quickly, accurately, and professionally in a reassuring manner.

Subsequent to telephone consultations, poison control center

staff should initiate follow-up calls to determine the effectiveness of the recommended treatment and the need for additional

evaluation or treatment.23,24

EFFECTIVE COMMUNICATION

Effective communication is essential to the assessment of potential poisonings. In most situations, the person seeking guidance

on the management of a potentially toxic exposure is the parent

of a small child who may have ingested a substance. The caller

is usually anxious about the child and may feel guilty about the

exposure. To calm the caller, the health care provider should

quickly reassure the parent that telephoning for help was appropriate and that the best assistance possible will be provided.24

If English is not the first language of the caller, or if there are

other communication barriers (e.g., panic), solutions must be

found to enhance outcomes. Most poison centers subscribe to

translation services or have bilingual staff to communicate with

non–English-speaking callers. Poison centers also have special

equipment to serve the hearing- and speech-impaired populations.

Once calm, effective communication is established, the health

care provider should first determine whether the patient is conscious and breathing and has a pulse. If life-threatening symptoms have occurred, the caller should call 9-1-1 for emergency

services. If the health care provider does not have the knowledge

or resources to provide poison information, he or she should

refer the caller to the closest poison control center. Information

on the location and phone number of the nearest poison control center can be found at http://www.aapcc.org or by calling

1-800-222-1222 in the United States.

GENERAL MANAGEMENT

Supportive Care and “ABCs”

Management of poisoned or overdosed patients is primarily based

on symptomatic and supportive care. Specific antidotes exist only

for a small percentage of the thousands of potential drugs and

chemicals that can cause a poisoning.

The first aspect of patient management should always be basic

support of airway, breathing, and circulation (the “ABCs”). The

assessment and treatment of the potentially poisoned patient

can be separated into seven primary functions: (a) gathering

history of exposure, (b) evaluating clinical presentation (i.e.,

“toxidromes”), (c) evaluating clinical laboratory patient data,

(d) removing the toxic source (e.g., irrigating eyes, decontaminating exposed skin), (e) considering antidotes and specific treatment, (f ) enhancing systemic clearance, and (g) monitoring

outcome.25–27

GATHERING HISTORY OF EXPOSURE

Comprehensive historical information about the toxic exposure

should be gathered from as many different sources as possible

(e.g., patient, family, friends, prehospital health care providers).

This information should be compared for consistency and evaluated relative to clinical findings and laboratory results. The

patient’s history of the exposure is often inaccurate and should be

confirmed with objective findings.25,26,28 For example, a patient

who presents to an ED with a supposed hydrocodone and carisoprodol overdose is expected to be lethargic or comatose. If the

patient arrives wide awake with tachycardia and agitation, the

caregiver should suspect exposure to other substances.

Specific information should be sought concerning the

patient’s state of consciousness, symptoms, probable intoxicant(s), and maximal amount and dosage form(s) of substance

ingested, as well as when the exposure occurred. Medications,

allergies, and prior medical problems also should be ascertained

to facilitate development of treatment plans (e.g., a history of

renal failure may indicate the need for hemodialysis to compensate for decreased renal drug clearance).25,26

EVALUATING CLINICAL PRESENTATION

AND TOXIDROMES

A thorough physical examination is needed to characterize the

signs and symptoms of overdose, and should be conducted serially to determine the evolution or resolution of the patient’s

intoxication. An evaluation of the presenting signs and symptoms can provide clues to the drug class causing the toxicity, confirm the historical data surrounding the toxic exposure, and suggest initial treatment.25,29–31 The patient may be asymptomatic

on presentation, even though a potentially severe exposure has

occurred, if absorption of the drug or toxic substance is incomplete or if the substance has not yet been metabolized to a toxic

substance.32–34

Characteristic toxidromes (i.e., a constellation of signs and

symptoms consistent with a syndrome) can be associated

with some specific classes of drugs.26,30,31 The most common

toxidromes are those associated with anticholinergic activity,

increased sympathetic activity, and central nervous system (CNS)

69Managing Drug Overdoses and Poisonings Chapter 4

stimulation or depression. Anticholinergic drugs can increase

heart rate and body temperature, decrease gastrointestinal (GI)

motility, dilate pupils, and produce drowsiness or delirium. Sympathomimetic drugs can increase CNS activity, heart rate, body

temperature, and blood pressure (BP). Opioids, sedatives, hypnotics, and antidepressants can depress the CNS, but the specific

class of CNS depressant often cannot be easily identified.

Classic findings may not be present for all drugs within a therapeutic class. For example, opioids generally induce miosis, but

meperidine can produce mydriasis. Furthermore, the association

of symptoms with a particular class of toxic substances is difficult

when more than one substance has been ingested. Practitioners

should not focus only on the specific clinical findings associated

with a toxidrome. Rather, they should consider all subjective

and objective data gathered from the history of exposure, the

patient’s medical history, physical examination, and laboratory

findings.30

INTERPRETATION OF LABORATORY DATA

DRUG SCREENS

A urine drug screen can be useful in identifying the presence

of drugs and their metabolites in selected patients but is not

indicated in all cases of drug overdose. Urine drug screens can

be useful in a patient with coma of unknown etiology, when the

presented history is inconsistent with clinical findings, or when

more than one drug might have been ingested.35,36

PHARMACOKINETIC CONSIDERATIONS

The absorption, distribution, metabolism, and elimination of

drugs in the overdosed patient can be quite different than

when the drug is taken in usual therapeutic doses.32–34 The

expected pharmacodynamic and pharmacokinetic features of

drugs can be substantially altered by large drug overdoses, especially with drugs that exhibit dose-dependent pharmacokinetics.

The rate of drug absorption is generally slowed by large overdoses, and the time to reach peak serum drug concentrations

can be delayed.35,37 For example, peak serum concentrations of

phenytoin can be delayed for 2 to 7 days after an orally ingested

overdose.38,39 The volume of distribution of an overdosed drug

can be increased, and when usual metabolic pathways become

saturated, secondary clearance pathways can be important. For

example, large overdoses of acetaminophen saturate glutathione

mechanisms of metabolism, resulting in hepatotoxicity.40

When the pharmacokinetic parameters of an overdosed drug

are altered, serial plasma concentration measurements can better define the absorption, distribution, and clearance phases of

the ingested substance. Pharmacokinetic parameters that have

been derived from therapeutic doses should not be used to predict whether absorption is complete or to predict the expected

duration of intoxication caused by large overdoses.34,41,42

DECONTAMINATION

After the airway and the cardiopulmonary system are supported,

efforts should be directed toward removing the toxic substance

from the patient (i.e., decontamination).25,43 Decontamination

presumes that both the dose and the duration of toxin exposure are important in determining the extent of toxicity and that

prevention of continued exposure will decrease toxicity.32–34,43

This intuitive concept is clearly relevant to ocular, dermal, and

respiratory exposures, when local tissue damage is the primary

problem. Respiratory decontamination involves removing the

patient from the toxic environment and providing fresh air or

oxygen to the patient. Decontamination of skin and eyes involves

flushing the affected area with large volumes of water or saline

to physically remove the toxic substance from the surface.25,26

GASTROINTESTINAL DECONTAMINATION

Because most poisonings and overdoses result from oral ingestions, measures to decrease or prevent continued GI absorption

have commonly been used to limit the extent of exposure.25,26,40

GI decontamination should be considered if the ingestion is large

enough to produce potentially significant toxicity, or if the potential severity of the ingestion is unknown and the time since ingestion is less than1 hour. The following methods have historically

been used: (a) evacuation of gastric contents by emesis or gastric

lavage, (b) administration of activated charcoal as an adsorbent

to bind the toxic substance remaining in the GI tract, (c) use of

cathartics or whole bowel irrigation (WBI) to increase the rectal

elimination of unabsorbed drug, or (d) a combination of any of

these methods.44–49

For a PowerPoint presentation about GI

decontamination, go to http://thepoint.

lww.com/AT10e.

The efficacy of GI decontamination varies, depending on

when the process is initiated relative to the time of ingestion,

dose ingested, and other factors. Furthermore, ipecac-induced

emesis, gastric lavage, cathartics, and activated charcoal are not

directly associated with improved patient outcomes.44–49

The most appropriate method for GI tract decontamination remains unclear because sound comparative data for different methods of GI decontamination are not available. Clinical research in healthy subjects, by necessity, must use nontoxic

doses of drugs. Studies using nontoxic doses are not applicable to

the overdose situation because alterations in GI absorption can

occur with large doses. In addition, low-dose studies generally

rely on pharmacokinetic end points such as peak plasma concentrations, area under the plasma concentration–time curve, or

quantity of drug recovered from the urine.44,45,47–49 In contrast,

clinical studies of GI decontamination methods in patients who

have ingested toxic doses of a substance use clinical outcomes

or a directional change in serum drug concentrations.44,45,48,49

These latter trials are not standardized with respect to the dose

ingested or to the time interval between drug ingestion and

GI decontamination.44–49

Ipecac-Induced Emesis and Gastric Lavage

Ipecac-induced emesis and gastric lavage primarily remove substances from the stomach. Their efficacy is affected significantly

by the time the ingested substance remains in the stomach. Gastric lavage and ipecac-induced emesis are most effective when

implemented before the substance moves past the stomach into

the intestine (usually within 1 hour).44,45

The commonly used adult gastric lavage tube (36F) has an

internal diameter too small to allow recovery of large tablet or

capsule fragments. An even smaller diameter lavage tube is used

for children.45 Gastric lavage may be useful only if large amounts

of a liquid substance were ingested and the patient arrived within

1 hour of the ingestion.45 However, patients usually arrive in

the ED more than an hour after ingestion, when absorption

of the toxin has most likely already occurred. As a result, the

efficacy of these procedures in overdose situations is minimal,

and no studies have confirmed that use of gastric lavage or ipecacinduced emesis improves the outcome of the patient.44,45,50 For

these reasons, ipecac is no longer used, and gastric lavage is used

only in rare, specific situations.

Activated Charcoal

In 1963, a review article concluded that activated charcoal was the

most valuable agent available for the treatment of poisoning.51

70 Section 1 General Care

This conclusion was based only on studies in fasting patients who

had nontoxic exposures. Nevertheless, data from those studies

were extrapolated to poisoned patients. Since then, activated

charcoal has become the preferred method of GI decontamination for the treatment of toxic ingestions.25,43,51–53

The goal of therapy is to decrease the absorption of the substance and reduce or prevent systemic toxicity.46 Unfortunately,

there are no satisfactorily designed clinical studies assessing benefit from the use of activated charcoal to guide the use of this

therapy. There is also no evidence that the administration of

activated charcoal improves clinical outcomes.46

The use of activated charcoal at a dose of 1 g/kg should be

considered when the patient has ingested a toxic substance that is

known to be absorbed by activated charcoal within 1 hour of the

ingestion. The potential for benefit is unknown if the activated

charcoal is given more than 1 hour after ingestion.46 It should

be noted that iron and lithium are not absorbed by activated

charcoal. Other forms of GI decontamination must be used to

remove those substances from the GI tract.46

Generally the use of activated charcoal is safe. Although there

are relatively few reports of adverse effects from the use of activated charcoal, there are numerous reports of complications,

usually involving aspiration. It is essential that the patient has an

intact or protected airway (intubation) before activated charcoal

is administered, especially in drowsy patients or patients who

may rapidly become obtunded.46

To see activated charcoal in a lung x-ray, go to

http://thepoint.lww.com/AT10e.

Vomiting with aspiration of activated charcoal occurs in about

5% of patients who receive activated charcoal.46,53–55 The resulting pulmonary problems can be caused by aspiration of acidic

stomach contents or the charcoal. Decreased oxygenation can

occur immediately, or pulmonary effects can occur later.55–59

Adult respiratory distress syndrome has resulted after the unintentional instillation of charcoal into the lung.55 Aspiration of

charcoal can result in chronic lung disease or fatalities, whereas

the toxic exposure, for which the charcoal was administered, is

often not lethal or even serious.56,60

Cathartics

Historically, sorbitol (a cathartic) was often administered with

activated charcoal to enhance passage of the charcoal-substance

complex through the GI tract. However, decreased transit time

through the bowel has not been proven to decrease absorption

as drug absorption does not take place in the large bowel.47 Sorbitol is also associated with vomiting and aspiration.47 Hypernatremia can also develop subsequent to the administration of

repeat doses of activated charcoal with sorbitol.61,62 Currently,

most EDs use aqueous activated charcoal mixtures rather than

charcoal–sorbitol combinations. Because cathartics are not effective in reducing drug absorption or increasing patient outcome,

their use is no longer advised.47

Whole Bowel Irrigation

Whole bowel irrigation with a polyethylene glycol–balanced

electrolyte solution (e.g., Colyte, GoLYTELY) can successfully

remove substances from the entire GI tract in a period of

several hours. WBI is effective with ingestions of sustainedrelease dosage forms, as well as substances that form bezoars

(concretions of tablets or capsules), such as ferrous sulfate or

phenytoin.26,48,63 WBI is also indicated when the toxic agent is

not adsorbed by activated charcoal (e.g., body-packer packets,

lithium, iron, potassium).25,26,48,63 This method of GI decontamination takes much longer to complete and is associated

with poor patient compliance because large volumes of fluid

(2 L/hour for adults until the effluent is clear) need to be ingested

to be effective.63 A nasogastric (NG) tube can be inserted, and

the WBI fluid can be administered via NG tube so that lack of

patient compliance is no longer a factor.48

ANTIDOTES AND SPECIFIC TREATMENTS

An antidote is a drug that neutralizes or reverses the toxicity

of another substance. Some antidotes can displace a drug from

receptor sites (e.g., naloxone for opioids, flumazenil for benzodiazepines), and some can inhibit the formation of toxic metabolites (e.g., N-acetylcysteine [NAC] for acetaminophen, fomepizole for methanol).26,64,65 Some treatments are highly effective

for the management of individual drug overdoses but do not

meet the definition of an antidote. For example, sodium bicarbonate is used to treat the cardiotoxicity arising from tricyclic

antidepressant (TCA) overdoses, and benzodiazepines are used

to treat CNS toxicity associated with cocaine and amphetamine

overdoses.26,66–68 However, it is important to note that for antidotes to be effective, they must be readily available at the health

care facility in adequate doses to treat the patient in a timely

manner.69

ENHANCING SYSTEMIC CLEARANCE

Hemodialysis and manipulation of urine pH can enhance

the clearance of substances. Hemodialysis can successfully

treat some specific intoxications (e.g., methanol, ethylene glycol, aspirin, theophylline, lithium). Hemodialysis can also be

used in patients with severe acid–base disturbances or renal

dysfunction.50 Alkalinization of the urine can enhance the elimination of drugs such as aspirin and phenobarbital.70–72

MONITORING OUTCOME

Selecting the appropriate parameters and length of time to

monitor a patient who has been exposed to a toxic agent

requires knowledge of toxic effects and the time course of the

intoxication.36,37 Most patients who are at risk for moderate or

severe toxicity should be monitored in an intensive care unit

(ICU) with careful assessments of cardiac, pulmonary, and CNS

function.73,74

ASSESSMENT OF SALICYLATE

INGESTION

Gathering a History

CASE 4-1

QUESTION 1: M.O., the mother of a 3-year-old child, states

that her daughter, D.O., has ingested some aspirin tablets.

What additional information should be obtained from or

given to M.O. at this time?

Obtaining an initial assessment of the patient’s status is essential. The caller’s telephone number should be obtained in the

event that the call is disconnected, initial recommendations need

to be modified, or subsequent follow-up is needed. The health

care provider should ask for patient-specific information with

questions that are nonthreatening and nonjudgmental. The caller

should be reassured that calling for help was the right thing

to do.

71Managing Drug Overdoses and Poisonings Chapter 4

Evaluating Clinical Presentation

CASE 4-1, QUESTION 2: On further questioning, M.O.

states that D.O. is crying and complaining of a stomachache.

Otherwise, the child appears to be acting normally. D.O.

was found sitting on the bathroom floor with an aspirin

bottle in her hand and some partially chewed tablets on

the floor next to her. M.O. states that the child had the

same look on her face that she has when she eats things

that she does not like. M.O. reports that she can see white

tablet material gummed on the child’s teeth. The mother

was gone no more than 5 minutes and had asked her 5- and

6-year-old sons to watch their sister. What additional information is needed to correctly assess the potential for

toxicity in D.O.?

To determine the potential toxicity for an unintentional ingestion, it is important to assess the presence of symptoms and to

identify the substance ingested. Inquiries should begin with openended questions to determine the facts that the caller is certain of

versus what may have been assumed. The answers usually point

to more specific information that is needed to accurately assess

the exposure.23

D.O.’s symptoms presently are not life-threatening. Her

behavior is consistent with being scared in response to the

mother’s anxiety. Once it has been established that the child does

not need immediate life-saving treatment, the caller is generally

more willing and able to answer additional questions.

M.O. already has provided information about the child’s

symptoms. More information is needed to determine the identity of the ingested substance, the time of ingestion, the brand of

aspirin (to ensure that the product is not an aspirin-combination

or even an aspirin-free formulation), the dosage form, the number of dosage units in a full container, and the number of remaining dosage units in the container. The parent should be careful to

look for tablets under beds, rugs, or other locations out of sight

(e.g., wastepaper baskets, toilets, pet food dishes, pockets). The

dosage forms in the container should be identical in appearance,

and the contents should be what are stated on the label. Information concerning the child’s weight and health status, as well

as whether the child is taking other medications, is also important. The child’s weight is useful in determining the maximum

milligram per kilogram dose of aspirin that was ingested.

When more than one child is present during an ingestion,

the caller should be questioned as to whether other children also

could have participated in the ingestion. In this situation, the

children could have shared equally in the missing medication,

all of the drug could have been fed to one child, or all of the

drug could have been ingested by the oldest or most aggressive

child. When it is unclear how much is missing among a group

of children, each child should be evaluated and managed as if

he or she may have ingested the total missing quantity.

Triage of Call

CASE 4-1, QUESTION 3: M.O. has now determined that a

total of five tablets each containing 325 mg per tablet of

aspirin are missing from the bottle. Because M.O. recalls

having taken two aspirin tablets from this bottle, it is not

likely that her daughter took more than three tablets. M.O.

states that D.O. weighs 36 pounds. What treatment is

needed for this child?

The maximal dose of aspirin ingested by this child is likely to

be much less than the minimal dose required to cause significant

symptoms based on her weight for her age (i.e., 36 pounds or

approximately 16 kg). A dose of 150 mg/kg of aspirin is the smallest dose at which treatment or assessment at a health care facility

is necessary.72,75 D.O. is likely to have ingested a maximum of

975 mg of aspirin (i.e., three 325-mg tablets), which is about

60 mg/kg (975 mg divided by 16 kg). If this child is healthy, takes

no medications, and is not allergic to aspirin, the child does not

require any treatment. With this history of ingestion, the only

adverse effect that might occur is some mild nausea. Providing

information to the mother that her child had not ingested a toxic

or dangerous amount will be reassuring.

For many years, aspirin was the most common cause of unintentional poisoning and poisoning deaths among children.75–77

However, safety closure packaging and reduction of the total

aspirin content in a full bottle of children’s aspirin to approximately 3 g has steadily reduced the frequency of pediatric aspirin

poisoning and deaths.76–78 Although acute aspirin poisoning

remains a problem, the largest percentage of life-threatening

intoxications now results from therapeutic overdose.72 Therapeutic overdoses occur when a dose is given too frequently,

when both parents unknowingly dose the child with the drug, or

when too large a dose is given. Therapeutic overdoses are especially problematic when excessive doses are given for a prolonged

period and the drug is able to accumulate.72

Outcome for M.O.

Follow-up telephone consultation on toxic ingestions is important to identify children who unexpectedly develop symptoms

that might need to be treated. A telephone call to M.O. 6 to

24 hours after her initial call would be appropriate to follow up

on the child. On a call back to M.O., the parent stated that she gave

D.O. lunch at the appropriate time. D.O. then watched cartoons,

took her usual nap, and remained asymptomatic.

Acute and Chronic Salicylism

SIGNS AND SYMPTOMS

CASE 4-2

QUESTION 1: V.K., a 65-year-old, 55-kg woman with a history of chronic headaches, has taken 10 to 12 aspirin tablets

daily for several months. On the evening of admission, she

became lethargic, disoriented, and combative. Additional

history revealed that she ingested up to 100 aspirin tablets

on the morning of admission (about 10 hours earlier) in

a suicide attempt. She complained of ringing in her ears,

nausea, and three episodes of vomiting. Vital signs were

BP 140/90 mm Hg, pulse 110 beats/minute, respirations

36 breaths/minute, and temperature 102.5◦F. V.K.’s laboratory data obtained on admission were as follows:

Serum sodium (Na), 148 mEq/L

Potassium (K), 2.8 mEq/L

Chloride (Cl), 105 mEq/L

Bicarbonate, 10 mEq/L

Glucose, 60 mg/dL

Blood urea nitrogen (BUN), 35 mg/dL

Creatinine, 2.2 mg/dL

Arterial blood gas (ABG) values (room air) were as follows: pH, 7.25; PCO2, 20 mm Hg; and PO2, 95 mm Hg.

A serum salicylate concentration measured approximately

12 hours after the acute ingestion was 88 mg/dL. Her

hemoglobin was 9.6 g/dL with a hematocrit of 28.9% and a

prothrombin time (PT) of 16.4 seconds. Is V.K. at high risk

because of her ingestion?

72 Section 1 General Care

The symptoms and severity of salicylate intoxication depend

on the dose consumed; the patient’s age; and whether the ingestion was acute, chronic, or a combination of the two.77,79,80 This

case illustrates an acute ingestion in someone who has also chronically ingested aspirin. Acute ingestion of 150 to 300 mg/kg of

aspirin is likely to produce mild to moderate intoxication, greater

than 300 mg/kg indicates severe poisoning, and greater than

500 mg/kg is potentially lethal.72,75 V.K., who ingested approximately 600 mg/kg, has taken a potentially lethal dose. Chronic salicylate intoxication is usually associated with ingestion of greater

than 100 mg/kg/day for more than 2 days.72,75 V.K. has been taking

70 mg/kg/day for her headaches in addition to her acute ingestion. V.K. demonstrates many of the findings typical of severe

acute salicylism (see Pathophysiology of Salicylate Intoxication

and Assessment of Toxicity sections). V.K.’s prognosis is potentially poor because she is elderly and has taken a potentially lethal

overdose of aspirin.

Pathophysiology of Salicylate

Intoxication

CASE 4-2, QUESTION 2: Describe the pathophysiology and

clinical features of acute and chronic salicylism.

Toxicity from salicylate exposure results in direct irritation of the GI tract, direct stimulation of the CNS respiratory center, stimulation of the metabolic rate, lipid and

carbohydrate metabolism disturbances, and interference with

hemostasis.72,75,77,79,80 Toxic doses of salicylate directly stimulate the medullary respiratory center leading to nausea, vomiting, tinnitus, delirium, tachypnea, seizures, and coma, and

influence several key metabolic pathways.72,77–81 Direct stimulation of the respiratory drive increases the rate and depth

of ventilation, which can result in primary respiratory alkalosis. The respiratory alkalosis causes increased renal excretion

of bicarbonate, resulting in decreased buffering capacity. The

 TOXICOLOGY LABORATORY SCREENING

1 Urine drug screens can be useful in a patient with coma of unknown etiology, when

the presented history is inconsistent with clinical findings, or when more than one

drug might have been ingested. Qualitative screening is intended to identify

unknown substances involved in the toxic exposure. A benzodiazepine screen can

detect oxazepam, a common benzodiazepine metabolite, but will not detect

alprazolam and lorazepam as they are not metabolized to oxazepam. Opioid

screens may not detect synthetic opioids such as fentanyl and methadone.

Quantitative testing determines how much of a known drug is present and can help

determine the severity of toxicity and the need for aggressive interventions (e.g.,

hemodialysis).

Case 4-4 (Questions 1, 7)

TOXIDROMES

1 A toxidrome is a consistent constellation of signs and symptoms associated with

some specific classes of drugs. The most common toxidromes are those associated

with anticholinergic activity, increased sympathetic activity, and central nervous

system (CNS) stimulation or depression. Anticholinergic drugs increase heart rate

and body temperature, decrease GI motility, dilate pupils, and produce drowsiness

or delirium. Sympathomimetic drugs increase CNS activity, heart rate, body

temperature, and blood pressure. Opioids, sedatives, hypnotics, and antidepressants depress the CNS, but the specific class of CNS depressant often cannot be

easily identified.

Case 4-4 (Questions 1, 2, 5)

SALICYLATES

1 Acute ingestion of 150 to 300 mg/kg aspirin causes mild to moderate intoxication,

greater than 300 mg/kg indicates severe poisoning, and greater than 500 mg/kg is

potentially lethal. Symptoms of intoxication include vomiting, tinnitus, delirium,

tachypnea, metabolic acidosis, respiratory alkalosis, hypokalemia, irritability,

hallucinations, stupor, coma, hyperthermia, coagulopathy, and seizures. Salicylate

intoxication mimics other medical conditions and can be easily missed. Patients

with a chronic salicylate exposure, acidosis, or CNS symptoms and those who are

elderly are high-risk and should be considered for early dialysis.

Case 4-1 (Question 3),

Case 4-2 (Questions 1–6)

IRON

1 Acute elemental iron ingestions of less than 20 mg/kg are usually nontoxic; doses

of 20 to 60 mg/kg result in mild to moderate toxicity, and doses of greater than

60 mg/kg are potentially fatal. Symptoms of toxicity include nausea, vomiting,

diarrhea, abdominal pain, hematemesis, bloody stools, CNS depression,

hypotension, and shock. Patients with severe iron poisoning do not exhibit the

second stage of so-called recovery but continue to deteriorate.

Case 4-3 (Questions 2–14)

TRICYCLIC ANTIDEPRESSANTS

1 Severe toxicity has been associated with doses of 15 to 25 mg/kg. Symptoms

include tachycardia with prolongation of the PR, QTc, and QRS intervals, ST and

T-wave changes, acidosis, seizures, coma, hypotension, and adult respiratory

distress syndrome. A QRS segment greater than 100 milliseconds is commonly

seen in severe tricyclic antidepressant overdoses.

Case 4-4 (Questions 9–17)

ACETAMINOPHEN

1 Toxicity is associated with acute ingestions greater than 150 mg/kg or more than

7.5 g total in adults. Symptoms in patients with toxicity include vomiting, anorexia,

abdominal pain, malaise, and progression to characteristic centrilobular hepatic

necrosis. Acetaminophen-induced hepatotoxicity is universal by 36 hours after

ingestion, but patients who receive NAC within 8 to 10 hours after ingestion rarely

exhibit hepatotoxicity. There is no consensus as to the best route of NAC

administration, the optimal dosage regimen, or the optimal duration of therapy.

Case 4-5 (Questions 1–15)

67Managing Drug Overdoses and Poisonings Chapter 4

This chapter reviews common strategies for the evaluation and

management of drug overdoses and poisonings. Information for

the management of specific drug overdoses is best obtained from

a poison control center (reached by calling 1-800-222-1222 anywhere in the United States).

Epidemiologic Data

AMERICAN ASSOCIATION OF POISON CONTROL

CENTERS AND DRUG ABUSE WARNING NETWORK

Toxicity secondary to drug and chemical exposure commonly

occurs in children. The incidence of exposure to specific agents

and the severity of outcomes varies based on the population

studied (Table 4-1).1–3 The number of reported toxic exposures

in the United States in 2009 was approximately 2.48 million,

according to the American Association of Poison Control Centers

(AAPCC).3 In most cases, little or no toxicity was associated with

the exposure. Although 24.1% of patients received treatment at

a health care facility, only 6.1% reported moderate or severe

symptoms and 0.06% resulted in fatalities.

According to the Drug Abuse Warning Network (DAWN),

almost 2 million US emergency department (ED) visits involved

drug misuse or abuse in the year 2008. Of those cases, illicit drug

use was mentioned more than 2.7 million times because many

of the visits involved multiple drugs of abuse.4 These disparate

statistics from two national sources underscore the difficulty in

determining the true incidence of poisoning and overdoses.5

AGE-SPECIFIC DATA

Stratifying patients by age can be useful in assessing the likelihood of severe toxicity from an exposure. Most unintentional

ingestions by children 1 to 6 years of age occur because children

are curious, becoming more mobile, and beginning to explore

their surroundings, and they often put objects or substances into

their mouths.6 Of all reported poisonings, 38.9% occur in children younger than 3 years and 51.9% occur in children younger

than 6 years of age.3 According to AAPCC statistics, 11.26% of

pediatric (younger than 6 years of age) poisoning cases were

treated in a health care facility, and the remaining cases were

TABLE 4-1

Substances Most Commonly Involved in Poisoningsa

Children Adults Fatal Exposures (All Ages)

Personal care products Analgesics Sedatives/hypnotics/antipsychotics

Analgesics Sedatives/hypnotics/antipsychotics Cardiovascular agents

Cleaning substances Antidepressants Opioids

Topical products Cleaning substances Acetaminophen-containing products

Vitamins Cardiovascular agents Antidepressants

Antihistamines Alcohols Acetaminophen

Cough and cold products Bites, envenomations Alcohols

Pesticides Pesticides Stimulants and street drugs

Plants Antiepileptic agents Muscle relaxants

GI products Personal care products Cyclic antidepressants

Antimicrobials Antihistamines Antiepileptic agents

Arts and office supplies Hormones and hormone antagonists Fumes/gases/vapors

Alcohols Antimicrobials Aspirin

Hormones and hormone

antagonists

Chemicals Nonsteroidal anti-inflammatory drugs

Cardiovascular agents Fumes/gases/vapors Antihistamines

Hydrocarbons

a

Poisoning exposures are listed in order of frequency encountered.

GI, gastrointestinal.

Source: Bronstein AC et al. 2009 Annual report of the American Association of Poison Control Centers’ National Poison Data

System (NPDS): 27th Annual Report. Clin Toxicol (Phila). 2010;48:979.

managed at home.3 Severe toxicity in young children is relatively

uncommon as exposures usually involve the ingestion of relatively small amounts of a single substance.6,7 Of pediatric cases

reported to AAPCC, there were 769 (0.06%) life-threatening outcomes and 31 (0.00%) fatalities from a total of 1,290,784 pediatric

cases.3

AAPCC epidemiologic data also report medication errors,

which in the pediatric population commonly result from confusing units of measurement (e.g., teaspoons vs. milliliters or tablespoons vs. teaspoons), incorrect formulation or concentration

administered, dispensing cup errors, and incorrect formulation

or concentration dispensed from the pharmacy.3

In children older than 6 years of age, the reasons for toxic

exposure to medications are less clear.8 Adolescent children generally have poor knowledge of the toxicity of medications and

can overdose themselves unintentionally.6,9 The potential for

suicide attempts or intentional substance abuse should not be

ignored in older children. These intentional overdoses commonly

involve mixed exposures to illicit drugs, prescribed medications,

or ethanol, and are associated with more severe toxicity and death

than unintentional toxic exposures.

For many teens, using prescription drugs is not considered

dangerous as the drugs are not illegal like heroin or cocaine. In

a 2007 survey, 9.5% of adolescents 12 to 17 years of age said they

had used an illicit substance in the past month.10 The lifetime

use of opiates or opioids, other than heroin, in 12th graders has

doubled from 6.6% in 1991 to 13.2% in 2008.10

In geriatric patients, overdoses tend to have a greater potential

for severe adverse effects compared with overdoses in other age

groups.11 Although the elderly constitute 13% of the population,

they account for 33% of the drug use and 16% of the suicides.12

Patients age 65 or older take an average of 5.7 prescription medications along with 2 to 4 nonprescription drugs daily.11,12 In

2007, the suicide rate for people 65 years and older was 14.3 per

100,000 population compared with the national average of

11.3 per 100,000.13 The elderly are more likely to have underlying illnesses and often have access to a variety of potentially

dangerous medications. This results in higher rates of completed

suicides than in other age groups.11,12

68 Section 1 General Care

Information Resources

COMPUTERIZED DATABASES

A vast number of substances can be involved in a poisoning or

overdose. Reliable data about the contents of products, toxicities of substances, and treatment approaches need to be readily accessible. POISINDEX, a computerized database,14 provides

information on thousands of drugs by brand name, generic name,

and street name, as well as foreign drugs, chemicals, pesticides,

household products, personal care items, cleaning products, poisonous insects, poisonous snakes, and poisonous plants. Annual

subscriptions to POISINDEX, updated quarterly, are expensive

and are generally available only in large medical centers.15

PRINTED PUBLICATIONS

Textbooks and manuals also provide useful clinical information

about the presentation, assessment, and treatment of toxicities.

Goldfrank’s Toxicologic Emergencies16 and the pocket-size Poisoning & Drug Overdose17 are valuable, less-expensive alternatives to

computerized database programs. Books, however, are less useful than computerized databases because information must be

condensed and cannot be updated as frequently. Some drug package inserts also refer to treatment of acute toxicities; however,

the information can be inadequate or inappropriate.18,19

POISON CONTROL CENTERS

Poison control centers provide the most cost-effective and accurate information to health care providers and to the general

public.20,21 Poison centers are staffed by trained poison information specialists who have a pharmacy, nursing, or medical

background. Physician backup is provided 24 hours a day by

board-certified medical toxicologists. The nonphysician clinical

toxicologists, pharmacists, and nurses who staff poison control

centers are certified as specialists in poison information by the

AAPCC or as clinical toxicologists by the American Board of

Applied Toxicology.22

The poison information specialist must accurately and efficiently assess event-specific toxicity by telephone, without the

benefit of direct observation of the patient. The specialist must

communicate this assessment along with treatment information

 practice.

To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax

orders to (301) 223-2320. International customers should call (301) 223-2300.

Visit Lippincott Williams & Wilkins on the Internet: at LWW.com. Lippincott Williams & Wilkins

customer service representatives are available from 8:30 am to 6 pm, EST.

987654321

ii

Dedication

The Editors wish to express their sincere thanks and longstanding

admiration to the creators of Applied Therapeutics, Drs. Mary Anne

Koda-Kimble and Lloyd Young. They are truly educational visionaries

whom we deeply respect as the innovators and pioneers in the teaching of patient-centered drug therapeutics. Their passion has touched

the lives of countless health care professional students, clinicians, and

patients throughout the world. As their colleagues and friends, we are

forever indebted for their contributions and we consider it a privilege to

carry forward their legacy—renamed as Koda-Kimble and Young’s

Applied Therapeutics—into future editions.

iii

Preface

It has been nearly 40 years since the first edition of Applied Therapeutics: The Clinical Use of Drugs was published. The landscape

of health care has evolved radically during this time, much of it

spurred by remarkable advancements in drug discovery and clinical therapeutics. Despite these changes, the founding principle

for this innovative text—a patient-centric, case-based approach

to learning—remains integral to the current edition. Our authors

present more than 860 patient cases that stimulate the reader to

integrate and apply therapeutic principles in the context of specific clinical situations. Students and practitioners are provided

with a glimpse into the minds of clinicians as they assess and

solve therapeutic problems toward the development of their own

critical-thinking and problem-solving skills. Every chapter in this

edition has been revised and updated to reflect our ever-changing

knowledge of drugs and the application of this knowledge to the

individualized therapy of patients. Additionally, content within

several sections has been extensively reorganized, with new chapters introduced to expand important topics. Among these are

new chapters in the Arthritic Disorders, Women’s Health, Neurologic Disorders, Neoplastic Disorders, and Pediatrics sections.

Readers familiar with past editions of the text will notice some

welcome changes in the tenth edition. The overall design has

been updated for visual appeal and to allow the reader to more

quickly distinguish cases from surrounding text. In lieu of the traditional chapter outline, all chapters now contain a Core Principles section at the beginning, which provides the most important

“take home” information from the chapter. Each Core Principle

is mapped to specific cases within the chapter where the principle is discussed in detail. Key references and websites are listed at

the end of each chapter, whereas the full reference lists for each

chapter have been moved online.

A particularly significant change to the tenth edition is the

incorporation of online multimedia content, much of it authorcreated, for many of the chapters. These include images, videos,

narrated presentations, animations, and podcasts, which can be

found on the textbook’s website (see the “Additional Resources”

section, which follows this preface, for more information). The

incorporation of supplemental multimedia into the tenth edition marks a commitment on the part of the editorial team to

ensure that Koda-Kimble and Young’s Applied Therapeutics increases

its role as a viable and dynamic resource that can appeal to multiple learning styles and future generations. We welcome your

feedback as we undertake planning for the next edition.

The authors have drawn on information from the literature,

current standards, and their own clinical experiences to share the

process involved in making sound and thoughtful therapeutic

decisions. However, it remains the responsibility of every practitioner

to evaluate the appropriateness of a particular opinion in the context of

the actual clinical situation, bearing in mind any recent developments

in the field. We strongly urge students and practitioners to consult

several appropriate information sources when working with new and

unfamiliar drugs.

ACKNOWLEDGMENTS

We are deeply indebted to the many dedicated people who have

given of themselves to complete the tenth edition of Koda-Kimble

and Young’s Applied Therapeutics. As always, we are most grateful

to our contributing authors who have been attentive to meeting our stringent time deadlines and unique writing format. We

especially thank those authors who graciously provided multimedia to accompany their chapter, and we gratefully recognize

the additional time and effort this entailed. We hold their creativity in the highest regard. The exceptional work of our section

editors, Judith Beizer, Marcia Buck, Shareen El-Ibiary, Marcus

Ferrone, Patrick Finley, Timothy Ives, Mark Kirstein, Lisa Kroon,

Kelly Lee, Myrna Munar, Jean Nappi, Tricia Russell, and Joseph

Saseen, cannot be overstated. These content experts gave us critical feedback necessary in both the organizational structure of the

textbook and in the individual editing of chapters; without their

dedication and assistance, this edition would not be possible. We

would also like to thank Facts and Comparisons for allowing us

to use their data for the construction of some of our tables.

Two individuals from Lippincott Williams and Wilkins,

Meredith Brittain and Loftin (Paul) Montgomery, Jr., deserve

special recognition for their efforts. Their exceptional patience,

attention to detail, and firm guidance helped us all stay on task.

This edition would not have come to completion without their

partnership. Mary Tod (copyediting), Ed Schultes, Jr. (multimedia

production), and Jeri Litteral (typesetting) all played key roles in

the production of the tenth edition, and we sincerely thank them

for their assistance in completing this edition. Most importantly,

we would be remiss not to acknowledge the love, understanding,

and support of our spouses, children, and in some cases, grandchildren. They selflessly gave to us the many early mornings, late

nights, and weekends we spent writing and editing.

As in past editions, we continue to dedicate our work to our

students who inspire us and to the many patients we have been

privileged to care for. Our patients have repeatedly taught us how

critical it is to tailor our knowledge to their specific circumstances,

to listen well, and to welcome them as true partners in their care.

Brian K. Alldredge

Robin L. Corelli

Michael E. Ernst

B. Joseph Guglielmo

Pamala A. Jacobson

Wayne A. Kradjan

Bradley R. Williams

iv

Additional Resources

The Tenth Edition of Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs includes additional resources for

both instructors and students, available on the book’s companion website at http://thepoint.lww.com/AT10e.

STUDENT RESOURCES

Students who have purchased Koda-Kimble and Young’s Applied

Therapeutics: The Clinical Use of Drugs, Tenth Edition have access

to the following additional resources for each chapter:

 An audio recording of that chapter’s core principles

 A full online reference list for that chapter

In addition, at least one of the following supplements each chapter to enhance the chapter content:

 Audio files (most recorded by author)

 PowerPoints (most created by author)

 PowerPoints with audio (most created/recorded by author)

 Animations

 Videos (some created by author)

 Additional content (created by author)

 Interactive versions of the algorithms found in the book

 Full-color images

INSTRUCTOR RESOURCES

Approved adopting instructors will be given access to the following additional resources:

 PowerPoint slides

 Image bank (includes all images and tables in the book)

 Pathophysiology image collection

In addition, purchasers of the text can access the searchable Full

Text On-line by going to the Koda-Kimble and Young’s Applied

Therapeutics: The Clinical Use of Drugs, Tenth Edition website at

http://thepoint.lww.com/AT10e. See the inside front cover for

more details, including the passcode you will need to gain access

to the website.

v

EPIDEMIOLOGY

1 In 2009, 2.48 million poisonings were reported to the American Association of

Poison Control Centers. Half of these exposures occur in children younger than

6 years of age and usually involve a single substance that is found in the home such

as personal care items, analgesics, and cleaning agents. The elderly have access to

numerous and dangerous medications and have a higher rate of completed suicide

attempts than other age groups.

Case 4-1 (Questions 2, 3)

GENERAL MANAGEMENT

1 The most important aspect of patient management is to support airway, breathing,

and circulation (the “ABCs”). There is no “cookbook” method to treat all poisoned

patients, so it is important to treat the patient, not the poison or the laboratory

values. The assessment and treatment of the potentially poisoned patient can be

separated into seven functions: (a) gather history of exposure, (b) evaluate clinical

presentation (i.e., “toxidromes”), (c) evaluate clinical laboratory patient data,

(d) remove the toxic source (e.g., irrigate eyes, decontaminate exposed skin),

(e) consider antidotes and specific treatment, (f) enhance systemic clearance, and

(g) monitor patient outcome.

Case 4-4 (Questions 1, 5, 6)

GASTROINTESTINAL DECONTAMINATION

1 The most appropriate method for gastrointestinal (GI) tract decontamination is

unclear because sound comparative data for different methods of GI

decontamination are not available. Lavage, emesis, and cathartics are rarely

performed as there is no evidence they improve patient outcome. Activated

charcoal is generally safe to use, but it should not be administered if the benefit is

not greater than the risk. Whole bowel irrigation using a polyethylene glycol–

balanced electrolyte solution can successfully remove substances (iron, lithium,

sustained-release dosage forms) from the entire GI tract in a period of several

hours.

Case 4-3 (Questions 6, 7),

Case 4-4 (Questions 11, 12,

16), Case 4-5 (Question 3)

ANTIDOTES

1 An antidote is a drug that neutralizes or reverses the toxicity of another substance.

Some antidotes displace drugs from receptor sites (e.g., naloxone for opioids,

flumazenil for benzodiazepines), and some can inhibit the formation of toxic

metabolites (e.g., N-acetylcysteine [NAC] for acetaminophen, fomepizole for

methanol).

Case 4-4 (Questions 2, 4)

continued

65

66 Section 1 General Care

CHAPTER CASES

 Applied

Therapeutics

The Clinical Use of Drugs

TENTH EDITION

Edited By

Brian K. Alldredge, PHARMD

Professor of Clinical Pharmacy and Associate

Dean, Academic Affairs

Department of Clinical Pharmacy

School of Pharmacy

University of California, San Francisco

San Francisco, California

Robin L. Corelli, PHARMD

Professor of Clinical Pharmacy

Department of Clinical Pharmacy

School of Pharmacy

University of California, San Francisco

San Francisco, California

Michael E. Ernst, PHARMD, BCPS, FCCP

Professor (Clinical)

Department of Pharmacy Practice and Science

College of Pharmacy

Department of Family Medicine

Carver College of Medicine

The University of Iowa

Iowa City, Iowa

B. Joseph Guglielmo, PHARMD

Professor and Chair

TA Oliver Chair in Clinical Pharmacy

Department of Clinical Pharmacy

School of Pharmacy

University of California, San Francisco

San Francisco, California

Pamala A. Jacobson, PHARMD

Associate Professor

Department of Experimental and Clinical Pharmacology

College of Pharmacy

University of Minnesota

Minneapolis, Minnesota

Wayne A. Kradjan, PHARMD, BCPS

Dean Emeritus and Professor Emeritus

College of Pharmacy

Oregon State University

Oregon Health & Science University

Corvallis, Oregon

Bradley R. Williams, PHARMD, FASCP, CGP

Professor of Clinical Pharmacy and Clinical Gerontology

Titus Family Department of Clinical Pharmacy and

Pharmaceutical Economics and Policy

Schools of Pharmacy and Gerontology

University of Southern California

Los Angeles, California

Acquisitions Editor: David B. Troy

Project Manager: Meredith L. Brittain

Marketing Manager: Joy Fisher-Williams

Designer: Doug Smock

Compositor: Aptara, Inc.

c 2013, 2009, 2005 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business

Two Commerce Square

2001 Market Street

Philadelphia, PA 19103 USA

LWW.com

Tenth Edition

All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any

form by any means, including photocopying, or utilized by any information storage and retrieval system

without written permission from the copyright owner, except for brief quotations embodied in critical

articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties

as U.S. government employees are not covered by the above-mentioned copyright.

Printed in China

Library of Congress Cataloging-in-Publication Data

Koda-Kimble and Young’s applied therapeutics : the clinical use of drugs.

– 10th ed. /edited by Brian K. Alldredge . . . [et al.].

p. ; cm.

Applied therapeutics

Rev. ed. of: Applied therapeutics : the clinical use of drugs /edited

by Mary Anne Koda-Kimble ... [et al.]. 9th ed. c2009.

Includes bibliographical references and index.

ISBN 978-1-60913-713-7

I. Koda-Kimble, Mary Anne. II. Alldredge, Brian K. III. Applied therapeutics.

IV. Title: Applied therapeutics.

[DNLM: 1. Drug Therapy–methods. WB 330]

615.5

8–dc23

2011047631

Care has been taken to confirm the accuracy of the information presented and to describe generally

accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions

or for any consequences from application of the information in this book and make no warranty, expressed

or implied, with respect to the currency, completeness, or accuracy of the contents of the publication.

Application of the information in a particular situation remains the professional responsibility of the

practitioner.

The authors, editors, and publisher have exerted every effort to ensure that drug selection and

dosage set forth in this text are in accordance with current recommendations and practice at the time of

publication. However, in view of ongoing research, changes in government regulations, and the constant

flow of information relating to drug therapy and drug reactions, the reader is urged to check the package

insert for each drug for any change in indications and dosage and for added warnings and precautions.

This is particularly important when the recommended agent is a new or infrequently employed drug.

Some drugs and medical devices presented in the publication have Food and Drug Administration

(FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care

provider to ascertain the FDA status of each drug or device planned for use in their clinical 

Applied Therapeutics 10th ed, Koda-Kimble.pdf