Organophosphate (OP) compounds are a diverse group of chemicals used in both domestic and industrial settings.

Examples of organophosphates include insecticides (malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion), nerve gases (soman, sarin, tabun, VX), ophthalmic agents (echothiophate, isoflurophate), and antihelmintics (trichlorfon). Herbicides (tribufos [DEF], merphos) are tricresyl phosphatecontaining industrial chemicals. Organophosphate compounds were first synthesized in the early 1800s when Lassaigne reacted alcohol with phosphoric acid. Shortly thereafter in 1854, Philip de Clermount described the synthesis of tetraethyl pyrophosphate at a meeting of the French Academy of Sciences. Eighty years later, Lange, in Berlin, and, Schrader, a chemist at Bayer AG, Germany, investigated the use of organophosphates as insecticides. However, the German military prevented the use of organophosphates as insecticides and instead developed an arsenal of chemical warfare agents (ie, tabun, sarin, soman). A fourth agent, VX, was synthesized in England a decade later. During World War II, in 1941, organophosphates were reintroduced worldwide for pesticide use, as originally intended. Massive organophosphate intoxication from suicidal and accidental events, such as the Jamaican ginger palsy incident in 1930, led to the discovery of the mechanism of action of organophosphates. In 1995, a religious sect, Aum Shinrikyo, used sarin to poison people on a Tokyo subway. Mass poisonings still occur today; in 2005, 15 victims were poisoned after accidentally ingesting ethioncontaminated food in a social ceremony in Magrawa, India. Nerve agents have also been used in battle, notably in Iraq in the 1980s. Additionally, chemical weapons still pose a very real concern in this age of terrorist activity. Exposure to organophosphates (OPs) is also possible via intentional or unintentional contamination of food sources. Although no clinical effects of chronic, low-level organophosphates (OPs) exposure from a food source have been shown, advancements in risk assessment and preparedness are ongoing.[1, 2]

Patophysiology
The primary mechanism of action of organophosphate pesticides is inhibition of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChE is an enzyme that degrades the neurotransmitter acetylcholine (ACh) into choline and acetic acid. ACh is found in the central and peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs). Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the active site of AChE. The phosphorylation occurs by loss of an organophosphate leaving group and establishment of a covalent bond with AChE. Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors. Clinical effects are manifested via activation of the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle. Once an organophosphate binds to AChE, the enzyme can undergo one of the following: Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases Reactivation by a strong nucleophile such as pralidoxime (2-PAM) Irreversible binding and permanent enzyme inactivation (aging) Organophosphates can be absorbed cutaneously, ingested, inhaled, or injected. Although most patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific compound, amount, route of exposure, and rate of metabolic degradation. [3]

Epidemiology

Frequency
United States In 2007, The American Association of Poison Control Centers' received 96,307 calls (3.4% of all human exposures) related to pesticide exposures, many of which involved organophosphate (OP) agents and 80 uses of 2-PAM.[4] However, poison center recorded exposures to organophosphates

(OPs) from 1995 to 2004 have declined because of the United States Environmental Protection Agency phasing out commonly used household and agricultural organophosphate (OP) agents.[5] International Pesticide poisonings are among the most common modes of poisoning fatalities. In countries such as India and Nicaragua, organophosphates (OPs) are easily accessible and, therefore, a source of both intentional and unintentional poisonings. The incidence of international organophosphate-related human exposures appears to be underestimated.[6]

Mortality/Morbidity
Worldwide mortality studies report mortality rates from 3-25%. The compounds most frequently involved include malathion, dichlorvos, trichlorfon, and fenitrothion/malathion. Mortality rates depend on the type of compound used, amount ingested, general health of the patient, delay in discovery and transport, insufficient respiratory management, delay in intubation, and failure in weaning off ventilatory support. Complications include severe bronchorrhea, seizures, weakness, and neuropathy. Respiratory failure is the most common cause of death.

Age
Organophosphates (OPs) may affect children or other at-risk populations differently. The increased susceptibility has not been elucidated but may involve delayed or persistent effects. More work in this area is underway and should help identify the true risk potential.[7]

History
Signs and symptoms of organophosphate poisoning can be divided into 3 broad categories, including (1) muscarinic effects, (2) nicotinic effects, and (3) CNS effects. Mnemonic devices used to remember the muscarinic effects of organophosphates are SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation). Muscarinic effects by organ systems include the following: Cardiovascular - Bradycardia, hypotension Respiratory - Rhinorrhea, bronchorrhea, bronchospasm, cough, severe respiratory distress Gastrointestinal - Hypersalivation, nausea and vomiting, abdominalpain, diarrhea, fecal incontinence Genitourinary - Incontinence Ocular - Blurred vision, miosis Glands - Increased lacrimation, diaphoresis Nicotinic signs and symptoms include muscle fasciculations, cramping, weakness, and diaphragmatic failure. Autonomic nicotinic effects include hypertension, tachycardia, mydriasis, and pallor. CNS effects include anxiety, emotional lability, restlessness, confusion, ataxia, tremors, seizures, and coma.

o o o o o o

Physical
Note that clinical presentation may vary, depending on the specific agent, exposure route, and amount. Symptoms are due to both muscarinic and nicotinic effects. Interestingly, a review of 31 children with organophosphate (OP) poisoning described that, in contrast to adults, the most common presentations were seizure and coma with relatively less muscarinic or nicotinic findings. [8] The authors hypothesized the difference may be due to difficulty in detecting muscarinic findings in infants (eg, crying) and ingestion of contaminated produce instead of organophosphate (OP) directly. Vital signs: Depressed respirations, bradycardia, and hypotension are possible symptoms. Alternatively, tachypnea, hypertension, and tachycardia are possible. Hypoxia should be monitored for with continuous pulse oximetry. Paralysis

Type I: This condition is described as acute paralysis secondary to continued depolarization at the neuromuscular junction. o Type II (intermediate syndrome): Intermediate syndrome was described in 1974 and is reported to develop 24-96 hours after resolution of acute organophosphate poisoning symptoms and manifests commonly as paralysis and respiratory distress. This syndrome involves weakness of proximal muscle groups, neck, and trunk, with relative sparing of distal muscle groups. Cranial nerve palsies can also be observed. Intermediate syndrome persists for 4-18 days, may require mechanical ventilation, and may be complicated by infections or cardiac arrhythmias. Although neuromuscular transmission defect and toxin-induced muscular instability were once thought to play a role, this syndrome may be due to suboptimal treatment. o Type III: Organophosphate-induced delayed polyneuropathy (OPIDP) occurs 2-3 weeks after exposure to large doses of certain organophosphates (OPs) and is due to inhibition of neuropathy target esterase. Distal muscle weakness with relative sparing of the neck muscles, cranial nerves, and proximal muscle groups characterizes OPIDP. Recovery can take up to 12 months. [9, 10] Neuropsychiatric effects: Impaired memory, confusion, irritability, lethargy, psychosis, and chronic organophosphate-induced neuropsychiatric disorders have been reported. The mechanism is not proven. Extrapyramidal effects: These are characterized by dystonia, cogwheel rigidity, and parkinsonian features (basal ganglia impairment after recovery from acute toxicity). Other neurological and/or psychological effects: Guillain-Barrlike syndrome and isolated bilateral recurrent laryngeal nerve palsy are possible. Ophthalmic effects: Optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis (due to direct ocular exposure to organophosphates) are possible. Ears: Ototoxicity is possible. Respiratory effects: Muscarinic, nicotinic, and central effects contribute to respiratory distress in acute and delayed organophosphate toxicity. Muscarinic effects: Bronchorrhea, bronchospasm, and laryngeal spasm, for instance, can lead to airway compromise. Respiratory failure is the most life-threatening effect and requires immediate intervention. Nicotinic effects: These effects lead to weakness and paralysis of respiratory oropharyngeal muscles. Central effects: These effects can lead to respiratory paralysis. Rhythm abnormalities: Sinus tachycardia, sinus bradycardia, extrasystoles, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation (often a result of, or complicated by, severe hypoxia from respiratory distress) are possible. Other cardiovascular effects: Hypotension, hypertension, and noncardiogenic pulmonary edema are possible. GI manifestations: Nausea, vomiting, diarrhea, and abdominal pain may be some of the first symptoms to occur after organophosphate exposure. Genitourinary and/or endocrine effects: Urinary incontinence, hypoglycemia, or hyperglycemia is possible.

DD
Gastroenteritis, Viral Toxicity, Mushroom

Laboratory study
Organophosphate (OP) toxicity is a clinical diagnosis. Confirmation of organophosphate poisoning is based on the measurement of cholinesterase activity; typically, these results are not readily available. Although RBC and plasma (pseudo) cholinesterase (PChE) levels can both be used, RBC cholinesterase correlates better with CNS acetylcholinesterase (AChE) and is, therefore, a more useful marker of organophosphate poisoning. The portable Test-mate ChE field test measures RBC AChE and PChE within 4 minutes. A study of patients with acute organophosphorus poisoning compared Test-mate ChE results with those of a

reference laboratory test and found good agreement between the two. Results show the Test-mate ChE field kit is a reliable test that provides rapid measurement of RBC AChE in acute organophosphorus poisoning.[11] If possible, draw blood for measurement of RBC and plasma cholinesterase levels prior to treatment with pralidoxime (2-PAM). Monitoring serial levels can be used to determine a response to therapy. RBC AChE represents the AChE found on RBC membranes, similar to that found in neuronal tissue. Therefore, measurement more accurately reflects nervous system OP AChE inhibition. Plasma cholinesterase is a liver acute-phase protein that circulates in the blood plasma. It is found in CNS white matter, the pancreas, and the heart. It can be affected by many factors, including pregnancy, infection, and medical illness. Additionally, a patient's levels can vary up to 50% with repeated testing. RBC cholinesterase is the more accurate of the 2 measurements, but plasma cholinesterase is easier to assay and is more readily available. Cholinesterase levels do not always correlate with severity of clinical illness. The level of cholinesterase activity is relative and is based on population estimates. Neonates and infants have baseline levels that are lower than adults. Because most patients do not know their baseline level, the diagnosis can be confirmed by observing a progressive increase in the cholinesterase value until the values plateau over time. Falsely depressed levels of RBC cholinesterase can be found in pernicious anemia, hemoglobinopathies, use of antimalarial drugs, and oxalate blood tubes. Falsely depressed levels of plasma cholinesterase are observed in liver dysfunction, low-protein conditions, neoplasia, hypersensitivity reactions, use of certain drugs (succinylcholine, codeine, morphine), pregnancy, and genetic deficiencies. Other laboratory findings include: leukocytosis, hemoconcentration, metabolic and/or respiratory acidosis, hyperglycemia, hypokalemia, hypomagnesemia and elevated amylase and liver function studies A retrospective analysis of OP poisoned patients by Liu et al found a direct correlation between the severity of poisoning and mortality and the presence of pretreatment metabolic and respiratory acidosis.[12]

Imaging Studies
A chest radiograph may reveal pulmonary edema but typically adds little to the clinical management of a poisoned patient. Other Tests The true etiology of intermediate syndrome is still being investigated. Facts involved in its etiology as well as objective diagnostic tests may, in the near future, involve already available nerve testing [10] techniques. ECG findings include prolonged QTc interval, elevated ST segments, and inverted T waves. Although sinus tachycardia is the most common finding in the poisoned patient, sinus bradycardia with PR prolongation can develop with increasing toxicity due to excessive parasympathetic activation. Procedures Endotracheal intubation and mechanical ventilation may be necessary in patients with organophosphate poisoning for airway protection and management of bronchorrhea and seizures. Central venous access and arterial lines may be needed to treat the patient with organophosphate toxicity who requires multiple medications and blood-gas measurements.

Medical Care
Airway control and adequate oxygenation are paramount in organophosphate (OP) poisonings. Intubation may be necessary in cases of respiratory distress due to laryngospasm, bronchospasm, bronchorrhea, or seizures. Immediate aggressive use of atropine may eliminate the need for

intubation. Succinylcholine should be avoided because it is degraded by acetylcholinesterase (AChE) and may result in prolonged paralysis. Continuous cardiac monitoring and pulse oximetry should be established; an ECG should be performed. Torsades de Pointes should be treated in the standard manner. The use of intravenous magnesium sulfate has been reported as beneficial for organophosphate toxicity. The mechanism of action may involve acetylcholine antagonism or ventricular membrane stabilization. Remove all clothing and gently cleanse patients suspected of organophosphate exposure with soap and water because organophosphates are hydrolyzed readily in aqueous solutions with a high pH. Consider clothing as hazardous waste and discard accordingly. Health care providers must avoid contaminating themselves while handling patients. Use personal protective equipment, such as neoprene gloves and gowns, when decontaminating patients because hydrocarbons can penetrate nonpolar substances such as latex and vinyl. Use charcoal cartridge masks for respiratory protection when decontaminating patients who are significantly contaminated. Irrigate the eyes of patients who have had ocular exposure using isotonic sodium chloride solution or lactated Ringer's solution. Morgan lenses can be used for eye irrigation.

Surgical Care
Patients with trauma or blast injury should be treated according to standard advanced trauma life support (ATLS) protocol. Patient decontamination should always be considered to prevent medical personnel poisoning.

Medication Summary
The mainstays of medical therapy in organophosphate (OP) poisoning include atropine, pralidoxime (2-PAM), and benzodiazepines (eg, diazepam). A novel route of administration of intraosseous (bone injection gun, BIG) midazolam demonstrated rapid peak concentrations in swine compared with intravenous and intramuscular routes; the authors concluded this may play a role in quickly terminating seizures, especially in the prehospital arena.[13] Initial management must focus on adequate use of atropine. Optimizing oxygenation prior to the use of atropine is recommended to minimize the potential for dysrhythmias. de Silva et al studied the treatment of organophosphate poisoning with atropine and 2-PAM and, later the same year, with atropine alone.[14] They found that atropine seemed to be as effective as atropine plus 2-PAM in the treatment of acute organophosphate poisoning. The controversy continued when other authors observed more respiratory complications and higher mortality rates with use of highdose 2-PAM. Low-dose (1-2 g slow IV) 2-PAM is the current recommendation. Studies are underway to assess the role of low-dose 2-PAM. Improved survival has been shown in moderately severe OP poisoned patients who received early, continuous 2-PAM infusion compared with those who received intermittent boluses.[15] A meta-analysis and review of the literature performed by Peter et al emphasized optimal supportive care along with discriminate use of 2-PAM, especially early in the course of treatment of moderately to severely OP poisoned patients, are the hallmarks of treatment.[16] More prospective data are required. Because large amounts of atropine may be required for patients with organophosphate poisoning, reconstitution of powdered atropine is a viable option, especially in mass-casualty settings.[17] Recently, Rajpal et al demonstrated the clinical safety and efficacy of sublingual atropine to healthy volunteers. This may offer another route of administration for the OP poisoned patient, especially in a mass-casualty scenario.[18] Intravenous glycopyrrolate or diphenhydramine may provide an alternative centrally acting anticholinergic agent used to treat muscarinic toxicity if atropine is unavailable or in limited supply. Additionally, Yavuz et al demonstrated reduced myocardial injury and troponin leak in fenthionpoisoned rats treated with diphenhydramine.[19] In a single-center, randomized, single-blind study by Pajoumand et al found a benefit to magnesium therapy in addition to standard oxime and atropine therapy in reducing hospitalization days and

mortality rate in patients with organophosphate poisoning.[20] The mechanisms appear to be inhibition of acetylcholine (ACh) and organophosphate antagonism. Larger randomized studies are needed to demonstrate magnesium efficacy in organophosphate (OP) poisoning. Possible future interventions include neuroprotective agents used to prevent nerve damage and bioscavengers aimed to prevent AChE inhibition by nerve agents or organophosphate. Investigations into adjunctive and alternative therapies have mostly used animal models and have resulted in variable conclusions.[21, 22]

Anticholinergic agents
Class Summary
These agents act as competitive antagonists at the muscarinic cholinergic receptors in both the central and the peripheral nervous system. These agents do not affect nicotinic effects.
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Atropine IV/IM (Isopto, Atropair)

Initiated in patients with OP toxicity who present with muscarinic symptoms. Competitive inhibitor at autonomic postganglionic cholinergic receptors, including receptors found in GI and pulmonary smooth muscle, exocrine glands, heart, and eye. The endpoint for atropinization is dried pulmonary secretions and adequate oxygenation. Tachycardia and mydriasis must not be used to limit or to stop subsequent doses of atropine. The main concern with OP toxicity is respiratory failure from excessive airway secretions.
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Glycopyrrolate (Robinul)
Indicated for use as an antimuscarinic agent to reduce salivary, tracheobronchial, and pharyngeal secretions. Does not cross the blood-brain barrier. Can be considered in patients at risk for recurrent symptoms (after initial atropinization) but who are developing central anticholinergic delirium or agitation. Since glycopyrrolate does not cross BBB, it is not expected to control central cholinergic toxicity. Bird et al suggested that atropine (rather than glycopyrrolate) was associated with lower, early OP-induced mortality

Antidotes, OP poisoning
Class Summary
These agents prevent aging of AChE and reverse muscle paralysis with OP poisoning.
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Pralidoxime (2-PAM, Protopam)

Nucleophilic agent that reactivates the phosphorylated AChE by binding to the OP molecule. Used as an antidote to reverse muscle paralysis resulting from OP AChE pesticide poisoning but is not effective once the OP compound has bound AChE irreversibly (aged). Current recommendation is administration within 48 h of OP poisoning. Because it does not significantly relieve depression of respiratory center or decrease muscarinic effects of AChE poisoning, administer atropine concomitantly to block these effects of OP poisoning. Signs of atropinization might occur earlier with addition of 2-PAM to treatment regimen. 2-PAM administration is not indicated for carbamate exposure since no aging occurs.

Benzodiazepines
Class Summary
These agents potentiate effects of gamma-aminobutyrate (GABA) and facilitate inhibitory GABA neurotransmission.
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Diazepam (Valium, Diastat, Diazemuls)

For treatment of seizures. Depresses all levels of CNS (eg, limbic and reticular formation) by increasing activity of GABA

Further Inpatient Care

Because of risks of respiratory compromise or recurrent symptoms, hospitalizing all symptomatic patients for at least 24 hours in a high acuity setting is recommended. Patients who are asymptomatic 12 hours after organophosphate exposure can be discharged since symptom onset should usually occur within this time frame. Optimal recommendations are made on a case-by-case scenario. Consider discussing each case with a medical toxicologist or the regional poison center (1-800-222-1222). Following occupational exposure, patients should not be allowed to return to work with organophosphates until serum cholinesterase activity returns to 75% of the known baseline level. Also, establishing base line cholinesterase levels for workers with known organophosphate (OP) exposure is recommended.[23]

Deterrence/Prevention
Health care providers must avoid contaminating themselves while handling patients poisoned by organophosphates. The potential for cross-contamination is highest in treating patients after massive dermal exposure. Use personal protective equipment, such as neoprene or nitrile gloves and gowns, when decontaminating patients because hydrocarbons can penetrate nonpolar substances such as latex and vinyl. Use charcoal cartridge masks for respiratory protection when caring for patients with significant contamination.

Complications
Complications include respiratory failure, seizures, aspiration pneumonia, delayed neuropathy, and death.

Patient Education
For excellent patient education resources, visit eMedicineHealth's First Aid and Injuries Center. Also, see eMedicineHealth's patient education articles Poisoning,Activated Charcoal, Poison Proofing Your Home, Chemical Warfare, and Personal Protective Equipment.

References
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4. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline]. 5. Sudakin DL, Power LE. Organophosphate exposures in the United States: a longitudinal analysis of incidents reported to poison centers. J Toxicol Environ Health A. Jan 15 2007;70(2):141-7. [Medline]. 6. Corriols M, Marin J, Berroteran J, Lozano LM, Lundberg I, Thorn A. The Nicaraguan Pesticide Poisoning Register: constant underreporting. Int J Health Serv. 2008;38(4):773-87. [Medline]. 7. Abdel Rasoul GM, Abou Salem ME, Mechael AA, Hendy OM, Rohlman DS, Ismail AA. Effects of occupational pesticide exposure on children applying pesticides. Neurotoxicology. Sep 2008;29(5):833-8.[Medline]. 8. Levy-Khademi F, Tenenbaum AN, Wexler ID, Amitai Y. Unintentional organophosphate intoxication in children. Pediatr Emerg Care. Oct 2007;23(10):716-8. [Medline]