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Part 18: Poisoning, Drug Overdose, and Envenomation 472e-1

that low-level arsenic may cause neurodevelopmental delays in chil-

472e Heavy Metal Poisoning

Howard Hu
dren and possibly diabetes, but the evidence remains uneven.
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 cadmium-
induced bone toxicity that led to painful bone fractures. Modest expo-
Metals pose a significant threat to health through low-level environ- sures from environmental contamination have recently been associ-
mental as well as occupational exposures. One indication of their

CHAPTER 472e Heavy Metal Poisoning

ated in some studies with a lower bone density, a higher incidence
importance relative to other potential hazards is their ranking by the of fractures, and a faster decline in height in both men and women,
U.S. Agency for Toxic Substances and Disease Registry, which main- effects that may be related to cadmium’s calciuric effect on the kidney.
tains an updated list of all hazards present in toxic waste sites according There is some evidence for synergy between the adverse impacts of
to their prevalence and the severity of their toxicity. The first, second, cadmium and lead on kidney function. Environmental exposures have
third, and seventh hazards on the list are heavy metals: lead, mercury, also been linked to lower lung function (even after adjusting for smok-
arsenic, and cadmium, respectively ( ing cigarettes, which contain cadmium) as well as increased risk of
Specific information pertaining to each of these metals, including cardiovascular disease and mortality, stroke, and heart failure. Several
sources and metabolism, toxic effects produced, diagnosis, and the studies have also raised concerns that cadmium may be carcinogenic
appropriate treatment for poisoning, is summarized in Table 472e-1. and contribute to elevated risks of prostate, breast, and pancreatic
Metals are inhaled primarily as dusts and fumes (the latter defined cancer. Overall, this growing body of research indicates that cadmium
as tiny particles generated by combustion). Metal poisoning can also exposure may be contributing significantly to morbidity and mortality
result from exposure to vapors (e.g., mercury vapor in creating dental rates in the general population.
amalgams). When metals are ingested in contaminated food or drink Advances in our understanding of lead toxicity have recently ben-
or by hand-to-mouth activity (implicated especially in children), their efited by the development of K x-ray fluorescence (KXRF) instruments
gastrointestinal absorption varies greatly with the specific chemical for making safe in vivo measurements of lead levels in bone (which, in
form of the metal and the nutritional status of the host. Once a metal is turn, reflect cumulative exposure over many years, as opposed to blood
absorbed, blood is the main medium for its transport, with the precise lead levels, which mostly reflect recent exposure). Higher bone lead
kinetics dependent on diffusibility, protein binding, rates of biotrans- levels measured by KXRF have been linked to increased risk of hyper-
formation, availability of intracellular ligands, and other factors. Some tension and accelerated declines in cognition in both men and women
organs (e.g., bone, liver, and kidney) sequester metals in relatively high from an urban population. Upon reviewing these studies in conjunc-
concentrations for years. Most metals are excreted through renal clear- tion with other epidemiologic and toxicologic studies, a recent federal
ance and gastrointestinal excretion; some proportion is also excreted expert panel concluded that the impact of lead exposure on hyperten-
through salivation, perspiration, exhalation, lactation, skin exfoliation, sion and cognition in adults was causal. Prospective studies have also
and loss of hair and nails. The intrinsic stability of metals facilitates demonstrated that higher bone lead levels are a major risk factor for
tracing and measurement in biologic material, although the clinical increased cardiovascular morbidity and mortality rates in both com-
significance of the levels measured is not always clear. munity-based and occupational-exposed populations. Lead exposure
Some metals, such as copper and selenium, are essential to normal at community levels has also been recently associated with increased
metabolic function as trace elements (Chap. 96e) but are toxic at high risks of hearing loss, Parkinson’s disease, and amyotrophic lateral scle-
levels of exposure. Others, such as lead and mercury, are xenobiotic and rosis. With respect to pregnancy-associated risks, high maternal bone
theoretically are capable of exerting toxic effects at any level of expo- lead levels were found to predict lower birth weight, head circumfer-
sure. Indeed, much research is currently focused on the contribution of ence, birth length, and neurodevelopmental performance in offspring
low-level xenobiotic metal exposure to chronic diseases and to subtle by age 2 years. In a randomized trial, calcium supplementation (1200
changes in health that may have significant public health consequences. mg daily) was found to significantly reduce the mobilization of lead
Genetic factors, such as polymorphisms that encode for variant from maternal bone into blood during pregnancy.
enzymes with altered properties in terms of metal binding, transport, The toxicity of low-level organic mercury exposure (as manifested by
and effects, also may modify the impact of metals on health and thereby neurobehavioral performance) is of increasing concern based on stud-
account, at least in part, for individual susceptibility to metal effects. ies of the offspring of mothers who ingested mercury-contaminated
The most important component of treatment for metal toxicity is fish. With respect to whether the consumption of fish by women during
the termination of exposure. Chelating agents are used to bind met- pregnancy is good or bad for offspring neurodevelopment, balancing
als into stable cyclic compounds with relatively low toxicity and to the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs)
enhance their excretion. The principal chelating agents are dimer- in fish versus the adverse effects of mercury contamination in fish has
caprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid led to some confusion and inconsistency in public health recommenda-
(EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicilla- tions. Overall, it would appear that it would be best for pregnant women
mine; their specific use depends on the metal involved and the clinical to either limit fish consumption to those species known to be low in
circumstances. Activated charcoal does not bind metals and thus is of mercury contamination but high in omega-3-FAs (such as sardines or
limited usefulness in cases of acute metal ingestion. mackerel) or to avoid fish and obtain omega-3-FAs through supple-
In addition to the information provided in Table 472e-1, several ments or other dietary sources. Current evidence has not supported the
other aspects of exposure, toxicity, or management are worthy of recent contention that ethyl mercury, used as a preservative in multiuse
discussion with respect to the four most hazardous toxicants (arsenic, vaccines administered in early childhood, has played a significant role
cadmium, lead, and mercury). in causing neurodevelopmental problems such as autism. With regard
Arsenic, even at moderate levels of exposure, has been clearly linked to adults, there is conflicting evidence as to whether mercury exposure
with increased risks for cancer of the skin, bladder, renal pelvis, ureter, is associated with increased risk of hypertension and cardiovascular
kidney, liver, and lung. These risks appear to be modified by smoking, disease. At this point, conclusions cannot be drawn.
folate and selenium status, genetic traits (such as ability to methylate Heavy metals pose risks to health that are especially burden-
arsenic), and other factors. Studies in community-based populations some in selected parts of the world. For example, arsenic expo-
are beginning to demonstrate that arsenic exposure is a risk factor for sure from natural contamination of shallow tube wells inserted
increased coronary heart disease and stroke. Evidence is also emerging for drinking water is a major environmental problem for millions of
472e-2   TABLE 472e-1    Heavy Metals
Main Sources Metabolism Toxicity Diagnosis Treatment
Smelting and micro- Organic arsenic (arseno- Acute arsenic poisoning results in Nausea, vomiting, diarrhea, abdomi- If acute ingestion, ipecac
electronics industries; betaine, arsenocholine) necrosis of intestinal mucosa with nal pain, delirium, coma, seizures; to induce vomiting, gastric
wood preservatives, is ingested in seafood hemorrhagic gastroenteritis, fluid loss, garlicky odor on breath; hyperkera- lavage, activated charcoal
pesticides, herbicides, and fish, but is nontoxic; hypotension, delayed cardiomyopathy, tosis, hyperpigmentation, exfoliative with a cathartic. Supportive
fungicides; contami- inorganic arsenic is acute tubular necrosis, and hemolysis. dermatitis, and Mees’ lines (trans- care in ICU.
nant of deep-water readily absorbed (lung Chronic arsenic exposure causes dia- verse white striae of the fingernails); Dimercaprol 3–5 mg/kg IM
wells; folk remedies; and GI); sequesters in betes, vasospasm, peripheral vascular sensory and motor polyneuritis, q4h × 2 days; q6h × 1 day,
and coal; incineration liver, spleen, kidneys, insufficiency and gangrene, peripheral distal weakness. Radiopaque sign on then q12h × 10 days; alter-
of these products. lungs, and GI tract; neuropathy, and cancer of skin, lung, abdominal x-ray; ECG–QRS broaden- native: oral succimer.
residues persist in skin, liver (angiosarcoma), bladder, and ing, QT prolongation, ST depression,

hair, and nails; biometh- kidney. T-wave flattening; 24-h urinary

ylation results in detoxi- arsenic >67 μmol/d or 50 μg/d; (no
fication, but this process Lethal dose: 120–200 mg (adults); seafood × 24 h); if recent exposure,
saturates. 2 mg/kg (children). serum arsenic >0.9 μmol/L (7 μg/dL).
High arsenic in hair or nails.
Metal-plating, pig- Absorbed through Acute cadmium inhalation causes With inhalation: pleuritic chest pain, There is no effective treat-
Poisoning, Drug Overdose, and Envenomation

ment, smelting, ingestion or inhalation; pneumonitis after 4–24 h; acute inges- dyspnea, cyanosis, fever, tachycardia, ment for cadmium poison-
battery, and plastics bound by metallo- tion causes gastroenteritis. nausea, noncardiogenic pulmonary ing (chelation not useful;
industries; tobacco; thionein, filtered at Chronic exposure causes anosmia, edema. With ingestion: nausea, vom- dimercaprol can exacerbate
incineration of these the glomerulus, but yellowing of teeth, emphysema, minor iting, cramps, diarrhea. Bone pain, nephrotoxicity).
products; ingestion reabsorbed by proximal LFT elevations, microcytic hypochro- fractures with osteomalacia. If recent Avoidance of further expo-
of food that con- tubules (thus, poorly mic anemia unresponsive to iron exposure, serum cadmium >500 sure, supportive therapy,
centrates cadmium excreted). Biologic half- therapy, proteinuria, increased urinary nmol/L (5 μg/dL). Urinary cadmium vitamin D for osteomalacia.
(grains, cereals). life: 10–30 y. Binds cel- β2- microglobulin, calciuria, leading to >100 nmol/L (10 μg/g creatinine)
lular sulfhydryl groups, chronic renal failure, osteomalacia, and and/or urinary β2-microglobulin
competes with zinc, cal- fractures. Possible risks of cardiovascu- >750 μg/g creatinine (but urinary
cium for binding sites. lar disease and cancer. β2-microglobulin also increased in
Concentrates in liver other renal diseases such as pyelo-
and kidneys. nephritis).
Manufacturing of Absorbed through Acute exposure with blood lead levels Abdominal pain, irritability, lethargy, Identification and correc-
auto batteries, lead ingestion or inhalation; (BPb) of >60–80 μg/dL can cause anorexia, anemia, Fanconi’s syn- tion of exposure sources is
crystal, ceramics, organic lead (e.g., tet- impaired neurotransmission and drome, pyuria, azotemia in children critical. In some U.S. states,
fishing weights, etc.; raethyl lead) absorbed neuronal cell death (with central and with blood lead level (BPb) >80 μg/ screening and reporting
demolition or sand- dermally. In blood, peripheral nervous system effects); dL; may also see epiphyseal plate to local health boards of
ing of lead-painted 95–99% sequestered impaired hematopoiesis and renal “lead lines” on long bone x-rays. children with BPb >10 μg/
houses, bridges; in RBCs—thus, must tubular dysfunction. At higher levels Convulsions, coma at BPb >120 μg/ dL and workers with BPb
stained glass–making, measure lead in whole of exposure (e.g., BPb >80–120 μg/dL), dL. Noticeable neurodevelopmental >40 μg/dL is required. In the
plumbing, solder- blood (not serum). acute encephalopathy with convul- delays at BPb of 40–80 μg/dL; may highly exposed individual
ing; environmental Distributed widely in sions, coma, and death may occur. also see symptoms associated with with symptoms, chelation
exposure to paint soft tissue, with half-life Subclinical exposures in children (BPb higher BPb levels. Screening of all is recommended with oral
chips, house dust (in ~30 days; 15% of dose 25–60 μg/dL) are associated with ane- U.S. children when they begin to DMSA (succimer); if acutely
homes built <1975), sequestered in bone mia; mental retardation; and deficits crawl (~6 months) is recommended toxic, hospitalization and IV
firing ranges (from with half-life of >20 in language, motor function, balance, by the CDC; source identification or IM chelation with ethyl-
bullet dust), food or years. Excreted mostly in hearing, behavior, and school perfor- and intervention is begun if the enediamine tetraacetic acid
water from improperly urine, but also appears mance. Impairment of IQ appears to BPb >10 μg/dL. In adults, acute calcium disodium (CaEDTA)
glazed ceramics, lead in other fluids including occur at even lower levels of exposure exposure causes similar symptoms may be required, with the
pipes; contaminated breast milk. Interferes with no measurable threshold above as in children as well as headaches, addition of dimercaprol
herbal remedies, can- with mitochondrial the limit of detection in most assays arthralgias, myalgias, depression, to prevent worsening of
dies; exposure to the oxidative phosphoryla- of 1 μg/dL. impaired short-term memory, loss encephalopathy. It is uncer-
combustion of leaded tion, ATPases, calcium- In adults, chronic subclinical expo- of libido. Physical exam may reveal a tain whether children with
fuels. dependent messengers; sures (BPb >40 μg/dL) are associated “lead line” at the gingiva-tooth bor- asymptomatic lead exposure
enhances oxidation and with an increased risk of anemia, der, pallor, wrist drop, and cognitive (e.g., BPb 20–40 μg/dL) ben-
cell apoptosis. demyelinating peripheral neuropathy dysfunction (e.g., declines on the efit from chelation; a recent
(mainly motor), impairments of reac- mini-mental state exam); lab tests randomized trial showed
tion time and hearing, accelerated may reveal a normocytic, normo- no benefit. Correction of
declines in cognition, hypertension, chromic anemia, basophilic stippling, dietary deficiencies in iron,
ECG conduction delays, higher risk an elevated blood protoporphyrin calcium, magnesium, and
of cardiovascular disease and death, level (free erythrocyte or zinc), and zinc will lower lead absorp-
interstitial nephritis and chronic renal motor delays on nerve conduction. tion and may also improve
failure, diminished sperm counts, and U.S. OSHA requires regular testing of toxicity. Vitamin C is a weak
spontaneous abortions. lead-exposed workers with removal if but natural chelating agent.
BPb >40 μg/dL. New guidelines have Calcium supplements (1200
been proposed recommending that mg at bedtime) have been
BPb be maintained at <10 μg/dL, shown to lower blood lead
removal of workers if BPb >20 μg/dL, levels in pregnant women.
and monitoring of cumulative expo-
sure parameters.
  TABLE 472e-1    Heavy Metals (Continued) 472e-3
Main Sources Metabolism Toxicity Diagnosis Treatment
Metallic, mercurous, Elemental mercury (Hg) Acute inhalation of Hg vapor causes Chronic exposure to metallic mer- Treat acute ingestion of
and mercuric mer- is not well absorbed; pneumonitis and noncardiogenic pul- cury vapor produces a characteristic mercuric salts with induced
cury (Hg, Hg+, Hg2+) however, it will volatilize monary edema leading to death, CNS intention tremor and mercurial emesis or gastric lavage and
exposures occur into highly absorb- symptoms, and polyneuropathy. erethism: excitability, memory loss, polythiol resins (to bind mer-
in some chemical, able vapor. Inorganic Chronic high exposure causes CNS insomnia, timidity, and delirium cury in the GI tract). Chelate
metal-processing, mercury is absorbed toxicity (mercurial erethism; see (“mad as a hatter”). On neurobehav- with dimercaprol (up to 24
electrical-equipment, through the gut and Diagnosis); lower exposures impair ioral tests: decreased motor speed, mg/kg per day IM in divided
automotive indus- skin. Organic mercury is renal function, motor speed, memory, visual scanning, verbal and visual doses), DMSA (succimer), or

CHAPTER 472e Heavy Metal Poisoning

tries; they are also in well absorbed through coordination. memory, visuomotor coordination. penicillamine, with 5-day
thermometers, dental inhalation and inges- Children exposed to mercury in any courses separated by several
amalgams, batteries. tion. Elemental and Acute ingestion of inorganic mercury days of rest. If renal failure
causes gastroenteritis, the nephritic form may develop acrodynia (“pink
Mercury is dispersed organic mercury cross disease”): flushing, itching, swelling, occurs, treat with peritoneal
the blood-brain barrier syndrome, or acute renal failure, dialysis, hemodialysis, or
by waste incinera- hypertension, tachycardia, and cardio- tachycardia, hypertension, excessive
tion. Environmental and placenta. Mercury salivation or perspiration, irritability, extracorporeal regional com-
is excreted in urine and vascular collapse, with death at a dose plexing hemodialysis and
bacteria convert of 10–42 mg/kg. weakness, morbilliform rashes, des-
inorganic to organic feces and has a half-life quamation of palms and soles. succimer.
mercury, which then in blood of ~60 days; Ingestion of organic mercury causes Chronic inorganic mercury
however, deposits will gastroenteritis, arrhythmias, and Toxicity from elemental or inorganic
bioconcentrates up mercury exposure begins when poisoning is best treated
the aquatic food chain remain in the kidney lesions in the basal ganglia, gray with N-acetyl penicillamine.
and brain for years. matter, and cerebellum at doses blood levels >180 nmol/L (3.6 μg/dL)
to contaminate tuna, and urine levels >0.7 μmol/L
swordfish, and other Exposure to mercury >1.7 mg/kg.
stimulates the kidney (15 μg/dL). Exposures that ended
pelagic fish. High exposure during pregnancy years ago may result in a >20-μg
to produce metallothio- causes derangement of fetal neuronal
nein, which provides increase in 24-h urine after a 2-g
migration resulting in severe mental dose of succimer.
some detoxification retardation.
benefit. Mercury binds Organic mercury exposure is best
sulfhydryl groups and Mild exposures during pregnancy measured by levels in blood (if
interferes with a wide (from fish consumption) are associ- recent) or hair (if chronic); CNS toxic-
variety of critical enzy- ated with declines in neurobehavioral ity in children may derive from fetal
matic processes. performance in offspring. exposures associated with maternal
Dimethylmercury, a compound hair Hg >30 nmol/g (6 μg/g).
only found in research labs, is
“supertoxic”—a few drops of exposure
via skin absorption or inhaled vapor
can cause severe cerebellar degenera-
tion 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.

residents in parts of Bangladesh and Western India. Contamination masked, expressionless face; tremor; and psychiatric symptoms. With
was formerly considered only a problem with deep wells; however, the the introduction of methylcyclopentadienyl manganese tricarbonyl
geology of this region allows most residents only a few alternatives for (MMT) as a gasoline additive, there is concern for the toxic potential
potable drinking water. The combustion of leaded gasoline with result- of environmental manganese exposure. For example, a recent study
ing contamination of air and soil with lead oxide remains a problem in found a high prevalence of parkinsonian disorders in a community
some countries of Central Asia, Southeast Asia, Africa, and the Middle with risks proportionate to estimated manganese exposures emitted by
East. Populations living in the Arctic have been shown to have particu- local ferroalloy industries. Epidemiologic studies have also suggested
larly high exposures to mercury due to long-range transport patterns that manganese may interfere with early childhood neurodevelopment
that concentrate mercury in the polar regions, as well as the traditional in ways similar to that of lead. Nickel exposure induces an allergic
dependence of Arctic peoples on the consumption of fish and other response, and inhalation of nickel compounds with low aqueous
wildlife that bioconcentrate methylmercury. solubility (e.g., nickel subsulfide and nickel oxide) in occupational set-
A few additional metals deserve brief mention but are not covered tings is associated with an increased risk of lung cancer. Overexposure
in Table 472e-1 because of the relative rarity of their being clinically to selenium may cause local irritation of the respiratory system and
encountered or the uncertainty regarding their potential toxicities. eyes, gastrointestinal irritation, liver inflammation, loss of hair, depig-
Aluminum contributes to the encephalopathy in patients with severe mentation, and peripheral nerve damage. Workers exposed to certain
renal disease, who are undergoing dialysis (Chap. 424). High levels organic forms of tin (particularly trimethyl and triethyl derivatives)
of aluminum are found in the neurofibrillary tangles in the cerebral have developed psychomotor disturbances, including tremor, convul-
cortex and hippocampus of patients with Alzheimer’s disease, as well sions, hallucinations, and psychotic behavior.
as in the drinking water and soil of areas with an unusually high inci- Thallium, which is a component of some insecticides, metal alloys,
dence of Alzheimer’s. The experimental and epidemiologic evidence and fireworks, is absorbed through the skin as well as by ingestion and
for the aluminum–Alzheimer’s disease link remains relatively weak, inhalation. Severe poisoning follows a single ingested dose of >1 g or
however, and it cannot be concluded that aluminum is a causal agent >8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis
or a contributing factor in neurodegenerative disease. Hexavalent precede confusion, psychosis, organic brain syndrome, and coma.
chromium is corrosive and sensitizing. Workers in the chromate and Thallium is radiopaque. Induced emesis or gastric lavage is indicated
chrome pigment production industries have consistently had a greater within 4–6 h of acute ingestion; Prussian blue prevents absorption
risk of lung cancer. The introduction of cobalt chloride as a fortifier in and is given orally at 250 mg/kg in divided doses. Unlike other types
beer led to outbreaks of fatal cardiomyopathy among heavy consum- of metal poisoning, thallium poisoning may be less severe when acti-
ers. Occupational exposure (e.g., of miners, dry-battery manufacturers, vated charcoal is used to interrupt its enterohepatic circulation. Other
and arc welders) to manganese can cause a parkinsonian syndrome measures include forced diuresis, treatment with potassium chloride
within 1–2 years, including gait disorders; postural instability; a (which promotes renal excretion of thallium), and peritoneal dialysis.
or social relationships; and onset of illness during work with chemicals 473e-1

473e Poisoning and Drug Overdose

Mark B. Mycyk
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 stuff-
ing” (ingesting or concealing illicit drugs in a body cavity) should
be suspected. Relevant information may be available from family,
Poisoning refers to the development of dose-related adverse effects friends, paramedics, police, pharmacists, physicians, and employers,
following exposure to chemicals, drugs, or other xenobiotics. To para- who should be questioned regarding the patient’s habits, hobbies,
phrase Paracelsus, the dose makes the poison. In excessive amounts, behavioral changes, available medications, and antecedent events.
substances that are usually innocuous, such as oxygen and water, A search of clothes, belongings, and place of discovery may reveal a
can cause toxicity. Conversely, in small doses, substances commonly suicide note or a container of drugs or chemicals. The imprint code
regarded as poisons, such as arsenic and cyanide, can be consumed

CHAPTER 473e Poisoning and Drug Overdose

on pills and the label on chemical products may be used to identify the
without ill effect. Although most poisons have predictable dose- ingredients and potential toxicity of a suspected poison by consult-
related effects, individual responses to a given dose may vary because ing a reference text, a computerized database, the manufacturer, or
of genetic polymorphism, enzymatic induction or inhibition in the a regional poison information center (800-222-1222). Occupational
presence of other xenobiotics, or acquired tolerance. Poisoning may exposures require review of any available material safety data sheet
be local (e.g., skin, eyes, or lungs) or systemic depending on the route (MSDS) from the worksite. Because of increasing globalization, unfa-
of exposure, the chemical and physical properties of the poison, and miliar poisonings may result in local emergency department evalua-
its mechanism of action. The severity and reversibility of poisoning tion. Pharmaceuticals, industrial chemicals, or drugs of abuse from
also depend on the functional reserve of the individual or target organ, foreign countries may be identified with the assistance of a regional
which is influenced by age and preexisting disease. poison center or via the World Wide Web.
More than 5 million poison exposures occur in the United States The physical examination should focus initially on vital signs, the car-
each year. Most are acute, are accidental (unintentional), involve a diopulmonary system, and neurologic status. The neurologic examina-
single agent, occur in the home, result in minor or no toxicity, and tion should include documentation of neuromuscular abnormalities
involve children <6 years of age. Pharmaceuticals are involved in 47% such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, and
of exposures and in 84% of serious or fatal poisonings. Unintentional tremors. The patient should also be examined for evidence of trauma
exposures can result from the improper use of chemicals at work or and underlying illnesses. Focal neurologic findings are uncommon in
play; label misreading; product mislabeling; mistaken identification poisoning, and their presence should prompt evaluation for a struc-
of unlabeled chemicals; uninformed self-medication; and dosing tural central nervous system (CNS) lesion. Examination of the eyes
errors by nurses, pharmacists, physicians, parents, and the elderly. (for nystagmus and pupil size and reactivity), abdomen (for bowel
Excluding the recreational use of ethanol, attempted suicide (deliber- activity and bladder size), and skin (for burns, bullae, color, warmth,
ate self-harm) is the most common reported reason for intentional moisture, pressure sores, and puncture marks) may reveal findings of
poisoning. Recreational use of prescribed and over-the-counter drugs diagnostic value. When the history is unclear, all orifices should be
for psychotropic or euphoric effects (abuse) or excessive self-dosing examined for the presence of chemical burns and drug packets. The
(misuse) is increasingly common and may also result in unintentional odor of breath or vomitus and the color of nails, skin, or urine may
self-poisoning. provide important diagnostic clues.
About 20–25% of exposures require bedside health-professional The diagnosis of poisoning in cases of unknown etiology primarily
evaluation, and 5% of all exposures require hospitalization. Poisonings relies on pattern recognition. The first step is to assess the pulse, blood
account for 5–10% of all ambulance transports, emergency depart- pressure, respiratory rate, temperature, and neurologic status and to
ment visits, and intensive care unit admissions. Up to 30% of psychi- characterize the overall physiologic state as stimulated, depressed,
atric admissions are prompted by attempted suicide via overdosage. discordant, or normal (Table 473e-1). Obtaining a complete set of
Overall, the mortality rate is low: <1% of all exposures. It is much vital signs and reassessing them frequently are critical. Measuring core
higher (1–2%) among hospitalized patients with intentional (sui- temperature is especially important, even in difficult or combative
cidal) overdose, who account for the majority of serious poisonings. patients, since temperature elevation is the most reliable prognos-
Acetaminophen is the pharmaceutical agent most often implicated in ticator of poor outcome in poisoning or drug withdrawal. The next
fatal poisoning. Overall, carbon monoxide is the leading cause of death step is to consider the underlying causes of the physiologic state and
from poisoning, but this prominence is not reflected in hospital or poi- to attempt to identify a pathophysiologic pattern or toxic syndrome
son center statistics because patients with such poisoning are typically (toxidrome) based on the observed findings. Assessing the severity of
dead when discovered and are referred directly to medical examiners. physiologic derangements (Table 473e-2) is useful in this regard and
also for monitoring the clinical course and response to treatment. The
DIAGNOSIS final step is to attempt to identify the particular agent involved by
looking for unique or relatively poison-specific physical or ancillary
Although poisoning can mimic other illnesses, the correct diagnosis test abnormalities. Distinguishing among toxidromes on the basis of
can usually be established by the history, physical examination, rou- the physiologic state is summarized next.
tine and toxicologic laboratory evaluations, and characteristic clinical
course. The Stimulated Physiologic State  Increased pulse, blood pressure, respi-
ratory rate, temperature, and neuromuscular activity characterize the
HISTORY stimulated physiologic state, which can reflect sympathetic, antimusca-
The history should include the time, route, duration, and circum- rinic (anticholinergic), or hallucinogen poisoning or drug withdrawal
stances (location, surrounding events, and intent) of exposure; the (Table 473e-1). Other features are noted in (Table 473e-2). Mydriasis,
name and amount of each drug, chemical, or ingredient involved; the a characteristic feature of all stimulants, is most marked in antimus-
time of onset, nature, and severity of symptoms; the time and type of carinic (anticholinergic) poisoning since pupillary reactivity relies on
first-aid measures provided; and the medical and psychiatric history. muscarinic control. In sympathetic poisoning (e.g., due to cocaine),
In many cases the patient is confused, comatose, unaware of an pupils are also enlarged, but some reactivity to light remains. The
exposure, or unable or unwilling to admit to one. Suspicious circum- antimuscarinic (anticholinergic) toxidrome is also distinguished by
stances include unexplained sudden illness in a previously healthy hot, dry, flushed skin; decreased bowel sounds; and urinary reten-
person or a group of healthy people; a history of psychiatric problems tion. Other stimulant syndromes increase sympathetic activity and
(particularly depression); recent changes in health, economic status, cause diaphoresis, pallor, and increased bowel activity with varying
473e-2   Table 473e-1    Differential Diagnosis of Poisoning Based on Physiologic State
Stimulated Depressed Discordant Normal
Sympathetics Sympatholytics Asphyxiants Nontoxic exposure
Sympathomimetics α1-Adrenergic antagonists Cytochrome oxidase inhibitors Psychogenic illness
Ergot alkaloids α2-Adrenergic agonists Inert gases “Toxic time-bombs”
Methylxanthines ACE inhibitors Irritant gases Slow absorption
Monoamine oxidase inhibitors Angiotensin receptor blockers Methemoglobin inducers Anticholinergics
Thyroid hormones Antipsychotics Oxidative phosphorylation inhibitors Carbamazepine
Anticholinergics β-Adrenergic blockers AGMA inducers Concretion formers
Antihistamines Calcium channel blockers Alcohol (ketoacidosis) Extended-release phenytoin sodium
Antiparkinsonian agents Cardiac glycosides Ethylene glycol capsules (Dilantin Kapseals)

Antipsychotics Cyclic antidepressants Iron Drug packets

Antispasmodics Cholinergics Methanol Enteric-coated pills
Belladonna alkaloids Acetylcholinesterase inhibitors Salicylate Diphenoxylate-atropine (Lomotil)
Cyclic antidepressants Muscarinic agonists Toluene Opioids
Mushrooms and plants Nicotinic agonists CNS syndromes Salicylates
Sustained-release pills
Poisoning, Drug Overdose, and Envenomation

Hallucinogens Opioids Extrapyramidal reactions

Cannabinoids (marijuana) Analgesics Hydrocarbon inhalation Valproate
LSD and analogues GI antispasmodics Isoniazid Slow distribution
Mescaline and analogues Heroin Lithium Cardiac glycosides
Mushrooms Sedative-hypnotics Neuroleptic malignant syndrome Lithium
Phencyclidine and analogues Alcohols Serotonin syndrome Metals
Withdrawal syndromes Anticonvulsants Strychnine Salicylate
Barbiturates Barbiturates Membrane-active agents Valproate
Benzodiazepines Benzodiazepines Amantadine Toxic metabolite
Ethanol GABA precursors Antiarrhythmics Acetaminophen
Opioids Muscle relaxants Antihistamines Carbon tetrachloride
Sedative-hypnotics Other agents Antipsychotics Cyanogenic glycosides
Sympatholytics GHB products Carbamazepine Ethylene glycol
Cyclic antidepressants Methanol
Local anesthetics Methemoglobin inducers
Opioids (some) Mushroom toxins
Orphenadrine Organophosphate insecticides
Quinoline antimalarials Paraquat
Metabolism disruptors
Antineoplastic agents
Antiviral agents
Hypoglycemic agents
Immunosuppressive agents
MAO inhibitors
Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyrate; GI, gastro-
intestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase.

  Table 473e-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
degrees of nausea, vomiting, abnormal distress, and occasionally time-bomb exposure be excluded and the time since exposure exceed 473e-3
diarrhea. The absolute and relative degree of vital-sign changes and the longest known or predicted interval between exposure and peak
neuromuscular hyperactivity can help distinguish among stimulant toxicity. Psychogenic illness (fear of being poisoned, mass hysteria)
toxidromes. Since sympathetics stimulate the peripheral nervous sys- may also follow a nontoxic exposure and should be considered when
tem more directly than do hallucinogens or drug withdrawal, mark- symptoms are inconsistent with exposure history. Anxiety reactions
edly increased vital signs and organ ischemia suggest sympathetic resulting from a nontoxic exposure can cause mild physiologic stimu-
poisoning. Findings helpful in suggesting the particular drug or class lation (Table 473e-2) and be indistinguishable from toxicologic causes
causing physiologic stimulation include reflex bradycardia from selec- without ancillary testing or a suitable period of observation.
tive α-adrenergic stimulants (e.g., decongestants), hypotension from
selective β-adrenergic stimulants (e.g., asthma therapeutics), limb LABORATORY ASSESSMENT
ischemia from ergot alkaloids, rotatory nystagmus from phencyclidine Laboratory assessment may be helpful in the differential diagnosis.

CHAPTER 473e Poisoning and Drug Overdose

and ketamine (the only physiologic stimulants that cause this finding), Increased AGMA is most common in advanced methanol, ethylene
and delayed cardiac conduction from high doses of cocaine and some glycol, and salicylate intoxication but can occur with any poisoning
anticholinergic agents (e.g., antihistamines, cyclic antidepressants, and that results in hepatic, renal, or respiratory failure; seizures; or shock.
antipsychotics). Seizures suggest a sympathetic etiology, an anticho- The serum lactate concentration is more commonly low (less than
linergic agent with membrane-active properties (e.g., cyclic antide- the anion gap) in the former and high (nearly equal to the anion gap)
pressants, orphenadrine, phenothiazines), or a withdrawal syndrome. in the latter. An abnormally low anion gap can be due to elevated
Close attention to core temperature is critical in patients with grade blood levels of bromide, calcium, iodine, lithium, or magnesium. An
4 physiologic stimulation (Table 473e-2). increased osmolal gap—a difference of >10 mmol/L between serum
osmolality (measured by freezing-point depression) and osmolality cal-
The Depressed Physiologic State  Decreased pulse, blood pressure, respi- culated from serum sodium, glucose, and blood urea nitrogen levels—
ratory rate, temperature, and neuromuscular activity are indicative of suggests the presence of a low-molecular-weight solute such as
the depressed physiologic state caused by “functional” sympatholytics acetone; an alcohol (benzyl, ethanol, isopropanol, methanol); a glycol
(agents that decrease cardiac function and vascular tone as well as sym- (diethylene, ethylene, propylene); ether (ethyl, glycol); or an “unmea-
pathetic activity), cholinergic (muscarinic and nicotinic) agents, opi- sured” cation (calcium, magnesium) or sugar (glycerol, mannitol, sor-
oids, and sedative-hypnotic γ-aminobutyric acid (GABA)-ergic agents bitol). Ketosis suggests acetone, isopropyl alcohol, salicylate poisoning,
(Table 473e-1 and 473e-2). Miosis is also common and is most pro- or alcoholic ketoacidosis. Hypoglycemia may be due to poisoning with
nounced in opioid and cholinergic poisoning. Miosis is distinguished β-adrenergic blockers, ethanol, insulin, oral hypoglycemic agents, qui-
from other depressant syndromes by muscarinic and nicotinic signs nine, and salicylates, whereas hyperglycemia can occur in poisoning
and symptoms (Table 473e-1). Pronounced cardiovascular depres- with acetone, β-adrenergic agonists, caffeine, calcium channel block-
sion in the absence of significant CNS depression suggests a direct or ers, iron, theophylline, or N-3-pyridylmethyl-N′-p-nitrophenylurea
peripherally acting sympatholytic. In contrast, in opioid and sedative- (PNU [Vacor]). Hypokalemia can be caused by barium, β-adrenergic
hypnotic poisoning, vital-sign changes are secondary to depression of agonists, caffeine, diuretics, theophylline, or toluene; hyperkalemia
CNS cardiovascular and respiratory centers (or consequent hypox- suggests poisoning with an α-adrenergic agonist, a β-adrenergic
emia), and significant abnormalities in these parameters do not occur blocker, cardiac glycosides, or fluoride. Hypocalcemia may be seen in
until there is a marked decrease in the level of consciousness (grade 3 ethylene glycol, fluoride, and oxalate poisoning.
or 4 physiologic depression; [Table 473e-2]). Other clues that suggest The electrocardiogram (ECG) can be useful for rapid diagnostic pur-
the cause of physiologic depression include cardiac arrhythmias and poses. Bradycardia and atrioventricular block may occur in patients
conduction disturbances (due to antiarrhythmics, β-adrenergic antag- poisoned by α-adrenergic agonists, antiarrhythmic agents, beta block-
onists, calcium channel blockers, digitalis glycosides, propoxyphene, ers, calcium channel blockers, cholinergic agents (carbamate and
and cyclic antidepressants), mydriasis (due to tricyclic antidepres- organophosphate insecticides), cardiac glycosides, lithium, or tricyclic
sants, some antiarrhythmics, meperidine, and diphenoxylate-atropine antidepressants. QRS- and QT-interval prolongation may be caused
[Lomotil]), nystagmus (due to sedative-hypnotics), and seizures (due by hyperkalemia, various antidepressants, and other membrane-active
to cholinergic agents, propoxyphene, and cyclic antidepressants). drugs (Table 473e-1). Ventricular tachyarrhythmias may be seen in
poisoning with cardiac glycosides, fluorides, membrane-active drugs,
The Discordant Physiologic State  The discordant physiologic state is
methylxanthines, sympathomimetics, antidepressants, and agents that
characterized by mixed vital-sign and neuromuscular abnormalities,
cause hyperkalemia or potentiate the effects of endogenous catechol-
as observed in poisoning by asphyxiants, CNS syndromes, membrane-
amines (e.g., chloral hydrate, aliphatic and halogenated hydrocarbons).
active agents, and anion-gap metabolic acidosis (AGMA) inducers
Radiologic studies may occasionally be useful. Pulmonary edema
(Table 473e-1). In these conditions, manifestations of physiologic
(adult respiratory distress syndrome (ARDS) can be caused by poison-
stimulation and physiologic depression occur together or at different
ing with carbon monoxide, cyanide, an opioid, paraquat, phencycli-
times during the clinical course. For example, membrane-active agents
dine, a sedative-hypnotic, or salicylate; by inhalation of irritant gases,
can cause simultaneous coma, seizures, hypotension, and tachyar-
fumes, or vapors (acids and alkali, ammonia, aldehydes, chlorine,
rhythmias. Alternatively, vital signs may be normal while the patient
hydrogen sulfide, isocyanates, metal oxides, mercury, phosgene, poly-
has an altered mental status or is obviously sick or clearly symptom-
mers); or by prolonged anoxia, hyperthermia, or shock. Aspiration
atic. Early, pronounced vital-sign and mental-status changes suggest
pneumonia is common in patients with coma, seizures, and petroleum
asphyxiant or membrane-active agent poisoning; the lack of such
distillate aspiration. The presence of radiopaque densities on abdomi-
abnormalities suggests an AGMA inducer; and marked neuromuscu-
nal x-rays suggests the ingestion of calcium salts, chloral hydrate,
lar dysfunction without significant vital-sign abnormalities suggests a
chlorinated hydrocarbons, heavy metals, illicit drug packets, iodinated
CNS syndrome.
compounds, potassium salts, enteric-coated tablets, or salicylates.
The Normal Physiologic State  A normal physiologic status and physical Toxicologic analysis of urine and blood (and occasionally of gas-
examination may be due to a nontoxic exposure, psychogenic illness, tric contents and chemical samples) can sometimes confirm or rule
or poisoning by “toxic time-bombs”: agents that are slowly absorbed, out suspected poisoning. Interpretation of laboratory data requires
are slowly distributed to their sites of action, require metabolic activa- knowledge of the qualitative and quantitative tests used for screening
tion, or disrupt metabolic processes (Table 473e-1). Because so many and confirmation (enzyme-multiplied, fluorescence polarization, and
medications have now been reformulated into a once-a-day prepara- radio-immunoassays; colorimetric and fluorometric assays; thin-layer,
tions for the patient’s convenience and adherence, toxic time-bombs gas-liquid, or high-performance liquid chromatography; gas chro-
are increasingly common. Diagnosing a nontoxic exposure requires matography; mass spectrometry), their sensitivity (limit of detection)
that the identity of the exposure agent be known or that a toxic and specificity, the preferred biologic specimen for analysis, and the
473e-4 optimal time of specimen sampling. Personal communication with   Table 473e-3    Fundamentals of Poisoning Management
the hospital laboratory is essential to an understanding of institutional
Supportive Care
testing capabilities and limitations.
Rapid qualitative hospital-based urine tests for drugs of abuse Airway protection Treatment of seizures
are only screening tests that cannot confirm the exact identity of the Oxygenation/ventilation Correction of temperature abnormalities
detected substance and should not be considered diagnostic or used Treatment of arrhythmias Correction of metabolic derangements
for forensic purposes: False-positive and false-negative results are com- Hemodynamic support Prevention of secondary complications
mon. A positive screen may result from other pharmaceuticals that Prevention of Further Poison Absorption
interfere with laboratory analysis (e.g., fluoroquinolones commonly
Gastrointestinal decontamination Decontamination of other sites
cause “false-positive” opiate screens). Confirmatory testing with gas
chromatography/mass spectrometry can be requested, but it often Gastric lavage Eye decontamination
takes weeks to obtain a reported result. A negative screening result may Activated charcoal Skin decontamination
mean that the responsible substance is not detectable by the test used or Whole-bowel irrigation Body cavity evacuation

that its concentration is too low for detection at the time of sampling. Dilution
For instance, recent new drugs of abuse that often result in emergency Endoscopic/surgical removal
department evaluation for unexpected complications, such as synthetic
Enhancement of Poison Elimination
cannabinoids (spice), cathinones (bath salts), and opiate substitutes
Multiple-dose activated charcoal Extracorporeal removal
(kratom), are not detectable by hospital-based tests. In cases where
administration Hemodialysis
a drug concentration is too low to be detected early during clinical
Poisoning, Drug Overdose, and Envenomation

Alteration of urinary pH
evaluation, repeating the test at a later time may yield a positive result. Hemoperfusion
Patients symptomatic from drugs of abuse often require immediate Chelation Hemofiltration
management based on the history, physical examination, and observed Plasmapheresis
toxidrome without laboratory confirmation (e.g., apnea from opioid Exchange transfusion
intoxication). When the patient is asymptomatic or when the clinical
Hyperbaric oxygenation
picture is consistent with the reported history, qualitative screening
is neither clinically useful nor cost-effective. Thus, qualitative drug Administration of Antidotes
screens are of greatest value for the evaluation of patients with severe or Neutralization by antibodies Metabolic antagonism
unexplained toxicities, such as coma, seizures, cardiovascular instabil- Neutralization by chemical binding Physiologic antagonism
ity, metabolic or respiratory acidosis, and nonsinus cardiac rhythms. Prevention of Reexposure
In contrast to qualitative drug screens, quantitative serum tests are Adult education Notification of regulatory agencies
useful for evaluation of patients poisoned with acetaminophen (Chap.
Child-proofing Psychiatric referral
361), alcohols (including ethylene glycol and methanol), anticonvul-
sants, barbiturates, digoxin, heavy metals, iron, lithium, salicylate, and
theophylline as well as for the presence of carboxyhemoglobin and
methemoglobin. The serum concentration in these cases guides clinical When an accurate history is not obtainable and a poison causing
management, and results are often available within an hour. delayed toxicity (i.e., a toxic time-bomb) or irreversible damage is
The response to antidotes is sometimes useful for diagnostic pur- suspected, blood and urine should be sent for appropriate toxico-
poses. Resolution of altered mental status and abnormal vital signs logic screening and quantitative analysis. During poison absorption
within minutes of IV administration of dextrose, naloxone, or fluma- and distribution, blood levels may be greater than those in tissue
zenil is virtually diagnostic of hypoglycemia, opioid poisoning, and and may not correlate with toxicity. However, high blood levels
benzodiazepine intoxication, respectively. The prompt reversal of of agents whose metabolites are more toxic than the parent com-
dystonic (extrapyramidal) signs and symptoms following an IV dose of pound (acetaminophen, ethylene glycol, or methanol) may indicate
benztropine or diphenhydramine confirms a drug etiology. Although the need for additional interventions (antidotes, dialysis). Most
complete reversal of both central and peripheral manifestations of patients who remain asymptomatic or who become asymptomatic
anticholinergic poisoning by physostigmine is diagnostic of this con- 6 h after ingestion are unlikely to develop subsequent toxicity and
dition, physostigmine may cause some arousal in patients with CNS can be discharged safely. Longer observation will be necessary for
depression of any etiology. 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
TREATMENT Poisoning and Drug Overdose begin sooner, peak later, and last longer than they do after a thera-
GENERAL PRINCIPLES peutic dose. A drug’s published pharmacokinetic profile in standard
Treatment goals include support of vital signs, prevention of fur- references such as the Physician’s Desk Reference (PDR) is usually
ther poison absorption (decontamination), enhancement of poison different from its toxicokinetic profile in overdose. Resuscitation
elimination, administration of specific antidotes, and prevention and stabilization are the first priority. Symptomatic patients should
of reexposure (Table 473e-3). Specific treatment depends on the have an IV line placed and should undergo oxygen saturation deter-
identity of the poison, the route and amount of exposure, the time mination, cardiac monitoring, and continuous observation. Baseline
of presentation relative to the time of exposure, and the severity of laboratory, ECG, and x-ray evaluation may also be appropriate.
poisoning. Knowledge of the offending agents’ pharmacokinetics Intravenous glucose (unless the serum level is documented to be
and pharmacodynamics is essential. normal), naloxone, and thiamine should be considered in patients
During the pretoxic phase, prior to the onset of poisoning, decon- with altered mental status, particularly those with coma or seizures.
tamination is the highest priority, and treatment is based solely on Decontamination should also be considered, but it is less likely to be
the history. The maximal potential toxicity based on the greatest effective during this phase than during the pretoxic phase.
possible exposure should be assumed. Since decontamination is Measures that enhance poison elimination may shorten the
more effective when accomplished soon after exposure and when duration and severity of the toxic phase. However, they are not
the patient is asymptomatic, the initial history and physical exami- without risk, which must be weighed against the potential benefit.
nation should be focused and brief. It is also advisable to establish IV Diagnostic certainty (usually via laboratory confirmation) is gener-
access and initiate cardiac monitoring, particularly in patients with ally a prerequisite. Intestinal (gut) dialysis with repetitive doses of
potentially serious ingestions or unclear histories. activated charcoal (see “Multiple-Dose Activated Charcoal,” later)
can enhance the elimination of selected poisons such as theophyl- a return of spontaneous circulation after resuscitative treatment for 473e-5
line or carbamazepine. Urinary alkalinization may enhance the elimi- cardiopulmonary arrest secondary to poisoning, therapeutic hypo-
nation of salicylates and a few other poisons. Chelation therapy can thermia should be used according to protocol. Bradyarrhythmias
enhance the elimination of selected metals. Extracorporeal elimina- associated with hypotension generally should be treated as described
tion methods are effective for many poisons, but their expense and in Chaps. 274 and 275. Glucagon, calcium, and high-dose insulin
risk make their use reasonable only in patients who would otherwise with dextrose may be effective in beta blocker and calcium channel
have an unfavorable outcome. blocker poisoning. Antibody therapy may be indicated for cardiac
During the resolution phase of poisoning, supportive care and glycoside poisoning.
monitoring should continue until clinical, laboratory, and ECG Supraventricular tachycardia associated with hypertension and
abnormalities have resolved. Since chemicals are eliminated sooner CNS excitation is almost always due to agents that cause general-
from the blood than from tissues, blood levels are usually lower than ized physiologic excitation (Table 473e–1). Most cases are mild or

CHAPTER 473e Poisoning and Drug Overdose

tissue levels during this phase and again may not correlate with moderate in severity and require only observation or nonspecific
toxicity. This discrepancy applies particularly when extracorporeal sedation with a benzodiazepine. In severe cases or those associ-
elimination procedures are used. Redistribution from tissues may ated with hemodynamic instability, chest pain, or ECG evidence
cause a rebound increase in the blood level after termination of of ischemia, specific therapy is indicated. When the etiology is
these procedures. When a metabolite is responsible for toxic effects, sympathetic hyperactivity, treatment with a benzodiazepine should
continued treatment may be necessary in the absence of clinical be prioritized. Further treatment with a combined alpha and
toxicity or abnormal laboratory studies. beta blocker (labetalol), a calcium channel blocker (verapamil or
diltiazem), or a combination of a beta blocker and a vasodilator
SUPPORTIVE CARE (esmolol and nitroprusside) may be considered for cases refractory
The goal of supportive therapy is to maintain physiologic homeo- to high doses of benzodiazepines. Treatment with an α-adrenergic
stasis until detoxification is accomplished and to prevent and treat antagonist (phentolamine) alone may sometimes be appropriate.
secondary complications such as aspiration, bedsores, cerebral and If the cause is anticholinergic poisoning, physostigmine alone can
pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sep- be effective. Supraventricular tachycardia without hypertension is
sis, thromboembolic disease, coagulopathy, and generalized organ generally secondary to vasodilation or hypovolemia and responds
dysfunction due to hypoxemia or shock. to fluid administration.
Admission to an intensive care unit is indicated for the following: For ventricular tachyarrhythmias due to tricyclic antidepres-
patients with severe poisoning (coma, respiratory depression, hypo- sants and other membrane-active agents (Table 473e-1), sodium
tension, cardiac conduction abnormalities, cardiac arrhythmias, bicarbonate is indicated, whereas class IA, IC, and III antiarrhythmic
hypothermia or hyperthermia, seizures); those needing close moni- agents are contraindicated because of similar electrophysiologic
toring, antidotes, or enhanced elimination therapy; those showing effects. Although lidocaine and phenytoin are historically safe for
progressive clinical deterioration; and those with significant under- ventricular tachyarrhythmias of any etiology, sodium bicarbonate
lying medical problems. Patients with mild to moderate toxicity can should be considered first for any ventricular arrhythmia suspected
be managed on a general medical service, on an intermediate care to have a toxicologic etiology. Intravenous emulsion therapy has
unit, or in an emergency department observation area, depend- shown benefit for treatment of arrhythmias and hemodynamic
ing on the anticipated duration and level of monitoring needed instability from various membrane-active agents. Beta blockers can
(intermittent clinical observation versus continuous clinical, cardiac, be hazardous if the arrhythmia is due to sympathetic hyperactiv-
and respiratory monitoring). Patients who have attempted suicide ity. Magnesium sulfate and overdrive pacing (by isoproterenol or a
require continuous observation and measures to prevent self-injury pacemaker) may be useful in patients with torsades des pointes and
until they are no longer suicidal. prolonged QT intervals. Magnesium and anti-digoxin antibodies
should be considered in patients with severe cardiac glycoside poi-
Respiratory Care  Endotracheal intubation for protection against the
soning. Invasive (esophageal or intracardiac) ECG recording may be
aspiration of gastrointestinal contents is of paramount importance
necessary to determine the origin (ventricular or supraventricular)
in patients with CNS depression or seizures as this complication can
of wide-complex tachycardias (Chaps. 276 and 277). If the patient
increase morbidity and mortality rates. Mechanical ventilation may
is hemodynamically stable, however, it is reasonable to simply
be necessary for patients with respiratory depression or hypoxemia
observe him or her rather than to administer another potentially
and for facilitation of therapeutic sedation or paralysis of patients
proarrhythmic agent. Arrhythmias may be resistant to drug therapy
in order to prevent or treat hyperthermia, acidosis, and rhabdomy-
until underlying acid-base, electrolyte, oxygenation, and tempera-
olysis associated with neuromuscular hyperactivity. Since clinical
ture derangements are corrected.
assessment of respiratory function can be inaccurate, the need
for oxygenation and ventilation is best determined by continuous
Central Nervous System Therapies  Neuromuscular hyperactivity and
pulse oximetry or arterial blood-gas analysis. The gag reflex is not
seizures can lead to hyperthermia, lactic acidosis, and rhabdomyoly-
a reliable indicator of the need for intubation. A patient with CNS
sis and should be treated aggressively. Seizures caused by excessive
depression may maintain airway patency while being stimulated
stimulation of catecholamine receptors (sympathomimetic or hal-
but not if left alone. Drug-induced pulmonary edema is usually
lucinogen poisoning and drug withdrawal) or decreased activity of
noncardiac rather than cardiac in origin, although profound CNS
GABA (isoniazid poisoning) or glycine (strychnine poisoning) recep-
depression and cardiac conduction abnormalities suggest the latter.
tors are best treated with agents that enhance GABA activity, such as
Measurement of pulmonary artery pressure may be necessary to
benzodiazepine or barbiturates. Since benzodiazepines and barbitu-
establish the cause and direct appropriate therapy. Extracorporeal
rates act by slightly different mechanisms (the former increases the
measures (membrane oxygenation, venoarterial perfusion, cardio-
frequency and the latter increases the duration of chloride channel
pulmonary bypass) and partial liquid (perfluorocarbon) ventilation
opening in response to GABA), therapy with both may be effective
may be appropriate for severe but reversible respiratory failure.
when neither is effective alone. Seizures caused by isoniazid, which
Cardiovascular Therapy  Maintenance of normal tissue perfusion is criti- inhibits the synthesis of GABA at several steps by interfering with the
cal for complete recovery to occur once the offending agent has been cofactor pyridoxine (vitamin B6), may require high doses of supple-
eliminated. If hypotension is unresponsive to volume expansion, mental pyridoxine. Seizures resulting from membrane destabiliza-
treatment with norepinephrine, epinephrine, or high-dose dopamine tion (beta blocker or cyclic antidepressant poisoning) require GABA
may be necessary. Intraaortic balloon pump counterpulsation and enhancers (benzodiazepines first, barbiturates second). Phenytoin
venoarterial or cardiopulmonary perfusion techniques should be is contraindicated in toxicologic seizures: Animal and human data
considered for severe but reversible cardiac failure. For patients with demonstrate worse outcomes after phenytoin loading, especially
473e-6 in theophylline overdose. For poisons with central dopaminergic decubitus positions to prevent aspiration (even if an endotracheal
effects (methamphetamine, phencyclidine) manifested by psychotic tube is in place). Lavage decreases ingestant absorption by an
behavior, a dopamine receptor antagonist, such as haloperidol, may average of 52% if performed within 5 min of ingestion administra-
be useful. In anticholinergic and cyanide poisoning, specific antidotal tion, 26% if performed at 30 min, and 16% if performed at 60 min.
therapy may be necessary. The treatment of seizures secondary to Significant amounts of ingested drug are recovered from <10% of
cerebral ischemia or edema or to metabolic abnormalities should patients. Aspiration is a common complication (occurring in up to
include correction of the underlying cause. Neuromuscular paralysis 10% of patients), especially when lavage is performed improperly.
is indicated in refractory cases. Electroencephalographic monitoring Serious complications (esophageal and gastric perforation, tube
and continuing treatment of seizures are necessary to prevent per- misplacement in the trachea) occur in ~1% of patients. For this
manent neurologic damage. Serotonergic receptor overstimulation reason, the physician should personally insert the lavage tube and
in serotonin syndrome may be treated with cyproheptadine. confirm its placement, and the patient must be cooperative dur-
ing the procedure. Gastric lavage is contraindicated in corrosive
Other Measures  Temperature extremes, metabolic abnormalities,
or petroleum distillate ingestions because of the respective risks

hepatic and renal dysfunction, and secondary complications should

of gastroesophageal perforation and aspiration pneumonitis. It is
be treated by standard therapies.
also contraindicated in patients with a compromised unprotected
PREVENTION OF POISON ABSORPTION airway and those at risk for hemorrhage or perforation due to
Gastrointestinal Decontamination  Whether or not to perform gastro- esophageal or gastric pathology or recent surgery. Finally, gastric
intestinal decontamination and which procedure to use depends lavage is absolutely contraindicated in combative patients or those
on the time since ingestion; the existing and predicted toxicity of who refuse, as most published complications involve patient resis-
Poisoning, Drug Overdose, and Envenomation

the ingestant; the availability, efficacy, and contraindications of the tance to the procedure.
procedure; and the nature, severity, and risk of complications. The Syrup of ipecac, an emetogenic agent that was once the sub-
efficacy of all decontamination procedures decreases with time, stance most commonly used for decontamination, no longer has
and data are insufficient to support or exclude a beneficial effect a role in poisoning management. Even the American Academy of
when they are used >1 h after ingestion. The average time from Pediatrics—traditionally the strongest proponent of ipecac—issued
ingestion to presentation for treatment is >1 h for children and >3 h a policy statement in 2003 recommending that ipecac should no lon-
for adults. Most patients will recover from poisoning uneventfully ger be used in poisoning treatment. Chronic ipecac use (by patients
with good supportive care alone, but complications of gastroin- with anorexia nervosa or bulimia) has been reported to cause elec-
testinal decontamination, particularly aspiration, can prolong this trolyte and fluid abnormalities, cardiac toxicity, and myopathy.
process. Hence, gastrointestinal decontamination should be per- Whole-bowel irrigation is performed by administering a bowel-
formed selectively, not routinely, in the management of overdose cleansing solution containing electrolytes and polyethylene glycol
patients. It is clearly unnecessary when predicted toxicity is minimal (Golytely, Colyte) orally or by gastric tube at a rate of 2 L/h (0.5 L/h in
or the time of expected maximal toxicity has passed without sig- children) until rectal effluent is clear. The patient must be in a sitting
nificant effect. position. Although data are limited, whole-bowel irrigation appears
Activated charcoal has comparable or greater efficacy; has fewer to be as effective as other decontamination procedures in volunteer
contraindications and complications; and is less aversive and inva- studies. It is most appropriate for those who have ingested foreign
sive than ipecac or gastric lavage. Thus it is the preferred method bodies, packets of illicit drugs, and agents that are poorly adsorbed
of gastrointestinal decontamination in most situations. Activated by charcoal (e.g., heavy metals). This procedure is contraindicated
charcoal suspension (in water) is given orally via a cup, straw, or in patients with bowel obstruction, ileus, hemodynamic instability,
small-bore nasogastric tube. The generally recommended dose is and compromised unprotected airways.
1 g/kg body weight because of its dosing convenience, although in Cathartics are salts (disodium phosphate, magnesium citrate
vitro and in vivo studies have demonstrated that charcoal adsorbs and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that
≥90% of most substances when given in an amount equal to historically have been given with activated charcoal to promote the
10 times the weight of the substance. Palatability may be increased rectal evacuation of gastrointestinal contents. However, no animal,
by adding a sweetener (sorbitol) or a flavoring agent (cherry, choco- volunteer, or clinical data have ever demonstrated any decon-
late, or cola syrup) to the suspension. Charcoal adsorbs ingested poi- tamination benefit from cathartics. Abdominal cramps, nausea, and
sons within the gut lumen, allowing the charcoal-toxin complex to occasional vomiting are side effects. Complications of repeated dos-
be evacuated with stool. Charged (ionized) chemicals such as min- ing include severe electrolyte disturbances and excessive diarrhea.
eral acids, alkalis, and highly dissociated salts of cyanide, fluoride, Cathartics are contraindicated in patients who have ingested corro-
iron, lithium, and other inorganic compounds are not well adsorbed sives and in those with preexisting diarrhea. Magnesium-containing
by charcoal. In studies with animals and human volunteers, charcoal cathartics should not be used in patients with renal failure.
decreases the absorption of ingestants by an average of 73% when Dilution (i.e., drinking water, another clear liquid, or milk at a
given within 5 min of ingestant administration, 51% when given at volume of 5 mL/kg of body weight) is recommended only after the
30 min, and 36% when given at 60 min. For this reason, charcoal ingestion of corrosives (acids, alkali). It may increase the dissolution
given before hospital arrival increases the potential clinical benefit. rate (and hence absorption) of capsules, tablets, and other solid
Side effects of charcoal include nausea, vomiting, and diarrhea or ingestants and should not be used in these circumstances.
constipation. Charcoal may also prevent the absorption of orally Endoscopic or surgical removal of poisons may be useful in rare
administered therapeutic agents. Complications include mechanical situations, such as ingestion of a potentially toxic foreign body that
obstruction of the airway, aspiration, vomiting, and bowel obstruc- fails to transit the gastrointestinal tract, a potentially lethal amount
tion and infarction caused by inspissated charcoal. Charcoal is not of a heavy metal (arsenic, iron, mercury, thallium), or agents that
recommended for patients who have ingested corrosives because have coalesced into gastric concretions or bezoars (heavy metals,
it obscures endoscopy. lithium, salicylates, sustained-release preparations). Patients who
Gastric lavage should be considered for life-threatening poisons become toxic from cocaine due to its leakage from ingested drug
that cannot be treated effectively with other decontamination, packets require immediate surgical intervention.
elimination, or antidotal therapies (e.g., colchicine). Gastric lavage
is performed by sequentially administering and aspirating ~5 mL Decontamination of Other Sites  Immediate, copious flushing with
of fluid per kilogram of body weight through a no. 40 French oro- water, saline, or another available clear, drinkable liquid is the initial
gastric tube (no. 28 French tube for children). Except in infants, treatment for topical exposures (exceptions include alkali metals, cal-
for whom normal saline is recommended, tap water is acceptable. cium oxide, phosphorus). Saline is preferred for eye irrigation. A triple
The patient should be placed in Trendelenburg and left lateral wash (water, soap, water) may be best for dermal decontamination.
Inhalational exposures should be treated initially with fresh air or oxy- Peritoneal dialysis and exchange transfusion are less effective but 473e-7
gen. The removal of liquids from body cavities such as the vagina or may be used when other procedures are unavailable, contraindi-
rectum is best accomplished by irrigation. Solids (drug packets, pills) cated, or technically difficult (e.g., in infants). Exchange transfusion
should be removed manually, preferably under direct visualization. may be indicated in the treatment of severe arsine- or sodium
chlorate–induced hemolysis, methemoglobinemia, and sulfhemo-
ENHANCEMENT OF POISON ELIMINATION globinemia. Although hemofiltration can enhance elimination of
Although the elimination of most poisons can be accelerated by aminoglycosides, vancomycin, and metal-chelate complexes, the
therapeutic interventions, the pharmacokinetic efficacy (removal of roles of hemofiltration and plasmapheresis in the treatment of poi-
drug at a rate greater than that accomplished by intrinsic elimina- soning are not yet defined.
tion) and clinical benefit (shortened duration of toxicity or improved Candidates for extracorporeal removal therapies include patients
outcome) of such interventions are often more theoretical than with severe toxicity whose condition deteriorates despite aggres-

CHAPTER 473e Poisoning and Drug Overdose

proven. Accordingly, the decision to use such measures should be sive supportive therapy; those with potentially prolonged, irrevers-
based on the actual or predicted toxicity and the potential efficacy, ible, or fatal toxicity; those with dangerous blood levels of toxins;
cost, and risks of therapy. those who lack the capacity for self-detoxification because of liver or
Multiple-Dose Activated Charcoal  Repetitive oral dosing with charcoal renal failure; and those with a serious underlying illness or complica-
can enhance the elimination of previously absorbed substances by tion that will adversely affect recovery.
binding them within the gut as they are excreted in the bile, are
Other Techniques  The elimination of heavy metals can be enhanced
secreted by gastrointestinal cells, or passively diffuse into the gut
by chelation, and the removal of carbon monoxide can be acceler-
lumen (reverse absorption or enterocapillary exsorption). Doses of
ated by hyperbaric oxygenation.
0.5–1 g/kg of body weight every 2–4 h, adjusted downward to avoid
regurgitation in patients with decreased gastrointestinal motility, ADMINISTRATION OF ANTIDOTES
are generally recommended. Pharmacokinetic efficacy approaches Antidotes counteract the effects of poisons by neutralizing them
that of hemodialysis for some agents (e.g., phenobarbital, theophyl- (e.g., antibody-antigen reactions, chelation, chemical binding) or by
line). Multiple-dose therapy should be considered only for selected antagonizing their physiologic effects (e.g., activation of opposing
agents (theophylline, phenobarbital, carbamazepine, dapsone, nervous system activity, provision of a competitive metabolic or
quinine). Complications include intestinal obstruction, pseudo- receptor substrate). Poisons or conditions with specific antidotes
obstruction, and nonocclusive intestinal infarction in patients with include acetaminophen, anticholinergic agents, anticoagulants,
decreased gut motility. Because of electrolyte and fluid shifts, benzodiazepines, beta blockers, calcium channel blockers, car-
sorbitol and other cathartics are absolutely contraindicated when bon monoxide, cardiac glycosides, cholinergic agents, cyanide,
multiple doses of activated charcoal are administered. drug-induced dystonic reactions, ethylene glycol, fluoride, heavy
Urinary Alkalinization  Ion trapping via alteration of urine pH may metals, hypoglycemic agents, isoniazid, membrane-active agents,
prevent the renal reabsorption of poisons that undergo excre- methemoglobinemia, opioids, sympathomimetics, and a variety of
tion by glomerular filtration and active tubular secretion. Since envenomations. Intravenous lipid emulsion has been shown to be
membranes are more permeable to non-ionized molecules than to a successful antidote for poisoning from various anesthetics and
their ionized counterparts, acidic (low-pKa) poisons are ionized and membrane-active agents (e.g., cyclic antidepressants), but the exact
trapped in alkaline urine, whereas basic ones become ionized and mechanism of benefit is still under investigation. Antidotes can sig-
trapped in acid urine. Urinary alkalinization (producing a urine pH nificantly reduce morbidity and mortality rates but are potentially
≥7.5 and a urine output of 3–6 mL/kg of body weight per hour by toxic if used for inappropriate reasons. Since their safe use requires
the addition of sodium bicarbonate to an IV solution) enhances the correct identification of a specific poisoning or syndrome, details of
excretion of chlorophenoxyacetic acid herbicides, chlorpropamide, antidotal therapy are discussed with the conditions for which they
diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides, and are indicated (Table 473e-4).
salicylates. Contraindications include congestive heart failure, renal
failure, and cerebral edema. Acid-base, fluid, and electrolyte param-
Poisoning is a preventable illness. Unfortunately, some adults
eters should be monitored carefully. Although acid diuresis may
and children are poison-prone, and recurrences are common.
make theoretical sense for some overdoses (amphetamines), it is
Unintentional polypharmacy poisoning has become especially
never indicated and is potentially harmful.
common among adults with developmental delays, among the
Extracorporeal Removal  Hemodialysis, charcoal or resin hemoperfu- growing population of geriatric patients who are prescribed a large
sion, hemofiltration, plasmapheresis, and exchange transfusion are number of medications, and among adolescents and young adults
capable of removing any toxin from the bloodstream. Agents most experimenting with pharmaceuticals for recreational euphoria.
amenable to enhanced elimination by dialysis have low molecular Adults with unintentional exposures should be instructed regard-
mass (<500 Da), high water solubility, low protein binding, small ing the safe use of medications and chemicals (according to
volumes of distribution (<1 L/kg of body weight), prolonged elimi- labeling instructions). Confused patients may need assistance
nation (long half-life), and high dialysis clearance relative to total- with the administration of their medications. Errors in dosing by
body clearance. Molecular weight, water solubility, and protein health care providers may require educational efforts. Patients
binding do not limit the efficacy of the other forms of extracorporeal should be advised to avoid circumstances that result in chemical
removal. exposure or poisoning. Appropriate agencies and health depart-
Dialysis should be considered in cases of severe poisoning due to ments should be notified in cases of environmental or workplace
carbamazepine, ethylene glycol, isopropyl alcohol, lithium, metha- exposure. The best approach to young children and patients with
nol, theophylline, salicylates, and valproate. Although hemoperfu- intentional overdose (deliberate self-harm or attempted suicide)
sion may be more effective in removing some of these poisons, it is to limit their access to poisons. In households where children
does not correct associated acid-base and electrolyte abnormali- live or visit, alcoholic beverages, medications, household products
ties, and most hospitals no longer have hemoperfusion cartridges (automotive, cleaning, fuel, pet-care, and toiletry products), ined-
readily available. Fortunately, recent advances in hemodialysis ible plants, and vitamins should be kept out of reach or in locked
technology make it as effective as hemoperfusion for removing or child-proof cabinets. Depressed or psychotic patients should
poisons such as caffeine, carbamazepine, and theophylline. Both undergo psychiatric assessment, disposition, and follow-up. They
techniques require central venous access and systemic antico- should be given prescriptions for a limited supply of drugs with a
agulation and may result in transient hypotension. Hemoperfusion limited number of refills and should be monitored for compliance
may also cause hemolysis, hypocalcemia, and thrombocytopenia. and response to therapy.
473e-8   Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Sympathomimetics α1-Adrenergic agonists Stimulation of central and Physiologic stimulation Phentolamine, a nonselective
(decongestants): phenyleph- peripheral sympathetic (Table 473e-2). Reflex brady-α1-adrenergic receptor antagonist,
rine, phenylpropanolamine receptors directly or indirectly cardia can occur with selec- for severe hypertension due to
β2-Adrenergic agonists (by promoting release or tive α1 agonists; β agonists α1-adrenergic agonists; propranolol, a
(bronchodilators): albuterol, inhibiting reuptake of can cause hypotension and nonselective β blocker, for hypoten-
terbutaline norepinephrine and hypokalemia. sion and tachycardia due to β2 ago-
sometimes dopamine) nists; either labetalol, a β blocker with
Nonspecific adrenergic ago- α-blocking activity, or phentolamine

nists: amphetamines, cocaine, with esmolol, metoprolol, or another

ephedrine cardioselective β blocker for hyper-
tension with tachycardia due to non-
selective agents (β blockers, if used
alone, can exacerbate hypertension
and vasospasm due to unopposed
α stimulation.); benzodiazepines;
Poisoning, Drug Overdose, and Envenomation

Ergot alkaloids Ergotamine, methysergide, Stimulation and inhibition of Physiologic stimulation Nitroprusside or nitroglycerine for
bromocriptine, pergolide serotonergic and α-adrenergic (Table 473e-2); formication; severe vasospasm; prazosin (an
receptors; stimulation of vasospasm with limb (isolated α1 blocker), captopril, nifedipine, and
dopamine receptors or generalized), myocardial, cyproheptadine (a serotonin recep-
and cerebral ischemia tor antagonist) for mild-to-moderate
progressing to gangrene limb ischemia; dopamine receptor
or infarction. Hypotension, antagonists (antipsychotics) for hallu-
bradycardia, and involuntary cinations and movement disorders
movements can also occur.
Methylxanthines Caffeine, theophylline Inhibition of adenosine syn- Physiologic stimulation Propranolol, a nonselective β blocker,
thesis and adenosine receptor (Table 473e-2); pronounced for tachycardia with hypotension;
antagonism; stimulation of gastrointestinal symptoms any β blocker for supraventricular
epinephrine and norepineph- and β agonist effects (see or ventricular tachycardia without
rine release; inhibition of above). Toxicity occurs at hypotension; elimination enhanced
phosphodiesterase resulting lower drug levels in chronic by multiple-dose charcoal, hemoper-
in increased intracellular cyclic poisoning than in acute fusion, and hemodialysis. Indications
adenosine and guanosine poisoning. for hemoperfusion or hemodialysis
monophosphate 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.
Monoamine oxidase Phenelzine, tranylcypromine, Inhibition of monoamine Delayed or slowly progressive Short-acting agents (e.g., nitroprus-
inhibitors selegiline oxidase resulting in impaired physiologic stimulation side, esmolol) for severe hypertension
metabolism of endogenous (Table 473e-2); terminal and tachycardia; direct-acting sym-
catecholamines and exog- hypotension and bradycardia pathomimetics (e.g., norepinephrine,
enous sympathomimetic in severe cases epinephrine) for hypotension and
agents bradycardia
Antihistamines Diphenhydramine, doxyl- Inhibition of central and post- Physiologic stimulation Physostigmine, an acetylcholinesterase
amine, pyrilamine ganglionic parasympathetic (Table 473e-2); dry skin inhibitor (see below), for delirium,
muscarinic cholinergic recep- and mucous membranes, hallucinations, and neuromuscular
tors. At high doses, aman- decreased bowel sounds, hyperactivity. Contraindications
tadine, diphenhydramine, flushing, and urinary retention; include asthma and non-
orphenadrine, phenothiazines, myoclonus and picking anticholinergic cardiovascular
and tricyclic antidepressants activity. Central effects may toxicity (e.g., cardiac conduction
have additional nonanticho- occur without significant abnormalities, hypotension, and
linergic activity (see below). autonomic dysfunction. ventricular arrhythmias).
Antipsychotics Chlorpromazine, olanzapine, Inhibition of α-adrenergic, Physiologic depression Sodium bicarbonate for ventricular
quetiapine, thioridazine dopaminergic, histaminergic, (Table 473e-2), miosis, tachydysrhythmias associated with
muscarinic, and serotonergic anticholinergic effects (see QRS prolongation; magnesium,
receptors. Some agents also above), extrapyramidal isoproterenol, and overdrive pacing
inhibit sodium, potassium, reactions (see below), for torsades des pointes. Avoid class
and calcium channels. tachycardia IA, IC, and III antiarrhythmics.
Belladonna alkaloids Atropine, hyoscyamine, sco- Inhibition of central and Physiologic stimulation Physostigmine, an acetylcholinesterase
polamine postganglionic (Table 473e-2); dry skin inhibitor (see below), for delirium,
parasympathetic muscarinic and mucous membranes, hallucinations, and neuromuscular
cholinergic receptors decreased bowel sounds, hyperactivity. Contraindications
flushing, and urinary retention; include asthma and non-
myoclonus and picking anticholinergic cardiovascular
activity. Central effects may toxicity (e.g., cardiac conduction
occur without significant abnormalities, hypotension, and
autonomic dysfunction. ventricular arrhythmias).

(Continued )
  Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued) 473e-9
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
 Cyclic antidepres- Amitriptyline, doxepin, Inhibition of α-adrenergic, Physiologic depression (Table Hypertonic sodium bicarbonate (or
sants imipramine dopaminergic, GABA-ergic, 473e-2), seizures, tachycardia, hypertonic saline) for ventricular
histaminergic, muscarinic, and cardiac conduction delays tachydysrhythmias associated with
serotonergic receptors; inhibi- (increased PR, QRS, JT, and QT QRS prolongation. Use of phenytoin is
tion of sodium channels (see intervals; terminal QRS right- controversial. Avoid class IA, IC, and III
membrane-active agents); axis deviation) with aberrancy antiarrhythmics. IV emulsion therapy
inhibition of norepinephrine and ventricular tachydys- may be beneficial in some cases.
and serotonin reuptake rhythmias; anticholinergic
toxidrome (see above)

CHAPTER 473e Poisoning and Drug Overdose

 Mushrooms and Amanita muscaria and Inhibition of central and Physiologic stimulation (Table Physostigmine, an acetylcholinester-
plants A. pantherina, henbane, postganglionic parasympa- 473e-2); dry skin and mucous ase inhibitor (see below), for delirium,
jimson weed, nightshade thetic muscarinic cholinergic membranes, decreased bowel hallucinations, and neuromuscular
receptors sounds, flushing, and urinary hyperactivity. Contraindications
retention; myoclonus and include asthma and nonanticholin-
picking activity. Central effects ergic cardiovascular toxicity (e.g., car-
may occur without significant diac conduction abnormalities, hypo-
autonomic dysfunction. tension, and ventricular arrhythmias).
α2-Adrenergic Clonidine, guanabenz, Stimulation of α2-adrenergic Physiologic depression (Table Dopamine and norepinephrine for
agonists tetrahydrozoline and other receptors leading to inhibition 473e-2), miosis. Transient ini- hypotension; atropine for symptom-
imidazoline decongestants, of CNS sympathetic outflow. tial hypertension may be seen. atic bradycardia; naloxone for CNS
tizanidine and other Activity at nonadrenergic depression (inconsistently effective)
imidazoline muscle relaxants imidazoline binding sites also
contributes to CNS effects.
Antipsychotics Chlorpromazine, clozapine, Inhibition of α-adrenergic, Physiologic depression (Table Sodium bicarbonate for ventricular
haloperidol, risperidone, dopaminergic, histaminergic, 473e-2), miosis, anticholinergic tachydysrhythmias associated with
thioridazine muscarinic, and serotonergic effects (see above), extrapyra- QRS prolongation; magnesium, iso-
receptors. Some agents also midal reactions (see below), proterenol, and overdrive pacing for
inhibit sodium, potassium, tachycardia. Cardiac conduc- torsades des pointes. Avoid class IA,
and calcium channels. tion delays (increased PR, IC, and III antiarrhythmics.
QRS, JT, and QT intervals) with
ventricular tachydysrhythmias,
including torsades des pointes,
can sometimes develop.
β-Adrenergic Cardioselective (β1) blockers: Inhibition of β-adrenergic Physiologic depression (Table Glucagon for hypotension and symp-
blockers atenolol, esmolol, metoprolol receptors (class II antiarrhythmic 473e-2), atrioventricular block, tomatic bradycardia. Atropine, iso-
Nonselective (β1 and β2) effect). Some agents have hypoglycemia, hyperkalemia, proterenol, dopamine, dobutamine,
blockers: nadolol, propranolol, activity at additional receptors seizures. Partial agonists can epinephrine, and norepinephrine
timolol or have membrane effects cause hypertension and may sometimes be effective. High-
Partial β agonists: acebutolol, (see below). tachycardia. Sotalol can cause dose insulin (with glucose and potas-
increased QT interval and sium to maintain euglycemia and
ventricular tachydysrhythmias. normokalemia), electrical pacing, and
α1 Antagonists: carvedilol, Onset may be delayed after mechanical cardiovascular support
labetalol sotalol and sustained-release for refractory cases
Membrane-active agents: ace- formulation overdose.
butolol, propranolol, sotalol
Calcium channel Diltiazem, nifedipine and Inhibition of slow (type L) Physiologic depression Calcium and glucagon for hypoten-
blockers other dihydropyridine deriva- cardiovascular calcium (Table 473e-2), atrioventricular sion and symptomatic bradycardia.
tives, verapamil channels (class IV block, organ ischemia and Dopamine, epinephrine, norepineph-
antiarrhythmic effect) infarction, hyperglycemia, rine, atropine, and isoproterenol are
seizures. Hypotension is less often effective but can be used
usually due to decreased adjunctively. High-dose insulin (with
vascular resistance rather than glucose and potassium to maintain
to decreased cardiac output. euglycemia and normokalemia), IV
Onset may be delayed for lipid emulsion therapy, electrical pac-
≥12 h after overdose of ing, and mechanical cardiovascular
sustained-release formulations. support for refractory cases
Cardiac glycosides Digoxin, endogenous cardio- Inhibition of cardiac Na+, Physiologic depression (Table Digoxin-specific antibody fragments
active steroids, foxglove and K+-ATPase membrane pump 473e-2); gastrointestinal, psy- for hemodynamically compromising
other plants, toad skin secre- chiatric, and visual symptoms; dysrhythmias, Mobitz II or third-
tions (Bufonidae spp.) atrioventricular block with or degree atrioventricular block, hyper-
without concomitant supra- kalemia (>5.5 meq/L; in acute poi-
ventricular tachyarrhythmia; soning only). Temporizing measures
ventricular tachyarrhythmias; include atropine, dopamine, epineph-
hyperkalemia in acute poison- rine, and external cardiac pacing for
ing. Toxicity occurs at lower bradydysrhythmias and magnesium,
drug levels in chronic poison- lidocaine, or phenytoin, for ventricular
ing than in acute poisoning. tachydysrhythmias. Internal cardiac
pacing and cardioversion can increase
ventricular irritability and should be
reserved for refractory cases.

(Continued )
473e-10   Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued)
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Cyclic antidepres- Amitriptyline, doxepin, Inhibition of α-adrenergic, Physiologic depression (Table Hypertonic sodium bicarbonate (or
sants imipramine dopaminergic, GABA-ergic, 473e-2), seizures, tachycardia, hypertonic saline) for ventricular
histaminergic, muscarinic, and cardiac conduction delays tachydysrhythmias associated with
serotonergic receptors; inhibi- (increased PR, QRS, JT, and QT QRS prolongation. Use of phenytoin is
tion of sodium channels (see intervals; terminal QRS right- controversial. Avoid class IA, IC, and III
membrane-active agents); axis deviation) with aberrancy antiarrhythmics. IV emulsion therapy
inhibition of norepinephrine and ventricular tachydys- may be beneficial in some cases.
and serotonin reuptake rhythmias; anticholinergic
toxidrome (see above)

Acetylcholin- Carbamate insecticides (aldi- Inhibition of acetylcholinester-

Physiologic depression (Table Atropine for muscarinic signs and
esterase inhibitors carb, carbaryl, propoxur) and ase leading to increased syn- 473e-2). Muscarinic signs and symptoms; 2-PAM, a cholinesterase
medicinals (neostigmine, aptic acetylcholine at musca- symptoms: seizures, exces- reactivator, for nicotinic signs and
physostigmine, tacrine); nerve rinic and nicotinic cholinergic
sive secretions (lacrimation, symptoms due to organophosphates,
gases (sarin, soman, tabun, receptor sites salivation, bronchorrhea and nerve gases, or an unknown anticho-
VX); organophosphate insec- wheezing, diaphoresis), and linesterase
ticides (diazinon, chlorpyrifos- increased bowel and bladder
Poisoning, Drug Overdose, and Envenomation

ethyl, malathion) activity with nausea, vomiting,

Muscarinic agonists Bethanechol, mushrooms Stimulation of CNS and post- diarrhea, abdominal cramps,
(Boletus, Clitocybe, Inocybe ganglionic parasympathetic and incontinence of feces
spp.), pilocarpine cholinergic (muscarinic) and urine. Nicotinic signs and
receptors symptoms: hypertension,
tachycardia, muscle cramps,
Nicotinic agonists Lobeline, nicotine (tobacco) Stimulation of preganglionic fasciculations, weakness, and
sympathetic and parasym- paralysis. Death is usually
pathetic and striated muscle due to respiratory failure.
(neuromuscular junction) cho- Cholinesterase activity in
linergic (nicotine) receptors plasma and red cells is <50%
of normal in acetylcholinester-
ase inhibitor poisoning.
Anticonvulsants Carbamazepine, ethosuxi- Potentiation of the inhibitory Physiologic depression (Table Benzodiazepines, barbiturates, or pro-
mide, felbamate, gabapentin, effects of GABA by binding 473e-2), nystagmus. pofol for seizures.
lamotrigine, levetiracetam, to the neuronal GABA–A Delayed absorption can occur
oxcarbazepine, phenytoin, chloride channel receptor with carbamazepine, phe-
tiagabine, topiramate, valpro- complex and increasing nytoin, and valproate.
ate, zonisamide the frequency or duration
of chloride channel open- Myoclonus, seizures, hyper-
ing in response to GABA tension, and tachyarrhythmias
stimulation. Baclofen and, to can occur with baclofen,
some extent, GHB act at the carbamazepine, and orphen-
GABA–B receptor complex. adrine.
Barbiturates Short-acting: butabarbital, Meprobamate, its metabolite Hemodialysis and hemoperfu-
pentobarbital, secobarbital carisoprodol, felbamate, and sion may be indicated for severe
orphenadrine antagonize poisoning by some agents (see
NDMA excitatory receptors. “Extracorporeal Removal,” in text).
Long-acting: phenobarbital, Ethosuximide, valproate,
primidone and zonisamide decrease
conduction through T-type
Benzodiazepines Ultrashort-acting: estazolam, calcium channels. Valproate Tachyarrhythmias can also See above and below for treatment
midazolam, temazepam, decreases GABA degradation, occur with chloral hydrate. of anticholinergic and sodium chan-
triazolam and tiagabine blocks GABA AGMA, hypernatremia, nel (membrane)–blocking effects.
Short-acting: alprazolam, reuptake. Carbamazepine, hyperosmolality, hyperam-
flunitrazepam, lorazepam, lamotrigine, oxcarbazepine, monemia, chemical hepatitis,
oxazepam phenytoin, topiramate, valpro- and hypoglycemia can be
ate, and zonisamide slow the seen in valproate poisoning.
Long-acting: chlordiazepox- Carbamazepine and oxcar-
ide, clonazepam, diazepam, rate of recovery of inactivated
sodium channels. Some bazepine may produce hypo-
flurazepam natremia from SIADH.
agents also have α2 agonist,
Pharmacologically related anticholinergic, and sodium
agents: zaleplon, zolpidem channel–blocking activity (see
above and below).
GABA precursors γ-Hydroxybutyrate Some agents can cause
(sodium oxybate; GHB), anticholinergic and sodium
γ-butyrolactone (GBL), channel (membrane) blocking
1,4-butanediol effects (see above and below).
Muscle relaxants Baclofen, carisoprodol,
cyclobenzaprine, etomidate,
metaxalone, methocarbamol,
orphenadrine, propofol, tiza-
nidine and other imidazoline
muscle relaxants

(Continued )
  Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued) 473e-11
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Other agents Chloral hydrate, ethchlorvynol,
glutethimide, meprobamate,
methaqualone, methyprylon
Cytochrome oxidase Cyanide, hydrogen sulfide Inhibition of mitochondrial Signs and symptoms of High-dose oxygen; IV hydroxocobala-
inhibitors cytochrome oxidase, with hypoxemia with initial physi- min or IV sodium nitrite and sodium
consequent blockage of elec- ologic stimulation and sub- thiosulfate (Lilly cyanide antidote kit)

CHAPTER 473e Poisoning and Drug Overdose

tron transport and oxidative sequent depression (Table for coma, metabolic acidosis, and
metabolism. Carbon monox- 473e-2); lactic acidosis; normal cardiovascular dysfunction in cyanide
ide also binds to hemoglobin Po2 and calculated oxygen poisoning
and myoglobin and prevents saturation but decreased
oxygen binding, transport, oxygen saturation by co-
and tissue uptake. (Binding to oximetry. (That measured by
hemoglobin shifts the oxygen pulse oximetry is falsely ele-
dissociation curve to the left.) vated 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 sul-
fide smells like rotten eggs.
Methemoglobin Aniline derivatives, dapsone, Oxidation of hemoglobin iron Signs and symptoms of High-dose oxygen; IV methylene blue
inducers local anesthetics, nitrates, from ferrous (Fe2+) to ferric hypoxemia with initial physi- for methemoglobin fraction >30%,
nitrites, nitrogen oxides, nitro- (Fe3+) state prevents oxygen ologic stimulation and sub- symptomatic hypoxemia, or ischemia
and nitrosohydrocarbons, binding, transport, and tissue sequent depression (Table (contraindicated in G6PD deficiency);
phenazopyridine, primaquine- uptake. (Methemoglobinemia 473e-2), gray-brown cyanosis exchange transfusion and hyperbaric
type antimalarials, sulfon- shifts oxygen dissociation unresponsive to oxygen at oxygen for severe or refractory cases
amides curve to the left.) Oxidation of methemoglobin fractions
hemoglobin protein causes >15–20%, headache, lactic
hemoglobin precipitation and acidosis (at methemoglobin
hemolytic anemia (manifest- fractions >45%), normal Po2
ing as Heinz bodies and "bite and calculated oxygen satura-
cells" on peripheral-blood tion but decreased oxygen
smear). saturation and increased
methemoglobin fraction by
co-oximetry (Oxygen satura-
tion by pulse oximetry may be
falsely increased or decreased
but is less than normal and
less than the calculated value.)
AGMA inducers Ethylene glycol Ethylene glycol causes CNS Initial ethanol-like intoxication, Sodium bicarbonate to correct
depression and increased nausea, vomiting, increased acidemia; thiamine, folinic acid, mag-
serum osmolality. Metabolites osmolar gap, calcium oxylate nesium, and high-dose pyridoxine
(primarily glycolic acid) cause crystalluria; delayed AGMA, to facilitate metabolism; ethanol
AGMA, CNS depression, and back pain, renal failure; coma, or fomepizole for AGMA, crystal-
renal failure. Precipitation of seizures, hypotension, ARDS in luria or renal dysfunction, ethylene
oxalic acid metabolite as cal- severe cases glycol level >3 mmol/L (20 mg/
cium salt in tissues and urine dL), and ethanol-like intoxication or
results in hypocalcemia, tissue increased osmolal gap if level not
edema, and crystalluria. readily obtainable; hemodialysis
for persistent AGMA, lack of clinical
improvement, and renal dysfunction;
hemodialysis also useful for enhanc-
ing ethylene glycol elimination and
shortening duration of treatment
when ethylene glycol level is
>8 mmol/L (50 mg/dL)
AGMA inducers Iron Hydration of ferric (Fe3+) ion Initial nausea, vomiting, Whole-bowel irrigation for large
generates H+. Non-transferrin- abdominal pain, diarrhea; ingestions; endoscopy and gastros-
bound iron catalyzes forma- AGMA, cardiovascular and tomy if clinical toxicity and large
tion of free radicals that cause CNS depression, hepatitis, number of tablets are still visible on
mitochondrial injury, lipid coagulopathy, and seizures x-ray; IV hydration; sodium bicarbon-
peroxidation, increased capil- in severe cases. Radiopaque ate for acidemia; IV deferoxamine
lary permeability, vasodilation, iron tablets may be seen on for systemic toxicity, iron level >90
and organ toxicity. abdominal x-ray. μmol/L (500 μg/dL)

(Continued )
473e-12   Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued)
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Methanol Methanol causes ethanol-like Initial ethanol-like intoxication, Gastric aspiration for recent ingestion;
CNS depression and increased nausea, vomiting, increased sodium bicarbonate to correct
serum osmolality. Formic acid osmolar gap; delayed AGMA, acidemia; high-dose folinic acid or
metabolite causes AGMA and visual (clouding, spots, blind- folate to facilitate metabolism;
retinal toxicity. ness) and retinal (edema, ethanol or fomepizole for AGMA,
hyperemia) abnormalities; visual symptoms, methanol level
coma, seizures, cardiovascular >6 mmol/L (20 mg/dL), and ethanol-
depression in severe cases; like intoxication or increased osmolal
possible pancreatitis 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)
Salicylate Increased sensitivity of CNS Initial nausea, vomiting, IV hydration and supplemental
respiratory center to changes hyperventilation, alkalemia, glucose; sodium bicarbonate to cor-
Poisoning, Drug Overdose, and Envenomation

in and stimulates respira- alkaluria; subsequent alka- rect acidemia; urinary alkalinization
tion. Uncoupling of oxidative lemia with both respiratory for systemic toxicity; hemodialysis
phosphorylation, inhibition alkalosis and AGMA and for coma, cerebral edema, seizures,
of Krebs cycle enzymes, and paradoxical aciduria; late aci- pulmonary edema, renal failure,
stimulation of carbohydrate demia with CNS and respira- progressive acid-base disturbances
and lipid metabolism gener- tory depression; cerebral and or clinical toxicity, salicylate level >7
ate unmeasured endogenous pulmonary edema in severe mmol/L (100 mg/dL) following acute
anions and cause AGMA. cases. Hypoglycemia, hypo- overdose
calcemia, hypokalemia, and
seizures can occur.
CNS syndromes
Extrapyramidal Antipsychotics (see above), Decreased CNS dopaminergic Akathisia, dystonia, parkin- Oral or parenteral anticholinergic
reactions some cyclic antidepressants activity with relative excess of sonism agent such as benztropine or diphen-
and antihistamines cholinergic activity hydramine
Isoniazid Interference with activation Nausea, vomiting, agitation, High-dose IV pyridoxine (vitamin B6)
and supply of pyridoxal- confusion; coma, respiratory for agitation, confusion, coma, and
5-phosphate, a cofactor for depression, seizures, lactic and seizures; diazepam or barbiturates for
glutamic acid decarboxylase, ketoacidosis in severe cases seizures
which converts glutamic acid
to GABA, results in decreased
levels of this inhibitory CNS
neurotransmitter; complex-
ation with and depletion of
pyridoxine itself; inhibition of
nicotine adenine dinucleotide–
dependent lactate and
hydroxybutyrate dehydroge-
nases, resulting in substrate
Lithium Interference with cell mem- Nausea, vomiting, diarrhea, Whole-bowel irrigation for large
brane ion transport, adenylate ataxia, choreoathetosis, ingestions; IV hydration; hemodialysis
cyclase and Na+, K+-ATPase encephalopathy, hyperre- for coma, seizures, encephalopathy or
activity, and neurotransmitter flexia, myoclonus, nystagmus, neuromuscular dysfunction (severe,
release nephrogenic diabetes insipi- progressive, or persistent), peak lith-
dus, falsely elevated serum ium level >4 meq/L following acute
chloride with low anion gap, overdose
tachycardia; coma, seizures,
arrhythmias, hyperthermia,
and prolonged or permanent
encephalopathy and move-
ment disorders in severe
cases; delayed onset after
acute overdose, particularly
with delayed-release formula-
tions. Toxicity occurs at lower
drug levels in chronic poison-
ing than in acute poisoning.
(Continued )
  Table 473e-4    Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings (Continued) 473e-13
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Serotonin syndrome Amphetamines, cocaine, dex- Promotion of serotonin Altered mental status (agita- Discontinue the offending agent(s);
tromethorphan, meperidine, release, inhibition of serotonin tion, confusion, mutism, the serotonin receptor antagonist
MAO inhibitors, selective sero- reuptake, or direct stimula- coma, seizures), neuromuscu- cyproheptadine may be helpful in
tonin (5-HT) reuptake inhibi- tion of CNS and peripheral lar hyperactivity (hyperreflexia, severe cases.
tors, tricyclic antidepressants, serotonin receptors (primarily myoclonus, rigidity, tremors),
tramadol, triptans, tryptophan 5-HT-1a and 5-HT-2), alone or and autonomic dysfunction
in combination (abdominal pain, diarrhea,
diaphoresis, fever, flushing,
labile hypertension, mydriasis,

CHAPTER 473e Poisoning and Drug Overdose

tearing, salivation, tachycar-
dia). Complications include
hyperthermia, lactic acidosis,
rhabdomyolysis, and multisys-
tem organ failure.
Membrane-active Amantadine, anti-arrhythmics Blockade of fast sodium QRS and JT prolongation Hypertonic sodium bicarbonate (or
agents (class I and III agents; some membrane channels prolongs (or both) with hypotension, hypertonic saline) for cardiac con-
beta blockers), antipsychotics phase 0 (depolarization) of ventricular tachyarrhythmias, duction delays and monomorphic
(see above), antihistamines the cardiac action potential, CNS depression, seizures; ventricular tachycardia; lidocaine
(particularly diphenhydr- which prolongs QRS dura- anticholinergic effects with for monomorphic ventricular tachy-
amine), carbamazepine, tion and promotes reentrant amantadine, antihistamines, cardia (except when due to class Ib
local anesthetics (including (monomorphic) ventricular carbamazepine, disopyramide, antiarrhythmics); magnesium, iso-
cocaine), opioids (meperidine, tachycardia. Class Ia, Ic, and antipsychotics, and cyclic proterenol, and overdrive pacing for
propoxyphene), orphenadrine, III antiarrhythmics also block antidepressants (see above); polymorphic ventricular tachycardia;
quinoline antimalarials (chlo- potassium channels during opioid effects with meperi- physostigmine for anticholinergic
roquine, hydroxychloroquine, phases 2 and 3 (repolariza- dine and propoxyphene (see effects (see above); naloxone for opi-
quinine), cyclic antidepres- tion) of the action potential, Chap. 468e); cinchonism oid effects (see Chap. 468e); extra-
sants (see above) prolonging the JT interval and (hearing loss, tinnitus, nau- corporeal removal for some agents
promoting early after-depolar- sea, vomiting, vertigo, ataxia, (see text).
izations and polymorphic (tor- headache, flushing, diapho-
sades des pointes) ventricular resis) and blindness with
tachycardia. Similar effects on quinoline
neuronal membrane channels antimalarials
cause CNS dysfunction. Some
agents also block α-adrenergic
and cholinergic receptors or
have opioid effects (see above
and Chap. 468e).
See above and Chap. 469e. bSee above and Chap. 468e.

Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; 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 inappropirate antidi-
uretic hormone secretion.

SPECIFIC TOXIC SYNDROMES AND POISONINGS nicotine addiction is discussed in Chap. 470; acetaminophen
poisoning is discussed in Chap. 361; the neuroleptic malignant
Table 473e-4 summarizes the pathophysiology, clinical features, and syndrome is discussed in Chap. 449; and heavy metal poisoning is
treatment of toxidromes and poisonings that are common, produce discussed in Chap. 472e.
life-threatening toxicity, or require unique therapeutic interventions.
In all cases, treatment should include attention to the general prin- Acknowledgment
ciples discussed above and, in particular, supportive care. Poisonings The author acknowledges the contributions of Christopher H. Linden
not covered in this chapter are discussed in specialized texts. and Michael J. Burns to this chapter in previous editions of this text.
Alcohol, cocaine, hallucinogen, and opioid poisoning and
alcohol and opioid withdrawal are discussed in Chaps. 467–469e;
Part 18: Poisoning, Drug Overdose, and Envenomation 2733

474 Disorders Caused by Venomous

Snakebites and Marine Animal
Charles Lei, Natalie J. Badowski, Paul S. Auerbach,
Robert L. Norris

This chapter outlines general principles for the evaluation and man-
agement of victims of envenomation and poisoning by venomous
snakes and marine animals. Because the incidence of serious bites and
stings is relatively low in developed nations, there is a paucity of rel-
evant clinical research; as a result, therapeutic decision making often is
based on anecdotal information.

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

The venomous snakes of the world belong to the families Viperidae
(subfamily Viperinae: Old World vipers; subfamily Crotalinae: New
World and Asian pit vipers), Elapidae (including cobras, coral snakes,
sea snakes, kraits, and all Australian venomous snakes), Lamprophiidae
(subfamily Atractaspidinae: burrowing asps), and Colubridae (a large
family in which most species are nonvenomous and only a few are
dangerously toxic to humans). Most snakebites occur in developing
countries with temperate and tropical climates in which populations
subsist on agriculture and fishing. Recent estimates indicate that some-
where between 1.2 million and 5.5 million snakebites occur worldwide
each year, with 421,000–1,841,000 envenomations and 20,000–94,000
deaths. Such wide-ranging estimates reflect the challenges of collecting
accurate data in the regions most affected by venomous snakes; many
victims do not seek hospital treatment, and reporting and record keep-
ing are generally poor.

The typical snake venom delivery apparatus consists of bilateral venom
glands situated below and behind the eyes and connected by ducts to
hollow anterior maxillary fangs. In viperids (vipers and pit vipers),
these fangs are long and highly mobile; they are retracted against the
roof of the mouth when the snake is at rest and brought to an upright
position for a strike. In elapids, the fangs are smaller and are relatively
fixed in an erect position. Approximately 20% of pit viper bites and
higher percentages of other snakebites (up to 75% for sea snakes) are
“dry” bites, meaning no venom is released. Significant envenomation
probably occurs in ~50% of all venomous snakebites.
Differentiation of venomous from nonvenomous snake species
can be difficult. Viperids are characterized by somewhat triangular
heads (a feature shared with many harmless snakes), elliptical pupils
(also seen in some nonvenomous snakes, such as boas and pythons),
enlarged maxillary fangs, and, in pit vipers, heat-sensing pits (foveal
organs) on each side of the head that assist with locating prey and aim-
ing strikes. The New World rattlesnakes possess a series of interlock-
ing keratin plates (the rattle) on the tip of the tail that emits a buzzing
sound when the snake rapidly vibrates its tail; this sound serves as a
warning signal to perceived threats. Identifying venomous snakes by
color pattern is notoriously misleading, as many harmless snakes have
color patterns that closely mimic those of venomous snakes found in
the same region.


Snake venoms are highly variable and complex mixtures of enzymes,
low-molecular-weight polypeptides, glycoproteins, and other con-
stituents. Among the deleterious components are hemorrhagins that
promote vascular leakage and cause both local and systemic bleeding.

HPIM19_Part18_p2733-p2752.indd 2733 2/9/15 4:40 PM

2734 Proteolytic enzymes cause local tissue necrosis, affect the coagulation
pathway at various steps, and impair organ function. Hyaluronidases
promote the spread of venom through connective tissue. Myocardial
depressant factors reduce cardiac output, and bradykinins cause
vasodilation and hypotension. Neurotoxins act either pre- or postsyn-
aptically to block transmission at the neuromuscular junction, causing
muscle paralysis. Most snake venoms have multisystem effects on their
After a venomous snakebite, the time to symptom onset and clinical
presentation can be quite variable and depend on the species involved,
the anatomic location of the bite, and the amount of venom injected.
Envenomations by most viperids and some elapids with necrotizing
venoms cause progressive local pain, swelling, ecchymosis (Fig. 474-1),

and (over a period of hours to days) hemorrhagic or serum-filled

vesicles and bullae. In serious bites, tissue loss can be significant
(Figs. 474-2 and 474-3). Systemic findings are extremely variable
and can include tachycardia or bradycardia, hypotension, generalized
weakness, changes in taste, mouth numbness, muscle fasciculations,
pulmonary edema, renal dysfunction, and spontaneous hemorrhage
Poisoning, Drug Overdose, and Envenomation

(from essentially any anatomic site). Envenomations by neurotoxic

elapids such as kraits (Bungarus species), many Australian elapids
(e.g., death adders [Acanthophis species] and tiger snakes [Notechis
species]), some cobras (Naja species), and some viperids (e.g., the
South American rattlesnake [Crotalus durissus] and some Indian
Russell’s vipers [Daboia russelii]) cause neurologic dysfunction. Early
findings may consist of nausea and vomiting, headache, paresthesias
or numbness, and altered mental status. Victims may develop cranial
nerve abnormalities (e.g., ptosis, difficulty swallowing) followed by Figure 474-2  Early stages of severe, full-thickness necrosis
peripheral motor weakness. Severe envenomation may result in muscle 5 days after a Russell’s viper (Daboia russelii) bite in southwestern
paralysis, including the muscles of respiration, and lead to death from India.
respiratory failure and aspiration. Sea snake envenomation results in
local pain (variable), generalized myalgias, trismus, rhabdomyolysis,
and progressive flaccid paralysis; these manifestations can be delayed
for several hours.

TREATMENT  V enomous Snakebite

The most important aspect of prehospital care of a person bitten by
a venomous snake is rapid transport to a medical facility equipped
to provide supportive care (airway, breathing, and circulation) and
antivenom therapy. Most of the first-aid measures recommended
in the past are of little benefit, and some actually worsen outcome.
It is reasonable to apply a splint to the bitten extremity to lessen
bleeding and discomfort and, if possible, to keep the extremity at
approximately heart level. In developing countries, indigenous peo-
ple should be encouraged to seek immediate care at a health care

Figure 474-1  Northern Pacific rattlesnake (Crotalus oreganus ore-
ganus) envenomations. A. Moderately severe envenomation. Note
edema and early ecchymosis 2 h after a bite to the finger. B. Severe
envenomation. Note extensive ecchymosis 5 days after a bite to the Figure 474-3  Severe necrosis 10 days after a pit viper bite in a
ankle. young child in Colombia. (Courtesy of Jay R. Stanka; with permission.)

HPIM19_Part18_p2733-p2752.indd 2734 2/9/15 4:40 PM

facility equipped with antivenom instead of consulting traditional and hepatic function; coagulation studies to diagnose consumptive 2735
healers and thus incurring significant delays in reaching appropriate coagulopathy; creatine kinase for suspected rhabdomyolysis; and
care. Attempting to capture and transport the offending snake, alive testing of urine for blood or myoglobin. In developing regions, the
or dead, is not advised; instead, digital photographs of the snake 20-min whole-blood clotting test can be used to reliably diagnose
taken from a safe distance may assist with snake identification and coagulopathy. A few milliliters of fresh blood are placed in a new,
treatment decisions. clean, plain glass receptacle (e.g., a test tube) and left undisturbed
Incising and/or applying suction to the bite site should be for 20 min. The tube is then tipped once to 45° to determine whether
avoided, as these measures are ineffective and exacerbate local a clot has formed. If it has not, coagulopathy is diagnosed. Arterial
tissue damage. Similarly ineffective and potentially harmful are blood gas studies, electrocardiography, and chest radiography may
the application of poultices, ice, and electric shock. Techniques or be helpful in severe envenomations or when there is significant
devices used in an effort to limit venom spread (e.g., lymphooc- comorbidity. Any arterial puncture in the setting of coagulopathy

clusive bandages or tourniquets) are ineffective and may result in requires great caution and must be performed at an anatomic site
greater local tissue damage by restricting the spread of potentially amenable to direct-pressure tamponade. After antivenom therapy
necrotizing venom. Tourniquet use can result in loss of function and (see below), laboratory values should be rechecked every 6 h until
amputation even in the absence of envenomation. clinical stability is achieved. If initial laboratory values are normal,
Elapid venoms that are primarily neurotoxic and have no signifi- the complete blood count and coagulation studies should be
cant effects on local tissue may be localized by pressure-immobili- repeated every hour until it is clear that no systemic envenomation
zation, a technique in which the entire limb is wrapped immediately has occurred.
with a bandage (e.g., crepe or elastic) and then immobilized. For The mainstay of treatment of a venomous snakebite resulting

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

this technique to be effective, the wrap pressure must be precise in significant envenomation is prompt administration of specific
(40–70 mmHg in upper-extremity application and 55–70 mmHg in antivenom. Antivenoms are produced by injecting animals (gener-
lower-extremity application) and the victim must be carried out of ally horses or sheep) with venoms from medically important snakes.
the field because walking generates muscle-pumping activity that— Once the stock animals develop antibodies to the venoms, their
regardless of the anatomic site of the bite—will disperse venom into serum is harvested and the antibodies are isolated for antivenom
the systemic circulation. Pressure-immobilization should be used preparation, which may involve varying degrees of digestion and
only in cases in which the offending snake is reliably identified and purification of the IgG molecules. The goal of antivenom adminis-
known to be primarily neurotoxic, the rescuer is skilled in pressure- tration is to allow antibodies (or antibody fragments) to bind and
wrap application, the necessary supplies are readily available, and deactivate circulating venom components before they can attach
the victim can be fully immobilized and carried to medical care—an to target tissues and cause deleterious effects. Antivenoms may be
uncommon combination of conditions, particularly in the regions of monospecific (directed against a particular snake species) or poly-
the world where such bites are most common. specific (covering several medically important species in the region)
but rarely offer cross-protection against snake species other than
HOSPITAL MANAGEMENT those used in their production unless the species are known to have
In the hospital, the victim should be closely monitored (vital signs, homologous venoms. Thus, antivenom selection must be specific
cardiac rhythm, oxygen saturation, urine output) while a history for the offending snake; if the antivenom chosen does not contain
is quickly obtained and a rapid, thorough physical examination is antibodies to that snake’s venom components, it will provide no
performed. To objectively evaluate the progression of local enven- benefit and may lead to unnecessary complications (see below). In
omation, the level of swelling in the bitten extremity should be the United States, assistance in finding appropriate antivenom can
marked and limb circumference should be measured every 15 min be obtained from regional poison control centers.
until the swelling has stabilized. During this period of observation, For victims of bites by viperids or cytotoxic elapids, indications
the extremity should be positioned at approximately heart level. for antivenom administration include significant progressive local
Measures applied in the field (such as bandages or wraps) should be findings (e.g., soft tissue swelling crossing a joint or involving more
removed once IV access has been obtained, with cognizance that than half the bitten limb) and any evidence of systemic enven-
the release of such ligatures may result in hypotension or dysrhyth- omation (systemic symptoms or signs, laboratory abnormalities).
mias when stagnant acidotic blood containing venom is released Caution must be used in determining the significance of isolated
into the systemic circulation. Two large-bore IV lines should be soft tissue swelling after the bite of an unidentified snake because
established in unaffected extremities. Because of the potential for the saliva of some relatively harmless species can cause mild edema
coagulopathy, venipuncture attempts should be minimized, and at the bite site; in such bites, antivenoms are useless and potentially
noncompressible sites (e.g., a subclavian vein) should be avoided. harmful. Antivenoms have limited efficacy in preventing tissue dam-
Early hypotension is due to pooling of blood in the pulmonary and age caused by necrotizing venoms, as venom components bind to
splanchnic vascular beds. Later, systemic bleeding, hemolysis, and local tissues very quickly, before antivenom administration can be
loss of intravascular volume into the soft tissues may play important initiated. Nevertheless, antivenom should be administered as soon
roles. Fluid resuscitation with isotonic saline (20–40 mL/kg IV) should as the need for it is identified to limit further tissue damage and
be initiated if there is any evidence of hemodynamic instability, and systemic effects. Antivenom administration after bites by neurotoxic
a trial of 5% albumin (10–20 mL/kg IV) may be given if the response elapids is indicated at the first sign of any evidence of neurotoxicity
to saline infusion is inadequate. Only after aggressive volume (e.g., cranial nerve dysfunction, peripheral neuropathy). In general,
resuscitation and antivenom administration (see below) are accom- antivenom is effective only in reversing active venom toxicity; it is
plished should vasopressors (e.g., dopamine) be added. Invasive of no benefit in reversing effects that already have been established
hemodynamic monitoring (central venous and/or continuous arte- (e.g., renal failure, established paralysis) and that will improve only
rial pressures) can be helpful in such cases, although obtaining cen- with time and other supportive therapies.
tral vascular access is risky if coagulopathy has developed. Victims of Specific comments related to the management of venomous
neurotoxic envenomation should be watched carefully for evidence snakebites in the United States and Canada appear in Table 474-1.
of cranial nerve dysfunction (e.g., ptosis) that may precede the onset The package insert for the selected antivenom can be consulted
of difficulty swallowing or respiratory insufficiency that necessitates regarding species covered, method of administration, starting dose,
definitive airway protection by endotracheal intubation. and need (if any) for re-dosing. The information in antivenom pack-
Blood should be drawn for typing and cross-matching and for age inserts, however, is not always accurate and reliable. Whenever
laboratory evaluation as soon as possible. Important studies include possible, it is advisable for treating physicians to seek advice from
a complete blood count to determine the degree of hemorrhage experts in snakebite management regarding indications for and
or hemolysis and to identify thrombocytopenia; studies of renal dosing of antivenom.

HPIM19_Part18_p2733-p2752.indd 2735 2/9/15 4:40 PM

2736   TABLE 474-1    Management of Venomous Snakebite in the United States and Canadaa
Pit viper bites (rattlesnakes [Crotalus and Sistrurus spp.], cottonmouth water moccasins [Agkistrodon piscivorus], and copperheads [Agkistrodon
•  Stabilize airway, breathing, and circulation.
•  Institute monitoring (vital signs, cardiac rhythm, and oxygen saturation).
•  Establish two large-bore IV lines.
•  If the patient is hypotensive, administer a normal saline bolus (20–40 mL/kg IV).
•  If hypotension persists, consider 5% albumin (10–20 mL/kg IV).
•  Take rapid history and perform thorough physical examination.
•  Identify offending snake if possible.
•  Measure and record circumference of bitten extremity every 15 min until swelling has stabilized.

•  Send laboratory studies (CBC, metabolic panel, PT/INR/PTT, fibrinogen level, FDP, blood type and cross-matching, urinalysis).
•  If normal, repeat CBC and coagulation studies every hour until it is clear that no systemic envenomation has occurred.
•  If abnormal, repeat 6 h after antivenom administration (see below).
•  Determine severity of envenomation.
•  None: fang marks only (“dry” bite)
•  Mild: local findings only (e.g., pain, ecchymosis, nonprogressive swelling)
Poisoning, Drug Overdose, and Envenomation

•  Moderate: swelling that is clearly progressing, systemic symptoms or signs, and/or laboratory abnormalities
•  Severe: neurologic dysfunction, respiratory distress, and/or cardiovascular instability/shock
•  Contact regional poison control center.
•  Locate and administer antivenom as indicated: Crotalidae Polyvalent Immune Fab (CroFab) (Ovine) (BTG International Inc., West Conshohocken, PA).
•  Starting dose
•  Based on severity of envenomation
•  None or mild: none
•  Moderate: 4–6 vials
•  Severe: 6 vials
•  Dilute reconstituted vials in 250 mL of normal saline.
•  No pretesting for potential hypersensitivity; no pretreatment
•  Infuse IV over 1 h (with physician in close attendance).
•  If acute reaction to antivenom:
•  Stop infusion.
•  Treat with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).
•  When reaction is controlled, restart antivenom as soon as possible (may further dilute in larger volume of normal saline).
•  Monitor clinical status over 1 h.
•  Stabilized or improved: Admit to hospital.
•  Progressing or unimproved: Repeat starting dose (and continue this pattern until patient’s condition is stable or improved).
•  Blood products are rarely needed; if required, they should be given only after antivenom administration.
•  Update tetanus immunization as needed.
•  Prophylactic antibiotics are unnecessary unless prehospital care included incision or mouth suction.
•  Pain management: acetaminophen and/or narcotics as needed; avoidance of salicylates and nonsteroidal anti-inflammatory agents
•  Admit to hospital. (If no evidence of envenomation, monitor for 8 h before discharge.)
•  Give additional CroFab (2 vials every 6 h for 3 additional doses, with close monitoring).
•  Monitor for evidence of rising intracompartmental pressures (see text).
•  Provide wound care (see text).
•  Start physical therapy (see text).
•  At discharge, warn patient of possible recurrent coagulopathy and symptoms/signs of delayed serum sickness.
Coral snakebites (Micrurus spp. and Micruroides euryxanthus)
•  Stabilize airway, breathing, and circulation.
•  Institute monitoring (vital signs, cardiac rhythm, and oxygen saturation).
•  Establish one large-bore IV line and initiate normal saline infusion.
•  Take rapid history and perform thorough physical examination.
•  Identify offending snake if possible.
•  Laboratory studies are unlikely to be helpful.
•  Contact regional poison control center.
•  Locate and administer antivenom as indicated: Antivenin (Micrurus fulvius) (equine) (commonly referred to as North American Coral Snake Antivenin; Wyeth
Pharmaceuticals, New York, NY).b
•  Refer to antivenom package insert.
•  Dilute 3–5 reconstituted vials of antivenom in 250 mL of normal saline.
•  Infuse IV over 1 h (with physician in close attendance).
•  If signs of envenomation progress despite initial antivenom, repeat the starting dose (up to 10 vials total may be required).
(Continued )

HPIM19_Part18_p2733-p2752.indd 2736 2/9/15 4:40 PM

  TABLE 474-1    Management of Venomous Snakebite in the United States and Canadaa (CONTINUED) 2737
•  If acute adverse reaction to antivenom:
•  Stop infusion.
•  Treat with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).
•  When reaction is controlled, restart antivenom as soon as possible (may further dilute in larger volume of normal saline).
•  If any evidence of neurologic dysfunction (e.g., any cranial nerve abnormalities such as ptosis):
•  Trial of acetylcholinesterase inhibitors (see Table 474-2)
•  With any evidence of difficulty swallowing or breathing, proceed with endotracheal intubation and ventilatory support (may be required for days or weeks).
•  Update tetanus immunization as needed.
•  Prophylactic antibiotics are unnecessary unless prehospital care included incision or mouth suction.

•  Admit to hospital (intensive care unit) even if there is no evidence of envenomation; monitor for at least 24 h.
These recommendations are specific to the care of victims of venomous snakebites in the United States and Canada and should not be applied to bites in other regions of the

world.  bAt the time of publication, a single lot of antivenom remains, with an extended expiration date of April 30, 2015.
Abbreviations: CBC, complete blood count; FDP, fibrin degradation products; PT/INR/PTT, prothrombin time/international normalized ratio/partial thromboplastin time.

Antivenom should be administered only by the IV route, and the administration and may present as fever, chills, urticaria, myalgias,

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

infusion should be started slowly, with the physician at the bed- arthralgias, lymphadenopathy, and renal or neurologic dysfunction.
side ready to intervene immediately at the first signs of an acute Treatment of serum sickness consists of systemic glucocorticoids
adverse reaction. In the absence of an adverse reaction, the rate of (e.g., oral prednisone, 1–2 mg/kg daily) until all symptoms have
infusion can be increased gradually until the full starting dose has resolved, followed by a taper over 1–2 weeks. Oral antihistamines
been administered (over a total period of ~1 h). Further antivenom and analgesics may provide additional relief of symptoms.
may be necessary if the patient’s acute clinical condition worsens Blood products are rarely necessary in the management of an
or fails to stabilize or if venom effects that were initially controlled envenomed patient. The venoms of many snake species can deplete
recur. The decision to administer further antivenom to a stabilized coagulation factors and cause a decrease in platelet count or hema-
patient should be based on clinical evidence of persistent circula- tocrit. Nevertheless, these components usually rebound within
tion of unbound venom components. For viperid bites, antivenom hours after administration of adequate antivenom. If the need for
administration generally should be continued until the victim blood products is thought to be great (e.g., a dangerously low
shows definite improvement (e.g., stabilized vital signs, reduced platelet count in a hemorrhaging patient), these products should be
pain, restored coagulation). Neurotoxicity from elapid bites may given only after adequate antivenom administration to avoid fuel-
be more difficult to reverse with antivenom. Once neurotoxicity is ing ongoing consumptive coagulopathy.
established and endotracheal intubation is required, further doses Rhabdomyolysis and hemolysis should be managed in standard
of antivenom are unlikely to be beneficial. In such cases, the victim fashion. Victims who develop acute renal failure should be evaluated
must be maintained on mechanical ventilation until recovery, which by a nephrologist and referred for hemodialysis or peritoneal dialysis
may take days or weeks. as needed. Such renal failure, which usually is due to acute tubular
Adverse reactions to antivenom administration include imme- necrosis, is frequently reversible. If bilateral cortical necrosis occurs,
diate (nonallergic and, less commonly, allergic anaphylaxis) and however, the prognosis for renal recovery is less favorable, and long-
delayed-type hypersensitivity reactions (serum sickness). Clinical term dialysis with possible renal transplantation may be necessary.
manifestations of immediate hypersensitivity include urticaria, Acetylcholinesterase inhibitors (e.g., edrophonium and neostig-
laryngeal edema, bronchospasm, and hypotension. Skin testing mine) may promote neurologic improvement in patients bitten by
for potential hypersensitivity, although recommended by some snakes with postsynaptic neurotoxins. Snakebite victims with objec-
antivenom manufacturers, is insensitive and nonspecific and should tive evidence of neurologic dysfunction should receive a test dose
be omitted. Worldwide, the quality of antivenoms is highly vari- of acetylcholinesterase inhibitors, as outlined in Table 474-2. If they
able. Rates of acute nonallergic anaphylactic reactions to some of exhibit improvement, additional doses of long-acting neostigmine
these products exceed 50%. For this reason, some authorities have can be administered as needed. Close monitoring is required to
recommended pretreatment with IV antihistamines (e.g., diphen- prevent aspiration if repetitive dosing of neostigmine is used in an
hydramine, 1 mg/kg to a maximum of 100 mg; and cimetidine, 5–10
mg/kg to a maximum of 300 mg) or even a prophylactic SC or IM
dose of epinephrine (0.01 mg/kg, up to 0.3 mg). Further research is   TABLE 474-2    Use of Acetylcholinesterase Inhibitors in Neurotoxic
necessary, however, to determine whether any pretreatment mea- Snake Envenomation
sures are truly beneficial. Modest expansion of the patient’s intra- 1.  Patients with clear, objective evidence of neurotoxicity (e.g., ptosis or
vascular volume with crystalloids may blunt acute adverse blood inability to maintain upward gaze) should receive a test dose of edropho-
pressure decline. Epinephrine and airway equipment should always nium (if available) or neostigmine.
be immediately available during antivenom infusion. An acute ana- a.  Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg with a minimum
phylactic reaction may be heralded by a single hive or mild itching of 0.1 mg)
or may present as bronchospasm or acute cardiovascular collapse. b.  Treat with:
If the patient develops an acute reaction to antivenom, the infu- Edrophonium: 10 mg IV (children, 0.25 mg/kg)
sion should be temporarily stopped and the reaction immediately
treated with IM epinephrine and IV antihistamines and glucocorti-
Neostigmine: 1.5–2.0 mg IM (children, 0.025–0.08 mg/kg)
coids. Once the reaction has been controlled, if the severity of the
envenomation warrants additional antivenom, the dose should be 2.  If objective improvement is evident after 5 min, treat with:
diluted further in isotonic saline and restarted as soon as possible. a.  Neostigmine: 0.5 mg IV or SC (children, 0.01 mg/kg) every 30 min as
Rarely, in cases of recalcitrant hypotension, a concomitant IV infu- needed
sion of epinephrine may be initiated and titrated to clinical effect b.  Atropine: 0.6 mg IV continuous infusion over 8 h (children, 0.02 mg/kg
while antivenom is administered. The patient must be monitored over 8 h)
very closely during such therapy, preferably in an intensive care set- 3.  Closely monitor the airway and perform endotracheal intubation as
ting. Serum sickness typically develops 1–2 weeks after antivenom needed.

HPIM19_Part18_p2733-p2752.indd 2737 2/9/15 4:40 PM

2738 attempt to obviate endotracheal intubation. Acetylcholinesterase developed in the acute stages of envenomation, it can recur during
inhibitors are not a substitute for administration of an appropriate the first 2–3 weeks after the bite. In such cases, victims should be
antivenom when available. warned to avoid elective surgery or activities posing a high risk of
Care of the bite wound includes simple cleansing with soap and trauma during this period. Outpatient analgesic treatment, wound
water; application of a dry, sterile dressing; and splinting of the management, and physical therapy should be provided.
affected extremity with padding between the digits. Once antive-
nom therapy has been initiated, the extremity should be elevated
above heart level to reduce swelling. Tetanus immunization should MORBIDITY AND MORTALITY
be updated as appropriate. Prophylactic antibiotics are generally The overall mortality rates for victims of venomous snakebites are low
unnecessary after bites by North American snakes, as the incidence in regions with rapid access to medical care and appropriate antiven-
of secondary infection is low. In some regions, secondary bacterial oms. In the United States, for example, the mortality rate is <1% for
infection is more common and the consequences are dire; in these victims who receive antivenom. Eastern and western diamondback
regions, prophylactic antibiotics (e.g., cephalosporins) are used rattlesnakes (Crotalus adamanteus and Crotalus atrox, respectively) are

commonly. Antibiotics may also be considered if misguided first aid responsible for the majority of snakebite deaths in the United States.
efforts have included incision or mouth suction of the bite site. Pain Snakes responsible for large numbers of deaths in other countries
control should be achieved with acetaminophen or narcotic analge- include cobras (Naja spp.), carpet and saw-scaled vipers (Echis spp.),
sics. Salicylates and nonsteroidal anti-inflammatory agents should Russell’s vipers (D. russelii), large African vipers (Bitis spp.), lancehead
be avoided because of their effects on blood clotting. pit vipers (Bothrops spp.), and tropical rattlesnakes (C. durissus).
Most snake envenomations involve SC deposition of venom. On The incidence of morbidity—defined as permanent functional
Poisoning, Drug Overdose, and Envenomation

occasion, however, venom can be injected more deeply into muscle loss in a bitten extremity—is difficult to estimate but is substantial.
compartments, particularly if the offending snake was large and Morbidity may be due to muscle, nerve, or vascular injury or to scar
the bite occurred on the lower leg, forearm, or hand. Intramuscular contracture. Such morbidity can have devastating consequences for
swelling of the affected extremity may be accompanied by severe victims in the developing world when they lose the ability to work and
pain, decreased strength, altered sensation, cyanosis, and apparent provide for their families. In the United States, functional loss tends to
pulselessness—signs suggesting a muscle compartment syndrome. be more common and severe after rattlesnake bites than after bites by
If there is clinical concern that subfascial muscle edema may be copperheads (Agkistrodon contortrix) or water moccasins (Agkistrodon
impeding tissue perfusion, intracompartmental pressures should piscivorus).
be measured by a minimally invasive technique (e.g., wick catheter
or digital readout device). If the intracompartmental pressure is GLOBAL CONSIDERATIONS
high (>30–40 mmHg), the extremity should be kept elevated while In many developing countries where snakebites are common,
antivenom is administered. A dose of IV mannitol (1 g/kg) can be scarce access to medical care and antivenom resources con-
given in an effort to reduce muscle edema if the patient is hemo- tributes to high rates of morbidity and mortality. In many
dynamically stable. If the intracompartmental pressure remains countries, the available antivenoms are inappropriate and ineffective
elevated after 1 h of such therapy, a surgical consultation should be against the venoms of medically important indigenous snakes. In those
obtained for possible fasciotomy. Although evidence from animal regions, further research is necessary to determine the actual impact of
studies suggests that fasciotomy may actually worsen myonecrosis, venomous snakebites and the specific antivenom needs in terms of
compartmental decompression is still necessary to preserve nerve both quantity and spectrum of coverage. Without accurate statistics, it
function. Fortunately, the incidence of compartment syndrome is is difficult to persuade antivenom manufacturers to begin and sustain
very low after a snakebite, with fasciotomies required in <1% of production of appropriate antisera in developing nations. There is
cases. Nevertheless, vigilance is essential. If a fasciotomy is deemed evidence that antivenoms can be produced in much more cost-effec-
necessary, it should be undertaken with the patient’s informed con- tive ways than those currently being used. Just as important as getting
sent whenever possible. the correct antivenoms into underserved regions is the need to educate
Wound care in the days after the bite should include careful asep- populations about snakebite prevention and to train medical care pro-
tic debridement of clearly necrotic tissue once coagulation has been viders in proper management approaches. Local protocols written with
restored. Intact serum-filled vesicles or hemorrhagic blebs should be significant input from experienced providers in the region of concern
left undisturbed. If ruptured, they should be debrided with sterile should be developed and distributed. Appropriate antivenoms must be
technique. Any debridement of damaged muscle should be conser- available at the likely first point of medical contact for patients (e.g.,
vative because there is evidence that such muscle may recover to a primary health centers) in order to minimize the common practice of
significant degree after antivenom therapy. referring victims to more distant, higher levels of care for the initiation
Physical therapy should be started as soon as possible so that the of antivenom therapy. Those who care for snakebite victims in these
victim can return to a functional state. The incidence of long-term often-remote clinics must have the skills and confidence required to
loss of function (e.g., reduced range of motion, impaired sensory begin antivenom treatment (and to treat possible reactions) as soon as
function) is unclear but is probably quite high (>30%), particularly possible when needed.
after viperid bites.
Any patient with signs of envenomation should be observed in
the hospital for at least 24 h. In North America, a patient with an Much of the management of envenomation by marine creatures is
apparently “dry” viperid bite should be watched for at least 8 h supportive in nature. A specific marine antivenom can be used when
before discharge, as significant toxicity occasionally develops after appropriate.
a delay of several hours. The onset of systemic symptoms com-
monly is delayed for a number of hours after bites by several of the INVERTEBRATES
elapids (including coral snakes, Micrurus species), some non–North Cnidarians  The Golgi apparatus of the cnidoblast cells within cnidar-
American viperids (e.g., the hump-nosed pit viper [Hypnale hyp- ians, such as hydroids, fire coral, jellyfish, Portuguese men-of-war,
nale]), and sea snakes. Patients bitten by these snakes should be and sea anemones, secretes specialized living stinging organelles called
observed in the hospital for at least 24 h. Patients whose condition cnidae (also referred to as cnidocysts, a term that encompasses nema-
is not stable should be admitted to an intensive care setting. tocysts, ptychocysts, and spirocysts). Within each organelle resides
At hospital discharge, victims of venomous snakebites should be a stinging mechanism (“thread tube”) and venom. In the stinging
warned about symptoms and signs of wound infection, antivenom- process, cnidocysts are released and discharged upon mechanosen-
related serum sickness, and potential long-term sequelae, such as pitu- sory stimulation. The venoms from these organisms contain bioac-
itary insufficiency from Russell’s viper (D. russelii) bites. If coagulopathy tive substances such as tetramine, 5-hydroxytryptamine, histamine,

HPIM19_Part18_p2733-p2752.indd 2738 2/9/15 4:40 PM

serotonin, and high-molecular-weight toxins, all of which can, among successfully against a number of marine stingers, and may prevent or 2739
other effects, change the permeability of cells to ions. Victims usu- diminish the effects of coelenterate stings. Whenever possible, a dive
ally report immediate prickling or burning, pruritus, paresthesias, skin or wet suit should be worn when entering ocean waters.
and painful throbbing with radiation. The skin becomes reddened,
darkened, edematous, and blistered and may show signs of super- Sea Sponges  Many sponges produce crinotoxins that are present on
ficial necrosis. A legion of neurologic, cardiovascular, respiratory, their surface or in their internal secretions. As a result, touching a sea
rheumatologic, gastrointestinal, renal, and ocular symptoms has been sponge may result in dermatitis or “sponge diver’s disease,” a necrotic
described, especially following stings from anemones, Physalia species, skin reaction. Irritant dermatitis may result if small spicules of silica
and scyphozoans. Anaphylaxis is possible. Hundreds of deaths have or calcium carbonate penetrate the skin. It is impossible to distinguish
been reported, many of them caused by Chironex fleckeri, Stomolophus between the allergic and spicule reactions, so the treatment is the same
nomurai, Physalia physalis, and Chiropsalmus quadrumanus. Irukandji for both. Afflicted skin should be gently dried and adhesive tape used
syndrome, associated with the Australian jellyfish Carukia barnesi and

to remove embedded spicules. Vinegar should be applied immediately
other species, is a potentially fatal condition that most commonly is and then for 10–30 min three or four times a day. Rubbing alcohol may
characterized by hypertension; severe back, chest, and abdominal pain; be used if vinegar is unavailable. After spicule removal and skin decon-
nausea and vomiting; headache; sweating; and, in the most serious tamination, glucocorticoid or antihistamine cream may be applied to
cases, myocardial troponin leak, pulmonary edema, and ultimately the skin. Severe vesiculation should be treated with a 2-week tapering
hypotension. This syndrome is thought to be mediated, at least in part, course of systemic glucocorticoids. Mild reactions subside in 3–7 days,
by the release of endogenous catecholamines followed by cytokines while involvement of large areas of the skin may result in systemic
and nitric oxide. symptoms of fever, dizziness, nausea, muscle cramps, and formication.

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

Rescuers should note that envenomations by different cnidar-
ians (typified by jellyfish) may respond differently to similar topical Annelid Worms  Annelid worms (bristleworms) possess rows of soft,
therapies; thus, the recommendations in this chapter must be tailored cactus-like spines capable of inflicting painful stings. Contact results
to local species and clinical practices. During stabilization, the skin in symptoms similar to those of nematocyst envenomation. Without
should be decontaminated immediately with a generous application treatment, pain usually subsides over several hours, but inflammation
of lidocaine (up to 4%), an all-purpose agent that appears to be use- may persist for up to a week (Fig. 474-4). Victims should resist the
ful for relieving pain caused by a large number of species. Vinegar urge to scratch because scratching may fracture retrievable spines.
(5% acetic acid), rubbing alcohol (40–70% isopropyl alcohol), baking Visible bristles should be removed with forceps and adhesive tape or
soda (sodium bicarbonate, especially for sea nettle stings), papain a commercial facial peel; alternatively, a thin layer of rubber cement
(unseasoned meat tenderizer), fresh lemon or lime juice, olive oil, or can be used to entrap and then peel away the spines. Use of vinegar or
sugar may be effective, depending on the species of stinging creature. rubbing alcohol or a brief application of lidocaine or unseasoned meat
Household ammonia may in and of itself cause skin irritation. tenderizer (papain) may provide additional relief. Local inflammation
The pressure-immobilization technique is no longer recommended should be treated with topical or systemic glucocorticoids.
for venom containment in the setting of any jellyfish sting. For the
Sea Urchins  Venomous sea urchins possess either hollow, venom-
sting of the venomous box jellyfish (C. fleckeri), vinegar should be
filled calcified spines or triple-jawed, globiferous pedicellariae with
used. Local application of heat (up to 45°C/113°F), commonly by
venom glands. Venom may also be found within the integumentary
immersion in hot water, may be as effective. A baking soda slurry
sheath on the external spine surface of certain species. The venom
(50% baking soda, 50% water) has been recommended for Cyanea and
contains toxic components, including steroid glycosides, hemolysins,
Chrysaora species. Commercial (chemical) cold packs or real ice packs
proteases, serotonin, and cholinergic substances. Contact with either
applied over a thin dry cloth or a plastic membrane have been shown
venom apparatus produces immediate and intensely painful stings.
to be effective in alleviating mild or moderate Physalia utriculus (blue-
One or more spines entering a joint can cause synovitis that may, over
bottle jellyfish) stings but may be less effective than application of heat.
time, progress to arthritis if the spine(s) remain in or near the joint. If
Perfume, aftershave lotion, and high-proof ethanol are not efficacious
multiple spines penetrate the skin, the patient may develop systemic
and may be detrimental; formalin, ether, gasoline, and other organic
symptoms, including nausea, vomiting, numbness, muscular paralysis,
solvents should not be used. Shaving the skin helps remove remaining
and respiratory distress. A delayed hypersensitivity reaction 7–10 days
nematocysts. Freshwater irrigation and rubbing lead to further sting-
after resolution of primary symptoms has been described.
ing by adherent nematocysts and should be avoided.
The affected part should be immersed immediately in hot water
After decontamination, topical application of an anesthetic oint-
to tolerance (up to 45°C/113°F). Pedicellariae should be removed by
ment (lidocaine, benzocaine), an antihistamine (diphenhydramine),
shaving so that envenomation cannot continue. Accessible embedded
or a glucocorticoid (hydrocortisone) may be helpful. Persistent severe
spines should be removed but may break off and remain lodged in
pain after decontamination may be treated with morphine, meperidine,
fentanyl, or another narcotic analgesic. Muscle spasms may respond
to diazepam (2–5 mg, titrated upward as necessary) or 10% calcium
gluconate (5–10 mL) given IV. An ovine-derived IgG antivenom is
available from Commonwealth Serum Laboratories (see “Sources of
Antivenoms and Other Assistance,” below) for stings from the box jel-
lyfish found in Australian and Indo-Pacific waters. However, despite
its reported clinical efficacy, one school of thought holds that perhaps
the antivenom is unable to bind the venom rapidly enough to account
for its effects. Until further notice, current recommendations for its
use apply. Treatment for Irukandji syndrome may require administra-
tion of opioid analgesics and MgSO4 as well as aggressive treatment
(phentolamine, 5 mg IV) of hypertension. All victims with systemic
reactions should be observed for at least 6–8 h for rebound from any
therapy, and all elderly adults should be checked for cardiac arrhyth-
mias. Patients may suffer postinflammatory hyperpigmentation and
persistent cutaneous hypersensitivity in areas of skin contact.
Safe Sea, a “jellyfish-safe” sunblock ( applied to
the skin before an individual enters the water, inactivates the recog- Figure 474-4  Rash on the hand of a diver from the spines of a
nition and discharge mechanisms of nematocysts, has been tested bristleworm. (Courtesy of Paul Auerbach, with permission.)

HPIM19_Part18_p2733-p2752.indd 2739 2/9/15 4:40 PM

2740 the victim. Residual dye from the surface of a spine remaining after lunulata). Although these animals rarely exceed 20 cm in length,
the spine’s removal may mimic a retained spine but is otherwise of no their salivary venom contains a potent neurotoxin (maculotoxin) that
consequence. Soft tissue radiography or MRI can confirm the presence inhibits peripheral nerve transmission by blocking sodium conduc-
of retained spines, which may warrant referral for attempted surgical tance. Oral numbness and facial numbness develop within several
removal if the spines are near vital structures (e.g., joints, neurovascu- minutes of a serious envenomation and rapidly progress to total flaccid
lar bundles). Retained spines may cause the formation of granulomas paralysis, including failure of respiratory muscles. Immediately after
that are amenable to excision or to intralesional injection with triam- envenomation, a circumferential pressure-immobilization dressing
cinolone hexacetonide (5 mg/mL). Chronic granulomatous arthritis of 15 cm wide should be applied over a gauze pad (~7 × 7 × 2 cm) that
the proximal interphalangeal joints has been treated with synovectomy has been placed directly over the sting. The dressing should be applied
and removal of granulation tissue. Erbium-YAG laser ablation has at venous-lymphatic pressure, with the preservation of distal arterial
been deployed to destroy multiple sea urchin spines embedded in the pulses. The limb should then be splinted. Once the victim has been
foot and identified visually at the surface level without causing thermal transported to the nearest medical facility, the bandage can be released.
necrosis of the adjacent tissues. Eosinophilic pneumonia and local and Because there is no antidote and passive immunotherapy (rabbit IgG

diffuse neuropathies have been observed separately after penetration antibody) has been proven effective only against tetrodotoxin in mice,
by multiple spines of the black sea urchin (presumed Diadema species). treatment is supportive. Patients with respiratory failure may need
The pathophysiologies of these phenomena have not been determined. to be mechanically ventilated. If respirations are assisted, the victim
may remain awake although completely paralyzed. Even with serious
Starfish  The crown-of-thorns Acanthaster planci produces venom
envenomations, significant recovery often takes place within 4–10
in glandular tissue underneath the epidermis, which is released via its
h, although complete recovery may require 2–4 days. Sequelae are
spiny surfaces (Fig. 474-5). Skin puncture causes pain, bleeding, and
Poisoning, Drug Overdose, and Envenomation

uncommon unless related to hypoxia.

local edema, usually with remission over 30–180 min. Multiple punc-
tures may result in reactions such as local muscle paralysis; retained
fragments may cause granulomatous lesions and synovitis. There has VERTEBRATES
also been a case report of elevated liver enzymes after A. planci enven- As for all penetrating injuries, first-aid care should be undertaken. In
omation. Envenomed persons benefit from acute immersion therapy addition, consideration must be given to local wound infection by marine
in hot water, local anesthesia, wound cleansing, and possible explora- Vibrio species and freshwater Aeromonas hydrophila as well as other
tion to remove foreign material. “aquatic bacteria,” particularly if spines and needles remain embedded.
Sea Cucumbers  Sea cucumbers produce holothurin (a cantharin-like Stingrays  A stingray injury is both an envenomation and a traumatic
liquid toxin) in their body walls. This toxin is concentrated in the wound. Thoracic and cardiac penetration, major vessel laceration, and
tentacular organs that are projected when the animal is threatened. compartment syndrome have all been observed. The venom, which
Underwater, holothurin induces minimal contact dermatitis in the contains serotonin, 5′-nucleotidase, and phosphodiesterase, causes
skin but can cause significant corneal and conjunctival irritation. A immediate, intense pain that may last up to 48 h. The wound is very
severe reaction can lead to blindness. Skin should be detoxified with painful (with the pain peaking at 30–60 min and lasting up to 48 h),
5% acetic acid (vinegar), papain, or isopropyl alcohol. The eye should often becomes ischemic in appearance, and heals poorly, with adjacent
be anesthetized with one or two drops of 0.5% proparacaine and irri- soft tissue swelling and prolonged disability. Systemic effects include
gated with 100–250 mL of normal saline, with subsequent slit-lamp weakness, diaphoresis, nausea, vomiting, diarrhea, dysrhythmias,
examination to identify corneal defects. syncope, hypotension, muscle cramps, fasciculations, paralysis, and
Cone Snails  Cone snails use a detachable dartlike tooth to inject cono- (in rare cases) death. Because of differences in the toxins present on
toxins into prey, inducing tetanus followed by paralysis. In an unknow- the tissues covering the stingers, freshwater stingrays may cause more
ing handler, stings result in small, burning punctate wounds followed severe injuries than marine stingrays.
by local ischemia, cyanosis, and numbness. Dysphagia, syncope, dysar-
Scorpionfish  The designation scorpionfish encompasses members of
thria, ptosis, blurred vision, and pruritus have also been documented.
the family Scorpaenidae and includes not only scorpionfish but also
Some envenomations induce paralysis leading to respiratory failure,
lionfish and stonefish. A complex venom with neuromuscular toxic-
coma, and death. There is no antivenom. Pressure-immobilization
ity is delivered through 12 or 13 dorsal, 2 pelvic, and 3 anal spines.
(see “Octopuses,” below), hot-water soaks, and local anesthetics have
In general, the sting of a stonefish is regarded as the most serious
been used empirically with success. The wound should be inspected for
(severe to life-threatening); that of the scorpionfish is of intermediate
a foreign body. Edrophonium has been recommended as therapy for
seriousness; and that of the lionfish is the least serious. Like that of a
paralysis if a Tensilon test is positive.
stingray, the sting of a scorpionfish is immediately and intensely pain-
Octopuses  Serious envenomations and deaths have followed bites of ful. Pain from a stonefish envenomation may last for days. Systemic
Australian blue-ringed octopuses (Octopus maculosus and Octopus manifestations of scorpionfish stings are similar to those of stingray
envenomations but may be more pronounced, particularly in the case
of a stonefish sting, which may cause severe local tissue necrosis in
addition to vital organ failure. The rare deaths that follow stonefish
envenomation usually occur within 6–8 h. There is a commercially
available stonefish antivenom.
Other Fish  Three species of marine catfish—Plotosus lineatus (oriental
catfish), Bagre marinus (sail catfish), and Galeichthys felis (common
sea catfish)—as well as several species of freshwater catfish are capable
of stinging humans. Venom is delivered through a single dorsal spine
and two pectoral spines. Clinically, a catfish sting is comparable to that
of a stingray, although marine catfish envenomations are generally
more severe than those of their freshwater counterparts. Surgeonfish
(doctorfish, tang), weeverfish, ratfish, and horned venomous sharks
have also envenomed humans.
Platypus  The platypus is a venomous mammal. The male has a kera-
Figure 474-5  Spines on the crown-of-thorns sea star (Acanthaster tinous spur on each hind limb; the spur is connected to a venom gland
planci). (Courtesy of Paul Auerbach, with permission.) within the upper thigh. Skin puncture causes soft tissue edema and

HPIM19_Part18_p2733-p2752.indd 2740 2/9/15 4:40 PM

pain that may last for days or weeks. Care is supportive, and hot-water 2741
therapy does not appear to benefit the victim.

TREATMENT  Marine Vertebrate Stings

The stings of all marine vertebrates are treated in a similar fashion.
Except for stonefish and serious scorpionfish envenomations (see
below), no antivenom is available. The affected part should be
immersed immediately in nonscalding hot water (45°C/113°F) for
30–90 min or until there is significant relief from pain. Recurrent

pain may respond to repeated hot-water treatment. Cryotherapy
is contraindicated, and no data support the use of antihistamines
or steroids. Opiates will help alleviate the pain, as will local wound
infiltration or regional nerve block with 1% lidocaine, 0.5% bupiva-
caine, and sodium bicarbonate mixed in a 5:5:1 ratio. After soaking
and anesthetic administration, the wound must be explored and
debrided. Radiography (in particular, MRI) may be helpful in iden-
tification of foreign bodies. After exploration and debridement,

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

the wound should be irrigated vigorously with warm sterile water,
saline, or 1% povidone-iodine in solution. Bleeding usually can be
controlled by sustained local pressure for 10–15 min. In general,
wounds should be left open to heal by secondary intention or
treated by delayed primary closure. Tetanus immunization should
be updated. Antibiotic treatment should be considered for serious
wounds and for envenomation in immunocompromised hosts. The
initial antibiotics should cover Staphylococcus and Streptococcus
species. If the victim is immunocompromised, if a wound is primar-
ily repaired and is more than minor, or if an infection develops,
antibiotic coverage should be broadened to include Vibrio species.
Infection with Aeromonas species is of similar concern for wounds
associated with natural freshwater.


Marine Envenomations
Figure 474-6  Spiny sea urchins. (Courtesy of Dr. Paul Auerbach, with
It is useful to be familiar with the local marine fauna and to recog- permission.)
nize patterns of injury.
A large puncture wound or jagged laceration (particularly on the
Divers Alert Network, a nonprofit organization designed to assist
lower extremity) that is more painful than one would expect from the
in the care of injured divers, also may help with the treatment of
size and configuration of the wound is likely to be a stingray enven-
marine injuries. The network can be reached on the Internet at www
omation. Smaller punctures, as described above, represent the activ- or by telephone 24 h a day at (919) 684-9111.
ity of a sea urchin (Fig. 474-6) or starfish. Stony corals cause rough
An antivenom for the box jellyfish (C. fleckeri) and another for stonefish
abrasions and, in rare instances, lacerations or puncture wounds.
Coelenterate (marine invertebrate) stings sometimes create
diagnostic skin patterns. A diffuse urticarial rash on exposed skin
is often indicative of exposure to fragmented hydroids or larval
anemones. A linear, whiplike print pattern appears where a jelly-
fish tentacle has contacted the skin. In the case of the dreaded box
jellyfish, a cross-hatched appearance, followed by development of
dark purple coloration within a few hours of the sting, heralds skin
necrosis. A frosted appearance may be created by aluminum salt–
based remedies applied to the wound. An encounter with fire coral
causes immediate pain and swollen red skin irritation in the pattern
of contact, similar to but more severe than the imprint left by expo-
sure to an intact feather hydroid. Seabather’s eruption, caused by
thimble jellyfishes and larval anemones, may produce a diffuse rash
that consists of clusters of erythematous macules or raised papules
and is accompanied by intense itching (Fig. 474-7). Toxic sponges
create a burning and painful red rash on exposed skin, which may
blister and later desquamate. Because virtually all marine stingers
invoke the sequelae of inflammation, local erythema, swelling, and
adenopathy are fairly nonspecific.


The best way to locate a specific antivenom in the United States Figure 474-7  Erythematous, papular rash typical of seabather’s
is to call a regional poison control center and ask for assistance. eruption caused by thimble jellyfish and larval anemones.

HPIM19_Part18_p2733-p2752.indd 2741 2/9/15 4:40 PM

2742 (and severe scorpionfish) envenomation are made in Australia by the with locomotor ataxia, dysmetria, and resting or kinetic tremor. This
Commonwealth Serum Laboratories (CSL; 45 Poplar Road, Parkville, syndrome may persist for 2–6 weeks.
Victoria, Australia 3052;; 61-3-9389-1911). When
Diagnosis  The differential diagnosis of ciguatera includes paralytic
administering the box jellyfish antivenom, time is of the essence.
shellfish poisoning, eosinophilic meningitis, type E botulism, organo-
For cardiac or respiratory decompensation, give a minimum of one
phosphate insecticide poisoning, tetrodotoxin poisoning, and psycho-
ampoule and up to six ampoules consecutively IV, preferably in a 1:10
genic hyperventilation. At present, the diagnosis of ciguatera poisoning
dilution with normal saline. For stonefish (or severe scorpionfish)
is made on clinical grounds because no routinely used laboratory test
envenomation, give one ampoule of specific antivenom IM for every
detects ciguatoxin in human blood. Liquid chromatography–mass
one or two punctures, to a maximum of three ampoules.
spectrometry is available for ciguatoxins but is of limited clinical
value because most health care institutions do not have the equipment
MARINE POISONINGS needed to perform the test. A ciguatoxin enzyme immunoassay or
CIGUATERA radioimmunoassay may be used to test small portions of the suspected

Epidemiology and Pathogenesis  Ciguatera poisoning is the most com- fish, but even these tests may not detect the very small amount of toxin
mon nonbacterial food poisoning associated with fish in the United (0.1 ppb) necessary to render fish flesh toxic. A newer neuroblastoma
States; most U.S. cases occur in Florida and Hawaii, although, with assay may be sufficiently sensitive to detect small amounts of toxin but
transportation of imported fish nationwide, all clinicians need to be is not readily available for clinical use.
aware of ciguatera. The poisoning almost exclusively involves tropical
and semitropical marine coral reef fish common in the Indian Ocean, TREATMENT Ciguatera Poisoning
the South Pacific, and the Caribbean Sea. Global estimates predict
Poisoning, Drug Overdose, and Envenomation

that 20,000–50,000 people may be affected by this poisoning each Therapy is supportive and based on symptoms. Nausea and vom-
year. More than 400 different fish have been associated with ciguatera iting may be controlled with an antiemetic such as ondansetron
toxicity, but 75% of poisonings involve the reef-dwelling barracuda, (4–8 mg IV). Syrup of ipecac and activated charcoal are not recom-
snapper, jack, or grouper. Ciguatera toxin is created by warm-water mended for ciguatera poisoning. Hypotension may require the
ocean reef microalgae of the genus Gambierdiscus toxicus, whose con- administration of IV crystalloid and, in rare cases, a pressor drug.
sumption by grazing fish allows the toxin to bioaccumulate in the food Bradyarrhythmias that lead to cardiac insufficiency and hypoten-
chain. Three major ciguatoxins are found in the flesh and viscera of sion generally respond well to atropine (0.5 mg IV, up to 2 mg).
ciguateric fish: CTX-1, -2, and -3. Recent research suggests that CTX-1 Goal-directed combination cardiovascular fluid and pressor therapy
activates astrocytes and astroglia. In addition, TRPV1, a nonselective may be required. Cool showers or the administration of hydroxyzine
cation channel expressed in nociceptive neurons, may play a role in (25 mg PO every 6–8 h) may relieve pruritus. Amitriptyline (25 mg
the neurologic disturbances unique to ciguatera poisoning. Most, if not PO twice a day) reportedly alleviates pruritus and dysesthesias. In
all, ciguatoxins are unaffected by freeze-drying, heat, cold, and gastric three cases unresponsive to amitriptyline, tocainide has appeared
acid. None of the toxins affects the odor, color, or taste of fish. Cooking to be efficacious. Nifedipine has been used to treat headache and
methods may alter the relative concentrations of the various toxins. poor circulation in order to prevent hypotension, but only after
the initial acute phase of the poisoning has passed. IV infusion of
Clinical Manifestations  The onset of symptoms may come within 15–30 mannitol may be beneficial in moderate or severe cases in fluid-
min of ingestion and typically takes place within 2–6 h. Symptoms repleted patients, particularly for the relief of distressing neurologic
increase in severity over the ensuing 4–6 h. Most victims develop or cardiovascular symptoms, although the efficacy of this therapy
symptoms within 12 h of ingestion, and virtually all are afflicted has been challenged and has not been definitively proved. The infu-
within 24 h. The more than 150 signs and symptoms reported include sion is rendered initially as 1 g/kg per day over 45–60 min during
those shown in Table 474-3. Diarrhea, vomiting, and abdominal pain the acute phase (days 1–5). If symptoms improve, a second dose
usually develop 3–6 h after ingestion of a ciguatoxic fish. Symptoms may be given within 3–4 h and a third dose may be administered
may persist for 48 h and then generally resolve (even without treat- the next day. Care must be taken to avoid dehydration in a treated
ment). A pathognomonic symptom is the reversal of hot and cold patient. The mechanism of the benefit against ciguatera intoxica-
tactile perception, which develops in some persons after 3–5 days and tion is perhaps hyperosmotic water-drawing action, which reverses
may last for months. More severe reactions tend to occur in persons ciguatoxin-induced Schwann cell edema. Mannitol may also act in
previously stricken with the disease. Persons who have ingested par- some fashion as a “hydroxyl scavenger” or may competitively inhibit
rotfish (scaritoxin) may develop classic ciguatera poisoning as well as ciguatoxin at the cell membrane.
a “second-phase” syndrome (after 5–10 days’ delay) of disequilibrium During recovery from ciguatera poisoning, the victim should
exclude the following from the diet for 6 months: fish (fresh or pre-
served), fish sauces, shellfish, shellfish sauces, alcoholic beverages,
  TABLE 474-3    Representative Signs and Symptoms of Ciguatera nuts, and nut oils. Consumption of fish in ciguatera-endemic regions
Poisoning should be avoided. All oversized fish of any predacious reef species
System Signs/Symptoms should be suspected of harboring ciguatoxin. Neither moray eels
nor the viscera of tropical marine fish should ever be eaten.
Gastrointestinal Abdominal pain, nausea, vomiting, diarrhea
Neurologic Paresthesias, pruritus, tongue and throat numbness or
burning, sensation of  “carbonation” during swallowing, DIARRHETIC SHELLFISH POISONING
odontalgia or dental dysesthesias, dysphagia, tremor, fas- Diarrhetic shellfish poisoning occurs with consumption of shell-
ciculations, athetosis, meningismus, aphonia, ataxia, ver-
tigo, pain and weakness in the lower extremities, visual fish producing diarrheal illness. The first suspected incident, which
blurring, transient blindness, hyporeflexia, seizures, coma occurred in the Netherlands in 1961, was followed by outbreaks in
Dermatologic Conjunctivitis, maculopapular rash, skin vesiculations, Japan, the United Kingdom, and (most recently) China. The causative
dermatographism agents are the lipophilic compound okadaic acid and the dinophysis-
Cardiovascular Bradycardia, heart block, hypotension, central respiratory toxins, which inhibit serine and threonine protein phosphatases, with
failurea consequent protein accumulation and continued secretion of fluid in
Other Chills, dysuria, dyspnea, dyspareunia, weakness, fatigue, intestinal cells leading to diarrhea. Shellfish acquire these toxins by
nasal congestion and dryness, insomnia, sialorrhea, dia- feeding on dinoflagellates, particularly of the genera Dinophysis and
phoresis, headache, arthralgias, myalgias Prorocentrum.
Tachycardia and hypertension may occur after potentially severe transient bradycardia Symptoms include diarrhea, nausea, vomiting, abdominal pain, and
and hypotension. Death is rare. chills. Onset occurs within 30 min to 12 h. The illness is usually

HPIM19_Part18_p2733-p2752.indd 2742 2/9/15 4:40 PM

self-limited; most patients recover in 3 or 4 days, and only a few tissue-culture bioassay. A polyclonal enzyme-linked immunosor- 2743
require hospitalization. Treatment is supportive and focused on hydra- bent assay (ELISA) to measure specific toxins is under development,
tion. Toxins can be detected in food samples by a mouse bioassay, an as is HPLC-FLD. In addition, an inhibition immunoassay that may be
immunoassay, and high-performance liquid chromatography with able to simultaneously detect paralytic shellfish, diarrhetic shellfish,
fluorometric detection (HPLC-FLD). and amnesic shellfish toxins is being investigated.


Paralytic shellfish poisoning is induced by ingestion of any of a variety DOMOIC ACID INTOXICATION (AMNESTIC SHELLFISH POISONING)
of feral or aquacultured filter-feeding organisms, including clams, In late 1987 in eastern Canada, an outbreak of gastrointestinal and
oysters, scallops, mussels, chitons, limpets, starfish, and sand crabs. neurologic symptoms (amnestic shellfish poisoning) was documented
The origin of their toxicity is the chemical toxin they accumulate and in persons who had consumed mussels found to be contaminated with
concentrate by feeding on various planktonic dinoflagellates (e.g., domoic acid. In this outbreak, the source of the toxin was Nitzschia

Protogonyaulax, Ptychodiscus, and Gymnodinium) and protozoan pungens, a diatom ingested by the mussels. Since the Canadian out-
organisms. The unicellular phytoplanktonic organisms form the foun- break, the toxin has been found in shellfish from the United States, the
dation of the food chain, and in warm summer months these organisms United Kingdom, and Spain. In 1991, an epidemic of domoic acid poi-
“bloom” in nutrient-rich coastal temperate and semitropical waters. In soning in the state of Washington was attributed to the consumption
the United States, paralytic shellfish poisoning is acquired primarily of razor clams. A water-soluble, heat-stable neuroexcitatory amino
from seafood harvested in the Northeast, the Pacific Northwest, and acid with biochemical analogues of kainic acid and glutamic acid,
Alaska. These planktonic species can release massive amounts of toxic domoic acid binds to the kainate type of glutamate receptor with three

Disorders Caused by Venomous Snakebites and Marine Animal Exposures

metabolites into the water and cause mortality in bird and marine times the affinity of kainic acid and is 20 times as powerful a toxin.
populations. The paralytic shellfish toxins are water soluble as well as Shellfish can be tested for domoic acid by mouse bioassay and HPLC.
heat and acid stable; they cannot be destroyed by ordinary cooking The regulatory limit for domoic acid in shellfish is 20 parts per million.
or freezing. Contaminated seafood looks, smells, and tastes normal. The abnormalities noted within 24 h of ingesting contaminated
The best-characterized, most potent, and most frequently identified mussels (Mytilus edulis) include arousal, confusion, disorientation,
paralytic shellfish toxin is saxitoxin, which takes its name from the and memory loss. The median time of onset is 5.5 h. Other prominent
Alaska butter clam Saxidomus giganteus. Saxitoxin appears to block signs and symptoms include severe headache, nausea, vomiting, diar-
sodium conductance, inhibiting neuromuscular transmission at the rhea, abdominal cramps, hiccups, arrhythmias, hypotension, seizures,
axonal and muscle membrane levels. A toxin concentration of >75 ophthalmoplegia, pupillary dilation, piloerection, hemiparesis, mut-
µg/100 g of foodstuff is considered hazardous to humans. In the 1972 ism, grimacing, agitation, emotional lability, coma, copious bronchial
New England “red tide,” the concentration of saxitoxin in blue mussels secretions, and pulmonary edema. Histologic study of brain tissue
exceeded 9000 µg/100 g of foodstuff. taken at autopsy has shown neuronal necrosis or cell loss and astro-
The onset of intraoral and perioral paresthesias (notably of the lips, cytosis, most prominently in the hippocampus and the amygdaloid
tongue, and gums) comes within minutes to a few hours after ingestion nucleus—findings similar to those in animals poisoned with kainic
of contaminated shellfish, and these paresthesias progress rapidly to acid. Several months after the primary intoxication, victims still dis-
involve the neck and distal extremities. The tingling or burning sensa- play chronic residual memory deficits and motor neuronopathy or
tion later changes to numbness. Other symptoms rapidly develop and axonopathy. Nonneurologic illness does not persist.
include light-headedness, disequilibrium, incoordination, weakness,
hyperreflexia, incoherence, dysarthria, sialorrhea, dysphagia, thirst,
diarrhea, abdominal pain, nausea, vomiting, nystagmus, dysmetria, TREATMENT Domoic Acid Intoxication
headache, diaphoresis, loss of vision, chest pain, and tachycardia. Therapy is supportive and based on symptoms. Because kainic acid
Flaccid paralysis and respiratory insufficiency may follow 2–12 h after neuropathology seems to be nearly entirely seizure mediated, the
ingestion. In the absence of hypoxia, the victim often remains alert but emphasis should be on anticonvulsive therapy, for which diazepam
paralyzed. Up to 12% of patients die. appears to be as effective as any other drug.


Treatment is supportive and based on symptoms. If the victim Scombroid fish poisoning may be the most common type of seafood
comes to medical attention within the first few hours after poison poisoning worldwide. It follows consumption of scombroid (mackerel-
ingestion, the stomach should be emptied by gastric lavage and like) fish, which include albacore, bluefin, and yellowfin tuna; mackerel;
then irrigated with 2 L (in 200-mL aliquots) of a solution of 2% saury; needlefish; wahoo; skipjack; and bonito, as well as nonscombroid
sodium bicarbonate; this intervention has not been proved to be of fish, such as dolphinfish (Hawaiian mahimahi, Coryphaena hippurus),
benefit but is based on the notion that gastric acidity may enhance kahawai, sardine, black marlin, pilchard, anchovy, herring, amberjack,
the potency of saxitoxin. Because breathing difficulty can be rapid and Australian ocean salmon. In the northeastern and mid-Atlantic
in onset, induction of emesis is not advised. The administration of United States, bluefish (Pomatomus saltatrix) has been linked to
activated charcoal (50–100 g) and a cathartic (sorbitol, 20–50 g) scombroid poisoning. Because greater numbers of nonscombroid fish
makes empirical sense because these shellfish toxins are believed to are being recognized as scombrotoxic, the syndrome may more appro-
bind well to charcoal. Some authors advise against administration priately be called pseudoallergic fish poisoning.
of magnesium-based solutions (e.g., certain cathartics), cautioning Under conditions of inadequate preservation or refrigeration, the
that hypermagnesemia may contribute to suppression of nerve musculature of these dark- or red-fleshed fish undergoes decomposi-
conduction. tion by Proteus morganii and Klebsiella pneumoniae bacteria, with con-
The most serious problem is respiratory paralysis. The victim sequent decarboxylation of the amino acid l-histidine to histamine,
should be closely observed for respiratory distress for at least 24 h histamine phosphate, and histamine hydrochloride. Histamine levels
in a hospital. With prompt recognition of ventilatory failure, endo- of 20–50 mg/100 g are noted in toxic fish, with levels >400 mg/100 g
tracheal intubation, and assisted ventilation, anoxic myocardial and on occasion. However, it is possible that some other compound may
brain injury may be prevented. If the patient survives for 18 h, the be responsible for this intoxication, because large doses of oral hista-
prognosis is good for a complete recovery. mine do not reproduce the affliction. It is proposed that this unknown
A direct human serum assay to identify the toxin responsible for agent works by inhibiting the metabolism of histamine, promoting
paralytic shellfish poisoning is not yet clinically available; the mouse degranulation of mast cells to release endogenous histamine, or acting
bioassay in widespread use may be replaced by an automated as a histamine receptor agonist. Whatever toxin or toxins are involved

HPIM19_Part18_p2733-p2752.indd 2743 2/9/15 4:40 PM

2744 are heat stable and are not destroyed by domestic or commercial cook- SCABIES
ing. Affected fish typically have a sharply metallic or peppery taste; The human itch mite, Sarcoptes scabiei var. hominis, is a common
however, they may be normal in appearance, color, and flavor. Not all cause of itching dermatosis, infesting ~300 million persons worldwide
persons who eat a contaminated fish necessarily become ill, perhaps at any one time. Gravid female mites (~0.3 mm in length) burrow
because of uneven distribution of decay within the fish. superficially within the stratum corneum, depositing three or fewer
Symptoms develop within 15–90 min of ingestion. Most cases are eggs per day. Six-legged larvae mature to eight-legged nymphs and
mild, with tingling of lips and mouth, mild abdominal discomfort, then to adults. Gravid adult females emerge to the surface of the skin
and nausea. The more severe and commonly described presentation about 8 days later and then (re)invade the skin of the same or another
includes flushing (sharply demarcated; exacerbated by ultraviolet host. Newly fertilized female mites are transferred from person to
exposure; particularly pronounced on the face, neck, and upper trunk), person mainly by direct skin-to-skin contact; transfer is facilitated by
a sensation of warmth without elevated core temperature, conjunc- crowding, poor hygiene, and sex with multiple partners. Generally,
tival hyperemia, pruritus, urticaria, and angioneurotic edema. This these mites die within a day or so in the absence of host contact.
syndrome may progress to bronchospasm, nausea, vomiting, diar- Transmission via sharing of contaminated bedding or clothing occurs

rhea, epigastric pain, abdominal cramps, dysphagia, headache, thirst, far less frequently than is often thought. In the United States, scabies
pharyngitis, gingival burning, palpitations, tachycardia, dizziness, may account for up to 5% of visits to dermatologists. Outbreaks
and hypotension. Without treatment, the symptoms generally resolve occur in preschools, hospitals, nursing homes, and other residential
within 8–12 h. Because of blockade of gastrointestinal tract histami- institutions.
nase, the reaction may be more severe in a person who is concurrently The itching and rash associated with scabies derive from a sensitiza-
ingesting isoniazid. tion reaction to the mites and their secretions/excretions. A person’s
Poisoning, Drug Overdose, and Envenomation

initial infestation remains asymptomatic for up to 6 weeks before the

onset of intense pruritus, but a reinfestation produces a hypersensitiv-
TREATMENT Scombroid Poisoning ity reaction without delay. Burrows become surrounded by inflamma-
Therapy is directed at reversing the histamine effect with antihis- tory infiltrates composed of eosinophils, lymphocytes, and histiocytes,
tamines, either H-1 or H-2. If bronchospasm is severe, an inhaled and a generalized hypersensitivity rash later develops in remote sites.
bronchodilator—or in rare, extremely severe circumstances, Immunity and associated scratching limit most infestations to <15
injected epinephrine—may be used. Glucocorticoids are of no mites per person. Hyperinfestation with thousands of mites, a condi-
proven benefit. Protracted nausea and vomiting, which may empty tion known as crusted scabies (formerly termed Norwegian scabies),
the stomach of toxin, may be controlled with a specific antiemetic, may result from glucocorticoid use, immunodeficiency, and neu-
such as ondansetron or prochlorperazine. The persistent headache rologic or psychiatric illnesses that limit the itch and/or the scratch
of scombroid poisoning may respond to cimetidine or a similar anti- response.
histamine if standard analgesics are not effective. Pruritus typically intensifies at night and after hot showers. Classic
burrows are often difficult to find because they are few in number and
may be obscured by excoriations. Burrows appear as dark wavy lines
in the upper epidermis and are 3–15 mm long. Scabetic lesions are
most common on the volar wrists and along the digital web spaces.
In males, the penis and scrotum become involved. Small papules and

vesicles, often accompanied by eczematous plaques, pustules, or nod-
Ectoparasite Infestations and ules, appear symmetrically at those sites; within intertriginous areas;
around the navel and belt line; in the axillae; and on the buttocks and
Arthropod Injuries upper thighs. Except in infants, the face, scalp, neck, palms, and soles
Richard J. Pollack, Scott A. Norton are usually spared. Crusted scabies often resembles psoriasis: both are
characterized by widespread thick keratotic crusts, scaly plaques, and
dystrophic nails. Characteristic burrows are not seen in crusted sca-
Ectoparasites include arthropods and creatures from other phyla that bies, and patients usually do not itch, although their infestations are
infest the skin or hair of animals; the host animals provide them with highly contagious and have been responsible for outbreaks of classic
sustenance and shelter. The ectoparasites may penetrate within or scabies in hospitals.
beneath the surface of the host or may attach by mouthparts and spe- Scabies should be considered in patients with pruritus and symmet-
cialized claws. These organisms may inflict direct mechanical injury, ric superficial, excoriated, papulovesicular skin lesions in characteristic
consume blood or nutrients, induce hypersensitivity reactions, inocu- locations, particularly if there is a history of household contact with
late toxins, transmit pathogens, and incite fear or disgust. Humans are an infested person. Burrows should be sought and unroofed with a
the sole or obligate hosts for many kinds of ectoparasites and serve as sterile needle or scalpel blade, and the scrapings should be examined
facultative or paratenic (accidental) hosts for many others. microscopically for mites, eggs, and fecal pellets. Examination of skin
Arthropods that are ectoparasitic or otherwise cause injury include biopsies (including superficial cyanoacrylate biopsy) or scrapings,
insects (such as lice, fleas, bedbugs, wasps, ants, bees, and flies), arach- dermatoscopic imaging of papulovesicular lesions, and microscopic
nids (spiders, scorpions, mites, and ticks), millipedes, and centipedes. inspection of clear cellophane tape lifted from lesions also may be
Certain nematodes (helminths), such as the hookworms (Chap. 256), diagnostic. In the absence of identifiable mites or eggs, the diagnosis
are ectoparasitic in that they penetrate and migrate through the skin. is based on a history of pruritus, a clinical examination, and an epide-
Infrequently encountered ectoparasites in other phyla include the pen- miologic link. Diverse kinds of dermatitis from other causes frequently
tastomes (tongue worms) and leeches. are misdiagnosed as scabies, particularly in presumed “outbreak” situ-
Arthropods may also cause injury when they attempt to take a blood ations. Scabies mites of other animals may cause transient irritation,
meal or as they defend themselves by biting, stinging, or exuding ven- but they do not reside or reproduce in human hosts.
oms. Various arachnids (spiders and scorpions), insects (bees, hornets,
wasps, ants, flies, true bugs, caterpillars, and beetles), millipedes, and
centipedes produce ill effects during these behaviors. Similarly, certain
ectoparasites (e.g., ticks, biting mites, and fleas) that typically infest Permethrin cream (5%) is less toxic than 1% lindane preparations
nonhuman animals can be medically significant. In the United States, and is effective against lindane-tolerant infestations. Scabicides are
lesions caused by arthropod bites and stings are so diverse and vari- applied thinly but thoroughly behind the ears and from the neck
able that it is rarely possible to identify the precise causative organism down after bathing—with careful application to interdigital spaces
without a bona fide specimen and taxonomic expertise. and the umbilicus and under the fingernails—and are removed

HPIM19_Part18_p2733-p2752.indd 2744 2/9/15 4:40 PM

8–14 h later with soap and water. Successful treatment of crusted lesions. Hard ticks are much more common and transmit most of the 2745
scabies requires preapplication of a keratolytic agent such as 6% tick-borne infections that are familiar to physicians and patients. Hard
salicylic acid and then of scabicides to the scalp, face, and ears. ticks attach to the host and feed for several days or sometimes for >1
Repeated treatments or the sequential use of several agents may week. At the site of hard-tick bites, small areas of induration, often
be necessary. Ivermectin has not been approved by the U.S. Food purpuric, develop and may be surrounded by an erythematous rim.
and Drug Administration (FDA) for treatment of any form of scabies, A necrotic eschar, called a tâche noire, occasionally develops. Chronic
but a single oral dose (200 μg/kg) is effective in otherwise healthy nodules (persistent tick-bite granulomas) can be several centimeters
persons; patients with crusted scabies may require two doses sepa- in diameter and may linger for months after the feeding tick has been
rated by an interval of 1–2 weeks. All FDA-approved scabicides are removed. These granulomas can be treated with injected intralesional
available solely by prescription. glucocorticoids or by surgical excision. Tick-induced fever, unas-
Within 1 day of effective treatment, scabies infestations become sociated with transmission of any pathogen, is often accompanied by
headache, nausea, and malaise but usually resolves ≤36 h after the tick

noncommunicable, but the pruritic hypersensitivity dermatitis
induced by the now-dead mites and their remnant products fre- is removed.
quently persists for weeks. Unnecessary re-treatment with topical Tick paralysis, an acute ascending flaccid paralysis that resembles
agents may provoke contact dermatitis. Antihistamines, salicylates, Guillain-Barré syndrome, is believed to be caused by one or more
and calamine lotion relieve itching during treatment, and topical toxins in tick saliva that block neuromuscular transmission and
glucocorticoids are useful for pruritus that lingers after effective decrease nerve conduction. This rare complication has followed the
treatment. To prevent reinfestations, bedding and clothing should bites of more than 60 kinds of ticks, although in the United States dog
be washed and dried on high heat or heat-pressed. Close con- and wood ticks (Dermacentor species) are most commonly involved.

Ectoparasite Infestations and Arthropod Injuries

tacts of confirmed cases, even if asymptomatic, should be treated Weakness begins symmetrically in the lower extremities ≤6 days after
simultaneously. the tick’s attachment, ascends symmetrically during several days, and
may culminate in complete paralysis of the extremities and cranial
nerves. Deep tendon reflexes are diminished or absent, but sensory
CHIGGERS AND OTHER BITING MITES examination and findings on lumbar puncture are typically normal.
Chiggers are the larvae of trombiculid (harvest) mites that normally Removal of the tick generally leads to rapid improvement within a few
feed on mice in grassy or brush-covered sites in tropical, subtropi- hours and complete recovery after several days, although the patient’s
cal, and (less frequently) temperate areas during warm months. They condition may continue to deteriorate for a full day. Failure to remove
reside on low vegetation and attach themselves to passing mammalian the tick may lead to dysarthria, dysphagia, and ultimately death from
hosts. While feeding, larvae secrete saliva with proteolytic enzymes aspiration or respiratory paralysis. Diagnosis depends on finding the
to create a tube-like invagination in the host’s skin; this stylostome tick, which is often hidden beneath scalp hair. An antiserum to the
allows the mite to imbibe tissue fluids. The stylostomal saliva is highly saliva of Ixodes holocyclus, the usual cause of tick paralysis in Australia,
antigenic and causes exceptionally pruritic papular, papulovesicular, effectively reverses paralysis caused by these ticks.
or papulourticarial lesions (≤2 cm in diameter). In people previously Removal of hard ticks during the first 36 h of attachment nearly
sensitized to salivary antigens, the papules develop within hours of always prevents transmission of the agents of Lyme disease, babesiosis,
attachment. While attached, mites appear as tiny red vesicles on the anaplasmosis, and ehrlichiosis, although several tick-borne viruses
skin. Generally, lesions vesicate and develop a hemorrhagic base. may be transmitted more quickly. Ticks should be removed by traction
Scratching, however, invariably destroys the body of a mite. Itching with fine-tipped forceps placed firmly around the tick’s mouthparts.
and burning often persist for weeks. The rash is common on the ankles Careful handling (to avoid rupture of ticks) and use of gloves may avert
and areas where clothing obstructs the further wanderings of the mites. accidental contamination with pathogens contained in tick fluids. Use
Repellents are useful for preventing chigger bites. of occlusive dressings, heat, or other substances (in an attempt to induce
Many kinds of mites that are associated with peridomestic birds and the tick to detach) merely delay tick removal. Afterward, the site of
rodents are particularly bothersome when they invade homes and bite attachment should be disinfected. Tick mouthparts sometimes remain
people. In North America, the northern fowl mite, chicken mite, tropi- in the skin but generally are shed spontaneously within days without
cal rat mite, and house mouse mite normally feed on poultry, various excision. Although somewhat controversial, current guidelines from the
songbirds, and small mammals and are abundant in and around their Centers for Disease Control and Prevention suggest that, rather than
hosts’ nests. After their natural hosts die or leave the nest, these mites awaiting the onset of erythema migrans, the results of tick testing, or
frequently invade human habitations. Although the mites are rarely seroconversion to antigens diagnostic for Lyme disease, administering
seen because of their small size, their bites can be painful and pruritic. prophylaxis with a single oral dose of doxycycline (200 mg) within 72 h
Once confirmed as the cause of irritation, rodent- and bird-associated of tick removal is appropriate in adult patients with bites thought to be
mites are best eliminated by excluding their hosts, removing the nests, associated with deer ticks (Fig. 475-1) in Lyme disease–endemic areas
and cleaning and treating the nesting area with appropriate acaricides. from Maryland to Maine and in Wisconsin and Minnesota.
Pyemotes and other mites that infest grain, straw, cheese, hay, or other
products occasionally produce similar episodes of rash and discom- LOUSE INFESTATION (PEDICULIASIS AND PTHIRIASIS)
fort and may produce a unique dermatologic “comet sign” lesion—a Nymphs and adults of all three kinds of human lice feed at least once
paisley-shaped urticarial plaque. a day, ingesting human blood exclusively. Head lice (Pediculus capitis)
Diagnosis of mite-induced dermatitides (including those caused by infest mainly the hair of the scalp, body lice (Pediculus humanus) the
chiggers) relies on confirmation of the mite’s identity or elicitation of a clothing, and crab or pubic lice (Pthirus pubis) mainly the hair of the
history of exposure to the mite’s source. Oral antihistamines or topical pubis. The saliva of lice produces a pruritic morbilliform or urticarial
steroids may suppress mite-induced pruritus temporarily but do not rash in some sensitized persons. Female head and pubic lice cement
eliminate the mites. their eggs (nits) firmly to hair, whereas female body lice cement their
eggs to clothing, particularly to threads along clothing seams. After
TICK BITES AND TICK PARALYSIS ~10 days of development within the egg, a nymph hatches. Empty eggs
Ticks attach superficially to skin and feed painlessly; blood is their may remain affixed for months thereafter.
only food. Their salivary secretions are biologically active and can pro- In North America, head lice infest ~1% of elementary school-age
duce local reactions, induce fevers, and cause paralysis in addition to children. Head lice are transmitted mainly by direct head-to-head
transmitting diverse pathogens. The two main families of ticks are the contact rather than by fomites such as shared headgear, bed linens,
hard (ixodid) and soft (argasid) ticks. Generally, soft ticks attach for hairbrushes, and other grooming implements. Chronic infestations by
<1 h, leaving red macules after they drop off. Some species in Africa, head lice tend to be asymptomatic. Pruritus, due mainly to hypersen-
the western United States, and Mexico produce painful hemorrhagic sitivity to the louse’s saliva, generally is transient and mild. Head lice

HPIM19_Part18_p2733-p2752.indd 2745 2/9/15 4:40 PM


Figure 475-2  Adult female human head louse (Pediculus capitis) on

a nit (louse-egg) comb.

Figure 475-1  Deer ticks (Ixodes scapularis, black-legged ticks) on from school, this practice increasingly is seen as unjustified and
a U.S. penny: larva (below ear), nymph (right), adult male (above), and ineffective.
Poisoning, Drug Overdose, and Envenomation

adult female (left). Body lice usually are eliminated by bathing and by changing
to laundered clothes. Application of topical pediculicides from head
to foot may be necessary for hirsute patients. Clothes and bedding
removed from a person succumb to desiccation and starvation within
are effectively deloused by heating in a clothes dryer at ≥55°C
~1 day. Head lice are not known to serve as a natural vector for any
(≥131°F) for 30 min or by heat-pressing. Emergency mass delous-
ing of persons and clothing may be warranted during periods of
Body lice remain on clothing except when feeding and generally
civil strife and after natural disasters to reduce the risk of pathogen
succumb in ≤2 days if separated from their host. In most Western
transmission by body lice.
countries, body lice are generally found on a small proportion of indi-
Pubic louse infestations are treated with topical pediculicides,
gent persons but may become increasingly prevalent after upheaval
except for eyelid infestations (pthiriasis palpebrum), which generally
associated with natural or human-caused disasters, when homeless
respond to a coating of petrolatum applied for 3–4 days.
victims are in close contact with infested individuals with whom they
share accommodations. Body lice are acquired by direct contact or by
sharing of infested clothing and bedding. These lice are vectors for MYIASIS (FLY INFESTATION)
the agents of louse-borne (epidemic) typhus (Chap. 211), louse-borne Myiasis refers to infestations by several kinds of fly larvae (maggots)
relapsing fever (Chap. 209), and trench fever (Chap. 197). Pruritic that invade living or necrotic tissues or body cavities and produce
lesions from their bites are particularly common around the neckline. different clinical syndromes, depending on the species of fly.
Chronic infestations result in a postinflammatory hyperpigmentation In forested parts of Central and South America, larvae of the human
and thickening of skin known as vagabond’s disease. botfly (Dermatobia hominis) produce furuncular (boil-like) papules or
The crab or pubic louse is transmitted mainly by sexual contact. subcutaneous nodules ≤3 cm in diameter. A gravid adult female bot-
These lice occur predominantly on pubic hair and less frequently on fly captures a mosquito or another bloodsucking insect and deposits
axillary or facial hair, including the eyelashes. Children and adults may her eggs on its abdomen. When the carrier insect attacks a human or
acquire pubic lice by sexual or close nonsexual contact. Intensely pru- bovine host several days later, the warmth and moisture of the host’s
ritic, bluish macules ~3 mm in diameter (maculae ceruleae) develop skin stimulate the eggs to hatch. The emerging larvae promptly pen-
at the site of bites. Blepharitis commonly accompanies infestations of etrate intact skin. After 6–12 weeks of development, mature larvae
the eyelashes. emerge from the skin and drop to the ground to pupate and then
Pediculiasis is often suspected upon the detection of nits firmly become adults.
cemented to hairs or in clothing. Many bona fide nits, however, are The African tumbu fly (Cordylobia anthropophaga) deposits its
dead or hatched relics of prior infestation, and pseudo-nits are fre- eggs on damp sand or leaf litter or on drying laundry, particularly that
quently misconstrued to be signs of a louse infestation. Confirmation of contaminated by urine or sweat. Larvae hatch from eggs upon contact
a louse infestation, therefore, best relies on the discovery of a live louse. with a host’s body and penetrate the skin, producing boil-like lesions
from which mature larvae emerge ~9 days later. Furuncular myiasis is
suggested by uncomfortable lesions with a central breathing pore that
TREATMENT Louse Infestation emits bubbles when submerged in water. A sensation of movement
Generally, treatment is warranted only if live lice are discovered. under the patient’s skin may cause severe emotional distress.
The presence of nits alone is evidence of a former—not necessarily Larvae that cause furuncular myiasis may be induced to emerge if
current—infestation. Mechanical removal of lice and their eggs the air pore is coated with petrolatum or another occlusive substance.
with a fine-toothed louse or nit comb (Fig. 475-2) often fails to Removal may be facilitated by injection of a local anesthetic into
eliminate infestations. Treatment of newly identified active infes- the surrounding tissue, but surgical excision is sometimes necessary
tations generally relies on a 10-min topical application of ~1% because upward-pointing spines of some species hold the larvae firmly
permethrin or pyrethrins, with a second application ~10 days later. in place.
Lice persisting after this treatment may be resistant to pyrethroids. Other fly larvae cause nonfuruncular myiasis. For example, lar-
Chronic infestations may be treated for ≤12 h with 0.5% malathion. vae of the horse botfly (Gasterophilus intestinalis) emerge from eggs
Lindane is applied for just 4 min but seems less effective and may deposited on the horse’s flanks and may come into contact with and
pose a greater risk of adverse reactions, particularly when misused. infest human beings. After penetrating human skin, these larvae rarely
Resistance of head lice to permethrin, malathion, and lindane has mature but instead may migrate for weeks in the dermis. The resulting
been reported. Newer FDA-approved topical pediculicides contain pruritic and serpiginous eruption resembles cutaneous larva migrans
benzyl alcohol, dimethicone, spinosad, and ivermectin. Although caused by canine or feline hookworms (Chap. 256). Larvae of rabbit
children infested by head lice—or those who simply have remnant and rodent botflies (Cuterebra species) occasionally cause dermal or
nits from a prior infestation—are frequently isolated or excluded tracheopulmonary myiasis.

HPIM19_Part18_p2733-p2752.indd 2746 2/9/15 4:40 PM

Certain flies are attracted to blood and pus, laying their eggs on open Internally attached leeches may detach on exposure to gargled saline 2747
or draining sores. Newly hatched larvae enter wounds or diseased skin. or may be removed by forceps.
Larvae of several types of green bottle flies (Lucilia/Phaenicia species)
usually remain superficial and confined to necrotic tissue. Specially SPIDER BITES
raised, sterile “surgical maggots” are sometimes used intentionally for Of the more than 30,000 recognized species of spiders, only ~100
wound debridement. Larvae of screwworm flies, Cochliomyia, and the defend themselves aggressively and have fangs sufficiently long to
flesh fly invade viable tissues more deeply and produce large suppu- penetrate human skin. The venom that some spiders use to immo-
rating lesions. Larvae that infest wounds also may enter body cavities bilize and digest their prey can cause necrosis of skin and systemic
such as the mouth, nose, ears, sinuses, anus, vagina, and lower urinary toxicity. Whereas the bites of most spiders are painful but not harmful,
tract, particularly in unconscious or otherwise debilitated patients. The envenomations by recluse or fiddleback spiders (Loxosceles species)
consequences range from harmless colonization to destruction of the and widow spiders (Latrodectus species) may be life-threatening.
nose, meningitis, and deafness. Treatment involves removal of mag- Identification of the offending spider is important because specific

gots and debridement of tissue. treatments exist for bites of widow spiders and because injuries attrib-
The maggots responsible for furuncular and wound myiasis also uted to spiders are frequently due to other causes. Except in cases
may cause ophthalmomyiasis. Sequelae include nodules in the eyelid, where the patient actually observes a spider immediately associated
retinal detachment, and destruction of the globe. Most instances in with the bite or fleeing from the site, lesions reported as spider-bite
which maggots are found in human feces result from deposition of reactions are most often due to other injuries or to infections with
eggs or larvae by flies on recently passed stools, not from an intestinal bacteria such as methicillin-resistant Staphylococcus aureus (MRSA).
maggot infestation.
Recluse Spider Bites and Necrotic Arachnidism  Brown recluse spiders

Ectoparasite Infestations and Arthropod Injuries

live mainly in the south-central United States and have close relatives
PENTASTOMIASIS in Central and South America, Africa, and the Middle East. Bites by
Pentastomids (tongue worms) inhabit the respiratory passages of brown recluse spiders usually cause only minor injuries, with edema
reptiles and carnivorous mammals. Human infestation by Linguatula and erythema. Envenomation, however, occasionally causes severe
serrata is common in the Middle East and results from the consump- necrosis of skin and subcutaneous tissue and more rarely causes sys-
tion of encysted larval stages in raw liver or lymph nodes of sheep temic hemolysis. These spiders are not aggressive toward humans and
and goats, which are true intermediate hosts for the tongue worms. will bite only if threatened or pressed against the skin. They hide under
Larvae migrate to the nasopharynx and produce an acute self-limiting rocks and logs or in caves and animal burrows. They invade homes and
syndrome—known as halzoun or marrara—characterized by pain and seek dark and undisturbed hiding spots in closets, in folds of clothing,
itching of the throat and ears, coughing, hoarseness, dysphagia, and or under furniture and rubbish in storage rooms, garages, and attics.
dyspnea. Severe edema may cause obstruction that requires trache- Despite their impressive abundance in some homes, these spiders
ostomy. In addition, ocular invasion has been described. Diagnostic rarely bite humans. Bites tend to occur while the victim is dressing and
larvae measuring ≤10 mm in length appear in copious nasal discharge are sustained primarily on the hands, arms, neck, and lower abdomen.
or vomitus. Individuals become infected with another type of tongue Initially, the bite is painless or may produce a stinging sensation.
worm, Armillifer armillatus, by consuming its eggs in contaminated Within the next few hours, the site becomes painful and pruritic, with
food or drink or after handling the definitive host, the African central induration surrounded by a pale ischemic zone that itself is
python. Larvae encyst in various organs but rarely cause symptoms. encircled by a zone of erythema. In most cases, the lesion resolves
Cysts may require surgical removal as they enlarge during molting, without treatment in just a few days. In severe cases, the erythema
but they usually are encountered as an incidental finding at autopsy. spreads, and the center of the lesion becomes hemorrhagic or necrotic
Parasite-induced lesions may be misinterpreted as a malignancy, with with an overlying bulla. A black eschar forms and sloughs several
the correct diagnosis confirmed histopathologically. Cutaneous larva weeks later, leaving an ulcer that eventually may create a depressed
migrans–type syndromes of other pentastomes have been reported scar. Healing usually takes place in ≤6 months but may take as long as
from Southeast Asia and Central America. 3 years if adipose tissue is involved. Local complications include injury
to nerves and secondary bacterial infection. Fever, chills, weakness,
headache, nausea, vomiting, myalgia, arthralgia, maculopapular rash,
LEECH INFESTATIONS and leukocytosis may develop ≤72 h after the bite. Reports of deaths
Medically important leeches are annelid worms that attach to their attributed to bites of North American brown recluse spiders have not
hosts with chitinous cutting jaws and draw blood through muscular been verified.
suckers. The medicinal leech (Hirudo medicinalis) is still used occa-
sionally for medical purposes to reduce venous congestion in surgical
flaps or replanted body parts. This practice has been complicated by TREATMENT Recluse Spider Bites
intractable bleeding, wound infections, myonecrosis, and sepsis due
to Aeromonas hydrophila, which colonizes the gullets of commercially Initial management includes RICE (rest, ice, compression, elevation).
available leeches. Analgesics, antihistamines, antibiotics, and tetanus prophylaxis
Ubiquitous aquatic leeches that parasitize fish, frogs, and turtles should be administered if indicated. Early debridement or surgical
readily attach to the skin of human beings and avidly suck blood. More excision of the wound without closure delays healing. Routine use
notorious are arboreal land leeches that live among moist vegetation of antibiotics or dapsone is unnecessary. Patients should be moni-
of tropical rain forests. Attachment is usually painless, and the leeches tored closely for signs of hemolysis, renal failure, and other systemic
will detach themselves when satiated with a blood meal. Hirudin, a complications.
powerful anticoagulant secreted by the leech, causes continued bleed-
ing after the leech has detached. Healing of a leech-bite wound is slow, Widow Spider Bites  The black widow spider, common in the south-
and bacterial infections are not uncommon. Several kinds of aquatic eastern United States, measures ≤1 cm in body length and 5 cm in leg
leeches in Africa, Asia, and southern Europe can enter the mouth, span and is shiny black with a red hourglass marking on the ventral
nose, and genitourinary tract and attach to mucosal surfaces at sites abdomen. Other dangerous Latrodectus species occur elsewhere in
as deep as the esophagus and trachea. Externally attached leeches temperate and subtropical parts of the world. The bites of the female
generally drop off after they have engorged, but removal is hastened widow spiders are notorious for their potent neurotoxins.
by gentle scraping aside of the anterior and posterior suckers the leech Widow spiders spin their webs under stones, logs, plants, or rock
uses for attachment and feeding. Some authorities dispute the wisdom piles and in dark spaces in barns, garages, and outhouses. Bites are
of removing leeches with alcohol, salt, vinegar, insect repellent, a flame most common in the summer and early autumn and occur when a
or heated instrument, or applications of other noxious substances. web is disturbed or a spider is trapped or provoked. The initial bite

HPIM19_Part18_p2733-p2752.indd 2747 2/9/15 4:40 PM

2748 is perceived as a sharp pinprick or may go unnoticed. Fang-puncture Of the 40 or so scorpion species in the United States, only bark
marks are uncommon. The venom that is injected does not produce scorpions—e.g., Centruroides sculpturatus (C. exilicauda) in the
local necrosis, and some persons experience no other symptoms. Southwest—produce venom that is potentially lethal to humans. This
α-Latrotoxin, the most active component of the venom, binds irrevers- venom contains neurotoxins that cause sodium channels to remain
ibly to presynaptic nerve terminals and causes release and eventual open. Such envenomations usually are associated with little swelling, but
depletion of acetylcholine, norepinephrine, and other neurotrans- prominent pain, paresthesia, and hyperesthesia can be accentuated by
mitters from those terminals. Painful cramps may spread within 60 tapping on the affected area (the tap test). These symptoms soon spread
min from the bite site to large muscles of the extremities and trunk. to other locations; dysfunction of cranial nerves and hyperexcitability
Extreme rigidity of the abdominal muscles and excruciating pain of skeletal muscles develop within hours. Patients present with restless-
may suggest peritonitis, but the abdomen is not tender on palpation ness, blurred vision, abnormal eye movements, profuse salivation, lac-
and surgery is not warranted. The pain begins to subside during the rimation, rhinorrhea, slurred speech, difficulty in handling secretions,
first 12 h but may recur during several days or weeks before resolving diaphoresis, nausea, and vomiting. Muscle twitching, jerking, and shak-
spontaneously. A wide range of other neurologic sequelae may include ing may be mistaken for a seizure. Complications include tachycardia,

salivation, diaphoresis, vomiting, hypertension, tachycardia, labored arrhythmias, hypertension, hyperthermia, rhabdomyolysis, and acido-
breathing, anxiety, headache, weakness, fasciculations, paresthesia, sis. Symptoms progress to maximal severity in ~5 h and subside within a
hyperreflexia, urinary retention, uterine contractions, and premature day or two, although pain and paresthesia can last for weeks. Fatal respi-
labor. Rhabdomyolysis and renal failure have been reported, and respi- ratory arrest is most common among young children and the elderly.
ratory arrest, cerebral hemorrhage, or cardiac failure may end fatally, Envenomations by Leiurus quinquestriatus in the Middle East
especially in very young, elderly, or debilitated persons. and North Africa, by Mesobuthus tamulus in India, by Androctonus
Poisoning, Drug Overdose, and Envenomation

species along the Mediterranean littoral and in North Africa and the
Middle East, and by Tityus serrulatus in Brazil cause massive release
TREATMENT Widow Spider Bites of endogenous catecholamines with hypertensive crises, arrhythmias,
pulmonary edema, and myocardial damage. Acute pancreatitis occurs
Treatment consists of RICE and tetanus prophylaxis. Hypertension with stings of Tityus trinitatis in Trinidad, and central nervous toxic-
that does not respond to analgesics and antispasmodics (e.g., ben- ity complicates stings of Parabuthus and Buthotus scorpions of South
zodiazepines or methocarbamol) requires specific antihypertensive Africa. Tissue necrosis and hemolysis may follow stings of the Iranian
medication. The efficacy and safety of antivenoms for black widow Hemiscorpius lepturus.
and redback spiders are controversial because of concerns about Stings of most other species cause immediate sharp local pain
potential anaphylaxis or serum sickness. followed by edema, ecchymosis, and a burning sensation. Symptoms
typically resolve within a few hours, and skin does not slough. Allergic
Tarantulas and Other Spiders  Tarantulas are hairy spiders of which reactions to the venom sometimes develop.
30 species are found in the United States, mainly in the Southwest.
The tarantulas that have become popular household pets are usually
imported from Central or South America. Tarantulas bite only when TREATMENT Scorpion Stings
threatened and usually cause no more harm than a bee sting, but on Identification of the offending scorpion helps to determine the
occasion the venom causes deep pain and swelling. Several species of course of treatment. Stings of nonlethal species require at most
tarantulas are covered with urticating hairs that are brushed off in ice packs, analgesics, or antihistamines. Because most victims
the thousands when a threatened spider rubs its hind legs across its ­experience only local discomfort, they can be managed at home
dorsal abdomen. These hairs can penetrate human skin and produce with instructions to return to the emergency department if signs
pruritic papules that may persist for weeks. Failure to wear gloves or of cranial-nerve or neuromuscular dysfunction develop. Aggressive
to wash the hands after handling the Chilean Rose tarantula, a popular supportive care and judicious use of antivenom can reduce or elimi-
pet spider, has resulted in transfer of hairs to the eye with subsequent nate deaths from more severe envenomations. Keeping the patient
devastating ocular inflammation. Treatment of bites includes local calm and applying pressure dressings and cold packs to the sting
washing and elevation of the bitten area, tetanus prophylaxis, and site are measures that decrease the absorption of venom. A con-
analgesic administration. Antihistamines and topical or systemic glu- tinuous IV infusion of midazolam controls the agitation, flailing, and
cocorticoids are given for exposure to urticating hairs. involuntary muscle movements produced by scorpion stings. Close
Atrax robustus, a funnel-web spider of Australia, and Phoneutria monitoring during treatment with this drug and other sedatives or
species, the South American banana spiders, are among the most narcotics is necessary for persons with neuromuscular symptoms
dangerous spiders in the world because of their aggressive behavior because of the risk of respiratory arrest. Hypertension and pul-
and potent neurotoxins. Envenomation by A. robustus causes a rapidly monary edema respond to nifedipine, nitroprusside, hydralazine,
progressive neuromotor syndrome that can be fatal within 2 h. The or prazosin. Dangerous bradyarrhythmias can be controlled with
bite of a banana spider causes severe local pain followed by profound atropine.
systemic symptoms and respiratory paralysis that can lead to death Commercially prepared antivenoms are available in several coun-
within 2–6 h. Specific antivenoms for use after bites by each of these tries for some of the most dangerous species. An FDA-approved
spiders are available. Yellow sac spiders (Cheiracanthium species) are C. sculpturatus antivenom in horse serum is now available. IV admin-
common in homes worldwide. Their bites, though painful, generally istration of antivenom rapidly reverses cranial-nerve dysfunction
lead to only minor erythema, edema, and pruritus. and muscular symptoms. Although effective, cost analyses s­ uggest
that antivenoms should be reserved for only the most severe
Scorpions are arachnids that feed on ground-dwelling arthropods
and small lizards. They paralyze their prey and defend themselves
by injecting venom from a stinger on the tip of the tail. Painful but HYMENOPTERA STINGS
relatively harmless scorpion stings need to be distinguished from Insects that sting in defense or to subdue their prey belong to the order
the potentially lethal envenomations that are produced by ~30 of the Hymenoptera, which includes bees, wasps, hornets, yellow jackets,
~1000 known species and that cause more than 5000 deaths worldwide and ants. Their venoms contain a wide array of amines, peptides, and
each year. Scorpions are nocturnal and remain hidden during the enzymes that cause local and systemic reactions. Although the toxic
day in crevices or burrows or under wood, loose bark, or rocks. They effect of multiple stings can be fatal to a human, nearly all of the ≥100
occasionally enter houses and tents and may hide in shoes, clothing, or deaths due to hymenopteran stings in the United States each year
bedding. Scorpions sting humans only when threatened. result from allergic reactions.

HPIM19_Part18_p2733-p2752.indd 2748 2/9/15 4:40 PM

Bee and Wasp Stings  The stinger of the honeybee (Apis mellifera) is solution administered by slow push) is indicated for profound shock. 2749
unique in being barbed. When a bee stings a foe, its stinging apparatus A tourniquet may slow the spread of venom. Parenteral antihista-
and attached venom sac tear loose from its body. Muscular contrac- mines, fluid resuscitation, bronchodilators, supplemental oxygen,
tion of the venom sac continues to inject venom into the skin. Other intubation, and vasopressors may be required. Patients should be
kinds of bees, ants, and wasps have smooth stinging mechanisms and observed for 24 h for recurrent anaphylaxis.
can sting numerous times in succession. Honeybees, bumblebees, Persons with a history of allergy to insect stings should carry an
and social wasps generally attack only when a colony is disturbed. anaphylaxis kit with a preloaded syringe containing epinephrine for
Africanized honeybees (now present in South and Central America self-administration. These patients should seek medical attention
and the southern and western United States) respond to minimal immediately after using the kit.
intrusions more aggressively. Whereas the sting of an Africanized bee Repeated injections of purified venom produce a blocking IgG
contains less venom than that of its non-Africanized relatives, victims antibody response to venom and reduce the incidence of recurrent
tend to sustain far more stings and therefore to receive a far greater

anaphylaxis. Honeybee, wasp, and yellow jacket venoms are com-
overall volume of venom. Most patients who report having sustained mercially available for desensitization and for skin testing. Results of
a “bee sting,” however, are more likely to have encountered stinging skin tests and venom-specific radioallergosorbent tests (RASTs) aid
wasps instead. in the selection of patients for immunotherapy and guide the design
The venoms of different species of hymenopterans are biochemi- of such treatment.
cally and immunologically distinct. Direct toxic effects are mediated
by mixtures of low-molecular-weight compounds such as serotonin,
­histamine, acetylcholine, and several kinins. Polypeptide toxins in hon-
Stinging Ants

Ectoparasite Infestations and Arthropod Injuries

eybee venom include mellitin that damages cell membranes, mast cell–
Stinging fire ants are an important medical problem in the United
degranulating protein that causes histamine release, the neurotoxin
States. Imported fire ants (Solenopsis species) infest southern states
apamin, and the anti-inflammatory compound adolapin. Enzymes in
from Texas to North Carolina, with colonies now established in
venom include hyaluronidase and phospholipases. There appears to be
California, New Mexico, Arizona, and Virginia. Slight disturbances of
little cross-sensitization between the venoms of honeybees and wasps.
their mound nests have provoked massive outpourings of ants and as
Uncomplicated hymenopteran stings cause immediate pain, a
many as 10,000 stings on a single person. Elderly and immobile per-
wheal-and-flare reaction, and local edema, all of which usually subside
sons are at high risk for attacks when fire ants invade dwellings.
in a few hours. Multiple stings can lead to vomiting, diarrhea, general-
Fire ants attach to skin with powerful mandibles and rotate their
ized edema, dyspnea, hypotension, and non-anaphylactic circulatory
bodies while repeatedly injecting venom with posteriorly situated
collapse. Rhabdomyolysis and intravascular hemolysis may cause
stingers. The alkaloid venom consists of cytotoxic and hemolytic
renal failure. Death from the direct (nonallergic) effects of venom has
piperidines and several proteins with enzymatic activity. The initial
followed stings of several hundred honeybees. Stings to the tongue or
wheal-and-flare reaction, burning, and itching resolve in ~30 min,
mouth may induce life-threatening edema of the upper airways.
and a sterile pustule develops within 24 h. The pustule ulcerates over
Large local reactions accompanied by erythema, edema, warmth,
the next 48 h and then heals in ≥1 week. Large areas of erythema and
and tenderness that spread ≥10 cm around the sting site over 1–2 days
edema lasting several days are not uncommon and in extreme cases
are not uncommon. These reactions may resemble bacterial cellulitis
may compress nerves and blood vessels. Anaphylaxis occurs in fewer
but are caused by hypersensitivity rather than by secondary infection.
than 2% of victims; seizures and mononeuritis have been reported.
Such reactions tend to recur on subsequent exposure but are sel-
Stings are treated with ice packs, topical glucocorticoids, and oral
dom accompanied by anaphylaxis and are not prevented by venom
antihistamines. Pustules should be cleansed and then covered with
bandages and antibiotic ointment to prevent bacterial infection.
An estimated 0.4–4.0% of the U.S. population exhibits clinical
Epinephrine administration and supportive measures are indicated
immediate-type hypersensitivity to hymenopteran stings, and 15%
for anaphylactic reactions. Fire ant whole-body extracts are available
may have asymptomatic sensitization manifested by positive skin
for skin testing and immunotherapy, which appears to lower the rate
tests. Persons who experience severe allergic reactions are likely to
of anaphylactic reactions.
have similar reactions after subsequent stings by the same or closely
European fire (red) ants (Myrmica rubra) have recently become
related species. Occasionally, persons who have had mild reactions
public health pests in the northeastern United States and south-
earlier in life will experience more serious reactions to subsequent
ern Canada. The western United States is home to harvester ants
stings. Mild anaphylactic reactions from insect stings, as from other
(Pogonomyrmex species). The painful local reaction that follows
causes, consist of nausea, abdominal cramping, generalized urticaria,
harvester ant stings often extends to lymph nodes and may be accom-
flushing, and angioedema. Serious reactions, including upper airway
panied by anaphylaxis. The bullet or conga ant (Paraponera clavata)
edema, bronchospasm, hypotension, and shock, may be rapidly fatal.
of South America is known locally as hormiga veinticuatro (“24-hour
Severe reactions usually begin within 10 min of the sting and only
ant”), a designation that refers to the 24 h of throbbing, excruciating
rarely develop after 5 h.
pain following a sting that delivers the potent paralyzing neurotoxin
TREATMENT Bee and Wasp Stings
Honeybee stingers embedded in the skin should be removed as DIPTERAN (FLY AND MOSQUITO) BITES
soon as possible to limit the quantity of venom delivered. The In the process of feeding on vertebrate blood and tissue fluids, adults
stinger and venom sac may be scraped off with a blade, the edge of certain flies inflict painful bites, produce local allergic reactions, and
of a credit card, or a fingernail or may be removed with forceps. The may transmit pathogenic agents. Bites of mosquitoes, tiny “no-see-
site should be cleansed and disinfected and ice packs applied to um” (ceratopogonid) midges, and phlebotomine sand flies typically
slow the spread of venom. Elevation of the affected site and admin- produce a wheal and a pruritic papule. Small humpbacked black flies
istration of analgesics, oral antihistamines, and topical calamine (simuliids) lacerate skin, resulting in a lesion with serosanguineous
lotion help relieve symptoms. Large local reactions may require discharge that is often painful and pruritic. Regional lymphadenopa-
a short course of oral therapy with glucocorticoids. Patients with thy, fever, or anaphylaxis occasionally ensues. The widely distributed
numerous stings should be monitored for 24 h for evidence of renal deerflies and horseflies as well as the tsetse flies of Africa are stout flies
failure or coagulopathy. measuring ≤25 mm in length that attack during the day and produce
Anaphylaxis is treated with SC injection of 0.3–0.5 mL of epi- large and painful bleeding punctures. Houseflies (Musca domestica) do
nephrine hydrochloride in a 1:1000 dilution; treatment is repeated not consume blood but use rasping mouthparts to scarify skin and feed
every 20–30 min as necessary. IV epinephrine (2–5 mL of a 1:10,000 upon tissue fluids and salt. Beyond direct injury from bites of any kind

HPIM19_Part18_p2733-p2752.indd 2749 2/9/15 4:40 PM

2750 of fly, risks include transmission of diverse pathogens and secondary been reported. Treatment includes washing of the site, application of
infection of the lesion. cold dressings, oral analgesic administration or local lidocaine infiltra-
tion, and tetanus prophylaxis.
Millipedes are docile and do not bite, but some secrete defensive flu-
TREATMENT Fly and Mosquito Bites ids that may burn and discolor human skin. Affected skin turns brown
Treatment of fly bites is symptom based. Topical application of overnight and may blister and exfoliate. Secretions in the eye cause
antipruritic agents, glucocorticoids, or antiseptic lotions may relieve intense pain and inflammation that can result in corneal ulcers and
itching and pain. Allergic reactions may require oral antihistamines. even blindness. Management includes irrigation with copious amounts
Antibiotics may be necessary for the treatment of large bite wounds of water or saline, use of analgesics, and local care of denuded skin.
that become secondarily infected.
Caterpillars of several moth species are covered with hairs or spines

FLEA BITES that produce mechanical irritation and may contain or be coated
Common human-biting fleas include the dog and cat fleas with venom. Contact with these caterpillars or their hairs may lead
(Ctenocephalides species) and the rat flea (Xenopsylla cheopis), which to lepidopterism or caterpillar envenomation. The response typically
infest their respective hosts and the hosts’ nests and resting sites. consists of an immediate burning sensation followed by local swelling
Sensitized persons develop erythematous pruritic papules (papular and erythema and occasionally by regional lymphadenopathy, nausea,
urticaria) and occasionally vesicles and bacterial superinfection at the vomiting, and headache. A rare reaction to a South American caterpil-
site of the bite. Symptom-based treatment consists of antihistamines, lar, Lonomia obliqua, can cause disseminated coagulopathy and fatal
Poisoning, Drug Overdose, and Envenomation

topical glucocorticoids, and topical antipruritic agents. hemorrhagic shock. In the United States, dermatitis is most often
Flea infestations are eliminated by removal and treatment of animal associated with caterpillars of the io, puss, saddleback, and brown-tail
nests, frequent cleaning of pet bedding, and application of contact and moths. Even contact with detached hairs of other caterpillars, such as
systemic insecticides to pets and the dwelling. Flea infestations in the gypsy moth larvae, can later produce a pruritic urticarial or papular
home may be abated or prevented if pets are regularly treated with rash called erucism. Spines may be deposited on tree trunks or drying
veterinary antiparasitic agents and insect growth regulators. laundry or may be airborne and cause irritation of the eyes and upper
Tunga penetrans, like other fleas, is a wingless, laterally flattened airways. Treatment of caterpillar stings consists of repeated application
insect that feeds on blood. Also known as the chigoe flea, sand flea, of adhesive or cellophane tape to remove the hairs, which can then be
or jigger (not to be confused with the chigger), it occurs in tropical identified microscopically. Local ice packs, topical glucocorticoids, and
regions of Africa and the Americas. Adult female chigoes live in sandy oral antihistamines relieve symptoms.
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 BEETLE VESICATION AND DERMITITIS
and grow from pinpoint to pea size during a 2-week interval. They Several families of beetles have independently developed the ability
produce lesions that resemble a white pustule with a central black to produce chemically unrelated vesicating toxins. When disturbed,
depression and that may be pruritic or painful. Occasional complica- blister beetles (family Meloidae) extrude cantharidin, a low-molecular-
tions include tetanus, bacterial infections, and autoamputation of toes weight toxin that produces thin-walled blisters (≤5 cm in diameter)
(ainhum). Tungiasis is treated by removal of the intact flea with a 2–5 h after contact. The blisters are not painful or pruritic unless
sterile needle or scalpel, tetanus vaccination, and topical application broken and resolve without treatment in ≤10 days. Nephritis may fol-
of antibiotics. low unusually heavy cantharidin exposure. Contact occurs when indi-
viduals sit on the ground, work in the garden, or deliberately handle
HEMIPTERAN (TRUE BUG) BITES the beetles. The hemolymph of certain rove beetles (Staphylinidae)
Several true bugs of the family Reduviidae inflict bites that produce contains pederin, a potent vesicant. When these beetles are crushed or
allergic reactions and are sometimes painful. The cone-nose bugs, brushed against the skin, the released fluid causes painful, red, flaccid
so called because of their elongated heads, include the assassin and bullae. These beetles occur worldwide but are most numerous and
wheel bugs, which feed on other insects and bite vertebrates only problematic in parts of Africa (where they are called “Nairobi fly”) and
in self-defense, and the kissing bugs, which routinely feed on verte- southwestern Asia. Ocular lesions may develop after impact with flying
brate blood. The bites of the night-feeding kissing bugs are painless. beetles at night or unintentional transfer of the vesicant on the fingers.
Reactions to such bites depend on prior sensitization and include Treatment is rarely necessary, although ruptured blisters should be
tender and pruritic papules, vesicular or bullous lesions, extensive urti- kept clean and bandaged.
caria, fever, lymphadenopathy, and (rarely) anaphylaxis. Bug bites are Larvae of common carpet beetles are adorned with dense arrays
treated with topical antipruritics or oral antihistamines. Persons with of ornate hairs called hastisetae. Contact with these larvae or their
anaphylactic reactions to reduviid bites should keep an epinephrine setae results in delayed dermal reactions in sensitized individuals. The
kit available. Some reduviids transmit Trypanosoma cruzi, the agent of lesions are commonly mistaken as bites of bedbugs.
New World trypanosomiasis (also called Chagas disease) (Chap. 252).
The cosmopolitan bedbugs (Cimex species) hide in crevices of mat- DELUSIONAL INFESTATIONS
tresses, bed frames and other furniture, walls, and picture frames and The groundless conviction that one is infested with arthropods or
under loose wallpaper. Bedbug populations have resurged, recently other parasites (Ekbom’s syndrome, delusory parasitosis, delusions
attaining levels and spreading to an extent not encountered since the of parasitosis, and perhaps Morgellons syndrome) is extremely dif-
mid-twentieth century. These bugs are now a common pest in homes, ficult to treat and, unfortunately, is not uncommon. Patients describe
dormitories, and hotels; on cruise ships; and even in medical facilities. uncomfortable sensations of something moving in or on their skin.
Generally, the bugs hide during the day and take blood meals at night. Excoriations and self-induced ulcerations typically accompany the
Their bite is painless, but minutes to days later, sensitized persons pruritus, dysesthesias, and imaginary insect bites. Patients often
develop erythema, itching, and wheals around a central hemorrhagic believe that some invisible or as yet undescribed creatures are infest-
punctum. Bedbugs are not known to transmit pathogens. ing their skin, clothing, homes, or environment in general. Frequently,
patients submit as evidence of infestation specimens that consist of
CENTIPEDE BITES AND MILLIPEDE DERMATITIS plant-feeding and nonbiting peridomestic arthropods, pieces of skin,
The fangs of centipedes of the genus Scolopendra can penetrate human vegetable matter, lint, and other inanimate detritus. When evaluating a
skin and deliver a venom that produces intense burning pain, swell- patient with possible delusional parasitosis, it is imperative to rule out true
ing, erythema, and sterile lymphangitis. Dizziness, nausea, and anxiety infestations and bites by arthropods, endocrinopathies, sensory disorders
are described occasionally, and rhabdomyolysis and renal failure have due to neuropathies, opiate and other drug use, environmental irritants

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(e.g., fiberglass threads), and other causes of tingling or prickling infested by a previously unknown pathogen, while their personal lives, 2751
sensations. Frequently, such patients repeatedly seek medical consulta- family support, and employment collapse around them.
tions, resist alternative explanations for their symptoms, and exacer-
bate their discomfort by self-treatment. Long-term pharmacotherapy
with pimozide or other psychotropic agents has been more helpful Acknowledgment
than psychotherapy in treating this disorder. Patients with delusional The substantial contributions of Andrew Spielman and James H.
parasitosis often develop the unshakeable conviction that they are Maguire to this chapter in previous editions are gratefully acknowledged.

Ectoparasite Infestations and Arthropod Injuries

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