SEMINARS I N NEUKOLOGY-VOLUME

10, NO. 1 MARCH 1990

Organophosphate Intoxication: Pharmacologic, Neurophysiologic, Clinical, and Therapeutic Considerations

The organophosphates are a class of compounds that irreversibly inhibit cholinesterases including acetylcholinesterase (AChE).' A knowledge of the organophosphates and their effects on the peripheral and central nervous systems in humans is important, since intoxication with insecticides containing these compounds is a worldwide problem.*."heir potential use in chemical warfare over the past 50 years continues to be a serious concern. Acute organophosphate intoxication is most commonly the result of suicide attempts and is said to be the most common mode of suicidal poisoning in India.x4 In Europe, it is a regular occurrence as, for example, at the University of Mainz, where approximately ten cases are seen annually, referrals coming from communities immediately surrounding Mainz, West Germany.' Organophosphate poisoning, as a result of accidental insecticide exposure, is much less frequent in the United States, and serious examples are only rarely seen. The use of these compounds in suicide attempts in the United States is virtually unknown, in part, because of their relative lack of availability and different cultural patterns. The irreversible inhibition of AChE results in a complex set of physiologic and clinical changes related to excessive amounts of acetylcholine (ACh) at the neuromuscular junction as well as central nervous system cholinergic and peripheral and autonomic nervous system muscarinic synapse^.^.^ AChE is responsible for the normal degradation of ACh at synapses, essential in their normal functioning.'

More than 50,000 organophosphate compounds have been synthesized and studied for their use as insecticides and their potential use as "nerve gases" in chemical warfare. DeClermont is credited with synthesizing the first of many highly potent organophosphate compounds, tetraethylpyrophosphate (TEPP), in 1854, 10 years prior to the isolation of physostigmine. Since this is such a deadly compound, it is amazing he survived tasting it. Modern investigations into these compounds began in 1932. During World War 11, these compounds were of particular interest to German scientists and this resulted in the development of such chemical warfare agents as tabun, sarin, and soman, highly lipid-soluble compounds with high vapor pressures at ambient temperatures. Following World War 11, increasing emphasis has been placed on their potential use as insecticides.'

PHARMACOLOGY The release of multiple quanta of ACh from the presynaptic membrane of cholinergic synapses occurs in response to an action potential. The released ACh combines with ACh receptors located on the postsynaptic membrane. The combination of the transmitter with AChK causes changes in the permeability properties of the postsynaptic membrane, most notably to Na+ and K'. This results in the endplate potential that triggers the action potential.' ACh receptors are also located on the presyn-

*West Virginia University School of Medicine, Morgantown, West Virginia +Universityof Mainz, Mainz, Federal Republic of Germany. Reprint requests: Dr. Gutrnann, Department of Neurology, West Virginia University School of Medicine, Morgantown, WV 26506 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avcnuc South, New York, N Y 10016. All rights reserved.

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Ludwig Gutmann, M.D. *, and Roland Besser, M.D.+

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aptic membrane of the neuromuscular j u n c t i ~ n . ~soning and suicide attempts than any other orThese play an important role in the autoregulation ganophosphate. Malathion has been used for aerof ACh released from the terminal axon. Their ac- ial spraying to control mosquitoes and fruit flies, tivation by ACh inhibits the release of ACh from with little evidence of acute human toxicity, since the presynaptic membrane." third set of ACh re- dermal exposure accounts for only a small fraction ceptors is thought to be located more proximally of systemic abs0rption.l on the terminal axon, distal to the last myelinated Organophosphate compounds may inhibit other internode; these are involved in backfiring, dis- enzymes, including neurotoxic esterase, responsicussed later.'" ble for the delayed polyneuropathy occasionally Following the release of the bolus of ACh in seen some weeks after exposure." This polyneuresponse to a nerve impulse and its interaction with ropathy, often associated with a myelopathy, is ACh receptors, the ACh is quickly hydrolyzed by much more likely to occur with subacute and AChE, allowing for the repolarization of the post- chronic exposure than in response to a single large synaptic membrane. This process of depolarization dose, as in suicide attempts.12 In addition, certain and repolarization is essential for the proper acti- of the organophosphates are much more likely to vation and functioning of the postsynaptic celL7 result in the delayed polyneuropathy. Most notable Inhibitors of AChE alter the normal function- in this group is triorthocresyl phosphate (TOCP), ing of the cholinergic synapses by allowing exces- which has little AChE inhibitory effect and was resive AChE to accumulate. There are three classes sponsible for the 1930 epidemic of TOCP-induced of AChE inhibitors. The first class, quaternary myeloneuropathy. It resulted from the popular use compounds, inhibits AChE reversibly. Edrophon- of Jamaica ginger at that time: the epidemic was ium is the best-known example of this group, hav- caused by TOCP, which had been substituted as a ing a brief duration of action following parenteral cheap liquid plasticizer in its production. This epadministration as a diagnostic agent for myas- idemic was popularized in songs such as T h e Jake thenia gravis. Walk Blues and The Jake Leg Rag. It resulted in The second class of compounds, the carba- 20,000 to 60,000 affected persons.'" mates, includes such clinically used drugs as physostigmine, neostigmine, and pyridostigmine, as well as commonly used insecticides such as carbaryl PATHOPHYSIOLOGY (Sevin). These, too, cause "reversible" AChE inhibition that lasts 3 to 4 hours. Carbaryl and its sevImportant concepts in understanding the pathoeral analogues are extensively used as agricultural physiology of the disorders of neuromuscular and garden insecticides because of their "reversi- transmission include the mechanisms of ACh reble" nature and low human toxicity from dermal lease from the terminal axon, activation of ACh reabsorption. The cholinergic symptoms resulting ceptors on the postsynaptic membrane by ACh, from excessive exposure to these drugs or insecti- generation of the endplate and muscle action pocides are relatively short-lived and reversib1e.l tentials, and the subsequent hydrolysis of ACh The organophosphates are irreversible inhib- by AChE.' Organophosphate intoxication involves itors of AChE, with the resultant phosphorylated additional concepts, including those of antidromic enzyme extremely stable. The return of AChE ac- axon backfiring,I0 prolongation of postsynaptic tivity depends on the synthesis of new enzyme.' endplate potentials,I4 and desensitization of ACh The organophosphate compounds in com- receptors.15 mon usage are highly lipid-soluble. Some of these The location of ACh receptors on the postsynagents (especially those designed for chemical war- aptic membrane of the neuromuscular junction is fare such as tabun, sarin, and soman) have high well appreciated by clinicians. However, they are vapor pressures at usual ambient temperatures. also located on the terminal axon in two different location^.'^ The presynaptic membrane of the neuThe less volatile agents are used in insecticides. Important organophosphate compounds with high romuscular junction has ACh receptors that are toxicity used as pesticides include TEPP, para- normally involved in the autoregulation of ACh rethion, and its active metabolite paraoxon, echo- lease: their activation decreases release.17 In addithiophate, disulfoton, and mevinphos. Those of tion, ACh receptors are located more proximally moderate toxicity include dichlorovos, hepteno- on the terminal axon, just distal to the last myeliphos, dimethoate, fenthion, Diazinon, and mala- nated internode.'" These axonal ACh receptors thion. Despite its high toxicity, parathion remains are not normally activated during neuromuscular widely used as an insecticide and has probably transmission. However, in the presence of excess been responsible for more cases of accidental poi- ACh at the neuromuscular junction, ACh leaks out

SEMINARS IN NEUKOLOGY V O L U M E 10, NUMBER I MARCH 1990

REPETITWE MUSCLE ACTION POTENTIALS

During the course of the illness, the CMAP in response to a single supramaximal nerve stimulus is followed by repetitive muscle action potentials (Fig. 1). The duration of the CMAP with repetitive discharges varies between 9 and 43 msec. During repetitive stimulation, the repetitive discharges decline in amplitude and duration or disappear. The manner in which this occurs depends on the type of repetitive nerve stimulation abnormality, and this is discussed later. These repetitive muscle action potentials associated with the CMAP following a single nerve stimulus are the earliest and most frequent alteration of AChE inhibition regardless of intoxication severity. They are therefore the

Figure 1. CMAP in response to a single supramaximal nerve stimulus from a patient with acute organophosphate intoxication. Note two prominent repetitive discharges following the initial portion of the CMAP.

most sensitive indicator of the action of AChE inhibitors at the endplate. They are observed as early as 4 hours after organophosphate ingestion. In addition to organophosphate intoxication they also occur with AChE inhibition due to reversible AChE inhibitor (such as edrophonium and pyridostigmine) as well in two congenital myasthenic syndromes involving prolonged open time of sodium channels and AChE defi~iency.~ DECREMENT-INCREMENT RESPONSE

The decrement-increment phenomenon is a unique one seen only in disorders of neuromuscular transmission involving AChE inhibition. In response to repetitive nerve stimulation, there is a decrease in amplitude of the primary portion of the CMAP that is always maximal with the second stimulus (Fig. 2). This is associated with a disappearance of repetitive discharges, the latter seen only with the initial CMAP. Following this change in the second CMAP, a progressive increment of subsequent potentials occurs, almost always without reappearance of the repetitive muscle discharges. The maximum amplitude of the CMAP is usually reattained by the fourth to sixth stimulus and equals that of the initial CMAP but never exceeds it. The decrement of the second potential is most pronounced with higher stimulation rates and with the greater prolongation of the muscle action potential and its attendant repetitive discharges. The decrement-increment phenomenon is not converted to a decrement response by altering frequency rates. The lowest stimulation frequency at which the phenomenon is seen depends on the duration of the CMAP. The longer its duration, the lower the frequency of nerve stimulation to elicit it. The decrement-increment phenom-

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of the junction and activates these receptors. When the more proximal ACh receptors are activated by ACh, antidromic firing (backfiring) occurs in the axon.I8 It is likely that the activation of these receptors is a major cause of spontaneous fasciculations, including those seen with organophosphate intoxication. Backfiring results in repetitive spontaneous nerve action potentials in response to the single nerve action potential. These travel antidromically and then, via the axon reflex, orthodromically in motor nerve axons. The antidromically conducted repetitive potentials can be recorded from anterior roots.I0 The backfiring with its repetitive axon discharges results in the release of additional ACh, contributing to the repetitive muscle action potentials in response to a single nerve stimulus characteristically seen in disorders of AChE i n h i b i t i ~ n . ~ The prolonged exposure of the postsynaptic ACh receptors also results in a prolonged endplate potential and desensitization of the postsynaptic membrane. T h e prolonged endplate potential contributes to the repetitive muscle action potentials in ' ~ desenresponse to a single nerve s t i m ~ l u s . The sitization is in large part responsible for the decremental response occurring with organophosphate intoxication.I5 The electrophysiologic features of the neuromuscular junction defect associated with organophosphate intoxication are distinctive and are, in our experience, the most sensitive indicators of intoxication severity and the recovery process. They represent the only mode of quantifying the organophosphate inhibition of AChE at cholinergic synapses. These electrophysiologic features include: (1) repetitive firing of the single evoked compound muscle action potential (CMAP); and (2) distinctive CMAP abnormalities in response to repetitive nerve stimulation referred to as the decrement-increment and decrement phenomena.'

ORGANOPHOSPHATE INTOXICATION-GUTMANN,BESSER

69 Hours

JIO~V SOms

Day I2

Figure 2. CMAPs in response to supramaximal median nerve stimulation at 20 Hz. At 69 hours after intoxication, a CMAP is seen only with the initial stimulus. At 4 days, improvement has occurred but a severe decrement response is present. In this example, a repetitive discharge occurs only with the first CMAP. At 12 days, the patient is markedly improved with little weakness and only a decrement-increment response is present. Note that the second CMAP shows the maximal decrement and that a repetitive discharge occurs only with the first CMAP.

the ninth stimulus. In its mildest form, the primary portion of the CMAP remains unchanged, with the decrement limited to the repetitive discharges. In contrast to the decrement-increment phenomenon, the repetitive discharges are not limited to just the first stimulus in a train. The decrement response occurring in the more severe stages of intoxication is best explained by desensitization of postsynaptic ACh receptor^.^ Overall, these various electrophysiologic abnormalities are useful in staging the severity of the intoxication and following its progress. The CMAP with repetitive discharges is seen early and virtually always present. The decrement-increment response occurs early or late in the course of the intoxication and may be associated with little or no clinical weakness. The decrement phenomenon occurs with more severe intoxications and may be profound at higher rates of repetitive stimulation, as already noted. The degree of decrement with this latter phenomenon actually reflects the severity of the weakness and the subsequent improvement in the decrement heralds the onset of clinical recovery.

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20 Hz Stimulation

CLINICAL FEATURES enon occurs only in slight early or late stages of AChE inhibition. It is at this slight stage of AChE inhibition that antidromic nerve backfiring occurs. At higher rates of repetitive stimulation, the backfiring and subsequent repetitive CMAP discharges occur only with the initial stimulus. The backfiring with prolonged, excessive release of ACh accounts for the smaller second CMAP, and the lack of subsequent backfiring allows for the improvement in CMAP amplitude with successive stimuli.= DECREMENT RESPONSE

A decrement phenomenon in response to repetitive nerve stimulation is seen in all patients in whom there is moderate to severe intoxication. The decrement occurs with successive stimuli and involves both the primary portion of the CMAP as well as its repetitive discharges (Fig. 2). When present, the decrement response occurs at slow and rapid rates of stimulation. The rate of stimulation has no effect on the overall pattern (no change to decrement-increment pattern occurs) but affects only the degree of decrement, which is greater at the more rapid rates. The degree of decrement ranges from disappearance of the CMAP and its repetitive discharges with the second stimulus (in severe cases) to only slight amplitude reductions by

The clinical features of organophosphate intoxication reflect the effects of AChE inhibition and the excess of ACh at peripheral (muscarinic and nicotinic) and central synapses. The number and severity of abnormalities reflect the degree of intoxication. Symptoms may begin within 3 hours and death may occur by 10 hours when the intoxication is severe. Death is usually secondary to respiratory failure, often associated with cardiovascular collapse. In the absence of any significant complication, recovery often occurs within 1 week. The muscarinic symptoms and findings reflect the AChE inhibition at autonomic synapses. These include miosis (virtually always present), conjunctival hyperemia, rhinorrhea and drooling, bronchospasms with wheezing and coughing, increased bronchial secretions with airway obstruction, respiratory distress, pulmonary edema, laryngeal spasms, sweating, anorexia, nausea and vomiting, diarrhea, epigastric distress, bradycardia, hypotension, and involuntary defecation and urination. The nicotinic effects reflect AChE inhibition at the neuromuscular junctions. The initial skeletal muscle symptoms reflect excessive stimulation, which is later followed by paralysis. The early stimu l a t o r ~phase involves fasciculations and cramps and coincides with axonal backfiring noted earlier. Fasciculations are first seen in the eyelids, spread 49

SEMINARS I N NEUROLOGY

electrophysiologic studies provide the best method for documenting the degree of intoxication and determining the height of illness as well as the course of recovery. In patients with severe intoxication requiring mechanical ventilation and sedation, the degree and time course of weakness may be difficult to determine. The neurophysiologic studies assist in determining when to wean the patient from the respirator. In our patients, with at least moderately severe intoxication, persistent decrement responses at various frequencies of spontaneous firing of motor units (10 to 20 Hz) predicted the continued need for mechanical ventilation. Other laboratory studies are of little value, although a slight to moderate leukocytosis is often present, in a range of 13,000 to 20,00O/cu ml. Careful monitoring of blood pressure, vital capacity, and mental status is clearly in order.2

THERAPY

The importance of prompt early diagnosis for the successful treatment of organophosphate intoxication cannot be overemphasized. Immediate attention should be given to removing the patient from further exposure. This is of critical importance. In organophosphate ingestion, in our experience, gastric lavage, with more than 100 liters of water, is essential, in order to remove as much of the ingested poison as possible. Along with activated charcoal, cathartics should be given repeatedly for several days. Contamination of skin and mucous membranes requires copious washing. In warfare, potential use of organophosphates requires the availability of gas masks. These maneuvers will significantly shorten the course and severDIAGNOSIS ity of the illness and avoid death. The maintenance Prompt diagnosis is essential in order to initi- of respiration and cardiovascular function may reate appropriate therapy that will shorten the quire endotracheal intubation, oxygen, and mecourse and decrease the severity of the illness. The chanical ventilation, depending on the severity of signs of muscarinic, nicotinic, and central nervous the intoxication. In severe intoxication, respiratory system abnormalities in association with a history failure may be the result of both muscle paralysis of organophosphate intoxication or exposure lead and central respiratory depression. Seizures reto the appropriate diagnosis. The rarity of the syn- quire anticonvulsant therapy but are exceedingly drome in the United States makes it an exception- rare in humans. Specific pharmacologic therapy involves the ally challenging diagnostic problem. Serum levels of organophosphates and cholinesterase ,activity use of atropine and, at least theoretically, cholinare the most important laboratory studies in the esterase reactivators. Atropine is primarily effecinitial diagnosis. Serum cholinesterase is markedly tive in treating the muscarinic side effects and has decreased early in the course of the intoxication no action on the dysfunction at the neuromuscular and remains so for a long time. Serum organo- junction. Furthermore, it is of little benefit in dealphosphate levels, initially elevated, decrease rap- ing with the central nervous system toxicity. We idly over the first 48 hours as they are cleared from recommend the use of atropine in doses of 1 to 2 the blood to other body tissues, and this in no way mg every hour largely to control the excessive pulrepresents a good prognostic sign.*s5The clinical monary or bronchial secretion over the first 4 to 5

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to the face and calves, and then become generalized. This occurs during the first 24 hours and is followed by weakness or paralysis, depending on the severity of the intoxication. Paralysis involves all skeletal muscles, including those of respiration, with labored, shallow, rapid breathing. Respiratory failure and cyanosis ensue. Weakness of the tongue and pharyngeal muscles further enhances respiratory failure by virtue of airway obstruction. Organophosphate intoxication leads to a broad spectrum of central nervous system effects secondary to the accumulation of ACh at central cholinergic synapses. Early signs include anxiety, restlessness, emotional lability, insomnia, and excessive dreaming. Larger doses of organophosphates lead to headaches, tremor, drowsiness, memory impairment, apathy, and depression. Severe intoxication ultimately results in confusion, ataxia, dysarthria, and absent myotatic reflexes and progresses to coma, Cheyne-Stokes respirations, tonic-clonic seizures, and central respiratory depression. With prompt initial diagnosis and therapeutic intervention, the maximum clinical features are attained within the first 3 or 4 days, at which time recovery begins. In most patients, complete recovery is expected within 1 to 3 weeks, depending on the severity of intoxication and the effectiveness of the initial the rap^.^.^ Intravenous edrophonium, a rapidly reversible AChE inhibitor, may be useful if the patient presents as a diagnostic dilemma. If at all possible, it is best avoided, since it will transiently worsen the depolarizing neuromuscular junction blockade and the clinical symptoms already present.lY

VOLUME 10, NUMBER 1 MARCH 1990

days. Larger doses have been recommended in the literature but create several serious problems, including thickening of pulmonary secretions that may lead to respiratory and cardiac arrest. In addition, the larger doses of atropine will inhibit the cathartic induced diarrhea that plays an important role in the initial treatment. Cholinesterase reactivators are oximes, of which pralidoxime is the one usually used. They are of theoretical usefulness but, practically, are of little benefit. Prompt utilization would be essential, since phosphorylated AChE becomes resistant to reactivation within a few hours. Failure of reactivation is common and is usually related to delayed initiation of therapy and failure of some organophosphate compounds to be antagonized by oximes. Dimethoate is an example of a compound resistant to oximes. If used in severe intoxication, 1 gm of pralidoxime is given intravenously at a rate of less than 500 mglmin. If weakness persists after 20 minutes, this dosage may be repeated. Pralidoxime has some side effects, including abdominal discomfort, headaches, dizziness, diplopia, nervousness, and malaise. In doses larger than those used clinically, it may also inhibit AChE.'O Benzodiazepines, such as midazolam, are useful as sedation in the treatment of the induced central nervous system hyperirritability. They also assist in the process of mechanical ventilation, as do opioid analgesics such as fentanyl.'

4. 5.

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ORGANOPHOSPHATE INTOXICATION-GUTMANN. BESSER

Organophosphate intoxication: pharmacologic, neurophysiologic, clinical, and therapeutic considerations.

SEMINARS I N NEUKOLOGY-VOLUME 10, NO. 1 MARCH 1990 Organophosphate Intoxication: Pharmacologic, Neurophysiologic, Clinical, and Therapeutic Consider...
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