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

3587Poisoning and Drug Overdose CHAPTER 459

Measures that enhance poison elimination may shorten the

duration and severity of the toxic phase. However, they are not

without risk, which must be weighed against the potential benefit.

Diagnostic certainty (usually via laboratory confirmation) is generally a prerequisite. Intestinal (gut) dialysis with repetitive doses of

activated charcoal (see “Multiple-Dose Activated Charcoal,” later)

can enhance the elimination of selected poisons such as theophylline or carbamazepine. Urinary alkalinization may enhance the

elimination of salicylates and a few other poisons. Chelation therapy can enhance the elimination of selected metals. Extracorporeal

elimination methods are effective for many poisons, but their

expense and risk make their use reasonable only in patients who

would otherwise have an unfavorable outcome.

During the resolution phase of poisoning, supportive care and

monitoring should continue until clinical, laboratory, and ECG

abnormalities have resolved. Since chemicals are eliminated sooner

from the blood than from tissues, blood levels are usually lower

than tissue levels during this phase and again may not correlate with

toxicity. This discrepancy applies particularly when extracorporeal

elimination procedures are used. Redistribution from tissues may

cause a rebound increase in the blood level after termination of

these procedures (e.g., lithium). When a metabolite is responsible

for toxic effects, continued treatment may be necessary in the

absence of clinical toxicity or abnormal laboratory studies.

SUPPORTIVE CARE

The goal of supportive therapy is to maintain physiologic homeostasis until detoxification is accomplished and to prevent and treat

secondary complications such as aspiration, bedsores, cerebral and

pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sepsis, thromboembolic disease, coagulopathy, and generalized organ

dysfunction due to hypoxemia or shock.

Admission to an intensive care unit is indicated for the following: patients with severe poisoning (coma, respiratory depression,

hypotension, cardiac conduction abnormalities, cardiac arrhythmias, hypothermia or hyperthermia, seizures); those needing close

monitoring, antidotes, or enhanced elimination therapy; those

showing progressive clinical deterioration; and those with significant underlying medical problems. Patients with mild to moderate

toxicity can be managed on a general medical service, on an intermediate care unit, or in an emergency department observation area,

depending on the anticipated duration and level of monitoring

needed (intermittent clinical observation vs continuous clinical,

cardiac, and respiratory monitoring). Patients who have attempted

suicide require continuous observation and measures to prevent

self-injury until they are no longer suicidal.

Respiratory Care Endotracheal intubation for protection against

the aspiration of gastrointestinal contents is of paramount importance in patients with CNS depression or seizures as this complication can increase morbidity and mortality rates. Mechanical

ventilation may be necessary for patients with respiratory depression or hypoxemia and for facilitation of therapeutic sedation or

paralysis of patients in order to prevent or treat hyperthermia, acidosis, and rhabdomyolysis associated with neuromuscular hyperactivity. Since clinical assessment of respiratory function can be

inaccurate, the need for oxygenation and ventilation is best determined by continuous pulse oximetry or arterial blood-gas analysis.

The gag reflex is not a reliable indicator of the need for intubation.

A patient with CNS depression may maintain airway patency while

being stimulated but not if left alone. Drug-induced pulmonary

edema is usually noncardiac rather than cardiac in origin, although

profound CNS depression and cardiac conduction abnormalities

suggest the latter. Measurement of pulmonary artery pressure may

be necessary to establish the cause and direct appropriate therapy.

Extracorporeal measures (membrane oxygenation, extracorporeal

membrane oxygenation [ECMO], venoarterial perfusion, cardiopulmonary bypass) and partial liquid (perfluorocarbon) ventilation

may be appropriate for severe but reversible respiratory failure. In

the last decade, ECMO has been increasingly used for critically ill

poisoned patients where standard resuscitative therapy or antidotes

have not been helpful, but further research is still needed to determine the right toxicologic indications for this treatment strategy.

Cardiovascular Therapy Maintenance of normal tissue perfusion

is critical for complete recovery to occur once the offending agent

has been eliminated. Focused bedside echocardiography or measurement of central venous pressure may help prioritize therapeutic

strategies. If hypotension is unresponsive to volume expansion and

appropriate goal-directed antidotal therapy, treatment with norepinephrine, epinephrine, or high-dose dopamine may be necessary.

Intraaortic balloon pump counterpulsation and venoarterial or

cardiopulmonary perfusion techniques should be considered for

severe but reversible cardiac failure. For patients with a return of

spontaneous circulation after resuscitative treatment for cardiopulmonary arrest secondary to poisoning, therapeutic hypothermia

should be used according to protocol. Bradyarrhythmias associated with hypotension generally should be treated as described in

Chaps. 244 and 245. Glucagon, calcium, and high-dose insulin

with dextrose may be effective in beta blocker and calcium channel

blocker poisoning. Antibody therapy may be indicated for cardiac

glycoside poisoning.

Supraventricular tachycardia associated with hypertension and

CNS excitation is almost always due to agents that cause generalized

physiologic excitation (Table 459–1). Most cases are mild or moderate in severity and require only observation or nonspecific sedation

with a benzodiazepine. In severe cases or those associated with

hemodynamic instability, chest pain, or ECG evidence of ischemia,

specific therapy is indicated. When the etiology is sympathetic

hyperactivity, treatment with a benzodiazepine should be prioritized. Further treatment with a combined alpha and beta blocker

(labetalol), a calcium channel blocker (verapamil or diltiazem),

or a combination of a beta blocker and a vasodilator (esmolol

and nitroprusside) may be considered for cases refractory to high

doses of benzodiazepines only when adequate sedation has been

achieved but cardiac conduction or blood pressure abnormalities

persist. Treatment with an α-adrenergic antagonist (phentolamine)

alone may sometimes be appropriate. If the cause is anticholinergic

poisoning, physostigmine alone can be effective. Supraventricular

tachycardia without hypertension is generally secondary to vasodilation or hypovolemia and responds to fluid administration.

For ventricular tachyarrhythmias due to tricyclic antidepressants

and other membrane-active agents (Table 459-1), sodium bicarbonate is indicated, whereas class IA, IC, and III antiarrhythmic

agents are contraindicated because of similar electrophysiologic

effects. Although lidocaine and phenytoin are historically safe for

ventricular tachyarrhythmias of any etiology, sodium bicarbonate

should be considered first for any ventricular arrhythmia suspected

to have a toxicologic etiology. Intravenous lipid emulsion therapy

has shown benefit for treatment of arrhythmias and hemodynamic

instability from various membrane-active agents. Beta blockers can

be hazardous if the arrhythmia is due to sympathetic hyperactivity.

Magnesium sulfate and overdrive pacing (by isoproterenol or a

pacemaker) may be useful in patients with torsades des pointes and

prolonged QT intervals. Magnesium and anti-digoxin antibodies

should be considered in patients with severe cardiac glycoside poisoning. Invasive (esophageal or intracardiac) ECG recording may

be necessary to determine the origin (ventricular or supraventricular) of wide-complex tachycardias (Chap. 246). If the patient is

hemodynamically stable, however, it is reasonable to simply observe

the patient rather than to administer another potentially proarrhythmic agent. Arrhythmias may be resistant to drug therapy until

underlying acid-base, electrolyte, oxygenation, and temperature

derangements are corrected.

Central Nervous System Therapies Neuromuscular hyperactivity and seizures can lead to hyperthermia, lactic acidosis,

and rhabdomyolysis and should be treated aggressively. Seizures

caused by excessive stimulation of catecholamine receptors (sympathomimetic or hallucinogen poisoning and drug withdrawal)

3588 PART 14 Poisoning, Drug Overdose, and Envenomation

or decreased activity of GABA (isoniazid poisoning) or glycine

(strychnine poisoning) receptors are best treated with agents that

enhance GABA activity, such as benzodiazepine or barbiturates.

Since benzodiazepines and barbiturates act by slightly different

mechanisms (the former increases the frequency via allosteric modulation at the receptor and the latter directly increases the duration

of chloride channel opening in response to GABA), therapy with

both may be effective when neither is effective alone. Seizures

caused by isoniazid, which inhibits the synthesis of GABA at several

steps by interfering with the cofactor pyridoxine (vitamin B6

), may

require high doses of supplemental pyridoxine. Seizures resulting

from membrane destabilization (beta blocker or cyclic antidepressant poisoning) require GABA enhancers (benzodiazepines first,

barbiturates second). Phenytoin is contraindicated in toxicologic

seizures: Animal and human data demonstrate worse outcomes

after phenytoin loading, especially in theophylline overdose. For

poisons with central dopaminergic effects (methamphetamine,

phencyclidine) manifested by psychotic behavior, a dopamine

receptor antagonist, such as haloperidol or ziprasidone, may be

useful. In anticholinergic and cyanide poisoning, specific antidotal

therapy may be necessary. The treatment of seizures secondary to

cerebral ischemia or edema or to metabolic abnormalities should

include correction of the underlying cause. Neuromuscular paralysis is indicated in refractory cases. Electroencephalographic monitoring and continuing treatment of seizures are necessary to prevent

permanent neurologic damage. Serotonergic receptor overstimulation in serotonin syndrome may be treated with cyproheptadine.

Other Measures Temperature extremes, metabolic abnormalities,

hepatic and renal dysfunction, and secondary complications should

be treated by standard therapies.

PREVENTION OF POISON ABSORPTION

Gastrointestinal Decontamination Whether or not to perform gastrointestinal decontamination and which procedure to use depends

on the time since ingestion; the existing and predicted toxicity of

the ingestant; the availability, efficacy, and contraindications of the

procedure; and the nature, severity, and risk of complications. The

efficacy of all decontamination procedures decreases with time, and

data are insufficient to support or exclude a beneficial effect when

they are used >1 h after ingestion. The average time from ingestion

to presentation for treatment is >1 h for children and >3 h for adults.

Most patients will recover from poisoning uneventfully with good

supportive care alone, but complications of gastrointestinal decontamination, particularly aspiration, can prolong this process. Hence,

gastrointestinal decontamination should be performed selectively,

not routinely, in the management of overdose patients. It is clearly

unnecessary when predicted toxicity is minimal or the time of

expected maximal toxicity has passed without significant effect.

Activated charcoal has comparable or greater efficacy; has fewer

contraindications and complications; and is less aversive and invasive than ipecac or gastric lavage. Thus, it is the preferred method

of gastrointestinal decontamination in most situations. Activated

charcoal suspension (in water) is given orally via a cup, straw, or

small-bore nasogastric tube. The generally recommended dose is

1 g/kg body weight because of its dosing convenience, although in

vitro and in vivo studies have demonstrated that charcoal adsorbs

≥90% of most substances when given in an amount equal to

10 times the weight of the substance. Palatability may be increased

by adding a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or cola syrup) to the suspension. Charcoal adsorbs ingested

poisons within the gut lumen, allowing the charcoal-toxin complex

to be evacuated with stool. Charged (ionized) chemicals such as

mineral acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron, lithium, and other inorganic compounds are not well

adsorbed by charcoal. In studies with animals and human volunteers, charcoal decreases the absorption of ingestants by an average

of 73% when given within 5 min of ingestant administration, 51%

when given at 30 min, and 36% when given at 60 min. For this

reason, charcoal given before hospital arrival by prehospital emergency medical services (EMS) increases the potential clinical benefit. Side effects of charcoal include nausea, vomiting, and diarrhea

or constipation. Charcoal may also prevent the absorption of orally

administered therapeutic agents, so the timing and the dose administered need to be adjusted. Complications include mechanical

obstruction of the airway, aspiration, vomiting, and bowel obstruction and infarction caused by inspissated charcoal. Charcoal is not

recommended for patients who have ingested corrosives because it

obscures endoscopy.

Gastric lavage should be considered for life-threatening poisons

that cannot be treated effectively with other decontamination,

elimination, or antidotal therapies (e.g., colchicine). Gastric lavage

is performed by sequentially administering and aspirating ~5 mL

of fluid per kilogram of body weight through a no. 40 French orogastric tube (no. 28 French tube for children). Except in infants, for

whom normal saline is recommended, tap water is acceptable. The

patient should be placed in Trendelenburg and left lateral decubitus

positions to prevent aspiration (even if an endotracheal tube is

in place). Lavage decreases ingestant absorption by an average of

52% if performed within 5 min of ingestion administration, 26% if

performed at 30 min, and 16% if performed at 60 min. Significant

amounts of ingested drug are recovered from <10% of patients.

Aspiration is a common complication (occurring in up to 10% of

patients), especially when lavage is performed improperly. Serious

complications (esophageal and gastric perforation, tube misplacement in the trachea) occur in ~1% of patients. For this reason, the

physician should personally insert the lavage tube and confirm its

placement, and the patient must be cooperative during the procedure. Gastric lavage is contraindicated in corrosive or petroleum

distillate ingestions because of the respective risks of gastroesophageal perforation and aspiration pneumonitis. It is also contraindicated in patients with a compromised unprotected airway and those

at risk for hemorrhage or perforation due to esophageal or gastric

pathology or recent surgery. Finally, gastric lavage is absolutely

contraindicated in combative patients or those who refuse, as most

published complications involve patient resistance to the procedure.

Syrup of ipecac, an emetogenic agent that was once the substance

most commonly used for decontamination, no longer has a role in

poisoning management. Even the American Academy of Pediatrics—

traditionally the strongest proponent of ipecac—issued a policy

statement in 2003 recommending that ipecac should no longer be

used in poisoning treatment. Chronic ipecac use (by patients with

anorexia nervosa or bulimia) has been reported to cause electrolyte

and fluid abnormalities, cardiac toxicity, and myopathy.

Whole-bowel irrigation is performed by administering a bowelcleansing solution containing electrolytes and polyethylene glycol

(Golytely, Colyte) orally or by gastric tube at a rate of 2 L/h (0.5 L/h

in children) until rectal effluent is clear. The patient must be in a

sitting position. Although data are limited, whole-bowel irrigation

appears to be as effective as other decontamination procedures

in volunteer studies. It is most appropriate for those who have

ingested foreign bodies, packets of illicit drugs, and agents that are

poorly adsorbed by charcoal (e.g., heavy metals). This procedure is

contraindicated in patients with bowel obstruction, ileus, hemodynamic instability, and compromised unprotected airways.

Cathartics are salts (disodium phosphate, magnesium citrate

and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that

historically have been given with activated charcoal to promote the

rectal evacuation of gastrointestinal contents. However, no animal,

volunteer, or clinical data have ever demonstrated any decontamination benefit from cathartics. Abdominal cramps, nausea, and

occasional vomiting are side effects. Complications of repeated dosing include severe electrolyte disturbances and excessive diarrhea.

Cathartics are contraindicated in patients who have ingested corrosives and in those with preexisting diarrhea. Magnesium-containing

cathartics should not be used in patients with renal failure.

Dilution (i.e., drinking water, another clear liquid, or milk at a

volume of 5 mL/kg of body weight) is recommended only after the

3589Poisoning and Drug Overdose CHAPTER 459

ingestion of corrosives (acids, alkali). It may increase the dissolution

rate (and hence absorption) of capsules, tablets, and other solid

ingestants and should not be used in these circumstances.

Endoscopic or surgical removal of poisons may be useful in rare

situations, such as ingestion of a potentially toxic foreign body that

fails to transit the gastrointestinal tract, a potentially lethal amount

of a heavy metal (arsenic, iron, mercury, thallium), or agents that

have coalesced into gastric concretions or bezoars (heavy metals,

lithium, salicylates, sustained-release preparations). Patients who

become toxic from cocaine due to its leakage from ingested drug

packets require immediate surgical intervention.

Decontamination of Other Sites Immediate, copious flushing

with water, saline, or another available clear, drinkable liquid is the

initial treatment for topical exposures (exceptions include alkali

metals, calcium oxide, phosphorus). Saline is preferred for eye

irrigation. A triple wash (water, soap, water) may be best for dermal

decontamination. Inhalational exposures should be treated initially

with fresh air or supplemental oxygen. The removal of liquids from

body cavities such as the vagina or rectum is best accomplished by

irrigation. Solids (drug packets, pills) should be removed manually,

preferably under direct visualization.

ENHANCEMENT OF POISON ELIMINATION

Although the elimination of most poisons can be accelerated by

therapeutic interventions, the pharmacokinetic efficacy (removal

of drug at a rate greater than that accomplished by intrinsic elimination) and clinical benefit (shortened duration of toxicity or

improved outcome) of such interventions are often more theoretical

than proven. Accordingly, the decision to use such measures should

be based on the actual or predicted toxicity and the potential efficacy, cost, and risks of therapy.

Multiple-Dose Activated Charcoal Repetitive oral dosing with

charcoal can enhance the elimination of previously absorbed substances by binding them within the gut as they are excreted in the

bile, are secreted by gastrointestinal cells, or passively diffuse into

the gut lumen (reverse absorption or enterocapillary exsorption).

Doses of 0.5–1 g/kg of body weight every 2–4 h, adjusted downward

to avoid regurgitation in patients with decreased gastrointestinal

motility, are generally recommended. Pharmacokinetic efficacy

approaches that of hemodialysis for some agents (e.g., phenobarbital, theophylline). Multiple-dose therapy should be considered only

for selected agents (theophylline, phenobarbital, carbamazepine,

dapsone, quinine). Complications include intestinal obstruction,

pseudo-obstruction, and nonocclusive intestinal infarction in

patients with decreased gut motility. Because of electrolyte and fluid

shifts, sorbitol and other cathartics are absolutely contraindicated

when multiple doses of activated charcoal are administered.

Urinary Alkalinization Ion trapping via alteration of urine pH

may prevent the renal reabsorption of poisons that undergo excretion by glomerular filtration and active tubular secretion. Since

membranes are more permeable to nonionized molecules than to

their ionized counterparts, acidic (low-pKa

) poisons are ionized and

trapped in alkaline urine, whereas basic ones become ionized and

trapped in acid urine. Urinary alkalinization (producing a urine pH

≥7.5 and a urine output of 3–6 mL/kg of body weight per hour by

the addition of sodium bicarbonate to an IV solution) enhances the

excretion of chlorophenoxyacetic acid herbicides, chlorpropamide,

diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides,

and salicylates. Contraindications include congestive heart failure,

renal failure, and cerebral edema. Acid-base, fluid, and electrolyte

parameters should be monitored carefully. Although acid diuresis

may make theoretical sense for some overdoses (amphetamines), it

is never indicated and is potentially harmful.

Extracorporeal Removal Hemodialysis, charcoal or resin hemoperfusion, hemofiltration, plasmapheresis, and exchange transfusion are capable of removing any toxin from the bloodstream.

Agents most amenable to enhanced elimination by dialysis have

low molecular mass (<500 Da), high water solubility, low protein

binding, small volumes of distribution (<1 L/kg of body weight),

prolonged elimination (long half-life), and high dialysis clearance

relative to total-body clearance. Molecular weight, water solubility,

and protein binding do not limit the efficacy of the other forms of

extracorporeal removal.

Dialysis should be considered in cases of severe poisoning due to

carbamazepine, ethylene glycol, isopropyl alcohol, lithium, methanol, theophylline, salicylates, and valproate. Although hemoperfusion may be more effective in removing some of these poisons, it

does not correct associated acid-base and electrolyte abnormalities,

and most hospitals no longer have hemoperfusion cartridges readily

available. Fortunately, recent advances in hemodialysis technology

make it as effective as hemoperfusion for removing poisons such as

caffeine, carbamazepine, and theophylline. Both techniques require

central venous access and systemic anticoagulation and may result

in transient hypotension. Hemoperfusion may also cause hemolysis, hypocalcemia, and thrombocytopenia. Peritoneal dialysis and

exchange transfusion are less effective but may be used when other

procedures are unavailable, contraindicated, or technically difficult

(e.g., in infants). Exchange transfusion may be indicated in the

treatment of severe arsine- or sodium chlorate–induced hemolysis,

methemoglobinemia, and sulfhemoglobinemia. Although hemofiltration can enhance elimination of aminoglycosides, vancomycin,

and metal-chelate complexes, the roles of hemofiltration and plasmapheresis in the treatment of poisoning are not yet defined.

Candidates for extracorporeal removal therapies include patients

with severe toxicity whose condition deteriorates despite aggressive

supportive therapy; those with potentially prolonged, irreversible,

or fatal toxicity; those with dangerous blood levels of toxins; those

who lack the capacity for self-detoxification because of liver or renal

failure; and those with a serious underlying illness or complication

that will adversely affect recovery.

Other Techniques The elimination of heavy metals can be

enhanced by chelation, and the removal of carbon monoxide can

be accelerated by hyperbaric oxygenation.

ADMINISTRATION OF ANTIDOTES

Antidotes counteract the effects of poisons by neutralizing them

(e.g., antibody-antigen reactions, chelation, chemical binding) or

by antagonizing their physiologic effects (e.g., activation of opposing nervous system activity, provision of a competitive metabolic

or receptor substrate). Poisons or conditions with specific antidotes include acetaminophen, anticholinergic agents, anticoagulants, benzodiazepines, beta blockers, calcium channel blockers,

carbon monoxide, cardiac glycosides, cholinergic agents, cyanide,

drug-induced dystonic reactions, ethylene glycol, fluoride, heavy

metals, hypoglycemic agents, isoniazid, membrane-active agents,

methemoglobinemia, opioids, sympathomimetics, and a variety of

envenomations. Intravenous lipid emulsion has been shown to be

a successful antidote for poisoning from various anesthetics and

membrane-active agents (e.g., cyclic antidepressants), but the exact

mechanism of benefit is still under investigation. Antidotes can significantly reduce morbidity and mortality rates but are potentially

toxic if used for inappropriate reasons. Since their safe use requires

correct identification of a specific poisoning or syndrome, details of

antidotal therapy are discussed with the conditions for which they

are indicated (Table 459-4).

PREVENTION OF REEXPOSURE

Poisoning is a preventable illness. Unfortunately, some adults and

children are poison-prone, and recurrences are common. Unintentional polypharmacy poisoning has become especially common

among adults with developmental delays, among the growing population of geriatric patients who are prescribed a large number of

medications, and among adolescents and young adults experimenting with pharmaceuticals for recreational euphoria. Adults with

unintentional exposures should be instructed regarding the safe use

of medications and chemicals (according to labeling instructions).

Confused patients may need assistance with the administration of

3590 PART 14 Poisoning, Drug Overdose, and Envenomation

TABLE 459-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings

PHYSIOLOGIC

CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS

Stimulated

Sympatheticsa

Sympathomimetics α1

-Adrenergic agonists

(decongestants):

phenylephrine,

phenylpropanolamine

β2

-Adrenergic agonists

(bronchodilators):

albuterol, terbutaline

Nonspecific adrenergic

agonists: amphetamines,

cocaine, ephedrine

Stimulation of central and

peripheral sympathetic receptors

directly or indirectly (by promoting

release or inhibiting reuptake of

norepinephrine and sometimes

dopamine)

Physiologic stimulation (Table

459-2). Reflex bradycardia

can occur with selective α1

agonists; β agonists can cause

hypotension and hypokalemia.

Phentolamine, a nonselective α1

-

adrenergic receptor antagonist,

for severe hypertension due to

α1

-adrenergic agonists; propranolol,

a nonselective β blocker, for

hypotension and tachycardia due

to β2

 agonists; either labetalol,

a β blocker with α-blocking

activity, or phentolamine with

esmolol, metoprolol, or another

cardioselective β blocker for

hypertension with tachycardia due

to nonselective agents (β blockers,

if used alone, can exacerbate

hypertension and vasospasm

due to unopposed α stimulation.);

benzodiazepines; propofol

Ergot alkaloids Ergotamine, methysergide,

bromocriptine, pergolide

Stimulation and inhibition of

serotonergic and α-adrenergic

receptors; stimulation of dopamine

receptors

Physiologic stimulation (Table

459-2); formication; vasospasm

with limb (isolated or

generalized), myocardial, and

cerebral ischemia progressing

to gangrene or infarction.

Hypotension, bradycardia, and

involuntary movements can

also occur.

Nitroprusside or nitroglycerine for

severe vasospasm; prazosin (an

α1

 blocker), captopril, nifedipine,

and cyproheptadine (a serotonin

receptor antagonist) for mild-tomoderate limb ischemia; dopamine

receptor antagonists (antipsychotics)

for hallucinations and movement

disorders

Methylxanthines Caffeine, theophylline Inhibition of adenosine synthesis

and adenosine receptor

antagonism; stimulation of

epinephrine and norepinephrine

release; inhibition of

phosphodiesterase resulting in

increased intracellular cyclic

adenosine and guanosine

monophosphate

Physiologic stimulation

(Table 459-2); pronounced

gastrointestinal symptoms and

β agonist effects (see above).

Toxicity occurs at lower drug

levels in chronic poisoning than

in acute poisoning.

Propranolol, a nonselective β

blocker, or esmolol for tachycardia

with hypotension; any β blocker

for supraventricular or ventricular

tachycardia without hypotension;

elimination enhanced by multipledose charcoal, hemoperfusion,

and hemodialysis. Indications for

hemoperfusion or hemodialysis

include unstable vital signs, seizures,

and a theophylline level of 80–100 μg/

mL after an acute overdose and

40–60 μg/mL with chronic exposure.

 Monoamine oxidase

inhibitors

Phenelzine,

tranylcypromine,

selegiline

Inhibition of monoamine oxidase

resulting in impaired metabolism

of endogenous catecholamines

and exogenous sympathomimetic

agents

Delayed or slowly progressive

physiologic stimulation

(Table 459-2); terminal

hypotension and bradycardia in

severe cases

Short-acting agents (e.g.,

nitroprusside, esmolol) for severe

hypertension and tachycardia;

direct-acting sympathomimetics (e.g.,

norepinephrine, epinephrine) for

hypotension and bradycardia

Anticholinergics

Antihistamines Diphenhydramine,

doxylamine, pyrilamine

Inhibition of central and

postganglionic parasympathetic

muscarinic cholinergic receptors.

At high doses, amantadine,

diphenhydramine, orphenadrine,

phenothiazines, and tricyclic

antidepressants have additional

nonanticholinergic activity

(see below).

Physiologic stimulation

(Table 459-2); dry skin

and mucous membranes,

decreased bowel sounds,

flushing, and urinary retention;

myoclonus and picking activity.

Central effects may occur

without significant autonomic

dysfunction.

Physostigmine, an

acetylcholinesterase inhibitor (see

below), for delirium, hallucinations,

and neuromuscular hyperactivity.

Contraindications include asthma and

non-anticholinergic cardiovascular

toxicity (e.g., cardiac conduction

abnormalities, hypotension, and

ventricular arrhythmias).

Antipsychotics Chlorpromazine,

olanzapine, quetiapine,

thioridazine

Inhibition of α-adrenergic,

dopaminergic, histaminergic,

muscarinic, and serotonergic

receptors. Some agents also inhibit

sodium, potassium, and calcium

channels.

Physiologic depression (Table

459-2), miosis, anticholinergic

effects (see above),

extrapyramidal reactions (see

below), tachycardia

Sodium bicarbonate for ventricular

tachydysrhythmias associated with

QRS prolongation; magnesium,

isoproterenol, and overdrive pacing

for torsades des pointes. Avoid class

IA, IC, and III antiarrhythmics.

 Belladonna alkaloids Atropine, hyoscyamine,

scopolamine

Inhibition of central and

postganglionic parasympathetic

muscarinic cholinergic receptors

Physiologic stimulation

(Table 459-2); dry skin

and mucous membranes,

decreased bowel sounds,

flushing, and urinary retention;

myoclonus and picking activity.

Central effects may occur

without significant autonomic

dysfunction.

Physostigmine, an

acetylcholinesterase inhibitor (see

below), for delirium, hallucinations,

and neuromuscular hyperactivity.

Contraindications include asthma and

non-anticholinergic cardiovascular

toxicity (e.g., cardiac conduction

abnormalities, hypotension, and

ventricular arrhythmias).

(Continued)

3591Poisoning and Drug Overdose CHAPTER 459

TABLE 459-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings

PHYSIOLOGIC

CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS

 Cyclic antidepressants Amitriptyline, doxepin,

imipramine

Inhibition of α-adrenergic,

dopaminergic, GABA-ergic,

histaminergic, muscarinic, and

serotonergic receptors; inhibition of

sodium channels (see membraneactive agents); inhibition of

norepinephrine and serotonin

reuptake

Physiologic depression (Table

459-2), seizures, tachycardia,

cardiac conduction delays

(increased PR, QRS, JT, and

QT intervals; terminal QRS

right-axis deviation) with

aberrancy and ventricular

tachydysrhythmias;

anticholinergic toxidrome (see

above)

Hypertonic sodium bicarbonate (or

hypertonic saline) for ventricular

tachydysrhythmias associated with

QRS prolongation. Use of phenytoin

is controversial. Avoid class IA, IC,

and III antiarrhythmics. IV emulsion

therapy may be beneficial in some

cases.

 Mushrooms and plants Amanita muscaria and

A. pantherina, henbane,

jimson weed, nightshade

Inhibition of central and

postganglionic parasympathetic

muscarinic cholinergic receptors

Physiologic stimulation (Table

459-2); dry skin and mucous

membranes, decreased bowel

sounds, flushing, and urinary

retention; myoclonus and

picking activity. Central effects

may occur without significant

autonomic dysfunction.

Physostigmine, an

acetylcholinesterase inhibitor (see

below), for delirium, hallucinations,

and neuromuscular hyperactivity.

Contraindications include asthma and

nonanticholinergic cardiovascular

toxicity (e.g., cardiac conduction

abnormalities, hypotension, and

ventricular arrhythmias).

Depressed

Sympatholytics

 α2

-Adrenergic agonists Clonidine, guanabenz,

tetrahydrozoline and

other imidazoline

decongestants, tizanidine

and other imidazoline

muscle relaxants

Stimulation of α2

-adrenergic

receptors leading to inhibition of

CNS sympathetic outflow. Activity

at nonadrenergic imidazoline

binding sites also contributes to

CNS effects.

Physiologic depression (Table

459-2), miosis. Transient initial

hypertension may be seen.

Dopamine and norepinephrine

for hypotension; atropine for

symptomatic bradycardia; naloxone

for CNS depression (inconsistently

effective)

Antipsychotics Chlorpromazine,

clozapine, haloperidol,

risperidone, thioridazine

Inhibition of α-adrenergic,

dopaminergic, histaminergic,

muscarinic, and serotonergic

receptors. Some agents also inhibit

sodium, potassium, and calcium

channels.

Physiologic depression

(Table 459-2), miosis,

anticholinergic effects (see

above), extrapyramidal

reactions (see below),

tachycardia. Cardiac

conduction delays (increased

PR, QRS, JT, and QT

intervals) with ventricular

tachydysrhythmias, including

torsades des pointes, can

sometimes develop.

Sodium bicarbonate for ventricular

tachydysrhythmias associated with

QRS prolongation; magnesium,

isoproterenol, and overdrive pacing

for torsades des pointes. Avoid class

IA, IC, and III antiarrhythmics.

 β-Adrenergic blockers Cardioselective (β1

)

blockers: atenolol,

esmolol, metoprolol

Nonselective (β1

 and

β2

) blockers: nadolol,

propranolol, timolol

Partial β agonists:

acebutolol, pindolol

α1

 Antagonists: carvedilol,

labetalol

Membrane-active agents:

acebutolol, propranolol,

sotalol

Inhibition of β-adrenergic receptors

(class II antiarrhythmic effect).

Some agents have activity at

additional receptors or have

membrane effects (see below).

Physiologic depression

(Table 459-2), atrioventricular

block, hypoglycemia,

hyperkalemia, seizures.

Partial agonists can cause

hypertension and tachycardia.

Sotalol can cause increased

QT interval and ventricular

tachydysrhythmias. Onset may

be delayed after sotalol and

sustained-release formulation

overdose.

Glucagon for hypotension and

symptomatic bradycardia. Atropine,

isoproterenol, dopamine, dobutamine,

epinephrine, and norepinephrine may

sometimes be effective. High-dose

insulin (with glucose and potassium

to maintain euglycemia and

normokalemia), electrical pacing, and

mechanical cardiovascular support

for refractory cases.

 Calcium channel

blockers

Diltiazem, nifedipine and

other dihydropyridine

derivatives, verapamil

Inhibition of slow (type L)

cardiovascular calcium channels

(class IV antiarrhythmic effect)

Physiologic depression

(Table 459-2), atrioventricular

block, organ ischemia and

infarction, hyperglycemia,

seizures. Hypotension is usually

due to decreased vascular

resistance rather than to

decreased cardiac output.

Onset may be delayed for ≥12

h after overdose of sustainedrelease formulations.

Calcium and glucagon for

hypotension and symptomatic

bradycardia. Dopamine, epinephrine,

norepinephrine, atropine, and

isoproterenol are less often effective

but can be used adjunctively. Highdose insulin (with glucose and

potassium to maintain euglycemia

and normokalemia), IV lipid emulsion

therapy, electrical pacing, and

mechanical cardiovascular support

for refractory cases.

(Continued)

(Continued)

3592 PART 14 Poisoning, Drug Overdose, and Envenomation

TABLE 459-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings

PHYSIOLOGIC

CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS

Cardiac glycosides Digoxin, endogenous

cardioactive steroids,

foxglove and other plants,

toad skin secretions

(Bufonidae spp.)

Inhibition of cardiac Na+

, K+

-ATPase

membrane pump

Physiologic depression

(Table 459-2); gastrointestinal,

psychiatric, and visual

symptoms; atrioventricular

block with or without

concomitant supraventricular

tachyarrhythmia; ventricular

tachyarrhythmias; hyperkalemia

in acute poisoning. Toxicity

occurs at lower drug levels in

chronic poisoning than in acute

poisoning.

Digoxin-specific antibody fragments

for hemodynamically compromising

dysrhythmias, Mobitz II or thirddegree atrioventricular block,

hyperkalemia (>5.5 meq/L; in

acute poisoning only). Temporizing

measures include atropine, dopamine,

epinephrine, and external cardiac

pacing for bradydysrhythmias and

magnesium, lidocaine, or phenytoin,

for ventricular tachydysrhythmias.

Internal cardiac pacing and

cardioversion can increase

ventricular irritability and should be

reserved for refractory cases.

Cyclic antidepressants Amitriptyline, doxepin,

imipramine

Inhibition of α-adrenergic,

dopaminergic, GABA-ergic,

histaminergic, muscarinic, and

serotonergic receptors; inhibition of

sodium channels (see membraneactive agents); inhibition of

norepinephrine and serotonin

reuptake

Physiologic depression (Table

459-2), seizures, tachycardia,

cardiac conduction delays

(increased PR, QRS, JT, and QT

intervals; terminal QRS right-axis

deviation) with aberrancy and

ventricular tachydysrhythmias;

anticholinergic toxidrome (see

above)

Hypertonic sodium bicarbonate (or

hypertonic saline) for ventricular

tachydysrhythmias associated with

QRS prolongation. Use of phenytoin

is controversial. Avoid class IA, IC,

and III antiarrhythmics. IV emulsion

therapy may be beneficial in some

cases.

Cholinergics

 Acetylcholinesterase

inhibitors

Muscarinic agonists

Nicotinic agonists

Carbamate insecticides

(aldicarb, carbaryl,

propoxur) and

medicinals (neostigmine,

physostigmine, tacrine);

nerve gases (sarin,

soman, tabun, VX);

organophosphate

insecticides (diazinon,

chlorpyrifos-ethyl,

malathion)

Bethanechol, mushrooms

(Boletus, Clitocybe,

Inocybe spp.), pilocarpine

Lobeline, nicotine

(tobacco)

Inhibition of acetylcholinesterase

leading to increased synaptic

acetylcholine at muscarinic and

nicotinic cholinergic receptor sites

Stimulation of CNS and

postganglionic parasympathetic

cholinergic (muscarinic) receptors

Stimulation of preganglionic

sympathetic and parasympathetic

and striated muscle (neuromuscular

junction) cholinergic (nicotine)

receptors

Physiologic depression (Table

459-2). Muscarinic signs and

symptoms: seizures, excessive

secretions (lacrimation,

salivation, bronchorrhea and

wheezing, diaphoresis), and

increased bowel and bladder

activity with nausea, vomiting,

diarrhea, abdominal cramps,

and incontinence of feces

and urine. Nicotinic signs

and symptoms: hypertension,

tachycardia, muscle cramps,

fasciculations, weakness, and

paralysis. Death is usually

due to respiratory failure.

Cholinesterase activity in

plasma and red cells is <50% of

normal in acetylcholinesterase

inhibitor poisoning.

Atropine for muscarinic signs and

symptoms; 2-PAM, a cholinesterase

reactivator, for nicotinic signs and

symptoms due to organophosphates,

nerve gases, or an unknown

anticholinesterase

Sedative-hypnoticsb

Anticonvulsants

Barbiturates

Benzodiazepines

Carbamazepine,

ethosuximide, felbamate,

gabapentin, lamotrigine,

levetiracetam,

oxcarbazepine, phenytoin,

tiagabine, topiramate,

valproate, zonisamide

Short-acting: butabarbital,

pentobarbital,

secobarbital

Long-acting:

phenobarbital, primidone

Ultrashort-acting:

estazolam, midazolam,

temazepam, triazolam

Short-acting: alprazolam,

flunitrazepam, lorazepam,

oxazepam

Long-acting:

chlordiazepoxide,

clonazepam, diazepam,

flurazepam

Pharmacologically related

agents: zaleplon, zolpidem

Potentiation of the inhibitory

effects of GABA by binding to the

neuronal GABA–A chloride channel

receptor complex and increasing

the frequency or duration of

chloride channel opening in

response to GABA stimulation.

Baclofen and, to some extent,

GHB act at the GABA–B receptor

complex. Meprobamate, its

metabolite carisoprodol, felbamate,

and orphenadrine antagonize

NDMA excitatory receptors.

Ethosuximide, valproate, and

zonisamide decrease conduction

through T-type calcium channels.

Valproate decreases GABA

degradation, and tiagabine blocks

GABA reuptake. Carbamazepine,

lamotrigine, oxcarbazepine,

phenytoin, topiramate, valproate,

and zonisamide slow the rate of

recovery of inactivated sodium

channels. Some agents also have α2

agonist, anticholinergic, and sodium

channel–blocking activity (see

above and below).

Physiologic depression (Table

459-2), nystagmus.

Delayed absorption can occur

with carbamazepine, phenytoin,

and valproate.

Myoclonus, seizures,

hypertension, and

tachyarrhythmias can occur

with baclofen, carbamazepine,

and orphenadrine.

Tachyarrhythmias can also

occur with chloral hydrate.

AGMA, hypernatremia,

hyperosmolality,

hyperammonemia, chemical

hepatitis, and hypoglycemia

can be seen in valproate

poisoning. Carbamazepine and

oxcarbazepine may produce

hyponatremia from SIADH.

Benzodiazepines, barbiturates, or

propofol for seizures.

Hemodialysis and hemoperfusion may

be indicated for severe poisoning by

some agents (see “Extracorporeal

Removal,” in text).

See above and below for treatment of

anticholinergic and sodium channel

(membrane)–blocking effects.

(Continued)

(Continued)

3593Poisoning and Drug Overdose CHAPTER 459

TABLE 459-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings

PHYSIOLOGIC

CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS

GABA precursors γ-Hydroxybutyrate

(sodium oxybate; GHB),

γ-butyrolactone (GBL),

1,4-butanediol

Stimulation at GABA receptor

complex increases chloride

channel opening

Physiologic depression

(Table 459-2)

Goal-directed supportive care

Muscle relaxants Baclofen, carisoprodol,

cyclobenzaprine,

etomidate, metaxalone,

methocarbamol,

orphenadrine, propofol,

tizanidine and other

imidazoline muscle

relaxants

Baclofen acts at GABA-B

receptor complex; Stimulation of

α2-adrenergic receptors inhibits

CNS sympathetic outflow. Activity at

nonadrenergic imidazoline binding

sites also contributes to CNS

effects. The others have centrallyacting and various other unknown

mechanisms of action

Physiologic depression

(Table 459-2)

Goal-directed supportive care;

benzodiazepines and barbiturates for

seizures

Other agents Chloral hydrate,

ethchlorvynol,

glutethimide,

meprobamate,

methaqualone,

methyprylon

Discordant

Asphyxiants

 Cytochrome oxidase

inhibitors

Cyanide, hydrogen sulfide Inhibition of mitochondrial

cytochrome oxidase, with

consequent blockage of electron

transport and oxidative metabolism.

Carbon monoxide also binds to

hemoglobin and myoglobin and

prevents oxygen binding, transport,

and tissue uptake. (Binding to

hemoglobin shifts the oxygen

dissociation curve to the left.)

Signs and symptoms of

hypoxemia with initial

physiologic stimulation and

subsequent depression

(Table 459-2); lactic acidosis;

normal PO2

 and calculated

oxygen saturation but

decreased oxygen saturation

by co-oximetry. (That measured

by pulse oximetry is falsely

elevated but is less than normal

and less than the calculated

value.) Headache and nausea

are common with carbon

monoxide. Sudden collapse

may occur with cyanide and

hydrogen sulfide exposure.

A bitter almond breath odor

may be noted with cyanide

ingestion, and hydrogen sulfide

smells like rotten eggs.

High-dose oxygen; IV

hydroxocobalamin or IV sodium nitrite

and sodium thiosulfate (Lilly cyanide

antidote kit) for coma, metabolic

acidosis, and cardiovascular

dysfunction in cyanide poisoning or

victims from a fire; ECMO

 Methemoglobin

inducers

Aniline derivatives,

dapsone, local

anesthetics, nitrates,

nitrites, nitrogen

oxides, nitro- and

nitrosohydrocarbons,

phenazopyridine,

primaquine-type

antimalarials,

sulfonamides

Oxidation of hemoglobin iron

from ferrous (Fe2+) to ferric (Fe3+)

state prevents oxygen binding,

transport, and tissue uptake.

(Methemoglobinemia shifts oxygen

dissociation curve to the left.)

Oxidation of hemoglobin protein

causes hemoglobin precipitation

and hemolytic anemia (manifesting

as Heinz bodies and “bite cells” on

peripheral-blood smear).

Signs and symptoms of

hypoxemia with initial

physiologic stimulation and

subsequent depression (Table

459-2), gray-brown cyanosis

unresponsive to oxygen at

methemoglobin fractions

>15–20%, headache, lactic

acidosis (at methemoglobin

fractions >45%), normal PO2

 and

calculated oxygen saturation

but decreased oxygen

saturation and increased

methemoglobin fraction by

co-oximetry (Oxygen saturation

by pulse oximetry may be

falsely increased or decreased

but is less than normal and less

than the calculated value.)

High-dose oxygen; IV methylene blue

for methemoglobin fraction >30%,

symptomatic hypoxemia, or ischemia

(contraindicated in G6PD deficiency);

exchange transfusion and hyperbaric

oxygen for severe or refractory cases

(Continued)

(Continued)

3594 PART 14 Poisoning, Drug Overdose, and Envenomation

TABLE 459-4 Pathophysiologic Features and Treatment of Specific Toxic Syndromes and Poisonings

PHYSIOLOGIC

CONDITION, CAUSES EXAMPLES MECHANISM OF ACTION CLINICAL FEATURES SPECIFIC TREATMENTS

AGMA inducers Ethylene glycol Ethylene glycol causes CNS

depression and increased serum

osmolality. Metabolites (primarily

glycolic acid) cause AGMA, CNS

depression, and renal failure.

Precipitation of oxalic acid

metabolite as calcium salt in tissues

and urine results in hypocalcemia,

tissue edema, and crystalluria.

Initial ethanol-like intoxication,

nausea, vomiting, increased

osmolar gap, calcium oxalate

crystalluria; delayed AGMA,

back pain, renal failure; coma,

seizures, hypotension, ARDS in

severe cases

Sodium bicarbonate to correct

acidemia; thiamine, folinic acid,

magnesium, and high-dose pyridoxine

to facilitate metabolism; ethanol or

fomepizole for AGMA, crystalluria

or renal dysfunction, ethylene

glycol level >3 mmol/L (20 mg/dL),

and ethanol-like intoxication or

increased osmolal gap if level not

readily obtainable; hemodialysis for

persistent AGMA, lack of clinical

improvement, and renal dysfunction;

hemodialysis also useful for

enhancing ethylene glycol elimination

and shortening duration of treatment

when ethylene glycol level is

>8 mmol/L (50 mg/dL).

Iron Hydration of ferric (Fe3+) ion

generates H+

. Non-transferrinbound iron catalyzes formation

of free radicals that cause

mitochondrial injury, lipid

peroxidation, increased capillary

permeability, vasodilation, and

organ toxicity.

Initial nausea, vomiting,

abdominal pain, diarrhea;

AGMA, cardiovascular and

CNS depression, hepatitis,

coagulopathy, and seizures

in severe cases. Radiopaque

iron tablets may be seen on

abdominal x-ray.

Whole-bowel irrigation for large

ingestions; endoscopy and

gastrostomy if clinical toxicity

and large number of tablets are

still visible on x-ray; IV hydration;

sodium bicarbonate for acidemia; IV

deferoxamine for systemic toxicity,

iron level >90 μmol/L (500 μg/dL)

Methanol Methanol causes ethanol-like CNS

depression and increased serum

osmolality. Formic acid metabolite

causes AGMA and retinal toxicity.

Initial ethanol-like intoxication,

nausea, vomiting, increased

osmolar gap; delayed AGMA,

visual (clouding, spots,

blindness) and retinal (edema,

hyperemia) abnormalities;

coma, seizures, cardiovascular

depression in severe cases;

possible pancreatitis

Gastric aspiration for recent

ingestion; sodium bicarbonate to

correct acidemia; high-dose folinic

acid or folate to facilitate metabolism;

ethanol or fomepizole for AGMA,

visual symptoms, methanol level

>6 mmol/L (20 mg/dL), and ethanollike intoxication or increased osmolal

gap if level not readily obtainable;

hemodialysis for persistent AGMA,

lack of clinical improvement, and

renal dysfunction; hemodialysis

also useful for enhancing methanol

elimination and shortening duration of

treatment when methanol level is

>15 mmol/L (50 mg/dL)

Salicylate Increased sensitivity of CNS

respiratory center to changes in and

stimulates respiration. Uncoupling

of oxidative phosphorylation,

inhibition of Krebs cycle enzymes,

and stimulation of carbohydrate

and lipid metabolism generate

unmeasured endogenous anions

and cause AGMA.

Initial nausea, vomiting,

hyperventilation, alkalemia,

alkaluria; subsequent alkalemia

with both respiratory alkalosis

and AGMA and paradoxical

aciduria; late acidemia

with CNS and respiratory

depression; cerebral and

pulmonary edema in severe

cases. Hypoglycemia,

hypocalcemia, hypokalemia,

and seizures can occur.

IV hydration and supplemental

glucose; sodium bicarbonate

to correct acidemia; urinary

alkalinization for systemic toxicity;

hemodialysis for coma, cerebral

edema, seizures, pulmonary edema,

renal failure, progressive acid-base

disturbances or clinical toxicity,

salicylate level >7 mmol/L (100 mg/dL)

following acute overdose

CNS syndromes

 Extrapyramidal

reactions

Antipsychotics (see

above), some cyclic

antidepressants and

antihistamines

Decreased CNS dopaminergic

activity with relative excess of

cholinergic activity

Akathisia, dystonia,

parkinsonism

Oral or parenteral anticholinergic

agent such as benztropine or

diphenhydramine

Isoniazid Interference with activation and

supply of pyridoxal-5-phosphate,

a cofactor for glutamic acid

decarboxylase, which converts

glutamic acid to GABA, results in

decreased levels of this inhibitory

CNS neurotransmitter; complexation

with and depletion of pyridoxine

itself; inhibition of nicotine adenine

dinucleotide–dependent lactate and

hydroxybutyrate dehydrogenases,

resulting in substrate accumulation

Nausea, vomiting, agitation,

confusion; coma, respiratory

depression, seizures, lactic and

ketoacidosis in severe cases

High-dose IV pyridoxine (vitamin B6

)

for agitation, confusion, coma, and

seizures; diazepam or barbiturates

for seizures

(Continued)

(Continued)