*Nerve Agents*
Introduction:
The nerve agents (NA) are a group of particularly toxic chemical warfare agents. They were developed just before and during World War II and are related chemically to the organophosphorus insecticides. The principle agents in this group are: GA (Tabun), GB (Sarin), GD (Soman), GF and VX
Physical and Chemical Properties:
1. Nerve agents are organophosphorus esters. The "G" agents tend to be non-persistent whereas the "V" agents are persistent. Some "G" agents may be thickened with various substances in order to increase their persistence, and therefore the total amount penetrating intact skin.
2. It may be seen that at room temperature GB is a comparatively volatile liquid and therefore non-persistent. GD is also significantly volatile, as is GA though to a lesser extent. VX is a relatively non-volatile liquid and therefore persistent. It is regarded as presenting little vapor hazard to people exposed to it. In the pure state nerve agents are colorless and mobile liquids. In an impure state nerve agents may be encountered as yellowish to brown liquids. Some nerve agents have a faint fruity odor.
3. In general, nerve agents are moderately soluble in water with slow hydrolysis, highly soluble in lipids, rapidly inactivated by strong alkalis and chlorinating compounds.
Protection:
1. To prevent inhalation of an incapacitating or lethal dose it is essential that the breath is held and the respirator put on at the first warning of the presence, or suspected presence, of a nerve agent.
2. These agents penetrate normal clothing whether contact is with liquid or vapor and specialized clothing including a respirator, nuclear, biological, and chemical (NBC) suit, gloves and overboots are required for protection when liquid agent is present. The respirator protects the eyes, mouth and respiratory tract against nerve agent spray vapor and aerosol. Nerve agent vapor in field concentrations is absorbed through the skin very slowly, if at all, so that where a vapor hazard exists alone, the respirator may provide adequate protection without the use of an NBC suit.
Decontamination
1. The importance of early decontamination cannot be over emphasized. Decontamination of the skin should be accomplished quickly if it is to be fully effective. Liquid agent may be removed by fullers' earth or chemically inactivated by the use of reactive decontaminants. Decontamination personnel should use a respirator and full protective equipment whilst decontamination is performed.
2. Once a casualty has been decontaminated, or the agent fully absorbed, no further risk of contamination exists. The casualty's body fluids, urine or feces do not present a chemical warfare (CW) hazard.
Mechanism of Action
1. Absorption. Nerve agents may be absorbed through any body surface. When dispersed as a spray or an aerosol, droplets can be absorbed through the skin, eyes and respiratory tract. When dispersed as a vapor at expected field concentrations, the vapor is primarily absorbed through the respiratory tract. If enough agent is absorbed, local effects are followed by generalized systemic effects. The rapidity with which effects occur is directly related to the amount of agent absorbed in a given period of time.
2. Inhibition by Agents.
a. The effects of the nerve agents are mainly due to their ability to inhibit acetyl-cholinesterase throughout the body. Since the normal function of this enzyme is to hydrolyse acetylcholine wherever it is released, such inhibition results in the accumulation of excessive concentrations of acetylcholine at its various sites of action. These sites include the endings of the parasympathetic nerves to the smooth muscle of the iris, ciliary body, bronchial tree, gastrointestinal tract, bladder and blood vessels; to the salivary glands and secretory glands of the gastrointestinal tract and respiratory tract; and to the cardiac muscle and endings of sympathetic nerves to the sweat glands. The accumulation of acetylcholine at these sites results in characteristic muscarinic signs and symptoms.
b. The accumulation of acetylcholine at the endings of motor nerves to voluntary muscles and in some autonomic ganglia results in nicotinic signs and symptoms.
c. The accumulation of excessive acetylcholine in the brain and spinal cord results in characteristic central nervous system symptoms
d. The inhibition of cholinesterase enzymes throughout the body by nerve agents may be irreversible and its effects prolonged.
e. Treatment with oximes should begin promptly.
f. Until the tissue cholinesterase enzymes are restored to normal activity, there is a period of increased susceptibility to the effects of another exposure to any nerve agent. The period of increased susceptibility occurs during the enzyme regeneration phase, which could last from weeks to months, depending on the severity of the initial exposure. During this period the effects of repeated exposures are cumulative.
3. Location of Acetylcholinesterase. Acetylcholinesterase is found associated with the post-junctional membrane at the neuromuscular junction and in the cell bodies and processes of cholinergic neurons. The concentration is particularly high in some central nervous system neurons. The location of acetylcholinesterase in autonomic ganglia is less well understood than that at the neuromuscular junction. Acetylcholinesterase is also found at sites where, as yet, no functional role has been identified: the musculotendinous junction, red blood cells, platelets and the placenta.
Signs and Symptoms
1. The order in which signs and symptoms appear and their relative severity depend on the route of exposure and whether the casualty has been exposed to liquid agent or vapor.
2. The signs and symptoms following exposure to nerve agents are given in Table 1.
Table 1
1. The local effects of vapor and liquid exposure are described followed by a description of the systemic effects, which occur after significant absorption of agent via any route.
Diagnosis and Therapy of Nerve Agent Poisoning:
1. Symptoms. Nerve agent poisoning may be identified from the characteristic signs and symptoms. If exposure to vapor has occurred, the pupils will be very small, usually pin-pointed. If exposure has been cutaneous or has followed ingestion of a nerve agent in contaminated food or water, the pupils may be normal or, in the presence of severe systemic symptoms, slightly to moderately reduced in size. In this event, the other manifestations of nerve agent poisoning must be relied on to establish the diagnosis. No other known chemical agent produces muscular twitching and fasciculations, rapidly developing pinpoint pupils, or the characteristic train of muscarinic, nicotinic and central nervous system manifestations.
2. Symptom Differentiation. It is important that individual service members know the following MILD and SEVERE signs and symptoms of nerve agent poisoning. Service members who have most or all of the symptoms listed below must IMMEDIATELY receive first aid (self-aid or buddy aid respectively).
3. MILD Poisoning (Self-Aid). Casualties with MILD symptoms may experience most or all of the following:
a. Unexplained runny nose.
b. Unexplained sudden headache.
c. Sudden drooling.
d. Difficulty in seeing (dimness of vision and miosis).
e. Tightness in the chest or difficulty in breathing.
f. Localized sweating and muscular twitching in the area of the contaminated skin.
g. Stomach cramps.
h. Nausea.
i. Bradycardia or tachycardia
4. MODERATE Poisoning. Casualties with MODERATE poisoning will experience an increase in the severity of most or all of the MILD symptoms. Especially prominent will be an increase in fatigue, weakness and muscle fasciculations. The progress of symptoms from mild to moderate indicates either inadequate treatment or continuing exposure to agent.
5. SEVERE Symptoms (Buddy Aid). Casualties with SEVERE symptoms may experience most or all of the MILD symptoms, plus most or all of the following:
a. Strange or confused behavior.
b. Wheezing, dyspnoea (severe difficulty in breathing), and coughing.
c. Severely pin-pointed pupils.
d. Red eyes with tearing.
e. Vomiting.
f. Severe muscular twitching and general weakness.
g. Involuntary urination and defecation.
h. Convulsions.
i. Unconsciousness.
j. Respiratory failure.
k. Bradycardia.
6. Aid for Severe Cases. Casualties with severe symptoms will not be able to treat themselves and must receive prompt buddy aid and follow-on medical treatment if they are to survive.
Treatment:
The lethal effects of nerve agent poisoning may be combated by a combination of pretreatment and post exposure therapy.
1. Pretreatment:
a. Poisoning by nerve agents that form rapidly aging complexes (for example Soman) may be particularly difficult to treat. These difficulties have been solved, in part, by the use of carbamates as pretreatment. The terms pretreatment or prophylaxis should perhaps be defined as used in this context:
1. Pretreatment: the administration of drugs in advance of poisoning designed to increase the efficacy of treatment administered post-poisoning.
2. Prophylaxis: the administration of drugs in advance of the poisoning designed to make post-poisoning therapy unnecessary.
b. The terms are to an extent interchangeable and as, in cases of severe poisoning, post-poisoning therapy is nearly always needed, the term pretreatment will be used here.
c. Carbamate anticholinesterases, e.g., pyridostigmine, may be used as pretreatments against nerve agent poisoning by virtue of their capacity to bind acetylcholinesterase reversibly, preventing the organophosphate (OP) binding to the enzyme. The term reversible is here used comparatively: the carbamate-acetylcholinesterase complex breaks down fairly rapidly, while organophosphate-acetylcholinesterase complexes break down very slowly. The aged soman-acetylcholinesterase complex breaks down virtually not at all.
d. When carbamates are used as pretreatments, carbamoylation of acetylcholinesterase prevents phosphorylation, but later the carbamate-acetylcholinesterase complex dissociates, freeing active enzyme. Current pretreatment regimes bind 30-40% of available red blood cell acetylcholinesterase, thereby allowing the carbamate to protect some of the acetylcholinesterase against attack by nerve agent.
e. The carbamate pyridostigmine, given in a dose of 30 mg every 8 hours, is used as a pretreatment. In conjunction with post exposure therapy, good protection against lethality is obtained within 2 hours of the first dose, but is not optimal until the third dose.
f. Pyridostigmine pretreatment should be stopped upon developing symptoms of nerve agent poisoning following a chemical warfare attack and post exposure therapy started.
g. Pyridostigmine tablets were taken over a 4 to 5 day period by large numbers of troops during the Gulf War of 1991
1. The effects of pyridostigmine were examined in several studies including one uncontrolled study of 42,000 troops when, following the recommended dose regime, under the stress of combat conditions, gastrointestinal intestinal changes including increased flatus, loose stools, abdominal cramps and nausea were noted by approximately half the population. Other reported effects were urinary urgency, headache, rhinorrhoea, diaphoresis and tingling of the extremities. These effects were considered tolerable. They did not noticeably interfere with performance of the full range of demanding physical and mental tasks required of service personnel.
2. Symptoms due to pyridostigmine may be ameliorated by taking the tablets with food.
3. Pyridostigmine pretreatment was discontinued on medical advice in less than 0.1% of individuals, generally because of intolerable nausea and diarrhoea.
h. When taken in excess of the recommended dosage, symptoms of carbamate poisoning will occur. These include diarrhea, gastrointestinal cramps, tight chest, nausea, rhinorrhoea, headache and miosis.
i. Good compliance is required if optimal protection is to be obtained. The importance of pyridostigmine pretreatment should therefore be stressed during training.
Post-Exposure Therapy:
The main principles of therapy for nerve agent poisoning are early treatment, assisted ventilation, bronchial suction, muscarinic cholinergic blockade (atropine), enzyme reactivation (oximes) and anticonvulsants (benzodiazepines).
Emergency Field Therapy
1. Self Aid (or Buddy Aid)
a. This comprises first aid measures, which the soldier can apply to help him or herself. The rapid action of nerve agents call for immediate self-treatment. Unexplained nasal secretion, salivation, tightness of the chest, shortness of breath, constriction of pupils, muscular twitching, or nausea and abdominal cramps call for the immediate intramuscular injection of 2 mg of atropine, combined if possible with oxime. From 1 to 3 automatic injection devices, each containing 2 mg atropine or mixture of atropine, oxime and/or anticonvulsant, are carried by each individual.
b. One device should be administered immediately when the symptoms and/or signs of nerve agent poisoning appear. This may be done by the casualty or by a buddy; the injection being given perpendicularly through the clothing into the lateral aspect of the middle of the thigh. Further devices, up to a total of 3, should be administered by the casualty or by his or her buddy during the following 30 minutes if the symptoms and/or signs of poisoning fail to resolve.
c. The timing of these further injections and whether they are given at one time or separately may depend on the casualty's condition and on instructions promulgated by individual nations.
d. NOTE: If automatic injectors are used in the absence of exposure to agent, the following signs and symptoms may be seen: Dry mouth, dry skin, fast pulse (>90 beats per minute), dilated pupils, retention of urine and central nervous system disturbance. Susceptibility to heat exhaustion or heat stroke is increased, particularly in closed spaces or while wearing protective clothing.
2. First Aid by Trained Personnel.
a. This comprises the emergency actions undertaken to restore or maintain vital bodily functions in a casualty. Wherever the casualty is not masked the respirator must be adjusted for him or her by the nearest available person. Attention should be given to decontamination at the earliest possible moment and any skin contamination must be removed with a personal decontamination kit.
b. After nerve agent poisoning, the administration of atropine is repeated at intervals until signs of atropinization (dry mouth and skin and tachycardia >90 per minute) are achieved. Miosis from vapor exposure is not relieved by systemic atropine.
c. Mild atropinization should be maintained for at least 24 hours by intramuscular injection of 1-2 mg of atropine at intervals of 1/2 to 4 hours, as required. The danger of ventricular arrhythmias arising from atropinization while the casualty is anoxic must be remembered.
d. Assisted ventilation is required for severely poisoned individuals as they will have:
1. Marked bronchoconstriction;
2. Copious secretions in the trachea and bronchi;
3. Paralysis of the respiratory muscles; and
4. Central respiratory depression, hypoxia, and convulsions.
3. Resuscitation:
a. Positive pressure resuscitation should be given but the pressure necessary to overcome the bronchoconstriction may be more than 65 cm of water so that intubation if possible is highly desirable. In an uncontaminated atmosphere assisted ventilation may be done by the standard mouth-to-mouth method after decontamination of the casualty's face and mouth. In a contaminated atmosphere ventilation may be given by a portable resuscitator with NBC filter attached. Both the casualty and the resuscitator should be decontaminated.
b. In a well equipped medical facility, mechanical resuscitation of the positive pressure type may be used with endotracheal intubation or tracheostomy - artificial respiration must be continued until the casualty is breathing normally or the medical personnel have pronounced the casualty dead. Due to the production of copious secretions, regular suction will be required.
Pharmacological Treatment of Nerve Agent Poisoning:
1. The pharmacological treatment of nerve agent poisoning involves the use of:
a. Anticholinergics to antagonise the muscarinic effects (atropine).
b. Oximes to reactivate inhibited enzyme.
c. Anticonvulsants to prevent CNS damage.
2. The effects of drugs used in nerve agent poisoning are described below
Atropine:
1. Atropine sulphate remains an essential drug in the treatment of nerve agent poisoning. It acts by blocking the effects of acetylcholine at muscarinic receptors and so produces relief from many of the symptoms previously listed. If given in large doses, some therapeutic effects are also produced within the central nervous system although atropine does not readily penetrate the blood brain barrier and central muscarinic receptors are thought not to be identical with those in the periphery. It is thought to counteract the respiratory depression in the medulla oblongata.
2. Urgent treatment with atropine in cases of nerve agent poisoning is essential. After the emergency field treatment, atropinisation should be maintained for at least 24 hours by intramuscular injection or slow intravenous infusion of 1 to 2 mg of atropine per hour as required. The dose should be repeated at intervals until signs of successful atropinisation are noted. Intervals of 5 to 15 minutes seem reasonable, but severe poisoning may require higher doses (4 mg to 6 mg per hour or more). Signs of successful atropinisation include the drying up of bronchial, salivary and skin secretions and an increase in heart rate to greater than 90 beats
per minute.
3. The effect of atropine in drying bronchial secretions may make the removal of mucus more difficult so suction is likely to be necessary. In excessive doses, atropine may render the ischaemic myocardium more liable to arrhythmias and electrocardiogram (ECG) monitoring should be undertaken in all patients if possible.
4. Atropine overdosage may produce euphoria, hallucinations, anxiety, and delirium and close observation of patients is necessary. Bladder dysfunction may necessitate catheterisation.
5. By inhibition of sweat production, atropine increases heat stress and in warm or hot weather care must be taken to avoid hyperthermia.
6. Atropine given parenterally has comparatively little effect on nerve agent induced miosis. The local application of cycloplegics (atropine eye drops) to the eye reduces both the degree of miosis, eye pain and headache. However, expert opinion on the value of atropine containing eye drops in the management of nerve agent induced miosis remains divided. It is believed by some that problems of accommodation may be made worse by the application of the drops and that, overall, little benefit may be produced.
7. If atropine is administered in the absence of nerve agent poisoning, the following effects may be noted: dryness of the mouth and pharynx, decreased sweating, slight flushing and tachycardia, some hesitancy of micturition, slightly dilated pupils, mild drowsiness, slowness of memory and recall and blurring of near vision. After 2mg these symptoms should not interfere with ordinary activity except in the occasional person, in hot environments or at high work rates. Higher doses, or repeated doses, will produce more marked symptoms which will usually not be totally incapacitating except in warm environments or high work rates. The effects of atropine are fairly prolonged, lasting 3 to 5 hours after one or two injections of 2mg and 12 to 24 hours after marked over-atropinisation.
Oximes:
1. Oximes
a. While atropine blocks the muscarinic effects of nerve agent poisoning it has little effect upon the nicotinic actions of the agent at the skeletal neuromuscular junction and at the autonomic ganglia.
b. Amelioration of the effects of nerve agents at these sites and also at muscarinic sites can, however, be obtained by reactivation of the inhibited acetylcholinesterase by means of oximes. Oximes, therefore, relieve the clinically important symptom of skeletal neuromuscular blockade. However, they penetrate into the central nervous system poorly, and the simultaneous administration of atropine is therefore still required.
Anticonvulsants
1. Atropine protects only partially against convulsions and the resulting brain damage in severe poisoning. Complementary treatment, including anticonvulsants, should be applied as necessary.
2. It has been shown in experimental soman poisoning that diazepam antagonises the convulsive action of soman and that addition of diazepam to the basic treatment regime greatly improves morbidity and mortality, independent of its anticonvulsive effect. Diazepam is the drug of choice and should be injected intramuscularly as a 10 mg dose initially and further doses should be given frequently enough to control convulsions. This may require injections at intervals ranging from a few minutes to several hours.
Supportive Care
Although pre and post exposure therapy will protect against lethality, casualties may still be incapacitated. A patient severely poisoned by an anticholinesterase is a critical medical emergency and may require intensive care for days or weeks. Assisted ventilation may be needed for many hours or days and the patient may be comatose for hours or days and brain damage may result from periods of hypoxia. General supportive care such as IV feeding, restoring electrolyte balance, treatment of shock and control of convulsions is needed. Therapy to control infection, should this occur, should be on the usual lines. Special care should be taken using muscle relaxants in patients poisoned by nerve agents.
BrainNJ
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