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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: William Freudenthal, MD, Staff Physician, Department of Emergency Medicine, St. Vincent Hospital Indianapolis, IN
William Freudenthal is a member of the following medical societies: American College of Emergency Physicians and Association of Military Surgeons of the US
Coauthor(s):
Mark Ralston, MD, Department of Pediatric Emergency Medicine, Clinical Assistant Professor, Mary Bridge Children's Hospital, Tacoma WA
Editors: Michael E Mullins, MD, Assistant Professor, Department of Emergency Medicine, Washington University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; 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
Author and Editor Disclosure
Synonyms and related keywords:
organophosphate, carbamate poisoning, organophosphate poisoning, organophosphate exposure, OP, OP poisoning, OP exposure, OP toxicity, insecticide poisoning, insecticide exposure, insecticide toxicity, pesticide poisoning, pesticide exposure, pesticide toxicity, pseudocholinesterase, cholinesterase, tachycardia, respiratory failure, diaphoresis, diarrhea, urination, miosis, bradycardia, bronchorrhea, bronchospasm, emesis, lacrimation, salivation, DUMBELS, pulmonary edema, SLUDGE
Background
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 clinical syndrome in adults often does not occur in young children.1
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.2
Pathophysiology
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 2 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.
Frequency
United States
In 2004, 102,754 exposures were reported. In children younger than 6 years, 52,174 exposures were reported; however, no deaths were reported in this age group. 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 cause more than one million serious poisonings annually.
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.
- 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.
Race
No known racial differences in mortality or morbidity are reported.
Sex
No differences in clinical effects between the sexes are known.
Age
- In 2004, more than 50% of the insecticide exposures in the United States occurred in children younger than 6 years.
- 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.
History
- Most symptoms appear within 12-24 hours of exposure.
- Exposure can occur by means of ingestion, dermal exposure, or inhalation.
- Children often ingest home pesticides they find in unmarked or poorly stored containers.
- Children can also be exposed when playing in areas recently treated with organophosphate compounds.
- A history of possible exposure combined with physical signs and symptoms consistent with exposure often lead to diagnosis.
- Many organophosphates can irritate the skin and mucous membranes. Some have a characteristic odor, such as a garliclike smell.
Physical
Physical findings vary according to the route of exposure, the age of patient, and the specific chemical.
- Muscarinic findings may include the following:3
- 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
- Hypertension
- 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
- Predominant symptoms and signs vary according to the age of the affected person. Children, particularly young children, present with altered levels of consciousness rather than the classic DUMBELS signs that are most commonly observed in adults.
- Zwiener and Ginsburg (1988) retrospectively examined 37 patients aged 1 month to 11 years who had been exposed to insecticides.4 The most common signs were miosis, excessive salivation, muscle weakness, and lethargy. Approximately 49% of these children presented with tachycardia.
- Lifshitz et al (1999) retrospectively examined 36 children aged 2-8 years who were exposed to organophosphates or carbamates in Israel.5 The authors observed a decreased level of consciousness, including coma, stupor, and hypotonicity in all children.
- Lima and Reis (1995) reported carbamate poisoning in Rio de Janeiro.6 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.7 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.
Causes
Exposure to organophosphates through the skin, mucous membranes, conjunctiva, GI tract, or respiratory systems is the cause of organophosphate toxicity. Other diagnostic considerations include the following:
- Toxicity due to various poisons, such as carbamates, phosgene, paraquat,8 and nerve agents, can cause symptoms similar to those of organophosphates.
- In young children, suspect organophosphate poisoning if they have any illness that depresses the level of consciousness.
Animal Bites
Other Problems to be Considered
Carbamate exposure
Phosgene exposure
Paraquat exposure
Nerve agent exposure
Lab Studies
- Obtain a CBC count to rule out infectious causes.
- Chemistry tests may be useful in ruling out electrolyte disturbances.
- RBC cholinesterase tests may reveal decreased activity, which confirms the diagnosis.
Imaging Studies
- Chest radiography may be performed to evaluate pulmonary edema.
- Nonenhanced head CT scanning may be required to assess structural lesions if the patient has an altered mental status.
Other Tests
- Perform ECG to evaluate for cardiac arrhythmias.
Medical Care
- Prehospital care
- Ensure airway support and ventilation and perform endotracheal intubation, if necessary, to support the patient before arrival. Perform endotracheal intubation 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.
- Hospital and emergency department care
- Patients who are inadequately decontaminated may expose rescue personnel and hospital staff to the toxin.
- Assess the patient's 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. 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. 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.9 Treat seizures that do not respond to 2-PAM with benzodiazepines. Administer 2-PAM as an IV infusion after a loading dose until signs of weakness improve.
- 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.
Consultations
- Consult a medical toxicologist or poison control center personnel early in the course of treatment.
- Consult a critical care specialist early in severe poisonings for ongoing care outside the emergency department.
Anticholinergic agents are important for controlling the life-threatening effects of organophosphate exposure. Initiate atropine therapy early to control secretions, bronchoconstriction, bronchospasm, and GI toxicity. 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.
Drug Category: Anticholinergic agents
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.
| Drug Name | Atropine |
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| Description | 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. |
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| Adult Dose | 0.05 mg/kg IV initially; then 1-2 mg IV q20-30min until cholinergic signs reverse |
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| Pediatric Dose | <12 years: 0.02-0.05 mg/kg IV q20-30min until cholinergic signs reverse
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity; thyrotoxicosis; narrow-angle glaucoma; tachycardia |
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| Interactions | Coadministration with other anticholinergics have additive effects; may increase pharmacologic effects of atenolol and digoxin; may decrease antipsychotic effects of phenothiazines; tricyclic antidepressants with anticholinergic activity may increase effects |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Caution in coronary heart disease, tachycardia, congestive heart failure, cardiac arrhythmias, and hypertension; caution in peritonitis, ulcerative colitis, hepatic disease, and hiatal hernia with reflux esophagitis; in prostatic hypertrophy, prostatism can cause dysuria and catheterization may be required; may impair regulation of body temperature (caution in hot and humid weather) |
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Drug Category: Cholinesterase reactivators
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.
| Drug Name | 2-PAM (Protopam) |
|---|
| Description | 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. |
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| Adult Dose | 1-2 g IV over 15 min, then 500 mg/h IV until muscle strength returns |
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| Pediatric Dose | <12 years: 25-50 mg/kg IV initially, then 10-20 mg/kg/h IV until muscle strength returns
>12 years: 0.5-1 g IV initially, then 500 mg/h IV until muscle strength returns |
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| Contraindications | Documented hypersensitivity |
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| Interactions | AChE inhibitors potential action of barbiturates; antagonism with neostigmine, pyridostigmine, and edrophonium; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazines can worsen condition of patients poisoned by organophosphate insecticides or nerve agents (do not administer) |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Rapid injection can cause tachycardia, laryngospasm, muscle rigidity, pain at injection site, blurred vision, diplopia, impaired accommodation, dizziness, drowsiness, nausea, tachycardia, hypertension, and hyperventilation; can precipitate myasthenia crisis in patients with myasthenia gravis and muscle rigidity in healthy volunteers; renal dysfunction increases serum levels because excreted in urine; can transiently increase creatinine phosphokinase level; aspartate aminotransferase and/or alanine aminotransferase levels increase in 1 of 6 patients |
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Further Inpatient Care
- 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.
Further Outpatient Care
- 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.
Transfer
- Transfer pediatric patients with severe life-threatening exposures to a facility with a pediatric intensivist and intensive care unit.
- Patients should be clinically stable before their transfer.
Deterrence/Prevention
- Use of safety lids on accessible containers of pesticides
- Proper storage of chemicals in the home
- Legislation regarding the sale and storage of dangerous chemicals
Complications
- Intermediate syndrome can develop 24-96 hours after exposure.10
- This syndrome is characterized by weakness in the motor cranial nerves, proximal limb muscles, neck flexors, and respiratory muscles.
- The syndrome tends to occur in patients with prolonged exposure before treatment.
- A combination of presynaptic and postsynaptic impairment of neuromuscular transmission probably causes the syndrome.
- 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.
- Shahar et al reported extrapyramidal parkinsonism as a complication of acute organophosphate poisoning.11, 12 Symptoms developed 5 days after exposure and completely resolved after treatment with amantadine.
Prognosis
- The prognosis for patients treated early is excellent; most patients fully recover in 7-10 days.
- Patients with toxicity untreated for more than 24 hours may have a prolonged and severe course with lasting neurologic complications.
Medical/Legal Pitfalls
- Organophosphate poisoning can have various atypical presentations, especially in young children.
- Physicians must consider and treat potential life-threatening complications, even if confirmatory laboratory or diagnostic tests are not available.
- The variation in presentations can potentially lead to misdiagnosis and subsequent medicolegal pitfalls.
- After acute organophosphate poisoning is confirmed, the patient should be admitted to intensive care with staff experienced in treating critically ill children. Physicians should be keenly aware of their hospitals' capabilities and criteria for transfer to a tertiary care center.
- Most organophosphate poisonings occur in the home and may be secondary to improper storage, the illegal use of chemicals, or suicidal or homicidal actions. All exposures should be thoroughly investigated to avoid missing potential cases of abuse or neglect.
- Exposures can occur on children's playgrounds, fields, and gardens and should be investigated to prevent the exposure of other children.
| Media file 1:
Chemical terrorism agents and syndromes. Agents, signs, symptoms, tests, routes of exposure, treatment, and differential diagnosis. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill. |
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Media type: PDF
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Toxicity, Organophosphates excerpt Article Last Updated: Jan 23, 2008
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