# 21 - PART 14 Poisoning, Drug Overdose, and Envenomation # 01 - 469 Heavy Metal Poisoning ## 469 Heavy Metal Poisoning Poisoning, Drug Overdose, and Envenomation PART 14 Howard Hu Heavy Metal Poisoning Toxic metals (hereafter referred to simply as “metals”) pose a significant threat to health through low-level as well as high level environmental and occupational exposures. One indication of their importance rela­ tive to other potential hazards is their ranking by the U.S. Agency for Toxic Substances and Disease Registry, which maintains an updated list of all hazards present in toxic waste sites according to their preva­ lence and the severity of their toxicity. The first, second, third, and seventh hazards on the list are heavy metals: arsenic, lead, mercury, and cadmium, respectively (http://www.atsdr.cdc.gov/spl/), positions they have held for many years. All four are also listed by the World Health Organization as among the 10 chemicals of highest concern in relation to health, globally. Specific information pertaining to each of these four metals, including sources and metabolism, toxic effects produced, diagnosis, and the appropriate treatment for poisoning, is summarized in Table 469-1. Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion). Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in creating dental amalgams). When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host. Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotrans­ formation, availability of intracellular ligands, and other factors. Some organs (e.g., bone, liver, and kidney) sequester metals in relatively high concentrations for years. Most metals are excreted through renal clear­ ance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails. The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear. Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements (Chap. 344) but are toxic at high levels of exposure. Others, such as lead and mercury, are xenobiotic and theoretically are capable of exerting toxic effects at any level of exposure. Indeed, much research is currently focused on the contribu­ tion of low-level xenobiotic metal exposure to subtle changes in health, chronic diseases, and/or increased risks of adverse events such as heart attacks, stroke, or cancer that may have significant public health consequences given the widespread nature of their exposures. Metals are well-known to be able to cause toxicity through the inhibition of enzymes, damage to subcellular organelles and DNA, covalent modifi­ cation of proteins, formation of reactive oxygen species, and displace­ ment of essential metals in metal dependent proteins. Recent research has also elucidated how metals may affect DNA methylation and other changes to the epigenome, thereby resulting in altered gene expression as well as the dysregulated expression of microRNAs. Genetic factors, such as polymorphisms that encode for variant enzymes with altered properties in terms of metal binding, transport, and effects, may modify the impact of metals on health. Nutritional status, comorbidi­ ties, and other factors can also contribute to variations in individual susceptibility to metal effects. The most important component of treatment for metal toxicity is the recognition and termination of exposure. Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion. The principal chelating agents are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tet­ raacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their specific use depends on the metal involved and the clinical circumstances. For the most part, they are reserved for treating acute, symptomatic metal toxicity. Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion. In addition to the information provided in Table 469-1, several other aspects of exposure, toxicity, or management are worthy of discussion with respect to the four most hazardous toxicants (arsenic, cadmium, lead, and mercury). Arsenic, even at moderate levels of exposure, has been clearly linked with increased risks for cancer of the skin, bladder, renal pelvis, ureter, kidney, liver, and lung. These risks appear to be modified by smoking, folate and selenium status, genetic traits (such as ability to methylate arsenic), and other factors. Based on the accumulation of evidence, the American Heart Association concluded that low-level exposures to arsenic, lead, and cadmium are risk factors for hypertension, sub­ clinical atherosclerosis, coronary artery stenosis, and calcification as well as ischemic heart disease and stroke, left ventricular hypertrophy and heart failure, and peripheral artery disease. Recent studies in community-based populations have also generated strong evidence that arsenic exposure is a risk factor for lung function impairment, acute respiratory tract infections, respiratory symptoms, and nonma­ lignant lung disease mortality. The association with cardiovascular disease may hold at levels of exposure in drinking water that are below the World Health Organization (WHO) provisional guideline value of 10 μg/L. Evidence has also continued to build indicating that low-level arsenic is a likely cause of neurodevelopmental delays in children and likely contributes to the development of type 2 diabetes and possibly nonalcoholic fatty liver disease and cirrhosis. Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak of “itai-itai” (“ouch-ouch”) disease, so named because of cadmiuminduced bone toxicity that led to painful bone fractures. Modest expo­ sures from environmental contamination have been associated in a growing number of studies with lower bone density, higher incidence of fractures, and faster decline in height in both men and women, effects that may be related to cadmium’s calciuric and other toxic effects on the kidney. Cadmium burdens have also been associated with an increased risk of long-term kidney graft failure, and there is evidence for synergy between the adverse impacts of cadmium and lead on kidney function. Environmental exposures have also been linked to lower lung function (even after adjusting for smoking cigarettes, which contain cadmium) and, as noted earlier, the American Heart Association considers cad­ mium as a risk factor for cardiovascular disease and mortality, stroke, and heart failure. Cadmium triggers pulmonary inflammation, and recent population-based studies of U.S. adults found that higher cad­ mium burdens are associated with higher mortality from influenza, pneumonia, and COVID-19. The International Agency for Research on Cancer has classified cadmium as a known carcinogen, with evi­ dence indicating it contributes to elevated risks of prostate, lung, breast, and endometrial cancer. Overall, this growing body of research indi­ cates that cadmium exposure is contributing significantly to morbidity and mortality rates in the general population. Advances in our understanding of lead toxicity have recently ben­ efited by the development of x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone, which, in turn, reflect cumulative exposure over many years, as opposed to blood lead levels, which mostly reflect recent exposure. Higher levels of cumulative lead exposure in the general population are now wellestablished as a risk factor for chronic disease, even though blood lead levels have continued to decline in the general population over the past few decades following the removal of lead from gasoline, plumb­ ing, solder in food cans, and other consumer products, with mean levels in the U.S. population now hovering in the 1–2 μg/dL range. For example, higher bone lead levels measured by KXRF have been linked to increased risk of hypertension and accelerated declines in TABLE 469-1  Heavy Metals MAIN SOURCES METABOLISM TOXICITY DIAGNOSIS TREATMENT Arsenic Smelting and microelectronics industries; wood preservatives, pesticides, herbicides, fungicides; contaminant of deepwater wells; folk remedies; and coal; incineration of these products. Organic arsenic (arsenobetaine, arsenocholine) is ingested in seafood and fish, but is nontoxic; inorganic arsenic is readily absorbed (lung and GI); sequesters in liver, spleen, kidneys, lungs, and GI tract; residues persist in skin, hair, and nails; biomethylation results in detoxification, but this process saturates. Acute arsenic poisoning results in necrosis of intestinal mucosa with hemorrhagic gastroenteritis, fluid loss, hypotension, delayed cardiomyopathy, acute tubular necrosis, and hemolysis. Chronic arsenic exposure causes diabetes, vasospasm, ischemic heart disease, peripheral vascular insufficiency and gangrene, peripheral neuropathy, and cancer of skin, lung, liver (angiosarcoma), bladder, and kidney. Lethal dose: 120–200 mg (adults); 2 mg/kg (children). Cadmium Metal plating, pigment, smelting, battery, and plastics industries; tobacco; incineration of these products; ingestion of food that concentrates cadmium (grains, cereals, organ meats). Absorbed through ingestion or inhalation; bound by metallothionein, filtered at the glomerulus, but reabsorbed by proximal tubules (thus, poorly excreted). Biologic half-life: 10–30 y. Binds cellular sulfhydryl groups, competes with zinc, calcium for binding sites. Concentrates in liver and kidneys. Acute cadmium inhalation causes pneumonitis after 4–24 h; acute ingestion causes gastroenteritis. Chronic exposure causes anosmia, yellowing of teeth, emphysema, minor LFT elevations, microcytic hypochromic anemia unresponsive to iron therapy, proteinuria, increased urinary β2-microglobulin, calciuria, leading to chronic renal failure, osteomalacia, and fractures, ischemic heart disease and stroke. Cadmium exposure now known to cause lung, prostate, and kidney cancers. PART 14 Poisoning, Drug Overdose, and Envenomation Lead Manufacturing of auto batteries, lead crystal, ceramics, fishing weights, etc.; demolition or sanding of lead-painted houses, bridges; stained glass making, plumbing, soldering; environmental exposure to paint chips, house dust (in homes built <1975), firing ranges (from bullet dust), food or water from improperly glazed ceramics or lead-contaminated cookware; lead pipes and plumbing; contaminated spices, herbal remedies, candies; exposure to environmental pollution from the combustion of leaded fuels, recycling of automobile batteries and electronic waste. Absorbed through ingestion or inhalation; organic lead (e.g., tetraethyl lead) absorbed dermally. In blood, 95–99% sequestered in RBCs— thus, must measure lead in whole blood (not serum). Distributed widely in soft tissue, with half-life ~30 days; 15% of dose sequestered in bone with half-life of >20 years. Excreted mostly in urine, but also appears in other fluids including breast milk. Interferes with mitochondrial oxidative phosphorylation, ATPases, calcium-dependent messengers; enhances oxidation and cell apoptosis. Acute exposure with blood lead levels (BPb) of >60–80 μg/dL can cause impaired neurotransmission and neuronal cell death (with central and peripheral nervous system effects); impaired hematopoiesis and renal tubular dysfunction. At higher levels of exposure (e.g., BPb >80– 120 μg/dL), acute encephalopathy with convulsions, coma, and death may occur. Subclinical exposures in children (BPb 25–60 μg/dL) are associated with anemia; mental retardation; and deficits in language, motor function, balance, hearing, behavior, and school performance. Impairment of IQ appears to occur at even lower levels of exposure with no measurable threshold above the limit of detection in most assays of 1 μg/dL. In adults, chronic subclinical exposures (BPb >40 μg/dL) are associated with an increased risk of anemia, demyelinating peripheral neuropathy (mainly motor), impairments of reaction time and hearing, accelerated declines in cognition, hypertension, ECG conduction delays, hypertension, higher risk of cardiovascular disease and death, interstitial nephritis and chronic renal failure, diminished sperm counts, and spontaneous abortions. Nausea, vomiting, diarrhea, abdominal pain, delirium, coma, seizures; garlicky odor on breath; hyperkeratosis, hyperpigmentation, exfoliative dermatitis, and Mees’ lines (transverse white striae of the fingernails); sensory and motor polyneuritis, distal weakness. Radiopaque sign on abdominal x-ray; ECG–QRS broadening, QT prolongation, ST depression, T-wave flattening; 24-h urinary arsenic >67 μmol/d or 50 μg/d; (no seafood × 24 h); if recent exposure, serum arsenic >0.9 μmol/L (7 μg/dL). High arsenic in hair or nails. If acute ingestion, ipecac to induce vomiting, gastric lavage, activated charcoal with a cathartic. Supportive care in ICU. Dimercaprol 3–5 mg/kg IM q4h × 2 days; q6h × 1 day, then q12h × 10 days; alternative: oral succimer. With inhalation: pleuritic chest pain, dyspnea, cyanosis, fever, tachycardia, nausea, noncardiogenic pulmonary edema. With ingestion: nausea, vomiting, cramps, diarrhea. Bone pain, fractures with osteomalacia. If recent exposure, serum cadmium >500 nmol/L (5 μg/dL). Urinary cadmium >100 nmol/L (10 μg/g creatinine) and/or urinary β2-microglobulin >750 μg/g creatinine (but urinary β2-microglobulin also increased in other renal diseases such as pyelonephritis). There is no effective treatment for cadmium poisoning (chelation not useful; dimercaprol can exacerbate nephrotoxicity). Avoidance of further exposure, supportive therapy, vitamin D for osteomalacia. Abdominal pain, irritability, lethargy, anorexia, anemia, Fanconi’s syndrome, pyuria, azotemia in children with blood lead level (BPb) >80 μg/dL; may also see epiphyseal plate “lead lines” on long bone x-rays. Convulsions, coma at BPb >120 μg/dL. Clinically-apparent neurodevelopmental delays can be seen at BPb of 40–80 μg/dL with subclinical declines in IQ expected at lower levels of BPb down to 1 μg/dL. Screening of all U.S. children when they begin to crawl (~6 months) is recommended by the CDC; source identification and intervention is begun if the BPb >3.5 μg/dL. In adults, acute exposure causes similar symptoms as in children as well as headaches, arthralgias, myalgias, depression, impaired short-term memory, loss of libido. Physical examination may reveal a “lead line” at the gingiva-tooth border, pallor, wrist drop, and cognitive dysfunction (e.g., declines on the mini-mental state exam); lab tests may reveal a normocytic, normochromic anemia, basophilic stippling, an elevated blood protoporphyrin level (free erythrocyte or zinc), and motor delays on nerve conduction. U.S. OSHA requires regular testing of lead-exposed workers with removal if BPb >40 μg/dL. Newer guidelines have been proposed recommending that BPb be maintained at <10 μg/dL, removal of workers if BPb >20 μg/dL, and monitoring of cumulative exposure parameters. Identification and correction of exposure sources are critical. In the United States, most states ask or require primary care physicians and/ or laboratories to report all BPbs to the appropriate health agency. In the highly exposed individual with symptoms, chelation is recommended with oral DMSA (succimer); if acutely toxic, hospitalization and IV or IM chelation with ethylenediaminetetraacetic acid calcium disodium (CaEDTA) may be required, with the addition of dimercaprol to prevent worsening of encephalopathy. A large multicenter randomized trial of chelation showed no improvement in measures of intelligence among children with asymptomatic lead exposure (e.g., BPb 20–40 μg/dL). It is possible but remains unclear whether chelation among adults with chronic lead exposure may improve cardiovascular outcomes. Correction of dietary deficiencies in iron, calcium, magnesium, and zinc will lower lead absorption and may also improve toxicity. Vitamin C is a weak but natural chelating agent. Calcium supplements (1200 mg at bedtime) have been shown to lower blood lead levels in pregnant women. (Continued) TABLE 469-1  Heavy Metals (Continued) MAIN SOURCES METABOLISM TOXICITY DIAGNOSIS TREATMENT Mercury Metallic, mercurous, and mercuric mercury (Hg, Hg+, Hg2+) exposures occur in some chemical, metalprocessing, electrical equipment, automotive industries; they are also in thermometers, dental amalgams, batteries. Mercury is dispersed by waste incineration. Environmental bacteria convert inorganic to organic mercury, which then bioconcentrates up the aquatic food chain to contaminate tuna, swordfish, and other pelagic fish. Elemental mercury (Hg) is not well absorbed; however, it will volatilize into highly absorbable vapor. Inorganic mercury is absorbed through the gut and skin. Organic mercury is well absorbed through inhalation and ingestion. Elemental and organic mercury cross the blood-brain barrier and placenta. Mercury is excreted in urine and feces and has a half-life in blood of ~60 days; however, deposits will remain in the kidney and brain for years. Exposure to mercury stimulates the kidney to produce metallothionein, which provides some detoxification benefit. Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes. Acute inhalation of Hg vapor causes pneumonitis and noncardiogenic pulmonary edema leading to death, CNS symptoms, and polyneuropathy. Chronic high exposure causes CNS toxicity (mercurial erethism; see Diagnosis); lower exposures impair renal function, motor speed, memory, coordination. Acute ingestion of inorganic mercury causes gastroenteritis, the nephritic syndrome, or acute renal failure, hypertension, tachycardia, and cardiovascular collapse, with death at a dose of 10–42 mg/kg. Ingestion of organic mercury causes gastroenteritis, arrhythmias, and lesions in the basal ganglia, gray matter, and cerebellum at doses >1.7 mg/kg. High exposure during pregnancy causes derangement of fetal neuronal migration resulting in severe mental retardation. Mild exposures during pregnancy (from fish consumption) are associated with declines in neurobehavioral performance in offspring. Dimethylmercury, a compound only found in research labs, is “supertoxic”—a few drops of exposure via skin absorption or inhaled vapor can cause severe cerebellar degeneration and death. Abbreviations: ATPase, adenosine triphosphatase; BPb, blood lead; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; DMSA, dimercaptosuccinic acid; ECG, electrocardiogram; GI, gastrointestinal; ICU, intensive care unit; IQ, intelligence quotient; LFT, liver function tests; OSHA, Occupational Safety and Health Administration; RBC, red blood cell. cognition in both men and women living in urban communities. These relationships, in conjunction with other epidemiologic and toxicologic studies, persuaded multiple federal expert panels to conclude they were causal. Prospective studies have also demonstrated that higher bone lead levels, as well as blood lead levels as low as 1–7 μg/dL, are a major risk factor for resistant hypertension, coronary artery calcifications, and increased cardiovascular morbidity and mortality rates in both community-based and occupational-exposed populations. Lead expo­ sure at community levels has also been associated with increased risks of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis. Occupational levels of lead exposures have been consistently linked with adverse indices of sperm health, such as reduction in semen volume, sperm concentration, total sperm count, sperm vitality, and total sperm motility. With respect to pregnancy-associated risks, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental perfor­ mance in offspring by age 2 years. Offspring have also been shown to have higher blood pressures at age 7–14 years, an age range at which higher blood pressures are known to predict an elevated risk of devel­ oping hypertension. In a randomized trial, calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization of lead from maternal bone into blood during pregnancy. The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on stud­ ies of the offspring of mothers who ingested mercury-contaminated fish. With respect to whether the consumption of fish by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury contamination in fish has led to some confusion and inconsistency in public health Chronic exposure to metallic mercury vapor produces a characteristic intention tremor and mercurial erethism: excitability, memory loss, insomnia, timidity, and delirium (“mad as a hatter”). On neurobehavioral tests: decreased motor speed, visual scanning, verbal and visual memory, visuomotor coordination. Children exposed to mercury in any form may develop acrodynia (“pink disease”): flushing, itching, swelling, tachycardia, hypertension, excessive salivation or perspiration, irritability, weakness, morbilliform rashes, desquamation of palms and soles. Toxicity from elemental or inorganic mercury exposure begins when blood levels >180 nmol/L (3.6 μg/dL) and urine levels >0.7 μmol/L (15 μg/dL). Exposures that ended years ago may result in a >20-μg increase in 24-h urine after a 2-g dose of succimer. Organic mercury exposure is best measured by levels in blood (if recent) or hair (if chronic); CNS toxicity in children may derive from fetal exposures associated with maternal hair Hg >30 nmol/g (6 μg/g). Treat acute ingestion of mercuric salts with induced emesis or gastric lavage and polythiol resins (to bind mercury in the GI tract). Chelate with dimercaprol (up to 24 mg/kg per day IM in divided doses), DMSA (succimer), or penicillamine, with 5-day courses separated by several days of rest. If renal failure occurs, treat with peritoneal dialysis, hemodialysis, or extracorporeal regional complexing hemodialysis and succimer. Chronic inorganic mercury poisoning is best treated with N-acetyl penicillamine. CHAPTER 469 Heavy Metal Poisoning recommendations. Overall, it would appear that it would be best for pregnant women to either limit fish consumption to those species known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources. Well-conducted studies have convincingly debunked the contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early child­ hood, has played a significant role in causing neurodevelopmental problems such as autism. With regard to adults, there is evidence that mercury exposure is associated with elevated markers of dyslipidemia and high-sensitivity C-reactive protein (a marker of chronic low-grade inflammation), but the direct evidence as to whether mercury exposure is associated with increased risk of hypertension and cardiovascular disease remains somewhat conflicting. There is also some evidence that mercury exposure in the general population is associated with the development of diabetes, perturbations in markers of autoimmunity, and depression. At this point, conclusions cannot be drawn and the clinical significance of these findings remains somewhat unclear. Heavy metals pose risks to health that are especially burdensome in selected parts of the world. For example, arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a major environmental problem for millions of residents in parts of Bangladesh and Western India. Contamination was formerly considered only a problem with deep wells; however, the geology of this region allows most residents only a few alternatives for potable drinking water. Arsenic contamination of drinking water is also a major problem in China, Argentina, Chile, Mexico, and some regions of the United States (Maine, New Hampshire, Massachusetts). The global campaign to phase out leaded gasoline has successfully con­ cluded. However, significant population exposures to lead remain, particularly in the United States with respect to older housing that contains lead paint or that receives drinking water through lead pipes, and evidence indicates that exposures are beginning to increase again in many low- and middle-income countries due to industrial pollution, the recycling of automobile batteries, electronic waste, mining, and a variety of contaminated consumer products. Populations living in the Arctic have been shown to have particularly high exposures to mercury due to long-range transport patterns that concentrate mercury in the polar regions, as well as the traditional dependence of Arctic peoples on the consumption of fish and other wildlife that bioconcentrate methylmercury. A few additional metals deserve brief mention but are not covered in Table 469-1 because of the relative rarity of their being clinically encountered or the uncertainty regarding their potential toxicities. Aluminum contributes to the encephalopathy in patients with severe renal disease, who are undergoing dialysis (Chap. 422). High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer’s disease, as well as in the drinking water and soil of areas with an unusually high inci­ dence of Alzheimer’s. The experimental and epidemiologic evidence for the aluminum–Alzheimer’s disease link remains relatively weak, however, and it cannot be concluded that aluminum is a causal agent or a contributing factor in neurodegenerative disease. Hexavalent chromium is corrosive and sensitizing. Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer. The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consum­ ers, a condition that has also recently been reported in conjunction with the cobalt exposure associated with metal implants used in hip arthroplasty. Occupational exposure (e.g., of miners, dry-battery manufacturers, and arc welders) to manganese (Mn) can cause a parkinsonian syndrome within 1–2 years, including gait disorders; postural instability; a masked, expressionless face; tremor; and psy­ chiatric symptoms. In contrast to typical cases of Parkinson’s disease, manganese-induced parkinsonism is nonresponsive to treatment with L-dopa. With the introduction of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive, there is concern for the toxic potential of environmental manganese exposure. Some epidemiologic studies have found an association between the prevalence of parkin­ sonian disorders and estimated manganese exposures emitted by local ferroalloy industries; others have found evidence suggesting that man­ ganese may interfere with early childhood neurodevelopment in ways similar to that of lead. Manganese toxicity is clearly associated with dopaminergic dysfunction, and its toxicity is likely influenced by age, gender, ethnicity, genetics, and preexisting medical conditions. Nickel exposure induces an allergic response, and inhalation of nickel com­ pounds with low aqueous solubility (e.g., nickel subsulfide and nickel oxide) in occupational settings is associated with an increased risk of lung cancer. Overexposure to selenium may cause local irritation of the respiratory system and eyes, gastrointestinal irritation, liver inflam­ mation, loss of hair, depigmentation, and peripheral nerve damage. Workers exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances, including tremor, convulsions, hallucinations, and psychotic behavior. PART 14 Poisoning, Drug Overdose, and Envenomation Thallium, which is a component of some insecticides, metal alloys, and fireworks, is absorbed through the skin as well as by ingestion and inhalation. Severe poisoning follows a single ingested dose of >1 g or >8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis precede confusion, psychosis, organic brain syndrome, and coma. Thallium is radiopaque. Induced emesis or gastric lavage is indicated within 4–6 h of acute ingestion; Prussian blue prevents absorption and is given orally at 250 mg/kg in divided doses. Unlike other types of metal poisoning, thallium poisoning may be less severe when acti­ vated charcoal is used to interrupt its enterohepatic circulation. Other measures include forced diuresis, treatment with potassium chloride (which promotes renal excretion of thallium), and peritoneal dialysis. Chelation therapy remains the treatment of choice for most toxic metals in the setting of severe acute clinical poisoning. However, the use of chelation for treating chronic diseases remains controversial, in part because of the lack of evidence from rigorous randomized clinical trials. One area for which there is moderate evidence is the use of che­ lation in patients with higher than average levels of accumulated lead burdens as a means of improving kidney function. The results from a series of randomized trials conducted in Taiwan suggest that among individuals with mildly elevated lead burdens (defined as between 150 and 600 μg of lead per 72-h urine upon an EDTA mobilization test [1 g EDTA]), weekly calcium disodium EDTA chelation treatments for between 2 and 27 months can improve renal function outcomes, both in individuals with and without type 2 diabetes. The Trial to Assess Chelation Therapy (TACT-1), a multicenter, double-blind, placebo-controlled, prospective randomized trial funded by the National Institutes of Health of 1708 patients aged ≥50 years who had experienced a myocardial infarction (MI), found that a protocol of repeated intravenous chelation with disodium EDTA, compared with placebo, modestly but significantly reduced the risk of adverse cardio­ vascular outcomes, many of which were revascularization procedures. The effect was particularly pronounced among those with concurrent diabetes. However, the trial did not include rigorous measures of expo­ sure to lead or other metals or any selection criteria based on metals exposure. By contrast, the recently released results of the TACT-2 trial, which reproduced the TACT-1 protocol with the addition of measures of metals, did not show benefit. However, the metals exposure levels among subjects was very low, likely reflecting the known decline in metals exposure over time in a study conducted more than 10 years after TACT-1, and it remains unclear whether chelation has a role in treating individuals with significant chronic metals exposure. ■ ■FURTHER READING Aalami AH et al: Carcinogenic effects of heavy metals by inducing dysregulation of microRNAs: A review. Mol Biol Rep 49:12227, 2022. Basu N et al: Our evolved understanding of the human health risks of mercury. Ambio 52:877, 2023. Chen H et al: Associations of blood lead, cadmium, and mercury with resistant hypertension among adults in NHANES, 1999-2018. Envi­ ron Health Prev Med 28:66, 2023. Elkin ER et al: Metals exposures and DNA methylation: Current evi­ dence and future directions. Curr Environ Health Rep 4:673, 2022. Giulioni C et al: The influence of lead exposure on male semen parameters: A systematic review and meta-analysis. Reprod Toxicol 118:108387, 2023. Lamas GA et al: Contaminant metals as cardiovascular risk factors: A scientific statement from the American Heart Association. J Am Heart Assoc 12:e029852, 2023. Lanphear BP et al: Low-level lead exposure and mortality in US adults: A population-based cohort study. Lancet Public Health 3:e177, 2018. Lucchini R, Tieu K: Manganese-induced parkinsonism: Evidence from epidemiological and experimental studies. Biomolecules 13:1190, 2023. Martínez-Castillo M et al: Arsenic exposure and non-carcinogenic health effects. Hum Exp Toxicol 40:S826, 2021. Parida L, Patel TN: Systemic impact of heavy metals and their role in cancer development: A review. Environ Monit Assess 195:766, 2023. Park SK et al: Environmental cadmium and mortality from influenza and pneumonia in U.S. adults. Environ Health Perspect 128:127004, 2020. Ravalli F et al: Chelation therapy in patients with cardiovascular dis­ ease: A systematic review. J Am Heart Assoc 11:e024648, 2022. Shvachiy L et al: Uncovering the molecular link between lead toxicity and Parkinson’s disease. Antioxid Redox Signal 39:321, 2023. Smereczański NM et al: Current levels of environmental exposure to cadmium in industrialized countries as a risk factor for kidney dam­ age in the general population: A comprehensive review of available data. Int J Mol Sci 24:8413, 2023. Xu L et al: Positive association of cardiovascular disease (CVD) with chronic exposure to drinking water arsenic (As) at concentrations below the WHO provisional guideline value: A systematic review and meta-analysis. Int J Environ Res Public Health 17:2536, 2020. # 02 - 470 Poisoning and Drug Overdose ## 470 Poisoning and Drug Overdose Mark B. Mycyk Poisoning and Drug Overdose Poisoning refers to the development of dose-related adverse effects following exposure to chemicals, drugs, or other xenobiotics. To para­ phrase Paracelsus, the dose makes the poison. Although most poisons have predictable dose-related effects, individual responses to a given dose may vary because of genetic polymorphism, enzymatic induction or inhibition in the presence of other xenobiotics, or acquired toler­ ance. Poisoning may be local (e.g., skin, eyes, or lungs) or systemic depending on the route of exposure, the chemical and physical prop­ erties of the poison, and its mechanism of action. The severity and reversibility of poisoning also depend on the functional reserve of the individual or target organ, which is influenced by age and preexisting disease. EPIDEMIOLOGY More than 5 million poison exposures occur in the United States each year. Most are acute, are accidental (unintentional), involve a single agent, occur in the home (>90%), result in minor or no toxicity, and involve children <6 years of age. Pharmaceuticals are involved in 47% of poisoning exposures and in 84% of serious or fatal poisonings. House­ hold cleaning substances and cosmetics/personal care products are the most common nonpharmaceutical exposures reported to the National Poison Data System (NPDS). Fatalities most commonly occur from intentional self-harm ingestions (suicide) of pharmaceuticals or from complications involving opioids and other psychoactive drugs of abuse. According to the Centers for Disease Control and Prevention (CDC), fatalities involving drugs have steadily increased since 1999. More than 106,600 deaths were attributed to drug overdose in the United States in 2021, with an age-adjusted overdose death rate of 32.4 per 100,000. Although prescription opioids have appropriately received attention as a major reason for the ongoing substance use disorder epidemic in the United States, the ever-expanding street availability of synthetic opioids (e.g., fentanyl) and the rapid proliferation of other psychoactive drugs of abuse (e.g., xylazine) are the main drivers of drug overdose deaths. State prescription monitoring programs, enhanced training in pain management for health care professionals, expanded harm reduction services, improved outreach education to the public, and improved partnerships with regional safety officials to monitor trends in the illicit drug supply continue to be the main prevention and response priori­ ties for addressing this worsening epidemic. Unintentional exposures can result from the improper use of chemicals at work or play; label misreading; product mislabeling; mistaken identification of unlabeled chemicals; uninformed self-medication; and dosing errors by nurses, pharmacists, physicians, parents, and the elderly. Excluding the recre­ ational use of ethanol, attempted suicide (deliberate self-harm) is the most common reported reason for intentional poisoning. Recreational use of prescribed and over-the-counter drugs for psychotropic or euphoric effects (abuse) or excessive self-dosing (misuse) is increas­ ingly common and may also result in unintentional self-poisoning. About 20–25% of exposures require bedside health-professional evaluation, and 5% of all exposures require hospitalization. Poisonings account for 5–10% of all ambulance transports, emergency depart­ ment visits, and intensive care unit admissions. Hospital admissions related to poisoning are also associated with longer lengths of stay and increase the utilization of resources such as radiography and other laboratory services. Up to 35% of psychiatric admissions are prompted by attempted suicide via overdosage with cases involving adolescents steadily increasing during the last decade. Overall, the mortality rate is low: <1% of all poisoning exposures. It is significantly higher (1–2%) among hospitalized patients with intentional (suicidal) overdose or complications from drugs of abuse, who account for the majority of serious poisonings. Acetaminophen is the pharmaceutical agent most often implicated in fatal poisoning. Overall, carbon monoxide is the leading cause of death from poisoning, but this prominence is not reflected in hospital or poison center statistics because patients with such poisoning are typically dead when discovered and are referred directly to medical examiners. DIAGNOSIS Although poisoning can mimic other illnesses, the correct diagnosis can usually be established by the history, physical examination, rou­ tine and toxicologic laboratory evaluations, and characteristic clinical course. ■ ■HISTORY The history should include the time, route, duration, and circum­ stances (location, surrounding events, and intent) of exposure; the name and amount of each drug, chemical, or ingredient involved; the time of onset, nature, and severity of symptoms; the time and type of first-aid measures provided; the medical and psychiatric history; and occupation. In many cases, the patient is confused, comatose, unaware of an exposure, or unable or unwilling to admit to one. Suspicious circum­ stances include unexplained sudden illness in a previously healthy person or a group of healthy people; a history of psychiatric problems (particularly depression or bipolar disorder); recent changes in health, economic status, or social relationships; and onset of illness dur­ ing work with chemicals or after ingestion of food, drink (especially ethanol), or medications. When patients become ill soon after arriving from a foreign country or being arrested for criminal activity, “body packing” or “body stuffing” (ingesting or concealing illicit drugs in a body cavity) should be suspected. Relevant information may be avail­ able from family, friends, paramedics, police, pharmacists, physicians, and employers, who should be questioned regarding the patient’s hab­ its, hobbies, behavioral changes, available medications, and anteced­ ent events. Patients need to be asked explicitly about their prescribed medications, use of over-the-counter or herbal medications, and recreational drug use. Drugs previously considered “illicit” such as can­ nabinoids are now legal in many states and prescribed for therapeutic purposes. A search of clothes, belongings, and place of discovery may reveal a suicide note or a container of drugs or chemicals. If available, a review of a patient’s recent social media posts may be helpful to the treating clinician because self-harm plans involving medications or drugs are often described there. Without a clear history in a patient clinically suspected to be poisoned, all medications available anywhere in the patient’s home or belongings should be considered as possible agents, including medications for pets. Review of the patient’s record in the state prescription monitoring program (PMP) may disclose rele­ vant history of Schedule II, III, IV, and V controlled substance use. The imprint code on pills and the label on chemical products may be used to identify the ingredients and potential toxicity of a suspected poison by consulting a reference text, a computerized database, the manufac­ turer, or a regional poison information center (800-222-1222). Occupa­ tional exposures require review of any available safety data sheet (SDS) from the worksite. Because of increasing globalization from travel and internet consumerism, unfamiliar poisonings may result in local emer­ gency department evaluation. Pharmaceuticals, industrial chemicals, or novel psychoactive drugs of abuse from foreign countries may be identified with the assistance of a local medical toxicologist, a regional poison center, or via the Internet. CHAPTER 470 Poisoning and Drug Overdose ■ ■PHYSICAL EXAMINATION AND CLINICAL COURSE The physical examination should focus initially on vital signs, the car­ diopulmonary system, and neurologic status. The neurologic examina­ tion should include documentation of neuromuscular abnormalities such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, and tremors. The patient should also be examined for evidence of trauma and underlying illnesses. Focal neurologic findings are uncommon in poisoning, and their presence should prompt evaluation for a struc­ tural central nervous system (CNS) lesion. Examination of the eyes (for nystagmus and pupil size and reactivity), abdomen (for bowel activity and bladder size), and skin (for burns, bullae, color, warmth, moisture, pressure sores, and puncture marks) may reveal findings of diagnostic value. When the history is unclear, all orifices should be examined for the presence of chemical burns and drug packets. The odor of breath or vomitus and the color of nails, skin, or urine may provide important diagnostic clues. The diagnosis of poisoning in cases of unknown etiology primarily relies on pattern recognition. The first step is to assess the pulse, blood pressure, respiratory rate, pulse oximetry, temperature, and neurologic status and to characterize the overall physiologic state as stimulated, depressed, discordant, or normal (Table 470-1). Obtaining a complete set of vital signs and reassessing them frequently are critical. Measuring core temperature is especially important, even in difficult or combative patients, since temperature elevation is the most reliable prognosticator of poor outcome in poisoning from stimulants (e.g., cocaine) or drug withdrawal (e.g., alcohol or γ-hydroxybutyric acid [GHB]). The next TABLE 470-1  Differential Diagnosis of Poisoning Based on Physiologic State STIMULATED DEPRESSED DISCORDANT NORMAL Sympathetics   Sympathomimetics   Ergot alkaloids   Methylxanthines   Monoamine oxidase inhibitors   Thyroid hormones Anticholinergics   Antihistamines   Antiparkinsonian agents   Antipsychotics   Antispasmodics   Belladonna alkaloids   Cyclic antidepressants   Mushrooms and plants Hallucinogens   Cannabinoids (marijuana)   LSD and analogues   Mescaline and analogues   Mushrooms   Phencyclidine and analogues Withdrawal syndromes   Barbiturates   Benzodiazepines   Ethanol   GHB products   Opioids   Sedative-hypnotics   Sympatholytics Sympatholytics   α1-Adrenergic antagonists   α2-Adrenergic agonists   ACE inhibitors   Angiotensin receptor blockers   Antipsychotics   β-Adrenergic blockers   Calcium channel blockers   Cardiac glycosides   Cyclic antidepressants Cholinergics   Acetylcholinesterase inhibitors   Muscarinic agonists   Nicotinic agonists Opioids   Analgesics   GI antispasmodics   Heroin Sedative-hypnotics   Alcohols   Anticonvulsants   Barbiturates   Benzodiazepines   GABA precursors   Muscle relaxants   Other agents   GHB products Xylazine PART 14 Poisoning, Drug Overdose, and Envenomation Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyrate; GI, gastrointestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase. step is to consider the underlying causes of the physiologic state and to attempt to identify a pathophysiologic pattern or toxic syndrome (toxidrome) based on the observed findings. Assessing the severity of physiologic derangements (Table 470-2) is useful in this regard and also for monitoring the clinical course and response to treat­ ment. In cases of polydrug overdose involving different drug classes, identifying a clear toxidrome can be challenging if the different drugs counteract the physiologic effects of one another. The final step is to attempt to identify the particular agent involved by looking for unique or relatively poison-specific physical or ancillary test abnormalities. Distinguishing among toxidromes on the basis of the physiologic state is summarized next. The Stimulated Physiologic State  Increased pulse, blood pres­ sure, respiratory rate, temperature, and neuromuscular activity charac­ terize the stimulated physiologic state, which can reflect sympathetic, Asphyxiants   Cytochrome oxidase inhibitors   Inert gases   Irritant gases   Methemoglobin inducers   Oxidative phosphorylation inhibitors AGMA inducers   Alcohol (ketoacidosis)   Ethylene glycol   Iron   Methanol   Other alcohols   Salicylate   Toluene CNS syndromes   Extrapyramidal reactions   Hydrocarbon inhalation   Isoniazid   Lithium   Neuroleptic malignant syndrome   Serotonin syndrome   Strychnine Membrane-active agents   Amantadine   Antiarrhythmics   Antihistamines   Antipsychotics   Carbamazepine   Cyclic antidepressants   Local anesthetics   Opioids (some)   Quinoline antimalarials Nontoxic exposure Psychogenic illness “Toxic time-bombs” Slow absorption   Anticholinergics   Carbamazepine   Concretion formers   Extended-release phenytoin sodium capsules (Dilantin Kapseals)   Drug packets   Enteric-coated pills   Diphenoxylate-atropine (Lomotil)   Opioids   Salicylates   Sustained-release pills   Valproate Slow distribution   Cardiac glycosides   Lithium   Metals   Salicylate   Valproate Toxic metabolite   Acetaminophen   Carbon tetrachloride   Cyanogenic glycosides   Ethylene glycol   Methanol   Methemoglobin inducers   Mushroom toxins   Organophosphate insecticides   Paraquat Metabolism disruptors   Antineoplastic agents   Antiviral agents   Colchicine   Hypoglycemic agents   Immunosuppressive agents   MAO inhibitors   Metals   Other oral anticoagulants   Salicylate   Warfarin TABLE 470-2  Severity of Physiologic Stimulation and Depression in Poisoning and Drug Withdrawal Physiologic Stimulation Grade 1 Anxious, irritable, tremulous; vital signs normal; diaphoresis, flushing or pallor, mydriasis, and hyperreflexia sometimes present Grade 2 Agitated; may have confusion or hallucinations but can converse and follow commands; vital signs mildly to moderately increased Grade 3 Delirious; unintelligible speech, uncontrollable motor hyperactivity; moderately to markedly increased vital signs; tachyarrhythmias possible Grade 4 Coma, seizures, cardiovascular collapse Physiologic Depression Grade 1 Awake, lethargic, or sleeping but arousable by voice or tactile stimulation; able to converse and follow commands; may be confused Grade 2 Responds to pain but not voice; can vocalize but not converse; spontaneous motor activity present; brainstem reflexes intact Grade 3 Unresponsive to pain; spontaneous motor activity absent; brainstem reflexes depressed; motor tone, respirations, and temperature decreased Grade 4 Unresponsive to pain; flaccid paralysis; brainstem reflexes and respirations absent; cardiovascular vital signs decreased anticholinergic, or hallucinogen poisoning or drug withdrawal (Table 470-1). Other features are noted in Table 470-2. Mydriasis, a characteristic feature of all stimulants, is most marked in anticholiner­ gic poisoning since pupillary reactivity relies on muscarinic control. In sympathetic poisoning (e.g., due to cocaine), pupils are also enlarged, but some reactivity to light remains. The anticholinergic toxidrome is also distinguished by hot, dry, flushed skin; decreased bowel sounds; and urinary retention. Other stimulant syndromes increase sympa­ thetic activity and cause diaphoresis, pallor, and increased bowel activ­ ity with varying degrees of nausea, vomiting, abnormal distress, and occasionally diarrhea. The absolute and relative degree of vital-sign changes and neuromuscular hyperactivity can help distinguish among stimulant toxidromes. Since sympathetics stimulate the peripheral ner­ vous system more directly than do hallucinogens or drug withdrawal, markedly increased vital signs and organ ischemia suggest sympathetic poisoning. Findings helpful in suggesting the particular drug or class causing physiologic stimulation include reflex bradycardia from selec­ tive α-adrenergic stimulants (e.g., decongestants), hypotension from selective β-adrenergic stimulants (e.g., asthma therapeutics), limb ischemia from ergot alkaloids, rotatory nystagmus from phencyclidine and ketamine (the only physiologic stimulants that cause this finding), and delayed cardiac conduction from high doses of cocaine and some anticholinergic agents (e.g., antihistamines, cyclic antidepressants, and antipsychotics). Seizures suggest a sympathetic etiology, an anticholin­ ergic agent with membrane-active properties (e.g., cyclic antidepres­ sants, phenothiazines), or a withdrawal syndrome. Close attention to core temperature is critical in patients with grade 4 physiologic stimu­ lation (Table 470-2). The Depressed Physiologic State  Decreased pulse, blood pres­ sure, respiratory rate, temperature, and neuromuscular activity are indicative of the depressed physiologic state caused by “functional” sympatholytics (agents that decrease cardiac function and vascular tone as well as sympathetic activity), cholinergic (muscarinic and nicotinic) agents, opioids, and sedative-hypnotic γ-aminobutyric acid (GABA)-ergic agents (Tables 470-1 and 470-2). Miosis is also common and is most pronounced in opioid and cholinergic poisoning. Miosis is distinguished from other depressant syndromes by muscarinic and nicotinic signs and symptoms (Table 470-1). Pronounced car­ diovascular depression in the absence of significant CNS depression suggests a direct or peripherally acting sympatholytic. In contrast, in opioid and sedative-hypnotic poisoning, vital-sign changes are sec­ ondary to depression of CNS cardiovascular and respiratory centers (or consequent hypoxemia), and significant abnormalities in these parameters do not occur until there is a marked decrease in the level of consciousness (grade 3 or 4 physiologic depression; Table 470-2). Other clues that suggest the cause of physiologic depression include cardiac arrhythmias and conduction disturbances (due to antiar­ rhythmics, β-adrenergic antagonists, calcium channel blockers, digi­ talis glycosides, propoxyphene, and cyclic antidepressants), mydriasis (due to tricyclic antidepressants, some antiarrhythmics, meperidine, and diphenoxylate-atropine [Lomotil]), nystagmus (due to sedativehypnotics), and seizures (due to cholinergic agents, propoxyphene, and cyclic antidepressants). The Discordant Physiologic State  The discordant physiologic state is characterized by mixed vital-sign and neuromuscular abnor­ malities, as observed in poisoning by asphyxiants, CNS syndromes, membrane-active agents, and anion-gap metabolic acidosis (AGMA) inducers (Table 470-1). In these conditions, manifestations of physi­ ologic stimulation and physiologic depression occur together or at different times during the clinical course. For example, membraneactive agents can cause simultaneous coma, seizures, hypotension, and tachyarrhythmias. Alternatively, vital signs may be normal while the patient has an altered mental status or is obviously sick or clearly symp­ tomatic. Early, pronounced vital-sign and mental-status changes sug­ gest asphyxiant or membrane-active agent poisoning; the lack of such abnormalities suggests an AGMA inducer; and marked neuromuscular dysfunction without significant vital-sign abnormalities suggests a CNS syndrome. The discordant physiologic state may also be evident in patients poisoned with multiple agents. CHAPTER 470 The Normal Physiologic State  A normal physiologic status and physical examination may be due to a nontoxic exposure, psychogenic illness, or poisoning by “toxic time-bombs”: agents that are slowly absorbed, are slowly distributed to their sites of action, require meta­ bolic activation, or disrupt metabolic processes (Table 470-1). Because so many medications have now been reformulated into once-a-day preparations for the patient’s convenience and adherence, toxic timebombs are increasingly common. Diagnosing a nontoxic exposure requires that the identity of the exposure agent be known or that a toxic time-bomb exposure be excluded and the time since exposure exceed the longest known or predicted interval between exposure and peak toxicity. Psychogenic illness (fear of being poisoned, mass hysteria) may also follow a nontoxic exposure and should be considered when symptoms are inconsistent with exposure history. Anxiety reactions resulting from a nontoxic exposure can cause mild physiologic stimu­ lation (Table 470-2) and be indistinguishable from toxicologic causes without ancillary testing or a suitable period of observation. Poisoning and Drug Overdose ■ ■LABORATORY ASSESSMENT Laboratory assessment may be helpful in the differential diagnosis. Increased AGMA is most common in advanced methanol, ethylene glycol, and salicylate intoxication but can occur with any poisoning that results in hepatic, renal, or respiratory failure; seizures; or shock. The serum lactate concentration is more commonly low (less than the anion gap) in the former and high (nearly equal to the anion gap) in the latter. An abnormally low anion gap can be due to elevated blood levels of bromide, calcium, iodine, lithium, or magnesium. An increased osmolal gap—a difference of >10 mmol/L between serum osmolality (measured by freezing-point depression) and osmolality calculated from serum sodium, glucose, and blood urea nitrogen levels—suggests the presence of a low-molecular-weight solute such as acetone; an alcohol (benzyl, ethanol, isopropanol, methanol); a glycol (diethyl­ ene, ethylene, propylene); ether (ethyl, glycol); or an “unmeasured” cation (calcium, magnesium) or sugar (glycerol, mannitol, sorbitol). Ketosis suggests acetone, isopropyl alcohol, salicylate poisoning, or alcoholic ketoacidosis. Hypoglycemia may be due to poisoning with β-adrenergic blockers, ethanol, insulin, oral hypoglycemic agents, qui­ nine, and salicylates, whereas hyperglycemia can occur in poisoning with acetone, β-adrenergic agonists, caffeine, calcium channel block­ ers, iron, theophylline, or N-3-pyridylmethyl-N-p-nitrophenylurea (PNU [Vacor]). Hypokalemia can be caused by barium, β-adrenergic agonists, caffeine, diuretics, theophylline, or toluene; hyperkalemia suggests poisoning with an α-adrenergic agonist, a β-adrenergic blocker, cardiac glycosides, or fluoride. Hypocalcemia may be seen in ethylene glycol, fluoride, and oxalate poisoning. Prothrombin time and international normalized ratio are useful for risk stratification in cases of warfarin or rodenticide poisoning but are not to be relied on when evaluating overdose or complications from direct oral antico­ agulant pharmaceuticals (direct thrombin inhibitors and direct factor Xa inhibitors). The electrocardiogram (ECG) can be useful for rapid diagnostic purposes. Bradycardia and atrioventricular block may occur in patients poisoned by α-adrenergic agonists, antiarrhythmic agents, beta block­ ers, calcium channel blockers, cholinergic agents (carbamate and organophosphate insecticides), cardiac glycosides, lithium, or tricyclic antidepressants. QRS- and QT-interval prolongation may be caused by hyperkalemia, various antidepressants, and other membrane-active drugs (Table 470-1). Ventricular tachyarrhythmias may be seen in poisoning with cardiac glycosides, fluorides, membrane-active drugs, methylxanthines, sympathomimetics, antidepressants, and agents that cause hyperkalemia or potentiate the effects of endogenous catechol­ amines (e.g., chloral hydrate, aliphatic and halogenated hydrocarbons). Radiologic studies may occasionally be useful. Pulmonary edema (adult respiratory distress syndrome [ARDS]) can be caused by poi­ soning with carbon monoxide, cyanide, an opioid, paraquat, phen­ cyclidine, a sedative-hypnotic, or salicylate; by inhalation of irritant gases, fumes, or vapors (acids and alkali, ammonia, aldehydes, chlo­ rine, hydrogen sulfide, isocyanates, metal oxides, mercury, phosgene, polymers); or by prolonged anoxia, hyperthermia, or shock. Aspiration pneumonia is common in patients with coma, seizures, and petroleum distillate aspiration. Chest x-ray is useful for identifying complications from metal fume fever or elemental mercury. The presence of radi­ opaque densities on abdominal x-rays or abdominal computed tomog­ raphy (CT) scan suggests the ingestion of chloral hydrate, chlorinated hydrocarbons, heavy metals, illicit drug packets, iodinated compounds, potassium salts, enteric-coated tablets, or salicylates. PART 14 Poisoning, Drug Overdose, and Envenomation Toxicologic analysis of urine and blood (and occasionally of gas­ tric contents and chemical samples) can sometimes confirm or rule out suspected poisoning. Interpretation of laboratory data requires knowledge of the qualitative and quantitative tests used for screening and confirmation (enzyme-multiplied, fluorescence polarization, and radio-immunoassays; colorimetric and fluorometric assays; thin-layer, gas-liquid, or high-performance liquid chromatography; gas chroma­ tography; mass spectrometry), their sensitivity (limit of detection) and specificity, the preferred biologic specimen for analysis, and the optimal time of specimen sampling. Personal communication with the hospital laboratory is essential to an understanding of institutional test­ ing capabilities and limitations. Rapid qualitative hospital-based urine tests for drugs of abuse are only screening tests that cannot confirm the exact identity of the detected substance and should not be considered diagnostic or used for forensic purposes. False-positive and false-negative results are common. A positive screen may result from other pharmaceuticals that interfere with laboratory analysis (e.g., fluoroquinolones com­ monly cause false-positive opiate screens). Confirmatory testing with gas chromatography/mass spectrometry can be requested, but it often takes weeks to obtain a reported result. A negative screening result may mean that the responsible substance is not detectable by the test used or that its concentration is too low for detection at the time of sampling. For instance, recent new drugs of abuse that often result in emergency department evaluation for unexpected complications, such as synthetic cannabinoids (spice), cathinones (bath salts), and opiate substitutes (kratom), are not detectable by hospital-based tests. In cases where a drug concentration is too low to be detected early during clinical evaluation, repeating the test at a later time may yield a positive result. Patients symptomatic from drugs of abuse often require immediate management based on the history, physical examination, and observed toxidrome without laboratory confirmation (e.g., apnea from opioid intoxication). When the patient is asymptomatic or when the clinical picture is consistent with the reported history, qualitative screening is neither clinically useful nor cost-effective. Thus, qualitative drug screens are of greatest value for the evaluation of patients with severe or unexplained toxicities, such as coma, seizures, cardiovascular instabil­ ity, metabolic or respiratory acidosis, and nonsinus cardiac rhythms. In contrast to qualitative drug screens, quantitative serum tests are useful for evaluation of patients poisoned with acetaminophen (Chap. 351), alcohols (including ethylene glycol and methanol), anticonvulsants, barbiturates, digoxin, heavy metals, iron, lithium, salicylate, and the­ ophylline, as well as for the presence of carboxyhemoglobin and met­ hemoglobin. The serum concentration in these cases guides clinical management, and results are often available within an hour. The response to antidotes is sometimes useful for diagnostic pur­ poses. Resolution of altered mental status and abnormal vital signs within minutes of IV administration of dextrose, naloxone, or flu­ mazenil is virtually diagnostic of hypoglycemia, opioid poisoning, and benzodiazepine intoxication, respectively. The prompt reversal of dystonic (extrapyramidal) signs and symptoms following an IV dose of benztropine or diphenhydramine confirms a drug etiology. Although complete reversal of both central and peripheral manifestations of anti­ cholinergic poisoning by physostigmine is diagnostic of this condition, physostigmine may cause some arousal in patients with CNS depres­ sion of any etiology. TREATMENT Poisoning and Drug Overdose GENERAL PRINCIPLES Treatment goals include support of vital signs, prevention of fur­ ther poison absorption (decontamination), enhancement of poison elimination, administration of specific antidotes, and prevention of reexposure (Table 470-3). Specific treatment depends on the identity of the poison, the route and amount of exposure, the time TABLE 470-3  Fundamentals of Poisoning Management Supportive Care Airway protection Treatment of seizures Oxygenation/ventilation Correction of temperature abnormalities Treatment of arrhythmias Correction of metabolic derangements Hemodynamic support Prevention of secondary complications Prevention of Further Poison Absorption Gastrointestinal decontamination Decontamination of other sites   Gastric lavage   Eye decontamination   Activated charcoal   Skin decontamination   Whole-bowel irrigation   Body cavity evacuation   Dilution   Endoscopic/surgical removal Enhancement of Poison Elimination Multiple-dose activated charcoal administration Alteration of urinary pH Chelation Hyperbaric oxygenation Extracorporeal removal   Hemodialysis   Hemoperfusion   Hemofiltration   Plasmapheresis   Exchange transfusion Continuous venovenous hemofiltration (CVVH) Administration of Antidotes Neutralization by antibodies Metabolic antagonism Neutralization by chemical binding Physiologic antagonism Prevention of Reexposure Adult education Notification of regulatory agencies Child-proofing Psychiatric referral Naloxone distribution Linkage to harm reduction services of presentation relative to the time of exposure, and the severity of poisoning. Knowledge of the offending agents’ pharmacokinetics and pharmacodynamics is essential. During the pretoxic phase, prior to the onset of poisoning, decon­ tamination is the highest priority, and treatment is based solely on the history. The maximal potential toxicity based on the greatest possible exposure should be assumed. Since decontamination is more effective when accomplished soon after exposure and when the patient is asymptomatic, the initial history and physical exami­ nation should be focused and brief. It is also advisable to establish IV access and initiate cardiac monitoring, particularly in patients with potentially serious ingestions or unclear histories. When an accurate history is not obtainable and a poison causing delayed toxicity (i.e., a toxic time-bomb) or irreversible damage is suspected, blood and urine should be sent for appropriate toxico­ logic screening and quantitative analysis. During poison absorption and distribution, blood levels may be greater than those in tissue and may not correlate with toxicity. However, high blood levels of agents whose metabolites are more toxic than the parent compound (acetaminophen, ethylene glycol, or methanol) may indicate the need for additional interventions (antidotes, dialysis). Most patients who remain asymptomatic or who become asymptomatic 6 h after ingestion are unlikely to develop subsequent toxicity and can be discharged safely. Longer observation will be necessary for patients who have ingested toxic time-bombs. During the toxic phase—the interval between the onset of poi­ soning and its peak effects—management is based primarily on clinical and laboratory findings. Effects after an overdose usually begin sooner, peak later, and last longer than they do after a thera­ peutic dose. A drug’s published pharmacokinetic profile in standard references such as the Physician’s Desk Reference (PDR) is usually different from its toxicokinetic profile in overdose. Resuscitation and stabilization are the first priority. Symptomatic patients should have an IV line placed and should undergo oxygen saturation deter­ mination, cardiac monitoring, and continuous observation. Base­ line laboratory, ECG, and x-ray evaluation may also be appropriate. Intravenous glucose (unless the serum level is documented to be normal), naloxone, and thiamine should be considered in patients with altered mental status, particularly those with coma or seizures. Decontamination should also be considered, but it is less likely to be effective during this phase than during the pretoxic phase. Measures that enhance poison elimination may shorten the duration and severity of the toxic phase. However, they are not without risk, which must be weighed against the potential benefit. Diagnostic certainty (usually via laboratory confirmation) is gener­ ally a prerequisite. Intestinal (gut) dialysis with repetitive doses of activated charcoal (see “Multiple-Dose Activated Charcoal,” later) can enhance the elimination of selected poisons such as the­ ophylline or carbamazepine. Urinary alkalinization may enhance the elimination of salicylates and a few other poisons. Chelation therapy can enhance the elimination of selected metals. Extracor­ poreal elimination methods are effective for many poisons, but their expense and risk make their use reasonable only in patients who would otherwise have an unfavorable outcome. During the resolution phase of poisoning, supportive care and monitoring should continue until clinical, laboratory, and ECG abnormalities have resolved. Since chemicals are eliminated sooner from the blood than from tissues, blood levels are usually lower than tissue levels during this phase and again may not correlate with toxicity. This discrepancy applies particularly when extracor­ poreal elimination procedures are used. Redistribution from tissues may cause a rebound increase in the blood level after termination of these procedures (e.g., lithium). When a metabolite is respon­ sible for toxic effects, continued treatment may be necessary in the absence of clinical toxicity or abnormal laboratory studies. SUPPORTIVE CARE The goal of supportive therapy is to maintain physiologic homeo­ stasis until detoxification is accomplished and to prevent and treat secondary complications such as aspiration, bedsores, cerebral and pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sep­ sis, thromboembolic disease, coagulopathy, and generalized organ dysfunction due to hypoxemia or shock. Admission to an intensive care unit is indicated for the following: patients with severe poisoning (coma, respiratory depression, hypo­ tension, cardiac conduction abnormalities, cardiac arrhythmias, hypothermia or hyperthermia, seizures); those needing close moni­ toring, antidotes, or enhanced elimination therapy; those showing progressive clinical deterioration; and those with significant under­ lying medical problems. Patients with mild to moderate toxicity can be managed on a general medical service, on an intermediate care unit, or in an emergency department observation area, depend­ ing on the anticipated duration and level of monitoring needed (intermittent clinical observation vs continuous clinical, cardiac, and respiratory monitoring). Patients who have attempted suicide require continuous observation and measures to prevent self-injury until they are no longer suicidal. Respiratory Care  Endotracheal intubation for protection against the aspiration of gastrointestinal contents is of paramount impor­ tance in patients with CNS depression or seizures as this com­ plication can increase morbidity and mortality rates. Mechanical ventilation may be necessary for patients with respiratory depres­ sion or hypoxemia and for facilitation of therapeutic sedation or paralysis of patients in order to prevent or treat hyperthermia, aci­ dosis, and rhabdomyolysis associated with neuromuscular hyper­ activity. Since clinical assessment of respiratory function can be inaccurate, the need for oxygenation and ventilation is best deter­ mined by continuous pulse oximetry or arterial blood-gas analysis. The gag reflex is not a reliable indicator of the need for intubation. A patient with CNS depression may maintain airway patency while being stimulated but not if left alone. Drug-induced pulmonary edema is usually noncardiac rather than cardiac in origin, although profound CNS depression and cardiac conduction abnormalities suggest the latter. Measurement of pulmonary artery pressure may be necessary to establish the cause and direct appropriate therapy. Extracorporeal measures (membrane oxygenation, extracorporeal membrane oxygenation [ECMO], venoarterial perfusion, cardio­ pulmonary bypass) and partial liquid (perfluorocarbon) ventilation may be appropriate for severe but reversible respiratory failure. In the last decade, ECMO has been increasingly used for critically ill poisoned patients where standard resuscitative therapy or antidotes have not been helpful, but further research is still needed to deter­ mine the right toxicologic indications for this treatment strategy. CHAPTER 470 Poisoning and Drug Overdose Cardiovascular Therapy  Maintenance of normal tissue perfusion is critical for complete recovery to occur once the offending agent has been eliminated. Focused bedside echocardiography or mea­ surement of central venous pressure may help prioritize therapeutic strategies. If hypotension is unresponsive to volume expansion and appropriate goal-directed antidotal therapy, treatment with norepi­ nephrine, epinephrine, or high-dose dopamine may be necessary. Intraaortic balloon pump counterpulsation and venoarterial or cardiopulmonary perfusion techniques should be considered for severe but reversible cardiac failure. For patients with a return of spontaneous circulation after resuscitative treatment for cardiopul­ monary arrest secondary to poisoning, therapeutic hypothermia should be used according to protocol. Bradyarrhythmias associ­ ated with hypotension generally should be treated as described in Chaps. 251 and 252. Glucagon, calcium, and high-dose insulin with dextrose may be effective in beta blocker and calcium channel blocker poisoning. Antibody therapy may be indicated for cardiac glycoside poisoning. Supraventricular tachycardia associated with hypertension and CNS excitation is almost always due to agents that cause generalized physiologic excitation (Table 470–1). Most cases are mild or moderate in severity and require only observation or nonspecific sedation with a benzodiazepine. In severe cases or those associated with hemodynamic instability, chest pain, or ECG evidence of ischemia, specific therapy is indicated. When the etiology is sympathetic hyperactivity, treatment with a benzodiazepine should be prioritized. Further treatment with a combined alpha and beta blocker (labetalol), a calcium chan­ nel blocker (verapamil or diltiazem), or a combination of a beta blocker and a vasodilator (esmolol and nitroprusside) may be considered for cases refractory to high doses of benzodiazepines only when adequate sedation has been achieved but cardiac con­ duction or blood pressure abnormalities persist. Treatment with an α-adrenergic antagonist (phentolamine) alone may sometimes be appropriate. If the cause is anticholinergic poisoning, phy­ sostigmine alone can be effective. Supraventricular tachycardia without hypertension is generally secondary to vasodilation or hypovolemia and responds to fluid administration. For ventricular tachyarrhythmias due to tricyclic antidepressants and other membrane-active agents (Table 470-1), sodium bicar­ bonate is indicated, whereas class IA, IC, and III antiarrhythmic agents are contraindicated because of similar electrophysiologic effects. Although lidocaine and phenytoin are historically safe for ventricular tachyarrhythmias of any etiology, sodium bicarbonate should be considered first for any ventricular arrhythmia suspected to have a toxicologic etiology. Intravenous lipid emulsion therapy has shown benefit for treatment of arrhythmias and hemodynamic instability from various membrane-active agents. Beta blockers can be hazardous if the arrhythmia is due to sympathetic hyperactiv­ ity. Magnesium sulfate and overdrive pacing (by isoproterenol or a pacemaker) may be useful in patients with torsades des pointes and prolonged QT intervals. Magnesium and anti-digoxin antibod­ ies should be considered in patients with severe cardiac glycoside poisoning. Invasive (esophageal or intracardiac) ECG recording may be necessary to determine the origin (ventricular or supraven­ tricular) of wide-complex tachycardias (Chap. 253). If the patient is hemodynamically stable, however, it is reasonable to simply observe the patient rather than to administer another potentially proar­ rhythmic agent. Arrhythmias may be resistant to drug therapy until underlying acid-base, electrolyte, oxygenation, and temperature derangements are corrected. PART 14 Poisoning, Drug Overdose, and Envenomation Central Nervous System Therapies  Neuromuscular hyperac­ tivity and seizures can lead to hyperthermia, lactic acidosis, and rhabdomyolysis and should be treated aggressively. Seizures caused by excessive stimulation of catecholamine receptors (sym­ pathomimetic or hallucinogen poisoning and drug withdrawal) or decreased activity of GABA (isoniazid poisoning) or glycine (strychnine poisoning) receptors are best treated with agents that enhance GABA activity, such as benzodiazepine or barbiturates. Since benzodiazepines and barbiturates act by slightly different mechanisms (the former increases the frequency via allosteric mod­ ulation at the receptor and the latter directly increases the duration of chloride channel opening in response to GABA), therapy with both may be effective when neither is effective alone. Seizures caused by isoniazid, which inhibits the synthesis of GABA at several steps by interfering with the cofactor pyridoxine (vitamin B6), may require high doses of supplemental pyridoxine. Seizures resulting from membrane destabilization (beta blocker or cyclic antidepres­ sant poisoning) require GABA enhancers (benzodiazepines first, barbiturates second). Phenytoin is contraindicated in toxicologic seizures: Animal and human data demonstrate worse outcomes after phenytoin loading, especially in theophylline overdose. For poisons with central dopaminergic effects (methamphetamine, phencyclidine) manifested by psychotic behavior, a dopamine receptor antagonist, such as haloperidol or ziprasidone, may be useful. In anticholinergic and cyanide poisoning, specific antidotal therapy may be necessary. The treatment of seizures secondary to cerebral ischemia or edema or to metabolic abnormalities should include correction of the underlying cause. Neuromuscular paraly­ sis is indicated in refractory cases. Electroencephalographic moni­ toring and continuing treatment of seizures are necessary to prevent permanent neurologic damage. Other Measures  Temperature extremes, metabolic abnormalities, hepatic and renal dysfunction, and secondary complications should be treated by standard therapies. PREVENTION OF POISON ABSORPTION Gastrointestinal Decontamination  Whether or not to perform gastrointestinal decontamination and which procedure to use depends on the time since ingestion; the existing and predicted tox­ icity of the ingestant; the availability, efficacy, and contraindications of the procedure; and the nature, severity, and risk of complications. The efficacy of all decontamination procedures decreases with time, and data are insufficient to support or exclude a beneficial effect when they are used >1 h after ingestion. The average time from ingestion to presentation for treatment is >1 h for children and >3 h for adults. Most patients will recover from poisoning uneventfully with good supportive care alone, but complications of gastrointestinal decontamination, particularly aspiration, can prolong this process. Hence, gastrointestinal decontamination should be performed selectively, not routinely, in the management of overdose patients. It is clearly unnecessary when predicted toxic­ ity is minimal or the time of expected maximal toxicity has passed without significant effect. Activated charcoal has comparable or greater efficacy; has fewer contraindications and complications; and is less aversive and inva­ sive than ipecac or gastric lavage. Thus, it is the preferred method of gastrointestinal decontamination in most situations. Activated charcoal suspension (in water) is given orally via a cup, straw, or small-bore nasogastric tube. The generally recommended dose is 1 g/kg body weight because of its dosing convenience, although in vitro and in vivo studies have demonstrated that charcoal adsorbs ≥90% of most substances when given in an amount equal to 10 times the weight of the substance. Palatability may be increased by add­ ing a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or cola syrup) to the suspension. Charcoal adsorbs ingested poisons within the gut lumen, allowing the charcoal-toxin complex to be evacuated with stool. Charged (ionized) chemicals such as mineral acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron, lithium, and other inorganic compounds are not well adsorbed by charcoal. In studies with animals and human volunteers, charcoal decreases the absorption of ingestants by an average of 73% when given within 5 min of ingestant administration, 51% when given at 30 min, and 36% when given at 60 min. For this reason, charcoal given before hospital arrival by prehospital emergency medical services (EMS) increases the potential clinical benefit. Side effects of charcoal include nausea, vomiting, and diarrhea or constipation. Charcoal may also prevent the absorption of orally administered therapeutic agents, so the timing and the dose administered need to be adjusted. Complications include mechanical obstruction of the airway, aspiration, vomiting, and bowel obstruction and infarc­ tion caused by inspissated charcoal. Charcoal is not recommended for patients who have ingested corrosives because it obscures endoscopy. Gastric lavage should be considered for life-threatening poisons that cannot be treated effectively with other decontamination, elimination, or antidotal therapies (e.g., colchicine). Gastric lavage is performed by sequentially administering and aspirating ~5 mL of fluid per kilogram of body weight through a no. 40 French oro­ gastric tube (no. 28 French tube for children). Except in infants, for whom normal saline is recommended, tap water is acceptable. The patient should be placed in Trendelenburg and left lateral decubi­ tus positions to prevent aspiration (even if an endotracheal tube is in place). Lavage decreases ingestant absorption by an average of 52% if performed within 5 min of ingestion administration, 26% if performed at 30 min, and 16% if performed at 60 min. Significant amounts of ingested drug are recovered from <10% of patients. Aspiration is a common complication (occurring in up to 10% of patients), especially when lavage is performed improperly. Serious complications (esophageal and gastric perforation, tube misplace­ ment in the trachea) occur in ~1% of patients. For this reason, the physician should personally insert the lavage tube and confirm its placement, and the patient must be cooperative during the proce­ dure. Gastric lavage is contraindicated in corrosive or petroleum distillate ingestions because of the respective risks of gastroesopha­ geal perforation and aspiration pneumonitis. It is also contraindi­ cated in patients with a compromised unprotected airway and those at risk for hemorrhage or perforation due to esophageal or gastric pathology or recent surgery. Finally, gastric lavage is absolutely contraindicated in combative patients or those who refuse, as most published complications involve patient resistance to the procedure. Syrup of ipecac, an emetogenic agent that was once the substance most commonly used for decontamination, no longer has a role in poisoning management. Even the American Academy of Pediatrics— traditionally the strongest proponent of ipecac—issued a policy statement in 2003 recommending that ipecac should no longer be used in poisoning treatment. Chronic ipecac use (by patients with anorexia nervosa or bulimia) has been reported to cause electrolyte and fluid abnormalities, cardiac toxicity, and myopathy. Whole-bowel irrigation is performed by administering a bowelcleansing solution containing electrolytes and polyethylene glycol (Golytely, Colyte) orally or by gastric tube at a rate of 2 L/h (0.5 L/h in children) until rectal effluent is clear. The patient must be in a sitting position. Although data are limited, whole-bowel irrigation appears to be as effective as other decontamination procedures in volunteer studies. It is most appropriate for those who have ingested foreign bodies, packets of illicit drugs, and agents that are poorly adsorbed by charcoal (e.g., heavy metals). This procedure is contra­ indicated in patients with bowel obstruction, ileus, hemodynamic instability, and compromised unprotected airways. Cathartics are salts (disodium phosphate, magnesium citrate and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that historically have been given with activated charcoal to promote the rectal evacuation of gastrointestinal contents. However, no animal, volunteer, or clinical data have ever demonstrated any decontami­ nation benefit from cathartics. Abdominal cramps, nausea, and occasional vomiting are side effects. Complications of repeated dosing include severe electrolyte disturbances and excessive diar­ rhea. Cathartics are contraindicated in patients who have ingested corrosives and in those with preexisting diarrhea. Magnesium-con­ taining cathartics should not be used in patients with renal failure. Dilution (i.e., drinking water, another clear liquid, or milk at a volume of 5 mL/kg of body weight) is recommended only after the ingestion of corrosives (acids, alkali). It may increase the dissolu­ tion rate (and hence absorption) of capsules, tablets, and other solid ingestants and should not be used in these circumstances. Endoscopic or surgical removal of poisons may be useful in rare situations, such as ingestion of a potentially toxic foreign body that fails to transit the gastrointestinal tract, a potentially lethal amount of a heavy metal (arsenic, iron, mercury, thallium), or agents that have coalesced into gastric concretions or bezoars (heavy metals, lithium, salicylates, sustained-release preparations). Patients who become toxic from cocaine due to its leakage from ingested drug packets require immediate surgical intervention. Decontamination of Other Sites  Immediate, copious flushing with water, saline, or another available clear, drinkable liquid is the initial treatment for topical exposures (exceptions include alkali metals, calcium oxide, phosphorus). Saline is preferred for eye irrigation. A triple wash (water, soap, water) may be best for dermal decontamination. Inhalational exposures should be treated initially with fresh air or supplemental oxygen. The removal of liquids from body cavities such as the vagina or rectum is best accomplished by irrigation. Solids (drug packets, pills) should be removed manually, preferably under direct visualization. ENHANCEMENT OF POISON ELIMINATION Although the elimination of most poisons can be accelerated by therapeutic interventions, the pharmacokinetic efficacy (removal of drug at a rate greater than that accomplished by intrinsic elimination) and clinical benefit (shortened duration of toxicity or improved outcome) of such interventions are often more theoretical than proven. Accordingly, the decision to use such measures should be based on the actual or predicted toxicity and the potential effi­ cacy, cost, and risks of therapy. Multiple-Dose Activated Charcoal  Repetitive oral dosing with charcoal can enhance the elimination of previously absorbed sub­ stances by binding them within the gut as they are excreted in the bile, are secreted by gastrointestinal cells, or passively diffuse into the gut lumen (reverse absorption or enterocapillary exsorption). Doses of 0.5–1 g/kg of body weight every 2–4 h, adjusted downward to avoid regurgitation in patients with decreased gastrointestinal motility, are generally recommended. Pharmacokinetic efficacy approaches that of hemodialysis for some agents (e.g., phenobar­ bital, theophylline). Multiple-dose therapy should be considered only for selected agents (theophylline, phenobarbital, carbamaze­ pine, dapsone, quinine). Complications include intestinal obstruc­ tion, pseudo-obstruction, and nonocclusive intestinal infarction in patients with decreased gut motility. Because of electrolyte and fluid shifts, sorbitol and other cathartics are absolutely contraindicated when multiple doses of activated charcoal are administered. Urinary Alkalinization  Ion trapping via alteration of urine pH may prevent the renal reabsorption of poisons that undergo excre­ tion by glomerular filtration and active tubular secretion. Since membranes are more permeable to nonionized molecules than to their ionized counterparts, acidic (low-pKa) poisons are ionized and trapped in alkaline urine, whereas basic ones become ionized and trapped in acid urine. Urinary alkalinization (producing a urine pH ≥7.5 and a urine output of 3–6 mL/kg of body weight per hour by the addition of sodium bicarbonate to an IV solution) enhances the excretion of chlorophenoxyacetic acid herbicides, chlorpropamide, diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides, and salicylates. Contraindications include congestive heart failure, renal failure, and cerebral edema. Acid-base, fluid, and electrolyte parameters should be monitored carefully. Although acid diuresis may make theoretical sense for some overdoses (amphetamines), it is never indicated and is potentially harmful. CHAPTER 470 Poisoning and Drug Overdose Extracorporeal Removal  Hemodialysis, charcoal or resin hemo­ perfusion, hemofiltration, plasmapheresis, and exchange transfu­ sion are capable of removing any toxin from the bloodstream. Agents most amenable to enhanced elimination by dialysis have low molecular mass (<500 Da), high water solubility, low protein binding, small volumes of distribution (<1 L/kg of body weight), prolonged elimination (long half-life), and high dialysis clearance relative to total-body clearance. Molecular weight, water solubility, and protein binding do not limit the efficacy of the other forms of extracorporeal removal. Dialysis should be considered in cases of severe poisoning due to carbamazepine, ethylene glycol, isopropyl alcohol, lithium, metha­ nol, theophylline, salicylates, and valproate. Although hemoperfu­ sion may be more effective in removing some of these poisons, it does not correct associated acid-base and electrolyte abnormalities, and most hospitals no longer have hemoperfusion cartridges readily available. Fortunately, recent advances in hemodialysis technology make it as effective as hemoperfusion for removing poisons such as caffeine, carbamazepine, and theophylline. Both techniques require central venous access and systemic anticoagulation and may result in transient hypotension. Hemoperfusion may also cause hemoly­ sis, hypocalcemia, and thrombocytopenia. Peritoneal dialysis and exchange transfusion are less effective but may be used when other procedures are unavailable, contraindicated, or technically difficult (e.g., in infants). Continuous venovenous hemofiltration (CVVH) has also been used successfully when conventional inter­ mittent hemodialysis is not well tolerated because of hemodynamic lability. Exchange transfusion may be indicated in the treatment of severe arsine- or sodium chlorate–induced hemolysis, methe­ moglobinemia, and sulfhemoglobinemia. Although hemofiltration can enhance elimination of aminoglycosides, vancomycin, and metal-chelate complexes, the roles of hemofiltration and plasma­ pheresis in the treatment of poisoning are not yet defined. Candidates for extracorporeal removal therapies include patients with severe toxicity whose condition deteriorates despite aggressive supportive therapy; those with potentially prolonged, irreversible, or fatal toxicity; those with dangerous blood levels of toxins; those who lack the capacity for self-detoxification because of liver or renal failure; and those with a serious underlying illness or complication that will adversely affect recovery. Other Techniques  The elimination of heavy metals can be enhanced by chelation, and the removal of carbon monoxide can be accelerated by hyperbaric oxygenation. ADMINISTRATION OF ANTIDOTES Antidotes counteract the effects of poisons by neutralizing them (e.g., antibody-antigen reactions, chelation, chemical binding) or by antagonizing their physiologic effects (e.g., activation of opposing TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings PHYSIOLOGIC CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS Stimulated PART 14 Poisoning, Drug Overdose, and Envenomation Sympatheticsa   Sympathomimetics α1-Adrenergic agonists (decongestants): phenylephrine, phenylpropanolamine β2-Adrenergic agonists (bronchodilators): albuterol, terbutaline Nonspecific adrenergic agonists: amphetamines, cocaine, ephedrine Stimulation of central and peripheral sympathetic receptors directly or indirectly (by promoting release or inhibiting reuptake of norepinephrine and sometimes dopamine)   Ergot alkaloids Ergotamine, methysergide, bromocriptine, pergolide Stimulation and inhibition of serotonergic and α-adrenergic receptors; stimulation of dopamine receptors   Methylxanthines Caffeine, theophylline Inhibition of adenosine synthesis and adenosine receptor antagonism; stimulation of epinephrine and norepinephrine release; inhibition of phosphodiesterase resulting in increased intracellular cyclic adenosine and guanosine monophosphate   Monoamine oxidase Phenelzine, tranylcypromine, selegiline Inhibition of monoamine oxidase resulting in impaired metabolism of endogenous catecholamines and exogenous sympathomimetic agents inhibitors nervous system activity, provision of a competitive metabolic or receptor substrate). Poisons or conditions with specific antidotes include acetaminophen, anticholinergic agents, anticoagulants, benzodiazepines, beta blockers, calcium channel blockers, car­ bon monoxide, cardiac glycosides, cholinergic agents, cyanide, drug-induced dystonic reactions, ethylene glycol, fluoride, heavy metals, hypoglycemic agents, isoniazid, membrane-active agents, methemoglobinemia, opioids, sympathomimetics, and a variety of envenomations. Intravenous lipid emulsion has been shown to be a successful antidote for poisoning from various anesthetics and membrane-active agents (e.g., cyclic antidepressants), but the exact mechanism of benefit is still under investigation. Antidotes can sig­ nificantly reduce morbidity and mortality rates but are potentially toxic if used for inappropriate reasons. Since their safe use requires correct identification of a specific poisoning or syndrome, details of antidotal therapy are discussed with the conditions for which they are indicated (Table 470-4). Physiologic stimulation (Table 470-2). Reflex bradycardia can occur with selective α1 agonists; β agonists can cause hypotension and hypokalemia. Phentolamine, a nonselective α1adrenergic receptor antagonist, for severe hypertension due to α1adrenergic agonists; propranolol, a nonselective β blocker, for hypotension and tachycardia due to β2 agonists; either labetalol, a β blocker with α-blocking activity, or phentolamine with esmolol, metoprolol, or another cardioselective β blocker for hypertension with tachycardia due to nonselective agents (β blockers, if used alone, can exacerbate hypertension and vasospasm due to unopposed α stimulation); benzodiazepines; propofol Physiologic stimulation (Table 470-2); formication; vasospasm with limb (isolated or generalized), myocardial, and cerebral ischemia progressing to gangrene or infarction. Hypotension, bradycardia, and involuntary movements can also occur. Nitroprusside or nitroglycerine for severe vasospasm; prazosin (an α1 blocker), captopril, nifedipine, and cyproheptadine (a serotonin receptor antagonist) for mildto-moderate limb ischemia; dopamine receptor antagonists (antipsychotics) for hallucinations and movement disorders Physiologic stimulation (Table 470-2); pronounced gastrointestinal symptoms and β agonist effects (see above). Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. Propranolol, a nonselective β blocker, or esmolol for tachycardia with hypotension; any β blocker for supraventricular or ventricular tachycardia without hypotension; elimination enhanced by multipledose charcoal, hemoperfusion, and hemodialysis. Indications for hemoperfusion or hemodialysis include unstable vital signs, seizures, and a theophylline level of 80–100 μg/mL after an acute overdose and 40–60 μg/mL with chronic exposure. Delayed or slowly progressive physiologic stimulation (Table 470-2); terminal hypotension and bradycardia in severe cases Short-acting agents (e.g., nitroprusside, esmolol) for severe hypertension and tachycardia; direct-acting sympathomimetics (e.g., norepinephrine, epinephrine) for hypotension and bradycardia (Continued) TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings PHYSIOLOGIC CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS Anticholinergics   Antihistamines Diphenhydramine, doxylamine, pyrilamine Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors. At high doses, amantadine, diphenhydramine, orphenadrine, phenothiazines, and tricyclic antidepressants have additional nonanticholinergic activity (see below).   Antipsychotics Chlorpromazine, olanzapine, quetiapine, thioridazine Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels.   Belladonna alkaloids Atropine, hyoscyamine, scopolamine Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors   Cyclic antidepressants Amitriptyline, doxepin, imipramine Inhibition of α-adrenergic, dopaminergic, GABA-ergic, histaminergic, muscarinic, and serotonergic receptors; inhibition of sodium channels (see membrane-active agents); inhibition of norepinephrine and serotonin reuptake   Mushrooms and plants Amanita muscaria and A. pantherina, henbane, jimson weed, nightshade Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors Depressed Sympatholytics   α2-Adrenergic agonists Clonidine, guanabenz, tetrahydrozoline and other imidazoline decongestants, tizanidine and other imidazoline muscle relaxants Stimulation of α2-adrenergic receptors leading to inhibition of CNS sympathetic outflow. Activity at nonadrenergic imidazoline binding sites also contributes to CNS effects.   Antipsychotics Chlorpromazine, clozapine, haloperidol, risperidone, thioridazine Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels. (Continued) Physiologic stimulation (Table 470-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction. Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias). Physiologic depression (Table 470-2), miosis, anticholinergic effects (see above), extrapyramidal reactions (see below), tachycardia Sodium bicarbonate for ventricular tachydysrhythmias associated with QRS prolongation; magnesium, isoproterenol, and overdrive pacing for torsades des pointes. Avoid class IA, IC, and III antiarrhythmics. Physiologic stimulation (Table 470-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction. Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias). CHAPTER 470 Poisoning and Drug Overdose Physiologic depression (Table 470-2), seizures, tachycardia, cardiac conduction delays (increased PR, QRS, JT, and QT intervals; terminal QRS right-axis deviation) with aberrancy and ventricular tachydysrhythmias; anticholinergic toxidrome (see above) Hypertonic sodium bicarbonate (or hypertonic saline) for ventricular tachydysrhythmias associated with QRS prolongation. Use of phenytoin is controversial. Avoid class IA, IC, and III antiarrhythmics. IV emulsion therapy may be beneficial in some cases. Physiologic stimulation (Table 470-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction. Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias). Physiologic depression (Table 470-2), miosis. Transient initial hypertension may be seen. Dopamine and norepinephrine for hypotension; atropine for symptomatic bradycardia; naloxone for CNS depression (inconsistently effective) Physiologic depression (Table 470-2), miosis, anticholinergic effects (see above), extrapyramidal reactions (see below), tachycardia. Cardiac conduction delays (increased PR, QRS, JT, and QT intervals) with ventricular tachydysrhythmias, including torsades des pointes, can sometimes develop. Sodium bicarbonate for ventricular tachydysrhythmias associated with QRS prolongation; magnesium, isoproterenol, and overdrive pacing for torsades des pointes. Avoid class IA, IC, and III antiarrhythmics. (Continued) TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings PHYSIOLOGIC CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS   β-Adrenergic blockers Cardioselective (β1) blockers: atenolol, esmolol, metoprolol Nonselective (β1 and β2) blockers: nadolol, propranolol, timolol Partial β agonists: acebutolol, pindolol α1 Antagonists: carvedilol, labetalol Membrane-active agents: acebutolol, propranolol, sotalol Inhibition of β-adrenergic receptors (class II antiarrhythmic effect). Some agents have activity at additional receptors or have membrane effects (see below).   Calcium channel Diltiazem, nifedipine and other dihydropyridine derivatives, verapamil Inhibition of slow (type L) cardiovascular calcium channels (class IV antiarrhythmic effect) blockers PART 14 Poisoning, Drug Overdose, and Envenomation   Cardiac glycosides Digoxin, endogenous cardioactive steroids, foxglove and other plants, toad skin secretions (Bufonidae spp.) Inhibition of cardiac Na+, K+-ATPase membrane pump   Cyclic antidepressants Amitriptyline, doxepin, imipramine Inhibition of α-adrenergic, dopaminergic, GABA-ergic, histaminergic, muscarinic, and serotonergic receptors; inhibition of sodium channels (see membrane-active agents); inhibition of norepinephrine and serotonin reuptake Cholinergics   Acetylcholinesterase Carbamate insecticides (aldicarb, carbaryl, propoxur) and medicinals (neostigmine, physostigmine, tacrine); nerve gases (sarin, soman, tabun, VX); organophosphate insecticides (diazinon, chlorpyrifos-ethyl, malathion) Bethanechol, mushrooms (Boletus, Clitocybe, Inocybe spp.), pilocarpine Lobeline, nicotine (tobacco) Inhibition of acetylcholinesterase leading to increased synaptic acetylcholine at muscarinic and nicotinic cholinergic receptor sites Stimulation of CNS and postganglionic parasympathetic cholinergic (muscarinic) receptors Stimulation of preganglionic sympathetic and parasympathetic and striated muscle (neuromuscular junction) cholinergic (nicotine) receptors inhibitors   Muscarinic agonists   Nicotinic agonists (Continued) Physiologic depression (Table 470-2), atrioventricular block, hypoglycemia, hyperkalemia, seizures. Partial agonists can cause hypertension and tachycardia. Sotalol can cause increased QT interval and ventricular tachydysrhythmias. Onset may be delayed after sotalol and sustained-release formulation overdose. Glucagon for hypotension and symptomatic bradycardia. Atropine, isoproterenol, dopamine, dobutamine, epinephrine, and norepinephrine may sometimes be effective. High-dose insulin (with glucose and potassium to maintain euglycemia and normokalemia), electrical pacing, and mechanical cardiovascular support for refractory cases. Physiologic depression (Table 470-2), atrioventricular block, organ ischemia and infarction, hyperglycemia, seizures. Hypotension is usually due to decreased vascular resistance rather than to decreased cardiac output. Onset may be delayed for ≥12 h after overdose of sustained-release formulations. Calcium and glucagon for hypotension and symptomatic bradycardia. Dopamine, epinephrine, norepinephrine, atropine, and isoproterenol are less often effective but can be used adjunctively. Highdose insulin (with glucose and potassium to maintain euglycemia and normokalemia), IV lipid emulsion therapy, electrical pacing, and mechanical cardiovascular support for refractory cases. Physiologic depression (Table 470-2); gastrointestinal, psychiatric, and visual symptoms; atrioventricular block with or without concomitant supraventricular tachyarrhythmia; ventricular tachyarrhythmias; hyperkalemia in acute poisoning. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. Digoxin-specific antibody fragments for hemodynamically compromising dysrhythmias, Mobitz II or third-degree atrioventricular block, hyperkalemia (>5.5 meq/L; in acute poisoning only). Temporizing measures include atropine, dopamine, epinephrine, and external cardiac pacing for bradydysrhythmias and magnesium, lidocaine, or phenytoin, for ventricular tachydysrhythmias. Internal cardiac pacing and cardioversion can increase ventricular irritability and should be reserved for refractory cases. Physiologic depression (Table 470-2), seizures, tachycardia, cardiac conduction delays (increased PR, QRS, JT, and QT intervals; terminal QRS rightaxis deviation) with aberrancy and ventricular tachydysrhythmias; anticholinergic toxidrome (see above) Hypertonic sodium bicarbonate (or hypertonic saline) for ventricular tachydysrhythmias associated with QRS prolongation. Use of phenytoin is controversial. Avoid class IA, IC, and III antiarrhythmics. IV emulsion therapy may be beneficial in some cases. Physiologic depression (Table 470-2). Muscarinic signs and symptoms: seizures, excessive secretions (lacrimation, salivation, bronchorrhea and wheezing, diaphoresis), and increased bowel and bladder activity with nausea, vomiting, diarrhea, abdominal cramps, and incontinence of feces and urine. Nicotinic signs and symptoms: hypertension, tachycardia, muscle cramps, fasciculations, weakness, and paralysis. Death is usually due to respiratory failure. Cholinesterase activity in plasma and red cells is <50% of normal in acetylcholinesterase inhibitor poisoning. Atropine for muscarinic signs and symptoms; 2-PAM, a cholinesterase reactivator, for nicotinic signs and symptoms due to organophosphates, nerve gases, or an unknown anticholinesterase (Continued) TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings PHYSIOLOGIC CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS Sedative-hypnoticsb   Anticonvulsants   Barbiturates   Benzodiazepines Carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, tiagabine, topiramate, valproate, zonisamide Short-acting: butabarbital, pentobarbital, secobarbital Long-acting: phenobarbital, primidone Ultrashort-acting: estazolam, midazolam, temazepam, triazolam Short-acting: alprazolam, flunitrazepam, lorazepam, oxazepam Long-acting: chlordiazepoxide, clonazepam, diazepam, flurazepam Pharmacologically related agents: zaleplon, zolpidem Potentiation of the inhibitory effects of GABA by binding to the neuronal GABA–A chloride channel receptor complex and increasing the frequency or duration of chloride channel opening in response to GABA stimulation. Baclofen and, to some extent, GHB act at the GABA–B receptor complex. Meprobamate, its metabolite carisoprodol, felbamate, and orphenadrine antagonize NDMA excitatory receptors. Ethosuximide, valproate, and zonisamide decrease conduction through T-type calcium channels. Valproate decreases GABA degradation, and tiagabine blocks GABA reuptake. Carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate, and zonisamide slow the rate of recovery of inactivated sodium channels. Some agents also have α2 agonist, anticholinergic, and sodium channel–blocking activity (see above and below).   GABA precursors γ-Hydroxybutyrate (sodium oxybate; GHB), γ-butyrolactone (GBL), 1,4-butanediol Stimulation at GABA receptor complex increases chloride channel opening   Muscle relaxants Baclofen, carisoprodol, cyclobenzaprine, etomidate, metaxalone, methocarbamol, orphenadrine, propofol, tizanidine and other imidazoline muscle relaxants Baclofen acts at GABA–B receptor complex; stimulation of α2-adrenergic receptors inhibits CNS sympathetic outflow. Activity at nonadrenergic imidazoline binding sites also contributes to CNS effects. The others have centrally acting and various other unknown mechanisms of action. Discordant Asphyxiants   Cytochrome oxidase Cyanide, hydrogen sulfide Inhibition of mitochondrial cytochrome oxidase, with consequent blockage of electron transport and oxidative metabolism. Carbon monoxide also binds to hemoglobin and myoglobin and prevents oxygen binding, transport, and tissue uptake. (Binding to hemoglobin shifts the oxygen dissociation curve to the left.) inhibitors (Continued) Physiologic depression (Table 470-2), nystagmus. Delayed absorption can occur with carbamazepine, phenytoin, and valproate. Myoclonus, seizures, hypertension, and tachyarrhythmias can occur with baclofen, carbamazepine, and orphenadrine. Tachyarrhythmias can also occur with chloral hydrate. AGMA, hypernatremia, hyperosmolality, hyperammonemia, chemical hepatitis, and hypoglycemia can be seen in valproate poisoning. Carbamazepine and oxcarbazepine may produce hyponatremia from SIADH. Benzodiazepines, barbiturates, or propofol for seizures. Hemodialysis and hemoperfusion may be indicated for severe poisoning by some agents (see “Extracorporeal Removal,” in text). See above and below for treatment of anticholinergic and sodium channel (membrane)– blocking effects. CHAPTER 470 Poisoning and Drug Overdose Physiologic depression (Table 470-2) Goal-directed supportive care Physiologic depression (Table 470-2) Goal-directed supportive care; benzodiazepines and barbiturates for seizures Signs and symptoms of hypoxemia with initial physiologic stimulation and subsequent depression (Table 470-2); lactic acidosis; normal PO2 and calculated oxygen saturation but decreased oxygen saturation by co-oximetry. (That measured by pulse oximetry is falsely elevated but is less than normal and less than the calculated value.) Headache and nausea are common with carbon monoxide. Sudden collapse may occur with cyanide and hydrogen sulfide exposure. A bitter almond breath odor may be noted with cyanide ingestion, and hydrogen sulfide smells like rotten eggs. High-dose oxygen; IV hydroxocobalamin or IV sodium nitrite and sodium thiosulfate (Lilly cyanide antidote kit) for coma, metabolic acidosis, and cardiovascular dysfunction in cyanide poisoning or victims from a fire; ECMO (Continued) TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings PHYSIOLOGIC CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS   Methemoglobin Aniline derivatives, dapsone, local anesthetics, nitrates, nitrites, nitrogen oxides, nitro- and nitrosohydrocarbons, phenazopyridine, primaquinetype antimalarials, sulfonamides Oxidation of hemoglobin iron from ferrous (Fe2+) to ferric (Fe3+) state prevents oxygen binding, transport, and tissue uptake. (Methemoglobinemia shifts oxygen dissociation curve to the left.) Oxidation of hemoglobin protein causes hemoglobin precipitation and hemolytic anemia (manifesting as Heinz bodies and “bite cells” on peripheral-blood smear). inducers   AGMA inducers Ethylene glycol Ethylene glycol causes CNS depression and increased serum osmolality. Metabolites (primarily glycolic acid) cause AGMA, CNS depression, and renal failure. Precipitation of oxalic acid metabolite as calcium salt in tissues and urine results in hypocalcemia, tissue edema, and crystalluria. PART 14 Poisoning, Drug Overdose, and Envenomation Iron Hydration of ferric (Fe3+) ion generates H+. Non-transferrinbound iron catalyzes formation of free radicals that cause mitochondrial injury, lipid peroxidation, increased capillary permeability, vasodilation, and organ toxicity. Methanol Methanol causes ethanol-like CNS depression and increased serum osmolality. Formic acid metabolite causes AGMA and retinal toxicity. Salicylate Increased sensitivity of CNS respiratory center to changes in and stimulates respiration. Uncoupling of oxidative phosphorylation, inhibition of Krebs cycle enzymes, and stimulation of carbohydrate and lipid metabolism generate unmeasured endogenous anions and cause AGMA. (Continued) Signs and symptoms of hypoxemia with initial physiologic stimulation and subsequent depression (Table 470-2), graybrown cyanosis unresponsive to oxygen at methemoglobin fractions >15–20%, headache, lactic acidosis (at methemoglobin fractions >45%), normal PO2 and calculated oxygen saturation but decreased oxygen saturation and increased methemoglobin fraction by co-oximetry. (Oxygen saturation by pulse oximetry may be falsely increased or decreased but is less than normal and less than the calculated value.) High-dose oxygen; IV methylene blue for methemoglobin fraction >30%, symptomatic hypoxemia, or ischemia (contraindicated in G6PD deficiency); exchange transfusion and hyperbaric oxygen for severe or refractory cases Initial ethanol-like intoxication, nausea, vomiting, increased osmolar gap, calcium oxalate crystalluria; delayed AGMA, back pain, renal failure; coma, seizures, hypotension, ARDS in severe cases Sodium bicarbonate to correct acidemia; thiamine, folinic acid, magnesium, and high-dose pyridoxine to facilitate metabolism; ethanol or fomepizole for AGMA, crystalluria or renal dysfunction, ethylene glycol level >3 mmol/L (20 mg/dL), and ethanol-like intoxication or increased osmolal gap if level not readily obtainable; hemodialysis for persistent AGMA, lack of clinical improvement, and renal dysfunction; hemodialysis also useful for enhancing ethylene glycol elimination and shortening duration of treatment when ethylene glycol level is >8 mmol/L (50 mg/dL). Initial nausea, vomiting, abdominal pain, diarrhea; AGMA, cardiovascular and CNS depression, hepatitis, coagulopathy, and seizures in severe cases. Radiopaque iron tablets may be seen on abdominal x-ray. Whole-bowel irrigation for large ingestions; endoscopy and gastrostomy if clinical toxicity and large number of tablets are still visible on x-ray; IV hydration; sodium bicarbonate for acidemia; IV deferoxamine for systemic toxicity, iron level >90 μmol/L (500 μg/dL) Initial ethanol-like intoxication, nausea, vomiting, increased osmolar gap; delayed AGMA, visual (clouding, spots, blindness) and retinal (edema, hyperemia) abnormalities; coma, seizures, cardiovascular depression in severe cases; possible pancreatitis Gastric aspiration for recent ingestion; sodium bicarbonate to correct acidemia; high-dose folinic acid or folate to facilitate metabolism; ethanol or fomepizole for AGMA, visual symptoms, methanol level >6 mmol/L (20 mg/ dL), and ethanol-like intoxication or increased osmolal gap if level not readily obtainable; hemodialysis for persistent AGMA, lack of clinical improvement, and renal dysfunction; hemodialysis also useful for enhancing methanol elimination and shortening duration of treatment when methanol level is >15 mmol/L (50 mg/dL) Initial nausea, vomiting, hyperventilation, alkalemia, alkaluria; subsequent alkalemia with both respiratory alkalosis and AGMA and paradoxical aciduria; late acidemia with CNS and respiratory depression; cerebral and pulmonary edema in severe cases. Hypoglycemia, hypocalcemia, hypokalemia, and seizures can occur. IV hydration and supplemental glucose; sodium bicarbonate to correct acidemia; urinary alkalinization for systemic toxicity; hemodialysis for coma, cerebral edema, seizures, pulmonary edema, renal failure, progressive acid-base disturbances or clinical toxicity, salicylate level >7 mmol/L (100 mg/dL) following acute overdose (Continued) TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings PHYSIOLOGIC CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS CNS syndromes   Extrapyramidal Antipsychotics (see above), some cyclic antidepressants and antihistamines Decreased CNS dopaminergic activity with relative excess of cholinergic activity reactions   Isoniazid Interference with activation and supply of pyridoxal-5phosphate, a cofactor for glutamic acid decarboxylase, which converts glutamic acid to GABA, results in decreased levels of this inhibitory CNS neurotransmitter; complexation with and depletion of pyridoxine itself; inhibition of nicotine adenine dinucleotide–dependent lactate and hydroxybutyrate dehydrogenases, resulting in substrate accumulation   Lithium Interference with cell membrane ion transport, adenylate cyclase and Na+, K+-ATPase activity, and neurotransmitter release   Serotonin syndrome Amphetamines, cocaine, dextromethorphan, meperidine, MAO inhibitors, selective serotonin (5-HT) reuptake inhibitors, tricyclic antidepressants, tramadol, triptans, tryptophan Promotion of serotonin release, inhibition of serotonin reuptake, or direct stimulation of CNS and peripheral serotonin receptors (primarily 5-HT-1a and 5-HT-2), alone or in combination   Membrane-active Amantadine, antiarrhythmics (class I and III agents; some β blockers), antipsychotics (see above), antihistamines (particularly diphenhydramine), carbamazepine, local anesthetics (including cocaine), opioids (meperidine, propoxyphene), orphenadrine, quinoline antimalarials (chloroquine, hydroxychloroquine, quinine), cyclic antidepressants (see above) Blockade of fast sodium membrane channels prolongs phase 0 (depolarization) of the cardiac action potential, which prolongs QRS duration and promotes reentrant (monomorphic) ventricular tachycardia. Class Ia, Ic, and III antiarrhythmics also block potassium channels during phases 2 and 3 (repolarization) of the action potential, prolonging the JT interval and promoting early afterdepolarizations and polymorphic (torsades des pointes) ventricular tachycardia. Similar effects on neuronal membrane channels cause CNS dysfunction. Some agents also block α-adrenergic and cholinergic receptors or have opioid effects (see above and Chap. 467). agent aSee above and Chap. 468. bSee above and Chap. 467. Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; ECMO, extracorporeal membrane oxygenation; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB, γ-hydroxybutyrate; G6PD, glucose-6-phosphate dehydrogenase; MAO, monoamine oxidase; NDMA, N-methyl-D-aspartate; 2-PAM, pralidoxime; SIADH, syndrome of inappropriate antidiuretic hormone secretion. (Continued) Akathisia, dystonia, parkinsonism Oral or parenteral anticholinergic agent such as benztropine or diphenhydramine Nausea, vomiting, agitation, confusion; coma, respiratory depression, seizures, lactic and ketoacidosis in severe cases High-dose IV pyridoxine (vitamin B6) for agitation, confusion, coma, and seizures; diazepam or barbiturates for seizures Nausea, vomiting, diarrhea, ataxia, choreoathetosis, encephalopathy, hyperreflexia, myoclonus, nystagmus, nephrogenic diabetes insipidus, falsely elevated serum chloride with low anion gap, tachycardia; coma, seizures, arrhythmias, hyperthermia, and prolonged or permanent encephalopathy and movement disorders in severe cases; delayed onset after acute overdose, particularly with delayed-release formulations. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. Whole-bowel irrigation for large ingestions; IV hydration; hemodialysis for coma, seizures, encephalopathy or neuromuscular dysfunction (severe, progressive, or persistent), peak lithium level >4 meq/L following acute overdose CHAPTER 470 Poisoning and Drug Overdose Altered mental status (agitation, confusion, mutism, coma, seizures), neuromuscular hyperactivity (hyperreflexia, myoclonus, rigidity, tremors), and autonomic dysfunction (abdominal pain, diarrhea, diaphoresis, fever, flushing, labile hypertension, mydriasis, tearing, salivation, tachycardia). Complications include hyperthermia, lactic acidosis, rhabdomyolysis, and multisystem organ failure. Discontinue the offending agent(s); benzodiazepines for agitation or signs of stimulation; the serotonin receptor antagonist cyproheptadine may be helpful in severe cases. QRS and JT prolongation (or both) with hypotension, ventricular tachyarrhythmias, CNS depression, seizures; anticholinergic effects with amantadine, antihistamines, carbamazepine, disopyramide, antipsychotics, and cyclic antidepressants (see above); opioid effects with meperidine and propoxyphene (see Chap. 467); cinchonism (hearing loss, tinnitus, nausea, vomiting, vertigo, ataxia, headache, flushing, diaphoresis), and blindness with quinoline antimalarials Hypertonic sodium bicarbonate (or hypertonic saline) for cardiac conduction delays and monomorphic ventricular tachycardia; lidocaine for monomorphic ventricular tachycardia (except when due to class Ib antiarrhythmics); magnesium, isoproterenol, and overdrive pacing for polymorphic ventricular tachycardia; physostigmine for anticholinergic effects (see above); naloxone for opioid effects (see Chap. 467); extracorporeal removal for some agents (see text). # 04 - 472 Ectoparasite Infestations and Arthropod Injuries ## 472 Ectoparasite Infestations and Arthropod Injuries dysrhythmias, hypotension, and pulmonary edema have also been reported. Postmortem examination of brain tissue has shown neuronal necrosis or cell loss and astrocytosis, most prominently in the hippo­ campus and amygdala. Several months after the primary intoxication, victims may still display chronic residual memory deficits and motor or sensory neuropathy. TREATMENT Amnesic Shellfish Poisoning Therapy is supportive and based on symptoms. IV fluids and antiemetics may be used for severe nausea, vomiting, and diar­ rhea. Domoic acid neurotoxicity is primarily seizure mediated; anticonvulsive therapy using GABA agonists (e.g., benzodiazepines, propofol, or barbiturates) should be instituted early. However, some patients without clinically evident seizure activity have developed neurologic sequelae. ■ ■DIARRHETIC SHELLFISH POISONING Diarrhetic shellfish poisoning occurs with consumption of shellfish containing the lipophilic compound okadaic acid. This toxin inhibits serine and threonine protein phosphatases, with consequent protein accumulation and continued secretion of fluid by intestinal cells lead­ ing to diarrhea. Shellfish acquire these toxins by feeding on dinoflagel­ lates, particularly of the genera Dinophysis and Prorocentrum. PART 14 Poisoning, Drug Overdose, and Envenomation Symptoms include diarrhea, nausea, vomiting, abdominal pain, and chills. Onset typically occurs between 30 min and 12 h after inges­ tion of contaminated shellfish. The illness is usually self-limited; most patients recover in 3–4 days and only a few require hospitalization. Treatment is supportive and focused on hydration. Toxins can be detected in food samples by a mouse bioassay, an immunoassay, and fluorometric HPLC. Acknowledgment Kirsten B. Hornbeak, Robert L. Norris, Alex Chen, and Charles Lei contributed to this chapter in the prior edition and material from that chapter has been retained here. We would like to dedicate this chapter to the late Dr. Paul S. Auerbach, who was a contributing author for the previous seven editions of Harrison’s Principles of Internal Medicine. Dr. Auerbach had a tremendous impact on the field of emergency medi­ cine and founded the subspecialty of wilderness medicine. Dr. Auerbach was a wonderful teacher, mentor, and friend, and will be deeply missed. ■ ■FURTHER READING Blohm E et al: Marine envenomations, in Goldfrank’s Toxicologic Emergencies, 11th ed. Nelson LS et al (eds). New York, McGraw-Hill Education, 2019, pp 1567-1580. Bush SP et al: Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, random­ ized clinical trial. Clin Toxicol 53:37, 2015. Cannon R et al: Acute hypersensitivity reactions associated with administration of crotalidae polyvalent immune Fab antivenom. Ann Emerg Med 51:407, 2008. Fil LJ et al: Food Poisoning, in Goldfrank’s Toxicologic Emergencies, 11th ed. Nelson LS et al (eds). New York, McGraw-Hill Education, 2019, pp 592-605. French LK et al: Marine vertebrates, cnidarians, and mollusks, in Critical Care Toxicology: diagnosis and management of the critically poisoned patient, 2nd ed. Brent J et al (eds). New York, Springer, 2017, pp 2045-2074. GBD 2019 Diseases and Injuries Collaborators: Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396:1204, 2020. Erratum in: Lancet 396:1562, 2020. Hornbeak KB, Auerbach PS: Marine envenomation. Emerg Med Clin North Am 35:321, 2017. Kang AM, Fisher ES: Thromboelastography with platelet studies (TEG with PlateletMapping) after rattlesnake envenomation in the southwestern United States demonstrates inhibition of ADP-induced platelet activation as well as clot lysis. J Med Toxicol 16:24, 2020. Pottier I et al: Ciguatera fish poisoning in the Caribbean Sea and Atlantic Ocean: Reconciling the multiplicity of ciguatoxins and ana­ lytical chemistry approach for public health safety. Toxins (Basel) 15:453, 2023. Thomas EG, Thomas DJ: Mimics of allergy and angioedema: Scom­ broid, mast cell activation disorders, and hereditary alpha tryptasemia. Immunol Allergy Clin North Am 43:553, 2023. Ubani CB et al: Emergency department management of North American snake envenomations. Emerg Med Pract 26:1, 2024. Warrell DA, Williams DJ: Clinical aspects of snakebite envenoming and its treatment in low-resource settings. Lancet 401:1382, 2023. Silas A. Davidson, Scott A. Norton Ectoparasite Infestations and Arthropod Injuries Ectoparasites include arthropods and creatures from other phyla that infest the skin or hair of animals; the host animals provide them with sustenance and shelter. The ectoparasites may remain on the superficial surfaces of the skin or hair, attached by mouthparts or with specialized claws. Other ectoparasites may penetrate the skin’s surface and reside in the epidermis, dermis, or subcutaneous tissues. Ectoparasites may inflict direct mechanical injury, consume blood or nutrients, induce hypersensitivity reactions, inoculate toxins, transmit pathogens, create openings in the skin for secondary bacterial infection, and incite fear or disgust. Human beings are obligate hosts for few ectoparasites but can serve as facultative, dead-end, or paratenic (accidental) hosts for many others. Of the organisms discussed in this chapter, only scabies mites (the hominis variety) and human-infesting lice are obligate parasites of humans. Arthropods that are capable of ectoparasitism or that can otherwise cause injury include insects (such as lice, fleas, bed bugs, wasps, ants, bees, and diverse kinds of flies), arachnids (spiders, scorpions, mites, and ticks), and myriapods (millipedes and centipedes). Several arthro­ pods can cause uncomfortable reactions when they, their setae (hairlike growths), or their exudates come into contact with skin, mucous membranes, or ocular tissues. Certain nematodes (helminths), such as the hookworms (Chap. 239), are ectoparasitic in that they must enter the skin in some manner, then traverse the skin to reach deeper tissues, or migrate within the skin. Infrequently encountered ectoparasites in other animal phyla include pentastomes (armillifers or tongue worms) and leeches. Arthropods may cause injury when they attempt to take a blood meal or as they defend themselves by biting, stinging, or exuding ven­ oms. Papular urticaria and other lesions caused by arthropod bites and stings are so diverse and variable (depending on the host’s health status and prior exposure to the arthropod’s saliva, venom, or other exu­ dates) that it is difficult to identify the precise causative organism with visual examination alone without a bona fide specimen and taxonomic expertise. Specimens of the presumably offending arthropod should, whenever possible, be sampled directly (taken from the patient, ideally by medical personnel) or indirectly by using traps or other monitoring devices in the patient’s home or workplace. Samples sent to laboratories for identification should be properly fixed, preserved, and packaged. The patient’s history of travel and precautionary behaviors; occupa­ tional, recreational, and environmental exposures; and proximity to animals often helps the clinician and parasitologist resolve the cause. ■ ■SCABIES The human itch mite, Sarcoptes scabiei var. hominis, is an obligate human ectoparasite and a common cause of itchy dermatosis, affecting ~250 million persons worldwide. Both the mites and the skin condition are called scabies. Gravid female mites (~0.3 mm in length) burrow superficially within the stratum corneum, depositing several eggs per day. Gravid adult females emerge to the skin’s surface about 8 days later, then (re)invade the skin of the same person or another host. Newly fertilized female mites are transferred between people mainly by direct skin-to-skin contact. Transmission is facilitated by crowding, poor hygiene, and close physical contact with other people. Generally, sca­ bies mites die within a day or so if not on a suitable host. Transmission by sharing contaminated bedding or clothing occurs less frequently than commonly thought. Outbreaks are known to occur in preschools, hospitals, nursing homes, prisons, other institutional residences, and other congregate settings. The rash and pruritus associated with scabies arise from a sensitiza­ tion reaction to mites and their secretions/excretions. A person’s initial infestation typically remains asymptomatic for up to 6 weeks before intense pruritus starts. Reinfestation, however, promptly induces a hypersensitivity reaction. Burrows become surrounded by inflamma­ tory infiltrates composed of eosinophils, lymphocytes, and histiocytes. Infested individuals often feel generalized pruritus, not just in the most heavily involved areas. Pruritus typically intensifies at night and after hot showers. Burrows appear as dark wavy lines in the upper epidermis and are 3–15 mm long (Fig. 472-1). Classic burrows are often difficult to find because most patients have perhaps only 10–15 burrows. However, most bur­ rows are obscured by excoriations or secondary bacterial infections. Scabietic lesions are most common on the volar wrists and along the digital web spaces. In males, the genitalia (penile glans and shaft and the scrotum) are nearly always involved. Small papules and vesicles, often accompanied by eczematous plaques, pustules, or nodules, appear symmetrically at those sites. The axillae and other intertrigi­ nous areas; around the navel and belt line; and the buttocks and upper thighs are also common sites. Except in infants, the face, scalp, neck, palms, and soles are usually spared. Hyperinfestation with thousands of mites, a condition known as crusted scabies (formerly Norwegian scabies), may result from gluco­ corticoid use, immunodeficiency (including that due to HIV/AIDS), and neurologic or psychiatric disorders that dampen the itch or impair the scratch response. Crusted scabies often resembles psoriasis: both are characterized by widespread thick yellowish-white keratotic crusts, scaly plaques, and dystrophic nails. Characteristic burrows are not seen in crusted scabies, and patients are often not itchy, even though their infestations are highly contagious and have been responsible for outbreaks of common scabies in hospitals. FIGURE 472-1  Scabies burrows. Scabies mites create short, delicate, linear burrows within the superficial epidermis. Although burrows are pathognomonic for scabies, most have been altered by scratching or secondary bacterial infection. Scabies should be in the differential diagnosis for patients with pruritus and symmetric superficial, excoriated, papulovesicular skin lesions in characteristic locations, particularly if they have had direct and prolonged contact with an infested person. The diagnosis can be confirmed by microscopic examination of material scraped from bur­ rows. Burrows should be sought and unroofed with a sterile needle or scalpel blade, and the scrapings should be examined microscopically for mites, eggs, and fecal pellets. Examination of skin scrapings; biopsy specimens; material obtained by clear cellophane tape or cyanoacrylate adhesive lifted from lesions; dermatoscopic imaging of papulovesicular lesions; and microscopic inspection of clear cellophane tape lifted from lesions also may be diagnostic. In the absence of identifiable mites or eggs, a clinical diagnosis is based on a triad of pruritus, findings on physical examination, and an epidemiologic link. Unrelated skin dis­ eases are frequently misdiagnosed as scabies, particularly in presumed “outbreak” situations. Sarcoptes mites of other mammals may cause transient irritation, but they do not reside or reproduce in human hosts. In some Australian Aboriginal communities, household dogs may serve as reservoirs for human scabies mites. TREATMENT Scabies CHAPTER 472 The U.S. Food and Drug Administration (FDA) has approved four scabicides: permethrin, crotamiton, spinosad, and lindane. They are topical products and available by prescription only. Permethrin cream (5%) is less toxic than 1% lindane preparations and is effec­ tive against lindane-resistant infestations. In adults, scabicides are applied thinly but thoroughly from the jawline to toes after bathing, with careful application to interdigital spaces, the navel, and under the nails. and washed off 6–14 h later with soap and water. These products are relatively ineffective against scabies eggs, so a second round of treatment 1 week later is advisable. Ectoparasite Infestations and Arthropod Injuries Treating crusted scabies is difficult and requires repeated courses of both topical (permethrin) and oral (ivermectin) agents. Pre­ application of a keratolytic agent, such as 6% salicylic acid, will help debulk the crusts. Permethrin should be applied to the skin’s entire surface, including the scalp, face, and ears. Oral ivermectin is not FDA-approved for treating scabies but is approved to treat the nematodal diseases hookworm and strongyloidiasis. A single oral dose of ivermectin (200 μg/kg) is effective in healthy patients with common (noncrusted) scabies. Patients with crusted scabies require three to seven doses of ivermectin over 8–30 days, along with repeated applications of topical permethrin and possibly a keratolytic compound. Within 1 day of properly administered treatment, a scabies infes­ tation is considered noncommunicable, thereby permitting a patient to return to work, school, and other public activities. Nevertheless, remind patients that dead mites and their detritus may continue to produce the pruritic hypersensitivity dermatitis for several weeks. Unnecessary retreatment with topical agents, especially permethrin cream, may cause an irritant contact dermatitis. Topical emollients and antipruritic agents, menthol and methyl salicylate products, calamine lotion, and oral antihistamines relieve itching during treatment. Topical glucocorticoids may calm pruritus that lingers after effective treatment. To prevent reinfestations, bedding and clothing should be washed and dried on high heat or heat-pressed, and other environmental surfaces or potential sources of fomites should be cleaned. Household members and other close contacts of confirmed cases, even if asymptomatic, should be treated simulta­ neously to help prevent back-and-forth reinfestations. Scabies infestations often lead to secondary bacterial infections, usually with Staphylococcus aureus, Streptococcus pyogenes, or both. Consequences of superinfections include impetigo, cellulitis, inva­ sive bacterial infections, poststreptococcal glomerulonephritis (and subsequent kidney disease), and possibly acute rheumatic fever (and subsequent cardiac valvular disease). ■ ■CHIGGERS AND OTHER BITING MITES Chiggers are the larvae of trombiculid (harvest) mites that feed mostly on mice and other small vertebrates in grassy or brush-covered sites in tropical, subtropical, and (less frequently) temperate areas during warm months. They reside on low vegetation and attach themselves to passing vertebrate hosts. While feeding, larvae secrete proteolytic saliva that penetrates the epidermis, creating a tube-like invagination, called a stylostome, in the host’s skin. The stylostome allows the mite to imbibe tissue fluids. The saliva is highly antigenic and causes small (usually <1 cm in diameter) but exceptionally itchy papular, urticarial, or pustulovesicu­ lar lesions. In people already sensitized to salivary antigens, the papules develop within hours of attachment. While attached, chiggers appear as minute (~0.5 mm diameter) red dots on the skin. Generally, lesions have a hemorrhagic base and are slightly elevated, resembling purpuric papules seen in cutaneous small-vessel vasculitis. Chiggers remain on their host animals for several days before fall­ ing to the ground to complete the nonparasitic stages of their life cycle. However, in humans, the intense pruritus leads to scratching that invariably destroys the chigger before it completes feeding, although the itching and burning often persist for weeks. The rash is common on the ankles and along the belt line and in areas where circumferentially tight clothing obstructs the further wanderings of the mites. Topical repellents on one’s skin and insecticide-treated clothing are useful for preventing chigger bites. PART 14 Poisoning, Drug Overdose, and Envenomation Chiggers (primarily Leptotrombidium species) serve as vectors for intracellular rickettsial organisms in the genus Orientia that cause scrub typhus. Scrub typhus caused by Orientia tsutsugamushi was traditionally confined to the eastern half of Asia and the Indomalayan and Australasian regions. Their bites may be asymptomatic. Endemic foci of closely related Orientia species have recently been identified in southern Chile, East Africa, and the Arabian peninsula, where they cause scrub typhus-like illnesses. Additional areas of transmission will likely be found outside the usual endemic regions. Only larval trombi­ culids are predatory on mammals, and the larvae acquire their Orientia load from transovarial transmission from their mother mites. Many kinds of mites feed on peridomestic birds or rodents and become particularly bothersome when they invade homes and bite people. In North America, the northern fowl mite, chicken mite, tropical rat mite, and house mouse mite normally feed on poultry, other birds, and small mammals. After their natural hosts leave the nest or die, the mites disperse and may invade homes. Although the mites are rarely seen because of their small size, their bites can be painful and pruritic. House mouse mites (Liponyssoides sanguineus) serve as vectors for the agent of rickettsialpox, Rickettsia akari, an uncommon disease characterized by mild fevers, an eschar at the bite site, and a papulovesicular eruption. Rickettsialpox (Chap. 192) has been recognized mainly in large northern temperate urban areas. Once these environmental mites are confirmed as causing pruritic eruptions, they are best eliminated by excluding their animal hosts, removing their nests, and cleaning and treatment of the nesting area with appropriate acaricides. Pyemotes mites are external parasites of insect larvae and commonly occur in insect-infested products such as grain, straw, cheese, hay, and oak leaf galls. Their saliva contains a potent neurotoxin they use to immobilize their prey. The straw itch mite (Pyemotes tritici) occurs worldwide and is an occupational hazard for agriculture workers and others who work with dry plant material. Bites in humans are associ­ ated with pruritic rashes and may produce a unique dermatologic “comet sign” lesion—a paisley-shaped urticarial plaque (Fig. 472-2). The oak leaf gall mite (Pyemotes herfsi) has been associated with several outbreaks of dermatosis in the central and eastern United States. These mites feed on oak gall midges and periodic cicada eggs in oak trees, and their populations fluctuate widely each year based on host availability. In the late summer and fall, mites drop or are wind-blown from oak trees and may land on a person. Bites in people are usually reported on exposed surfaces, such as neck, face, arms, and upper torso. Intense itching is reported 10–16 h after the initial bite, which most people do not recall. Diagnosis of mite-induced dermatitis (including those caused by chiggers) relies on confirmation of the mite’s identity or elicitation of a history of exposure to the mite’s source. Unlike scabies mites that burrow and live in one’s skin, environmental mites do not reside on humans. Therefore, treatment of the patient with acaricides (e.g., per­ methrin) is discouraged. Oral antihistamines or topical steroids may reduce mite-induced pruritus temporarily. The mites that cause house dust–related allergic conditions neither bite nor infest humans. ■ ■TICK BITES AND TICK PARALYSIS Ticks attach superficially to skin and usually feed painlessly; blood is their only food. Their salivary secretions are biologically active, pre­ venting the host’s blood from coagulating while the tick feeds. Tick saliva can transmit various pathogens and can induce several “sterile reactions” in the host, such as a local inflammatory response, fevers, and tick-bite paralysis. The two main families of ticks are the hard ticks (Ixodidae) and soft ticks (Argasidae). Because no ticks are obli­ gate parasites on humans, all tick-borne diseases (bacterial, viral, and protozoal) are zoonotic. Generally, soft (argasid) ticks feed quickly, attaching to a host, com­ pleting a meal in <1 h, and then dropping off the host. Because of their rapid feeding habits, soft ticks are not carried widely by their vertebrate hosts. Soft tick–associated infections usually have fairly focal distribu­ tions. On humans, red macules may develop at the bite site. Some spe­ cies in Africa, the western United States, and Mexico produce painful hemorrhagic lesions. Hard (ixodid) ticks are much more common than soft ticks, and they transmit most tick-borne infections that are familiar to physicians, patients, and the public. Hard ticks attach to the host and feed for sev­ eral days to >1 week, with the exact duration depending upon the tick’s species and stage of development. At the site of hard-tick bites, small areas of induration, often purpuric, develop and may be surrounded by an erythematous rim. A necrotic eschar, called a tâche noire (“black spot”), occasionally develops. Long-lasting dermal nodules, called persistent tick-bite granulomas, occasionally appear where the host is bitten. The nodules are roughly 1–3 cm in diameter and may linger for months after the feeding tick has fallen off or been removed. The granulomas can be treated with injected intralesional glucocorticoids, by simple local excision, or simply left to resolve on their own over perhaps a year or more. Tick-induced fever, unassociated with any pathogen, is often accompanied by headache, nausea, and malaise but usually resolves ≤36 h after the tick is removed. Tick bites are also associated with a recently recognized allergic condition known as alpha-gal syndrome (AGS) or red meat allergy. This syndrome occurs in humans when exposure to tick saliva induces production of IgE antibodies that cross-react with a carbohydrate mol­ ecule, galactose-α-1,3-galactose (alpha-gal), found in muscle tissues of all mammals except humans, other apes, and Old World monkeys. In the United States, AGS is attributed to bites from the lone star tick (Amblyomma americanum). The geographic distribution of human cases closely aligns with that tick’s geographic range. In Australia and Europe, AGS is associated with Ixodes spp., and in Asia, it is associated with Haemaphysalis longicornis. It is important for individuals with AGS to avoid additional tick bites as this may prolong or worsen their allergic reactions. Tick paralysis, an acute ascending flaccid paralysis, is believed to be caused by one or more unidentified toxins in tick saliva that block neuromuscular transmission and decrease nerve conduction. This rare complication has been associated with >70 species of ticks. Although it has been reported worldwide, most cases occur in the Rocky Moun­ tain region, in northwestern United States and southwestern Canada, and along Australia’s eastern seaboard. In North America, dog and wood ticks (Dermacentor species) are most commonly implicated. Weakness begins several days after the tick attaches to the host. The Guillain-Barré-like paralysis starts in the lower legs and ascends sym­ metrically over several days. The paralysis may culminate in complete paralysis of the extremities and cranial nerves. Deep tendon reflexes are diminished or absent, but sensory examination and findings on lumbar puncture are typically normal. Diagnosis and treatment depend on finding the tick, which is often hidden beneath scalp hair. Removal FIGURE 472-2  Comet signs in individuals with known or suspected mite-bite reactions, likely due to Pyemotes species. Note central punctum at bite site, surrounded by edematous erythema. Linear or serpiginous “comet tails” emanate from the central site. Pyemotes-induced comet tails generally do not follow typical patterns of ascending lymphatic drainage. of the tick generally leads to improvement within a few hours and com­ plete recovery after several days, although the patient’s condition may continue to deteriorate for a full day. Failure to remove the tick may lead to dysarthria, dysphagia, and ultimately death from aspiration or respiratory paralysis. Removal of hard ticks during the first 24 h of attachment gener­ ally prevents transmission of the agents of Lyme disease, babesiosis, anaplasmosis, and ehrlichiosis, although tick-borne viruses may be transmitted more quickly. Ticks should be removed by traction with fine-tipped forceps placed firmly around the tick’s mouthparts where they enter the skin. Careful handling (to avoid rupture of ticks) and use of gloves may avert accidental contamination with pathogens contained in the tick’s body fluids. Attempting to induce the tick to detach by applying heat or occlusive compounds or dressings merely delays tick removal. After removal, the site of attachment should be disinfected. Tick mouthparts sometimes remain in the skin but gener­ ally are shed spontaneously within days without the need for surgical removal. Current guidelines from the Centers for Disease Control and Prevention suggest that, rather than awaiting the onset of erythema migrans, the results of tick testing, or seroconversion to antigens diagnostic for Lyme disease, physicians may appropriately administer prophylaxis—a one-time oral dose of doxycycline (200 mg) within 72 h of tick removal—to adult patients with bites thought to be from Ixodes scapularis (black-legged or deer ticks) in Lyme disease–endemic areas. Whereas antibiotic prophylaxis may help prevent Lyme disease, it is not recommended as a way to prevent other tick-borne infections. CHAPTER 472 Ectoparasite Infestations and Arthropod Injuries The Asian longhorned tick (Haemaphysalis longicornis) is a newly invasive species in the United States, first detected in the northeast­ ern states in 2017. Although it carries several pathogens to domestic animals, wildlife, and humans in its natural range (northeastern Asia), it has not yet been implicated in disease transmission in the United States. ■ ■LOUSE INFESTATION (PEDICULOSIS AND PTHIRIASIS) Three kinds of biting lice are obligate blood-feeding ectoparasites of human beings. These include the human head louse and the human body louse that represent distinct genetic clades of Pediculus humanus, and the pubic (“crab”) louse (Pthirus pubis). Nymphs and adults of these lice feed at least once a day, ingesting human blood exclusively, and they partition ecologically on the host. Head lice infest mainly the scalp and scalp hair; body lice infest clothing; and pubic lice infest mainly pubic hair. The saliva of lice produces a pruritic morbilliform or urticarial rash in some sensitized persons. Female head lice and pubic lice cement their eggs (nits) firmly to human hair, whereas female body lice cement their eggs to clothing, particularly to threads along cloth­ ing seams. After ~10 days of development within the egg, a nymph emerges. Empty eggs may remain affixed to hair for months thereafter. Body lice are acquired by direct contact with an infested person or their recently used clothing or bedding. These lice venture for just minutes to the skin to feed, but otherwise sequester on clothing. They generally succumb in ≤2 days if separated from their host. In developed countries, body lice are generally uncommon, found only on indigent persons who have relevant exposure and lack the wherewithal or desire to change or appropriately launder their clothing and bedding. Body lice are vectors for the agents of louse-borne (epidemic) typhus (Chap. 192), louse-borne relapsing fever (Chap. 190), and trench fever (Chap. 177). Body lice and their associated diseases may proliferate whenever societal upheaval and disasters limit access to clean clothes or laundry facilities. This scenario was exacerbated during the trench warfare of World War I, when troops often wore one uniform for weeks or months at a time. During damp, cold months, entrenched soldiers huddled together to stay warm, enabling body lice and their pathogens to spread easily from person to person. Infestations result in a postinflammatory hyperpigmentation and thickening of the skin known as vagabond’s disease. When inspecting a patient for signs of a body lice infestation, one must examine their clothing seams for nits and live lice. Head lice are acquired mainly by direct head-to-head contact rather than via fomites such as shared hats, caps, headgear, bed linens, and grooming implements. Worldwide, the prevalence of head lice varies widely as a function of age, geography, and cultural habits. In North America, the overall prevalence of head lice infestation is generally low, but most communities, irrespective of socioeconomic circum­ stances, experience episodic high-prevalence focal outbreaks among younger school-aged children. Although these events generally spare adults, they can create considerable distress among families in those communities. PART 14 Poisoning, Drug Overdose, and Envenomation An infested person generally hosts 10 or fewer head lice, but the nits, even when empty or nonviable, remain cemented to one’s scalp hairs as they grow. Thus, accumulated nits make it seem that a person has hundreds of head lice, even after successful treatment. Consequently, many schools retain unnecessarily onerous “no nit” policies for school attendance, even though a child has been treated successfully. Bite reactions appear as small, <1 cm diameter edematous pink wheals and are most evident along the posterior hairline. Pruritus, attributed to hypersensitivity to the louse’s saliva, leads to scratching, which may lead to secondary impetigo with S. aureus or S. pyogenes. Body lice are well known to transmit diseases, but can head lice (besides superficial secondary bacterial infections)? Several studies using polymerase chain reaction on freshly caught head lice have detected pathogenic bacteria, but clinical and epidemiologic data are generally interpreted to show that head lice are not natural vectors of any disease. On the other hand, experimental models suggest that head lice may have some competence as vectors for Rickettsia prowazekii (louse-borne typhus) and Bartonella quintana (trench fever). Indeed, sporadic reports indicate that cycles of trench fever are maintained in Ethiopia and elsewhere in Africa by head lice in the absence of body lice. Crab or pubic lice are found mostly on pubic hair and are transmit­ ted mainly by direct sexual contact. They also occur uncommonly on axillary or facial hair, including the eyelashes, as the result of either sexual or close nonsexual contact. Intensely pruritic, bluish mac­ ules <5 mm in diameter (maculae ceruleae) may develop at bite sites. Blepharitis commonly accompanies infestations of the eyelashes. Eye­ lash infestations in children should not be construed as incontrovert­ ible evidence of inappropriate sexual contact. Pediculosis is often suspected upon the detection of presumed nits to hairs or simply on the basis of an itchy scalp. Objects presumed to be louse eggs are often pseudo-nits composed of debris, flakes of dry skin, and hair-associated fungi. Hatched and dead eggs remain firmly affixed to scalp hair for months. Such relics are frequently misconstrued to be signs of an active louse infestation. Confirmation of a louse infestation, therefore, should rely on the discovery of a live louse. TREATMENT Louse Infestation Body lice usually are eliminated by bathing and by changing to new or properly laundered clothes. Fabric is effectively deloused by heat, such as in a clothes dryer at ≥55°C (≥131°F) for 30 min or by heatpressing. Emergency mass delousing may be warranted in congre­ gate settings during periods of civil strife and after natural disasters to reduce the high risk of disease transmission by body lice. Head lice and nits may be removed with a fine-toothed louse or nit comb, but this effort is time-consuming and often fails to eradi­ cate the lice. Treatment of newly identified, active infestations tra­ ditionally relies on a 10-min topical application of a FDA-approved 1% permethrin lotion or pyrethrin-based shampoo, which are available over the counter. Also FDA-approved, but requiring a pre­ scription, are 0.5% malathion lotion, 0.5% ivermectin lotion, and 0.9% spinosad suspension. These products do not kill viable nits, so a second application roughly 10 days later is required to clear newly hatched lice. Lice persisting after this treatment may be due to backand-forth reinfestations within a family, or the lice may be resistant to chemical treatment. Resistance to permethrin, malathion, and lindane is well documented, with less resistance associated with ivermectin and spinosad products. Although children infested by head lice—or those who simply have remnant nits from a previous infestation—are frequently isolated or excluded from school, this practice increasingly is considered to be unjustified, ineffective, and counterproductive. Pubic louse infestations are treated with topical pediculicides, except for eyelid infestations (pthiriasis palpebrum), which gener­ ally respond to a coating of petrolatum applied for 3–4 days. ■ ■MYIASIS (FLY INFESTATION) Myiasis refers to infestations by fly larvae (maggots) that invade living or necrotic tissues or body cavities and produce different clinical syn­ dromes, depending on the species of fly. In forested parts of Central and South America, larvae of the human botfly (Dermatobia hominis) produce furuncular (boil-like) dermal and subcutaneous nodules ≤3 cm in diameter. A gravid adult female botfly captures a mosquito or another bloodsucking insect and depos­ its her eggs on its abdomen. When the carrier insect attacks a human or another mammalian host (often cattle) several days later, the warmth and moisture of the host’s skin stimulate the eggs to hatch. The emerg­ ing larvae, ~1 mm long, promptly penetrate the skin. After 6–12 weeks of development, mature larvae emerge from the skin, drop to the ground, pupate, and finally metamorphose into adults. The African tumbu fly (Cordylobia anthropophaga, also called mango fly or mputsi fly) deposits its eggs on damp sand, leaf litter, dry­ ing laundry, or damp clothing contaminated by urine or sweat. Larvae hatch from eggs upon contact with a host’s body and penetrate the skin, producing boil-like lesions from which mature larvae emerge ~9–10 days later. Furuncular myiasis is suggested by uncomfortable lesions with a central breathing pore that emit bubbles when submerged in water. The sensation of movement within the patient’s skin may cause severe (and understandable) emotional distress (Fig. 472-3). Larvae that cause furuncular myiasis may be induced to emerge if the breathing pore is coated with petrolatum or another occlusive substance. Removal may be facilitated by injection of a local anesthetic (or sterile injectable saline) into the subjacent tissue to uplift the larva through the breathing pore. Surgical excision is sometimes necessary because upward-pointing spines of some species hold larvae firmly in place. Other fly larvae cause several forms of nonfuruncular myiasis. Lar­ vae of the horse botfly (Gasterophilus intestinalis) emerge from eggs that typically are laid on the hairs of a horse’s front legs. Direct contact with a person’s skin may cause the eggs to hatch and the new larvae to invade human skin. After penetrating human skin, these larvae rarely mature but instead may migrate for weeks in the dermis. The resulting pruritic and serpiginous eruption resembles cutaneous larva migrans caused by canine or feline hookworms (Chap. 238). Larvae of rabbit and rodent botflies (Cuterebra species) occasionally cause cutaneous or tracheopulmonary myiasis. Larvae of the sheep botfly, Oestrus ovis, and other flies responsible for furuncular and wound myiasis also may cause ophthalmomyiasis. Sequelae include nodules in the eyelid, retinal detachment, and destruction of the globe. FIGURE 472-3  Furuncular myiasis with larva of Cordylobia anthropophaga in the thigh of a teenage girl who recently returned from visiting relatives in East Africa (left). The central pore shows the respiratory elements of the embedded fly larva (right). Certain flies are attracted to blood and pus, laying their eggs on open or draining sores. Newly hatched larvae enter wounds or diseased skin. Larvae of several species of green bottle flies (Lucilia spp.) usually consume only necrotic tissues. Specially raised, sterile “surgical mag­ gots” are available as FDA-approved medical devices for debridement of chronic wounds, such as deeply infected diabetic ulcers. On the other hand, larvae of screwworm flies (Cochliomyia spp.) and flesh flies (Wohlfahrtia spp.) can invade viable tissues more deeply and cause large suppurating lesions. These can be extraordinarily harmful to domesticated herd animals. Larvae of the sheep botfly, Oestrus ovis, may cause nasal or external ophthalmomyiasis, involving tear ducts, eyelids, and conjunctivae. Larvae that infest decaying tissues may enter body cavities such as the mouth, nose, ears, sinuses, anus, vagina, and lower urinary tract, particularly in unconscious or otherwise debilitated patients. The con­ sequences range from harmless colonization to destruction of the nose, meningitis, and deafness. Treatment involves removal of maggots, surgical debridement of tissue, and treatment of secondary infections. Maggots are occasionally found in human feces, usually the result of a fly laying eggs on recently passed stools, and not as evidence of an intestinal maggot infestation. ■ ■PENTASTOMIASIS Pentastomids (tongue worms), an obscure type of crustacean, inhabit respiratory passages of reptiles and carnivorous mammals. Human infestation by Linguatula serrata is common in the Middle East and results from eating encysted larval stages in raw liver or lymph nodes of sheep and goats, which are true intermediate hosts for the tongue worms. In areas where raw sheep and goat liver are served, pentasto­ mid larvae migrate to the person’s nasopharynx and produce an acute self-limiting syndrome—known as halzoun in Lebanon and marrara in Sudan—characterized by rapid onset (within <12 h) of pain and itching of the throat and ears, coughing, hoarseness, dysphagia, and dyspnea. Severe edema may cause obstruction that requires tracheostomy. In addition, ocular invasion has been described. Diagnostic larvae mea­ suring ≤10 mm in length appear in copious nasal discharge or vomitus. Another type of tongue worm, Armillifer armillatus, infects people who consume its eggs in contaminated food or drink or after han­ dling the definitive host, the African python. Larvae encyst in various organs, usually the liver or peritoneum, but rarely cause symptoms. Cysts may require surgical removal as they enlarge during worm molting, but they usually are encountered as an incidental finding at CHAPTER 472 autopsy. Parasite-induced lesions may be misinterpreted as a malig­ nancy, with the correct diagnosis only confirmed histopathologically. Larva migrans–type syndromes caused by other pentastomes have been reported from Southeast Asia and Central America. Ectoparasite Infestations and Arthropod Injuries ■ ■LEECH INFESTATIONS Medically important leeches are annelid worms that attach to their hosts with chitinous cutting jaws and draw blood through muscular suckers. Medicinal leeches (Europe: Hirudo medicinalis and other Hirudo species; Asia: Hirudinaria manillensis; North America: Macrob­ della decora) are still used occasionally for medical purposes to reduce venous congestion in surgical flaps or replanted body parts. This prac­ tice has been complicated by intractable bleeding, wound infections, myonecrosis, and sepsis due to Aeromonas hydrophila, which colonizes the gullets of commercially available leeches. Ubiquitous aquatic leeches that parasitize fish, frogs, and turtles readily attach to human skin—most often the nasal mucosa—and avidly suck blood. Attachment is usually painless, and the leeches will detach themselves when satiated with a blood meal. Hirudin, a pow­ erful anticoagulant secreted by the leech, causes continued bleeding after the leech has detached. Healing of a leech-bite wound is slow, and secondary bacterial infections are not uncommon. Several kinds of aquatic leeches in Africa, Asia, and southern Europe can enter the mouth, nose, and genitourinary tract and attach to mucosal surfaces at sites as deep as the esophagus and trachea. Leeches may detach on exposure to gargled saline or may be removed by forceps or medical suction. Arboreal land leeches, which live amid rain forest vegetation, are attracted by heat and can drop from a leaf onto one’s skin. Externally attached leeches generally drop off after they have engorged, but removal is hastened by gentle scraping aside of the anterior and poste­ rior suckers the leech uses for attachment and feeding. Some authori­ ties dispute the wisdom of removing leeches with alcohol, salt, vinegar, insect repellent, a flame or heated instrument, or applications of other noxious substances. ■ ■SPIDER BITES All spiders are carnivores and most have venomous bites intended to immobilize and digest their prey. However, very few spiders are capable of biting humans, and the vast majority of putative spider bites have nothing to do with spiders. Of >45,000 recognized species of spiders, only about 60 are medically important to humans. In the United States, only recluse spiders (Loxosceles spp.) and widow spiders (Latrodectus spp.) are considered medically important. Most spider bites are painful but do not require medical attention. Identification of the offending spider is important because specific treatments exist. Except when the patient actually observes a spider bit­ ing them or fleeing from a site of sudden sharp pain, most acute tender noduloulcerative lesions reported as spider-bite reactions are due to an unrelated minor injury or caused by an acute bacterial infection, particularly by methicillin-resistant S. aureus (MRSA). Recluse Spider Bites and Necrotic Arachnidism  Brown recluse spiders (Loxosceles reclusa) live mainly in the southcentral United States and have close relatives in Central and South America, Africa, the Mediterranean basin, and the Middle East. Recluse spi­ ders are not aggressive toward humans and bite only if threatened or pressed against the skin. They generally live beneath rocks and logs or in caves and animal burrows. They invade homes and seek dark and undisturbed hiding spots in closets, garages, crawl spaces, and attics; under furniture and rubbish in storage rooms; and in folds of cloth­ ing. Despite their impressive abundance in some homes, these spiders rarely bite humans. Bites tend to occur while the victim is donning clothing in which the spider has hidden itself and are sustained primar­ ily on the hands, arms, neck, and lower abdomen. A brown recluse spider’s bite may cause minor injury with edema and erythema, and envenomation can cause severe necrosis of skin and subcutaneous tissue and, more rarely, systemic hemolysis. Initially, the bite is painless or may produce a stinging sensation. Within a few hours, the site becomes painful and sensitive to touch, with central induration surrounded by a pale ischemic zone that itself is encircled by a zone of erythema. In most cases, the lesion resolves without treatment in just a few days. In severe cases, systemics signs, such as fever, chills, weakness, headache, nausea, vomiting, myalgia, arthralgia, and leukocytosis, may soon develop. As the bite site evolves, the erythematous zone expands, and the center becomes hemorrhagic or necrotic with an overlying bulla. A black eschar forms and sloughs several weeks later, leaving an ulcer that eventually may create a depressed scar. Healing usually takes place in ≤3 months. Local complications include injury to nerves and secondary bacterial infection. Reports of deaths attributed to bites of North American brown recluse spiders have not been verified. PART 14 Poisoning, Drug Overdose, and Envenomation The Mediterranean recluse spider (Loxosceles rufescens) is a widely invasive species in urban areas of both the Old and New Worlds. The dorsal surfaces of L. rufescens and L. reclusa are adorned with a fiddleshaped pattern. L. rufescens is warier than L. reclusa, is less likely to bite, and rarely causes necrosis. Misidentification of this spider may create spurious reports of L. reclusa activity outside the known range of that species. TREATMENT Recluse Spider Bites Initial management includes rest, ice, compression, and elevation (RICE). Analgesics, antihistamines, antibiotics, and tetanus pro­ phylaxis should be administered if indicated. Early debridement or surgical excision of the wound without closure delays healing. Routine use of antibiotics or dapsone lacks utility. Patients should be monitored closely for signs of hemolysis, renal failure, and other systemic complications. Widow Spider Bites  The southern black widow spider (Latrodectus mactans) is common in the southeastern United States. Female bodies are ~1 cm in length, but the leg span may be ~5 cm across. Their bodies are shiny black with a red hourglass marking on the ventral abdomen. Other dangerous Latrodectus species occur elsewhere in temperate and subtropical parts of the world. The bites of the female widow spiders are notorious for their potent neurotoxins. Widow spiders spin their webs under stones, logs, plants, or rock piles and in dark spaces in barns, garages, and outhouses. Bites are most common in the summer and early autumn and occur when a web is disturbed or a spider is trapped or provoked. The initial bite is per­ ceived as a sharp pinprick or may go unnoticed. Fang-puncture marks are uncommon. Envenomation does not cause local tissue damage, and some persons experience no further symptoms. α-Latrotoxin, the most active component of the venom, is a neuro­ toxin. It binds irreversibly to presynaptic nerve terminals and causes release and eventual depletion of acetylcholine, norepinephrine, and other neurotransmitters from those terminals. Painful cramps may spread within 60 min from the bite site to large muscles of the extremi­ ties and trunk. Extreme abdominal pain and rigidity may resemble peritonitis, but the abdomen is not tender on palpation and surgery is not warranted. The pain begins to subside during the first 12 h but may recur over the next few days or weeks before resolving spontane­ ously. A wide range of other sequelae, largely neurologic, may include salivation, diaphoresis, vomiting, hypertension, tachycardia, labored breathing, anxiety, headache, weakness, fasciculations, paresthesia, hyperreflexia, urinary retention, uterine contractions, and premature labor. Rhabdomyolysis and renal failure have been reported, and respi­ ratory arrest, cerebral hemorrhage, or cardiac failure may end fatally, especially in very young, elderly, or debilitated persons. TREATMENT Widow Spider Bites Treatment consists of RICE and tetanus prophylaxis. Hypertension that does not respond to analgesics and antispasmodics (e.g., ben­ zodiazepines or methocarbamol) requires specific antihypertensive medication. The efficacy and safety of antivenin made from equine immunoglobulins are controversial for black widow bites because of potential anaphylaxis or serum sickness. Antivenins made from monoclonal antibodies are in development. Tarantulas and Other Spiders  Tarantulas are large hairy spiders of which 30 species are found in the United States, mainly in the South­ west. Several species of tarantulas have become popular household pets and are usually imported from Central or South America. Tarantulas bite people only when threatened and usually cause no more harm than a bee sting, but on occasion, the venom causes deep pain and swelling. Several species of tarantulas are covered with urticating hairs that are brushed off in the thousands when a threatened spider rubs its hind legs across its dorsal abdomen. These hairs can penetrate human skin and produce pruritic papules that may persist for weeks. Failure to wear gloves or to wash the hands after handling the Chilean Rose tarantula, a popular pet spider, has resulted in transfer of hairs to the eye with subsequent devastating ocular inflammation. Treatment of bites includes local washing and elevation of the bitten area, tetanus prophylaxis, and analgesic administration. Antihistamines and topical or systemic glucocorticoids are given for exposure to urticating hairs. Atrax robustus, a funnel-web spider of Australia, and Phoneutria species, the South American banana spiders, are among the world’s most dangerous spiders because of their aggressive behavior and potent neurotoxins. Envenomation by A. robustus causes a rapidly progres­ sive neuromotor syndrome that can be fatal within 2 h. The bite of a banana spider causes severe local pain followed by profound systemic symptoms and respiratory paralysis that can lead to death within 2–6 h. Specific antivenins for use after bites by each of these spiders are available. Yellow sac spiders (Cheiracanthium species) are common in homes worldwide. Their bites, though painful, generally lead to only minor erythema, edema, and pruritus. ■ ■SCORPION STINGS Scorpions are arachnids that feed on arthropods and other small animals. They paralyze their prey and defend themselves by inject­ ing venom from a stinger on the tip of the tail. Painful but relatively harmless scorpion stings need to be distinguished from the potentially lethal envenomations from about 30 of roughly 1000 known species, which cause several thousand deaths worldwide each year. Scorpions are nocturnal and remain hidden during the day in crevices or burrows or under wood, loose bark, or rocks. They occasionally enter houses and tents and may hide in shoes, clothing, or bedding. Scorpions sting humans only when threatened. Of approximately 40 scorpion species in the United States, only bark scorpions (Centruroides sculpturatus/C. exilicauda) in the South­ west produce venom that is potentially lethal to humans. This venom contains neurotoxins that cause sodium channels to remain open. Such envenomations usually are associated with little swelling, but prominent pain, paresthesia, and hyperesthesia can be accentuated by tapping on the affected area (the tap test). These symptoms soon spread to other locations; dysfunction of cranial nerves and hyperexcitability of skeletal muscles develop within hours. Patients present with rest­ lessness, blurred vision, abnormal eye movements, profuse salivation, lacrimation, rhinorrhea, slurred speech, difficulty in handling secre­ tions, diaphoresis, nausea, and vomiting. Muscle twitching, jerking, and shaking may be mistaken for a seizure. Complications include tachycardia, arrhythmias, hypertension, hyperthermia, rhabdomyoly­ sis, and acidosis. Symptoms progress to maximal severity in ~5 h and subside within a day or two, although pain and paresthesia can last for weeks. Fatal respiratory arrest is most common among young children and the elderly. Envenomations by Leiurus quinquestriatus in the Middle East and North Africa, by Mesobuthus tamulus in India, by Androctonus species along the Mediterranean littoral and in North Africa and the Middle East, and by Tityus serrulatus in Brazil cause massive release of endoge­ nous catecholamines with hypertensive crises, arrhythmias, pulmonary edema, and myocardial damage. Acute pancreatitis occurs with stings of Tityus trinitatis in Trinidad, and central nervous toxicity complicates stings of Parabuthus and Buthotus scorpions of South Africa. In Iran and adjacent countries, Hemiscorpius lepturus causes the most scorpion envenomations. Its stings are relatively asymptomatic at first, but its cytotoxic venom causes pain, hemolysis, and tissue necro­ sis after the first day. Systemic complications include hemoglobinuria and subsequent acute kidney injury. Stings of most other species cause immediate sharp local pain fol­ lowed by edema, ecchymosis, and a burning sensation. Symptoms typically resolve within a few hours, and skin does not slough. Allergic reactions to the venom may occur. TREATMENT Scorpion Stings Identification of the offending scorpion helps to determine the course of treatment. Stings of nonlethal species require at most ice packs, analgesics, or antihistamines. Because most victims experi­ ence only local discomfort, they can be managed at home with instructions to return to the emergency department if signs of cranial-nerve or neuromuscular dysfunction develop. Aggressive supportive care and judicious use of antivenom can reduce or elimi­ nate deaths from more severe envenomations. Keeping the patient calm and applying pressure dressings and cold packs to the sting site are measures that decrease the absorption of venom. A continu­ ous IV infusion of midazolam reduces the agitation and involuntary movements produced by scorpion stings. Treating people with neuromuscular symptoms with sedatives or opiates requires close monitoring due to potential respiratory compromise. Hyperten­ sion and pulmonary edema respond to nifedipine, nitroprusside, hydralazine, or prazosin. Dangerous bradydysrhythmia can be controlled with atropine. Commercially prepared antivenins are available in several coun­ tries for some of the most dangerous scorpion species. The FDA has approved equine-derived C. sculpturatus IgG F(ab’)2 antivenin. IV administration of antivenin rapidly reverses cranial-nerve dysfunc­ tion and muscular symptoms. ■ ■HYMENOPTERA STINGS Bees, wasps, hornets, yellow jackets, and ants (all of the insect order Hymenoptera) sting in defense or to subdue their prey. Their venoms contain a wide array of amines, peptides, and enzymes that cause local and systemic reactions. Although the toxic effect of multiple stings can be fatal to a human, nearly all of the ≥100 deaths due to hymenopteran stings in the United States each year result from type 1, immediate-type allergic reactions. Bee and Wasp Stings  The stinger of the honeybee (Apis mellifera) is unique in being barbed. The stinging apparatus and attached venom sac tear loose from the honeybee’s body, and muscular contractions of the venom sac continue to infuse venom into the skin. Other kinds of bees, ants, and wasps have smooth stinging mechanisms and can sting numerous times in succession. Generally, a person sustains just one sting from a bee or social wasp unless a nest was disturbed. African­ ized honeybees (now present in South and Central America and the southern and western United States) respond to minimal intrusions more aggressively. The sting of an Africanized bee contains less venom than that of its non-Africanized relatives, but victims tend to sustain far more stings and thus receive a far greater overall volume of venom. Most patients who report having sustained a “bee sting” are more likely to have encountered stinging wasps instead. The venoms of different kinds of hymenopterans are biochemically and immunologically distinct. Direct toxic effects are mediated by mixtures of low-molecular-weight compounds such as serotonin, hista­ mine, acetylcholine, and several kinins. Polypeptide toxins in honeybee venom include mellitin, which damages cell membranes; mast cell– degranulating protein, which causes histamine release; the neurotoxin apamin; and the anti-inflammatory compound adolapin. Enzymes in venom include hyaluronidase and phospholipases. There appears to be little cross-sensitization between the venoms of honeybees and wasps. CHAPTER 472 Ectoparasite Infestations and Arthropod Injuries Uncomplicated hymenopteran stings cause immediate pain, a wheal-and-flare reaction, and local edema, all of which usually subside in a few hours. Multiple stings can lead to vomiting, diarrhea, general­ ized edema, dyspnea, hypotension, and nonanaphylactic circulatory collapse. Rhabdomyolysis and intravascular hemolysis may cause renal failure. Death from the direct (nonallergic) effects of venom has fol­ lowed stings of several hundred honeybees. Stings to the tongue or mouth may induce life-threatening edema of the upper airways. Large local reactions accompanied by erythema, edema, warmth, and tenderness that spread ≥10 cm around the sting site over 1–2 days are not uncommon. These reactions may resemble bacterial cellulitis but are caused by hypersensitivity rather than by secondary infec­ tion. Such reactions tend to recur on subsequent exposure but are seldom accompanied by anaphylaxis and are not prevented by venom immunotherapy. An estimated 0.4–4.0% of the U.S. population exhibits clinical immediate-type hypersensitivity to hymenopteran stings, and 15% may have asymptomatic sensitization manifested by positive skin tests. Per­ sons who experience severe allergic reactions are likely to have similar or more severe reactions after subsequent stings by the same or closely related species. Mild anaphylactic reactions to insect stings, as to other causes, consist of nausea, abdominal cramping, generalized urticaria or angioedema, and flushing. Serious reactions, including upper airway edema, bronchospasm, hypotension, and shock, may be rapidly fatal. Severe reactions usually begin within 10 min of the sting and only rarely develop after 5 h. TREATMENT Bee and Wasp Stings Honeybee stingers embedded in the skin should be removed as soon as possible to limit the quantity of venom delivered. The stinger and venom sac may be scraped off with a blade, a fingernail, or the edge of a credit card or may be removed with forceps. The site should be cleansed and disinfected and ice packs applied to slow the spread of venom. Elevation of the affected site and administration of oral analgesics, oral antihistamines, and topical calamine lotion help relieve symptoms. Anaphylactic reactions to bee or wasp venom can be a lifethreatening emergency that requires prompt life-saving actions. If the individual carries a bee-sting kit, then a subcutaneous injec­ tion of epinephrine hydrochloride (0.3 mL of a 1:1000 dilution) should be considered, with treatment repeated every 20–30 min as necessary. A tourniquet may slow the spread of venom. The patient should be transferred to a hospital emergency room where treat­ ment for profound shock, if required, can be administered safely. Such treatment may entail the use of IV epinephrine and other vasopressors, intubation or provision of supplemental oxygen, fluid resuscitation, use of bronchodilators, and parenteral administration of antihistamines. Patients should be observed for 24 h for recurrent anaphylaxis, renal failure, or coagulopathy. Persons with a history of allergy to insect stings should carry an anaphylaxis kit with a preloaded syringe containing epinephrine for self-administration. These patients should seek medical attention immediately after using the kit. Prophylactic immunotherapy may greatly reduce the risk of lifethreatening reactions to bee and wasp stings. Repeated injections of purified venom produce a blocking IgG antibody response to venom and reduce the incidence of recurrent anaphylaxis. Hon­ eybee, wasp, and yellow jacket venoms are commercially available for desensitization and for skin testing. Results of skin tests and venom-specific radioallergosorbent tests (RASTs) aid in the selec­ tion of patients for immunotherapy and guide the design of such treatment. PART 14 Poisoning, Drug Overdose, and Envenomation ■ ■STINGING ANTS Stinging ants are an important medical problem in the United States. Imported fire ants (Solenopsis species) infest southern states from Texas to North Carolina, with colonies now established in California, New Mexico, Arizona, and Virginia. Slight disturbances of their mound nests have provoked massive outpourings of ants and as many as 10,000 stings on a single person. Elderly and immobile persons are at high risk for attacks when fire ants invade dwellings. Fire ants attach to skin with powerful mandibles and rotate their bodies while repeatedly injecting venom with posteriorly situated stingers. The alkaloid venom consists of cytotoxic and hemolytic piperidines and several proteins with enzymatic activity. The initial wheal-and-flare reaction, burning, and itching resolve in ~30 min, and a sterile pustule develops within 24 h. The pustule ulcerates over the next 48 h and then heals in ≥1 week. Large areas of erythema and edema lasting several days are not uncommon and, in extreme cases, may compress nerves and blood vessels. Anaphylaxis occurs in <2% of victims; seizures and mononeuritis have been reported. Stings are treated with ice packs, topical glucocorticoids, and oral antihistamines. Pustules should be cleansed and then covered with bandages and anti­ biotic ointment to prevent bacterial infection. Epinephrine administra­ tion and supportive measures are indicated for anaphylactic reactions. Fire ant whole-body extracts are available for skin testing and immu­ notherapy, which appear to lower the rate of anaphylactic reactions. European fire (red) ants (Myrmica rubra) have recently become pub­ lic health pests in the northeastern United States and southern Canada. The western United States is home to harvester ants (Pogonomyrmex species). The painful local reaction that follows harvester ant stings often extends to lymph nodes and may be accompanied by anaphy­ laxis. The bullet or conga ant (Paraponera clavata) of South America is known locally as hormiga veinticuatro (“24-hour ant”), a designation that refers to the 24 h of throbbing, excruciating pain following a sting that delivers the potent paralyzing neurotoxin poneratoxin. ■ ■DIPTERAN (FLY AND MOSQUITO) BITES In the process of feeding on vertebrate blood and tissue fluids, adults of certain fly species inflict painful bites, inject saliva that may cause vaso­ dilation and produce local allergic reactions, and may transmit diverse pathogenic agents. Bites of mosquitoes (culicids), tiny “no-see-um” midges (ceratopogonids), and sand flies (phlebotomines) typically produce a wheal and a pruritic papule. Small humpbacked black flies (simuliids) lacerate skin, resulting in a lesion with serosanguineous discharge that is often painful and pruritic. Regional lymphadenopathy, fever, or anaphylaxis occasionally ensues. The widely distributed deer­ flies and horseflies as well as the tsetse flies of Africa are stout flies that attack during the day and produce large and painful bleeding punctures. House flies (Musca domestica) do not consume blood but use rasping mouthparts to scarify skin and feed upon tissue fluids and salt. Beyond direct injury from bites of any kind of fly, risks include transmission of diverse pathogens and secondary bacterial infection of the lesion. TREATMENT Fly and Mosquito Bites Treatment of fly bites is symptom based. Topical application of antipruritic agents, glucocorticoids, or antiseptic lotions may relieve itching and pain. Allergic reactions may require oral antihista­ mines. Antibiotics may be necessary for the treatment of large bite wounds that become secondarily infected. ■ ■FLEA BITES Common human-biting fleas include the dog and cat fleas (Cteno­ cephalides species) and the rat flea (Xenopsylla cheopis), which infest their respective hosts and their nests and resting sites. Sensitized persons develop erythematous pruritic papules (papular urticaria) and occasionally vesicles and bacterial superinfection at the site of the bite. Symptom-based treatment consists of antihistamines, topical glucocor­ ticoids, and topical antipruritic agents. Flea infestations are eliminated by removal and treatment of animal nests, frequent cleaning of pet bedding, and application of contact and systemic insecticides to pets and the dwelling. Flea infestations in the home may be abated or prevented if pets are regularly treated with veterinary antiparasitic agents, insect growth regulators, or chitin inhibitors. Tunga penetrans, like other fleas, is a wingless, laterally flattened insect that feeds on blood. Also known as the chigoe flea, sand flea, or jigger (not to be confused with the chigger), it occurs in tropical regions of Africa and the Americas. Adult female chigoes live in sandy soil and burrow under the skin, usually between toes, under nails, or on the soles of bare feet. Gravid chigoes engorge on the host’s blood and grow from pinpoint to pea size during a 2-week interval. They produce lesions that resemble a white pustule with a central black depression and that may be pruritic or painful. Occasional complications include tetanus, bacterial infections, and autoamputation of toes (ainhum). Tungiasis is treated by removal of the intact flea with a sterile needle or scalpel, tetanus vaccination, and topical application of antibiotics. ■ ■HEMIPTERAN/HETEROPTERAN (TRUE BUG) BITES Most true bugs feed on plants, but some are predaceous or feed on blood. In order to feed or to defend themselves, they may inflict bites that produce allergic reactions and are sometimes painful. Bites of the cone-nose or “kissing bugs” (family Reduviidae) tend to occur at night and are painless. Reactions to such bites depend on prior sensitization and include tender and pruritic papules, vesicular or bullous lesions, extensive urticaria, fever, lymphadenopathy, and (rarely) anaphylaxis. Bug bites are treated with topical antipruritic agents or oral antihista­ mines. Persons with anaphylactic reactions to reduviid bites should keep an epinephrine kit available. Some reduviids transmit Trypano­ soma cruzi, the agent of New World trypanosomiasis (Chagas disease) (Chap. 234). The cosmopolitan and tropical bed bugs (Cimex lectularius and C. hemipterus) hide in crevices of mattresses, bed frames and other fur­ niture, walls, and picture frames and under loose wallpaper, actively seeking blood meals at night. These bugs are now a common pest in homes, dormitories, and hotels; on cruise ships; and even in medical facilities. Their bite is painless. Bites on persons without prior exposure to bedbugs may not be noticeable. Persons sensitized to bed bug saliva develop erythema, itching, and wheals around a central hemorrhagic punctum. Reactions may manifest within minutes of the bites, or they may be delayed for days or even a week or more. Bed bugs are not known to transmit pathogens. ■ ■CENTIPEDE BITES AND MILLIPEDE DERMATITIS Two groups of myriapods (“many-footed” arthropods) can harm humans. Centipedes, with one pair of legs per body segment, are fast-moving, aggressive, and carnivorous. They stun and kill their prey—usually other arthropods, earthworms, and rarely small verte­ brates—with a venomous bite. The fangs of centipedes of the genus Scolopendra can penetrate human skin and deliver a venom that produces intense burning pain, swelling, erythema, and sterile lym­ phangitis. Dizziness, nausea, and anxiety are described occasionally, and rhabdomyolysis and renal failure have been reported. Treatment includes washing of the site, application of cold dressings, oral analgesic administration or local lidocaine infiltration, and tetanus prophylaxis. Millipedes, with two pairs of legs per segment, are slow-moving, docile, and feed mostly on decaying plant materials. They do not bite, but some secrete defensive fluids that may burn and discolor human skin. Affected skin turns brown overnight and may blister and exfoli­ ate. Secretions in the eye cause intense pain and inflammation that can result in corneal ulcers and even blindness. Management includes irrigation with copious amounts of water or saline, use of analgesics, and local care of denuded skin. ■ ■CATERPILLAR STINGS AND DERMATITIS Caterpillars of several moth species are covered with hairs or spines that produce mechanical irritation and may contain or be coated with venom. Contact with these caterpillars or their hairs may lead to eru­ cism (a pruritic urticarial or papular rash) or caterpillar envenomation. The response typically consists of an immediate burning sensation followed by local swelling and erythema and occasionally by regional lymphadenopathy, nausea, vomiting, and headache. A rare reaction to a South American caterpillar, Lonomia obliqua, can cause disseminated coagulopathy and fatal hemorrhagic shock. Dermatitis is most often associated with caterpillars of io, puss, saddleback, and browntail moths in North America and with the oak processionary moth in Europe. Even contact with detached hairs of FIGURE 472-4  Real (left) versus delusional (right) infestation: comparable images of the lower backs of two young adults with multiple lesions. Left: A young woman developed innumerable widespread lesions during a camping ecotour near Manaus, Brazil. Note scattered clusters of irregularly spaced lesions, accompanied by dozens of single or isolated lesions, consistent with the semi-random feeding pattern of biting flies. Lesions appear to be in roughly the same stage of development, a feature indicating that they were acquired at roughly the same time. No lesions were present before her ecotour; none have arisen since. This patient scratches the intensely pruritic lesions and causes superficial erosions. Unexcoriated lesions are also present on her midback, where she cannot scratch. Right: A young man has innumerable widespread lesions that have accumulated for several years, with a few new lesions appearing several times a week. His lesions are in various stages of development (fresh, crusted, reepithelialized, pigmented, and scarred), a feature indicating a long-standing process. The lesions are distributed in a regular pattern consistent with periodic “excavations” to remove alleged parasites that he believes are crawling through his skin. Scarring is due to manipulations that create dermal ulcers rather than superficial excoriations and erosions. Parts of his upper midback, where he cannot scratch, are free of lesions. other caterpillars, such as gypsy moth larvae, can later produce eru­ cism. Spines may be deposited on tree trunks or drying laundry or may be airborne and cause irritation of the eyes and upper airways. Treat­ ment of caterpillar stings consists of repeated application of adhesive or cellophane tape to remove the hairs, which can then be identified microscopically. Local ice packs, topical glucocorticoids, and oral anti­ histamines relieve symptoms. Few adult moths cause human health problems. Adult yellowtail moths (Hylesia species), found mainly in coastal mangrove zones along the eastern coast of Central and South America, have bodies that are covered by fine hairs or setae. The hairs on the ventral surface can detach and, when in contact with human skin, cause an extremely pru­ ritic reaction called “Carapito itch.” This issue is especially problematic when the moths have population booms, creating swarms around coastal communities. ■ ■BEETLE VESICATION AND DERMATITIS Several families of beetles have independently developed the ability to produce chemically unrelated vesicating toxins. When disturbed, blister beetles (family Meloidae) exude cantharidin, a low-molecularweight toxin that produces thin-walled blisters (≤5 cm in diameter) 2–5 h after contact. The blisters are not painful or pruritic unless bro­ ken. They resolve without treatment in ≤10 days. Nephritis may follow unusually heavy cantharidin exposure. CHAPTER 472 The hemolymph of certain rove beetles (Paederus species, Staphylin­ idae family) contains pederin, a potent vesicant. When these beetles are crushed or brushed against the skin, the released fluid causes painful, red, flaccid bullae. These beetles occur worldwide but are most numer­ ous and problematic in parts of Africa (where they are called “Nairobi fly”) and southwestern Asia. Ocular lesions may develop after impact with flying beetles at night or unintentional transfer of the vesicant on the fingers. Treatment is rarely necessary, although ruptured blisters should be kept clean and bandaged. Ectoparasite Infestations and Arthropod Injuries Larvae of common carpet beetles are adorned with dense arrays of ornate hairs called hastisetae. Contact with these larvae or their setae results in delayed dermal reactions in sensitized individuals. The lesions are commonly mistaken for bites of bed bugs. ■ ■DELUSIONAL INFESTATIONS The groundless conviction that one is infested with arthropods or other parasites (Ekbom syndrome, delusory parasitosis, delusions of parasitosis, delusion of infestation, and perhaps Morgellons syndrome) is extremely difficult to treat and, unfortunately, is not uncommon (Fig. 472-4). Patients describe uncomfortable sensations of something moving in or on their skin. Excoriations and self-induced ulcerations typically accompany the pruritus, dysesthesias, and imaginary insect bites. Patients often believe that some invisible or as-yet-undescribed creatures are infesting their skin, clothing, homes, or environment in general. Frequently, patients submit as evidence of infestation specimens that consist of plant-feeding and nonbiting peridomestic arthropods, pieces of skin, vegetable matter, lint, and other inanimate detritus. In the evaluation of a patient with possible delusional parasit­ osis, it is imperative to rule out true infestations and bites by arthro­ pods, endocrinopathies, sensory disorders due to neuropathies, opiate and other drug use, environmental irritants (e.g., fiberglass threads), and other causes of tingling or prickling sensations. Frequently, such patients repeatedly seek medical consultations, resist alternative expla­ nations for their symptoms, and exacerbate their discomfort by selftreatment. Recent evidence suggests that high levels of central nervous system dopamine, endogenous or pharmaceutical, may promote these delusions. Long-term pharmacotherapy with pimozide or other psy­ chotropic agents has been more helpful than psychotherapy in treat­ ing this disorder. Patients with delusory parasitosis often develop the unshakeable conviction that they are infested by a previously unknown pathogen, while their personal lives, family support, and employment collapse around them. PART 14 Poisoning, Drug Overdose, and Envenomation Acknowledgment Richard J. Pollack contributed to this chapter in previous editions and some material from that chapter has been retained here. ■ ■FURTHER READING Amanzougaghene N et al: Where are we with human lice? A review of the current state of knowledge. Front Cell Infect Microbiol 21:9, Arlia LG, Morgan MS: A review of Sarcoptes scabiei: Past, present and future. Parasit Vectors 10:297, 2017. Goddard J: Infectious Diseases and Arthropods, 3rd ed. Totowa, NJ, Humana Press, 2018. Hinkle N: Ekbom syndrome: The challenge of “invisible bug” infesta­ tions. Annu Rev Entomol 55:77, 2010. Moraru GM, Goddard J II: The Goddard Guide to Arthropods of Medical Importance, 7th ed. Boca Raton, FL, CRC Press, 2019. Mullen G, Durden L: Medical and Veterinary Entomology, 3rd ed. London, Academic Press, 2019. Saucier JR: Arachnid envenomation. Emerg Med Clin North Am 22:405, 2004. Steen CJ et al: Insect sting reactions to bees, wasps, and ants. Int J Dermatol 44:91, 2005. Thomas C et al: Ectoparasites: Scabies. J Am Acad Dermatol 82:533, 2020. Vetter RS, Isbister GK: Medical aspects of spider bites. Annu Rev Entomol 53:409, 2008.