PART 14 Poisoning, Drug Overdose,

and Envenomation
458 Heavy Metal Poisoning
Howard Hu

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 relative 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 prevalence 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/). 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 458-1.

TABLE 458-1 Heavy Metals

 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 biotransformation, 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 clearance 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. 333) 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 contribution of low-level xenobiotic metal exposure to chronic
diseases and to subtle changes in health that may have significant
public health consequences. Genetic factors, such as
polymorphisms that encode for variant enzymes with altered
properties in terms of metal binding, transport, and effects, also may
modify the impact of metals on health and thereby account, at least
in part, for individual susceptibility to metal effects.
The most important component of treatment for metal toxicity is
the 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 tetraacetic
acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and
penicillamine; their specific use depends on the metal involved and
the clinical circumstances. 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 458-1, 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. Recent studies in
community-based populations have generated strong evidence that
arsenic exposure is also a risk factor for increased risk of
hypertension, coronary heart disease and stroke, lung function
impairment, acute respiratory tract infections, respiratory symptoms,

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and nonmalignant 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 diabetes.
Serious cadmium poisoning from the contamination of food and
water by mining effluents in Japan contributed to the 1946 outbreak
of “itai-itai” (“ouch-ouch”) disease, so named because of cadmium-
induced bone toxicity that led to painful bone fractures. Modest
exposures from environmental contamination have been associated
in some studies with a lower bone density, a higher incidence of
fractures, and a 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) as well as increased risk of
cardiovascular disease and mortality, stroke, and heart failure.
Cadmium triggers pulmonary inflammation, and a recent population-
based study of U.S. adults found that higher cadmium burdens are
associated with higher mortality from influenza or pneumonia. The
International Agency for Research on Cancer has classified
cadmium as a known carcinogen, with evidence indicating it
contributes to elevated risks of prostate, lung, breast, and
endometrial cancer. Overall, this growing body of research indicates
that cadmium exposure is contributing significantly to morbidity and
mortality rates in the general population.
Advances in our understanding of lead toxicity have recently
benefited by the development of K 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 are now known
to be 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, plumbing,
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
cognition in both men and women living in urban communities.
These relationships, in conjunction with other epidemiologic and
toxicologic studies, persuaded a federal expert panel 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 increased cardiovascular morbidity
and mortality rates in both community-based and occupational-
exposed populations. Lead exposure at community levels has also
been associated with increased risks of hearing loss, Parkinson’s
disease, and amyotrophic lateral sclerosis. With respect to
pregnancy-associated risks, high maternal bone lead levels were
found to predict lower birth weight, head circumference, birth length,
and neurodevelopmental performance 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 developing 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
studies 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 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. Accumulated evidence has
not supported the contention that ethyl mercury, used as a
preservative in multiuse vaccines administered in early childhood,
has played a significant role in causing neurodevelopmental
problems such as autism. With regard to adults, there is conflicting
evidence as to whether mercury exposure is associated with
increased risk of hypertension and cardiovascular disease. 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 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 had continued success, with only a few
countries still remaining (Algeria, Iraq, Yemen, Myanmar, North
Korea, and Afghanistan). 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 there are indications that exposures are
beginning to increase again in many low- and middle-income
countries due to industrial pollution, electronic waste, 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 458-1 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. 410).
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 incidence 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 consumers. 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 psychiatric symptoms.
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 parkinsonian disorders and estimated manganese
exposures emitted by local ferroalloy industries; others have found
evidence suggesting that manganese 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
compounds 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 inflammation, 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.
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 activated 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 chelation 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), a multicenter,
double-blind, placebo-controlled, prospective randomized trial
funded by the National Institutes of Health of 1708 patients aged ≥50

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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 cardiovascular 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 exposure to lead or other metals or any
selection criteria based on metals exposure; thus, even though
chelation reduces metal burdens, which have been associated with
adverse cardiovascular effects (especially lead), it remains unclear
whether the beneficial effects result from a reduction in metal
burden. In view of the risks of side effects associated with chelation,
by themselves, the results are not sufficient to support the routine
use of chelation therapy for treatment of patients either who have
had an MI or who have had low-level lead exposure. A follow-up trial
with rigorous measures of metals exposure is ongoing.

■ FURTHER READING
ALAMOLHODAEI NS et al: Arsenic cardiotoxicity: An overview. Environ
Toxicol Pharmacol 40:1005, 2015.
ANENI EC et al: Chronic toxic metal exposure and cardiovascular
disease: Mechanisms of risk and emerging role of chelation
therapy. Curr Atheroscler Rep 18:81, 2016.
GIDLOW DA: Lead toxicity. Occup Med (Lond) 65:348, 2015.
KIM KH et al: A review on the distribution of Hg in the environment
and its human health impacts. J Hazard Mater 306:376, 2016.
LAMAS GA et al: Heavy metals, cardiovascular disease, and the
unexpected benefits of chelation therapy. J Am Coll Cardiol
67:2411, 2016.
LANPHEAR BP et al: Low-level lead exposure and mortality in US
adults: A population-based cohort study. Lancet Public Health
3:e177, 2018.
O’NEAL SL, ZHENG W: Manganese toxicity upon overexposure: A
decade in review. Curr Environ Health Rep 2:315, 2015.
PARK SK et al: Environmental cadmium and mortality from influenza
and pneumonia in U.S. adults. Environ Health Perspect
128:127004, 2020.
TELLEZ-PLAZA M et al: Cadmium exposure and all-cause and
cardiovascular mortality in the U.S. general population. Environ
Health Perspect 120:1017, 2012.
WEAVER VM et al: Does calcium disodium EDTA slow CKD
progression? Am J Kidney Dis 60:503, 2012.
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.
459 Poisoning and Drug Overdose
Mark B. Mycyk

Poisoning refers to the development of dose-related adverse effects

following exposure to chemicals, drugs, or other xenobiotics. To
paraphrase 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 tolerance. Poisoning may be local (e.g., skin, eyes, or
lungs) or systemic depending on the route of exposure, the chemical
and physical properties 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. Household cleaning substances and cosmetics/personal
care products are the most common nonpharmaceutical exposures
reported to the National Poison Data System (NPDS). In the last
decade, the rate of injury-related deaths from poisoning has
overtaken the rate of deaths related to motor-vehicle crashes in the
United States. According to the Centers for Disease Control and
Prevention (CDC), twice as many Americans died from drug
overdoses in 2014 compared to 2000. Although prescription opioids
have appropriately received attention as a major reason for the
increased number of poisoning deaths, the availability of other
pharmaceuticals and rapid proliferation of novel drugs of abuse also
contribute to the increasing death rate. In many parts of the United
States, where these issues are particularly prevalent, there are
efforts to develop better prescription drug databases and enhanced
training for health care professionals in pain management and the
use of opioids. 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
recreational 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 increasingly 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 department 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,
routine and toxicologic laboratory evaluations, and characteristic
clinical course.

■ HISTORY
The history should include the time, route, duration, and
circumstances (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
circumstances 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 during 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 available from family, friends,
paramedics, police, pharmacists, physicians, and employers, who
should be questioned regarding the patient’s habits, hobbies,
behavioral changes, available medications, and antecedent events.
Patients need to be asked explicitly about their prescribed
medications and recreational drug use. Drugs previously considered
“illicit” such as cannabinoids 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. 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

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relevant 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 manufacturer, or a regional poison information center
(800-222-1222). Occupational 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 emergency department
evaluation. Pharmaceuticals, industrial chemicals, or drugs of abuse
from foreign countries may be identified with the assistance of a
regional poison center or via the World Wide Web.

■ PHYSICAL EXAMINATION AND CLINICAL COURSE

The physical examination should focus initially on vital signs, the
cardiopulmonary system, and neurologic status. The neurologic
examination 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 structural 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, temperature, and neurologic status
and to characterize the overall physiologic state as stimulated,
depressed, discordant, or normal (Table 459-1). 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 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 459-2) is useful in this regard and also for
monitoring the clinical course and response to treatment. 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.

TABLE 459-1 Differential Diagnosis of Poisoning Based on

Physiologic State
The Stimulated Physiologic State Increased pulse, blood
pressure, respiratory rate, temperature, and neuromuscular activity
characterize the stimulated physiologic state, which can reflect
sympathetic, anticholinergic, or hallucinogen poisoning or drug
withdrawal (Table 459-1). Other features are noted in Table 459-2.
Mydriasis, a characteristic feature of all stimulants, is most marked in
anticholinergic 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 sympathetic activity and cause diaphoresis,
pallor, and increased bowel activity 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 nervous 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 selective 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 anticholinergic agent with membrane-active
properties (e.g., cyclic antidepressants, phenothiazines), or a
withdrawal syndrome. Close attention to core temperature is critical
in patients with grade 4 physiologic stimulation (Table 459-2).

TABLE 459-2 Severity of Physiologic Stimulation and

Depression in Poisoning and Drug Withdrawal
The Depressed Physiologic State Decreased pulse, blood
pressure, 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 459-1 and 459-2).
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
459-1). Pronounced cardiovascular 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 secondary to depression of CNS
cardiovascular and respiratory centers (or consequent hypoxemia),

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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 459-2). Other clues that suggest the
cause of physiologic depression include cardiac arrhythmias and
conduction disturbances (due to antiarrhythmics, β-adrenergic
antagonists, calcium channel blockers, digitalis glycosides,
propoxyphene, and cyclic antidepressants), mydriasis (due to
tricyclic antidepressants, some antiarrhythmics, meperidine, and
diphenoxylate-atropine [Lomotil]), nystagmus (due to sedative-
hypnotics), 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
abnormalities, as observed in poisoning by asphyxiants, CNS
syndromes, membrane-active agents, and anion-gap metabolic
acidosis (AGMA) inducers (Table 459-1). In these conditions,
manifestations of physiologic stimulation and physiologic depression
occur together or at different times during the clinical course. For
example, membrane-active 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 symptomatic. Early, pronounced vital-
sign and mental-status changes suggest 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.

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 metabolic activation, or disrupt metabolic processes (Table
459-1). Because so many medications have now been reformulated
into once-a-day preparations for the patient’s convenience and
adherence, toxic time-bombs 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 stimulation (Table 459-2) and
be indistinguishable from toxicologic causes without ancillary testing
or a suitable period of observation.

■ 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 (diethylene, 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,
quinine, and salicylates, whereas hyperglycemia can occur in
poisoning with acetone, β-adrenergic agonists, caffeine, calcium
channel blockers, 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 novel oral anticoagulant 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 blockers, 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 459-1).
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
catecholamines (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
poisoning with carbon monoxide, cyanide, an opioid, paraquat,
phencyclidine, a sedative-hypnotic, or salicylate; by inhalation of
irritant gases, fumes, or vapors (acids and alkali, ammonia,
aldehydes, chlorine, 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 radiopaque densities on
abdominal x-rays or abdominal computed tomography (CT) scan
suggests the ingestion of chloral hydrate, chlorinated hydrocarbons,
heavy metals, illicit drug packets, iodinated compounds, potassium
salts, enteric-coated tablets, or salicylates.
 Toxicologic analysis of urine and blood (and occasionally of
gastric 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 chromatography; 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 testing 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
commonly 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
instability, 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. 340), alcohols (including ethylene glycol and
methanol), anticonvulsants, barbiturates, digoxin, heavy metals, iron,
lithium, salicylate, and theophylline, as well as for the presence of
carboxyhemoglobin and methemoglobin. The serum concentration in
these cases guides clinical management, and results are often
available within an hour.
The response to antidotes is sometimes useful for diagnostic
purposes. Resolution of altered mental status and abnormal vital
signs within minutes of IV administration of dextrose, naloxone, or
flumazenil 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 anticholinergic poisoning by physostigmine is
diagnostic of this condition, physostigmine may cause some arousal
in patients with CNS depression of any etiology.

TREATMENT
Poisoning and Drug Overdose

GENERAL PRINCIPLES
Treatment goals include support of vital signs, prevention of further
poison absorption (decontamination), enhancement of poison
elimination, administration of specific antidotes, and prevention of
reexposure (Table 459-3). Specific treatment depends on the
identity of the poison, the route and amount of exposure, the time of
presentation relative to the time of exposure, and the severity of
poisoning. Knowledge of the offending agents’ pharmacokinetics
and pharmacodynamics is essential.

TABLE 459-3 Fundamentals of Poisoning Management

 During the pretoxic phase, prior to the onset of poisoning,
decontamination 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 examination 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
toxicologic 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
poisoning 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
therapeutic 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 determination, cardiac monitoring, and continuous
observation. Baseline 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 generally
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
theophylline or carbamazepine. Urinary alkalinization may enhance
the elimination of salicylates and a few other poisons. Chelation
therapy can enhance the elimination of selected metals.
Extracorporeal 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 extracorporeal
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 responsible
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
homeostasis until detoxification is accomplished and to prevent and
treat secondary complications such as aspiration, bedsores,
cerebral and pulmonary edema, pneumonia, rhabdomyolysis, renal
failure, sepsis, 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,
hypotension, cardiac conduction abnormalities, cardiac arrhythmias,
hypothermia or hyperthermia, seizures); those needing close
monitoring, antidotes, or enhanced elimination therapy; those
showing progressive clinical deterioration; and those with significant
underlying 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,
depending 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
importance in patients with CNS depression or seizures as this
complication can increase morbidity and mortality rates. Mechanical
ventilation may be necessary for patients with respiratory
depression or hypoxemia and for facilitation of therapeutic sedation
or paralysis of patients in order to prevent or treat hyperthermia,
acidosis, and rhabdomyolysis associated with neuromuscular
hyperactivity. Since clinical assessment of respiratory function can
be inaccurate, the need for oxygenation and ventilation is best
determined 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, cardiopulmonary 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 determine the right toxicologic indications
for this treatment strategy.
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
measurement of central venous pressure may help prioritize
therapeutic strategies. If hypotension is unresponsive to volume
expansion and appropriate goal-directed antidotal therapy,
treatment with norepinephrine, 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 cardiopulmonary arrest secondary to poisoning, therapeutic
hypothermia should be used according to protocol.
Bradyarrhythmias associated with hypotension generally should be
treated as described in Chaps. 244 and 245. 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 459–1). 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 channel
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 conduction or
blood pressure abnormalities persist. Treatment with an α-
adrenergic antagonist (phentolamine) alone may sometimes be
appropriate. If the cause is anticholinergic poisoning, physostigmine
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 459-1), sodium
bicarbonate 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 hyperactivity.
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 antibodies
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
supraventricular) of wide-complex tachycardias (Chap. 246). If the
patient is hemodynamically stable, however, it is reasonable to
simply observe the patient rather than to administer another
potentially proarrhythmic agent. Arrhythmias may be resistant to
drug therapy until underlying acid-base, electrolyte, oxygenation,
and temperature derangements are corrected.
Central Nervous System Therapies Neuromuscular hyperactivity
and seizures can lead to hyperthermia, lactic acidosis, and
rhabdomyolysis and should be treated aggressively. Seizures
caused by excessive stimulation of catecholamine receptors
(sympathomimetic 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
modulation 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
antidepressant 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 paralysis is indicated in refractory
cases. Electroencephalographic monitoring and continuing
treatment of seizures are necessary to prevent permanent
neurologic damage. Serotonergic receptor overstimulation in
serotonin syndrome may be treated with cyproheptadine.
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
toxicity 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 toxicity 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
invasive 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 adding 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 infarction
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 orogastric
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 decubitus
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
misplacement 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 procedure. Gastric lavage is contraindicated in corrosive or
petroleum distillate ingestions because of the respective risks of
gastroesophageal perforation and aspiration pneumonitis. It is also
contraindicated 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 bowel-
cleansing 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
contraindicated 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
decontamination benefit from cathartics. Abdominal cramps,
nausea, and occasional vomiting are side effects. Complications of
repeated dosing include severe electrolyte disturbances and
excessive diarrhea. Cathartics are contraindicated in patients who
have ingested corrosives and in those with preexisting diarrhea.
Magnesium-containing 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 dissolution
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
efficacy, cost, and risks of therapy.
Multiple-Dose Activated Charcoal Repetitive oral dosing with
charcoal can enhance the elimination of previously absorbed
substances 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., phenobarbital, theophylline). Multiple-dose therapy
should be considered only for selected agents (theophylline,
phenobarbital, carbamazepine, dapsone, quinine). Complications
include intestinal obstruction, 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 excretion 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.
Extracorporeal Removal Hemodialysis, charcoal or resin
hemoperfusion, hemofiltration, plasmapheresis, and exchange
transfusion 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,
methanol, theophylline, salicylates, and valproate. Although
hemoperfusion 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 hemolysis, 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).
Exchange transfusion may be indicated in the treatment of severe
arsine- or sodium chlorate–induced hemolysis,
methemoglobinemia, and sulfhemoglobinemia. Although
hemofiltration can enhance elimination of aminoglycosides,
vancomycin, and metal-chelate complexes, the roles of
hemofiltration and plasmapheresis 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
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, carbon
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 significantly 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 459-4).
TABLE 459-4 Pathophysiologic Features and Treatment of
Specific Toxic Syndromes and Poisonings
PREVENTION OF REEXPOSURE
Poisoning is a preventable illness. Unfortunately, some adults and
children are poison-prone, and recurrences are common.
Unintentional polypharmacy poisoning has become especially
common among adults with developmental delays, among the
growing population of geriatric patients who are prescribed a large
number of medications, and among adolescents and young adults
experimenting with pharmaceuticals for recreational euphoria.
Adults with unintentional exposures should be instructed regarding
the safe use of medications and chemicals (according to labeling
instructions). Confused patients may need assistance with the
administration of their medications. Errors in dosing by health care
providers may require educational efforts. Patients should be
advised to avoid circumstances that result in chemical exposure or
poisoning. Appropriate agencies and health departments (e.g.,
Occupational Health and Safety Administration [OSHA]) should be
notified in cases of environmental or workplace exposure. The best
approach to young children and patients with intentional overdose
(deliberate self-harm or attempted suicide) is to limit their access to
poisons. In households where children live or visit, alcoholic
beverages, medications, household products (automotive, cleaning,
fuel, pet-care, and toiletry products), inedible plants, and vitamins
should be kept out of reach or in locked or child-proof cabinets.
Depressed, bipolar, or psychotic patients should undergo
psychiatric assessment, disposition, and follow-up. They should be
given prescriptions for a limited supply of drugs with a limited
number of refills and should be monitored for compliance and
response to therapy.

SPECIFIC TOXIC SYNDROMES AND

POISONINGS
Table 459-4 summarizes the pathophysiology, clinical features, and
treatment of toxidromes and poisonings that are common, produce
life-threatening toxicity, or require unique therapeutic interventions.
In all cases, treatment should include attention to the general
principles discussed above and, in particular, supportive care.
Poisonings not covered in this chapter are discussed in specialized
texts.
Alcohol, cocaine, hallucinogen, and opioid poisoning and
alcohol and opioid withdrawal are discussed in Chaps. 453, 456,
and 457; nicotine addiction is discussed in Chap. 454;
acetaminophen poisoning is discussed in Chap. 340; the
neuroleptic malignant syndrome is discussed in Chap. 435; and
heavy metal poisoning is discussed in Chap. 458.
■ GLOBAL CONSIDERATIONS
Risks of poisoning in the United States and throughout the world are
in transition. Patterns of travel, immigration, and internet
consumerism should always be considered in patients suspected of
poisoning or overdose without a clear etiology. Immigrants into
various countries may have underlying poisoning from various
metals from work or the environment where they previously lived;
herbal remedies, food products, and cosmetics imported from
overseas or ordered from the internet may be contaminated with
metals, toxic plants, or other pharmaceutical contaminants; and new
drugs of abuse that originate in one part of the world quickly circulate
due to the ease afforded by the internet. Expanding the history at the
time of evaluation, recruiting the assistance of global health
specialists, and ordering expanded laboratory panels may be
indicated. For instance, during the COVID-19 pandemic, poisoning
from household cleaning substances and novel untested therapies
increased worldwide.

■ FURTHER READING
DART RC et al: Expert consensus guidelines for stocking of antidotes
in hospitals that provide emergency care. Ann Emerg Med
71:314, 2018.
GUMMIN DD et al: 2018 annual report of the American Association of
Poison Control Centers’ National Poison Data System (NPDS):
36th annual report. Clin Toxicol 57:1220, 2019.
MYCYK MB: ECMO shows promise for treatment of poisoning some
of the time: The challenge to do better by aiming higher. Crit Care
Med 48:1235, 2020.
NELSON LS et al (eds): Goldfrank’s Toxicologic Emergencies, 11th ed.
New York, McGraw-Hill, 2019.
SPYRES MB et al: The Toxicology Investigators Consortium Case
Registry: The 2019 annual report. J Med Toxicol 16:361, 2020.
THOMPSON TM et al: The general approach to the poisoned patient.
Dis Mon 60:509, 2014.
WELKER K, MYCYK MB: Pharmacology in the geriatric patient. Emerg
Med Clin North Am 34:469, 2016.
460 Disorders Caused by Venomous
Snakebites and Marine Animal Exposures
Erik Fisher, Alex Chen, Charles Lei

This chapter outlines general principles for the evaluation and

management of victims of envenomation and poisoning by
venomous snakes and marine animals. Because the incidence of
serious bites and stings is relatively low in developed nations, there
is a paucity of relevant clinical research; as a result, therapeutic
decision-making often is based on anecdotal information.

VENOMOUS SNAKEBITE
■ EPIDEMIOLOGY
The venomous snakes of the world belong to the families Viperidae
(subfamily Viperinae: Old World vipers; subfamily Crotalinae: New
World and Asian pit vipers), Elapidae (including cobras, coral
snakes, sea snakes, kraits, and all Australian venomous snakes),
Lamprophiidae (subfamily Atractaspidinae: burrowing asps), and
Colubridae (a large family in which most species are nonvenomous).
Most snakebites occur in developing countries with temperate and
tropical climates in which populations subsist on agriculture and
fishing (Fig. 460-1). Recent estimates indicate that somewhere
between 1.2 million and 5.5 million snakebites occur worldwide each
year, with 421,000–1,200,000 envenomations and 81,000–138,000
deaths. Such wide-ranging estimates reflect the challenges of
collecting accurate data in the regions most affected by venomous
snakes; many victims in these areas either do not seek medical
attention or have insufficient access to antivenom, and reporting and
record-keeping are generally poor.

hinhanhykhoa.com
FIGURE 460-1 Geographic distribution of venomous snakes.

■ SNAKE ANATOMY/IDENTIFICATION
The typical snake venom delivery apparatus consists of bilateral
venom glands situated behind the eyes and hollow anterior maxillary
fangs. In viperids, these fangs are long and highly mobile; they are
retracted against the roof of the mouth when the snake is at rest,
then brought to an upright position when about to strike. In elapids,
the fangs are fixed in an erect position and smaller in size, which can
lead to fewer distinct wounds after an envenomation. Colubrids do
not possess venom glands but have homologous structures known
as Duvernoy’s glands. Approximately 20–25% of pit viper bites and
higher percentages of other snakebites (up to 75% for sea snakes)
are “dry” bites, in which no venom is released.
Differentiating between venomous and nonvenomous snake
species can be challenging. Identifying venomous snakes by color
pattern can be misleading, as many nonvenomous snakes have
color patterns that closely mimic those of venomous snakes found in
the same region. Viperids are characterized by triangular heads (a
feature shared with many harmless snakes), elliptical pupils (also
seen in some nonvenomous snakes, such as boas and pythons),
and enlarged maxillary fangs; pit vipers also possess heat-sensing
organs (pits) on each side of the head that assist with locating prey
and aiming strikes. Rattlesnakes possess a series of interlocking
hollow keratin plates (the rattle) on the tip of the tail that emits a
buzzing sound when vibrated rapidly; this sound serves as a warning
signal to perceived threats.

■ VENOMS AND CLINICAL MANIFESTATIONS

Snake venoms consist of highly complex mixtures of enzymes,
polypeptides, glycoproteins, and other constituents. Venom
components may vary greatly depending on the species, age, and
geographic location of the snake. Snake venoms can cause local
tissue necrosis, affect the coagulation pathway at various steps,
impair organ function, or act at the neuromuscular junction to cause
paralysis.
After an envenomation, the time to symptom onset and clinical
presentation can be quite variable depending on the species
involved, the anatomic location of the bite, and the amount of venom
injected. Envenomations by most viperids and some elapids cause
progressive local pain, soft-tissue swelling, and ecchymosis (Fig.
460-2). Hemorrhagic or serum-filled vesicles and bullae may develop
at the bite site over a period of hours to days. In serious bites, tissue
loss can be significant (Fig. 460-3). Systemic findings are variable
and can include generalized fatigue, nausea, changes in taste,
mouth numbness, tachycardia or bradycardia, hypotension, muscle
fasciculations, pulmonary edema, renal dysfunction, and
spontaneous hemorrhage. Envenomations by neurotoxic elapids,
such as kraits (Bungarus species), many Australian elapids (e.g.,
death adders [Acanthophis species] and tiger snakes [Notechis
species]), and some cobras (Naja species), as well as some viperids
(e.g., the South American rattlesnake [Crotalus durissus], Mojave
rattlesnake [Crotalus scutulatus], and certain Indian Russell’s vipers
[Daboia russelii]), cause neurologic dysfunction. Early findings may
consist of nausea and vomiting, headache, paresthesias or
numbness, and altered mental status. Victims may develop cranial
nerve abnormalities (e.g., ptosis, difficulty swallowing), followed by
peripheral motor weakness. Severe envenomation may result in
diaphragmatic paralysis and lead to death from respiratory failure
and aspiration. Sea snake envenomation results in local pain
(variable), generalized myalgias, trismus, rhabdomyolysis, and
progressive flaccid paralysis; these manifestations can be delayed
for several hours.

FIGURE 460-2 Northern Pacific rattlesnake (Crotalus oreganus oreganus)

envenomations. A. Moderately severe envenomation. Note edema and early
ecchymosis 2 h after a bite to the finger. B. Severe envenomation. Note extensive
ecchymosis 5 days after a bite to the ankle. (Courtesy of Robert Norris, with
permission.)

FIGURE 460-3 Early stages of severe, full-thickness necrosis 5 days after a

Russell’s viper (Daboia russelii) bite in southwestern India. (Courtesy of Robert
Norris, with permission.)

TREATMENT
Venomous Snakebite

FIELD MANAGEMENT
The most important aspect of prehospital care of a person bitten by
a venomous snake is rapid transport to a medical facility equipped
to provide supportive management (airway, breathing, and
circulation) and antivenom therapy. Any jewelry or tight-fitting
clothing near the bite should be removed to avoid constriction from
anticipated soft-tissue swelling. Although wound care should not
delay transport, the wound should be cleaned with soap and
running water then covered with a sterile dressing. It is reasonable
to apply a splint to the bitten extremity to limit movement and assist
with positioning. If possible, the extremity should be maintained in a
neutral position of comfort at approximately heart level. Attempting
to capture and transport the offending snake is not advised; instead,
digital photographs taken from a safe distance may assist with
snake identification and treatment decisions.
Most of the first-aid measures recommended in the past are of
little benefit and may worsen outcomes. Incising and/or applying
suction to the bite site should be avoided, as these measures
exacerbate local tissue damage, increase the risk of infection, and
have not been shown to be effective. Venom sequestration devices
(e.g., lympho-occlusive bandages or tourniquets) are not advised,
as they may intensify local tissue damage by restricting the spread
of potentially necrotizing venom. Tourniquet use can result in loss of
function, ischemia, and limb amputation, even in the absence of
envenomation. In developing countries, victims should be
encouraged to seek immediate treatment at a medical facility
equipped with antivenom instead of consulting traditional healers
and thus incurring significant delays in reaching appropriate care.
Elapid envenomations that are primarily neurotoxic and have no
significant effects on local tissue may be managed with pressure-
immobilization, in which the entire bitten limb is immediately
wrapped with a bandage and then immobilized. This technique is
meant to restrict lymphatic drainage and has been shown to delay
the systemic absorption of venom from predominantly neurotoxic
species. For pressure-immobilization to be effective, the wrap
pressure should not exceed 40–70 mmHg in upper-extremity
application and 55–70 mmHg in lower-extremity application. As an
estimate, the bandage should be snug enough to apply pressure
but loose enough for a finger to slip underneath. Additionally, the
victim must be carried out of the field because walking generates
muscle-pumping activity that—regardless of the anatomic site of the
bite—will disperse venom into the systemic circulation. Pressure-
immobilization should be used only in cases in which the offending
snake is reliably identified and known to be primarily neurotoxic, the
rescuer is skilled in pressure-wrap application, the necessary
supplies are readily available, and the victim can be fully
immobilized and carried to medical care—a rare combination of
conditions, particularly in the regions of the world where such bites
are most common.

HOSPITAL MANAGEMENT
Initial hospital management should focus on the victim’s airway,
breathing, and circulation. Patients with bites to the face or neck
may require early endotracheal intubation to prevent loss of airway
patency caused by rapid soft-tissue swelling. Vital signs, cardiac
rhythm, oxygen saturation, and urine output should be closely
monitored. Two large-bore IV lines should be established in
unaffected extremities. Because of the potential for coagulopathy,
venipuncture attempts should be minimized and noncompressible
sites (e.g., subclavian vein) avoided. Early hypotension may be
caused by bradykinin-potentiating factors, which lead to vasodilation
and pooling of blood in the pulmonary and splanchnic vascular
beds. Additionally, systemic bleeding, hemolysis, and loss of
intravascular volume into the soft tissues may play important roles
in hypotension. Fluid resuscitation with isotonic saline (20–40 mL/kg
IV) should be initiated if there is any evidence of hemodynamic
instability. Vasopressors (e.g., norepinephrine, epinephrine) should
be considered if venom-induced shock persists after aggressive
volume resuscitation and antivenom administration (see below), as
the victim may be experiencing anaphylaxis to the venom
components or the antivenom itself.
A thorough history (including the time of the bite and any
symptoms of envenomation) should be obtained and a complete
physical examination performed, with a focus on the neurovascular
status of the site of envenomation. For envenomation of a limb,
palpation of axillary or inguinal lymph nodes can provide information
about lymphatic spread. Bandages or wraps applied in the field
should be removed as soon as possible, with cognizance that the
release of such ligatures may result in hypotension or dysrhythmias
when stagnant acidotic blood containing venom is released into the
systemic circulation. To objectively evaluate the progression of local
envenomation, the leading edge of swelling, ecchymosis, and
tenderness should be marked and limb circumference should be
measured at three points (e.g., at the bite site, the joint proximal,
and the joint distal) every 15 min until the local-tissue effects have
stabilized. Once stabilized, measurements can be taken every 1–2
h. During this period of observation, the bitten extremity should be
positioned at approximately heart level. Victims of neurotoxic
envenomation should be monitored closely for evidence of cranial
nerve dysfunction (e.g., ptosis) that may precede more overt signs
of impending airway compromise (e.g., difficulty swallowing,
respiratory insufficiency) necessitating endotracheal intubation and
mechanical ventilation.
Blood should be drawn for laboratory evaluation as soon as
possible. Important studies include a complete blood count to
determine the degree of hemorrhage or hemolysis and to detect
thrombocytopenia; blood type and cross-matching; assessment of
renal and hepatic function; coagulation studies such as prothrombin
time and fibrinogen level; measurement of fibrin degradation
products such as D-dimer; measurement of creatine kinase for
suspected rhabdomyolysis; and testing of urine for blood or
myoglobin. In developing regions, the 20-min whole-blood clotting
test can be used to diagnose coagulopathy when access to
laboratory tests is limited. To perform this test, 1–2 mL of venous
blood are placed in a clean, dry glass receptacle (e.g., a test tube)
and left undisturbed for 20 min. The sample is then inverted. If the
blood is still liquid and a clot has not formed, coagulopathy is
present. There have been some recent studies examining the utility
of thromboelastography (TEG) in detecting venom-induced
consumptive coagulopathy. In vitro studies have shown that TEG
may be more sensitive than conventional coagulation studies in
detecting coagulopathy at lower venom concentrations; however, it
remains to be seen if this bears any clinical significance. At this
time, there is insufficient evidence to suggest routine use of TEG.
Electrocardiography and chest radiography may be helpful in
severe envenomations or when there is significant comorbidity.
After antivenom therapy (see below), laboratory values should be
rechecked every 6 h until clinical stability is achieved.
The mainstay of treatment of a venomous snakebite resulting in
significant envenomation is prompt administration of specific
antivenom. Antivenoms are produced by injecting animals
(generally horses or sheep) with venoms from medically important
snakes. Once the stock animals develop antibodies to the venoms,
their serum is harvested and the antibodies are isolated for
antivenom preparation. The goal of antivenom administration is to
allow antibodies (or antibody fragments) to bind and deactivate
circulating venom components before they can attach to target
tissues and cause deleterious effects. Antivenoms may be
monospecific (directed against a particular snake species) or
polyspecific (covering several species in a geographic region).
Unless the species are known to have homologous venoms,
antivenoms rarely offer cross-protection against snake species
other than those used in their production. Thus, antivenom selection
must be specific for the offending snake; if the antivenom chosen
does not contain antibodies to that snake’s venom components, it
will provide no benefit and may lead to unnecessary complications
(see below). In the United States, assistance in finding appropriate
antivenom can be obtained from a regional poison control center,
which can be reached by telephone 24 h a day at (800) 222-1222.
For victims of bites by viperids or cytotoxic elapids, indications
for antivenom administration include significant progressive local
findings (e.g., soft-tissue swelling that crosses a joint, involves more
than half the bitten limb, or is rapidly spreading; extensive blistering
or bruising; severe pain) and any evidence of systemic
envenomation (e.g., systemic symptoms or signs, laboratory
abnormalities). Caution must be used when determining the
significance of isolated pain or soft-tissue swelling after the bite of
an unidentified snake because the saliva of some relatively
harmless species can cause mild discomfort or edema at the bite
site; in such bites, antivenoms are useless and potentially harmful.
Antivenoms have limited efficacy in preventing local-tissue damage
caused by necrotizing venoms, as venom components bind to local
tissues very quickly. Nevertheless, antivenom should be
administered as soon as the need for it is identified to limit further
tissue damage and systemic effects. Antivenom administration after
bites by neurotoxic elapids is indicated at the first sign of
neurotoxicity (e.g., cranial nerve dysfunction, peripheral
neuropathy). In general, antivenom is effective only in reversing
active venom toxicity; it is of little benefit in reversing effects that
have already been established (e.g., renal failure, established
paralysis) and will improve only with time and other supportive
therapies.
Specific comments related to the management of venomous
snakebites in the United States and Canada appear in Table 460-1.
The package insert for the selected antivenom should be consulted
regarding species covered, method of administration, starting dose,
and need (if any) for redosing. Whenever possible, it is advisable for
health care providers to seek advice from experts in snakebite
management regarding indications for and dosing of antivenom.

TABLE 460-1 Management of Venomous Snakebites in the

United States and Canadaa
 Antivenom should be administered only by the IV route, and the
infusion should be started slowly, with the treating clinician at the
bedside ready to immediately intervene at the first signs of an acute
adverse reaction. In the absence of an adverse reaction, the rate of
infusion can be increased gradually until the full starting dose has
been administered (over a total period of ∼1 h). Further antivenom
may be necessary if the patient’s acute clinical condition worsens or
fails to stabilize or if venom effects recur. The decision to administer
further antivenom to a stabilized patient should be based on clinical
evidence of the persistent circulation of unbound venom
components. For viperid bites, antivenom administration should
generally be continued until the victim shows definite improvement
(e.g., reduced pain, stabilized vital signs, restored coagulation).
Neurotoxicity from elapid bites may be more difficult to reverse with
antivenom. Once neurotoxicity is established and endotracheal
intubation is required, further doses of antivenom are unlikely to be
beneficial. In such cases, the victim must be maintained on
mechanical ventilation until recovery, which may take days to
weeks.
Adverse reactions to antivenom administration include early
(anaphylaxis) and late (serum sickness) hypersensitivity reactions.
Clinical manifestations of early hypersensitivity may include
tachycardia, rigors, vomiting, urticaria, dyspnea, laryngeal edema,
bronchospasm, and hypotension. Although recommended by some
antivenom manufacturers, skin testing for potential early
hypersensitivity is neither sensitive nor specific and is of no benefit.
The quality of antivenoms is highly variable worldwide; rates of
acute anaphylactic reactions to some of these products exceed
50%. More recent data on North American snakebites suggest that
the incidence of anaphylaxis to Crotalidae Polyvalent Immune Fab
(CroFab®) (Ovine) (BTG International Inc., West Conshohocken,
PA) antivenom may be closer to 1.1%. There is some evidence
supporting routine pretreatment with low-dose SC epinephrine (0.25
mg of 1:1000 aqueous solution) to prevent acute anaphylactic
reactions after antivenom infusion. Although widely practiced,
prophylactic use of antihistamines and glucocorticoids has not
proved beneficial. Modest expansion of the patient’s intravascular
volume with crystalloids may blunt episodes of acute hypotension
during antivenom infusion. Epinephrine and airway equipment
should always be immediately available. If the patient develops an
anaphylactic reaction to antivenom, the infusion should be stopped
temporarily and the reaction treated immediately with IM
epinephrine (0.01 mg/kg up to 0.5 mg), an IV antihistamine (e.g.,
diphenhydramine, 1 mg/kg up to 50 mg), and a glucocorticoid (e.g.,
hydrocortisone, 2 mg/kg up to 100 mg). Once the reaction has been
controlled, if the severity of the envenomation warrants additional
antivenom, the dose should be restarted as soon as possible at a
slower rate (5–10 mL/h) and titrated upward as tolerated. In rare
cases of refractory hypotension, a concomitant IV infusion of
epinephrine may be initiated and titrated to clinical effect while
antivenom is administered. The patient must be monitored very
closely during such therapy, preferably in an emergency department
or intensive care setting. Serum sickness typically develops 1–2
weeks after antivenom administration and may present as myalgias,
arthralgias, fever, chills, urticaria, lymphadenopathy, or renal or
neurologic dysfunction. Treatment for serum sickness consists of
systemic glucocorticoids (e.g., oral prednisone, 1–2 mg/kg daily)
until all symptoms have resolved, with a subsequent taper over 1–2
weeks. Oral antihistamines and analgesics may provide additional
relief of symptoms.
Blood products are rarely necessary in the management of an
envenomated patient. The venoms of many snake species can
deplete coagulation factors and cause a decrease in platelet count
or hematocrit. Nevertheless, these components usually rebound
within hours after administration of adequate antivenom. If the need
for blood products is thought to be great (e.g., a dangerously low
platelet count in a hemorrhaging patient), these products should be
given only after adequate antivenom administration to avoid fueling
ongoing consumptive coagulopathy.
Rhabdomyolysis should be managed in standard fashion with IV
fluids and close monitoring of urine output. Victims who develop
acute renal failure should be evaluated by a nephrologist and
referred for hemodialysis or peritoneal dialysis as needed. Such
renal failure is usually due to acute tubular necrosis and is
frequently reversible. If bilateral cortical necrosis occurs, however,
the prognosis for renal recovery is less favorable, and long-term
dialysis with possible renal transplantation may be necessary.
Most snake envenomations involve subcutaneous deposition of
venom. On occasion, venom can be injected more deeply into
muscle compartments, particularly if the offending snake was large
and the bite occurred on the hand, forearm, or anterior
compartment of the lower leg. Intramuscular swelling of the affected
extremity may be accompanied by severe pain, decreased strength,
altered sensation, cyanosis, and apparent pulselessness—signs
suggesting a muscle compartment syndrome. If there is clinical
concern that subfascial muscle edema may be impeding tissue
perfusion, intracompartmental pressures should be measured by a
minimally invasive technique (e.g., with a wick catheter or digital
readout device). If the intracompartmental pressure is high (>30–40
mmHg), the extremity should be kept elevated while antivenom is
administered. If the intracompartmental pressure remains elevated
after 1 h of such therapy, a surgical consultation should be obtained
for possible fasciotomy. Although evidence from animal studies
suggests that fasciotomy may actually worsen myonecrosis,
compartmental decompression may still be necessary to preserve
neurologic function. Fortunately, the incidence of compartment
syndrome is very low after a snakebite, with fasciotomies required
in <1% of cases. Nevertheless, vigilance is essential.
Acetylcholinesterase inhibitors (e.g., edrophonium and
neostigmine) may promote neurologic improvement in patients
bitten by snakes with postsynaptic neurotoxins. Snakebite victims
with objective evidence of neurologic dysfunction may receive a test
dose of acetylcholinesterase inhibitors, as outlined in Table 460-2. If
they exhibit improvement, additional doses of long-acting
neostigmine can be administered as needed. Acetylcholinesterase
inhibitors are not a substitute for endotracheal intubation or the
administration of appropriate antivenom when available.

TABLE 460-2 Use of Acetylcholinesterase Inhibitors in

Envenomations by Neurotoxic Snakes and Cone Snails

Care of the bite wound includes simple cleansing with soap and
water; application of a dry, sterile dressing; and splinting of the
affected extremity with padding between the digits. Once antivenom
therapy has been initiated, the extremity should be elevated above
heart level to reduce swelling. Patients should receive tetanus
immunization as appropriate. Prophylactic antibiotics are generally
unnecessary after bites by North American snakes because the
incidence of secondary infection is low. In some regions, secondary
bacterial infection is more common and the consequences are
serious; as such, prophylactic treatment with broad-spectrum
antibiotics may be appropriate. Antibiotics may also be considered if
misguided first-aid efforts included incision or mouth suction of the
bite site. Pain control may be achieved with acetaminophen or
opioid analgesics. Salicylates and nonsteroidal anti-inflammatory
agents should be avoided because of their potential effects on
blood clotting.
Wound care in the days after the bite should include careful
aseptic debridement of clearly necrotic tissue once coagulopathy
has been fully reversed. Intact serum-filled vesicles or hemorrhagic
blebs should be left undisturbed. If ruptured, they should be
debrided with sterile technique. Any debridement of damaged
muscle should be conservative because there is evidence that such
muscle may recover to a significant degree after antivenom therapy.
Physical therapy should be started as soon as possible to assist
the patient in returning to a functional state. The incidence of long-
term loss of function (e.g., reduced range of motion, impaired
sensory function) is unclear.
Any patient with signs of envenomation should be observed in
the hospital for at least 24 h. In North America, a patient with an
apparently “dry” viperid bite should be closely monitored for at least
8–12 h before discharge, as significant toxicity occasionally
develops after a delay of several hours. The onset of systemic
symptoms commonly is delayed for a number of hours after bites by
certain elapids (including coral snakes, Micrurus species), some
non–North American viperids (e.g., the hump-nosed pit viper
[Hypnale hypnale]), and sea snakes. Patients bitten by these
snakes should be observed in the hospital for at least 24 h.
Admission to an intensive care setting is advised for patients with
progressive clinical findings despite initial antivenom administration;
those bitten in the head, neck, or other high-risk sites; and those
who develop an acute hypersensitivity reaction to antivenom.
At hospital discharge, victims of venomous snakebites should be
warned about symptoms and signs of wound infection, antivenom-
related serum sickness, and potential long-term sequelae, such as
pituitary insufficiency from Russell’s viper (D. russelii) bites. If
coagulopathy developed in the acute stages of envenomation, it can
recur during the first 2–3 weeks after the bite as venom antigens
may have longer half-lives than their corresponding antivenoms; in
such cases, victims should be warned to avoid elective surgery or
activities posing a high risk of trauma during this period. Repeat
laboratory tests (e.g., complete blood count, prothrombin time,
fibrinogen level) should be scheduled to monitor for recurrent
coagulopathy. Outpatient analgesic treatment, wound management,
and physical therapy should be provided.

■ MORBIDITY AND MORTALITY

The overall mortality rates for victims of venomous snakebites are
low in regions with rapid access to medical care and appropriate
antivenoms. In the United States, for example, the mortality rate is
<1% for victims who receive antivenom. Eastern and western
diamondback rattlesnakes (Crotalus adamanteus and Crotalus atrox,
respectively) are responsible for the majority of snakebite deaths in
the United States. Snakes responsible for a large number of deaths
in other countries include cobras (Naja species), carpet and saw-
scaled vipers (Echis species), Russell’s vipers (D. russelii), large
African vipers (Bitis species), lancehead pit vipers (Bothrops
species), and tropical rattlesnakes (C. durissus).
The incidence of morbidity—defined as permanent functional loss
in a bitten extremity—is difficult to estimate but is substantial.
Morbidity may be due to muscle, nerve, or vascular injury or to scar
contracture. Such morbidity can have devastating consequences for
victims in the developing world when they lose the ability to work and
provide for their families. In the United States, functional loss tends
to be more common and severe after rattlesnake bites than after
bites by copperheads (Agkistrodon contortrix) or water moccasins
(Agkistrodon piscivorus).

■ GLOBAL CONSIDERATIONS
In May 2019, the World Health Organization announced a
comprehensive strategy to control and prevent snake
envenomations worldwide, with the goal to reduce the number of
deaths and cases of disability from snakebites by 50% by 2030. This
strategy has been developed around four central tenets: empowering
and engaging communities, ensuring safe and effective treatments,
strengthening health systems, and improving partnerships,
coordination, and resources. In many developing countries where
snakebites are common, limited access to medical care and
antivenoms contributes to high rates of morbidity and mortality.
Recent data show that 6.85 billion people live within the regions
inhabited by snakes, with >10% of people living >1 h from an urban
center. Often, the available antivenoms are inappropriate and
ineffective against the venoms of medically important indigenous
snakes. In those regions, further research is necessary to determine
the actual impact of venomous snakebites and the specific
antivenoms needed in terms of both quantity and spectrum of
coverage. Appropriate antivenoms must be available at the most
likely first point of medical contact for patients (e.g., primary health
centers) in order to minimize the common practice of referring
victims to more distant, higher levels of care for the initiation of
antivenom therapy. Just as important as getting the correct
antivenoms into underserved regions is the need to educate
populations about snakebite prevention and train medical care
providers in proper management approaches. Local protocols written
with significant input from experienced providers in the region of
concern should be developed and distributed. Those who care for
snakebite victims in these often-remote clinics must have the skills
and confidence required to begin antivenom treatment (and to treat
possible reactions) as soon as possible when indicated.

MARINE ENVENOMATIONS
The global incidence of marine envenomation is likely
underestimated, as the majority of cases are mild. Much of the
management of envenomation by marine animals is supportive, but
a few specific antivenoms are available. This section provides
general guidance, and patient management should be tailored to the
practice patterns and known prevalence of specific venomous
species in the region (Fig. 460-4).
FIGURE 460-4 Geographic distribution of venomous marine animals.

■ INVERTEBRATES
Cnidarians Cnidarians, such as hydroids, fire coral, jellyfish,
Portuguese men-of-war, and sea anemones, possess thousands of
specialized stinging organelles called cnidocysts (a term that
encompasses nematocysts, ptychocysts, and spirocysts) distributed
along their tentacles. Nematocysts contain a coiled hollow thread
bathed in venom that is discharged when provoked by mechanical
stimuli, osmotic changes, or other chemical stimuli (Fig. 460-5). The
venom contains enzymes (phospholipases, metalloproteases), pore-
forming toxins, neurotoxins, and nonprotein bioactive substances,
such as tetramine, 5-hydroxytryptamine, histamine, and serotonin.
Venom flows through the hollow thread into the victim’s skin.
Cnidocysts that possess barbs on the ends of their threads can
penetrate human skin; thus, only a subset of cnidarians are toxic to
humans.
FIGURE 460-5 Schematic of a nematocyst. A. Undischarged. Note coiled hollow
thread bathed in venom. B. Discharged.

Victims usually report immediate burning, pruritus, paresthesias,

and painful throbbing with radiation. The skin becomes reddened,
darkened, edematous, and blistered and may show signs of
superficial necrosis. A minority of victims develop systemic toxicity
affecting the cardiovascular, respiratory, gastrointestinal, and
nervous systems, especially following stings from anemones,
Physalia species, and scyphozoans. Anaphylaxis and secondary
infection with marine bacteria can also occur.
 Hundreds of deaths have been reported, many of them caused
by Chironex fleckeri, Stomolophus nomurai, Physalia physalis, and
Chiropsalmus quadrumanus. Irukandji syndrome is a potentially fatal
condition associated with envenomation by the Australian jellyfish
Carukia barnesi and Malo species. Symptoms generally manifest
within 30 min and include hypertension; tachycardia; severe chest,
abdominal, and back pain; nausea and vomiting; and headache. In
the most serious cases, victims may develop cerebral hemorrhage,
cerebral edema, cardiomyopathy, pulmonary edema, and systemic
hypotension. Massive release of endogenous catecholamines
induced by venom components appears to be the underlying cause
of this syndrome.
Initial management should focus on removing the victim from the
water and decontaminating the skin. Drowning is a common cause of
death after significant Cnidarian envenomation. Once the victim is on
land or a boat, the skin should be decontaminated with saline or
seawater. Providers wearing protective equipment should carefully
remove any adherent tentacles. Vinegar (5% acetic acid) appears to
be useful for relieving pain caused by a large number of species,
especially in the Indo-Pacific region where C. fleckeri and C. barnesi
are common. In that region, decontamination with vinegar should be
followed by hot water immersion up to 45°C (113°F). Vinegar may
increase nematocyst discharge in P. physalis and C. quinquecirrha,
species common in the United States. Victims in the United States
should be decontaminated with seawater and then have affected
areas immersed in hot water. Alternatively, vinegar may be tested on
a small area of affected skin to assess effects before performing
complete decontamination. If hot water is unavailable, commercial
(chemical) cold packs or ice packs applied over a thin dry cloth or
plastic membrane can be effective in alleviating pain, but do not
denature venom components. In general, rubbing leads to further
stinging by adherent cnidocysts and should be avoided.
After decontamination, topical application of a local anesthetic,
antihistamine, or glucocorticoid may be helpful for symptom control.
Persistent severe pain may be treated with opioid analgesics.
Muscle spasms may respond to IV diazepam (2–5 mg, titrated
upward as necessary). An antivenom is available from Seqirus (an
affiliate of Commonwealth Serum Laboratories) for stings from the
box jellyfish found in Australian and Indo-Pacific waters. Recent
studies have raised questions about the efficacy of the antivenom,
and there are no reports of survival directly attributable to its
administration. Use of the antivenom is still recommended when it is
available but should not replace aggressive supportive care (see
“Sources of Antivenoms and Other Assistance,” below). Adverse
reactions to the antivenom include early (anaphylaxis) and late
(serum sickness) hypersensitivity reactions. Acute allergic reactions
should be treated with systemic antihistamines, glucocorticoids, and
epinephrine when appropriate. Delayed serum sickness is relatively
common, typically occurs 5–10 days after antivenom administration,
and generally responds well to 5 days of oral glucocorticoids.
Treatment of Irukandji syndrome may require administration of
opioid analgesics and aggressive treatment of hypertension.
Appropriate antihypertensive agents include phentolamine,
nicardipine, nitroprusside, nitroglycerin, and IV magnesium sulfate.
Beta-adrenergic antagonists should be avoided due to the risk of
worsening hypertension from unopposed alpha-adrenergic effects.
All victims with systemic reactions should be observed for at least 6–
8 h for rebound from any therapy and should be monitored for
cardiac arrhythmias.
Safe Sea (Nidaria Technology Ltd.), a “jellyfish-safe” sunblock
applied to the skin before an individual enters the water, inactivates
the recognition and discharge mechanisms of nematocysts; it may
prevent or diminish the effects of coelenterate stings. Whenever
possible, a dive skin or wetsuit should be worn when entering ocean
waters.

Sea Sponges Many sponges produce irritants known as crinotoxins.

Touching a sea sponge may result in allergic contact dermatitis.
Irritant dermatitis may result if the sponge’s spicules of silica or
calcium carbonate penetrate the skin. Affected skin should be dried
and adhesive tape, a commercial facial peel, or a thin layer of rubber
cement used to remove embedded spicules. Vinegar should then be
applied immediately, with repeated application for 10–30 min three or
four times a day thereafter. Corticosteroid cream or oral
antihistamines may provide additional symptomatic relief. Systemic
corticosteroids should be reserved for severe allergic reactions (such
as severe vesiculation) or erythema multiforme. Mild reactions
generally subside within 7 days. Severe envenomation can lead to
fevers, chills, and muscle spasms. Desquamation of affected skin
has also been described and can occur up to 2 months after
exposure. Outpatient wound care is essential to monitor for
secondary infection.

Annelid Worms Annelid worms (bristleworms) are covered with

chitinous spines capable of penetrating human skin and producing
dermal symptoms similar to those of Cnidarian envenomation,
including pain, prickling, urticaria, and discoloration. Pain usually
subsides within hours, but urticaria can persist for days and
discoloration for weeks (Fig. 460-6). Victims should be instructed not
to scratch as it may fracture the spines, complicating their removal
and increasing the risk of secondary infection. Visible bristles should
be removed with forceps, adhesive tape, rubber cement, or a
commercial facial peel. Soaking the affected skin in vinegar may
provide additional relief. Severe inflammation can be treated with
systemic antihistamines or corticosteroids.
FIGURE 460-6 Rash on the hand of a diver from the spines of a bristleworm.
(Courtesy of Paul Auerbach, with permission.)

Sea Urchins Venomous sea urchins possess either hollow, venom-

filled, calcified spines or pincer-like, flexible pedicellariae with venom
glands. The venom contains bradykinin-like substances, steroid
glycosides, hemolysins, proteases, serotonin, and cholinergic
substances. Envenomation causes immediate onset of severe pain,
edema, and erythema. If multiple spines penetrate the skin, the
patient may develop systemic symptoms, including nausea,
vomiting, numbness, muscular paralysis, and respiratory distress.
Synovitis and arthritis have been reported after joint-space
penetration. Retained spines can cause the formation of painful
granulomas.
The affected part should be immersed in hot water up to 45°C
(113°F). Embedded spines should be removed with care as they
may fracture and leave remnants lodged in the victim. Soft-tissue
radiography, ultrasonography, or MRI can be used to evaluate for the
presence of retained fragments. Surgical removal may be necessary,
especially if the spines are in close proximity to vital structures (e.g.,
joints, neurovascular bundles). Granulomas from retained spines are
amenable to excision or intralesional injection with triamcinolone
hexacetonide. Arthritis from joint penetration has been treated with
synovectomy.

Starfish The crown-of-thorns starfish (Acanthaster planci) produces

viscous venom that coats the surface of its spines (Fig. 460-7). The
venom contains saponins with hemolytic, myotoxic, hepatotoxic, and
anticoagulant properties. Skin puncture causes immediate pain,
bleeding, and local edema. Multiple punctures may result in
reactions such as local muscle paralysis. The spines fracture easily
and retained fragments may cause granulomatous lesions and
synovitis. Envenomated persons benefit from acute immersion
therapy in hot water, local anesthesia, wound cleansing, imaging,
and possible exploration to remove spines and foreign material. The
hemolytic and hepatotoxic components are less heat labile than
other venom constituents; hot water immersion may not prevent
systemic toxicity.
FIGURE 460-7 Spines on the crown-of-thorns sea star (Acanthaster planci).
(Courtesy of Paul Auerbach, with permission.)

Sea Cucumbers Sea cucumbers excrete holothurin (a cantharidin-

like liquid toxin) from their anus. This toxin is then concentrated in
the tentacular organs that are projected when the animal is
threatened. Underwater, holothurin induces minimal contact
dermatitis but can cause significant corneal and conjunctival irritation
should ocular contact occur. A severe reaction can lead to blindness.
Skin should be decontaminated with vinegar. The eyes should be
anesthetized with 1–2 drops of 0.5% proparacaine and irrigated
copiously with normal saline, with subsequent slit-lamp examination
to identify corneal defects.

Cone Snails Cone snails use a detachable dartlike tooth to inject

conotoxins into victims. Numerous conotoxins have been identified
including some that interfere with neuronal and cardiac ion channels
and others that antagonize neuromuscular acetylcholine receptors.
Punctures result in small, painful wounds followed by local ischemia,
cyanosis, and numbness. Syncope, dysphagia, dysarthria, ptosis,
blurred vision, and pruritus also have been documented. Some
envenomations induce paralysis leading to respiratory failure.
Cardiac dysrhythmias have also been reported. Pressure-
immobilization (see “Octopuses,” below), hot-water soaks, and local
anesthetics have been successful for localized symptoms.
Respiratory failure may necessitate mechanical ventilation. Cardiac
dysrhythmias should be treated with electrical cardioversion as ion
channel-blocking antidysrhythmic medications may worsen the
dysrhythmia. No antivenom is available. Edrophonium has been
recommended as therapy for paralysis if an edrophonium test is
positive (see Table 460-2).

Octopuses Serious envenomations and deaths have followed bites

of Australian blue-ringed octopuses (Hapalochlaena maculosa and
Hapalochlaena lunulata). The classic blue rings appear only when
the animal is threatened. These species are not aggressive and
human envenomations have typically occurred when handling the
octopus. Their salivary glands contain symbiotic bacteria that
produce tetrodotoxin, a potent sodium channel blocker that inhibits
transmissions in the peripheral nervous system. The bite is minimally
painful but oral and facial numbness develop within minutes of a
serious envenomation. Mild weakness can rapidly progress to total
flaccid paralysis. Mentation is typically unaffected. The venom can
also cause peripheral vasodilation leading to profound hypotension.
Deaths from these envenomations are due to respiratory failure or
vasodilatory shock and hypoperfusion.
Immediately after envenomation, a wide circumferential pressure-
immobilization bandage should be applied over a gauze pad placed
directly over the sting. The dressing should be applied at venous-
lymphatic pressure with the preservation of distal arterial pulses, and
the limb should be splinted. The bandage can be released when the
victim has been transported to a medical facility. There is no antidote
and treatment is supportive. Respiratory failure may necessitate
mechanical ventilation. Appropriate analgesia and sedation are
critical as mental status is generally unaffected even in cases of
complete paralysis. Hypotension should be treated with crystalloid
and vasopressors if needed. In animal studies, phenylephrine and
norepinephrine were more effective than dopamine or epinephrine
for treatment of vasodilatory shock. Recovery usually occurs within
24−48 h and long-term sequelae are uncommon unless related to
hypoxia or hypoperfusion. Tetrodotoxin is also found in the flesh of
fish in the order Tetraodontiformes, which contains a number of
“pufferfish” including blowfish, globefish, and balloonfish. The toxin
can be absorbed orally when these fish are consumed. Fugu, a
traditional Japanese delicacy, is a reported source of poisoning.
When properly prepared by a licensed chef, fugu is meant to contain
a sufficient dose of tetrodotoxin to cause mild perioral paresthesia
without systemic toxicity. When larger doses of the toxin are
consumed due to improper preparation, symptoms are similar to
envenomation by the blue-ringed octopus.

■ VERTEBRATES
As for all penetrating injuries, first-aid care should be provided and
tetanus immunization administered when indicated. Victims should
be monitored for secondary infection by aquatic bacteria such as
Vibrio species and Aeromonas hydrophila. Risk of infection is much
higher if spines and needles remain embedded.

Stingrays A stingray injury is both an envenomation and a traumatic

wound. Stingrays possess serrated spines with venom glands that
can easily penetrate human skin. The venom contains serotonin, 5′-
nucleotidase, and phosphodiesterase. Victims experience severe
pain, bleeding, and edema at the site of injury that peak within 30−60
min and may persist for up to 2 days. Penetrating injuries to the
thorax and heart as well as lacerations to major vessels (especially
of the lower extremity) have been reported. The wound often
becomes ischemic in appearance and heals poorly, with adjacent
soft-tissue swelling and prolonged disability. Systemic effects of the
venom include weakness, diaphoresis, nausea, vomiting, diarrhea,
hypotension, dysrhythmias, syncope, seizures, muscle cramps,
fasciculations, and paralysis. While the venom effects can be fatal in
rare cases, most deaths are attributable to the traumatic injury.

Stonefish Stonefish (Synanceia species) are members of the

Scorpaenidae family and generally considered the most venomous
bony fish in the world. Their venom contains pore-forming toxins,
proteases, hyaluronidase, 5’-nucleotidase, acetylcholinesterase, and
cardiac calcium channel-blockers. The venom is delivered through
12 or 13 dorsal, 2 pelvic, and 3 anal spines when provoked by
mechanical stimuli. Victims experience immediate, intense pain that
peaks within 90 min, local edema, and wound cyanosis. Local
symptoms most often resolve within 12 h but can persist for days.
Signs of systemic toxicity include abdominal pain, vomiting, delirium,
seizures, paralysis, respiratory distress, dysrhythmias, and
congestive heart failure. An antivenom from Seqirus (see “Sources
of Antivenoms and Other Assistance,” below) can be used in cases
of severe envenomation but should not replace supportive care.

Lionfish Also members of the family Scorpaenidae, lionfish (Pterois

species) are much less toxic to humans than stonefish. The venom
is delivered by curved dorsal spines and contains heat-labile, high-
molecular-weight proteins. Reported symptoms include localized
pain, blistering, edema, sensory changes (paresthesia, anesthesia,
or hyperesthesia), and necrosis (rare).

Platypuses The platypus is a venomous mammal. The male has a

keratinous spur on each hind limb that is connected to a venom
gland within the upper thigh. Skin puncture causes soft-tissue edema
and pain that may last for days to weeks. Care is supportive and
should focus on appropriate analgesia and wound care. Hot water
immersion does not appear to be beneficial.

TREATMENT
Marine Vertebrate Stings
The stings of all marine vertebrates are treated in a similar fashion.
Antivenom is currently available only for stonefish and severe
scorpionfish envenomations. The affected part should be immersed
immediately in hot water up to 45°C (113°F) for 30–90 min or until
there is significant pain relief. Recurrent pain may respond to
repeated hot water treatment. Systemic opioids as well as wound
infiltration or regional nerve block with local anesthetics can help
alleviate pain and facilitate wound exploration and debridement.
Advanced imaging (in particular, ultrasound or MRI) may be helpful
in identification of retained foreign bodies. After exploration and
debridement, the wound should be irrigated vigorously with warm,
sterile saline. Bleeding is generally controlled with local pressure.
Most wounds should be left open to heal by secondary intention or
treated by delayed primary closure. Early primary repair is
occasionally preferred for cosmetic reasons but increases the risk of
wound infection. Tetanus immunization should be provided as
appropriate. Antibiotic treatment should be considered for serious
wounds and for envenomations in immunocompromised hosts. The
initial antibiotics should cover Staphylococcus and Streptococcus
species. If the victim is immunocompromised, if a wound is primarily
repaired, or if an infection develops, antibiotic coverage should be
broadened to include Vibrio species for wounds sustained in salt
water or Aeromonas species for wounds sustained in freshwater.

APPROACH TO THE PATIENT

Marine Envenomations
It is useful to be familiar with the local marine fauna and to
recognize patterns of injury.
Coelenterate (marine invertebrate) stings sometimes create
diagnostic skin patterns. A diffuse urticarial rash on exposed skin
is often indicative of exposure to fragmented hydroids or larval
anemones. A linear, whiplike print pattern appears where a
jellyfish tentacle has contacted the skin. In the case of the box
jellyfish, a crosshatched appearance, followed by development of
dark purple coloration within a few hours of the sting, heralds skin
necrosis. An encounter with fire coral causes immediate pain,
erythema, and swelling in the pattern of contact, similar to but
more severe than the imprint left by exposure to an intact feather
hydroid. Seabather’s eruption, caused by thimble jellyfish and
larval anemones, is a diffuse, intensely pruritic rash consisting of
clusters of erythematous macules or papules that follow the
pattern of bathing attire (Fig. 460-8). Toxic sponges create a
burning and painful red rash on exposed skin, which may blister
and later desquamate. Virtually all marine stingers cause
cutaneous inflammation; thus, local erythema, swelling, and
adenopathy are fairly nonspecific.

FIGURE 460-8 Erythematous, papular rash typical of seabather’s eruption

caused by thimble jellyfish and larval anemones. (Courtesy of Paul Auerbach,
with permission.)

A large puncture wound or jagged laceration (particularly on

the lower extremity) that is more painful than one would expect
from the size and configuration of the wound is likely to be a
stingray envenomation. Smaller puncture wounds, sometimes
associated with purple or dark discoloration, represent the activity
of a sea urchin or starfish. Stony corals cause rough abrasions
and, in rare instances, lacerations or puncture wounds.

■ SOURCES OF ANTIVENOMS AND OTHER ASSISTANCE

In the United States, assistance in locating a specific antivenom can
be obtained from a regional poison control center (800-222-1222).
Divers Alert Network, a nonprofit organization designed to assist in
the care of injured divers, also may help with the treatment of marine
injuries. The network can be reached at www.diversalertnetwork.org
or by telephone 24 h a day at 919-684-9111. The antivenoms for box
jellyfish (C. fleckeri) and stonefish or severe scorpionfish
envenomations are made in Australia by Seqirus (63 Poplar Road,
Parkville, Victoria, Australia 3052; www.seqirus.com.au; 61-3-9389-
2000). When administering the box jellyfish antivenom, time is of the
essence. For cardiac or respiratory decompensation, a minimum of 1
ampule and up to 6 ampules consecutively should be given IV,
preferably in a 1:10 dilution with normal saline. For stonefish or
severe scorpionfish envenomation, 1 ampule of specific antivenom
should be administered IM for every one or two punctures, to a
maximum of 3 ampules.

MARINE POISONINGS
■ HISTAMINE (SCOMBROID) FISH POISONING
Histamine fish poisoning, most often referred to as scombroid or
pseudoallergenic fish poisoning, may be the most common type of
seafood poisoning worldwide. It was originally described after
consumption of scombroid (mackerel-like) fish (including albacore,
bluefin, and yellowfin tuna; mackerel; saury; needlefish; wahoo;
skipjack; and bonito), but is now more commonly reported with
consumption of nonscombroid fish (including dolphinfish, kahawai,
sardine, black marlin, pilchard, anchovy, herring, amberjack,
Australian ocean salmon, and bluefish).
Under conditions of inadequate preservation or refrigeration, the
amino acid L-histidine in the musculature of these fish undergoes
decarboxylation to histamine, histamine phosphate, and histamine
hydrochloride by Morganella morganii, Escherichia coli, Proteus
species, and Klebsiella species. Histamine levels of 20–50 mg/100 g
are noted in toxic fish, with levels >400 mg/100 g on occasion. Toxic
levels can be reached with as few as 12 h of inadequate
refrigeration. The pathophysiology of this intoxication remains
unclear, as large doses of oral histamine do not reproduce the
condition. It has been proposed that other biogenic amines such as
cadaverine and putrescine may inhibit the metabolism of histamine.
Another potential mechanism is the induction of mast cell
degranulation by an unidentified toxin. However, affected individuals
may have normal levels of mast cell–derived prostaglandins, which
argues against this mechanism.
The toxin or toxins involved are heat stable and are not destroyed
by cooking or freezing. Affected fish may have a sharply metallic or
peppery taste, although more often they are normal in appearance,
color, and flavor. Not all persons who eat a contaminated fish
necessarily become ill, perhaps because of uneven distribution of
decay within the fish.
Symptoms develop within 15–90 min of ingestion. Most cases are
mild, with tingling of the lips and mouth, mild abdominal discomfort,
and nausea. The more severe and commonly described presentation
includes intense, sharply demarcated flushing of the face, neck, and
upper trunk, pruritus, urticaria, and angioedema. This syndrome may
progress to bronchospasm, nausea, vomiting, diarrhea, epigastric
pain, abdominal cramps, dysphagia, headache, palpitations,
tachycardia, dizziness, hypotension, and cardiogenic shock. Without
treatment, the symptoms generally resolve within 8–12 h. Because
of blockade of gastrointestinal tract histaminase, the reaction may be
more severe in a person who is concurrently ingesting isoniazid.

TREATMENT
Scombroid Poisoning
Therapy is directed at reversing the histamine effect with systemic
antihistamines. In case literature, H2 receptor antagonists (e.g.,
cimetidine, ranitidine) appear to further decrease the severity and
duration of illness when added to H1 receptor antagonists (e.g.,
diphenhydramine, hydroxyzine). If bronchospasm is severe, an
inhaled bronchodilator (e.g., albuterol) can be used. In rare cases,
parenteral epinephrine may be needed. The use of activated
charcoal is not recommended. Protracted nausea and vomiting may
be controlled with antiemetics (e.g., ondansetron, prochlorperazine).
Hypotension should be treated with IV fluids. It is important to
inform the patient that the symptoms are related to eating
improperly refrigerated fish and are not due to a fish allergy.

■ CIGUATERA
Epidemiology and Pathogenesis Ciguatera poisoning is the most
common nonbacterial food poisoning associated with fish in the
United States and accounts for approximately half of all cases.
Florida and Hawaii account for 90% of reported U.S. cases,
although, with transportation of imported fish worldwide, all clinicians
need to be aware of ciguatera. The poisoning almost exclusively
involves carnivorous, bottom-dwelling reef fish native to the Indian
Ocean, the South Pacific, and the Caribbean Sea. More than 500
different fish species have been implicated in ciguatera poisoning,
but the most common are barracuda, snapper, moray eel, grouper,
sea bass, and Spanish mackerel. Global estimates of incidence vary
widely from 20,000–500,000 cases per year; it is suspected that a
large majority of cases go unreported. Ciguatoxins are produced
primarily by the bottom-dwelling, photosynthetic marine
dinoflagellate Gambierdiscus toxicus. These lipophilic toxins
bioaccumulate in the marine food chain when large carnivorous fish
consume the grazing fish that feed on these dinoflagellates.
Ciguatoxins are heat stable and unaffected by freezing, drying,
cooking, or gastric acid. The toxins do not affect the odor, taste, or
appearance of the fish, making identification and prevention difficult.
Ciguatoxins are potent activators of neuronal sodium channels but
may also have other effects such as antagonism of voltage-gated
potassium channels. Toxins are found in the highest concentrations
in the fish’s skin, head, and viscera; therefore, consumption of these
portions should be avoided.

Clinical Manifestations Symptoms can develop within 15–30 min of

ingestion but more commonly in 2–6 h. Most victims develop
symptoms within 12 h of ingestion, and virtually all are afflicted within
24 h. Numerous ciguatoxins have been identified, and their relative
abundance in different species of fish and geographic regions likely
explains the wide array of reported symptoms (Table 460-3). Early
symptoms include nausea, vomiting, diarrhea, abdominal cramps,
headache, and diaphoresis. Neurologic manifestations include
vertigo, dysesthesia, paresthesia, visual disturbance, dysgeusia, and
reversal of hot and cold temperature discrimination. Some victims
describe a sensation of loose teeth. Bradycardia, hypotension, and
orthostasis have also been reported. Gastrointestinal symptoms
generally resolve after 24−48 h but neurologic manifestations may
persist for days to weeks. More severe reactions tend to occur on
repeat exposure. Persons who have ingested parrotfish (scaritoxin)
may develop classic ciguatera poisoning as well as a “second-
phase” syndrome (after a delay of 5–10 days) of disequilibrium with
ataxia, dysmetria, and resting or kinetic tremor. This syndrome may
persist for 2–6 weeks.

TABLE 460-3 Representative Symptoms and Signs of Ciguatera

Poisoning

Diagnosis Ciguatera poisoning is a clinical diagnosis. The toxin can

be detected by liquid chromatography and tandem mass
spectrometry, and fish suspected of contamination can be tested
using a ciguatoxin-specific enzyme immunoassay, but these
techniques are generally not available in most health care
institutions. The differential diagnosis of ciguatera includes paralytic
shellfish poisoning, eosinophilic meningitis, type E botulism,
organophosphate insecticide poisoning, tetrodotoxin poisoning, and
psychogenic hyperventilation.

TREATMENT
Ciguatera Poisoning
Therapy is supportive and based on symptoms. Volume losses from
vomiting and diarrhea should be treated with crystalloids and
electrolyte repletion. Hypotension may rarely be unresponsive to
fluids and require vasopressors. Symptomatic bradyarrhythmias
generally respond well to atropine (0.5 mg IV, up to 2 mg).
Problematic orthostasis can be treated with direct alpha-adrenergic
agonists (e.g., phenylephrine). IV infusion of mannitol may be
beneficial in moderate or severe cases in fluid-replete patients;
however, the efficacy of this therapy has not been definitively
proven. An initial IV dose of mannitol at 1 g/kg may be given over
45–60 min. If symptoms are alleviated, a second dose may be given
within 3–4 h and a third dose the next day. Care must be taken to
avoid dehydration. The mechanism of the drug’s benefit against
ciguatera poisoning is unclear but may be due to decreased sodium
conductance across neuronal cell membranes. Hyperosmotic water-
drawing action is another proposed mechanism but no changes in
neuronal cell edema have been observed in vitro. Amitriptyline (25
mg orally twice a day) reportedly alleviates pruritus and
dysesthesias and may decrease rates of subsequent development
of chronic nerve symptoms. Gabapentin and pregabalin have
shown some efficacy in the treatment of long-term nerve pain in
case reports, but evidence from controlled trials is lacking.
During recovery from ciguatera poisoning, the victim should
exclude the following from the diet for 6 months: fish (fresh or
preserved), fish sauces, shellfish, shellfish sauces, alcoholic
beverages, nuts, and nut oils. Consumption of fish in ciguatera-
endemic regions should be avoided.
■ PARALYTIC SHELLFISH POISONING
Paralytic shellfish poisoning is induced by ingestion of filter-feeding
organisms, including clams, oysters, scallops, mussels, chitons,
limpets, starfish, and sand crabs. The most common agent is
saxitoxin, produced by dinoflagellates in the genera Alexandrium,
Gonyaulax, and Pyrodinium. These unicellular phytoplankton form
the foundation of the food chain for many filter-feeding organisms
and the toxin accumulates in their tissues. In the United States,
paralytic shellfish poisoning is acquired primarily from seafood
harvested in the Northeast, the Pacific Northwest, and Alaska.
During algal blooms (“red tides”) in the summer months, these
planktonic species can release massive amounts of toxic metabolites
into the water and cause mortality in bird and marine populations.
The paralytic shellfish toxins are water soluble as well as heat and
acid stable; ordinary cooking or freezing does not destroy them.
Contaminated seafood looks, smells, and tastes normal. Saxitoxin
appears to block sodium conductance, inhibiting neuromuscular
transmission at the axonal and muscle membrane levels. A toxin
concentration of >75 μg/100 g of foodstuff is considered hazardous
to humans. During an algal bloom, the concentration of saxitoxin in
shellfish can exceed 9000 μg/100 g. A mouse bioassay that
identifies saxitoxin in suspected shellfish is currently in use.
Saxitoxin can be detected in body fluids by high-performance liquid
chromatography, but this method is generally not available in the
clinical setting.
Intraoral and perioral paresthesia can occur within minutes to a
few hours after ingestion of contaminated shellfish and can progress
rapidly to involve the neck and distal extremities. Other neurologic
symptoms can include headache, vertigo, ataxia, diffuse muscle
weakness, hyperreflexia, and cranial neuropathies such as
dysarthria, dysphagia, dysphonia, and transient vision loss.
Gastrointestinal symptoms can include nausea, vomiting, diarrhea,
and abdominal pain. Flaccid paralysis and respiratory insufficiency
may follow 2–12 h after ingestion. In the absence of hypoxia, the
victim often remains alert but paralyzed. Up to 12% of patients may
die.
TREATMENT
Paralytic Shellfish Poisoning
Treatment is supportive and based on symptoms. If the victim seeks
medical attention within the first few hours after ingestion, activated
charcoal (50–100 g) can be administered in the absence of
vomiting. Gastric lavage and cathartics have been attempted but
there is no evidence of benefit and most authors recommend
against their use.
The most serious concern is respiratory paralysis. The victim
should be closely observed for respiratory distress for at least 24 h
in a hospital. With prompt recognition of respiratory failure and
establishment of ventilatory support, anoxic myocardial and brain
injury may be prevented. If the patient survives for 18 h, the
prognosis is good for a complete recovery.

■ AMNESIC SHELLFISH POISONING

Amnesic shellfish poisoning occurs when humans consume shellfish
containing domoic acid. Marine diatoms of the genera Nitzschia and
Pseudonitzchia produce the toxin, which can bioaccumulate in filter
feeders during algal blooms. Clams, mussels, oysters, anchovies,
and Dungeness crabs have all been found to cause amnesic
shellfish poisoning. Domoic acid is an excitotoxic amino acid capable
of binding to kainate and AMPA-type glutamate receptors in the
central nervous system. Uncontrolled calcium influx into neurons
stimulated by domoic acid binding causes neurodegeneration and
apoptosis. The toxin is heat stable and is not affected by cooking or
freezing. Shellfish can be tested for domoic acid by mouse bioassay
and high-performance liquid chromatography (HPLC). The regulatory
limit for domoic acid in shellfish is 20 parts per million. An enzyme-
linked immunoassay has been developed to detect domoic acid in
human body fluids but is generally not available in clinical
laboratories.
Most victims will report symptoms within 5 h of ingesting
contaminated shellfish but delayed onset of up to 40 h has been
reported. Symptoms include nausea, vomiting, diarrhea, abdominal
cramps, and a variety of neurologic manifestations, such as severe
headache, memory loss, seizures, hemiparesis, ophthalmoplegia,
grimacing, purposeless chewing, agitation, emotional lability, and
coma. Cardiac 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 hippocampus 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 diarrhea.
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
leading to diarrhea. Shellfish acquire these toxins by feeding on
dinoflagellates, particularly of the genera Dinophysis and
Prorocentrum.
Symptoms include diarrhea, nausea, vomiting, abdominal pain,
and chills. Onset typically occurs between 30 min and 12 h after
ingestion 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 and Robert L. Norris 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 medicine 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. LS Nelson 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,
randomized 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. LS Nelson 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. J Brent et al (eds). New York,
Springer, 2017, pp 2045-2074.
GREEN S: Ciguatera, in Critical Care Toxicology: Diagnosis and
Management of the Critically Poisoned Patient, 2nd ed. J Brent et
al (eds). New York, Springer, 2017, pp 2033-2043.
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.
LAVONAS EJ et al: Unified treatment algorithm for the management of
crotaline snakebite in the United States: results of an evidence-
informed consensus workshop. BMC Emerg Med 11:2, 2011.
LONGBOTTOM J et al: Vulnerability to snakebite envenoming: A global
mapping of hotspots. Lancet 392:673, 2018.
RUHA A et al: Native (US) venomous snakes and lizards, in
Goldfrank’s Toxicologic Emergencies, 11th ed. LS Nelson et al
(eds). New York, McGraw-Hill Education, 2019, pp 1617-1626.
SUGUITAN MA et al: Scombroid, in Critical Care Toxicology: Diagnosis
and Management of the Critically Poisoned Patient, 2nd ed. J
Brent et al (eds). New York, Springer, 2017, pp 2075-2083.
WORLD HEALTH ORGANIZATION: Snakebite envenoming−A strategy for
prevention and control. Available from
https://www.who.int/snakebites/resources/9789241515641/en/.
Accessed May 11, 2020.
461 Ectoparasite Infestations and Arthropod
Injuries
Richard J. Pollack, Scott A. Norton

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 superficially
on the skin or hair, attached by mouthparts and specialized claws.
Other ectoparasites may penetrate the skin and reside in the
epidermis, dermis, or subcutis. 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 the sole or obligate hosts for
only a few kinds of ectoparasites but 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 arthropods can cause uncomfortable reactions
when they or their setae and exudates contact skin, mucous
membranes, and ocular tissues.
Certain nematodes (helminths), such as the hookworms (Chap.
231), are ectoparasitic in that they penetrate and migrate through the
skin. Infrequently encountered ectoparasites in other phyla include
the 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
venoms. Papular urticaria and other lesions caused by arthropod
bites and stings are so diverse and variable (depending upon the
host’s health status and prior exposure to the arthropod’s saliva,
venom, or other exudates) that it is difficult to identify the precise
causative organism without a bona fide specimen and taxonomic
expertise. Specimens of the presumably offending arthropod should,
whenever possible, be sampled (ideally by medical personnel)
directly (when taken from the patient) or indirectly by the use of traps
or other monitoring devices in the patient’s home or workplace.
Samples sent to laboratorians for evaluation should be properly
fixed, preserved, and packaged. Information on the patient’s travel
history, occupation and avocation, and exposure to animals—pets
and pests—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. Gravid female mites (∼0.3
mm in length) burrow superficially within the stratum corneum,
depositing several eggs per day. Six-legged larvae mature to eight-
legged nymphs and then to adults. Gravid adult females emerge to
the surface of the skin about 8 days later and then (re)invade the
skin of the same or another host. Newly fertilized female mites are
transferred from person to person mainly by direct skin-to-skin
contact; transfer is facilitated by crowding, poor hygiene, and close
physical contact with other persons. Generally, scabies mites die
within a day or so in the absence of a suitable host. Transmission via
sharing of contaminated bedding or clothing occurs less frequently
than is often thought. In the United States, scabies may account for
up to 5% of visits to dermatologists. Outbreaks are known to occur in
preschools, hospitals, nursing homes, prisons, and other institutional
residences.
The itching and rash associated with scabies derive from a
sensitization reaction to mites and their secretions/excretions. A
person’s initial infestation typically remains asymptomatic for up to 6
weeks before the onset of intense pruritus, but a reinfestation
produces a hypersensitivity reaction without delay. Burrows become
surrounded by inflammatory infiltrates composed of eosinophils,
lymphocytes, and histiocytes. Infested individuals often feel
generalized pruritus, not just in the most heavily involved areas.
Hyperinfestation with thousands of mites, a condition known as
crusted scabies (formerly termed Norwegian scabies), may result
from glucocorticoid use, immunodeficiency (including that due to
HIV/AIDS), and neurologic or psychiatric illnesses that limit the itch
and/or the scratch response.
Pruritus typically intensifies at night and after hot showers.
Classic burrows are often difficult to find because they are few in
number and may be obscured by excoriations. Burrows appear as
dark wavy lines in the upper epidermis and are 3–15 mm long.
Scabietic lesions are most common on the volar wrists and along the
digital web spaces. In males, the penis and scrotum almost
invariably become involved. Small papules and vesicles, often
accompanied by eczematous plaques, pustules, or nodules, appear
symmetrically at those sites and within intertriginous areas, around
the navel and belt line, in the axillae, and on the buttocks and upper
thighs. Except in infants, the face, scalp, neck, palms, and soles are
usually spared. Crusted scabies often resembles psoriasis: both are
characterized by widespread thick keratotic crusts, scaly plaques,
and dystrophic nails. Characteristic burrows are not seen in crusted
scabies, and patients usually do not itch, although their infestations
are highly contagious and have been responsible for outbreaks of
common scabies in hospitals.
Scabies should be considered in patients with pruritus and
symmetric superficial, excoriated, papulovesicular skin lesions in
characteristic locations, particularly if there is a history of direct and
prolonged contact with an infested person. 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 biopsied skin samples (including those
obtained by superficial cyanoacrylate biopsy) or scrapings,
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 history of pruritus, a physical examination,
and an epidemiologic link. Unrelated skin diseases 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 aboriginal communities, household dogs may serve as
reservoirs for human scabies mites.

TREATMENT
Scabies
The four scabicides approved by the U.S. Food and Drug
Administration (FDA)—permethrin, crotamiton, spinosad, and
lindane—are topical and available solely by prescription. Permethrin
cream (5%) is less toxic than 1% lindane preparations and is
effective against lindane-resistant infestations. Scabicides are
applied thinly but thoroughly from the jawline down after bathing,
with careful application to interdigital spaces, the navel, and under
the nails, and are removed 6–14 h later with soap and water.
Treatment of crusted scabies is difficult and may require
preapplication of a keratolytic agent such as 6% salicylic acid and
then of scabicides to the skin’s entire surface, including the scalp,
face, and ears. Repeated treatments or the sequential use of
several agents may be necessary. Ivermectin, which is approved by
the FDA for the treatment of two nematodal diseases, has not been
approved for the treatment of scabies; however, a single oral dose
(200 μg/kg) is effective in otherwise healthy persons. Patients with
crusted scabies require three to seven doses of ivermectin over 8–
30 days, along with topical permethrin and possibly a keratolytic
compound.
Within 1 day of effective treatment, scabies infestations become
noncommunicable, but the pruritic hypersensitivity dermatitis
induced by dead mites and their detritus frequently persists for
weeks. Unnecessary retreatment with topical agents may provoke
contact dermatitis, especially from repeated applications of
permethrin cream. Topical emollients, 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 fomites should be
cleaned. Close contacts of confirmed cases, even if asymptomatic,
should be treated simultaneously.
Scabies infestations often lead to secondary bacterial infections,
usually with Staphylococcus aureus or Streptococcus pyogenes (or
both). Consequences of these superinfections include impetigo,
cellulitis, invasive bacterial infections, poststreptococcal
glomerulonephritis, and possibly acute rheumatic fever.

■ CHIGGERS AND OTHER BITING MITES

Chiggers are the larvae of trombiculid (harvest) mites that normally
feed 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 saliva with proteolytic enzymes to create a tube-like
invagination in the host’s skin; this stylostome allows the mite to
imbibe tissue fluids. The saliva is highly antigenic and causes small
(usually <1 cm in diameter) but exceptionally pruritic papular,
urticarial, or pustulovesicular lesions. In persons previously
sensitized to salivary antigens, the papules develop within hours of
attachment. While attached, mites appear as minute (∼0.5-mm
diameter) red dots on the skin. Generally, lesions have a
hemorrhagic base and are slightly elevated, resembling vasculitic
papules. Scratching invariably destroys the body of a mite, but
itching and burning often persist for weeks. The rash is common on
the ankles and in areas where circumferentially tight clothing
obstructs the further wanderings of the mites. Repellents are useful
for preventing chigger bites. Chiggers (Leptotrombidium species)
serve as vectors for Orientia tsutsugamushi, the agent of scrub
typhus in the eastern half of Asia and the Indomalayan and
Australasian regions. Endemic foci of scrub typhus were recently
identified in southern Chile and in East Africa, far outside the
traditional endemic region.
Many kinds of mites associated with peridomestic birds and
rodents are 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. 187)
has been recognized mainly in large northern temperate cities. Once
confirmed as the cause of a skin disorder, rodent- and bird-
associated mites are best eliminated by exclusion of their animal
hosts, removal of the nests, and cleaning and treatment of the
nesting area with appropriate acaricides.
Pyemotes and other mites that infest grain, straw, cheese, hay,
oak leaf galls, or other products occasionally produce similar
episodes of rash and discomfort and may produce a unique
dermatologic “comet sign” lesion—a paisley-shaped urticarial plaque
(Fig. 461-1).
FIGURE 461-1 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.

Diagnosis of mite-induced dermatitides (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. Because the mites do
not reside on humans, treatment of the patient with acaricides (e.g.,
permethrin) 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
(intended to prevent blood coagulation while the tick feeds) and can
produce local reactions, induce fevers, and cause paralysis in
addition to transmitting diverse pathogens. The two main families of
ticks are the hard (ixodid) ticks and soft (argasid) ticks. Because no
ticks are obligate parasites on humans, all tick-borne diseases
(bacterial, viral, and protozoal) are zoonoses.
Generally, soft ticks feed quickly, attaching for <1 h, and then
drop off. Because of this rapid feeding behavior, the ticks are not
carried widely by animal or bird hosts. Soft tick–associated infections
usually have fairly focal distributions. When a soft tick finishes the
blood meal on a human and drops off, red macules may develop at
the bite site. Some species in Africa, the western United States, and
Mexico produce painful hemorrhagic lesions.
Hard ticks are much more common than are soft ticks, and they
transmit most of the tick-borne infections that are familiar to
physicians and patients. Hard ticks attach to the host and feed for
several 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. Chronic nodules
(persistent tick-bite granulomas) can be several centimeters in
diameter and may linger for months after the feeding tick has been
removed. These granulomas can be treated with injected
intralesional glucocorticoids or by simple local excision. Tick-induced
fever, unassociated with transmission of any pathogen, is often
accompanied by headache, nausea, and malaise but usually
resolves ≤36 h after the tick is removed. Salivary antigens of certain
ticks, particularly the Lone Star tick, Amblyomma americanum, may
induce antibodies to galactose-α-1,3-galactose (alpha-gal) that result
in mammalian meat allergy–alpha-gal syndrome.
Tick paralysis, an acute ascending flaccid paralysis that
resembles Guillain-Barré syndrome, is believed to be caused by one
or more toxins in tick saliva that block neuromuscular transmission
and decrease nerve conduction. This rare complication has followed
the bites of >60 species of ticks. It is reported worldwide, but most
cases arise in the Rocky Mountain region, in the northwestern United
States and southeastern Canada, and on the east coast of Australia.
In North America, dog and wood ticks (Dermacentor species) are
most commonly involved. Weakness begins symmetrically in the
lower extremities ≤6 days after the tick’s attachment, ascends
symmetrically during several days, and may culminate in complete
paralysis of the extremities and cranial nerves. Deep tendon reflexes
are diminished or absent, but sensory examination and findings on
lumbar puncture are typically normal. Diagnosis depends on finding
the tick, which is often hidden beneath scalp hair. Removal of the tick
generally leads to improvement within a few hours and complete
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. An antiserum to the saliva of Ixodes
holocyclus, the usual cause of tick paralysis in Australia, effectively
reverses paralysis caused by these ticks.
Removal of hard ticks during the first 36 h of attachment
generally 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 tick fluids. Use of
occlusive dressings, heat, or various substances (in an attempt to
induce the tick to detach) merely delays tick removal. Afterward, the
site of attachment should be disinfected. Tick mouthparts sometimes
remain in the skin but generally 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 single oral dose of
doxycycline (200 mg) within 72 h of tick removal—to adult patients
with bites thought to be associated with Ixodes scapularis (deer
ticks) in Lyme disease–endemic areas. Whereas prophylactic
antibiotic treatment may have value in preventing Lyme disease, it is
not recommended as a means to prevent other tick-borne infections.
The Asian longhorned tick (Haemaphysalis longicornis) is a
newly invasive species in the United States, first detected in the
northeastern 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 (PEDICULIASIS AND PTHIRIASIS)

Three kinds of biting lice are obligate blood-feeding ectoparasites of
human beings. These include the human head and body lice that
represent distinct genetic clades of Pediculus humanus, and the
pubic (“crab”) lice (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
hair of the scalp, body lice the clothing, and pubic lice mainly the hair
of the pubis. The saliva of lice produces a pruritic morbilliform or
urticarial rash in some sensitized persons. Female head and pubic
lice cement their eggs (nits) firmly to hair, whereas female body lice
cement their eggs to clothing, particularly to threads along clothing
seams. After ∼10 days of development within the egg, a nymph
emerges. Empty eggs may remain affixed for months or years
thereafter.
Body lice are acquired by direct contact with an infested person
or that individual’s 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. Body lice tend to be limited to a small proportion of
indigent persons or others who have relevant exposure and lack the
wherewithal or desire to change or appropriately launder their
clothing and bedding. Body lice, as well as the pathogens they
transmit, may become increasingly prevalent after societal upheaval
and disasters. These lice are vectors for the agents of louse-borne
(epidemic) typhus (Chap. 187), louse-borne relapsing fever (Chap.
185), and trench fever (Chap. 172). Chronic infestations result in a
postinflammatory hyperpigmentation and thickening of the skin
known as vagabond’s disease.
Head lice are acquired mainly by direct head-to-head contact
rather than via fomites such as shared headgear, bed linens, and
grooming implements. The prevalence of head lice varies widely as
a function of age, geography, and cultural habits. In North America,
the prevalence is greatest (∼1%) among 6- to 10-year-old children
and is considerably lower among persons of other ages. Infestations
can be far more prevalent elsewhere. Generally, an infested person
hosts 10 or fewer head lice. Chronically infested persons tend to be
asymptomatic, and some may host >100 lice. Pruritus, due mainly to
hypersensitivity to the louse’s saliva, usually is transient and mild
and is most evident around the posterior hairline. Head lice removed
from a person succumb to desiccation and starvation within ∼1 day.
Head lice are generally considered unimportant as natural vectors
for any pathogens.
The crab or pubic louse is transmitted mainly by sexual contact.
These lice occur predominantly on pubic hair and less frequently on
axillary or facial hair, including the eyelashes. Children and adults
may acquire pubic lice by sexual or close nonsexual contact.
Intensely pruritic, bluish macules ∼3 mm in diameter (maculae
ceruleae) develop at the site of bites. Blepharitis commonly
accompanies infestations of the eyelashes.
Pediculiasis is often suspected upon the detection of presumed
nits firmly cemented to hairs or in clothing or on the basis of pruritus.
Often, objects presumed to be louse eggs are, instead, pseudo-nits
composed of debris and hair-associated fungi. Hatched and dead
eggs remain firmly affixed to scalp hair for months. Such relicts 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
laundered clothes. Application of topical pediculicides from head to
foot may be necessary for hirsute patients. Clothes and bedding are
effectively deloused by heating in a clothes dryer at ≥55°C (≥131°F)
for 30 min or by heat-pressing. Emergency mass delousing of
persons and clothing may be warranted during periods of civil strife
and after natural disasters to reduce the risk of pathogen
transmission by body lice.
Head lice and their eggs may be removed with a fine-toothed
louse or nit comb, but this effort can be difficult and time-consuming
and often fails to eradicate the lice. Treatment of newly identified,
active infestations traditionally relies on a 10-min topical application
of ∼1% permethrin or pyrethrins, with a second application ∼10
days later. Lice persisting after this treatment may be resistant to
pyrethroids. Chronic infestations may be treated for ≤12 h with 0.5%
malathion. Lindane is applied for just 4 min but seems less effective
and may pose a greater risk of adverse reactions, particularly when
misused. Resistance of head lice to permethrin, malathion, and
lindane is well documented. Newer FDA-approved topical
pediculicides contain benzyl alcohol, dimethicone, spinosad, and
ivermectin. Although children infested by head lice—or those who
simply have remnant nits from a prior 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 generally
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 syndromes, 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 deposits 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 emerging larvae, ∼1 mm long, promptly
penetrate intact skin. After 6–12 weeks of development, mature
larvae emerge from the skin and drop to the ground to pupate and
then become adults.
The African tumbu fly (Cordylobia anthropophaga) deposits its
eggs on damp sand, leaf litter, or drying laundry, particularly items
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. A
sensation of movement under the patient’s skin may cause severe
emotional distress.
Larvae that cause furuncular myiasis may be induced to emerge
if the air 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 the larvae firmly in place.
Other fly larvae cause nonfuruncular myiasis. Larvae of the horse
botfly (Gasterophilus intestinalis) emerge from eggs, usually
deposited on the hairs of a horse’s front legs. Direct contact with a
person’s bare hands or legs may result in the larvae’s hatching from
the eggs and invading 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. 231). Larvae of rabbit and rodent botflies (Cuterebra species)
occasionally cause cutaneous or tracheopulmonary myiasis.
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 types of green bottle flies (Lucilia
species) usually remain superficial and confined to necrotic tissue.
Specially raised, sterile “surgical maggots” are sometimes used
deliberately for wound debridement. Larvae of screwworm flies
(Cochliomyia) and flesh flies (Wohlfahrtia species) invade viable
tissues more deeply and produce large suppurating lesions. Larvae
that infest wounds also 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
consequences range from harmless colonization to destruction of the
nose, meningitis, and deafness. Treatment involves removal of
maggots and debridement of tissue.
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. Most instances in which
maggots are found in human feces result from deposition of eggs or
larvae by flies on recently passed stools, not from an intestinal
maggot infestation.

■ PENTASTOMIASIS
Pentastomids (tongue worms), an obscure type of crustacean,
inhabit the respiratory passages of reptiles and carnivorous
mammals. Human infestation by Linguatula serrata is common in the
Middle East and results from the consumption of 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, larvae migrate to the 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 measuring ≤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
handling 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 autopsy. Parasite-induced lesions may be
misinterpreted as a malignancy, with the correct diagnosis confirmed
histopathologically. Cutaneous larva migrans–type syndromes of
other pentastomes have been reported from Southeast Asia and
Central America.

■ 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:
Macrobdella decora) are still used occasionally for medical purposes
to reduce venous congestion in surgical flaps or replanted body
parts. This practice 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
powerful 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
posterior suckers the leech uses for attachment and feeding. Some
authorities 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
Of the >30,000 recognized species of spiders, only ∼100 defend
themselves aggressively and have fangs sufficiently long to
penetrate human skin. The venom that some spiders use to
immobilize and digest their prey can cause necrosis of the skin and
systemic toxicity. Whereas the bites of most spiders may be painful
but not harmful, envenomations by recluse or fiddleback spiders
(Loxosceles species) and widow spiders (Latrodectus species) may
be life-threatening. Identification of the offending spider is important
because specific treatments exist for bites of widow spiders. Except
when the patient actually observes a spider immediately associated
with the bite or fleeing from the site, painful noduloulcerative and
other lesions reported as spider-bite reactions are most often due to
other injuries or to infections with bacteria, particularly 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
spiders are not aggressive toward humans and bite only if
threatened or pressed against the skin. They generally dwell
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 clothing. 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 primarily on the hands, arms,
neck, and lower abdomen.
Whereas a bite by a brown recluse spider may cause minor injury
with edema and erythema, 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 pruritic,
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, the
erythema spreads, and the center of the lesion 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. Fever, chills, weakness, headache, nausea,
vomiting, myalgia, arthralgia, morbilliform eruption, and leukocytosis
may develop ≤72 h after the bite. Reports of deaths attributed to
bites of North American brown recluse spiders have not been
verified.
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 fiddle-shaped 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
prophylaxis 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 black widow spider, common in the

southeastern United States, measures ≤1 cm in body length and 5
cm in leg span and is 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
perceived as a sharp pinprick or may go unnoticed. Fang-puncture
marks are uncommon. The venom that is injected does not produce
local necrosis, and some persons experience no other symptoms.
α-Latrotoxin, the most active component of the venom, 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 extremities
and trunk. Extreme rigidity of the abdominal muscles and
excruciating pain may suggest 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 during several days or
weeks before resolving spontaneously. A wide range of other
sequelae 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
respiratory 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.,
benzodiazepines or methocarbamol) requires specific
antihypertensive medication. The efficacy and safety of antivenin
(i.e., antivenom) made from equine immunoglobulins are
controversial for bites of the black widow and the closely related
Australian redback spider because of concerns about 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
Southwest. Several species of tarantulas that have become popular
household pets are usually imported from Central or South America.
Tarantulas bite persons 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 most
dangerous spiders in the world because of their aggressive behavior
and potent neurotoxins. Envenomation by A. robustus causes a
rapidly progressive 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
injecting 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 that are produced by ∼30 of the
∼1000 known species and that cause >5000 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 the 40 or so scorpion species in the United States, only bark
scorpions (Centruroides sculpturatus/C. exilicauda) in the Southwest
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 restlessness, blurred vision, abnormal eye movements,
profuse salivation, lacrimation, rhinorrhea, slurred speech, difficulty
in handling secretions, diaphoresis, nausea, and vomiting. Muscle
twitching, jerking, and shaking may be mistaken for a seizure.
Complications include tachycardia, arrhythmias, hypertension,
hyperthermia, rhabdomyolysis, 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 endogenous 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
necrosis after the first day. Systemic complications include
hemoglobinuria and subsequent acute kidney injury.
Stings of most other species cause immediate sharp local pain
followed by edema, ecchymosis, and a burning sensation.
Symptoms typically resolve within a few hours, and skin does not
slough. Allergic reactions to the venom sometimes develop.

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
experience 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
eliminate 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
continuous IV infusion of midazolam controls the agitation, flailing,
and involuntary muscle movements produced by scorpion stings.
Close monitoring during treatment with this drug and other
sedatives or narcotics is necessary for persons with neuromuscular
symptoms because of the risk of respiratory arrest. Hypertension
and pulmonary edema respond to nifedipine, nitroprusside,
hydralazine, or prazosin. Dangerous bradydysrhythmia can be
controlled with atropine.
Commercially prepared antivenins are available in several
countries for some of the most dangerous scorpion species. An
FDA-approved C. sculpturatus IgG F(ab’)2 antivenin in horse serum
is available. IV administration of antivenin rapidly reverses cranial-
nerve dysfunction 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. Africanized 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, histamine, 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.
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,
generalized edema, dyspnea, hypotension, and non-anaphylactic
circulatory collapse. Rhabdomyolysis and intravascular hemolysis
may cause renal failure. Death from the direct (nonallergic) effects of
venom has followed 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
infection. 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. Persons 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 life-
threatening emergency that requires prompt life-saving actions. If
the individual carries a bee-sting kit, then a subcutaneous injection
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 treatment 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 life-
threatening 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.
Honeybee, 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 selection of patients for immunotherapy and guide the design of
such treatment.

■ 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 antibiotic ointment to
prevent bacterial infection. Epinephrine administration and
supportive measures are indicated for anaphylactic reactions. Fire
ant whole-body extracts are available for skin testing and
immunotherapy, which appear to lower the rate of anaphylactic
reactions.
European fire (red) ants (Myrmica rubra) have recently become
public 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 anaphylaxis. 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
vasodilation 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 deerflies 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 antihistamines.
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
(Ctenocephalides 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 glucocorticoids, 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 antihistamines. Persons with anaphylactic reactions to
reduviid bites should keep an epinephrine kit available. Some
reduviids transmit Trypanosoma cruzi, the agent of New World
trypanosomiasis (Chagas disease) (Chap. 227).
The cosmopolitan and tropical bed bugs (Cimex lectularius and
C. hemipterus) hide in crevices of mattresses, bed frames and other
furniture, 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
vertebrates—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
lymphangitis. 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
exfoliate. 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
erucism (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
other caterpillars, such as gypsy moth larvae, can later produce
erucism. Spines may be deposited on tree trunks or drying laundry
or may be airborne and cause irritation of the eyes and upper
airways. Treatment 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 antihistamines 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 pruritic 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-molecular-
weight toxin that produces thin-walled blisters (≤5 cm in diameter) 2–
5 h after contact. The blisters are not painful or pruritic unless
broken. They resolve without treatment in ≤10 days. Nephritis may
follow unusually heavy cantharidin exposure.
The hemolymph of certain rove beetles (Paederus species,
Staphylinidae 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 numerous 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.
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, and perhaps Morgellons syndrome) is extremely difficult
to treat and, unfortunately, is not uncommon (Fig. 461-2). 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 parasitosis, it is imperative to rule out true infestations and
bites by arthropods, 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 explanations for their symptoms, and
exacerbate their discomfort by self-treatment. Long-term
pharmacotherapy with pimozide or other psychotropic agents has
been more helpful than psychotherapy in treating 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.
FIGURE 461-2 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, re-
epithelialized, 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.

■ FURTHER READING
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