March 3, 2009
Since WWII, nerve agents have had the dominant role in chemical warfare planning by military strategists and tacticians. Nerve agents are supertoxic compounds that produce convulsions and rapid death by inactivation of acetylcholinesterase. The nerve agents belong to the class of organophosphorus chemicals which contain a phosphorus atom surrounded by four chemical groups, one of which is double-bonded oxygen.
Although many organophosphorus compounds are highly toxic, only a limited number of them have the physical properties which give them military utility. The difference in toxicity between pesticides and nerve agents results from the chemical groups that surround the phosphorus atom. In general, the nerve agents are 100 to 1000 times more poisonous than the organophosphorus pesticides.
Nerve gases in current use, storage, or production include Tabun (GA), Sarin (GB), Soman (GD) [ "G" for German - found in German military stores after World War II ], and VX. (There was no code GC as that was thought to be too confusing with the standard abbreviation for gonorrhea.) These nerve agents were produced in large quantities in the 1950's and 1960's by both the United States and the former Soviet Union.
The first three agents discovered, the so-called "G" agents, are highly toxic organophosphate compounds that were discovered between World War I and World War II. A man named Schrader had been in charge of a program to develop new types of insecticides since 1934, working first with fluorine-containing compounds such as acyl fluorides, sulfonyl fluorides, fluoroethanol derivatives, and fluoroacetic acid derivatives. In 1935, he prepared dimethylphosphoramido-fluoridic acid during his research. He then began to systematically investigate the dimethylphosphoramides, eventually leading to the preparation of Tabun.
In January 1937, Schrader was the first to observe the effects of nerve agents on human beings when he and a laboratory assistant began to experience contraction of the pupils of their eyes and shortness of breath because of their exposure to Tabun vapor in the laboratory.
In 1935, the Nazis had passed a decree which requiring all inventions of possible military significance to be reported to the Ministry of War. In compliance with this law, a sample of Tabun was sent to the chemical warfare section of the Army Weapons Office. Schrader was asked to give a demonstration of Tabun at Berlin-Spandau in May 1937. Colonel Rudringer, head of the German Army chemical warfare section, ordered the construction of new laboratories for the further investigation of Tabun and related organophosphate compounds after seeing this demonstration.
In 1938, a second potent organophosphate nerve agent was discovered. This agent, Sarin, was named for its four discoverers: Schrader, Ambrose, Rudringer, and van der Linde.
The Germans started to manufacture Tabun and Sarin at several sites, including Dyernfurth, Spandau, and Falkenhagen. The plant designed to manufacture of these gases took an extraordinarily long time to begin production because the reactions were so corrosive to the equipment. Vessels were lined with silver or quartz and piping was double walled with air circulating between the two walls. Workers were equipped with respirators and clothing made from a rubber/cloth/rubber sandwich; the clothing was discarded after the tenth wearing. Despite these precautions, over 300 accidents occurred during early production and at least 10 workers were killed.
On 11 May 1943, the British captured a German chemist who had worked at the main Army CW research laboratory in Spandau. The prisoner told the British the code name for Tabun (Trilon 83), the chemical reactions by which it was produced, its effects, the German doctrine for use of the agent and the known methods of defense against Tabun. This was compiled into an MI9 intelligence report of 3 July 1943.
In 1944, Dr. Richard Kuhn synthesized Soman for the German Military. No Soman was known to have been produced in other than laboratory quantities.
Sarin molecular structure
In early 1945, Dyernfurth was to be abandoned and tons of liquid nerve agents were simply poured into the Oder river. The plant was rigged for demolition, but the Russians surrounded the plant before it could be destroyed. The Luftwaffe was then ordered to bomb the plant, but they also failed to destroy it. It is believed that the Soviets captured both the full-scale Tabun plant and the pilot Sarin plant intact. The Soviets later captured the near complete full-scale Sarin plant at Falkenhagen.
A more persistent nerve agent, O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) was discovered by the British chemist, R. Ghosh, soon after WWII. Dr. Ghosh was searching for a new pesticide to replace DDT.
Since the discovery of VX, there have been only minor developments in the toxic science of lethal chemicals. Military development was conducted by the United States, Great Britain, and the Soviet Union and large scale production of V agents was conducted in the 1960's.
Although the Nazis had these agents during WWII, they were never used by the German military. The reason why Adolph Hitler never deployed these lethal chemicals is a subject of controversy for modern historians. The most popular explanation is that Hitler was temporarily blinded during WWI by gas and was unwilling to introduce these toxic agents. It is more likely that the agents were simply not produced in sufficient quantities, the German troops were not equipped with appropriate protective gear, and the Allies moved too rapidly for effective deployment of the agents.
The only known military use of nerve agents was in the Iran-Iraqi war in the 1980's. According to Iranian sources, Iraqi chemical weapons accounted for some 50,000 Iranian casualties, including about 5,000 deaths.
The United States had a chemical weapons accident involving a leak of VX from an aereal spray tank that drifted over the boundaries of the United States military base in Skull Valley, Utah. Fortunately, there were no human casualties, but 6000 sheep were killed.
Nerve agents were forcibly brought to EMS provider's attention by Aum Shinrikyo in 1994 and 1995 when Sarin was employed as a terrorist weapon first in Matsumoto, Japan and then in the Tokyo subway system. The Shinrikyo cult was found to have a well developed production facility that was capable of making Sarin in significant quantities.
In the Shinrikyo cult's second use of Sarin, five open containers of Sarin were placed on three of Tokyo's subway lines in 1995. In all, 6000 people were exposed, 3227 were evaluated in emergency departments, 493 were admitted to hospitals, and 12 people died as a result of this terrorist exposure. The concentration within the rail cars with the containers was high, but the agent was not spread well through the subway system and most exposures were mild. Of the ambulance personnel taking care of these victims, 135 developed symptoms and 33 were hospitalized. Many of the hospital staff also required treatment, but none required hospitalization. Neither ambulance personnel nor hospital staff had any chemical weapon protection.
In 1996, the United States government acknowledged that troops operating during the Gulf War in 1991 were potentially exposed to nerve agents. This reportedly occurred after an Iraqi chemical weapons depot was destroyed at Khamisiyah.
Mechanism of action
Nerve agents act by first binding and then irreversibly inactivating acetylcholinesterase (AChE), producing a toxic accumulation of acetylcholine (ACh) at muscarinic, nicotinic, and CNS synapses. Acetylcholine normally causes activation of these receptors as a result of a nerve impulse and is then destroyed by acetylcholinesterase. The hydrolysis products of choline and acetic acid are rapidly cleared from the enzyme, leaving it free to deactivate the next nerve impulse’s release of acetylcholine. Acetylcholine that is not hydrolyzed still can interact with the receptor, resulting in a persistent and uncontrolled stimulation of that receptor. The excess concentrations of acetylcholine produce excessive stimulation of the muscarinic and nicotinic receptors. After persistent activation of the muscular acetylcholine receptor, fatigue occurs. This is the same principle used by the depolarizing neuromuscular blocker succinylcholine
This explains the peripheral and central effects of these agents, but no direct evidence exists unequivocally relating the nerve agent toxicity solely to acetylcholinesterase inhibition.
Route of Exposure
Nerve agents may be delivered by vapor, droplet, or both. Any artillery or mortar capable of delivering a chemical munition is suitable. M55 rockets and M23 land mines are two such munitions. Low flying missiles or aircraft that deliver a droplet spray are ideal. The Soviets have adapted SCUD missiles to “splatter” these agents with a small explosive charge. Finally, release of the vapor or droplets from pressurized containers in aerosol forms can be accomplished. Delivery patterns will be dependent on the munition, capacity of the chemical container and weather patterns. Delivery indoors will be dependent on heating/air conditioning and airflows as well as the munition used.
The route for entering the body is of significant importance for the time required for onset of the symptoms of a nerve agent’s effects. Symptoms appear much more slowly from absorption through the skin than from respiratory exposure. This is because the lungs contain a large surface area and numerous blood vessels that allows rapid diffusion into the circulation. If inhaled or absorbed through eye or mucous membranes, the agent kills in 1-10 minutes. With inhalation exposure, affected patients typically do not deteriorate after removal from the area of vapor exposure.
Although the initial skin absorption of a lethal dose may occur within 1-2 minutes, it may take up to 1-2 hours for death to occur. With some nerve agents (particularly VX), patients may not become symptomatic for hours after skin exposure. With dermal exposure, deterioration of the patient may continue even after the agent is removed from the surface of the skin. If food or water contaminated with nerve agents is ingested, the victim may experience symptoms in about a half hour.
The toxic effect of nerve agents depends on both the concentration of the nerve agent in the air inhaled [C] and duration of exposure (t) [C—t]. In high concentration, the C—t product determines a specific relationship between the inhaled dose and the effect. The lethal dose for the most sensitive people is about 70 mg/min/m3 and about twice this level for the most resistant individuals. At low concentrations, the C—t product does not apply, since the body is capable of limited detoxification of the agents.
The importance of nerve agent’s peripheral effects is paramount. Acetylcholine is a neurotransmitter that is found throughout the central nervous system, the sympathetic and the parasympathetic autonomic ganglia, the postganglionic parasympathetic nervous system, most sympathetic sweat glands, and the skeletal muscle motor end plates.
There are popular mnemonics for the effects of the nerve agents:
Defecation, drooling, diarrhea
Gastric upset and cramps
Unfortunately, none of the mnemonics cover all of the symptoms that the nerve agent can cause and are particularly lacking in covering the nicotinic symptoms of the nerve agent.
Many of the clinical effects of the nerve agents are due to the characteristic muscarine-like signs and symptoms associated with cholinergic excess (muscarinic effects). These include the simulation of the endings of the parasympathetic nerves at the smooth muscle of the iris, the ciliary body, the bronchial tree, gastrointestinal tract, bladder and blood vessel. The patient may have: conjunctival injection, lacrimation, miosis, loss of dark adaptation, diminished visual acuity, and ciliary muscle spasm exacerbated by attempting to focus. The respiratory effects due to muscarinic stimulation include rhinorrhea, wheezing, cough, increased bronchial secretions, dyspnea, and apnea. The cardiovascular effects of muscarinic stimulation include bradydysrhythmia, prolongation of the PR interval, and atrioventricular blocks. Sympathetic stimulation includes nerves to the sweat glands and causes flushing and sweating.
Salivation, lacrimation, and involuntary defecation and urination result from these effects of the nerve agent on gastrointestinal and genitourinary muscarinic end organs. The patient may develop crampy abdominal pain or tenesmus. Nausea and vomiting are common effects.
Motor end plates
The accumulation of acetylcholine at the endings of the motor nerves to voluntary muscles and the autonomic ganglia results in nicotinic-like signs and symptoms. For muscle, this would mean the following sequence of events would occur:
Spontaneous activation of myofibrils (fasciculations) as acetylcholine accumulates and paralyzes random neuromuscular junctions.
Tremors and twitching as entire muscle groups are lost
The patient would develop progressive weakness culminating in flaccid paralysis as the muscle group loses the effective function of the neuromuscular junction.
The nicotinic mediated sympathetic discharge causes tachydysrhythmia and hypertension.
The metabolic effects of excess acetylcholine on nicotinic receptors cause metabolic abnormalities: hyperglycemia, ketosis, and metabolic acidosis are common.
Finally, the accumulation of excessive acetylcholine in the brain and spinal cord is thought to result in central nervous system symptoms of twitching, jerking, staggering gait, convulsions, respiratory depression, and coma. Objective changes in the electroencephalogram may be demonstrated. Early manifestations may include anxiety, restlessness, confusion, and ataxia.
Individuals poisoned by a nerve agent display similar symptoms regardless of exposure route. The intensity and sequence of the symptoms is, however, influenced by the route of absorption and by individual sensitivity.
Eye exposure to the nerve agents may produce and pupillary constriction (miosis), ocular pain, and dimness of vision as first effects of the cholinesterase inhibitors. (The accommodation capacity of the eye is reduced so that the short-range vision deteriorates and the victim feels pain when he tries to focus on a nearby object.)
Miosis (pupillary contraction) causes dimness and impairment of night vision. Miosis appears to be a consistent clinical finding with nerve agent vapor exposure. Ciliary spasm also may cause eye pain. This is most likely from direct effect of the agent on the eye.
Eye findings in patients exposed by skin contact are less common. This is probably because the eye usually is not exposed directly to the agent, unlike with the vapor of the G agents. Miosis may be a delayed in VX exposure, since this agent is most commonly absorbed from the skin..
Nasal and oral
Rhinorrhea is most common after a vapor exposure but also can be observed with exposures by other routes.
The patient will have increased secretions and salivation early in the exposure. These increased secretions may complicate airway management of the patient.
The respiratory effects of the nerve agents are ultimately responsible for most deaths due to these chemicals. The nerve agents cause respiratory failure in three ways: increased airway resistance, weakness and paralysis of the muscles of respiration, and central depression of the respiratory drive.
Patients may describe shortness of breath, chest tightness, respiratory distress, or gasping. These sensations are caused by bronchoconstriction and increased intrabronchial secretions. The patients often develop prolonged expiration, cough, and wheezing. Patients with asthma or chronic obstructive pulmonary disease may be at significant increased risk due to their increased sensitivity and potentially diminished reserves.
The respiratory paralysis caused by the nerve agents was originally thought to be the major cause of respiratory arrest. Weakness of the diaphragm and accessory muscles of respiration does occur; however respiratory arrest will often occur prior to neuromuscular blockade and is not always due to muscle paralysis. The patient may develop weakness of the muscles of the upper airway resulting in obstruction from the tongue within the oral pharynx. Laryngeal muscle paralysis may cause vocal cord dysfunction and subsequent stridor.
With severe intoxication, the patient may rapidly develop centrally mediated apnea. Multiple animal studies have shown that the respiratory depression occurs before the neuromuscular blockade and the bronchoconstriction have reached significant proportions . These studies support the contention that a major contribution to respiratory failure is central nervous system rather peripheral toxicity.
Fortunately the need for ventilatory support and intensive care for Sarin casualties treated in Tokyo was only 24-48 hours when both atropine and an oxime were given. Even patients with severe signs of poisoning recovered completely if adequate supportive therapy and antidotes were given early.
Fasciculations are often seen with these agents. The fasciculation is often confined to the area of exposure early in the intoxication; they then spread to cause generalized involvement of the entire musculature. Myoclonic jerks (twitches) may be observed. Eventually, muscles fatigue and a flaccid paralysis ensues. This includes the muscles of respiration.
When exposed to a high dose of nerve agent, the muscular symptoms are more pronounced. The victim may rapidly suffer convulsions and lose consciousness. The process of intoxication may be so rapid that the patient does not have time to develop the minor symptoms before respiratory arrest occurs.
Most of the sweat glands are controlled by sympathetic cholinergic receptors. Skin exposure may produce localized sweating and fasciculations as the first effect. Generalized diaphoresis can be observed with larger exposures and with systemic absorption.
The muscarinic receptors stimulate secretion from the salivary glands, the gastric parietal cells, goblet cells, chief cells. In addition the muscarinic receptors contract the gallbladder, increase gastric and intestinal motility and relax the anal sphincter. The stimulation of these receptors results in the Salivation, Defecation, Emesis, and Gastric cramping described in the mnemonic SLUDGE. This is true even when the nerve agent is inhaled. The time of onset and the severity of the gastrointestinal symptoms is related to the duration of exposure, amount of exposure (C—t) and the route of exposure.
The patient intoxicated with a nerve agent may present with either bradycardia or tachycardia. The cardiac rate of the intoxicated patient depends on the predominance of adrenergic stimulation (resulting in tachycardia) or of the parasympathetic tone (causing bradycardia via vagal stimulation).
These cardiac toxicities from the anticholinesterase inhibitors can be divided into three phases: Tachycardia and hypertension may result from the initial intense sympathetic activity. The victims then develop bradydysrhythmia, prolongation of the PR interval, atrioventricular blocks, and hypotension as the parasympathetic stimulus predominates. The final phase is QT prolongation and possible torsades de pointes. (It should be noted that Torsade de pointes has been noted with the organophosphate insecticides, but not yet with the nerve agents.)
At least one patient had marked ST-segment elevation in leads V2-6 on presentation to the ED following Sarin intoxication. This ischemic change was related to coronary vasospasm.
Heart blocks and premature ventricular contractions can be observed after intoxication with the nerve agents, although these are also often seen with hypoxia.
Among the delayed effects are sudden cardiac failure in patients who have apparently recovered from the effects of organophosphate exposure. Cardiomyopathy has been reported in animals exposed to Sarin, but no human cases have been noted in the literature.
Cholinergic stimulation causes contraction of the detrusor muscle of the bladder and relaxation of the trigone and sphincter muscles. This leads to the involuntary Urination described in the mnemonic SLUDGE.
Central nervous system
There are cholinergic receptors throughout the central nervous system with the highest concentrations within the reticular activating system, the basal ganglia, the limbic system, the cortex, the cerebellum, and the synapses found in the ventral and dorsal spinal cord. Since there are so many CNS cholinergic receptors, there are a wide variety of symptoms and signs caused by intoxication with a cholinesterase inhibitor.
Minor exposures to the nerve agents may result in behavioral changes such as anxiety, psychomotor depression, intellectual impairment, and unusual dreams.
Large exposures to the nerve agents result in rapid loss of consciousness and seizures.
Organophosphate exposure can produce both central and peripheral nervous system signs and symptoms if the patient survives the respiratory failure and other immediately lethal events. These symptoms may include impaired memory, hallucinations, fatigue, balance problems, confusion, and concentration deficits. Signs may include both central and peripheral neuropathies and late seizures. Severely intoxicated patients may remain unconscious for hours or days.
Other effects and complications include hypoxia, ischemia, acidosis, hyperthermia, hypothermia, peripheral neuropathy and cerebral edema. These have been seen in patients who have received convulsive doses of nerve agents. It is obvious that many of the longer term effects are directly related to the problems of providing adequate ventilation to the contaminated, seizing patient who has copious airway secretions.
There is animal evidence that prolonged nerve agents-induced toxic convulsions produce irreversible brain damage. Benzodiazepine anticonvulsants appear to reduce the morbidity associated with these convulsions.
Recent work has proposed that the sole toxic effect of the nerve agents is not just the inactivation of acetylcholinesterase. Albuquerque and associates have described agonistic effects at the nicotinic cholinesterase receptor sites from Tabun, Sarin, and Soman . These agents are capable of activation of the ionic channel in a manner similar to acetylcholine. He also noted that VX prevents ionic conductance through the channel, even if acetylcholine binds to the nicotinic receptor site. This means that there is no single site of treatment for an antidote for the CNS effects.
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