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.