Pesticides include insecticides, herbicides, and rodenticides.1 Pesticide toxicity results from intentional, accidental, and occupational exposures. More than 150,000 pesticide poisoning deaths occur each year worldwide, with insecticides accounting for the majority of the mortality.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. Human toxicity can occur from many ingredients in proprietary formulations, including solvents and surfactants. 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. Cornerstones of management are meticulous supportive care and early identification of exposures that may benefit from administration of an antidote. The World Health Organization classifies pesticides according to
toxicity based on rodent median lethal oral and dermal exposures. However, 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.
INSECTICIDES
Chemical insecticides are toxic to the human nervous system, producing 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 repellents.
Commonly used organophosphates include diazinon, acephate, malathion, parathion, and chlorpyrifos. Organophosphate and carbamate compounds are the insecticide exposures most commonly resulting in healthcare facility attendance in the United States.4 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.2 The organophosphate structure can be modified into chemical agents of mass destruction (see Chapter 8, “Chemical Disasters”). Globally, organophosphate poisoning results most commonly from deliberate self-poisoning.2,5
Accidental exposures occur in agricultural
and industrial settings through use of pesticide spray applicators or spills during transport.6 Inadvertent exposure can occur from flea-dip products in pet groomers and children and from contaminated food. Systemic absorption of organophosphates occurs by inhalation and after mucous membrane, transdermal, transconjunctival, or GI exposure. Consultation with a poison control center or medical toxicologist can
be useful to assist in patient management and to collect data for surveillance reports. When consulting, precise communication of the specific product name from the container label is essential to identify both active and inert ingredients. As noted, confusion can arise because similar brand names are used for more than one agent.
Pathophysiology Organophosphate and carbamate compounds inhibit the enzyme cholinesterase.3 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. The term aging describes 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 are more effective if given before aging occurs.
Clinical Features Clinical presentations depend on the specific agent involved, the quantity absorbed, route of exposure, and the amount and character of additives (including solvents) in any preparation.7,8 Organophosphate insecticide poisoning can have substantial variability in clinical course, response to treatment, and outcome.8,9
Four clinical
syndromes are described following organophosphate exposure: acute poisoning, intermediate syndrome, chronic toxicity, and organophosphateinduced delayed neuropathy.10 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 (dermatitis) and respiratory tract (wheezing) without evidence of systemic absorption. Acute organophosphate poisoning results in CNS, muscarinic, tinic, and somatic motor manifestations (Table 201-2). In mild to
nico moderate poisoning, symptoms occur in various combinations. In severe exposures, nicotinic features may be observed first. Time to symptom onset varies according to exposure route, occurring within minutes of massive ingestion. Symptom onset is most rapid with inhalation and Treatment Treatment consists of airway control, intensive respiratory support, general supportive measures, decontamination, prevention of absorption, and the administration of antidotes (Table 201-3).8,19
Death
occurs in untreated patients through a combination of bronchorrhea, respiratory muscle paralysis, and CNS depression. Therefore, immediate priorities following decontamination are airway protection, provision of ventilation, reduction of bronchorrhea via adequate atropinization, and reversal of respiratory muscle paralysis through administration of an oxime. 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 and transported to the ED, in a manner that is safe for patients and healthcare workers (e.g., no transport by helicopter). All clothes and accessories must be removed completely, placed in plastic bags, and disposed of as hazardous materials.21
The patient should be 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 resulting from hypersalivation, bronchorrhea, or emesis. Coma, seizures, respiratory failure, excessive respiratory secretions, or severe bronchospasm necessitates endotracheal intubation. Establish an IV line with baseline blood sampling that can include determination of cholinesterase levels. A nondepolarizing
agent should be used when neuromuscular blockade is needed. Succinylcholine is metabolized by plasma butyrylcholinesterase; therefore, prolonged paralysis may result. Hypotension is initially treated with fluid boluses of isotonic crystalloid. There is no published evidence demonstrating that gastric lavage improves outcome following organophosphate ingestion.23
Gastric lavage
undertaken within 1 hour of a very large ingestion (following airway protection via endotracheal intubation) may be beneficial, but its performance should not delay timely administration of antidotal therapy. 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.24
H emodialysis,
hemofiltration, and hemoperfusion are of no proven value. Atropine is the antidote for significant organophosphate poisonings (Table 201-3).8,25-27
As a competitive antagonist of acetylcholine
at central and peripheral muscarinic receptors, atropine will reverse the effects secondary to excessive cholinergic stimulation. Pinpoint pupils, excessive sweating and secretions, and respiratory distress are triggers for treatment with atropine. In adults, an initial dose of 1.2 to 3.0 milligrams is given depending on severity of symptoms. The dose is doubled every 5 minutes until the following are achieved: chest clear on auscultation, heart rate >80 beats/min, and systolic blood pressure >80 mm Hg. Large amounts of atropine, on the order of hundreds of milligrams, may be necessary in massive ingestions. Proactive contact with the hospital pharmacy (or even other centers) may be necessary to ensure access to adequate amounts of atropine. 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 clinically obvious antimuscarinic symptoms; absence of anticholinergic symptoms after an initial dose is thus consistent with organophosphate poisoning. Once an effective amount of atropine has been given, an infusion of 10% to 20% per hour of the initial dose of atropine that was required to achieve adequate atropinization should be started in order to maintain an anticholinergic state. Importantly, atropine reduces respiratory tract secretions but does not reverse muscle weakness. Respiratory support through endotracheal intubation and artificial ventilation is required in severe poisoning. Glycopyrrolate, an alternate anticholinergic agent that does not
produce CNS toxicity, may be used. However, its dosing is not well defined, and there is no proven benefit compared to atropine. The need for glycopyrrolate is unclear because adequate atropinization (using atropine) without significant CNS toxicity can be achieved via monitoring for anticholinergic effects (e.g., absent bowel sounds, hyperthermia, delirium) and adjusting the atropine infusion rate as needed.8 Compounds called oximes are used to displace organophosphates
from the active site of acetylcholinesterase, thus reactivating the enzyme.8,25,28
Pralidoxime is the oxime in common use and ameliorates 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 later than 24 to 48 hours after exposure. The pralidoxime dose recommended by the World Health ganization is a 30-milligram/kg IV bolus followed by an IV infusion
Or 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 reduce mortality or the complication rate in acute organophosphate poisoning.28-30
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.8 Atropine may prevent or abort seizures (due to cholinergic overstimulation) that occur within the first few minutes of exposure. 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. Although there is some evidence for the benefit of magnesium sulfate
and calcium channel blockers in the treatment of organophosphate p oisoning, they are not yet recommended for routine clinical use.31 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 result in cumulative toxicity. Patients returning to work should be limited from further exposure. 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 post-hypoxic 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 may be 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 of pralidoxime.