Organophosphorus (OP) compounds and carbamates, also known as cholinesterase inhibitors, are widely used pesticides. These agents, which comprise thousands of structurally related substances, are responsible for a large number of suicidal or accidental poisonings, with the greatest mortality (an estimated 150,000 deaths per year) in rural areas of developing countries.

During the 1930s, German military scientists synthesized numerous OP compounds, including parathion and several highly potent chemical warfare agents (eg, GA [tabun], GB [sarin], and GD [soman]; see warfare agents and Table II-62). Because these chemical weapons affect the autonomic nervous system, they are sometimes referred to as “nerve agents.” Chemical attacks on civilians in Japan (1994 and 1995) and Syria (2013 and 2017) affected thousands of urban civilians who were exposed to the OP compound sarin. Accidental poisoning with cholinesterase inhibitors can also occur from the contamination of food or beverages.

Carbamates, although less deadly than OP agents, are used frequently as pesticides, fungicides, herbicides, rodenticides, and medications (eg, pyridostigmine) to treat neurologic disorders such as myasthenia gravis.

1. Organophosphorus compounds inhibit two enzymes: acetylcholinesterase (AChE), found in synaptic junctions and in red blood cells (RBCs), and butyrylcholinesterase, also known as pseudocholinesterase (PChE) or plasma cholinesterase, found in the blood. Each of these enzymes breaks down acetylcholine.
   1. Blockade of AChE is the most clinically significant effect of OPs and carbamates because this leads to the accumulation of excessive amounts of acetylcholine at muscarinic receptors (found on various cholinergic secretory cells), at nicotinic receptors (located on skeletal neuromuscular junctions and autonomic ganglia), and in the CNS.
   2. Permanent inhibition of AChE (“aging”) may occur when there is covalent binding by the OP to the enzyme. The rate of aging is highly variable, from several minutes to days, depending on the route of exposure and the specific OP. Dimethyl OP compounds (eg, dimethoate) generally age more quickly than diethyl agents (eg, chlorpyrifos), and lipophilic OP compounds can be released into the systemic circulation from fat stores for many days to weeks following exposure, prolonging both the duration of clinical toxicity and the aging window. Antidotal treatment with an oxime (see “Pralidoxime,”) is considered beneficial only if administered before aging occurs.
2. Carbamates also inhibit the AChEs and lead to accumulation of acetylcholine, with similar acute clinical effects.
   1. CNS effects from carbamates are often less pronounced because they have more difficulty crossing the blood-brain barrier.
   2. Carbamates do not “age” the AChE enzyme, and toxicity is usually shorter in duration and self-limited compared with the OP compounds.
   3. Patients with myasthenia gravis, Alzheimers disease, and other neurologic disorders may be at increased risk for carbamate-induced cholinergic toxicity because they are frequently prescribed the carbamate pyridostigmine or related “-stigmine” compounds.
   4. Aldicarb is relatively more potent and is translocated systemically by certain plants (eg, melons) and concentrated in their fruit. An acute outbreak of poisoning occurred in California in 1985 after ingestion of watermelons that had been grown in a field previously sprayed with aldicarb. The use of an imported rodenticide (Tres Pasitos) led to an epidemic of aldicarb poisoning in New York in 1994-1997.
3. In addition, the effects of the hydrocarbon solvents in which these compounds are frequently formulated (eg, xylene, cyclohexanone, naphtha) must also be considered in evaluating the clinical toxicity from these compounds.
4. Pharmacokinetics. Signs and symptoms of acute OP poisoning may be immediate or delayed several hours, depending on the agent, route, co-ingested toxins, and degree of exposure. Most OPs and carbamates can be absorbed by any route: inhalation, ingestion, or absorption through the skin. Highly lipophilic organophosphates (disulfoton, fenthion, and others) are stored in fat tissue, with the potential to cause prolonged toxicity. The severity and tempo of intoxication are also affected by the rate of exposure (acute vs. chronic), the ongoing metabolic degradation and elimination of the agent, and, for some OP compounds (eg, malathion, parathion), the rate of metabolism to their clinically active “oxon” derivatives.

There is a wide spectrum of relative potency of the OP and carbamate compounds (Tables II-46, II-47, and II-48).

Respiratory failure is a major cause of mortality in patients with acute cholinesterase inhibitor toxicity. Acute clinical manifestations may be classified into muscarinic, nicotinic, and CNS effects (see below), all of which can contribute to respiratory failure. In addition, acute lung injury, pulmonary edema, and chemical pneumonitis due to aspiration of hydrocarbon solvents may compound the multiple respiratory derangements that characterize cholinesterase inhibitor poisoning.

1. Muscarinic manifestations include bronchospasm, bradycardia, abdominal pain, vomiting, diarrhea, miosis, and excessive sweating. Fluid losses can result in shock. Note: Cholinesterase inhibition can produce either bradycardia or tachycardia, and either miosis or mydriasis, as a result of the competing effects of ganglionic stimulation of both parasympathetic and sympathetic pathways.
2. Nicotinic effects are mainly due to acetylcholine excess in skeletal muscles and include muscle weakness and tremors/fasciculations. Respiratory muscle dysfunction, complicated by bronchorrhea and bronchospasm due to muscarinic effects, can be fatal unless aggressive and timely care is rendered. These effects resemble toxicity from nicotine and related alkaloids.
3. Central nervous system manifestations include agitation, seizures, and coma. Respiratory center dysfunction can also cause apneic episodes.
4. Late peripheral neuropathy. Some cholinesterase inhibitors may cause a delayed, often permanent peripheral neuropathy affecting the long motor axons of the legs (OP-induced delayed neuropathy, or OPIDN). The mechanism appears to be the result of inhibition of neuropathy target esterase (NTE), a metabolic enzyme affecting nerve cell membranes that is distinct from other AChEs. The epidemic outbreak of “ginger jake paralysis” in the 1930s was due to drinking rum contaminated with triorthocresyl phosphate (TOCP). More recent outbreaks have been reported from Asia in which contaminated cooking oils were implicated.
5. Intermediate syndrome. Patients can develop proximal motor weakness 2-4 days after exposure, termed “intermediate” because it coincides with resolution of the acute cholinergic crisis but occurs before the period during which delayed peripheral neuropathy typically manifests. Weakness in neck flexion (“broken neck” sign) can progress to bulbar and proximal limb weakness. This syndrome is important to recognize early because fatal respiratory muscle weakness may occur abruptly, after apparent clinical improvement from muscarinic effects. Although the pathophysiology of this entity is unclear, the intermediate syndrome is likely a myopathy related to dysregulation at the neuromuscular junction. Other explanations include delayed toxin redistribution (eg, liberation of lipophilic pesticide from fat stores), inadequate oxime therapy, or a complication related to solvent-toxin effects on muscles. Symptoms may last 1-3 weeks and do not usually respond to additional treatment with oximes or atropine, making mechanical ventilation a key component of treatment.
6. Miscellaneous toxic effects of cholinesterase inhibitor pesticides have been reported in acute or chronic toxicity, with unclear pathophysiologic mechanisms. These relatively rare complications include the Guillain-Barré syndrome, mononeuritis, cognitive-behavioral or choreiform movement disorders, parkinsonian symptoms, glucose abnormalities, metabolic acidosis, acute coronary syndrome, severe hypotension, pancreatitis, and infertility.

Is based on the history of exposure and the presence of characteristic muscarinic, nicotinic, and CNS manifestations of acetylcholine excess. In the majority of cases, the most prominent symptoms are due to excessive muscarinic stimulation. (A useful mnemonic for muscarinic toxicity is DUMBBELSS: diarrhea, urinary incontinence, miosis, bronchospasm, bronchorrhea, emesis, lacrimation, salivation, and sweating.) There may be a noxious solvent odor, and some agents have a strong “garlic” aroma. A Glasgow Coma Scale (GCS) score of 13 or lower at presentation is considered a poor prognostic indicator. Other drugs or toxins that increase cholinergic activity, such as nicotine alkaloids, should be considered in the differential diagnosis, and some unrelated classes of pesticides (eg, pyrethroids, amitraz, phosphides) may cause symptoms that resemble OP and carbamate toxicity.

1. Specific levels
   1. Organophosphorus compounds depress plasma pseudocholinesterase (PChE) and red blood cell acetylcholinesterase (AChE) activities. In emergency practice, these tests are not readily available, nor are they considered central to management. Moreover, because of wide interindividual variability, significant depression of enzyme activity may occur but still fall within the “normal” range. It is most helpful if the patient had a pre-exposure baseline measurement for comparison (eg, as part of a workplace health surveillance program). Proper storage and handling of specimens must be maintained after venipuncture because enzyme activity can continue to be affected by the toxin in vitro or artifactually depressed by fluoride preservatives in certain blood tubes. A point-of-care test for bedside measurement of cholinesterase activity is currently being investigated.
      1. The RBC AChE activity provides a more reliable measure of the toxic effect; a 50% or greater depression in activity from baseline generally indicates a true exposure effect. The level of RBC AChE activity can be altered in patients using oral contraceptive agents or antimalarial drugs, those with pernicious anemia, and infants younger than 4 months of age.
      2. PChE activity is a sensitive indicator of exposure but is not as specific as AChE activity. PChE may be depressed owing to genetic deficiency, pregnancy, medical illness, malnutrition, or chronic OP exposure. PChE activity usually falls before RBC AChE and recovers faster.
   2. Carbamate poisoning produces reversible cholinesterase inhibition, and spontaneous recovery of enzyme activity may occur within several hours, making both of the above tests less useful.
   3. Assay of blood, urine, gastric lavage fluid, and excrement for specific agents and their metabolites may also provide evidence of exposure, but these tests are not widely available.
2. Other useful laboratory studies: arterial blood gases, pulse oximetry, ECG, electrolytes, glucose, BUN, creatinine, lactic acid, creatine kinase (CK), lipase and liver function tests, and chest radiography.
   1. Respiratory function tests such as spirometry and negative inspiratory force (NIF) can help assess the severity of respiratory weakness. This test is broadly available and simple to administer.
   2. Electromyographic and nerve stimulation studies can identify patients at high risk for respiratory failure due to intermediate syndrome or rebound toxicity due to continued absorption or redistribution. These tests require specialized resources, training, and experience to administer and interpret.

1. Emergency and supportive measures. Caution: Rescuers and health care providers should take measures to prevent direct contact with the skin or clothing of contaminated victims because secondary contamination and serious illness may result, especially with nerve agents or potent pesticides (Section IV). In addition, respiratory protective measures are required for persons working in areas contaminated by nerve agent vapors or aerosols.
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Pay careful attention to respiratory muscle weakness and the presence of bronchial secretions. Respiratory arrest is often preceded by increasing weakness of neck flexion muscles. If intubation is required, a nondepolarizing agent should be used because the effect of succinylcholine will be markedly prolonged secondary to the inhibition of PChE.
   2. Anticipate and treat hydrocarbon pneumonitis, bradycardia and other dysrhythmias, hypotension, seizures, and coma if they occur. Seizures should be treated with a benzodiazepine such as diazepam.
   3. Observe asymptomatic patients for at least 8-12 hours to rule out delayed-onset symptoms, especially after extensive skin exposure or ingestion of a highly fat-soluble agent.
2. Specific drugs and antidotes. Specific treatment includes the antimuscarinic agent atropine and the enzyme reactivator pralidoxime. These agents are also packaged together as an auto-injector kit (Mark-1 or Nerve Agent Antidote Kit) for prehospital, disaster, or military settings.
   1. Give atropine in escalating doses until clinical improvement is evident. Begin with 2-5 mg IV initially, and double the dose administered every 5 minutes until respiratory secretions have cleared. Note: Atropine will reverse muscarinic but not nicotinic effects.
      1. Reassess the patient's secretions, oxygen saturation, and respiratory rate every 5-10 minutes. The most important indication for redosing atropine is persistent wheezing or bronchorrhea. Tachycardia is not necessarily a contraindication to additional atropine in the context of severe respiratory secretions.
      2. Once the respiratory secretions have been initially controlled, continuous infusions of atropine may be useful in selected cases, but clinical vigilance is required to prevent over-atropinization. Large cumulative doses of atropine (up to 100 mg or more) may be required in severe cases.
      3. Other antimuscarinic agents (eg, glycopyrrolate) have been demonstrated to reverse the peripheral muscarinic toxicity of OP agents, but they do not penetrate the CNS and are thus less beneficial than atropine, which has good CNS penetration.
   2. Pralidoxime is an oxime that reactivates the cholinesterase enzymes when administered before enzyme aging. It is used primarily for reversal of OP associated nicotinic toxicity such as muscle weakness and paralysis that is unresponsive to atropine. Evidence regarding the use of oximes is inconclusive. Oximes may be more effective against diethyl compounds than against dimethyl agents, which cause a faster aging of the AChE enzyme. Recent evidence from placebo-controlled clinical trials indicates that pralidoxime may not benefit some OP-poisoned patients; however, oximes are still recommended in the treatment of OP poisoning until more selective and evidence-based guidelines are formulated.
      1. Pralidoxime should be given as a loading dose (30-50 mg/kg, total of 1-2 g in adults) over 30 minutes, followed by a continuous infusion of 8- 20 mg/kg/h (up to 650 mg/h). It is most effective if started early, before irreversible phosphorylation of the cholinesterase occurs (aging), but may still be effective if given later, particularly after exposure to highly lipid-soluble compounds released into the blood from fat stores over days to weeks. It is unclear how long oxime therapy should be continued, but it seems reasonable to continue pralidoxime for 24 hours after the patient becomes asymptomatic, or at least as long as atropine infusion is required.
      2. Pralidoxime generally is not recommended for carbamate intoxication because in such cases the cholinesterase inhibition is spontaneously reversible and short lived. However, if the exact agent is not identified and the patient has significant toxicity, pralidoxime should be given empirically.
   3. Many other treatments (magnesium; clonidine; bicarbonate; glutamate and calcium antagonists; fresh-frozen plasma; exogenous hydrolases; lipid emulsion; alternative oximes; and hemoperfusion) have been proposed and/or are currently being investigated.
3. Decontamination . Note: Rescuers should wear chemical-protective clothing and gloves when handling a grossly contaminated victim. If there is heavy liquid contamination with a volatile solvent such as xylene or toluene, clothing removal and victim decontamination should be carried out outdoors or in a room with high-flow ventilation. However, decontamination procedures must not delay the administration of atropine and airway management in the severely poisoned patient.
   1. Skin and mucous membranes. Remove all contaminated clothing and wash exposed areas with soap and water, including the hair and under the nails. Irrigate exposed eyes with copious tepid water or saline.
   2. Ingestion. Gastric lavage or aspiration of liquid stomach contents by a small nasogastric tube may be appropriate soon after moderate-to-large ingestions, but because of the possibility of seizures or rapidly changing mental status, lavage should be done only after the airway has been secured. Administer activated charcoal orally if conditions are appropriate (see Table I-37,).
4. Enhanced elimination. Dialysis and hemoperfusion generally are not indicated because of the large volume of distribution of organophosphates.