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1312 SECTION 15: Toxicology of the small but increased risk of adverse effects in patients without anticholinergic toxicity.41,42 Physostigmine may be repeated in the same dose if required. Patients who remain asymptomatic for more than 6 hours after the first dose of physostigmine will not require repeat physostigmine dosing. 49 Contraindications to physostigmine use include asthma, nonpharmacologically mediated intestinal or bladder obstruction, cardiac conduction distur bances, and suspected concomitant sodium channel antagonist poisoning. DISPOSITION AND FOLLOW-UP Patients with mild symptoms of anticholinergic toxicity that resolve after 6 hours of ED observation may be medically cleared. Because the dura tion of action of physostigmine is generally shorter than the duration of action of many anticholinergic agents, the reversal effect may dissipate, resulting in recurrent toxicity. Patients with more than mild symptoms, as well as those who have received physostigmine, require hospital observation until symptoms resolve or approximately 12 hours after the last dose of physostigmine. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Metals and Metalloids Eddie Charles Michael Garcia Lewis S. Nelson INTRODUCTION Acute metal and metalloid toxicity can cause significant morbidity and mortality if unrecognized and inappropriately treated. Metals are chemical elements that possess three general properties: (1) they are a good conductor of heat and electricity, (2) they are able to form cations, and (3) they can combine with nonmetals through ionic bonds. The terms heavy metal and toxic metals have a historical tradition in clinical medicine, but lack precise definition and scientific merit. In order of ascending atomic weight, the following metals are toxic to humans: beryllium, vanadium, cadmium, barium, osmium, mercury, thallium, and lead. Lead and mercury produce the most clinically significant cases of human metal poisoning. Metalloids are chemical elements with properties intermediate to those of metals and nonmetals. Although there is no precise definition, metalloids tend to have these two general properties: (1) they are semi conductors of electricity, and (2) they form amphoteric oxides. In order of ascending atomic weight, the following metalloids are considered toxic to humans: boron, silicon, germanium, arsenic, antimony, tellu rium, and polonium, with arsenic being the most clinically significant toxic metalloid. Exposure to either metals or nonmetals can be from (1) the pure ele ment, (2) an organic compound containing the toxic element (defined as those compounds that contain carbon), or (3) an inorganic compound containing the element (defined as those that do not contain carbon). Depending on the metal or metalloid, potential toxicity is affected by which chemical form is responsible for the exposure. Because of their effects on numerous enzymatic systems in the body, patients with metal or metalloid poisoning often present with protean manifestations primarily affecting five systems: neurologic, cardiovascular, GI, hematologic, and renal. Effects on the endocrine and reproduc tive systems are less clinically apparent. It is important to recognize an initial “index case” of metal poisoning to prevent others from being exposed or poisoned (Table 203-1).

anifestations primarily affecting five systems: neurologic, cardiovascular, GI, hematologic, and renal. Effects on the endocrine and reproduc tive systems are less clinically apparent. It is important to recognize an initial “index case” of metal poisoning to prevent others from being exposed or poisoned (Table 203-1). CHAPTER TABLE 203-1 Sources of Lead, Arsenic, and Mercury Exposure Element Source Lead Elemental, inorganic Soldering; battery burning/reclamation; bronzing; brassmaking; glassmaking; ingesting ceramic lead glaze; stripping old paint; lead abatement; “moonshine”; liquids in improperly glazed pottery; contaminated herbal medications and cosmet ics; indoor shooting ranges; ingestion of paint chips, lead-laden floor dust, lead foreign bodies; lead bullets in abdomen or joint spaces; contaminated municipal water supplies Workers at risk: jewelers, painters, lead smelters, stained glass designers, pipe cutters, pigment makers, printers, welders, pottery makers, radiator repair personnel, battery reclamation workers, construction workers Organic Leaded gasoline (tetraethyl lead) [no longer legally produced] Arsenic Inorganic (arsenite [trivalent] or arsenate [pentavalent]) Insecticides, rodenticides, herbicides, mining, smelting/refining, Ayurvedic and homeopathic medicines, well water contami nated by leaching mineral ores and/or industrial waste; wood preservatives Organic Seafood, parasitical medicines Gas (arsine) Mining smelting/refining, semiconductor industry; made by mixing acids with arsenic-containing insecticides Mercury Elemental Battery and thermometer manufacture; sphygmomanometer repair; dentistry; jewelry and lamp manufacture; photography; mercury mining; manufacture of scientific instruments Inorganic (mercury salts) Cosmetic products, especially skin-lightening products; taxidermy; fur processing; tannery work; chemical laboratories; manufacture of explosives, fireworks, disinfectants, button bat teries, inks, and vinyl chloride Organic (methyl mercury, ethyl mercury, and phenyl mercury) Contaminated seafood; embalming; manufacture of drugs, fun gicides, bactericides; handling of insecticides; pesticides, coated seeds; use of chlor-alkali process LEAD  EPIDEMIOLOGY Lead is the most common cause of chronic metal poisoning and remains a major environmental contaminant, especially in developing countries. Exposure to lead can occur from inhalation or ingestion, and both inorganic and organic forms of lead produce clinical toxicity. Nonpaint sources include foreign medications, herbal and dietary supplements, Ayurvedic medications, traditional remedies, metallic charms, and cos metics, especially products from Asia and Africa. Chronic lead exposure and toxicity in children is considered a public health concern because of the potential impact on intellectual develop ment.2 Most industrialized countries have banned lead in household paints, gasoline, plumbing systems, food, and drink cans; created lead abatement programs; and enforced standards for industrial use of lead. 2-4 In the United States, continued lead exposure is associated with residence in urban dwellings, residence in dwellings built before 1974 (especially before 1946), poverty, non-Hispanic black race or ethnicity, and higher population density. 5,6 The town of Flint, Michigan, became the focus of national attention in 2014 when a change in water supply resulted in a 5% incidence of elevated blood lead levels in children <6 years old from a prior baseline of 3.1%. Elevated lead levels in children are common in low-income countries where substandard or marginal living conditions exist near landfills and industries such as smelters, mines, and refineries.

n water supply resulted in a 5% incidence of elevated blood lead levels in children <6 years old from a prior baseline of 3.1%. Elevated lead levels in children are common in low-income countries where substandard or marginal living conditions exist near landfills and industries such as smelters, mines, and refineries. 2,5 In developing countries, informal recycling of used lead-acid batteries and processing of gold ore rich in lead have caused mass lead poisonings. 8,9 Tintinalli_Sec15_p1187-1332.indd 1312 8/2/19 8:40 PM

n water supply resulted in a 5% incidence of elevated blood lead levels in children <6 years old from a prior baseline of 3.1%. Elevated lead levels in children are common in low-income countries where substandard or marginal living conditions exist near landfills and industries such as smelters, mines, and refineries. 2,5 In developing countries, informal recycling of used lead-acid batteries and processing of gold ore rich in lead have caused mass lead poisonings. 8,9 Tintinalli_Sec15_p1187-1332.indd 1312 8/2/19 8:40 PM CHAPTER 203: Metals and Metalloids 1313 lines. Lead poisoning also causes constitutional symptoms, including arthralgias, generalized weakness, and weight loss. Conversely, adult and pediatric patients may appear asymptomatic in the face of significantly elevated blood lead levels. With organic lead poisoning, neurologic abnormalities predominate. Findings range from behavioral changes, with irritability, insomnia, restlessness, and nausea and vomiting, to tremor, chorea, convulsions, and mania.  DIAGNOSIS A detailed history, including potential occupational, environmental, travel-related, or recreational exposures, is the most important part in making a diagnosis of lead toxicity. Focus on clinical findings, the age of the home as well as any remodeling, and work, school, or day care locale. Ask adults about medication, dietary supplements, cosmetics, and hobbies and evaluate children who may be secondarily exposed to lead from adult activities. Additionally, screen children for abnormal development and the presence of pica or excessive hand-to-mouth behavior. Toxicity due to retained lead bullets may manifest several decades after being shot. Hyperthyroidism, pregnancy, fever, reinjury, or immobilization of the affected extremity can promote lead release from these retained objects after years of dormancy. The combination of abdominal pain or neurologic dysfunction with anemia should raise suspicion for lead toxicity. Consider the diagnosis in all children presenting with acute encephalopathy. The definitive diagnosis of lead poisoning rests on finding an elevated blood lead level. Fingerstick capillary blood may be used as screening, but results maybe be misleading due to the potential for environ mental lead contamination. Elevated concentrations always should be confirmed using a venous blood sample. 16 The reference value for an elevated blood lead level per the Centers for Disease Control and Pre vention has decreased from 60 micrograms/dL (2.88 micromol/L) in the 1960s to its current value of 5 micrograms/dL (0.24 micromol/L). 3,17 Although it is important to order a blood lead level for confirma tory diagnosis and assistance in monitoring therapy, the laboratory turnaround time for results may be days. Diagnostic studies in the ED should therefore focus on evaluation for anemia and examination of radiographs for evidence of lead exposure. The anemia from lead toxicity can be normocytic or microcytic, with or without evidence of hemolysis. Basophilic stippling in red blood cells from impaired clearing of cellular RNA degradation products is sometimes seen in lead-poisoned patients. This finding is nonspecific for lead poisoning; it is also found in arsenic toxicity, sideroblastic anemia, and  PHARMACOLOGY Absorption of inorganic lead is usually via the respiratory and GI tracts; skin absorption is negligible. Dietary deficiencies in calcium, iron, cop per, and zinc may contribute to increased GI absorption in children. Absorption of lead from bullets or shot lodged in bone or muscle is typically minimal, but increased absorption and toxicity have been reported when these are in contact with body fluids, such as synovial fluid or cerebrospinal fluid. Absorption of organic lead, such as tetraethyl lead from “leaded gasoline, ” can occur after inhalation, ingestion, and dermal exposure.

one or muscle is typically minimal, but increased absorption and toxicity have been reported when these are in contact with body fluids, such as synovial fluid or cerebrospinal fluid. Absorption of organic lead, such as tetraethyl lead from “leaded gasoline, ” can occur after inhalation, ingestion, and dermal exposure. After absorption, tetraethyl lead is metabolized to inorganic lead and triethyl lead; the latter is responsible for the acute neurotoxicity from leaded gasoline. Greater than 90% of the total body lead is stored in bone, where it easily exchanges with the blood. Lead can be transferred across the placenta, a process exacerbated by increased bone turnover during pregnancy. Excretion of lead occurs slowly; the biologic half-life of lead in bone has been estimated to be 30 years.  PATHOPHYSIOLOGY Lead toxicity primarily affects the nervous, cardiovascular, hematopoietic, and renal systems. Toxic effects of lead in the CNS include (1) injuries to astrocytes, with secondary damage to the microvasculature and resultant disruption of the blood–brain barrier, cerebral edema, and increased intracranial pressure; (2) decreases in cyclic adenosine monophosphate and protein phosphorylation, which contribute to memory and learning deficits; and (3) alteration with calcium homeostasis, which leads to spontaneous and uncontrolled neurotransmitter release. 10 In the peripheral nervous system, lead causes primary segmental demyelination, followed by secondary axonal degeneration, mostly of the motor nerves. In the cardiovascular system, increases in the prevalence of hypertension and atherosclerotic vascular disease are found in individuals with elevated blood lead levels. Worldwide, it is estimated that chronic lead toxicity contributes to 2.5% of ischemic heart disease and 3.1% of stroke. In the hematopoietic system, lead interferes with porphyrin metabo lism, which contributes to lead-induced anemia. Coexisting iron defi ciency may act synergistically with lead toxicity to produce a more profound anemia. Hemolytic anemia also occurs as a result of inhibition of red blood cell pyrimidine 5 ′-nucleotidase, an enzyme responsible for clearing cellular RNA degradation products. In the kidney, lead affects the proximal tubule, producing Fanconi’s syndrome with aminoaciduria, glycosuria, phosphaturia, and renal tubular acidosis. 13 Chronic interstitial nephritis and increased uric acid levels are due to increased tubular reabsorption of urate. Chronic lead toxicity has been linked to gout and chronic renal failure. Lead adversely affects osteoblast and osteoclast function in bone. With chronic lead exposure, increased calcium deposition at growth plates may be seen as “ lead lines” on radiographs of long bones. Leadinduced adverse effects on the reproductive system include increased fetal demise, premature rupture of membranes, depressed sperm counts, abnormal or nonmotile sperm, and sterility.  CLINICAL FEATURES Signs and symptoms of lead poisoning vary according to the type of exposure (acute vs. chronic) and, to a lesser extent, according to the age of the individual and type of lead (inorganic vs. organic) involved (Table 203-2). Y oung children are more susceptible than adults to the CNS effects of lead. Delayed cognitive development can occur in infants and children whose blood lead levels are 5 micrograms/dL (0.24 micromol/L) or higher. 14 Encephalopathy due to lead poisoning typically occurs in toddlers age 15 to 30 months old with blood lead levels >100 micrograms/dL (4.8 micromol/L), but may occur with lower blood lead levels. Encephalopathy may begin dramatically with seizures or coma or may develop indolently over weeks to months with decreased alertness and memory progressing to delirium.

cally occurs in toddlers age 15 to 30 months old with blood lead levels >100 micrograms/dL (4.8 micromol/L), but may occur with lower blood lead levels. Encephalopathy may begin dramatically with seizures or coma or may develop indolently over weeks to months with decreased alertness and memory progressing to delirium. GI and hematologic manifestations occur more frequently with acute than with chronic poisoning, and the colicky abdominal pains may be associated with concurrent hemolysis. Patients may complain of a metallic taste and, with long-term exposure, have bluish-gray gingival lead TABLE 203-2 Clinical Features of Lead Poisoning System Clinical Manifestations CNS Acute toxicity: encephalopathy, seizures, altered mental status, papilledema, optic neuritis, ataxia Chronic toxicity: headache, irritability, depression, fatigue, mood and behavioral changes, memory deficit, sleep disturbance Peripheral nervous system Paresthesias, motor weakness (classic is wrist drop), depressed or absent deep tendon reflexes, sensory function intact GI Abdominal pain (mostly with acute poisoning), constipation, diarrhea, toxic hepatitis Renal Acute toxicity: Fanconi’s syndrome (renal tubular acidosis with aminoaciduria, glucosuria, and phosphaturia) Chronic toxicity: interstitial nephritis, renal insufficiency, hypertension, gout Hematologic Hypoproliferative and/or hemolytic anemia; basophilic stippling (nonspecific) Reproductive Decreased libido, impotence, sterility, abortions, premature births, decreased or abnormal sperm production Tintinalli_Sec15_p1187-1332.indd 1313 8/2/19 8:40 PM

itial nephritis, renal insufficiency, hypertension, gout Hematologic Hypoproliferative and/or hemolytic anemia; basophilic stippling (nonspecific) Reproductive Decreased libido, impotence, sterility, abortions, premature births, decreased or abnormal sperm production Tintinalli_Sec15_p1187-1332.indd 1313 8/2/19 8:40 PM 1314 SECTION 15: Toxicology the thalassemias. Anemia and basophilic stippling occur variably, and their absence does not exclude lead toxicity. Following acute or subacute ingestion of lead, abdominal radiographs may show radiopaque material in the GI tract. In children with chronic lead poisoning, radiographs of long bones, especially of the knee, may reveal horizontal, metaphyseal “lead lines, ” which represent failure of bone remodeling rather than deposition of lead. The differential diagnosis of lead poisoning includes Wernicke’s encephalopathy; withdrawal from ethanol and other sedative-hypnotic drugs; meningitis; encephalitis; human immunodeficiency virus infec tion; intracerebral hemorrhage; hypoglycemia; severe fluid and electro lyte imbalances; hypoxia; arsenic, thallium, and mercury toxicity; and poisoning with cyclic antidepressants, anticholinergic drugs, ethylene glycol, or carbon monoxide. The abdominal pains of lead poisoning can mimic sickle cell crisis, the hepatic porphyrias, or appendicitis. Chronic lead poisoning can mimic major depression, hypothyroidism, polyneuritis, gout, iron deficiency anemia, and learning disability.  TREATMENT Patients with appropriate signs and symptoms and an elevated blood lead level are classified as lead poisoned and should be treated. For acute encephalopathy, provide standard life support measures and treat seizures with benzodiazepines. If lead encephalopathy is suspected, initiate chelation therapy promptly (i.e., in the ED) without waiting for the results of a blood lead level ( Table 203-3). If abdominal films demonstrate GI foreign bodies consistent with lead, institute whole-bowel irrigation with a polyethylene glycol electrolyte solution. Larger lead bodies, such as fishing sinkers and jewelry, may require endoscopic or surgical removal. Chelation therapy for lead toxicity uses dimercaprol (previously known as British anti-Lewisite or BAL ), edetate calcium disodium (sometimes abbreviated CaNa 2-EDTA), and succimer (also known as dimercaptosuccinic acid or DMSA) (Table 203-3 ).18,19 Penicillamine, another chelating agent, is not approved by the U.S. Food and Drug Administration for treatment of lead toxicity, but penicillamine is used in Europe for lead poisoning. The chelation dosing schedules are guided by the blood lead levels, the presence or absence of findings, and the age of the patient. 20,21 Adverse side effects from chelation therapy are common, and consultation with a medical toxi cologist or other lead poisoning expert is recommended to assist in management. Dimercaprol crosses the blood–brain barrier and is indicated when neurotoxicity or high blood lead levels are present. Dimercaprol is administered IM and is typically used with edetate calcium disodium to prevent lead from being transported into the brain. The diluent for dimercaprol includes peanut oil, and therefore, anticipate an allergic reaction and provide careful monitoring for patients with peanut allergy. Side effects of dimercaprol include hypertension; fever, pain, and sterile abscess at injection site; nausea; vomiting; diarrhea; abdominal pain; headache; lacrimation; rhinorrhea; and hemolysis in glucose-6-phosphate dehydrogenase–deficient patients. Side effects with dimercaprol are dose dependent and occur in up to 65% of treated patients using recommended doses.

; fever, pain, and sterile abscess at injection site; nausea; vomiting; diarrhea; abdominal pain; headache; lacrimation; rhinorrhea; and hemolysis in glucose-6-phosphate dehydrogenase–deficient patients. Side effects with dimercaprol are dose dependent and occur in up to 65% of treated patients using recommended doses. Edetate calcium disodium can be used as a single agent in the treat ment of lead toxicity, but because this agent does not cross the blood– brain barrier, dimercaprol should be given before and during the entire course of edetate calcium disodium when there are CNS symptoms. An important precaution: do not confuse this product with edetate disodium, which is used to treat hypercalcemia. Side effects from edetate calcium disodium include renal toxicity, dermatitis, headache, fever, chills, and myalgias. Succimer, an oral analog of dimercaprol, effectively chelates lead. Although succimer does not cross the blood–brain barrier, its use as a sole agent is not associated with exacerbation of lead-induced encepha lopathy. 22 Some toxicologists consider succimer the preferred chela tor for lead poisoning in all but the most severe cases. Its advantages include oral administration without increasing lead absorption from the GI tract, no serious adverse effects, and minimal chelation of essential metals. Side effects from succimer include nausea, vomiting, diarrhea, abdominal pain, rash, pruritus, sore throat, rhinorrhea, drowsiness, paresthesias, transient elevations in serum transaminases and alkaline phosphatase, thrombocytosis, and eosinophilia. Chelation was not associated with any increased risk of birth defects in the few published cases, and pregnant women with elevated blood lead levels should be chelated following the same guidelines ( Table 203-3). Neonatal blood lead levels may be elevated despite maternal chelation, and neonates may require chelation following birth. Abdominal colic usually subsides within days after beginning chelation therapy, and other acute manifestations clear within 1 to 16 weeks with therapy. Lead-induced nephropathy may be partly reversible with chelation therapy. Approximately 85% of patients who suffer lead encephalopathy develop permanent central neurologic damage, including seizures, mental retardation in children, and cognitive deficits in adults.  DISPOSITION AND FOLLOW-UP Removal of the source of lead is the most important action for lead poisoning, and patients should not be returned to the home environ ment until lead decontamination and abatement measures have been addressed. Family members and coworkers should be evaluated for occult lead toxicity. Hospital admission is recommended for (1) children with symptoms or with a blood lead level >70 micrograms/dL (>3.4 micromol/L), (2) adults with central neurologic symptoms, and (3) patients with suspected lead toxicity when returning to the environment is considered dangerous. ARSENIC  EPIDEMIOLOGY Arsenic is a nearly tasteless, odorless metalloid that causes significant acute and chronic toxicity worldwide.

70 micrograms/dL (>3.4 micromol/L), (2) adults with central neurologic symptoms, and (3) patients with suspected lead toxicity when returning to the environment is considered dangerous. ARSENIC  EPIDEMIOLOGY Arsenic is a nearly tasteless, odorless metalloid that causes significant acute and chronic toxicity worldwide. 24 Arsenicals are found in a variety of compounds and industries ( Table 203-1) and continue to be used as TABLE 203-3 Guidelines for Chelation Therapy in Lead-Poisoned Patients* Severity and Blood Lead Level Dose Encephalopathy Dimercaprol, 75 milligrams/m2 (or 4 milligrams/kg) IM every 4 h for 5 d and Edetate calcium disodium, 1500 milligrams/ 2 per day via continuous infusion or in 2–4 divided doses IV for 5 d; max 3 grams/d; start 4 h after dimercaprol Symptomatic and/or severe poisoning Adults: blood lead >100 micrograms/dL (4.8 micromol/L) Children: blood lead >70 micrograms/dL (3.4 micromol/L) Dimercaprol and Edetate calcium disodium (as described above) Edetate calcium disodium (alone) Succimer (as described below) Asymptomatic Adults: blood lead 70–100 micrograms/ dL (3.4–4.8 micromol/L) Children: blood lead 45–69 micrograms/ dL (2.2–3.3 micromol/L) Succimer, 350 milligrams/m 2 (or 10 milligrams/kg) PO every 8 h for 5 d, then every 12 h for 14 d Asymptomatic Adults: blood lead <70 micrograms/dL (3.4 micromol/L) Children: blood lead <45 micrograms/dL (2.2 micromol/L) Routine chelation not indicated; remove patient from source of exposure *General guidelines. Consult with medical toxicologist or regional poison center for specifics and dosing. Tintinalli_Sec15_p1187-1332.indd 1314 8/2/19 8:40 PM

0 micrograms/dL (3.4 micromol/L) Children: blood lead <45 micrograms/dL (2.2 micromol/L) Routine chelation not indicated; remove patient from source of exposure *General guidelines. Consult with medical toxicologist or regional poison center for specifics and dosing. Tintinalli_Sec15_p1187-1332.indd 1314 8/2/19 8:40 PM CHAPTER 203: Metals and Metalloids 1315 a means for homicide and suicide. Chronic arsenic toxicity from unsafe drinking water has the potential to threaten the health of millions of people worldwide, particularly in Bangladesh. Arsenic exists in elemental, inorganic salts, organic salts, and gaseous forms. Elemental and organic forms have limited toxicity, whereas inorganic compounds, including arsenite (trivalent or As 3+) and arsenate (pentavalent or As5+), are highly toxic.  PHARMACOLOGY Arsenic is well absorbed by GI, respiratory, and parenteral routes and may be absorbed through nonintact skin. Due to its water solubility, pentavalent arsenic (arsenate) is more readily absorbed across mucous membranes, such as the GI tract, than is trivalent arsenic (arsenite), which penetrates the skin more readily due to its increased lipid solu bility. Within 24 hours, inorganic arsenic redistribution into the liver, kidney, spleen, lung, GI tract, muscle, and nervous tissues occurs, with subsequent integration into hair, nails, and bone. Elimination from the blood is rapid, and excretion is predominantly renal. Toxicity of the various forms is partly determined by excretory rates, with the more toxic arsenite being excreted at a slower rate than arsenate or the organic arsenical compounds. Arsenic crosses the placenta and is teratogenic in animals and humans.  PATHOPHYSIOLOGY Arsenic reversibly binds with sulfhydryl groups found in many tissues and enzyme systems. Acute exposure produces dilatation and increased permeability of small blood vessels, resulting in GI mucosal and sub mucosal inflammation and necrosis, cerebral edema and hemorrhage, myocardial tissue destruction, and fatty degeneration of the liver and kidneys. Subacute or chronic exposure can cause a primary periph eral axonal neuropathy with secondary demyelination. Inhaled arsine attaches to sulfhydryl groups of hemoglobin, producing an acute hemolytic anemia with resulting jaundice, abdominal pain, and hemoglobin uria-induced acute renal failure.  CLINICAL FEATURES The signs and symptoms of toxicity vary with the form, amount, and concentration ingested and the rates of absorption and excretion of the various arsenical compounds (Table 203-4). Following ingestion of inorganic arsenic, clinical effects usually develop within minutes to hours of ingestion. Severe gastroenteritis with nausea, vomiting, and cholera-like diarrhea is the hallmark of acute poisoning and may last several days to weeks, frequently neces sitating hospitalization. Patients may complain of a metallic taste. Hypotension and tachycardia secondary to volume depletion, capil lary leak, and myocardial dysfunction occur in moderate to severe cases. The ECG may demonstrate nonspecific ST-segment and T-wave changes with a prolonged QT interval, although these findings are more common in chronic intoxication. Ventricular tachycardia with a torsades de pointes morphology may occur. 27 Acute encephalopathy, acute respiratory distress syndrome, acute kidney injury, and rhabdo myolysis may ensue. Survivors of acute poisonings and patients who are poisoned slowly may develop subacute toxicity, typically presenting with weakness, muscle aches, abdominal pain, memory loss, personality changes, periorbital and extremity edema, or skin rash, often with a history of gastroenteritis occurring 1 to 6 weeks earlier.

ue. Survivors of acute poisonings and patients who are poisoned slowly may develop subacute toxicity, typically presenting with weakness, muscle aches, abdominal pain, memory loss, personality changes, periorbital and extremity edema, or skin rash, often with a history of gastroenteritis occurring 1 to 6 weeks earlier. 28 Central neurologic symptoms include headache, confusion, delirium, and personality changes, which may become chronic. Peripheral neuropathy develops in a stocking-glove distribution and is initially sensory, with motor symptoms developing later. Rarely, an ascending paralysis mimicking Guillain-Barré syndrome may develop. Dermatologic manifestations vary and include morbilliform rash, alopecia, and desquamation. Mees lines (1- to 2-mm–wide transverse white lines in the nails) due to disrupted keratinization of the nail matrix may be seen 4 to 6 weeks after an acute exposure. Chronic toxicity from arsenic occurs with ongoing low-level occu pational or environmental exposure and has been linked to the devel opment of hypertension, peripheral vascular disease, diabetes mellitus, epidermoid cancer, respiratory tract cancer, hepatic angiosarcoma, and, possibly, leukemia. Dermatologic findings are prominent and include hyperpigmentation, hyperkeratosis of the palms and soles, Bowen’s disease, and squamous and basal cell carcinomas. Perforation of the nasal septum has been found in workers exposed occupationally to arsenic.  DIAGNOSIS The diagnosis is easily missed without a history of exposure to arse nic, and physicians rarely encounter arsenic toxicity. Consider acute arsenic poisoning in a patient with hypotension that was preceded by severe gastroenteritis with no apparent explanation . Chronic arsenic toxicity should be considered in a patient with a peripheral neuropathy, typical skin manifestations, or recurrent bouts of unex plained gastroenteritis. An abdominal radiograph may demonstrate intestinal radiopaque metallic flecks following ingestion. The ECG often reveals a prolonged QT interval, especially in subacute poisoning. The CBC may reveal a normocytic, normochromic, or megaloblastic anemia, and/or a throm bocytopenia. The WBC count may be elevated in acute toxicity and decreased in chronic toxicity. A relative eosinophilia and red cell baso philic stippling may be observed. Elevated reticulocyte counts are found in cases with a component of hemolytic anemia. Definitive diagnosis of acute poisoning is made by finding elevated arsenic levels in a 24-hour urine collection. All urinary measurements of metals should be collected in metal-free containers after a 5-day seafood-free diet (there is a large amount of organic arsenic in seafood). Normal urinary arsenic level is <50 micrograms/L (0.67 micromol/L), and total urinary arsenic excretion in an unexposed patient typically does not exceed 100 micrograms/d (1.3 micromol/d). If the baseline urinary level is within normal limits and arsenic intoxication is still suspected, hair and nail clippings should be harvested for laboratory analysis. Due to the rapid distribution of arsenic in tissues, blood arsenic levels are often unreliable. Include arsenic toxicity in the differential diagnosis for shock of unknown cause, encephalopathy, peripheral neuropathy (including Guillain-Barré syndrome), Addison’s disease, hypo- and hyperthy roidism, patients with the previously mentioned dermatologic man ifestations, Korsakoff ’s syndrome, persistent gastroenteritis and/or cholera-like diarrhea, porphyria, other metal toxicities such as thallium and mercury, and unexplained, prolonged malaise and weakness.

syndrome), Addison’s disease, hypo- and hyperthy roidism, patients with the previously mentioned dermatologic man ifestations, Korsakoff ’s syndrome, persistent gastroenteritis and/or cholera-like diarrhea, porphyria, other metal toxicities such as thallium and mercury, and unexplained, prolonged malaise and weakness. TABLE 203-4 Clinical Features of Inorganic Arsenic Toxicity Onset of Symptoms Clinical Features Acute toxicity (10 min to several hours) GI: nausea, vomiting, cholera-like diarrhea Cardiovascular: hypotension; tachycardia; dysrhythmias, including torsades de pointes; secondary myocardial ischemia Pulmonary: acute respiratory distress syndrome Renal: acute renal failure Central neurologic: encephalopathy Subacute toxicity (1–3 wk after acute exposure or with chronic exposure) Central neurologic: headache, confusion, delirium, personality changes Peripheral neurologic: sensory and motor neuropathy Cardiovascular: QT interval prolongation Pulmonary: cough, alveolar infiltrates Dermatologic: rash, alopecia, Mees lines Chronic toxicity (ongoing low-level occupational or environmental exposure) Dermatologic: hyperpigmentation, keratoses, Bowen’s disease, squamous and basal cell carcinoma Cardiovascular: hypertension, peripheral arterial disease Endocrine: diabetes mellitus Oncologic: lung and skin cancer Tintinalli_Sec15_p1187-1332.indd 1315 8/2/19 8:40 PM

ing low-level occupational or environmental exposure) Dermatologic: hyperpigmentation, keratoses, Bowen’s disease, squamous and basal cell carcinoma Cardiovascular: hypertension, peripheral arterial disease Endocrine: diabetes mellitus Oncologic: lung and skin cancer Tintinalli_Sec15_p1187-1332.indd 1315 8/2/19 8:40 PM 1316 SECTION 15: Toxicology  TREATMENT Acute arsenic toxicity is a life-threatening illness requiring aggressive management. Hypotension and dysrhythmias are the most common causes of death. Hypotension, usually due to volume depletion, should be managed initially with crystalloid volume replacement, and vaso pressor therapy with dopamine or norepinephrine may be required. Avoid overhydration because pulmonary and cerebral edema can occur. Ventricular tachycardia and fibrillation may be treated with lidocaine, amiodarone, and electrical defibrillation as necessary. Magnesium sul fate, isoproterenol, and overdrive pacing therapies should be considered for torsades de pointes. Monitor and correct potassium, calcium, and magnesium levels. Institute gastric lavage with a large-bore orogastric tube for acute ingestion. Activated charcoal poorly adsorbs arsenic but may be effec tive for co-ingestants. Whole-bowel irrigation should be considered if abdominal radiographs reveal intestinal radiopaque materials consistent with arsenic. Chelation therapy for arsenic toxicity uses dimercaprol or succimer (Table 203-5). Treat patients with acute arsenical poisoning or severe, life-threatening toxicity with dimercaprol until the clinical condition stabilizes and succimer, the less toxic oral chelating agent, can be substituted. 29 Do not delay chelation in severely ill patients until laboratory confirmation because chelation is most effective when given within minutes to hours of exposure. Conversely, hold chela tion therapy in clinically stable patients with suspected chronic arsenic toxicity pending diagnosis. Chelation with the oral agent succimer may lower the tissue content of arsenic and speed urinary excretion but does not appear to decrease morbidity or mortality in chronic arsenic poisoning. 29 Obtain early consultation with a regional poi son control center or medical toxicologist for treatment. For chronic toxicity, prevent further arsenic absorption and, if appropriate, GI decontamination. Dermatologic manifestations of chronic toxicity are unresponsive to chelation.  DISPOSITION AND FOLLOW-UP Hospitalization is recommended for (1) patients with acute or lifethreatening known or suspected arsenic poisoning, (2) chronically poisoned patients requiring dimercaprol therapy, and (3) patients in whom suicidal or homicidal intent is suspected. In patients with acute arsenic poisoning, prognosis may be influenced favorably by the rapid institution of dimercaprol therapy. Recovery from arsenical neuropathy appears to be related more to the initial severity of symptoms than to chelation therapy, although in patients who do recover, dimercaprol appears to significantly shorten the duration of illness. Often, neurologic recovery occurs slowly over months to years.  ARSINE GAS Arsine is a colorless, nonirritating toxic gas encountered in the semiconductor industry, ore smelting, and refining processes and is produced when arsenic-containing insecticides are mixed with acids. Arsine gas is highly toxic and extremely flammable. It has a garlic or fishy odor, but there may be no odor detectable with toxic exposure. Exposure is by inhalation. Malaise, dizziness, nausea, and abdominal pain occur within a few hours. Intravascular hemolysis and renal failure then develop. Arsine gas does not cause acute arsenic poisoning.

and extremely flammable. It has a garlic or fishy odor, but there may be no odor detectable with toxic exposure. Exposure is by inhalation. Malaise, dizziness, nausea, and abdominal pain occur within a few hours. Intravascular hemolysis and renal failure then develop. Arsine gas does not cause acute arsenic poisoning. Treat ment is supportive, with blood transfusions, exchange transfusion to remove the nondialyzable arsine, and hemodialysis for the acute kidney injury. 30 Chelation therapy has no role in the management of arsine toxicity. MERCURY  EPIDEMIOLOGY Mercury occurs in elemental (quicksilver), inorganic, and organic forms. Inorganic mercury compounds are subdivided largely into mercurous (Hg +) (e.g., mercurous chloride or calomel) and mercuric (Hg2+) salts (e.g., cinnabar or mercuric sulfide). Organic mercurials exist as short- and long-chained alkyl and aryl compounds. The shortchained alkyls, such as methyl mercury and ethyl mercury, are more toxic to humans, with dimethyl mercury being lethal in small amounts. All forms of mercury are toxic but differ in the means of exposure, routes of absorption, constellations of clinical findings, and responses to therapy ( Table 203-1).  PHARMACOLOGY Elemental mercury is absorbed primarily by vapor inhalation or trans dermally. For example, attempting to clean up elemental mercury from a broken thermometer with a vacuum causes volatilization due to both the heat and the airflow through the canister. Absorption by the GI tract is usually negligible so that swallowing elemental mercury contained in a glass thermometer does not produce adverse effects unless the mucosa is damaged . IM injections of mercury can induce abscess and granuloma formation. IV injections have produced mercury pulmonary and systemic emboli. 32 Elemental mercury crosses the blood–brain bar rier, where it is ionized and trapped in the CNS. Inorganic mercury salts are absorbed primarily through the GI tract, but they may also be slowly absorbed across intact skin.33 Mercuric salts deposit in the ionized form primarily in the kidney, liver, and spleen. Mercury salts do not enter the CNS in consequential amounts nor do they cross the placenta. Organic mercury compounds are also primarily absorbed by the GI tract. The highly lipid-soluble short-chained alkyls easily cross mem branes, accumulating in red blood cells, the CNS, liver, kidney, and fetus. Longer chained alkyl and the aryl compounds are biotransformed into inorganic mercuric ions in the body; thus, their toxicity more closely resembles inorganic mercury toxicity. Inorganic and the aryl organic mercurials are eliminated in the urine and feces. The short-chained alkyl compounds are excreted primarily in the bile, where they undergo significant enterohepatic circulation.  PATHOPHYSIOLOGY Mercury binds with sulfhydryl groups, affecting a diverse number of enzyme and protein systems in the various organs in which they deposit. For example, mercuric salts produce proximal renal tubular necrosis.  CLINICAL FEATURES The clinical effects of mercury poisoning depend on the form and, in some cases, the route of exposure. 31 In general, the neurologic, GI, and renal systems are predominantly affected. Elemental Mercury Acute symptoms following inhalation of elemental mercury vapor include shortness of breath, fever/chills, cough, nau sea, vomiting, diarrhea, metallic taste, headaches, weakness, and blurry vision. In severe cases, patients may develop acute respiratory distress syndrome. Following metabolism of absorbed elemental mercury to inorganic salts, patients may also develop signs of inorganic mercury toxicity, including tremor and renal failure.

vomiting, diarrhea, metallic taste, headaches, weakness, and blurry vision. In severe cases, patients may develop acute respiratory distress syndrome. Following metabolism of absorbed elemental mercury to inorganic salts, patients may also develop signs of inorganic mercury toxicity, including tremor and renal failure. Inorganic Mercury Mercury salts are highly irritating, and an acute ingestion produces a severe hemorrhagic gastroenteritis with abdominal pain often associated with a characteristic graying of the oral mucosa TABLE 203-5 Guidelines for Chelation Therapy in Arsenic-Poisoned Patients Chelator Dose Dimercaprol 3–5 milligrams/kg deep IM every 4 h for 2 d, followed by 3–5 milligrams/kg IM every 6–12 h until able to switch to succimer, up to 10 d total Succimer 10 milligrams/kg PO every 8 h for 5 d, followed by 10 milligrams/kg PO every 12 h for 14 days; children <5 years old: 350 milligrams/m PO on adult schedule Note: These are general guidelines. Consult with medical toxicologist or regional poison center for specifics and dosing. Tintinalli_Sec15_p1187-1332.indd 1316 8/2/19 8:40 PM

ams/kg PO every 8 h for 5 d, followed by 10 milligrams/kg PO every 12 h for 14 days; children <5 years old: 350 milligrams/m PO on adult schedule Note: These are general guidelines. Consult with medical toxicologist or regional poison center for specifics and dosing. Tintinalli_Sec15_p1187-1332.indd 1316 8/2/19 8:40 PM CHAPTER 203: Metals and Metalloids 1317 and metallic taste. Shock and cardiovascular collapse may rapidly ensue. Acute kidney injury results from both direct toxicity of the mercury ions and from decreased renal perfusion due to shock. GI findings of chronic inorganic mercury toxicity include metallic taste, burning sensation in the mouth, loose teeth, mucosal lesions and fissures, excessive salivation, and nausea. Hallmarks of chronic neurologic toxicity include tremor, neurasthenia, and erethism. Neurasthenia is characterized by fatigue, depression, headaches, and difficulty concentrating. Erethism refers to behavioral changes char acterized by shyness, emotional lability, irritability, insomnia, and delirium. Chronic renal toxicity ranges from reversible proteinuria to the nephrotic syndrome. Acrodynia, also known in small children as pink disease , is an immune-mediated reaction to mercury character ized by a generalized rash; edema and erythema of the palms, soles, and face; excessive sweating; fever; irritability; splenomegaly; and generalized hypotonia with particular weakness of the pelvic and pectoral muscles. Organic Mercury The short-chained alkyl compounds, methyl, dimethyl, and ethyl mercury, have the most devastating effects on the CNS. After a latent period of weeks to months, orofacial paresthesias are a common initial symptom, followed by headache, tremor, and fatigue. In severe cases, patients may develop ataxia, muscle rigidity and spasticity, blindness, hearing deficits, and dementia. 31 Mild GI, renal, and pulmonary abnormalities may develop with organic mer cury poisoning.  DIAGNOSIS An exposure history in either the patient or a household member, along with typical physical findings, especially tremor or those of erethism or acrodynia, suggests mercury poisoning. Ingestion of mercuric chlo ride can produce a rapidly fatal course and should be considered in a patient presenting with a corrosive gastroenteritis. 34 Often, however, the diagnosis of mercury toxicity is subtle and only made after many other diagnoses have been investigated. For all forms of mercury, except short-chained alkyls, a 24-hour urinary measurement of mercury should be performed after a 5-day seafood-free diet. A seafood meal (which contains organic mercury) can temporarily elevate the mercury level to the toxic range until the mer cury is eliminated. Most unexposed individuals will have 24-hour urine mercury levels <10 to 15 micrograms/L (<0.05 to 0.075 micromol/L). A level >20 micrograms/L (>0.1 micromol/L) may indicate meaning ful exposure, but does not diagnose poisoning without an appropriate exposure and clinical syndrome. Short-chained alkyl mercury compounds are excreted predominantly by the bile, rendering urinary measurements invalid to assess toxicity from these agents. Laboratory diagnosis after this exposure rests on finding elevated whole-blood mercury levels, because these compounds concentrate in erythrocytes. Whole-blood mercury levels are normally <5 micrograms/L (<0.025 micromol/L). Although elevated blood or urine values are necessary to confirm the diagnosis, levels correlate poorly with toxicity and do not distinguish asymptomatic exposure from mercury poisoning. Furthermore, blood or urine levels do not represent total-body burden. Levels are most useful in confirming exposure and in following the effects of chelation therapy (see following section, “Treatment”).

agnosis, levels correlate poorly with toxicity and do not distinguish asymptomatic exposure from mercury poisoning. Furthermore, blood or urine levels do not represent total-body burden. Levels are most useful in confirming exposure and in following the effects of chelation therapy (see following section, “Treatment”). MRI findings in methyl mercury toxicity from ingestion of contami nated seafood include marked atrophy of the visual cortex, cerebellar vermis and hemispheres, and postcentral cortex. Behavioral changes or tremor similar to those caused by mercury can be seen with hypothyroidism, apathetic hyperthyroidism, metabolic encephalopathy, senile dementia, adverse effects of therapeutic drugs, Parkinson disease, delayed neuropsychiatric sequelae of carbon mon oxide poisoning, lacunar infarction, cerebellar degenerative disease or tumor, and ethanol or sedative-hypnotic drug withdrawal. Corrosive gastroenteritis can be caused by iron, arsenic, phosphorus, acids, or alkali ingestion. Cerebral palsy, intrauterine hypoxia, and teratogenic effects of therapeutic and illicit drugs and environmental contaminants should be considered when evaluating an infant thought to be affected in utero by short-chained alkyl mercury compounds.  TREATMENT General therapeutic measures include removal from exposure and sup portive therapy. Hemodialysis does not enhance mercury clearance but may be indicated for treatment of acute kidney injury. For elemental mercury , the severe respiratory failure following inhalation of volatilized elemental mercury or aspiration of elemental mercury may require endotracheal intubation and positive-pressure ventilation. For ingestion of inorganic mercury salts , treat with aggressive IV hydration and GI decontamination, including gastric lavage if the patient has not had significant emesis, and consider activated charcoal unless contraindicated (e.g., bleeding). For organic mercury toxicity, institute gastric decontamination in the setting of acute ingestion, and supportive care. Chelation is indicated if it can be given within several hours after ingestion of mercury salts. 29 Chelation therapy for patients with chronic poisoning, especially to organic mercury, is less effective. A history of significant mercury exposure, signs and symptoms consistent with mercury poisoning, and substan tially elevated blood or urine mercury levels may assist in the decision making and help determine duration of treatment for chronic mercury toxicity. Dimercaprol and succimer are Food and Drug Administra tion approved for mercury poisoning (Table 203-6). In Germany, the chelator dimercapto-propane sulfonate is widely used to treat mercury poisoning. 19,31,36 The chelation regimen is adjusted according to clinical response and development of adverse reactions. Adverse reactions with dimercaprol increase with dose and include nausea, vomiting, headache, pares thesias, and diaphoresis. Fever is frequently seen in children during dimercaprol therapy. The dimercaprol–mercury complex is dialyzable, and hemodialysis may be helpful in patients receiving dimercaprol who have diminished renal function. Plasma exchange transfusion also was beneficial in a case of mercuric chloride ingestion. 34 Dimercaprol is contraindicated in methyl mercury poisoning due to the potential for exacerbation of central neurologic symptoms. Succimer is gener ally well tolerated. Consultation with a poison control center or medi cal toxicologist is recommended for further assistance with chelation treatment.  DISPOSITION AND FOLLOW-UP Hospital admission is recommended for (1) patients known or sus pected to have ingested mercury salts, (2) patients known or suspected to have inhaled elemental mercury vapor with pulmonary injury, and (3) patients requiring dimercaprol therapy.

r further assistance with chelation treatment.  DISPOSITION AND FOLLOW-UP Hospital admission is recommended for (1) patients known or sus pected to have ingested mercury salts, (2) patients known or suspected to have inhaled elemental mercury vapor with pulmonary injury, and (3) patients requiring dimercaprol therapy. Outcome depends on the form of mercury and the severity of toxic ity. Mild cases of elemental and mercury salt poisoning and very mild cases of organic mercury toxicity may have complete recovery. Death can occur in severe cases of mercuric chloride poisoning and with TABLE 203-6 Guidelines for Chelation Therapy in Mercury-Poisoned Patients Elemental and Inorganic Mercury Organic Mercury Severe acute poisoning Dimercaprol, 75 milligrams/m (5 milligrams/kg) IM every 4 h for 2 d, followed by 2.5 milligrams/kg IM every 6 h for 2 d, followed by 2.5 milligrams/kg IM every 12–24 h until clinical improve ment occurs or until able to switch to succimer therapy, for up to 10 d total Succimer, 10 milligrams/kg PO every 8 h for 5 d, then every 12 h for 14 d; children <5 years old: 350 milligrams/m 2 orally on adult schedule Mild acute poisoning and chronic poisoning Succimer, 10 milligrams/kg PO every 8 h for 5 d, then every 12 h for 14 d No proven benefit for chelation therapy Note: These are general guidelines. Consult with medical toxicologist or regional poison center for specifics and dosing. Tintinalli_Sec15_p1187-1332.indd 1317 8/2/19 8:40 PM