Jebenson@salud.unm.edu
Program Objectives
1. Know available forms of lead, arsenic and mercury. 2. Describe the manifestations of poisoning from lead, arsenic and mercury. 3. Assess the severity of poisoning from lead, mercury and arsenic based on signs, symptoms and laboratory information. 4. Develop a treatment plan for lead, arsenic and mercury poisoned patients.
Example Case
A 3-year-old boy presents to the emergency department via ambulance after having a 20minute seizure at home. According to the mother, there had been a gradual change in the childs disposition over a two day period before the seizure. He had an upper respiratory infection. He was less active, had vomited several times and had developed twitching and abnormal eye movements.
He had no access to medications or household products. The mother commented that she did find paint chips in his mouth three weeks earlier. The child was developmentally delayed in terms of speech and social skills. Prior to the seizure he spoke only single words, was not toilet trained and could not dress himself. He appeared postical, with flaccid muscle tone and minimal response to painful stimulation. The patients vital signs were: HR 110, BP 130/80, RR 10 shallow, T 98.6 F, Pulse oximetry 85% on room air
Cerebral spinal fluid analysis: clear, colorless; 3 WBCs/mm3, 0 RBCs, glucose 108 mg/dL, protein 96 mg/dL WBC: 11,300/mm3 Hemoglobin: 6.6 g/dL (normal: 11.8 0.5) Mean corpuscular volume 50 m (normal: 87 7) Platelet count: 473,000/mm3 Peripheral blood smear: RBC basophilic stippling Electrolytes: Na 139, K 4.3, Cl 105, HCO3 22, BUN 15, S.Cr 0.3, Glucose 170
An Overview Of Chelation
Chelator forms a stable complex with the metal and redistributes the metal away from the target organ. The stability of the complex depends on the metal. The most useful chelators have a low order of toxicity, do not redistribute to other organs (ie brain) and are eliminated quickly without breakdown.
Dimercaprol (BAL)
Activity
Diffuses into brain and RBC's Enhances fecal and urinary elimination PB: 75 mg/m2 (4-5 mg/kg) IM q 4 hours for 5 days Hg, As: 3 mg/kg IM every 4-6 hours for 2 days then every 12 hours for 7-10 days
Dose
Side Effects
Local pain at injection site Transient dose-related hypertension and tachycardia Nephrotoxicity (keep urine alkaline) Liver failure Glucose 6 phosphate dehydrogenase deficiency Peanut allergy During iron supplementation
Contraindications
Activity
Chelates extracellular lead only Excretion enhanced via compartment equilibration Pb Encephalopathy: 1500 mg/m2/d (30 mg/kg/d) in two or three doses IV for 5 days Symptomatic Pb poisoning, Pb 50-100 g/dL: 1000-1500 mg/m2/d for 3-5 days.
Dose
Side Effects
Contraindications
Succimer (DMSA)
Agents
Dimercaptosuccinic acid (DMSA) More effective than BAL Can be used to chelate Hg, As, and Pb Wider therapeutic index than BAL Does not re-distribute Pb to brain May produce transient elevation of serum alanine transaminase
Efficacy
Safety
Succimer (continued)
Dose
10 mg/kg (or 350 mg/m2) PO every 8 hours for 5 days then 10 mg/kg every 12 hours for 2 weeks Nausea, vomiting, flatus, diarrhea Mild elevations of aminotransferases Allergy to the drug
Side Effects
Contraindications
Occupational Exposures
Battery makers Brass worker Bronzers Cable makers/splicers Chemical operators Foundrymen Glass makers/polishers Gunshot/gun barrel makers Jewelers
Lead burners/smelters Metal grinders /burners/refiners Painters Pigment makers Pipe cutters Pottery workers Printers (linotype/electotype) Stained glass makers Welders
Non-Occupational Exposures
Battery burning Bullet retention Ceramic making Eating from unfired pottery Cooking in leaden pots Home distilled wine/wiskey Folk medicines (azarcon, greta) Home abortifacients Target shooting Ingestion of leadcontaining herbal medicines Use of leadcontaining cosmetics Soldering
Absorption
GI Tract
Adults: 10% - 15% Children : 40% - 50% Increased with Fe, Ca, Zn deficiency 50% - 70% if < 1 m Inorganic lead is non-absorbable
Lungs
Skin
Distribution
Diet + Air
Bone
Blood
Soft Tissue
Urine
Elimination
Process is dependent on glomerular filtration rate and renal plasma flow Biliary excretion is responsible for 35% of leads elimination Integumentary: nails, sweat, hair Alimentary : salivary, biliary, gastric,and pancreatic
Key Mechanisms
High affinity for electron-donor ligands Substitutes as calcium interfering with calcium dependent processes.
Mitochondrial metabolic pathways Second messenger systems that regulate energy production (calmodulin, protein kinase C, Na/K ATPase)
Mutagenic
Clinical Effects
Organ Bone Marrow RBC Kidneys Vascular Heart CNS Reproductive Skeletal Endocrine Gastrointestinal Effect Derangement of heme synthesis Increased fragility and decreased survival Falconi-like syndrome, chronic nephritis, gout Hypertension Myocarditis, fibrosis Encephalopathy, peripheral neuropathy, cognitive impairment Infertility Impaired bone growth, shortened stature Reduced thyroid and adrenopituitary function Abdominal pain, constipation, colic
RBC Pathophysiology
Succinyl-CoA + Glycine aminolevulinic acid
Delta ALA Dehydratase
Excreted in urine
Excreted in urine
Coproporphyrinogen Decarboxylase
Heme
Routine Monitoring
Lead Lines
Effects
Decits in neurobehavioral development; ALA-D inhibition; Reduced gestational age & wt at birth EP elevation; Impaired vitamin D metabolism Lower IQ, slower reaction time Slowed nerve conduction velocity Reduced hemoglobin; elevated CP & ALA-U Peripheral neuropathies; Frank anemia Encephalopathy; Colic; Kidney effects
Symptomatic
Acute Encephalopathy Symptoms, Blood PB >70 Blood Pb >70 g/dl Blood Pb 45-69 g/dl Blood Pb 20-44 g/dl
BAL + CaNa2EDTA BAL + CaNa2EDTA BAL + CaNa2EDTA DMSA or CaNa2EDTA Abatement, nutritional supplementation and further assessment
Asymptomatic
Symptomatic
Acute Encephalopathy Abdominal Syndromes Painless peripheral neurophathy Blood Pb >100 g/dl Blood Pb 70-100 g/dl Blood Pb <70 g/dl
BAL + CaNa2EDTA BAL + CaNa2EDTA DMSA BAL + CaNa2EDTA DMSA Remove from exposure
Asymptomatic
Monitoring Therapy
Maintain generous urine flow Monitor blood lead daily Daily urinary protein & serum creatinine Measure blood lead in 10 - 12 days after chelation
Types of Mercury
Elemental (metallic)
Hg0 Example: liquid metallic mercury Hg+2X Example: mercuric chloride (HgCl2), mercuric bichloride; calomel or mercurous chloride (Hg2Cl2) Short chain: methyl mercury, ethyl mercury Long chain: phenyl mercury, methoxyethyl mercury
Organic mercury
Mechanism
Covalently binds to sulfur replacing hydrogen Reacts with phosphoryl, carboxyl, and amide groups found in enzymes, membranes, structural proteins and transport mechanisms => interrupts cell function and metabolism. Most vulnerable tissues are CNS, kidneys and lungs
Acute
Inhalation is the most common route Cough, fever, chills, dysnpnea, metallic taste, headaches Tremor, oral cavity lesions, rash, salivation, headaches, diaphoresis, erethism Peripheral neuropathy
Chronic
Acute
Nausea, vomiting, abdominal pain, hematemesis, shock and cardiovascular collapse Renal failure Tremor, stomatitis, gingivitis, sensorymotor deficits, peripheral vision loss, and erethism
Chronic
Short chain
Tremor, ataxia, dysarthria, parethesias of hands, feet, and mouth, tunnel vision, hearing impairment, spasticity Congenital abnormalities (microcephaly, blindness, mental retardation, symmetric motor defects, microagnathia) Similar to chronic inorganic mercury
Long chain
Idiosyncratic hypersensitivity Pink swollen hands and feet, desquamation, evanescent rashes, burning and pain of extremities Primarily affected young children treated with calomel teething powder.
Laboratory Assessment
Mercury levels
Inorganic/elemental
Whole blood: nl 10-20 g/L; toxic: >35 g/L Urine (24 hr): nl <20 g/L; toxic: >100 g/L Whole blood: toxic: >20 g/L
Organic
Mercury Treatment
Preventing absorption
Ingestions of Elemental Hg
GI decontamination usually not required Lavage within 2 hours Consider adding milk or egg white (sulhydryl groups) WBI (when confirmed by Xray)
Sources of Arsenic
Types of Arsenic
More toxic than pentavalent Interferes with conversion of pyruvate to acetyl coenzyme A Interferes with alpha-ketoglutarate dehydrogenase Substitutes for inorganic phosphate during production of ATP Uncouples oxidative-phosphorolation by forming adenosine di-phosphate arsenate complexes
Clinical Presentation
Acute
Dysphagia, metallic taste, nausea, vomiting, abdominal pain, rice-like diarrhea, cardiovascular collapse, peripheral neuropathy, renal insufficiency Peripheral neuropathy, headache, and dermal manifestations. Lung cancer and skin cancer
Chronic
Laboratory Assessment
General Workup
CBC, renal function tests, liver function tests, urinary analysis, ECG Acute: abdominal x-ray Urinary arsenic (>50 g/L, >100 g/g creatinine, or >100 g/24 urine collection) Hair or nail analysis
Specific Tests
Arsenic Treatment
Supportive
Rehydration and replenishment of glucose and glycogen stores with dextrose and hyperalimentation Avoid class IA, IC, and III antidysrhythmics (increase QT interval) WBI Continuous nasogastric suctioning
Prevent Absorption
Antidote
Acute: BAL Chronic: Succimer Endpoint: 24-hour urinary As <50 g/L Consider hemodialysis only if the patient is being chelated and has renal failure
Enhancing elimination
Subjective - Continued
He had no access to medications or household products. The mother commented that she did find paint chips in his mouth three weeks earlier. The child was developmentally delayed in terms of speech and social skills. Prior to the seizure he spoke only single words , was not toilet trained and could not dress himself. He appeared postical, with flaccid muscle tone and minimal response to painful stimulation.
Objective
O: The patients vital signs were: HR 110, BP 130/80, RR 10 shallow, T 98.6 F, Pulse oximetry 85% on room air Initial laboratory values were as follows: Cerebral spinal fluid analysis: clear, colorless; 3 WBCs/mm3, 0 RBCs, glucose 108 mg/dL,, protein 96 mg/dL
Objective-Continued
WBC: 11,300/mm3 Hemoglobin: 6.6 g/dL (normal: 11.8 0.5) Mean corpuscular volume 50 m (normal: 87 7) Platelet count: 473,000/mm3 Peripheral blood smear: RBC basophilic stippling Electrolytes: Na 139, K 4.3, Cl 105, HCO3 22, BUN 15, S.Cr 0.3, Glucose 170
Assessment
A: Seizure of unknown etiology that could be toxicologic in origin. Consider:
W= withdrawl I= isoniazid T= theophylline, tricyclics H= hypoglycemia, hypoxia L= lead, lithium, local anesthetics A= anticholinergics C= camphor, cholinergics, CO, CN O= organophosphates P= phencyclidine, phenothiazines, propoxyphene S= salicylates, strychnine, sympathomimetics
Assessment-Continued
The most likely agent is lead since 1) the patient has symptoms consistent with encephalopathy (nausea, vomiting, lethargy, convulsion), 2) there is a history of possible lead exposure 3) he has a microcytic anemia. The patient is at risk for permanent brain damage or death. Emergent chelation should be performed.
Plan
Supportive Care 1)Consider 40 mg IV furosemide, 1 gram/kg of mannitol, 250 mg acetazolamide QID, a short course of prednisone for treatment of cerebral edema. 2)Seizures: Diazepam , 0.2 mg/kg IV; If a longer-acting agent is required, change to Phenobarbital 15 mg/kg IV or midazolam 0.1 mg/kg (load) followed by 2 g/kg/min. Patient will also need to be mechanically ventilated.
Plan-Continued
Antidote 3)BAL: 75 mg/m2 (4-5 mg/kg) IM q 4 hours for 5 days 4)Four hours after 1st dose of BAL, begin Edetate Calcium Disodium, 1500 mg/m2/d (30 mg/kg/d) in three divided doses IV for 5 days Additional Labs To Order: Blood lead, urinalysis (glucosuria, proteinuria), radiologic evaluation (paint flecks in gastrointestinal tract, evidence lead in long bones)