Commonly used organophosphates include diazinon, orthene, malathion, parathion, and chlorpyrifos. In addition to their use as insecticides, organophosphates have been used as chemical warfare agents since World War II. Most recently, the organophosphate sarin was used in the terrorist attack on the Tokyo subway in 1995. 3 Organophosphates and carbamates are the most common insecticides associated with systemic illness. Potency does vary, however. Highly potent compounds such as parathion are used primarily in agriculture. Those of intermediate potency include coumaphos and trichlorfon, which are used in animal care. Low-potency products used in the household and on golf courses include diazinon and malathion. These compounds are very toxic at higher exposures. Poisoning results primarily from accidental exposure in the home, in agriculture, in industry (in workers involved in the manufacture and transport of these products), and in areas of insect control. Exposure to flea-dip products has been reported in pet groomers and children. Widespread food contamination and the potential for mass toxic exposure are always a risk. In addition, these chemicals are involved in intentional poisonings and occasionally in homicides. Systemic absorption of organophosphates occurs by inhalational, transdermal, transconjunctival, and gastrointestinal exposure.
PATHOPHYSIOLOGY The mechanism of action of organophosphates involves the inhibition of the enzyme cholinesterase in the nervous system. Acetylcholinesterase (true or red blood cell acetylcholinesterase) is found primarily in erythrocytes and in nervous tissue. Plasma cholinesterase (pseudocholinesterase) is found in the serum, liver, heart, pancreas, and brain. Acetylcholine is a major neurotransmitter in the central, autonomic, and somatic nervous systems. The role of the cholinesterases is to hydrolyze acetylcholine into the inactive components choline and acetic acid after neurochemical transmission. Inhibition of cholinesterase leads to acetylcholine accumulation at nerve synapses and neuromuscular junctions, resulting in overstimulation of acetylcholine receptors. This initial overstimulation is followed by paralysis of cholinergic synaptic transmission in the central nervous system (CNS), in autonomic ganglia, at parasympathetic and some sympathetic nerve endings (e.g., sweat glands), and in somatic nerves. A cholinergic crisis results in a central and peripheral clinical toxidrome.
Organophosphates bind irreversibly to cholinesterase, thus inactivating the enzyme through the process of phosphorylation. A concept known as "aging" is used to describe the latency of permanent, irreversible binding of the organophosphate to the cholinesterase. This takes approximately 24 to 48 h to occur. The organophosphate-cholinesterase bond is irreversible without pharmacologic intervention. This time period of 24 to 48 h after exposure is therefore the critical interval during which administration of an antidote can reverse the process. Once "aging" occurs, however, the enzymatic activity of cholinesterase is permanently destroyed, and new enzyme must be resynthesized over a period of weeks before clinical symptoms resolve and normal enzymatic function returns. Therapeutic agents that remove the organophosphate and reactivate the cholinesterases are ineffective after "aging" is complete.
CLINICAL FEATURES Clinical presentations depend on the specific agent involved, the quantity absorbed, and the type of exposure. A number of organophosphates are associated with local irritation of the skin and respiratory tract with resulting dermatitis and wheezing, respectively, without evidence of systemic absorption. A few cases of persistent reactive airway disease independent of cholinesterase inhibition have been reported. 4
Acute systemic organophosphate poisoning results in a variety of clinical CNS, muscarinic, nicotinic, and somatic motor manifestations. In mild to moderate poisoning, symptoms occur in various combinations. Time to onset varies with route and chemical but usually occurs within 12 to 24 h. Onset is most rapid with inhalation and least rapid with transdermal absorption; however, dermatitis or skin excoriation may hasten this. Symptoms can occur within minutes with massive ingestion.
CNS symptoms of cholinergic excess include anxiety, restlessness, emotional lability, tremor, headache, dizziness, mental confusion, delirium, hallucinations, and seizures. Coma with depression of respiratory and circulatory centers may result. Aggressive behavior has been described.
Muscarinic receptor stimulation by acetylcholine is usually predominant and leads to salivation, lacrimation/sweating, urinary incontinence, diarrhea, gastrointestinal distress, emesis (SLUDGE), and bradycardia. Bradycardia is usually predominant, but tachycardia may occur.5 Bradycardia may present as rate-related dizziness or syncope. Bronchospasm and bronchorrhea resulting from acetylcholine excess can lead to hypoxia and tachycardia. Miotic pupils and blurred vision are due to cholinergic effects on the pupillary constrictors and ciliary body.
Acetylcholine is the presynaptic neurotransmitter that stimulates nicotinic receptors in the sympathetic ganglia and adrenal medulla. Overstimulation results in pallor, mydriasis, tachycardia, and hypertension. Parasympathetic stimulation usually dominates, but sympathetic domination with tachycardia and hypertension are seen. Nicotinic stimulation at neuromuscular junctions results in muscle fasciculations, cramps, and muscle weakness. This syndrome may progress to paralysis and areflexia. Respiratory muscle paralysis results in acute respiratory failure and death. Miosis and muscle fasciculations are considered by some as reliable clinical signs of toxicity.
An intermediate syndrome may occur 1 to 4 days following an acute organophosphate poisoning.6 The patient appears to be recovering from an acute poisoning when this manifests. Clinically, there is paralysis of neck flexor muscles, muscles innervated by the cranial nerves, and proximal limb and respiratory muscles to the extent that some patients may require respiratory support. Electromyography (EMG) may assist in making the diagnosis by indicating a problem at the neuromuscular junction. Aggressive, early antidote therapy and supportive measures may prevent this syndrome. Symptoms usually resolve within 4 to 18 days.
A non-cholinesterase-related neurotoxic syndrome known as organophosphate-induced delayed neuropathy (OPIDN) may occur 2 to 3 weeks after acute poisoning with a flaccid paralysis of the lower limbs. This is thought to be due to the inhibition of a neuropathy target enzyme. Delayed bilateral recurrent laryngeal nerve paralysis has been reported as a manifestation of this syndrome.
Chronic neurologic and neurobehavioral sequelae after acute organophosphate poisoning include neuropsychiatric deficits and paralysis. Z More lipid-soluble organophosphates may not produce immediate symptoms of toxicity, and symptoms may persist for several weeks. Low-grade chronic organophosphate exposures occur among farm workers, pesticide manufacturing plant workers, and exterminators. Symptoms and signs are often less dramatic and nonspecific, with varying degrees of headache, nausea, weakness, or fatigue and a subtle cholinergic syndrome. Neuropsychological effects have been described with chronic exposure.
Special Considerations Organophosphates are the principal toxins found in nerve gases. Chemical warfare nerve agents referred to as G agents were synthesized in search of better insecticides. Their mechanism involves the inactivation of acetylcholinesterase. These chemicals, however, produce "aging" within minutes, thus making them particularly toxic. They are rapid acting and extremely potent, and death occurs within minutes of inhalation or dermal exposure. Accordingly, those exposed are unlikely to present to the emergency department (ED) alive.
DIAGNOSIS Suspicion of exposure to organophosphates is based on the history, the presence of a suggestive toxidrome, and laboratory cholinesterase assays. Diagnosis is often difficult owing to a constellation of clinical findings that may be vague in both acute and chronic poisonings. Toxicity may masquerade as a nonspecific flulike syndrome. Degree of toxicity may be based on the presence of specific signs and symptoms. Mild, moderate, and severe toxicities are described.
Clinically, noting a characteristic petroleum or garlic-like odor may assist in diagnosis. The cholinergic toxidrome may vary depending on the predominance of muscarinic, nicotinic, and CNS manifestations of the toxin and the severity of the intoxication. An initial test dose of intravenous atropine that does not result in the expected improvement in signs and symptoms in the case of poisoning may assist in making a diagnosis. Differential diagnosis of CNS alterations includes all nontoxic causes of mental status changes, coma, and seizures. Muscarinic manifestations may imitate asthma, exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary edema, acute gastroenteritis, and primary cardiac brachycardia or hypotension. Miosis may appear late, whereas the presence of mydriasis may indicate hypoxia. Ocular exposure may cause persistent miosis. Nicotinic manifestations may imitate other causes of striated muscle dysfunction and respiratory failure. Sympathomimetic toxins and other causes of sympathetic hyperactivity should be considered when signs and symptoms of nicotinic stimulation predominate.
Functional assays of plasma and red blood cell (RBC) cholinesterases are helpful for diagnosis and as a guide for therapy but may not be readily available. Clinical toxicity is predominately due to the toxic effect of the organophosphate on RBC acetylcholinesterase; therefore, this enzyme assay is a more accurate indicator of synaptic cholinesterase inhibition. However, plasma cholinesterase is easier to assay and more available. The degree of cholinesterase inhibition necessary to produce symptomatic illness is variable, with symptoms generally occurring only after more than 50 percent inhibition from baseline determinations. Although there is patient variability, a high-normal cholinesterase level excludes acute systemic poisoning. The degree of depression from baseline cholinesterase levels is thought to correlate with toxicity. A patient may show mild clinical toxicity with normal levels. With a 60 percent decrease in cholinesterase level, headache and parasympathetic stimulation develop. Moderate symptoms develop, including muscle weakness, tremor, and neuropsychiatric symptoms, with a 60 to 90 percent decrease. After a 90 percent decrease, severe symptoms include seizures, cyanosis, pulmonary edema, respiratory failure due to muscle weakness, and coma, and death may occur.
Without treatment, plasma cholinesterase takes up to 4 to 6 weeks and RBC acetylcholinesterase as long as 90 to 120 days to return to baseline after exposure. Plasma cholinesterase levels have poor prognostic value in patients with acute organophosphate poisoning. Levels do not correlate with the amount of atropine required or the need for mechanical ventilation.8 When the rate of cholinesterase falls gradually, as in chronic exposure, clinical symptoms may be minimal. Plasma cholinesterase levels may be depressed in genetic variants, chronic disease states, liver dysfunction, cirrhosis, malnutrition and low serum albumin states, neoplasia, infection, and pregnancy. RBC acetylcholinesterase is affected by factors that influence the circulating life of erythrocytes such as hemoglobinopathies.
Routine laboratory test abnormalities are nondiagnostic but may include evidence of pancreatitis, hypo- or hyperglycemia, and liver function abnormalities. A chest radiograph may show pulmonary edema in severe cases.
The electrocardiogram (ECG) may be abnormal and correlate with degree of toxicity and outcome. Common abnormalities include ventricular dysrhythmias, torsade de pointes, and idioventricular rhythms. Heart blocks and prolongation of the QT c interval are common.9
TREATMENT Treatment consists of intensive respiratory support, general supportive measures, decontamination, and prevention of absorption. Therapy includes the administration of antidotes and is based on the degree of toxicity. Therapy should not be withheld pending determination of cholinesterase levels.
Secondary contamination of health care workers must be prevented during patient resuscitation. Protective gloves and gowns must be worn. Patients with suspected exposure must be removed from the contaminated environment. All clothes and accessories must be removed completely and placed in plastic bags for disposal. The patient is immediately decontaminated externally with copious amounts of soapy water and possibly a second washing with dilute ethanol. Decontamination must include the scalp, hair, fingernails, skin, and conjunctivae. Abrasion or irritation of the skin should be avoided. Contaminated runoff water should be drained and discarded separately and safely.
The patient is placed on 100% oxygen, a cardiac monitor, and pulse oximeter. A 100 percent non-rebreather mask will optimize oxygenation in the patient with excessive airway secretions and bronchospasm and may reduce the chance of ventricular dysrhythmias during antidote therapy. Gentle suction will assist in clearing airway secretions from hypersalivation, bronchorrhea, or emesis. Coma, seizures, respiratory failure, excessive respiratory secretions, or severe bronchospasm may necessitate endotracheal intubation. A nondepolarizing agent should be used when neuromuscular blockade is needed. An intravenous line is established, and baseline blood sampling and determination of cholinesterase levels should be done. Hypotension may necessitate initial fluid boluses of normal saline. Substrates such as dextrose and naloxone should be considered. In a recent or large ingestion, gastric lavage may be of value. Activated charcoal is recommended. Protection of the airway must be ensured before lavage in the event a hydrocarbon vehicle is involved. When there is significant diarrhea due to cholinergic effects, catharsis is withheld. Hemodialysis and hemoperfusion are of no proven value.
Pharmacologic intervention consists of concomitant atropine and pralidoxime (2-PAM) therapy in significant poisonings. Atropine, a competitive antagonist of acetylcholine at CNS and peripheral muscarinic receptors, is used to reverse muscarinic and central effects secondary to excessive parasympathetic stimulation. The dose is titrated to dry copious tracheobronchial secretions. Pupillary dilatation is not a therapeutic end point. Atropine should not be withheld in the face of a tachycardia that may be the result of hypoxia due to secretions, respiratory muscle paralysis, or ganglionic stimulation. In moderate to severe poisoning, atropine is administered in a dose of 2 to 4 mg intravenously in the adult and 0.05 mg/kg in children as a test dose. Intramuscular administration is possible, if not ideal. Failure to respond to a trial dose of atropine is indicative of organophosphate poisoning. If no effect is noted, this dose is doubled every 5 to 10 min until muscarinic symptoms are relieved. The dose necessary to dry secretions may be on the order of hundreds of milligrams in massive overdoses, and prolonged therapy may be necessary. Atropine infusion for as long as several weeks has been reported.10 The most common cause of treatment failure is inadequate atropinization.
Compounds called oximes are used to displace organophosphates from the cholinesterases. Pralidoxime, or 2-PAM, is a specific antidote available in the United States. This antidote restores acetylcholinesterase activity by regenerating phosphorylated acetylcholinesterase and appears to prevent toxicity by detoxifying the remaining organophosphate molecules. Clinically, this compound ameliorates muscarinic, nicotinic, and CNS symptoms and can reverse organophosphate-related muscle paralysis. The cholinergic nicotinic effects not reversed by atropine are reversed by pralidoxime. After blood samples are obtained for determination of cholinesterase levels, it is important that pralidoxime is administered early before permanent and irreversible binding or "aging" occurs. It is ideal to administer this within 24 to 36 h of acute exposure. If there is a strong clinical suspicion of organophosphate toxicity, administration of 2-PAM should not be delayed. It is more effective in acute than in chronic intoxications. The recommended dose is 1 g for adults and 20 to 40 mg/kg up to 1 g for children. It should be infused in normal saline over 30 min. This may be repeated in 1 h, and multiple doses may be needed. Administration of 2-PAM should occur every 6 to 8 h for 24 to 48 h, or until signs and symptoms resolve. A continuous infusion may be administered. Combination therapy does reduce atropine requirements. This antidote is not administered to asymptomatic patients or to patients with known carbamate exposures presenting with minimal symptoms.
Response to 2-PAM therapy with a decrease in muscle weakness and fasciculation and relief of muscarinic effects with atropine usually occurs within 10 to 40 min of administration. Use of 2-PAM may prevent later subacute or chronic sequelae.11
Seizures are treated with airway manipulation, oxygen, benzodiazepines, and antidotal therapy. Pulmonary edema and bronchospasm are treated with oxygen, intubation, positive-pressure ventilation, atropine, and 2-PAM. Altered heart rate is treated with supportive therapy and antidotes. Management of dysrhythmias follows advanced cardiac life support guidelines. Succinylcholine, ester anesthetics, and beta blockers may potentiate poisoning and should be avoided.
DISPOSITION Mild exposure may require only decontamination and 6 to 8 h of observation in the ED. Reexposure must be avoided until cholinesterase activity returns to baseline. Patients may return to work if it does not involve reexposure risk. Admission to the intensive care unit is necessary for all significant exposures. Most patients respond to 2-PAM therapy within 48 h. If toxins are fat soluble, the patient may be symptomatic for prolonged periods of time and dependent on 2-PAM.12 During a period of weeks while awaiting resynthesis of new enzyme, supportive care and respiratory support may be needed. The end point of therapy is determined by the absence of signs and symptoms on withholding 2-PAM therapy. Following an acute exposure, the patient may have a variety of neurologic sequelae and nonspecific symptoms lasting days to months. Chronic exposure may necessitate serial enzyme determinations to identify a trend. Death from organophosphate poisoning usually occurs in 24 h in untreated patients. If there is no posthypoxic brain damage, and if the patient is treated early, symptomatic recovery occurs in 10 days. Respiratory failure secondary to paralysis of respiratory muscles or CNS depression and bronchorrhea is the usual cause of death.
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