Emergent Management of Lead Toxicity

Background

The International Programme on Chemical Safety of the World Health Organization (WHO) has identified lead as one of the 10 chemicals of major public health concern.^[1]Lead is a heavy metal that is present at low levels in the earth’s crust but has become pervasive in the environment because of its use in products such as gasoline, paint, jewelry, water pipes, lead solder, and lead-acid batteries.^[2]

Lead is toxic to many body systems, including the neurological, gastrointestinal, and hematological systems.Both adults and children may suffer adverse effects from lead toxicity; however, children are especially vulnerable to the neurotoxic effects of lead. Overall, the WHO estimates that lead exposure accounts for 0.6% of the global burden of disease.^[2]

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Pathophysiology

Lead typically enters the body through inhalation or ingestion.^{[2, 3]}Once lead is absorbed into the bloodstream, some of it is cleared from the body by excretion in the urine and bile. The clearance rate is approximately 1-3 mL/min and the half-life of lead in blood is approximately 30 days.^[4]

The lead that remains binds to red blood cells and is then distributed to the soft tissues and bone.^[4]Lead eventually accumulates in bone, where it has a half-life of 20-30 years.^[4]Once lead is deposited in bone, it may be released back into the bloodstream during conditions of rapid bone tissue turnover such as pregnancy, menopause, and lactation.^[4]

Lead exerts toxic effects through a variety of mechanisms on many different organ systems. Two systems that are particularly sensitive to lead toxicity are the hematologic system and the developing nervous system.^{[5, 6]}In the hematologic system, lead destabilizes the red cell membrane, causing oxidative stress and early cell death.^[6]Lead also inhibits the activities of several enzymes involved in heme biosynthesis and may trigger inappropriate production of erythropoietin.^[5]These effects contribute to hemolytic anemia.^[6]

In the nervous system, lead crosses the blood-brain barrier by displacing calcium ions.^[6]Within the brain, it accumulates in astroglial cells and prevents myelin sheath formation.^[6]These effects can lead to demyelination and disturbances in neural excitation and memory-related neurotransmitter activity.^[6]

Lead has more pronounced adverse effects on the developing brain because it disrupts processes required to establish necessary connections between brain structures, eventually leading to permanent alterations in brain function.^{[5, 4]}These effects can cause irreversible neurobehavioral developmental abnormalities in affected children, even at very low lead levels.^{[5, 6]}

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Etiology

In children, elevated blood lead levels are most commonly caused by inhalation or ingestion of lead dust and chips of deteriorating lead-based paint.^[7]Other sources of exposure include the following^[7]:

Imported or antique toys painted with lead paint
Imported cookware
Toy jewelry made of lead
Contaminated tap water
Ingested foreign bodies
Dietary supplements

Adult exposures tend to occur from inhalation of lead dust and fumes in the occupational setting or from hobbies that involve use of lead.^[3]Individuals with occupational exposure to lead may also expose family members by bringing lead dust into their homes on their shoes and clothing.^{[3, 7]}Infrequently, toxic lead exposures have resulted from retained bullets or shrapnel fragments.^{[8, 9]}

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Prognosis

Lead toxicity from acute or chronic exposurecan have profound clinical effects. Neurologic effects are particularly problematic.^[4]

Elevated blood lead levels in children are associated with lower IQ scores, language problems, learning disorders, attention disorders, and behavioral problems.^{[5, 7]}Cognitive deficits in children may persist into adulthood.^[5]Adults with chronic lead exposure may develop cognitive deficits in many domains, including memory and executive functioning.^[4]Severe lead toxicity in adults and children can lead to encephalopathy, convulsions, coma, and death.^{[5, 6, 7]}

Effects on other organ systems may also be significant. Lead toxicity can lead to hemolytic anemia, elevated blood pressure, and decreased glomerular filtration rate.^{[6, 5]}

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Clinical Presentation

The greatest danger in the emergent management of lead toxicity is failure to recognize the possibility of lead poisoning. This is not uncommon, because the symptoms and signs of lead toxicity are subtle and easily overlooked.^[10]

Children with lead toxicity may present without specific symptoms, or they may complain of gastrointestinal (GI) symptoms such as constipation, nonspecific abdominal pain, vomiting, loss of appetite, or weight-loss.^[7]Children with more severe toxicity may present with behavioral changes or neurologic symptoms such as headaches, confusion, lethargy, irritability, somnolence, clumsiness or agitation. In children, signs of encephalopathy such as coma, stupor, or convulsions suggest severe toxicity.^{[5, 7]}

One case developed after a child was seen in several hospital emergency departments (EDs), presenting with poor appetite, vomiting, and sore throat. After a throat culture obtained at one ED revealed beta-hemolytic streptococcus, the child received appropriate penicillin therapy, only to return several days later actively convulsing, with a lead level higher than 170 μg/dL.^[10]

Adults with lead toxicity may present with the same symptoms as those noted for children. Encephalopathy may be seen in patients with very high levels of blood lead: 100-120 µg/dl in adults, and 70 – 100 µg/dl in children.^[5]

Other complaints in adults may include erectile dysfunction, decreased libido, weakness, and paresthesias.^[5]Gonulalan et al report that chronic lead intoxication (mean, 71.5 mo; range, 6-360 mo) is associated with erectile dysfunction and depression, as determined based on the erectile function domain (EFD) and Beck Depression Inventory (BDI), respectively.^[11]

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Lead line on the gingival border of an adult with lead poisoning.

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Wrist-drop in adult with lead poisoning and renal failure.

It is vital to diagnose and treat other family members or friends with similar lead exposure. It should be noted that lead can be transmitted from a mother to her child via breast milk.^[12]Lead toxicity or encephalopathy should be suspected in patients presenting with afebrile seizures. However, lumbar puncture performed on patients with lead encephalopathy and increased intracranial pressure can precipitate cerebral herniation and death.

The differential diagnosis should include the following^[7]:

Acute abdomen
Other toxic ingestion
Encephalitis
Other causes of encephalopathy

Consultation with a clinical toxicologist or a physician conversant with treating lead poisoning is beneficial. Consultations with a hematologist and a nephrologist may be helpful. The local poison control center may provide useful information to facilitate treatment and follow-up.

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Workup

The most commonly used and accurate method of assessing lead exposure is to measure the concentration of lead in the blood.^[5]Venous blood lead levels (BLL) are used to guide diagnosis and management of lead poisoning.^[7]In some clinical situations, bone lead levels may be used to provide information about the patient’s long-term, cumulative lead exposure.^[5]

In children, blood lead levels of less than 5 µg/dl can be associated with cognitive dysfunction.{ref 28} Levels of 10–44 µg/dl may be associated with cognitive and nervous system dysfunction, as well as anemia. Gastrointestinal effects such as abdominal pain, constipation, vomiting, and anorexia are seen at BLLs of 45–69 µg/dL, and severe nervous system dysfunction—including convulsions, coma, and death—may be seen at BLLs of ≥70 µg/dL.^[7]

All children with BLLs of 5 µg/dL or higher require investigation, management and close follow-up.^[7]The initial history and physical examination should try to identify the source of the exposure, and the clinician should consider the possibility of a retained lead-containing foreign body or dangerous lead contamination in the household.^[7]

Obtain laboratory work (see the first image below) and imaging studies (see the second and third images below) without delay.

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Peripheral smear taken from an 8-year-old Pakistani girl who presented with an acute hemolytic anemia and a lead level of 125 mcg/dL.

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Growth arrest lines, also known as lead lines, in bones of a child who recovered from lead poisoning.

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Abdominal flat plate showing multiple radio-opaque foreign bodies including paint chips and an earring.

Children with symptomatic lead toxicity or BLLs of ≥45 µg/dL may require hospitalization.^[7]

In adults who have not been exposed to lead, BLLs should be ≤25 µg/dL.^[6]Individuals with chronic workplace exposure to lead may have higher blood lead levels. Lower birth weight has been reported in children born to mothers with BLLs of 10–19 µg/dL, and BLLs of 20-39 µg/dl are associated with spontaneous abortion.^[13]Individuals may also develop nonspecific abdominal colic symptoms, decreased libido, fatigue, and mood swings at this BLL range.

At BLLs of 40–79 µg/dl, exposed adults may experience memory and attention deficits, as well as lowered sperm counts and abnormal sperm.^[13]BLLs of ≥80 µg/dL are associated with more severe central nervous system symptoms, gastrointestinal colic, anemia, peripheral neuropathy, hypertension, and nephropathy.^[13]

As with lead-exposed children, it is important to identify the source of lead exposure in adults, so that the risk may be reduced or mitigated. Adult patients with elevated lead levels should be referred to the local public health authority and/or their workplace occupational medicine specialist for further investigation and risk mitigation. Lead-exposed pregnant patients and patients of child-bearing age may require additional counseling and risk mitigation.^[13]

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Treatment

Treatment of lead poisoning consists of separating the child from the source of lead exposure. Children and their families should be referred to the local public health office for further investigation and identification of the source of lead exposure.^[7]Chelation is used only when separation fails to drop the lead fast enough or far enough or when the lead level is in the potentially encephalopathogenic range (>60 μg/dL).

If the patient is comatose or seizing, the airway must be protected. Aside from initial workup and treatment, immediate transportation to a hospital with experienced personnel and facilities for treating patients with lead poisoning is imperative.

Initial therapy is based on the history, the likelihood of actual lead toxicity, the symptoms present, and the physical examination findings. All patients should be offered appropriate symptom relief. Guidelines and recommendations on prevention, treatment, diagnosis, and screening are available from the following organizations:

American Academy of Pediatrics (AAFP)^[14]
Centers for Disease Control and Prevention (CDC)^{[15, 16]}
United States Preventive Services Task Force (USPSTF)^[17]

The following measures are indicated for severely symptomatic patients with lead poisoning:

Begin an intravenous (IV) drip of normal saline.
In a child with acute lead ingestion, consider placing an orogastric or nasogastric catheter to enable whole-bowel irrigation (WBI) with polyethylene glycol
Do not delay administration of chelation therapy to clear any pica from the gut; immediately institute chelation therapy if lead poisoning is seriously considered, and simultaneously initiate therapy to evacuate the lead-laden particles from the gastrointestinal (GI) tract

Patients who do not have severe poisoning or in whom the diagnosis is unclear can be treated symptomatically while laboratory work results are pending.

Patients who have lead levels below the range that is considered potentially encephalopathogenic (ie, < 60 μg/dL) and who can successfully be kept away from further lead exposure can probably be treated on an outpatient basis.

Symptomatic pregnant patients with elevated lead levels should be treated with chelation in consultation with and under the supervision of a medical toxicologist. Treatment of asymptomatic pregnant patients with elevated lead levels should not be initiated without consultation with a medical toxicologist. Only very limited data are available on the teratogenicity of chelation therapy.

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Adjunctive Care

Recently, evidence has accumulated that lead exerts oxidative stress by both increasing the production of reactive free radicals and decreasing the natural antioxidant mechanisms by depleting the natural body stores of such and interfering with the manufacture of such.^[18]In addition, it is believed that lead competes with zinc binding sites of many enzyme systems, thus causing deficiency in their functionally. Evidence also suggests that lead interferes with the viscosity of blood and various rheological parameters, leading to hemolysis.^[19]

Therefore, antioxidants, which although have not been shown to enhance the effect of chelators, may have a role in helping restore antioxidant activity and thus mitigate some symptoms and signs. Since most recommended antioxidants are considered safe, the use of them adjunctive to chelation or at levels of lead below those at which chelation would be indicated, may be beneficial.

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Chelation Therapy

Chelators are used to remove heavy metals from the body. The term chelator is derived from the Greek word chēlē (“claw”); chelators form a chemical claw around the heavy metal, creating a chemically inert compound that can be excreted in the urine.^[7]

Chelation therapy is indicated for children with lead toxicity that is moderate to severe, or life-threatening (BLLs ≥45 µg/dL).^[7]Symptomatic adults with BLLs of >50 µg/dL can be considered for chelation therapy, and those with BLLs of ≥80 µg/dl should receive urgent referral and evaluation for chelation therapy.^[13]Chelation therapy is not generally indicated for children or adults with BLLs of 6</ref>^[7]

Any use of chelation therapy should be done in consultation with a toxicologist or other specialist experienced in managing lead toxicity.^{[7, 13]}

Two parenteral and two oral chelators for lead exist. Dimercaprol, also known as BAL (British antilewisite), is the prototype chelator. A bisulfide molecule, this lipid-soluble drug must be administered intramuscularly (IM). It has the typical sulfide odor, and patients often complain of the taste and bad feeling when they receive the drug. Calcium disodium edetate (CaNa₂ EDTA) may be administered IM or intravenously (IV); in many centers, the IM route has been abandoned in favor of a continuous IV drip that appears to provide improved outcome and decreased adverse effects.

Some controversy exists regarding the use of parenteral CaNa₂ EDTA and the possible increase in brain lead in the first 24 hours of therapy.^{[20, 21, 22]}Chisolm, in his classic article describing chelation therapy for children with symptomatic lead poisoning, reported that children often deteriorated during the early stages of treatment and postulated that this deterioration was due to shifts in lead subsequent to the use of CaNa₂ EDTA.^[23]Accordingly, he suggested combined therapy with both BAL and EDTA.

No significant studies have been undertaken to allow any evidence-based decision on whether this approach is warranted. The author is aware of at least 3 patients whose clinical course deteriorated during the first three days of therapy with CaNa₂ EDTA chelation and in whom severe hyponatremia and elevated vasopressin levels were found. Thus, use of combined therapy for the first few days to prevent such deterioration may be prudent.

The two oral chelators currently used in the United States are D-penicillamine and succimer. Although the US Food and Drug Administration (FDA) approved succimer for use in children with lead levels higher than 45 μg/dL, D-penicillamine has not yet been approved, despite its widespread use for the past 2 decades. Because lead impacts gastrointestinal (GI) motility, the use of an oral chelator in patients with significantly increased lead levels (eg, >60 μg/dL) seems counterintuitive and has not been studied for efficacy.

Some controversy exists regarding the use of chelation while the patient has ongoing exposure, either to external lead sources or to lead possibly present in the GI tract.^{[24, 25, 26]}Although it has long been the dogma that chelation should not be delayed to empty the intestines, just how to chelate in such a circumstance has not been subjected to scientific investigation. The controversy regarding possible redistribution of lead to brain during EDTA therapy adds to this conundrum.

In commenting on children with moderate levels of lead in the blood without encephalopathy, Chisolm suggested that there is no evidence that chelation with EDTA does anything to lower the brain lead level.^[27]While studying the effects of treatment with the chelator succimer in the primate model, Cremin et al failed to find a significant effect on brain lead levels with chelation with this agent beyond that achieved simply by separation from the source of lead.^[28]

Another chelator, 2,3-dimercaptopropane-1-sulfonic acid sodium salt (DMPS), is available in Europe for both oral and parenteral use. It has not been approved or licensed in the United States, but it has been used in various forms in alternative medicine clinics.

The use of multiple chelators at once has often been suggested. However, data suggest that it may not be more advantageous than the use of a single chelator.^[29]

Some have proposed the use of alternative medicines, such as various vitamins and other antioxidants. Data suggest that this approach does not alter the efficacy of chelation with standard medications.^{[29, 30]}

It must be kept in mind that all chelators have nonspecific effects, which means that they will chelate other metals as well as lead. Thus, chelation must be carefully considered according to the principle of primum non nocere (“first, do no harm”).^[31]

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Further Inpatient Care

Careful attention to renal and hepatic function is important during the administration of chelation therapy. Fluid and electrolyte levels must be monitored carefully because fluid shifts may occur during therapy.

Reports from the 1960s have documented cases of children whose condition deteriorated after the initiation of chelation therapy. Several children have been reported to develop the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) shortly after beginning chelation therapy.

All patients must have careful follow-up at weekly intervals to watch for unexpected reexposure or reequilibration of lead from bony stores after discontinuance of chelation.

Considerations for discharge include the following:

The source of lead must have been determined and the possibility of reexposure eliminated
If outpatient chelation is indicated, the medication must be in the hands of the individual responsible for its administration
The individual must demonstrate knowledge of dosing and the ability to dose the patient
The lead level must have dropped an appreciable amount during inpatient chelation therapy

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Author

Adrienne M Buggs, MD, FACEP, FAAEM, Medical Policy Advisor, Office of Merchant Mariner Credentialing, United States Coast Guard