Epidemiology

Organophosphate (OP) compounds and carbamates are used extensively worldwide for agricultural, industrial, and domestic pest control and, as a result, represent a significant public health issue in the developing world. An estimated 3 million poisonings and more than 200,000 deaths occur from OP compounds each year worldwide.¹ In the United States in 2008, 4642 exposures to OP compounds and 2644 exposures to carbamates were reported to the National Poison Data System of the American Association of Poison Control Centers.²

Pathophysiology

The clinical severity and toxicodynamics vary according to the agent, the route of absorption, and whether the exposure was intentional. Regardless of these factors, the toxicologic mechanism of acetylcholinesterase (AChE) inhibition remains consistent. The end result is an excess of the neurotransmitter acetylcholine (ACh), which results in overstimulation of muscarinic and nicotinic receptors and production of a cholinergic toxidrome.

Under normal circumstances, ACh is hydrolyzed by AChE to yield acetic acid and choline. In the presence of OP insecticides, AChE is phosphorylated, whereas in the presence of carbamate insecticides, the enzyme is carbamylated. As a result, the rate of regeneration of active AChE is slowed, and its function is inhibited. Within 24 to 72 hours of OP poisoning, an alkyl group may dissociate from the AChE-OP complex and thereby result in “aging” of the AChE. Once aging occurs, reactivation of AChE is no longer possible, and only synthesis of new enzyme can restore activity. In the case of carbamate poisoning, breakdown of the carbamate-AChE complex occurs much more rapidly and aging does not occur (Box 146.1).³

ACh accumulates in the autonomic nervous system at postganglionic muscarinic (parasympathetic and sympathetic) receptors and preganglionic nicotinic (sympathetic) receptors. It also accumulates at the neuromuscular junction and in the central nervous system (CNS). Overstimulation of these receptors is responsible for the cholinergic toxidrome seen with OP and carbamate insecticide poisoning (Table 146.1).

See Table 146.1, Effects of Organophosphorus and Carbamate Insecticides, at www.expertconsult.com

Table 146.1 Effects of Organophosphorus and Carbamate Insecticides

RECEPTOR	TARGET TISSUE	CLINICAL EFFECT
Autonomic nervous system: Postganglionic muscarinic (parasympathetic)—”DUMBBELS” (defecation, urination, miosis, bronchorrhea, bradycardia, emesis, lacrimation, salivation) or “SLUDGE” (salivation, lacrimation, urination, defecation, gastric secretions, emesis) Postganglionic muscarinic (sympathetic) Preganglionic nicotinic

Gastrointestinal tract Vomiting, diarrhea, cramping Genitourinary tract Urination Heart Bradycardia Lungs Bronchorrhea, bronchospasm Eye Miosis, lacrimation Salivary glands Salivation Sweat glands Diaphoresis Adrenal glands ↑ Catecholamines—tachycardia Central nervous system (nicotinic/muscarinic) Brain Agitation, seizures, coma (organophosphates > carbamates) Neuromuscular junction (nicotinic) Skeletal muscle Weakness, fasciculations, paralysis

Presenting Signs and Symptoms

The onset of symptoms can occur within minutes after massive exposure and intentional ingestions or be delayed up to 12 hours after accidental dermal, inhalational, or oral exposure in the occupational arena. Clinical effects may also be somewhat delayed because of the need for bioactivation of some OP insecticides after absorption (e.g., malathion). The mnemonic SLUDGE (salivation, lacrimation, urination, defecation, gastric secretions, emesis) has traditionally been used to describe the cholinergic toxidrome. However, the mnemonic DUMBBELS (defecation, urination, miosis, bronchorrhea, bradycardia, emesis, lacrimation, salivation) is probably more appropriate because it includes the life-threatening conditions bronchorrhea and bradyarrhythmias, as well as miosis, the distinguishing feature.

The clinical effects are summarized in Table 146.1; only caveats in the clinical findings are emphasized here. Bronchorrhea occurs commonly with moderate to severe poisonings⁴ and can progress to pulmonary edema and respiratory failure. Miosis in the setting of cholinergic symptoms is fairly specific for OP and carbamate insecticide poisoning and may help make the diagnosis. Unfortunately, it is not consistently present.

Although the parasympathetic muscarinic effects are most often emphasized, certain sympathetic effects may predominate. Sinus tachycardia is more common than bradycardia,^4,5 and mydriasis may even be seen.⁵ Nicotinic effects often predominate in mild cases and occur early in severe cases. Excessive nicotinic stimulation at the neuromuscular junction has effects that resemble the actions of a depolarizing neuromuscular blocking agent. Therefore, patients with OP or carbamate insecticide poisoning may exhibit muscle fasciculations and weakness. Paralysis occurs as the toxicity worsens, and the primary cause of death in acute poisonings is probably respiratory arrest secondary to paralysis and bronchorrhea.

One to 3 days after apparent resolution of the symptoms, patients may experience profound weakness and paralysis of the proximal muscles, neck flexor muscles, and cranial nerves. This development, termed the intermediate syndrome,⁶ is probably explained by ongoing AChE inhibition (Box 146.2).

Finally, carbamates produce peripheral effects similar to those of OP compounds, but generally to a much lesser extent. A distinguishing clinical feature of carbamate toxicity is the paucity of central effects, which is secondary to their poor penetration of the CNS.

Differential Diagnosis and Medical Decision Making

A detailed history in a patient with signs and symptoms of cholinergic excess often elucidates exposure to OP or carbamate insecticides. The diagnosis of OP or carbamate insecticide poisoning is therefore usually straightforward; however, certain clinical aspects may be mimicked by other entities. Table 146.2 is a partial list of other agents or diagnoses to consider.

Table 146.2 Differential Diagnosis of Organophosphorus and Carbamate Poisoning

Other acetylcholinesterase inhibitors	Physostigmine, neostigmine, pyridostigmine
Other organophosphorus cholinesterase inhibitors (chemical weapon nerve agents)	Sarin, tabun, soman, Vx
Cholinomimetics	Pilocarpine, carbachol, methacholine, bethanechol, muscarine-containing mushrooms
Nicotinic alkaloids	Nicotine, coniine, lobeline
Other (symptom based)	Coma, miosis, paralysis: Pontine hemorrhage Salivation, fasciculations: Bark scorpion (Centruroides spp.) Vomiting, diarrhea: Gastroenteritis Respiratory failure: Any cause of pulmonary edema, status asthmaticus Weakness: Myasthenic crisis, electrolyte disturbance, botulism

All patients with potential OP poisoning should undergo erythrocyte (red blood cell [RBC], or true) cholinesterase and plasma (pseudo) cholinesterase measurement from specimens obtained after arrival at the emergency department (ED). Though not often useful or necessary for making a diagnosis in the ED, the results of this measurement may help guide continued therapy. RBC cholinesterase hydrolyzes ACh and correlates with toxicity, whereas plasma cholinesterase is the first to decline and may be a more sensitive marker of exposure.⁷ Both substances should be measured because one may exhibit greater inhibition than the other, depending on the specific OP to which the patient was exposed. Box 146.3 summarizes the tests that may be helpful in evaluating a patient with moderate to severe toxicity.

Cholinesterase values may prove useful in diagnosing OP toxicity if the history or findings on physical examination are unclear. The values must be interpreted with caution, however. There is great interindividual and intraindividual variation in baseline cholinesterase values. A patient may have a 50% depression in cholinesterase activity, yet the level still falls within the “normal” reference range. This makes cholinesterase measurements of limited value in the initial diagnosis of poisoning. The levels are helpful in confirming poisoning only if they are extremely low or undetectable at initial evaluation. The finding of “normal” levels does not necessarily rule out poisoning if the history and clinical picture are otherwise supportive.

Treatment

Treatment focuses on aggressive airway management, liberal use of atropine for control of excessive airway secretions, and in the case of OP compounds, early administration of the antidote pralidoxime. Prompt recognition of toxicity and early intervention usually result in complete recovery.

The treatment algorithm for OP and carbamate insecticide poisoning is summarized in Figure 146.1. The first step is adequate decontamination of the patient by removal of wet clothing and washing of contaminated skin with soap and water. ED personnel should wear gowns, gloves, and masks to prevent exposure to contaminated body fluids.⁸

As the patient is being decontaminated, the emergency physician (EP) should focus on the ABCs (airway, breathing circulation), with particular attention paid to early airway, management for copious secretions, seizures, coma, severe weakness, and paralysis. If intubation is necessary, only a nondepolarizing neuromuscular blocking agent, such as vecuronium or rocuronium, should be used. Succinylcholine is metabolized by plasma cholinesterase, so prolonged paralysis may result if this agent is used a patient with OP poisoning.⁹

Treatment should next be directed at controlling muscarinic activity. Atropine is the drug of choice and should be administered intravenously at a dose of 2 to 5 mg (pediatric dose, 0.05 mg/kg) every 3 to 5 minutes, with the end point being control of respiratory secretions. Tachycardia is not a contraindication to atropine administration. Mild poisonings may resolve with just 1 to 2 mg of atropine, and severe poisonings may require more than 1000 mg.¹⁰ Large doses of atropine may lead to antimuscarinic CNS toxicity. If such toxicity occurs, glycopyrrolate (1 to 2 mg; pediatric dose, 0.025 mg/kg) can be used in place of atropine.

Pralidoxime is the antidote for OP insecticide poisoning. Although its efficacy may vary according to the structure of the OP compound, it should be given to all OP-poisoned patients. It works by increasing the rate of AChE regeneration. It is a common belief that pralidoxime is not beneficial if given after 24 hours because of the “aging” of AChE. However, OP insecticides have been detected in blood weeks after exposure. Their presence may be secondary to redistribution from fat. Therefore, late pralidoxime therapy may still be of benefit. The adult dose is 1 to 2 g via the intravenous (IV) route delivered over a 15- to 30-minute period followed by a continuous infusion of 500 mg/hr. Pediatric dosing consists of a 25- to 50-mg/kg load followed by a 10- to 20-mg/kg/hr infusion. Pralidoxime is not indicated for carbamate poisoning, which is usually mild and self-limited.

Epidemiology

Organochlorines are heavily chlorinated aromatic compounds that are nonvolatile and poorly water soluble. They are divided into four classes on the basis of their structural characteristics, and they vary tremendously with respect to dermal absorption, lipid solubility, and toxic doses. The clinical toxicity, which is similar for each of the classes, is summarized in (Table 146.3).

See Table 146.3, Major Organophosphorus Insecticides, at www.expertconsult.com

Most organochlorines have been banned in North America because of concern about their environmental persistence and bioconcentration. The only organochlorine still in common use in the United States is lindane (Kwell). It is used in agriculture as a seed treatment and medicinally as a topical scabicide in a 1% formulation. Toxicity from therapeutic lindane application is exceedingly rare, and most clinically relevant toxicity events occur as a result of inappropriate dermal application or ingestion.^11–13

Pathophysiology

Lindane acts as an antagonist of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS.¹⁴ Toxicity results from loss of inhibitory tone and subsequent CNS hyperexcitability.

Presenting Signs and Symptoms

Symptoms, which can occur within 30 minutes of the ingestion of lindane,¹² often include nausea and vomiting. With excessive or repeated topical applications, the onset of symptoms may be delayed from a few hours up to 4 to 5 days.^11,14 CNS excitation is the hallmark of lindane toxicity. It is manifested by paresthesias, agitation, tremor, myoclonus, hallucinations, and most important, seizures. Seizures may occur suddenly and without prodrome. Complications of prolonged seizures may develop, including respiratory failure, metabolic acidosis, rhabdomyolysis, and hyperthermia.

Differential Diagnosis and Medical Decision Making

The differential diagnosis for suspected lindane poisoning is extremely broad because it can potentially include any cause of seizures. Appropriate, therapeutic use of lindane is not expected to produce toxicity. Unless a patient has ingested lindane before the onset of symptoms, an alternative explanation should be sought to explain the seizures. Although some laboratories can measure lindane levels, the results will not be immediately available to the EP. Therefore, the diagnosis is primarily clinical.

Treatment

No specific antidote is available for lindane toxicity. Although activated charcoal can be considered early after ingestion, it may be dangerous in a patient who may have seizures without warning. The mainstay of treatment is supportive. Benzodiazepines should be used to treat seizures. If that therapy is unsuccessful, barbiturates (phenobarbital) should be administered. As with other toxin-induced seizures, phenytoin is not indicated.

All symptomatic patients with lindane toxicity should be admitted to the hospital. Asymptomatic patients seen after the ingestion of lindane may be observed for 6 hours from the time of ingestion; if no symptoms develop, the patient can be medically cleared.

Epidemiology

Pyrethrins are naturally occurring esters of chrysanthemum resin that possess insecticidal activity, whereas pyrethroids are synthetic derivatives of pyrethrins. Exposures to these agents are commonly reported to poison centers. Most are accidental, and serious clinical effects are rare.²

Pathophysiology

Pyrethrins and pyrethroids delay closure of sodium channels. The delay results in prolonged depolarization, repetitive firing, and eventually conduction blockade.¹⁵ Some pyrethroids may inhibit GABA chloride channels, but it is unlikely that such inhibition plays a significant role in toxicity.

Presenting Signs and Symptoms

Most cases of clinically relevant toxicity from pyrethrins result from pulmonary allergic reactions rather than from direct toxic effects. The signs and symptoms are similar to those of asthma exacerbations and consist of wheezing, cough, dyspnea, and chest pain. Most reactions are mild and easily treated. However, fatal status asthmaticus has been reported with exposure to pyrethrin-containing shampoo.^16,17

Accidental or occupational exposure to pyrethroids usually produces minimal, if any, toxicity. The most common symptoms reported are facial paresthesias, dizziness, headache, nausea, anorexia, and fatigue.¹⁸ Massive exposures or large intentional ingestions may lead to more serious manifestations: seizures, altered mental status, coma, respiratory failure, and death.

Differential Diagnosis and Medical Decision Making

The differential diagnosis for pyrethrin and pyrethroid poisoning includes any other cause of allergic or asthmatic symptoms in most cases, but because treatment is the same, it is not important to know whether the exposure caused the symptoms. If the symptoms are neurologic or gastrointestinal, the differential diagnosis is quite broad; unfortunately, no laboratory or other test will help in differentiation.

Treatment

Activated charcoal may be given to a patient initially seen within 1 hour of a large oral ingestion of pyrethrin or pyrethroid. Skin decontamination is accomplished with soap and water. Pyrethrin-induced bronchospasm is treated with oxygen, β-adrenergic agonists, and corticosteroids as needed. No specific antidote is available, and the symptoms resolve with supportive care.

Epidemiology

Fipronil is a relatively new insecticide that was first introduced in 1996, and over the past several years it has increasingly been used to control common household insects, in addition to being used in flea and tick treatment for pets. Until recently, limited human toxicity data existed. It is commonly found in Frontline and Maxforce products.

Pathophysiology

Fipronil acts as a GABA antagonist, which leads to excessive CNS excitation and death of the insect. It is more specific for the insect GABA receptor than it is for its mammalian counterpart.

Presenting Signs and Symptoms

The majority of human exposures are unintentional and most commonly result in neurologic symptoms such as dizziness and headache. Ocular and upper respiratory irritation has been reported commonly in addition to nausea and vomiting.¹⁹ More severe exposures or large intentional ingestions can cause CNS excitation and seizures.

Differential Diagnosis and Medical Decision Making

Again, depending on the neurologic or gastrointestinal symptoms, the differential diagnosis may be broad and cannot be narrowed with any laboratory or diagnostic test. A history of exposure or potential exposure remains the most important key.

Treatment

Treatment of fipronil exposure remains primarily supportive and symptomatic. In patients with significant exposure who arrive at the ED in a state of CNS excitation or with seizures, the mainstay of treatment is airway protection and liberal use of benzodiazepines for sedation and control of the seizures.

Epidemiology

Paraquat and diquat belong to the bipyridyl class of herbicides. They are both commonly used worldwide for weed control in the agricultural, horticultural, and forestry industries, and paraquat is marketed in more than 130 countries. Both compounds are available for home and commercial use in varying concentrations. Paraquat is commonly sold as a 0.2% solution for home use but can be found in 10% to 24% concentrated commercial solutions.

Paraquat and diquat account for only 4.9% of herbicide poisonings but are responsible for more than 50% of herbicide-related deaths.²⁰ This fact points to the extremely toxic nature of these compounds. Most serious toxicity events and deaths are secondary to intentional ingestion.²¹

Pathophysiology

Paraquat is rapidly absorbed after ingestion and is concentrated in type I and type II alveolar epithelial cells. It is subsequently reduced to a free radical, which then reacts with oxygen to form a superoxide anion (O₂⁻). This anion then may form H₂O₂, which in the presence of Fe²⁺, will generate highly reactive species such as the hydroxyl radical (OH). These reactive molecules cause lipid peroxidation and cellular destruction.²² Initially, acute alveolitis may occur. Later, proliferative changes and pulmonary fibrosis are seen. Although paraquat concentrates mostly in the lungs, it is also distributed throughout the entire body and causes cellular destruction in multiple organs.

The pathophysiologic mechanism of diquat is similar to that of paraquat. Diquat does not concentrate in the lungs, however, and does not produce pulmonary fibrosis.²³

Presenting Signs and Symptoms

Paraquat poisoning can be classified as mild, moderate, or severe according to the amount ingested.²¹ Physical examination findings are summarized in Table 146.4. Mild poisonings, which occur when small amounts of dilute preparations are ingested, are characterized by the development of gastrointestinal symptoms without other organ toxicity. As the amount of paraquat or diquat ion ingested rises, worsening gastrointestinal effects are seen, including severe oropharyngeal, esophageal, and gastric ulceration. Large ingestions produce renal and hepatic failure within a few days. Paraquat toxicity results in pulmonary fibrosis and refractory hypoxemia several days to weeks after ingestion, and death usually occurs within a few weeks. Massive ingestions cause multiorgan failure and death within a few days. Diquat toxicity does not produce pulmonary fibrosis. Diquat ingestion has been associated with brainstem infarction.²³ Effects from dermal exposure to paraquat and diquat are usually mild, but ulcers and blistering can occur with highly concentrated formulations.

Table 146.4 Clinical Manifestations of Paraquat Poisoning

DEGREE	AMOUNT INGESTED	CLINICAL FEATURES
Mild	<20 mg/kg paraquat ion	Asymptomatic or gastrointestinal symptoms Patients recover fully

Moderate to severe 20-40 mg/kg