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)

3595Poisoning 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

Lithium Interference with cell membrane

ion transport, adenylate cyclase

and Na+

, K+

-ATPase activity, and

neurotransmitter release

Nausea, vomiting, diarrhea,

ataxia, choreoathetosis,

encephalopathy, hyperreflexia,

myoclonus, nystagmus,

nephrogenic diabetes insipidus,

falsely elevated serum

chloride with low anion gap,

tachycardia; coma, seizures,

arrhythmias, hyperthermia,

and prolonged or permanent

encephalopathy and movement

disorders in severe cases;

delayed onset after acute

overdose, particularly with

delayed-release formulations.

Toxicity occurs at lower drug

levels in chronic poisoning than

in acute poisoning.

Whole-bowel irrigation for large

ingestions; IV hydration; hemodialysis

for coma, seizures, encephalopathy

or neuromuscular dysfunction

(severe, progressive, or persistent),

peak lithium level >4 meq/L following

acute overdose

Serotonin syndrome Amphetamines, cocaine,

dextromethorphan,

meperidine, MAO

inhibitors, selective

serotonin (5-HT) reuptake

inhibitors, tricyclic

antidepressants, tramadol,

triptans, tryptophan

Promotion of serotonin release,

inhibition of serotonin reuptake,

or direct stimulation of CNS and

peripheral serotonin receptors

(primarily 5-HT-1a and 5-HT-2),

alone or in combination

Altered mental status (agitation,

confusion, mutism, coma,

seizures), neuromuscular

hyperactivity (hyperreflexia,

myoclonus, rigidity, tremors),

and autonomic dysfunction

(abdominal pain, diarrhea,

diaphoresis, fever, flushing,

labile hypertension,

mydriasis, tearing, salivation,

tachycardia). Complications

include hyperthermia, lactic

acidosis, rhabdomyolysis, and

multisystem organ failure.

Discontinue the offending agent(s);

benzodiazepines for agitation or signs

of stimulation; the serotonin receptor

antagonist cyproheptadine may be

helpful in severe cases.

Membrane-active agent Amantadine, antiarrhythmics (class I and III

agents; some β blockers),

antipsychotics (see

above), antihistamines

(particularly

diphenhydramine),

carbamazepine,

local anesthetics

(including cocaine),

opioids (meperidine,

propoxyphene),

orphenadrine, quinoline

antimalarials (chloroquine,

hydroxychloroquine,

quinine), cyclic

antidepressants (see

above)

Blockade of fast sodium

membrane channels prolongs

phase 0 (depolarization) of the

cardiac action potential, which

prolongs QRS duration and

promotes reentrant (monomorphic)

ventricular tachycardia. Class Ia, Ic,

and III antiarrhythmics also block

potassium channels during phases

2 and 3 (repolarization) of the

action potential, prolonging the JT

interval and promoting early afterdepolarizations and polymorphic

(torsades des pointes) ventricular

tachycardia. Similar effects on

neuronal membrane channels

cause CNS dysfunction. Some

agents also block α-adrenergic and

cholinergic receptors or have opioid

effects (see above and Chap. 456).

QRS and JT prolongation

(or both) with hypotension,

ventricular tachyarrhythmias,

CNS depression, seizures;

anticholinergic effects with

amantadine, antihistamines,

carbamazepine, disopyramide,

antipsychotics, and cyclic

antidepressants (see above);

opioid effects with meperidine

and propoxyphene (see

Chap. 456); cinchonism (hearing

loss, tinnitus, nausea, vomiting,

vertigo, ataxia, headache,

flushing, diaphoresis), and

blindness with quinoline

antimalarials

Hypertonic sodium bicarbonate

(or hypertonic saline) for cardiac

conduction delays and monomorphic

ventricular tachycardia; lidocaine

for monomorphic ventricular

tachycardia (except when due to

class Ib antiarrhythmics); magnesium,

isoproterenol, and overdrive

pacing for polymorphic ventricular

tachycardia; physostigmine for

anticholinergic effects (see above);

naloxone for opioid effects (see

Chap. 456); extracorporeal removal

for some agents (see text).

a

See above and Chap. 457. b

See above and Chap. 456.

Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; ECMO, extracorporeal membrane

oxygenation; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB, γ-hydroxybutyrate; G6PD, glucose-6-phosphate dehydrogenase; MAO, monoamine oxidase; NDMA,

N-methyl-D-aspartate; 2-PAM, pralidoxime; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

their medications. Errors in dosing by health care providers may

require educational efforts. Patients should be advised to avoid circumstances that result in chemical exposure or poisoning. Appropriate agencies and health departments (e.g., Occupational Health

and Safety Administration [OSHA]) should be notified in cases of

environmental or workplace exposure. The best approach to young

children and patients with intentional overdose (deliberate selfharm or attempted suicide) is to limit their access to poisons. In

households where children live or visit, alcoholic beverages, medications, household products (automotive, cleaning, fuel, pet-care,

and toiletry products), inedible plants, and vitamins should be kept

out of reach or in locked or child-proof cabinets. Depressed, bipolar, or psychotic patients should undergo psychiatric assessment,

disposition, and follow-up. They should be given prescriptions for a

limited supply of drugs with a limited number of refills and should

be monitored for compliance and response to therapy.

SPECIFIC TOXIC SYNDROMES

AND POISONINGS

Table 459-4 summarizes the pathophysiology, clinical features, and

treatment of toxidromes and poisonings that are common, produce

life-threatening toxicity, or require unique therapeutic interventions. In

all cases, treatment should include attention to the general principles

discussed above and, in particular, supportive care. Poisonings not

covered in this chapter are discussed in specialized texts.

Alcohol, cocaine, hallucinogen, and opioid poisoning and alcohol and opioid withdrawal are discussed in Chaps. 453, 456, and

(Continued)

3596 PART 14 Poisoning, Drug Overdose, and Envenomation

457; nicotine addiction is discussed in Chap. 454; acetaminophen

poisoning is discussed in Chap. 340; the neuroleptic malignant

syndrome is discussed in Chap. 435; and heavy metal poisoning is

discussed in Chap. 458.

■ GLOBAL CONSIDERATIONS

Risks of poisoning in the United States and throughout the world are

in transition. Patterns of travel, immigration, and internet consumerism should always be considered in patients suspected of poisoning or

overdose without a clear etiology. Immigrants into various countries

may have underlying poisoning from various metals from work or

the environment where they previously lived; herbal remedies, food

products, and cosmetics imported from overseas or ordered from

the internet may be contaminated with metals, toxic plants, or other

pharmaceutical contaminants; and new drugs of abuse that originate

in one part of the world quickly circulate due to the ease afforded by

the internet. Expanding the history at the time of evaluation, recruiting

the assistance of global health specialists, and ordering expanded laboratory panels may be indicated. For instance, during the COVID-19

pandemic, poisoning from household cleaning substances and novel

untested therapies increased worldwide.

■ FURTHER READING

Dart RC et al: Expert consensus guidelines for stocking of antidotes in

hospitals that provide emergency care. Ann Emerg Med 71:314, 2018.

Gummin DD et al: 2018 annual report of the American Association of

Poison Control Centers’ National Poison Data System (NPDS): 36th

annual report. Clin Toxicol 57:1220, 2019.

Mycyk MB: ECMO shows promise for treatment of poisoning some of

the time: The challenge to do better by aiming higher. Crit Care Med

48:1235, 2020.

Nelson LS et al (eds): Goldfrank’s Toxicologic Emergencies, 11th ed.

New York, McGraw-Hill, 2019.

Spyres MB et al: The Toxicology Investigators Consortium Case Registry:

The 2019 annual report. J Med Toxicol 16:361, 2020.

Thompson TM et al: The general approach to the poisoned patient.

Dis Mon 60:509, 2014.

Welker K, Mycyk MB: Pharmacology in the geriatric patient. Emerg

Med Clin North Am 34:469, 2016.

This chapter outlines general principles for the evaluation and management of victims of envenomation and poisoning by venomous snakes

and marine animals. Because the incidence of serious bites and stings is

relatively low in developed nations, there is a paucity of relevant clinical

research; as a result, therapeutic decision-making often is based on

anecdotal information.

VENOMOUS SNAKEBITE

■ EPIDEMIOLOGY

The venomous snakes of the world belong to the families Viperidae

(subfamily Viperinae: Old World vipers; subfamily Crotalinae: New

World and Asian pit vipers), Elapidae (including cobras, coral snakes,

sea snakes, kraits, and all Australian venomous snakes), Lamprophiidae

(subfamily Atractaspidinae: burrowing asps), and Colubridae (a large

460 Disorders Caused by

Venomous Snakebites and

Marine Animal Exposures

Erik Fisher, Alex Chen, Charles Lei

family in which most species are nonvenomous). Most snakebites

occur in developing countries with temperate and tropical climates

in which populations subsist on agriculture and fishing (Fig. 460-1).

Recent estimates indicate that somewhere between 1.2 million and

5.5 million snakebites occur worldwide each year, with 421,000–1,200,000

envenomations and 81,000–138,000 deaths. Such wide-ranging estimates

reflect the challenges of collecting accurate data in the regions most

affected by venomous snakes; many victims in these areas either do not

seek medical attention or have insufficient access to antivenom, and

reporting and record-keeping are generally poor.

■ SNAKE ANATOMY/IDENTIFICATION

The typical snake venom delivery apparatus consists of bilateral venom

glands situated behind the eyes and hollow anterior maxillary fangs.

In viperids, these fangs are long and highly mobile; they are retracted

against the roof of the mouth when the snake is at rest, then brought to

an upright position when about to strike. In elapids, the fangs are fixed

in an erect position and smaller in size, which can lead to fewer distinct wounds after an envenomation. Colubrids do not possess venom

glands but have homologous structures known as Duvernoy’s glands.

Approximately 20–25% of pit viper bites and higher percentages of

other snakebites (up to 75% for sea snakes) are “dry” bites, in which no

venom is released.

Differentiating between venomous and nonvenomous snake species

can be challenging. Identifying venomous snakes by color pattern can

be misleading, as many nonvenomous snakes have color patterns that

closely mimic those of venomous snakes found in the same region.

Viperids are characterized by triangular heads (a feature shared with

many harmless snakes), elliptical pupils (also seen in some nonvenomous snakes, such as boas and pythons), and enlarged maxillary fangs;

pit vipers also possess heat-sensing organs (pits) on each side of the

head that assist with locating prey and aiming strikes. Rattlesnakes

possess a series of interlocking hollow keratin plates (the rattle) on the

tip of the tail that emits a buzzing sound when vibrated rapidly; this

sound serves as a warning signal to perceived threats.

■ VENOMS AND CLINICAL MANIFESTATIONS

Snake venoms consist of highly complex mixtures of enzymes, polypeptides, glycoproteins, and other constituents. Venom components

may vary greatly depending on the species, age, and geographic location of the snake. Snake venoms can cause local tissue necrosis, affect

the coagulation pathway at various steps, impair organ function, or act

at the neuromuscular junction to cause paralysis.

After an envenomation, the time to symptom onset and clinical

presentation can be quite variable depending on the species involved,

the anatomic location of the bite, and the amount of venom injected.

Envenomations by most viperids and some elapids cause progressive

local pain, soft-tissue swelling, and ecchymosis (Fig. 460-2). Hemorrhagic or serum-filled vesicles and bullae may develop at the bite

site over a period of hours to days. In serious bites, tissue loss can

be significant (Fig. 460-3). Systemic findings are variable and can

include generalized fatigue, nausea, changes in taste, mouth numbness, tachycardia or bradycardia, hypotension, muscle fasciculations,

pulmonary edema, renal dysfunction, and spontaneous hemorrhage.

Envenomations by neurotoxic elapids, such as kraits (Bungarus species), many Australian elapids (e.g., death adders [Acanthophis species]

and tiger snakes [Notechis species]), and some cobras (Naja species), as

well as some viperids (e.g., the South American rattlesnake [Crotalus

durissus], Mojave rattlesnake [Crotalus scutulatus], and certain Indian

Russell’s vipers [Daboia russelii]), cause neurologic dysfunction. Early

findings may consist of nausea and vomiting, headache, paresthesias

or numbness, and altered mental status. Victims may develop cranial

nerve abnormalities (e.g., ptosis, difficulty swallowing), followed by

peripheral motor weakness. Severe envenomation may result in diaphragmatic paralysis and lead to death from respiratory failure and

aspiration. Sea snake envenomation results in local pain (variable),

generalized myalgias, trismus, rhabdomyolysis, and progressive flaccid

paralysis; these manifestations can be delayed for several hours.

3597 Disorders Caused by Venomous Snakebites and Marine Animal Exposures CHAPTER 460

Viperidae

Key:

Elapidae

FIGURE 460-1 Geographic distribution of venomous snakes.

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

envenomations. A. Moderately severe envenomation. Note edema and early

ecchymosis 2 h after a bite to the finger. B. Severe envenomation. Note extensive

ecchymosis 5 days after a bite to the ankle. (Courtesy of Robert Norris, with

permission.)

A

B

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

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

Norris, with permission.)

TREATMENT

Venomous Snakebite

FIELD MANAGEMENT

The most important aspect of prehospital care of a person bitten by

a venomous snake is rapid transport to a medical facility equipped

to provide supportive management (airway, breathing, and circulation) and antivenom therapy. Any jewelry or tight-fitting clothing

near the bite should be removed to avoid constriction from anticipated soft-tissue swelling. Although wound care should not delay

transport, the wound should be cleaned with soap and running

water then covered with a sterile dressing. It is reasonable to apply

a splint to the bitten extremity to limit movement and assist with

positioning. If possible, the extremity should be maintained in a

neutral position of comfort at approximately heart level. Attempting

to capture and transport the offending snake is not advised; instead,

digital photographs taken from a safe distance may assist with snake

identification and treatment decisions.

Most of the first-aid measures recommended in the past are of

little benefit and may worsen outcomes. Incising and/or applying

3598 PART 14 Poisoning, Drug Overdose, and Envenomation

suction to the bite site should be avoided, as these measures exacerbate local tissue damage, increase the risk of infection, and have

not been shown to be effective. Venom sequestration devices (e.g.,

lympho-occlusive bandages or tourniquets) are not advised, as

they may intensify local tissue damage by restricting the spread of

potentially necrotizing venom. Tourniquet use can result in loss

of function, ischemia, and limb amputation, even in the absence

of envenomation. In developing countries, victims should be

encouraged to seek immediate treatment at a medical facility

equipped with antivenom instead of consulting traditional healers and thus incurring significant delays in reaching appropriate

care.

Elapid envenomations that are primarily neurotoxic and

have no significant effects on local tissue may be managed with

pressure-immobilization, in which the entire bitten limb is immediately wrapped with a bandage and then immobilized. This technique is meant to restrict lymphatic drainage and has been shown

to delay the systemic absorption of venom from predominantly

neurotoxic species. For pressure-immobilization to be effective, the

wrap pressure should not exceed 40–70 mmHg in upper-extremity

application and 55–70 mmHg in lower-extremity application. As

an estimate, the bandage should be snug enough to apply pressure

but loose enough for a finger to slip underneath. Additionally,

the victim must be carried out of the field because walking generates muscle-pumping activity that—regardless of the anatomic

site of the bite—will disperse venom into the systemic circulation.

Pressure-immobilization should be used only in cases in which the

offending snake is reliably identified and known to be primarily

neurotoxic, the rescuer is skilled in pressure-wrap application, the

necessary supplies are readily available, and the victim can be fully

immobilized and carried to medical care—a rare combination of

conditions, particularly in the regions of the world where such bites

are most common.

HOSPITAL MANAGEMENT

Initial hospital management should focus on the victim’s airway,

breathing, and circulation. Patients with bites to the face or neck

may require early endotracheal intubation to prevent loss of airway

patency caused by rapid soft-tissue swelling. Vital signs, cardiac

rhythm, oxygen saturation, and urine output should be closely

monitored. Two large-bore IV lines should be established in unaffected extremities. Because of the potential for coagulopathy, venipuncture attempts should be minimized and noncompressible sites

(e.g., subclavian vein) avoided. Early hypotension may be caused

by bradykinin-potentiating factors, which lead to vasodilation and

pooling of blood in the pulmonary and splanchnic vascular beds.

Additionally, systemic bleeding, hemolysis, and loss of intravascular volume into the soft tissues may play important roles in

hypotension. Fluid resuscitation with isotonic saline (20–40 mL/

kg IV) should be initiated if there is any evidence of hemodynamic

instability. Vasopressors (e.g., norepinephrine, epinephrine) should

be considered if venom-induced shock persists after aggressive

volume resuscitation and antivenom administration (see below), as

the victim may be experiencing anaphylaxis to the venom components or the antivenom itself.

A thorough history (including the time of the bite and any symptoms of envenomation) should be obtained and a complete physical

examination performed, with a focus on the neurovascular status

of the site of envenomation. For envenomation of a limb, palpation of axillary or inguinal lymph nodes can provide information

about lymphatic spread. Bandages or wraps applied in the field

should be removed as soon as possible, with cognizance that the

release of such ligatures may result in hypotension or dysrhythmias

when stagnant acidotic blood containing venom is released into

the systemic circulation. To objectively evaluate the progression

of local envenomation, the leading edge of swelling, ecchymosis,

and tenderness should be marked and limb circumference should

be measured at three points (e.g., at the bite site, the joint proximal, and the joint distal) every 15 min until the local-tissue effects

have stabilized. Once stabilized, measurements can be taken every

1–2 h. During this period of observation, the bitten extremity

should be positioned at approximately heart level. Victims of neurotoxic envenomation should be monitored closely for evidence of

cranial nerve dysfunction (e.g., ptosis) that may precede more overt

signs of impending airway compromise (e.g., difficulty swallowing,

respiratory insufficiency) necessitating endotracheal intubation and

mechanical ventilation.

Blood should be drawn for laboratory evaluation as soon as

possible. Important studies include a complete blood count to

determine the degree of hemorrhage or hemolysis and to detect

thrombocytopenia; blood type and cross-matching; assessment of

renal and hepatic function; coagulation studies such as prothrombin

time and fibrinogen level; measurement of fibrin degradation products such as D-dimer; measurement of creatine kinase for suspected

rhabdomyolysis; and testing of urine for blood or myoglobin. In

developing regions, the 20-min whole-blood clotting test can be

used to diagnose coagulopathy when access to laboratory tests is

limited. To perform this test, 1–2 mL of venous blood are placed in

a clean, dry glass receptacle (e.g., a test tube) and left undisturbed

for 20 min. The sample is then inverted. If the blood is still liquid

and a clot has not formed, coagulopathy is present. There have been

some recent studies examining the utility of thromboelastography

(TEG) in detecting venom-induced consumptive coagulopathy.

In vitro studies have shown that TEG may be more sensitive than

conventional coagulation studies in detecting coagulopathy at lower

venom concentrations; however, it remains to be seen if this bears

any clinical significance. At this time, there is insufficient evidence

to suggest routine use of TEG. Electrocardiography and chest radiography may be helpful in severe envenomations or when there is

significant comorbidity. After antivenom therapy (see below), laboratory values should be rechecked every 6 h until clinical stability

is achieved.

The mainstay of treatment of a venomous snakebite resulting in significant envenomation is prompt administration of specific antivenom. Antivenoms are produced by injecting animals

(generally horses or sheep) with venoms from medically important snakes. Once the stock animals develop antibodies to the

venoms, their serum is harvested and the antibodies are isolated for

antivenom preparation. The goal of antivenom administration is

to allow antibodies (or antibody fragments) to bind and deactivate

circulating venom components before they can attach to target

tissues and cause deleterious effects. Antivenoms may be monospecific (directed against a particular snake species) or polyspecific

(covering several species in a geographic region). Unless the species

are known to have homologous venoms, antivenoms rarely offer

cross-protection against snake species other than those used in

their production. Thus, antivenom selection must be specific for

the offending snake; if the antivenom chosen does not contain antibodies to that snake’s venom components, it will provide no benefit

and may lead to unnecessary complications (see below). In the

United States, assistance in finding appropriate antivenom can

be obtained from a regional poison control center, which can be

reached by telephone 24 h a day at (800) 222-1222.

For victims of bites by viperids or cytotoxic elapids, indications

for antivenom administration include significant progressive local

findings (e.g., soft-tissue swelling that crosses a joint, involves more

than half the bitten limb, or is rapidly spreading; extensive blistering

or bruising; severe pain) and any evidence of systemic envenomation (e.g., systemic symptoms or signs, laboratory abnormalities).

Caution must be used when determining the significance of isolated

pain or soft-tissue swelling after the bite of an unidentified snake

because the saliva of some relatively harmless species can cause

mild discomfort or edema at the bite site; in such bites, antivenoms

are useless and potentially harmful. Antivenoms have limited

efficacy in preventing local-tissue damage caused by necrotizing

venoms, as venom components bind to local tissues very quickly.

Nevertheless, antivenom should be administered as soon as the

need for it is identified to limit further tissue damage and systemic

3599 Disorders Caused by Venomous Snakebites and Marine Animal Exposures CHAPTER 460

effects. Antivenom administration after bites by neurotoxic elapids

is indicated at the first sign of neurotoxicity (e.g., cranial nerve

dysfunction, peripheral neuropathy). In general, antivenom is effective only in reversing active venom toxicity; it is of little benefit

in reversing effects that have already been established (e.g., renal

failure, established paralysis) and will improve only with time and

other supportive therapies.

Specific comments related to the management of venomous

snakebites in the United States and Canada appear in Table 460-1.

The package insert for the selected antivenom should be consulted

regarding species covered, method of administration, starting dose,

and need (if any) for redosing. Whenever possible, it is advisable

for health care providers to seek advice from experts in snakebite

management regarding indications for and dosing of antivenom.

Antivenom should be administered only by the IV route, and

the infusion should be started slowly, with the treating clinician at

the bedside ready to immediately intervene at the first signs of an

acute adverse reaction. In the absence of an adverse reaction, the

rate of infusion can be increased gradually until the full starting

dose has been administered (over a total period of ~1 h). Further

antivenom may be necessary if the patient’s acute clinical condition

worsens or fails to stabilize or if venom effects recur. The decision

to administer further antivenom to a stabilized patient should be

based on clinical evidence of the persistent circulation of unbound

venom components. For viperid bites, antivenom administration

should generally be continued until the victim shows definite

improvement (e.g., reduced pain, stabilized vital signs, restored

coagulation). Neurotoxicity from elapid bites may be more difficult

to reverse with antivenom. Once neurotoxicity is established and

endotracheal intubation is required, further doses of antivenom are

unlikely to be beneficial. In such cases, the victim must be maintained on mechanical ventilation until recovery, which may take

days to weeks.

Adverse reactions to antivenom administration include early

(anaphylaxis) and late (serum sickness) hypersensitivity reactions.

Clinical manifestations of early hypersensitivity may include tachycardia, rigors, vomiting, urticaria, dyspnea, laryngeal edema, bronchospasm, and hypotension. Although recommended by some

antivenom manufacturers, skin testing for potential early hypersensitivity is neither sensitive nor specific and is of no benefit. The

quality of antivenoms is highly variable worldwide; rates of acute

anaphylactic reactions to some of these products exceed 50%.

More recent data on North American snakebites suggest that the

incidence of anaphylaxis to Crotalidae Polyvalent Immune Fab

(CroFab®) (Ovine) (BTG International Inc., West Conshohocken,

PA) antivenom may be closer to 1.1%. There is some evidence

supporting routine pretreatment with low-dose SC epinephrine

(0.25 mg of 1:1000 aqueous solution) to prevent acute anaphylactic

reactions after antivenom infusion. Although widely practiced,

prophylactic use of antihistamines and glucocorticoids has not

proved beneficial. Modest expansion of the patient’s intravascular

volume with crystalloids may blunt episodes of acute hypotension

during antivenom infusion. Epinephrine and airway equipment

should always be immediately available. If the patient develops

an anaphylactic reaction to antivenom, the infusion should be

stopped temporarily and the reaction treated immediately with IM

epinephrine (0.01 mg/kg up to 0.5 mg), an IV antihistamine (e.g.,

diphenhydramine, 1 mg/kg up to 50 mg), and a glucocorticoid

(e.g., hydrocortisone, 2 mg/kg up to 100 mg). Once the reaction

has been controlled, if the severity of the envenomation warrants

additional antivenom, the dose should be restarted as soon as possible at a slower rate (5–10 mL/h) and titrated upward as tolerated.

In rare cases of refractory hypotension, a concomitant IV infusion

of epinephrine may be initiated and titrated to clinical effect while

antivenom is administered. The patient must be monitored very

closely during such therapy, preferably in an emergency department or intensive care setting. Serum sickness typically develops

1–2 weeks after antivenom administration and may present as myalgias, arthralgias, fever, chills, urticaria, lymphadenopathy, or renal

or neurologic dysfunction. Treatment for serum sickness consists

of systemic glucocorticoids (e.g., oral prednisone, 1–2 mg/kg daily)

until all symptoms have resolved, with a subsequent taper over

1–2 weeks. Oral antihistamines and analgesics may provide additional relief of symptoms.

Blood products are rarely necessary in the management of an

envenomated patient. The venoms of many snake species can

deplete coagulation factors and cause a decrease in platelet count

or hematocrit. Nevertheless, these components usually rebound

within hours after administration of adequate antivenom. If the

need for blood products is thought to be great (e.g., a dangerously

low platelet count in a hemorrhaging patient), these products

should be given only after adequate antivenom administration to

avoid fueling ongoing consumptive coagulopathy.

Rhabdomyolysis should be managed in standard fashion with

IV fluids and close monitoring of urine output. Victims who

develop acute renal failure should be evaluated by a nephrologist

and referred for hemodialysis or peritoneal dialysis as needed. Such

renal failure is usually due to acute tubular necrosis and is frequently reversible. If bilateral cortical necrosis occurs, however, the

prognosis for renal recovery is less favorable, and long-term dialysis

with possible renal transplantation may be necessary.

Most snake envenomations involve subcutaneous deposition

of venom. On occasion, venom can be injected more deeply into

muscle compartments, particularly if the offending snake was

large and the bite occurred on the hand, forearm, or anterior compartment of the lower leg. Intramuscular swelling of the affected

extremity may be accompanied by severe pain, decreased strength,

altered sensation, cyanosis, and apparent pulselessness—signs

suggesting a muscle compartment syndrome. If there is clinical

concern that subfascial muscle edema may be impeding tissue

perfusion, intracompartmental pressures should be measured by

a minimally invasive technique (e.g., with a wick catheter or digital readout device). If the intracompartmental pressure is high

(>30–40 mmHg), the extremity should be kept elevated while

antivenom is administered. If the intracompartmental pressure

remains elevated after 1 h of such therapy, a surgical consultation

should be obtained for possible fasciotomy. Although evidence

from animal studies suggests that fasciotomy may actually worsen

myonecrosis, compartmental decompression may still be necessary to preserve neurologic function. Fortunately, the incidence

of compartment syndrome is very low after a snakebite, with

fasciotomies required in <1% of cases. Nevertheless, vigilance is

essential.

Acetylcholinesterase inhibitors (e.g., edrophonium and neostigmine) may promote neurologic improvement in patients bitten

by snakes with postsynaptic neurotoxins. Snakebite victims with

objective evidence of neurologic dysfunction may receive a test dose

of acetylcholinesterase inhibitors, as outlined in Table 460-2. If they

exhibit improvement, additional doses of long-acting neostigmine

can be administered as needed. Acetylcholinesterase inhibitors are

not a substitute for endotracheal intubation or the administration

of appropriate antivenom when available.

Care of the bite wound includes simple cleansing with soap

and water; application of a dry, sterile dressing; and splinting of

the affected extremity with padding between the digits. Once

antivenom therapy has been initiated, the extremity should be

elevated above heart level to reduce swelling. Patients should

receive tetanus immunization as appropriate. Prophylactic antibiotics are generally unnecessary after bites by North American

snakes because the incidence of secondary infection is low. In

some regions, secondary bacterial infection is more common and

the consequences are serious; as such, prophylactic treatment with

broad-spectrum antibiotics may be appropriate. Antibiotics may

also be considered if misguided first-aid efforts included incision

or mouth suction of the bite site. Pain control may be achieved with

acetaminophen or opioid analgesics. Salicylates and nonsteroidal

anti-inflammatory agents should be avoided because of their potential effects on blood clotting.

3600 PART 14 Poisoning, Drug Overdose, and Envenomation

TABLE 460-1 Management of Venomous Snakebites in the United States and Canadaa

Pit Viper Bites: Rattlesnakes (Crotalus and Sistrurus spp.), Cottonmouth Water Moccasins (Agkistrodon piscivorus), and Copperheads

 (Agkistrodon contortrix)

• Stabilize airway, breathing, and circulation.

• Institute monitoring (vital signs, cardiac rhythm, and oxygen saturation).

• Establish two large-bore IV lines.

• If patient is hypotensive, administer normal saline bolus (20–40 mL/kg IV).

• Take thorough history and perform complete physical examination.

• Identify offending snake (if possible).

• Measure and record circumference of bitten extremity every 15 min until swelling has stabilized. Can take measurements every 1 h once stabilized.

• Order laboratory studies (CBC, blood type and cross-matching, metabolic panel, PT/INR/PTT, fibrinogen level, FDP, CK, urinalysis).

• If normal, repeat CBC and coagulation studies every 4 h until it is clear that no systemic envenomation has occurred.

• If abnormal, repeat every 6 h after antivenom administration until swelling has stabilized (see below).

• Determine severity of envenomation.

• None: fang marks only (“dry” bite)

• Mild: local findings only (e.g., pain, ecchymosis, nonprogressive swelling)

• Moderate: swelling that is clearly progressing, systemic symptoms or signs, and/or laboratory abnormalities

• Severe: neurologic dysfunction, respiratory distress, and/or cardiovascular instability/shock

• Contact regional poison control center.

• Locate and administer antivenom as indicated: Crotalidae Polyvalent Immune Fab (CroFab®) (Ovine) (BTG International Inc., West Conshohocken, PA) or Crotalidae

Immune F(ab’)2 (Anavip®) (Equine) (Instituto Bioclon S.A de C.V., Tlalpan CDMX, Mexico).

• Starting dose:

• Based on severity of envenomation

• None or mild: none

• Moderate: CroFab® (4–6 vials), Anavip® (10 vials)

• Severe: CroFab® (6 vials), Anavip® (10 vials)

• Dilute reconstituted vials in 250 mL of normal saline.

• Infuse IV over 1 h (with medical provider in close attendance).

• Start at rate of 25–50 mL/h for first 10 min.

• If there is no allergic reaction, increase rate to 250 mL/h.

• If there is an acute reaction to antivenom:

• Stop infusion.

• Treat with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).

• When reaction is controlled, restart antivenom as soon as possible (at rate of 5–10 mL/h; titrate up as tolerated).

• Monitor clinical status over 1 h.

• Stabilized or improved: Admit to hospital.

• Progressing or unimproved: Repeat starting dose. Continue this pattern until patient’s condition is stabilized or improved. Admit to ICU if possible.

• Blood products are rarely needed; if required, they should be given only after antivenom administration.

• Provide tetanus immunization as needed.

• Prophylactic antibiotics are unnecessary unless prehospital care included incision or mouth suction.

• Pain management: Administer acetaminophen and/or opioids as needed; avoid salicylates and nonsteroidal anti-inflammatory agents.

• Admit patient to hospital. (If there is no evidence of envenomation, monitor for 8–12 h before discharge.)

• Give additional antivenom: CroFab® (2 vials every 6 h for 3 additional doses), Anavip® (4 vials for recurrent coagulopathy).

• Monitor for evidence of rising intracompartmental pressures (see text).

• Provide wound care (see text).

• Start physical therapy (see text).

• At discharge, warn patient of possible recurrent coagulopathy and symptoms/signs of serum sickness. Schedule repeat laboratory testing to monitor

for recurrent coagulopathy.

Coral Snake Bites: Eastern coral snake (Micrurus fulvius), Texas coral snake (Micrurus tener), and Sonoran coral snake (Micruroides euryxanthus)

• Stabilize airway, breathing, and circulation.

• Institute monitoring (vital signs, cardiac rhythm, and oxygen saturation).

• Establish two large-bore IV lines and initiate normal saline infusion.

• Take thorough history and perform complete physical examination.

• Identify offending snake (if possible).

• Laboratory studies are unlikely to be helpful.

• Contact regional poison control center.

• Locate and administer antivenom as indicated: Antivenin (Micrurus fulvius) (Equine) (commonly referred to as North American Coral Snake Antivenin; Pfizer Inc.,

Philadelphia, PA).b

• Refer to antivenom package insert.

• Dilute 3–5 reconstituted vials in 250–500 mL of normal saline.

• Infuse IV over 1 h (with medical provider in close attendance).

• If signs of envenomation progress despite initial dosing, repeat starting dose; up to 10 vials total may be required.

(Continued)

3601 Disorders Caused by Venomous Snakebites and Marine Animal Exposures CHAPTER 460

TABLE 460-1 Management of Venomous Snakebites in the United States and Canadaa

• If there is an acute adverse reaction to antivenom:

• Stop infusion.

• Treat with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).

• When reaction is controlled, restart antivenom as soon as possible (at rate of 5–10 mL/h; titrate up as tolerated).

• If there is evidence of neurologic dysfunction (e.g., any cranial nerve abnormalities):

• Administer trial of acetylcholinesterase inhibitors (see Table 460-2).

• If there is evidence of difficulty swallowing or breathing, proceed with endotracheal intubation and ventilatory support (may be required for days to weeks).

• Provide tetanus immunization as needed.

• Prophylactic antibiotics are unnecessary unless prehospital care included incision or mouth suction.

• Admit patient to hospital (ICU) even if there is no evidence of envenomation; monitor for at least 24 h.

a

These recommendations are specific to the care of victims of venomous snakebites in the United States and Canada and should not be applied to bites in other regions of

the world. b

At the time of this writing, Lot L67530 of Antivenin had an extended expiration date of January 31, 2020.

Abbreviations: CBC, complete blood count; CK, creatine kinase; FDP, fibrin degradation products; ICU, intensive care unit; PT/INR/PTT, prothrombin time/international

normalized ratio/partial thromboplastin time.

(Continued)

Wound care in the days after the bite should include careful

aseptic debridement of clearly necrotic tissue once coagulopathy

has been fully reversed. Intact serum-filled vesicles or hemorrhagic blebs should be left undisturbed. If ruptured, they should

be debrided with sterile technique. Any debridement of damaged

muscle should be conservative because there is evidence that such

muscle may recover to a significant degree after antivenom therapy.

Physical therapy should be started as soon as possible to assist

the patient in returning to a functional state. The incidence of

long-term loss of function (e.g., reduced range of motion, impaired

sensory function) is unclear.

Any patient with signs of envenomation should be observed in

the hospital for at least 24 h. In North America, a patient with an

apparently “dry” viperid bite should be closely monitored for at least

8–12 h before discharge, as significant toxicity occasionally develops after a delay of several hours. The onset of systemic symptoms

commonly is delayed for a number of hours after bites by certain

elapids (including coral snakes, Micrurus species), some non–North

American viperids (e.g., the hump-nosed pit viper [Hypnale hypnale]), and sea snakes. Patients bitten by these snakes should be

observed in the hospital for at least 24 h. Admission to an intensive

care setting is advised for patients with progressive clinical findings

despite initial antivenom administration; those bitten in the head,

neck, or other high-risk sites; and those who develop an acute

hypersensitivity reaction to antivenom.

At hospital discharge, victims of venomous snakebites should

be warned about symptoms and signs of wound infection,

antivenom-related serum sickness, and potential long-term sequelae, such as pituitary insufficiency from Russell’s viper (D. russelii)

bites. If coagulopathy developed in the acute stages of envenomation, it can recur during the first 2–3 weeks after the bite as venom

antigens may have longer half-lives than their corresponding

antivenoms; in such cases, victims should be warned to avoid elective surgery or activities posing a high risk of trauma during this

period. Repeat laboratory tests (e.g., complete blood count, prothrombin time, fibrinogen level) should be scheduled to monitor for

recurrent coagulopathy. Outpatient analgesic treatment, wound

management, and physical therapy should be provided.

■ MORBIDITY AND MORTALITY

The overall mortality rates for victims of venomous snakebites are

low in regions with rapid access to medical care and appropriate

antivenoms. In the United States, for example, the mortality rate is <1%

for victims who receive antivenom. Eastern and western diamondback

rattlesnakes (Crotalus adamanteus and Crotalus atrox, respectively) are

responsible for the majority of snakebite deaths in the United States.

Snakes responsible for a large number of deaths in other countries

include cobras (Naja species), carpet and saw-scaled vipers (Echis

species), Russell’s vipers (D. russelii), large African vipers (Bitis species), lancehead pit vipers (Bothrops species), and tropical rattlesnakes

(C. durissus).

The incidence of morbidity—defined as permanent functional

loss in a bitten extremity—is difficult to estimate but is substantial.

Morbidity may be due to muscle, nerve, or vascular injury or to scar

contracture. Such morbidity can have devastating consequences for

victims in the developing world when they lose the ability to work and

provide for their families. In the United States, functional loss tends to

be more common and severe after rattlesnake bites than after bites by

copperheads (Agkistrodon contortrix) or water moccasins (Agkistrodon

piscivorus).

■ GLOBAL CONSIDERATIONS

In May 2019, the World Health Organization announced a comprehensive strategy to control and prevent snake envenomations worldwide,

with the goal to reduce the number of deaths and cases of disability

from snakebites by 50% by 2030. This strategy has been developed

around four central tenets: empowering and engaging communities,

ensuring safe and effective treatments, strengthening health systems,

and improving partnerships, coordination, and resources. In many

developing countries where snakebites are common, limited access to

medical care and antivenoms contributes to high rates of morbidity

and mortality. Recent data show that 6.85 billion people live within

the regions inhabited by snakes, with >10% of people living >1 h from

an urban center. Often, the available antivenoms are inappropriate

and ineffective against the venoms of medically important indigenous

snakes. In those regions, further research is necessary to determine

the actual impact of venomous snakebites and the specific antivenoms

needed in terms of both quantity and spectrum of coverage. Appropriate antivenoms must be available at the most likely first point of

medical contact for patients (e.g., primary health centers) in order to

minimize the common practice of referring victims to more distant,

higher levels of care for the initiation of antivenom therapy. Just as

important as getting the correct antivenoms into underserved regions

TABLE 460-2 Use of Acetylcholinesterase Inhibitors in Envenomations

by Neurotoxic Snakes and Cone Snails

1. Patients with clear, objective evidence of neurotoxicity (e.g., ptosis or

inability to maintain upward gaze) should receive a test dose of edrophonium

(if available) or neostigmine.

a. Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg with a minimum of

0.1 mg)

b. Treat with:

Edrophonium: 10 mg IV (children, 0.25 mg/kg)

or

Neostigmine: 0.02 mg/kg IV or IM (children, 0.04 mg/kg)

2. If objective improvement is evident after 30 min, treat with:

a. Neostigmine: 0.5 mg IV, IM, or SC (children, 0.01 mg/kg) every 1 h as

needed

b. Atropine: 0.6 mg as IV continuous infusion over 8 h (children, 0.02 mg/kg

over 8 h)

3. Closely monitor airway and perform endotracheal intubation if needed.

3602 PART 14 Poisoning, Drug Overdose, and Envenomation

is the need to educate populations about snakebite prevention and

train medical care providers in proper management approaches. Local

protocols written with significant input from experienced providers in

the region of concern should be developed and distributed. Those who

care for snakebite victims in these often-remote clinics must have the

skills and confidence required to begin antivenom treatment (and to

treat possible reactions) as soon as possible when indicated.

MARINE ENVENOMATIONS

The global incidence of marine envenomation is likely underestimated, as the majority of cases are mild. Much of the management

of envenomation by marine animals is supportive, but a few specific

antivenoms are available. This section provides general guidance,

and patient management should be tailored to the practice patterns

and known prevalence of specific venomous species in the region

(Fig. 460-4).

■ INVERTEBRATES

Cnidarians Cnidarians, such as hydroids, fire coral, jellyfish,

Portuguese men-of-war, and sea anemones, possess thousands of specialized stinging organelles called cnidocysts (a term that encompasses

nematocysts, ptychocysts, and spirocysts) distributed along their tentacles. Nematocysts contain a coiled hollow thread bathed in venom that

is discharged when provoked by mechanical stimuli, osmotic changes,

or other chemical stimuli (Fig. 460-5). The venom contains enzymes

(phospholipases, metalloproteases), pore-forming toxins, neurotoxins,

and nonprotein bioactive substances, such as tetramine, 5-hydroxytryptamine, histamine, and serotonin. Venom flows through the hollow thread into the victim’s skin. Cnidocysts that possess barbs on the

ends of their threads can penetrate human skin; thus, only a subset of

cnidarians are toxic to humans.

Victims usually report immediate burning, pruritus, paresthesias,

and painful throbbing with radiation. The skin becomes reddened,

darkened, edematous, and blistered and may show signs of superficial

necrosis. A minority of victims develop systemic toxicity affecting

the cardiovascular, respiratory, gastrointestinal, and nervous systems,

especially following stings from anemones, Physalia species, and scyphozoans. Anaphylaxis and secondary infection with marine bacteria

can also occur.

Hundreds of deaths have been reported, many of them caused by

Chironex fleckeri, Stomolophus nomurai, Physalia physalis, and Chiropsalmus quadrumanus. Irukandji syndrome is a potentially fatal

condition associated with envenomation by the Australian jellyfish

Carukia barnesi and Malo species. Symptoms generally manifest within

30 min and include hypertension; tachycardia; severe chest, abdominal,

and back pain; nausea and vomiting; and headache. In the most serious

cases, victims may develop cerebral hemorrhage, cerebral edema, cardiomyopathy, pulmonary edema, and systemic hypotension. Massive

release of endogenous catecholamines induced by venom components

appears to be the underlying cause of this syndrome.

Initial management should focus on removing the victim from the

water and decontaminating the skin. Drowning is a common cause

of death after significant Cnidarian envenomation. Once the victim

Chironex fleckeri-1

Key:

Physalia physalis Cone snails

Hapalochlaena maculosa Synanceia verrucosa Platypuses

FIGURE 460-4 Geographic distribution of venomous marine animals.

A B

Cnidocyte

(stinging cell)

Cnidocil (trigger)

Operculum

(lid)

Extended

thread

Barb

Coiled

thread

Nematocyst

(stinging

organelle)

Nucleus

FIGURE 460-5 Schematic of a nematocyst. A. Undischarged. Note coiled hollow

thread bathed in venom. B. Discharged.

3603 Disorders Caused by Venomous Snakebites and Marine Animal Exposures CHAPTER 460

is on land or a boat, the skin should be decontaminated with saline

or seawater. Providers wearing protective equipment should carefully

remove any adherent tentacles. Vinegar (5% acetic acid) appears to be

useful for relieving pain caused by a large number of species, especially

in the Indo-Pacific region where C. fleckeri and C. barnesi are common.

In that region, decontamination with vinegar should be followed by hot

water immersion up to 45°C (113°F). Vinegar may increase nematocyst

discharge in P. physalis and C. quinquecirrha, species common in the

United States. Victims in the United States should be decontaminated

with seawater and then have affected areas immersed in hot water.

Alternatively, vinegar may be tested on a small area of affected skin

to assess effects before performing complete decontamination. If hot

water is unavailable, commercial (chemical) cold packs or ice packs

applied over a thin dry cloth or plastic membrane can be effective in

alleviating pain, but do not denature venom components. In general,

rubbing leads to further stinging by adherent cnidocysts and should

be avoided.

After decontamination, topical application of a local anesthetic,

antihistamine, or glucocorticoid may be helpful for symptom control.

Persistent severe pain may be treated with opioid analgesics. Muscle

spasms may respond to IV diazepam (2–5 mg, titrated upward as

necessary). An antivenom is available from Seqirus (an affiliate of

Commonwealth Serum Laboratories) for stings from the box jellyfish

found in Australian and Indo-Pacific waters. Recent studies have

raised questions about the efficacy of the antivenom, and there are

no reports of survival directly attributable to its administration. Use

of the antivenom is still recommended when it is available but should

not replace aggressive supportive care (see “Sources of Antivenoms

and Other Assistance,” below). Adverse reactions to the antivenom

include early (anaphylaxis) and late (serum sickness) hypersensitivity

reactions. Acute allergic reactions should be treated with systemic

antihistamines, glucocorticoids, and epinephrine when appropriate. Delayed serum sickness is relatively common, typically occurs

5–10 days after antivenom administration, and generally responds well

to 5 days of oral glucocorticoids.

Treatment of Irukandji syndrome may require administration of opioid analgesics and aggressive treatment of hypertension. Appropriate

antihypertensive agents include phentolamine, nicardipine, nitroprusside, nitroglycerin, and IV magnesium sulfate. Beta-adrenergic antagonists should be avoided due to the risk of worsening hypertension

from unopposed alpha-adrenergic effects. All victims with systemic

reactions should be observed for at least 6–8 h for rebound from any

therapy and should be monitored for cardiac arrhythmias.

Safe Sea (Nidaria Technology Ltd.), a “jellyfish-safe” sunblock

applied to the skin before an individual enters the water, inactivates the

recognition and discharge mechanisms of nematocysts; it may prevent

or diminish the effects of coelenterate stings. Whenever possible, a dive

skin or wetsuit should be worn when entering ocean waters.

Sea Sponges Many sponges produce irritants known as crinotoxins. Touching a sea sponge may result in allergic contact dermatitis.

Irritant dermatitis may result if the sponge’s spicules of silica or calcium

carbonate penetrate the skin. Affected skin should be dried and adhesive tape, a commercial facial peel, or a thin layer of rubber cement

used to remove embedded spicules. Vinegar should then be applied

immediately, with repeated application for 10–30 min three or four

times a day thereafter. Corticosteroid cream or oral antihistamines may

provide additional symptomatic relief. Systemic corticosteroids should

be reserved for severe allergic reactions (such as severe vesiculation) or

erythema multiforme. Mild reactions generally subside within 7 days.

Severe envenomation can lead to fevers, chills, and muscle spasms.

Desquamation of affected skin has also been described and can occur

up to 2 months after exposure. Outpatient wound care is essential to

monitor for secondary infection.

Annelid Worms Annelid worms (bristleworms) are covered with

chitinous spines capable of penetrating human skin and producing

dermal symptoms similar to those of Cnidarian envenomation, including pain, prickling, urticaria, and discoloration. Pain usually subsides

within hours, but urticaria can persist for days and discoloration for

weeks (Fig. 460-6). Victims should be instructed not to scratch as it may

fracture the spines, complicating their removal and increasing the risk

of secondary infection. Visible bristles should be removed with forceps,

adhesive tape, rubber cement, or a commercial facial peel. Soaking the

affected skin in vinegar may provide additional relief. Severe inflammation can be treated with systemic antihistamines or corticosteroids.

Sea Urchins Venomous sea urchins possess either hollow, venomfilled, calcified spines or pincer-like, flexible pedicellariae with venom

glands. The venom contains bradykinin-like substances, steroid glycosides, hemolysins, proteases, serotonin, and cholinergic substances.

Envenomation causes immediate onset of severe pain, edema, and erythema. If multiple spines penetrate the skin, the patient may develop

systemic symptoms, including nausea, vomiting, numbness, muscular

paralysis, and respiratory distress. Synovitis and arthritis have been

reported after joint-space penetration. Retained spines can cause the

formation of painful granulomas.

The affected part should be immersed in hot water up to 45°C

(113°F). Embedded spines should be removed with care as they may

fracture and leave remnants lodged in the victim. Soft-tissue radiography, ultrasonography, or MRI can be used to evaluate for the presence

of retained fragments. Surgical removal may be necessary, especially if

the spines are in close proximity to vital structures (e.g., joints, neurovascular bundles). Granulomas from retained spines are amenable

to excision or intralesional injection with triamcinolone hexacetonide.

Arthritis from joint penetration has been treated with synovectomy.

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

viscous venom that coats the surface of its spines (Fig. 460-7). The

venom contains saponins with hemolytic, myotoxic, hepatotoxic, and

anticoagulant properties. Skin puncture causes immediate pain, bleeding, and local edema. Multiple punctures may result in reactions such

FIGURE 460-6 Rash on the hand of a diver from the spines of a bristleworm.

(Courtesy of Paul Auerbach, with permission.)

FIGURE 460-7 Spines on the crown-of-thorns sea star (Acanthaster planci).

(Courtesy of Paul Auerbach, with permission.)

3604 PART 14 Poisoning, Drug Overdose, and Envenomation

as local muscle paralysis. The spines fracture easily and retained fragments may cause granulomatous lesions and synovitis. Envenomated

persons benefit from acute immersion therapy in hot water, local

anesthesia, wound cleansing, imaging, and possible exploration to

remove spines and foreign material. The hemolytic and hepatotoxic

components are less heat labile than other venom constituents; hot

water immersion may not prevent systemic toxicity.

Sea Cucumbers Sea cucumbers excrete holothurin (a cantharidinlike liquid toxin) from their anus. This toxin is then concentrated in

the tentacular organs that are projected when the animal is threatened.

Underwater, holothurin induces minimal contact dermatitis but can

cause significant corneal and conjunctival irritation should ocular

contact occur. A severe reaction can lead to blindness. Skin should be

decontaminated with vinegar. The eyes should be anesthetized with

1–2 drops of 0.5% proparacaine and irrigated copiously with normal

saline, with subsequent slit-lamp examination to identify corneal

defects.

Cone Snails Cone snails use a detachable dartlike tooth to inject

conotoxins into victims. Numerous conotoxins have been identified

including some that interfere with neuronal and cardiac ion channels

and others that antagonize neuromuscular acetylcholine receptors.

Punctures result in small, painful wounds followed by local ischemia, cyanosis, and numbness. Syncope, dysphagia, dysarthria, ptosis, blurred vision, and pruritus also have been documented. Some

envenomations induce paralysis leading to respiratory failure. Cardiac

dysrhythmias have also been reported. Pressure-immobilization (see

“Octopuses,” below), hot-water soaks, and local anesthetics have been

successful for localized symptoms. Respiratory failure may necessitate mechanical ventilation. Cardiac dysrhythmias should be treated

with electrical cardioversion as ion channel-blocking antidysrhythmic

medications may worsen the dysrhythmia. No antivenom is available.

Edrophonium has been recommended as therapy for paralysis if an

edrophonium test is positive (see Table 460-2).

Octopuses Serious envenomations and deaths have followed bites

of Australian blue-ringed octopuses (Hapalochlaena maculosa and

Hapalochlaena lunulata). The classic blue rings appear only when

the animal is threatened. These species are not aggressive and human

envenomations have typically occurred when handling the octopus.

Their salivary glands contain symbiotic bacteria that produce tetrodotoxin, a potent sodium channel blocker that inhibits transmissions in

the peripheral nervous system. The bite is minimally painful but oral

and facial numbness develop within minutes of a serious envenomation. Mild weakness can rapidly progress to total flaccid paralysis.

Mentation is typically unaffected. The venom can also cause peripheral

vasodilation leading to profound hypotension. Deaths from these

envenomations are due to respiratory failure or vasodilatory shock and

hypoperfusion.

Immediately after envenomation, a wide circumferential pressureimmobilization bandage should be applied over a gauze pad placed

directly over the sting. The dressing should be applied at venouslymphatic pressure with the preservation of distal arterial pulses, and

the limb should be splinted. The bandage can be released when the

victim has been transported to a medical facility. There is no antidote and treatment is supportive. Respiratory failure may necessitate

mechanical ventilation. Appropriate analgesia and sedation are critical

as mental status is generally unaffected even in cases of complete paralysis. Hypotension should be treated with crystalloid and vasopressors

if needed. In animal studies, phenylephrine and norepinephrine were

more effective than dopamine or epinephrine for treatment of vasodilatory shock. Recovery usually occurs within 24−48 h and long-term

sequelae are uncommon unless related to hypoxia or hypoperfusion.

Tetrodotoxin is also found in the flesh of fish in the order Tetraodontiformes, which contains a number of “pufferfish” including blowfish,

globefish, and balloonfish. The toxin can be absorbed orally when

these fish are consumed. Fugu, a traditional Japanese delicacy, is a

reported source of poisoning. When properly prepared by a licensed

chef, fugu is meant to contain a sufficient dose of tetrodotoxin to cause

mild perioral paresthesia without systemic toxicity. When larger doses

of the toxin are consumed due to improper preparation, symptoms are

similar to envenomation by the blue-ringed octopus.

■ VERTEBRATES

As for all penetrating injuries, first-aid care should be provided and

tetanus immunization administered when indicated. Victims should

be monitored for secondary infection by aquatic bacteria such as Vibrio

species and Aeromonas hydrophila. Risk of infection is much higher if

spines and needles remain embedded.

Stingrays A stingray injury is both an envenomation and a traumatic wound. Stingrays possess serrated spines with venom glands

that can easily penetrate human skin. The venom contains serotonin,

5′-nucleotidase, and phosphodiesterase. Victims experience severe

pain, bleeding, and edema at the site of injury that peak within

30−60 min and may persist for up to 2 days. Penetrating injuries to the

thorax and heart as well as lacerations to major vessels (especially of the

lower extremity) have been reported. The wound often becomes ischemic in appearance and heals poorly, with adjacent soft-tissue swelling

and prolonged disability. Systemic effects of the venom include weakness, diaphoresis, nausea, vomiting, diarrhea, hypotension, dysrhythmias, syncope, seizures, muscle cramps, fasciculations, and paralysis.

While the venom effects can be fatal in rare cases, most deaths are

attributable to the traumatic injury.

Stonefish Stonefish (Synanceia species) are members of the Scorpaenidae family and generally considered the most venomous bony

fish in the world. Their venom contains pore-forming toxins, proteases, hyaluronidase, 5’-nucleotidase, acetylcholinesterase, and cardiac calcium channel-blockers. The venom is delivered through 12 or

13 dorsal, 2 pelvic, and 3 anal spines when provoked by mechanical

stimuli. Victims experience immediate, intense pain that peaks within

90 min, local edema, and wound cyanosis. Local symptoms most often

resolve within 12 h but can persist for days. Signs of systemic toxicity include abdominal pain, vomiting, delirium, seizures, paralysis,

respiratory distress, dysrhythmias, and congestive heart failure. An

antivenom from Seqirus (see “Sources of Antivenoms and Other Assistance,” below) can be used in cases of severe envenomation but should

not replace supportive care.

Lionfish Also members of the family Scorpaenidae, lionfish (Pterois species) are much less toxic to humans than stonefish. The

venom is delivered by curved dorsal spines and contains heat-labile,

high-molecular-weight proteins. Reported symptoms include localized

pain, blistering, edema, sensory changes (paresthesia, anesthesia, or

hyperesthesia), and necrosis (rare).

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

keratinous spur on each hind limb that is connected to a venom gland

within the upper thigh. Skin puncture causes soft-tissue edema and

pain that may last for days to weeks. Care is supportive and should

focus on appropriate analgesia and wound care. Hot water immersion

does not appear to be beneficial.

TREATMENT

Marine Vertebrate Stings

The stings of all marine vertebrates are treated in a similar fashion.

Antivenom is currently available only for stonefish and severe

scorpionfish envenomations. The affected part should be immersed

immediately in hot water up to 45°C (113°F) for 30–90 min or

until there is significant pain relief. Recurrent pain may respond

to repeated hot water treatment. Systemic opioids as well as wound

infiltration or regional nerve block with local anesthetics can help

alleviate pain and facilitate wound exploration and debridement.

Advanced imaging (in particular, ultrasound or MRI) may be helpful in identification of retained foreign bodies. After exploration

and debridement, the wound should be irrigated vigorously with