A Toxic Metal

Toxicology Talks with Toxijawn

A Toxic Metal

Author: Samara Albazzaz, MD, Emergency Medicine Resident PGY1
Fellow: Laura Roper, MD, Medical Toxicology Fellow PGY4
Fellow: Alexis Cates, DO, Medical Toxicology Fellow PGY6
Faculty: James Krueger, MD, Medical Toxicology / Emergency Medicine Attending

The case:

It’s a busy Friday night – STEMIs, Stroke Alerts, and traumas galore! You finally have a second to sit at your computer and you see a pediatric patient on your tracking board. You sign up and enter the room to see a 4-year-old boy with his mother. He looks lethargic and pale, and his mom is holding an emesis basin next to his face. You note this child looks unwell, and you get him connected to the monitor while obtaining a history from mom. She states for the past 5 days he’s been vomiting and occasionally has episodes of lethargy. He’s also been more irritable for the last week. They went to their pediatrician, who noted an elevated capillary lead test and sent them to the Emergency Department.  You immediately start a work up for lead toxicity.

Learning Point 1: Mechanism of Lead Toxicity

Though lead can be absorbed through different routes, such as pulmonary and gastrointestinal, children tend to have higher gastrointestinal absorption rates than adults. Once absorbed, lead binds to erythrocytes and is distributed to bone and soft tissues.  This includes the liver, bone marrow, kidneys, and brain. Lead has a proclivity for concentration in gray matter, in particular the cerebellum, cerebral cortex, medulla, and hippocampus.

Lead exerts its toxic effects through binding electron-donor ligands, resulting in interference with enzyme and receptor function as well as structural proteins. Lead is also chemically similar to divalent cations, particularly calcium. Through this similarity, it interferes in calcium-dependent processes in the mitochondria and calcium-reliant second messenger systems. This disruption of calcium-dependent metabolic pathways results in cell death. Lastly, lead affects DNA, with a possible impact on DNA methylation.

Through these pathways, lead accumulation results in neurotoxicity, cardiotoxicity, nephrotoxicity, gastrointestinal toxicity and hematologic toxicity. Lead causes synaptic pruning through its impact on acetylcholine, dopamine, GABA, and glutamate release, especially in the hippocampus. Lead’s effect on the hippocampus is notable due to lead’s classic impact on learning and memory. Lead also impacts protein folding in the brain, potentially leading to Alzheimer disease and parkinsonism. In adults, lead toxicity is a known cause of peripheral neuropathy.  Chronic lead toxicity may lead to hyperuricemia and saturnine gout.  Lead exposure may also subsequently lead to hypertension and the development of cardiovascular disease.

Lead causes contractility of vascular smooth muscle, notably leading to hypertension. It also inhibits processes in the heme biosynthetic pathway, causing RBC membrane fragility and leading to hemolysis. On peripheral smear, RBCs can also demonstrate basophilic stippling. In the kidneys, lead decreases uric acid excretion, leading to gout and progressive interstitial fibrosis. In the gastrointestinal system, lead results in constipation, vomiting, anorexia, and colicky abdominal pain.

Case Continued:

You find that your patient has lethargy, vomiting, and irritability, hallmark signs of lead toxicity. In conjunction with the elevated capillary lead level, you have high suspicion for lead toxicity. You remember that at severe levels of toxicity, cerebral edema is a risk. You order a whole blood lead level, CBC, BMP, LFTs, and a urinalysis. You also order an abdominal plain film to evaluate for radiopaque lead products.  Given his clinical condition, you consider starting chelation therapy.

Learning Point 2: Management of Lead Toxicity

Children with lead levels greater than 70 mcg/dL are in danger of cerebral edema and encephalopathy. If a child presents with signs of encephalopathy, and lead toxicity is high on the differential, chelation is recommended before whole lead blood levels return.  

Capillary blood levels can return falsely elevated blood lead levels, perhaps from contamination or lab error, so one should always confirm with a whole blood lead level. However, whole blood lead levels do not typically rapidly result, causing a dilemma if one relies on the confirmatory level before starting therapy.  Whole blood lead levels may be delayed, depending on availability of the lab at any particular institution.

When lead toxicity is suspected, there are several treatment options available to consider. If a large acute exposure is suspected – for example, if a child presents after consuming a large amount of paint chips– and radiopaque objects are identified on plain film, whole bowel irrigation can be considered to reduce gastrointestinal absorption. If a discrete foreign body was ingested, such as a lead bullet, endoscopy can also be considered. Occasionally, there are reports of lead accumulation if a bullet remains in the tissues following a gunshot wound.  Often, these are not surgically removed due to the potential for further damage to neighboring structures, but long-term lead accumulation should be considered as a potential downstream effect. 

Chelation is the primary management method for lead toxicity. Chelation therapy is unfortunately inefficient, only decreasing the body’s lead content by 1-2%, with minimal evidence that chelation accesses critical sites such as the brain. Dimercaprol (BAL), CaNa2 EDTA, and succimer are the major agents used for chelation.

Succimer is the agent of choice for asymptomatic lead poisoning in children with lead levels of 45-69 μg/dL. It is administered orally. For children who present encephalopathic, treatment should be initiated with dimercaprol and IV CaNa2 EDTA. Dimercaprol should be started first as CaNa2 EDTA initially induces an increased lead level in the CNS, while dimercaprol does not. Chelation therapy should be continued for 5 days.

Succimer can cause neutropenia and elevated LFTs, in addition to hemolysis in patients with G6PD deficiency. Dimercaprol is contraindicated in children with peanut allergies, as it is dissolved in peanut oil. As it is a deep intramuscular injection, there is also a risk of deep sterile abscess, and common additional side effects are tachycardia, hypertension, and chest, limb, and abdominal tightness. CaNa2 EDTA can be easily mistaken for Na2 EDTA – used as chelation, Na2 EDTA can cause significant hypocalcemia and death. CaNa2 EDTA can itself also cause hypocalcemia and renal dysfunction.

Specific management strategies, including dosing of chelation therapy for mild, moderate and severe cases of lead toxicity, can be discussed with your local Poison Control Center or Medical Toxicologist.  An example can be found below.

Pediatric Chelation Dosing For Lead Toxicity

(adapted from Goldfrank’s Toxicologic Emergencies)

Symptoms, Serum Lead LevelChelating Agent, Dose
Asymptomatic, 45-69 μg/dLSuccimer 1050mg/m2/day for 5 days, then 700mg/m2 for 14 daysor CaNa2 EDTA 1000 mg/m2/day for 5 days*begin CaNa2 EDTA 48 hours after succimer, if using both
Symptomatic (not encephalopathic) OR >69 μg/dLDimercaprol 300-450mg/m2/day for 3-5 daysandEDTA 1000-1050mg/m2/day for 5 days*begin CaNa2 EDTA 4 hours after dimercaprol
Encephalopathic (any level)Dimercaprol 450mg/m2/day for 5 daysandEDTA 1500mg/m2/day for 5 days*begin CaNa2 EDTA 4 hours after dimercaprol

Case Conclusion:

You start your patient on dimercaprol and begin the process to transfer your patient to a hospital with a Pediatric Intensive Care Unit. Because of your quick intervention, your patient has a better chance of a good outcome! Social work is consulted to arrange for home lead testing and a housing assessment to ensure that this child has a safe, lead-free environment to return to.

References:

Hauptman M, Bruccoleri R, Woolf AD. An Update on Childhood Lead Poisoning. Clin Pediatr Emerg Med. 2017;18(3):181-192. doi:10.1016/j.cpem.2017.07.010

Nelson, L., Goldfrank, L. R, et al. (2011). Goldfrank’s Toxicologic Emergencies (9th ed.). New York: McGraw-Hill Medical. 1292-1305.

Sample, J. (2020). Childhood lead poisoning: Management. UpToDate.

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