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Home , Carbamate, Cyclosarin, Nerve agent, Obidoxime, Physostigmine, Pyridostigmine

J R Army Med Corps 2002; 148: 344-357 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Nerve Agents

Introduction persistent. It is regarded as presenting little The nerve agents (NA) are a group of vapour hazard to people exposed to it. In the particularly toxic agents. pure state nerve agents are colourless and They were developed just before and during mobile liquids. In an impure state, nerve World War II. Although chemically related to agents may be encountered as yellowish to the organophosphorus , their brown liquids. Some nerve agents have a clinical presentation and medical faint fruity odour. management may differ. The principal nerve In general, nerve agents are moderately agents are: GA (), GB (), GD soluble in water with slow hydrolysis, highly (), GF () and VX soluble in lipids, and are rapidly inactivated (methylphosphonothioic acid). In some by strong alkalis and chlorinating countries the "V" agents are known as "A" compounds. agents. Detection Physical and Chemical Nerve agents may be detected by a variety of Properties means. Single and three colour detector Nerve agents are organophosphorus . papers are available for individual issue to The "G" agents tend to be non-persistent detect liquid . Area detectors and whereas the "V" agents are persistent. Some monitors of various sensitivities are available agents may be thickened in order to increase (Figures 9,10,11). Highly sensitive and their persistence, and therefore the total specific water testing kits are also available. amount penetrating intact skin. At room temperature, GB is a comp- Protection aratively volatile liquid and therefore non- To prevent inhalation of an incapacitating or persistent. GD is also significantly volatile, as lethal dose, it is essential that the breath is is GA though to a lesser extent. VX is a held and the put on at the first relatively non-volatile liquid and therefore warning of the presence, or suspected http://militaryhealth.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Fig 9. Lightweight Chemical Agent Detector LCAD) shortly to enter service. It uses mobility spectrometry to detect CW agents. 345 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Fig 10. Man-Portable Chemical Agent Detector (MCAD) shortly to enter service. http://militaryhealth.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Fig 11. Nerve Agent Immobilised- and Detector (NAIAD).This was the world’s first biologically-based nerve agent detector.

presence, of a nerve agent. In addition, it is vapour at field concentrations is generally not recommended that the eyes are shut whilst a percutaneous hazard over short periods of masking. time, so that where a vapour hazard exists Normal is penetrated by these alone, the respirator may provide adequate agents whether contact is with liquid or respiratory and eye protection without the vapour and specialised clothing including a use of an NBC suit. respirator, NBC suit, gloves and foot protection are required when liquid agent is Decontamination present. The respirator protects the eyes, The importance of early skin decon- mouth and respiratory tract against nerve tamination cannot be over emphasised. agent spray vapour and . Nerve agent Decontamination of the skin should be 346 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Table 3.Likely Signs and Symptoms of GB (Sarin) Shown in Terms of Vapour Exposure and Approximate Blood Acetyl- Depression. Short term Approximate Symptoms and signs* Ct AChE Vapour Systemic exposure only mg.min.m-3 depression eyes protected <2 <5% Incipient miosis (miosis Nil produced at Ct=2, t=30 min), slight headache 5 20% + 10% Increased miosis, headache, Tightness in chest eye pain, rhinorrhoea, conjunctival injection, tightness in chest 5-15 20-50% +10% Eye signs maximal, Bronchospasm Symptoms beginning to appear. and all the effects already described Bronchospasm 15 50% +10% Bronchospasm and all the effects Wheezing, alivation, eye effects, already described , . (Local sweating and fasciculation in liquid contamination of the skin). 40 80% + 10% Symptoms and signs as for systemic Weakness, , . Paralysis, convulsions 100 100% Respiratory failure, death Respiratory failure, death * All symptoms and signs will be subject to very considerable inter-subject variation accomplished immediately after exposure to tree, , bladder and blood liquid agent if it is to be fully effective. vessels; to the salivary glands and secretory However, a late degree of protection is glands of the gastrointestinal tract and provided by late decontamination. Liquid respiratory tract; and to the cardiac muscle agent may be removed by an adsorbant, such and endings of sympathetic nerves to the as Fullers' Earth, or chemically inactivated by sweat glands. the use of reactive decontaminants. The accumulation of at these Decontamination personnel should use a sites results in characteristic muscarinic signs respirator and full protective equipment. If and symptoms. The accumulation of combat clothing is contaminated. it should acetylcholine at the endings of motor nerves be removed as soon as possible. Once a to voluntary muscles and in some autonomic casualty has been decontaminated or the ganglia results in nicotinic signs and agent fully absorbed, no further risk of symptoms. The accumulation of excessive contamination exists. The casualty's body acetylcholine in the brain and spinal cord fluids, or faeces do not present a CW results in characteristic central hazard. symptoms - see Table 3. The inhibition of http://militaryhealth.bmj.com/ cholinesterase throughout the body Mechanism of Action by nerve agents may be irreversible and its Absorption effects prolonged. Nerve agents may be absorbed through any body surface. When dispersed as a spray or Location of an aerosol, agents can be absorbed through Acetylcholinesterase is found associated with the skin, eyes and respiratory tract. When the post-junctional membrane at the dispersed as a vapour at expected field and in the cell concentrations, the vapour is primarily bodies and processes of neurons. absorbed through the respiratory tract and is The concentration is particularly high in on September 28, 2021 by guest. Protected copyright. also a direct hazard to the eye. If enough some central nervous system neurons. The agent is absorbed, local effects are followed location of acetylcholinesterase in autonomic by generalised systemic effects. The rapidity ganglia is less well understood than that at with which effects occur is directly related to the neuromuscular junction. Acetylcholin- the amount of agent absorbed in a given esterase is also found at sites where, as yet, no period of time. functional role has been identified: the musculotendinous junction, red blood cells, Inhibition of platelets and the placenta. The effects of the nerve agents are mainly due to their ability to inhibit acetyl- Pathology cholinesterase throughout the body. Since Aside from the decrease in the activity of the normal function of this enzyme is to cholinesterase enzymes throughout the body hydrolyse acetylcholine wherever it is (which may be detected by chemical released, such inhibition results in the methods or by special staining), no specific accumulation of excessive concentrations of lesions are detectable by gross examination. acetylcholine at its various sites of action. At post-mortem examination there is usually These sites include the endings of the capillary dilatation, hyperaemia and oedema parasympathetic nerves to the smooth of the lungs; there may be similar changes in muscle of the iris, ciliary body, bronchial the brain and the remaining organs. 347 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Neuropathological changes have been behind the eyes. Usually, vision is not grossly reported in animals following severe impaired, although there may be a slight intoxication. During the acute phase these dimness especially in the peripheral fields or include damage within the central nervous when in dim or artificial light. system and at the neuromuscular endplate. Exposure to a level of a nerve agent vapour Following severe exposure to some nerve slightly above the minimal symptomatic dose agent, lesions to the peripheral motor nerves results in miosis, pain in and behind the eyes may be identified subsequently. attributable to ciliary spasm (especially on focusing), some difficulty of accommodation CLINICAL AND and frontal headache. The pain becomes PHARMACOLOGICAL worse when the casualty tries to focus the eyes or looks at a bright light. Some twitching EFFECTS of the eyelids may occur. Occasionally there is nausea and vomiting which, in the absence Signs and Symptoms of systemic absorption, may be due to a The order in which signs and symptoms reflex initiated by the ocular effects. These appear and their relative severity depend on local effects may result in moderate the route of exposure and whether the discomfort and some loss of efficiency but casualty has been exposed to liquid agent or may not necessarily produce casualties. vapour.The local effects of vapour and liquid Following minimal symptomatic exposure, exposure are described below, followed by a the miosis lasts from 24 to 72 hours. After description of the systemic effects which exposure to at least the minimal symptomatic occur after significant absorption of agent via dose, miosis is well established within half an any route. hour. Miosis remains marked during the first day after exposure and then diminishes Effects of Nerve Agent Vapour gradually over 2 to 3 days after moderate exposure but may persist for as long as 14 Absorption days after severe exposure. The conjunctival The lungs and the eyes absorb nerve agents erythema, eye pain, and headache may last rapidly. Changes occur in the smooth muscle from 2 to 15 days depending on the dose. of the eye (resulting in miosis) and in the smooth muscle and secretory glands of the Local Respiratory Effects bronchi (producing bronchial constriction Following minimal exposure, the earliest and excessive secretions in the upper and effects on the respiratory tract are a watery lower airways). In high vapour nasal discharge, nasal hyperaemia, sensation concentrations, the nerve agent is carried of tightness in the chest and occasionally

from the lungs throughout the circulatory prolonged wheezing expiration suggestive of http://militaryhealth.bmj.com/ system; widespread systemic effects may bronchoconstriction or increased bronchial appear in less than 1 minute. secretion. The rhinorrhoea usually lasts for several hours after minimal exposure and for Local Ocular Effects about 1 day after more severe exposure. The These effects begin within seconds or respiratory symptoms are usually minutes after exposure, before there is any intermittent for several hours duration after evidence of systemic absorption. The earliest mild exposure and may last for 1 or 2 days ocular effect which follows minimal after more severe exposure. symptomatic exposure to vapour is miosis (Figure 12). This is an invariable sign of Effects of Liquid Nerve Agent ocular exposure to enough vapour to on September 28, 2021 by guest. Protected copyright. produce symptoms. It is also the last ocular Local Ocular Effects manifestation to disappear. The pupillary The local ocular effects are similar to the constriction may be different in each eye. effects of nerve agent vapour. If the Within a few minutes after the onset of concentration of the liquid nerve agent exposure, there also occurs redness of the contaminating the eye is high, the effects will eyes due to conjunctival hyperaemia, and a be instantaneous and marked. If the sensation of pressure with heaviness in and exposure of the two eyes is unequal, the local

Fig 12. Miosis (right) from a very low dose of nerve agent. 348 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from manifestations may be unequal. Hyperaemia bronchial and upper airway secretions occur may occur but there is no immediate local and may become very profuse, causing inflammatory reaction such as may occur coughing, airway obstruction and respiratory following ocular exposure to more irritating distress. Audible wheezing may occur, with substances (for example, ). prolonged expiration and difficulty in moving air into and out of the lungs, due to Local Skin Effects the increased bronchial secretion or to Following cutaneous exposure, there is bronchoconstriction, or both. Some pain localised sweating at and near the site of may occur in the lower thorax and salivation exposure and localised muscular twitching increases. and fasciculation. However, these may not be Salivation may be so profuse that watery noticed, causing the skin absorption to go secretions run out of the sides of the mouth. undetected until systemic symptoms begin. Bronchial secretion may be thick and tenacious. If postural drainage or suction is Local Gastrointestinal Effects not employed, these secretions may add to Following the ingestion of substances the airway obstruction. Laryngeal spasm containing a nerve agent (which is essentially followed by collapse of the hypopharyngeal tasteless), the initial symptoms include musculature may also obstruct the airway. abdominal cramps, nausea, vomiting and The casualty may gasp for breath, froth at the diarrhoea. mouth, and become cyanotic. If the upper airway becomes obstructed by Systemic Effects of Nerve Agent secretions, laryngeal spasm or hypo- Poisoning pharyngeal musculature collapse, or if the bronchial tree becomes obstructed by The sequence of symptoms varies with the secretions or bronchoconstriction, little route of exposure. Respiratory symptoms are ventilation may occur despite respiratory generally the first to appear after inhalation movements. As hypoxaemia and cyanosis of nerve agent vapour, although gastro- increase, the casualty will fall exhausted and intestinal symptoms are usually the first after become unconscious. ingestion. Following comparable degrees of Following inhalation of nerve agent exposure, respiratory manifestations are vapour, the respiratory manifestations most severe after inhalation, and gastro- predominate over the other muscarinic intestinal symptoms may be most severe after effects; they are likely to be most severe in ingestion. Otherwise, the systemic manifest- older casualties and in those with a history of ations are, in general, similar after any respiratory disease, particularly bronchial exposure to nerve agent poisoning by any asthma. However, if the exposure is not so route. If local ocular exposure has not

overwhelming as to cause death within a few http://militaryhealth.bmj.com/ occurred, the ocular manifestations minutes, other muscarinic effects appear. (including miosis) may initially be absent. These include sweating, anorexia, nausea Following systemic absorption and epigastric and sub-sternal tightness with may occur due to a nicotinic effect on the heartburn and eructation. If absorption of superior cervical ganglion. nerve agent has been great enough (whether The systemic effects may be considered to due to a single large exposure or to repeated be nicotinic, muscarinic or central. The smaller exposures), there may follow predominance of muscarinic, nicotinic or abdominal cramps, increased peristalsis, central nervous system effects will influence vomiting, diarrhoea, tenesmus, increased the amount of , or anti- lachrymation and urinary frequency. which must be given as therapy. Cardiovascular effects can include on September 28, 2021 by guest. Protected copyright. These effects will be considered separately. bradycardia, and cardiac Acute or delayed (up to 50 hours) arrhythmias.The casualty perspires profusely pulmonary oedema has been described and may have involuntary defecation and during the course of poisoning. Its urination; this may lead to circulatory exact mechanism is not known and may be collapse and cardiorespiratory arrest due to a direct cardiac effect, haemodynamic followed by death. modifications or both. Soman and other have been reported to Nicotinic Effects produce histopathological changes in the With the appearance of moderate muscarinic myocardium. Similar effects may thus occur systemic effects, the casualty begins to have with nerve agents. increased and mild generalised weakness which is increased by exertion.This Muscarinic Effects is followed by involuntary muscular Tightness in the chest is an early local twitching, scattered muscular fasciculations symptom of respiratory exposure. This and occasional muscle cramps.The skin may symptom progressively increases as the nerve be pale due to vasoconstriction and is absorbed into the systemic pressure moderately elevated (transitory) circulation, whatever the route of exposure. together with a tachycardia, resulting from After moderate or severe exposure, excessive cholinergic stimulation of sympathetic 349 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

ganglia and possibly from the release of obvious symptoms. Death is usually due to epinephrine. If the exposure has been severe, respiratory arrest and anoxia, and requires the muscarinic cardiovascular symptoms will prompt initiation of assisted ventilation to dominate and the fascicular twitching (which prevent death. Depression of the circulatory usually appear first in the eyelids and in the centres may also occur, resulting in a marked facial and calf muscles) becomes generalised. reduction in heart rate with a fall of blood Many rippling movements are seen under pressure some time before death. the skin and twitching movements appear in all parts of the body. This is followed by Cumulative Effects of Repeated severe generalised muscular weakness, Exposure including the muscles of respiration. The Repeated exposure to concentrations of a respiratory movements become more nerve agent insufficient to produce laboured, shallow and rapid; then they symptoms following a single exposure, may become slow and finally intermittent. Later, result in the onset of symptoms. Continued respiratory muscle weakness may become exposure, possibly over several days, may be profound and contribute to the respiratory followed by increasingly severe effects. depression. After symptomatic exposure, increased susceptibility may persist for up to 3 months Central Nervous System Effects (the body synthesises acetylcholinesterase at In mild exposures, the systemic a rate of approximately 1% new enzyme manifestations of nerve agent poisoning activity per day). A period of increased usually include tension, anxiety, jitteriness, susceptibility occurs during the enzyme restlessness, emotional lability, and regeneration phase which could last from giddiness. There may be or weeks to months, depending on the severity excessive dreaming, occasionally with of the initial exposure. During this period the nightmares. effects of repeated exposures are cumulative. If the exposure is more marked, the Increased susceptibility is not limited to the following symptoms may be evident: particular nerve agent or other cholinesterase - Headache. inhibitors initially absorbed. - . - Drowsiness. Potential Long Term Effects - Difficulty in concentration. Minor EEG changes have been noted more - Impairment of memory with slow recall of than a year after a clinically relevant, recent events. symptomatic nerve agent exposure; averaged - Slowing of reactions. EEGs in a group of people who had been exposed to a nerve agent were compared to a In some casualties there is apathy, http://militaryhealth.bmj.com/ withdrawal and depression.With the appear- control group. Since changes could not be ance of moderate symptoms, abnormalities identified in individual EEGs, the clinical of the EEG occur, characterised by irreg- relevance is unknown. Neuropsychiatric ularities in rhythm, variations in potential, changes have been noted in individuals for and intermittent bursts of abnormally slow weeks to months after poisoning. waves of elevated voltage similar to those Polyneuropathy, reported after organo- seen in patients with epilepsy. These phosphate insecticide poisoning, has not abnormal waves become more marked after been reported in humans exposed to nerve one or more minutes of hyperventilation agents. It has been produced in animals only which, if prolonged, may occasionally at doses of nerve agents so high that survival precipitate a generalised convulsion. would be unlikely. The Intermediate on September 28, 2021 by guest. Protected copyright. If absorption of nerve agent has been great Syndrome (polyneuropathy in the medium enough, the casualty becomes confused and term – weeks) has not been reported in ataxic. The casualty may have changes in humans after nerve agent exposure, nor has speech, consisting of slurring, difficulty in it been produced in animals by nerve agent forming words, and multiple repetition of the administration. Muscular necrosis has been last syllable. The casualty may then become produced in animals after high dose nerve comatose, reflexes may disappear and agent exposure but resolves within weeks; it respiration may become Cheyne-Stokes in has not been reported in humans. character. Finally, generalised seizures may ensue, but not all of these may be associated Cause of Death with convulsive activity. In the absence of treatment, death is With the appearance of severe central caused by resulting from airway nervous system symptoms, central respira- obstruction, paralysis of the muscles of tory depression will occur (adding to the respiration and central depression of respiratory embarrassment that may already respiration. Airway obstruction is due to be present) and may progress to respiratory pharyngeal muscular collapse, upper airway arrest. However, after severe exposure the and bronchial secretions, bronchial casualty may lose consciousness and constriction and occasionally laryngospasm convulse within a minute without other and paralysis of the respiratory muscles. 350 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Respiration is shallow, laboured, and rapid equally timely administration of necessary and the casualty may gasp and struggle for therapeutic measures. Urgent skin air. Cyanosis increases. Finally, respiration decontamination and continued respiratory becomes slow and then ceases. Unconsc- protection must be applied alongside the iousness ensues. The blood pressure (which administration of for self and may have been transitorily elevated) falls. buddy aid, all of which must be maintained Cardiac rhythm may become irregular and during rapid evacuation to medical care. death may ensue. Triage priorities must be reviewed If assisted ventilation is initiated via frequently, with subsequent delivery of cricothyroidotomy or endotracheal tube and appropriate therapy and continued airway secretions are removed (by postural respiratory support, where necessary. This drainage and suction, and diminished by the must be administered in a timely and administration of atropine), the individual confident manner if emergency medical may survive several lethal doses of a nerve management is to be successful and the agent, albeit with a potential for severe ultimate prognosis favourable. Field medical irreversible brain damage. However, if the management may have to be conducted exposure has been overwhelming, amounting initially in a contaminated environment, to many times the lethal dose, death may requiring practised procedures to avoid occur despite treatment as a result of cross-contamination and unnecessary respiratory arrest and cardiac arrhythmia. exposure of the already compromised When overwhelming doses of the agent are casualty. absorbed quickly, death occurs rapidly without orderly progression of symptoms. Pre-treatment Figure 13 shows victims in , Poisoning by nerve agents which form from the probable use of GB in March 1998 rapidly ageing complexes may be particularly (although UN Inspectors consider that the difficult to treat. Ageing is the biochemical deaths may have resulted from the use of process by which the agent-enzyme complex cyanide). becomes completely resistant to oxime reactivation. In the case of soman (GD), the agent-enzyme complex ages within minutes. These difficulties have been mitigated, in part, by the use of as pre- treatment. The terms pre-treatment or prophylaxis are differentiated thus: - Pre-treatment: the administration of in advance of poisoning designed to increase the efficacy of treatment http://militaryhealth.bmj.com/ administered post-poisoning. - Prophylaxis: the administration of drugs in advance of the poisoning designed to make post-poisoning therapy unnecessary. Current pretreatments utilise anticholinesterases, for example, pyrido- , which may be used either alone or in combination with other drugs (Figure 14).They bind cholinesterases on September 28, 2021 by guest. Protected copyright. Fig 13. Dead in Halabja, Iraq, probably from GB. reversibly, preventing the binding to the enzyme. The term reversible is used here comparatively: the carbamate- MANAGEMENT OF NERVE acetylcholinesterase complex breaks down AGENT POISONING fairly rapidly, while organophosphate- acetylcholinesterase complexes break down Introduction very slowly. In comparison, the aged organo- The medical management of nerve agent phosphate acetylcholinesterase complex is poisoning consists of pre-treatment, stable. diagnosis and treatment with a combination When carbamates are used as pre- of pharmacological, respiratory and other treatments, carbamoylation of acetyl- general supportive measures, as dictated by cholinesterase prevents phosphorylation, but the condition of the casualty. later the carbamate-acetylcholinesterase The life-threatening effects of acute nerve complex dissociates, freeing active enzyme. agent poisoning occur much more rapidly Current pre-treatment regimen (pyrdi- and for a generally shorter duration than stigmine, 30 mg 8 hourly) are designed to those produced by organophosphate (OP) give 20 – 40% binding of peripheral insecticides. Following pre-treatment, acetylcholinesterase, thereby allowing the successful post-exposure treatment relies on carbamate to protect a proportion of the the rapid recognition of effects and the acetylcholinesterase against binding by nerve 351 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Fig 14. Nerve Agent Pre-treatment Set (NAPS) – .

agent. There are no significant signs and dosage, symptoms of carbamate poisoning symptoms associated with this level of will occur. These include diarrhoea, inhibition since: gastrointestinal cramps, tight chest, nausea, rhinorrhoea, headache and miosis. Good - the process of inhibition of the enzyme is compliance is required if optimal protection slower than that due to nerve agent. is to be obtained. The importance of - there is negligible inhibition of central Pyridostigmine pre-treatment should acetylcholinesterase. therefore be stressed during training. In conjunction with post exposure therapy, Medical officers must be aware of potential good protection against lethality is obtained drug interactions and contraindications within 2 hours of the first dose, but is when dealing with personnel on pre- enhanced by continued intake of treatment.This is of particular relevance with

pyridostigmine pre-treatment, according to respect to some muscle relaxants used in http://militaryhealth.bmj.com/ the accepted dosage regimen. anaesthesia. Pyridostigmine has been used in Pyridostigmine pre-treatment should be clinical situations for up to 50 years. At this stopped when the symptoms of nerve agent time there is no evidence of long term side poisoning following a chemical warfare effects. attack are observed; post exposure therapy Note that the national policy for the use of must be started immediately. Pyridostigmine pre-treatment varies within NATO; it cannot is not an , and it should not be taken be assumed that allied casualties will have after nerve agent exposure. Its continued use received pre-treatment. post-exposure may well enhance the effects of nerve agent poisoning. It is ineffective Diagnosis and Therapy of Nerve unless standard therapy is also used in the Agent Poisoning on September 28, 2021 by guest. Protected copyright. appropriate manner. The recognised side effects of prolonged Symptoms use of pyridostigmine include gastro- Nerve agent poisoning may be identified intestinal intestinal changes including from characteristic signs and symptoms. If increased flatus, loose stools, abdominal exposure to vapour has occurred, the cramps and nausea. Other reported effects will be very small, usually pin-pointed. If are urinary urgency, headache, rhinorrhoea, exposure has been cutaneous or has followed diaphoresis and tingling of the extremities. ingestion of a nerve agent in contaminated However, several studies have concluded that food or water, the pupils may be normal or, these side effects are tolerable by most in the presence of severe systemic symptoms, personnel and lead to negligible degradation slightly to moderately reduced in size. In this of military performance - symptoms due to event, the other manifestations of nerve agent pyridostigmine may be ameliorated by taking poisoning must be relied on to establish the the tablets with food, and Pyridostigmine diagnosis. No other known chemical agent pre-treatment was discontinued on medical produces muscular twitching and fasc- advice in less than 0.1% of individuals, iculations, rapidly developing pin-point generally because of intolerable nausea and pupils, or the characteristic muscarinic, diarrhoea. nicotinic and central nervous system When taken in excess of the recommended manifestations. 352 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Differential Diagnosis - Wheezing, dyspnoea, and coughing. The effects caused by a mild vapour - Severely pin-pointed pupils. exposure, namely rhinorrhea and tightness in - Red eyes with tearing. the chest, may easily be confused with an - Vomiting. upper respiratory malady or an . - Severe muscular twitching and general Miosis, if present, will help to distinguish weakness. these, but the eyes must be examined in very - Involuntary urination and defecation. dim light to detect this. Similarly, GI - Convulsions. symptoms from another illness may be - Unconsciousness. confused with those from nerve agent, and in - Respiratory failure. this instance there will be no useful physical - Bradycardia. signs. A history of possible exposure will be helpful, and laboratory evidence (decreased Post-Exposure Therapy RBC-Cholinesterase activity) will be useful The main principles of post exposure treat- to distinguish the two.The diagnosis is easier ment for nerve agent poisoning are based on in the severely intoxicated patient. The early drug therapy in combination where combination of miosis, copious secretions necessary with measures to support respir- and generalised muscular fasciculations in a ation and provide general supportive care. gasping, cyanotic and convulsing patient is characteristic. Pharmacological Treatment of Nerve Agent Poisoning Symptom Differentiation The pharmacological treatment of nerve It is important that individual service agent poisoning involves the use of: members know the following MILD and SEVERE signs and symptoms of nerve agent - to antagonise the poisoning. Servicemen and servicewomen muscarinic effects. who have most or all of the symptoms listed - to reactivate inhibited enzyme and below must IMMEDIATELY receive first antagonise the nicotinic effects. aid (self-aid or buddy aid respectively). - to prevent seizure activity Casualties with severe symptoms will not be and protect against subsequent CNS able to treat themselves and must receive damage. prompt buddy aid and subsequent medical The effects of drugs used in nerve agent treatment if they are to survive. poisoning are described below.

MILD Poisoning (Self-Aid) Anticholinergic - Atropine Casualties with MILD symptoms may Atropine sulphate is an essential drug in the treatment of nerve agent poisoning. It acts by experience most or all of the following: http://militaryhealth.bmj.com/ blocking the effects of acetylcholine at - Unexplained runny nose. muscarinic receptors and so produces relief - Unexplained sudden headache. from many of the symptoms previously - Sudden drooling. listed. Some therapeutic effects are also - Difficulty in seeing (dimness of vision and produced within the central nervous system; miosis). at high doses (> 6 mg) atropine may help - Tightness in the chest or difficulty in reduce central respiratory depression, and if breathing. administered early after poisoning (5 – 10 - Localised sweating and muscular minutes), may have some beneficial twitching in the area of the contaminated action.

skin. on September 28, 2021 by guest. Protected copyright. - Stomach cramps. Dose Regimen - Nausea. Immediate treatment with atropine in cases - Bradycardia or tachycardia. of systemic nerve agent poisoning is essential, and the absolute requirement will MODERATE Poisoning depend on both the severity of effects and Casualties with MODERATE poisoning will whether pre-treatment has been used. experience an increase in the severity of most Following therapy for first aid or all of the MILD symptoms. Especially (Figure 15,16), doses should be repeated prominent will be an increase in fatigue, regularly until signs of successful weakness and muscle fasciculations. The atropinisation are noted. Intervals of 5 – 15 progress of symptoms from mild to moderate minutes may be required for continuing but indicates either inadequate treatment or non life-threatening effects of poisoning; the continuing exposure to agent. intravenous route of administration is preferred. SEVERE Symptoms (Buddy Aid) In cases of severe poisoning, higher doses Casualties with SEVERE symptoms may may well be required. Atropine is given experience most or all of the MILD intravenously at a rate of 2 mg every 3-5 symptoms, plus most or all of the following: minutes until the casualty is atropinised. - Strange or confused behaviour. Subcutaneous or intramuscular routes of 353 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Fig 15. NAPS, and Combopen Autoinjectors. http://militaryhealth.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Fig 16. Self-injection using a ComboPen.

administration are alternatives, and Signs of successful atropinisation include recommended until significant hypoxia is decreased bronchospasm, reduced airways corrected, as in such cases intravenous resistance, the drying-up of bronchial and administration of atropine may precipitate salivary secretions, reduced sweating and a life-threatening ventricular arrythmias. In the stabilisation in the heart rate to around 90 Iran-Iraq War, intravenous infusion of beats per minute. The effect of atropine in atropine at 2 mg/min for over an hour was drying bronchial secretions may make the administered with considerable success for removal of mucus more difficult, so suction is casualties severely poisoned by nerve agent likely to be necessary. vapour who had not received pre-treatment. After the emergency field treatment, In severe cases that have previously received atropinisation should be maintained for at pre-treatment, it is estimated that 30 – 50 mg least 24 hours by intramuscular injection or of atropine in total may be required to slow intravenous infusion of 1 to 2 mg of achieve atropinisation. atropine per hour as required. 354 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Complications Other Anticholinergics Atropine, especially in the presence of On the basis of experimental data, other hypoxia, may render the myocardium more anticholinergic drugs are considered to be susceptible to arrhythmias. Correction of beneficial in the treatment of nerve agent hypoxia, and ECG monitoring if available, is poisoning. Anticholinergics with pronounced essential during atropinisation. Overdosage central antimuscarinic effects (e.g. bena- may produce euphoria, hallucinations, ctyzine, , , scopo- anxiety, and delirium. Close observation is lamine) have the potential to suppress seizure necessary and sedation of casualties may be activity without further anticonvulsant required. Bladder dysfunction may therapy, if administered early after poisoning. necessitate catheterisation. By the reduction Drug combinations with atropine (e.g. of sweating, atropine increases the risk of benactyzine and atropine) have been heat stress. introduced by some nations in specific clinical situations, but caution must be Inappropriate Administration exercised when using these regimen. If atropine is administered in the absence of nerve agent poisoning, the following effects Oximes may be noted: - dryness of the mouth and pharynx While atropine blocks the cholinergic effects - decreased sweating of nerve agent poisoning at muscarinic sites, - slight flushing and tachycardia it has little effect upon the nicotinic effects at - some hesitancy of micturition skeletal neuromuscular junctions and the - slightly dilated pupils autonomic ganglia. Amelioration of nerve - mild drowsiness agent effects at these sites and also at - impaired memory and recal muscarinic sites can, however, be obtained - blurring of near vision by the reactivation of inhibited AChE by means of oximes. After 2 mg, these symptoms should not Three oximes are available in autoinjectors interfere with ordinary activity except in the for self- or buddy-administration and these occasional person, in hot environments or at are: high work rates. Higher doses, or repeated doses, will produce more marked symptoms - N-methyl derivative of 2--2- which may become totally incapacitating, aldoxime () as the methane- particularly in warm environments or high sulphonate; methyl sulphate and chloride work rates. The effects of atropine are fairly . prolonged, lasting 3 to 5 hours after one or - toxogonin () dichloride. - HI-6 chloride. two injections of 2 mg and 12 to 24 hours http://militaryhealth.bmj.com/ after significant over-atropinisation. Note that atropine and oximes are The traditional antidote for atropine synergistic in their effects and the overdose is . This is a administration of atropine and oxime in carbamate anticholinesterase, like pyrido- combination has been shown experimentally stigmine, but crosses the blood brain barrier. to raise the LD50’s of some nerve agents by As physostigmine acts by inhibiting a factor in excess of 20. anticholinesterase, it must be used with caution in treating over-atropinisation Enzyme Reactivation following nerve agent poisoning, where the The relative potency of the different oximes levels of enzyme may be reduced below in reactivating inhibited AChE varies normal. In such cases, the risk of repeated according to the nature of the nerve agent. on September 28, 2021 by guest. Protected copyright. cholinergic effects is greater. Its use should The choice of oxime (if more than one is therefore be reserved only for those cases available) is not only dependent on the with severe symptoms of atropine overdose, identity of the nerve agent responsible for the refractive to general supportive measures. poisoning; the effectiveness of a given oxime is also dependent on whether the casualty Atropine For Eye Effects has received pyridostigmine pre-treatment Atropine given parenterally has comp- and the administration of other anti- aratively little effect on nerve agent induced cholinergic and anticonvulsant drugs. miosis. The local application of cycloplegics In the field, immediate post-exposure (homatropine or similar eye drops) to the eye therapy consisting of atropine, oxime and reduces both the degree of miosis, eye pain will be given by intramuscular and associated nausea, vomiting and injection from an autoinjector device on the headache. However, expert opinion on the appearance of the first significant signs of value of atropine-containing eye drops in the nerve agent poisoning. Following the use of management of nerve agent induced miosis the autoinjector, if casualties remain remains divided. It is believed by some that symptomatic, they will require further doses problems of accommodation may be made of oxime (and atropine) to alleviate the worse by the application of the drops and clinical situation and reactivate inhibited that, overall, little benefit may be produced. enzyme. Opinion remains divided as to the 355 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

Table 4.Intravenous Bolus Dosing of Oximes. Degree of Pralidoxime Pralidoxime Obidoxime HI-6 Poisoning Chloride Methanesulphonate Mild 1000 mg. 400 mg. 250 mg. 500 mg. Moderate 1000 mg. (1) 400 mg. (2) 250 mg. (3) 500 mg. Severe 1000 mg. (1) 500 mg. (2) 250 mg. (3) 500 mg. (3) (1).Dose repeated every 8-12 hours. (2).Second dose of 400-500 mg 30 minutes after the initial dose followed by further doses of 200-400 mg every 4-12 hours. (3).Second dose administered 2 hours after the initial dose and followed by a further dose every 6-12 hours.

Table 5.Theoretical Loading Doses and Infusion Rates For Intravenous Oxime Administration. Oxime Loading Dose Total Dose Infusion Rate Total Rate (mg.kg -1) (1) (mg) (2) (mg.kg-1.h-1) (3) (mg.h-1) (2) 2-PAM 4.2 300 2.2 160 P2S 4.4 310 2.1 150 Obidoxime 0.8 56 0.5 34 HI-6 1.6 110 0.8 54 Key: 2-PAM = Pralidoxime chloride P2S = Pralidoxime methanesulphonate (1) Loading dose = Therapeutic Plasma Concentration x Volume of Distribution. (2) The total dose and total rate of infusion have been calculated assuming a man weighing 70 kg. (3) Infusion Rate = Therapeutic Plasma Concentration x Renal Clearance.

most appropriate way of achieving administration of anticonvulsants should be therapeutic blood levels of oxime. mandatory. The intravenous injection of bolus doses of Experimental evidence shows that the early oxime is probably the only practical solution administration (5 – 10 min) of the benzo- on the battlefield; doses are shown in Table 4. diazepines antagonises the seizure activity of Under field conditions, single bolus doses nerve agent. The addition of this class of can also be given by intramuscular injection. drugs to the basic treatment regimen greatly An alternative method of administering improves morbidity and mortality, in therapeutic doses of oxime is by intravenous addition to its anti-seizure effect. Currently infusion. Sundwall reported experimentally Diazepam is the most widely fielded and that a plasma concentration of 4 µg.ml-1 should be administered as a 5 - 10 mg dose pralidoxime methanesulphonate was needed initially and further doses should be given to counteract the neuromuscular block, frequently enough to control seizures. This bradycardia, hypotension and respiratory may require additional injections, at intervals

failure caused by organophosphate anti- ranging from a few minutes to several hours. http://militaryhealth.bmj.com/ cholinesterases. This concentration has been In the absence of anticonvulsant therapy, assumed since then to be the minimum irreversible brain damage may result; this is concentration of oxime required to counter- exacerbated by periods of hypoxia. act nerve agent intoxication in man. Based on this assumption, it is possible to calculate Respiratory Supportive Care the loading and maintenance doses for the intravenous administration of oximes that Airway management will achieve this level. The calculated dosing A patent airway should always be regimen for various oximes are summarised maintained, with postural drainage and suction. In an unconscious casualty,

in Table 5. on September 28, 2021 by guest. Protected copyright. There is only limited experience in human adequate atropine should be administered to poisoning by organophosphorus nerve reduce airway resistance. Cricothyroidotomy agents but it is generally accepted that the and/or endotracheal intubation may be persistence of clinically relevant amounts of needed. nerve agent in the blood is shorter than that of insecticides or . However, as a Respiratory support result of ageing of the inhibited AchE (which Dyspnoeic casualties may require respiratory may be very rapid following poisoning with support; this should be started at the lowest GD), it is suggested that in the absence of possible level. In a casualty that is dyspnoeic, clinical improvement, administration of the respirator should be removed and oxime for periods in excess of 24-48 hours is replaced with a casualty hood which will unlikely to achieve further reactivation of the reduce the ventilatory resistance. enzyme. Positive pressure ventilation Anticonvulsants Assisted ventilation may range from mouth- In severe poisoning by nerve agent, atropine to-mouth ventilation (in the absence of a protects only partially against seizure activity liquid or vapour hazard and after appropriate and the resulting brain damage; other decontamination) to the use of an automatic anticholinergics vary in this ability. Early ventilator. Manual or automatic ventilators must be capable of delivering uncontam- 356 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from inated air, with supplementary (if and central nervous system disturbance. available). Atropine will be required to Susceptibility to heat exhaustion or heat reduce airway resistance and endotracheal stroke is increased, particularly in closed atropine should be considered in difficult spaces or whilst wearing protective clothing. cases. Assisted ventilation with supple- mentary oxygen may be needed for some First Aid by Trained Personnel hours. This comprises the emergency actions undertaken to restore or maintain vital Oxygen bodily functions in a casualty. Wherever the Dyspnoeic casualties should receive oxygen casualty is not masked, the respirator must at the lowest possible level.This may result in be adjusted for him or her by the nearest a high demand for oxygen. If available, available person. Attention should be given oxygen saturation should be monitored. to decontamination at the earliest possible moment and any skin contamination must General Supportive Care be removed with a personal decontamination Although pre- and post-exposure therapy kit. will reduce lethality, casualties may still be After nerve agent poisoning, the incapacitated. A patient severely poisoned by administration of atropine is repeated at an anticholinesterase is a critical medical intervals until signs of atropinization (dry emergency and may require intensive care for mouth and skin and tachycardia >90 per days or weeks. General supportive care such minute) are achieved. Miosis from vapour as restoring fluid and electrolyte balance, exposure is not relieved by systemic correction of acid base balance, control of atropine. body temperature and control of infection Mild atropinization should be maintained should follow normal medical practice. for at least 24 hours by intramuscular Special precautions should be taken when injection of 1-2 mg of atropine at intervals of using muscle relaxants in patients poisoned 1/2 to 4 hours, as required.There is a danger by nerve agents. of ventricular arrhythmias arising from atropinization if the casualty is anoxic. Emergency Field Therapy Assisted ventilation is required for severely poisoned individuals as they will have: Self Aid (or Buddy Aid) This comprises first aid measures which the - Marked bronchoconstriction. soldier can apply to help him- or herself.The - Copious secretions in the trachea and rapid action of nerve agents calls for bronchi. immediate self treatment. Unexplained nasal - Paralysis of the respiratory muscles. - Central respiratory depression, hypoxia, secretion, salivation, tightness of the chest, http://militaryhealth.bmj.com/ shortness of breath, constriction of pupils, and convulsions. muscular twitching, or nausea and abdominal cramps call for the immediate Assisted Ventilation intramuscular injection of 2 mg of atropine, Positive pressure resuscitation should be combined if possible with oxime. From 1 to undertaken but the pressure necessary to 3 automatic injection devices, each overcome the bronchoconstriction may be containing 2 mg atropine or mixture of more than 65 cm H2O and if possible, atropine, oxime and/or anticonvulsant, are intubation is highly desirable. In the absence carried by each individual. of a liquid or vapour hazard, assisted One device should be administered ventilation may be attempted by the standard immediately when the symptoms and/or mouth-to-mouth method after decon- on September 28, 2021 by guest. Protected copyright. signs of nerve agent poisoning appear. This tamination of the casualty's face and mouth. may be done by the casualty or by a buddy, In the presence of a liquid or vapour hazard, the injection being given perpendicularly ventilation may be given by a portable through the clothing into the lateral aspect of resuscitator with NBC filter attached. the middle of the thigh. Further devices, up In a medical care facility, mechanical to a total of 3, should be administered by the resuscitation of the positive pressure type casualty or by his or her buddy during the may be used with endotracheal intubation or following 30 minutes if the symptoms and/or tracheostomy; artificial respiration must be signs of poisoning fail to resolve. continued until the casualty is breathing The timing of these further injections and normally or the medical personnel have whether they are given at one time or pronounced the casualty dead. Due to the separately may depend on the casualty's production of copious secretions, regular condition (and on instructions promulgated suction will be required. by individual NATO nations). Note that if automatic injectors are used in Return To Duty the absence of exposure to agent, the As with all other injuries in military following signs and symptoms may be seen: operations, return to duty depends on the dry mouth, dry skin, fast pulse (>90 beats clinical recovery of the casualty, his military per minute), dilated pupils, retention of urine assignment, and the tactical situation. In 357 J R Army Med Corps: first published as 10.1136/jramc-148-04-04 on 1 December 2002. Downloaded from

principle, the soldier with reduced Phosphate Anticholinesterase Compounds." Arch Int. cholinesterase activity may be at a higher risk Med., Vol 98, 1956. Grob D, Johns RI. "Use of Oximes in the Treatment of if re-exposed to any . Intoxication by Anticholinesterase Compounds in The use of pre-treatment is not advised in Normal Subjects." The American Journal of Medicine, these cases, until recovery of cholinesterase Vol XXIV; 4:497-518. activity can be confirmed. If cholinesterase Hayes WJ. "Organic Pesticides." Pesticide activity cannot be measured, then a period of Studies in Man. Williams and Wilkins, Baltimore, 1982. at least 4 weeks without pre-treatment is Martin LJ, Doebler JA. et al. "Protective Effect of recommended. Diazepam Pre-treatment on Soman Induced Brain Most individuals triaged as minimal could Lesion Formation." Brain Research, 325:287-289, return to duty within several hours if the 1985. McCloud CG, Singer A, Harrington DG. "Acute tactical situation required all available Neuropathy in Soman Poisoned Rats." Neurotoxicology, manpower. The lingering ocular and CNS 5(2):53-58, 1984. effects may be limiting factors in these cases. McDonagh JH, Jaax NK. et al. "Atropine and/or These individuals might be able to fire a rifle, Diazepam Therapy Protects Against Soman Induced but their performance on a tracking screen Neural and Cardiac Patholgy." Fundamental and Applied , 13:256-276, 1989. might be severely disturbed because of both Nambe, T. Nolte CT. et al. "Poisoning Due to visual problems and difficulty in concen- Organophosphate Insecticides; Acute and Chronic trating. These prolonged effects must be Manifestations." American Journal of Medicine, Vol 50, thoroughly evaluated before the casualties Apr 1971. Rickett DL, Glenn JF, Beers ET. "Central Respiratory are returned to duty. Effects Versus Neuromuscular Actions of Nerve A casualty who has had severe effects Agents." Neurotoxicology, 7(1):225-326, 1986. might be walking and talking after 6 to 24 Sidell FR, Groff WA. "The Reactivatability of hours but will still be unfit for most duties. Cholinesterase Inhibited by VX and Sarin in Man." Ideally, he should be kept under medical Toxicology and Applied Pharmacology, 27:241-252, 1974. observation for a week or longer and not Sundwall A. Minimum concentrations of N- returned until recovery of cholinesterase methylpyridinium-2-aldoxime methanesulphonate activity. However, the tactical situation may (P2S) which reverse neuromuscular block. Biochemical lead to modification of these guidelines. Pharmacology. 8: 413-417, 1961. Kusic R, Jovanovic D, Randjelovic S. et al. HI-6 in man : efficacy of the oxime in poisoning by organo- Further Reading phosphorus insecticides. Human and Experimental Gall D. "The Use of Theraputic Mixtures in the Toxicology. 10: 113-118, 1991. Treatment of Cholinesterase Inhibition." Dawson RM. Review of oximes available for treatment Fundamental and Applied Toxicology, 1:214-216, 1981. of nerve agent poisoing. Journal of Applied Toxicology. Grob D, Harvey, JC "Effects in Man of the 14(5): 317-331, 1994. Anticholinesterase Compound Sarin." Dept. of Kassa J. A comparison of the efficacy of the new Medicine, Johns Hopkins University, Baltimore, MD, asymmetric bispyridinium oxime BI-6 with other Vol 37, 1958. oximes (obidoxime, HI-6) against soman in rats. http://militaryhealth.bmj.com/ Grob D, "The Manifestations and Treatment of Human and Experimental Toxicology. 17: 331-225, Poisoning Due to Nerve Gas and Other Organic 1996. on September 28, 2021 by guest. Protected copyright.