations, the finding of increased urine lead excretion, and the normalization of circulating delta-aminolevulinic acid dehydrase levels.

• Currently, 3 agents are recommended for the chelation of lead in the United States. Dimercaprol (BAL) and Ca-Na₂-EDTA are administered parenterally (often concomitantly), and succimer (dimercaptosuccinic acid [DMSA]) is administered orally. D-penicillamine, which historically enjoyed widespread use as an oral agent, currently only is recommended for persistent lead toxicity despite maximal therapy with the above chelating agents. An additional drug, 2,3-dimercaptopropane-1-sulfonic acid (DMPS) currently is used in Europe and Asia.

• Parenteral chelation is indicated in both adults and children exhibiting signs of lead encephalopathy, including severe headaches, seizures, altered mental status, and coma; for patients with severe, painful, and debilitating symptoms such as abdominal pain, myalgias, and arthralgias; and for patients with end-organ damage such as renal failure and peripheral neuropathies. Lead levels exceeding 70 mcg/dL in children and 100 mcg/dL in adults also require parenteral chelation, even in the absence of symptoms.

• Lead levels from 45-70 mcg/dL in asymptomatic children and 70-100 mcg/dL in asymptomatic adults may be treated with oral chelation therapy. Lead levels below 45 mcg/dL in asymptomatic children and below 70 mcg/dL in asymptomatic adults usually only require removal of the patient from the environment in which they were exposed to the lead.

Surgical Care:

• Surgical care includes placement of an ICP monitor with consultation with the neurosurgical service and removal of cerebrospinal fluid when indicated to reduce ICP.

• Surgery is indicated for removal of bullets believed to be the source of lead poisoning.

Consultations:

• Consultation with a clinical toxicology service or the poison control center

• Neurosurgery consultation (for the placement of an ICP monitor)

• General surgery consultation (for the removal of a bullet)

Diet: Oral feedings are withheld during the first 3 days of chelation therapy. Avoid iron when oral chelation with BAL is performed because iron combines with BAL to form a toxic emetic compound.

	MEDICATION	Section 7 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Regardless of the blood lead concentration, the most important step in the treatment of lead toxicity is removal from the source of poisoning. Once the patient is admitted to the hospital, chelation therapy is the mainstay of the treatment of symptomatic lead poisoning.

Drug Category: Metal chelators -- Chelators are agents that are capable of binding to substances and forming a stable water-soluble compound that may be excreted easily. The indications for chelation therapy in the setting of lead poisoning depend on patient's age, symptoms, and blood lead levels.

Currently in the United States, 3 chelating agents are used for lead toxicity. Calcium disodium EDTA and BAL (dimercaprol) are available in parenteral form only, and succimer (DMSA) is available in oral form. The use of oral D-penicillinamine for lead toxicity largely has been abandoned because of the availability of the less toxic succimer. Other agents, such as DMPS, are available in Europe and Asia and are awaiting Food and Drug Administration (FDA) approval in the United States. In the setting of lead encephalopathy, both calcium disodium EDTA and BAL are used concomitantly. BAL generally is administered first (about 4 h prior to EDTA) because calcium disodium EDTA is able to mobilize a large amount of lead from the soft tissues, thus increasing the amount of lead that is free to diffuse to the brain and worsening encephalopathy.

Drug Name	Ca-Na2-EDTA (Versenate) -- Combines with lead to form a stable water-soluble compound that is excreted in the urine. Early treatment is capable of limiting effects of lead on hemoglobin and possibly the CNS. Second drug used in lead toxicity. Chelates only extracellular lead and may induce CNS toxicity if BAL therapy is not initiated first. Therapy should begin 4 h after BAL is administered. Only administered IV, and continuous infusion is recommended. Symptomatic nonencephalopathic adults may be treated with a combination of BAL and EDTA or with EDTA alone.
Adult Dose	50 mg/kg/d (or 1500 mg/m2/d) continuous IV infusion over 8-24 h for 5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; renal failure
Interactions	Enhances hypoglycemic effects of insulin in diabetic patients
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patient should be well hydrated; EDTA may worsen CNS toxicity if administered prior to BAL therapy; adverse effects include fever, chills, malaise, fatigue, anorexia, anemia, hypotension, urinary complaints, lacrimation, and sneezing; transient elevations in ALT and AST have been reported; not recommended for patients in renal failure; nephrotoxicity may be reduced by limiting daily dose to 2 g in adults and 1 g in children; patient should be well hydrated; to prevent hypocalcemia, only use calcium disodium salt of EDTA for chelation in heavy metal toxicity; IV infusion concentrations >0.5% may lead to thrombophlebitis

Drug Name	Dimercaprol (British antilewisite, BAL) -- DOC for treatment of lead toxicity. Chelates intracellular and extracellular lead and is excreted in urine and bile. May be administered to patients with renal failure. Chelates many other metals, including mercury and arsenic. Used in conjunction with Ca-Na2-EDTA in the treatment of severe lead toxicity and lead encephalopathy. When lead encephalopathy is present, BAL is administered about 4 h prior to the infusion of Ca-Na2-EDTA in order to prevent the redistribution of lead into the brain, which is observed with Ca-Na2-EDTA infusions.
Adult Dose	25 mg/kg/d (or 75 mg/m2/d) mixed in a peanut oil base IM in divided doses q4h for 5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity (includes peanut oil sensitivity); G-6-PD deficiency; concurrent iron supplementation therapy; hepatic disease
Interactions	Toxicity may increase when coadministered with selenium, uranium, iron, or cadmium
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	BAL-chelate compound may dissociate in acidic urine and, thus, liberate lead into the kidneys, maintaining an alkaline urine and may, therefore, protect the kidneys; may cause hypertension; caution when administering to patients with oliguria or G-6-PD deficiency; may induce hemolysis in G-6-PD deficient patients

Drug Name	Dimercaptosuccinic acid, DMSA, succimer -- Analog of dimercaprol that is available in an oral formulation. Has same mechanism of action as BAL and is indicated for moderate lead toxicity in adults and for asymptomatic children with lead levels >45 mcg/dL.
Adult Dose	10 mg/kg PO q8h for 5 d, then 10 mg/kg PO q12h for 14 d; repeat dosing may be necessary
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Do not administer concomitantly with edetate calcium disodium or penicillamine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse reactions include GI distress, transient elevation of AST and ALT; caution in renal or hepatic impairment; hydrate patient to prevent toxicity

Drug Name	DMPS, 2,3-dimercaptopropane-1-sulfonate -- Presently is the chelator of choice in Europe and Asia and currently is under investigation by the US FDA. May be used intravenously or orally and is less toxic than succimer.
Adult Dose	250 mg IV q4h for 7 d, then 100 mg PO q6h; blood lead levels are monitored, and, as they begin to drop, oral dosing may be reduced to 100 mg q12h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects include fever, shaking chills, rash, and aphthous ulcers

	FOLLOW-UP	Section 8 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

• Chelation therapy for lead encephalopathy and asymptomatic high–blood lead concentrations is continued for 5 days and requires the concomitant use of both BAL and Ca-Na₂-EDTA. As lead initially and primarily is mobilized from the soft tissues and only a fraction is mobilized from the bone, soft tissue and blood lead content may rebound after cessation of therapy because these lead pools equilibrate. A second course of chelation therapy may be administered 2 days after therapy is discontinued if the patient's symptoms persist or reappear in the face of rebound increases in blood lead levels (>50 mcg/dL). A third course of chelation rarely may be required. In this case, a chelator-free interval of 1 week is recommended prior to initiation of the third course.

• Patients with lead encephalopathy may develop SIADH, heralded by a sharp reduction in urine output. Therefore, pay meticulous attention to urine output, electrolytes, and renal function.

• Patients with lead encephalopathy may develop cerebral edema, heralded by worsening of neurologic status and requiring immediate measures to reduce brain edema. Also, closely monitor hepatic function.

Further Outpatient Care:

• Outpatient care only can begin after removal of lead from the patient's environment.

• A follow-up of the lead level is recommended 14 days after completion of chelation. Subsequent courses for chelation are based on this determination.

Transfer:

• Transfer to a nonmonitored setting may be considered for a stable asymptomatic patient with blood lead levels less than 50 mcg/dL.

Deterrence/Prevention:

• Appropriate lead abatement in older homes

• Lead screening programs

• Occupational safety programs

Complications:

• Permanent neurologic damage

• Renal damage

• Hepatic damage

• Cardiomyopathy

Prognosis:

• Lead encephalopathy carries a far worse prognosis than asymptomatic elevations of blood lead levels.

• As many as 25% of children who survive an episode of lead encephalopathy sustain permanent brain damage.

• Asymptomatic increases of lead levels, while having a low risk of mortality, carries a high incidence of subtle changes in CNS function in both children and adults, such as changes in behavior, personality, learning ability, and IQ.

Patient Education:

• Inform patients and families about the sources and dangers of lead in the environment.

• Occupational safety programs must be instituted in all occupations with high lead exposure.

• For excellent patient education resources, visit eMedicine's Poisoning Center. Also, see eMedicine's patient education article Poisoning.

	MISCELLANEOUS	Section 9 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

• Failure to consider the diagnosis of lead poisoning in children presenting with encephalopathy

	BIBLIOGRAPHY	Section 10 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

• al Khayat A, Menon NS, Alidina MR: Acute lead encephalopathy in early infancy--clinical presentation and outcome. Ann Trop Paediatr 1997 Mar; 17(1): 39-44[Medline].
• Berthier M: [Current problems of lead poisoning]. Presse Med 1998 Apr 25; 27(16): 763-5[Medline].
• Campbell JR: Treatment of acute lead encephalopathy. Arch Pediatr Adolesc Med 1999 Nov; 153(11): 1202[Medline].
• Chisolm JJ Jr: BAL, EDTA, DMSA and DMPS in the treatment of lead poisoning in children. J Toxicol Clin Toxicol 1992; 30(4): 493-504[Medline].
• Cullen MR, Robins JM, Eskenazi B: Adult inorganic lead intoxication: presentation of 31 new cases and a review of recent advances in the literature. Medicine (Baltimore) 1983 Jul; 62(4): 221-47[Medline].
• Ellenhorn MJ: Lead. In: Ellenhorn MJ, ed. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997: 1564-1579.
• Finkelstein Y, Markowitz ME, Rosen JF: Low-level lead-induced neurotoxicity in children: an update on central nervous system effects. Brain Res Brain Res Rev 1998 Jul; 27(2): 168-76[Medline].
• Garnier R, Dollfus C, Konczaty H: [Treatment of lead poisoning]. Presse Med 1998 May 23-30; 27(19): 916[Medline].
• Graziano JH, Lolacono NJ, Moulton T: Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication. J Pediatr 1992 Jan; 120(1): 133-9[Medline].
• Henretig FM: Lead. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, Hoffman RA, eds. Goldfrank's Toxicologic Emergencies. 6th ed. Stamford, Conn: Appleton & Lange; 1998: 1277-1302.
• Jorgensen FM: Succimer: the first approved oral lead chelator. Am Fam Physician 1993 Dec; 48(8): 1496-502[Medline].
• Klassen CD: Heavy metals and heavy metal antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996: 1649-1672.
• Levin SM, Goldberg M: Clinical evaluation and management of lead-exposed construction workers. Am J Ind Med 2000 Jan; 37(1): 23-43[Medline].
• Loghman-Adham M: Aminoaciduria and glycosuria following severe childhood lead poisoning. Pediatr Nephrol 1998 Apr; 12(3): 218-21[Medline].
• Markowitz M: Lead poisoning: a disease for the next millennium. Curr Probl Pediatr 2000 Mar; 30(3): 62-70[Medline].
• MMWR: Update: blood lead levels--United States, 1991-1994 [published erratum appears in MMWR Morb Mortal Wkly Rep 1997 Jul 4;46(26):607]. MMWR Morb Mortal Wkly Rep 1997 Feb 21; 46(7): 141-6[Medline].
• MMWR: Adult Blood Lead Epidemiology and Surveillance--United States, first quarter 1998, and Annual 1994-1997. MMWR Morb Mortal Wkly Rep 1998 Oct 30; 47(42): 907-11[Medline].
• Needleman HL: The current status of childhood lead toxicity. Adv Pediatr 1993; 40: 125-39[Medline].
• Philip AT, Gerson B: Lead poisoning--Part I. Incidence, etiology, and toxicokinetics. Clin Lab Med 1994 Jun; 14(2): 423-44[Medline].
• Philip AT, Gerson B: Lead poisoning--Part II. Effects and assay. Clin Lab Med 1994 Sep; 14(3): 651-70[Medline].
• Pirkle JL, Kaufmann RB, Brody DJ: Exposure of the U.S. population to lead, 1991-1994. Environ Health Perspect 1998 Nov; 106(11): 745-50[Medline].
• Roberge RJ, Martin TG: Whole bowel irrigation in an acute oral lead intoxication. Am J Emerg Med 1992 Nov; 10(6): 577-83[Medline].
• Weitzman M, Glotzer D: Lead poisoning. Pediatr Rev 1992 Dec; 13(12): 461-8[Medline].
• Yip Luke: Heavy Metal Poisoning. In: Irwin RS, et al, eds. Irwin & Rippe's Intensive Care Medicine. 4th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1999: 1637-1653.

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

Toxicity, Lead excerpt

© Copyright 2004, eMedicine.com, Inc.