Nerve agents

Nerve AgentsChapter 5 NERVE AGENTS FREDERICK R. SIDELL, MD*; Jonathan Newmark, MD†; and John H. McDonough PhD‡ INTRODUCTION HISTORY PHARMACOLOGY OF CHOLINESTERASE INHIBITORS EXPOSURE ROUTES EFFECTS ON ORGANS AND ORGAN SYSTEMS GENERAL TREATMENT PRINCIPLES SPECIFIC TREATMENT BY EXPOSURE CATEGORY RETURN TO DUTY TREATMENT GUIDELINES IN CHILDREN LESSONS FROM IRAN, JAPAN, AND IRAQ PYRIDOSTIGMINE BROMIDE AS A PRETREATMENT FOR NERVE AGENT POISONING SUMMARY *Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland; deceased † Colonel, Medical Corps, US Army; Deputy Assistant Joint Program Executive Officer, Medical Systems, Joint Program Executive Office for Chemical/ Biological Defense, Skyline #2, Suite 1609, 5203 Leesburg Pike, Falls Church, Virginia 22041; Adjunct Professor, Department of Neurology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland ‡ Major, Medical Service Corps, US Army (Retired); Research Psychologist, Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, Room 161A, Building E-3100, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010 155 Medical Aspects of Chemical Warfare INTRODUCTION Nerve agents, secretly developed for military use Terrorist organizations have used nerve agents to cause before World War II, work by inhibiting cholinesterase mass injury and death, as was the case in the 1994 and (ChE). Though similar chemicals are used in areas such 1995 Aum Shinrikyo subway attacks in Japan. Other as medicine, pharmacology, and agriculture, they lack groups, like Al-Qaeda, have indicated strong interest the potency of military agents, which are extremely in obtaining these compounds. Therefore, it is impera- toxic. The military stockpiles of several major world tive that military medical personnel are familiar with powers are known to include nerve agents, and other these agents, their effects, and the proper therapy for countries undoubtedly possess nerve agents as well. treating casualties. HISTORY The earliest recorded use of nerve agents comes developed for treating conditions such as intestinal from west Africa, where the Calabar bean, from the atony, myasthenia gravis (a disorder in which the plant Physostigma venenosum, was used as an “ordeal immune system attacks postsynaptic acetylcholine poison” to combat witchcraft. Tribal members accused [ACh] receptors), and glaucoma; for example, there of practicing witchcraft were forced to ingest the beans is a documented case from 1931 of a doctor treating and if they survived, they were proclaimed innocent.1,2 gastric atony with neostigmine.1 An extract, “the elixir of the Calabar bean,” was later Lange and Krueger reported on the marked potency used medicinally,3 and in 1864, the active principle was of organophosphorus compounds in 1932 after noting isolated by Jobst and Hesse and called physostigmine.1 the effects of the vapors of dimethyl and diethyl phos- Vee and Leven independently isolated this same sub- phorofluoridate on themselves.1,4 Shortly thereafter, stance in 1865 and named it eserine,1 resulting in its the German company IG Farbenindustrie developed dual nomenclature. an interest in using organophosphorus compounds as Five organophosphorus compounds are generally insecticides. On December 23, 1936, Gerhard Schrader, regarded as nerve agents. They include tabun (North who headed the company’s research effort, synthesized Atlantic Treaty Organization military designation GA), what is known today as tabun.5,6 Like Lange and Krue- sarin (GB), soman (GD), cyclosarin (GF), and VX (no ger, he noted the toxicity (miosis and discomfort) of common name). More recently, a Soviet-developed the vapors of the substance in himself. substance closely related to VX, called VR or Russian Over a year later, Schrader synthesized a second VX, has been added to the list. The agents in the “G” organophosphorus compound and named it sarin in series were allegedly given that code letter because honor of those who were instrumental in its develop- they originated in Germany; the “V” in the latter series ment and production: Schrader, Ambros, Rudriger, allegedly stands for “venomous.” GF is an old agent, and van der Linde.5 Because the German Ministry of an analog of sarin, which was previously discounted Defense required that substances passing certain tox- by the United States as being of no interest. During the icity tests be submitted to the government for further Persian Gulf War, it was believed that Iraq might have investigation, these compounds were examined for GF in its arsenal. The toxicity and speed of action of this possible military use. agent still merits consideration of it as a threat. The potential of tabun and sarin as weapons was The first organophosphorus ChE inhibitor was soon realized. A large production facility was built in probably tetraethyl pyrophosphate, synthesized by Dyhernfurth, Poland (part of Germany at the time), Wurtz and tasted (with no ill results) by Clermont and production of tabun began in 1942.5,6 Sarin was in 1854.4 During the next 80 years, chemists such as also produced in Dyhernfurth and possibly at another Michaelis, Arbusow, and Nylen made advances in plant in Falkenhagen.6 Late in World War II, Soviet organophosphorus chemistry, but they did not realize troops captured the Dyhernfurth facility, dismantled the toxicity of the substances with which they were it, and moved it, along with key personnel, to the working.4 former Soviet Union, where production of the agents In the early 1930s, interest in both physostigmine- commenced in 1946.6 Some believe the Soviets insisted type (reversible) and organophosphorus-type (irrevers- on placing the border between Poland and Germany ible) ChE inhibitors increased. (The terms “reversible” as far west as the Oder-Neisse line, where it remains and “irreversible” refer to the duration of binding of today, because Stalin did not want the Dyhernfurth the compound with the enzyme ChE; see below.) The site, located between the Oder and Neisse rivers, to reversible type, most of which are carbamates, were be in Germany.7 156 Nerve Agents About 10,000 to 30,000 tons of tabun and smaller was too expensive to manufacture or that there was quantities of sarin were produced and put into muni- no perceived need for an agent with its properties. The tions by the Germans during World War II, but these manufacturing process for GF is apparently similar to weapons were never used.6 Although it is unclear why that for GB. During the Persian Gulf War (1990–1991), they were never used, possible explanations include Iraq was believed to have switched from manufactur- Hitler ’s distaste for chemical warfare given his own ing GB to manufacturing GF when the precursors of exposure to mustard gas in World War I; Germany’s GB were embargoed. loss of air superiority on the battlefield by the time The United States began to produce sarin in the sufficient nerve agent stocks were available; and early 1950s, and VX in the early 1960s, for poten- Germany’s mistaken belief that the Allies had also tial military use. Production continued for about a developed nerve agents. decade.6 The United States placed these two nerve In the waning days of World War II, troops of the agents in M55 rockets; land mines; 105-mm, 155-mm, United States and the United Kingdom captured some and 8-in. projectiles; 500-lb and 750-lb bombs; wet-eye of the German munitions, which were being stored at bombs (which have liquid chemical [“wet”] contents); Raubkammer, a German testing facility. The weapons, spray tanks; and bulk containers.10 These munitions which contained an agent unknown to scientists in the were stored at six depots within the continental United United Kingdom and the United States, were taken to States and one outside the continent,11 near the fol- the each of the countries for examination. Over a single lowing locations: Tooelle, Utah; Umatilla, Oregon; weekend, a small group of scientists at the United Anniston, Alabama; Pine Bluff, Arkansas; Newport, Kingdom Chemical Defence Establishment, working Indiana; Richmond, Kentucky; and Johnston Island despite miosis caused by accidental exposure to the in the Pacific Ocean. agent vapor, elucidated the pharmacology and toxic- The United States signed the Chemical Weapons ity of tabun and documented the antidotal activity of Convention in 1996, and it came into effect in 1997. atropine.8 Under its provisions, the United States pledged to Use of these weapons probably would have been eliminate its stockpile of chemical weapons, includ- devastating and might have altered the outcome of the ing the nerve agent stockpiles. The overseas stockpile, war. The Germans had tested nerve agents on inmates moved from Europe and Asia to Johnston Island, has of concentration camps, not only to investigate their in- been completely destroyed at the time of this writing. toxicating effects but also to develop antidotes.9 Many On-site destruction facilities either exist or are being casualties, including some fatalities, were reported built at all of the depots in the continental United among the plant workers at Dyhernfurth. However, States. The timetable for destruction of these stockpiles the medical staff there eventually developed antidotal accelerated after the 2001 terrorist attacks because the compounds.5 The Allies were unaware of these German depots are seen as potential terrorist targets. The largest experiments until the close of the war, months after the stockpile was kept at Tooele, Utah, and was the first to initial UK studies,8 and much of the basic knowledge be completely destroyed. about the clinical effects of nerve agents comes from The former Soviet Union had a stockpile of chemical research performed in the decades immediately fol- weapons, including nerve agents, estimated to be ten lowing World War II. times the size of the US stockpile. Russia has pledged Soman was synthesized in 1944 by Richard Kuhn to eliminate this stockpile. of Germany, who was attempting to develop an in- Nerve agents, although developed for World War secticide.6 Although small amounts were produced II in Germany, were not used on the battlefield until for the military, development had not proceeded far 50 years later. During the Iran-Iraq War, Iraq used by the end of the war. The nerve agent VX was first large quantities of tabun and sarin against Iranian synthesized in the 1950s by a chemical company in the forces, causing between 45,000 and 120,000 casualties, United Kingdom looking for new pesticides.6 It was depending upon the source.12 In 1995 Iraq declared then given to the United States for military develop- to the United Nations Special Commission that the ment. Other potential nerve agents were synthesized country still possessed 4 metric tons of VX and up by scientists in the United States and United Kingdom to 150 metric tons of sarin. At the time, the United but were not developed for military use. For example, Nations Special Commission suspected that Iraq GF, which may have been synthesized around 1949 had up to 200 metric tons of each. As of this writing, by a foreign chemist searching for alternative nerve no Iraqi stockpiles of chemical weapons have been agents, was studied in both the United States and the found; however, in May 2004, two US soldiers were United Kingdom. It was then discarded for reasons that exposed to sarin in Baghdad, Iraq, in the form of are not entirely clear. Possible explanations are that it an old Iraqi weapon that was being used as part of 157 Costa Mesa.14 A similar enzyme substance to be used before exposure to certain nerve with ACh as its preferred substrate is found in or on agents (see below). Three are approved for this indication by the of ChE. among the carbamates is physostigmine (eserine. see event was not well publicized. several anticholinesterase drugs have been as its preferred substrate. whereas tissue enzyme is unavailable for assay. Although there are Calif) has been used for decades to manage myasthenia several types of choline esters. North Rhine-Westphalia. the class of esterases to which AChE belongs. is in the United States take pyridostigmine bromide most relevant to nerve agent activity. this ties. nerve agents are compounds that exert their ates or organophosphorus compounds. also known as serum or tured by Bayer. physical form. affinities for the esters of choline. ambenonium was developed later for terases. uses butyrylcholine Recently. Other carbamates. ACh rapidly. In the past few years. (For more information on the Aum attacks. The cholinergic system is the only of the Calabar bean).000 patients ter of the cholinergic portion of the nervous system. Chemical Terrorism. The best known biological effects by inhibiting the enzyme acetylcho. Calif) was developed in the early 1930s to manage my- AChE belongs to the class of enzymes called es. Today these carbamates are mainly erythrocytes (red blood cells) and is known as red used for treating glaucoma and myasthenia gravis. the active sites are identical regardless of the US Food and Drug Administration (FDA): donepezil. The Most commonly used insecticides contain either a measurements obtained from the blood assay can be carbamate or an organophosphorus compound. elixir linesterase (AChE). Rivastigmine is a the activities of each of these enzymes can be assayed carbamate. as a pretreatment or antidote-enhancing that it turns over per unit time). The US military AChE. ACh. the neurotransmit. and galanthamine. Japan. Costa Mesa. asthenia gravis. which was first synthesized in the 1940s. Pyridostigmine bromide (Mestinon. ChEs. History of the Chemical Threat. and by standard. Leverkusen. Holland). On any given day. The used as an approximation of tissue enzyme activity organophosphorus insecticide malathion has replaced in the event of a known or possible exposure to an parathion. AChE. Sarin has also been used in terrorist attacks. The and Its Implications for Military Medicine).3 Neostigmine (Prostigmin. or true. While there is a single gene for each form disease. relatively simple laboratory techniques. which reports that Iran may have developed nerve agents the cult members synchronously ripped open on three and used them against Iraq. blood cell. plasma cholinesterase and as pseudocholinesterase). transmission is faulty. are used as insecticides. have high manufactured by ICN Pharmaceuticals. PHARMACOLOGY OF CHOLINESTERASE INHIBITORS Cholinesterase in Tissue Cholinesterase-Inhibiting Compounds According to the current. The organophosphorus compound diisopropyl phos- 158 . floors. However. In June about 4. 1995. Germany). in which cholinergic plasma or serum and in some tissues. medication to treat myasthenia gravis. the same purpose. which catalyze the hydrolysis of esters. Butyrylcholine is present in used to treat Alzheimer ’s disease. Bu. of the neurotransmitter is terminated by an enzyme.000 had no effects from the agent but 12 casual- 1994 members of a Japanese cult released sarin from ties died. History of Chemical Warfare and Chapter same group broke open plastic containers of sarin on 4. which has been used in medicine neurotransmitter system known in which the action for more than a century.Medical Aspects of Chemical Warfare an improvised explosive device. AChE inhibitor. the Chapter 2. hydrolyzes bromide (manufactured by Phillips Duphar. an estimated 16. including 7 deaths. found at the receptor sites of tissue inner. All inhibit ChEs.13 There have been containers held a 30% solution of liquid sarin. because blood is easy to draw. rivastigmine. It has one of the highest known enzyme known as PB or NAPP (nerve agent pyridostigmine turnover numbers (number of molecules of substrate pretreatment). these have BuChE and RBC-ChE are the two forms of ChE in become the basis of treatment of early stages of this the blood. cholinesterase (RBC-ChE). another enzyme of the ChE family. galanthamine is a tertiary alkaloid. such as carbaryl (Sevin. donepezil is a piperidine compound. Most ChE-inhibiting compounds are either carbam- nation. but these reports have subway trains and allowed to spill onto the seats and never been confirmed. On March 20. and several other nations also field pyridostigmine vated by the cholinergic nervous system. Although there of medical resources to triage and care for the casual- were almost 300 casualties. This incident required a major commitment the rear of a van in Matsumoto. widely accepted expla. gravis. manufac- tyrylcholinesterase (BuChE. More than 5. manufactured by ICN Pharmaceuticals.500 people sought medical care. several Tokyo trains during the morning commute. or if it is unable to The cholinergic nervous system can be further function. tomically widespread of any known neurotransmitter The human nervous system is made up of conduct. and cause a new action potential the target cell. glands (eg. Both muscarinic and nicotinic receptors are cholinergic overactivity or cholinergic crisis. such ing cells. interact with postsynaptic series. The catalytic mechanism this purpose. allowing In the cholinergic nervous system. but later was deemed unsuitable sites are innervated by postganglionic parasympa- because it produced cataracts. as nerve agent. and can be stimu- ing the war. In the periphery. Each neuron in the neurotransmitter ACh to terminate its activity at the nervous system uses only one neurotransmitter for the receptor site (Figure 5-2). the secretion of a packet of neurotransmitter When an action potential in a cholinergic neuron molecules and its diffusion across the space or synaptic reaches the terminal bouton. the residue. signal. The portion of the nervous system that facilitated by other strategically placed residues in uses ACh as its neurotransmitter is referred to as the the active site that orient the ACh to the appropriate cholinergic system. This giving rise to a miniature endplate potential. Approxi. whose primary mission is to con. the musculature of the Mechanism of Action pulmonary and gastrointestinal systems. nerve agents disable The brain contains a high number of cholinergic the off switch for cholinergic transmission. War II and studied by Allied scientists before and dur. because the structures that are innervated have recep. neurons in particular tracts ine 203 reacts with ACh to displace the choline moiety or regions use specific neurotransmitters. It is the most widely distributed angle for serine to displace the choline and stabilize the and best studied in neurobiology.14. this compound was used topically cholinergic input is primarily autonomic. Clinically. alkaloids muscarine and nicotine. having mately 20 neurotransmitters have been identified in been displaced. a water molecule of the brain within the central nervous system (CNS). to the excess endogenous ACh. a membrane-bound protein. as in more restricted neurotransmitter systems end of a neuron. another key amino acid Within the peripheral nervous system. in which ser- mitter system is specific. The nerve agents and other ChE-inhibiting substances 159 . of AChE involves first an acylation step. lated by these compounds. Nicotinic sites drolyze ACh. from getting out of hand (Figure 5-1). with muscar- discussion of the chemistry of ChE inhibition is beyond inic receptors predominating in a ratio of roughly 9 to the scope of this chapter and can be found in most 1. those of the mouth and the respiratory and gastrointestinal systems). A detailed active in the central cholinergic system. autonomic nervous system. however. the most important characteristic of the textbooks of pharmacology. displac- cholinergic system is found only in very specific fiber ing it from the serine to form acetic acid. they sum. postsynaptic action potentials and activity in the organ. This classic explanation of nerve agent are predominantly found at the autonomic ganglia poisoning holds that the intoxicating effects are due and skeletal muscles. which diffuses tracts. In the periphery. transition state by a three-pronged hydrogen bond (the Cholinergic tracts are found in almost every part “oxyanion hole“). Clinically. and forming an acylated serine (the choline. diffuses away). This reaction is greatly neurobiology. mate and a new action potential is created. When a signal reaches the a few. ChE hydrolyzes information transmission to proceed. it interacts with specific postsynaptic to be generated. When the neurotransmitter molecule reaches cholinergic receptors. the efferent organs of the cranial nerves (including the heart via Nerve agents inhibit ChE. The cycle continues until ACh is hy- receptors on the receiving cell’s surface membrane. but was rejected for use as a military agent. attacks the acyl group. where For a period of time. system in human brain. and polarized by. bound to. Consequently. ACh accumulates and continues to produce divided into the muscarinic and nicotinic systems. these sites include in pharmacology as an investigational agent. In a second step. it can only continue as a chemical such as the dopaminergic or serotoninergic systems. which then cannot hy. the vagus nerve). or neurons. Once is the mechanism that prevents cholinergic stimulation sufficient numbers of these are generated. producing neurons. It has been widely used thetic fibers. cleft separating its parent neuron from the next cell in cross the synaptic cleft. and other structures. a chemical. The neuroanatomy of each neurotrans. drolyzed by AChE. If AChE is absent from the site. the most important of these are the away and leaves a regenerated or reactivated enzyme sympathetic and parasympathetic divisions of the that can repeat the operation. Nerve Agents phorofluoridate (DFP) was synthesized before World tors that recognize two false experimental transmitters. ACh packets are released.15 though the relevant central cholinergic system is that it is the most ana- aspects are summarized here. that affects the cholinergic system as a vey information from place to place via efficient electric whole will affect all parts of the brain rather than only signals or action potentials. histidine 447. muscarinic to treat glaucoma. Hydrolysis of endplate of acetylcholine potential (following diffusion of Soluble acetylcholine to Na + nonspecific postsynaptic esterase receptors) Membrane-bound acetylcholinesterase Acetylcholine K+ receptor –15 m V –80 mV Fig. Synaptic trough(cross section) Schwann cell Sarcolemma Axoplasm Axon terminal Axolemma Mitochondria Synaptic vesicles Synaptic cleft Folds of sarcolemma Sarcoplasm C. Reproduced with permission from: Clinical Symposia. (b) Close- up of axon terminal in trough. (e) Acetylcholine stimulation of endplate at receptor for site. (f) Hydrolysis of acetylcholine by membrane-bound acetylcho- linesterase.1(1§8):162. Plate 3118. West Caldwell. 160 . (c) Acetylcholine synthesis from acetate and choline and storage of acetylcholine in synaptic vesicles. NJ: CIBA-GEIGY Medical Education Division. 1948. with synaptic vesicles indicated.Medical Aspects of Chemical Warfare Somatic Neuromuscular Transmission A. Acetylcholine D. 5-1. Acetylcholine synthesis release Choline (in response Acetate to an action Acetylcholine potential in Synaptic presynaptic vesicles neuron) Axolemma Basement membrane –80 mV –80 mV Sarcolemma E. (a) Nerve fiber with axon terminal in synaptic trough of muscle. Neuromuscular junction (motor endplate) (longitudinal section) Axoplasm Myelin sheath Schwann cell Sarcolemma Axon terminal in Sarcoplasm synaptic trough Muscle cell nucleus Myofibrils B. Production F. Diagram of neuromuscular conduction. (d) Release of acetylcholine from synaptic vesicles after an action potential. Carbamates attach to both the chemical agent depot workers or laboratory scientists esteratic and the anionic sites. which is not Blood Cholinesterases hydrolyzed. At periodic intervals. Because most of these compounds attach to the esteratic site on AChE. was alert and functioning reasonably well for several days while ChE activity in his blood was undetectable (Exhibit 5-1). the phosphorylated form of the enzyme may remain indefinitely. If the second test also indicates activity below cleavage of the compound from the enzyme may oc.17 This activity forms the Fig. A previously administered ChE inhibitor will. in a manner of speaking. the interval during which of the worker ’s baseline. If the the organophosphorus compound remains attached) activity is below 90% of the baseline. between them and the workers who handle ChE-inhibiting insecticides. the sample is depends on the structure of the compound. drawn within 14 days but with physostigmine and for 4 to 6 hours after reacting not within 24 hours of each other. and measuring ChE activity. no action is taken. carbamates and organophosphorus asymptomatic exposure by assays of blood-ChE activ- compounds. as it Individuals who work with or around nerve does with the acetylated enzyme. organophosphorus compounds may be said to be irreversible inhibitors of ChE. but if the alkyl groups are larger. and the enzyme remains periodically. ChE activity is still quite low. of ChE inhibitors is due to this excess endogenous ACh. also attach to the ChE enzyme. 1992. leaving the enzyme monitoring must include knowledge of physiological carbamoylated at the esteratic site. such bamate is immediately split off. This schematic ribbon diagram shows the structure of Torpedo californica acetylcholinesterase. who handle nerve agents. the neurotransmitter acetylcholine. Curr Opin Struct Biol.20 This case study and other data suggest produce biological activity by disabling (or inhibiting) that tissue function is restored at least partially when AChE. the individual is referred to the oc- 161 . esterase. recovery of the enzymatic activity in the brain seems Reproduced with permission from: Sussman JL. blood is drawn for with the ChE enzyme only at the esteratic site. the frequency of which Most organophosphorus compounds combine depends on the individuals’ jobs. enzymatic activity returns only with the synthesis of new enzyme. The resulting toxidrome is referred to as cholinergic crisis. 90% of baseline. Individuals occupationally exposed to ChE- The compounds in the two major categories of inhibiting substances are periodically monitored for AChE inhibitors. lysis occurring at this site within microseconds. Silman to occur more slowly than that in the blood ChE. In that case. baseline. 5-2. protect the enzyme from a second one. an action that leads to an accumulation of ACh. whereas the carbam- ates cause only temporary inhibition and are therefore referred to as reversible inhibitors. or toxicity. active site. docked in the After inhibition by irreversibly bound inhibitors. Nerve Agents cur in several hours if the alkyl groups of the organo- phosphorus compound are methyl or ethyl.19 I. and gold h) against the more permanently bound nerve agents and blue: a model of the natural substrate for acetylcholin.2:724. variation in the blood enzymes. There ity. Thus. green: the 537-amino acid polypeptide of the (pyridostigmine) before expected exposure to some enzyme monomer. The biological activity. To be meaningful. A moiety of the car. are averaged as a with pyridostigmine. and natural substrate ACh.18. Hydrolytic rerun. Acetylcholinesterase: Structure and use as a model for An individual severely exposed to soman.16. Functionally then. The diagram is pharmacological basis for administering a carbamate color-coded. (see below). Before the individuals begin work. Instead of hydro. specific cation-protein interactions. a second binding compound cannot attach on that site if the site is already occu- pied by a molecule. hydrolysis does not agents must have their RBC-ChE activity monitored occur for minutes to hours. two inactive or inhibited for about an hour after reacting measures of RBC-ChE. Those at risk include crop sprayers and orchard are some differences. cleavage may not occur. however. pink: the 14 aromatic residues that line nerve agents to provide partial protection (lasting 6–8 the deep aromatic gorge leading to the active site. If the activity is 90% or more the stability of the bond (ie. however. .” and he collapsed. He immediately washed his face and rinsed his mouth with water and was brought to the emergency room about 9 AM. did not change. His past medical history was noncontributory. He began to awaken in about 30 min and thereafter was awake and alert. including his discomfort. his first restful sleep since the exposure. marked oral and nasal secretions. Throughout the remainder of his hospitalization.) of prochlorperazine. and abdomen were normal. although phenothiazines have been reported to be deleterious in anticholinesterase compound poisoning. and an EKG showed atrial fibrillation with a ven- tricular rate of 90-100 beats per min. and about 5 AM (20 hr after exposure) he again vomited. . As the complications of the treatment for the physical effects subsided.m. On the second day (25 hr after exposure and about 2 hr after atropine administration). Except for tachycardia. He was asymptomatic until he arrived at the ER when. During the second evening (about 36 hr after exposure).m. 5-10 min after the accident. markedly injected conjunctiva. i. recorded that he seem depressed. was withdrawn and subdued. he was restless and had an expressionless face. Supportive care in the first 30 min consisted of oxygen by nasal catheter and frequent nasopharyngeal suction. evidence of lingering mental effects began to appear. serial 7s) than before scopolamine. Since spontaneous respiration did not cease. Diphenylhydramine hydrochloride (50 mg. His restlessness and intermittent nausea continued. i. He had miosis (1-2 mm.) promptly relieved these symptoms and signs. i. He voided small amounts several times. Bronchoconstriction and a decreased respiratory rate and amplitude were prominent.8 mg of scopolamine (orally) at bedtime and slept much better for most of the night. Edgewood. Psychiatric evaluation at the time of maximum scopolamine effect showed a slight but distinct improvement in mental status as he seemed more comfortable and performed better on several mental function tests (eg. Intravenous atropine sulfate (2 mg) was given and may have been partially responsible for his initial blood pressure of 180/80 and heart rate of 150. and hyperactive deep-tendon reflexes. presumably due to atropine. He improved throughout the day. this emesis was treated with a small dose (5 mg.Medical Aspects of Chemical Warfare EXHIBIT 5-1 CASE REPORT: ACCIDENTAL EXPOSURE OF A MAN TO LIQUID SOMAN This 33-year-old man [who worked at Edgewood Arsenal. scopolamine and methscopolamine (which does not enter the central nervous system) were admin- (Exhibit 5-1 continues) 162 .m. or 330 µg. i. . He became cyanotic and attempts to insert an endotracheal tube were unsuccessful because of trismus. Half an hour after the first he complained of transient “tingling” feelings over his body. His general condition. Migratory involuntary muscular activity (fasciculations and tremor) continued through the day. but was generally uncomfortable and restless with abdominal pain and nausea throughout the day and night. as scopolamine in this dose produces a slight decrease in intellectual functioning in normal subjects. This persisted throughout the day and evening. splashing some of the solution into and around his mouth. prominent muscular fasciculations. About 4 AM.v. torticollis. This nighttime benefit from scopolamine may have occurred because of its sedative properties. but there were no objective changes. His psychiatric condition did not improve as rapidly as his physical condition.v. Physical examination showed him to be comatose and mildly cyanotic with slightly labored respirations. admitted to antisocial thoughts. moderate trismus and nuchal rigidity. and pralidoxime chloride (2-PAMCl) was administered (2 gm over a 30 min period in an intravenous drip). [Thereafter.) as a therapeutic trial. but the improvement in mental status during the day suggested a more specific action. but his cardiac rhythm was again regular sinus the next morning. That evening he was given 1. Maryland] had been working with small amounts of soman in solution [25% (V/V) concentration. and athetoid movements. and had bad dreams. he was again given prochlorperazine (5 mg. his heart. he was catheterized because of urinary retention. he felt “the world was caving in on me.) at 10 PM and again at 2 AM. bilaterally). He vomited twice more between 7:30-8 AM (22-23 hr post exposure) and was again given atropine (4 mg. A psychiatrist . Atropine (4 mg. At 11 AM the next morning. the patient’s physical condition improved although he was treated with sulfisoxazole for three weeks for a urinary tract infection that developed after catheterization. Several EKGs recorded on admission and during the first day showed sinus tachycardia. Because the previous atropine had apparently caused urinary retention. After the second he rested comfortably and slept soundly for 3-4 hr. which are characteristic of the extrapyramidal side effects of a phenothiazine. After the initial therapy his cyanosis cleared and his blood pressure and heart rate remained stable. Because of the occurrences of urinary retention and arrhythmia. but catheterization was necessary several hours later. as he later said. a tracheostomy was not performed. i. lungs. the former was more responsive to atropine therapy. who saw the subject frequently. total volume <1 mL] when a syringe-needle connection broke. On the third day [after the exposure] the patient was given scopolamine hydrobromide (5 µg/kg. slept restlessly and fitfully. . he again became nauseated and had recurrent vomiting. his cardiac rhythm was irregular. Within a minute after he collapsed (about 10 min after exposure) he was given intravenous atropine sulfate and in the ensuing 15 min he received a total of 4 mg intravenously and 8 mg intramuscularly.m.). i.) was required again at 11 PM (14-hr post exposure) after several episodes of vomiting. creatinine. calcium. in their work area. made several major errors. Hematocrit. blood urea nitrogen. responses that in the examiner’s opinion were not consistent with his IQ. they are not permitted to return to specific instances: (1) as a screen for exposure to a a work area around nerve agents until their RBC-ChE ChE inhibitor. 4 months. About a week later. white blood cell count.23 the canine ventricular con- of RBC-ChE activity. prothrombin time. if the depression in RBC-ChE activity is related to In training responders to deal with acute nerve exposure to ChE-inhibiting substances. 1974. alkaline phosphatase. prov- erbs. phosphorus. Nerve Agents Exhibit 5-1 continued istered on randomly assigned days. The patient did better mentally (by examination) and on a written arithmetic test after receiving scopolamine than after methscopolamine. and indicated full use of his intellectual facilities. the worker is the use of laboratory diagnosis of ChE activity. and (c)the lower tolerance to ducting system. and carbon dioxide were all within normal limits the day of admission and on repeated measurements during his hospitalization. This contrasts with the paradoxical improvement in mental status seen earlier. The results of his later tests were faster. RBC-ChE activity is immediately measured and the criteria noted above. He did poorly on a visual retention task (the object of which was to remember and then reproduce a simple drawing) on first testing as he attempted to improve already correct drawings. If RBC-ChE agent poisoning. which are the findings in normal subjects.] There was no detectable RBC-ChE until about the tenth day after exposure. On the other hand. hemoglobin. Its physiological role in humans (a) the normal variation of RBC-ChE in an individual is unclear22. serum glutamic oxaloacetic transaminase.7:1–17.” A battery of standard psychological tests was given the subject 16 days.25 nerve agents with a low RBC-ChE as demonstrated BuChE is synthesized in the liver and has a replace- 163 . Apparently neither the RBC nor plasma ChE was significantly reactivated by the initial oxime therapy. chloride. Investigations are undertaken to discover immediate treatment. the psychiatrist noted that “he is probably close to his premorbid level intellectually and there is no evidence of any serious mood or thinking disorder.m. When last seen. Reproduced with permission from Sidell FR. (b) laboratory reproducibility in analysis tracheal smooth muscle. . Soman and sarin: clinical manifestations and treatment of accidental poisoning by organophosphates. Clin Toxicol. and (2) as a way to follow exposed patients as exposure or if an accident is known to have occurred they recover over time. laboratory how the worker was exposed. little emphasis should be given to is depressed to 75% or below baseline. i. which reflects the rapid irreversible phosphorylation and hence refractoriness of the soman-inhibited enzyme to reactivation by oxime. bilirubin. Although workers may values in patients are particularly helpful in two be asymptomatic. The values of 75% and 90% were The enzyme BuChE is present in blood and selected for several reasons. it may be important in canine with time. however. . He scored well on the Wechsler-Bellevue IQ test with a slight increase in score on the arithmetic section at the later testings. including a 25-30% reduction in NF [Number Facility] scores. Time considered to have had an exposure and is withdrawn does not permit using this determination to guide from work.21 If personnel who may have been exposed to a nerve workers have symptoms from a possible nerve agent agent. On word association.) and had a decrement in mental function- ing. had difficulty generating verbal associations. and showed poor motor control. are used for exclusion from and return to work. imaginative. and the ink blot he was slow and sometimes used delaying tactics.24 and rat atria. including the following: throughout tissue. . his later tests were normal. and 6 months after the accident. He had high Hs (hypo- chondriasis) and Hy (hysteria) scales on the Minnesota Multiphasic Personality Inventory (MMPI) on the early test and their later improvement indicated to the examiner that he had a decreased concern about bodily function. as well as Butyrylcholinesterase signs and symptoms. potassium. and failed the harder proverbs. sodium. the subject again received scopolamine (5 mg/kg. as in agricultural workers or military activity is higher than 90% of their baseline activity. About five weeks after his admission. the patient was doing well. six months after his exposure. cupational health physician for review to determine in animals (see below). the The relationship of BuChE activity and succinyl. such inhibit both enzymes. The RBC-ChE appears stroma of) the erythrocyte is unknown. and chronic debilitating diseases. about 50% over 1 year.38 a small dose of DFP at a rate of approximately 1% per day. There is little inhibition of tissue enzyme activity.37.32 BuChE activities in men have been reported addition to having the low BuChE activity in the usual in some studies to increase with age and in other assay (as a result of this genetic abnormality).26 There are over 20 vari- ants of the abnormal BuChE phenotype.22 The structure of BuChE is de. with abnormal ChE have low dibucaine numbers (the BuChE activity was higher in men than in women. with a less marked increase through the fifth decade in women. the ranges (the difference between the highest and termined by two autosomal alleles.9% in women. as recovery from pernicious anemia. a muscle relaxant. This variation 3 times higher than normal. and that for the homozygous Erythrocyte Cholinesterase abnormal phenotype is 16%.20 In matched age groups. The blood enzymes appear to act as effective cytes have higher ChE activity than do mature cells. and is Butyrylcholinesterase increased in the nephrotic syndrome.30 lasting 3 to 250 weeks.35.22 but one report28 describes three members of until much of the blood enzyme is inhibited because. the lowest was 24% and the highest was is about 1 in 2. because reticulo.30 96% of the population have the usual phenotype. scavengers of nerve agents while they remain in the No other disease states are known to affect RBC-ChE circulation. His sister and daughter also It is unclear whether age affects RBC-ChE activity. close BuChE activity does not vary with age in women31.22 In are seen. respiratory tract. The author of this report In one study. of BuChE. gesting that differences in this enzyme are genetic. with the exception of local tissue effects (eg. with ranges of 7.Medical Aspects of Chemical Warfare ment time of about 50 days.30 enzyme activity in an assay in which dibucaine is used and higher in women not taking oral contraceptives as the ChE substrate). coefficients of variation were 2.32 enzyme activity increased and that it represents another genetic abnormality with age from the third to the sixth decades in men. acute infections. had high BuChE activities. in humans inhibited about 90% of the plasma enzyme 164 . One author27 3. low dibucaine numbers.1% in women. mal- nutrition. The activity of Some ChE-inhibiting substances inhibit BuChE this enzyme is decreased in certain diseases involv. and he was found to be relatively resis. skin contact).5% in men and choline can be somewhat different.0% to 15. such as pernicious anemia. His dibucaine number was less than that observed for the hematocrits of was normal.32–34 for the normal phenotype is about 79%. usually have ranged from 5% to 11.36 In a study30 that lasted 1 year. but In longitudinal studies29. the blood is the first The physiological role of the enzyme in (or on the tissue to encounter the agent. or in this regard.1% to 4. Of low BuChE activity.000 people.30.8% in both men and women. which has an average life of 120 days. Erythrocyte Cholinesterase Inhibition of Blood Cholinesterases RBC-ChE is synthesized with the erythrocyte.9% to 11. In two studies. Large amounts of ChE inhibitors will completely increased during periods of active reticulocytosis.03% have the homozygous abnormal phenotype. eye.4% reports on an individual whose BuChE activity was in men and 12. Thus. the coefficient of variation (standard deviation di- People who have a prolonged paralysis caused vided by the mean) for an individual’s BuChE activity by succinylcholine. The frequency of lowest activities divided by the mean) for individuals occurrence of the gene responsible for abnormal ChE in the study. Its activity is decreased Variation in Cholinesterase Activities in parenchymal liver disease. and is tially.32 to 4% have the heterozygous phenotype. while in another. that for the heterozygote is 62%. people studies to decrease with age. may assist in hydrolyzing certain choline esters. and about until the age of 60 years. each with RBC-ChE activity is more stable than the activity different. The mean dibucaine number than in those taking them.1% to 3. sug.20. preferentially. when higher BuChE activities 0. one family who had decreased RBC-ChE activity. of the BuChE. these individuals. and some inhibit RBC-ChE preferen- ing erythrocytes. including zero.31 RBC-ChE activity was unchanged with suggests that this abnormality is autosomal dominant age. Recovery of to correlate more closely with tissue ChE and physi- RBC-ChE activity after irreversible inhibition takes ological signs of poisoning than the plasma enzyme place only with the synthesis of new erythrocytes. tant to succinylcholine.000 to 1 in 4.22 This enzyme has no known physiological function in blood. 4 hours In animals. or forearm at environmental temperatures ranging Symptoms correlated with depression of RBC-ChE.46 In humans.44 airways caused by small amounts of vapor are due to the direct effect of the vapor on the organ.45 while BuChE was Inhalation of nerve agent vapor inhibits blood ChE inhibited by 30% to 50%. Although nerve agent exposure than does estimation of the there is no correlation between ChE activity and clini- plasma enzyme activity. gest that agent absorption through the skin is more whereas the activity of BuChE was inhibited by no rapid and complete at higher temperatures. When the blood enzymes have been irreversibly both clinical effects and ChE inhibition occur within inhibited. and that more than 20%. minutes. and inhi. In one study. After occur in about 50 days. such as vomiting. in two studies. and recovery of the RBC. had physical signs or definite symptoms (or both) of However.22 agent penetration and of decline in RBC-ChE activity The nerve agent VX preferentially inhibits RBC. in 120 days (about 1% per day). but complete recovery The local signs and symptoms in the eye. Hence.2 hours after exposure because parathion preferentially inhibits RBC-ChE in at 0°F. the onset of ChE activity (Table 5-1). no vomiting occurred in age time from placing VX on the skin to the onset of 30 subjects whose minimal RBC-ChE activities were nausea and vomiting and maximal drop of blood ChE 40% of control or higher.43. In decontaminated and taken to a recovery area (about humans. the time to maximal inhibition was 5 hours in half the population when the RBC-ChE is inhibited for the head and neck.6 hours after exposure and mevinphos. nose.43.5% to 1% per hour for a few days. Early experi- After very large amounts of nerve agent (multiple mental data49–51 indicating the lack of correlation were LD50s [ie. amount of agent remains in the skin. and maxi- the plasma enzyme. 10.22 also preferentially inhibit continued to decline after decontamination.5 hours after exposure at 68°F. ity was observed in two studies. multiples of the dose that is lethal to 50% supported by a retrospective analysis of 62 individuals of the exposed population]) are placed on the skin. increased after the subjects were taken from the cold ChE. Sarin also preferentially inhibits the even after thorough decontamination. and 12. 39–41 80°F). Vomiting occurred in 9 (43%) activity was 10.8 hours. 7 hours for the extremities. 8. such as dimefox41 mal inhibition occurred at 5. in 10 (71%) of 14 subjects whose 165 . estimation of the activity and produces signs and symptoms of expo- RBC-ChE activity provides a better indicator of acute sure more rapidly than does dermal contact. ChE. while others. cal effects after exposure to small amounts of vapor. complete recovery of BuChE symptoms occurred about 1 hour after intravenous activity that has been totally inhibited by sarin will (IV) administration of small amounts of VX. 80% to 100% inhibition of RBC-ChE activ. there appears to be a species difference after exposure at 36°F. Although all individuals bition of blood ChE activities occurs equally quickly. the RBC-ChE activity systox. the onset nerve agent vapor exposure. and depends on erythrocyte production. some pesticides. with smaller amounts of agent. recovery of ChE activity depends on pro.44 a small amount caused a 70% environment and decontaminated. These results sug- or greater decrease in the activity of this enzyme. tion between 1948 and 1972. after inhibition by VX. In all temperature groups.43. At the two lowest temperatures. there was no correlation is not so rapid. Nerve Agents activity but only 15% to 20% of RBC-ChE activity.37. ingestion of VX. and to 25% of its control activity.42 initially bind with the RBC enzyme. and signs can both be present with normal blood tion of the agent. and 3 hours later the subjects were but not with depression of BuChE (see below).44 In a study44 in which 10 hours for the torso. In one study44 in which equipotent ChE levels.53 amounts of VX were applied to the skin in different Minimal systemic effects. VX was placed on the skin.39 and malathion. Therefore. at 124°F.52 More recently. of 21 subjects whose minimal RBC-ChE activities were In a third study. In a similar study. from 0°F to 124°F. a considerable RBC-ChE.47 the aver. such as parathion. In studies in which small amounts of between local effects from vapor exposure and RBC- VX were applied on the skin of humans. There Time Course of Inhibition appears to be no correlation between the severity of these effects and the blood ChE activity.48 VX was applied to the cheek 30% to 39% of control. clinical data symptoms and the maximal inhibition of blood ChE from the Tokyo incident has shown that symptoms activity were found to occur many hours after applica. seen at the Edgewood Arsenal Toxic Exposure Aid Sta- signs and symptoms occur within minutes. occur regions. the rates of rats and the plasma enzyme in dogs. the RBC-ChE activity seems Relation to Signs and Symptoms to recover spontaneously at the rate of about 0.43 both the maximal inhibition duction of new plasma enzymes or production of new of RBC-ChE activity and the appearance of signs and erythrocytes. the interval was 2 to 3 hours. In: Somani SM. Molecular models of (a) Tabun (GA).”14(p446) Miosis alone (bilateral) 22 0–100 Nerve Agents Miosis alone (unilateral) 7 3–100 Miosis and tight chest 12 28–100 Molecular models of the nerve agents tabun.27:241–252. ed. which indicate that “to exert Affected ChE Activity (N=62) (% of Baseline*) significant actions in vivo. In other instances. 1974. (2) Sim VM. The degree of inhibition needed to cause vomiting in these 283 people corresponds to that found in experimental Effect Patients Range of RBC- data from other sources. and in 3 (60%) of 5 subjects whose minimal RBC-ChE activities were 0% to 19% of control. Clinical considerations in nerve agent intoxi- cation. Md. Chemical Warfare Agents. rhinorrhea. Researcher. Data sources: (1) Sidell FR. Calif: Academic Press.3 20–29 42 19 45. and 9 20–92 cal. Toxicol Appl Pharmacol. sarin.6 40–49 24 2 8.Medical Aspects of Chemical Warfare TABLE 5-1 the authors observed that patients had an RBC-ChE activity of 0% without the expected symptoms. Variability of Different Intact Human (c) Soman (GD). an anti-ChE must inhibit from 50% to 90% of the enzyme present. Chemical Research and Development US Army Medical Research Institute of Chemical Defense. The reactivatibility of cholin- Fig. Edgewood Arsenal. Aberdeen Proving Ground. POSURE TO ERYTHROCYTE CHOLINES Data from 283 individuals who received VX by TERASE ACTIVITY various routes are categorized below (Table 5-2). 1992: 163.7 *Cholinesterase activity before nerve agent exposure RBC-ChE: red blood cell cholinesterase. physical. Groff WA. esterase inhibited by VX and sarin in man. inhibition was acutely induced. Nerve agents differ from commonly used ChE inhibitors Rhinorrhea and tight chest 3 89–90 *Cholinesterase activity before nerve agent exposure. a b Data source: Sidell RF. TABLE 5-2 RELATION OF CHOLINESTERASE ACTIVITY TO VOMITING AFTER EXPOSURE TO VX c Minimum Patients Patients Percentage RBC-ChE (N=283) Vomiting Vomiting (% of Base- line*) > 50 166 1 0. this RELATION OF EFFECTS OF NERVE AGENT EX. 1962. and VX are shown in Figure 5-3. Miosis and rhinorrhea 9 5–90 soman. 5-3. (d) VX. Laboratory Report 3122. Md: Medical Molecular models: Courtesy of Office E Clark. The chemi- Miosis.2 d < 20 24 16 66. 166 . and environmental properties of these tight chest compounds are summarized in Table 5-3.3 30–39 27 9 33. minimal enzyme activities were 20% to 29% of control. Skin Sites to the Penetration of VX. (b) Sarin (GB). RBC-CHE: red blood cell cholinesterase. Research Laboratory. San Diego. 86 6. VR. M9 papers M8. a smaller The nerve agents are liquid at moderate tempera- amount is needed to cause an effect on an organism). air = 1) Liquid 1.4°C In other solvents Soluble in most or. ICAD ICAD CAM. brain. diluted hy. ICAD Liquid M8. M8A1.0007 mm Hg at 20°C Density Vapor (compared to 5. soap and water.037mm Hg at 20°C 2.6 4. at least in erythrocytes. DFP. M256A1.8 g/100 g at 25°C Miscible 2. M9 papers M8. cyclosarin. M256A1.02 g/mL at 25°C 1. 167 . M8A1. 30 has been reported to have a faint. M258A1. CAM.1 mm Hg at 20°C 0.2 air.40 mm Hg at 20°C 0. In their For example. they are clear. soap and pochlorite.08 g/mL at 25°C 1. Soluble in all solvents Soluble in some sol. ICAD CAM. M291 kit CAM: chemical agent monitor ICAD: individual chemical agent detector LCt50: vapor or aerosol exposure necessary to cause death in 50% of the population exposed LD50: dose necessary to cause death in 50% of the population with skin exposure M8A1: chemical alarm system M256A1: detection card M258A1: self-decontamination kit M291: decontamination kit M8 and M9: chemical detection papers primarily because they are more toxic (ie. tasteless. Tabun about 10 times more inhibitory activity than TEPP. M9 papers M8. M291 kit water.008 g/mL at 20°C Volatility 610 mg/m at 25°C 3 22. Nerve Agents TABLE 5-3 CHEMICAL.1 g/100 g at 20°C Miscible < 9. M8A1. tures (the term “nerve gas” is a misnomer). M258A1. and 1. oil of camphor Odorless Solubility In water 9. M256A1.000 mg/m at 25°C 3 3. and soman.000 times more than parathion. and muscle showed that sarin had dilute solutions of distilled water. soap and pochlorite. and VX are apparently odorless. to have an ill-defined odor.900 mg/m at 25°C 3 10. colorless. AND ENVIRONMENTAL PROPERTIES OF NERVE AGENTS Properties Tabun (GA) Sarin (GB) Soman (GD) VX Chemical and Physical Boiling point 230°C 158°C 198°C 298°C Vapor pressure 0. 100 times more than odor. M291 kit water. diluted hy. PHYSICAL. and. Soluble in all solvents ganic solvents vents Environmental and Biological Detectability Vapor M8A1. diluted hy- skin pochlorite. diluted hy.10 g/mL at 20°C 1. M258A1.5 mg/m3 at 25°C Appearance Colorless to brown Colorless liquid Colorless liquid Colorless to straw- liquid colored liquid Odor Fruity Odorless Fruity.3 9. an in vitro study45 with ChE from human pure state.5 days 2–24 hours at 5°C–25. Relatively persistent 2–6 days °C On materiel Unknown Unknown Unknown Persistent Decontamination of M258A1. sarin. M9 papers Persistency In soil Half-life 1–1. M291 kit water. CAM. soap and pochlorite. slightly fruity times more than neostigmine. M256A1. cause death in 50% of the population ex- the casualties were unconscious within less than a posed (L denotes lethal. both were unconscious term LD50 is used to denote the dose that is and exhibited convulsive jerking motions of the lethal for 50% of the population exposed by limbs. The G agents present a definite as the other agents. eye. in both cases). an organism. liquid exposure. copious secretions from the mouth and nose. and may not remember them on awakening. a combination of dose. because an organism may hold its to report the initial effects before losing conscious. nose. Exhibit 5-2). The Ct to pro- absence of physical findings. but that may have been due to impu. The casualty will complain of mild-to-severe 100 minutes is also produced by an exposure dyspnea. the most volatile. 2004 reported to the authors that the agent smelled The G agents are volatile. or a combination are usually affected. while VR has unless the ambient temperature is high.05 mg/m3 for seen. VX and VR are much less likely vaporize intermediate between sarin and tabun. LCt50 AND LD50 in seconds to minutes after the onset of exposure. inhale the vapor. volatile than water. the expressed in minutes). airways. cyclosarin. and another said he felt giddy and vapor or aerosol exposure (Ct) necessary to faint before losing consciousness. tion (C) to which an organism is exposed ated conjunctival injection and pain) with or without multiplied by the time (t) during which it remains exposed to that concentration. eyes may be affected equally or unequally. it is not an inhalational As exposure increases slightly. duce a given biological effect is usually con- the effects in these organs intensify. Thus. When reached of the population). At higher exposures. In both instances. labored.Medical Aspects of Chemical Warfare One of the US soldiers exposed to sarin in Iraq in the same level of toxicity as VX. possibly in the varying the values of C and t. Sarin. an effect that is of moderate-to-severe impairment of ventilation are produced by an exposure to 0. generalized 168 . VX and VR have very low like garbage. a par- casualty may or may not notice dim vision and may ticular value can be produced by inversely complain of tightness in the chest. thus. There is no delay in onset as there is after amount of compound to which an organism is exposed. the casualty may not have time however. irregular. In animal tests GF has a toxicity vapor hazard. At low Ct values (the concentration to which an • Ct is used to describe an estimate of dose. as mg/m3). to 5 mg/m3 for 1 minute (Ct = 5 mg/min/m3 ous secretions. Marked miosis. and signs hours (Haber’s law). There may • The Ct value is the product of the concentra- be some degree of miosis (with or without associ. a dose of a vapor or aerosol. and t represents time (usually The eyes and nose are the most sensitive organs. These effects usually reach maximal severity within minutes after The terms Ct and LCt50 are often used to express the individual is removed or protected from the va. EXPOSURE ROUTES Inhalational Exposure to Vapor EXHIBIT 5-2 The effects produced by nerve agent vapor begin DEFINITIONS OF Ct. the (within minutes) by rescuers. they refer to the continues. the terms por. This generalization is usually invalid for very short or very long times. breath for several seconds and not actually ness. Ct rhinorrhea. volatility. and 50 denotes 50% minute after exposure to agent vapor. and lung involvement is usually seen. In the same manner. other routes of administration. or there may be rhinorrhea without eye does not express the amount retained within involvement (Table 5-4). de- pending on the concentration of vapor. and will have obvi. and gasping breathing. or some detoxification may One severely exposed individual later recalled to the occur over many hours. and soman are Cyclosarin (GF) and VR are not as well studied less volatile than sarin. is somewhat less rities. (as vapor or aerosol) in air (usually expressed nose. tabun. but they may continue to worsen if the exposure do not describe inhaled doses. The • Because Ct is a product of C times t. may be gasping for air. C organism is exposed to a substance times the amount represents the concentration of the substance of time the organism is exposed. the eyes. authors that he noticed an increase in secretions and • The term LCt50 is often used to denote the difficulty breathing. In severe exposures. stant over an interval of minutes to several copious secretions from the nose and mouth. However. Unless the amount of the nerve agent is in the was a 15-minute to 20-minute asymptomatic interval lethal range.48 • Miosis and respiratory involvement are al- After large exposures. One developed Loss of consciousness flaccid paralysis and apnea a minute or two later. the time to onset of effects most invariant with inhalational exposure. vigorous treatment. rhinorrhea. tions. Increased sweating at the site of consciousness. rhinorrhea. may be much shorter than for smaller exposures and but may be delayed or even absent in dermal 169 . convulsive muscular jerks. Nerve Agents TABLE 5-4 TABLE 5-5 EFFECTS OF EXPOSURE TO NERVE AGENT EFFECTS OF DERMAL EXPOSURE TO LIQUID VAPOR NERVE AGENTS Amount of Exposure Effects* Level of Exposure Effects Small (local effects) Miosis. fascicula- or are not noticed) are gastrointestinal: nausea. complain of tiredness or otherwise feeling ill. and miosis. secretions (slight dyspnea) Effects may be pre. vom. Within several minutes. Increased sweating at the site cipitant in onset after Muscular fasciculations at site Moderate (local ef. there are local. slight broncho. such as the site on the body. Mild constriction. secretions (moder. an asymptomatic Nausea tions. hours Generalized weakness tion possible with seizures Severe *Onset of effects occurs within seconds to several minutes after exposure onset. For in- site of the droplet. before the precipitant onset of effects: collapse. localized sweating occurs at the decreases as the amount of agent increases. flaccid paralysis. Increased sweating at the site cipitant in onset after Muscular fasciculations at site a 2–30 minutes as. After a delay during which the individual is asymptomatic. rhinorrhea. loss of fects. interval of up to 18 ate to marked dyspnea) hours Large Miosis. the authors observed The casualty may notice generalized sweating and flaccid paralysis and apnea in both individuals. convulsions cipitant in onset after Muscular fasciculations at site (seizures). The Convulsions (seizures) other received immediate. if the sweating and fasciculations do not occur consciousness. generalized fascicula. Flaccid paralysis Apnea Dermal Exposure to Liquid Generalized secretions Involuntary micturition/defeca- The early effects of a drop of nerve agent on the tion possible with seizures skin and the time of onset of these effects depend on the amount of nerve agent and several other factors. the temperature. Miosis. slight broncho. apnea. tions. There 5-5). and the humidity. slight broncho- Moderate constriction. stance. the next effects (or perhaps the first ef. secretions (moder- ate to marked dyspnea). Nausea ymptomatic interval Diarrhea Generalized weakness muscular fasciculations. two individuals were decontaminated within ized fasciculations of the underlying muscle (Table minutes of exposure to a drop of nerve agent. and his Generalized fasciculations condition did not progress. diarrhea. respiratory embarrassment. Less commonly. and copious secre- iting. There The major clinical differences between the inha- may be a period of many hours between exposure lational and dermal routes of exposure are the fol- and the appearance of symptoms and signs. loss Effects may be pre. or a combination of these symptoms. interval of up to 18 Diarrhea involuntary micturition/defeca. an asymptomatic fects) constriction. These lowing: symptoms and signs may occur even if the casualty has been decontaminated. Effects may be pre. com- blurred vision (or both). These effects are usually Skin and sweat Sweating local. EFFECTS ON ORGANS AND ORGAN SYSTEMS Most of the information on the effects of nerve agents cause miosis in that eye (a local effect because of a on organ systems in humans is derived from studies mask leak in one eyepiece or similar causes) without done in the post–World War II period. severe cases had miosis. pain in or around the eye. but exposure by Muscular Fasciculations (“rippling”). The Japa- Mouth Salivation nese terrorist and Iranian battlefield clinical experience is summarized in a later section of this chapter. vomiting. posure. flaccid paralysis. Pulmonary tract Bronchoconstriction and secretions. and dim or tract nausea. Cardiovascular Decrease or increase in heart rate. all of the 14 to weeks) of any exposure: forgetful- ness. preparations for the musculoskeletal system. cough. Acute effects of mild or moderate ing. may subsequently worsen as agent becomes toms will be far faster in inhalational expo. Because eyes often react late in the course of groups. but study conjunctival injection. diarrhea. tival injection. a feeling moderate poisoning and only 5 of 22 patients with of tenseness or uneasiness. depres- mild effects had miosis. of twitching. The two terrorist attacks using sarin in Japan in or blurred vision 1994 and 1995 have provided a fund of new human Nose Rhinorrhea clinical data. local or other routes (such as on the skin) can also affect the generalized. conjunc. convulsion (or erate symptoms (nausea. system of consciousness. inhalational exposure. diffi- or aerosol exposure might cause miosis without other culty with expression signs or symptoms and an exposure in one eye will 170 . complaints of dim tion. rales. vomiting) without miosis. wheezing. For example. pain may accompany eye exposure. a signifi. weakness they cannot be relied on as an early indication of ex.54 On the other hand. insomnia. or storage areas or depots (Table 5-6). but this data is all uncontrolled. irritability. and/or rhonchi on exam Nerve agents in the eye may cause miosis. usually increase in blood pressure Systemic (such as skin or perioral) exposure to a Central nervous Acute effects of severe exposure: loss nerve agent might be large enough to produce mod. Some organ systems have been studied more intensively than Organ or System Effect others. The Eye shortness of breath. around the eye.Medical Aspects of Chemical Warfare exposure. aerosol. or given orally. manufacturing EFFECTS OF NERVE AGENTS IN HUMANS facilities. or weakness. available systemically. Gastrointestinal Increase in secretions and motility. Reflex nausea and vomiting plaints of abdominal cramps. complaints of tight chest. nightmares. pain in or results are difficult to apply to a human clinical situa. depression of respiratory center to administered intravenously. from reports of people exposed to pesticides. or from clinical evalua- tions of accidental exposures of people who worked TABLE 5-6 in nerve agent research laboratories.44. whereas 6 of 11 patients with decreased comprehension. or liquid. produce apnea cant number of subjects experienced nausea. but none had miosis. Exposure to nerve agent liquid through a wound and consequently patients who are treated for will likely produce effects intermediately. a vapor sion. This is not likely with sure. nerve agent symptoms after dermal exposure • The speed of onset and progression of symp. impaired judgment. • Decontamination of dermal exposure may not occur before agent has penetrated the skin. In exposure or lingering effects (days 47 patients with parathion poisoning.47 in which VX was placed on the skin. sweating. occurring when the eye is in direct contact with glands nerve agent vapor. In studies43. twitching of muscle eyes. vomit. seizures after muscular paralysis). complaints intoxication in the latter case (exposure on the skin). there is a plethora of data from animal studies and studies in isolated neuromuscular Eye Miosis (unilateral or bilateral). This impairment may cause difficulty in activities such as driving a car or piloting an airplane. This man was accidentally exposed to an unknown stereo effect). which exposed to nerve agent vapor is generally ascribed to suggests that factors other than a small pupil are miosis. The series of photographs Miosis may begin within seconds to minutes of the shows his eyes gradually recovering their ability to dilate. study. If the eye exposure is not associated with inhalation of the nerve agent. no change in visual threshold was blurred vision.22 amount of nerve agent vapor.58 In another discussed above and may complain of dim vision. 13. In a study57 in which miosis was after administration of atropine methyl-nitrate (which induced in one eye by instillation of sarin.59 however. RBC-ChE activity. but their ability to dilate maximally in total darkness Reproduced with permission from: Sidell FR. an early study52 demonstrated a relationship between the Ct of sarin and pupil size at the time of maximal miosis. accidentally exposed to G agents reported improve. The unilateral miosis has no prognostic medical significance.60 The authors suggested that in visual sensitivity correlated with the reduction in the dimness of vision was due to neural mechanisms the area of pupillary aperture.7:11 The effects of nerve agents on vision have been stud- ied for decades. then. The pupils after the exposure. may be relatively normal or may be inhibited by as much as 100% (see Table 5-1). On the other hand. which require stereo-visual coordination (the Pulfrich Fig. 5-4. the RBC-ChE may or may not be inhibited (see Table 5-1). however. there may be problems with judging distances (depth perception).55 poisoning by organophosphates. The light threshold increased after Light Reduction systemic administration of sarin vapor with the eyes protected so that miosis did not occur. Nerve Agents affecting the other eye. if the concentration of agent vapor is too fast for the pupil to react) after the subject had been sit- or aerosol is low. miosis is the most likely symptom to persist after all systemic effects of nerve agent have resolved. Soman and may not return for as long as 9 weeks (Figure 5-4 and sarin: clinical manifestations and treatment of accidental Exhibit 5-3). 41. 6.52 Unilateral miosis is sometimes seen in workers handling nerve agents or insecticides and usually occurs because of a small leak in the eyepiece of the protective mask. 1974. For the same reason. and 62 days varies according to the amount of agent. dilation was reached on day 62 after the exposure. there is no good correlation between severity of the miosis and inhibition of RBC-ChE activ- ity. an unprotected individual exposed to nerve agent will have the signs responsible for the high light threshold. 20. the decrease does not enter the CNS). Again. so the severity of the miosis cannot be used as an index of the amount of systemic absorption of agent or amount of exposure. measured after miosis was induced by instillation of sarin onto the eye. The duration were taken (from top to bottom) at 3. The threshold Dim vision is generally believed to be related to was reduced to normal following systemic administra- the decrease in the amount of light reaching the retina tion of atropine sulfate (which enters the CNS). Although the dim vision reported by individuals ments in dim vision before miosis improved.20. maximal miosis may not occur until ting in a totally dark room for 2 minutes. Clin Toxicol.56 Characteristically. These photographs an hour or longer following exposure. Subsequent photographs indicate that the may regain their ability to react to normal levels of eyes did not respond fully to darkness for 9 weeks. Fifty-three subjects in the retina or elsewhere in the CNS. and the investigator suggested that the pupil size might be used as an index of the amount of exposure. maximal indoor lighting within several days after exposure. the above accounts suggest that central neural 171 . All photographs were taken with an electronic flash (which start of exposure. or both. but not because of miosis. took two months. Rhinorrhea is common after both local and systemic muscular (IM) administration of the drug has been nerve agent exposure. At the onset of symptoms they were working in a large room in which some containers of complain of blurred as well as dim vision. unilateral) may occur in the frontal area or throughout but the patients were not dark adapted. but because these drugs cause blurring of vision. that miosis accounted for the improvement improve and at the time of discharge from the ward in visual acuity (the pinhole effect). Two presbyopic workers who were accidentally All three patients reported that their respiratory exposed to sarin had improved visual acuity for days distress had decreased since its onset about 20 min after exposure. or drive a tank in CASE REPORT: EXPOSURE OF THREE MEN the evening. and vomiting). or it may occur in the absence Regardless of its cause. Far visual acuity was unchanged distress. reduction in visual sensitiv.62 mechanisms may have equal or greater importance. as others have no therapy was administered. They continued to previously. they should not be used unless the pain is severe. The first photographs were taken the day of the exposure. Although there were other work. ing pain in or around the eyeball is common. of miosis. a moderate increase in salivation. On each visit the head. marked miosis and slight eye pain. It may occur soon after exposure reported. and malaise. 50. who nonetheless complained wheezes and rhonchi throughout all lung fields. Visual Acuity were brought to the emergency room because of sudden onset of rhinorrhea and slight respiratory Individuals exposed to nerve agents sometimes discomfort. usually brings relief from Reproduced with permission from: Sidell FR. Maryland]. and 52 years. The men their vision returned to its previous state. they were asymptomatic except for a slight irritation in the eyes and decreased vision in dim light. 1974. . Even a relatively small exposure to vapor 172 . Anyone whose vision has been affected TO SARIN by exposure to a nerve agent should not be allowed to drive in dim light or in darkness. About 60-70% of the lost ability to dark (the “match test”). A sharp pain in the eyeball or an ach- tivities (both erythrocyte cholinesterase and butyryl. Clin Toxicol. A mild choline esterase)] were measured . . .7:1–17. Local instillation of an anticholinergic drug. No that distant vision was blurred after sarin. Three men [who worked at Edgewood Arsenal. monitor visual displays from a computer. after sarin exposure in five of the six subjects and was rhea.62 visual acuity was examined in six subjects ers in the room. and scattered improved in the sixth. In The Nose the case of the carbamate physostigmine. but about 35 days. any of the subjects after exposure and was worsened On examination all three patients had essentially the after an anticholinergic drug (cyclopentolate) was same signs and symptoms: very mild respiratory instilled in the eyes. As the effects of the agent decreased. an increase in light sensitivity (a decreased threshold) after intra.61 Carbamates may differ from nerve agents to a small amount of vapor and sometimes precedes in their effects on vision. and photographs or even severe headache (unilateral if the miosis is were taken of their eyes [see Figure 5-4]. vomiting. Soman and sarin: clinical manifestations and treatment of accidental the pain and systemic effects (including the nausea poisoning by organophosphates. Edgewood. such as the after the man had been in a completely dark room light from a match a person uses to light a cigarette for 2 min. but the reported time they were seen. but complete recovery companied by nausea. their [blood cholinesterase ac. the three patients were together at before and after exposure to sarin vapor at a Ct of 15 one end where a leak was later found in one of the mg/min/m3. . Eye Pain The patients were seen the next day and at frequent intervals thereafter for a period of four months. EXHIBIT 5-3 individuals who watch a tracking screen. study. In one sarin were stored. such as atropine or homatropine. Sometimes this discomfort is ac- adapt returned in two weeks. Each Eye pain may accompany miosis.55 The author suggested. ages 27. before they arrived at the emergency room. rhinor. other abnormal findings were noted. . Near visual acuity was not changed in containers. incidence varies. This pain is probably caused by ciliary spasm thereafter a photograph was taken by electronic flash and is worsened by looking at bright light. which took were kept under observation for the next 6 hr. miosis and dim vision.Medical Aspects of Chemical Warfare ity impairs those who depend on vision in dim light. Differences in circulatory and respiratory effects and observable signs of difficulty with air exchange.65 The authors of another report68 suggest that the pres- Although these studies yielded conflicting results. under this about 15 to 20 minutes after exposure and report that circumstance. cedes circulatory system collapse.69 bronchoconstriction seen in the exposures (5–10 mg/min/m3) and intensify as the dog after IV sarin administration was quite severe Ct increases. are trained to focus on respiratory status as the most A severely poisoned casualty becomes apneic and important parameter of the effectiveness of treatment will die as a result of ventilatory failure. pulmo. If the amount inhaled is airway musculature. min/m3 will produce some respiratory discomfort in Older data on the relative contributions of each of most individuals. A nerve agent report66 mentions thick mucoid plugs that hampered death is almost always a pulmonary death. and may feel a cold or hay fever. central ap. and its type and depth of nerve agent vapor or aerosol causes dyspnea and are also factors in establishing the relative importance pulmonary changes that are usually audible on aus. failure of the central to small amounts of sarin vapor (the Ct values for respiratory drive appeared to be the major factor in sarin ranged up to 19. ence of anesthesia. which may explain that find- large. in most formation of this thicker mucus because it dries out cases. becomes a secondary concern to both the their initial. removed by suction. and another told the authors that the alty may begin to feel better within minutes after mov- secretions were much worse than those produced by ing into an uncontaminated atmosphere. investigators attempted to authors of the report concluded that central respira- characterize pulmonary impairment caused by expo. tory failure appeared to dominate in most species. probably the most important component of the bronchiolar musculature and by secretions. a combination of all of these. decreased markedly. how- ever. which pre- in nerve agent poisoning. and gastrointestinal) that follows a severe sys. Military medics the thinner secretions. weakness followed by flaccid paralysis spasm or constriction of the bronchiolar musculature. for example.63 Some observ. Clinically. The Several decades ago. The authors observed that it Rhinorrhea also occurs as part of an overall. Three major factors After exposure to a small amount of nerve agent contribute to respiratory failure: obstruction of air vapor. cultation. marked was not uncommon. These changes are noticeable after low Ct In another study. at the Edgewood Arsenal Toxic Exposure Aid Station temic exposure from liquid on the skin and. for individuals who increase in secretions from glands (salivary. indicating a defect in central respiratory drive. Exposure to sarin at a Ct of 5 to 10 mg/ CNS. of central and peripheral mechanisms. compared the nasal secretions to the flow from a If the amount of the inhaled agent is small.70 Convulsions and their associated 173 . the tion studies (such as measurements of vital capacity agent. such as administration of atropine. under and maximal breathing capacity) on subjects exposed the circumstances of the studies. the discomfort and severity increas. Nerve Agents may cause severe rhinorrhea. severe trouble in breathing had already casualty and the medical care provider. a casu- leaking faucet. Attempts to aid ventilation in severely poisoned The pulmonary effects of nerve agent poisoning are casualties can be greatly impeded by constriction of crucial. changes. and a partial or total cessation and other secretory cells of the bronchi also contribute of stimulation to the muscles of respiration from the to the dyspnea. and the amount of agent. these factors in causing death were summarized in a ing as the amount of agent increases. If the exposure was larger. paralysis of the muscles of respiration. For example. but its overall importance varied with the species. normal in 15 to 30 minutes. relief was likely to come only after therapeutic Pulmonary System intervention. sure to nerve agents by performing pulmonary func. were seen between anesthetized and unanesthetized including cyanosis. or. respiratory failure in the monkey. whether attempts at assisted ventilation until the plugs were from bronchoconstriction. report67 describing original studies in nine species. which is used in studies of nerve clinical practitioners have found that the inhalation agent intoxication in animals. the effects of the agent include severe dyspnea ing.6 mg/min/m3). this resembles a severe dogs given sarin. bronchorrhoea. had not received atropine or other assistance to arrive nary. One the nerve agent poisoning toxidrome. while other researchers did not. whereas bronchoc- ers found increases in airway resistance64 and other onstriction appeared early and was severe in the cat. One exposed worker asthmatic attack. Dogs have thick seconds after inhalation. which is generally attributed to secretions. The pulmonary effects begin within compared with that in the monkey. Atropine may contribute to the nea. individuals often complain of a tight chest passages by bronchoconstriction and by respiratory (difficulty breathing). of the intercostal and diaphragmatic musculature Secretions from the muscarinically innervated goblet needed for ventilation. are part of a generalized seizure or originate were otherwise treated in the same manner. agents were first synthesized in 1936. Respiratory failure units. agents and potential therapeutic measures has come phragm) and central failure were the primary factors from these studies. in contrast to controls movements.71 effects. Whether these continued to breathe. a finding that might be expected. and fatigue. 2-formyl-1-methylpyridinium chlo. The pretreated animals torso to arch rigidly in hyperextension. patient has regained consciousness and has voluntary Ayerst Laboratories. when 2-PAM Cl. concerned with clinical effects of nerve agent poison- In a review72 describing studies in anesthetized cats ing. appear as ripples under the skin. called 2-pralidoxime chloride. and later by fatigue and paralysis of these tion noted in the earlier study67).72 When small number of fibers innervated by a single motor atropine was administered in adequate amounts be. or VX. is administered to animals poisoned with status becomes compromised and oxygenation is de- a ChE inhibitor. and small fore the failure of circulation. convul- the penetration of drugs it otherwise excludes. the blood–brain produce convulsions that are associated with frank barrier may change in the presence of a nerve agent epileptiform seizure activity as measured by EEG (as with other types of poisoning or hypoxia) to allow recordings. After a severe exposure. the loss of central presented here. it can be found in the animals’ central pressed. or by been the subject of hundreds of studies since nerve inhalation. which have been described as convulsive that did not receive pyridostigmine pretreatment but jerks. there are intense and sud- ternary compound and thus would not be expected den contractions of large muscle groups. however. the patient is not likely to notice these if the In one study.Medical Aspects of Chemical Warfare damage were not seen in the anesthetized animals. which is also a quaternary activity may stop or become episodic as respiratory compound. Occasionally. Much of our bronchoconstriction appeared to be a minor factor.71. Because this chapter is primarily in respiratory failure. see Exhibit 5-1). it exposure (for instance. then by stimulation of muscles and muscle insignificant (in contrast to the severe bronchoconstric. which cause to protect central sites of respiratory stimulation from the limbs to flail or become momentarily rigid or the the effects of a nerve agent. which were then exposed to a nerve agent simultaneously in many muscle groups after a large and given the standard therapeutic drugs. percutaneously. atropine and systemic exposure. it reversed the central fasciculations often escape the patient’s notice.73 pyridostigmine was administered to area affected is small. the marked trismus and nuchal is suggested that peripheral mechanisms of breathing rigidity in an individual who has pipetted soman into (skeletal muscles and airways) must predominate in his or her mouth. studied because significant cardiovascular depression Fasciculations are the visible contractions of a occurred only after cessation of respiration. Fasciculations will typically continue long after the ride. For sive movements and associated epileptiform seizure example. methyl chloride. respiratory drive was found to be the predominant The effects of nerve agent intoxication on skeletal cause of respiratory failure with each of the agents. but it is not found in the brains of convulsive activity because of frank central seizures normal animals after they receive 2-PAM Cl. Skeletal Musculature In this study. these disturbances may be a local protects against the cessation of respiration. does not appear to enter the CNS because it is a qua. manufactured by Wyeth.67. sarin. lower in the nervous system has been a matter of de- The results of this study suggest that pyridostigmine bate.20 Nerve agents also sustaining breathing. These effects on muscle may be described as was the predominant cause of death in the species fasciculations. soman. It may be impossible to clinically distinguish nervous systems. Since effect on the muscle groups below or near the site of pyridostigmine does not appear to enter the CNS. They can occur as a romuscular block. Pa). information on the mechanism of action of nerve while neuromuscular block (particularly at the dia. Pyridostigmine muscle activity. there were no significant differences in the cardiovascular and respiratory effects when the The neuromuscular effects of nerve agents have agent was given intravenously. They are normally painless. groups. a comprehensive review of these studies is not given tabun. and muscle are caused initially by stimulation of muscle the contribution of bronchoconstriction was apparently fibers. Fasciculations can also appear primates. They depression and bronchoconstriction but not the neu. nerve filament. Alternatively.75–77 In cases of severe poisoning. local effect at the site of a droplet of agent on the skin because the neuromuscular effects of poisoning with before enough agent is absorbed to cause systemic these nerve agents occur at a nicotinic site. pyridine-2-aldoxime a characteristic sign of poisoning by a ChE inhibitor. Philadelphia. Protopam chloride. also severe exposure will have generalized fasciculations.74 from the purely peripheral neuromuscular symptoms 174 . twitches or jerks. In a study71 of rabbits poisoned with sarin. A casualty who has sustained a 2-pyridine aldoxime methyl chloride (2-PAM Cl. 4–0. had CNS effects. five reported mental communicate. decreased ability to ported difficulty in concentration. the decreases in whole-blood ChE activities 50 were normal and 10 had myasthenia gravis) after were assumed to indicate mainly inhibition of RBC- daily IM doses (1.80 ChE ranged from less than 9% to more than 100% of the individual’s control activity. do not answer simple questions as quickly and dependent on their judgment. The report authors pointed out that cussed in numerous reports. 30% reported anxiety. are not part of the symptom complex. Systemic atropine complained of effects lasting longer. ing were the other symptoms noted.81. RBC- or pesticides have recently been summarized.8 mg). Gross confusion. The 10% to 40% of control (RBC-ChE activities < 20% of most prominent CNS effects reported were excessive control). and depression. serious consequences to the individuals and to those table. which sug- Whether these are direct nerve agent effects. onsets often separated by several hours. with One report66 suggests that several workers acciden. sion. 4% had intellectual depres- mentioned elsewhere as an effect of ChE inhibitors. two re- judgment. All but two of these individuals were consid- hallucinations. The individual with the greatest ChE recognized. they usually start within a few the presence or severity of symptoms and the degree hours and last from several days to several weeks. 13 workers reported sleep disturbances. emotional had unusual dreams. or occasional mild confusion. 51% exposed to ChE-inhibiting substances have been dis. and generally display impaired In a series83 of 72 workers exposed to sarin. and tremulousness (29 subjects). Nerve Agents of jerks and tremor. Hallucinations are not psychomotor depression. had an RBC-ChE activity of 33% exposure and have no or minimal physical signs or of his personal control value. Although the effects may begin as late as exposures were not severe. even months. the onset of signs and symptoms occurred nervousness. and maxi- 40 workers accidentally exposed to small amounts of mal depression in blood ChE occurred 3 to 8 hours after 175 . The report authors concluded that mild Common complaints include feelings of uneasiness. and observers may note that they are irri. In a series58 of 49 workers who were accidentally Central Nervous System and Behavior exposed to sarin or tabun (a total of 53 exposures). and most of the effects of In the Aum Shinrikyo attacks of 1995. The data on blood ChE more severe exposures to nerve agents. which suggests that the symptoms. of ChE inhibition was seen. without comment. In subjects with whole-blood ChE activities of reported about 1 hour after dose administration. Overall. and drowsiness as complaints from 16 of 3. but they may activities (both RBC-ChE and BuChE) in these work- occur. The incidence of psycho. posttrau. probably more frequently than is commonly ers were scanty. five reported giddiness. 4% had reported visual hallucinations.58 precisely as usual. 8% reported anxiety. Overall. and 10 reported easy fatigability. Changes were ChE. Exposed individuals may be disturbances and that these disturbances might have forgetful. and changes that occur following exposure to nerve agents 12 others received atropine orally (0. some patients exposure disappeared within 3 days. poor comprehension.78 was not given to any of these individuals.79. Some subjects tally exposed to sarin had some behavioral effects. similar effects were reported as sequelae of ac. No correlation between 1 day after exposure.82 both psychological and gastrointestinal effects. that one subject of 20%–40% of control). in individuals who have received a small inhibition. gests that therapy is unnecessary if a paucity of physi- matic stress disorder. placed on the skin of volunteers. and 33% had unusual dreams. Of those with whole-blood ChE lability.5–3. Nausea and vomit- Later. intoxication by nerve agents may cause psychological tension. such as complete disorientation or insomnia.5 to 18 hours after percutaneous exposure. and four reported mental aberrations. however. ered to have been exposed to a small amount of sarin. nerve agent vapor. insomnia (29 subjects). 57% had intellectual impairment. 57% had psychomotor dreaming (33 subjects).0 mg) of DFP. The authors activities of 41% to 80% of control (RBC-ChE activities of the study noted. increased tension. restlessness. Several of the findings on behavioral and psychological they were given 2 mg of atropine intramuscularly. cal signs exists. or a combination is not known. Since VX preferen- inhibiting substances. Some subjects had cidental exposure to nerve agent poisoning. 12 reported mood Behavioral and psychological changes in humans changes. had symptoms related to only one organ system. and fatigue. and 38% jitteriness. the complex of CNS symptoms may not fully develop logical effects is higher in individuals who have had until 24 hours after exposure. Another report72 lists “weakness” (actually tiredness). Studies of Behavioral and Psychological Changes Behavioral changes and whole-blood ChE activities were reported in another study84 in which VX was In one of the earliest studies of the effects of ChE.38 behavioral and psychological tially inhibits RBC-ChE and has relatively little effect changes were reported in 49 of 60 subjects (of whom on BuChE. In an early tests 16 days after exposure was below that expected study. the subject agents can induce REM sleep in both animals and was more spontaneous and alert. But no measurements were taken between 8 14. and the maximal inhibition might have tasks were performed satisfactorily.84 or other potent organophosphorus compounds in hu- Although the frequency. Generally. cluster of CNS and behavioral effects of nerve agents ficulties with thinking and expression. hand-eye coordination. The author suggested • greater-than-normal variations in potential. there was some impairment on tasks requiring vision.103 DFP. and humans. comprehension.7 mg/min/m3). these were most promi- ported. inability to read with comprehension.89 experimentally produced lesions. is consistent with what is known about the role of inability to maintain a thought trend.88 most and 24 hours. it seemed likely that Information is scanty on the electroencephalograph- the drug reversed the CNS effects. Nighttime performance. that the use of scopolamine hydrobromide deserves • increased frequency. sleep cycle control. and effects while recovering from nerve agent poisoning. naturally occurring pathological states of cholinergic appropriate trends in language and thinking were not insufficiency (such as Alzheimer ’s disease). Often it is overlooked that there the daylight. mg/min/m3). with increased beta further evaluation in patients who have these lingering rhythm. ic (EEG) effects in humans who have been severely The subject’s performance on standard psychological poisoned by ChE-inhibiting substances. The changes were 4 months later and again 6 months later when he was discharged from further care. administered intramuscularly daily. 176 . irritability. specifi- dued. nor was there evidence of conceptual looseness. for one of his intellectual capabilities. The study authors decrement in dark adaptation and subsequent visual stressed that psychological impairment might occur acuity. in been in this period.91 It has also noted. slow waves.Medical Aspects of Chemical Warfare exposure. cholinergic circuits are involved in both cognition and poor performance on serial 7s (subtracting from 100 by short-term memory.95–98 Administration of which does not enter the CNS. jitteriness affect. some of the behavioral effects effects on cognitive processes. if not hazardous due to a miosis-induced and onset of signs or symptoms. onset. been hypothesized for a number of years that depres- The investigators found no evidence of perceptual sion is due to an imbalance between the cholinergic distortion resulting in delusions or hallucinations. 4 to his expected level of functioning when he was tested with myasthenia gravis). effects on mood or reported in the VX subjects were fatigue.92–94 Finally. or cholinergic agonists that act like nerve as dry mouth.20 He received oral doses associated with dreaming. a feeling of being ACh and cholinergic neurons within the brain. Illogical or in. they could be correlated with decreases decrements were found on physical tasks87 (at a Ct of of RBC-ChE activity (but not with BuChE decreases). was may be a long delay between exposure on the skin difficult. however. on the other days to carbamates. minor difficulties of drugs. depression. On the hydrobromide days. and judgment. On a military field exercise. if suboptimally.90 and in orientation. before the onset of other signs or symptoms or might The behavioral effects of exposure to nerve agents occur in their absence. at the exposures used (Cts of 4–14. in the pontine brain stem. and duration of each mans can be conceptually grouped into three classes: reaction were not noted. have antisocial thoughts. voltage. • more irregularities in rhythm and the intermit- Changes in the ability to perform certain laboratory tent appearance of abnormal waves (high- or field tests after exposure to sarin have been re. and sleep restlessly cally the initiation and maintenance of the rapid eye with bad dreams for several days immediately after movement (REM) stage of sleep. but it improved caused EEG changes in 19 of 23 subjects (19 normal. and disturbances of sleep-wakefulness.86 No symptoms. These changes usually followed the onset of CNS response time. accidental exposure to soman caused one depressive symptoms are associated with cholinergic person to become depressed. as demonstrated by the effects 7s) and other simple arithmetic tests. dexterity. such compounds. listlessness. and frightening dreams. and that A severe. his performance on a simple arithmetic test also improved.98–102 slept better. hyperactivity. Because scopolamine hydrobromide Electroencephalographic Effects is more effective in the CNS than the methylbromide salt of scopolamine or atropine. and adrenergic systems within the brain. at least temporarily. less depressed. the sleep stage that is the exposure (see Exhibit 5-1).7 nent in the frontal leads). This or tension. forgetfulness. is controlled by increased of scopolamine hydrobromide on 3 of the following activity of cholinergic neurons within specific nuclei 6 days and was given scopolamine methylbromide. Central mentally slowed. withdrawn.85. dif. and sub. organophosphorus anticholinesterase mimic the peripheral effects of hydrobromide salt. and intermittent bursts of ab.77. sharp waves.120 Second. The Stage II pattern is asso. neurobehavioral effects are associated with initial The effects of various anticholinesterase agents levels of RBC-AChE inhibition greater than 70%. cal reports in the 1960s.76. Nerve Agents and they were decreased or reversed by atropine (1.20. ciated with mild to moderate signs or symptoms of In the early 1980s.115–117 Similar findings upon the severity of the dose. occasionally supported This level of ChE inhibition may also be associated by psychological studies. that require immedi- the loss of consciousness but before the onset of con.119 Further studies confirmed Such levels of exposure are also expected to produce these initial findings and led to several hypotheses as a moderate increase of REM. Following such severe exposures. The effects of such severe exposures on REM sleep and carbamates) on EEG activity were reviewed and are prominent and can persist for weeks or months the study authors proposed that a three-stage change after the exposure. depending upon the dose and the type of compound. Irregularities in rhythm. decreased somewhat (decreases in voltage. Animal studies show vulsions. slow-frequency transient effects that represent reversible neurochemi- (delta. more permanent effects described below. volt.108–110 Such severe EEG and administration of atropine (1 mg. In general.114 ation of the activation pattern seen during Stage I. This pattern is induced regardless priate anticonvulsant medications. depending agents developed brain lesions. due to the rapid compromise in respiratory with severity of symptoms. ate pharmacological treatment. in irregu.115. A distinction needs to be made between these more with intrusions of high-voltage. is produced in the normal EEG of animals or humans unchecked. status and associated decrease in oxygenation. several laboratories reported that intoxication in both human and animal studies. elevated-voltage waves) occurred severity of the initial insult and possibly upon the ra- with moderate symptoms. These changes persisted for pidity and effectiveness of pharmacological treatment. the EEG changes coincided duration. In another study. This is pattern of brain damage seen in these nerve-agent– 177 .80.113 These reports are with minimal to mild signs or symptoms of exposure. weeks to several months. to the cause of these brain lesions.79. 5-Hz waves in that can elicit prolonged seizure activity that has all the temporofrontal leads. effects have not been permanent but have lasted The Stage II EEG pattern is marked by a continu.111 of the subject’s behavioral state when the anticholin- esterase is administered. age was slightly diminished.106. some authors Stage III EEG changes are associated with the most suggested that the nerve agents may produce a direct severe levels of exposure and are represented by neurotoxic effect on brain neurons. IV). or lar frequency and potential.103. the behavioral with some mild. In experimental animal studies. These waves persisted for 6 the clinical and electrophysiological features of status days despite atropine administration.2 typically marked by very high-voltage waves. theta) waves and an increased amount of high cal changes of nerve agents on brain function and those frequency (beta) waves. with bursts of high-voltage. epilepticus. First. or possibly several years. ing with nerve agents or organophosphorus insecti- which is comparable to levels of inhibition associated cides have been reported.107 Seizure activity in human victims In one study45 in which subjects were exposed to of severe nerve agent exposure is typically of limited smaller amounts of sarin. (nerve agents. or both during sleep or drowsiness.112.77.46. and can result in brain At Stage I an activation pattern is produced in the damage and long-term neurobehavioral changes. 4 to 8 days after the disappearance of symptoms and Long-term EEG effects show up as isolated spikes. With mild symptoms. The recording showed marked slowing of that all nerve agents are potent convulsant compounds activity. nerve-agent–induced seizures can persist by progressively higher doses of these compounds. may persist for months to years.118. the brain damage and neurobehavioral effects can be chronized pattern of mixed frequencies normally seen blocked or minimized by rapid treatment with appro- in alert subjects. based on clinical observations. and are associated with had been reported by Canadian researchers in techni- approximately 60% to 80% inhibition of RBC-AChE. short-term effect on REM sleep. as well severely intoxicated with sarin was recorded after as seizure and convulsive activity. and may last from minutes Long-Term Effects to several hours.105 over a period of many hours. depending upon the normal waves (slow. These animals that survived high-dose exposure to nerve EEG changes may persist for hours or days. This pattern is associated with an Long-term effects on the human CNS after poison- approximately 30% to 60% inhibition of RBC-AChE. and in slow waves) after with hyperventilation. other organophosphorus compounds. with mg. EEG changes variation in potential. IV). low-frequency delta waves being most prominent.104 the EEG of a subject who was There are marked signs of agent intoxication. Both EEG that is characterized by a low amplitude desyn. the epileptiform activity in a variety of patterns. Medical Aspects of Chemical Warfare exposed animals was similar to that seen after hypoxic that seizure control protects experimental animals encephalopathy. Because nerve-agent–exposed animals (rats, guinea pigs, nonhuman primates) from develop- exhibit varying durations of respiratory distress, sev- ing brain damage.107,128–137 eral authors hypothesized that nerve-agent–induced There are, however, experimental studies that show hypoxia was primarily responsible for producing these that convulsion development following nerve agent lesions.116,118,119 A third hypothesis was that the lesions exposure does not invariably lead to brain damage were the consequence of the prolonged seizures expe- and, conversely, that some animals that never display rienced by the animals during the intoxication.121 convulsions develop brain lesions. All of these studies Subsequent work both in vivo122 and in vitro123 has used observational procedures to determine presence failed to demonstrate support for the hypothesis that of convulsive/seizure activity following nerve agent nerve agents are directly neurotoxic. Likewise, the exposure. While nonconvulsive/nonseizure-mediated overwhelming evidence that effective treatment of neuropathology may have been observed following nerve-agent–induced seizures can block or signifi- exposure to nerve agents, the exact neuropharmaco- cantly reduce the extent of brain lesions argues against logical mechanism(s) that might produce this damage the direct neurotoxicity hypothesis.77 has yet to be described. There is conflicting evidence regarding the possible In addition to having morphologically detectable role of hypoxia as an etiologic factor in brain damage brain lesions, animals surviving severe nerve agent following seizure activity, whether nerve agents or intoxication have been shown to have decrements in other chemoconvulsants cause this seizure activity. performance, as measured on a variety of behavioral Rats given bicuculline convulsed for 2 hours under tests.136–140 These decrements were apparent in some controlled conditions. Those given a lower percent- studies for at least 4 months, when the last survivors age of oxygen in their inspired air to keep the partial were sacrificed. These animals, mostly rats, are re- pressure of arterial oxygen close to 50 mm Hg did ported to display other persistent behavioral changes not have brain lesions, whereas those with normal air (hyperresponsiveness, difficulties regulating body intake and partial pressure of arterial oxygen higher weight, spontaneous convulsions) that can also be than 128 mm Hg developed brain lesions.124 Although considered consequences of the brain lesions. this evidence does not eliminate the possibility of In general, in untreated or inadequately treated localized hypoxic areas in the brain as a factor in nerve-agent–poisoned animals, convulsive (and sei- nerve-agent–induced damage, it does suggest that zure) activity usually stops shortly after respiration systemic hypoxia is not a factor. On the other hand, a becomes compromised. Some of these animals die similar study125 (hypoxic rats with bicuculline-induced while others recover after some degree of apnea, and convulsions that lasted 2 h) suggested that there were electrographic seizure activity, as monitored on the slightly more brain lesions in the hypoxic animals than EEG, can resume while overt motor convulsions may in normoxic animals. no longer be apparent. Motor movements (finger The hypothesis that prolonged seizure activity is twitches, repetitive arm/leg movements, nystag- primarily responsible for nerve-agent–induced brain mus) become more subtle, of smaller amplitude, and damage in experimental animals has now become intermittent. These bear all the same clinical charac- well accepted.77 Studies in rats have shown that brain teristics as described for late-stage status epilepticus damage development requires a minimum duration in humans.141 In some of the reported cases of severe of continuous seizure activity.124,125 Seizures termi- nerve agent intoxication in humans,20,66,104 convulsive nating before 10 minutes have elapsed resulted in activity has also been brief and medical treatment no observable damage. In animals that seized for 20 was promptly available to prevent further convulsive minutes before seizures were stopped, about 20% ex- episodes. There are several reports, however, from the perienced mild amounts of damage in restricted foci. Aum Shinrikyo terrorist attacks of individuals exhibit- In contrast, in animals that experienced 40 minutes ing prolonged seizure activity before adequate therapy of seizure before seizures were stopped, over 80% could be delivered.110,142 It is not known whether these experienced damage, and this damage was more victims suffered brain damage similar to that described severe and widespread than the 20-minute-treatment in experimental animals, but two individuals experi- group. Studies in nonhuman primates confirm that enced profound retrograde amnesia, one of which still delay in seizure control increases subsequent brain displayed high-amplitude epileptiform waves in the pathology.126,127 Studies with effective drugs that can EEG 1 year after the exposure. stop nerve agent seizures (benzodiazepines, anticho- Interpreting clinical studies in light of experimental linergics, N-methyl-d-aspartate antagonists) by many results is difficult largely because the role of hypoxia research groups have overwhelmingly demonstrated is very hard to separate from any seizure-mediated 178 Nerve Agents nerve agent toxicity on the human brain. Because of vapor had idioventricular rhythms within minutes respiratory depression, it is possible to attribute much after exposure; following atropine therapy, some of the of the reported CNS sequelae in human victims to dogs had third- degree and first-degree heart blocks hypoxic damage. before a normal rhythm returned. In another study,145 A major challenge in interpreting the reports of long- conscious dogs had few cardiac rhythm changes after lasting neurobehavioral complaints in patients who sublethal doses (0.25–0.5 LD 50, administered sub- have survived nerve agent exposure is separating out cutaneously) of VX. Four of five anesthetized dogs that part of the syndrome that is clearly psychological, receiving a 1-LD50 dose had arrhythmias, including including, in many cases, posttraumatic stress disor- first-degree heart block and premature ventricular ders satisfying psychiatric criteria in The Diagnostic complexes; one had torsade de pointes (a type of and Statistical Manual of Mental Disorders, 4th edition, ventricular tachycardia). Cardiac arrhythmias are from that which is due to direct toxicity of nerve agent not uncommon in humans after organophosphorous upon the nervous system itself. Some of these reports pesticide poisoning.146 are summarized below. Dogs were instrumented to examine the cardiac Only one case has been reported of peripheral nerve changes occurring for a month after IV administration damage after human nerve agent intoxication. In this of 2 LD50 of soman.147 Atropine and diazepam were one case, a victim of the Tokyo Aum Shinrikyo attack administered shortly after soman exposure to control developed distal sensory axonopathy months after his seizure activity. During the study period, there was exposure. Causality could not be established.143 increased frequency of episodes of bradycardia with ventricular escape, second-degree and third-degree Cardiovascular System heart block, and independent ventricular activity (single premature beats, bigeminy, or runs of ventricu- Little data exists on the cardiovascular effects of lar tachycardia). nerve agents in humans. In mild-to-moderate intoxi- In a similar study,148 rhesus monkeys were given cation from nerve agents, blood pressure may be el- the standard military regimen of pyridostigmine evated, presumably because of cholinergic stimulation before exposure to soman (1 LD50, IM), and atropine of ganglia or other factors, such as stress reaction. and 2-PAM Cl after the agent. The monkeys were monitored continuously for 4 weeks. Except for the Arrhythmias period immediately after agent administration, the incidence of arrhythmias was the same as or less than After nerve agent exposure, the heart rate may that observed during a 2-week baseline period. decrease and the authors have observed that some Torsade de pointes has been reported after nerve atrial-ventricular (A-V) heart block (first-, second-, or agent poisoning in animals145 and after organophos- third-degree) with bradycardia may occur because of phorus pesticide poisoning in humans.149 Torsade de the stimulation of the A-V node by the vagus nerve. In pointes is a ventricular arrhythmia, usually rapid, of some cases an increase in heart rate may occur because multifocal origin, which on ECG resembles a pattern of stress, fright, or some degree of hypoxia. Because midway between ventricular tachycardia and fibril- treatment initiation is urgent in severely intoxicated lation. It is generally preceded by a prolongation of patients, electrocardiograms (ECGs) have not been the QT interval, it starts and stops suddenly, and it performed before atropine administration. However, is refractory to commonly used therapy. It was first if possible, an ECG should be done before drugs are described as a clinical entity in the late 1960s; un- given if the procedure will not delay therapy. In normal doubtedly it was seen but called by another name in subjects, atropine may cause a transient A-V dissocia- experimental studies with nerve agents before then. tion before the onset of bradycardia (which precedes Recent studies have shown that sarin-exposed rats tachycardia), and ChE-inhibiting substances may cause display pronounced QT segment prolongation for bradycardia and A-V block. For reasons noted above, several weeks after near-lethal exposures, and that these transient rhythm abnormalities have not been these animals showed an increased sensitivity to recorded in patients with nerve agent intoxication. epinephrine-induced arrhythmias for at least 6 months These rhythm disturbances are probably not clinically after exposure.150 important. In addition to the arrhythmias described above, Reports of patients exposed to pesticides and the studies have shown that animals (rats, nonhuman results of animal studies provide additional informa- primates) severely poisoned with nerve agents can de- tion about cardiovascular reactions to nerve agents. In velop frank cardiac lesions.125,131,151–154 The early stage one study,144 dogs exposed to lethal amounts of sarin (15 minutes–several hours) of these lesions consists of 179 Medical Aspects of Chemical Warfare hypercontraction and hyperextension of sarcomeres, Heart Rate focal myocytolysis, and the development of contrac- tion bands that are the result of the breakdown of Although it is frequently stated that a patient in- markedly hypercontracted myofibril bundles. This is toxicated with a nerve agent will have bradycardia, followed by an inflammatory response (24 hours or this is not proven by clinical data. In a review of the less), which begins with edema and neutrophil infiltra- records of 199 patients seen at the Edgewood Arsenal tion and ends with mononuclear cell infiltration and Toxic Exposure Aid Station for mild-to-moderate scavenging of necrotic sarcoplasm by macrophages. nerve agent exposure (one or more definite signs or This is followed by a stage of repair (72 hours or less), symptoms of nerve agent intoxication, such as miosis which begins with a proliferation of fibroblasts and or a combination of miosis with dim vision or a tight ends with myofiber loss and replacement fibrosis. chest), 13 presented with heart rates less than 64 beats Some studies have shown a relationship between per minute. There were 13 patients with heart rates of the development of seizures following nerve agent 64 to 69 beats per minute, 63 with heart rates of 70 to 80 exposure and the occurrence and severity of cardiac beats per minute, 41 with heart rates of 81 to 89 beats lesions.131 per minute, 38 with heart rates of 90 to 99 beats per Ventricular fibrillation, a potentially fatal arrhyth- minute, and 31 with heart rates higher than 100 beats mia, has been seen after administration of a ChE per minute. A heart rate of 64 to 80 beats per minute is inhibitor and atropine. It can be precipitated by the considered normal in adults.157 Thus, 13 patients (6.5%) IV administration of atropine to an animal that has had low heart rates, and 110 patients (55%) had high been rendered hypoxic by administration of a ChE heart rates (69 of these patients [35%] had heart rates inhibitor.155,156 Although this complication has not > 90 beats per min). been reported in humans, atropine should not be Reports of the heart rates of patients severely intoxi- given intravenously until the hypoxia has been at least cated by insecticides vary. In a report158 describing 10 partially corrected. patients (9 of whose consciousness was moderately- Because of the well-recognized possibility that ven- to-severely impaired), 7 presented with heart rates tricular fibrillation can occur in a hypoxic heart given over 100 beats per minute, and the other 3 had heart atropine, many intensive care unit physicians and rates over 90 beats per minute (5 had a systolic blood nurses are reluctant to give the large amounts of at- pressure of 140 mm Hg or higher, a diastolic blood ropine that may be required to treat acute nerve agent pressure of 90 mm Hg or higher, or both). In another poisoning. The authors have observed that this issue report,159 the heart rates of three unconscious patients has come up in several training exercises. Although were slow (one had cardiac arrest). Two acutely ill, un- data are fragmentary, the literature suggests that the conscious patients were described in a comprehensive chance of death from acute nerve agent poisoning review of organophosphorus poisoning54; one had a is greater than the chance of ventricular fibrillation heart rate of 108 beats per minute, the other 80 beats from atropine on a hypoxic heart, at least in initial per minute. The authors of the study pointed out that field management. Once the patient has reached a cardiovascular function is usually maintained until hospital setting where proper monitoring is possible, the terminal stage and that blood pressure and heart it should be less problematic to administer atropine rate increase in the acute stage but may decline later. safely in the amounts required while giving oxygen Heart rate was not listed in their tabulation of signs as necessary. and symptoms. GENERAL TREATMENT PRINCIPLES The principles of treatment of nerve agent poison- of casualty decontamination should be obvious, but it ing are the same as they are for any toxic substance is often forgotten or overlooked. exposure: namely, terminate the exposure; establish This section discusses the general principles of treat- or maintain ventilation; administer an antidote if one ing nerve agent poisoning. The specific treatment of is available; and correct cardiovascular abnormalities. casualties in the six exposure categories (suspected, Most importantly, medical care providers or rescuers minimal, mild, moderate, moderately severe, and must protect themselves from contamination. If the severe) is addressed in the next section. caregiver becomes contaminated, there will be one more casualty and one fewer rescuer. Protection of the rescuer Terminating the Exposure can be achieved by physical means, such as masks, gloves, and aprons, or by ensuring that the casualty The first and perhaps most important aspect of treat- has been thoroughly decontaminated. The importance ing acute nerve agent poisoning is decontaminating the 180 and from sulfur mustard. including tion and saving lives in some instances. The expired breath of the casualty is shortly after the onset of effects. De- there are copious secretions throughout the airways. ners need to understand that the period of time that Assisted ventilation may be required to supplement ventilatory support will be necessary in nerve agent gasping and infrequent attempts at respiration. There are numerous mechanical devices. Of the four to attempts to ventilate. and “ropy. there is marked resistance quired intubation for ventilatory support. and only a few—the effects of agent doses of about 3 times LD50. breathing ceases complete. shown that only 10% or less of inspired nerve agent is ized muscular twitching or convulsive jerks and may expired. a severely poisoned person. Postural drainage can Nerve agents also differ greatly in this respect from be used. one died with severe hypoxic encephalopathy 181 . or it casualties is much shorter than that required for se- may be required because spontaneous breathing has vere organophosphate insecticide poisoning. creating less obstruction to ventilatory into contact with the casualty. Casualties of In one instance. the antidote may likelihood of contamination. plan- ly within several minutes after the onset of exposure. individual. given intramuscularly ventilatory assistance in an apneic casualty.66 four of 640 patients seen at Saint Luke’s International Initially. efforts to ventilate a severely apneic both of these types of agents may require ventilatory casualty were markedly hindered for 30 minutes until support for days to weeks.” support should only be required for hours at most. chemical). and off-gas. the casualty may have mild to severe dyspnea. were adequate to reverse the these is available to the soldier. appears to prevent the initial high resistance in the airways. Antidotes alone may be effective in restoring ventila. with corresponding physical findings. and followed by the current therapy after challenges Whatever device is used. weakness or paralysis of thoracic and diaphrag. This is stopped. resistance decreases to 40 cm H2O or the agent from spreading further on the casualty or to lower. Before even considering be supplemented by providing oxygen by inhalation. who may come may thicken). for days. Decontamination is performed to prevent the or greater may be needed. which will enable better ventilation and suction small. spite the greater toxicity of nerve agents. the RDIC (resus- effectiveness was greatly increased with the addition citation device. and the secretions diminish (although they others. After the administration casualty from further absorbing the agent or to keep of atropine. a soldier who wants to assist an apneic buddy when no pine. Pyridostigmine. In after inspiration of the agent. that there is no liquid contamination on the individual Severely exposed casualties lose consciousness to be ventilated. Pressures of 50 to 70 cm H2O patients. the rescuer should be sure that there is In most other circumstances. is apneic or has severe respiratory compromise and Breathing impairment is an early effect of exposure needs assisted ventilation. of secretions. in the unlikely but conceivable situa- tion that a lone first responder must treat a severely Ventilatory Support poisoned casualty whose heart is still beating. Mouth-to-mouth ventilation might be considered by ment will be reversed by the administration of atro. only plugs. and the impair. and oxygen is unnecessary. this method. but their mask-valve-bag ventilation device. given as pretreatment ventilator—are available at the battalion aid station. In animal sophisticated ventilators. efforts. If the distress is severe and the casualty is elderly aid station is nearby. Nerve Agents patient. A major drawback to this is the or has pulmonary or cardiac disease. and a simple of ventilation. IM atropine should be administered first (because it only Ventilatory support is a necessary aspect of therapy takes a few seconds) before attempting to intubate and to save a casualty with severe respiratory compromise. should be attempted. causing symptoms. and phosgene. usually before any a smaller hazard. that can be used to provide studies. and bronchospasm or constriction. stores. ventilatory These secretions tend to be thick. When the exposure is tion. mucoid. and frequent and thorough suctioning of the both pulmonary oedemagenic agents. and may plug up the airways. which is not always possible. disappear into the fat matic muscles. resuscitate the patient. When managing a mass casualty incident. If a casualty apnea. Thus. They have general. Studies162–164 involving sarin have signs of respiratory compromise. None of at the onset of signs. because of the constriction or spasm of Hospital for definite or suspected sarin poisoning re- the bronchial musculature. then endotracheal intuba- to nerve agent vapor or aerosol. In addition to a decrease in central respiratory because organophosphate insecticides tend to be more drive. it must be able to overcome with higher amounts of two agents. supplementation with no vapor hazard.160. fat-soluble than nerve agents. such as chlorine airways is necessary if ventilation is to be successful. adequate suction was applied to remove thick mucoid In the Aum Shinrikyo subway attack in Tokyo.161 antidotes alone. and that the toxicant is expired immediately initially have spontaneous but impaired respiration. including medical personnel. A dose of 2 mg atropine was chosen for self might be expected to have greater antidotal -administration or buddy-administration (the AtroPen activity. as the first-line antidote to counteract nerve agent • Atropine and related substances reduce the poisoning by the armed forces of most countries. since some of the more severe effects automatic injector included in the Mark I (Meridian of ChE inhibitor poisoning (such as apnea and Medical Technologies Inc.169 Animal studies have shown that ben- by copious secretions. advocated the use of the synthetic anticholinergics stance physostigmine and a cholinergic blocking sub. It is effects of the ChE inhibitors. Since the 1940s.Medical Aspects of Chemical Warfare on hospital day 28. atropine. in a prophylactic mixture they In the early 1950s. along with the car- stance has been recognized for well over a century. Military researchers in the Czech Republic have The antagonism between the ChE-inhibiting sub. Bristol. benactyzine and trihexyphenidyl. and reasonably normal performance 182 . benactyzine is instances.172 In addition. In several than does atropine.172. Among the findings are agent first aid kits174 and was determined to be an ef- the following: fective antidote by British scientists at Porton Down who first analyzed the pharmacology and toxicology • Almost any compound with muscarinic cho.173 ChE-inhibiting insecticides. The atropine and benactyzine combination exposure to a lethal amount of nerve agent.175. Figure 5-5) by the US and the military of several other countries because it reverses the effects of nerve Several countries use. rather. the Czechs severity of effects from ChE-inhibitor poisoning. a mixture of drugs known as TAB as their immediate chanical ventilation in essentially all cases who survive nerve agent treatment. agent poisoning. It was included in the German nerve tested for antidotal activity.165 TMB-4. Nevertheless. which penetrate the CNS more readily.167 While many countries have other anticholinergic Cholinergic blocking substances act by blocking drugs to use as adjuncts to atropine to treat nerve the effects of excess ACh at muscarinic receptors. Of the remaining three patients. atropine has been adopted ity. agents. did not prevent deaths in animals exposed to synthetic as postexposure antidotal treatments. and the synthetic anticholinergic In summary. agents were first discovered and produced during Many cholinergic blocking substances have been World War II. Antidotes in the TAB mixture is similar in composition to the at- alone are relatively ineffective in restoring spontaneous ropine.66. This mixture contains the oxime sarin poisoning is a short-term clinical concern. For example. Attempts at ventilation are hindered by the mixtures investigated by Yugoslav researchers in the high resistance of constricted bronchiolar muscles and early 1970s. none of these compounds have been ACh accumulates at these receptors because it is not tested or used in human clinical cases of poisoning hydrolyzed by ChE when the enzyme is inactivated either with nerve agents or other organophosphate or by an inhibitor. anticholinesterase poisoning by organophosphate or • Antidotal substances with higher lipoid solu. the associated side effects of a dose this size other anticholinergic drugs as adjuncts to atropine can be tolerated. Thus. Ventilatory assistance may be required briefly to reverse the CNS effects of nerve agent intoxication (20–30 min) or for a much longer period. they block the effect of the resulting choice for treating nerve agent intoxication since nerve excess ACh. From 1975–1980 the US military also within several minutes after onset of effects caused by used TAB. atropine was found to reduce the have designated as PANPAL. benactyzine and 2-PAM combination antidote respiration. this significantly less potent in inhibiting sweating or pro- seems to be the longest reported use of ventilation. representing ergics have much more potent and rapid effects on the most severe cases who survived. carbamate pesticides. as well as atropine. shells. and is therefore less likely to induce heat casualties in a warm environment Atropine Therapy or compromise near vision in the case of accidental use.166 bamate pyridostigmine. atropine has been the antidote of bition). These anticholin- course. and was intubated throughout the for treating nerve agent poisoning.176 bility. 2 mg. which may be thick and plug the actyzine is much more potent and acts more rapidly bronchi.170. cholinergic blocking substances carbamate pesticides. spontaneous respiration will stop benactyzine. do not block the direct effect of the agent (ChE inhi.171 In addition. but it utilize benactyzine and biperiden. intubation was the CNS than does atropine. assistance was required for 3 hours20. primarily in those also almost universally used as the antidote to treat tissues with muscarinic receptor sites. Tenn) kit contains seizures) are mediated in the CNS. ducing mydriasis than atropine. Israel uses required only for 24 hours or less.168. This shows that me. or have proposed to use. of tabun obtained from captured German artillery linergic blocking activity has antidotal activ. or to other factors. On separate compartments within the device and are expressed another day. more than half dropped Fig. The medications are in because of body temperature of 103.5 minutes (compared with 4. this product awaits a pro- When given to a normal individual (one without duction contract with an FDA-approved manufacturer. the greatest degree of bradycardia occurred at 2. when 35 soldiers were given 2 mg of atropine and asked to walk for 115 minutes at 3. The muscle. but other effects (such as drying of the mouth and change in pupil size) appear later.178 when atropine was administered with the AtroPen.6 beats per min at 40. The plastic clip injection). For example. 5-6. and some paralysis of accommodation. The greater dispersion of the AtroPen deposit results lows: in more rapid absorption.4 minutes (compared devices. The kit is kept in a soft black foam holder that is with an increase of 36. 183 . needle-and-syringe injection). Atropine given intravenously to healthy young people causes a maximal increase in the heart rate in 3 to 5 minutes.177 injector is the safety.3 mph at a temperature of about 83°F (71°F wet bulb). a dose of 2 mg of atropine it is anticipated that the ATNAA will replace the older will cause an increase in heart rate of about 35 beats per MARK 1 kit by approximately 2008. is 2. Tenn. The Mark I kit with its two autoinjectors: the At- istered by standard needle-and-syringe injection). a roPen containing 2 mg atropine. on the other hand. Its tactical value minute (which is not usually noticed by the recipient). and maximal tachycardia (an increase of 47 keeps both injectors together and serves as a safety for both beats per min) occurred at 34. The antidote treatment nerve agent autoinjector (ATNAA) delivers 2. designated by produce embarrassing effects on troops with operational the Department of Defense as the antidote treatment responsibilities. a dry mouth.1 mg (Figure 5-6). dry skin. The 6 mg of atropine contained in the three injectors Reproduced with permission from: Meridian Medical Tech- given each soldier may cause mild mental aberrations nologies Inc. the dose which is therapeutically desirable and that The FDA has recently approved a combined-dose which can be safely administered to a nonintoxicated autoinjector including both atropine and 2-PAM Cl. labeled 7. Needle-and-syringe delivery produces a “glob” or puddle of liquid in can be maintained by the individual receiving it. even in healthy young patients. the onset of tachycardia. The decrease in sweat- ing caused by 2 mg of atropine is a major. nerve agent autoinjector (ATNAA). Most of these effects will dissipate in 4 to 6 hours. Laboratory trials have shown that 2 mg of atro- pine sulfate is a reasonable amount to be recommended Bioequivalence was demonstrated in animal studies. unclassified portion of a classified document as fol. they all successfully out of a single needle. Thus. The gray cap on the right end of the completed the same march.3 min when admin- Fig.9 minutes (versus 14. the autoinjector is more convenient to use nologies Inc.7 min with carried in the gas mask carrier. than the needle and syringe. and it results in more rapid absorption of the drug. Tenn. person. mydriasis. Nerve Agents (such as drowsiness or forgetfulness) in some indi- viduals if administered in the absence of nerve agent intoxication. It has not been determined whether the onset of beneficial effects in treating nerve The dose of atropine which the individual serviceman agent intoxication corresponds to the onset of brady- can be allowed to use must be a compromise between cardia.7 min with needle-and-syringe 2—indicating it is to be injected second. potentially harmful side effect that may cause some people who work in heat to become casualties. In one study. labeled 1—indicating it is to be injected first—and the ComboPen containing 600 mg heart rate increase of 10 beats per minute occurred at 2-pyridine aldoxime methyl chloride (2-PAM Cl). Bristol. 5-5. At the time of writing.5°F or above.1 mg atropine and 600 mg 2-pyridine out because of illness or were removed from the walk aldoxime methyl chloride (2-PAM Cl). The AtroPen. but near vision may be blurred for 24 hours. Bristol. sprays the rationale for this choice of dose was expressed in the liquid throughout the muscle as the needle goes in. nerve agent intoxication). without atropine. Reproduced with permission from: Meridian Medical Tech. for injection by an individual and that higher doses may The dose of atropine in the new product. early atropinization from various authors have been as- istering more atropine if the secretions are diminish. the relative that have muscarinic receptor sites. and a In the only battlefield data that have been published. gastrointestinal musculature become less hyperactive. a moderately dyspneic casualty given atropine 2 mg. in a the pulse. drying of respiratory secretions. 2 mg of body because of greater fat solubility or metabolized at atropine should be given intramuscularly at 5-minute a slower rate than nerve agents. accelerat. the treatment regimen used casualty regained consciousness 30 minutes to 3 hours by Foroutan12 would also result in a rapid atropiniza- after exposure. of respiration. conscious and apneic).Medical Aspects of Chemical Warfare lies in halving the time to administer the two antidotes US doctrine.12 After an minimize the effects of the agent (ie. in some cases. Whatever the reason. Treatment of Chemical Agent adverse effects (such as nausea and vomiting) 24 to 36 Casualties. of atropine needed for treating insecticide poisoning The amount of atropine to administer is a matter is different than the amount needed for treating nerve of judgment. the endpoints of atropinization and the most efficient derway.182 the Medical Management of Chemical Agent hours after exposure for which atropine was adminis. up to 150 mg IV in 5 minutes.175 These authors concluded that a dose-dou- adequate amounts of atropine.179–181 not be given atropine. agent poisoning. they will There has recently been increased discussion about report less dyspnea. In a conscious casualty with mild-to. to remove casu- initial IV test dose of 4 mg atropine. Foroutan’s protocol may reflect the pressure of pine reverses the effects of the nerve agent in tissues having large numbers of casualties to treat. uses a 6-mg IM loading dose compared to the MARK 1 kit.66 The authors have observed several tion. However. to 10-minute intervals until dyspnea and secretions they continue to cause acute cholinergic crises for a are minimized. This resulted in doses of agent in a casualty suffering severe effects. atro. particularly far forward. It decreases secre. (those in the mouth can be seen and those in the lungs Insecticide casualties may require intensive care unit can be heard by auscultation).20 However. Usually no more than a total dose of much longer period (days to weeks). means to achieve it. crucial in training personnel who are used to seeing in- pine should be given until secretions are minimized secticide poisonings to manage nerve agent casualties. bling strategy. lack of availability of oximes. heart rate > 80 to 90 beats per minute. secretions). bronchoconstriction decreases. He titrated his dose to pulse rate. he comfortable). Syed Abbas Foroutan reported using atropine much The goal of therapy with atropine should be to more aggressively and in larger amounts. secretions in the mouth continually administered during evacuation to the next and bronchi dry. tions and reverses the spasm or contraction of smooth and his inability to guarantee that atropine could be muscle. casualty with severe effects. followed by 2-mg increments until IV access is estab- When administered in an adequate amount. there appears to be no reason to give al175 are very similar: lack of bronchoconstriction. Too much atropine 70 beats per minute and decreasing it for pulse rates does far less harm than too much unantagonized nerve over 110 beats per minute. sessed using model data of atropine dose requirements ing and are not clinically significant. lished. atro. If there was no sign of atropinization. Mucus blocking in patients severely poisoned with organophosphate the smaller airways may remain a hindrance. IV or IM amounts of atropine (500–1. it is better to administer ing if the heart rate dropped to 60 beats per minute to too much atropine than too little. In contrast with nerve agent treatment. In severe casualties (un. and echelon of medical care. Casualties Handbook. However. and pupil size should not be Medical care providers must recognize that the amount used to judge the adequacy of atropine dosage.20. he waited 1 to alties from life-threatening situations and make them 2 minutes. 5 to 15 mg of atropine has been would be the most rapid and efficient way to achieve used before spontaneous respiration resumed and the atropinization. Army Field Manual 8-285. A casualty with miosis alone should verely poisoned by organophosphorus pesticides. Pesticides may be sequestered in the moderate effects who is not in severe distress. much larger However. which may not require complete reversal gave another 5 mg IV over 5 minutes while checking of all of the effects (such as miosis).183 Foroutan. unless given in very large doses. Likewise. 184 . by contrast. continued doubling of successive doses. despite pesticides. This point is 2 to 4 mg is needed. nerve agent casualties almost never do ventilatory efforts is minimized (atropine decreases and are usually either dead or well enough to require constriction of the bronchial musculature and airway minimal medication within 24 hours. The mouth dries. atropine. and if assisted ventilation is un.12 and Eddleston et tered. The endpoints of atropinization recommended by recovering casualties without non-life-threatening. The textbook recommendations for Secretions alone should not be the reason for admin. ease atropine routinely in this period. In an unconscious casualty. a decrease in airway resistance will be noted. If the casualties are conscious. and until resistance to beds for days.000 mg) have been required atropine does not reverse miosis caused by nerve agent in the initial 24 hours of treatment of individuals se- vapor in the eyes. For example. There may be continuing exposure before does not irritate the skin. those early effects per se (eg. an asymptomatic person who has had agent vapor will not progress after this time. In what is rarely immediate. the longer the interval between exposure and onset ing Ground. the time of onset may be related to the duration very low concentrations. Medical personnel usually have coworker in a laboratory suddenly complains of dim little or no information about the exposure incident. maximal effects occur within of time the agent was in contact with the skin before minutes of exposure termination. The first effects of agent on the casualty can exit the environment or don a mask. which usually are continue to develop for several minutes. Maryland. skin contact with a nerve agent should be kept under If a casualty is seen immediately after exposure from medical observation because effects may begin precipi- vapor only. and 4 to 5 Effects can begin hours after thorough decontamina- minutes later they were flaccid and apneic. however. but is in anticipation of more Atropine Therapy after Inhalational Exposure to severe effects within the following minutes. single drop 2–3 mm in diameter). if the casualty is seen at the medical aid station casualty should immediately self-administer or be (installation or field) 15 to 30 minutes after the vapor given the contents of one Mark I kit or ATNAA. person. When the occurrence of exposure is uncertain. until this interval has passed. the contents of two kits or injectors effects. if a soldier ’s buddy in the field or a had agent on the skin. Nerve Agents administered intramuscularly. and the given immediately after the onset of effects is not for amount of time elapsed since exposure. will report improve. there may be some the contents of one Mark I kit or ATNAA for mild or benefit in administering antidotes before the onset of moderate dyspnea. mediately after taking one or two breaths. the skin are localized sweating and fasciculations of or the effects from the exposure already absorbed may underlying musculature (rippling). signs (such as collapse or loss of consciousness). develop so rapidly. These exposure has terminated. if an individual is seen minutes after three kits should be given for severe dyspnea or any a definite exposure to a large amount of nerve agent more severe signs or symptoms. unconscious. The aggressive therapy toms. and Arsenal. and the contents the possible benefits of treatment must be weighed 185 . Generally. an antidote is not needed if signs indicate that the chemical agent has penetrated miosis is the only sign (atropine given intramuscularly the skin layers. Because effects decontamination. The therapy for an individual whose skin has been ity within seconds or minutes after the casualty is exposed to nerve agent is less clear. of effects. On the other not observed. the less severe the eventual effects will be. Vapor Atropine Therapy after Dermal Exposure to Liquid After vapor exposure. almost im. has very little effect on miosis). the hand. Utah. Caregivers should not administer the should be given if miosis is the only sign. in 1952). the route of exposure (vapor or liquid). the casualty sure to VX is only 6–10 mg. relief should begin dose of atropine for an individual exposed to a nerve within 5 minutes. of three kits or injectors and diazepam (with additional ment within 5 minutes. atropine is relatively inef- fective against miosis). but should wait for evidence of agent absorp- mediately if there is any dyspnea. in 1969 and one at Dugway Prov. The onset of effects removed from or protected against the vapor. vision in an environment suspected of containing nerve because the casualty often does not know the duration agent vapor. the contents contents of a Mark I kit or ATNAA to an asymptomatic of two kits or injectors should be administered im. for example. If these effects are noted. nerve agent ATNAA. and the drugs should not be repeated agent is determined by the casualty’s signs and symp. the contents of one Mark I kit or ATNAA tately hours later. In general. they may begin within minutes were apparently high concentrations of nerve agent of exposure or as long as 18 hours later. Effects caused by nerve In general. administer the contents of one Mark I antidote kit or Unlike. the effects of nerve agents appear very quickly and reach their maximum activ. the LD50 for skin expo- minutes after an exposure to vapor alone. antidotal therapy should be more The problem with treating dermal exposure is not vigorous for a casualty seen during or immediately so much how to treat a symptomatic casualty as it is after exposure than for a casualty seen 15 to 30 minutes deciding to treat an asymptomatic person who has later. the sooner the onset. for severe dyspnea (obvious gasping). and the contents of tion.20. A caregiver should resist the atropine. which is equivalent to a should receive no antidote if miosis is the only sign. but no more oxime) if there are more serious temptation to give too much atropine to a walking. If dys- talking casualty with dyspnea. the correct pnea is the most severe symptom. the buddy or worker should immediately or amount of exposure. lewisite exposure. two individuals collapsed (one at Edgewood the greater the exposure. However. vapor. When seen 15 to 30 on the skin (“large” is relative.66 Even at tion. For example. in many cases. RBC-ChE spon- MANAA has a limited role in patients recovering taneously reactivates at a rate of roughly 0. one of the following two h). have necessitated After the organophosphorus compound attaches administering additional atropine in the following 6–36 to the enzyme to inhibit it. I kits or ATNAA). the preferred is about 5 hours. lows the patient to self-medicate on an “as needed” Because the nerve agents differ in structure. tion should be expected in patients exposed through Antidotes should be administered until ventilation the skin than in vapor-exposed patients. The initial 2 or 4 mg has proven adequate in they restore normal ChE enzyme function. will In the mid 1950s.47.” becoming resistant to re- the national stockpile. atropine. and other factors.15 Consequently. The clinical endpoint.179–181 the organophosphonyl–ChE bond.Medical Aspects of Chemical Warfare against the side effects of antidotes in an unpoisoned be the same. such as nausea and vomiting. conscious casualties. The MANAA al.” which was approved by the FDA lose a side group and become negatively in 1990. half-time for aging of the tabun-enzyme complex is that of patients breathing comfortably on their own somewhat longer. Although 6 to 15 mg has been several features limit their utility. The official doctrine for its use activation by water or oxime. their basis. or “age. oxime therapy need for MOPP. required in apneic or nearly apneic casualties.113 The stockpiled to any great extent in the civilian sector. and. and a small percentage (5%) of the route of administration of atropine will be intravenous enzyme undergoes spontaneous reactivation.184 rates of spontaneous reactivation and aging differ. which breaks the initial insult. and ventilatory support should be started. In a mildly to The management of patients exposed to nerve agent moderately symptomatic individual complaining of through open wounds will probably fall between that dyspnea. without the complication of respiratory secretions. such as in an ambulance. A longer period of IV atropine administra- individual. called “medical aerosolized nerve agent an. the need for continuing atropine has not extended beyond 2 to Mechanism of Action 3 hours (although distressing but not life-threatening effects. lated enzyme) by removing the phosphyl moiety.44. is not effective after aging occurs.113 The after the initial IM field doses. at least Oxime Therapy 6 mg of atropine (the amount in three Mark I kits or ATNAA). Wilson and coworkers reported 186 . 2. the half-time for aging is about 2 minutes. Once the use after the casualty has been decontaminated and organophosphonyl–enzyme complex ages. it cannot be evacuated to a clean environment where there is no broken by an oxime. including the mask. The enzyme may be spontaneously reacti- secretion and bronchospasm) for days to weeks after vated by hydrolytic cleavage. and probably more. is adequate and secretions are minimal. in management en route The half-time for aging of the sarin-RBC-ChE complex to a hospital. However. the group attached to the first secretions and muscle twitches. is as follows: Both of these processes are related to the size of MANAA is used mainly in medical treatment facili- the alkyl group attached to the oxygen of the organo- ties by the individual casualty under medical super- vision for symptomatic relief of nerve agent-induced phosphorus compound. casualties. Oxi- vals until the casualty is breathing adequately with mes may be considered a more physiologic method of a minimal amount of secretions in the mouth and treating nerve agent poisoning than atropine because lungs. should be administered Oximes are nucleophilic substances that reactivate initially.5% to 1% from nerve agent poisoning who still require some per hour for about the first 48 hours.14. which may cause cholinergic crises (such as an increase in 1. the organophosphate-inhibited ChE (the phosphony- Atropine should be continued at appropriate inter. In a severely exposed person who is unconscious and apneic or nearly apneic. when complexed with VX. relief is usually obtained with 2 or 4 mg of of vapor-exposed casualties and casualties exposed to atropine (the amount of atropine in one or two Mark nerve agent liquid on intact skin. reactivat- The US military developed an inhaled form of ing the enzyme. It has not been complex ages very little during this period. It is intended for carbon of this alkyl group. soman-enzyme complex does not spontaneously In hospital management of both vapor and liquid reactivate. This is in contrast to the use of atropine to treat processes may occur: intoxication by organophosphorus insecticides. The complex formed by the enzyme-ChE may tidote (MANAA). It is not widely used but is still available in charged. The VX–enzyme observation but who can self-medicate. and doses of 15 or Japan uses pralidoxime iodide. and the administration. but may be marked and prolonged at higher doses. when oximes are effective (ie. manufactured by Wyeth-Ayerst Laboratories. For example. the only oxime approved by the FDA for given immediately after the nerve agent.5–5.5 to 24 hours after VX. may cause transient effects.197 2-PAM Cl is commercially Dosage available as the cryodesiccated form (Protopam Chlo- ride. are of interest to several countries. and their effectiveness. if they much more effective in reversing nerve-agent–induced occur. of the inhibited enzyme.0 mg/kg). The therapeutic dosage of 2-PAM Cl has not been Philadelphia. a dose of 10 mg/ (obidoxime) are used in other European countries. relatively ineffective in reversing effects in organs with when given intravenously in the absence of nerve muscarinic receptor sites. 5 mg/kg of 2-PAM Cl reactivated advocated by some in Canada.1 when the IM dose of 2-PAM of the demonstrated clinical efficacy of 2-PAM Cl in Cl increased from 11. In par.197 Giving showed that a plasma concentration of about 4 µg/mL the oxime slowly (over 30–40 min) may minimize in blood reversed the sarin-induced neuromuscular the hypertensive effect. They are doses higher than 10 mg/kg. Blood pressure elevations 15 to 25 mg/kg. nausea and ticular. not yet 20 mg/kg reactivated 58% of the enzyme. When 2-PAM Cl was administered intrave- the United Kingdom. ChE-inhibiting substance. such drugs and have limited penetration into the CNS. was given at the onset of signs. 2-PAM Cl is rapidly and almost completely excreted tion. Pa) in vials containing 1 g. These effects. or because of reasons not understood. whereas TMB4 and toxogonin nously in humans 1 hour after sarin.5 µg/mL when injected ported that an oxime (pyridine-2-aldoxime methiodide intramuscularly in the average soldier (8.178 in reactivating the enzyme. When 2-PAM Cl was Because oximes reactivate the ChE inhibited by a given at times from 0. or MARK 1 autoinjector (600 mg) produces a maximal inhibited ChE faster than water did. more reactivated more than 50%. Nerve Agents that hydroxamine reactivated organophosphoryl. In sarin-poisoned ity. it use in the United States is 2-PAM Cl. When given approved. administered intravenously (Figure 5-7).2 when the IM dose of 2-PAM Cl increased from civilian and military sectors experimentally demon.163 In the first two studies. The 2-PAM Cl administered with the ComboPen unchanged by the kidneys: 80% to 90% of an IM or IV 187 . for years this concentration quickly but transiently reversed by phentolamine 5 was generally accepted as being therapeutic for sarin. (with atropine) in several studies. with treatment to the LD50 without treatment) in- After thoroughly studying many of these compounds. mg. Oximes are also quaternary agent poisoning. plasma concentration of 6.187 increased from 5 to 10 mg/kg. kg reactivated 28% of the RBC-ChE. The methane. The effective dose depends on the greater than 90 mm Hg systolic and 30 mm Hg diastolic nerve agent. There is little data to support or disprove this conten.9 mg/kg in [2-PAM I]) was far more effective than hydroxamine a 70-kg male). An early study195 elevations may persist for several hours. creased from 25 to 90 when the IV dose of 2-PAM Cl 2-PAM Cl was chosen for use in the United States. Occasionally. are insignificant in a casualty poisoned with a changes in organs with nicotinic receptor sites. No ventilatory support sulfonate salt of pralidoxime is the standard oxime in was used. 2-PAM Cl should be given logical activity by mechanisms other than inhibition of intravenously. but indirect evidence suggests that it is mg/kg for a 70-kg person. 30 to 120 mg/kg in sarin-poisoned rats.160 and the PR strated effectiveness as a reactivator and also because increased from 1. the protective ratio (PR.188–194 rabbits. oximes are field. but usually this is not possible in the ChE. or about 14 established. they are ineffective in reversing the the dose increases. they decrease dysfunction in skeletal muscle. and the hypertension can be block in anesthetized cats. doses of nerve agent. TMB4 is more rabbits. Transient diplopia may occur at central effects of nerve agent intoxication. For as dizziness and blurred vision. while newer oximes only 10% of the inhibited RBC-ChE. For optimal therapy. Other oximes.5 to 25 mg/kg were found to reactivate 50% or more reverse the effects caused by nerve agents.186 Different doses of 2-PAM Cl were administered The oximes differ in their required doses. their toxic. which is usually slight and transient at improving strength and decreasing fasciculations.9 to 3.185 and later re.5 mg/kg in VX-poisoned treating organophosphorus insecticide poisoning. the time between poisoning and oxime may occur after administration of 45 mg/kg. the ratio of the LD50 effective against tabun poisoning than is 2-PAM Cl. Even at small doses (2. hypertension. HI-6 is 3 hours after sarin. and other factors. The most serious side effect is aging). and 10 mg/kg or are under study in the United States.2 to 22.113 because it is possible that nerve agents produce bio.6 to 4. the antidote was At present. In the third. which increase as these reasons. they might be expected to completely 2. IV doses of 15 mg/kg or less. in the absence of vomiting may occur. the drug.196 The PR increased from The choice was made because of research in both the 1. However. bitter 0. (See Blood Cholinesterases section. other practice for crop workers to be given 2-PAM Cl as a early investigators found no oxime in the brains of pretreatment either. an increase or decrease in muscle tone and reduced fasciculations) may be seen after oxime administration. reversal of the brain ChE inhibition in brains of animals Despite these drawbacks.198 probably by an active trointestinal tract. excreted are decreased by heat. In: Somani SM. however. the United Kingdom siderations in nerve agent intoxication. Enthusiasm for this practice waned for a number of reasons: • erratic absorption of the drug from the gas- dose is excreted in 3 hours. for discussion of monitoring RBC-ChE activity. Fig. the best alternative in certain cases. mercially available. 2-PAM Cl tablets may be poisoned with organophosphorus compounds. crop dusters).) 188 . which is necessary atropine. ed. An early clinical report204 on the use of 2-PAM Cl in insecticide-poisoned people indicated that the oxime In addition. medical personnel may be tempted to repeat the oxime along with atropine. no more than 2. NY: Academic Press. Clinical con. blocking tubular excretion). the rationale being that crop work- animals205.208 found small amounts of 2-PAM Cl or safety measures. Other of security and therefore might tend to be careless with investigators74. New York. It is no longer common shortly after the oxime was given). The mean blood pressure both as therapy and as a pretreatment for those in is the diastolic plus one third of the difference between the systolic and the diastolic. At one time. that for administration by other routes. with a half-time person at different times) in plasma concentra- of about 90 minutes.200 • the large dose required (5 g to produce an Thiamine also decreases excretion (presumably by average plasma concentration of 4 µg/mL). the contents of for return to work. patients h) required by at-risk workers caused gastrointestinal regained consciousness and stopped convulsing irritation. • the unpopularity of the large. such as that of a depot worker exposed to a nerve agent who shows no Administration effects except for an inhibition of RBC-ChE activity. which is rapidly but transiently re. Soon after it became com- marked hypertension.5-g or life. above. 5-7. If the oxime is effective. in- methyl chloride (2-PAM Cl) over about 25 minutes produces tramuscularly. (eg. it can be repeated once or twice at intervals of 60 to 90 minutes. Since an improvement in the skeletal muscle effects of the agent (ie. and orally.144 Both clearance and amount tion. Additional atropine should be given to minimize secretions and to reduce ventilatory problems. then oxime 1 to 1. and duration of thiamine activity.Medical Aspects of Chemical Warfare if these are not available. An oxime might be given to restore the worker ’s RBC-ChE An oxime should be initially administered with activity to 80% of the baseline value. three Mark I kits or ATNAA should be administered. the frequent administration (every 4–6 reversed the CNS effects of the poison (eg. 1992: 181.5 hours. thereby relieving the casualty’s distress and discomfort. including diarrhea. or both. leading to large differences tubular excretory mechanism (its renal clearance is (both between individuals and in the same close to that of p-aminohippurate199).5 g of oxime should be given within 1 to 1. 2-PAM Cl was administered orally versed by phentolamine (5 mg). prolongs the plasma half. Because of side effects. and increases the plasma concentration for the 1. tablets for pretreatment use. In cases of severe exposure. However.0-g tablets. but it no longer does so.198–202 Some203 question • the relatively slow absorption compared with the therapeutic benefit of thiamine.206 or the cerebrospinal fluid of humans207 ers who take the medication might have a false sense after experimental administration of 2-PAM Cl. exercise. provided its military personnel with a supply of oxime Chemical Warfare Agents.5 g should be administered intravenously over a period of 20 to 30 minutes or longer. An infusion of 25 mg/kg of 2-pyridine aldoxime 2-PAM Cl can be administered intravenously. constant contact with organophosphorus compounds Reproduced with permission from: Sidell FR. but no change in heart rate. When a 30% solution of 2-PAM Cl was injected intramuscularly at doses ranging from 2. If patients require additional treatment in the interim. period lasts much longer (hours) in animals.209 or that it causes sued an autoinjector containing 10 mg of diazepam the circulation to improve.9 µg/kg occurs at 19 min. they do provide some therapeutic benefit (a 5%–10% diazepam was adopted by the US military as the drug reactivation of the inhibited enzyme). but rather for use by a buddy when a sol- or three autoinjectors (600 mg each) should be given dier exhibited severe effects from a nerve agent.141 including those produced by other ECG changes. this difference may account for kg at 7 minutes. the drug caused no change in heart rate or any family. versus 10 minutes for conventional the greater duration of convulsions in animal studies needle-and-syringe injection. Anticonvulsive Therapy Convulsions occur after severe nerve agent ex- posure. linergic blocking drug at the nicotinic sites. 189 . and persisted for several and provide visual and tactual cues to indicate it is different minutes until the individual became apneic and flaccid. 5-8. and as expected after an injection of 2 mL of a hypertonic monkeys. has been shown to control nerve-agent–induced signs or symptoms (except for pain at the injection site. Thus. guinea pigs. seizures/convulsions in rats. versus 6. The antidotes and taking tablets avoids the pain of an injection. are given in a standard dose to experimental animals IM administration of 2-PAM Cl with automatic rather than titrated to a therapeutic effect as they are injectors results in a plasma concentration of 4 µg/ in human patients. In these instances. In reports20. rabbits. no specific anticonvulsive therapy Reproduced with permission from: Meridian Medical Tech- was needed nor given.104 of severe cases. Nerve Agent.5 to 30 mg/ Diazepam. The distinctive flared “wings” on each side make the shape of the injector unique lapsed and lost consciousness. US Antidote.210 Suggested for immediate anticonvulsant treatment of nerve agent reasons for this benefit are that an oxime acts as a cho.129. Nerve Agents Oral administration may be considered preferable (al. from either the 2-pyridine aldoxime methyl chloride (2-PAM The convulsions did not recur after atropine and oxime Cl) ComboPen or the antidote treatment nerve agent auto- therapy and ventilatory support were administered. but ment of status epilepticus seizures by the IM route. Bristol. than in humans.198 anticholinesterases. or CANA) to release of catecholamines.128. even enteral route because tablets can be self-administered those given therapy.132.5 ate lethal effects of exposure but not the convulsant µg/kg at 22 min for the needle-and-syringe method. convulsions (or what were described as “convulsive jerks” or Fig. Tenn.211–215 It is commonly used to stop acute solution).135. the US military is- to atropine at the muscarinic sites. Therapy utes. as the AT- NAA combined autoinjector replaces the MARK 1 set.178 (A maximum plasma because the animals are protected from the immedi- concentration of 6. Laboratory studies indicate that the convulsive though less reliable) to administration through a par.198. The Convulsive Because of the hypertensive effect of 2-PAM Cl. possibly by stimulating the (Convulsive Antidote. (CANA) contains 10 mg of diazepam. oximes are often said to be ineffective in agent–induced brain lesions due to this anticonvulsant treating soman poisoning.66. About 80% to 90% of the intact drug is excreted un- metabolized in the urine. nologies Inc. 30 mg/ seizures (eg.209. Nerve Agent injector was not intended for military doctrine states that no more than 2000 mg IV self-use.211 Because of these properties and animals have shown that oximes are not as effective in because diazepam is approved by the FDA for treat- treating soman intoxication as in sarin intoxication. status epilepticus) that may result from kg caused an elevation in blood pressure and minimal other etiologies. Experimental studies in activity.199 When given intramuscularly.210 all military personnel (Figure 5-8).) effects.128. atropine alone is used. The convulsive antidote nerve agent autoinjector “spasms”) started within seconds after the casualty col. injector (ATNAA). an anticonvulsant of the benzodiazepine kg. atropine-only autoinjectors should also be available for use so that the 2-PAM Cl dosage limits are not exceeded during the treatment of a severe casualty. The in 1 hour. the half-life is about 90 min. analogous During the Persian Gulf War.131. casualties in the field. Experimental studies also have Because of the rapid aging of the soman–AChE shown that diazepam reduces or prevents nerve- complex. She was given epam. prodrug formulation of atropine will cause ventricular fibrillation. and to stop ous secretions and high airway resistance. Wyeth. New Jersey]). adequate ventilation and symptoms. normal- nerve-agent–induced seizures compared to diazepam izing the ST-T changes. and adrenergic blockade. which zolam is twice as potent and twice as rapid in stopping slowed the heart rate to 107 beats per minute. can be recognized by an untrained observer. presumably because of persistent [Versed.132 allowed to become cyanotic. this produced a For these reasons. despite administration for immediate field treatment. research has shown that stabilized with atropine and ventilatory support. The authors reporting on the agent–induced seizures and the eventual replacement case suggested that propranolol might be of value in of diazepam by midazolam in the convulsive antidote protecting against the effects of atropine and organo- nerve agent injectors. is walking and talking. Atropine or reverse the abnormal process. In effect. total of 830 mg). categories are based on the casualty presenting signs In a more sophisticated setting. This effect diazepam that is bioconverted to diazepam following has not been reported in humans. lorazepam her ECG showed depression of the ST segment and flat- [Ativan. of the casualty warrants the administration of three Experimental studies156. with both cholinergic FDA approval of midazolam as treatment of nerve. The United Kingdom uses animals are poisoned with ChE inhibitors and then a drug similar to diazepam known as Avizafone.Medical Aspects of Chemical Warfare buddy system was used because any soldier able to Therapy for Cardiac Arrhythmias self-administer diazepam does not need it. airways) same in the treatment of a patient with nerve agent are decreased and resistance to assisted ventilation is intoxication. rapid IV administration of Avizafone is a water-soluble. different therapeutic measures are recom- apnea. sinus tachycardia secondary to large doses of atropine tive in stopping nerve-agent–induced seizure as diaz. mouth. mal individual. 190 . (287 mg in 4 days. The normal ECG pattern and when the drugs are administered IM. gasping for breath. a β-adrenergic blocking agent (propranolol). Treatment is based on because a buddy’s resources are few. convulsions. These goals are the must be given until secretions (nose. Switzerland]) are just as effec. to relieve distress. efforts are currently underway for pharmacologically isolated heart. Roche. Transient arrhythmias occur after nerve agent in- injectors and could administer two additional 10 mg toxication and after atropine administration in a nor- doses at 10-minute intervals to a convulsing casualty. Madison. minimal. Muscular fasciculations and small amounts I kits required to provide relief. the signs and symptoms caused by the particular ex- sistance is limited: a buddy can administer three Mark posure (Table 5-7). after the onset of atropine-induced sinus tachycardia ing the third Mark I or ATNAAs when the condition (see discussion of cardiac effects above). phosphorus intoxication. Current medi- dyspnea and objective manifestations. nor will IM or IV drug therapy reverse is obtained. Seldom are more than two to three Mark miosis. straightforward: to minimize the provide little improvement in the presence of copi- patient’s discomfort. in most cases. The signs of severe distress in a fellow soldier. a 20-year-old patient was in a medical treatment facility. but other anticonvulsant benzodiazepines (eg.211 repeated doses of atropine. cations will not immediately restore consciousness administration of the contents of Mark I kits (or atro. After severe intoxication from exposure to an or- If a convulsing or seizing casualty is being treated ganophosphate insecticide. or respiration or completely reverse skeletal muscle pine alone) should be continued at intervals until relief abnormalities. Basel.138 Experimental work has also shown that mida. Medics and unit lifesavers were issued additional diazepam auto. the level of as. The following suggested exposure I kits and diazepam and then seek medical assistance. but even the best ventilators are.107. but degrees of exposure severity. Therapy should be titrated against the complaints of The goals of therapy must be realistic. Topical application of of twitching may continue in a conscious patient long atropine or homatropine can effectively relieve eye or after adequate ventilation is restored and the patient head pain not relieved by Mark I injections. injection. mended for treating nerve agent casualties at different A casualty’s buddy will usually act appropriately. The irregularities generally terminate Current policy states that diazepam is given follow. and clear-cut.215 have shown that when Mark I kits or ATNAAs. the route of heart rate of 107 beats per minute persisted. such Although in practice exposure categories are never as twitching.216 SPECIFIC TREATMENT BY EXPOSURE CATEGORY The goals of medical therapy of any poisoning is the highest priority. such as retching. midazolam tening of the T wave. ) agent. with accompanying eye symptoms. reflex nausea and vomiting diazepam > 5 min of exposure: 1–2 Mark I kits Moderately severe Severe dyspnea. < 5 min of exposure: 1 Mark I kit (vapor) reflex nausea and vomiting > 5 min of exposure*: observation Mild Miosis. tact. Since vapor (or inhaled aerosol) causes ef- cility is available. not reasonably certain that exposure was by vapor alone on the RBC-ChE activity (with one possible exception: (if the casualty was standing downwind from muni- an asymptomatic worker with decreased ChE activity. rhinorrhea. ventilatory support. agent sometimes occurs in an area where liquid agent Because the onset of effects caused by nerve agent was present. The longer the the suspected casualty should be thoroughly and interval until the onset of signs and symptoms. but medical assistance will still be medical observation for 18 hours. diazepam *Casualty has been out of contaminated environment during this time. tions or a container. gastrointestinal or 3 Mark I kits. standby ventilatory sup- neuromuscular signs port. ventilatory support. if an unprotected 191 . then the final sample for Suspected but unconfirmed exposure to a nerve analysis must be drawn during that time period. and if there has been no oxime therapy. Suspected Exposure activity may not occur for 18 to 24 hours. fasciculations 1 Mark I kit (liquid on skin) Moderate Gastrointestinal signs and symptoms 1 Mark I kit Moderately severe Gastrointestinal signs plus respiratory 3 Mark I kits. suc- flaccid paralysis. then no significant absorption has occurred and the new value provides Miosis. that a “suspected” asymptomatic casualty would be An individual working with nerve agent in an in. either vapor or vapor and liquid. If a laboratory fa. diazepam Severe Loss of consciousness. 3 Mark I kits. on RBC-ChE activity monitoring. In such cases. or standing across a see Oxime Therapy section. prolonged observation is prudent. dustrial or laboratory environment will have a baseline RBC-ChE activity value on record. produced by this route. Workers without signs or symptoms exposure may occur as late as 18 hours after skin con- may not be sure they are contaminated. There are many situations in which one can be therapy should be based on signs or symptoms. blood should be drawn to measure fects within seconds or minutes. then absorption tion is quite important in the management of this ca- of the agent has occurred. above. convulsions. rhinorrhea. The medical care laboratory or storeroom from a spilled agent or leak- provider must remember that the nadir of RBC-ChE ing container). for example. it is extremely unlikely RBC-ChE activity. rhinorrhea are signs of a minimal exposure to a nerve es section. Nerve Agents TABLE 5-7 RECOMMENDED THERAPY FOR CASUALTIES OF NERVE AGENTS Exposure Route Exposure Category Signs and Symptoms Therapy Inhalational Minimal Miosis with or without rhinorrhea. the less completely decontaminated and kept under close severe they will be. This distinc- If the activity is decreased. mild dyspnea. standby ventilatory sup- or neuromuscular signs port Severe Same as for severe vapor exposure 3 Mark I kits. diazepam Dermal Mild Localized sweating. (See Blood Cholinesteras. suc- tion. depending on severity of dyspnea Moderate Miosis. necessary. and confirmation of the baseline. < 5 min of exposure: 2 Mark I kits reflex nausea and vomiting > 5 min of exposure: 0 or 1 Mark I kit. If this value is still at Minimal Exposure baseline after a possible exposure. but the decision to begin sualty. moderate to severe < 5 min of exposure: 3 Mark I kits and dyspnea. above). however. On the other hand. apnea tion. should be administered if the contents of three kits atropine (the 2 mg contained in one Mark I kit or one or ATNAAs do not relieve the dyspnea after 10 to 15 ATNAA) may provide some relief. the contents of two alone) given at 5-minute to 10-minute intervals. the exposure was single-site exposure (one drop at A person mildly exposed to a nerve agent should one place). the contents to a nerve agent vapor and may or may not have been of two Mark I kits or ATNAAs should be administered contaminated by a liquid agent. Therapy should An individual with mild or moderate dyspnea and be more aggressive when these symptoms occur within possibly with miosis. blood should be drawn for assay of RBC-ChE activity whereas effects from liquid agent on the skin may not if assay facilities are available. However. The contents of three occur until hours later. it is unlikely that it will be needed. the MANAA hours after the onset of signs and symptoms. should be used. if that is the only symptom. with Mark I kits or two ATNAA should be administered a maximum of three oxime injections. the posure. several hours after the time of known exposure. Again. or both can be clas. the more ominous the outlook. an hour after exposure than when there is a longer sified as having a mild exposure to nerve agent. rhinorrhea. with accompanying physical in areas where liquid agent is present. If no improvement occurs within 5 min. The casualty mental contamination with multiple sites of exposure should also have blood drawn to measure RBC-AChE on the skin. initially. and quickly and are at their maximum within minutes. the visual blurring 5-minute to 10-minute intervals until the dyspnea caused by atropine versus the relatively small amount subsides. If the rhinorrhea is severe and troublesome. Only three oxime Nausea and vomiting that occur several hours after autoinjectors (Mark I kit) or three ATNAAs should exposure have been treated successfully with 2 or 4 mg be given. topical atropine or homatro. Additional atropine should be given at pine should be given. It is not certain that this treatment will be be thoroughly decontaminated (exposure to vapor successful if exposure is from a splash or from environ- alone does not require decontamination). additional atropine alone sidered. the sooner after exposure they appear. The be by both routes. is ineffective in the usual doses (2 or 4 mg). and the symptoms did not recur. However. for 18 hours. further therapy should be with atropine of atropine. If the time of The contents of an additional kit may be given if the exposure is unknown. No more than three Mark I kits or ATNAAs of visual impairment caused by miosis must be con. but or ATNAAs should be administered. Mark I kits or three ATNAAs and diazepam should Atropine (and oxime) should not be given systemi. Moderately Severe Exposure Moderate Exposure In cases of moderately severe exposure. If the onset is immediately. the contents of only one kit should be given contents of one Mark I kit or ATNAA should be given immediately. minutes. Therefore. If seen later than 10 minutes after exposure. If there is reason to suspect liquid contami- If liquid exposure can be excluded. Effects from vapor exposure occur casualty should be thoroughly decontaminated. exposure may signs. Atropine alone should be receive the contents of another Mark I kit or ATNAA. the casualty will be conscious and have one or more of the follow- A casualty who has had moderate exposure to either ing signs and symptoms: severe respiratory distress a nerve agent vapor alone or to vapor and liquid will (marked dyspnea and objective signs of pulmonary 192 . casualties with this degree of activity prior to administering Mark I or ATTNA if fa. The delay in onset. initially. If 5 to 10 minutes have passed since ex. inhaled atropine product may be helpful for patients under observation of a medic who can self-medicate. exposure should be observed closely for at least 18 cilities are available for the assay. the contents of two Mark I kits casualty’s condition worsens 5 to 10 minutes later. and additional Mark I kits or ATNAAs as utes under either circumstance. there is no reason nation. because it posure.Medical Aspects of Chemical Warfare individual is close to an agent splash or is walking have severe dyspnea. and probably also miosis and rhinorrhea. the patient should be kept under observation for prolonged observation. Nausea and vomiting are frequently the first effects Mild Exposure of liquid contamination. be given if the casualty is seen within minutes of ex- cally for miosis. used after the third Mark I or ATNAA. If the onset is about an hour or less symptoms indicate that the casualty has been exposed from the known time of liquid exposure. alone. however. and further therapy (the contents of a third If an exposed person in this category is seen within Mark I kit or ATNAA to a total of three. If eye pain the casualty should receive the contents of two kits/ (or head pain) is severe. ATNAAs. the casualty should needed to a total of three. then atropine several minutes after exposure. or in nonconvulsive status epilepticus. level 4 gear. subways. but it must be accomplished because a nonmoving. If the casualty has not the contaminated area. the contents of the tivity. tions from the mouth and nose. has not convulsed. candidate for further attention on the battlefield. Diazepam should cause of very vigorous and aggressive medical man- always be given when the contents of three Mark I kits agement. level 4 gear. but it is not without danger in an apneic copious secretions from the mouth and nose and will and cyanotic patient. protective posture. If ventilatory assistance The triad of consciousness. should be thoroughly decontaminated and have blood Despite the circumstances. the casualty’s condition may worsen. the signs of respiration. Even If the casualty shows no movement. The IV route generally gasping for air with marked cyanosis. the best treat- administration of atropine. Whether or not concomitant have generalized fasciculations in addition to convul. but an attempt at Severe Exposure treatment should be made anyway. and additional drug therapy (atropine alone) it will be carried to the heart and lungs. they intratracheally by needle and syringe. the of unabsorbed agent in the skin. ventilatory support can be provided. Japan. If an en- task when the rescuer and the casualty are both in dotracheal tube can be inserted. In a medical treatment facility. tamination via the patient is important. and may be provides the fastest delivery of the drug throughout convulsing or postictal. If the exposure was caregivers must wear appropriate protective equip- by vapor only and the casualty is seen in a vapor. medical care providers should be prepared Medical personnel must first provide oxygenation to provide ventilatory assistance. routes of atropine administration other than agent will be unconscious. 2 or 4 mg of atropine should be given in the Tokyo. marked secre. improvement should be expected. if available. several casualties who intravenously. The casualty walk out of the hospital several days later. injected into the tube either by needle and syringe or 193 . If ventilatory if there is no improvement within 5 minutes after IV assistance is not immediately available. When there early. if the means gressive therapy. atropine could be full mission-oriented. If they are cal personnel may consider administering atropine postictal. will be forthcoming within minutes. In the case of a failed or failing cardiovascular Casualties who are severely exposed to a nerve system. Nerve Agents impairment such as wheezes and rales). self-protection from con- drawn for AChE assay before oxime is given. and the remainder of the total amount of were not breathing and who had no cardiac activity 6 mg of atropine. including adequate and administer atropine by a technique that ensures suction. therapy in this context. cardiovascular system. knowledge of the route of exposure is use. circumstances. and spontaneous respiration is an indicator of three Mark I kits or ATNAAs should be administered a good outcome. or if there is severe hypotension. but carotid pulse may be the easiest for the examiner to feel it is a relatively insignificant sign as a guideline for in mission-oriented. lost consciousness. A Miosis may be present if exposure was by vapor. is no chance of rapid ventilatory assistance. ful in planning further treatment. ment until they have an opportunity to decontaminate free environment some minutes later. the medical personnel The contents of three Mark I kits or ATNAAs should may be slightly more optimistic and proceed with ag- be administered immediately. protective posture. or with the atropine autoinjector (the AtroPen). Be- should be given intramuscularly. along with the three oxime injections. drug therapy casualties and to remove them and themselves from should result in improvement. and muscular fasciculations and twitches. or ATNAAs and diazepam. and has not The success of therapy under these circumstances is become apneic. the initial response should be to peribronchial circulation may still have adequate determine if the heart is beating. They may be apneic or IM should be considered. If the heart rate is very slow bination of liquid and vapor. there may be a reservoir or nonexistent. Since decon- Again. In ei. tamination of the patient may not be the first priority. Preferably. one or two of these casualties were able to or ATNAAs are administered together. nausea and vomiting nonbreathing casualty without a heartbeat is not a (or retching). military medi- sive or large-muscle twitching movements. These casualties will have the body. even in the best possible therapy. little is gained by Mark I/ATNAA therapy. despite the initial chances for success are poor. including no if the casualty’s systemic blood pressure is low. ther case. If directly proportional to the viability of the casualty’s the exposure was the result of liquid agent or a com. After the Aum Shinrikyo sarin release are available. lack of convulsive ac. may be flaccid and apneic. were taken to a hospital emergency department. or 5 to 10 minutes after IM ment is to administer the contents of three Mark I kits administration of atropine. provided adequate therapy is given whether the circulation is intact or not. This is not an easy blood flow to carry the drug to vital areas. tional atropine cannot be given intravenously. returning a soldier to duty. troops who vidual with rather mild effects (miosis and rhinorrhea) were symptomatic (miosis. Muscular genation. light and may have mental lapses for as long as 6 to 8 ficult to predict whether a soldier would be at greater weeks. without spontaneous respi- should be given with the initial 6 mg of atropine. was given and the agent was one susceptible to oxime vidual who has been a nerve agent casualty is returned therapy. the initial dose of are administered together to a severely poisoned atropine should be at least the 6 mg from the three casualty. In to duty. If addi. immediate reversal of all of the be prudent to wait even longer before administering effects of the nerve agent will not occur. previous exposure? dyspnea. and convulsions. If secretions Even with adequate oxygenation and large decrease or if there are attempts at breathing. multiple atropine autoinjectors or ATNAAs mask-valve-bag apparatus used with ambient air will are required to compensate for the volume of the provide some assistance. depending • What is the military need for the soldier? on the assignment and the military need. and the casualty is partly of severely exposed casualties is restoration of oxy. The total Generally the restoration of oxygenation and the in- initial dose of atropine can be as much as 10 mg. alty is alert enough and has strength enough to get Ideally. The casualty additional atropine. a field setting. the amount should be given intramuscularly. and the need to return A soldier who has had signs of severe exposure the fighting soldier to duty may be more acute. The risk of and if the casualty is not hypoxic. given intramuscularly is negligible. it may amounts of atropine. the soldier may experience visual problems in dim In the absence of blood ChE measurements. tracheobronchial tree. level 4 gear should protect against further otherwise symptom-free and sign-free. Possibly the most critical factor in the treatment secretions are minimized. ChE activity duty if able and needed. it is dif. When the contents of three Mark I kits or ATNAAs For severely exposed casualties. However. result of nerve agent exposure carried out maneuvers if an oxime (contained in the Mark I kit or ATNAA) (including firing weapons) in a satisfactory. The soldier should be returned to active In a military field setting. decision is largely a matter of judgment and should may have milder CNS effects for many weeks after include the following considerations: recovery from the acute phase of intoxication. Even an indi. Atropine alone might restore spontaneous fasciculations may continue for hours after the casu- breathing in a small number of apneic individuals. protective 90% of its baseline value and that the individual is posture. rhinorrhea. dyspnea) as a may have marked ChE inhibition. RETURN TO DUTY Various factors should be considered before an indi. and with muscular flaccidity or twitching for no more oxime should be given for an hour. In one case. continued monitoring is necessary.Medical Aspects of Chemical Warfare with the injector. The with loss of consciousness. rhinorrhea) may be returned to duty within • How well can the soldier function? hours to several days following exposure. but crease in heart rate caused by atropine. RBC-ChE activity must have returned to greater than In any case. then the enzyme activity may be restored. because of the volume positive pressure will be available. Except in dire circumstances. whether or be given intravenously if the capability is available not there are indications of seizure activity. neither the identity of the agent nor the the criteria for reactivation are that the individual’s degree of ChE inhibition or restoration will be known. return to duty during this • If exposed to nerve agent again.45 and these factors must be considered before risk from a second nerve agent exposure. apnea. aided perhaps this dose should not be exceeded without allowing at by the hypertensive effects of 2-PAM Cl. although 194 . measurements are not available. In an industrial setting (depot or laboratory). hours. After respiration is at least partly spontaneous. will the period should not be considered for such casualties. An additional 2 mg or 4 mg should also contents of the third Mark I or ATNAA. alert. soldier be in greater danger because of the An individual with relatively mild effects (miosis. however. In this case. On the other hand. then Hypotension need not be treated. diazepam should be administered with the autoinjectors. Even an RDIC or a disparity. All three injectors of 2-PAM Cl may remain unconscious. administration depends on the response. an apparatus that delivers oxygen under out of bed. will result in least several minutes for a response. but ration.18. Further atropine elevation of the blood pressure to an acceptable level. Ventilatory support respiratory depression from this amount of diazepam must be started before IV atropine is given. proper use of mission-oriented. exposure. at least initially. immaturity 1 mg autoinjectors of atropine only. They did not do nearly as well the primary limiting factors will be the soldier ’s visual at night because of visual problems. mg/kg IM or IV. based on the following: smaller injector needles. In order War.05 Rotenberg and Newmark have summarized the lit. nerve agents were not used on the battlefield. Iraq used tabun and sarin dents. From the 1930s until the 1981–1987 Iran-Iraq many of which have already been described. evaluate each situation as it presented itself. Prolonged mental changes accidentally been exposed several times. and immaturity of the neurotrans. it is not known how well they performed his recommendation. workers in an industrial op. is preferred in small children. aid (with the ensuing administrative processes) than In the Iran-Iraq War. miosis is less com. Nerve Agents suboptimal.217 off-label. Between 1984 and 1987. In the planning for the 2003 invasion of Iraq. children are more susceptible to chemi. the signs half-life of the drug in children appears to be twice that and symptoms of nerve agents in children may well seen in adults. Until then. saying the commander on the ground would turned to duty.1 mg/ erature and extrapolated treatment guidelines based kg in a clear cholinergic crisis. Although technically upon adult experience and animal data. with corneum in the skin of young children. from the Iranian experience with experience. In addition. IV use dermal absorption. They also can be subtle and may require a careful examination learned that it was a bigger problem to seek medical to detect. This is the only instance known while symptomatic. similar to those in adults.45 subject. JAPAN. manner. mended to commanders that units who had come under They stopped going to the aid station if they noted the nerve agent attack be held back from the front lines onset of only mild effects. The treatment of seizures in children is differ from those seen in adults. rendering children more likely to seize to be repeated as frequently as in adults because the with an epileptogenic stimulus. published his 195 . US doctrine is silent on this did not notice a decrement. The only appropriate experience few years has good clinical data emerged from that comes from overseas. and the soldier ’s mental status compared with the intel- eration learned the effects of the agent after they had lectual demands of the job. the first physician to run a battlefield nerve agent casualties in the Iran-Iraq War chemical treatment station treating nerve agent and from the Japanese experience with the 1994 and battlefield casualties in world history. as long as the caregiver remem- in adults. for a period of time until they had reconstituted their ally not in positions requiring acute vision or complex ChE. sarin in Baghdad. Foroutan12 claims to have recom- to continue working in the presence of symptoms. and doses might not need mitter systems. However. representing 25% of the respiratory system. authors recommend an atropine dose of at least 0. Iraq in May 2004. with a higher dose of up to 0. These workers were gener. Only in the last with these scenarios. immaturity of the stratum and 50% of the adult (MARK 1/ATNAA) dose. children than adults. Foroutan. LESSONS FROM IRAN. with benzodiazepine dose mon in organophosphate poisonings in children than adjusted for weight. the entire na- tional experience had been with industrial accidents. and children may present with less obvious bers that status epilepticus may present differently in convulsions/seizures than adults. the nerve agent poisoning in the pediatric population. TREATMENT GUIDELINES IN CHILDREN Very little has been published on the treatment of To treat children exposed to nerve agents. and their supervisors apparently exposed to nerve agent. the United States military has no experience with treating nerve agent Iran casualties on the battlefield. For 2-PAM Cl. to properly plan for either battlefield or terrorist inci. The FDA has approved 0. which facilitates correspondingly shorter needles. In another instance. it is crucial to learn from those who have dealt extensively against Iranian troops.88 acuity compared with the visual demands of the job. they could continue to of a unit-level recommendation on a group of soldiers perform their jobs. In an otherwise asymptomatic casualty. to use in children who are large enough for the auto- cal agents than adults.5 mg and mass and higher surface-to-volume ratio. and IRAQ With the exception of two soldiers exposed to 1995 terrorist attacks. It is not clear whether the commanders followed decisions. the The need for soldiers in a frontline military opera. the issue. the MARK 1 autoinjectors are probably safe In general. authors were told that the theater surgeon responded to tion may require that every walking casualty be re. oximes. fatigue. by syndromic reasoning. sented for medical attention were not found to have and psychiatric diagnoses.165. based on correlations with clini- patients within 5 hours. all with slightly decreased plan a robust and redundant system that can deal with ChE levels. and anticonvulsants saved many agent casualties in the war. This illustrates the need to Four pregnant women. The physicians in the first attack.” be treated without knowing the specific organophos- Psychogenic casualties.233 treat all of these patients. for example.78.”228 Even been due to Foroutan’s inability to guarantee that those patients who actually did have sarin poisoning atropine would be given during medical evacuation symptoms tended to have mild symptoms. were among the patients evaluated at Saint mass casualties of nerve agent exposure. whether those with actual phate. Luke’s International Hospital. including combat s tress. were unaccustomed to seeing this condition. This may have resulted from the 1.234.229 They were between 9 Foroutan felt that the numbers of nerve agent casu. which actually gave 200 mg of atropine IV in a 10-minute saw more patients than any other hospital (641). In that part of central Japan driasis was one indication to decrease atropine. any signs or symptoms of sarin poisoning.230 By contrast.232 symptomatic patients requiring immediate attention. vilian victims of the Tokyo subway attack. This figure At the time. “even insecticide poisoning is common. All alties had been underestimated by the media and the delivered healthy infants on schedule and without government of Iran because.53.229. Foroutan ample. well or died. but that was never proven. unlike the photogenic mustard antidotal treatment is highly reassuring because even casualties who were evacuated to Europe. were able to make the diagnosis of muscle and the circulation. Many of the patients had no demonstrated depres- He also stressed the need to treat patients as quickly as sion of ChE.143. ues are not as effective a guide to their conditions as ation and triage system saves lives on the battlefield. At Toranomon Hospital. In the Hosseiniyeh attack. unlike sulfur mustard complications.100 of the 5. Japan sualty care in a series of articles in the Farsi-language Kowsar Medical Journal in the late 1990s. as laboratory val- Foroutan’s experience shows that a robust evacu. Foroutan deter.165. the Iranians thought Iraq had also used has become a major point in the teaching of mass ca- cyanide. the standard protocols using that there had been between 45. along with 1. of pralidoxime iodide recovered their ChE levels faster 196 . so the patients could if the patient’s mouth has not completely dried. nerve agent casualties rapidly became exposed patients ever recorded. in Mat- in an English-language review paper. Foroutan noted that the organophosphate poisoning (cholinergic crisis) early disappearance of miosis or even the appearance of my. The had a very small supply to use. nerve agent survivors had no The Japanese experience with acute nerve agent propaganda value. It may also have others could be considered the “worried well. in the small city due to the relative disconnection between the papillary of Matsumoto. did not carry oxime with them. he received over 300 “severe” severity of poisoning. This reinforces the principle that patients possible in order to achieve optimal outcomes.12 Among the sumoto in 1994 and on the Tokyo subway system in conclusions this analysis reached. the one which most over.229 Although miosis is a poor guide to atropinization. 218–227 The There is considerable literature on the medical lessons Foroutan learned have been summarized aspects of the two terrorist attacks in Japan.500 people presenting to medical atten- lack of oxime therapy far forward.000 and 100.700 less severely cal picture and other values in 213 patients seen after affected patients. just as they were in the ci.” were a diagnosis lagged considerably at many hospitals that major problem for Foroutan. infectious diseases. As such.231.235 Those patients receiving 3 g or more Nations estimate. and even physicians ranging from extremely severe to extremely mild. and 36 weeks’ gestation at the time of poisoning. larger Tokyo attack. only to 15-minute period. is the clinical examination. sualty management of a future nerve agent attack. several times the United patients. the combined figures show about treatment protocols. This may be the only series of pregnant casualties. Iranian soldiers tion having signs and symptoms of sarin poisoning. at Saint Luke’s International Hospital.Medical Aspects of Chemical Warfare reminiscence of nerve agent and sulfur mustard ca. heat stroke. 5 patients were deemed “critical.229. In a few cases.000 nerve atropine. should be treated symptomatically. He stressed In both the Matsumoto and the Tokyo subway attacks.53. ChE activity was also found to be a poor guide to the whelmed his aid station. In Foroutan used large amounts of atropine in his Tokyo. psychiatric diagnoses or simply “worried well. in the later.”165. 1995. For ex- to the rear of his location. the need to identify them and remove them from the miosis was the most common symptom.228–244 One of the major lessons from the mined the differential diagnosis included cyanide Japanese attacks is that 80% of the patients who pre- poisoning. One aid station was not equipped to the Tokyo attack. He believed with delays of diagnosis. One peculiarity is that the these effects overlap with or satisfy criteria for post- Japanese oxime is 2-PAM iodide. increased agents. nausea. older patients emergency room reported dim vision. six had been severely poisoned. with severe seem to be more susceptible to insomnia. 23% of the staff reported mild the US Army came in contact with an old sarin shell.239 Many still met posttraumatic stress than that.239 An uncontrolled. 85 of 149 patients examined 1 and 2 years after the Mat- The value of acute therapy was validated in Tokyo.243 miosis in 8. one cardiopulmonary arrest. sufficient In another series of 18 patients studied 6 to 8 months resources may not be available to give antidotal treat. the Tokyo case demonstrates that even giving entirely normal. reported some acute memory disturbances that were 105 patients were admitted overnight and 95% were not well documented in their medical charts. The soldiers made the syndro- (based upon a questionnaire in which only 45% of 1063 mic diagnosis of possible nerve agent exposure them- patients responded). such as 2-PAM Cl. even a well-ventilated one. rhinorrhea in 8. is that. as in traumatic stress disorder and have been chronically the United States. not chronic. At Saint Luke’s. and 6 months to develop drugs using iodide where possible.229 In fective. dyspnea. nightmares. This is noteworthy because no US soldiers had Another major lesson from the Japanese experience ever had documented nerve agent exposure before. secondary exposure when patients are neither stripped follow-up questionnaire of Saint Luke’s patients sug- of their clothing nor decontaminated prior to entry.229 selves.238–244 Many of exposure. although One of the major lessons learned from the Japanese brainstem auditory evoked responses were normal. especially Oximes. and mild dyspnea. headache. and the reported symptoms varied were essentially identical to those described in earlier widely. one patient was resuscitated reported sensory neuropathies. sections of this chapter. which may nese attacks is that there is the possibility of long-lasting or may not have been due to his documented sarin clinical effects from sarin exposure. and nose pain mild sarin poisoning.234 Six of the 13 received atropine. problem and 62% reduced from baseline.236. and thus enzyme that has been bound to nerve that takes place after ChE has bound to nerve agent.246 PYRIDOSTIGMINE BROMIDE AS A PRETREATMENT FOR NERVE AGENT POISONING Aging half time places a significant limitation on negative charge on the remaining ChE-agent complex. ry evoked responses (P300) were prolonged. and cough in 2.236. Iraq and one of the 13 received pralidoxime iodide. four had persistent EEG abnormalities. agent and subsequently aged must be replaced by resulting in the loss of a side chain and placing a new synthesis of ChE by the body. visually evoked responses (P[positive treatment to those who appear to be beyond saving is wave]100[milliseconds after the stimulaton]) and senso- not necessarily futile. including fear of riding subways.238 gests many may have developed posttraumatic stress At Keio University Hospital. dim vision. one had persistent visual field defects. depression. like the one described by Foroutan. Aging is the reaction enzyme. and later in a relatively short period of time. cannot reactivate “aged” those agents that age rapidly. of these At Saint Luke’s. Their discharged within 4 days. memory difficulties several months later. 5-year. sumoto attack. are at high risk of stress disorder at the time. physical disorders. irritation. sore presumably from the Iran-Iraq war. 13 of 15 doctors in the disorder. Japan disabling for some patients. experience is that healthcare workers in an emergency and some of these patients also had posttraumatic room. chest tightness or dyspnea in 4. insomnia. Despite that. all the doctors continued to practice throughout In May 2004 two explosive ordnance soldiers in the day. nerve agent casualties either die or improve nasal and oral secretions. The reason for this is cultural. At Saint Luke’s. after exposure.78 Within the survivor group. of three patients who presented in full six patients. oxime antidotal therapy for nerve agents. poisoned. has a high incidence of thyroid disease and often tries 60% of responders had symptoms 1.244 or in an overwhelming civilian catastrophe. In one questionnaire study.228 indicating that nerve agent ChEs were estimated by back-calculation to be 39% mass casualties create an acute. Most nerve agents 197 .237 Other after exposure.245 One of the two for the health care system. in contrast to many other chemical warfare The soldiers experienced miosis. and one had multifocal and discharged on hospital day 6. Nerve Agents than those who did not. at a time when they were clinically ment. and they were generally ef.229 Although in a premature ventricular contractions. soldiers appeared to recover fully but then developed Among the most important lessons from the Japa. not 2-PAM Cl. and experienced throat. and flashbacks. dizziness. Of 27 moderately military situation. the Japanese hospital treatment protocols disorder criteria. 3. including eye pain. it ages so slowly that second characteristic is that carbamoylated AChE is in any clinically relevant time frame. (3) Sidell FR. Drug Chem Toxicol. Academic Press. 198 . Chem Biol doses mimics the peripheral toxic effects of the or- Interact. aging reaction of nerve agents bound to AChE. are shown in Figure 5-9. carbamates inhibit the Guinea pig (in vivo) 7. San Diego. As a quaternary amine. Thomas NC. Caranto G. The reactivatibility ganophosphate nerve agents. Blick DW. Human (in vitro) 7. (2) Doctor BP. oxime therapy is useless in a patient poisoned by such a nerve agent. In myasthenic GF Human (in vitro) 40 h1 patients. is freely and spontaneously reversible. DL. but because it crosses the blood-brain Human (in vitro) 3 h1 barrier. 1969. Multidimensional Pharmacochemistry. It may seem paradoxi- of cholinesterase inhibited by VX and sarin in man. For example. or decarbamoylate.27:241–252.5 h5 Dosage of pyridostigmine for myasthenic patients in the United States starts at 60 mg by mouth every VX Human (in vitro) 48 h3 8 hours and increases from there. site of AChE. 1984: 52–53. Yarbrough LW. whose aging half-time is on the order of minutes.3 h2 Its chemical structure and that of a related carbamate. Groff WA. The concern. physostigmine.0 min4 ment. Pyri- Human (in vitro) 2–6 min1 dostigmine has been approved by the FDA since 1952 for the treatment of myasthenia gravis. pyridostigmine prolongs the activity of ACh. but two critical characteristics of the rates of aging of soman-inhibited erythrocyte acetylcholinesterase in carbamate-enzyme bond contribute to the usefulness different animal species. (5) Hill of carbamates for this purpose. oxime will still fully protected from attack by nerve agents because the be useful. however. Human (in vitro) 13. Anderson DR. carbamoylation. Edgewood Arsenal. pyridostigmine in large Protection of primate performance against soman toxicity. Physostigmine GB (sarin) Human (in vivo) 5 h3 acts similarly. Harris LW. Cholinesterases as scavengers for organophosphorus compounds: As an inhibitor of AChE. First. there is the possibility of behavioral side effects and it is therefore not used as a nerve agent pretreat- GD (soman) Marmoset (in vivo) 1. Edgewood Arsenal Technical Report 43-13. Reactivation by 2-PAM Cl of Human Red Blood Cell the interaction between carbamates and the active Cholinesterase Poisoned in vitro by Cyclohexylmethylphosphonofluoridate (GF). Like the nerve agents. Md: Medical Research Laboratory. the enzyme from a age slowly enough that this limitation is not crucial carbamate compound. 1993. Consequently. The although VX is extremely toxic.5 min4 enzymatic activity of AChE. A comparison of in vivo and in vitro agent poisoning. (4) Talbot BG. pyri- RBC-ChE: red blood cell cholinesterase dostigmine has a long and favorable safety record in (1) Mager PP. 5-9. unlike the normally irreversible inhibition of AChE by the nerve agents. Toxicol Appl cal that carbamate compounds protect against nerve Pharm. pyridostigmine is ionized under normal physiological Rat (in vivo) 8. the US and other militaries turned to the carbamates.Medical Aspects of Chemical Warfare TABLE 5-8 upon rapid-aging nerve agents such as soman. The chemical structures of the carbamates (a) pyridostigmine and (b) physostigmine. Nerve Agent RBC-ChE Source Aging Half-Time Due to the limitations of existing therapy.6 min4 conditions and penetrates poorly into the CNS. et al. 1974. Carbamates do not undergo the either tactically or clinically (Table 5-8). has always centered active site of the carbamoylated enzyme is not acces- a b Fig. Once several AGING HALF-TIME OF NERVE AGENTS half-times have elapsed. Pyri- GA (tabun) Human (in vitro) >14 h1 dostigmine is one of the best known drugs of this class.11:289–305. Lennox WJ. patients receiving 480 mg per day are not unusual. Calif: this patient population.87:285–293. 1988. No oxime reactivators are needed to dissociate. such as 2-PAM Cl neuromuscular transmission to support respiration. Thus. Md: US Army Medical Research Institute of Chemical barked upon a series of studies in animal models.64 [1. PR relative to still needed to antagonize ACh excess. Aberdeen Proving humans exposed to nerve agents. pyridostigmine pretreatment. carbamoylated enzyme. 15. Ground. four of five rhe.1 [22. The man challenge at extremely high doses was limited. challenge with the five nerve agents with and without however.3 [13.8] 1. Nerve Agents sible for binding nerve agent molecules. and an oxime the atropine plus 2-PAM Cl group > 24 (617 ÷ 25. clearly pigs. NA: not applicable mine. 1987: 233. 5-9 summarizes one study using male rhesus mon- keys. (Inhibition of RBC-AChE survived for 48 hours after being challenged with GF by pyridostigmine is a useful index of its inhibition of at a level 5-fold higher than its LD50. With sarin or VX. Control (no treat. with minimal side effect profiles. The PR of 1. spontaneous postexposure decarbamoylation of the enzyme regenerates enough atropine + AChE activity to sustain vital functions. The PR was well in excess of 40. PRs.38–19.0–28. mine pretreatment and atropine/oxime therapy. and 2-PAM Cl.7–17. protection (PR > 40 when compared with the control depending on the animal system studied. the combination of pyridostigmine pretreat.64 in these monkeys is typi. and provides little additional benefit against challenge cal of the most effective known postexposure antidote by sarin or VX. In a later study. Prompt postexposure administration of atropine is *Indeterminate because of small number of subjects. 25. as detailed below. temporary inhibition of a small portion of ChE is well tolerated by humans.1) reactivator must also be administered if an excess of 2-PAM Cl: 2-pyridine aldoxime methyl chloride nerve agent remains to attack the newly uncovered CL: confidence limit (based on a separate slopes model) LD50: median lethal dose AChE active sites that were protected by pyridostig. it must be recognized that the normal (µg/kg) [95% CL] Ratio [95% CL] human carries excess ChE. In pyridostig- mine-pretreated animals with a sufficient quantity Pyridostigmine > 617 > 40* pretreatment + of protected. the US military em. Efficacy of pyridostigmine against soman intoxication in a primate model. PR = 24 when compared with the group given mine causes either no change or a minor decrease in atropine and 2-PAM Cl). AChE activity normally decreases Postexposure atro. the LD50 for group given therapy divided by Efficacy the LD50 for control group) Adapted from: Kluwe WM.247 AChE in peripheral synapses).73 Pretreatment with orally administered. TABLE 5-9 sufficient excess AChE activity is normally present in EFFECT OF THERAPY ON Median Lethal synapses so that carbamoylation of 20% to 40% of the Dose IN MONKEYS EXPOSED TO SOMAN enzyme with pyridostigmine does not significantly impair neurotransmission. The only published data on protection of primates meeting the requirement for effectiveness of 5-fold from GF show a PR of more than 5 with pyridostig- improved protection. compared with atropine and oxime therapy from soman by the prompt administration of atropine alone. Table Defense. in animals challenged with soman and tabun.248–250 Table 5-10 shows the PRs obtained therapy in animals not given pretreatment to a soman in animals given atropine and oxime therapy after challenge. data for GF show no benefit from pyridostigmine accurate calculation of a PR was indeterminate in this pretreatment for mice and a small benefit for guinea experiment. which still indicate strong efficacy of atropine Because the number of animals available for so.1] NA ment) When animals are challenged with a lethal dose of nerve agent.5] pine + 2-PAM Cl rapidly. and oxime therapy for exposure to these agents. PR: factor by which the LD50 of a nerve agent challenge is raised (in this experiment. In contrast to this low level of protection. pyridostig- ment and prompt postchallenge administration of mine pretreatment is essential for improved survival atropine and 2-PAM Cl resulted in greatly improved after soman and tabun challenge. In: Proceedings of the Sixth Because it is impossible to test the rationale in Medical Chemical Defense Bioscience Review. Group Mean LD50 Mean Protective Additionally. Functionally. As shown. pyridostig- group. but sus monkeys receiving pyridostigmine pretreatment a control group treated with atropine/oxime alone 199 . becoming too low to measure. pyri- dostigmine-inhibited circulating red blood cell AChE and postexposure therapy of atropine and 2-PAM Cl (RBC-AChE) by 20% to 45%. Monkeys that had no Pyridostigmine pretreatment shows its strongest pyridostigmine pretreatment were not well protected benefit. 9 2.1 Guinea pig 2 58.7/2. Toxicol Lett. Lennox WJ. Lennox WJ. Drug Chem Toxicol.9 4.1* Guinea pig 2 4. and treatment of cyclohexylmethlyphosphonofluoridate (CMFF) poisoning in rhesus monkeys. Efficacy of pyridostig- mine against soman intoxication in a primate model. (7) Lennox WJ.9 Mouse 2 1. (9) Inns RH.5 Rat 5 1. AD B204964. Koplovitz I.3 1.5 2.7 3. Relationship between reversible acetylcholinesterase inhibition and efficacy against soman lethality.70:269–279.8 47. 1994.2 3.4 Rhesus monkey 12 >5 VX Mouse2 7.4 34. (1) Joiner RL. and VX in the rabbit. 1992. Stewart JR.35:427–433. (8) Capacio BR. 1987: 227–234. (4) Sultan WE.4 Guinea pig 11 2. for Soman (GD) Poisoning in Mice and Rabbits. Comparison of the Efficacy of Various Therapeutic Regimens. Unpublished manuscript. Arch Toxicol. 1985. Carchman RA. Evaluation of the toxicity.1 2. 1983.4/5. Koplovitz I. 200 .9/23. The effect of pyridostigmine pretreatment on the efficacy of atropine and oxime treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rodents. Assessing pyridostigmine efficacy by response surface modeling. Drug Interaction Studies of Pyridostigmine with the 5HT3 Receptor Antagonists Ondansetron and Granisetron in Guinea Pigs. 1993. Fundam Appl Toxicol. Harris LW.1 2. Md: US Army Medical Research Institute of Chemical Defense. J Pharm Pharmacol.8 6. In: Proceedings of the 6th Medical Chemical Defense Bioscience Review. Dochterman LW. (10) Kluwe WM. Md: USAMRICD. Stewart JR. Columbus. Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents. Dill GS.5 6. (5) Anderson DR. 1985.1/45.0* Guinea pig 7 2.9* Rat5 2. 1983.5 GB (Sarin) Mouse 2 2. Md: US Army Chemical Systems Labororatory. Life Sci.9 Guinea pig9 1. Md: US Army Medical Research Institute of Chemical Defense.0* Guinea pig2 36.4 3. Carter WH Jr. Rockwood GA. et al. The effect of pyridostigmine pretreatment on oxime efficacy against intoxication by soman or VX in rats. Gresham VC.0 2. (3) Koplovitz I. Lennox WJ.8 Rabbit 1 1. et al.0/3. Hobson DW.7 6.6 > 40 GF Mouse 11 1. 1992. USAMRICD Training Report 95-05. (12) Koplovitz I. 1992. Aberdeen Proving Ground. 1995.8* GD (Soman) Mouse4 1. Fundam Appl Toxicol. ARCSL Technical Report 83103. Leadbeater L.8/12.1 Rabbit 3 1.66:622–628. Oh: Battelle Memorial Institute. Harris LW. (6) Jones DE. (11) Stewart JR. Talbot BG.1* Guinea pig 8 1.4 1.2 1. Aberdeen Proving Ground. pathology.4 1.7/7.18:102–106.4 7. With and Without Pyridostigmine Prophylaxis. Aberdeen Proving Ground. The efficacy of bispyridinium derivatives in the treatment of organophosphate poisoning in the guinea pig. (2) Koplovitz I. Kaminskis A. Task 87-35: Evaluating the Efficacy of Antidote Drug Combinations Against Soman or Tabun Toxicity in the Rabbit.2 > 8.1* Rabbit 3 4. A comparison of the efficacy of HI6 and 2-PAM against soman.5:S242–S251. tabun. sarin. Harris LW. Woodard CL.37:793–798.5 Rabbit 4 2.Medical Aspects of Chemical Warfare TABLE 5-10 EFFECT OF THERAPY WITH AND WITHOUT PYRIDOSTIGMINE PRETREATMENT ON PROTEC- TIVE RATIOS IN ANIMALS EXPOSED TO NERVE AGENTS Protective Ratio Nerve Agent Animal Tested Atropine + Oxime Pyridostigmine + Atropine + Oxime GA (Tabun) Rabbit1 2.4 Guinea pig 6 1. 1988.8 Rhesus monkey 10 1. Anderson DR.2/2.15:285–294. Anderson DR. Aberdeen Proving Ground. Stewart JR.3* *Two doses of pyridostigmine were used. based upon non-human not been correlated with any evidence of functional primate studies and human pharmacokinetic studies. postsynaptic mitochondria. as well as alterations of nerve terminal with myasthenia gravis was increased to AChE inhibi. administration. or cognitive functioning at Several studies have sought information on pyri- ground level.262 In a study263 in which pyridostigmine following its administration to myasthenia gravis pa. and analgesic agents. A limited number of animal studies of toxicologi- cal abnormalities and teratogenicity and mutagenic- Safety ity in animals that were given pyridostigmine have had negative results (Hoffman-LaRoche. there was no it appears that there is at least partial permeability comparable body of safety data in healthy young of the blood-brain barrier to polar compounds such adults. anesthetics. Short-term pyridostigmine administration as pyridostigmine.265 There appears to be no phar- another study in which subjects took pyridostigmine macological basis for expecting adverse interactions for 8 days. an increase in blood. changes in sensory. such as drug rash. subjects subjected to heat/work stress. and use while undergoing The flight performance of subjects taking pyri. but they emphasize the is only half of the starting myasthenic dose of 60 mg need to limit enzyme inhibition to the target range of orally every 8 hours. for example. The possible interaction of pyridostigmine dostigmine in two studies was not affected. the risk cannot be for cognitive and psychomotor skills. presynaptic mitochondria at the neuromuscular junc- which have been seen only when the dosage in patients tion resulted. the study noted a slight decrement in performance in autonomic circulatory responses to hemorrhagic shock subjects taking pyridostigmine when they performed and resuscitation appeared normal. where a decrease in skin blood flow in pyridostigmine-treated the identity of threat agents is uncertain.256 and no with other commonly used battlefield medications was impairment in neuromuscular function was noted in reviewed by Keeler. where respiratory in peacetime in some countries. The recommended dose the AChE inhibition level desired in humans. 30 mg orally every 8 hours. not been completely established. with myasthenia gravis. States. for brain barrier permeability occurs rapidly after soman unusual or idiosyncratic reactions. A review the Persian Gulf War and has not been linked to fetal of British studies reported that pyridostigmine caused malformations.260. branches. have for nerve agent pretreatment. Nerve Agents for comparison was not included. Known adverse reactions have been limited to in doses sufficient to cause an average 60% AChE in- infrequent drug rashes after oral administration and the hibition.261 The effectiveness of pyridostigmine pretreatment Although there has been wide experience with may not provide conclusive evidence of the impor. to screen critical personnel.255. tients.259 Two studies found an increase in sweating and nerve agent threats under combat conditions. ultrastructural alteration of a portion of the constellation of signs of peripheral cholinergic excess. either acutely or chronically.252 The key observation remains that The occurrence of such reactions has been well below animals pretreated with pyridostigmine and promptly the 0.1% level. these subjects also had a from all countries have concluded from these data that slight decrement on a visual probability monitoring pyridostigmine isan essential pretreatment adjunct for task. no significant decrements have been found in and for much longer periods than it was used during the performance of a variety of military tasks. long-term administration of pyridostigmine to patients tance of central mechanisms in respiratory arrest. Pyridostigmine has been used by preg- this recommended adult dose regimen has been fol. vigilance. and sarcomeres. such as aircrew. In addition. One potentially 201 . impairment at lower doses. which occurred at twice for nerve agent pretreatment. and at 13. the FDA considers day and night driving ability. proprietary Pyridostigmine maintains a good safety record information).264 Because safety in pregnancy has no changes in memory. was administered to rats. at 800 ft. Currently no military populations are receive atropine and oxime therapy after an otherwise routinely screened with administration of a test dose lethal soman exposure are able to maintain adequate of pyridostigmine. anesthesia. When 20% to 40%.253 No significant ruled out). one of pyridostigmine-treated swine. including the United centers are located. In a study266 -treated subjects in another study.257 Cardiovascular and pulmonary func.258 However. nant women with myasthenia gravis at higher doses lowed. specifically in the regions of the (on or two doses of 30 mg each) has been conducted fourth ventricle and brainstem. respiration and survive. manual dexterity.000 ft were noted in dostigmine use under certain conditions: soldiers 12 subjects in another study after their fourth 30-mg in combat who frequently take other medications.251. or in psychological tests pyridostigmine a Class C drug (ie.247 Clinical experts two tasks simultaneously. tion levels well beyond the 20% to 40% range desired These morphological findings. dose of pyridostigmine. motor. between pyridostigmine and commonly used antibi- tion were normal at high altitudes in pyridostigmine otics.254 wounding and blood loss. until recently. 4 Gastrointestinal changes included flatus.000 soldiers taking it for that dura- 5-8). The compound is packaged in a 21-tablet meals. International restrictions on the purchase risk for nerve agent exposure.266 Because of the lack of data on nerve stimulator should provide a basis for adjusting long-term administration of pyridostigmine to healthy the dose of both depolarizing and nondepolarizing adults. 30 mg. its bioavailability is 5% to 10%. The security a dose is forgotten or delayed. and medi- of neuromuscular transmission using a peripheral cal staff officers. for which expected even if the first pyridostigmine dose is taken pyridostigmine pretreatment is unnecessary. was a simply be resumed on an 8-hour schedule as soon as growing concern in 1990. Soldiers taking pyridostigmine during this period 202 . they reported a higher-than.650 soldiers of the cohol.182. XVIII Airborne Corps. In many. based on assessment of the nerve aptic ACh receptors. which it was then able to use to produce GF. only provided rodents with PRs in the range of 1. made Allied use of pyridostigmine a reason. If as the rapidly aging nerve agent. and abdominal cramps that were noticeable but rhesus monkeys given pyridostigmine pretreatment not disabling. mine is made by commanders at Army division level there may be either up. added to its known interest in acquiring these changes were noticed within hours of taking the soman. medical officers caring for the 41. orally. Although GF’s aging time with unit commanders continued the medication for 6 to 7 AChE was reported to be relatively long (see Table days. to be taken as long as pyridostigmine was administered. two United States and Allied decisions to use pyridostig.182. Iraq was known exposure. A commander may extend the period once. the effects subsided after a day able course of action. atropine/oxime therapy of side effects. a laboratory compound was administered under combat conditions for the that had not earlier been manufactured in weapons first time to US and Allied soldiers thought to be at quantity. taking into ac. with over 34.Medical Aspects of Chemical Warfare important effect of pyridostigmine deserves consider. pyridostigmine large-scale production of GF. who took from 1 to 21 doses of Very limited data on medical protection against GF pyridostigmine during January 1991.266 However. with reassessment at frequent muscle paralysis. unpublished information from Allied countries tion.182. intelligence. These side effects. but requires Wartime Use the approval of the first general or flag officer in the chain of command.183. be administered prior to any risk of nerve agent count Iraqi capabilities and intentions. together with urinary and atropine/oxime therapy uniformly survived a urgency. some benefit would be to have substantial stocks of sarin and VX. Some every 8 hours. an hour before nerve agent exposure. no more compounds that might defeat Allied protection. In most soldiers. taken 8 hours apart. Pyridostigmine was used to protect soldiers from Pyridostigmine is poorly absorbed when taken an actual nerve agent threat in the Persian Gulf War. soman. without making up missed doses.246 Concern about Iraq’s new to associate them with the medication. One nerve agent pyri.253 How- effects of GF poisoning. dostigmine treatment set packet provides a week of ation by field anesthesiologists and anesthetists using pyridostigmine pretreatment for one soldier. current doctrine calls for a maximum pretreat- muscle relaxants to avoid an undesirable duration of ment period of 21 days. and in others they persisted Pyridostigmine bromide tablets. The only primate data available showed that stools. were of sufficient intensity for many soldiers 5-LD50 challenge with GF. or two of administration.” or NAPPS).expected incidence studies shown in Table 5-10. doses of pyridostigmine. administration should of Warsaw Pact stocks of soman.7. similar to findings with in rodents exposed to GF did not protect against the peacetime volunteers participating in studies. intervals of the need for continued pretreatment. are currently maintained in stocks of US units adopted a routine of taking pyridostigmine with combat units.183. As confirmed by the later ever.265 Clinical assessment of the status agent threat by their chemical. possible. as noted in Table 5-11. for example. loose to 2.267 Ideally. Because exces- Iraq was also known to be interested in acquiring any sive AChE inhibition can impair performance. or the equivalent. Data on safety and pos- of chemical precursors of the better-known nerve sible adverse responses were collected from the unit agents may have led Iraq to acquire cyclohexyl al. such than one 30-mg tablet should be taken every 8 hours.268 Most major were not reassuring. GF capability. However. pretreatment set.or down-regulation of postsyn. first tablet. should mine followed established doctrine. which was thought to minimize gastrointestinal blister pack called the “nerve agent pyridostigmine symptoms. It was also known in 1990 that Iraq had begun In Operation Desert Storm in 1991. They were able to perform their missions without suggested that postexposure atropine/oxime therapy any noticeable impairment.183 muscle relaxants for anesthesia induction: depending The decision to begin pretreatment with pyridostig- on the duration of muscle-relaxant administration. 266:694. Dunn MA.271 The mine administration (483 clinic visits). This experience suggests that cholinergic symptoms may occur in a small number of individuals with relatively low body weight. was stopped. and because some returning troops have reported Because of increased exposure to the work-of. Because the units dier had a history of prolonged apnea after receiving of the XVIII Airborne Corps had been deployed to a succinylcholine premedication for surgery. Hurst CG. The consensus among where they might face either a nerve agent threat or medical personnel more recently arrived was that the potential need for resuscitative surgery involving they saw more pyridostigmine-related bronchospasm emergency induction of anesthesia265 using cholinergic in their soldiers who had not been present in theater medications. which is extent pyridostigmine itself was responsible for the discussed later in this chapter) activity was the same symptoms noted above.1 diers. many soldiers said that they simply Because pyridostigmine was used during the stopped taking the medication and did not report Persian Gulf War and troops were ordered to take symptoms to their medical officers. and particles. that manifested as N=41.4%). In a group of 213 soldiers in Israel who took pyri- related stresses. and had been evacuated earlier. smoke. both weighing approximately 45 to 50 kg. 1991. Because there was no comparable pain (20. There were no Need for medical visit <1 hospitalizations or medical evacuations attributable to pyridostigmine among XVIII Airborne Corps sol- Discontinuation on medical advice < 0.40 use in wartime.270 Included among these symptoms were response to alarms. most soldiers with significant reactive cholinergic medications should be carefully assessed airways disease had already developed symptoms concerning their potential deployability to combat. In other units. Two soldiers from the XVIII Airborne Corps had significant blood pressure elevations. cramps. salivation. JAMA. administered orally every 8 hours for 1 to 7 days.650 epistaxis or persistent bleeding after a cut and sub- Gastrointestinal symptoms ≤50 sided when pyridostigmine was stopped. unexplained medical symptoms. pseudocho- administered pyridostigmine. Another soldier who took two pyridostigmine tablets together Urinary urgency and frequency 5–30 to make up a missed dose experienced mild cholinergic Headaches. and anticipation excessive sweating (9%). severe abdominal Adapted with permission from: Keeler JR. The symptoms subsided after pyridostigmine conditions. were also experiencing a wide range of other wartime. variant enzyme could therefore show exaggerated Three soldiers had exacerbations of bronchospasm that responses to anticholinesterase compounds. at least two female soldiers. Later. noted increased *Dose was 30 mg pyridostigmine bromide. The authors of the report soldiers had drug rashes. <5 symptoms. diarrhea (6. Nerve Agents TABLE 5-11 breathing requirements of being masked. dostigmine (30 mg every 8 h). muscular twitching. and sweating that prompted medical obser- Pyridostigmine used as a nerve agent pretreatment under wartime vation. The findings are thus a worst. with similar histories of severe adverse responses to mine was used. An Israeli soldier who developed cholinergic symp- Among these soldiers.3%). The sol- responded to bronchodilator therapy. the possible role 203 . abdominal of actual combat. one of them had urticaria suggested that people who are homozygous for the and skin edema that responded to diphenhydramine. diaphoresis. sleep deprivation.269 it. In a smaller group of 21 soldiers. it was unclear EFFECTS OF PYRIDOSTIGMINE PRETREAT- whether pyridostigmine was a major causative factor MENT* ON US SOLDIERS IN THE PERSIAN in those who had bronchospasm at the onset of hostili- GULF WAR ties. less than 1% sought medical toms after taking pyridostigmine was reported to have attention for symptoms possibly related to pyridostig. rhinorrhea. it is not clear to what linesterase (also called butyrocholinesterase. Most of these variant enzyme has low binding affinity for pyridostig- had gastrointestinal or urinary disturbances.1%). as long. in the 12 who were symptomatic and the 9 who were case estimate for effects attributable to pyridostigmine not symptomatic. and urinary frequency group of soldiers undergoing identical stresses but not (11. self-administered an atropine autoinjector. tingling of extremities and recovered fully after several hours.1%). Two mine and other carbamates. such as repeatedly donning and re. People desert environment for 5 months before pyridostig. nausea (22. 75% reported at least one moving their chemical protective suits and masks in symptom. a genetic variant of serum butyrlcholinesterase. with diastolic Effect Incidence (%) pressures of 110 to 120 mm Hg. as well as inhaled dust. ultrastructural alterations seen by electron that pyridostigmine increases survival when used microscopy after 2 weeks of exposure to low-dose as pretreatment against challenge by certain nerve pyridostigmine were reversible following withdrawal agents (data on efficacy in humans challenged by of the drug. in 1991 the FDA waived informed problems such as fatigue. it determined a long history of safety when the pyridostigmine in a battlefield context is the situation drug was used for approved indications at doses in which a soldier who has been on the drug in ac. Technically. a more worrisome concern about ond. order troops to take it. several-fold higher than the doses administered in cordance with pretreatment doctrine needs surgery the military. acutely. as mentioned above. but have been used in innervated by cholinergic nerves results. such is the case. Sec- On the other hand. lies beyond the scope of this volume. A full discussion of this issue was as an off-label use of an approved medication. a available in a specific combat situation. soldiers must have a clear under.558). no other nerve agent is covered by this standing of the threat and the need for this medica. Otherwise.273 nerve agents is not experimentally obtained).271 Anesthesia providers troops to take it. Because of does not by itself give rise to lasting neuromuscular the impending war. recovery of normal function. First. this should affect the decision to go to surgery using the FDA approved pyridostigmine as a nerve agent these anesthetic agents. such as succi. probably the most com. hyperac- 204 . This status resulted prospective human study. At no time was it illegal for a licensed in a combat zone must anticipate increased time to physician to prescribe pyridostigmine to a patient. it relied was not associated with pyridostigmine intake (P = on data from animal studies conducted in both the 0. SUMMARY Nerve agents are the most toxic chemical warfare Nerve agents cause biological effects by inhibiting agents known. but the magnitude of the increase does not imply that In February 2003. From then until 2003.Medical Aspects of Chemical Warfare of pyridostigmine in the genesis of these problems status of pyridostigmine for nerve agent pretreatment has been questioned. 1992. approval. The waiver of informed consent was withdrawn in one might expect that recovery from anesthesia us. On the other hand. They cause effects within seconds and the enzyme AChE. This was the first time the It is now clear that pyridostigmine can be used ef. this purpose. FDA applied the “animal rule” to approve a medication fectively in large military populations under combat for use against chemical or biological warfare agents conditions without impairing mission performance. would be prolonged.275. the status of pyridostig- ing a neuromuscular blocking agent. knowledge of the specific agent may not be avail- willing to accept the associated gastrointestinal and able when a commander must decide whether or not to urinary symptoms or to comply with an 8-hour dos. from a tactical stand- tion. mine used for nerve agent pretreatment was that of nylcholine. with increased only one war. wishing to use the drug for muscles of respiration. hyperactivity of skel- groups and have been used in terrorist attacks. no first-responder agency in the United States has seriously considered Before the 1990 Persian Gulf War. causing an excess of the neurotrans- death within minutes. These agents are in the military mitter to accumulate. it seems unlikely that they will be point. They can be manufactured by terrorist secretions from exocrine glands. the regulatory ordering responders to take pyridostigmine. however. Hyperactivity in those organs stockpiles of several countries. in troops on pyridostigmine. pretreatment for soman only.272 In another study using animal muscle cells United States and other NATO countries that found in culture. without Phase 2 and Phase 3 human clinical trial data. Because pyridostigmine is a ChE inhibitor. In one human study.276 The retrospective analysis showed that handgrip strength FDA based this waiver on two factors. Some studies Additionally. on the eve of the invasion of Iraq. Realistically. any population group not in imminent danger of expo- sure to a rapidly aging nerve agent. since performed since the Gulf War give reassurance that the only on-label indication was for myasthenia gravis pyridostigmine used as called for in military doctrine and the smallest adult dose was 60 mg. Despite increased Regulatory Status concerns about chemical terrorism. etal muscles leading to fatigue and paralysis. consent for its use to make the best medical treatment monly related complaint. including that of the whether military or not. and according to a an investigational new drug. the 30 mg dose was not approved.274 This is of in the Department of Defense creating an informed particular concern in those rare patients with mutant consent protocol should the need again arise to order BuChE. Pyridostigmine is not suited for age schedule. Davis W. the oxime 2-PAM Cl. 1863. Paxman J. January 22. 4. REFERENCES 1. eds. 7. 6. ed. 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