3578 PART 13 Neurologic Disorders

■ FURTHER READING

Compton WM: Polysubstance use in the U.S. Opioid Crisis. Mol Psychiatry 26:41, 2021.

Farrell M et al: Responding to global stimulant use: challenges and

opportunities. Lancet 394:1652, 2019.

Trivedi MH et al: Bupropion and naltrexone in methamphetamine use

disorder. N Engl J Med 384:140, 2021.

Volkow ND et al: Neurobiologic advances from the brain disease

model of addiction. N Engl J Med 374:363, 2016.

■ WEBSITES

American Society of Addiction Medicine: https://www.asam.org/

public-resources

National Institute on Drug Abuse: https://www.drugabuse.gov/

drugs-abuse

World Health Organization: http://www.who.int/substance_abuse/en/

Poisoning, Drug Overdose, and Envenomation PART 14

Heavy Metal Poisoning

Howard Hu

458

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.

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, 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 cadmiuminduced 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 occupationalexposed 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

3580 PART 14 Poisoning, Drug Overdose, and Envenomation

TABLE 458-1 Heavy Metals

MAIN SOURCES METABOLISM TOXICITY DIAGNOSIS TREATMENT

Arsenic

Smelting and

microelectronics

industries; wood

preservatives,

pesticides, herbicides,

fungicides; contaminant

of deep-water wells;

folk remedies; and coal;

incineration of these

products.

Organic arsenic

(arsenobetaine, arsenocholine)

is ingested in seafood and

fish, but is nontoxic; inorganic

arsenic is readily absorbed

(lung and GI); sequesters in

liver, spleen, kidneys, lungs, and

GI tract; residues persist in skin,

hair, and nails; biomethylation

results in detoxification, but this

process saturates.

Acute arsenic poisoning results

in necrosis of intestinal mucosa

with hemorrhagic gastroenteritis,

fluid loss, hypotension, delayed

cardiomyopathy, acute tubular

necrosis, and hemolysis.

Chronic arsenic exposure causes

diabetes, vasospasm, peripheral

vascular insufficiency and

gangrene, peripheral neuropathy,

and cancer of skin, lung, liver

(angiosarcoma), bladder, and

kidney.

Lethal dose: 120–200 mg (adults);

2 mg/kg (children).

Nausea, vomiting, diarrhea,

abdominal pain, delirium, coma,

seizures; garlicky odor on breath;

hyperkeratosis, hyperpigmentation,

exfoliative dermatitis, and Mees’

lines (transverse white striae of

the fingernails); sensory and motor

polyneuritis, distal weakness.

Radiopaque sign on abdominal

x-ray; ECG–QRS broadening, QT

prolongation, ST depression, T-wave

flattening; 24-h urinary arsenic

>67 μmol/d or 50 μg/d; (no seafood

× 24 h); if recent exposure, serum

arsenic >0.9 μmol/L (7 μg/dL). High

arsenic in hair or nails.

If acute ingestion, ipecac to

induce vomiting, gastric lavage,

activated charcoal with a

cathartic. Supportive care in

ICU.

Dimercaprol 3–5 mg/kg IM

q4h × 2 days; q6h × 1 day, then

q12h × 10 days; alternative: oral

succimer.

Cadmium

Metal plating, pigment,

smelting, battery, and

plastics industries;

tobacco; incineration

of these products;

ingestion of food that

concentrates cadmium

(grains, cereals, organ

meats).

Absorbed through ingestion

or inhalation; bound by

metallothionein, filtered at the

glomerulus, but reabsorbed

by proximal tubules (thus,

poorly excreted). Biologic

half-life: 10–30 y. Binds cellular

sulfhydryl groups, competes

with zinc, calcium for binding

sites. Concentrates in liver and

kidneys.

Acute cadmium inhalation causes

pneumonitis after 4–24 h; acute

ingestion causes gastroenteritis.

Chronic exposure causes

anosmia, yellowing of

teeth, emphysema, minor

LFT elevations, microcytic

hypochromic anemia

unresponsive to iron therapy,

proteinuria, increased urinary

β2

-microglobulin, calciuria,

leading to chronic renal failure,

osteomalacia, and fractures.

Possible risks of cardiovascular

disease and cancer.

With inhalation: pleuritic

chest pain, dyspnea, cyanosis,

fever, tachycardia, nausea,

noncardiogenic pulmonary edema.

With ingestion: nausea, vomiting,

cramps, diarrhea. Bone pain,

fractures with osteomalacia. If

recent exposure, serum cadmium

>500 nmol/L (5 μg/dL). Urinary

cadmium >100 nmol/L (10 μg/g

creatinine) and/or urinary β2

-

microglobulin >750 μg/g creatinine

(but urinary β2

-microglobulin also

increased in other renal diseases

such as pyelonephritis).

There is no effective treatment

for cadmium poisoning

(chelation not useful;

dimercaprol can exacerbate

nephrotoxicity).

Avoidance of further exposure,

supportive therapy, vitamin D

for osteomalacia.

Lead

Manufacturing of auto

batteries, lead crystal,

ceramics, fishing

weights, etc.; demolition

or sanding of leadpainted houses, bridges;

stained glass making,

plumbing, soldering;

environmental exposure

to paint chips, house

dust (in homes built

<1975), firing ranges

(from bullet dust), food

or water from improperly

glazed ceramics, lead

pipes; contaminated

herbal remedies,

candies; exposure to the

combustion of leaded

fuels.

Absorbed through ingestion

or inhalation; organic lead

(e.g., tetraethyl lead) absorbed

dermally. In blood, 95–99%

sequestered in RBCs—thus,

must measure lead in whole

blood (not serum). Distributed

widely in soft tissue, with

half-life ~30 days; 15% of

dose sequestered in bone

with half-life of >20 years.

Excreted mostly in urine,

but also appears in other

fluids including breast milk.

Interferes with mitochondrial

oxidative phosphorylation,

ATPases, calcium-dependent

messengers; enhances

oxidation and cell apoptosis.

Acute exposure with blood lead

levels (BPb) of >60–80 μg/dL

can cause impaired

neurotransmission and neuronal

cell death (with central and

peripheral nervous system

effects); impaired hematopoiesis

and renal tubular dysfunction.

At higher levels of exposure

(e.g., BPb >80–120 μg/dL),

acute encephalopathy with

convulsions, coma, and death

may occur. Subclinical exposures

in children (BPb 25–60 μg/dL)

are associated with anemia;

mental retardation; and deficits

in language, motor function,

balance, hearing, behavior, and

school performance. Impairment

of IQ appears to occur at even

lower levels of exposure with no

measurable threshold above the

limit of detection in most assays

of 1 μg/dL.

In adults, chronic subclinical

exposures (BPb >40 μg/dL) are

associated with an increased

risk of anemia, demyelinating

peripheral neuropathy (mainly

motor), impairments of reaction

time and hearing, accelerated

declines in cognition,

hypertension, ECG conduction

delays, hypertension, higher risk

of cardiovascular disease and

death, interstitial nephritis and

chronic renal failure, diminished

sperm counts, and spontaneous

abortions.

Abdominal pain, irritability, lethargy,

anorexia, anemia, Fanconi’s

syndrome, pyuria, azotemia in

children with blood lead level

(BPb) >80 μg/dL; may also see

epiphyseal plate “lead lines” on

long bone x-rays. Convulsions,

coma at BPb >120 μg/dL. Noticeable

neurodevelopmental delays at BPb of

40–80 μg/dL; may also see symptoms

associated with higher BPb levels.

Screening of all U.S. children when

they begin to crawl (~6 months) is

recommended by the CDC; source

identification and intervention is

begun if the BPb >10 μg/dL. In adults,

acute exposure causes similar

symptoms as in children as well as

headaches, arthralgias, myalgias,

depression, impaired short-term

memory, loss of libido. Physical

examination may reveal a “lead line”

at the gingiva-tooth border, pallor,

wrist drop, and cognitive dysfunction

(e.g., declines on the mini-mental

state exam); lab tests may reveal a

normocytic, normochromic anemia,

basophilic stippling, an elevated

blood protoporphyrin level (free

erythrocyte or zinc), and motor delays

on nerve conduction. U.S. OSHA

requires regular testing of leadexposed workers with removal if BPb

>40 μg/dL. Newer guidelines have

been proposed recommending that

BPb be maintained at <10 μg/dL,

removal of workers if BPb >20 μg/dL,

and monitoring of cumulative

exposure parameters.

Identification and correction

of exposure sources is critical.

In some U.S. states, screening

and reporting to local health

boards of children with BPb

>10 μg/dL and workers with

BPb >40 μg/dL are required. In

the highly exposed individual

with symptoms, chelation

is recommended with oral

DMSA (succimer); if acutely

toxic, hospitalization and

IV or IM chelation with

ethylenediaminetetraacetic

acid calcium disodium

(CaEDTA) may be required, with

the addition of dimercaprol

to prevent worsening of

encephalopathy. It is uncertain

whether children with

asymptomatic lead exposure

(e.g., BPb 20–40 μg/dL) benefit

from chelation; a recent

randomized trial showed no

benefit. Correction of dietary

deficiencies in iron, calcium,

magnesium, and zinc will lower

lead absorption and may also

improve toxicity. Vitamin C is

a weak but natural chelating

agent. Calcium supplements

(1200 mg at bedtime) have been

shown to lower blood lead

levels in pregnant women.

(Continued)

3581Heavy Metal Poisoning CHAPTER 458

TABLE 458-1 Heavy Metals

MAIN SOURCES METABOLISM TOXICITY DIAGNOSIS TREATMENT

Mercury

Metallic, mercurous,

and mercuric mercury

(Hg, Hg+

, Hg2+) exposures

occur in some chemical,

metal-processing,

electrical equipment,

automotive industries;

they are also in

thermometers, dental

amalgams, batteries.

Mercury is dispersed

by waste incineration.

Environmental bacteria

convert inorganic to

organic mercury, which

then bioconcentrates up

the aquatic food chain

to contaminate tuna,

swordfish, and other

pelagic fish.

Elemental mercury (Hg) is not

well absorbed; however, it will

volatilize into highly absorbable

vapor. Inorganic mercury is

absorbed through the gut and

skin. Organic mercury is well

absorbed through inhalation

and ingestion. Elemental

and organic mercury cross

the blood-brain barrier and

placenta. Mercury is excreted

in urine and feces and has a

half-life in blood of ~60 days;

however, deposits will remain

in the kidney and brain for

years. Exposure to mercury

stimulates the kidney to

produce metallothionein, which

provides some detoxification

benefit. Mercury binds

sulfhydryl groups and interferes

with a wide variety of critical

enzymatic processes.

Acute inhalation of Hg vapor

causes pneumonitis and

noncardiogenic pulmonary

edema leading to death, CNS

symptoms, and polyneuropathy.

Chronic high exposure causes

CNS toxicity (mercurial erethism;

see Diagnosis); lower exposures

impair renal function, motor

speed, memory, coordination.

Acute ingestion of inorganic

mercury causes gastroenteritis,

the nephritic syndrome, or acute

renal failure, hypertension,

tachycardia, and cardiovascular

collapse, with death at a dose of

10–42 mg/kg.

Ingestion of organic mercury

causes gastroenteritis,

arrhythmias, and lesions in the

basal ganglia, gray matter, and

cerebellum at doses >1.7 mg/kg.

High exposure during pregnancy

causes derangement of fetal

neuronal migration resulting in

severe mental retardation.

Mild exposures during pregnancy

(from fish consumption) are

associated with declines in

neurobehavioral performance in

offspring.

Dimethylmercury, a compound

only found in research labs, is

“supertoxic”—a few drops of

exposure via skin absorption or

inhaled vapor can cause severe

cerebellar degeneration and

death.

Chronic exposure to metallic

mercury vapor produces a

characteristic intention tremor and

mercurial erethism: excitability,

memory loss, insomnia, timidity, and

delirium (“mad as a hatter”). On

neurobehavioral tests: decreased

motor speed, visual scanning, verbal

and visual memory, visuomotor

coordination.

Children exposed to mercury in

any form may develop acrodynia

(“pink disease”): flushing, itching,

swelling, tachycardia, hypertension,

excessive salivation or perspiration,

irritability, weakness, morbilliform

rashes, desquamation of palms and

soles.

Toxicity from elemental or inorganic

mercury exposure begins when

blood levels >180 nmol/L (3.6 μg/dL)

and urine levels >0.7 μmol/L

(15 μg/dL). Exposures that ended

years ago may result in a >20-μg

increase in 24-h urine after a 2-g

dose of succimer.

Organic mercury exposure is best

measured by levels in blood (if

recent) or hair (if chronic); CNS

toxicity in children may derive from

fetal exposures associated with

maternal hair Hg >30 nmol/g (6 μg/g).

Treat acute ingestion of

mercuric salts with induced

emesis or gastric lavage

and polythiol resins (to bind

mercury in the GI tract). Chelate

with dimercaprol (up to

24 mg/kg per day IM in divided

doses), DMSA (succimer),

or penicillamine, with 5-day

courses separated by several

days of rest. If renal failure

occurs, treat with peritoneal

dialysis, hemodialysis, or

extracorporeal regional

complexing hemodialysis and

succimer.

Chronic inorganic mercury

poisoning is best treated with

N-acetyl penicillamine.

Abbreviations: ATPase, adenosine triphosphatase; BPb, blood lead; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; DMSA,

dimercaptosuccinic acid; ECG, electrocardiogram; GI, gastrointestinal; ICU, intensive care unit; IQ, intelligence quotient; LFT, liver function tests; OSHA, Occupational Safety

and Health Administration; RBC, red blood cell.

(Continued)

based on studies of the offspring of mothers who ingested mercurycontaminated 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 omega3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega3-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

3582 PART 14 Poisoning, Drug Overdose, and Envenomation

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, doubleblind, placebo-controlled, prospective randomized trial funded by the

National Institutes of Health of 1708 patients aged ≥50 years who had

experienced a myocardial infarction (MI), found that a protocol of

repeated intravenous chelation with disodium EDTA, compared with

placebo, modestly but significantly reduced the risk of adverse 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.

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

459 Poisoning and Drug

Overdose

Mark B. Mycyk

3583Poisoning and Drug Overdose CHAPTER 459

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 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.

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

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 selfmedication; 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

3584 PART 14 Poisoning, Drug Overdose, and Envenomation

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).

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

TABLE 459-1 Differential Diagnosis of Poisoning Based on Physiologic State

STIMULATED DEPRESSED DISCORDANT NORMAL

Sympathetics

Sympathomimetics

Ergot alkaloids

Methylxanthines

Monoamine oxidase inhibitors

Thyroid hormones

Anticholinergics

Antihistamines

Antiparkinsonian agents

Antipsychotics

Antispasmodics

Belladonna alkaloids

Cyclic antidepressants

Mushrooms and plants

Hallucinogens

Cannabinoids (marijuana)

LSD and analogues

Mescaline and analogues

Mushrooms

Phencyclidine and analogues

Withdrawal syndromes

Barbiturates

Benzodiazepines

Ethanol

GHB products

Opioids

Sedative-hypnotics

Sympatholytics

Sympatholytics

α1

-Adrenergic antagonists

α2

-Adrenergic agonists

ACE inhibitors

Angiotensin receptor blockers

Antipsychotics

β-Adrenergic blockers

Calcium channel blockers

Cardiac glycosides

Cyclic antidepressants

Cholinergics

Acetylcholinesterase inhibitors

Muscarinic agonists

Nicotinic agonists

Opioids

Analgesics

GI antispasmodics

Heroin

Sedative-hypnotics

Alcohols

Anticonvulsants

Barbiturates

Benzodiazepines

GABA precursors

Muscle relaxants

Other agents

GHB products

Asphyxiants

Cytochrome oxidase inhibitors

Inert gases

Irritant gases

Methemoglobin inducers

Oxidative phosphorylation inhibitors

AGMA inducers

Alcohol (ketoacidosis)

Ethylene glycol

Iron

Methanol

Other alcohols

Salicylate

Toluene

CNS syndromes

Extrapyramidal reactions

Hydrocarbon inhalation

Isoniazid

Lithium

Neuroleptic malignant syndrome

Serotonin syndrome

Strychnine

Membrane-active agents

Amantadine

Antiarrhythmics

Antihistamines

Antipsychotics

Carbamazepine

Cyclic antidepressants

Local anesthetics

Opioids (some)

Quinoline antimalarials

Nontoxic exposure

Psychogenic illness

“Toxic time-bombs”

Slow absorption

Anticholinergics

Carbamazepine

Concretion formers

 Extended-release phenytoin sodium

capsules (Dilantin Kapseals)

Drug packets

Enteric-coated pills

Diphenoxylate-atropine (Lomotil)

Opioids

Salicylates

Sustained-release pills

Valproate

Slow distribution

Cardiac glycosides

Lithium

Metals

Salicylate

Valproate

Toxic metabolite

Acetaminophen

Carbon tetrachloride

Cyanogenic glycosides

Ethylene glycol

Methanol

Methemoglobin inducers

Mushroom toxins

Organophosphate insecticides

Paraquat

Metabolism disruptors

Antineoplastic agents

Antiviral agents

Colchicine

Hypoglycemic agents

Immunosuppressive agents

MAO inhibitors

Metals

Other oral anticoagulants

Salicylate

Warfarin

Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA, γ-aminobutyric acid; GHB,

γ-hydroxybutyrate; GI, gastrointestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase.

3585Poisoning and Drug Overdose CHAPTER 459

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), 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, membraneactive agents can cause simultaneous coma, seizures, hypotension,

and tachyarrhythmias. Alternatively, vital signs may be normal while

the patient has an altered mental status or is obviously sick or clearly

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 timebombs are increasingly common. Diagnosing a nontoxic exposure

requires that the identity of the exposure agent be known or that a toxic

time-bomb exposure be excluded and the time since exposure exceed

the longest known or predicted interval between exposure and peak

toxicity. Psychogenic illness (fear of being poisoned, mass hysteria)

may also follow a nontoxic exposure and should be considered when

symptoms are inconsistent with exposure history. Anxiety reactions

resulting from a nontoxic exposure can cause mild physiologic 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

TABLE 459-2 Severity of Physiologic Stimulation and Depression in

Poisoning and Drug Withdrawal

Physiologic Stimulation

Grade 1 Anxious, irritable, tremulous; vital signs normal; diaphoresis,

flushing or pallor, mydriasis, and hyperreflexia sometimes

present

Grade 2 Agitated; may have confusion or hallucinations but can converse

and follow commands; vital signs mildly to moderately increased

Grade 3 Delirious; unintelligible speech, uncontrollable motor

hyperactivity; moderately to markedly increased vital signs;

tachyarrhythmias possible

Grade 4 Coma, seizures, cardiovascular collapse

Physiologic Depression

Grade 1 Awake, lethargic, or sleeping but arousable by voice or tactile

stimulation; able to converse and follow commands; may be

confused

Grade 2 Responds to pain but not voice; can vocalize but not converse;

spontaneous motor activity present; brainstem reflexes intact

Grade 3 Unresponsive to pain; spontaneous motor activity absent;

brainstem reflexes depressed; motor tone, respirations, and

temperature decreased

Grade 4 Unresponsive to pain; flaccid paralysis; brainstem reflexes and

respirations absent; cardiovascular vital signs decreased

3586 PART 14 Poisoning, Drug Overdose, and Envenomation

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.

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.

TABLE 459-3 Fundamentals of Poisoning Management

Supportive Care

Airway protection Treatment of seizures

Oxygenation/ventilation Correction of temperature

abnormalities

Treatment of arrhythmias Correction of metabolic derangements

Hemodynamic support Prevention of secondary complications

Prevention of Further Poison Absorption

Gastrointestinal decontamination Decontamination of other sites

Gastric lavage Eye decontamination

Activated charcoal Skin decontamination

Whole-bowel irrigation Body cavity evacuation

Dilution

Endoscopic/surgical removal

Enhancement of Poison Elimination

Multiple-dose activated charcoal

administration

Alteration of urinary pH

Chelation

Hyperbaric oxygenation

Extracorporeal removal

Hemodialysis

Hemoperfusion

Hemofiltration

Plasmapheresis

Exchange transfusion

Administration of Antidotes

Neutralization by antibodies Metabolic antagonism

Neutralization by chemical binding Physiologic antagonism

Prevention of Reexposure

Adult education Notification of regulatory agencies

Child-proofing Psychiatric referral