GA GB GD GF VX
Summary
Immediate management: Administration of MARK I's (atropine and pralidoxime chloride); diazepam in addition if casualty is severe; ventilation and suction of airways for respiratory distress
Nerve agents are the most toxic of the known chemical agents.
They are hazards in their liquid and vapor states and can cause
death within minutes after exposure. Nerve agents inhibit
acetylcholinesterase in tissue, and their effects are caused by
the resulting excess acetylcholine.
Nerve agents were developed in pre-World War II Germany.
Germany had stockpiles of nerve agent munitions during World War
II (WWII), but did not use them for reasons that are still
unclear. In the closing days of the war, the U.S. and its allies
discovered these stockpiles, developed the agents, and
manufactured nerve agent munitions. The U.S. chemical agent
stockpile contains the nerve agents GB and VX.
Nerve agents are considered major military threat agents. The
only known battlefield use of nerve agents was in the Iraq-Iran
conflict. Intelligence analysts indicate that many countries have
the technology to manufacture nerve agent munitions.
Nerve agents are liquids under temperate conditions. When
dispersed, the more volatile ones constitute both a vapor and a
liquid hazard. Others are less volatile and represent primarily a
liquid hazard. The "G-agents" are more volatile than
VX. GB (sarin) is the most volatile, but it evaporates less
readily than water. GF is the least volatile of the G-agents.
Nerve agents can be dispersed from missiles, rockets, bombs,
howitzer shells, spray tanks, land mines, and other large
munitions.
Nerve agents are organophosphorous cholinesterase inhibitors.
They inhibit the butyrylcholinesterase in the plasma, the
acetylcholinesterase on the red cell, and the
acetylcholinesterase at cholinergic receptor sites in tissue. The
three enzymes are not the same; even the two
acetylcholinesterases have slightly different properties,
although both have a high affinity for acetylcholine. The blood
enzymes provide an estimate of the tissue enzyme activity. After
acute exposure to a nerve agent, the erythrocyte enzyme activity
most closely reflects the activity of the tissue enzyme, but
during recovery the plasma enzyme activity more closely parallels
tissue enzyme activity.
After a nerve agent inhibits the tissue enzyme, the enzyme
cannot hydrolyze acetylcholine, the neurotransmitter at
cholinergic receptor sites. Acetylcholine accumulates and
continues to stimulate the affected organ. The clinical effects
from nerve agent exposure are caused by excess acetylcholine.
The attachment of the agent to the enzyme is permanent (unless removed by therapy). Erythrocyte enzyme activity returns at the rate of erythrocyte turnover, about 1% per day. Tissue and plasma enzyme activities return with synthesis of new enzymes. The rate of return of the tissue and plasma enzymes is not the same, nor is the rate the same for all tissue enzymes. However, the agent can be removed from the enzyme and the enzyme "reactivated" by several types of compounds, the most useful of which are the oximes. If the agent-enzyme complex has not "aged," oximes are useful therapeutically. Aging is a biochemical process by which the agent-enzyme complex becomes refractory to oxime reactivation of the enzyme. For most nerve agents the aging time is longer than the time within which acute casualties will be seen. However, the aging time of the GD-enzyme complex is about two minutes, and the usefulness of oximes in GD poisoning is greatly decreased after this period.
Organs with cholinergic receptor sites include the smooth
muscles, the skeletal muscles, the central nervous system, and
most exocrine glands. In addition, cranial efferents and
ganglionic afferents are cholinergic nerves.
Muscarine will stimulate some of the cholinergic sites, and
these are known as muscarinic sites. Organs with these sites
include the smooth muscles and glands. Nicotine will stimulate
other cholinergic sites, known as nicotinic sites, which are
those in skeletal muscle and ganglia. The central nervous system
(CNS) contains both types of receptors, but the pharmacology in
the CNS is more complex and less well understood. Atropine and
similar compounds block the effects of excess acetylcholine more
effectively at muscarinic sites than at nicotinic sites.
Some commonly used pesticides (for example, the
organophosphate (OP) Malathion and the carbamate Sevin) and some
common therapeutic drugs (the carbamates pyridostigmine
[Mestinon] and physostigmine [Antilirium]) also inhibit
acetylcholinesterase and can be considered "nerve
agents." However, while the OP pesticides cause the same
biological effects as nerve agents, there are some important
differences in the duration of biological activity and response
to therapy.
The initial effects of exposure to a nerve agent depend on the
dose and on the route of exposure. The initial effects from a
sublethal amount of agent by vapor exposure are different from
the initial effects from a similar amount of liquid agent on the
skin.
Toxicities: The estimated amounts to cause certain effects in man are shown in Table I and Table II. In Table I, L indicates lethal, I indicates incapacitating (severe), and M indicates miosis. The large amounts of GA and GB required to produce effects after skin application reflect the volatility of these agents. They evaporate rather than penetrate the skin. However, if these agents are occluded and prevented from evaporating they penetrate the skin very well.
Table I
Vapor toxicity
mg-min/m3
| Agent | LCt50 | ICt50 | MCt50 |
| GA | 400 | 300 | 2-3 |
| GB | 100 | 75 | 3 |
| GD | 70 | UNK | <1 |
| GF | UNK | UNK | <1 |
| VX | 50 | 35 | 0.04 |
Table II
LD50
on skin
| Agent | Amount |
| GA | 1000 mg |
| GB | 1700 mg |
| GD | 50 mg |
| GF | 30 mg |
| VX | 10 mg |
GB, the agent studied most thoroughly in man, will cause
miosis, rhinorrhea, and a feeling of tightness in the throat or
chest at a Ct of 3 to 5 mg·min/m3.
Effects: Exposure to a small amount of nerve agent
vapor causes effects in the eyes, nose, and airways. These
effects are from local contact of the vapor with the organ and do
not indicate systemic absorption of the agent. In this
circumstance, the erythrocyte-ChE may be normal or depressed. A
small amount of liquid agent on the skin causes systemic effects
initially in the gastrointestinal (GI) tract. Lethal amounts of
vapor or liquid cause a rapid cascade of events culminating
within a minute or two with loss of consciousness and convulsive
activity followed by apnea and muscular flaccidity within several
more minutes.
Eye: Miosis is a characteristic sign of
exposure to nerve agent vapor. It occurs as a result of direct
contact of vapor with the eye. Liquid agent on the skin will not
cause miosis if the amount of liquid is small; a moderate amount
of liquid may or may not cause miosis; and a lethal or
near-lethal amount of agent usually causes miosis. A droplet of
liquid in or near the eye will also cause miosis. Miosis will
begin within seconds or minutes after the onset of exposure to
agent vapor, but it may not be complete for many minutes if the
vapor concentration is low. Miosis is bilateral in an unprotected
individual, but occasionally may be unilateral in a masked person
with a leak in his mask eyepiece.
Miosis is often accompanied by complaints of pain, dim vision,
blurred vision, conjunctival injection, nausea, and occasionally
vomiting. The pain may be sharp or dull in or around the eyeball,
but more often is a dull ache in the frontal part of the head.
Dim vision is due in part to the small pupil, and cholinergic
mechanisms in the visual pathways also contribute. The complaint
of blurred vision is less easily explained, as objective testing
usually indicates an improvement in visual acuity because of the
"pin-hole" effect. Conjunctival injection may be mild
or severe, and occasionally subconjunctival hemorrhage is
present. Nausea (and sometimes vomiting) are part of a
generalized complaint of not feeling well. Miosis, pain, dim
vision, and nausea can be relieved by topical homatropine or
atropine in the eye.
Nose: Rhinorrhea may be the first indication of nerve agent vapor exposure. Its severity is dose dependent.
Airways: Nerve agent vapor causes
bronchoconstriction and increased secretions of the glands in the
airways in a dose-related manner. The exposed person may feel a
slight tightness in his chest after a small amount of agent and
may be in severe distress after a large amount of agent.
Cessation of respiration occurs within minutes after the onset of
effects from exposure to a large amount of nerve agent. This
apnea is probably mediated through the CNS, although peripheral
factors (skeletal muscle weakness, e.g., the intercostal muscles,
and bronchoconstriction) may contribute.
Gastrointestinal tract: After they are
absorbed, nerve agents cause an increase in the motility of the
GI tract and an increase in secretions by the glands in the wall
of the GI tract. Nausea and vomiting are early signs of liquid
exposure on the skin. Diarrhea may occur with large amounts of
agent.
Glands: Nerve agent vapor causes
increases in secretions from the glands it contacts, such as the
lacrimal, nasal, salivary, and bronchial glands. Localized
sweating around the site of liquid agent on the skin is common,
and generalized sweating after a large liquid or vapor exposure
is common. Increased secretions of the glands of the GI tract
occur after systemic absorption of the agent by either route.
Skeletal Muscle: The first effect of
nerve agents on skeletal muscle is stimulation producing muscular
fasciculations and twitching. After a large amount of agent,
fatigue and weakness of muscles are rapidly followed by muscular
flaccidity.
Fasciculations are sometimes seen early at the site of a
droplet of liquid agent on the skin, and generalized
fasciculations are common after a large exposure. These may
remain long after most of the other acute signs decrease.
Central Nervous System: The acute CNS
signs of exposure to a large amount of nerve agent are loss of
consciousness, seizure activity, and apnea. These begin within a
minute after exposure to a large amount of agent vapor and may be
preceded by an asymptomatic period of one to 30 minutes after
contact of liquid with the skin.
After exposure to smaller amounts of nerve agents, CNS effects
vary and are nonspecific. They may include forgetfulness, an
inability to concentrate fully, insomnia, bad dreams,
irritability, impaired judgement, and depression. They do not
include frank confusion and misperceptions (i.e.,
hallucinations). These may occur in the absence of physical signs
or other symptoms of exposure. After a severe exposure these
symptoms occur upon recovery from the acute severe effects. In
either case they may persist for as long as four to six weeks.
Cardiovascular: The heart rate may be
decreased because of stimulation by the vagus nerve, but it is
often increased because of other factors, such as fright,
hypoxia, and the influence of adrenergic stimulation secondary to
ganglionic stimulation. Thus, the heart rate may be high, low, or
in the normal range. Bradyarrhythmias, such as first-, second-,
or third-degree heart block may occur. The blood pressure may be
elevated from adrenergic factors, but is generally normal until
the terminal decline.
Physical findings depend on the amount and route of exposure.
After exposure to small to moderate amounts of vapor, there are
usually miosis and conjunctival injection, rhinorrhea, and
pulmonary signs, although the latter may be absent even in the
face of mild to moderate pulmonary complaints. In addition to
these signs, an exposure to a high Ct may precipitate copious
secretions from the nose and mouth, generalized muscular
fasciculations, twitching or seizure activity, loss of
consciousness, and apnea. Cyanosis, hypotension, and bradycardia
may be present just before death.
Exposure to a small droplet of liquid on the skin may produce
few physical findings. Sweating, blanching, and occasionally
fasciculations at the site may be present soon after exposure,
but may no longer be present at the onset of GI effects. After a
large exposure, the signs are the same as after vapor exposure.
Miosis is a useful sign of exposure to vapor, but does not
occur after a liquid exposure unless the amount of exposure is
large or the exposure is in or close to the eye.
Effects from nerve agent vapor begin within seconds to several
minutes after exposure. Loss of consciousness and onset of
seizure activity have occurred within a minute of exposure to a
high Ct. After exposure to a very low Ct, miosis and other
effects may not begin for several minutes, and miosis may not be
complete for 15 to 30 minutes after removal from the vapor. There
is no latent period or delay in onset from vapor exposure.
Effects may continue to progress for a period of time, but
maximal effects usually occur within minutes after exposure
stops.
A large amount of liquid on the skin causes effects within
minutes. Commonly there is an asymptomatic period of one to 30
minutes, and then the sudden onset of an overwhelming cascade of
events, including loss of consciousness, seizure activity, apnea,
and muscular flaccidity. After small amounts of liquid agent on
the skin the onset of effects has been delayed for as long as 18
hours after contact. These effects are initially gastrointestinal
and are usually not life threatening. Generally, the longer the
interval the less severe are the effects.
The effects caused by a mild vapor exposure, namely rhinorrhea
and a tightness in the chest, may easily be confused with an
upper respiratory malady or an allergy. Miosis, if present, will
help to distinguish these, but the eyes must be examined in very
dim light to detect this. Similarly, GI symptoms from another
illness may be confused with those from nerve agent effects, and
in this instance there will be no useful physical signs. History
of possible exposure will be helpful, and laboratory evidence
(decreased RBC-ChE activity), if available, will be useful to
distinguish the two.
The diagnosis is easier in the severely intoxicated patient.
The combination of miosis, copious secretions, and generalized
muscular fasciculations in a gasping, cyanotic, and convulsing
patient is characteristic.
The cholinesterase activity of the blood components is
inhibited by nerve agents, and estimation of this activity is
useful in detecting exposure to these agents. The erythrocyte
enzyme activity is more sensitive to acute nerve agent exposure
than is the plasma enzyme activity.
The amount of inhibition of this enzyme activity does not
correlate well with the severity of local effects from mild to
moderate vapor exposure. The enzyme activity may be from 0% to
100% of the individual's normal activity in the face of miosis,
rhinorrhea, and/or airway symptoms. Normal or nearly normal
erythrocyte acetylcholinesterase activity may be present with
moderate effects in these organs. At the other extreme, the
enzyme may be inhibited by 60% to 70% when miosis or rhinorrhea
is the only sign of exposure. Severe systemic effects generally
indicate inhibition of the erythrocyte acetylcholinesterase by
70% to 80% or greater.
Other laboratory findings will relate to complications. For
example, acidosis may occur after prolonged hypoxia.
Management of a casualty with nerve agent intoxication
consists of decontamination, ventilation, administration of the
antidotes, and supportive therapy. The condition of the patient
dictates the need for each of these and the order in which they
are done.
Decontamination is described elsewhere in this manual. Skin
decontamination is not necessary after exposure to vapor alone,
but clothing should be removed because it may contain
"trapped" vapor.
The need for ventilation will be obvious, and the means
of ventilation will depend on available equipment. Airway
resistance is high (50-70 cm of water) because of
bronchoconstriction and secretions, and initial ventilation is
difficult. The resistance decreases after atropine
administration, after which ventilation will be easier. The
copious secretions, which may be thickened by atropine, also
impede ventilatory efforts and require frequent suctioning. In
reported cases of severe nerve agent exposure, ventilation has
been required from 0.5 to 3 hours.
Three drugs are used to treat nerve agent exposure, and
another is used as pretreatment for potential nerve agent
exposure. The three therapeutic drugs are atropine, pralidoxime
chloride, and diazepam. The use of the pretreatment drug,
pyridostigmine bromide, is discussed later in this chapter.
Atropine is a cholinergic blocking, or anticholinergic,
compound. It is extremely effective in blocking the effects of
excess acetylcholine at peripheral muscarinic sites. Under
experimental conditions, very large amounts may block some
cholinergic effects at nicotinic sites, but these antinicotinic
effects are not evident even at high clinical doses. When small
amounts (2 mg) are given to normal individuals without nerve
agent intoxication, atropine causes mydriasis, a decrease in
secretions (including a decrease in sweating), mild sedation, a
decrease in GI motility, and tachycardia. The amount in three
MARK I kits may cause adverse effects on military performance in
a normal person. In people not exposed to nerve agents, amounts
of 10 mg or higher may cause delirium. Potentially, the most
hazardous effect of inadvertent use of atropine (2 mg, i.m.) in a
young person not exposed to a cholinesterase inhibiting compound
in a warm or hot atmosphere is inhibition of sweating, which may
lead to heat injury. In the military, atropine is packaged in
autoinjectors, each containing 2 mg.
Pralidoxime chloride (Protopam chloride; 2-PAMCl) is an
oxime. Oximes attach to the nerve agent that is inhibiting the
cholinesterase and break the agent-enzyme bond to restore the
normal activity of the enzyme. Clinically, this is noticable in
those organs with nicotinic receptors. Abnormal activity in
skeletal muscles decreases, and normal strength returns. The
effects of an oxime are not apparent in organs with muscarinic
receptors; oximes do not cause a decrease in secretions, for
example. They also are less useful after aging occurs, but with
the exception of GD (soman) intoxicated individuals, casualties
will be treated before significant aging occurs. Pralidoxime
chloride (600 mg) is in an autoinjector for self-use along with
the atropine injector. These atropine and pralidoxime chloride
autoinjectors are packaged together in a MARK I kit. Each
military person is issued three MARK I kits.
Diazepam is an anticonvulsant drug used to decrease
convulsive activity and to reduce the brain damage caused by
prolonged seizure activity. Without the use of pyridostigmine
pretreatment, experimental animals died quickly after superlethal
doses of nerve agents despite conventional therapy. With
pyridostigmine pretreatment (followed by conventional therapy)
animals survived superlethal doses of soman, but had prolonged
periods of seizure activity before recovery. They later had
performance decrements and anatomic lesions in their brains. The
administration of diazepam with other standard therapy to
soman-poisoned animals pretreated with pyridostigmine reduced the
seizure activity and its sequelae. Current military doctrine is
to administer diazepam with other therapy (three MARK I's) at the
onset of severe effects from a nerve agent, whether or not
seizure activity is among those effects. Each military person
carries one autoinjector containing 10 mg of diazepam for his
buddy to administer to him (if he could self-administer it, he
would not need it). Diazepam should be administered with the
three MARK I's when the casualty's condition warrants the use of
three MARK I's at the same time. Medical personnel can
administer more diazepam to a casualty if necessary. The medical
corpsman carries extra diazepam injectors and is authorized to
administer two additional injectors at 10 minute intervals to a
convulsing casualty.
The doctrine for self-aid for nerve agent intoxication
states that if an individual has effects from the agent he/she
should self-administer one MARK I. If there is no improvement in
10 minutes, he/she should seek out a buddy to assist in the
evaluation of his/her condition before further MARK I's are
given. If a buddy finds an individual severely intoxicated (e.g.,
gasping respirations, twitching, etc.) so that the individual can
not self-administer a MARK I, the buddy should administer three
MARK I's and diazepam immediately. The discussion below is advice
for medical assistance.
The appropriate number of MARK I kits to administer initially
to a casualty from nerve agent vapor depends on the severity of
the effects. Systemic atropine will not reverse miosis (unless
administered in very large amounts), and miosis alone is not an
indication for a MARK I. If the eye or head pain and nausea
associated with the miosis are severe, topical application of
atropine (or homatropine) in the eye will bring relief. Topical
atropine should not be used without good reason (severe pain),
because it causes blurred vision for a day or longer. A casualty
with miosis and rhinorrhea should be given one MARK I only if the
rhinorrhea is severe and troublesome (he can not keep his mask on
because of fluid). A casualty with mild to moderate dyspnea
should be given one or two MARK I's, depending on the severity of
his distress and the time between exposure and therapy. Some of
the respiratory distress from a mild exposure will spontaneously
decrease within 15 to 30 minutes after termination of exposure,
so if the casualty is not severely uncomfortable only one MARK I
should be used initially. Atropine is quite effective, and care
should be taken not to give too much in a casualty who does not
need it.
A severe casualty from nerve agent vapor has miosis, copious
secretions from the nose and mouth, severe difficulty breathing
or apnea, possibly some degree of cyanosis, muscular
fasciculations, and twitching or convulsive activity, and is
unconscious. He should be given three MARK I's and diazepam
immediately. Ventilation will be needed and should be done via an
endotracheal airway if possible. Suctioning of the excessive
airway secretions will be necessary to enhance air exchange and
will make ventilatory efforts easier. Atropine, 2 mg, should be
repeated at three- to five-minute intervals and should be
titrated to a reduction of secretions and to reduction of
ventilatory resistance. When the intravenous preparation is
available, the preferred route of atropine administration is via
the intravenous route, but this route should be avoided until
hypoxia is corrected, because intravenously administered atropine
in hypoxic animals has produced ventricular fibrillation. In a
hypotensive patient or a patient with poor veins, atropine might
be given intratracheally, either via the endotracheal tube or
directly into the trachea, for more rapid absorption via the
peribronchial vessels.
The medical care provider might err in giving too much
atropine to a mild to moderate casualty. More importantly, the
care provider might err by giving too little atropine to a severe
casualty. In a severe casualty, atropine should be pushed at
frequent intervals until secretions are dry (or nearly dry) and
until ventilation can be accomplished with ease. In reported
cases this has required 10 to 20 mg of atropine within the first
several hours. A conscious, less-severely exposed casualty should
receive atropine until he is breathing comfortably, and he will
be able to communicate this. Dry secretions need not be an end
point in mild to moderate casualties.
The casualty with skin exposure to liquid is more difficult to
evaluate and manage than is a casualty from vapor exposure. Agent
on the surface of the skin can be decontaminated, but agent
absorbed into the skin cannot be removed. The initial effects
from absorbed liquid agent can start two to three hours after
thorough decontamination of agent droplets on the skin. A
casualty from liquid exposure on the skin may continue to worsen
because of continued absorption of the agent from the skin depot.
The first effects of a liquid droplet on the skin are sweating
with or without blanching and occasionally with muscular
fasciculations at the site. Gastrointestinal effects (nausea,
vomiting, and sometimes diarrhea) are the first systemic effects,
and these may start from 0.5 to 18 hours after contact with the
agent. If these effects occur within the first several hours
after exposure, they may portend more severe effects, and initial
therapy should be two MARK I's. If effects begin later, initial
therapy should be one MARK I.
A large amount of liquid agent on the skin will cause effects
1 to 30 minutes after contact, whether or not decontamination was
done. Nevertheless, early decontamination may lessen the
magnitude of the effects. After a one- to thirty-minute latent or
asymptomatic period, the casualty will suddenly lose
consciousness and begin seizure activity. The condition of the
casualty and management are the same as described for a severe
casualty from vapor exposure.
Further care of the severe casualty consists of atropine administration to minimize secretions and of ventilation until spontaneous respiration resumes. Oxime administration should be repeated at hourly intervals for two or three additional doses. The preferred method of administration of the oxime is by intravenous drip of 1 gram over 20 to 30 minutes (more rapid administration will cause hypertension), but three additional oxime autoinjectors (total dose of 1.8 grams) may be given if the intravenous route cannot be used. The need for ventilation may continue for 0.5 to 3 hours. Unless prolonged hypoxia or other complications have occurred, the casualty will eventually begin having spontaneous muscular activity and make sporadic attempts to breathe. Muscles will become stronger and breathing more regular, and the casualty will have intermittent episodes of conscious behavior. Within an hour or two he will be breathing, moving, and conscious, although he will be weak and intermittently obtunded.
Table III
NERVE AGENT EFFECTS
Vapor Exposure
Mild
Eyes: Miosis, Dim vision, Headache
Nose: Rhinorrhea
Mouth: Salivation
Lungs: Dyspnea ("tightness in the chest")
Time of onset: Seconds to minutes after exposure
Self-aid: 1 MARK I
Buddy-aid: Stand by
Severe
All the above, plus
Severe breathing difficulty or cessation of respiration
Generalized muscular twitching, weakness or paralysis
Convulsions
Loss of consciousness
Loss of bladder, bowel control
Time of onset: Seconds to minutes after exposure
Self-aid: None. Soldier will be unable to help self.
Buddy-aid: 3 MARK I's and diazepam immediately
Table IV
NERVE AGENT EFFECTS
Liquid on skin
Mild/moderate
- Muscle twitching at site of exposure
- Sweating at site of exposure
- Nausea, vomiting
- Feeling of weakness
- Time of onset: 10 minutes to 18 hours after exposure
- Self-aid: 1-2 MARK I's, depending on severity of symptoms
- Buddy-aid: Stand by
Severe
- All the above, plus
- Severe breathing difficulty or cessation of breathing
- Generalized muscular twitching, weakness, or paralysis
- Convulsions
- Loss of consciousness
- Loss of bladder and bowel control
- Time of onset: Minutes to an hour after exposure
- Self-aid: None. Soldier will be unable to help himself
- Buddy-aid: 3 MARK I's and diazepam immediately
In late 1990, the U.S. military fielded pyridostigmine bromide
as a pretreatment for nerve agent exposure. Each individual
received a blister pack containing 21 30-mg tablets. The dose
regimen is one 30-mg tablet every eight hours. When to start and
stop dosing is a division or corps command decision, and this
decision is made with the advice of the intelligence, chemical,
and medical staffs. To use or to stop the pretreatment is not a
local decision, nor is it an individual decision.
When given before soman exposure and when that exposure is
followed by the standard MARK I therapy, the use of pretreatment
will increase the LD50 several fold over the LD50
obtained without the use of the pretreatment. When soman is the
nerve agent, the use of pyridostigmine increases survival. When
the agent is GB or VX, survival after standard MARK I therapy is
essentially the same whether or not pyridostigmine pretreatment
is used, i.e., pyridostigmine use provides no benefit in GB or VX
poisoning. Current data are not adequate to evaluate the
effectiveness of pyridostigmine pretreatment for GA or GF
exposure.
Pyridostigmine is not an antidote, and it should not be taken
after soman exposure. Its use will not decrease the effects of
soman. It is ineffective unless standard MARK I therapy is also
used in the appropriate manner.
One consequence of the greater survival from the use of
pyridostigmine is prolonged seizure activity and subsequent brain
damage in the survivors. The early administration of diazepam
will decrease these effects.
About 50 years ago it was noted that carbamates bind to the
active site of cholinesterase in a similar manner to the binding
of organophosphorus cholinesterase inhibitors to cholinesterase,
and that while the carbamate was attached to the active site an
organophosphorus compound could not attach to the enzyme. The
carbamate-enzyme binding, or carbamylation, lasts only for hours,
rather than for the lifetime of the enzyme as the
organophosphorus compound attachment does. While the enzyme is
carbamylated, the active site is protected from attack by other
compounds, such as organophosphorous cholinesterase inhibitors
including nerve agents. After several hours, the carbamate leaves
the enzyme (that is, decarbamylation occurs), and the enzyme
becomes completely functional again. Thus the carbamate provides
temporary protection for the enzyme against nerve agent attack.
Over the past several decades many carbamates were
investigated for their effectiveness in animals and their safety
in man. Pyridostigmine was chosen and underwent extensive testing
in humans. Investigations indicated that it did not interfere
with the performance of military tasks, and that it caused no
adverse physiological disturbances. The incidence of side effects
from the drug during these studies was reported as under 5%.
Tens of thousands of U.S. troops took pyridostigmine during
the recent Gulf Conflict. The incidence of side effects
(primarily gastrointestinal and urinary) was over 50%, but only a
few percent of the troops sought medical help because of the
severity of these effects. The drug was discontinued in fewer
than 1% of cases.
A severe nerve agent casualty, who is unconscious, convulsing
or post-ictal, breathing with difficulty or apneic, and possibly
flaccid, will survive with appropriate immediate therapy
(including ventilation) if he still has an intact circulation. He
should be triaged as immediate if that therapy can be
provided. If a blood pressure cannot be obtained, he should be
considered expectant.
The casualty with severe symptoms who is spontaneously
breathing, who has not lost consciousness, and who has not seized
has an excellent chance of survival with a minimal amount of
therapeutic effort. He should be categorized as immediate
and given three MARK I's and diazepam. He may worsen if his
exposure was to liquid, and atropine administration should be
repeated at frequent intervals. If he loses consciousness,
seizes, and becomes apneic he will be retriaged, and his further
care will depend on available resources.
Casualties who are walking and talking will usually be triaged
as minimal. If a casualty can walk and talk, he is
breathing and his circulation is intact. He would not appear to
need immediate, life-saving care. This does not preclude
self-administration or medic-administration of further antidotes
for symptoms, and these should be given as necessary.
A casualty recovering from a severe exposure who has received
large amounts of antidotes and has been ventilated will be
triaged as delayed, because he is in need of further
medical observation or care.
Return to duty depends on the status of the casualty, his
military assignment, and the tactical situation.
Studies indicate that animals with decreased erythrocyte
acetylcholinesterase activity from a nerve agent exposure have a
decreased LD50 for another nerve agent exposure (they
are more susceptible to the agent) until that cholinesterase
activity returns to at least 75% of its baseline, or preexposure,
activity. Nerve agent exposed workers in a depot or research
facility are prevented from returning to work with agents until
this recovery occurs. In a battlefield situation, this
conservative management should be balanced against the need for
the person and his risk of being exposed to a large amount of
agent.
In a military field situation, the capability to analyze blood
for erythrocyte cholinesterase activity is usually not available,
and the "normal," or baseline, activity of each
individual is not known. The erythrocyte cholinesterase activity
in a casualty with severe systemic effects will be inhibited by
70% or greater (30% or less of his preexposure activity), and 45
days or longer will be required for cholinesterase activity to
return to 75% of preexposure activity. The enzyme activity of a
casualty with mild or moderate effects from agent vapor might be
nearly normal or might be markedly inhibited, and a prediction of
erythrocyte cholinesterase recovery time is unreliable.
Most individuals triaged as minimal could return to duty within several hours if the tactical situation required all available manpower. The lingering ocular and CNS effects may be limiting factors in these cases. These individuals might be able to fire a rifle, but their performance on a tracking screen might be severely decremented because of both visual problems and difficulty in concentrating. These prolonged effects must be thoroughly evaluated before these casualties are returned. Whether these individuals should be evacuated to a facility with the capability for analysis of erythrocyte cholinesterase activity and retained there until this activity returns will be dictated by the tactical situation.
A casualty who has had severe effects might be walking and
talking after six to 24 hours, but will still be unfit for most
duties. Ideally, he should be kept under medical observation for
a week or longer and not returned until recovery of
cholinesterase activity. However, the tactical situation may lead
to modification of these guidelines.
Minor electroencephalographic changes were noted more than a
year after nerve agent exposure when averaged EEGs in a group of
people who had been exposed to a nerve agent were compared to a
control group. Changes could not be identified in individuals.
Neuropsychiatric changes have been noted in individuals for weeks
to months after exposure to insecticides.
Polyneuropathy, reported after OP insecticide poisoning, has
not been reported in humans exposed to nerve agents and has been
produced in animals only at doses of nerve agents so high that
survival would be unlikely. The Intermediate Syndrome has not
been reported in humans after nerve agent exposure, nor has it
been produced in animals by nerve agent administration. Muscular
necrosis has been produced in animals after high-dose nerve agent
exposure, but reverses within weeks; it has not been reported in
humans.