Organophosphates and carbamates are the most frequently used insecticides worldwide. These compounds cause 80% of the reported toxic exposures to insecticides. Organophosphates produce a clinical syndrome that can be effectively treated if recognized early. The typically described muscarinic clinical syndrome in adults often does not occur in young children, who instead are more likely to present with altered levels of consciousness (see Presentation).[1, 2, 3, 4] Severe exposures require expeditious anticholinergic therapy (see Treatment and Medication).
Organophosphates were first discovered more than 150 years ago; however, their widespread use began in Germany in the 1920s, when these compounds were first synthesized as insecticides and chemical warfare agents. Interest in the effects of these compounds on humans has increased in recent years due to their potential use as weapons of mass destruction.[5]
Organophosphates form an initially reversible bond with the enzyme cholinesterase. The organophosphate-cholinesterase bond can spontaneously degrade, reactivating the enzyme, or can undergo a process called aging. The process of aging results in irreversible enzyme inactivation.
Cholinesterase is found in two forms: an RBC form, which is known as true cholinesterase, and a plasma form, which is known as pseudocholinesterase. Cholinesterases rapidly hydrolyze the neurotransmitter acetylcholine into inactive fragments. Acetylcholine is found in sympathetic and parasympathetic ganglia and in the terminal nerve endings of postganglionic parasympathetic nerves at the motor endplates of nerves in the skeletal muscle. Inactivation of the enzyme allows acetylcholine to accumulate at the synapse, leading to overstimulation and disruption of nerve impulses. Skeletal-muscle depolarization and fasciculations occur secondary to nicotinic stimulation at the motor endplate.
Muscarinic effects occur at the postganglionic parasympathetic synapses, causing smooth-muscle contractions in various organs including the GI tract, bladder, and secretory glands. Conduction can be delayed in the sinus and atrioventricular (AV) nodes. Dysrhythmias are frequently reported; these typically include bradycardia, though tachycardia can also occur.
Acetylcholine receptors are widely dispersed throughout the CNS. The activation of these receptors causes a wide range of effects, including CNS stimulation, seizures, confusion, ataxia, coma, and respiratory or cardiovascular depression.
Organophosphates are generally highly lipid soluble and are well absorbed from the skin, mucous membranes, conjunctiva, GI system, and respiratory system.
The American Association of Poison Control Centers' (AAPCC's) National Poison Data System reported 1994 single exposures to organophosphate insecticides alone in 2016; 582 of those were in children younger than 6 years, 91 in children 6 to 12 years, and 61 in teenagers. These resulted in 17 major outcomes and one death. In addition, the AAPCC reported 537 single exposures to organophosphate insecticides in combination with other insecticides (mostly non-carbamate), none of which were fatal. Of the exposures to combined insecticides, 109 occurred in children younger than 6 years and 73 in older pediatric patients.[6] Many more exposures probably occur, but patients with minor symptoms often do not seek medical care.
International
Worldwide, pesticide poisonings cause an estimated 20,000 deaths and more than one million serious poisonings annually.[7]
Mortality/Morbidity
Most morbidity and mortality results from anoxic injury due to respiratory failure. Clinical effects range from mild flulike symptoms with low-level exposures to life-threatening respiratory failure with larger exposures.
Race-, Sex-, and Age-related Demographics
No known racial differences in mortality or morbidity are reported. No differences in clinical effects between the sexes are known.
Children are at a significantly increased risk worldwide, particularly in Africa and other developing regions, where the widespread availability and use of organophosphates and the lack of regulation and safety packaging are high risk factors for exposure. Childhood deaths and reported poisonings in the United States have declined over the last few decades, partly because of educational efforts and improved regulation and packaging.
Physical findings vary according to the route of exposure, the age of patient, and the specific chemical. In general, the signs and symptoms of organophosphate poisoning fall into the following three broad categories:
Muscarinic
Nicotinic
Central nervous system (CNS)
Muscarinic findings may include the following[8] :
Diaphoresis and diarrhea, urination, miosis, bradycardia, bronchorrhea, bronchospasm, emesis, lacrimation and salivation (DUMBELS)
Wheezing and/or bronchoconstriction
Pulmonary edema
Increased pulmonary and oropharyngeal secretions
Sweating
Bradycardia
Abdominal cramping and intestinal hypermotility
Miosis
Nicotinic findings may include the following:
Muscle fasciculations (twitching)
Fatigue
Paralysis
Respiratory muscle weakness
Diminished respiratory effort
Tachycardia
Hypertensio
CNS findings may include the following:
Anxiety
Restlessness
Confusion
Headache
Slurred speech
Ataxia
Seizures
Coma
Central respiratory paralysis
Altered level of consciousness and/or hypotonia
Children, particularly young children, are more likely to present with altered levels of consciousness than with the classic DUMBELS signs that are most commonly observed in adults. Studies of pediatric organophosphate poisoning have yielded the following results:
Lifshitz et al (1999) retrospectively examined 36 children aged 2-8 years who were exposed to organophosphates or carbamates in Israel.[9] The authors observed a decreased level of consciousness, including coma, stupor, and hypotonicity in all children.
Zwiener and Ginsburg (1988) retrospectively examined 37 patients aged 1 month to 11 years who had been exposed to insecticides.[10] The most common signs were miosis, excessive salivation, muscle weakness, and lethargy. Approximately 49% of these children presented with tachycardia.
Lima and Reis (1995) reported carbamate poisoning in Rio de Janeiro.[11] Symptoms included salivation, lacrimation, urination, defecation, GI distress, and emesis (SLUDGE) and were more commonly observed in adults than in children.
Sofer et al (1989) retrospectively examined 25 patients aged 3 months to 7 years with carbamate or organophosphate poisoning in Israel.[12] The most common presenting symptoms were CNS depression, stupor, coma, and flaccidity. The classic SLUDGE symptoms were more likely to be absent in these children.
Ensure airway support and ventilation and perform endotracheal intubation, if necessary, in patients with respiratory failure.
Circulatory support with intravenous (IV) access, fluids, and cardiac and pulse oximetry monitoring can facilitate safe transport.
Decontamination is of the utmost importance in minimizing continued exposure and to protect providers and other patients from contamination. Decontamination involves removing all of the patient's clothing and washing him or her with water and soap.
By describing the scene, prevalent odors, or other casualties, prehospital providers may provide important clues to the presence of exposure.
Emergency department care
Assess the patient's airway, breathing, and circulation (ABCs). Secure the airway and perform cardiovascular resuscitation if needed. Endotracheal intubation may be necessary for airway protection and ventilatory support.
If the patient's condition is stable, decontamination is the next priority. Patients who are inadequately decontaminated may expose rescue personnel and hospital staff to the toxin. Prehospital providers may also need decontamination. The dermal decontamination of exposed individuals is a priority before they enter the emergency department, where they can contaminate other patients and staff members. Gastric decontamination with activated charcoal should be performed in cases of ingestion.
Severe exposures require expeditious anticholinergic therapy. Atropine antagonizes the central and muscarinic effects by blocking these receptors. Atropine does not bind to nicotinic receptors; hence, muscular weakness, including respiratory muscle weakness, is not affected.
Anticholinergic agents should be used in doses large enough to reverse the cholinergic signs. Some authors recommend giving atropine until signs of atropinization appears. These signs include warm, dry, flushed skin; dilated pupils; and an increased heart rate.
Atropine should be used for at least 24 hours to reverse the cholinergic signs while the organophosphate is metabolized.[14] Atropine is indicated when evidence of bronchorrhea and other secretions is present.
Pralidoxime (2-PAM) is a cholinesterase reactivator and the antidote for organophosphate poisoning. Administer 2-PAM to patients with organophosphate exposure and signs of muscle and respiratory muscle weakness. This drug primarily affects the nicotinic receptors and does not reverse the CNS effects. Administer 2-PAM as soon as possible because its effectiveness decreases with prolonged exposure due to the aging of the organophosphate-cholinesterase bond.[15] Administer 2-PAM as an IV infusion after a loading dose until signs of weakness improve.
Treat seizures that do not respond to 2-PAM with benzodiazepines. In experimental models, midazolam effectively terminates seizures caused by organophosphates; however, the efficacy of benzodiazepines decreases when these drugs are given 30 minutes or more after organophosphate exposure or seizure onset.[16]
In a child with acute, severe organophosphate poisoning that was unresponsive to standard treatments, Yesilbas and colleagues reported successful treatment with high-volume continuous venovenous hemodiafiltration and therapeutic plasma exchange combined with lipid infusion.[17]
Avoid the use of morphine, caffeine, loop diuretics, theophylline, and succinylcholine in patients with organophosphate poisoning because these drugs can increase the toxicity of the exposure.
Anticholinergic agents are important for controlling the life-threatening effects of organophosphate exposure. Initiate atropine therapy early to control secretions, bronchoconstriction, bronchospasm, and gastrointestinal toxicity. Pralidoxime (2-PAM) is an oxime that reactivates cholinesterase, restoring respiratory and skeletal muscle strength. 2-PAM does not cross the blood-brain barrier; hence, the central effects are not reversed.
Clinical Context:
Competitive antagonist of acetylcholine and other muscarinic agonists. Competes for common binding site on muscarinic receptor. Used to treat GI, pulmonary, and upper airway symptoms after known or suspected organophosphate exposure. Administer until cholinergic signs reverse. Large doses may be needed.
These agents are thought to work centrally by suppressing conduction in the vestibular cerebellar pathways. They may have an inhibitory effect on the parasympathetic nervous system. Anticholinergic agents also improve conduction through the AV node by reducing vagal tone by means of muscarinic receptor blockade.
Clinical Context:
Nucleophilic agent that reactivates phosphorylated AChE by binding to organophosphate molecule. Used to treat muscle weakness and respiratory muscle weakness in known or suspected exposure. Must be administered within 24 h, before organophosphate-cholinesterase bond ages. Earlier administered, better result. Effects should occur within 20-30 min.
Because it does not substantially relieve respiratory center depression or decrease muscarinic effects of AChE poisoning, concomitantly administer atropine to block effects of organophosphate poison on these areas. Signs of atropinization might occur earlier with addition of 2-PAM.
These medications are used as antidotes to reverse the inhibition of acetylcholinesterase (AChE). The effectiveness of oxime compounds is attributed to their 2-formyl-1-methylpyridinium ions.
Patients with minor or no symptoms of toxicity after organophosphate exposure may be discharged from the emergency department after 6 hours of observation. Discharged patients usually do not require outpatient medications.
Admit patients to the hospital if they require therapy with anticholinergenic agents or 2-PAM. Monitoring, respiratory support, and ventilation may be needed.
Consult poison control center personnel for information regarding the specific agent, the length of inpatient treatment, and the duration of likely toxicity.
Intermediate syndrome can develop 24-96 hours after exposure.[18, 19] A combination of presynaptic and postsynaptic impairment of neuromuscular transmission probably causes the syndrome. Features of intermediate syndrome as as follows:
The syndrome tends to occur in patients with prolonged exposure before treatment.
The syndrome is characterized by weakness in the motor cranial nerves, proximal limb muscles, neck flexors, and respiratory muscles.
A delayed peripheral neuropathy may develop days to weeks after the exposure.
Patients may also have persistent CNS effects, weakness, lethargy, fatigue, and memory impairment.[20]
Shahar et al reported extrapyramidal parkinsonism as a complication of acute organophosphate poisoning.[21, 22] Symptoms developed 5 days after exposure and completely resolved after treatment with amantadine
William Freudenthal, MD, Staff Physician, Department of Emergency Medicine, St Vincent Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Mark E Ralston, MD, MPH, Staff Pediatrician, Naval Hospital Oak Harbor; Assistant Professor of Pediatrics, F Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center
Disclosure: Received salary from Merck for employment.
Chief Editor
Stephen L Thornton, MD, Associate Clinical Professor, Department of Emergency Medicine (Medical Toxicology), University of Kansas Hospital; Medical Director, University of Kansas Hospital Poison Control Center; Staff Medical Toxicologist, Children’s Mercy Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Michael E Mullins, MD, Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital
Disclosure: Received stock ownership from Johnson & Johnson for none; Received stock ownership from Savient Pharmaceuticals for none.
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Shahar E, Bentur Y, Bar-Joseph G, et al. Extrapyramidal parkinsonism complicating acute organophosphate insecticide poisoning. Pediatr Neurol. 2005 Nov. 33(5):378-82.
Ellenhorn MJ. Organophosphates. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Lippincott, Williams and Wilkins; 1997. 1614-21.