Principles of Disease

Organophosphorus insecticides are highly lipid soluble and are readily absorbed through dermal, gastrointestinal, and respiratory routes. This lipid solubility results in the buildup of organophosphorus compounds in body fat, and toxic systemic levels often occur from repeated low-level exposures. The parent compound and its metabolites are acetylcholinesterase inhibitors, and because many parent organophosphorus compounds are less potent than their metabolites (e.g., parathion to paraoxon), delayed onset of clinical toxicity can occur.

Organophosphorus pesticides work by persistently inhibiting the enzyme acetylcholinesterase, the enzymatic deactivator of the ubiquitous neurotransmitter acetylcholine. Because of the global penetration of organophosphorus compounds, inhibition occurs at tissue sites (true acetylcholinesterase and represented by erythrocyte or red blood cell [RBC] cholinesterase) and in plasma (circulating pseudocholinesterase).² Inhibition of cholinesterase results in the accumulation and subsequent prolonged effect of acetylcholine at a variety of neurotransmitter receptors, including sympathetic and parasympathetic ganglionic nicotinic sites, postganglionic cholinergic sympathetic and parasympathetic muscarinic sites, skeletal muscle nicotinic sites, and central nervous system sites (Fig. 163-1).

Clinical Features

Diagnostic Strategies

Any patient with a clinically apparent cholinergic syndrome should be treated empirically without waiting for laboratory confirmation of decreased cholinesterase activity. Known or suspected exposure to cholinesterase inhibitors can be evaluated by ordering of plasma and erythrocyte (RBC) cholinesterase levels. However, these levels will not be readily available in most clinical settings. The patient’s signs and symptoms should guide the management in the emergent time frame.

After acute exposures, the plasma cholinesterase levels decrease first, followed by decreases in RBC cholinesterase levels. The RBC cholinesterase level correlates best with activity at the nerve terminal.² Patients with chronic exposures may have a normal plasma cholinesterase level but have reduced RBC cholinesterase activity, which will confirm the poisoning. The true reflection of depressed cholinesterase activity is found in the RBC activity, and even a mild acute exposure may result in severe clinical poisoning. The RBC cholinesterase level recovers at a rate of 1% per day in untreated patients and takes approximately 6 to 12 weeks to normalize, whereas plasma cholinesterase levels may recover in 4 to 6 weeks. Other laboratory studies should focus on the evaluation of pulmonary, cardiovascular, and renal function and fluid and electrolyte balance. Patients presenting with no acidosis or only a metabolic acidosis on the arterial blood gas analysis have mortality lower than that of patients with a respiratory or mixed acidosis.⁶

Differential Diagnosis

Few toxins or other clinical conditions produce the same constellation of symptoms as acetylcholinesterase inhibitors. A species of mushroom, Amanita muscaria, historically has been mentioned in the differential diagnosis, but it actually contains alkaloids that usually produce an anticholinergic (antimuscarinic) syndrome. Conditions that induce excessive vagal responses (e.g., inferior wall myocardial infarction) may also produce some signs suggesting acetylcholinesterase inhibition, but other symptoms should make the primary cause apparent.

Management

Treatment is directed toward four goals: (1) decontamination, (2) supportive care, (3) reversal of acetylcholine excess at muscarinic sites, and (4) reversal of toxin binding at active sites on the cholinesterase molecule.

Decontamination should start in the out-of-hospital phase to prevent further absorption and subsequent toxicity and to protect care providers. Because dermal exposure is most likely, removal and destruction of clothing and thorough flushing of exposed skin may limit absorption and subsequent toxicity. Alternatively, dermal decontamination can be done with dry agents, such as military resins, flour, sand, or bentonite. Caregivers are at risk for contamination from splashes or handling of contaminated clothing. Treating personnel may be rotated to limit their exposure to the organophosphates.⁴ Caregivers should use universal precautions, including eye shields, protective clothing, and nitrile or butyl rubber gloves. In the case of ingestion, gastrointestinal decontamination procedures are of questionable benefit because of the rapid absorption of these compounds. Profuse vomiting and diarrhea are seen early in ingestion and may limit⁷ or negate any beneficial effect of additional gastrointestinal decontamination.^8,9 The administration of activated charcoal after ingestion has no proven benefit in these poisonings.¹⁰

Equipment, but not skin, may be washed with a 5% hypochlorite solution to inactivate the cholinesterase inhibitor.

Because death is due to airway and respiratory failure, supportive care should be directed primarily toward airway management and include suctioning of secretions and vomitus, oxygenation, and, when necessary, ventilatory support. Succinylcholine can be used for intubation but may have an extremely prolonged duration (up to 3 to 7 hours) as it is metabolized by acetylcholinesterase, which is inhibited in this setting.² It is preferable to use a competitive neuromuscular blocking agent, such as rocuronium, for rapid sequence intubation in these patients, but increased dosing may be necessary. Although some authors have advocated the use of beta-blockers to control tachycardia, this may increase cardiovascular instability and worsen bronchospasm.^8,11 Most cardiovascular effects from organophosphates rarely require specific therapy.

The definitive treatment of acetylcholinesterase inhibition starts with atropine. A competitive inhibitor of acetylcholine at muscarinic receptor sites, atropine reverses the clinical effects of cholinergic excess at parasympathetic end-organs and sweat glands. Large doses of atropine may be required.¹² Data suggest that the more rapid the atropinization, the faster control is obtained.^8,9 Suggested dosing is 1 or 2 mg of atropine (0.02-0.05 mg/kg) intravenously, with doubling of each subsequent dose every 5 minutes until there is control of mucous membrane hypersecretion and the airway clears.^4,8,9,13 If intravenous access is not immediately available, atropine may be administered intramuscularly. Patients may require 200 to 500 mg of atropine intravenously during the first hour, followed by prolonged continuous infusions of 5 to 100 mg/hr to maintain adequate secretion control.¹³ Tachycardia and mydriasis may occur at these doses, but they are not indications to stop atropine administration. The endpoint of atropinization is drying of respiratory secretions, easing of respiration, and mean arterial pressure greater than 60 mm Hg.¹³ Animal evidence suggests that early rapid atropinization may limit seizure propagation and, in conjunction with diazepam, prevent status epilepticus.⁵ Atropine is not active at nicotinic sites and does not reverse the skeletal muscle effects (e.g., muscle fatigue and respiratory failure).^2,9 Other anticholinergic medications, such as diphenhydramine or ophthalmic agents, may have benefit if atropine is scarce or unavailable; however, optimal intravenous dosing is not known.¹⁴

The second part of acetylcholinesterase inhibition treatment is the use of an oxime, such as pralidoxime (2-PAM, Protopam) or obidoxime (Toxogonin), to regenerate the organophosphate-acetylcholinesterase complex and to restore cholinesterase activity at muscarinic and nicotinic sites.2,4,9,15 There are several dosing regimens; the most common dose of pralidoxime is 1 or 2 g intravenously (pediatric dose, 25-50 mg/kg); additional doses may be given on the basis of clinical response. The medication may be given in a bolus of 1 or 2 g intravenously during 30 to 60 minutes every 4 to 8 hours or 500 mg/hr (pediatric dose, 10-25 mg/kg/hr).^15,16 The World Health Organization recommends an initial dose of 30 mg/kg, followed by 8 mg/kg/hr continued for at least 24 hours or, if an infusion cannot be used, 30 mg/kg every 4 hours.¹⁷ The infusion may be continued for several days with no adverse effects attributable to the pralidoxime; however, rapid administration can lead to hypertension, vomiting, and a transient reversible neuromuscular blockade.¹⁸ The ideal dose of pralidoxime should be determined by monitoring of the clinical condition of the patient and serial cholinesterase levels; the patient may require higher doses of oxime than are recommended here. The World Health Organization–recommended infusion dose of obidoxime is 4 mg/kg, followed by 0.5 mg/kg/hr; alternatively, intermittent intravenous doses of 4 mg/kg, then 2 mg/kg, every 4 hours are given.¹⁷ Pralidoxime and obidoxime can be administered by intramuscular injection. Indications for oxime therapy include respiratory depression or apnea, fasciculations, seizures, arrhythmias, cardiovascular instability, and use of large amounts of atropine. Oxime therapy can be used whenever the patient requires more than a limited amount of atropine (2-4 mg) to completely reverse the signs and symptoms of intoxication or in any patient who requires repeated doses of atropine. Oxime therapy and atropine are synergistic.

In the past, pralidoxime was used only within the first 24 hours because of aging of the organophosphate-acetylcholinesterase complex, but not all organophosphates behave in a similar manner. Dimethyl and diethyl phosphoryl insecticides react differently at variable rates with acetylcholinesterase and oxime therapy. Many organophosphates are highly lipid soluble and slowly leach out of fat stores for up to 6 weeks, resulting in newly formed complexes with excellent clinical reversal of the cholinesterase inhibition by pralidoxime and by measurements of cholinesterase activity. Pralidoxime can also combine with unbound organophosphates and prevent their subsequent binding to nerve terminals. Even with optimal treatment, seriously intoxicated patients may require long-term supportive care, including ventilator support.4,16

Several studies have looked at the efficacy of pralidoxime.19,20 The results have been mixed and may be due to the variability among different organophosphates. Until this variability is further elucidated, pralidoxime administration in patients with organophosphate toxicity is still recommended.

In conjunction with atropine and the oxime pralidoxime, patients with agitation, seizures, and coma should be treated with adequate doses of a benzodiazepine after the airway has been secured.4,5,21 Although diazepam is most studied, any parenteral benzodiazepine may be used. The military has classically used diazepam autoinjectors for intramuscular injection, but midazolam is the best intramuscular agent, with lorazepam as an alternative.

Sarin, soman, tabun, and VX are nerve agents that might be used in a terrorist attack. These agents have important differences from the common household or commercial organophosphorus insecticides. These agents tend to age very quickly; tabun (GA) ages in 14 hours, sarin (GB) in 5 hours, soman (GD) in 5 or 6 minutes, and VX in 48 hours. Because of this rapid aging, reversal of nerve agent poisoning with pralidoxime is time sensitive. VX is an oily but highly toxic agent with low volatility. It does not readily vaporize, and because it has a low risk of inhalation, exposure is predominantly transcutaneous. The other agents can be mostly dispersed into the air by explosion or vaporization, resulting in inhalation exposure. These agents do not require the extremely large doses of atropine but do require pralidoxime.22–24

New therapies for treatment of organophosphorus poisoning, including the use of N-acetylcysteine and exogenous acetylcholinesterase, show promise in research studies.25,26 When they are added to anticholinergics, NMDA receptor antagonists may decrease organophosphorus compound–induced seizures.²⁷

Disposition

Because of the prolonged effects of acetylcholinesterase inhibition, most patients with significant exposures require hospital admission. On occasion, a person with chronic exposure, depressed cholinesterase levels, and mild visual or gastrointestinal symptoms may be observed on an outpatient basis; however, some patients, particularly those exposed to fenthion, initially present with signs and symptoms of mild exposure and progress to severe, life-threatening toxicity over time.²⁸ If plasma cholinesterase levels are available, they may be useful for treatment and disposition decisions. Asymptomatic or minimally symptomatic patients with normal or minimally depressed levels may be discharged after 4 to 6 hours with close outpatient follow-up to ensure that progressive toxicity does not occur. Patients who arrive with known severely depressed levels (usually associated with significant symptoms) require admission and close monitoring, usually in a high-intensity care unit. Patients may have rebound toxicity several days after apparently satisfactory response to initial treatment. Rebound toxicity may occur for many reasons, including persistent release of organophosphates from lipid stores.

A secondary syndrome, the intermediate syndrome (IMS), occurs 24 to 96 hours after exposure and consists of proximal muscle weakness specifically of the respiratory muscles. It is believed to be an abnormality at the neuromuscular junction. Patients with IMS present with respiratory failure several days after the acute cholinergic symptoms have resolved and may require several weeks of ventilatory support. It is theorized that this may be a result of inadequate initial oxime treatment or premature discontinuation of oxime therapy.4,29 Oximes may be beneficial for IMS; however, this is controversial.³⁰

Finally, organophosphorus delayed neuropathy has been reported as a different entity. It affects an axonal enzyme, neurotoxic esterase, with a peripheral sensorimotor neuropathy 7 to 21 days after exposure.⁴

Principles of Disease

Chlorinated hydrocarbon pesticides are highly lipid soluble. They are readily absorbed through dermal, respiratory, and gastrointestinal routes. Dermal and gastrointestinal exposures account for most clinical poisonings, including inappropriate external use of lindane or other compounds and the occasional accidental oral administration of lindane. Because they are so lipid soluble, these compounds are stored in fatty tissues, and repeated small exposures result in accumulation and eventual clinical toxicity.

Chlorinated hydrocarbon insecticides primarily affect axonal membranes, resulting in neuronal irritability and excitation. Toxicity occurs in central and peripheral neurons. Some of the organochlorines can inhibit the chloride channel of γ-aminobutyric acid (GABA) receptors, leading to decreased inhibition of the central nervous system. Chlorinated hydrocarbons induce hepatic microsomal enzymes and produce hepatic tumors in some animals. This potential carcinogenicity is the basis for human health concerns, but it is only theoretic. Chlorinated hydrocarbon insecticides, including chlorinated hydrocarbon solvents, may sensitize the myocardium to circulating catecholamines and increase susceptibility to ventricular dysrhythmias, such as tachycardia and fibrillation.

Clinical Features

Diagnostic Strategies

Diagnosis should be confirmed by history or by investigation at the site of the exposure to establish the offending agent with certainty. No specific tests are readily available to confirm the diagnosis of chlorinated hydrocarbon pesticide poisoning. Some reference laboratories can measure fat and plasma levels, but results are difficult to interpret and seldom available during the acute phase of toxicity. Ancillary laboratory and other studies should be based on the clinical condition, complications, and consideration of alternative diagnoses on an individual basis.

Differential Considerations

The differential diagnosis includes virtually every condition that produces seizures. The specific diagnosis depends on obtaining the history of significant acute or chronic chlorinated hydrocarbon pesticide exposure.

Management and Disposition

Skin decontamination with soap and water may reduce toxicity in acute dermal exposure. High lipid solubility results in rapid absorption, and gastrointestinal decontamination is not of benefit. Elimination of some chlorinated hydrocarbon insecticides can be increased, and repeated doses of cholestyramine (4 g orally every 8 hours) given during a mass exposure of chlordecone (a chlorinated hydrocarbon insecticide) enhanced the fecal elimination of this compound.35–37

The primary objective is seizure control, best accomplished with short-acting benzodiazepines or barbiturates. Recurrent seizures or status epilepticus may require high-dose barbiturates and paralyzing agents (e.g., pancuronium or vecuronium) to prevent secondary morbidity from continuous motor activity in prolonged seizures. The seizure activity is usually self-limited, lasting only 1 or 2 days even in severe cases.34,36,38

Continuous cardiac monitoring during the acute phase is indicated because of the potential for myocardial sensitization. Ventricular dysrhythmias are most likely to occur during seizure activity because of the high circulating catecholamine levels and other metabolic abnormalities present during seizures. Dysrhythmias should be treated with beta-adrenergic antagonists, such as propranolol, metoprolol, or esmolol, to reduce the effect of catecholamines on the myocardium.

Additional treatment should focus on the complications of prolonged seizure activity, such as rapid external cooling measures for hyperthermia. Metabolic acidosis is almost always transient and resolves spontaneously without treatment. Rhabdomyolysis and myoglobinuria should be anticipated. Because of their high lipid solubility, chlorinated hydrocarbon pesticides are distributed largely in tissues and are not amenable to hemoperfusion or dialysis.

Patients who have acute or cumulative chlorinated hydrocarbon pesticide toxicity require hospitalization until their seizures are controlled, complications have resolved, and they have returned to their neurologic baselines, usually within 1 or 2 days. Severe complications, such as renal failure from rhabdomyolysis, may prolong the clinical course.

Principles of Disease

Substituted phenols are readily absorbed through the skin and gastrointestinal tract, and aerosols may be absorbed through the respiratory tract. There is some potential for cumulative toxicity with repeated exposures, but much less than with the organophosphorus and chlorinated hydrocarbon pesticides.

Substituted phenols produce their toxicity by uncoupling cellular oxidative phosphorylation; this leads to inefficient production of high-energy phosphate substrates and increased cellular use of oxygen, glucose, and water, with subsequent excess heat production. These compounds are commonly used during the summer when the external heat predisposes users to increased toxicity.⁴⁰ In addition, nitro-substituted phenols may produce methemoglobinemia.

Clinical Features

Patients with substituted phenol toxicity present hypermetabolic and hyperthermic, tachycardic, tachypneic, and profusely diaphoretic. They may also have a relative hypovolemia from excessive insensible fluid losses through sweating and metabolic consumption. Loss of energy production in the brain results in neurologic changes ranging from confusion to seizures and coma. Renal and hepatic injury is common, as is rhabdomyolysis with myoglobinuria. Because phenols are corrosive, patients with dermal exposures often have irritation or chemical burns, and some substituted phenols, such as DNP, produce a characteristic yellow staining of the skin or mucous membranes at the site of absorption. This same staining can be found throughout the internal organs at autopsy.

Cataracts are a complication of long-term exposure. This condition was common in patients who used substituted phenols as part of a weight reduction regimen and was partially responsible for the banning of this substance. The cataracts regress spontaneously after exposure is discontinued.

Diagnostic Strategies

Laboratory evaluation of patients with substituted phenol toxicity is aimed at identification of deficiency of aerobic metabolic substrates, including oxygen, glucose, and water. A complete blood count may reveal hemoconcentration and a nonspecific leukocytosis. Electrolyte abnormalities depend on the duration and severity of symptoms, environmental factors, and complications or underlying disease states. Arterial blood gas measurements show varying degrees of acidosis, depending on the extent of anaerobic metabolic activity due to oxidative phosphorylation uncoupling and associated tissue hypoperfusion from dehydration. Serum enzyme determinations document the extent of hepatic, renal, and skeletal muscle injury. The presence of phenolic compounds in the urine of a patient with this clinical picture strongly suggests substituted phenol pesticides as the cause.

Differential Considerations

Acute toxicity from substituted phenol poisoning is difficult to distinguish from environmental heat-related emergencies or toxicity from sympathomimetics or salicylates. Continued evidence of hypermetabolic activity and metabolic acidosis after routine cooling measures, rehydration, and other supportive care should suggest toxin-induced states. Persistent hyperthermia and acidosis in a weight lifter should trigger concern for DNP abuse. The presence of yellow staining virtually clinches the diagnosis.

Management and Disposition

Initial treatment is directed toward control of body temperature; treatment of acidosis; protection of the kidneys, brain, and liver from hyperthermic damage; and provision of the basic substrates for excessive metabolic activity—oxygen, glucose, and water. If the chemical exposure is known or recognized, early skin decontamination is important. Therapy should be directed toward prevention or minimization of the associated complications discussed previously.

Patients with mild toxicity can usually be stabilized after a few hours and discharged from the emergency department. Patients with significant organ system injury or prolonged or recurrent seizures, significant alteration of consciousness, and rhabdomyolysis require admission, usually to the intensive care unit.

Principles of Disease

Chlorophenoxy compounds may be absorbed through the skin, gastrointestinal tract, and respiratory tract, but almost all significant poisonings are a result of accidental or intentional ingestion. The lipid solubility of these compounds is low, and excretion is fairly rapid, so cumulative toxicity from repeated exposures does not occur.⁴²

Although skeletal muscle is the target organ for chlorophenoxy herbicides, the exact mechanism is unknown. Depending on severity, muscle abnormalities may range from generalized muscle weakness to acute rhabdomyolysis. Higher doses may also uncouple oxidative phosphorylation and cause a hypermetabolic state similar to that seen with the substituted phenols.

Clinical Features

Similar to most organic pesticides in an organic solvent, the chlorophenoxy herbicides may produce mild, nonspecific dermal and gastrointestinal irritation with nausea, vomiting, and gastrointestinal distress. Large exposures are likely to cause systemic symptoms ranging from diffuse myotonia and muscle fasciculations progressing to rhabdomyolysis, hyperthermia, and a hypermetabolic state with metabolic acidosis.⁴³

Diagnostic Strategies

There are no specific tests for the detection of the chlorophenoxy compounds. Laboratory evaluation should be aimed at evaluation of skeletal muscle injury and its complications. Severely poisoned patients require generalized organ system evaluation, including hepatic and renal function, because of the effects of rhabdomyolysis and hyperthermia.

Differential Considerations

Differential diagnostic possibilities include other causes of acute myopathy. The manifestation of chlorophenoxy compound toxicity is extremely rare, however, and without a definite history or strong suspicion of exposure, other explanations for acute myopathy should be pursued.

Management and Disposition

Treatment consists of initial skin decontamination and basic supportive care. Serious toxic effects develop within 4 to 6 hours after ingestion, and treatment can be directed toward the specific problems of muscle weakness, airway and ventilatory support, and rhabdomyolysis. Treatment of hyperthermia and acidosis has been discussed previously.

Asymptomatic or minimally symptomatic patients may be discharged after 4 to 6 hours of observation. Patients with muscle effects should be admitted for close observation and monitoring of respiratory effort.

Principles of Disease

Of the two bipyridyl compounds in use, paraquat is the most significant in terms of number of cases and toxic effects. Paraquat use is tightly regulated in the United States but is widespread throughout the world. Diquat is less regulated in the United States and is included in some formulations of herbicides sold for residential use. Paraquat is absorbed through the skin, gastrointestinal tract, and respiratory tract. Almost all fatal exposures have resulted from the ingestion of paraquat, although a few case reports have involved extensive skin contamination. Toxicity has occurred, but no fatal cases have been reported from inhalation of paraquat vapor or aerosols. Diquat is poorly absorbed through intact skin, and most cases of toxicity result from ingestion.⁴⁵

Paraquat’s toxic effect is from the production of superoxides created during cyclic oxidation-reduction reactions of the compound in tissues. Lipid peroxidation of cellular membranes seems to be one significant pathway of cellular injury.^46,47

Paraquat selectively concentrates in the lungs because of an amine uptake mechanism in alveolar cells. In addition, high concentrations of oxygen significantly increase the extent of paraquat-induced injury so that the lungs are the major target organs. The pathophysiologic lesions include direct injury to the alveolar-capillary membrane followed by surfactant loss, adult respiratory distress syndrome, progressive pulmonary fibrosis, and respiratory failure. Paraquat damages other major organ systems by the same cellular membrane effects, including the liver, kidneys, heart, and central nervous system. Diquat has similar effects, with most of its toxicity concentrated in the kidneys rather than in lung tissue.⁴⁵

Clinical Features

Diagnostic Strategies

Paraquat is measurable in the blood. As long as the time of acute exposure is known, the level serves as an accurate prognostic marker. The assay is not readily available in the United States, and by the time the results are obtained, nothing can be done to change the eventual outcome. There is a qualitative bedside test that uses the reduction of paraquat or diquat in alkalinized urine by sodium dithionite, but the reagent frequently is not available.⁴³ Studies should evaluate caustic gastrointestinal injury and pulmonary and renal damage.

Differential Considerations

A person with acute paraquat or diquat ingestion is likely to present with an acute corrosive injury; the differential diagnosis should encompass all corrosive agents. Successful therapeutic intervention for paraquat toxicity is extremely time dependent, and patient outcome depends on the history. Any patient who has evidence of pulmonary or other organ injury from paraquat exposure is probably already beyond recovery.

Management and Disposition

There are no studies comparing various treatment strategies, but the key to successful treatment of an acute paraquat exposure probably depends on early decontamination measures to limit absorption. There are no effective treatments once clinical effects are seen. Thorough skin cleansing is obvious and straightforward in dermal exposures. Careful gastric lavage and administration of activated charcoal may be lifesaving and should be undertaken in consultation with a poison center or a medical toxicologist. These treatments may be hazardous in the context of a corrosive ingestion. Early endoscopy and surgical intervention may be necessary if there is evidence of esophageal perforation and mediastinitis. Although fuller’s earth and bentonite are recommended as adsorbents in paraquat ingestions, activated charcoal is much more readily available in the United States and has equal if not greater efficacy.

Oxygen treatment can theoretically exacerbate paraquat toxicity by the production of superoxides. Therefore, oxygen should be used only as minimally necessary in these cases.

Although it is controversial, many experts recommend rapid initiation of charcoal hemoperfusion to rapidly lower plasma paraquat levels and to limit pulmonary and other organ system uptake of paraquat. Many also recommend serial and combined hemoperfusion and hemodialysis, particularly during the first 24 hours after exposure.

Cyclophosphamides in combination with corticosteroids have also been investigated as a means to attenuate paraquat toxicity.48,49 Whereas the results have been mixed, this therapy has been recommended by some experts in the setting of significant paraquat toxicity.

There are other suggested treatment adjuncts, such as N-acetylcysteine, nitric oxide, deferoxamine, and cytoprotective agents such as amifostine, but no single therapy has proved consistently successful.⁵⁰

Patients with any significant dermal paraquat exposure and all patients with ingested paraquat require hospitalization and consideration of enhanced elimination therapy. These patients should be observed and treated expectantly until paraquat levels, if available, are reported to be nonexistent or nontoxic.

Principles of Disease

Because pyrethrins and pyrethroids are most commonly aerosolized, inhalation is the most likely route of exposure. The patient may not be aware of an exposure because pyrethrin and pyrethroid aerosols are used frequently as automated insect sprays in public areas, such as in airplanes. In these situations, concentrations rarely reach levels likely to produce symptoms in any but the most sensitized patient. Occasional ingestions have been reported, and significant toxicity is possible by this route. Systemic absorption through the dermal route is unlikely, but topical effects are possible. Most pyrethrins and pyrethroids are rapidly metabolized and deactivated in human exposure, so cumulative toxicity is not a problem. Piperonyl butoxide, which is added as an insect “knock-down” agent, may increase the toxicity of the pyrethrum derivatives.

Pyrethrins and pyrethroids have a variety of effects in humans and other mammals.51,52 Clinically, the naturally occurring pyrethrins can cause sensitization and allergic phenomena, but this does not occur with the synthetic pyrethroids. Both classes are associated with sodium channel blockade, slowing the rate of activation of the sodium channel and extending the time during which the channel is open. In addition, both classes affect GABA receptors, inhibiting chloride channel function. Less significant effects include potentiation of nicotinic cholinergic neurotransmission, enhancement of norepinephrine release, and inhibition of calcium adenosine triphosphatase interference with sodium-calcium exchange across membranes.^51,52

Clinical Features

Effects are very rare. Allergic manifestations, including potentially life-threatening events, may occur after acute inhalation or dermal exposure. Inhalation exposure often occurs with the use of a pyrethrin-based aerosol in an enclosed, poorly ventilated space. Local effects include lacrimation, rhinitis, rhinorrhea, sneezing, throat irritation, and pharyngeal and laryngeal edema. Lower respiratory effects include cough, shortness of breath, chest pain, and wheezing. Rashes are consistent with a contact or allergic dermatitis, and photosensitivity may contribute to the dermatologic picture. There is potential for allergic cross-reactivity in patients who are allergic to ragweed.

Sodium channel–mediated and GABA-mediated chloride channel effects mediate neurologic signs and symptoms. Facial paresthesias have been reported, and seizures occur with massive ingestions.51,52 Nonspecific symptoms, such as headache, fatigue, dizziness, and weakness, are also reported.

Diagnostic Strategies

No laboratory tests are available to measure pyrethrins or pyrethroids in a clinical setting.

Differential Considerations

The differential diagnosis of the signs and symptoms of pyrethrin or pyrethroid toxicity includes the usual causes of bronchospasm and seizures and other acute neurologic complications.

Management and Disposition

Decontamination, including removal from a contaminated environment or washing, should be the first step. Definitive treatment is supportive and directed at the respiratory and neurologic complications.

Disposition of a patient with exposure to pyrethrins depends on the severity of the underlying complications. If discharge from the emergency department is anticipated, the patient should be counseled with regard to the possibility of recurrent allergic phenomena on reexposure.

Principles of Disease

Glyphosate is poorly absorbed through the skin so that most exposures result from ingestion. The concentrated solution is extremely irritating, and patients may vomit with subsequent aspiration. The concentrated solution is provided as 41% glyphosate in 15% POEA. The directions state that it should be diluted to a 1% glyphosate solution.

Glyphosate is toxic to plants by inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase in the shikimic acid metabolic pathway. After application of glyphosate on the leaves, it is transported to the roots, where the enzyme is active. Humans lack this enzyme and do not have enzyme-related toxicity. Reported toxicity is believed to result largely from the surfactant POEA and may reflect the direct corrosive effect from the amine salt, or it may uncouple oxidative phosphorylation.⁵³

Clinical Features

Most ingestions of the dilute solution cause only minimal symptoms, including gastrointestinal distress. Patients ingesting large volumes of dilute solutions or moderate volumes of concentrated solutions complain of sore throat, nausea, abdominal pain, and fever. They may have vomiting, diarrhea, respiratory distress, noncardiogenic pulmonary edema, dysrhythmias, shock, coma, and renal failure. Acidosis reflects poor tissue perfusion and cardiovascular compromise.⁵³ Negative prognostic indicators include shock, acidosis, and persistent hyperkalemia.⁵³

Diagnostic Strategies

The critical element in diagnosis is history of ingestion. Laboratory analysis may demonstrate an anion gap metabolic acidosis, hypoxemia, and hyperkalemia. Elevated transaminases may occur in 30% of ill patients, and signs of renal failure may develop in persistent shock states. The electrocardiogram may show ventricular dysrhythmias and secondary signs of hypoxemia.⁵³

Differential Diagnosis

The differential diagnosis includes most corrosive ingestions and causes of shock. The findings of hyperkalemia and metabolic acidosis may suggest hydrofluoric acid ingestions. A normal ionized calcium level may help rule out hydrofluoric acid exposure. Any cause of aspiration should also be considered. The history is the most useful factor in the differential diagnosis.

Management and Disposition

Treatment is supportive. The patient may require positive-pressure ventilation to overcome the noncardiogenic pulmonary edema. POEA may also be a direct cardiac depressant; inotropic agents can be useful. Hyperkalemia should be treated in the usual manner with fluids, medications to shift potassium into the cell (e.g., bicarbonate, calcium, and beta-adrenergic agonists), and Kayexalate. If there is an indication of significant corrosive ingestion, early endoscopy with placement of stent, high-dose steroids, and laparotomy may be considered.

Asymptomatic patients with small ingestions of dilute substances may be observed for 6 hours and discharged. Patients with complaints consistent with corrosive ingestions should be admitted and have a gastrointestinal evaluation. Patients with pulmonary complaints require admission and intensive supportive care.

Principles of Disease

DEET is lipophilic and can be absorbed through the skin. Skin absorption and toxicity increase with repeated applications, increased ambient temperatures, sweating, and abraded, thin skin. Ingestion may lead to toxicity.⁵⁶ DEET primarily affects the central nervous system. Its mechanism of action is unknown. It may sensitize the skin and cause allergic reactions.

Clinical Features

Prolonged skin contact may lead to contact dermatitis, and prolonged contact with high concentrations has led to skin blisters. Patients who have ingested DEET or have repeated skin applications in a hot enclosed environment that enhances absorption have developed liver function test abnormalities and neurologic findings, including encephalopathy, seizures, movement disorders, and coma.⁵⁶ Most exposures to DEET result in no or minimal toxicity and should not preclude its use in susceptible populations in which significant arthropod-borne diseases are prevalent.⁵⁷

Diagnostic Strategies

Exposure history is central to the diagnosis. Although DEET can be detected in urine, most laboratories are not able to do this testing during the acute toxicity phase. An electroencephalogram may be useful in a patient with coma or encephalopathy and seizures.

Differential Diagnosis

The differential diagnosis includes conditions that may cause encephalopathy, seizures, and movement disorders. Such conditions include drug intoxication, infectious causes, drug interactions, and structural defects.

Management and Disposition

Treatment is supportive. If DEET exposure is suspected, the skin should be thoroughly decontaminated. Oils or lipophilic agents should be avoided because they enhance skin absorption. After DEET ingestion, milk products and oil-containing foods should be avoided until the gastrointestinal tract has eliminated the offending agent. Seizures should be treated with benzodiazepines.

Asymptomatic patients who have ingested DEET-containing repellents should be observed for 4 to 6 hours. Patients who have neurologic symptoms should be admitted and observed.

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