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 multiple formulations, often under shared brand names; therefore, complex clinical syndromes can result from exposure to both active and other ingredients. Ingredients in proprietary formulations, such as petroleum distillates, are inert to pests during typical exposures, but can be toxic to humans, especially with excessive amounts. Pesticides have class-specific toxicities, with many having both local and systemic effects. Management often includes consultation with a hazardous materials and toxins database or with a poison control 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 for oral and dermal exposure in rats. This classification has been criticized because human case-fatality rates display 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 after human exposure.

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

ORGANOPHOSPHATES

Commonly used organophosphates include diazinon, acephate, malathion, parathion, and chlorpyrifos and many others in different countries. Organophosphate and carbamate compounds are the insecticides most commonly associated with systemic illness.^4,5 Potency among organophosphates varies; highly potent compounds, 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 out from 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 can be 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 after mucous membrane, transdermal, transconjunctival, and GI exposure.

Pathophysiology

Organophosphate and carbamate compounds inhibit the enzyme cholinesterase.¹ Acetylcholinesterase (true or red blood cell acetylcholinesterase) is found primarily in erythrocyte membranes, nervous tissue, and skeletal muscle. Plasma cholinesterase (pseudocholinesterase or butyrylcholinesterase) is found in the serum, liver, pancreas, heart, and brain. Inhibition of cholinesterase leads to acetylcholine accumulation at nerve synapses and neuromuscular junctions, resulting in overstimulation of acetylcholine receptors. This initial overstimulation is followed by paralysis of cholinergic synaptic transmission in the CNS, in autonomic ganglia, at parasympathetic and some sympathetic nerve endings (e.g., sweat glands), and in somatic nerves. Excess acetylcholine results in a cholinergic crisis that manifests as a central and peripheral clinical toxidrome.

Organophosphate compounds bind irreversibly to acetylcholinesterase, thus inactivating the enzyme through the process of phosphorylation. Aging is a term describing the permanent, irreversible binding of the organophosphorus compound to the cholinesterase. The time to aging is highly variable among different agents and can range from minutes to a day or more. Once aging occurs, the enzymatic activity of cholinesterase is permanently destroyed, and new enzyme must be resynthesized over a period of weeks before clinical symptoms resolve and normal enzymatic function returns. Antidotes must be given before aging occurs to be effective.

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 organophosphate exposure: 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 and nearly all within the first 24 hours. Organophosphate agents such as malathion are associated with local irritation of the skin and respiratory tract with resulting dermatitis and wheezing, respectively, without evidence 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 symptom onset varies according to exposure route; it is most rapid with inhalation and least rapid with transdermal absorption; however, dermatitis or skin excoriation may hasten this. Symptoms can occur within minutes after massive ingestion that is uniformly fatal.

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

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

Nicotinic stimulation at neuromuscular junctions results in muscle fasciculations, cramps, and muscle weakness. This syndrome may progress to paralysis and areflexia, making it difficult to detect seizure activity. Respiratory muscle paralysis can lead to ventilatory failure.

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

More lipid-soluble organophosphates may not produce immediate symptoms of toxicity, but instead produce delayed 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 often less dramatic and nonspecific, occurring without the cholinergic syndrome.

An intermediate syndrome may occur 1 to 5 days after an organophosphate exposure, reported in up to 40% of patients following ingestion.¹² Clinical features include paralysis of neck flexor muscles, muscles innervated by the cranial nerves, proximal limb muscles, and respiratory muscles; respiratory support may be 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 or ameliorate the severity of this syndrome. Symptoms usually resolve within 7 days. Nerve gas poisoning has not 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 to weakness 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 fatigue syndrome and multiple chemical sensitivity have been reported in some patients, predominantly female, after exposure to very low doses of organophosphate insecticides.¹⁵ Children are at greater risk of toxicity when 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 that inactivate acetylcholinesterases. They are rapid acting and extremely potent; death can occur within minutes of inhalation or dermal exposure, as occurred in the subway terrorist attack in Tokyo 1985. Soman ages within minutes, giving little time to administer antidotes.

Diagnosis

Diagnosis and treatment are based on history and the presence of a suggestive toxidrome; laboratory cholinesterase assays and reference laboratory testing for specific compounds take time and have limitations, and waiting for results delays administration of potentially life-saving therapy. Diagnosis is often difficult 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

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

Cholinesterase activity is used to assess potential toxicity, with red cell acetylcholinesterase enzymatic activity a more accurate indicator of synaptic cholinesterase inhibition, but plasma butyrylcholinesterase is easier to assay and more available (Table 201-2). The degree of cholinesterase inhibition necessary to produce 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 among laboratories is poor, so deviation from a symptomatic patient’s baseline may be significant when values are reported 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, liver dysfunction, cirrhosis, malnutrition and low serum albumin states, neoplasm, infection, and pregnancy. Red blood cell acetylcholinesterase is affected by factors that influence the circulating life of erythrocytes such as hemoglobinopathies. Unless pralidoxime is given before aging occurs, plasma butyrylcholinesterase takes up to 4 to 6 weeks and red blood cell acetylcholinesterase takes as long as 90 to 120 days to return to baseline after exposure.

Routine laboratory test abnormalities are nondiagnostic but may include evidence of pancreatitis, hypo- or hyperglycemia, leukocytosis, and abnormal liver function. In severe cases, a chest radiograph may show pulmonary 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 QT_c interval correlates with severity and mortality in severe organophosphate poisoning.¹⁷ Electromyography may identify and quantify 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 Therapy should not be withheld pending determination of cholinesterase levels.

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 suspected exposure 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 is immediately decontaminated externally with copious amounts of a mild detergent such as dishwashing liquid 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. Contaminated runoff water should be contained and disposed of as hazardous material. Instruments used can 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 and bronchospasm; 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 severe bronchospasm necessitate endotracheal intubation. An IV line should be established with baseline blood sampling and determination of cholinesterase levels. A nondepolarizing agent should be used when neuromuscular blockade is needed. Succinylcholine is metabolized by plasma butyrylcholinesterase, and therefore, prolonged paralysis may result. Hypotension is initially treated with fluid boluses of isotonic crystalloid.

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 after ingestion, it is unlikely that gastric lavage will be of benefit except in patients who present within 2 hours after 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 Urinary alkalinization is often 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, a competitive antagonist of acetylcholine at central and peripheral muscarinic receptors, will reverse the effects secondary to excessive cholinergic stimulation. The dose is repeated every 5 minutes until copious tracheobronchial secretions attenuate; large amounts may be necessary, in the order of hundreds of milligrams in massive ingestions. Pupillary dilatation is not a therapeutic end point. Tachycardia is not a contraindication to the use of atropine in organophosphorus poisoning because tachycardia can occur secondary 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 access is not possible. Normally, this initial dose of atropine should produce antimuscarinic symptoms; therefore, absence of anticholinergic symptoms after an initial dose is indicative of organophosphate poisoning. Once an effective 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 improve pulmonary symptoms. Glycopyrrolate and ipratropium do not cross the blood–brain barrier and are ineffective in treating central neurologic symptoms.

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 if given early, before aging occurs. If possible, blood samples for acetylcholinesterase levels are obtained before administration of pralidoxime, but it is important that pralidoxime be administered as soon as possible before permanent and irreversible aging occurs. Although pralidoxime is more effective in acute than in chronic intoxications, it is recommended for use even after >24 to 48 hours after exposure.

Response to pralidoxime therapy with a decrease in muscle weakness and fasciculations and relief of muscarinic effects with atropine usually occurs within 10 to 40 minutes of administration. Pralidoxime can also be given by the IM route. A continuous infusion is preferable to repeated bolus dosing if paralysis does not resolve after the initial dose or if paralysis returns. The pralidoxime dose recommended by the World Health 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. Despite theoretical and experimental benefit and worldwide clinical use, current evidence is inadequate to show that oximes, 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 known carbamate exposures presenting with minimal symptoms.

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

Disposition and Follow-Up

Minimal exposures may require only decontamination and 6 to 8 hours of observation in the ED to detect delayed effects. 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 after washing or cleaning.²¹

Admission to the intensive care unit is necessary for significant poisonings. Most patients respond to pralidoxime therapy with an increase in acetylcholinesterase levels within 48 hours. If there is no posthypoxic brain damage, and if the patient is treated early, symptomatic recovery occurs in 10 days. If toxins are fat soluble, the patient may be symptomatic for prolonged periods of time and dependent on continuous pralidoxime 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 the absence of signs and symptoms on withholding pralidoxime therapy.

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 organophosphate poisoning 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 after dermal, inhalation, and GI exposure. Carbamates transiently and reversibly bind to and inhibit the cholinesterase enzyme. Regeneration of enzyme activity by dissociation of the carbamyl-cholinesterase bond occurs within minutes to a few hours involving rapid, spontaneous hydrolysis of the carbamate-cholinesterase bond. Therefore, aging does not occur, and as a major difference from organophosphate poisoning, new enzyme does not need to be synthesized before normal function is restored after carbamate poisoning.

Clinical Features

In adults, symptoms of acute carbamate poisoning are similar to the cholinergic syndrome observed with organophosphate agents but are of shorter duration. Because carbamates do not effectively penetrate the CNS in adults, less central toxicity is seen, and seizures do not occur. However, in children, presentation of acute carbamate poisoning differs, with a predominance of CNS depression and nicotinic effects. Carbamates can also produce the intermediate syndrome.¹²

Diagnosis

Diagnosis is based on clinical history and findings. Measurement of acetylcholinesterase activity is generally not helpful because enzymatic activity may return spontaneously to normal 4 to 8 hours after a carbamate exposure.

Treatment

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

The use of pralidoxime in carbamate poisoning is controversial. The carbamate-binding half-life to cholinesterase is approximately 30 minutes, and irreversible binding does not occur; therefore, there is little need 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

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