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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e >

Chapter 201: PesticidesGuillermo Burillo-Putze; Santiago Nogue Xarau

INTRODUCTION

Pesticides include insecticides, herbicides, and rodenticides.1 Pesticide toxicity results from intentional,accidental, and occupational exposures. More than 300,000 pesticide-poisoning deaths occur each year

worldwide, with insecticides accounting for the majority of deaths.2 Pesticides are marketed as multipleformulations, o�en under shared brand names; therefore, complex clinical syndromes can result fromexposure to both active and other ingredients. Ingredients in proprietary formulations, such as petroleumdistillates, are inert to pests during typical exposures, but can be toxic to humans, especially with excessiveamounts. Pesticides have class-specific toxicities, with many having both local and systemic e�ects.Management o�en includes consultation with a hazardous materials and toxins database or with a poisoncontrol center. Supportive care is of utmost importance in pesticide poisonings, but for some compounds,antidotes are essential.

The World Health Organization classifies pesticides according to toxicity based on the median lethal dose fororal and dermal exposure in rats. This classification has been criticized because human case-fatality ratesdisplay large variation for compounds within the same chemical and/or World Health Organization toxicity

classification.3 Toxicity classification should not be used to predict severity a�er human exposure.

INSECTICIDES

Chemical insecticides are toxic to the nervous system, with acute and chronic manifestations, as well asdelayed sequelae a�er acute exposure. Six major classes of insecticides are in common use (Table 201-1).Other compounds used to control insects include repellants.

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TABLE 201-1

Insecticides and Repellants

Insecticides Repellants

Organophosphates Amitraz

Carbamates N,N-diethyl-3-methylbenzamide (DEET)

Organochlorines

Pyrethrins/pyrethroids

Neonicotinoids

Nereistoxin analogs

ORGANOPHOSPHATES

Commonly used organophosphates include diazinon, acephate, malathion, parathion, and chlorpyrifos andmany others in di�erent countries. Organophosphate and carbamate compounds are the insecticides most

commonly associated with systemic illness.4,5 Potency among organophosphates varies; highly potentcompounds, such as parathion, are used primarily in agriculture, whereas those of intermediate potency,including coumaphos and trichlorfon, are used in animal care. Diazinon and chlorpyrifos were phased outfrom household use in the United States in 2000 due to neurotoxicity, particularly on the developing brains of

children, but they continue to be used in many other parts of the world.6 The organophosphate structure canbe modified into chemical agents of mass destruction (see chapter 8, Chemical Disasters).

Organophosphate poisoning results primarily from accidental exposure in the home, recently sprayed or

fogged areas using pesticide applicators, agriculture, industry, and the transport of these products.4

Inadvertent exposure can occur from flea-dip products in pet groomers and children and from contaminated

food. In addition, these chemicals are involved in intentional poisonings from homicides and suicides.7

Systemic absorption of organophosphates occurs by inhalation and a�er mucous membrane, transdermal,transconjunctival, and GI exposure.

Pathophysiology

Organophosphate and carbamate compounds inhibit the enzyme cholinesterase.1 Acetylcholinesterase (trueor red blood cell acetylcholinesterase) is found primarily in erythrocyte membranes, nervous tissue, and

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skeletal muscle. Plasma cholinesterase (pseudocholinesterase or butyrylcholinesterase) is found in theserum, liver, pancreas, heart, and brain. Inhibition of cholinesterase leads to acetylcholine accumulation atnerve synapses and neuromuscular junctions, resulting in overstimulation of acetylcholine receptors. Thisinitial overstimulation is followed by paralysis of cholinergic synaptic transmission in the CNS, in autonomicganglia, at parasympathetic and some sympathetic nerve endings (e.g., sweat glands), and in somaticnerves. Excess acetylcholine results in a cholinergic crisis that manifests as a central and peripheral clinicaltoxidrome.

Organophosphate compounds bind irreversibly to acetylcholinesterase, thus inactivating the enzymethrough the process of phosphorylation. Aging is a term describing the permanent, irreversible binding ofthe organophosphorus compound to the cholinesterase. The time to aging is highly variable among di�erentagents and can range from minutes to a day or more. Once aging occurs, the enzymatic activity ofcholinesterase is permanently destroyed, and new enzyme must be resynthesized over a period of weeksbefore clinical symptoms resolve and normal enzymatic function returns. Antidotes must be given beforeaging occurs to be e�ective.

Clinical Features

Clinical presentations depend on the specific agent involved, the quantity absorbed, and the route of

exposure.7,8 Organophosphate insecticide poisoning can have substantial variability in clinical course,

response to treatment, and outcome.7 Four clinical syndromes are described following organophosphateexposure: acute poisoning, intermediate syndrome, chronic toxicity, and organophosphate-induced delayed

neuropathy.9

In acute organophosphate poisoning, most poisoned patients are symptomatic within the first 8 hours andnearly all within the first 24 hours. Organophosphate agents such as malathion are associated with localirritation of the skin and respiratory tract with resulting dermatitis and wheezing, respectively, withoutevidence of systemic absorption.

Acute organophosphate poisoning results in CNS, muscarinic, nicotinic, and somatic motor manifestations(Table 201-2). In mild to moderate poisoning, symptoms occur in various combinations. Time to symptomonset varies according to exposure route; it is most rapid with inhalation and least rapid with transdermalabsorption; however, dermatitis or skin excoriation may hasten this. Symptoms can occur within minutesa�er massive ingestion that is uniformly fatal.

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*The correlation between cholinesterase activity, clinical symptoms, and atropine dose is inconsistent, and treatment

should be guided predominately by clinical symptoms.

TABLE 201-2

Acute Organophosphate Poisoning Severity Grading*

Severity

Butyrylcholinesterase

Activity (% normal)

Measured from

Plasma

Acetylcholinesterase

Activity (% normal)

Measured from Red

Blood Cells

Clinical Features

Typical Initial

Atropine

Amount to

Control

Symptoms

Mild 40–50 50–90 Lightheadedness, nausea,

headache, dyspnea

Lacrimation, rhinorrhea,

salivation, diaphoresis

<2 milligrams

IV/IM

Moderate 10–40 10–50 Restless, confusion,

vomiting, diarrhea,

drowsiness

Autonomic instability:

bradycardia or tachycardia,

hypotension or

hypertension, miosis or

mydriasis

Muscle fasciculations

Bronchorrhea and

bronchospasm

2–10

milligrams

IV/IM

Severe <10 <10 Coma, seizures, flaccid

paralysis, urinary or fecal

incontinence, respiratory

arrest

>10

milligrams

IV/IM

CNS symptoms of cholinergic excess include anxiety, restlessness, emotional lability, tremor, headache,dizziness, mental confusion, delirium, hallucinations, and seizures. Coma with depression of respiratory andcirculatory centers may result. Inhibition of acetylcholinesterase in the parasympathetic system producesmuscarinic e�ects (Table 201-3).

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TABLE 201-3

Mnemonics for the Muscarinic E�ects of Cholinesterase Inhibition

S Salivation

L Lacrimation

U Urinary incontinence

D Defecation

G GI pain

E Emesis

D Defecation

U Urination

M Muscle weakness, miosis

B Bradycardia, bronchorrhea, bronchospasm

E Emesis

L Lacrimation

S Salivation

"Killer B's" Bradycardia, bronchorrhea, bronchospasm

Acetylcholine is the presynaptic neurotransmitter at nicotinic receptors in the sympathetic ganglia andadrenal medulla. Inhibition of acetylcholinesterase at these locations results in sympathetic stimulation,producing pallor, mydriasis, tachycardia, and hypertension. In most patients, parasympathetic stimulationusually predominates, but mixed autonomic e�ects are common.

Nicotinic stimulation at neuromuscular junctions results in muscle fasciculations, cramps, and muscleweakness. This syndrome may progress to paralysis and areflexia, making it di�icult to detect seizureactivity. Respiratory muscle paralysis can lead to ventilatory failure.

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Abdominal pain is common with rare cases of pancreatitis and peritonitis.10 The clinical course may becomplicated by broncho-aspiration of gastric contents contributing to respiratory distress. Many of theseinsecticide preparations contain hydrocarbons that act as solvents, and in cases of aspiration, they causelipoid pneumonia, with severe respiratory failure.

More lipid-soluble organophosphates may not produce immediate symptoms of toxicity, but instead producedelayed sequelae. Low-grade chronic organophosphate exposures occur among farm workers, pesticide

manufacturing plant workers, exterminators, and patients taking cholinergic ophthalmologic preparations.11

Symptoms and signs are o�en less dramatic and nonspecific, occurring without the cholinergic syndrome.

An intermediate syndrome may occur 1 to 5 days a�er an organophosphate exposure, reported in up to 40%

of patients following ingestion.12 Clinical features include paralysis of neck flexor muscles, musclesinnervated by the cranial nerves, proximal limb muscles, and respiratory muscles; respiratory support maybe needed. Symptoms or signs of cholinergic excess are absent in this syndrome. Electromyography may

assist in making the diagnosis.13 Aggressive, early antidote therapy and supportive measures may prevent orameliorate the severity of this syndrome. Symptoms usually resolve within 7 days. Nerve gas poisoning hasnot been reported to cause the intermediate syndrome.

Chronic toxicity is seen primarily in agricultural workers with daily exposure, manifesting as symmetrical

sensorimotor axonopathy.14 This mixed sensorimotor syndrome may begin with leg cramps and progress toweakness and paralysis, mimicking features of the Guillain-Barré syndrome.

Organophosphate-induced delayed neuropathy is characterized by cognitive dysfunction, impaired memory,

mood changes, autonomic dysfunction, peripheral neuropathy, and extrapyramidal signs.11 Chronic fatiguesyndrome and multiple chemical sensitivity have been reported in some patients, predominantly female,

a�er exposure to very low doses of organophosphate insecticides.15 Children are at greater risk of toxicitywhen exposed due to smaller body size and lower baseline levels of cholinesterase activity.

Chemical warfare nerve agents, such as soman, sarin, tabun, and VX, are organophosphate compounds thatinactivate acetylcholinesterases. They are rapid acting and extremely potent; death can occur within minutesof inhalation or dermal exposure, as occurred in the subway terrorist attack in Tokyo 1985. Soman ageswithin minutes, giving little time to administer antidotes.

Diagnosis

Diagnosis and treatment are based on history and the presence of a suggestive toxidrome; laboratorycholinesterase assays and reference laboratory testing for specific compounds take time and havelimitations, and waiting for results delays administration of potentially life-saving therapy. Diagnosis is o�endi�icult due to a constellation of clinical findings that can be variable in both acute and chronic poisonings.

Point-of-care testing tools are in development.16

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Noting a characteristic hydrocarbon or garlic-like odor may assist in diagnosis. The cholinergic toxidromemay vary depending on the predominance of muscarinic, nicotinic, and CNS manifestations and the severityof the intoxication. Organophosphate insecticide poisoning should be considered in the di�erentialdiagnosis of a patient with altered mental status and pinpoint pupils. Miosis and muscle fasciculations areconsidered reliable signs of organophosphate toxicity.

Cholinesterase activity is used to assess potential toxicity, with red cell acetylcholinesterase enzymaticactivity a more accurate indicator of synaptic cholinesterase inhibition, but plasma butyrylcholinesterase iseasier to assay and more available (Table 201-2). The degree of cholinesterase inhibition necessary toproduce symptomatic illness is variable, so although cholinesterase levels should correlate with toxicity,there is large individual variability in baseline measurements, and standardization of normal ranges amonglaboratories is poor, so deviation from a symptomatic patient's baseline may be significant when values arereported within the normal range for the testing laboratory.

When the cholinesterase function falls gradually, as in chronic exposure, clinical symptoms may be subtle.Plasma butyrylcholinesterase levels may be depressed in genetic variants, chronic disease states, liverdysfunction, cirrhosis, malnutrition and low serum albumin states, neoplasm, infection, and pregnancy. Redblood cell acetylcholinesterase is a�ected by factors that influence the circulating life of erythrocytes such ashemoglobinopathies. Unless pralidoxime is given before aging occurs, plasma butyrylcholinesterase takes upto 4 to 6 weeks and red blood cell acetylcholinesterase takes as long as 90 to 120 days to return to baselinea�er exposure.

Routine laboratory test abnormalities are nondiagnostic but may include evidence of pancreatitis, hypo- orhyperglycemia, leukocytosis, and abnormal liver function. In severe cases, a chest radiograph may showpulmonary edema. The ECG may be abnormal and correlate with the degree of toxicity and outcome.Common abnormalities include ventricular dysrhythmias, torsade de pointes, and idioventricular rhythms.Atrioventricular blocks and prolongation of the QT interval are common. A prolonged QTc interval correlates

with severity and mortality in severe organophosphate poisoning.17 Electromyography may identify andquantify acetylcholinesterase inhibition at neuromuscular junctions.

Treatment

Treatment consists of airway control, intensive respiratory support, general supportive measures,

decontamination, prevention of absorption, and the administration of antidotes (Table 201-4).9,18,19 Therapyshould not be withheld pending determination of cholinesterase levels.

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TABLE 201-4

Treatment for Organophosphate Poisoning

Decontamination Protective clothing must be worn to prevent secondary poisoning of healthcare workers.

Handle and dispose of all clothes as hazardous waste.

Wash patient with soap and water.

Handle and dispose of water runo� as hazardous waste.

Monitoring Cardiac monitor, pulse oximeter, 100% oxygen.

Gastric lavage No proven benefit (see text).

Activated

charcoal

No proven benefit (see text).

Urinary

alkalinization

No proven benefit (see text).

Atropine 1–3 milligrams IV in an adult or 0.01–0.04 milligram/kg IV (but never <0.1 milligram per

dose) in children.

Repeat every 5 min until tracheobronchial secretions attenuate.

Followed by continuous infusion to maintain the anticholinergic state.

Dose varies from 0.4 to 4 milligrams/h IV infusion in adults.

Pralidoxime No proven benefit (see text).

1–2 grams for adults or 20–40 milligrams/kg IV (up to 1 gram) in children, mixed with

normal saline and infused over 5–10 min.

Followed by continuous infusion: 500 milligrams/h in adults or 5–10 milligrams/kg per

hour in children.

Seizures Benzodiazepines IV.

In cases of acute cutaneous exposure, protective clothing must be worn to prevent secondary poisoning of

healthcare workers.20 Neoprene or nitrile gloves should be used instead of latex. Patients with suspectedexposure must be removed from the contaminated environment. All clothes and accessories must be

removed completely, placed in plastic bags, and disposed of as hazardous materials.21 The patient isimmediately decontaminated externally with copious amounts of a mild detergent such as dishwashingliquid and water. Decontamination includes the scalp, hair, fingernails, skin, conjunctivae, and skin folds.Body fluids should be treated as contaminated. Abrasion or irritation of the skin should be avoided.

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Contaminated runo� water should be contained and disposed of as hazardous material. Instruments usedcan be decontaminated using chlorine bleach.

Patients with acute exposures should be placed on oxygen, a cardiac monitor, and pulse oximeter. A 100%nonrebreather mask will optimize oxygenation in the patient with excessive airway secretions andbronchospasm; however, atropine administration should not be delayed or withheld if oxygen is not

immediately available.22 Gentle suction will assist in clearing airway secretions from hypersalivation,bronchorrhea, or emesis. Coma, seizures, respiratory failure, excessive respiratory secretions, or severebronchospasm necessitate endotracheal intubation. An IV line should be established with baseline bloodsampling and determination of cholinesterase levels. A nondepolarizing agent should be used whenneuromuscular blockade is needed. Succinylcholine is metabolized by plasma butyrylcholinesterase, andtherefore, prolonged paralysis may result. Hypotension is initially treated with fluid boluses of isotoniccrystalloid.

Gastric lavage is widely used in Asia following organophosphate ingestion despite the lack of evidence for

improved outcome.19,23 Given the sometimes rapid onset of symptoms a�er ingestion, it is unlikely thatgastric lavage will be of benefit except in patients who present within 2 hours a�er a large ingestion.Activated charcoal is sometimes recommended because organophosphates do bind in vitro, although there

is no evidence that single or multiple doses of activated charcoal improve patient outcome.19 Urinaryalkalinization is o�en used in Brazil and Iran for organophosphate poisoning, but there is no controlled

evidence that shows benefit.19 Hemodialysis, hemofiltration, and hemoperfusion are of no proven value.19

Atropine is the antidote for significant organophosphate poisonings (Table 201-4).9,18,19 Atropine, acompetitive antagonist of acetylcholine at central and peripheral muscarinic receptors, will reverse thee�ects secondary to excessive cholinergic stimulation. The dose is repeated every 5 minutes until copioustracheobronchial secretions attenuate; large amounts may be necessary, in the order of hundreds ofmilligrams in massive ingestions. Pupillary dilatation is not a therapeutic end point. Tachycardia is not acontraindication to the use of atropine in organophosphorus poisoning because tachycardia can occursecondary to bronchospasm or bronchorrhea with hypoxia, which can be reversed with atropine.

The initial atropine should be IV when possible, but 2 to 6 milligrams IM should be considered when IV accessis not possible. Normally, this initial dose of atropine should produce antimuscarinic symptoms; therefore,absence of anticholinergic symptoms a�er an initial dose is indicative of organophosphate poisoning. Oncean e�ective amount of atropine has been given, an infusion should be started to maintain an anticholinergic

state; the dose required varies according to severity,24 and prolonged therapy may be necessary.Importantly, atropine does not reverse muscle weakness.

Glycopyrrolate, an alternate anticholinergic agent, may be used, but dosing is not well defined, and there is

no proven benefit compared to atropine.19 Nebulized atropine or ipratropium may be used to improvepulmonary symptoms. Glycopyrrolate and ipratropium do not cross the blood–brain barrier and areine�ective in treating central neurologic symptoms.

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Compounds called oximes are used to displace organophosphates from the active site of

acetylcholinesterase, thus reactivating the enzyme.9,18,19 Pralidoxime is the oxime in common use,ameliorating muscarinic, nicotinic, and CNS symptoms. Importantly, pralidoxime reverses muscle paralysis ifgiven early, before aging occurs. If possible, blood samples for acetylcholinesterase levels are obtainedbefore administration of pralidoxime, but it is important that pralidoxime be administered as soon aspossible before permanent and irreversible aging occurs. Although pralidoxime is more e�ective in acutethan in chronic intoxications, it is recommended for use even a�er >24 to 48 hours a�er exposure.

Response to pralidoxime therapy with a decrease in muscle weakness and fasciculations and relief ofmuscarinic e�ects with atropine usually occurs within 10 to 40 minutes of administration. Pralidoxime canalso be given by the IM route. A continuous infusion is preferable to repeated bolus dosing if paralysis doesnot resolve a�er the initial dose or if paralysis returns. The pralidoxime dose recommended by the WorldHealth Organization is a 30-milligram/kg IV bolus followed by an IV infusion of 8 milligrams/kg per hour.

Pralidoxime should be continued for 24 to 48 hours while monitoring acetylcholinesterase levels. Despitetheoretical and experimental benefit and worldwide clinical use, current evidence is inadequate to show thatoximes, such as pralidoxime, reduce mortality or complication rate in acute organophosphate

poisoning.19,25,26 Pralidoxime is not recommended for asymptomatic patients or for patients with knowncarbamate exposures presenting with minimal symptoms.

Seizures are treated with airway protection, oxygen, atropine, and benzodiazepines.19 Atropine may preventor abort seizures due to cholinergic overstimulation that occur within the first few minutes. Pulmonaryedema and bronchospasm are treated with oxygen, intubation, positive-pressure ventilation, atropine, andpralidoxime. Succinylcholine, ester anesthetics, and β-adrenergic blockers may potentiate poisoning andshould be avoided.

Disposition and Follow-Up

Minimal exposures may require only decontamination and 6 to 8 hours of observation in the ED to detectdelayed e�ects. Reexposure should be avoided because sequential exposures can have cumulative toxicity,so patients returning to work should be limited from further exposure. All clothing, including shoes and belts,should be discarded properly as hazardous materials and not returned to the patient; recrudescence of

poisoning has occurred from contaminated clothes and leather, even a�er washing or cleaning.21

Admission to the intensive care unit is necessary for significant poisonings. Most patients respond topralidoxime therapy with an increase in acetylcholinesterase levels within 48 hours. If there is no posthypoxicbrain damage, and if the patient is treated early, symptomatic recovery occurs in 10 days. If toxins are fatsoluble, the patient may be symptomatic for prolonged periods of time and dependent on continuouspralidoxime infusion. During this period, which may last weeks while awaiting resynthesis of new enzyme,supportive care and respiratory support may be needed. The end point of therapy is determined by theabsence of signs and symptoms on withholding pralidoxime therapy.

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Following an acute exposure, the patient may have neurologic sequelae, such a paresthesias or limb

weakness, along with nonspecific symptoms lasting days to months.27 Death from organophosphatepoisoning usually occurs in 24 hours in untreated patients, usually from respiratory failure secondary to

paralysis of respiratory muscles,28 neurologic depression, or bronchorrhea.

CARBAMATES

The carbamate insecticides (aldicarb, carbofuran, carbaryl, ethienocarb, fenobucarb, oxamyl, methomyl,pirimicarb, propoxur, and trimethacarb) are cholinesterase inhibitors that are structurally related to the

organophosphate compounds.1 These agents are primarily used as insecticides, but illegally imported

rodenticides may contain aldicarb.29

Pathophysiology

Carbamates can be toxic a�er dermal, inhalation, and GI exposure. Carbamates transiently and reversiblybind to and inhibit the cholinesterase enzyme. Regeneration of enzyme activity by dissociation of thecarbamyl-cholinesterase bond occurs within minutes to a few hours involving rapid, spontaneous hydrolysisof the carbamate-cholinesterase bond. Therefore, aging does not occur, and as a major di�erence fromorganophosphate poisoning, new enzyme does not need to be synthesized before normal function isrestored a�er carbamate poisoning.

Clinical Features

In adults, symptoms of acute carbamate poisoning are similar to the cholinergic syndrome observed withorganophosphate agents but are of shorter duration. Because carbamates do not e�ectively penetrate theCNS in adults, less central toxicity is seen, and seizures do not occur. However, in children, presentation ofacute carbamate poisoning di�ers, with a predominance of CNS depression and nicotinic e�ects.

Carbamates can also produce the intermediate syndrome.12

Diagnosis

Diagnosis is based on clinical history and findings. Measurement of acetylcholinesterase activity is generallynot helpful because enzymatic activity may return spontaneously to normal 4 to 8 hours a�er a carbamateexposure.

Treatment

Initial treatment of carbamate poisoning is the same as for organophosphorus compounds. Atropine is theantidote of choice and is administered for muscarinic symptoms. Atropine is usually all that is necessarywhile waiting for the carbamylated acetylcholinesterase complex to dissociate spontaneously and recoverfunction, usually within 24 hours. Therapy usually is not needed for more than 6 to 12 hours.

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The use of pralidoxime in carbamate poisoning is controversial. The carbamate-binding half-life tocholinesterase is approximately 30 minutes, and irreversible binding does not occur; therefore, there is littleneed for pralidoxime. Human case reports and some but not all animal studies suggest that pralidoxime may

potentiate the toxicity of carbamates, such as carbaryl.30 Therefore, pralidoxime should be avoided in knownsingle-agent carbaryl poisonings. However, pralidoxime should be considered in mixed poisonings with anorganophosphorus compound and a carbamate or if the type of insecticide is unknown.

Disposition and Follow-Up

Because carbamate poisonings have transient cholinesterase inhibition and rapid enzyme reactivation, theclinical course tends to be more benign than seen with organophosphates, and most patients recovercompletely within 24 hours. However, patients with depressed levels of consciousness have a significant

mortality,31 and methomyl poisoning is associated with a high risk of cardiac arrest at presentation and

subsequent death a�er resuscitation.32

In mild poisonings, observation su�ices, and the patient may be discharged with follow-up. Moderatepoisonings necessitate 24 hours of observation that includes evaluation for possible concomitant exposureto or toxicity from inactive ingredients or vehicles such as hydrocarbons.

ORGANOCHLORINES

Dichlorodiphenyltrichloroethane (DDT) is the prototype insecticide of these chlorinated hydrocarbons.Chlordane, heptachlor, dieldrin, and aldrin are compounds used for termite and roach control. Most havebeen restricted or banned in the United States, Europe, and many other countries because of theirpersistence in the environment, long half-life in the human body, and toxicity. Worldwide, these insecticidescontinue to be used. Hexachlorocyclohexane (lindane) is a general garden organochlorine insecticide that isalso used in some countries to treat scabies and head lice infestations. This compound is well absorbed byingestion and inhalation. Dermal absorption occurs, particularly if the skin is abraded or repeatedapplications are used. Children and the elderly can develop neurotoxicity and seizures with therapeutic useof lindane.

Pathophysiology

Organochlorines are central neurologic stimulants that can be toxic a�er dermal, inhalation, and GIexposures. The physical state of the agent, whether a liquid or a solid, and the type of vehicle a�ecttransdermal absorption. Organochlorines antagonize γ-aminobutyric acid–mediated inhibition of the centralneurons, leading to hyperexcitability with repetitive neuronal discharges following the action potential.Organochlorines are highly lipid soluble and accumulate in human tissues. Most are capable of inducing thehepatic microsomal enzyme system. Therefore, the therapeutic e�icacy of other chemicals and drugs thatare inactivated by this system is reduced in the presence of organochlorines.

Clinical Features

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Neurologic symptoms predominate in acute organochlorine intoxication.33 Mild poisoning presents withdizziness; ataxia; fatigue; malaise; headache; neurologic stimulation with hyperexcitability, irritability, anddelirium; apprehension; tremulousness; myoclonus; and facial paresthesias. Fever is common. More severe

exposures may result in seizures, coma, renal injury, and death.34 Seizures may occur early, withoutprodromal syndromes, and are usually short lived, although some patients may have status epilepticus.Organochlorines are used dissolved in hydrocarbon solvents that, by themselves, can cause sedation, coma,and pneumonitis from aspiration. Sensitization of the myocardium to endogenous catecholamines withcardiac dysrhythmia can occur from both organochlorines and the solvents. Chronic neurotoxic e�ects fromlow-level exposure to the organochlorine compound chlordane include deficits in tests of balance, reactiontime, and verbal recall.

A related agent, the halogenated pyrrole chlorfenapyr, has two unusual features. First, it is a prodrug that is

converted into the active form a�er absorption by the insect. Second, it manifests biphasic neurotoxicity.35

Initial symptoms are nonspecific and include headaches, body aches, drowsiness, and weakness; thesesymptoms last for a few days, followed by a latent period of apparent recovery. Around the seventh day a�eringestion, neurologic symptoms recur with rapidly progressing paralysis and stupor leading to coma with afatal outcome. No treatment is e�ective once the delayed symptoms start. The requirement for metabolismto an active toxin and the latent period suggest it may be possible to develop an agent to inhibit thismetabolic conversion and reduce the risk of progression to the delayed fatal neurologic course.

Diagnosis

History is important, and valuable information can be obtained from the package label regarding the productand vehicle involved. Laboratory evaluation generally is not helpful, but organochlorines can be detected inthe serum and urine by specialty laboratories.

Treatment

Treatment includes administration of oxygen, with intubation indicated to treat hypoxia secondary toseizures, aspiration, and respiratory failure. Benzodiazepines are indicated for seizure control. Dysrhythmiacontrol may be indicated, but epinephrine should be avoided because both organochlorines and organicsolvents can sensitize the myocardium to endogenous catecholamines. Hyperthermia is managed byexternal cooling techniques. Removal of clothing and skin decontamination with mild detergent and waterare important. Avoid using oils on the skin because they promote absorption. Activated charcoal andpossibly gastric lavage in large, recent ingestions are potentially useful. The exchange resin cholestyramine ispotentially useful for symptomatic patients exposed to chlordecone.

Disposition and Follow-Up

Exposed patients should be observed for 6 hours and admitted to the hospital if signs of toxicity develop or ifingestion involved a hydrocarbon.

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PYRETHRINS AND PYRETHROIDS

Pyrethroid use and poisonings have increased since the phase-out of organophosphate insecticides for usein human dwellings. Pyrethrins are naturally occurring active extracts derived from the chrysanthemumplant. Pyrethroids are synthetic analogues of the pyrethrins with greater potency and environmental

persistence, but are considered safer than organochlorine and organophosphate insecticides.36 Pyrethroidsare used commonly as aerosols in automated insect sprays in public areas; therefore, inhalation is the mostcommon source of exposure. These agents are available as dusts and liquids in a hydrocarbon base.Pyrethrins are common ingredients in over-the-counter household insecticides, pediculicides, andscabicides. They are rapidly metabolized and therefore are of low toxicity in humans.

Pathophysiology

Toxicity results from dermal absorption, inhalation, or ingestion. Pyrethroids block the sodium channel at

the neuronal cell membrane, causing repetitive neuronal discharge.1,37 Additional e�ects include inhibitionon γ-aminobutyric acid receptors, increased nicotinic cholinergic transmission, norepinephrine release, andinterference with sodium–calcium exchange across cell membranes. Pyrethrin antigens are cross-antigenicwith ragweed pollen, so allergic reactions are common a�er exposure

Clinical Features

These compounds can cause dermal, pulmonary, GI, and neurologic illness. Allergic hypersensitivityreactions are the most common e�ects of pyrethrins, producing dermatitis, bronchospasm, rhinitis,

hypersensitivity pneumonitis, or anaphylaxis.36,38 Skin contact may lead to paresthesias and burning within30 minutes of exposure that usually dissipates within 24 hours. These compounds are well absorbed but arerapidly metabolized in the liver, usually resulting in minimal systemic toxicity.

Systemic toxicity can occur from occupational poisonings and following large intentional ingestions.Features of systemic toxicity include fatigue and lethargy, nausea and vomiting, paresthesias,

hyperexcitability, tremors, muscle fasciculations, pulmonary edema, respiratory failure, and seizures.39,40

Diagnosis

Diagnosis is dependent on a history of exposure. Di�erential diagnosis includes allergic reactions andingestions with neurologic stimulants. Laboratory tests have no diagnostic value.

Treatment

Treatment includes removal from exposure; dermal, ocular, and GI decontamination; treatment of allergicmanifestations; and supportive care.

Disposition and Follow-Up

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Disposition is usually related to the severity of asthmatic and allergic manifestations. The clinical course isusually benign, and hospitalization is not necessary for most accidental exposures.

NEONICOTINOIDS

Neonicotinoids are structurally similar to nicotine, acting as agonists at the postsynaptic acetylcholinereceptor. Neonicotinoids have high a�inity for the receptors within the insect CNS, producing paralysis anddeath. Commercially available agents from this family include imidacloprid, thiamethoxam, clothianidin,acetamiprid, thiacloprid, dinotefuran, and nitenpyram.

Data regarding human toxicity are limited to case reports. Toxicity from imidacloprid poisoning is relatively

mild to moderate in most cases, with symptoms of nausea, emesis, diarrhea, and headache.41 However,uncommon cases of respiratory failure, encephalopathy, hypotension, rhabdomyolysis, and renal failure

have occurred.42,43,44 Toxicity from acetamiprid poisoning has been associated with severe nausea and

vomiting, muscle weakness, hypothermia, convulsions, and hypothermia.45 Treatment is supportive.

NEREISTOXIN ANALOGS

Analogs of nereistoxin are considered low-toxicity insecticides. Agents in common use include nensultap,cartap, thiocyclam and thiosultap. These insecticides induce neurotoxicity by promoting extracellularcalcium influx and stimulating the release of intracellular calcium from the sarcoplasmic reticulum.

Case reports of toxicity from occupational skin exposure report nausea, vomiting, muscles tremors, dyspnea,and mydriasis. Intentional ingestions are associated with depressed level of consciousness, muscle

fasciculations and spasms, seizures, hypotension, and hypoxia.46,47,48

Animal studies suggest that sulfhydryl-containing compounds, such as l-cysteine, acetylcysteine, d-penicillamine, and dimercaprol, are e�ective antidotes, but human data are lacking, and suggested doses areconjectures. Recovery from severe toxicity associated with coma is possible, although death from multipleorgan failure may occur.

AMITRAZ

Amitraz is a topical insecticide and acaricide, as well as an insect repellant. Amitraz is used as a spray onagricultural crops and as a wash-solution to treat ectoparasites found on farm animals, dogs, and cats.Amitraz possesses agonist activity at the postsynaptic α2-adrenergic receptor, and interacts with the

neuromodulator octopamine, inhibits monoamine oxidase, and impairs prostaglandin synthesis.

The clinical manifestations following human overdose include mental status depression, bradycardia,

respiratory depression, miosis, hypotension, and hypothermia.49,50 Mechanical ventilation may be required,and with supportive therapy, recovery is expected.

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N,N-DIETHYL-3-METHYLBENZAMIDE (DEET)

DEET is used extensively as an over-the-counter insect repellant that comes in a variety of productformulations ranging in concentrations from 5% to 100%. When used as directed, they are generally safe.Toxicity can occur with ingestion or prolonged exposure on covered or damaged skin. DEET is absorbedthrough the skin and is a neurotoxin that causes seizures a�er large ingestions and extensive dermalexposures of high-concentration products. Small children are most susceptible to systemic toxicity from skinabsorption. Skin absorption occurs within 2 hours of topical application, but peak concentrations may bedelayed several hours.

Systemic toxicity is rare but manifests as restlessness, insomnia, altered behavior, confusion, neurologicdepression, slurred speech, ataxia, tremors, muscle cramps, hypertonia, and seizures occurring with orwithout prodrome. DEET-induced hypotension and bradycardia have been reported with heavy dermal ororal exposure. Treatment includes benzodiazepines for seizures, skin decontamination with mild detergentand water, and activated charcoal for recent ingestions. Most patients recover with supportive care.

HERBICIDES

Herbicides are used to kill weeds. Mechanisms of plant toxicity includes inhibition of photosynthesis,respiration, protein synthesis, or growth stimulation mimicking plant hormones called auxins. Some classespose a health hazard to humans (Table 201-5). Herbicidal formulations contain multiple ingredients such asorganic solvents, surfactants, and preservatives that may have their own toxic e�ects; these may not bealways disclosed on the product label.

TABLE 201-5

Selected Herbicide Classes that Pose Potential Harm to Humans

Chlorophenoxy compounds

Bipyridyls: paraquat and diquat

Urea-substituted

Organophosphates

Glyphosate

CHLOROPHENOXY HERBICIDES

Chlorophenoxy herbicides are synthetic plant hormones. The most commonly used compounds are 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxy-acetic acid. 2,4,5-Trichlorophenoxy aceticacid (2,4,5-T) has been banned in the United States because of its contamination with 2,3,7,8,-tetrachlorodibenzo-p-dioxin. The aerially applied defoliant Agent Orange used during the Vietnam War was a

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mixture of 2,4-D and 2,4,5-T. These compounds are e�ective against broadleaf plants and are used as weedkillers on lawns and grain crops.

Pathophysiology

The metabolic pathway or mechanism related to human toxicity is unknown. Toxicity can result from dermalcontact, inhalation, or ingestion. Systemic absorption can produce neurologic, cardiac, and skeletal muscletoxicity.

Clinical Features

Local exposure leads to eye and mucous membrane irritation that may last for days. A�er ingestion, nausea,vomiting, and diarrhea occur. Pulmonary toxicity may produce dyspnea, tachypnea, and signs of pulmonaryedema. Cardiovascular findings include hypotension, tachycardia, and dysrhythmias. Mental status changesand seizures may occur. Muscle toxicity manifests as muscle tenderness, fasciculations, myotonia, andrhabdomyolysis. The patient may become hyperthermic. Peripheral neuropathy has been described in therecovery phase a�er acute exposure and with chronic exposure.

Diagnosis

Diagnosis is based on a history of exposure. Ancillary tests generally are nonspecific but may demonstrate ametabolic acidosis, rhabdomyolysis, or evidence of hepatorenal dysfunction. Toxin levels are notimmediately available. Di�erential diagnosis includes other causes of acute myopathy.

Treatment

Treatment is supportive, including decontamination measures and respiratory support for myopathic-related

respiratory failure.51,52 Urinary alkalinization will increase the elimination of these compounds and is

recommended for severely poisoned patients.53 Hemodialysis can also be used to enhance chlorophenoxyherbicide clearance. Patients should be monitored for rhabdomyolysis and treated as necessary.

Disposition and Follow-Up

Severe toxicity and serious complications are not common following chlorophenoxy herbicides. Becausetoxic e�ects usually appear within 4 to 6 hours, patients with mild symptoms can be observed anddischarged a�er that time. Significant toxicity warrants admission.

BIPYRIDYL HERBICIDES

The bipyridyl compounds, paraquat and diquat, are nonselective contact herbicides. Both are used widely

and are responsible for significant morbidity if ingested.54 Paraquat is a fast-acting, nonselective herbicide. Itis used for killing grass and weeds; is manufactured as a liquid, granules, or an aerosol; and is commonly

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combined with diquat and other herbicides. Most products contain a blue dye, a stenchant, and an emetic.

Ingestion is responsible for the majority of paraquat deaths,54 although deaths have been reported a�ertransdermal exposure. Inhalation exposure to sprays can be very irritating to conjunctiva and the airway butare unlikely to cause systemic toxicity.

Pathophysiology

Paraquat is a severe local irritant and devastating systemic toxin.55 There is minimal transdermal absorptionof paraquat in the absence of preexisting skin lesions. Ingested paraquat is absorbed rapidly, particularly ifthe stomach is empty. Plasma concentration peaks within minutes to 2 hours a�er ingestion. Paraquat isthen distributed to most organs, with the highest concentrations found in the kidneys and lungs. A lethal oraldose of the 20% concentrate solution is about 10 to 20 mL in an adult and 4 to 5 mL in a child.

Paraquat actively accumulates in the alveolar cells of the lungs, where it is transformed into a reactive

oxygen species, the superoxide radical.55 This anion is responsible for lipid peroxidation that leads todegradation of cell membranes, cell dysfunction, and necrosis. Lung injury has two phases. An initialdestructive phase is characterized by loss of type I and type II alveolar cells, infiltration by inflammatory cells,and hemorrhage. These changes may be reversible. The later, proliferative phase is characterized by fibrosisin the interstitium and alveolar spaces. Paraquat and oxygen enhance each other's toxicity by sustaining theredox cycle. Myocardial injury and necrosis of the adrenal glands may occur.

Diquat has a similar structure and mechanism as paraquat. Formulations containing diquat do not containthe dye, stenching agent, or emetic usually added to paraquat. The lethal dose for diquat is similar to that ofparaquat, but there is less occurrence of pulmonary injury and fibrosis because of diquat's lower a�inity forpulmonary tissue. Diquat is caustic to the skin and GI tract, and exposure can result in renal and livernecrosis.

Clinical Features

Clinical features depend on the route of exposure and amount. Paraquat's severe caustic e�ects producelocal skin irritation and ulceration of epithelial surfaces. Severe corrosive corneal injury may result from eyeexposure. Upper respiratory tract exposure may result in mucosal injury and epistaxis. Inhalation may lead tocough, dyspnea, chest pain, pulmonary edema, epistaxis, and hemoptysis. Respiratory symptoms maypersist for several weeks a�er inhalation exposure.

Ingestion causes GI irritation and mucosal damage with ulcerations (Table 201-6). A burning sensation of thelips or mouth may occur within a few minutes to hours followed by ulceration 1 to 2 days later. Nausea,vomiting, diarrhea, buccopharyngeal pain, esophageal pain, and abdominal pain may develop. Hypovolemiaoccurs from GI fluid losses and decreased oral intake.

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TABLE 201-6

Paraquat Toxicity from Ingestion

Category Clinical Features Approximate Amount Ingested

Mild Asymptomatic or nausea, vomiting, and diarrhea.

Renal and hepatic injury minimal or absent.

Decreased pulmonary di�usion capacity may be

present.

Complete recovery expected.

<20 milligrams/kg or <7.5 mL of 20%

concentrated solution in average adult

Severe Initially nausea, vomiting, diarrhea, abdominal

pain, mouth and throat ulceration.

Positive colorimetric test for paraquat in the urine.

1–4 d: renal failure, hepatic impairment,

hypotension.

1–2 wk: cough, hemoptysis, pleural e�usion,

pulmonary fibrosis.

Survival possible, but majority of cases die within

2–3 wk from pulmonary failure.

Between 20 and 40 milligrams/kg or

between 7.5 and 15 mL of 20%

concentrated solution in average adult

Fulminant Initially nausea, vomiting, diarrhea, and abdominal

pain.

Rapid development of renal and hepatic failure, GI

ulceration, pancreatitis, toxic myocarditis,

refractory hypotension, coma, convulsions.

Death from cardiogenic shock and multiorgan

failure within 1–4 d.

>40–50 milligrams/kg or >15–20 mL of

20% concentrated solution in average

adult

Multisystem e�ects include GI tract corrosion, acute renal failure, cardiac failure, hepatic failure, andextensive pulmonary injury. The e�ects can be evident within a few hours following large ingestions, but,more typically, manifestations of renal failure and hepatocellular necrosis develop between the second andfi�h days, with progressive pulmonary fibrosis leading to refractory hypoxemia 5 days to several weeks later.Metabolic (lactic) acidosis is common as a result of pulmonary e�ects (hypoxemia) and multisystem failure.

Diagnosis

Early diagnosis and therapy are important. Obtain details of the exposure, including accidental orintentional, route of exposure, concentration of the product, time of occurrence, and estimated amount. Thedi�erential diagnosis includes exposure to other corrosive agents and herbicides. Qualitative and

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quantitative analyses for paraquat in urine and blood can assist in the diagnosis, and nomograms are used

for predicting survival based on plasma paraquat concentration and time of ingestion.55 A commercially

available semi-qualitative colorimetric test (Paraquat Test Kit®; Syngenta CTL, Surrey, United Kingdom) canbe done on urine or plasma to detect paraquat within a few hours a�er ingestion; such detection indicatespotentially severe course. Serial pulmonary function tests, chest radiographs, and arterial blood gas

determinations, including alveolar-arterial gradient, and arterial lactate may be used to monitor toxicity.56

Laboratory abnormalities generally reflect multiorgan necrosis. Chest radiographs may showpneumomediastinum or pneumothorax due to corrosive rupture of the esophagus. Radiographicabnormalities of di�use consolidation indicating parenchymal injury on the chest radiograph may notparallel the severity of clinical symptoms. Upper GI endoscopy should be performed to identify the extentand severity of mucosal lesions.

Treatment

The goal of early and vigorous decontamination is to prevent absorption and pulmonary toxicity. Anyexposure to paraquat is a medical emergency, with hospitalization indicated even if the patient isasymptomatic. Early treatment is mainly supportive but is an important determinant of survival. Do notadminister supplemental oxygen unless the patient is severely hypoxic, because added oxygen stimulatessuperoxide radical formation and promotes oxidative stress.

Remove clothing and decontaminate skin with mild detergent and water. Take care to avoid skin abrasionsthat may increase absorption. If there is conjunctival irritation, irrigate with copious amounts of water orsaline. Fluid and electrolytic losses can occur from GI tract damage, vomiting, and cathartics. Maintainintravascular volume and urine output to prevent prerenal kidney injury. Pain associated with oropharyngeal

lesions should be treated with opioids. Emesis is common, and there is no proven benefit to gastric lavage.55

In patients with pharyngeal or esophageal burns, prophylactic placement of a nasogastric tube for

subsequent enteral nutrition is recommended.55

Immediate GI decontamination with absorbents that bind paraquat is indicated in patients with a protectedairway. A single dose of activated charcoal (1 to 2 grams/kg), diatomaceous fuller's earth (1 to 2 grams/kg in

15% aqueous suspension), or bentonite (1 to 2 grams/kg in a 7% aqueous slurry) should be used.55 Charcoalhemoperfusion can remove paraquat and has been recommended to be started as soon as possible and

continued for 6 to 8 hours, but there is no evidence to show that prognosis is improved.55 Repeated pulse

doses of glucocorticoids and cyclophosphamide may improve survival in severe cases.57,58,59

Supportive care includes airway protection, maintaining intravascular volume, pain relief, treatment of renalfailure and complications, and treatment of infection. Maintaining renal function will assist in avoiding toxicaccumulation in other tissues.

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Treatment for diquat poisoning is similar to that for paraquat, and despite the lower toxicity for diquat,mortality approaches 50% following intentional diquat ingestion.

Disposition and Follow-Up

Outcome is determined by the amount ingested; therefore, intentional ingestions tend to have a worse

prognosis.60 Prognosis is worse ingesting a highly concentrated liquid formulation on an empty stomach.Conversely, ingestion of dilute solid formulations rarely cause death.

UREA-SUBSTITUTED HERBICIDES

Urea-substituted herbicides such as chlorimuron, diuron, fluometuron, and isoproturon are inhibitors of

photosynthesis and have low systemic toxicity. In humans, methemoglobinuria may occur with ingestion.61

Treatment includes decontamination, supportive care, and treatment for methemoglobinemia withmethylene blue, as appropriate (see chapter 207, "Dyshemoglobinemias").

ORGANOPHOSPHATE HERBICIDES

In addition to their use as insecticides, some organophosphate compounds are e�ective herbicides.Butiphos is used commonly as a cotton defoliant before mechanical harvesting. Treatment is identical to thatfor organophosphate insecticides.

GLYPHOSATE

Glyphosate is the active ingredient in many widely used preparations available for consumer use on lawnsand gardens. A problem with lawn and garden chemicals is that some products sold using a common orgroup brand name may contain di�erent active ingredients; a common brand name may contain eitherglyphosate or the more toxic herbicide diquat.

Glyphosate can produce severe toxicity with massive ingestions of the diluted product or ingestions of

concentrated solutions.62 Preparations may contain the toxic surfactant polyoxyethyleneamine, which is acorrosive, and the combination is more toxic than glyphosate alone. Inhalational exposures cause respiratoryirritation. Dermal absorption is poor, so symptomatic poisonings are generally from ingestion.

Clinical e�ects include mucous membrane irritation and erosions with nausea, vomiting, abdominal pain,

and diarrhea.63 Widespread organ failure with refractory cardiovascular collapse and dysrhythmias has beenreported. Respiratory distress requiring intubation, metabolic acidosis, tachycardia, renal failure, andhyperkalemia portend a fatal outcome.

Treatment includes activated charcoal following a recent ingestion and supportive care, with attention tosupport of oxygenation and ventilation, ameliorating complications due to the corrosive e�ects on the GItract, treating hyperkalemia, and supporting the circulation. Intravenous lipid emulsion is reported as useful

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in preventing hypotension64 and treating refractory hypotension.65 Hemodialysis may be supportive when

severe acidosis and acute kidney injury are present.66

Patients with small, asymptomatic ingestions can be discharged a�er 6 hours of observation. Significant GIsymptoms, altered level of consciousness, hypoxemia, metabolic acidosis, and cardiovascular abnormalitiesindicate admission to an intensive care unit.

RODENTICIDES

A number of agents with distinct toxicities are used as rodenticides. Rodenticides are commonly classifiedbased on whether they are anticoagulants or nonanticoagulants. Although intentional ingestions are o�enassociated with significant morbidity and mortality, most unintentional exposures occur in young childrenand result in minimal or no toxicity.

NONANTICOAGULANTS

A number of nonanticoagulant rodenticides have been used throughout history. Many have beendiscontinued, although poisonings still occur from old product stored in garages, barns, and homes (Table201-7).

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TABLE 201-7

Nonanticoagulant Rodenticides

Rodenticide Toxicity Mechanism Clinical E�ects Treatment

Arsenic Severe Binds sulfhydryl

groups on

proteins

Dysphagia, muscle

cramps, nausea and

vomiting, bloody

diarrhea, cardiovascular

collapse, altered mental

status, seizures, and late

peripheral neuropathies

Gastric lavage,

activated

charcoal,

catharsis,

chelation therapy

using succimer,

dimercaprol, or

penicillamine

Barium carbonate and

other soluble forms

such as barium

chlorides, hydroxides,

and sulfides

Severe Depolarizing

neuromuscular

blockade

Onset occurs within 1–8 h

with nausea, vomiting,

diarrhea, abdominal pain,

dysrhythmias, respiratory

failure, muscular

weakness, paresthesias,

and paralysis

Gastric lavage

with sodium or

magnesium

sulfate added to

lavage solution to

convert

carbonate to less

toxic sulfate;

potassium

replacement

Elemental or yellow

phosphorus

Severe,

early

cardiac

and

neurologic

toxicity is

a poor

prognostic

sign

Caustic;

uncouples

oxidative

phosphorylation

Skin irritation, cutaneous

burns, oral burns,

abdominal pain,

hematemesis, possible

"smoking" luminescent

vomitus and stool,

garlicky odor, direct toxic

e�ects on the

myocardium, kidney, and

peripheral vessels,

cardiovascular collapse;

late neurologic

depression with

multisystem toxicity and

hepatorenal syndrome

Gastric lavage

with dilute

potassium

permanganate

solution may

convert

phosphorus to

less toxic

phosphates;

activated

charcoal; avoid

emesis

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Rodenticide Toxicity Mechanism Clinical E�ects Treatment

N-3-Pyridylmethyl-Nʹ-

p-nitrophenylurea

(PNU or Vacor)

Severe Destroys

pancreatic β

cells within

hours of

ingestion by

interfering with

nicotinamide

metabolism

Within 24 h of ingestion,

GI symptoms, perforation,

autonomic nervous

system dysfunction,

insulin-deficient

hyperglycemia or diabetic

ketoacidosis,

dysrhythmias,

neuropathies

Nicotinamide

(niacinamide) IV

or IM is an

antidote; lavage

for recent

ingestions;

activated

charcoal and

insulin for

treatment of

hyperglycemia

and ketoacidosis

Sodium fluoroacetate

(SFA)67

Severe Blocks Krebs

cycle

Nausea, vomiting,

apprehension, lactic

acidosis, seizures, coma,

respiratory depression,

cardiac dysrhythmias, and

pulmonary edema;

electrocardiographic

abnormalities include ST-

segment and T-wave

changes, tachycardia,

premature ventricular

contractions, ventricular

tachycardia, and

ventricular fibrillation;

hyperkalemia and

hypocalcemia are

common

Activated

charcoal, seizure

and dysrhythmia

control, and

supportive care;

experimental

regimens include

glycerol

monoacetate,

calcium

gluconate,

sodium

succinate, and

ethanol loading;

consultation with

a toxicologist is

recommended

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Rodenticide Toxicity Mechanism Clinical E�ects Treatment

Strychnine Severe Competitive

antagonism of

the inhibitory

neurotransmitter

glycine at the

postsynaptic

brainstem and

spinal cord

motor neuron

Restlessness, muscle

twitching, painful

extensor spasms,

opisthotonos, trismus,

inability to swallow, and

facial grimacing;

medullary paralysis and

death can follow

Airway control,

quiet

environment

(minimize

sensory

stimulation), and

activated

charcoal; avoid

lavage (may

precipitate

seizures);

benzodiazepines,

barbiturates,

analgesia;

neuromuscular

blockage if

necessary

Tetramine68,69,70 Severe Blocks γ-

aminobutyric

acid receptors in

the CNS

Rapidly acting; initial

features include

headache, nausea,

dizziness, fatigue,

anorexia, numbness, and

listlessness; severe

symptoms include loss of

consciousness, seizures,

and coma; death usually

caused by respiratory

failure

The median

lethal dose for

tetramine is ~0.1

milligram/kg; 6–

12 milligrams

su�icient to kill

an adult; no

antidote;

supportive care;

benzodiazepines

or barbiturates

for seizures

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Rodenticide Toxicity Mechanism Clinical E�ects Treatment

Thallium sulfate71 Severe Combines with

mitochondrial

sulfhydryl

groups,

interfering with

oxidative

phosphorylation

Early GI symptoms:

nausea, vomiting, and

abdominal pain; a�er 2–5

d, painful paresthesias,

myalgias, muscle

weakness, headache,

lethargy, tremors, ataxia,

delirium, seizures, and

coma; death from

respiratory failure and

dysrhythmias; alopecia

a�er approximately 2 wk;

chronic neurologic

sequelae

Supportive care;

multiple doses of

activated

charcoal or

Prussian blue

(potassium ferric

hexaniacinate) to

interrupt

enterohepatic

circulation and

increase

elimination in

stool;

hemodialysis

Zinc or aluminium

phosphide72,73,74,75,76

Severe Combines with

water and

stomach acid to

produce

phosphine gas;

cellular toxicity

and necrosis to

the GI tract,

kidney, and liver

if ingested and

to the lungs if

inhaled

Immediate nausea,

vomiting, epigastric pain,

phosphorous or fishy

breath, black vomitus,

and GI irritation or

ulceration; myocardial

toxicity, shock, and acute

lung injury; agitation,

coma, seizures,

hepatorenal injury,

metabolic acidosis,

hypocalcemia, tetany

Gastric lavage

with potassium

permanganate or

combination

coconut oil and

sodium

bicarbonate;

magnesium

sulfate IV77; treat

acidosis and

hypocalcemia;

consider

acetylcysteine78;

supportive care

α-Naphthyl-thiourea

(ANTU)

Moderate Increases

alveolar

capillary

permeability,

causing

pulmonary

edema

Dyspnea, cyanosis, cough,

pleuritic chest pain,

noncardiogenic

pulmonary edema, and

pleural e�usion

Supportive care;

activated

charcoal

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Rodenticide Toxicity Mechanism Clinical E�ects Treatment

Cholecalciferol

(vitamin D3)

Moderate Mobilization of

calcium from

bones

Hypercalcemia,

osteomalacia, and

systemic metastatic

calcifications

Treat

hypercalcemia

with IV normal

saline,

furosemide,

steroids,

calcitonin, and

biphosphates as

needed

Bromethalin Low Uncouples

oxidative

phosphorylation

in CNS

mitochondria,

interrupting

nerve

conduction

Muscle tremors,

myoclonic jerks,

contractions of flexor

muscles, ataxia, and focal

motor seizures;

personality changes,

confusion, and coma

Decontamination;

benzodiazepines

for seizures

Norbormide or

dicarboximide

Low Irreversible

smooth muscle

vasoconstriction

Tissue hypoxia and

ischemia

Supportive care;

decontamination

Red squill Low

(limited

toxicity in

humans

due to

early

onset of

emesis

with

gastric

emptying)

Blocks sodium-

potassium

adenosine

triphosphatase

(similar to

digoxin

poisoning)

Nausea, protracted

vomiting, diarrhea,

abdominal pain; massive

ingestion causes

hyperkalemia,

atrioventricular block,

ventricular irritability with

dysrhythmias, and death

Treat as digoxin

toxicity (atropine,

external pacing,

digoxin-specific

antibody

fragments,

activated

charcoal)

ANTICOAGULANTS

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Warfarin-type anticoagulants were the first generation of anticoagulant rodenticides and distributed

commonly disguised as yellow corn meal or rolled oats.79 Most one-time warfarin rodenticide ingestions areinsignificant accidental poisonings and do not cause any bleeding problems. Significant coagulopathyrequires large amounts in a single exposure or a repetitive exposure over several days. Following a singlelarge ingestion, onset of the anticoagulant e�ect takes place within 12 to 48 hours. Warfarin's biologic half-life is approximately 42 hours.

Therapy is not necessary for ingestion of a single mouthful of a warfarin rodenticide. For potentially toxicrecent ingestion, consider activated charcoal. Obtain a baseline prothrombin time and INR determinationand repeat it in 12 to 24 hours. Vitamin K1 (phytonadione) administration is indicated if the INR is >2.0. The

suggested total PO daily dose is 1 to 5 milligrams in children and 20 milligrams in adults, administered in twoto four divided doses.

Second-generation superwarfarins and the indandione derivatives were introduced when rodent resistance

to warfarin began to appear.79 They are currently responsible for approximately 80% of human rodenticideexposures reported in the United States. Their mechanisms are the same as that of warfarin, but they aremore potent, have more prolonged anticoagulant activity, and therefore have the potential to be highly toxic.Poisonings involving the indandione derivatives pindone, diphacinone, chlorophacinone, and valone havetoxic and clinical characteristics similar to those of the superwarfarins.

The superwarfarins include the 4-hydroxy-coumarins brodifacoum, diphenacoum, coumafuryl, andbromadoline. These are readily available over the counter as grain-based bait. A�er intentional ingestions,adults o�en develop a coagulopathy within 24 to 48 hours. Because the biologic half-life of brodifacoum isapproximately 120 days, a single ingestion may result in marked anticoagulation e�ects for weeks to

months.80 Intentional repeated ingestions can cause severe bleeding.

The diagnosis may not be readily apparent. Some patients may not report an intentional ingestion. Smallchildren and depressed patients with an unexplained coagulopathy and/or bleeding should raise suspicionof superwarfarin poisoning. Although the prothrombin time and INR are usually monitored, large doses ofwarfarin can also cause prolongation of the activated partial thromboplastin time. Superwarfarins are notdetected by warfarin assays, but specific serum assays are available in reference laboratories.

Unintentional superwarfarin ingestions in the pediatric patient are unlikely to result in significant toxicity.81

Obtain a baseline INR and repeat 24 and 48 hours a�er ingestion. For acute intentional ingestions, gastriclavage is indicated for early presentations, and activated charcoal should be administered. Obtain a baselineINR and repeat in 12 and 24 hours. If the INR is elevated but there is no active hemorrhage, oral vitamin K1 is

recommended. Because of the extended half-life of the anticoagulant, prolonged therapy with high doses of

vitamin K1 may be required to maintain hemostasis.82,83 Initial daily doses of 1 to 5 milligrams in children

and 20 milligrams in adults are recommended with titration to maintain a normal INR. Doses up to 100

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1. 

2. 

3. 

4. 

5. 

milligrams per day for 10 months have been reported. Upon discontinuation of vitamin K1 therapy, serial INR

determinations are required to ensure that further therapy is not needed.

Patients with acute hemorrhage may require repletion of volume losses with normal saline or bloodtransfusions. Fresh frozen plasma should be used if bleeding is severe or unresponsive to vitamin therapy.Vitamin K1, 10 milligrams, should be administered by slow IV infusion to minimize the risk of a hypotensive

reaction. Forms of vitamin K other than vitamin K1 are ine�ective because the conversion of these other

forms to the active form is blocked by superwarfarins. Administration of prothrombin complex concentratesor recombinant activated factor VII can be considered for patients with ongoing hemorrhage despite freshfrozen plasma and vitamin K1 therapy.

For asymptomatic patients who have accidentally ingested a superwarfarin, follow-up in 24 and 48 hours forcoagulation studies should be arranged. Prevention measures should be emphasized.

CONSULTATION

Consultation with a poison control center or medical toxicologist is recommended to assist in patientmanagement and to collect data for surveillance reports. When consulting, precise communication of thespecific product name from the container label is essential to identify both active and inert ingredients. Asnoted, confusion can arise because similar brand names are used for more than one agent.

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Dawson  AH, Eddlestomn  M, Senarathna  L  et al.: Acute human lethal toxicity of agricultural pesticides: aprospective cohort study. PLoS Med 7: e1000357, 2010.

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Dharmani  C, Jaga  K: Epidemiology of acute organophosphate poisoning in hospital emergency roompatients. Rev Environ Health 20: 215, 2005.

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Tsai  JR, Sheu  CC, Cheng  MH  et al.: Organophosphate poisoning: 10 years of experience in southernTaiwan. Kaohsiung J Med Sci 23: 112, 2007.

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USEFUL WEB RESOURCES

The American Academy of Clinical Toxicology—http://www.clintox.org/index.cfm

The American Association of Poison Control Centers—http://www.aapcc.org/DNN

The Asia Pacific Association of Medical Toxicology—http://www.asiatox.org

The European Association of Poisons Centres and Clinical Toxicologists—http://www.eapcct.org

The South Asian Clinical Toxicology Research Collaboration—http://www.sactrc.org

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