Practice Essentials
Emergency department (ED) physicians 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 require 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).
Pathophysiology
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.
Etiology
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. [4]
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. [5]
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. [6]
Epidemiology
In the United States, more than 18,000 OPC and carbamate products are licensed for use. [7] 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. [8] In 2019, 1978 cases of OPC exposure, 1238 cases of carbamate exposure, and 42 cases of combined OPC and carbamate exposure were reported to Poison Control Centers in the United States. One OPC-related death but no carbamate-related deaths were reported that year. [9]
The US Environmental Protection Agency (EPA) reports that the amount of OPC insecticides used in the US declined more than 70% from 2000 to 2012, from an estimated 70 million pounds in 2000 to 20 million pounds in 2012. This decrease is due to a shift in usage to other classes of pesticides because of the phasing out and use restrictions placed on OPC insecticides since the passage of the Food Quality Protection Act (FQPA) in 1996. [7]
Globally, each year more than 6 billion pounds of pesticides are applied to crops, homes, schools, parks, and forests, and the widespread use and availability of pesticides results in a high incidence of OPC and carbamate poisoning. 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. [10]
No racial predilection exists. Men have an increased incidence because of increased work-related exposure and increased suicidal attempts with OPC 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. [11]
Prognosis
Most patients with minimal symptoms fully recover. 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. [12]
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. [13] A delay in treatment can also lead to late and permanent neurologic sequelae.
Complications of OPC and carbamate poisoning include the following:
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Intermediate syndrome
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OPC-induced delayed neurotoxicity
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Pancreatitis
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Cardiac complications
Intermediate syndrome
Intermediate syndrome was first described in 1987 as a sudden respiratory paresis, with weakness in cranial nerves and proximal-limb and neck flexor muscles. [14] 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. [15] Repetitive nerve stimulation studies may help in predicting which patients with intermediate syndrome are at risk for developing respiratory failure. [16]
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. [17, 18]
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. [15]
OPC-induced delayed neurotoxicity
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. [19]
Pancreatitis
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. [20, 21]
Cardiac complications
Cardiac arrhythmias have been associated with OPC poisoning. The most common ECG abnormality is QTc prolongation. [22] Cardiac complications may be due to direct cardiac toxicity. [23] Acute myocardial infarction is a rare complication with a high mortality rate. [24]
Patient Education
Advise patients to destroy the clothes they were wearing at the time of exposure because of the risk of repeat contamination.
For patient education information, see Poisoning and Poison Proofing Your Home.
