21 - PART 14 Poisoning, Drug Overdose, and Envenomation

01 - 469 Heavy Metal Poisoning
469 Heavy Metal Poisoning
Poisoning, Drug Overdose, and Envenomation
PART 14
Howard Hu
Heavy Metal Poisoning
Toxic metals (hereafter referred to simply as “metals”) pose a significant
threat to health through low-level as well as high level environmental
and occupational exposures. One indication of their importance rela­
tive to other potential hazards is their ranking by the U.S. Agency for
Toxic Substances and Disease Registry, which maintains an updated
list of all hazards present in toxic waste sites according to their preva­
lence and the severity of their toxicity. The first, second, third, and
seventh hazards on the list are heavy metals: arsenic, lead, mercury, and
cadmium, respectively (http://www.atsdr.cdc.gov/spl/), positions they
have held for many years. All four are also listed by the World Health
Organization as among the 10 chemicals of highest concern in relation
to health, globally. Specific information pertaining to each of these
four metals, including sources and metabolism, toxic effects produced,
diagnosis, and the appropriate treatment for poisoning, is summarized
in Table 469-1.
Metals are inhaled primarily as dusts and fumes (the latter defined
as tiny particles generated by combustion). Metal poisoning can also
result from exposure to vapors (e.g., mercury vapor in creating dental
amalgams). When metals are ingested in contaminated food or drink
or by hand-to-mouth activity (implicated especially in children), their
gastrointestinal absorption varies greatly with the specific chemical
form of the metal and the nutritional status of the host. Once a metal is
absorbed, blood is the main medium for its transport, with the precise
kinetics dependent on diffusibility, protein binding, rates of biotrans­
formation, availability of intracellular ligands, and other factors. Some
organs (e.g., bone, liver, and kidney) sequester metals in relatively high
concentrations for years. Most metals are excreted through renal clear­
ance and gastrointestinal excretion; some proportion is also excreted
through salivation, perspiration, exhalation, lactation, skin exfoliation,
and loss of hair and nails. The intrinsic stability of metals facilitates
tracing and measurement in biologic material, although the clinical
significance of the levels measured is not always clear.
Some metals, such as copper and selenium, are essential to normal
metabolic function as trace elements (Chap. 344) but are toxic at high
levels of exposure. Others, such as lead and mercury, are xenobiotic
and theoretically are capable of exerting toxic effects at any level of
exposure. Indeed, much research is currently focused on the contribu­
tion of low-level xenobiotic metal exposure to subtle changes in health,
chronic diseases, and/or increased risks of adverse events such as
heart attacks, stroke, or cancer that may have significant public health
consequences given the widespread nature of their exposures. Metals
are well-known to be able to cause toxicity through the inhibition of
enzymes, damage to subcellular organelles and DNA, covalent modifi­
cation of proteins, formation of reactive oxygen species, and displace­
ment of essential metals in metal dependent proteins. Recent research
has also elucidated how metals may affect DNA methylation and other
changes to the epigenome, thereby resulting in altered gene expression
as well as the dysregulated expression of microRNAs. Genetic factors,
such as polymorphisms that encode for variant enzymes with altered
properties in terms of metal binding, transport, and effects, may
modify the impact of metals on health. Nutritional status, comorbidi­
ties, and other factors can also contribute to variations in individual
susceptibility to metal effects.
The most important component of treatment for metal toxicity
is the recognition and termination of exposure. Chelating agents are
used to bind metals into stable cyclic compounds with relatively low
toxicity and to enhance their excretion. The principal chelating agents
are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tet­
raacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]),
and penicillamine; their specific use depends on the metal involved
and the clinical circumstances. For the most part, they are reserved for
treating acute, symptomatic metal toxicity. Activated charcoal does not
bind metals and thus is of limited usefulness in cases of acute metal
ingestion.
In addition to the information provided in Table 469-1, several other
aspects of exposure, toxicity, or management are worthy of discussion
with respect to the four most hazardous toxicants (arsenic, cadmium,
lead, and mercury).
Arsenic, even at moderate levels of exposure, has been clearly linked
with increased risks for cancer of the skin, bladder, renal pelvis, ureter,
kidney, liver, and lung. These risks appear to be modified by smoking,
folate and selenium status, genetic traits (such as ability to methylate
arsenic), and other factors. Based on the accumulation of evidence,
the American Heart Association concluded that low-level exposures
to arsenic, lead, and cadmium are risk factors for hypertension, sub­
clinical atherosclerosis, coronary artery stenosis, and calcification as
well as ischemic heart disease and stroke, left ventricular hypertrophy
and heart failure, and peripheral artery disease. Recent studies in
community-based populations have also generated strong evidence
that arsenic exposure is a risk factor for lung function impairment,
acute respiratory tract infections, respiratory symptoms, and nonma­
lignant lung disease mortality. The association with cardiovascular
disease may hold at levels of exposure in drinking water that are below
the World Health Organization (WHO) provisional guideline value of
10 μg/L. Evidence has also continued to build indicating that low-level
arsenic is a likely cause of neurodevelopmental delays in children and
likely contributes to the development of type 2 diabetes and possibly
nonalcoholic fatty liver disease and cirrhosis.
Serious cadmium poisoning from the contamination of food and
water by mining effluents in Japan contributed to the 1946 outbreak
of “itai-itai” (“ouch-ouch”) disease, so named because of cadmiuminduced bone toxicity that led to painful bone fractures. Modest expo­
sures from environmental contamination have been associated in a
growing number of studies with lower bone density, higher incidence of
fractures, and faster decline in height in both men and women, effects
that may be related to cadmium’s calciuric and other toxic effects on the
kidney. Cadmium burdens have also been associated with an increased
risk of long-term kidney graft failure, and there is evidence for synergy
between the adverse impacts of cadmium and lead on kidney function.
Environmental exposures have also been linked to lower lung function
(even after adjusting for smoking cigarettes, which contain cadmium)
and, as noted earlier, the American Heart Association considers cad­
mium as a risk factor for cardiovascular disease and mortality, stroke,
and heart failure. Cadmium triggers pulmonary inflammation, and
recent population-based studies of U.S. adults found that higher cad­
mium burdens are associated with higher mortality from influenza,
pneumonia, and COVID-19. The International Agency for Research
on Cancer has classified cadmium as a known carcinogen, with evi­
dence indicating it contributes to elevated risks of prostate, lung, breast,
and endometrial cancer. Overall, this growing body of research indi­
cates that cadmium exposure is contributing significantly to morbidity
and mortality rates in the general population.
Advances in our understanding of lead toxicity have recently ben­
efited by the development of x-ray fluorescence (KXRF) instruments
for making safe in vivo measurements of lead levels in bone, which,
in turn, reflect cumulative exposure over many years, as opposed to
blood lead levels, which mostly reflect recent exposure. Higher levels
of cumulative lead exposure in the general population are now wellestablished as a risk factor for chronic disease, even though blood lead
levels have continued to decline in the general population over the
past few decades following the removal of lead from gasoline, plumb­
ing, solder in food cans, and other consumer products, with mean
levels in the U.S. population now hovering in the 1–2 μg/dL range.
For example, higher bone lead levels measured by KXRF have been
linked to increased risk of hypertension and accelerated declines in
TABLE 469-1  Heavy Metals
MAIN SOURCES
METABOLISM
TOXICITY
DIAGNOSIS
TREATMENT
Arsenic
Smelting and
microelectronics
industries; wood
preservatives,
pesticides, herbicides,
fungicides;
contaminant of deepwater wells; folk
remedies; and coal;
incineration of these
products.
Organic arsenic
(arsenobetaine,
arsenocholine) is ingested
in seafood and fish, but
is nontoxic; inorganic
arsenic is readily
absorbed (lung and GI);
sequesters in liver, spleen,
kidneys, lungs, and GI
tract; residues persist
in skin, hair, and nails;
biomethylation results in
detoxification, but this
process saturates.
Acute arsenic poisoning results
in necrosis of intestinal mucosa
with hemorrhagic gastroenteritis,
fluid loss, hypotension, delayed
cardiomyopathy, acute tubular
necrosis, and hemolysis.
Chronic arsenic exposure causes
diabetes, vasospasm, ischemic
heart disease, peripheral vascular
insufficiency and gangrene,
peripheral neuropathy, and cancer
of skin, lung, liver (angiosarcoma),
bladder, and kidney.
Lethal dose: 120–200 mg (adults);
2 mg/kg (children).
Cadmium
Metal plating, pigment,
smelting, battery, and
plastics industries;
tobacco; incineration
of these products;
ingestion of food that
concentrates cadmium
(grains, cereals, organ
meats).
Absorbed through
ingestion or inhalation;
bound by metallothionein,
filtered at the glomerulus,
but reabsorbed by
proximal tubules (thus,
poorly excreted). Biologic
half-life: 10–30 y. Binds
cellular sulfhydryl groups,
competes with zinc,
calcium for binding sites.
Concentrates in liver and
kidneys.
Acute cadmium inhalation causes
pneumonitis after 4–24 h; acute
ingestion causes gastroenteritis.
Chronic exposure causes anosmia,
yellowing of teeth, emphysema,
minor LFT elevations, microcytic
hypochromic anemia unresponsive
to iron therapy, proteinuria,
increased urinary β2-microglobulin,
calciuria, leading to chronic renal
failure, osteomalacia, and fractures,
ischemic heart disease and stroke.
Cadmium exposure now known to
cause lung, prostate, and kidney
cancers.
PART 14
Poisoning, Drug Overdose, and Envenomation
Lead
Manufacturing of
auto batteries, lead
crystal, ceramics,
fishing weights, etc.;
demolition or sanding
of lead-painted
houses, bridges;
stained glass making,
plumbing, soldering;
environmental
exposure to paint
chips, house dust (in
homes built <1975),
firing ranges (from
bullet dust), food or
water from improperly
glazed ceramics or
lead-contaminated
cookware; lead
pipes and plumbing;
contaminated spices,
herbal remedies,
candies; exposure to
environmental pollution
from the combustion of
leaded fuels, recycling
of automobile batteries
and electronic waste.
Absorbed through
ingestion or inhalation;
organic lead (e.g.,
tetraethyl lead) absorbed
dermally. In blood, 95–99%
sequestered in RBCs—
thus, must measure
lead in whole blood
(not serum). Distributed
widely in soft tissue, with
half-life ~30 days; 15%
of dose sequestered in
bone with half-life of >20
years. Excreted mostly in
urine, but also appears
in other fluids including
breast milk. Interferes with
mitochondrial oxidative
phosphorylation, ATPases,
calcium-dependent
messengers; enhances
oxidation and cell
apoptosis.
Acute exposure with blood lead
levels (BPb) of >60–80 μg/dL can
cause impaired neurotransmission
and neuronal cell death (with central
and peripheral nervous system
effects); impaired hematopoiesis and
renal tubular dysfunction. At higher
levels of exposure (e.g., BPb >80–
120 μg/dL), acute encephalopathy
with convulsions, coma, and death
may occur. Subclinical exposures
in children (BPb 25–60 μg/dL) are
associated with anemia; mental
retardation; and deficits in language,
motor function, balance, hearing,
behavior, and school performance.
Impairment of IQ appears to occur at
even lower levels of exposure with
no measurable threshold above the
limit of detection in most assays of
1 μg/dL.
In adults, chronic subclinical
exposures (BPb >40 μg/dL) are
associated with an increased
risk of anemia, demyelinating
peripheral neuropathy (mainly
motor), impairments of reaction time
and hearing, accelerated declines
in cognition, hypertension, ECG
conduction delays, hypertension,
higher risk of cardiovascular disease
and death, interstitial nephritis and
chronic renal failure, diminished
sperm counts, and spontaneous
abortions.
Nausea, vomiting, diarrhea,
abdominal pain, delirium, coma,
seizures; garlicky odor on breath;
hyperkeratosis, hyperpigmentation,
exfoliative dermatitis, and Mees’
lines (transverse white striae of
the fingernails); sensory and motor
polyneuritis, distal weakness.
Radiopaque sign on abdominal
x-ray; ECG–QRS broadening, QT
prolongation, ST depression, T-wave
flattening; 24-h urinary arsenic >67
μmol/d or 50 μg/d; (no seafood × 24 h);
if recent exposure, serum arsenic
0.9 μmol/L (7 μg/dL). High arsenic in
hair or nails.
If acute ingestion, ipecac to
induce vomiting, gastric lavage,
activated charcoal with a
cathartic. Supportive care in ICU.
Dimercaprol 3–5 mg/kg IM
q4h × 2 days; q6h × 1 day, then
q12h × 10 days; alternative: oral
succimer.
With inhalation: pleuritic chest pain,
dyspnea, cyanosis, fever, tachycardia,
nausea, noncardiogenic pulmonary
edema. With ingestion: nausea,
vomiting, cramps, diarrhea. Bone pain,
fractures with osteomalacia. If recent
exposure, serum cadmium
500 nmol/L (5 μg/dL). Urinary cadmium
100 nmol/L (10 μg/g creatinine)
and/or urinary β2-microglobulin
750 μg/g creatinine (but urinary
β2-microglobulin also increased
in other renal diseases such as
pyelonephritis).
There is no effective treatment
for cadmium poisoning (chelation
not useful; dimercaprol can
exacerbate nephrotoxicity).
Avoidance of further exposure,
supportive therapy, vitamin D for
osteomalacia.
Abdominal pain, irritability, lethargy,
anorexia, anemia, Fanconi’s syndrome,
pyuria, azotemia in children with blood
lead level (BPb) >80 μg/dL; may also
see epiphyseal plate “lead lines” on
long bone x-rays. Convulsions, coma
at BPb >120 μg/dL. Clinically-apparent
neurodevelopmental delays can be
seen at BPb of 40–80 μg/dL with subclinical declines in IQ expected at
lower levels of BPb down to 1 μg/dL.
Screening of all U.S. children when
they begin to crawl (~6 months) is
recommended by the CDC; source
identification and intervention is
begun if the BPb >3.5 μg/dL. In adults,
acute exposure causes similar
symptoms as in children as well as
headaches, arthralgias, myalgias,
depression, impaired short-term
memory, loss of libido. Physical
examination may reveal a “lead line”
at the gingiva-tooth border, pallor,
wrist drop, and cognitive dysfunction
(e.g., declines on the mini-mental
state exam); lab tests may reveal a
normocytic, normochromic anemia,
basophilic stippling, an elevated blood
protoporphyrin level (free erythrocyte
or zinc), and motor delays on nerve
conduction. U.S. OSHA requires
regular testing of lead-exposed
workers with removal if BPb >40 μg/dL.
Newer guidelines have been
proposed recommending that BPb
be maintained at <10 μg/dL, removal
of workers if BPb >20 μg/dL, and
monitoring of cumulative exposure
parameters.
Identification and correction
of exposure sources are
critical. In the United States,
most states ask or require
primary care physicians and/
or laboratories to report all
BPbs to the appropriate health
agency. In the highly exposed
individual with symptoms,
chelation is recommended
with oral DMSA (succimer); if
acutely toxic, hospitalization
and IV or IM chelation with
ethylenediaminetetraacetic acid
calcium disodium (CaEDTA) may
be required, with the addition
of dimercaprol to prevent
worsening of encephalopathy.
A large multicenter randomized
trial of chelation showed no
improvement in measures of
intelligence among children with
asymptomatic lead exposure
(e.g., BPb 20–40 μg/dL). It is
possible but remains unclear
whether chelation among adults
with chronic lead exposure
may improve cardiovascular
outcomes. Correction of dietary
deficiencies in iron, calcium,
magnesium, and zinc will lower
lead absorption and may also
improve toxicity. Vitamin C is
a weak but natural chelating
agent. Calcium supplements
(1200 mg at bedtime) have been
shown to lower blood lead levels
in pregnant women.
(Continued)
TABLE 469-1  Heavy Metals
(Continued)
MAIN SOURCES
METABOLISM
TOXICITY
DIAGNOSIS
TREATMENT
Mercury
Metallic, mercurous,
and mercuric mercury
(Hg, Hg+, Hg2+)
exposures occur in
some chemical, metalprocessing, electrical
equipment, automotive
industries; they are also
in thermometers, dental
amalgams, batteries.
Mercury is dispersed
by waste incineration.
Environmental bacteria
convert inorganic to
organic mercury, which
then bioconcentrates
up the aquatic food
chain to contaminate
tuna, swordfish, and
other pelagic fish.
Elemental mercury (Hg)
is not well absorbed;
however, it will volatilize
into highly absorbable
vapor. Inorganic mercury
is absorbed through the
gut and skin. Organic
mercury is well absorbed
through inhalation and
ingestion. Elemental and
organic mercury cross
the blood-brain barrier
and placenta. Mercury
is excreted in urine and
feces and has a half-life
in blood of ~60 days;
however, deposits will
remain in the kidney
and brain for years.
Exposure to mercury
stimulates the kidney to
produce metallothionein,
which provides some
detoxification benefit.
Mercury binds sulfhydryl
groups and interferes with
a wide variety of critical
enzymatic processes.
Acute inhalation of Hg vapor causes
pneumonitis and noncardiogenic
pulmonary edema leading to death,
CNS symptoms, and polyneuropathy.
Chronic high exposure causes CNS
toxicity (mercurial erethism; see
Diagnosis); lower exposures impair
renal function, motor speed, memory,
coordination.
Acute ingestion of inorganic mercury
causes gastroenteritis, the nephritic
syndrome, or acute renal failure,
hypertension, tachycardia, and
cardiovascular collapse, with death
at a dose of 10–42 mg/kg.
Ingestion of organic mercury causes
gastroenteritis, arrhythmias, and
lesions in the basal ganglia, gray
matter, and cerebellum at doses
1.7 mg/kg.
High exposure during pregnancy
causes derangement of fetal
neuronal migration resulting in
severe mental retardation.
Mild exposures during pregnancy
(from fish consumption) are
associated with declines in
neurobehavioral performance in
offspring.
Dimethylmercury, a compound
only found in research labs, is
“supertoxic”—a few drops of
exposure via skin absorption or
inhaled vapor can cause severe
cerebellar degeneration and death.
Abbreviations: ATPase, adenosine triphosphatase; BPb, blood lead; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; DMSA,
dimercaptosuccinic acid; ECG, electrocardiogram; GI, gastrointestinal; ICU, intensive care unit; IQ, intelligence quotient; LFT, liver function tests; OSHA, Occupational Safety
and Health Administration; RBC, red blood cell.
cognition in both men and women living in urban communities. These
relationships, in conjunction with other epidemiologic and toxicologic
studies, persuaded multiple federal expert panels to conclude they were
causal. Prospective studies have also demonstrated that higher bone
lead levels, as well as blood lead levels as low as 1–7 μg/dL, are a major
risk factor for resistant hypertension, coronary artery calcifications,
and increased cardiovascular morbidity and mortality rates in both
community-based and occupational-exposed populations. Lead expo­
sure at community levels has also been associated with increased risks
of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis.
Occupational levels of lead exposures have been consistently linked
with adverse indices of sperm health, such as reduction in semen
volume, sperm concentration, total sperm count, sperm vitality, and
total sperm motility. With respect to pregnancy-associated risks, high
maternal bone lead levels were found to predict lower birth weight,
head circumference, birth length, and neurodevelopmental perfor­
mance in offspring by age 2 years. Offspring have also been shown to
have higher blood pressures at age 7–14 years, an age range at which
higher blood pressures are known to predict an elevated risk of devel­
oping hypertension. In a randomized trial, calcium supplementation
(1200 mg daily) was found to significantly reduce the mobilization of
lead from maternal bone into blood during pregnancy.
The toxicity of low-level organic mercury exposure (as manifested by
neurobehavioral performance) is of increasing concern based on stud­
ies of the offspring of mothers who ingested mercury-contaminated
fish. With respect to whether the consumption of fish by women
during pregnancy is good or bad for offspring neurodevelopment,
balancing the trade-offs of the beneficial effects of the omega-3-fatty
acids (FAs) in fish versus the adverse effects of mercury contamination
in fish has led to some confusion and inconsistency in public health
Chronic exposure to metallic mercury
vapor produces a characteristic
intention tremor and mercurial
erethism: excitability, memory loss,
insomnia, timidity, and delirium (“mad
as a hatter”). On neurobehavioral
tests: decreased motor speed, visual
scanning, verbal and visual memory,
visuomotor coordination.
Children exposed to mercury in any
form may develop acrodynia (“pink
disease”): flushing, itching, swelling,
tachycardia, hypertension, excessive
salivation or perspiration, irritability,
weakness, morbilliform rashes,
desquamation of palms and soles.
Toxicity from elemental or inorganic
mercury exposure begins when blood
levels >180 nmol/L (3.6 μg/dL) and
urine levels >0.7 μmol/L (15 μg/dL).
Exposures that ended years ago may
result in a >20-μg increase in 24-h
urine after a 2-g dose of succimer.
Organic mercury exposure is best
measured by levels in blood (if recent)
or hair (if chronic); CNS toxicity
in children may derive from fetal
exposures associated with maternal
hair Hg >30 nmol/g (6 μg/g).
Treat acute ingestion of
mercuric salts with induced
emesis or gastric lavage and
polythiol resins (to bind mercury
in the GI tract). Chelate with
dimercaprol (up to 24 mg/kg per
day IM in divided doses), DMSA
(succimer), or penicillamine,
with 5-day courses separated
by several days of rest. If
renal failure occurs, treat with
peritoneal dialysis, hemodialysis,
or extracorporeal regional
complexing hemodialysis and
succimer.
Chronic inorganic mercury
poisoning is best treated with
N-acetyl penicillamine.
CHAPTER 469
Heavy Metal Poisoning
recommendations. Overall, it would appear that it would be best for
pregnant women to either limit fish consumption to those species
known to be low in mercury contamination but high in omega-3-FAs
(such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs
through supplements or other dietary sources. Well-conducted studies
have convincingly debunked the contention that ethyl mercury, used
as a preservative in multiuse vaccines administered in early child­
hood, has played a significant role in causing neurodevelopmental
problems such as autism. With regard to adults, there is evidence that
mercury exposure is associated with elevated markers of dyslipidemia
and high-sensitivity C-reactive protein (a marker of chronic low-grade
inflammation), but the direct evidence as to whether mercury exposure
is associated with increased risk of hypertension and cardiovascular
disease remains somewhat conflicting. There is also some evidence
that mercury exposure in the general population is associated with the
development of diabetes, perturbations in markers of autoimmunity,
and depression. At this point, conclusions cannot be drawn and the
clinical significance of these findings remains somewhat unclear.
Heavy metals pose risks to health that are especially burdensome
in selected parts of the world. For example, arsenic exposure from
natural contamination of shallow tube wells inserted for drinking
water is a major environmental problem for millions of residents in
parts of Bangladesh and Western India. Contamination was formerly
considered only a problem with deep wells; however, the geology of
this region allows most residents only a few alternatives for potable
drinking water. Arsenic contamination of drinking water is also a
major problem in China, Argentina, Chile, Mexico, and some regions
of the United States (Maine, New Hampshire, Massachusetts). The
global campaign to phase out leaded gasoline has successfully con­
cluded. However, significant population exposures to lead remain,
particularly in the United States with respect to older housing that
contains lead paint or that receives drinking water through lead pipes,
and evidence indicates that exposures are beginning to increase again
in many low- and middle-income countries due to industrial pollution,
the recycling of automobile batteries, electronic waste, mining, and a
variety of contaminated consumer products. Populations living in the
Arctic have been shown to have particularly high exposures to mercury
due to long-range transport patterns that concentrate mercury in the
polar regions, as well as the traditional dependence of Arctic peoples
on the consumption of fish and other wildlife that bioconcentrate
methylmercury.
A few additional metals deserve brief mention but are not covered
in Table 469-1 because of the relative rarity of their being clinically
encountered or the uncertainty regarding their potential toxicities.
Aluminum contributes to the encephalopathy in patients with severe
renal disease, who are undergoing dialysis (Chap. 422). High levels
of aluminum are found in the neurofibrillary tangles in the cerebral
cortex and hippocampus of patients with Alzheimer’s disease, as well
as in the drinking water and soil of areas with an unusually high inci­
dence of Alzheimer’s. The experimental and epidemiologic evidence
for the aluminum–Alzheimer’s disease link remains relatively weak,
however, and it cannot be concluded that aluminum is a causal agent
or a contributing factor in neurodegenerative disease. Hexavalent
chromium is corrosive and sensitizing. Workers in the chromate and
chrome pigment production industries have consistently had a greater
risk of lung cancer. The introduction of cobalt chloride as a fortifier in
beer led to outbreaks of fatal cardiomyopathy among heavy consum­
ers, a condition that has also recently been reported in conjunction
with the cobalt exposure associated with metal implants used in hip
arthroplasty. Occupational exposure (e.g., of miners, dry-battery
manufacturers, and arc welders) to manganese (Mn) can cause a
parkinsonian syndrome within 1–2 years, including gait disorders;
postural instability; a masked, expressionless face; tremor; and psy­
chiatric symptoms. In contrast to typical cases of Parkinson’s disease,
manganese-induced parkinsonism is nonresponsive to treatment with
L-dopa. With the introduction of methylcyclopentadienyl manganese
tricarbonyl (MMT) as a gasoline additive, there is concern for the toxic
potential of environmental manganese exposure. Some epidemiologic
studies have found an association between the prevalence of parkin­
sonian disorders and estimated manganese exposures emitted by local
ferroalloy industries; others have found evidence suggesting that man­
ganese may interfere with early childhood neurodevelopment in ways
similar to that of lead. Manganese toxicity is clearly associated with
dopaminergic dysfunction, and its toxicity is likely influenced by age,
gender, ethnicity, genetics, and preexisting medical conditions. Nickel
exposure induces an allergic response, and inhalation of nickel com­
pounds with low aqueous solubility (e.g., nickel subsulfide and nickel
oxide) in occupational settings is associated with an increased risk of
lung cancer. Overexposure to selenium may cause local irritation of
the respiratory system and eyes, gastrointestinal irritation, liver inflam­
mation, loss of hair, depigmentation, and peripheral nerve damage.
Workers exposed to certain organic forms of tin (particularly trimethyl
and triethyl derivatives) have developed psychomotor disturbances,
including tremor, convulsions, hallucinations, and psychotic behavior.
PART 14
Poisoning, Drug Overdose, and Envenomation
Thallium, which is a component of some insecticides, metal alloys,
and fireworks, is absorbed through the skin as well as by ingestion and
inhalation. Severe poisoning follows a single ingested dose of >1 g or
8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis
precede confusion, psychosis, organic brain syndrome, and coma.
Thallium is radiopaque. Induced emesis or gastric lavage is indicated
within 4–6 h of acute ingestion; Prussian blue prevents absorption
and is given orally at 250 mg/kg in divided doses. Unlike other types
of metal poisoning, thallium poisoning may be less severe when acti­
vated charcoal is used to interrupt its enterohepatic circulation. Other
measures include forced diuresis, treatment with potassium chloride
(which promotes renal excretion of thallium), and peritoneal dialysis.
Chelation therapy remains the treatment of choice for most toxic
metals in the setting of severe acute clinical poisoning. However, the
use of chelation for treating chronic diseases remains controversial, in
part because of the lack of evidence from rigorous randomized clinical
trials. One area for which there is moderate evidence is the use of che­
lation in patients with higher than average levels of accumulated lead
burdens as a means of improving kidney function. The results from a
series of randomized trials conducted in Taiwan suggest that among
individuals with mildly elevated lead burdens (defined as between 150
and 600 μg of lead per 72-h urine upon an EDTA mobilization test
[1 g EDTA]), weekly calcium disodium EDTA chelation treatments for
between 2 and 27 months can improve renal function outcomes, both
in individuals with and without type 2 diabetes.
The Trial to Assess Chelation Therapy (TACT-1), a multicenter,
double-blind, placebo-controlled, prospective randomized trial funded
by the National Institutes of Health of 1708 patients aged ≥50 years who
had experienced a myocardial infarction (MI), found that a protocol of
repeated intravenous chelation with disodium EDTA, compared with
placebo, modestly but significantly reduced the risk of adverse cardio­
vascular outcomes, many of which were revascularization procedures.
The effect was particularly pronounced among those with concurrent
diabetes. However, the trial did not include rigorous measures of expo­
sure to lead or other metals or any selection criteria based on metals
exposure. By contrast, the recently released results of the TACT-2 trial,
which reproduced the TACT-1 protocol with the addition of measures
of metals, did not show benefit. However, the metals exposure levels
among subjects was very low, likely reflecting the known decline in
metals exposure over time in a study conducted more than 10 years
after TACT-1, and it remains unclear whether chelation has a role in
treating individuals with significant chronic metals exposure.
■
■FURTHER READING
Aalami AH et al: Carcinogenic effects of heavy metals by inducing
dysregulation of microRNAs: A review. Mol Biol Rep 49:12227, 2022.
Basu N et al: Our evolved understanding of the human health risks of
mercury. Ambio 52:877, 2023.
Chen H et al: Associations of blood lead, cadmium, and mercury with
resistant hypertension among adults in NHANES, 1999-2018. Envi­
ron Health Prev Med 28:66, 2023.
Elkin ER et al: Metals exposures and DNA methylation: Current evi­
dence and future directions. Curr Environ Health Rep 4:673, 2022.
Giulioni C et al: The influence of lead exposure on male semen
parameters: A systematic review and meta-analysis. Reprod Toxicol
118:108387, 2023.
Lamas GA et al: Contaminant metals as cardiovascular risk factors:
A scientific statement from the American Heart Association. J Am
Heart Assoc 12:e029852, 2023.
Lanphear BP et al: Low-level lead exposure and mortality in US
adults: A population-based cohort study. Lancet Public Health
3:e177, 2018.
Lucchini R, Tieu K: Manganese-induced parkinsonism: Evidence
from epidemiological and experimental studies. Biomolecules
13:1190, 2023.
Martínez-Castillo M et al: Arsenic exposure and non-carcinogenic
health effects. Hum Exp Toxicol 40:S826, 2021.
Parida L, Patel TN: Systemic impact of heavy metals and their role in
cancer development: A review. Environ Monit Assess 195:766, 2023.
Park SK et al: Environmental cadmium and mortality from influenza
and pneumonia in U.S. adults. Environ Health Perspect 128:127004,
2020.
Ravalli F et al: Chelation therapy in patients with cardiovascular dis­
ease: A systematic review. J Am Heart Assoc 11:e024648, 2022.
Shvachiy L et al: Uncovering the molecular link between lead toxicity
and Parkinson’s disease. Antioxid Redox Signal 39:321, 2023.
Smereczański NM et al: Current levels of environmental exposure to
cadmium in industrialized countries as a risk factor for kidney dam­
age in the general population: A comprehensive review of available
data. Int J Mol Sci 24:8413, 2023.
Xu L et al: Positive association of cardiovascular disease (CVD) with
chronic exposure to drinking water arsenic (As) at concentrations
below the WHO provisional guideline value: A systematic review and
meta-analysis. Int J Environ Res Public Health 17:2536, 2020.

02 - 470 Poisoning and Drug Overdose
470 Poisoning and Drug Overdose
Mark B. Mycyk
Poisoning and Drug
Overdose
Poisoning refers to the development of dose-related adverse effects
following exposure to chemicals, drugs, or other xenobiotics. To para­
phrase Paracelsus, the dose makes the poison. Although most poisons
have predictable dose-related effects, individual responses to a given
dose may vary because of genetic polymorphism, enzymatic induction
or inhibition in the presence of other xenobiotics, or acquired toler­
ance. Poisoning may be local (e.g., skin, eyes, or lungs) or systemic
depending on the route of exposure, the chemical and physical prop­
erties of the poison, and its mechanism of action. The severity and
reversibility of poisoning also depend on the functional reserve of the
individual or target organ, which is influenced by age and preexisting
disease.
EPIDEMIOLOGY
More than 5 million poison exposures occur in the United States each
year. Most are acute, are accidental (unintentional), involve a single
agent, occur in the home (>90%), result in minor or no toxicity, and
involve children <6 years of age. Pharmaceuticals are involved in 47% of
poisoning exposures and in 84% of serious or fatal poisonings. House­
hold cleaning substances and cosmetics/personal care products are the
most common nonpharmaceutical exposures reported to the National
Poison Data System (NPDS). Fatalities most commonly occur from
intentional self-harm ingestions (suicide) of pharmaceuticals or from
complications involving opioids and other psychoactive drugs of abuse.
According to the Centers for Disease Control and Prevention (CDC),
fatalities involving drugs have steadily increased since 1999. More than
106,600 deaths were attributed to drug overdose in the United States
in 2021, with an age-adjusted overdose death rate of 32.4 per 100,000.
Although prescription opioids have appropriately received attention as
a major reason for the ongoing substance use disorder epidemic in the
United States, the ever-expanding street availability of synthetic opioids
(e.g., fentanyl) and the rapid proliferation of other psychoactive drugs
of abuse (e.g., xylazine) are the main drivers of drug overdose deaths.
State prescription monitoring programs, enhanced training in pain
management for health care professionals, expanded harm reduction
services, improved outreach education to the public, and improved
partnerships with regional safety officials to monitor trends in the illicit
drug supply continue to be the main prevention and response priori­
ties for addressing this worsening epidemic. Unintentional exposures
can result from the improper use of chemicals at work or play; label
misreading; product mislabeling; mistaken identification of unlabeled
chemicals; uninformed self-medication; and dosing errors by nurses,
pharmacists, physicians, parents, and the elderly. Excluding the recre­
ational use of ethanol, attempted suicide (deliberate self-harm) is the
most common reported reason for intentional poisoning. Recreational
use of prescribed and over-the-counter drugs for psychotropic or
euphoric effects (abuse) or excessive self-dosing (misuse) is increas­
ingly common and may also result in unintentional self-poisoning.
About 20–25% of exposures require bedside health-professional
evaluation, and 5% of all exposures require hospitalization. Poisonings
account for 5–10% of all ambulance transports, emergency depart­
ment visits, and intensive care unit admissions. Hospital admissions
related to poisoning are also associated with longer lengths of stay and
increase the utilization of resources such as radiography and other
laboratory services. Up to 35% of psychiatric admissions are prompted
by attempted suicide via overdosage with cases involving adolescents
steadily increasing during the last decade. Overall, the mortality rate is
low: <1% of all poisoning exposures. It is significantly higher (1–2%)
among hospitalized patients with intentional (suicidal) overdose or
complications from drugs of abuse, who account for the majority of
serious poisonings. Acetaminophen is the pharmaceutical agent most
often implicated in fatal poisoning. Overall, carbon monoxide is the
leading cause of death from poisoning, but this prominence is not
reflected in hospital or poison center statistics because patients with
such poisoning are typically dead when discovered and are referred
directly to medical examiners.
DIAGNOSIS
Although poisoning can mimic other illnesses, the correct diagnosis
can usually be established by the history, physical examination, rou­
tine and toxicologic laboratory evaluations, and characteristic clinical
course.
■
■HISTORY
The history should include the time, route, duration, and circum­
stances (location, surrounding events, and intent) of exposure; the
name and amount of each drug, chemical, or ingredient involved; the
time of onset, nature, and severity of symptoms; the time and type of
first-aid measures provided; the medical and psychiatric history; and
occupation.
In many cases, the patient is confused, comatose, unaware of an
exposure, or unable or unwilling to admit to one. Suspicious circum­
stances include unexplained sudden illness in a previously healthy
person or a group of healthy people; a history of psychiatric problems
(particularly depression or bipolar disorder); recent changes in health,
economic status, or social relationships; and onset of illness dur­
ing work with chemicals or after ingestion of food, drink (especially
ethanol), or medications. When patients become ill soon after arriving
from a foreign country or being arrested for criminal activity, “body
packing” or “body stuffing” (ingesting or concealing illicit drugs in a
body cavity) should be suspected. Relevant information may be avail­
able from family, friends, paramedics, police, pharmacists, physicians,
and employers, who should be questioned regarding the patient’s hab­
its, hobbies, behavioral changes, available medications, and anteced­
ent events. Patients need to be asked explicitly about their prescribed
medications, use of over-the-counter or herbal medications, and
recreational drug use. Drugs previously considered “illicit” such as can­
nabinoids are now legal in many states and prescribed for therapeutic
purposes. A search of clothes, belongings, and place of discovery may
reveal a suicide note or a container of drugs or chemicals. If available,
a review of a patient’s recent social media posts may be helpful to the
treating clinician because self-harm plans involving medications or
drugs are often described there. Without a clear history in a patient
clinically suspected to be poisoned, all medications available anywhere
in the patient’s home or belongings should be considered as possible
agents, including medications for pets. Review of the patient’s record
in the state prescription monitoring program (PMP) may disclose rele­
vant history of Schedule II, III, IV, and V controlled substance use. The
imprint code on pills and the label on chemical products may be used
to identify the ingredients and potential toxicity of a suspected poison
by consulting a reference text, a computerized database, the manufac­
turer, or a regional poison information center (800-222-1222). Occupa­
tional exposures require review of any available safety data sheet (SDS)
from the worksite. Because of increasing globalization from travel and
internet consumerism, unfamiliar poisonings may result in local emer­
gency department evaluation. Pharmaceuticals, industrial chemicals,
or novel psychoactive drugs of abuse from foreign countries may be
identified with the assistance of a local medical toxicologist, a regional
poison center, or via the Internet.
CHAPTER 470
Poisoning and Drug Overdose
■
■PHYSICAL EXAMINATION AND CLINICAL COURSE
The physical examination should focus initially on vital signs, the car­
diopulmonary system, and neurologic status. The neurologic examina­
tion should include documentation of neuromuscular abnormalities
such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, and
tremors. The patient should also be examined for evidence of trauma
and underlying illnesses. Focal neurologic findings are uncommon in
poisoning, and their presence should prompt evaluation for a struc­
tural central nervous system (CNS) lesion. Examination of the eyes (for
nystagmus and pupil size and reactivity), abdomen (for bowel activity
and bladder size), and skin (for burns, bullae, color, warmth, moisture,
pressure sores, and puncture marks) may reveal findings of diagnostic
value. When the history is unclear, all orifices should be examined for
the presence of chemical burns and drug packets. The odor of breath
or vomitus and the color of nails, skin, or urine may provide important
diagnostic clues.
The diagnosis of poisoning in cases of unknown etiology primarily
relies on pattern recognition. The first step is to assess the pulse, blood
pressure, respiratory rate, pulse oximetry, temperature, and neurologic
status and to characterize the overall physiologic state as stimulated,
depressed, discordant, or normal (Table 470-1). Obtaining a complete
set of vital signs and reassessing them frequently are critical. Measuring
core temperature is especially important, even in difficult or combative
patients, since temperature elevation is the most reliable prognosticator
of poor outcome in poisoning from stimulants (e.g., cocaine) or drug
withdrawal (e.g., alcohol or γ-hydroxybutyric acid [GHB]). The next
TABLE 470-1  Differential Diagnosis of Poisoning Based on Physiologic State
STIMULATED
DEPRESSED
DISCORDANT
NORMAL
Sympathetics
  Sympathomimetics
  Ergot alkaloids
  Methylxanthines
  Monoamine oxidase inhibitors
  Thyroid hormones
Anticholinergics
  Antihistamines
  Antiparkinsonian agents
  Antipsychotics
  Antispasmodics
  Belladonna alkaloids
  Cyclic antidepressants
  Mushrooms and plants
Hallucinogens
  Cannabinoids (marijuana)
  LSD and analogues
  Mescaline and analogues
  Mushrooms
  Phencyclidine and analogues
Withdrawal syndromes
  Barbiturates
  Benzodiazepines
  Ethanol
  GHB products
  Opioids
  Sedative-hypnotics
  Sympatholytics
Sympatholytics
  α1-Adrenergic antagonists
  α2-Adrenergic agonists
  ACE inhibitors
  Angiotensin receptor blockers
  Antipsychotics
  β-Adrenergic blockers
  Calcium channel blockers
  Cardiac glycosides
  Cyclic antidepressants
Cholinergics
  Acetylcholinesterase inhibitors
  Muscarinic agonists
  Nicotinic agonists
Opioids
  Analgesics
  GI antispasmodics
  Heroin
Sedative-hypnotics
  Alcohols
  Anticonvulsants
  Barbiturates
  Benzodiazepines
  GABA precursors
  Muscle relaxants
  Other agents
  GHB products
Xylazine
PART 14
Poisoning, Drug Overdose, and Envenomation
Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA, γ-aminobutyric acid; GHB,
γ-hydroxybutyrate; GI, gastrointestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase.
step is to consider the underlying causes of the physiologic state and
to attempt to identify a pathophysiologic pattern or toxic syndrome
(toxidrome) based on the observed findings. Assessing the severity
of physiologic derangements (Table 470-2) is useful in this regard
and also for monitoring the clinical course and response to treat­
ment. In cases of polydrug overdose involving different drug classes,
identifying a clear toxidrome can be challenging if the different drugs
counteract the physiologic effects of one another. The final step is to
attempt to identify the particular agent involved by looking for unique
or relatively poison-specific physical or ancillary test abnormalities.
Distinguishing among toxidromes on the basis of the physiologic state
is summarized next.
The Stimulated Physiologic State 
Increased pulse, blood pres­
sure, respiratory rate, temperature, and neuromuscular activity charac­
terize the stimulated physiologic state, which can reflect sympathetic,
Asphyxiants
  Cytochrome oxidase inhibitors
  Inert gases
  Irritant gases
  Methemoglobin inducers
  Oxidative phosphorylation inhibitors
AGMA inducers
  Alcohol (ketoacidosis)
  Ethylene glycol
  Iron
  Methanol
  Other alcohols
  Salicylate
  Toluene
CNS syndromes
  Extrapyramidal reactions
  Hydrocarbon inhalation
  Isoniazid
  Lithium
  Neuroleptic malignant syndrome
  Serotonin syndrome
  Strychnine
Membrane-active agents
  Amantadine
  Antiarrhythmics
  Antihistamines
  Antipsychotics
  Carbamazepine
  Cyclic antidepressants
  Local anesthetics
  Opioids (some)
  Quinoline antimalarials
Nontoxic exposure
Psychogenic illness
“Toxic time-bombs”
Slow absorption
  Anticholinergics
  Carbamazepine
  Concretion formers
  Extended-release phenytoin sodium
capsules (Dilantin Kapseals)
  Drug packets
  Enteric-coated pills
  Diphenoxylate-atropine (Lomotil)
  Opioids
  Salicylates
  Sustained-release pills
  Valproate
Slow distribution
  Cardiac glycosides
  Lithium
  Metals
  Salicylate
  Valproate
Toxic metabolite
  Acetaminophen
  Carbon tetrachloride
  Cyanogenic glycosides
  Ethylene glycol
  Methanol
  Methemoglobin inducers
  Mushroom toxins
  Organophosphate insecticides
  Paraquat
Metabolism disruptors
  Antineoplastic agents
  Antiviral agents
  Colchicine
  Hypoglycemic agents
  Immunosuppressive agents
  MAO inhibitors
  Metals
  Other oral anticoagulants
  Salicylate
  Warfarin
TABLE 470-2  Severity of Physiologic Stimulation and Depression in
Poisoning and Drug Withdrawal
Physiologic Stimulation
Grade 1
Anxious, irritable, tremulous; vital signs normal; diaphoresis, flushing
or pallor, mydriasis, and hyperreflexia sometimes present
Grade 2
Agitated; may have confusion or hallucinations but can converse
and follow commands; vital signs mildly to moderately increased
Grade 3
Delirious; unintelligible speech, uncontrollable motor hyperactivity;
moderately to markedly increased vital signs; tachyarrhythmias
possible
Grade 4
Coma, seizures, cardiovascular collapse
Physiologic Depression
Grade 1
Awake, lethargic, or sleeping but arousable by voice or tactile
stimulation; able to converse and follow commands; may be
confused
Grade 2
Responds to pain but not voice; can vocalize but not converse;
spontaneous motor activity present; brainstem reflexes intact
Grade 3
Unresponsive to pain; spontaneous motor activity absent; brainstem
reflexes depressed; motor tone, respirations, and temperature
decreased
Grade 4
Unresponsive to pain; flaccid paralysis; brainstem reflexes and
respirations absent; cardiovascular vital signs decreased
anticholinergic, or hallucinogen poisoning or drug withdrawal
(Table 470-1). Other features are noted in Table 470-2. Mydriasis, a
characteristic feature of all stimulants, is most marked in anticholiner­
gic poisoning since pupillary reactivity relies on muscarinic control. In
sympathetic poisoning (e.g., due to cocaine), pupils are also enlarged,
but some reactivity to light remains. The anticholinergic toxidrome is
also distinguished by hot, dry, flushed skin; decreased bowel sounds;
and urinary retention. Other stimulant syndromes increase sympa­
thetic activity and cause diaphoresis, pallor, and increased bowel activ­
ity with varying degrees of nausea, vomiting, abnormal distress, and
occasionally diarrhea. The absolute and relative degree of vital-sign
changes and neuromuscular hyperactivity can help distinguish among
stimulant toxidromes. Since sympathetics stimulate the peripheral ner­
vous system more directly than do hallucinogens or drug withdrawal,
markedly increased vital signs and organ ischemia suggest sympathetic
poisoning. Findings helpful in suggesting the particular drug or class
causing physiologic stimulation include reflex bradycardia from selec­
tive α-adrenergic stimulants (e.g., decongestants), hypotension from
selective β-adrenergic stimulants (e.g., asthma therapeutics), limb
ischemia from ergot alkaloids, rotatory nystagmus from phencyclidine
and ketamine (the only physiologic stimulants that cause this finding),
and delayed cardiac conduction from high doses of cocaine and some
anticholinergic agents (e.g., antihistamines, cyclic antidepressants, and
antipsychotics). Seizures suggest a sympathetic etiology, an anticholin­
ergic agent with membrane-active properties (e.g., cyclic antidepres­
sants, phenothiazines), or a withdrawal syndrome. Close attention to
core temperature is critical in patients with grade 4 physiologic stimu­
lation (Table 470-2).
The Depressed Physiologic State 
Decreased pulse, blood pres­
sure, respiratory rate, temperature, and neuromuscular activity are
indicative of the depressed physiologic state caused by “functional”
sympatholytics (agents that decrease cardiac function and vascular
tone as well as sympathetic activity), cholinergic (muscarinic and
nicotinic) agents, opioids, and sedative-hypnotic γ-aminobutyric acid
(GABA)-ergic agents (Tables 470-1 and 470-2). Miosis is also common
and is most pronounced in opioid and cholinergic poisoning. Miosis
is distinguished from other depressant syndromes by muscarinic
and nicotinic signs and symptoms (Table 470-1). Pronounced car­
diovascular depression in the absence of significant CNS depression
suggests a direct or peripherally acting sympatholytic. In contrast, in
opioid and sedative-hypnotic poisoning, vital-sign changes are sec­
ondary to depression of CNS cardiovascular and respiratory centers
(or consequent hypoxemia), and significant abnormalities in these
parameters do not occur until there is a marked decrease in the level
of consciousness (grade 3 or 4 physiologic depression; Table 470-2).
Other clues that suggest the cause of physiologic depression include
cardiac arrhythmias and conduction disturbances (due to antiar­
rhythmics, β-adrenergic antagonists, calcium channel blockers, digi­
talis glycosides, propoxyphene, and cyclic antidepressants), mydriasis
(due to tricyclic antidepressants, some antiarrhythmics, meperidine,
and diphenoxylate-atropine [Lomotil]), nystagmus (due to sedativehypnotics), and seizures (due to cholinergic agents, propoxyphene, and
cyclic antidepressants).
The Discordant Physiologic State 
The discordant physiologic
state is characterized by mixed vital-sign and neuromuscular abnor­
malities, as observed in poisoning by asphyxiants, CNS syndromes,
membrane-active agents, and anion-gap metabolic acidosis (AGMA)
inducers (Table 470-1). In these conditions, manifestations of physi­
ologic stimulation and physiologic depression occur together or at
different times during the clinical course. For example, membraneactive agents can cause simultaneous coma, seizures, hypotension, and
tachyarrhythmias. Alternatively, vital signs may be normal while the
patient has an altered mental status or is obviously sick or clearly symp­
tomatic. Early, pronounced vital-sign and mental-status changes sug­
gest asphyxiant or membrane-active agent poisoning; the lack of such
abnormalities suggests an AGMA inducer; and marked neuromuscular
dysfunction without significant vital-sign abnormalities suggests a
CNS syndrome. The discordant physiologic state may also be evident
in patients poisoned with multiple agents.
CHAPTER 470
The Normal Physiologic State 
A normal physiologic status and
physical examination may be due to a nontoxic exposure, psychogenic
illness, or poisoning by “toxic time-bombs”: agents that are slowly
absorbed, are slowly distributed to their sites of action, require meta­
bolic activation, or disrupt metabolic processes (Table 470-1). Because
so many medications have now been reformulated into once-a-day
preparations for the patient’s convenience and adherence, toxic timebombs are increasingly common. Diagnosing a nontoxic exposure
requires that the identity of the exposure agent be known or that a toxic
time-bomb exposure be excluded and the time since exposure exceed
the longest known or predicted interval between exposure and peak
toxicity. Psychogenic illness (fear of being poisoned, mass hysteria)
may also follow a nontoxic exposure and should be considered when
symptoms are inconsistent with exposure history. Anxiety reactions
resulting from a nontoxic exposure can cause mild physiologic stimu­
lation (Table 470-2) and be indistinguishable from toxicologic causes
without ancillary testing or a suitable period of observation.
Poisoning and Drug Overdose
■
■LABORATORY ASSESSMENT
Laboratory assessment may be helpful in the differential diagnosis.
Increased AGMA is most common in advanced methanol, ethylene
glycol, and salicylate intoxication but can occur with any poisoning
that results in hepatic, renal, or respiratory failure; seizures; or shock.
The serum lactate concentration is more commonly low (less than the
anion gap) in the former and high (nearly equal to the anion gap) in the
latter. An abnormally low anion gap can be due to elevated blood levels
of bromide, calcium, iodine, lithium, or magnesium. An increased
osmolal gap—a difference of >10 mmol/L between serum osmolality
(measured by freezing-point depression) and osmolality calculated
from serum sodium, glucose, and blood urea nitrogen levels—suggests
the presence of a low-molecular-weight solute such as acetone; an
alcohol (benzyl, ethanol, isopropanol, methanol); a glycol (diethyl­
ene, ethylene, propylene); ether (ethyl, glycol); or an “unmeasured”
cation (calcium, magnesium) or sugar (glycerol, mannitol, sorbitol).
Ketosis suggests acetone, isopropyl alcohol, salicylate poisoning, or
alcoholic ketoacidosis. Hypoglycemia may be due to poisoning with
β-adrenergic blockers, ethanol, insulin, oral hypoglycemic agents, qui­
nine, and salicylates, whereas hyperglycemia can occur in poisoning
with acetone, β-adrenergic agonists, caffeine, calcium channel block­
ers, iron, theophylline, or N-3-pyridylmethyl-N-p-nitrophenylurea
(PNU [Vacor]). Hypokalemia can be caused by barium, β-adrenergic
agonists, caffeine, diuretics, theophylline, or toluene; hyperkalemia
suggests poisoning with an α-adrenergic agonist, a β-adrenergic
blocker, cardiac glycosides, or fluoride. Hypocalcemia may be seen
in ethylene glycol, fluoride, and oxalate poisoning. Prothrombin time
and international normalized ratio are useful for risk stratification in
cases of warfarin or rodenticide poisoning but are not to be relied on
when evaluating overdose or complications from direct oral antico­
agulant pharmaceuticals (direct thrombin inhibitors and direct factor
Xa inhibitors).
The electrocardiogram (ECG) can be useful for rapid diagnostic
purposes. Bradycardia and atrioventricular block may occur in patients
poisoned by α-adrenergic agonists, antiarrhythmic agents, beta block­
ers, calcium channel blockers, cholinergic agents (carbamate and
organophosphate insecticides), cardiac glycosides, lithium, or tricyclic
antidepressants. QRS- and QT-interval prolongation may be caused
by hyperkalemia, various antidepressants, and other membrane-active
drugs (Table 470-1). Ventricular tachyarrhythmias may be seen in
poisoning with cardiac glycosides, fluorides, membrane-active drugs,
methylxanthines, sympathomimetics, antidepressants, and agents that
cause hyperkalemia or potentiate the effects of endogenous catechol­
amines (e.g., chloral hydrate, aliphatic and halogenated hydrocarbons).
Radiologic studies may occasionally be useful. Pulmonary edema
(adult respiratory distress syndrome [ARDS]) can be caused by poi­
soning with carbon monoxide, cyanide, an opioid, paraquat, phen­
cyclidine, a sedative-hypnotic, or salicylate; by inhalation of irritant
gases, fumes, or vapors (acids and alkali, ammonia, aldehydes, chlo­
rine, hydrogen sulfide, isocyanates, metal oxides, mercury, phosgene,
polymers); or by prolonged anoxia, hyperthermia, or shock. Aspiration
pneumonia is common in patients with coma, seizures, and petroleum
distillate aspiration. Chest x-ray is useful for identifying complications
from metal fume fever or elemental mercury. The presence of radi­
opaque densities on abdominal x-rays or abdominal computed tomog­
raphy (CT) scan suggests the ingestion of chloral hydrate, chlorinated
hydrocarbons, heavy metals, illicit drug packets, iodinated compounds,
potassium salts, enteric-coated tablets, or salicylates.
PART 14
Poisoning, Drug Overdose, and Envenomation
Toxicologic analysis of urine and blood (and occasionally of gas­
tric contents and chemical samples) can sometimes confirm or rule
out suspected poisoning. Interpretation of laboratory data requires
knowledge of the qualitative and quantitative tests used for screening
and confirmation (enzyme-multiplied, fluorescence polarization, and
radio-immunoassays; colorimetric and fluorometric assays; thin-layer,
gas-liquid, or high-performance liquid chromatography; gas chroma­
tography; mass spectrometry), their sensitivity (limit of detection)
and specificity, the preferred biologic specimen for analysis, and the
optimal time of specimen sampling. Personal communication with the
hospital laboratory is essential to an understanding of institutional test­
ing capabilities and limitations.
Rapid qualitative hospital-based urine tests for drugs of abuse are
only screening tests that cannot confirm the exact identity of the
detected substance and should not be considered diagnostic or used
for forensic purposes. False-positive and false-negative results are
common. A positive screen may result from other pharmaceuticals
that interfere with laboratory analysis (e.g., fluoroquinolones com­
monly cause false-positive opiate screens). Confirmatory testing with
gas chromatography/mass spectrometry can be requested, but it often
takes weeks to obtain a reported result. A negative screening result may
mean that the responsible substance is not detectable by the test used or
that its concentration is too low for detection at the time of sampling.
For instance, recent new drugs of abuse that often result in emergency
department evaluation for unexpected complications, such as synthetic
cannabinoids (spice), cathinones (bath salts), and opiate substitutes
(kratom), are not detectable by hospital-based tests. In cases where
a drug concentration is too low to be detected early during clinical
evaluation, repeating the test at a later time may yield a positive result.
Patients symptomatic from drugs of abuse often require immediate
management based on the history, physical examination, and observed
toxidrome without laboratory confirmation (e.g., apnea from opioid
intoxication). When the patient is asymptomatic or when the clinical
picture is consistent with the reported history, qualitative screening
is neither clinically useful nor cost-effective. Thus, qualitative drug
screens are of greatest value for the evaluation of patients with severe or
unexplained toxicities, such as coma, seizures, cardiovascular instabil­
ity, metabolic or respiratory acidosis, and nonsinus cardiac rhythms. In
contrast to qualitative drug screens, quantitative serum tests are useful
for evaluation of patients poisoned with acetaminophen (Chap. 351),
alcohols (including ethylene glycol and methanol), anticonvulsants,
barbiturates, digoxin, heavy metals, iron, lithium, salicylate, and the­
ophylline, as well as for the presence of carboxyhemoglobin and met­
hemoglobin. The serum concentration in these cases guides clinical
management, and results are often available within an hour.
The response to antidotes is sometimes useful for diagnostic pur­
poses. Resolution of altered mental status and abnormal vital signs
within minutes of IV administration of dextrose, naloxone, or flu­
mazenil is virtually diagnostic of hypoglycemia, opioid poisoning,
and benzodiazepine intoxication, respectively. The prompt reversal of
dystonic (extrapyramidal) signs and symptoms following an IV dose of
benztropine or diphenhydramine confirms a drug etiology. Although
complete reversal of both central and peripheral manifestations of anti­
cholinergic poisoning by physostigmine is diagnostic of this condition,
physostigmine may cause some arousal in patients with CNS depres­
sion of any etiology.
TREATMENT
Poisoning and Drug Overdose
GENERAL PRINCIPLES
Treatment goals include support of vital signs, prevention of fur­
ther poison absorption (decontamination), enhancement of poison
elimination, administration of specific antidotes, and prevention
of reexposure (Table 470-3). Specific treatment depends on the
identity of the poison, the route and amount of exposure, the time
TABLE 470-3  Fundamentals of Poisoning Management
Supportive Care
Airway protection
Treatment of seizures
Oxygenation/ventilation
Correction of temperature
abnormalities
Treatment of arrhythmias
Correction of metabolic derangements
Hemodynamic support
Prevention of secondary complications
Prevention of Further Poison Absorption
Gastrointestinal decontamination
Decontamination of other sites
  Gastric lavage
  Eye decontamination
  Activated charcoal
  Skin decontamination
  Whole-bowel irrigation
  Body cavity evacuation
  Dilution
  Endoscopic/surgical removal
Enhancement of Poison Elimination
Multiple-dose activated charcoal
administration
Alteration of urinary pH
Chelation
Hyperbaric oxygenation
Extracorporeal removal
  Hemodialysis
  Hemoperfusion
  Hemofiltration
  Plasmapheresis
  Exchange transfusion
Continuous venovenous hemofiltration
(CVVH)
Administration of Antidotes
Neutralization by antibodies
Metabolic antagonism
Neutralization by chemical binding
Physiologic antagonism
Prevention of Reexposure
Adult education
Notification of regulatory agencies
Child-proofing
Psychiatric referral
Naloxone distribution
Linkage to harm reduction services
of presentation relative to the time of exposure, and the severity of
poisoning. Knowledge of the offending agents’ pharmacokinetics
and pharmacodynamics is essential.
During the pretoxic phase, prior to the onset of poisoning, decon­
tamination is the highest priority, and treatment is based solely on
the history. The maximal potential toxicity based on the greatest
possible exposure should be assumed. Since decontamination is
more effective when accomplished soon after exposure and when
the patient is asymptomatic, the initial history and physical exami­
nation should be focused and brief. It is also advisable to establish
IV access and initiate cardiac monitoring, particularly in patients
with potentially serious ingestions or unclear histories.
When an accurate history is not obtainable and a poison causing
delayed toxicity (i.e., a toxic time-bomb) or irreversible damage is
suspected, blood and urine should be sent for appropriate toxico­
logic screening and quantitative analysis. During poison absorption
and distribution, blood levels may be greater than those in tissue
and may not correlate with toxicity. However, high blood levels of
agents whose metabolites are more toxic than the parent compound
(acetaminophen, ethylene glycol, or methanol) may indicate the
need for additional interventions (antidotes, dialysis). Most patients
who remain asymptomatic or who become asymptomatic 6 h after
ingestion are unlikely to develop subsequent toxicity and can be
discharged safely. Longer observation will be necessary for patients
who have ingested toxic time-bombs.
During the toxic phase—the interval between the onset of poi­
soning and its peak effects—management is based primarily on
clinical and laboratory findings. Effects after an overdose usually
begin sooner, peak later, and last longer than they do after a thera­
peutic dose. A drug’s published pharmacokinetic profile in standard
references such as the Physician’s Desk Reference (PDR) is usually
different from its toxicokinetic profile in overdose. Resuscitation
and stabilization are the first priority. Symptomatic patients should
have an IV line placed and should undergo oxygen saturation deter­
mination, cardiac monitoring, and continuous observation. Base­
line laboratory, ECG, and x-ray evaluation may also be appropriate.
Intravenous glucose (unless the serum level is documented to be
normal), naloxone, and thiamine should be considered in patients
with altered mental status, particularly those with coma or seizures.
Decontamination should also be considered, but it is less likely to be
effective during this phase than during the pretoxic phase.
Measures that enhance poison elimination may shorten the
duration and severity of the toxic phase. However, they are not
without risk, which must be weighed against the potential benefit.
Diagnostic certainty (usually via laboratory confirmation) is gener­
ally a prerequisite. Intestinal (gut) dialysis with repetitive doses of
activated charcoal (see “Multiple-Dose Activated Charcoal,” later)
can enhance the elimination of selected poisons such as the­
ophylline or carbamazepine. Urinary alkalinization may enhance
the elimination of salicylates and a few other poisons. Chelation
therapy can enhance the elimination of selected metals. Extracor­
poreal elimination methods are effective for many poisons, but their
expense and risk make their use reasonable only in patients who
would otherwise have an unfavorable outcome.
During the resolution phase of poisoning, supportive care and
monitoring should continue until clinical, laboratory, and ECG
abnormalities have resolved. Since chemicals are eliminated sooner
from the blood than from tissues, blood levels are usually lower
than tissue levels during this phase and again may not correlate
with toxicity. This discrepancy applies particularly when extracor­
poreal elimination procedures are used. Redistribution from tissues
may cause a rebound increase in the blood level after termination
of these procedures (e.g., lithium). When a metabolite is respon­
sible for toxic effects, continued treatment may be necessary in the
absence of clinical toxicity or abnormal laboratory studies.
SUPPORTIVE CARE
The goal of supportive therapy is to maintain physiologic homeo­
stasis until detoxification is accomplished and to prevent and treat
secondary complications such as aspiration, bedsores, cerebral and
pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sep­
sis, thromboembolic disease, coagulopathy, and generalized organ
dysfunction due to hypoxemia or shock.
Admission to an intensive care unit is indicated for the following:
patients with severe poisoning (coma, respiratory depression, hypo­
tension, cardiac conduction abnormalities, cardiac arrhythmias,
hypothermia or hyperthermia, seizures); those needing close moni­
toring, antidotes, or enhanced elimination therapy; those showing
progressive clinical deterioration; and those with significant under­
lying medical problems. Patients with mild to moderate toxicity can
be managed on a general medical service, on an intermediate care
unit, or in an emergency department observation area, depend­
ing on the anticipated duration and level of monitoring needed
(intermittent clinical observation vs continuous clinical, cardiac,
and respiratory monitoring). Patients who have attempted suicide
require continuous observation and measures to prevent self-injury
until they are no longer suicidal.
Respiratory Care  Endotracheal intubation for protection against
the aspiration of gastrointestinal contents is of paramount impor­
tance in patients with CNS depression or seizures as this com­
plication can increase morbidity and mortality rates. Mechanical
ventilation may be necessary for patients with respiratory depres­
sion or hypoxemia and for facilitation of therapeutic sedation or
paralysis of patients in order to prevent or treat hyperthermia, aci­
dosis, and rhabdomyolysis associated with neuromuscular hyper­
activity. Since clinical assessment of respiratory function can be
inaccurate, the need for oxygenation and ventilation is best deter­
mined by continuous pulse oximetry or arterial blood-gas analysis.
The gag reflex is not a reliable indicator of the need for intubation.
A patient with CNS depression may maintain airway patency while
being stimulated but not if left alone. Drug-induced pulmonary
edema is usually noncardiac rather than cardiac in origin, although
profound CNS depression and cardiac conduction abnormalities
suggest the latter. Measurement of pulmonary artery pressure may
be necessary to establish the cause and direct appropriate therapy.
Extracorporeal measures (membrane oxygenation, extracorporeal
membrane oxygenation [ECMO], venoarterial perfusion, cardio­
pulmonary bypass) and partial liquid (perfluorocarbon) ventilation
may be appropriate for severe but reversible respiratory failure. In
the last decade, ECMO has been increasingly used for critically ill
poisoned patients where standard resuscitative therapy or antidotes
have not been helpful, but further research is still needed to deter­
mine the right toxicologic indications for this treatment strategy.
CHAPTER 470
Poisoning and Drug Overdose
Cardiovascular Therapy  Maintenance of normal tissue perfusion
is critical for complete recovery to occur once the offending agent
has been eliminated. Focused bedside echocardiography or mea­
surement of central venous pressure may help prioritize therapeutic
strategies. If hypotension is unresponsive to volume expansion and
appropriate goal-directed antidotal therapy, treatment with norepi­
nephrine, epinephrine, or high-dose dopamine may be necessary.
Intraaortic balloon pump counterpulsation and venoarterial or
cardiopulmonary perfusion techniques should be considered for
severe but reversible cardiac failure. For patients with a return of
spontaneous circulation after resuscitative treatment for cardiopul­
monary arrest secondary to poisoning, therapeutic hypothermia
should be used according to protocol. Bradyarrhythmias associ­
ated with hypotension generally should be treated as described in
Chaps. 251 and 252. Glucagon, calcium, and high-dose insulin
with dextrose may be effective in beta blocker and calcium channel
blocker poisoning. Antibody therapy may be indicated for cardiac
glycoside poisoning.
Supraventricular tachycardia associated with hypertension
and CNS excitation is almost always due to agents that cause
generalized physiologic excitation (Table 470–1). Most cases
are mild or moderate in severity and require only observation
or nonspecific sedation with a benzodiazepine. In severe cases
or those associated with hemodynamic instability, chest pain,
or ECG evidence of ischemia, specific therapy is indicated.
When the etiology is sympathetic hyperactivity, treatment with
a benzodiazepine should be prioritized. Further treatment with
a combined alpha and beta blocker (labetalol), a calcium chan­
nel blocker (verapamil or diltiazem), or a combination of a beta
blocker and a vasodilator (esmolol and nitroprusside) may be
considered for cases refractory to high doses of benzodiazepines
only when adequate sedation has been achieved but cardiac con­
duction or blood pressure abnormalities persist. Treatment with
an α-adrenergic antagonist (phentolamine) alone may sometimes
be appropriate. If the cause is anticholinergic poisoning, phy­
sostigmine alone can be effective. Supraventricular tachycardia
without hypertension is generally secondary to vasodilation or
hypovolemia and responds to fluid administration.
For ventricular tachyarrhythmias due to tricyclic antidepressants
and other membrane-active agents (Table 470-1), sodium bicar­
bonate is indicated, whereas class IA, IC, and III antiarrhythmic
agents are contraindicated because of similar electrophysiologic
effects. Although lidocaine and phenytoin are historically safe for
ventricular tachyarrhythmias of any etiology, sodium bicarbonate
should be considered first for any ventricular arrhythmia suspected
to have a toxicologic etiology. Intravenous lipid emulsion therapy
has shown benefit for treatment of arrhythmias and hemodynamic
instability from various membrane-active agents. Beta blockers can
be hazardous if the arrhythmia is due to sympathetic hyperactiv­
ity. Magnesium sulfate and overdrive pacing (by isoproterenol or
a pacemaker) may be useful in patients with torsades des pointes
and prolonged QT intervals. Magnesium and anti-digoxin antibod­
ies should be considered in patients with severe cardiac glycoside
poisoning. Invasive (esophageal or intracardiac) ECG recording
may be necessary to determine the origin (ventricular or supraven­
tricular) of wide-complex tachycardias (Chap. 253). If the patient is
hemodynamically stable, however, it is reasonable to simply observe
the patient rather than to administer another potentially proar­
rhythmic agent. Arrhythmias may be resistant to drug therapy until
underlying acid-base, electrolyte, oxygenation, and temperature
derangements are corrected.
PART 14
Poisoning, Drug Overdose, and Envenomation
Central Nervous System Therapies  Neuromuscular hyperac­
tivity and seizures can lead to hyperthermia, lactic acidosis,
and rhabdomyolysis and should be treated aggressively. Seizures
caused by excessive stimulation of catecholamine receptors (sym­
pathomimetic or hallucinogen poisoning and drug withdrawal)
or decreased activity of GABA (isoniazid poisoning) or glycine
(strychnine poisoning) receptors are best treated with agents that
enhance GABA activity, such as benzodiazepine or barbiturates.
Since benzodiazepines and barbiturates act by slightly different
mechanisms (the former increases the frequency via allosteric mod­
ulation at the receptor and the latter directly increases the duration
of chloride channel opening in response to GABA), therapy with
both may be effective when neither is effective alone. Seizures
caused by isoniazid, which inhibits the synthesis of GABA at several
steps by interfering with the cofactor pyridoxine (vitamin B6), may
require high doses of supplemental pyridoxine. Seizures resulting
from membrane destabilization (beta blocker or cyclic antidepres­
sant poisoning) require GABA enhancers (benzodiazepines first,
barbiturates second). Phenytoin is contraindicated in toxicologic
seizures: Animal and human data demonstrate worse outcomes
after phenytoin loading, especially in theophylline overdose. For
poisons with central dopaminergic effects (methamphetamine,
phencyclidine) manifested by psychotic behavior, a dopamine
receptor antagonist, such as haloperidol or ziprasidone, may be
useful. In anticholinergic and cyanide poisoning, specific antidotal
therapy may be necessary. The treatment of seizures secondary to
cerebral ischemia or edema or to metabolic abnormalities should
include correction of the underlying cause. Neuromuscular paraly­
sis is indicated in refractory cases. Electroencephalographic moni­
toring and continuing treatment of seizures are necessary to prevent
permanent neurologic damage.
Other Measures  Temperature extremes, metabolic abnormalities,
hepatic and renal dysfunction, and secondary complications should
be treated by standard therapies.
PREVENTION OF POISON ABSORPTION
Gastrointestinal Decontamination  Whether or not to perform
gastrointestinal decontamination and which procedure to use
depends on the time since ingestion; the existing and predicted tox­
icity of the ingestant; the availability, efficacy, and contraindications
of the procedure; and the nature, severity, and risk of complications.
The efficacy of all decontamination procedures decreases with
time, and data are insufficient to support or exclude a beneficial
effect when they are used >1 h after ingestion. The average time
from ingestion to presentation for treatment is >1 h for children
and >3 h for adults. Most patients will recover from poisoning
uneventfully with good supportive care alone, but complications
of gastrointestinal decontamination, particularly aspiration, can
prolong this process. Hence, gastrointestinal decontamination
should be performed selectively, not routinely, in the management
of overdose patients. It is clearly unnecessary when predicted toxic­
ity is minimal or the time of expected maximal toxicity has passed
without significant effect.
Activated charcoal has comparable or greater efficacy; has fewer
contraindications and complications; and is less aversive and inva­
sive than ipecac or gastric lavage. Thus, it is the preferred method
of gastrointestinal decontamination in most situations. Activated
charcoal suspension (in water) is given orally via a cup, straw, or
small-bore nasogastric tube. The generally recommended dose is
1 g/kg body weight because of its dosing convenience, although in
vitro and in vivo studies have demonstrated that charcoal adsorbs
≥90% of most substances when given in an amount equal to 10 times
the weight of the substance. Palatability may be increased by add­
ing a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or
cola syrup) to the suspension. Charcoal adsorbs ingested poisons
within the gut lumen, allowing the charcoal-toxin complex to be
evacuated with stool. Charged (ionized) chemicals such as mineral
acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron,
lithium, and other inorganic compounds are not well adsorbed by
charcoal. In studies with animals and human volunteers, charcoal
decreases the absorption of ingestants by an average of 73% when
given within 5 min of ingestant administration, 51% when given at
30 min, and 36% when given at 60 min. For this reason, charcoal
given before hospital arrival by prehospital emergency medical
services (EMS) increases the potential clinical benefit. Side effects
of charcoal include nausea, vomiting, and diarrhea or constipation.
Charcoal may also prevent the absorption of orally administered
therapeutic agents, so the timing and the dose administered need
to be adjusted. Complications include mechanical obstruction of
the airway, aspiration, vomiting, and bowel obstruction and infarc­
tion caused by inspissated charcoal. Charcoal is not recommended
for patients who have ingested corrosives because it obscures
endoscopy.
Gastric lavage should be considered for life-threatening poisons
that cannot be treated effectively with other decontamination,
elimination, or antidotal therapies (e.g., colchicine). Gastric lavage
is performed by sequentially administering and aspirating ~5 mL
of fluid per kilogram of body weight through a no. 40 French oro­
gastric tube (no. 28 French tube for children). Except in infants, for
whom normal saline is recommended, tap water is acceptable. The
patient should be placed in Trendelenburg and left lateral decubi­
tus positions to prevent aspiration (even if an endotracheal tube is
in place). Lavage decreases ingestant absorption by an average of
52% if performed within 5 min of ingestion administration, 26% if
performed at 30 min, and 16% if performed at 60 min. Significant
amounts of ingested drug are recovered from <10% of patients.
Aspiration is a common complication (occurring in up to 10% of
patients), especially when lavage is performed improperly. Serious
complications (esophageal and gastric perforation, tube misplace­
ment in the trachea) occur in ~1% of patients. For this reason, the
physician should personally insert the lavage tube and confirm its
placement, and the patient must be cooperative during the proce­
dure. Gastric lavage is contraindicated in corrosive or petroleum
distillate ingestions because of the respective risks of gastroesopha­
geal perforation and aspiration pneumonitis. It is also contraindi­
cated in patients with a compromised unprotected airway and those
at risk for hemorrhage or perforation due to esophageal or gastric
pathology or recent surgery. Finally, gastric lavage is absolutely
contraindicated in combative patients or those who refuse, as most
published complications involve patient resistance to the procedure.
Syrup of ipecac, an emetogenic agent that was once the substance
most commonly used for decontamination, no longer has a role in
poisoning management. Even the American Academy of Pediatrics—
traditionally the strongest proponent of ipecac—issued a policy
statement in 2003 recommending that ipecac should no longer be
used in poisoning treatment. Chronic ipecac use (by patients with
anorexia nervosa or bulimia) has been reported to cause electrolyte
and fluid abnormalities, cardiac toxicity, and myopathy.
Whole-bowel irrigation is performed by administering a bowelcleansing solution containing electrolytes and polyethylene glycol
(Golytely, Colyte) orally or by gastric tube at a rate of 2 L/h (0.5 L/h
in children) until rectal effluent is clear. The patient must be in a
sitting position. Although data are limited, whole-bowel irrigation
appears to be as effective as other decontamination procedures in
volunteer studies. It is most appropriate for those who have ingested
foreign bodies, packets of illicit drugs, and agents that are poorly
adsorbed by charcoal (e.g., heavy metals). This procedure is contra­
indicated in patients with bowel obstruction, ileus, hemodynamic
instability, and compromised unprotected airways.
Cathartics are salts (disodium phosphate, magnesium citrate
and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that
historically have been given with activated charcoal to promote the
rectal evacuation of gastrointestinal contents. However, no animal,
volunteer, or clinical data have ever demonstrated any decontami­
nation benefit from cathartics. Abdominal cramps, nausea, and
occasional vomiting are side effects. Complications of repeated
dosing include severe electrolyte disturbances and excessive diar­
rhea. Cathartics are contraindicated in patients who have ingested
corrosives and in those with preexisting diarrhea. Magnesium-con­
taining cathartics should not be used in patients with renal failure.
Dilution (i.e., drinking water, another clear liquid, or milk at a
volume of 5 mL/kg of body weight) is recommended only after the
ingestion of corrosives (acids, alkali). It may increase the dissolu­
tion rate (and hence absorption) of capsules, tablets, and other solid
ingestants and should not be used in these circumstances.
Endoscopic or surgical removal of poisons may be useful in rare
situations, such as ingestion of a potentially toxic foreign body that
fails to transit the gastrointestinal tract, a potentially lethal amount
of a heavy metal (arsenic, iron, mercury, thallium), or agents that
have coalesced into gastric concretions or bezoars (heavy metals,
lithium, salicylates, sustained-release preparations). Patients who
become toxic from cocaine due to its leakage from ingested drug
packets require immediate surgical intervention.
Decontamination of Other Sites  Immediate, copious flushing
with water, saline, or another available clear, drinkable liquid is the
initial treatment for topical exposures (exceptions include alkali
metals, calcium oxide, phosphorus). Saline is preferred for eye
irrigation. A triple wash (water, soap, water) may be best for dermal
decontamination. Inhalational exposures should be treated initially
with fresh air or supplemental oxygen. The removal of liquids from
body cavities such as the vagina or rectum is best accomplished by
irrigation. Solids (drug packets, pills) should be removed manually,
preferably under direct visualization.
ENHANCEMENT OF POISON ELIMINATION
Although the elimination of most poisons can be accelerated by
therapeutic interventions, the pharmacokinetic efficacy (removal
of drug at a rate greater than that accomplished by intrinsic
elimination) and clinical benefit (shortened duration of toxicity or
improved outcome) of such interventions are often more theoretical
than proven. Accordingly, the decision to use such measures should
be based on the actual or predicted toxicity and the potential effi­
cacy, cost, and risks of therapy.
Multiple-Dose Activated Charcoal  Repetitive oral dosing with
charcoal can enhance the elimination of previously absorbed sub­
stances by binding them within the gut as they are excreted in the
bile, are secreted by gastrointestinal cells, or passively diffuse into
the gut lumen (reverse absorption or enterocapillary exsorption).
Doses of 0.5–1 g/kg of body weight every 2–4 h, adjusted downward
to avoid regurgitation in patients with decreased gastrointestinal
motility, are generally recommended. Pharmacokinetic efficacy
approaches that of hemodialysis for some agents (e.g., phenobar­
bital, theophylline). Multiple-dose therapy should be considered
only for selected agents (theophylline, phenobarbital, carbamaze­
pine, dapsone, quinine). Complications include intestinal obstruc­
tion, pseudo-obstruction, and nonocclusive intestinal infarction in
patients with decreased gut motility. Because of electrolyte and fluid
shifts, sorbitol and other cathartics are absolutely contraindicated
when multiple doses of activated charcoal are administered.
Urinary Alkalinization  Ion trapping via alteration of urine pH
may prevent the renal reabsorption of poisons that undergo excre­
tion by glomerular filtration and active tubular secretion. Since
membranes are more permeable to nonionized molecules than to
their ionized counterparts, acidic (low-pKa) poisons are ionized and
trapped in alkaline urine, whereas basic ones become ionized and
trapped in acid urine. Urinary alkalinization (producing a urine pH
≥7.5 and a urine output of 3–6 mL/kg of body weight per hour by
the addition of sodium bicarbonate to an IV solution) enhances the
excretion of chlorophenoxyacetic acid herbicides, chlorpropamide,
diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides,
and salicylates. Contraindications include congestive heart failure,
renal failure, and cerebral edema. Acid-base, fluid, and electrolyte
parameters should be monitored carefully. Although acid diuresis
may make theoretical sense for some overdoses (amphetamines), it
is never indicated and is potentially harmful.
CHAPTER 470
Poisoning and Drug Overdose
Extracorporeal Removal  Hemodialysis, charcoal or resin hemo­
perfusion, hemofiltration, plasmapheresis, and exchange transfu­
sion are capable of removing any toxin from the bloodstream.
Agents most amenable to enhanced elimination by dialysis have
low molecular mass (<500 Da), high water solubility, low protein
binding, small volumes of distribution (<1 L/kg of body weight),
prolonged elimination (long half-life), and high dialysis clearance
relative to total-body clearance. Molecular weight, water solubility,
and protein binding do not limit the efficacy of the other forms of
extracorporeal removal.
Dialysis should be considered in cases of severe poisoning due to
carbamazepine, ethylene glycol, isopropyl alcohol, lithium, metha­
nol, theophylline, salicylates, and valproate. Although hemoperfu­
sion may be more effective in removing some of these poisons, it
does not correct associated acid-base and electrolyte abnormalities,
and most hospitals no longer have hemoperfusion cartridges readily
available. Fortunately, recent advances in hemodialysis technology
make it as effective as hemoperfusion for removing poisons such as
caffeine, carbamazepine, and theophylline. Both techniques require
central venous access and systemic anticoagulation and may result
in transient hypotension. Hemoperfusion may also cause hemoly­
sis, hypocalcemia, and thrombocytopenia. Peritoneal dialysis and
exchange transfusion are less effective but may be used when
other procedures are unavailable, contraindicated, or technically
difficult (e.g., in infants). Continuous venovenous hemofiltration
(CVVH) has also been used successfully when conventional inter­
mittent hemodialysis is not well tolerated because of hemodynamic
lability. Exchange transfusion may be indicated in the treatment
of severe arsine- or sodium chlorate–induced hemolysis, methe­
moglobinemia, and sulfhemoglobinemia. Although hemofiltration
can enhance elimination of aminoglycosides, vancomycin, and
metal-chelate complexes, the roles of hemofiltration and plasma­
pheresis in the treatment of poisoning are not yet defined.
Candidates for extracorporeal removal therapies include patients
with severe toxicity whose condition deteriorates despite aggressive
supportive therapy; those with potentially prolonged, irreversible,
or fatal toxicity; those with dangerous blood levels of toxins; those
who lack the capacity for self-detoxification because of liver or renal
failure; and those with a serious underlying illness or complication
that will adversely affect recovery.
Other Techniques  The elimination of heavy metals can be
enhanced by chelation, and the removal of carbon monoxide can
be accelerated by hyperbaric oxygenation.
ADMINISTRATION OF ANTIDOTES
Antidotes counteract the effects of poisons by neutralizing them
(e.g., antibody-antigen reactions, chelation, chemical binding) or by
antagonizing their physiologic effects (e.g., activation of opposing
TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
PHYSIOLOGIC
CONDITION, CAUSES
EXAMPLES
MECHANISM OF ACTION
CLINICAL FEATURES
SPECIFIC TREATMENTS
Stimulated
PART 14
Poisoning, Drug Overdose, and Envenomation
Sympatheticsa
  Sympathomimetics
α1-Adrenergic agonists
(decongestants):
phenylephrine,
phenylpropanolamine
β2-Adrenergic agonists
(bronchodilators): albuterol,
terbutaline
Nonspecific adrenergic
agonists: amphetamines,
cocaine, ephedrine
Stimulation of central and
peripheral sympathetic
receptors directly or indirectly
(by promoting release
or inhibiting reuptake of
norepinephrine and sometimes
dopamine)
  Ergot alkaloids
Ergotamine, methysergide,
bromocriptine, pergolide
Stimulation and inhibition of
serotonergic and α-adrenergic
receptors; stimulation of
dopamine receptors
  Methylxanthines
Caffeine, theophylline
Inhibition of adenosine
synthesis and adenosine
receptor antagonism;
stimulation of epinephrine
and norepinephrine release;
inhibition of phosphodiesterase
resulting in increased
intracellular cyclic adenosine
and guanosine monophosphate
  Monoamine oxidase
Phenelzine, tranylcypromine,
selegiline
Inhibition of monoamine
oxidase resulting in impaired
metabolism of endogenous
catecholamines and exogenous
sympathomimetic agents
inhibitors
nervous system activity, provision of a competitive metabolic or
receptor substrate). Poisons or conditions with specific antidotes
include acetaminophen, anticholinergic agents, anticoagulants,
benzodiazepines, beta blockers, calcium channel blockers, car­
bon monoxide, cardiac glycosides, cholinergic agents, cyanide,
drug-induced dystonic reactions, ethylene glycol, fluoride, heavy
metals, hypoglycemic agents, isoniazid, membrane-active agents,
methemoglobinemia, opioids, sympathomimetics, and a variety of
envenomations. Intravenous lipid emulsion has been shown to be
a successful antidote for poisoning from various anesthetics and
membrane-active agents (e.g., cyclic antidepressants), but the exact
mechanism of benefit is still under investigation. Antidotes can sig­
nificantly reduce morbidity and mortality rates but are potentially
toxic if used for inappropriate reasons. Since their safe use requires
correct identification of a specific poisoning or syndrome, details of
antidotal therapy are discussed with the conditions for which they
are indicated (Table 470-4).
Physiologic stimulation
(Table 470-2). Reflex bradycardia
can occur with selective α1
agonists; β agonists can cause
hypotension and hypokalemia.
Phentolamine, a nonselective α1adrenergic receptor antagonist,
for severe hypertension due to α1adrenergic agonists; propranolol,
a nonselective β blocker, for
hypotension and tachycardia due
to β2 agonists; either labetalol,
a β blocker with α-blocking
activity, or phentolamine with
esmolol, metoprolol, or another
cardioselective β blocker for
hypertension with tachycardia
due to nonselective agents (β
blockers, if used alone, can
exacerbate hypertension and
vasospasm due to unopposed α
stimulation); benzodiazepines;
propofol
Physiologic stimulation (Table
470-2); formication; vasospasm
with limb (isolated or generalized),
myocardial, and cerebral
ischemia progressing to gangrene
or infarction. Hypotension,
bradycardia, and involuntary
movements can also occur.
Nitroprusside or nitroglycerine for
severe vasospasm; prazosin (an
α1 blocker), captopril, nifedipine,
and cyproheptadine (a serotonin
receptor antagonist) for mildto-moderate limb ischemia;
dopamine receptor antagonists
(antipsychotics) for hallucinations
and movement disorders
Physiologic stimulation
(Table 470-2); pronounced
gastrointestinal symptoms and
β agonist effects (see above).
Toxicity occurs at lower drug
levels in chronic poisoning than in
acute poisoning.
Propranolol, a nonselective β
blocker, or esmolol for tachycardia
with hypotension; any β blocker
for supraventricular or ventricular
tachycardia without hypotension;
elimination enhanced by multipledose charcoal, hemoperfusion,
and hemodialysis. Indications for
hemoperfusion or hemodialysis
include unstable vital signs,
seizures, and a theophylline level
of 80–100 μg/mL after an acute
overdose and 40–60 μg/mL with
chronic exposure.
Delayed or slowly progressive
physiologic stimulation (Table
470-2); terminal hypotension and
bradycardia in severe cases
Short-acting agents (e.g.,
nitroprusside, esmolol) for severe
hypertension and tachycardia;
direct-acting sympathomimetics
(e.g., norepinephrine, epinephrine)
for hypotension and bradycardia
(Continued)
TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
PHYSIOLOGIC
CONDITION, CAUSES
EXAMPLES
MECHANISM OF ACTION
CLINICAL FEATURES
SPECIFIC TREATMENTS
Anticholinergics
  Antihistamines
Diphenhydramine,
doxylamine, pyrilamine
Inhibition of central and
postganglionic parasympathetic
muscarinic cholinergic
receptors. At high doses,
amantadine, diphenhydramine,
orphenadrine, phenothiazines,
and tricyclic antidepressants
have additional
nonanticholinergic activity
(see below).
  Antipsychotics
Chlorpromazine, olanzapine,
quetiapine, thioridazine
Inhibition of α-adrenergic,
dopaminergic, histaminergic,
muscarinic, and serotonergic
receptors. Some agents also
inhibit sodium, potassium, and
calcium channels.
  Belladonna alkaloids
Atropine, hyoscyamine,
scopolamine
Inhibition of central and
postganglionic parasympathetic
muscarinic cholinergic
receptors
  Cyclic antidepressants
Amitriptyline, doxepin,
imipramine
Inhibition of α-adrenergic,
dopaminergic, GABA-ergic,
histaminergic, muscarinic,
and serotonergic receptors;
inhibition of sodium channels
(see membrane-active agents);
inhibition of norepinephrine and
serotonin reuptake
  Mushrooms and plants
Amanita muscaria and
A. pantherina, henbane,
jimson weed, nightshade
Inhibition of central and
postganglionic parasympathetic
muscarinic cholinergic
receptors
Depressed
Sympatholytics
  α2-Adrenergic agonists
Clonidine, guanabenz,
tetrahydrozoline and other
imidazoline decongestants,
tizanidine and other
imidazoline muscle relaxants
Stimulation of α2-adrenergic
receptors leading to inhibition
of CNS sympathetic outflow.
Activity at nonadrenergic
imidazoline binding sites also
contributes to CNS effects.
  Antipsychotics
Chlorpromazine, clozapine,
haloperidol, risperidone,
thioridazine
Inhibition of α-adrenergic,
dopaminergic, histaminergic,
muscarinic, and serotonergic
receptors. Some agents also
inhibit sodium, potassium, and
calcium channels.
(Continued)
Physiologic stimulation (Table
470-2); dry skin and mucous
membranes, decreased bowel
sounds, flushing, and urinary
retention; myoclonus and picking
activity. Central effects may occur
without significant autonomic
dysfunction.
Physostigmine, an
acetylcholinesterase inhibitor
(see below), for delirium,
hallucinations, and neuromuscular
hyperactivity. Contraindications
include asthma and nonanticholinergic cardiovascular
toxicity (e.g., cardiac conduction
abnormalities, hypotension, and
ventricular arrhythmias).
Physiologic depression
(Table 470-2), miosis,
anticholinergic effects (see
above), extrapyramidal reactions
(see below), tachycardia
Sodium bicarbonate for
ventricular tachydysrhythmias
associated with QRS prolongation;
magnesium, isoproterenol, and
overdrive pacing for torsades des
pointes. Avoid class IA, IC, and III
antiarrhythmics.
Physiologic stimulation (Table
470-2); dry skin and mucous
membranes, decreased bowel
sounds, flushing, and urinary
retention; myoclonus and picking
activity. Central effects may occur
without significant autonomic
dysfunction.
Physostigmine, an
acetylcholinesterase inhibitor
(see below), for delirium,
hallucinations, and neuromuscular
hyperactivity. Contraindications
include asthma and nonanticholinergic cardiovascular
toxicity (e.g., cardiac conduction
abnormalities, hypotension, and
ventricular arrhythmias).
CHAPTER 470
Poisoning and Drug Overdose
Physiologic depression (Table
470-2), seizures, tachycardia,
cardiac conduction delays
(increased PR, QRS, JT, and QT
intervals; terminal QRS right-axis
deviation) with aberrancy and
ventricular tachydysrhythmias;
anticholinergic toxidrome (see
above)
Hypertonic sodium bicarbonate (or
hypertonic saline) for ventricular
tachydysrhythmias associated
with QRS prolongation. Use
of phenytoin is controversial.
Avoid class IA, IC, and III
antiarrhythmics. IV emulsion
therapy may be beneficial in some
cases.
Physiologic stimulation
(Table 470-2); dry skin and mucous
membranes, decreased bowel
sounds, flushing, and urinary
retention; myoclonus and picking
activity. Central effects may occur
without significant autonomic
dysfunction.
Physostigmine, an
acetylcholinesterase inhibitor
(see below), for delirium,
hallucinations, and neuromuscular
hyperactivity. Contraindications
include asthma and
nonanticholinergic cardiovascular
toxicity (e.g., cardiac conduction
abnormalities, hypotension, and
ventricular arrhythmias).
Physiologic depression (Table
470-2), miosis. Transient initial
hypertension may be seen.
Dopamine and norepinephrine
for hypotension; atropine for
symptomatic bradycardia;
naloxone for CNS depression
(inconsistently effective)
Physiologic depression (Table
470-2), miosis, anticholinergic
effects (see above),
extrapyramidal reactions (see
below), tachycardia. Cardiac
conduction delays (increased PR,
QRS, JT, and QT intervals) with
ventricular tachydysrhythmias,
including torsades des pointes,
can sometimes develop.
Sodium bicarbonate for
ventricular tachydysrhythmias
associated with QRS prolongation;
magnesium, isoproterenol, and
overdrive pacing for torsades des
pointes. Avoid class IA, IC, and III
antiarrhythmics.
(Continued)
TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
PHYSIOLOGIC
CONDITION, CAUSES
EXAMPLES
MECHANISM OF ACTION
CLINICAL FEATURES
SPECIFIC TREATMENTS
  β-Adrenergic blockers
Cardioselective (β1) blockers:
atenolol, esmolol, metoprolol
Nonselective (β1 and β2)
blockers: nadolol, propranolol,
timolol
Partial β agonists: acebutolol,
pindolol
α1 Antagonists: carvedilol,
labetalol
Membrane-active agents:
acebutolol, propranolol, sotalol
Inhibition of β-adrenergic
receptors (class II antiarrhythmic
effect). Some agents have
activity at additional receptors
or have membrane effects (see
below).
  Calcium channel
Diltiazem, nifedipine and other
dihydropyridine derivatives,
verapamil
Inhibition of slow (type L)
cardiovascular calcium channels
(class IV antiarrhythmic effect)
blockers
PART 14
Poisoning, Drug Overdose, and Envenomation
  Cardiac glycosides
Digoxin, endogenous
cardioactive steroids, foxglove
and other plants, toad skin
secretions (Bufonidae spp.)
Inhibition of cardiac Na+,
K+-ATPase membrane pump
  Cyclic antidepressants
Amitriptyline, doxepin,
imipramine
Inhibition of α-adrenergic,
dopaminergic, GABA-ergic,
histaminergic, muscarinic,
and serotonergic receptors;
inhibition of sodium channels
(see membrane-active agents);
inhibition of norepinephrine and
serotonin reuptake
Cholinergics
  Acetylcholinesterase
Carbamate insecticides
(aldicarb, carbaryl, propoxur)
and medicinals (neostigmine,
physostigmine, tacrine);
nerve gases (sarin, soman,
tabun, VX); organophosphate
insecticides (diazinon,
chlorpyrifos-ethyl, malathion)
Bethanechol, mushrooms
(Boletus, Clitocybe, Inocybe
spp.), pilocarpine
Lobeline, nicotine (tobacco)
Inhibition of acetylcholinesterase
leading to increased synaptic
acetylcholine at muscarinic and
nicotinic cholinergic receptor
sites
Stimulation of CNS and
postganglionic parasympathetic
cholinergic (muscarinic)
receptors
Stimulation of preganglionic
sympathetic and
parasympathetic and striated
muscle (neuromuscular junction)
cholinergic (nicotine) receptors
inhibitors
  Muscarinic agonists
  Nicotinic agonists
(Continued)
Physiologic depression
(Table 470-2), atrioventricular
block, hypoglycemia,
hyperkalemia, seizures. Partial
agonists can cause hypertension
and tachycardia. Sotalol can
cause increased QT interval and
ventricular tachydysrhythmias.
Onset may be delayed after
sotalol and sustained-release
formulation overdose.
Glucagon for hypotension and
symptomatic bradycardia.
Atropine, isoproterenol, dopamine,
dobutamine, epinephrine, and
norepinephrine may sometimes be
effective. High-dose insulin (with
glucose and potassium to maintain
euglycemia and normokalemia),
electrical pacing, and mechanical
cardiovascular support for
refractory cases.
Physiologic depression
(Table 470-2), atrioventricular
block, organ ischemia and
infarction, hyperglycemia,
seizures. Hypotension is usually
due to decreased vascular
resistance rather than to
decreased cardiac output. Onset
may be delayed for ≥12 h after
overdose of sustained-release
formulations.
Calcium and glucagon for
hypotension and symptomatic
bradycardia. Dopamine,
epinephrine, norepinephrine,
atropine, and isoproterenol are
less often effective but can
be used adjunctively. Highdose insulin (with glucose and
potassium to maintain euglycemia
and normokalemia), IV lipid
emulsion therapy, electrical
pacing, and mechanical
cardiovascular support for
refractory cases.
Physiologic depression
(Table 470-2); gastrointestinal,
psychiatric, and visual
symptoms; atrioventricular block
with or without concomitant
supraventricular tachyarrhythmia;
ventricular tachyarrhythmias;
hyperkalemia in acute poisoning.
Toxicity occurs at lower drug
levels in chronic poisoning than in
acute poisoning.
Digoxin-specific antibody
fragments for hemodynamically
compromising dysrhythmias,
Mobitz II or third-degree
atrioventricular block,
hyperkalemia (>5.5 meq/L;
in acute poisoning only).
Temporizing measures include
atropine, dopamine, epinephrine,
and external cardiac pacing
for bradydysrhythmias and
magnesium, lidocaine, or
phenytoin, for ventricular
tachydysrhythmias. Internal
cardiac pacing and cardioversion
can increase ventricular irritability
and should be reserved for
refractory cases.
Physiologic depression
(Table 470-2), seizures,
tachycardia, cardiac conduction
delays (increased PR, QRS, JT, and
QT intervals; terminal QRS rightaxis deviation) with aberrancy and
ventricular tachydysrhythmias;
anticholinergic toxidrome (see
above)
Hypertonic sodium bicarbonate
(or hypertonic saline) for
ventricular tachydysrhythmias
associated with QRS prolongation.
Use of phenytoin is controversial.
Avoid class IA, IC, and III
antiarrhythmics. IV emulsion
therapy may be beneficial in some
cases.
Physiologic depression (Table
470-2). Muscarinic signs and
symptoms: seizures, excessive
secretions (lacrimation,
salivation, bronchorrhea and
wheezing, diaphoresis), and
increased bowel and bladder
activity with nausea, vomiting,
diarrhea, abdominal cramps, and
incontinence of feces and urine.
Nicotinic signs and symptoms:
hypertension, tachycardia,
muscle cramps, fasciculations,
weakness, and paralysis. Death is
usually due to respiratory failure.
Cholinesterase activity in plasma
and red cells is <50% of normal
in acetylcholinesterase inhibitor
poisoning.
Atropine for muscarinic signs
and symptoms; 2-PAM, a
cholinesterase reactivator, for
nicotinic signs and symptoms
due to organophosphates,
nerve gases, or an unknown
anticholinesterase
(Continued)
TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
PHYSIOLOGIC
CONDITION, CAUSES
EXAMPLES
MECHANISM OF ACTION
CLINICAL FEATURES
SPECIFIC TREATMENTS
Sedative-hypnoticsb
  Anticonvulsants
  Barbiturates
  Benzodiazepines
Carbamazepine, ethosuximide,
felbamate, gabapentin,
lamotrigine, levetiracetam,
oxcarbazepine, phenytoin,
tiagabine, topiramate,
valproate, zonisamide
Short-acting: butabarbital,
pentobarbital, secobarbital
Long-acting: phenobarbital,
primidone
Ultrashort-acting: estazolam,
midazolam, temazepam,
triazolam
Short-acting: alprazolam,
flunitrazepam, lorazepam,
oxazepam
Long-acting: chlordiazepoxide,
clonazepam, diazepam,
flurazepam
Pharmacologically related
agents: zaleplon, zolpidem
Potentiation of the inhibitory
effects of GABA by binding to
the neuronal GABA–A chloride
channel receptor complex and
increasing the frequency or
duration of chloride channel
opening in response to GABA
stimulation. Baclofen and, to
some extent, GHB act at the
GABA–B receptor complex.
Meprobamate, its metabolite
carisoprodol, felbamate, and
orphenadrine antagonize
NDMA excitatory receptors.
Ethosuximide, valproate,
and zonisamide decrease
conduction through T-type
calcium channels. Valproate
decreases GABA degradation,
and tiagabine blocks GABA
reuptake. Carbamazepine,
lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate,
and zonisamide slow the rate of
recovery of inactivated sodium
channels. Some agents also
have α2 agonist, anticholinergic,
and sodium channel–blocking
activity (see above and below).
  GABA precursors
γ-Hydroxybutyrate
(sodium oxybate; GHB),
γ-butyrolactone (GBL),
1,4-butanediol
Stimulation at GABA receptor
complex increases chloride
channel opening
  Muscle relaxants
Baclofen, carisoprodol,
cyclobenzaprine, etomidate,
metaxalone, methocarbamol,
orphenadrine, propofol,
tizanidine and other
imidazoline muscle relaxants
Baclofen acts at GABA–B
receptor complex; stimulation of
α2-adrenergic receptors inhibits
CNS sympathetic outflow.
Activity at nonadrenergic
imidazoline binding sites also
contributes to CNS effects. The
others have centrally acting
and various other unknown
mechanisms of action.
Discordant
Asphyxiants
  Cytochrome oxidase
Cyanide, hydrogen sulfide
Inhibition of mitochondrial
cytochrome oxidase, with
consequent blockage of
electron transport and oxidative
metabolism. Carbon monoxide
also binds to hemoglobin and
myoglobin and prevents oxygen
binding, transport, and tissue
uptake. (Binding to hemoglobin
shifts the oxygen dissociation
curve to the left.)
inhibitors
(Continued)
Physiologic depression
(Table 470-2), nystagmus.
Delayed absorption can occur
with carbamazepine, phenytoin,
and valproate.
Myoclonus, seizures,
hypertension, and
tachyarrhythmias can occur with
baclofen, carbamazepine, and
orphenadrine.
Tachyarrhythmias can also occur
with chloral hydrate. AGMA,
hypernatremia, hyperosmolality,
hyperammonemia, chemical
hepatitis, and hypoglycemia
can be seen in valproate
poisoning. Carbamazepine and
oxcarbazepine may produce
hyponatremia from SIADH.
Benzodiazepines, barbiturates, or
propofol for seizures.
Hemodialysis and hemoperfusion
may be indicated for severe
poisoning by some agents (see
“Extracorporeal Removal,” in text).
See above and below for
treatment of anticholinergic and
sodium channel (membrane)–
blocking effects.
CHAPTER 470
Poisoning and Drug Overdose
Physiologic depression
(Table 470-2)
Goal-directed supportive care
Physiologic depression
(Table 470-2)
Goal-directed supportive care;
benzodiazepines and barbiturates
for seizures
Signs and symptoms of hypoxemia
with initial physiologic stimulation
and subsequent depression (Table
470-2); lactic acidosis; normal PO2
and calculated oxygen saturation
but decreased oxygen saturation
by co-oximetry. (That measured
by pulse oximetry is falsely
elevated but is less than normal
and less than the calculated
value.) Headache and nausea are
common with carbon monoxide.
Sudden collapse may occur with
cyanide and hydrogen sulfide
exposure. A bitter almond breath
odor may be noted with cyanide
ingestion, and hydrogen sulfide
smells like rotten eggs.
High-dose oxygen; IV
hydroxocobalamin or IV sodium
nitrite and sodium thiosulfate
(Lilly cyanide antidote kit) for
coma, metabolic acidosis, and
cardiovascular dysfunction in
cyanide poisoning or victims from
a fire; ECMO
(Continued)
TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
PHYSIOLOGIC
CONDITION, CAUSES
EXAMPLES
MECHANISM OF ACTION
CLINICAL FEATURES
SPECIFIC TREATMENTS
  Methemoglobin
Aniline derivatives, dapsone,
local anesthetics, nitrates,
nitrites, nitrogen oxides, nitro-
and nitrosohydrocarbons,
phenazopyridine, primaquinetype antimalarials,
sulfonamides
Oxidation of hemoglobin iron
from ferrous (Fe2+) to ferric (Fe3+)
state prevents oxygen binding,
transport, and tissue uptake.
(Methemoglobinemia shifts
oxygen dissociation curve to the
left.) Oxidation of hemoglobin
protein causes hemoglobin
precipitation and hemolytic
anemia (manifesting as Heinz
bodies and “bite cells” on
peripheral-blood smear).
inducers
  AGMA inducers
Ethylene glycol
Ethylene glycol causes CNS
depression and increased serum
osmolality. Metabolites (primarily
glycolic acid) cause AGMA,
CNS depression, and renal
failure. Precipitation of oxalic
acid metabolite as calcium salt
in tissues and urine results in
hypocalcemia, tissue edema, and
crystalluria.
PART 14
Poisoning, Drug Overdose, and Envenomation
Iron
Hydration of ferric (Fe3+) ion
generates H+. Non-transferrinbound iron catalyzes formation
of free radicals that cause
mitochondrial injury, lipid
peroxidation, increased capillary
permeability, vasodilation, and
organ toxicity.
Methanol
Methanol causes ethanol-like
CNS depression and increased
serum osmolality. Formic acid
metabolite causes AGMA and
retinal toxicity.
Salicylate
Increased sensitivity of CNS
respiratory center to changes
in and stimulates respiration.
Uncoupling of oxidative
phosphorylation, inhibition
of Krebs cycle enzymes, and
stimulation of carbohydrate
and lipid metabolism generate
unmeasured endogenous anions
and cause AGMA.
(Continued)
Signs and symptoms of
hypoxemia with initial physiologic
stimulation and subsequent
depression (Table 470-2), graybrown cyanosis unresponsive
to oxygen at methemoglobin
fractions >15–20%, headache,
lactic acidosis (at methemoglobin
fractions >45%), normal PO2 and
calculated oxygen saturation but
decreased oxygen saturation
and increased methemoglobin
fraction by co-oximetry. (Oxygen
saturation by pulse oximetry may
be falsely increased or decreased
but is less than normal and less
than the calculated value.)
High-dose oxygen; IV methylene
blue for methemoglobin fraction
30%, symptomatic hypoxemia, or
ischemia (contraindicated in G6PD
deficiency); exchange transfusion
and hyperbaric oxygen for severe
or refractory cases
Initial ethanol-like intoxication,
nausea, vomiting, increased
osmolar gap, calcium oxalate
crystalluria; delayed AGMA, back
pain, renal failure; coma, seizures,
hypotension, ARDS in severe
cases
Sodium bicarbonate to correct
acidemia; thiamine, folinic acid,
magnesium, and high-dose
pyridoxine to facilitate metabolism;
ethanol or fomepizole for AGMA,
crystalluria or renal dysfunction,
ethylene glycol level >3 mmol/L
(20 mg/dL), and ethanol-like
intoxication or increased osmolal
gap if level not readily obtainable;
hemodialysis for persistent AGMA,
lack of clinical improvement, and
renal dysfunction; hemodialysis
also useful for enhancing ethylene
glycol elimination and shortening
duration of treatment when
ethylene glycol level is >8 mmol/L
(50 mg/dL).
Initial nausea, vomiting,
abdominal pain, diarrhea;
AGMA, cardiovascular and
CNS depression, hepatitis,
coagulopathy, and seizures in
severe cases. Radiopaque iron
tablets may be seen on abdominal
x-ray.
Whole-bowel irrigation for large
ingestions; endoscopy and
gastrostomy if clinical toxicity
and large number of tablets are
still visible on x-ray; IV hydration;
sodium bicarbonate for acidemia;
IV deferoxamine for systemic
toxicity, iron level >90 μmol/L
(500 μg/dL)
Initial ethanol-like intoxication,
nausea, vomiting, increased
osmolar gap; delayed AGMA,
visual (clouding, spots, blindness)
and retinal (edema, hyperemia)
abnormalities; coma, seizures,
cardiovascular depression
in severe cases; possible
pancreatitis
Gastric aspiration for recent
ingestion; sodium bicarbonate
to correct acidemia; high-dose
folinic acid or folate to facilitate
metabolism; ethanol or fomepizole
for AGMA, visual symptoms,
methanol level >6 mmol/L (20 mg/
dL), and ethanol-like intoxication
or increased osmolal gap if
level not readily obtainable;
hemodialysis for persistent AGMA,
lack of clinical improvement, and
renal dysfunction; hemodialysis
also useful for enhancing
methanol elimination and
shortening duration of treatment
when methanol level is >15 mmol/L
(50 mg/dL)
Initial nausea, vomiting,
hyperventilation, alkalemia,
alkaluria; subsequent alkalemia
with both respiratory alkalosis
and AGMA and paradoxical
aciduria; late acidemia with
CNS and respiratory depression;
cerebral and pulmonary edema
in severe cases. Hypoglycemia,
hypocalcemia, hypokalemia, and
seizures can occur.
IV hydration and supplemental
glucose; sodium bicarbonate
to correct acidemia; urinary
alkalinization for systemic toxicity;
hemodialysis for coma, cerebral
edema, seizures, pulmonary
edema, renal failure, progressive
acid-base disturbances or clinical
toxicity, salicylate level >7 mmol/L
(100 mg/dL) following acute
overdose
(Continued)
TABLE 470-4  Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings
PHYSIOLOGIC
CONDITION, CAUSES
EXAMPLES
MECHANISM OF ACTION
CLINICAL FEATURES
SPECIFIC TREATMENTS
CNS syndromes
  Extrapyramidal
Antipsychotics (see above),
some cyclic antidepressants
and antihistamines
Decreased CNS dopaminergic
activity with relative excess of
cholinergic activity
reactions
  Isoniazid
Interference with activation
and supply of pyridoxal-5phosphate, a cofactor for
glutamic acid decarboxylase,
which converts glutamic acid
to GABA, results in decreased
levels of this inhibitory CNS
neurotransmitter; complexation
with and depletion of pyridoxine
itself; inhibition of nicotine
adenine dinucleotide–dependent
lactate and hydroxybutyrate
dehydrogenases, resulting in
substrate accumulation
  Lithium
Interference with cell membrane
ion transport, adenylate cyclase
and Na+, K+-ATPase activity, and
neurotransmitter release
  Serotonin syndrome
Amphetamines, cocaine,
dextromethorphan,
meperidine, MAO inhibitors,
selective serotonin (5-HT)
reuptake inhibitors, tricyclic
antidepressants, tramadol,
triptans, tryptophan
Promotion of serotonin release,
inhibition of serotonin reuptake,
or direct stimulation of CNS and
peripheral serotonin receptors
(primarily 5-HT-1a and 5-HT-2),
alone or in combination
  Membrane-active
Amantadine, antiarrhythmics
(class I and III agents;
some β blockers),
antipsychotics (see above),
antihistamines (particularly
diphenhydramine),
carbamazepine, local
anesthetics (including
cocaine), opioids
(meperidine, propoxyphene),
orphenadrine, quinoline
antimalarials (chloroquine,
hydroxychloroquine, quinine),
cyclic antidepressants (see
above)
Blockade of fast sodium
membrane channels prolongs
phase 0 (depolarization) of
the cardiac action potential,
which prolongs QRS duration
and promotes reentrant
(monomorphic) ventricular
tachycardia. Class Ia, Ic, and
III antiarrhythmics also block
potassium channels during phases
2 and 3 (repolarization) of the
action potential, prolonging the JT
interval and promoting early afterdepolarizations and polymorphic
(torsades des pointes) ventricular
tachycardia. Similar effects on
neuronal membrane channels
cause CNS dysfunction. Some
agents also block α-adrenergic
and cholinergic receptors or have
opioid effects (see above and
Chap. 467).
agent
aSee above and Chap. 468. bSee above and Chap. 467.
Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; ECMO, extracorporeal membrane
oxygenation; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB, γ-hydroxybutyrate; G6PD, glucose-6-phosphate dehydrogenase; MAO, monoamine oxidase; NDMA,
N-methyl-D-aspartate; 2-PAM, pralidoxime; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
(Continued)
Akathisia, dystonia, parkinsonism
Oral or parenteral anticholinergic
agent such as benztropine or
diphenhydramine
Nausea, vomiting, agitation,
confusion; coma, respiratory
depression, seizures, lactic and
ketoacidosis in severe cases
High-dose IV pyridoxine (vitamin
B6) for agitation, confusion,
coma, and seizures; diazepam or
barbiturates for seizures
Nausea, vomiting, diarrhea,
ataxia, choreoathetosis,
encephalopathy, hyperreflexia,
myoclonus, nystagmus,
nephrogenic diabetes insipidus,
falsely elevated serum chloride
with low anion gap, tachycardia;
coma, seizures, arrhythmias,
hyperthermia, and prolonged or
permanent encephalopathy and
movement disorders in severe
cases; delayed onset after acute
overdose, particularly with
delayed-release formulations.
Toxicity occurs at lower drug
levels in chronic poisoning than in
acute poisoning.
Whole-bowel irrigation for
large ingestions; IV hydration;
hemodialysis for coma, seizures,
encephalopathy or neuromuscular
dysfunction (severe, progressive,
or persistent), peak lithium level
4 meq/L following acute overdose
CHAPTER 470
Poisoning and Drug Overdose
Altered mental status (agitation,
confusion, mutism, coma,
seizures), neuromuscular
hyperactivity (hyperreflexia,
myoclonus, rigidity, tremors), and
autonomic dysfunction (abdominal
pain, diarrhea, diaphoresis, fever,
flushing, labile hypertension,
mydriasis, tearing, salivation,
tachycardia). Complications
include hyperthermia, lactic
acidosis, rhabdomyolysis, and
multisystem organ failure.
Discontinue the offending
agent(s); benzodiazepines for
agitation or signs of stimulation;
the serotonin receptor antagonist
cyproheptadine may be helpful in
severe cases.
QRS and JT prolongation
(or both) with hypotension,
ventricular tachyarrhythmias,
CNS depression, seizures;
anticholinergic effects with
amantadine, antihistamines,
carbamazepine, disopyramide,
antipsychotics, and cyclic
antidepressants (see above);
opioid effects with meperidine
and propoxyphene (see Chap. 467);
cinchonism (hearing loss, tinnitus,
nausea, vomiting, vertigo, ataxia,
headache, flushing, diaphoresis),
and blindness with quinoline
antimalarials
Hypertonic sodium bicarbonate
(or hypertonic saline) for
cardiac conduction delays
and monomorphic ventricular
tachycardia; lidocaine for
monomorphic ventricular
tachycardia (except when due
to class Ib antiarrhythmics);
magnesium, isoproterenol, and
overdrive pacing for polymorphic
ventricular tachycardia;
physostigmine for anticholinergic
effects (see above); naloxone for
opioid effects (see Chap. 467);
extracorporeal removal for some
agents (see text).

04 - 472 Ectoparasite Infestations and Arthropod Injuries
472 Ectoparasite Infestations and Arthropod Injuries
dysrhythmias, hypotension, and pulmonary edema have also been
reported. Postmortem examination of brain tissue has shown neuronal
necrosis or cell loss and astrocytosis, most prominently in the hippo­
campus and amygdala. Several months after the primary intoxication,
victims may still display chronic residual memory deficits and motor
or sensory neuropathy.
TREATMENT
Amnesic Shellfish Poisoning
Therapy is supportive and based on symptoms. IV fluids and
antiemetics may be used for severe nausea, vomiting, and diar­
rhea. Domoic acid neurotoxicity is primarily seizure mediated;
anticonvulsive therapy using GABA agonists (e.g., benzodiazepines,
propofol, or barbiturates) should be instituted early. However, some
patients without clinically evident seizure activity have developed
neurologic sequelae.
■
■DIARRHETIC SHELLFISH POISONING
Diarrhetic shellfish poisoning occurs with consumption of shellfish
containing the lipophilic compound okadaic acid. This toxin inhibits
serine and threonine protein phosphatases, with consequent protein
accumulation and continued secretion of fluid by intestinal cells lead­
ing to diarrhea. Shellfish acquire these toxins by feeding on dinoflagel­
lates, particularly of the genera Dinophysis and Prorocentrum.
PART 14
Poisoning, Drug Overdose, and Envenomation
Symptoms include diarrhea, nausea, vomiting, abdominal pain, and
chills. Onset typically occurs between 30 min and 12 h after inges­
tion of contaminated shellfish. The illness is usually self-limited; most
patients recover in 3–4 days and only a few require hospitalization.
Treatment is supportive and focused on hydration. Toxins can be
detected in food samples by a mouse bioassay, an immunoassay, and
fluorometric HPLC.
Acknowledgment
Kirsten B. Hornbeak, Robert L. Norris, Alex Chen, and Charles Lei
contributed to this chapter in the prior edition and material from that
chapter has been retained here. We would like to dedicate this chapter
to the late Dr. Paul S. Auerbach, who was a contributing author for the
previous seven editions of Harrison’s Principles of Internal Medicine.
Dr. Auerbach had a tremendous impact on the field of emergency medi­
cine and founded the subspecialty of wilderness medicine. Dr. Auerbach
was a wonderful teacher, mentor, and friend, and will be deeply missed.
■
■FURTHER READING
Blohm E et al: Marine envenomations, in Goldfrank’s Toxicologic
Emergencies, 11th ed. Nelson LS et al (eds). New York, McGraw-Hill
Education, 2019, pp 1567-1580.
Bush SP et al: Comparison of F(ab’)2 versus Fab antivenom for pit
viper envenomation: A prospective, blinded, multicenter, random­
ized clinical trial. Clin Toxicol 53:37, 2015.
Cannon R et al: Acute hypersensitivity reactions associated with
administration of crotalidae polyvalent immune Fab antivenom. Ann
Emerg Med 51:407, 2008.
Fil LJ et al: Food Poisoning, in Goldfrank’s Toxicologic Emergencies,
11th ed. Nelson LS et al (eds). New York, McGraw-Hill Education,
2019, pp 592-605.
French LK et al: Marine vertebrates, cnidarians, and mollusks, in
Critical Care Toxicology: diagnosis and management of the critically
poisoned patient, 2nd ed. Brent J et al (eds). New York, Springer, 2017,
pp 2045-2074.
GBD 2019 Diseases and Injuries Collaborators: Global burden of
369 diseases and injuries in 204 countries and territories, 1990-2019:
a systematic analysis for the Global Burden of Disease Study 2019.
Lancet 396:1204, 2020. Erratum in: Lancet 396:1562, 2020.
Hornbeak KB, Auerbach PS: Marine envenomation. Emerg Med
Clin North Am 35:321, 2017.
Kang AM, Fisher ES: Thromboelastography with platelet studies
(TEG with PlateletMapping) after rattlesnake envenomation in the
southwestern United States demonstrates inhibition of ADP-induced
platelet activation as well as clot lysis. J Med Toxicol 16:24, 2020.
Pottier I et al: Ciguatera fish poisoning in the Caribbean Sea and
Atlantic Ocean: Reconciling the multiplicity of ciguatoxins and ana­
lytical chemistry approach for public health safety. Toxins (Basel)
15:453, 2023.
Thomas EG, Thomas DJ: Mimics of allergy and angioedema: Scom­
broid, mast cell activation disorders, and hereditary alpha tryptasemia.
Immunol Allergy Clin North Am 43:553, 2023.
Ubani CB et al: Emergency department management of North American
snake envenomations. Emerg Med Pract 26:1, 2024.
Warrell DA, Williams DJ: Clinical aspects of snakebite envenoming
and its treatment in low-resource settings. Lancet 401:1382, 2023.
Silas A. Davidson, Scott A. Norton
Ectoparasite Infestations
and Arthropod Injuries
Ectoparasites include arthropods and creatures from other phyla that
infest the skin or hair of animals; the host animals provide them with
sustenance and shelter. The ectoparasites may remain on the superficial
surfaces of the skin or hair, attached by mouthparts or with specialized
claws. Other ectoparasites may penetrate the skin’s surface and reside
in the epidermis, dermis, or subcutaneous tissues. Ectoparasites may
inflict direct mechanical injury, consume blood or nutrients, induce
hypersensitivity reactions, inoculate toxins, transmit pathogens, create
openings in the skin for secondary bacterial infection, and incite fear or
disgust. Human beings are obligate hosts for few ectoparasites but can
serve as facultative, dead-end, or paratenic (accidental) hosts for many
others. Of the organisms discussed in this chapter, only scabies mites
(the hominis variety) and human-infesting lice are obligate parasites
of humans.
Arthropods that are capable of ectoparasitism or that can otherwise
cause injury include insects (such as lice, fleas, bed bugs, wasps, ants,
bees, and diverse kinds of flies), arachnids (spiders, scorpions, mites,
and ticks), and myriapods (millipedes and centipedes). Several arthro­
pods can cause uncomfortable reactions when they, their setae (hairlike growths), or their exudates come into contact with skin, mucous
membranes, or ocular tissues.
Certain nematodes (helminths), such as the hookworms (Chap. 239),
are ectoparasitic in that they must enter the skin in some manner, then
traverse the skin to reach deeper tissues, or migrate within the skin.
Infrequently encountered ectoparasites in other animal phyla include
pentastomes (armillifers or tongue worms) and leeches.
Arthropods may cause injury when they attempt to take a blood
meal or as they defend themselves by biting, stinging, or exuding ven­
oms. Papular urticaria and other lesions caused by arthropod bites and
stings are so diverse and variable (depending on the host’s health status
and prior exposure to the arthropod’s saliva, venom, or other exu­
dates) that it is difficult to identify the precise causative organism with
visual examination alone without a bona fide specimen and taxonomic
expertise. Specimens of the presumably offending arthropod should,
whenever possible, be sampled directly (taken from the patient, ideally
by medical personnel) or indirectly by using traps or other monitoring
devices in the patient’s home or workplace. Samples sent to laboratories
for identification should be properly fixed, preserved, and packaged.
The patient’s history of travel and precautionary behaviors; occupa­
tional, recreational, and environmental exposures; and proximity to
animals often helps the clinician and parasitologist resolve the cause.
■
■SCABIES
The human itch mite, Sarcoptes scabiei var. hominis, is an obligate
human ectoparasite and a common cause of itchy dermatosis, affecting
~250 million persons worldwide. Both the mites and the skin condition
are called scabies. Gravid female mites (~0.3 mm in length) burrow
superficially within the stratum corneum, depositing several eggs per
day. Gravid adult females emerge to the skin’s surface about 8 days later,
then (re)invade the skin of the same person or another host. Newly
fertilized female mites are transferred between people mainly by direct
skin-to-skin contact. Transmission is facilitated by crowding, poor
hygiene, and close physical contact with other people. Generally, sca­
bies mites die within a day or so if not on a suitable host. Transmission
by sharing contaminated bedding or clothing occurs less frequently
than commonly thought. Outbreaks are known to occur in preschools,
hospitals, nursing homes, prisons, other institutional residences, and
other congregate settings.
The rash and pruritus associated with scabies arise from a sensitiza­
tion reaction to mites and their secretions/excretions. A person’s initial
infestation typically remains asymptomatic for up to 6 weeks before
intense pruritus starts. Reinfestation, however, promptly induces a
hypersensitivity reaction. Burrows become surrounded by inflamma­
tory infiltrates composed of eosinophils, lymphocytes, and histiocytes.
Infested individuals often feel generalized pruritus, not just in the most
heavily involved areas.
Pruritus typically intensifies at night and after hot showers. Burrows
appear as dark wavy lines in the upper epidermis and are 3–15 mm
long (Fig. 472-1). Classic burrows are often difficult to find because
most patients have perhaps only 10–15 burrows. However, most bur­
rows are obscured by excoriations or secondary bacterial infections.
Scabietic lesions are most common on the volar wrists and along the
digital web spaces. In males, the genitalia (penile glans and shaft and
the scrotum) are nearly always involved. Small papules and vesicles,
often accompanied by eczematous plaques, pustules, or nodules,
appear symmetrically at those sites. The axillae and other intertrigi­
nous areas; around the navel and belt line; and the buttocks and upper
thighs are also common sites. Except in infants, the face, scalp, neck,
palms, and soles are usually spared.
Hyperinfestation with thousands of mites, a condition known as
crusted scabies (formerly Norwegian scabies), may result from gluco­
corticoid use, immunodeficiency (including that due to HIV/AIDS),
and neurologic or psychiatric disorders that dampen the itch or impair
the scratch response. Crusted scabies often resembles psoriasis: both
are characterized by widespread thick yellowish-white keratotic crusts,
scaly plaques, and dystrophic nails. Characteristic burrows are not
seen in crusted scabies, and patients are often not itchy, even though
their infestations are highly contagious and have been responsible for
outbreaks of common scabies in hospitals.
FIGURE 472-1  Scabies burrows. Scabies mites create short, delicate, linear
burrows within the superficial epidermis. Although burrows are pathognomonic for
scabies, most have been altered by scratching or secondary bacterial infection.
Scabies should be in the differential diagnosis for patients with
pruritus and symmetric superficial, excoriated, papulovesicular skin
lesions in characteristic locations, particularly if they have had direct
and prolonged contact with an infested person. The diagnosis can be
confirmed by microscopic examination of material scraped from bur­
rows. Burrows should be sought and unroofed with a sterile needle or
scalpel blade, and the scrapings should be examined microscopically
for mites, eggs, and fecal pellets. Examination of skin scrapings; biopsy
specimens; material obtained by clear cellophane tape or cyanoacrylate
adhesive lifted from lesions; dermatoscopic imaging of papulovesicular
lesions; and microscopic inspection of clear cellophane tape lifted from
lesions also may be diagnostic. In the absence of identifiable mites or
eggs, a clinical diagnosis is based on a triad of pruritus, findings on
physical examination, and an epidemiologic link. Unrelated skin dis­
eases are frequently misdiagnosed as scabies, particularly in presumed
“outbreak” situations. Sarcoptes mites of other mammals may cause
transient irritation, but they do not reside or reproduce in human
hosts. In some Australian Aboriginal communities, household dogs
may serve as reservoirs for human scabies mites.
TREATMENT
Scabies
CHAPTER 472
The U.S. Food and Drug Administration (FDA) has approved four
scabicides: permethrin, crotamiton, spinosad, and lindane. They
are topical products and available by prescription only. Permethrin
cream (5%) is less toxic than 1% lindane preparations and is effec­
tive against lindane-resistant infestations. In adults, scabicides are
applied thinly but thoroughly from the jawline to toes after bathing,
with careful application to interdigital spaces, the navel, and under
the nails. and washed off 6–14 h later with soap and water. These
products are relatively ineffective against scabies eggs, so a second
round of treatment 1 week later is advisable.
Ectoparasite Infestations and Arthropod Injuries
Treating crusted scabies is difficult and requires repeated courses
of both topical (permethrin) and oral (ivermectin) agents. Pre­
application of a keratolytic agent, such as 6% salicylic acid, will
help debulk the crusts. Permethrin should be applied to the skin’s
entire surface, including the scalp, face, and ears. Oral ivermectin
is not FDA-approved for treating scabies but is approved to treat
the nematodal diseases hookworm and strongyloidiasis. A single
oral dose of ivermectin (200 μg/kg) is effective in healthy patients
with common (noncrusted) scabies. Patients with crusted scabies
require three to seven doses of ivermectin over 8–30 days, along
with repeated applications of topical permethrin and possibly a
keratolytic compound.
Within 1 day of properly administered treatment, a scabies infes­
tation is considered noncommunicable, thereby permitting a patient
to return to work, school, and other public activities. Nevertheless,
remind patients that dead mites and their detritus may continue to
produce the pruritic hypersensitivity dermatitis for several weeks.
Unnecessary retreatment with topical agents, especially permethrin
cream, may cause an irritant contact dermatitis. Topical emollients
and antipruritic agents, menthol and methyl salicylate products,
calamine lotion, and oral antihistamines relieve itching during
treatment. Topical glucocorticoids may calm pruritus that lingers
after effective treatment. To prevent reinfestations, bedding and
clothing should be washed and dried on high heat or heat-pressed,
and other environmental surfaces or potential sources of fomites
should be cleaned. Household members and other close contacts of
confirmed cases, even if asymptomatic, should be treated simulta­
neously to help prevent back-and-forth reinfestations.
Scabies infestations often lead to secondary bacterial infections,
usually with Staphylococcus aureus, Streptococcus pyogenes, or both.
Consequences of superinfections include impetigo, cellulitis, inva­
sive bacterial infections, poststreptococcal glomerulonephritis (and
subsequent kidney disease), and possibly acute rheumatic fever
(and subsequent cardiac valvular disease).
■
■CHIGGERS AND OTHER BITING MITES
Chiggers are the larvae of trombiculid (harvest) mites that feed mostly
on mice and other small vertebrates in grassy or brush-covered sites
in tropical, subtropical, and (less frequently) temperate areas during
warm months. They reside on low vegetation and attach themselves to
passing vertebrate hosts. While feeding, larvae secrete proteolytic saliva
that penetrates the epidermis, creating a tube-like invagination, called a
stylostome, in the host’s skin. The stylostome allows the mite to imbibe
tissue fluids. The saliva is highly antigenic and causes small (usually <1 cm in
diameter) but exceptionally itchy papular, urticarial, or pustulovesicu­
lar lesions. In people already sensitized to salivary antigens, the papules
develop within hours of attachment. While attached, chiggers appear
as minute (~0.5 mm diameter) red dots on the skin. Generally, lesions
have a hemorrhagic base and are slightly elevated, resembling purpuric
papules seen in cutaneous small-vessel vasculitis.
Chiggers remain on their host animals for several days before fall­
ing to the ground to complete the nonparasitic stages of their life cycle.
However, in humans, the intense pruritus leads to scratching that
invariably destroys the chigger before it completes feeding, although
the itching and burning often persist for weeks. The rash is common on
the ankles and along the belt line and in areas where circumferentially
tight clothing obstructs the further wanderings of the mites. Topical
repellents on one’s skin and insecticide-treated clothing are useful for
preventing chigger bites.
PART 14
Poisoning, Drug Overdose, and Envenomation
Chiggers (primarily Leptotrombidium species) serve as vectors for
intracellular rickettsial organisms in the genus Orientia that cause
scrub typhus. Scrub typhus caused by Orientia tsutsugamushi was
traditionally confined to the eastern half of Asia and the Indomalayan
and Australasian regions. Their bites may be asymptomatic. Endemic
foci of closely related Orientia species have recently been identified in
southern Chile, East Africa, and the Arabian peninsula, where they
cause scrub typhus-like illnesses. Additional areas of transmission will
likely be found outside the usual endemic regions. Only larval trombi­
culids are predatory on mammals, and the larvae acquire their Orientia
load from transovarial transmission from their mother mites.
Many kinds of mites feed on peridomestic birds or rodents and
become particularly bothersome when they invade homes and bite
people. In North America, the northern fowl mite, chicken mite, tropical
rat mite, and house mouse mite normally feed on poultry, other birds,
and small mammals. After their natural hosts leave the nest or die, the
mites disperse and may invade homes. Although the mites are rarely seen
because of their small size, their bites can be painful and pruritic. House
mouse mites (Liponyssoides sanguineus) serve as vectors for the agent of
rickettsialpox, Rickettsia akari, an uncommon disease characterized by
mild fevers, an eschar at the bite site, and a papulovesicular eruption.
Rickettsialpox (Chap. 192) has been recognized mainly in large northern
temperate urban areas. Once these environmental mites are confirmed
as causing pruritic eruptions, they are best eliminated by excluding their
animal hosts, removing their nests, and cleaning and treatment of the
nesting area with appropriate acaricides.
Pyemotes mites are external parasites of insect larvae and commonly
occur in insect-infested products such as grain, straw, cheese, hay, and
oak leaf galls. Their saliva contains a potent neurotoxin they use to
immobilize their prey. The straw itch mite (Pyemotes tritici) occurs
worldwide and is an occupational hazard for agriculture workers and
others who work with dry plant material. Bites in humans are associ­
ated with pruritic rashes and may produce a unique dermatologic
“comet sign” lesion—a paisley-shaped urticarial plaque (Fig. 472-2).
The oak leaf gall mite (Pyemotes herfsi) has been associated with several
outbreaks of dermatosis in the central and eastern United States. These
mites feed on oak gall midges and periodic cicada eggs in oak trees, and
their populations fluctuate widely each year based on host availability.
In the late summer and fall, mites drop or are wind-blown from oak
trees and may land on a person. Bites in people are usually reported
on exposed surfaces, such as neck, face, arms, and upper torso. Intense
itching is reported 10–16 h after the initial bite, which most people do
not recall.
Diagnosis of mite-induced dermatitis (including those caused by
chiggers) relies on confirmation of the mite’s identity or elicitation of
a history of exposure to the mite’s source. Unlike scabies mites that
burrow and live in one’s skin, environmental mites do not reside on
humans. Therefore, treatment of the patient with acaricides (e.g., per­
methrin) is discouraged. Oral antihistamines or topical steroids may
reduce mite-induced pruritus temporarily.
The mites that cause house dust–related allergic conditions neither
bite nor infest humans.
■
■TICK BITES AND TICK PARALYSIS
Ticks attach superficially to skin and usually feed painlessly; blood is
their only food. Their salivary secretions are biologically active, pre­
venting the host’s blood from coagulating while the tick feeds. Tick
saliva can transmit various pathogens and can induce several “sterile
reactions” in the host, such as a local inflammatory response, fevers,
and tick-bite paralysis. The two main families of ticks are the hard
ticks (Ixodidae) and soft ticks (Argasidae). Because no ticks are obli­
gate parasites on humans, all tick-borne diseases (bacterial, viral, and
protozoal) are zoonotic.
Generally, soft (argasid) ticks feed quickly, attaching to a host, com­
pleting a meal in <1 h, and then dropping off the host. Because of their
rapid feeding habits, soft ticks are not carried widely by their vertebrate
hosts. Soft tick–associated infections usually have fairly focal distribu­
tions. On humans, red macules may develop at the bite site. Some spe­
cies in Africa, the western United States, and Mexico produce painful
hemorrhagic lesions.
Hard (ixodid) ticks are much more common than soft ticks, and
they transmit most tick-borne infections that are familiar to physicians,
patients, and the public. Hard ticks attach to the host and feed for sev­
eral days to >1 week, with the exact duration depending upon the tick’s
species and stage of development. At the site of hard-tick bites, small
areas of induration, often purpuric, develop and may be surrounded
by an erythematous rim. A necrotic eschar, called a tâche noire (“black
spot”), occasionally develops. Long-lasting dermal nodules, called
persistent tick-bite granulomas, occasionally appear where the host
is bitten. The nodules are roughly 1–3 cm in diameter and may linger
for months after the feeding tick has fallen off or been removed. The
granulomas can be treated with injected intralesional glucocorticoids,
by simple local excision, or simply left to resolve on their own over
perhaps a year or more. Tick-induced fever, unassociated with any
pathogen, is often accompanied by headache, nausea, and malaise but
usually resolves ≤36 h after the tick is removed.
Tick bites are also associated with a recently recognized allergic
condition known as alpha-gal syndrome (AGS) or red meat allergy.
This syndrome occurs in humans when exposure to tick saliva induces
production of IgE antibodies that cross-react with a carbohydrate mol­
ecule, galactose-α-1,3-galactose (alpha-gal), found in muscle tissues
of all mammals except humans, other apes, and Old World monkeys.
In the United States, AGS is attributed to bites from the lone star tick
(Amblyomma americanum). The geographic distribution of human
cases closely aligns with that tick’s geographic range. In Australia and
Europe, AGS is associated with Ixodes spp., and in Asia, it is associated
with Haemaphysalis longicornis. It is important for individuals with
AGS to avoid additional tick bites as this may prolong or worsen their
allergic reactions.
Tick paralysis, an acute ascending flaccid paralysis, is believed to
be caused by one or more unidentified toxins in tick saliva that block
neuromuscular transmission and decrease nerve conduction. This rare
complication has been associated with >70 species of ticks. Although
it has been reported worldwide, most cases occur in the Rocky Moun­
tain region, in northwestern United States and southwestern Canada,
and along Australia’s eastern seaboard. In North America, dog and
wood ticks (Dermacentor species) are most commonly implicated.
Weakness begins several days after the tick attaches to the host. The
Guillain-Barré-like paralysis starts in the lower legs and ascends sym­
metrically over several days. The paralysis may culminate in complete
paralysis of the extremities and cranial nerves. Deep tendon reflexes
are diminished or absent, but sensory examination and findings on
lumbar puncture are typically normal. Diagnosis and treatment depend
on finding the tick, which is often hidden beneath scalp hair. Removal
FIGURE 472-2  Comet signs in individuals with known or suspected mite-bite reactions, likely due to Pyemotes species. Note central punctum at bite site, surrounded by
edematous erythema. Linear or serpiginous “comet tails” emanate from the central site. Pyemotes-induced comet tails generally do not follow typical patterns of ascending
lymphatic drainage.
of the tick generally leads to improvement within a few hours and com­
plete recovery after several days, although the patient’s condition may
continue to deteriorate for a full day. Failure to remove the tick may
lead to dysarthria, dysphagia, and ultimately death from aspiration or
respiratory paralysis.
Removal of hard ticks during the first 24 h of attachment gener­
ally prevents transmission of the agents of Lyme disease, babesiosis,
anaplasmosis, and ehrlichiosis, although tick-borne viruses may be
transmitted more quickly. Ticks should be removed by traction with
fine-tipped forceps placed firmly around the tick’s mouthparts where
they enter the skin. Careful handling (to avoid rupture of ticks) and
use of gloves may avert accidental contamination with pathogens
contained in the tick’s body fluids. Attempting to induce the tick to
detach by applying heat or occlusive compounds or dressings merely
delays tick removal. After removal, the site of attachment should be
disinfected. Tick mouthparts sometimes remain in the skin but gener­
ally are shed spontaneously within days without the need for surgical
removal. Current guidelines from the Centers for Disease Control and
Prevention suggest that, rather than awaiting the onset of erythema
migrans, the results of tick testing, or seroconversion to antigens
diagnostic for Lyme disease, physicians may appropriately administer
prophylaxis—a one-time oral dose of doxycycline (200 mg) within 72 h
of tick removal—to adult patients with bites thought to be from Ixodes
scapularis (black-legged or deer ticks) in Lyme disease–endemic areas.
Whereas antibiotic prophylaxis may help prevent Lyme disease, it is not
recommended as a way to prevent other tick-borne infections.
CHAPTER 472
Ectoparasite Infestations and Arthropod Injuries
The Asian longhorned tick (Haemaphysalis longicornis) is a newly
invasive species in the United States, first detected in the northeast­
ern states in 2017. Although it carries several pathogens to domestic
animals, wildlife, and humans in its natural range (northeastern Asia),
it has not yet been implicated in disease transmission in the United
States.
■
■LOUSE INFESTATION (PEDICULOSIS AND
PTHIRIASIS)
Three kinds of biting lice are obligate blood-feeding ectoparasites of
human beings. These include the human head louse and the human
body louse that represent distinct genetic clades of Pediculus humanus,
and the pubic (“crab”) louse (Pthirus pubis). Nymphs and adults of
these lice feed at least once a day, ingesting human blood exclusively,
and they partition ecologically on the host. Head lice infest mainly
the scalp and scalp hair; body lice infest clothing; and pubic lice infest
mainly pubic hair. The saliva of lice produces a pruritic morbilliform or
urticarial rash in some sensitized persons. Female head lice and pubic
lice cement their eggs (nits) firmly to human hair, whereas female body
lice cement their eggs to clothing, particularly to threads along cloth­
ing seams. After ~10 days of development within the egg, a nymph
emerges. Empty eggs may remain affixed to hair for months thereafter.
Body lice are acquired by direct contact with an infested person
or their recently used clothing or bedding. These lice venture for just
minutes to the skin to feed, but otherwise sequester on clothing. They
generally succumb in ≤2 days if separated from their host. In developed
countries, body lice are generally uncommon, found only on indigent
persons who have relevant exposure and lack the wherewithal or desire
to change or appropriately launder their clothing and bedding.
Body lice are vectors for the agents of louse-borne (epidemic) typhus
(Chap. 192), louse-borne relapsing fever (Chap. 190), and trench fever
(Chap. 177). Body lice and their associated diseases may proliferate
whenever societal upheaval and disasters limit access to clean clothes
or laundry facilities. This scenario was exacerbated during the trench
warfare of World War I, when troops often wore one uniform for weeks
or months at a time. During damp, cold months, entrenched soldiers
huddled together to stay warm, enabling body lice and their pathogens
to spread easily from person to person.
Infestations result in a postinflammatory hyperpigmentation and
thickening of the skin known as vagabond’s disease. When inspecting
a patient for signs of a body lice infestation, one must examine their
clothing seams for nits and live lice.
Head lice are acquired mainly by direct head-to-head contact rather
than via fomites such as shared hats, caps, headgear, bed linens, and
grooming implements. Worldwide, the prevalence of head lice varies
widely as a function of age, geography, and cultural habits. In North
America, the overall prevalence of head lice infestation is generally
low, but most communities, irrespective of socioeconomic circum­
stances, experience episodic high-prevalence focal outbreaks among
younger school-aged children. Although these events generally spare
adults, they can create considerable distress among families in those
communities.
PART 14
Poisoning, Drug Overdose, and Envenomation
An infested person generally hosts 10 or fewer head lice, but the nits,
even when empty or nonviable, remain cemented to one’s scalp hairs
as they grow. Thus, accumulated nits make it seem that a person has
hundreds of head lice, even after successful treatment. Consequently,
many schools retain unnecessarily onerous “no nit” policies for school
attendance, even though a child has been treated successfully. Bite
reactions appear as small, <1 cm diameter edematous pink wheals and
are most evident along the posterior hairline. Pruritus, attributed to
hypersensitivity to the louse’s saliva, leads to scratching, which may
lead to secondary impetigo with S. aureus or S. pyogenes.
Body lice are well known to transmit diseases, but can head lice
(besides superficial secondary bacterial infections)? Several studies
using polymerase chain reaction on freshly caught head lice have
detected pathogenic bacteria, but clinical and epidemiologic data are
generally interpreted to show that head lice are not natural vectors of
any disease. On the other hand, experimental models suggest that head
lice may have some competence as vectors for Rickettsia prowazekii
(louse-borne typhus) and Bartonella quintana (trench fever). Indeed,
sporadic reports indicate that cycles of trench fever are maintained in
Ethiopia and elsewhere in Africa by head lice in the absence of body
lice.
Crab or pubic lice are found mostly on pubic hair and are transmit­
ted mainly by direct sexual contact. They also occur uncommonly on
axillary or facial hair, including the eyelashes, as the result of either
sexual or close nonsexual contact. Intensely pruritic, bluish mac­
ules <5 mm in diameter (maculae ceruleae) may develop at bite sites.
Blepharitis commonly accompanies infestations of the eyelashes. Eye­
lash infestations in children should not be construed as incontrovert­
ible evidence of inappropriate sexual contact.
Pediculosis is often suspected upon the detection of presumed nits
to hairs or simply on the basis of an itchy scalp. Objects presumed to be
louse eggs are often pseudo-nits composed of debris, flakes of dry skin,
and hair-associated fungi. Hatched and dead eggs remain firmly affixed
to scalp hair for months. Such relics are frequently misconstrued to be
signs of an active louse infestation. Confirmation of a louse infestation,
therefore, should rely on the discovery of a live louse.
TREATMENT
Louse Infestation
Body lice usually are eliminated by bathing and by changing to new
or properly laundered clothes. Fabric is effectively deloused by heat,
such as in a clothes dryer at ≥55°C (≥131°F) for 30 min or by heatpressing. Emergency mass delousing may be warranted in congre­
gate settings during periods of civil strife and after natural disasters
to reduce the high risk of disease transmission by body lice.
Head lice and nits may be removed with a fine-toothed louse or
nit comb, but this effort is time-consuming and often fails to eradi­
cate the lice. Treatment of newly identified, active infestations tra­
ditionally relies on a 10-min topical application of a FDA-approved
1% permethrin lotion or pyrethrin-based shampoo, which are
available over the counter. Also FDA-approved, but requiring a pre­
scription, are 0.5% malathion lotion, 0.5% ivermectin lotion, and
0.9% spinosad suspension. These products do not kill viable nits, so
a second application roughly 10 days later is required to clear newly
hatched lice. Lice persisting after this treatment may be due to backand-forth reinfestations within a family, or the lice may be resistant
to chemical treatment. Resistance to permethrin, malathion, and
lindane is well documented, with less resistance associated with
ivermectin and spinosad products. Although children infested by
head lice—or those who simply have remnant nits from a previous
infestation—are frequently isolated or excluded from school, this
practice increasingly is considered to be unjustified, ineffective, and
counterproductive.
Pubic louse infestations are treated with topical pediculicides,
except for eyelid infestations (pthiriasis palpebrum), which gener­
ally respond to a coating of petrolatum applied for 3–4 days.
■
■MYIASIS (FLY INFESTATION)
Myiasis refers to infestations by fly larvae (maggots) that invade living
or necrotic tissues or body cavities and produce different clinical syn­
dromes, depending on the species of fly.
In forested parts of Central and South America, larvae of the human
botfly (Dermatobia hominis) produce furuncular (boil-like) dermal
and subcutaneous nodules ≤3 cm in diameter. A gravid adult female
botfly captures a mosquito or another bloodsucking insect and depos­
its her eggs on its abdomen. When the carrier insect attacks a human or
another mammalian host (often cattle) several days later, the warmth
and moisture of the host’s skin stimulate the eggs to hatch. The emerg­
ing larvae, ~1 mm long, promptly penetrate the skin. After 6–12 weeks of
development, mature larvae emerge from the skin, drop to the ground,
pupate, and finally metamorphose into adults.
The African tumbu fly (Cordylobia anthropophaga, also called
mango fly or mputsi fly) deposits its eggs on damp sand, leaf litter, dry­
ing laundry, or damp clothing contaminated by urine or sweat. Larvae
hatch from eggs upon contact with a host’s body and penetrate the skin,
producing boil-like lesions from which mature larvae emerge ~9–10 days
later. Furuncular myiasis is suggested by uncomfortable lesions with a
central breathing pore that emit bubbles when submerged in water. The
sensation of movement within the patient’s skin may cause severe (and
understandable) emotional distress (Fig. 472-3).
Larvae that cause furuncular myiasis may be induced to emerge if the
breathing pore is coated with petrolatum or another occlusive substance.
Removal may be facilitated by injection of a local anesthetic (or sterile
injectable saline) into the subjacent tissue to uplift the larva through
the breathing pore. Surgical excision is sometimes necessary because
upward-pointing spines of some species hold larvae firmly in place.
Other fly larvae cause several forms of nonfuruncular myiasis. Lar­
vae of the horse botfly (Gasterophilus intestinalis) emerge from eggs
that typically are laid on the hairs of a horse’s front legs. Direct contact
with a person’s skin may cause the eggs to hatch and the new larvae to
invade human skin. After penetrating human skin, these larvae rarely
mature but instead may migrate for weeks in the dermis. The resulting
pruritic and serpiginous eruption resembles cutaneous larva migrans
caused by canine or feline hookworms (Chap. 238). Larvae of rabbit
and rodent botflies (Cuterebra species) occasionally cause cutaneous
or tracheopulmonary myiasis. Larvae of the sheep botfly, Oestrus ovis,
and other flies responsible for furuncular and wound myiasis also may
cause ophthalmomyiasis. Sequelae include nodules in the eyelid, retinal
detachment, and destruction of the globe.
FIGURE 472-3  Furuncular myiasis with larva of Cordylobia anthropophaga in the thigh of a teenage girl who recently returned from visiting relatives in East Africa (left). The
central pore shows the respiratory elements of the embedded fly larva (right).
Certain flies are attracted to blood and pus, laying their eggs on
open or draining sores. Newly hatched larvae enter wounds or diseased
skin. Larvae of several species of green bottle flies (Lucilia spp.) usually
consume only necrotic tissues. Specially raised, sterile “surgical mag­
gots” are available as FDA-approved medical devices for debridement
of chronic wounds, such as deeply infected diabetic ulcers. On the
other hand, larvae of screwworm flies (Cochliomyia spp.) and flesh
flies (Wohlfahrtia spp.) can invade viable tissues more deeply and
cause large suppurating lesions. These can be extraordinarily harmful
to domesticated herd animals. Larvae of the sheep botfly, Oestrus ovis,
may cause nasal or external ophthalmomyiasis, involving tear ducts,
eyelids, and conjunctivae.
Larvae that infest decaying tissues may enter body cavities such as
the mouth, nose, ears, sinuses, anus, vagina, and lower urinary tract,
particularly in unconscious or otherwise debilitated patients. The con­
sequences range from harmless colonization to destruction of the nose,
meningitis, and deafness. Treatment involves removal of maggots,
surgical debridement of tissue, and treatment of secondary infections.
Maggots are occasionally found in human feces, usually the result
of a fly laying eggs on recently passed stools, and not as evidence of an
intestinal maggot infestation.
■
■PENTASTOMIASIS
Pentastomids (tongue worms), an obscure type of crustacean, inhabit
respiratory passages of reptiles and carnivorous mammals. Human
infestation by Linguatula serrata is common in the Middle East and
results from eating encysted larval stages in raw liver or lymph nodes
of sheep and goats, which are true intermediate hosts for the tongue
worms. In areas where raw sheep and goat liver are served, pentasto­
mid larvae migrate to the person’s nasopharynx and produce an acute
self-limiting syndrome—known as halzoun in Lebanon and marrara in
Sudan—characterized by rapid onset (within <12 h) of pain and itching
of the throat and ears, coughing, hoarseness, dysphagia, and dyspnea.
Severe edema may cause obstruction that requires tracheostomy. In
addition, ocular invasion has been described. Diagnostic larvae mea­
suring ≤10 mm in length appear in copious nasal discharge or vomitus.
Another type of tongue worm, Armillifer armillatus, infects people
who consume its eggs in contaminated food or drink or after han­
dling the definitive host, the African python. Larvae encyst in various
organs, usually the liver or peritoneum, but rarely cause symptoms.
Cysts may require surgical removal as they enlarge during worm
molting, but they usually are encountered as an incidental finding at
CHAPTER 472
autopsy. Parasite-induced lesions may be misinterpreted as a malig­
nancy, with the correct diagnosis only confirmed histopathologically.
Larva migrans–type syndromes caused by other pentastomes have
been reported from Southeast Asia and Central America.
Ectoparasite Infestations and Arthropod Injuries
■
■LEECH INFESTATIONS
Medically important leeches are annelid worms that attach to their
hosts with chitinous cutting jaws and draw blood through muscular
suckers. Medicinal leeches (Europe: Hirudo medicinalis and other
Hirudo species; Asia: Hirudinaria manillensis; North America: Macrob­
della decora) are still used occasionally for medical purposes to reduce
venous congestion in surgical flaps or replanted body parts. This prac­
tice has been complicated by intractable bleeding, wound infections,
myonecrosis, and sepsis due to Aeromonas hydrophila, which colonizes
the gullets of commercially available leeches.
Ubiquitous aquatic leeches that parasitize fish, frogs, and turtles
readily attach to human skin—most often the nasal mucosa—and
avidly suck blood. Attachment is usually painless, and the leeches will
detach themselves when satiated with a blood meal. Hirudin, a pow­
erful anticoagulant secreted by the leech, causes continued bleeding
after the leech has detached. Healing of a leech-bite wound is slow,
and secondary bacterial infections are not uncommon. Several kinds
of aquatic leeches in Africa, Asia, and southern Europe can enter the
mouth, nose, and genitourinary tract and attach to mucosal surfaces
at sites as deep as the esophagus and trachea. Leeches may detach on
exposure to gargled saline or may be removed by forceps or medical
suction.
Arboreal land leeches, which live amid rain forest vegetation, are
attracted by heat and can drop from a leaf onto one’s skin. Externally
attached leeches generally drop off after they have engorged, but
removal is hastened by gentle scraping aside of the anterior and poste­
rior suckers the leech uses for attachment and feeding. Some authori­
ties dispute the wisdom of removing leeches with alcohol, salt, vinegar,
insect repellent, a flame or heated instrument, or applications of other
noxious substances.
■
■SPIDER BITES
All spiders are carnivores and most have venomous bites intended to
immobilize and digest their prey. However, very few spiders are capable
of biting humans, and the vast majority of putative spider bites have
nothing to do with spiders. Of >45,000 recognized species of spiders,
only about 60 are medically important to humans. In the United States,
only recluse spiders (Loxosceles spp.) and widow spiders (Latrodectus
spp.) are considered medically important.
Most spider bites are painful but do not require medical attention.
Identification of the offending spider is important because specific
treatments exist. Except when the patient actually observes a spider bit­
ing them or fleeing from a site of sudden sharp pain, most acute tender
noduloulcerative lesions reported as spider-bite reactions are due to
an unrelated minor injury or caused by an acute bacterial infection,
particularly by methicillin-resistant S. aureus (MRSA).
Recluse Spider Bites and Necrotic Arachnidism 
Brown
recluse spiders (Loxosceles reclusa) live mainly in the southcentral
United States and have close relatives in Central and South America,
Africa, the Mediterranean basin, and the Middle East. Recluse spi­
ders are not aggressive toward humans and bite only if threatened or
pressed against the skin. They generally live beneath rocks and logs or
in caves and animal burrows. They invade homes and seek dark and
undisturbed hiding spots in closets, garages, crawl spaces, and attics;
under furniture and rubbish in storage rooms; and in folds of cloth­
ing. Despite their impressive abundance in some homes, these spiders
rarely bite humans. Bites tend to occur while the victim is donning
clothing in which the spider has hidden itself and are sustained primar­
ily on the hands, arms, neck, and lower abdomen.
A brown recluse spider’s bite may cause minor injury with edema
and erythema, and envenomation can cause severe necrosis of skin and
subcutaneous tissue and, more rarely, systemic hemolysis. Initially, the
bite is painless or may produce a stinging sensation. Within a few hours,
the site becomes painful and sensitive to touch, with central induration
surrounded by a pale ischemic zone that itself is encircled by a zone of
erythema. In most cases, the lesion resolves without treatment in just a
few days. In severe cases, systemics signs, such as fever, chills, weakness,
headache, nausea, vomiting, myalgia, arthralgia, and leukocytosis, may
soon develop. As the bite site evolves, the erythematous zone expands,
and the center becomes hemorrhagic or necrotic with an overlying
bulla. A black eschar forms and sloughs several weeks later, leaving an
ulcer that eventually may create a depressed scar. Healing usually takes
place in ≤3 months. Local complications include injury to nerves and
secondary bacterial infection. Reports of deaths attributed to bites of
North American brown recluse spiders have not been verified.
PART 14
Poisoning, Drug Overdose, and Envenomation
The Mediterranean recluse spider (Loxosceles rufescens) is a widely
invasive species in urban areas of both the Old and New Worlds. The
dorsal surfaces of L. rufescens and L. reclusa are adorned with a fiddleshaped pattern. L. rufescens is warier than L. reclusa, is less likely to
bite, and rarely causes necrosis. Misidentification of this spider may
create spurious reports of L. reclusa activity outside the known range
of that species.
TREATMENT
Recluse Spider Bites
Initial management includes rest, ice, compression, and elevation
(RICE). Analgesics, antihistamines, antibiotics, and tetanus pro­
phylaxis should be administered if indicated. Early debridement
or surgical excision of the wound without closure delays healing.
Routine use of antibiotics or dapsone lacks utility. Patients should
be monitored closely for signs of hemolysis, renal failure, and other
systemic complications.
Widow Spider Bites 
The southern black widow spider (Latrodectus
mactans) is common in the southeastern United States. Female bodies are
~1 cm in length, but the leg span may be ~5 cm across. Their bodies
are shiny black with a red hourglass marking on the ventral abdomen.
Other dangerous Latrodectus species occur elsewhere in temperate and
subtropical parts of the world. The bites of the female widow spiders
are notorious for their potent neurotoxins.
Widow spiders spin their webs under stones, logs, plants, or rock
piles and in dark spaces in barns, garages, and outhouses. Bites are
most common in the summer and early autumn and occur when a web
is disturbed or a spider is trapped or provoked. The initial bite is per­
ceived as a sharp pinprick or may go unnoticed. Fang-puncture marks
are uncommon. Envenomation does not cause local tissue damage, and
some persons experience no further symptoms.
α-Latrotoxin, the most active component of the venom, is a neuro­
toxin. It binds irreversibly to presynaptic nerve terminals and causes
release and eventual depletion of acetylcholine, norepinephrine, and
other neurotransmitters from those terminals. Painful cramps may
spread within 60 min from the bite site to large muscles of the extremi­
ties and trunk. Extreme abdominal pain and rigidity may resemble
peritonitis, but the abdomen is not tender on palpation and surgery
is not warranted. The pain begins to subside during the first 12 h but
may recur over the next few days or weeks before resolving spontane­
ously. A wide range of other sequelae, largely neurologic, may include
salivation, diaphoresis, vomiting, hypertension, tachycardia, labored
breathing, anxiety, headache, weakness, fasciculations, paresthesia,
hyperreflexia, urinary retention, uterine contractions, and premature
labor. Rhabdomyolysis and renal failure have been reported, and respi­
ratory arrest, cerebral hemorrhage, or cardiac failure may end fatally,
especially in very young, elderly, or debilitated persons.
TREATMENT
Widow Spider Bites
Treatment consists of RICE and tetanus prophylaxis. Hypertension
that does not respond to analgesics and antispasmodics (e.g., ben­
zodiazepines or methocarbamol) requires specific antihypertensive
medication. The efficacy and safety of antivenin made from equine
immunoglobulins are controversial for black widow bites because
of potential anaphylaxis or serum sickness. Antivenins made from
monoclonal antibodies are in development.
Tarantulas and Other Spiders 
Tarantulas are large hairy spiders
of which 30 species are found in the United States, mainly in the South­
west. Several species of tarantulas have become popular household pets
and are usually imported from Central or South America. Tarantulas
bite people only when threatened and usually cause no more harm
than a bee sting, but on occasion, the venom causes deep pain and
swelling. Several species of tarantulas are covered with urticating hairs
that are brushed off in the thousands when a threatened spider rubs its
hind legs across its dorsal abdomen. These hairs can penetrate human
skin and produce pruritic papules that may persist for weeks. Failure
to wear gloves or to wash the hands after handling the Chilean Rose
tarantula, a popular pet spider, has resulted in transfer of hairs to the
eye with subsequent devastating ocular inflammation. Treatment of
bites includes local washing and elevation of the bitten area, tetanus
prophylaxis, and analgesic administration. Antihistamines and topical
or systemic glucocorticoids are given for exposure to urticating hairs.
Atrax robustus, a funnel-web spider of Australia, and Phoneutria
species, the South American banana spiders, are among the world’s
most dangerous spiders because of their aggressive behavior and potent
neurotoxins. Envenomation by A. robustus causes a rapidly progres­
sive neuromotor syndrome that can be fatal within 2 h. The bite of a
banana spider causes severe local pain followed by profound systemic
symptoms and respiratory paralysis that can lead to death within
2–6 h. Specific antivenins for use after bites by each of these spiders
are available. Yellow sac spiders (Cheiracanthium species) are common
in homes worldwide. Their bites, though painful, generally lead to only
minor erythema, edema, and pruritus.
■
■SCORPION STINGS
Scorpions are arachnids that feed on arthropods and other small
animals. They paralyze their prey and defend themselves by inject­
ing venom from a stinger on the tip of the tail. Painful but relatively
harmless scorpion stings need to be distinguished from the potentially
lethal envenomations from about 30 of roughly 1000 known species,
which cause several thousand deaths worldwide each year. Scorpions
are nocturnal and remain hidden during the day in crevices or burrows
or under wood, loose bark, or rocks. They occasionally enter houses
and tents and may hide in shoes, clothing, or bedding. Scorpions sting
humans only when threatened.
Of approximately 40 scorpion species in the United States, only
bark scorpions (Centruroides sculpturatus/C. exilicauda) in the South­
west produce venom that is potentially lethal to humans. This venom
contains neurotoxins that cause sodium channels to remain open.
Such envenomations usually are associated with little swelling, but
prominent pain, paresthesia, and hyperesthesia can be accentuated by
tapping on the affected area (the tap test). These symptoms soon spread
to other locations; dysfunction of cranial nerves and hyperexcitability
of skeletal muscles develop within hours. Patients present with rest­
lessness, blurred vision, abnormal eye movements, profuse salivation,
lacrimation, rhinorrhea, slurred speech, difficulty in handling secre­
tions, diaphoresis, nausea, and vomiting. Muscle twitching, jerking,
and shaking may be mistaken for a seizure. Complications include
tachycardia, arrhythmias, hypertension, hyperthermia, rhabdomyoly­
sis, and acidosis. Symptoms progress to maximal severity in ~5 h and
subside within a day or two, although pain and paresthesia can last for
weeks. Fatal respiratory arrest is most common among young children
and the elderly.
Envenomations by Leiurus quinquestriatus in the Middle East and
North Africa, by Mesobuthus tamulus in India, by Androctonus species
along the Mediterranean littoral and in North Africa and the Middle
East, and by Tityus serrulatus in Brazil cause massive release of endoge­
nous catecholamines with hypertensive crises, arrhythmias, pulmonary
edema, and myocardial damage. Acute pancreatitis occurs with stings
of Tityus trinitatis in Trinidad, and central nervous toxicity complicates
stings of Parabuthus and Buthotus scorpions of South Africa.
In Iran and adjacent countries, Hemiscorpius lepturus causes the
most scorpion envenomations. Its stings are relatively asymptomatic at
first, but its cytotoxic venom causes pain, hemolysis, and tissue necro­
sis after the first day. Systemic complications include hemoglobinuria
and subsequent acute kidney injury.
Stings of most other species cause immediate sharp local pain fol­
lowed by edema, ecchymosis, and a burning sensation. Symptoms
typically resolve within a few hours, and skin does not slough. Allergic
reactions to the venom may occur.
TREATMENT
Scorpion Stings
Identification of the offending scorpion helps to determine the
course of treatment. Stings of nonlethal species require at most ice
packs, analgesics, or antihistamines. Because most victims experi­
ence only local discomfort, they can be managed at home with
instructions to return to the emergency department if signs of
cranial-nerve or neuromuscular dysfunction develop. Aggressive
supportive care and judicious use of antivenom can reduce or elimi­
nate deaths from more severe envenomations. Keeping the patient
calm and applying pressure dressings and cold packs to the sting
site are measures that decrease the absorption of venom. A continu­
ous IV infusion of midazolam reduces the agitation and involuntary
movements produced by scorpion stings. Treating people with
neuromuscular symptoms with sedatives or opiates requires close
monitoring due to potential respiratory compromise. Hyperten­
sion and pulmonary edema respond to nifedipine, nitroprusside,
hydralazine, or prazosin. Dangerous bradydysrhythmia can be
controlled with atropine.
Commercially prepared antivenins are available in several coun­
tries for some of the most dangerous scorpion species. The FDA has
approved equine-derived C. sculpturatus IgG F(ab’)2 antivenin. IV
administration of antivenin rapidly reverses cranial-nerve dysfunc­
tion and muscular symptoms.
■
■HYMENOPTERA STINGS
Bees, wasps, hornets, yellow jackets, and ants (all of the insect order
Hymenoptera) sting in defense or to subdue their prey. Their venoms
contain a wide array of amines, peptides, and enzymes that cause local
and systemic reactions. Although the toxic effect of multiple stings can
be fatal to a human, nearly all of the ≥100 deaths due to hymenopteran
stings in the United States each year result from type 1, immediate-type
allergic reactions.
Bee and Wasp Stings 
The stinger of the honeybee (Apis mellifera)
is unique in being barbed. The stinging apparatus and attached venom
sac tear loose from the honeybee’s body, and muscular contractions of
the venom sac continue to infuse venom into the skin. Other kinds of
bees, ants, and wasps have smooth stinging mechanisms and can sting
numerous times in succession. Generally, a person sustains just one
sting from a bee or social wasp unless a nest was disturbed. African­
ized honeybees (now present in South and Central America and the
southern and western United States) respond to minimal intrusions
more aggressively. The sting of an Africanized bee contains less venom
than that of its non-Africanized relatives, but victims tend to sustain
far more stings and thus receive a far greater overall volume of venom.
Most patients who report having sustained a “bee sting” are more likely
to have encountered stinging wasps instead.
The venoms of different kinds of hymenopterans are biochemically
and immunologically distinct. Direct toxic effects are mediated by
mixtures of low-molecular-weight compounds such as serotonin, hista­
mine, acetylcholine, and several kinins. Polypeptide toxins in honeybee
venom include mellitin, which damages cell membranes; mast cell–
degranulating protein, which causes histamine release; the neurotoxin
apamin; and the anti-inflammatory compound adolapin. Enzymes in
venom include hyaluronidase and phospholipases. There appears to be
little cross-sensitization between the venoms of honeybees and wasps.
CHAPTER 472
Ectoparasite Infestations and Arthropod Injuries
Uncomplicated hymenopteran stings cause immediate pain, a
wheal-and-flare reaction, and local edema, all of which usually subside
in a few hours. Multiple stings can lead to vomiting, diarrhea, general­
ized edema, dyspnea, hypotension, and nonanaphylactic circulatory
collapse. Rhabdomyolysis and intravascular hemolysis may cause renal
failure. Death from the direct (nonallergic) effects of venom has fol­
lowed stings of several hundred honeybees. Stings to the tongue or
mouth may induce life-threatening edema of the upper airways.
Large local reactions accompanied by erythema, edema, warmth,
and tenderness that spread ≥10 cm around the sting site over 1–2 days
are not uncommon. These reactions may resemble bacterial cellulitis
but are caused by hypersensitivity rather than by secondary infec­
tion. Such reactions tend to recur on subsequent exposure but are
seldom accompanied by anaphylaxis and are not prevented by venom
immunotherapy.
An estimated 0.4–4.0% of the U.S. population exhibits clinical
immediate-type hypersensitivity to hymenopteran stings, and 15% may
have asymptomatic sensitization manifested by positive skin tests. Per­
sons who experience severe allergic reactions are likely to have similar
or more severe reactions after subsequent stings by the same or closely
related species. Mild anaphylactic reactions to insect stings, as to other
causes, consist of nausea, abdominal cramping, generalized urticaria or
angioedema, and flushing. Serious reactions, including upper airway
edema, bronchospasm, hypotension, and shock, may be rapidly fatal.
Severe reactions usually begin within 10 min of the sting and only
rarely develop after 5 h.
TREATMENT
Bee and Wasp Stings
Honeybee stingers embedded in the skin should be removed as
soon as possible to limit the quantity of venom delivered. The
stinger and venom sac may be scraped off with a blade, a fingernail,
or the edge of a credit card or may be removed with forceps. The site
should be cleansed and disinfected and ice packs applied to slow the
spread of venom. Elevation of the affected site and administration
of oral analgesics, oral antihistamines, and topical calamine lotion
help relieve symptoms.
Anaphylactic reactions to bee or wasp venom can be a lifethreatening emergency that requires prompt life-saving actions.
If the individual carries a bee-sting kit, then a subcutaneous injec­
tion of epinephrine hydrochloride (0.3 mL of a 1:1000 dilution)
should be considered, with treatment repeated every 20–30 min as
necessary. A tourniquet may slow the spread of venom. The patient
should be transferred to a hospital emergency room where treat­
ment for profound shock, if required, can be administered safely.
Such treatment may entail the use of IV epinephrine and other
vasopressors, intubation or provision of supplemental oxygen, fluid
resuscitation, use of bronchodilators, and parenteral administration
of antihistamines. Patients should be observed for 24 h for recurrent
anaphylaxis, renal failure, or coagulopathy.
Persons with a history of allergy to insect stings should carry an
anaphylaxis kit with a preloaded syringe containing epinephrine for
self-administration. These patients should seek medical attention
immediately after using the kit.
Prophylactic immunotherapy may greatly reduce the risk of lifethreatening reactions to bee and wasp stings. Repeated injections
of purified venom produce a blocking IgG antibody response to
venom and reduce the incidence of recurrent anaphylaxis. Hon­
eybee, wasp, and yellow jacket venoms are commercially available
for desensitization and for skin testing. Results of skin tests and
venom-specific radioallergosorbent tests (RASTs) aid in the selec­
tion of patients for immunotherapy and guide the design of such
treatment.
PART 14
Poisoning, Drug Overdose, and Envenomation
■
■STINGING ANTS
Stinging ants are an important medical problem in the United States.
Imported fire ants (Solenopsis species) infest southern states from Texas
to North Carolina, with colonies now established in California, New
Mexico, Arizona, and Virginia. Slight disturbances of their mound
nests have provoked massive outpourings of ants and as many as 10,000
stings on a single person. Elderly and immobile persons are at high risk
for attacks when fire ants invade dwellings.
Fire ants attach to skin with powerful mandibles and rotate their
bodies while repeatedly injecting venom with posteriorly situated
stingers. The alkaloid venom consists of cytotoxic and hemolytic
piperidines and several proteins with enzymatic activity. The initial
wheal-and-flare reaction, burning, and itching resolve in ~30 min,
and a sterile pustule develops within 24 h. The pustule ulcerates over
the next 48 h and then heals in ≥1 week. Large areas of erythema and
edema lasting several days are not uncommon and, in extreme cases,
may compress nerves and blood vessels. Anaphylaxis occurs in <2%
of victims; seizures and mononeuritis have been reported. Stings are
treated with ice packs, topical glucocorticoids, and oral antihistamines.
Pustules should be cleansed and then covered with bandages and anti­
biotic ointment to prevent bacterial infection. Epinephrine administra­
tion and supportive measures are indicated for anaphylactic reactions.
Fire ant whole-body extracts are available for skin testing and immu­
notherapy, which appear to lower the rate of anaphylactic reactions.
European fire (red) ants (Myrmica rubra) have recently become pub­
lic health pests in the northeastern United States and southern Canada.
The western United States is home to harvester ants (Pogonomyrmex
species). The painful local reaction that follows harvester ant stings
often extends to lymph nodes and may be accompanied by anaphy­
laxis. The bullet or conga ant (Paraponera clavata) of South America
is known locally as hormiga veinticuatro (“24-hour ant”), a designation
that refers to the 24 h of throbbing, excruciating pain following a sting
that delivers the potent paralyzing neurotoxin poneratoxin.
■
■DIPTERAN (FLY AND MOSQUITO) BITES
In the process of feeding on vertebrate blood and tissue fluids, adults of
certain fly species inflict painful bites, inject saliva that may cause vaso­
dilation and produce local allergic reactions, and may transmit diverse
pathogenic agents. Bites of mosquitoes (culicids), tiny “no-see-um”
midges (ceratopogonids), and sand flies (phlebotomines) typically
produce a wheal and a pruritic papule. Small humpbacked black flies
(simuliids) lacerate skin, resulting in a lesion with serosanguineous
discharge that is often painful and pruritic. Regional lymphadenopathy,
fever, or anaphylaxis occasionally ensues. The widely distributed deer­
flies and horseflies as well as the tsetse flies of Africa are stout flies
that attack during the day and produce large and painful bleeding
punctures. House flies (Musca domestica) do not consume blood but
use rasping mouthparts to scarify skin and feed upon tissue fluids and
salt. Beyond direct injury from bites of any kind of fly, risks include
transmission of diverse pathogens and secondary bacterial infection
of the lesion.
TREATMENT
Fly and Mosquito Bites
Treatment of fly bites is symptom based. Topical application of
antipruritic agents, glucocorticoids, or antiseptic lotions may relieve
itching and pain. Allergic reactions may require oral antihista­
mines. Antibiotics may be necessary for the treatment of large bite
wounds that become secondarily infected.
■
■FLEA BITES
Common human-biting fleas include the dog and cat fleas (Cteno­
cephalides species) and the rat flea (Xenopsylla cheopis), which infest
their respective hosts and their nests and resting sites. Sensitized
persons develop erythematous pruritic papules (papular urticaria) and
occasionally vesicles and bacterial superinfection at the site of the bite.
Symptom-based treatment consists of antihistamines, topical glucocor­
ticoids, and topical antipruritic agents.
Flea infestations are eliminated by removal and treatment of animal
nests, frequent cleaning of pet bedding, and application of contact
and systemic insecticides to pets and the dwelling. Flea infestations
in the home may be abated or prevented if pets are regularly treated
with veterinary antiparasitic agents, insect growth regulators, or chitin
inhibitors.
Tunga penetrans, like other fleas, is a wingless, laterally flattened
insect that feeds on blood. Also known as the chigoe flea, sand flea,
or jigger (not to be confused with the chigger), it occurs in tropical
regions of Africa and the Americas. Adult female chigoes live in sandy
soil and burrow under the skin, usually between toes, under nails, or on
the soles of bare feet. Gravid chigoes engorge on the host’s blood and
grow from pinpoint to pea size during a 2-week interval. They produce
lesions that resemble a white pustule with a central black depression
and that may be pruritic or painful. Occasional complications include
tetanus, bacterial infections, and autoamputation of toes (ainhum).
Tungiasis is treated by removal of the intact flea with a sterile needle
or scalpel, tetanus vaccination, and topical application of antibiotics.
■
■HEMIPTERAN/HETEROPTERAN
(TRUE BUG) BITES
Most true bugs feed on plants, but some are predaceous or feed on
blood. In order to feed or to defend themselves, they may inflict bites
that produce allergic reactions and are sometimes painful. Bites of the
cone-nose or “kissing bugs” (family Reduviidae) tend to occur at night
and are painless. Reactions to such bites depend on prior sensitization
and include tender and pruritic papules, vesicular or bullous lesions,
extensive urticaria, fever, lymphadenopathy, and (rarely) anaphylaxis.
Bug bites are treated with topical antipruritic agents or oral antihista­
mines. Persons with anaphylactic reactions to reduviid bites should
keep an epinephrine kit available. Some reduviids transmit Trypano­
soma cruzi, the agent of New World trypanosomiasis (Chagas disease)
(Chap. 234).
The cosmopolitan and tropical bed bugs (Cimex lectularius and C.
hemipterus) hide in crevices of mattresses, bed frames and other fur­
niture, walls, and picture frames and under loose wallpaper, actively
seeking blood meals at night. These bugs are now a common pest in
homes, dormitories, and hotels; on cruise ships; and even in medical
facilities. Their bite is painless. Bites on persons without prior exposure
to bedbugs may not be noticeable. Persons sensitized to bed bug saliva
develop erythema, itching, and wheals around a central hemorrhagic
punctum. Reactions may manifest within minutes of the bites, or they
may be delayed for days or even a week or more. Bed bugs are not
known to transmit pathogens.
■
■CENTIPEDE BITES AND MILLIPEDE DERMATITIS
Two groups of myriapods (“many-footed” arthropods) can harm
humans. Centipedes, with one pair of legs per body segment, are
fast-moving, aggressive, and carnivorous. They stun and kill their
prey—usually other arthropods, earthworms, and rarely small verte­
brates—with a venomous bite. The fangs of centipedes of the genus
Scolopendra can penetrate human skin and deliver a venom that
produces intense burning pain, swelling, erythema, and sterile lym­
phangitis. Dizziness, nausea, and anxiety are described occasionally,
and rhabdomyolysis and renal failure have been reported. Treatment
includes washing of the site, application of cold dressings, oral analgesic
administration or local lidocaine infiltration, and tetanus prophylaxis.
Millipedes, with two pairs of legs per segment, are slow-moving,
docile, and feed mostly on decaying plant materials. They do not bite,
but some secrete defensive fluids that may burn and discolor human
skin. Affected skin turns brown overnight and may blister and exfoli­
ate. Secretions in the eye cause intense pain and inflammation that
can result in corneal ulcers and even blindness. Management includes
irrigation with copious amounts of water or saline, use of analgesics,
and local care of denuded skin.
■
■CATERPILLAR STINGS AND DERMATITIS
Caterpillars of several moth species are covered with hairs or spines
that produce mechanical irritation and may contain or be coated with
venom. Contact with these caterpillars or their hairs may lead to eru­
cism (a pruritic urticarial or papular rash) or caterpillar envenomation.
The response typically consists of an immediate burning sensation
followed by local swelling and erythema and occasionally by regional
lymphadenopathy, nausea, vomiting, and headache. A rare reaction to
a South American caterpillar, Lonomia obliqua, can cause disseminated
coagulopathy and fatal hemorrhagic shock.
Dermatitis is most often associated with caterpillars of io, puss,
saddleback, and browntail moths in North America and with the oak
processionary moth in Europe. Even contact with detached hairs of
FIGURE 472-4  Real (left) versus delusional (right) infestation: comparable images of the lower backs of two young adults with multiple lesions. Left: A young woman
developed innumerable widespread lesions during a camping ecotour near Manaus, Brazil. Note scattered clusters of irregularly spaced lesions, accompanied by dozens
of single or isolated lesions, consistent with the semi-random feeding pattern of biting flies. Lesions appear to be in roughly the same stage of development, a feature
indicating that they were acquired at roughly the same time. No lesions were present before her ecotour; none have arisen since. This patient scratches the intensely
pruritic lesions and causes superficial erosions. Unexcoriated lesions are also present on her midback, where she cannot scratch. Right: A young man has innumerable
widespread lesions that have accumulated for several years, with a few new lesions appearing several times a week. His lesions are in various stages of development
(fresh, crusted, reepithelialized, pigmented, and scarred), a feature indicating a long-standing process. The lesions are distributed in a regular pattern consistent with
periodic “excavations” to remove alleged parasites that he believes are crawling through his skin. Scarring is due to manipulations that create dermal ulcers rather than
superficial excoriations and erosions. Parts of his upper midback, where he cannot scratch, are free of lesions.
other caterpillars, such as gypsy moth larvae, can later produce eru­
cism. Spines may be deposited on tree trunks or drying laundry or may
be airborne and cause irritation of the eyes and upper airways. Treat­
ment of caterpillar stings consists of repeated application of adhesive
or cellophane tape to remove the hairs, which can then be identified
microscopically. Local ice packs, topical glucocorticoids, and oral anti­
histamines relieve symptoms.
Few adult moths cause human health problems. Adult yellowtail
moths (Hylesia species), found mainly in coastal mangrove zones along
the eastern coast of Central and South America, have bodies that are
covered by fine hairs or setae. The hairs on the ventral surface can
detach and, when in contact with human skin, cause an extremely pru­
ritic reaction called “Carapito itch.” This issue is especially problematic
when the moths have population booms, creating swarms around
coastal communities.
■
■BEETLE VESICATION AND DERMATITIS
Several families of beetles have independently developed the ability
to produce chemically unrelated vesicating toxins. When disturbed,
blister beetles (family Meloidae) exude cantharidin, a low-molecularweight toxin that produces thin-walled blisters (≤5 cm in diameter)
2–5 h after contact. The blisters are not painful or pruritic unless bro­
ken. They resolve without treatment in ≤10 days. Nephritis may follow
unusually heavy cantharidin exposure.
CHAPTER 472
The hemolymph of certain rove beetles (Paederus species, Staphylin­
idae family) contains pederin, a potent vesicant. When these beetles are
crushed or brushed against the skin, the released fluid causes painful,
red, flaccid bullae. These beetles occur worldwide but are most numer­
ous and problematic in parts of Africa (where they are called “Nairobi
fly”) and southwestern Asia. Ocular lesions may develop after impact
with flying beetles at night or unintentional transfer of the vesicant on
the fingers. Treatment is rarely necessary, although ruptured blisters
should be kept clean and bandaged.
Ectoparasite Infestations and Arthropod Injuries
Larvae of common carpet beetles are adorned with dense arrays
of ornate hairs called hastisetae. Contact with these larvae or their
setae results in delayed dermal reactions in sensitized individuals. The
lesions are commonly mistaken for bites of bed bugs.
■
■DELUSIONAL INFESTATIONS
The groundless conviction that one is infested with arthropods or
other parasites (Ekbom syndrome, delusory parasitosis, delusions of
parasitosis, delusion of infestation, and perhaps Morgellons syndrome)
is extremely difficult to treat and, unfortunately, is not uncommon
(Fig. 472-4). Patients describe uncomfortable sensations of something
moving in or on their skin. Excoriations and self-induced ulcerations
typically accompany the pruritus, dysesthesias, and imaginary insect
bites. Patients often believe that some invisible or as-yet-undescribed
creatures are infesting their skin, clothing, homes, or environment
in general. Frequently, patients submit as evidence of infestation
specimens that consist of plant-feeding and nonbiting peridomestic
arthropods, pieces of skin, vegetable matter, lint, and other inanimate
detritus. In the evaluation of a patient with possible delusional parasit­
osis, it is imperative to rule out true infestations and bites by arthro­
pods, endocrinopathies, sensory disorders due to neuropathies, opiate
and other drug use, environmental irritants (e.g., fiberglass threads),
and other causes of tingling or prickling sensations. Frequently, such
patients repeatedly seek medical consultations, resist alternative expla­
nations for their symptoms, and exacerbate their discomfort by selftreatment. Recent evidence suggests that high levels of central nervous
system dopamine, endogenous or pharmaceutical, may promote these
delusions. Long-term pharmacotherapy with pimozide or other psy­
chotropic agents has been more helpful than psychotherapy in treat­
ing this disorder. Patients with delusory parasitosis often develop the
unshakeable conviction that they are infested by a previously unknown
pathogen, while their personal lives, family support, and employment
collapse around them.
PART 14
Poisoning, Drug Overdose, and Envenomation
Acknowledgment
Richard J. Pollack contributed to this chapter in previous editions and
some material from that chapter has been retained here.
■
■FURTHER READING
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Goddard J: Infectious Diseases and Arthropods, 3rd ed. Totowa, NJ,
Humana Press, 2018.
Hinkle N: Ekbom syndrome: The challenge of “invisible bug” infesta­
tions. Annu Rev Entomol 55:77, 2010.
Moraru GM, Goddard J II: The Goddard Guide to Arthropods of
Medical Importance, 7th ed. Boca Raton, FL, CRC Press, 2019.
Mullen G, Durden L: Medical and Veterinary Entomology, 3rd ed.
London, Academic Press, 2019.
Saucier JR: Arachnid envenomation. Emerg Med Clin North Am
22:405, 2004.
Steen CJ et al: Insect sting reactions to bees, wasps, and ants. Int J
Dermatol 44:91, 2005.
Thomas C et al: Ectoparasites: Scabies. J Am Acad Dermatol 82:533,
2020.
Vetter RS, Isbister GK: Medical aspects of spider bites. Annu Rev
Entomol 53:409, 2008.