The emergency department (ED) physician may encounter organophosphorous compound (OPC) and carbamate poisoning in a variety of clinical scenarios. Pesticide poisoning is the most common cause of OPC and carbamate poisoning as the vast majority of pesticides still contain OPCs and carbamates.[1, 2] OPC nerve agents may also be used in the military setting or in terrorist attacks such as the use of sarin in the 1995 Tokyo subway attacks.[3] Carbamates, such as physostigmine and neostigmine, are commonly used to treat diseases such as glaucoma and myasthenia gravis.
Although OPC and carbamates are structurally distinct, they have similar clinical manifestations and generally the same management. Although most patients with OPC and carbamate poisoning have a good prognosis, severe poisoning is potentially lethal. Early diagnosis and initiation of treatment are important. The ED physician has access to a number of therapeutic options that can decrease morbidity and mortality (see Treatment and Medication).
OPCs and carbamates bind to an active site of acetylcholinesterase (AChE) and inhibit the functionality of this enzyme by means of steric inhibition. The main purpose of AChE is to hydrolyze acetylcholine (ACh) to choline and acetic acid. Therefore, the inhibition of AChE causes an excess of ACh in synapses and neuromuscular junctions, resulting in muscarinic and nicotinic symptoms and signs.
Excess ACh in the synapse can lead to 3 sets of symptoms and signs.
First, accumulation of ACh at postganglionic parasympathetic muscarinic acetylcholine receptors leads to parasympathetic activity of smooth muscle in the lungs, GI tract, heart, eyes, bladder, and secretory glands and increased activity in postganglionic sympathetic receptors for sweat glands. This results in the symptoms and signs that can be remembered with the mnemonic SLUDGE/BBB (see Presentation/Physical Examination).
Second, excessive ACh at nicotinic acetylcholine receptors in preganglionic sympathetic synapses and at motor end plates may cause mydriasis, tachycardia, weakness, hypertension, and fasciculations that can be remembered with the mnemonic "days of the week MTWHF". Third, as OPs cross the blood-brain barrier, they may cause seizures, respiratory depression, and CNS depression for reasons not completely understood.
OPCs and carbamates also bind to erythrocyte cholinesterase (also known as red blood cell [RBC] cholinesterase) on RBCs and plasma cholinesterase (also known as pseudocholinesterase, serum cholinesterase, or butyrylcholinesterase) in the serum. This binding seems to have only minimal clinical effects but is useful in confirmatory diagnostic studies.
The main difference in the mechanisms of action between OPCs and carbamates is that carbamates spontaneously hydrolyze from the AChE site within 24 hours, whereas OPCs undergo aging. Aging occurs when the phosphorylated AChE nonenzymatically loses an alkyl side chain, becoming irreversibly inactivated. Carbamates, however, reversibly bind to the active site and do not undergo aging.
United States
In the United States, more than 18,000 products are licensed for use, and each year more than 2 billion pounds of pesticides are applied to crops, homes, schools, parks, and forests.[4] Occupational exposure is known to result in an annual incidence of 18 cases of pesticide-related illness reported for every 100,000 full-time workers in the United States.[5] In 2016, 2484 cases of OPC exposure, 1404 cases of carbamate exposure, and 47 cases of combined OPC and carbamate exposure were reported to Poison Control Centers in the United States. One OPC-related death and two carbamate-related deaths were reported that year.[6]
International
Because of the increased use and availability of pesticides (especially in developing countries), the incidence of OPC and carbamate poisoning is high. In China alone, pesticide poisoning, mainly with OPCs, cause an estimated 170,000 deaths per year. Virtually all of these are the result of deliberate self-poisoning by ingestion.[7]
Many OPC and carbamate exposures are mild, and symptoms resolve rapidly. The severity of poisoning is largely due to a number of factors, including the type of agent, the amount and route of exposure, and the time to initial treatment. The most common cause of mortality in OPC and carbamate poisoning is respiratory failure; however, death is rare, occurring in 0.04-1% of typical pesticide poisonings.[8]
No racial predilection exists. Men have an increased incidence because of increased work-related exposure and increased suicidal attempts with OP and carbamate compounds.
Children have an increased incidence of unintentional exposure at home. One retrospective study revealed a difference in clinical presentation in children with OPC and carbamate poisoning compared with adults. In pediatric patients, CNS depression and severe hypotonia predominated, whereas muscarinic symptoms were infrequent.[9]
Patients with organophosphorous compound (OPC) or carbamate toxicity usually have a history of exposure, which may be self-injurious, occupational, environmental, or exploratory in nature. Pesticides may be rapidly be absorbed through the skin, lungs, gastrointestinal (GI) tract, and mucous membranes. The rate of absorption depends on the route of absorption and the type of OPC or carbamate. Symptoms usually occur within a few hours after GI ingestion and appear almost immediately after inhalational exposure.
In the Tokyo sarin attack, miosis was the most common (> 90%) indicator of OP poisoning.[10] Bradycardia is not a reliable finding, and patients may be tachycardic, for 2 reasons: First, hypoxia due to bronchorrhea and bronchospasm can lead to sympathetic outflow, which overrides parasympathetic vagal stimulation of the heart and which causes tachycardia. Second, nicotinic acetylcholine (ACh) receptors are present in both sympathetic and parasympathetic ganglia. These ganglionic effects in the sympathetic system may contribute to tachycardia.
Patients often present with evidence of a cholinergic toxic syndrome, or toxidrome. It is useful to remember the toxidrome in terms of the following 3 clinical effects on nerve endings:
Nicotinic signs and symptoms may include mydriasis, tachycardia, weakness, hypertension, and fasciculations (mnemonic days of the weak MTWHF). CNS effects may lead to seizures and CNS depression. Two common mnemonics to remember the muscarinic signs and symptoms of the cholinergic toxidrome are SLUDGE/BBB and DUMBELS. The SLUDGE/BBB mnemonic is as follows:
The DUMBELS mnemonic is as follows:
Agricultural exposure is the most common cause of OPC and carbamate poisoning. The World Health Organization (WHO) classifies these poisonings as class I (extremely toxic) to class III (slightly hazardous). WHO advocates banning or strong restrictions on the use of class I pesticides and a reduction in the use of pesticides to a minimal number of compounds that are less hazardous than others.[11]
However, a 2-year longitudinal study comparing cholinesterase activity levels and depressions in farmworkers and non-farmworkers found that the farmworkers had significantly greater likelihood of cholinesterase depression across the agricultural season. The researchers called into question the effectiveness of current regulations designed to prevent pesticide exposure.[12]
OPCs may also be encountered in the military setting or as the result of a terrorist attack with nerve agents such as sarin, VX, or soman. Other agents designated as Novichok agents were developed by the Soviet Union during the Cold War.
In addition to their use as insecticides, carbamates are used to treat certain medical diseases, such as glaucoma and myasthenia gravis (neostigmine, physostigmine). Some case reports describe clinical illness from foodborne outbreaks due to contamination with OPC-containing pesticides.[13]
The most common tests to determine organophosphorous compound (OPC) and carbamate poisoning are measurements of serum cholinesterase and red blood cell acetylcholinesterase (RBC AChE) activity, which are used to estimate neuronal AChE activity. The RBC AChE test provides a better indicator of neuronal AChE activity than serum AChE, but may not be as readily available.[14] In many health care centers, neither of these tests are immediately available and therefore are of no assistance in the acute setting or in guiding therapy.
Moreover, normal levels of enzyme activity vary widely in populations and in individuals.[15] Butyryl-cholinesterase activity may vary after exposure to cocaine, succinylcholine, morphine, and codeine.
These tests are most useful for confirming the diagnosis. In the ideal case, the diagnosis is confirmed with a decrease in enzyme activity from baseline (50% for RBC cholinesterase activity); unfortunately, a baseline, preexposure enzyme level is not available for most patients.
In patients with respiratory distress due to bronchorrhea, chest radiograph findings may range from haziness to pulmonary edema. Serial chest radiographs in conjunction with pulse oximetry and auscultation may be used to guide therapy.
An electrocardiogram (ECG) may be considered. Retrospective studies have shown that a prolonged QTc interval is the most common ECG abnormality.[16, 17] Elevation of the ST segment, sinus tachycardia, sinus bradycardia, and complete heart block (rare) may also occur. Sinus tachycardia occurs just as commonly as sinus bradycardia.
Identification of the type of chemical is important in determining the patient's clinical course and prognosis. Emergency Medical Service (EMS) personnel should attempt to bring in the labels or the names of chemicals the patient was exposed to because different organophosphorous compounds (OPCs) have different aging and reactivation times, which may help in guiding treatment. As a general rule, dimethyl OPCs undergo rapid aging, which makes early initiation of oximes critical. In comparison, diethyl compounds may cause delayed toxicity, and oxime therapy may need to be prolonged.[18]
Emergency department (ED) treatment measures include the following:
Care of the ABCs should be initiated first. Providers with appropriate personal protective equipment (PPE) can address the ABCs before decontamination.
Intubation may be necessary in cases of severe poisoning. Because succinylcholine is metabolized by means of plasma cholinesterase, OPC or carbamate poisoning may cause prolonged paralysis. Increased doses of nondepolarizing agents, such as pancuronium or vecuronium, may be required to achieve paralysis because of the excess acetylcholine (ACh) at the receptor.[14]
Decontamination is an important part of the initial care. In general, the importance of decontamination depends on the route of poisoning. Patients with dermal and inhalation poisonings must be decontaminated before being brought into the ED if it was not done in the prehospital setting. The patient's clothes must be removed and isolated, and his or her body washed with soap and water. For nerve agent exposure, a 0.5% solution of sodium hypochlorite, which can be made with a 1:10 dilution of household bleach (5% sodium hypochlorite), is believed to be superior to soap and water due to inactivation of the agent through oxidative chlorination. However, decontamination should not be delayed and if 0.5% sodium hypochlorite is not immediately available, soap and water should be used. Sodium hypochlorite 5% may be used to decontaminate soiled surfaces.
Patients with GI exposure should also be decontaminated, but ED staff should not delay urgent treatment with excessive decontamination, given that nosocomial poisoning from GI exposure is rare and controversial. Case reports have described nosocomial poisoning in staff members treating patients who have been exposed to OPCs and carbamates[7, 19, 20] ; one describes OPC toxicity from mouth-to-mouth resuscitation.[21] Only one case discusses serious poisoning in which a staff member required treatment and eventual intubation.[22]
However, none of these cases was confirmed with diagnostic studies. In addition, nosocomial OPC poisoning has not been reported in developing countries with a high incidence of severe OPC poisoning. Moreover, the odors often smelled when one cares for a patient poisoned from pesticide are commonly due to the hydrocarbon solvent, which may cause symptoms independent of the OPC agent.[23]
GI decontamination
Oral administration of activated charcoal is a reasonable intervention after GI poisoning. However, as with any poisoned patient, the risks and benefits must be weighed.
Although a systematic review did not find any clear evidence supporting gastric lavage, the authors recommend lavage in patients who present early after ingestion and have no vomiting, and in patients who require intubation due to acute ingestion of an OPC or carbamate.[24]
Atropine is a pure muscarinic antagonist that competes with ACh at the muscarinic receptor. Most sources recommend starting atropine on patients with anything more than ocular effects and then observing the drying of secretions and resolution of bronchorrhea as an endpoint in titrating to the appropriate dose.
Atropine is most commonly given in intravenous (IV) form at the recommended dose of 2-5 mg for adults and 0.05 mg/kg for children, with a minimum dose of 0.1 mg to prevent reflex bradycardia. Atropine may be redosed every 5-10 minutes.
Atropine requirements may vary substantially from patient to patient. Severe OPC poisonings often require hundreds of milligrams of atropine. In one case report, a patient required frequent doses of atropine and was eventually converted to an atropine infusion to a total of 30 g over 5 days.[25] On the other hand, in the Tokyo sarin episode, patients poisoned by nerve agents had modest atropine requirements, with none requiring more than 10 mg.
Atropine does not bind to nicotinic receptors; therefore, it is ineffective in treating neuromuscular toxicity (particularly weakness of respiratory muscles). Those manifestations require oxime antidotal therapy.
The only oxime available in the United States is pralidoxime (2-PAM). OPCs and carbamates bind and phosphorylate one of the active sites of AChE and inhibit the functionality of this enzyme. Oximes bind to the OPC or carbamate, causing the compound to break its bond with AChE. Most of the effects are on the peripheral nervous system because entry into the CNS is limited.
The main therapeutic effect of pralidoxime is predicted to be recovery of neuromuscular transmission at nicotinic synapses. However, oximes also enhance cholinesterase activity at muscarinic sites, decreasing the requirement for atropine. In vitro experiments have shown that oximes are effective reactivators of human AChE inhibited by OPCs.[26]
In some situations, reactivation of inhibited AChE by oximes is likely to be absent or limited when affinity for the particular OP-AChE complex is poor, the dose or duration of treatment is insufficient, the OP persists in the patient and therefore rapid reinhibition of the newly reactivated enzyme occurs, and the inhibited AChE ages.
The degree of reactivation depends on the specific identities and concentrations of the oxime and the OP.[27, 28, 29, 26] Because diethyl-OP–inhibited AChEs reactivate and age notably slower than the dimethyl analogs, they generally require prolonged oxime treatment.[30] The half-lives of aging of dimethyl phosphorylated or diethyl phosphorylated AChE, as determined in isolated human RBCs in vitro, are 3.7 or 33 hours, respectively, and the therapeutic windows (4 times the half-life) are a maximum of 13 or 132 hours, respectively.[31, 32]
Although animal data[32] and observational clinical data[29, 31, 33] suggest regeneration of AChE and improved outcome, only a few randomized controlled studies have been done. One study by Johnson et al was a comparison of pralidoxime 1 g as a bolus, with pralidoxime 12 g as an infusion (no bolus) over 4 days. Mortality rates, need for ventilation, and rates of intermediate syndrome were higher with the infusion group than with the bolus group.[34]
Another study by Cherian et al was a comparison of pralidoxime 12 g given over 3 days with placebo. Results were similar in both groups, with increased rates of mortality, ventilatory support, and intermediate syndrome.[35]
A more recent randomized study by Pawar et al in patients with moderately severe anticholinesterase pesticide poisoning (all patients received initial 2 g bolus dosing of pralidoxime over 30 min) compared continuous pralidoxime infusion of 1 g/h versus pralidoxime 1 g every 4 hours. Patients with the continuous pralidoxime infusion were found to have decreased atropine requirements and decreased need for intubation.[36]
Both the 1-g bolus dose and the 12-g infusion dose fall short of World Health Organization (WHO)–recommended dosing for adults, which is a bolus of at least 30 mg/kg followed by an infusion of at least 8 mg/kg/h. Pediatric dosing is a 25-50 mg/kg bolus given over 30 minutes then an infusion of 10-20 mg/kg/h. This WHO recommendation is based on the doses known to achieve serum pralidoxime concentration of greater than 4 mg/L, the minimum effective concentration reported in an early study.[37] Randomized controlled studies with oxime therapy at the WHO-recommended doses are needed to further delineate its effectiveness. The WHO protocol for oxime therapy is recommended for any patient with clinically significant poisoning.
Seizures are an uncommon complication of OPC poisoning. When they occur, they represent severe toxicity. As with most seizures of toxic etiology, benzodiazepines are first-line therapy. Benzodiazepine-refractory seizures may be treated with phenobarbital.
The following agents have shown benefit as adjunctive treatment in OPC poisoning, in preliminary studies:
Consult a regional poison control center or medical toxicologist for further recommendations for patient care. Consult a psychiatrist in any intentional or suspected intentional ingestions.
Researchers in Washington State conducted a longitudinal study among agricultural pesticide handlers during the OP/CB spray season (March-July) over a 6-year period. The use of multiple OP/CBs and mixing/loading activities were found to be significant risk factors for butyrylcholinesterase (BuChE) inhibition, and the use of chemical-resistant boots and lockers for personal protective equipment (PPE) storage were found to be protective factors. These findings supported interventions to reduce exposure such as the implementation of engineering controls for mixing/loading activities, requirements for appropriate footwear, and the regular use of lockers for PPE storage.[39]
Control of clinically significant cholinergic excess is the key to management. Anticholinergic agents can be used to substantially reduce or eliminate the secretory effects of muscarinic excess. Endpoints for therapy include elimination of bronchorrhea (atropine) and improved muscle strength (oximes). Reaching these endpoints may require more medication than commonly prescribed.
Clinical Context: Reduces systemic absorption through the alimentary tract. Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present adsorbs 100-1000 mg of drug per gram charcoal. Does not dissolve in water. For maximum effect, administer within 30 min of poison ingestion.
This drug is used to bind recently ingested agents, thereby limiting systemic absorption. It is not useful for noningestion exposures.
Clinical Context: Used for GI or pulmonary distress in known or suspected OP or carbamate poisonings. Continue until bronchoconstriction and bronchorrhea controlled. High doses may be required in first 24 h of treatment. Treatment may be required for 48 h in severe cases. May need to reduce doses with concurrent oximes.
Clinical Context: Indications include muscle weakness (especially respiratory) in known or suspected OP poisoning. Rarely needed in carbamate poisonings. Muscle strength should increase in 30 min. Must be used early in poisoning, before OP-AChE bond has aged, to be effective. May help prevent intermediate and delayed neuromuscular and neuropsychiatric OP syndromes.
Anticholinergics, such as atropine, cause pharmacologic antagonism of excess anticholinesterase activity at muscarinic receptors. Oximes reverse the inhibition of AChE and nicotinic effects, including muscle paralysis.
Clinical Context: Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing GABA activity.
Clinical Context: DOC for treatment of status epilepticus because persists in CNS longer than diazepam. Rate of injection not to exceed 2 mg/min. May be administered IM if IV access not available.
Clinical Context: Alternative to terminate refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Wait 2-3 min to fully evaluate sedative effects before starting procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if vascular access unavailable.
See the list below:
See the list below:
Complications of OPC and carbamate poisoning include the following:
Intermediate syndrome was first described in 1987 as a sudden respiratory paresis, with weakness in cranial nerves and proximal-limb and neck flexor muscles.[41] These clinical features appear 24-96 hours after exposure and are distinct from the previously described delayed neurotoxicity. Neck muscle weakness may be an early sign of intermediate syndrome.[42] Repetitive nerve stimulation studies may help in predicting which patients with intermediate syndrome are at risk for developing respiratory failure.[43]
Although intermediate syndrome is incompletely understood, more recent reports suggest that this is due to presynaptic and postsynaptic dysfunction of neuromuscular transmission and that it may result from insufficient oxime treatment.[44, 45]
Possible clinical indications of increased risk for intermediate syndrome are age ≥45 years and, on admission, an International Program on Chemical Safety Poison Severity Score (IPCS PSS) >2, and a Glasgow Coma Scale score of ≤10.[42]
OPC-induced delayed neurotoxicity (OPCIDN) is a sensorimotor polyneuropathy that typically occurs 9-14 days after OP exposure. The patient initially presents with distal motor weakness and sensory paresthesias in the lower extremities, which may progress proximally and eventually affect the upper extremities. Most sources suggest that the mechanism involves inhibition of neuropathy target esterase (NTE), an enzyme that metabolizes esters in nerve cells. Some patients may recover over 12-15 months, but permanent losses, with spasticity and persistent upper motor neuron findings, have been reported.[14]
Pancreatitis has been reported as a rare complication. One case series reported that 12.76% of OP poisonings were associated with acute pancreatitis, although this has not been the experience in other series.[46, 47]
Cardiac arrhythmias have been associated with OPC poisoning. The most common ECG abnormality is QTc prolongation.[17] Cardiac complications may be due to direct cardiac toxicity.[48]
In severe poisoning, death usually occurs within the first 24 hours if it is untreated. With nerve-agent poisoning, death may occur within minutes if untreated. Even with adequate respiratory support, intensive care, and specific treatment with atropine and oximes, the mortality rate is still high in severe poisonings.[49] A delay in treatment can also lead to late and permanent neurologic sequelae.
Most patients with minimal symptoms fully recover.
See the list below: