2.11 Exposure to Chemical Agents:

Types of chemical warfare agents

Effects of exposure

Evaluation and management of exposure

Prevention and countermeasures

**SECTION, II, 2.11 Exposure to Chemical Warfare Agents**

The material for this section was taken from various governmental and
private agencies including and especially the Department of Defense
([http://ccc.apgea.army.mil](http://ccc.apgea.army.mil/)) and the
National Library of Medicine Hazardous Substances Data Bank (HSDB)
([www.nlm.nih.gov](http://www.nlm.nih.gov/)) .

THE PSYCHOSOCIAL ASPECTS OF CHEMICAL, BIOLOGICAL AND RADIATION WARFARE

People's perceptions of chemical, biological and radiation agents are
often justifiably perceived by most as those things which can cause
significant discomfort, injury and even death.

From observations gained from persons where chemical and/or biological
agents were used, there was understandably, panic, fear, anxiety,
helplessness, cognitive impairment and unpredictable behavior. In a
military setting, this often led to a breakdown in command and control,
reduction of combat readiness. All this can be further complicated by
enhanced helplessness fueled by rumors.

The trauma and effects of these agents for the survivors have
significant sequelae and often manifest themselves in the later "ripple
effect" of such conditions as posttraumatic stress disorder.

Though this presentation will deal with the anatomical, physiological
and biochemical effects of these various destructive agents, there must
always be a realization that an important aspect of these exposures is
the psychological effect as well.

Forms of Exposure

Chemical agents exist in the form of solids, liquids or gases, depending
on the agent and environmental circumstances. Primarily, after
detonation, most chemical agents are released as liquids or aerosols. An
aerosol consists of small solid particles or liquid droplets suspended
in a gas. Agents commonly considered gases, such as tear gas, mustard
gas and nerve gas, are actually aerosolized solids.

The form of some agents may vary depending on environmental conditions.
Hydrogen cyanide, chlorine and phosgene may be gases when encountered in
warm conditions at sea level. However, they are volatile, meaning they
evaporate to form an invisible vapor. Water, for example, becomes a gas
at its boiling point. However, below boiling, the liquid water slowly
evaporates forming a water vapor, rather than a gas.

Evaporation of chemical agents depends on numerous factors including the
agent, temperature, air pressure, wind velocity and surface with which
the agent is in contact. Agents evaporate more readily in higher
temperatures, in stronger winds or in contact with a surface such as
glass rather than porous fabric.

The more volatile an agent is, the less persistent it is. Higher
volatility translates to more rapid evaporation, resulting in decreased
tendency to remain, or persist, as a liquid contaminating the
surroundings. Persistent and nonpersistent agents are arbitrarily
defined by the liquid hazard created. Persistent agents will pose a
liquid hazard for 24 hours or longer. Nonpersistent agents will pose a
liquid hazard for less than 24 hours. Nonpersistent agents generally
pose a serious vapor hazard but evaporate quickly enough to poses little
liquid hazard for an extended period of time. The converse is true for
persistent agents, such as mustard and VX. Persistent agents are
suitable for use in denying territory and materiel to the enemy.
Nonpersistent agents are employed in direct assault into enemy territory
since they will no longer pose a hazard in the territory within 24
hours.

The effects of various agents are dependent upon their form, manner of
exposure, length of exposure and the amount of an agent encountered
during exposure. Aerosols, vapor or gas may directly contact eyes, skin
or respiratory tree. Local effects may be seen in all these sites, but
absorption through intact skin is of less concern with nonpersistent
agents. Liquid exposure is the most important factor with persistent
agents. Persistent agents may contact eyes, skin and the respiratory
tree causing local effects, but can also be absorbed, causing systemic
effects as well.

CHEMICAL AGENTS

There are six categories of chemical agents.

**Lung damaging (pulmonary) agents** include the World War I agent,
phosgene. The remainder of these agents are hazards of conventional
warfare rather than chemical weapons. They include perflurorisobutylene
(PFIB), a product of Teflon® combustion (Teflon® lines many military
vehicles), HC smoke (a smoke containing zinc), and oxides of nitrogen
(from burning munitions).

**Cyanide** has an undeserved reputation as a good warfare agent. Its
LCt~50~ (the vapor or aerosol exposure that is lethal to 50% of the
exposed population) is large, and exposures slightly below the lethal Ct
cause few effects. Its high volatility means that effective
concentrations are difficult to achieve on the battleground, and that
even high concentrations cannot be maintained for more that a few
minutes in the open air. However, at high concentrations, cyanide kills
quickly. Potential agents are hydrocyanic acid (AC) and cyanogen
chloride (CK).

**Vesicants** include mustard (sulfur mustard, H, HD), Lewisite (L), and
phosgene oxime (CX). Vesicants are so named because of the vesicles
(blisters) they cause on the skin; however, these agents also damage the
eyes and airways by direct contact and have other effects.

**Nerve agents** inhibit the enzyme acetylcholinesterase and effects are
the result of excess acetylcholine. Nerve agents to be discussed are GA
(tabun), GB (sarin), GD (soman), GF, and VX.

**Incapacitating agents** to be discussed include BZ, a glycolate
anticholinergic compound related to atropine, scopolamine, and
hyoscyamine, and Agent 15, an alleged Iraqi incapacitating agent that is
likely to be chemically either identical to BZ or closely related to it.

**Riot control agents** have been used on the battlefield, although they
are not considered major agents of threat today. However, the National
Guard may encounter or employ them during civil disturbances. The major
ones are CS (tear gas), which is used by law enforcement officials and
the military, and CN (Mace®), which is sold in devices for
self-protection.

EFFECTS OF EXPOSURE

Effects of chemical agents may vary depending on the concentration and
duration of exposure. With the exception of cyanide, the concentration
(usually in mg/m^3^) multiplied by the exposure time in minutes results
in a concentration-time product. For example, exposure to a
concentration of 4 mg/m^3^ of soman (GD) vapor for ten minutes results
in a Ct of 40 mg·min/m. \[***Comparison of the amounts of chemical agent
encountered as aerosol, vapor, or gas requires use of the
concentration-time product or Ct, which refers to the agent
concentration (usually in mg/m^3^) multiplied by the time (usually in
minutes) of exposure\]***

Exposure to 8 mg/m^3^ for five minutes results in the same Ct (40
mg·min/m^3^). For most agents the concentration-time associated with a
biological effect is relatively constant even though the concentration
and time components may vary within certain limits.

DECONTAMINATION

OVERVIEW

Decontamination is the reduction or removal of chemical agents.
Decontamination may be accomplished by removal of these agents by
physical means or by chemical neutralization or detoxification.
Decontamination of skin is the primary concern, but decontamination of
eyes and wounds must also be done when necessary. Personal
decontamination is decontamination of self; casualty decontamination
refers to the decontamination of casualties; and personnel
decontamination usually refers to decontamination of non-casualties.

**The most important and most effective decontamination of any chemical
exposure is that decontamination done within the first minute or two
after exposure.** This is self-decontamination, and this is more likely
to be accomplished by the trained military in the field and can make the
difference between survival (minimal injury) and death (severe injury).
Good training can save lives.

Liquids and solids are the only substances that can be effectively
removed from the skin. It is generally not possible or necessary to
decontaminate vapor. Removal from the atmosphere containing the vapor is
all that is required.

The first, without equal, is timely physical removal of the agent. To
remove the substance by the best means available is the primary
objective. Chemical destruction (detoxification) of the offending agent
is a desirable secondary objective. Physical removal is imperative
because none of the chemical means of destroying these agents do so
instantaneously. While decontamination preparations such as fresh
hypochlorite react rapidly with some agents (e.g., the half time for
destruction of VX by hypochlorite at a pH of 10 is 1.5 minutes), the
half times of destruction of other agents, such as mustard, are much
longer. If a large amount of agent is present initially, a longer time
is needed to completely neutralize the agent to a harmless substance.

PHYSICAL REMOVAL

Several types of physical and chemical methods are at least potentially
suitable for decontaminating equipment and material. Flushing or
flooding contaminated skin or material with water or aqueous solutions
can remove or dilute significant amounts of agent. Scraping with a
wooden stick, i.e., a tongue depressor or Popsicle stick, can remove
bulk agent by physical means. For the decontamination of clothing only,
adsorbents and containment materials (to be used on outer garments
before their removal and disposal) have been considered. A significant
advantage of most physical methods is their non specificity. Since they
work nearly equally well on chemical agents regardless of chemical
structure, knowledge of the specific contaminating agent(s) is not
required.

Flushing with Water or Aqueous Solutions***.*** When animal skin
contaminated with GB was flushed with water (a method in which physical
removal predominates over hydrolysis of the agent), 10.6 times more GB
was required to produce the same mortality rate as when no
decontamination occurred. In another study, the use of water alone
produced better results than high concentrations of hypochlorite (i.e.,
5.0% or greater, which are not recommended for skin). Timely, copious
flushing with water physically removes the agent and will produce good
result.

Absorbent Materials*.* Adsorption refers to the formation and
maintenance of a condensed layer of a substance, such as a chemical
agent, on the surface of a decontaminant as illustrated by the
adsorption of gases by charcoal particles and by the decontaminants
described in this section. Some NATO nations use adsorbent
decontaminants in an attempt to reduce the quantity of chemical agent
available for uptake through the skin. In emergency situations, dry
powders such as soap detergents, earth, and flour, may be useful. Flour,
followed by wiping with wet tissue paper, is reported to be effective
against GD, VX, and HD.

CHEMICAL METHODS OF REMOVAL

Three types of chemical mechanisms have been used for decontamination:
water/soap wash, oxidation, and acid/base hydrolysis.

Mustard (HD) and the persistent nerve agent VX contain sulfur molecules
that are readily subject to oxidation reactions. VX and the other nerve
agents (GA, GB, GD, and GF) contain phosphorus groups that can be
hydrolyzed. Therefore, most chemical decontaminants are designed to
oxidize HD and VX and to hydrolyze nerve agents (VX and the G series).

Water/Soap Wash*.* Both fresh water and seawater have the capacity to
remove chemical agents not only through mechanical force, but also via
slow hydrolysis; however, the generally low solubility and slow rate of
diffusion of chemical warfare agents in water significantly limit the
agent hydrolysis rate.

The predominant effect of water and water/soap solutions is the physical
removal or dilution of agents; however, slow hydrolysis does occur
particularly with alkaline soaps. In the absence of hypochlorite
solutions or other appropriate means of removing chemical agents, these
methods are considered reasonable options.

Oxidation/Hydrolysis***.*** The most important category of chemical
decontamination reactions is oxidative chlorination. This term covers
the \"active chlorine\" chemicals like hypochlorite. The pH of a
solution is important in determining the amount of active chlorine
concentration. An alkaline solution is advantageous. Hypochlorite
solutions act universally against the organophosphorous and mustard
agents.

Both VX and HD contain sulfur atoms that are readily subject to
oxidation. Current doctrine specifies the use of a 0.5% sodium or
calcium hypochlorite solution for decontamination of skin and a 5%
solution for equipment.

Hydrolysis. Chemical hydrolysis reactions are of two types, acid and
alkaline. Acid hydrolysis is of negligible importance for agent
decontamination because the hydrolysis rate of most chemical agents is
slow, and adequate acid catalysis is rarely observed. Alkaline
hydrolysis is initiated by the nucleophilic attack of the hydroxide ion
on the phosphorus atoms found in VX and the G agents. The hydrolysis
rate is dependent on the chemical structure and reaction conditions such
as pH, temperature, the kind of solvent used, and the presence of
catalytic reagents. The rate increases sharply at pH values higher than
8 and increases by a factor of 4 for every 10^o^C rise in temperature.
Several of the hydrolytic chemicals are effective in detoxifying
chemical warfare agents; unfortunately, many of these (e.g., NaOH) are
unacceptably damaging to the skin. Alkaline pH hypochlorite hydrolyzes
VX and the G agents quite well.

INTRODUCTION

 Nerve agents are extremely toxic chemicals that were first developed in
secrecy before and during World War II primarily for military use.
Related substances are used in medicine, in pharmacology, and for other
purposes, such as insecticides, but they lack the potency of the
military agents. Much of the basic knowledge about the clinical effects
of nerve agents comes from research performed in the decades immediately
following World War II.

Cholinesterase-Inhibiting (ChE) Compounds\
     

Most ChE-inhibiting compounds are either carbamates or organophosphorus
compounds. Among the carbamates is physostigmine (eserine; elixir of the
Calabar bean), which has been used in medicine for more than a century.
Neostigmine (Prostigmin) was developed in the early 1930s for management
of myasthenia gravis; ambenonium was developed later for this same
purpose. Pyridostigmine bromide (Mestinon) has been used for decades for
the management of myasthenia gravis. The military of the United States
and several other nations also field pyridostigmine bromide , known as
PB or NAPP (nerve agent pyridostigmine pretreatment), as a pretreatment,
or antidote-enhancing substance, to be used before exposure to certain
nerve agents. Today these carbamates are mainly used for treating
glaucoma and myasthenia gravis. Other carbamates, such as Sevin are used
as insecticides.\
     

Most commonly used insecticides contain either a carbamate or an
organophosphorus compound. The organophosphorus insecticide malathion
has replaced parathion, which was first synthesized in the 1940s. The
organophosphorus compound diisopropyl phosphorofluoridate (DFP) was
synthesized before World War II and studied by Allied scientists before
and during the war, but was rejected for use as a military agent. For a
period of time, this compound was used topically for treatment of
glaucoma but later was rejected as unsuitable because it was found to
produce cataracts. It has been widely used in pharmacology as an
investigational agent.\
\
Mechanism of Action

Nerve agents inhibit ChE ***(Cholinesterase)***, which then cannot
hydrolyze acetylcholine (Ach). This classic explanation of nerve agent
poisoning holds that the intoxicating effects are due to the excess
endogenous ACh. This explanation, however, may not account for all nerve
agent effects.\
     

This portion of the cholinergic nervous system can be further subdivided
into the muscarinic and nicotinic systems, because the structures that
are innervated have receptors for the alkaloids muscarine (mAChR) and
nicotine (nAChR), respectively, and can be stimulated by these
compounds. Muscarinic sites are innervated by postganglionic
parasympathetic fibers. These sites include glands (eg, those of the
mouth and the respiratory and gastrointestinal systems), the musculature
of the pulmonary and gastrointestinal systems, the efferent organs of
the cranial nerves (including the heart via the vagus nerve), and other
structures. Nicotinic sites are at the autonomic ganglia and skeletal
muscles.

After inhibition by irreversibly bound inhibitors, recovery of the
enzymatic activity in the brain seems to occur more slowly than that in
the blood ChE. However, one individual severely exposed to sarin was
alert and functioning reasonably well for several days while ChE
activity in his blood was undetectable thus suggesting that tissue
function is restored at least partially when ChE activity is still quite
low.

Blood Cholinesterases

There are two forms of ChE in the blood: BuChE, which is found in plasma
or serum, and RBC-ChE, which is associated with erythrocytes. Neither
enzyme is identical to the tissue enzyme with the corresponding
substrate specificity (butyrylcholine and ACh, respectively). However,
because blood can be withdrawn, the activities of each of these enzymes
can be assayed by standard, relatively simple laboratory techniques,
whereas tissue enzyme is unavailable for assay. The measurements
obtained from the blood assay can be used as an approximation of tissue
enzyme activity in the event of a known or possible exposure of an
animal, such as man, to an AChE inhibitor. Persons who are
occupationally exposed to ChE-inhibiting substances are periodically
monitored for asymptomatic exposure by assays of blood-ChE activity.

*Erythrocyte Cholinesterase*\
     

RBC-ChE is synthesized with the erythrocyte, which has an average life
of 120 days. The activity of this enzyme is decreased in certain
diseases involving erythrocytes (such as pernicious anemia) and is
increased during periods of active reticulocytosis (such as recovery
from pernicious anemia) because reticulocytes have higher ChE activity
than do mature cells. The physiological role of the enzyme in (or on the
stroma of) the erythrocyte is unknown. Recovery of RBC-ChE activity
after irreversible inhibition takes place only with the synthesis of new
erythrocytes, or at a rate of approximately 1% per day.

Inhibition of Blood Cholinesterases\
     

Some ChE-inhibiting substances inhibit BuChE preferentially, and some
inhibit RBC-ChE preferentially. Large amounts of ChE inhibitors will
completely inhibit both enzymes.

Time Course of Inhibition

Estimation of the RBC-ChE activity provides a better indicator of acute
nerve agent exposure than does estimation of the plasma enzyme activity.
When the blood enzymes have been irreversibly inhibited, recovery of ChE
activity depends on production of new plasma enzymes or production of
new erythrocytes. In humans, after inhibition by VX, the RBC-ChE
activity seems to recover spontaneously at the rate of about 0.5% to 1%
per hour for a few days, but complete recovery depends on erythrocyte
production.

Inhalation of nerve agent vapor inhibits blood ChE activity and produces
signs and symptoms of exposure more rapidly than does dermal contact.
Although there is no correlation between ChE activity and clinical
effects after exposure to small amounts of vapor, both clinical effects
and ChE inhibition occur within minutes. The maximal inhibition of
RBC-ChE activity and the appearance of signs and symptoms occurred about
1 hour after intravenous administration of small amounts of VX. After
ingestion of VX, the interval was 2 to 3 hours.

Relation to Signs and Symptoms*.*

The local signs and symptoms in the eye, nose, and airways caused by
small amounts of vapor are due to the direct effect of the vapor on the
organ; no correlation between the severity of these effects and the
blood ChE activity seems to exist.

Minimal systemic effects, such as vomiting, occur in half the population
when the RBC-ChE is inhibited to 25% of its control activity, according
to the literature. Vomiting occurred in 9 (43%) of 21 subjects whose
minimal RBC-ChE activities were 30% to 39% of control, in 10 (71%) of 14
subjects whose minimal enzyme activities were 20% to 29% of control, and
in 3 (60%) of 5 subjects whose minimal RBC-ChE activities were 0% to 19%
of control.

EXPOSURE ROUTES

Inhalation :The effects produced by nerve agent vapor begin in seconds
to minutes after the onset of exposure, depending on the concentration
of vapor. These effects usually reach maximal severity within minutes
after the individual is removed from or protected from the vapor or may
continue to worsen if the exposure continues. There is no delay in onset
as there is after liquid exposure.

  --------------------- -------------------------------------------------
  **TABLE 5-4\          
  EFFECTS OF EXPOSURE   
  TO NERVE AGENT        
  VAPOR**               

  **Amount of           **Effects\***
  Exposure**            

                        

  Small (Local effects) Miosis; rhinorrhea; slight bronchoconstriction;
                        secretions (slight dyspnea)

  Moderate (Local       Miosis; rhinorrhea; slight bronchoconstriction;
  effects)              secretions (moderate to marked dyspnea)

  Large                 Same as for moderate exposure, plus: loss of
                        consciousness; convulsions (seizures);
                        generalized fasciculations; flaccid paralysis;
                        apnea; involuntary micturition/defecation
                        possible with seizures

  \*Onset of effects    
  occurs within seconds 
  to several minutes    
  after exposure onset  
  --------------------- -------------------------------------------------

At low C*t*s, the eyes, nose, airways, or a combination of these organs
are usually affected. The eyes and nose are the most sensitive organs;
the eyes may be affected equally or unequally. There may be some degree
of miosis (with or without associated conjunctival injection and pain)
with or without rhinorrhea, or there may be rhinorrhea without eye
involvement (See table above).\
     

As exposure increases slightly, the triad of eye, nose, and lung
involvement is usually seen. The casualty may or may not notice dim
vision and may complain of "tightness in the chest." "Tightness in the
chest" may occur in the absence of physical findings. At higher
exposures, the effects in these organs intensify. Marked miosis, copious
secretions from the nose and mouth, and signs of moderate-to-severe
impairment of ventilation are seen. The casualty will complain of
mild-to-severe dyspnea, may be gasping for air, and will have obvious
secretions.\
     

In severe exposures, the casualty may not have time to report the
initial effects before losing consciousness, and may not remember them
on awakening. One severely exposed individual later recalled that he
noticed an increase in secretions and difficulty in breathing, and
another said he felt giddy and faint before losing consciousness. In
both instances, the casualties were unconscious within less than a
minute after exposure to agent vapor. When reached (within minutes) by
rescuers, both were unconscious and exhibited convulsive jerking motions
of the limbs; copious secretions from the mouth and nose; very labored,
irregular, and gasping breathing; generalized muscular fasciculations;
and miosis. One developed flaccid paralysis and apnea a minute or two
later. The other received immediate, vigorous treatment, and his
condition did not progress (personal observation).

+--------------------------------------+-------------------------------+
| **EFFECTS OF DERMAL EXPOSURE TO      |                               |
| LIQUID NERVE AGENTS**                |                               |
+--------------------------------------+-------------------------------+
| **Level of Exposure**                |            **Effects**        |
+--------------------------------------+-------------------------------+
|                                      |                               |
+--------------------------------------+-------------------------------+
| **Mild**                             |                               |
+--------------------------------------+-------------------------------+
| Effects may be precipitant in onset  | Increased sweating at the     |
| after an asymptomatic interval of up | site\                         |
| to 18 h                              | Muscular fasciculations at    |
|                                      | site                          |
+--------------------------------------+-------------------------------+
| **Moderate**                         |                               |
+--------------------------------------+-------------------------------+
| Effects may be precipitant in onset  | Same as for mild exposure,    |
| after an asyptomatic interval of up  | plus:                         |
| to 18 h                              |                               |
|                                      | Nausea\                       |
|                                      | Diarrhea\                     |
|                                      | Generalized weakness          |
+--------------------------------------+-------------------------------+
| **Severe**                           |                               |
+--------------------------------------+-------------------------------+
| Effects may be precipitant in onset  | Same as for moderate          |
| after a 2-30 min asyptomatic         | exposure, plus:               |
| interval                             |                               |
|                                      | Loss of consciousness\        |
|                                      | Convulsions (seizures)\       |
|                                      | Generalized fasciculations\   |
|                                      | Flaccid paralysis\            |
|                                      | Apnea\                        |
|                                      | Generalized secretions\       |
|                                      | Involuntary                   |
|                                      | micturition/defecation        |
|                                      | possible with seizures        |
+--------------------------------------+-------------------------------+

Dermal Exposure to Liquid\
     

The early effects of a drop of nerve agent on the skin and the time of
onset of these effects depend on the amount of nerve agent and several
other factors, such as the site on the body, the temperature, and the
humidity. After a delay during which the individual is asymptomatic,
localized sweating occurs at the site of the droplet; less commonly,
there are localized fasciculations of the underlying muscle (See table
above). Unless the amount of the nerve agent is in the lethal range, the
next effects (or perhaps the first effects, if the sweating and
fasciculations do not occur or are not noticed) are gastrointestinal:
nausea, vomiting, diarrhea, or a combination of these symptoms. The
casualty may notice generalized sweating and complain of tiredness or
otherwise feeling ill. There may be a period of many hours between
exposure and the appearance of symptoms and signs. These signs and
symptoms might occur even if the casualty has been decontaminated.\
     

After large exposures, the time to onset of effects may be much shorter
than for smaller exposures and decreases as the amount of agent
increases. For instance, two individuals were decontaminated within
minutes of exposure to a drop of nerve agent. There was a 15- to
20-minute, asymptomatic interval before the precipitant onset of
effects: collapse, loss of consciousness, convulsive muscular jerks,
fasciculations, respiratory embarrassment, and copious secretions

EFFECTS ON ORGANS AND ORGAN SYSTEMS

The Eye\
     

Nerve agents in the eye may cause miosis, conjunctival injection, pain
in or around the eye, and dim or blurred vision (or both). Reflex nausea
and vomiting may accompany eye exposure. These effects are usually
local, occurring when the eye is in direct contact with nerve agent
vapor, aerosol, or liquid, but exposure by other routes (such as on the
skin) can also affect the eyes. Because eyes often react late in the
course of intoxication in the latter case (exposure on the skin), they
cannot be relied on as an early indication of exposure.

If the eye exposure is not associated with inhalation of the nerve
agent, there is no good correlation between severity of the miosis and
inhibition of RBC-ChE activity. The latter may be relatively normal or
may be inhibited by as much as 100% (See table below), so the severity
of the miosis cannot be used as an index of the amount of systemic
absorption of agent or amount of exposure.

  ------------------- -------------------------------------------------------
  **EFFECTS OF NERVE  
  AGENTS IN HUMANS**  

  **Organ or System** **Effect**

                      

  Eye                 Miosis (unilateral or bilateral), conjunctival
                      injection; pain in or around the eye; complaints of dim
                      or blurred vision

  Nose                Rhinorrhea

  Mouth               Salivation

  Pulmonary tract     Bronchoconstriction and secretions, cough; complaints
                      of tight chest, shortness of breath; on exam: wheezing,
                      rales, rhonchi

  Gastrointestional   Increase in secretions and motility; nausea, vomiting,
  tract               diarrhea; complaints of abdominal cramps, pain

  Skin and sweat      Sweating
  glands              

  Muscular            Fasciculations (\"rippling\"), local or generalized;
                      twitching of muscle groups, flaccid paralysis;
                      complaints of twitching, weakness

  Cardiovascular      Decrease or increase in heart rate; usually increase in
                      blood pressure

  Central nervous     Acute effects of severe exposure: loss of
  system              consciousness, convulsion (or seizures after muscular
                      paralysis), depression of respiratory center to produce
                      apnea\
                      Acute effects of mild or moderate exposure or lingering
                      effects (days to weeks) of any exposure: forgetfulness,
                      irritability, impaired judgement, decreased
                      comprehension, a feeling of tenseness or uneasiness,
                      depression, insomnia, nightmares, difficulties with
                      expression
  ------------------- -------------------------------------------------------

Light Reduction

Dim vision is generally believed to be related to the decrease in the
amount of light reaching the retina because of miosis. As a practical
matter, anyone whose vision has been affected by exposure to a nerve
agent should not be allowed to drive in dim light or in darkness.

Visual Acuity\
     

Persons exposed to nerve agents sometimes complain of blurred as well as
dim vision

Eye Pain\
     

Eye pain may accompany miosis, but the reported incidence varies. A
sharp pain in the eyeball or an aching pain in or around the eyeball is
common. A mild or even severe headache (unilateral if the miosis is
unilateral) may occur in the frontal area or throughout the head.
Sometimes this discomfort is accompanied by nausea, vomiting, and
malaise. Local instillation of an anticholinergic drug such as atropine
or homatropine usually brings relief from the pain and systemic effects
(including the nausea and vomiting), but because these drugs cause
blurring of vision, they should not be used unless the pain is severe.

The Nose\
     

Rhinorrhea is common after both local and systemic nerve agent exposure.
It may occur soon after exposure to a small amount of vapor and
sometimes precedes miosis and dim vision, or it may occur in the absence
of miosis. Rhinorrhea also occurs as part of an overall, marked increase
in secretions from glands (salivary, pulmonary, and gastrointestinal)
that follows a severe systemic exposure from liquid on the skin and,
under this circumstance, becomes a secondary concern to both the
casualty and the medical care provider.

Pulmonary System\
     

After exposure to a small amount of nerve agent vapor, individuals often
complain of a tight chest (difficulty in breathing), which is generally
attributed to spasm or constriction of the bronchiolar musculature. .
Secretions from the goblet and other secretory cells of the bronchi also
contribute to the dyspnea. Exposure to sarin can produce some
respiratory discomfort in most individuals, with the discomfort and
severity increasing as the amount of agent increases.

The pulmonary effects begin within seconds after inhalation. If the
amount inhaled is large, the effects of the agent include severe dyspnea
and observable signs of difficulty with air exchange, including
cyanosis. If the amount of the inhaled agent is small, the individual
may begin to feel better within minutes after moving into an
uncontaminated atmosphere, and may feel normal in 15 to 30 minutes.

Attempts to aid ventilation in severely poisoned casualties can be
greatly impeded by constriction of the bronchiolar musculature and by
secretions. It has been suggested that thick mucoid plugs could hamper
attempts at assisted ventilation until these plugs were removed by
suction. Atropine may contribute to the formation of this thicker mucus
because it dries out the thinner secretions.

A severely poisoned casualty becomes totally apneic and will die as a
result of ventilatory failure, which precedes collapse of the
circulatory system. Many factors contribute to respiratory failure,
including obstruction of air passages by broncho-constriction and
secretions; weakness followed by flaccid paralysis of the intercostal
and diaphragmatic musculature, which is needed for ventilation; and a
partial or total cessation of stimulation to the muscles of respiration
from the CNS, indicating a defect in central respiratory drive.

The Skeletal Musculature

The effects of nerve agent intoxication on skeletal muscle are caused
initially by stimulation of muscle fibers, then by stimulation of
muscles and muscle groups, and later by fatigue and paralysis of these
units. These effects on muscle may be described as fasciculations,
twitches (or jerks), and fatigue.

Fasciculations are the visible contractions of a small number of fibers
innervated by a single motor nerve filament. They appear as ripples
under the skin. They can occur as a local effect at the site of a
droplet of agent on the skin before enough agent is absorbed to cause
systemic effects. They also can appear simultaneously in many muscle
groups after a large systemic exposure. A person who has sustained a
severe exposure will have generalized fasciculations, a characteristic
sign of poisoning by a ChE inhibitor; typically, fasciculations will
continue long after the patient has regained consciousness and has
voluntary muscle activity. After a severe exposure, there are intense
and sudden contractions of large muscle groups, which cause the limbs to
flail about or momentarily become rigid or the torso to arch rigidly in
hyperextension.

Whether these movements, which have been described as convulsive jerks,
are part of a generalized seizure or originate lower in the nervous
system is unclear. Occasionally, these disturbances may be a local
effect on the muscle groups below or near the site of exposure---for
instance, the marked trismus and nuchal rigidity in an individual who
pipetted soman into his mouth After several minutes of hyperactivity
(fasciculations or twitching), the muscles fatigue and flaccid paralysis
occurs. This, of course, stops convulsive activity and respiration.\
\
Central Nervous System and Behavior

Although the effects may begin as late as 1 day after exposure, they
usually start within a few hours and last from several days to several
weeks. Common complaints include feelings of uneasiness, tenseness, and
fatigue. Exposed individuals may be forgetful, and observers may note
that they are irritable, do not answer simple questions as quickly and
precisely as usual, and generally display impaired judgment, poor
comprehension, decreased ability to communicate, or occasional mild
confusion. Gross mental aberrations, such as complete disorientation or
hallucinations, are not part of the symptom complex.

Studies of Behavioral and Psychological Changes

In a series of 49 workers who were accidentally exposed to sarin or
tabun (a total of 53 exposures), 13 workers reported sleep disturbances,
12 reported mood changes, and 10 reported easy fatigability. Overall,
51% had CNS effects. The authors pointed out that the complex of CNS
symptoms may not fully develop until 24 hours after exposure.

Although the frequency, onset, and duration of each reaction were not
noted, some of the behavioral effects reported in the VX subjects were
fatigue, jitteriness or tenseness, inability to read with comprehension,
difficulties with thinking and expression, forgetfulness, inability to
maintain a thought trend, a feeling of being mentally slowed,
depression, irritability, listlessness, poor performance on serial 7s
and other simple arithmetic tests, minor difficulties in orientation,
and frightening dreams. Illogical or inappropriate trends in language
and thinking were not noted, nor was there evidence of conceptual
looseness. The investigators found no evidence of perceptual distortion
resulting in delusions or hallucinations.

Long-Term Effects\
     

Long-term effects on the human CNS after poisoning with nerve agents or
organophosphate insecticides have been reported. These reports are based
on clinical observations, which occasionally are supported by
psychological studies. In general, the behavioral effects have not been
permanent but have lasted weeks to several months, or possibly several
years.\
     

Necropsy findings from animal studies suggest that there are
long-lasting or permanent CNS effects after exposures to lethal or
near-lethal amounts of nerve agents.  Although most studies have been
with soman, similar damage has been reported after exposure to sarin.

The efficacy of diazepam in stopping seizures is generally accepted, and
there is evidence that the drug also reduces brain damage. Most reports
in the clinical literature recommend stopping the convulsion within 1
hour, using drastic measures, such as hypothermia and barbiturate coma,
if necessary. The mortality of status epilepticus (usually defined as a
convulsion lasting 60 min, or a series of convulsions lasting 60 min
without consciousness intervening) is said to be 6% to 30%. Moreover,
twice that number of victims acquire irreversible neurological deficits
as a result of status epilepticus.

Cardiovascular System\
     

Few data on the cardiovascular effects of nerve agents in humans exist.
In mild-to-moderate intoxication from nerve agents, blood pressure may
be elevated, presumably because of cholinergic stimulation of ganglia or
other factors, such as stress reaction.

Arrhythmias\
     

After nerve agent exposure, the heart rate may decrease and some
atrial-ventricular (A-V) heart block (first-, second-, or third-degree)
with bradycardia (personal observation) may occur because of the
stimulation of the A-V node by the vagus nerve. In some cases, an
increase in heart rate may occur because of stress, fright, or some
degree of hypoxia. Since the initiation of treatment is of great urgency
in severely intoxicated patients, electrocardiograms (ECGs) have not
been done before administration of atropine. However, if possible, an
ECG should be done before drugs are given if the procedure will not
delay therapy. In normal subjects, atropine may cause a very transient
A-V dissociation before the onset of bradycardia (which precedes the
familiar tachycardia), and ChE-inhibiting substances may cause
bradycardia and A-V block.

For reasons noted above, these transient rhythm abnormalities have not
been recorded in patients with nerve agent intoxication. These rhythm
disturbances are probably not important clinically.

Torsade de pointes has been reported after nerve agent and
organophosphate pesticide poisoning in humans. Torsade de pointes is a
ventricular arrhythmia, usually rapid, of multifocal origin, which on
ECGs resembles a pattern midway between ventricular tachycardia and
fibrillation.

*Ventricular fibrillation, a potentially fatal arrhythmia, has been seen
after administration of a ChE inhibitor and atropine. It can be
precipitated by the intravenous administration of atropine to an animal
that has been rendered hypoxic by administration of a ChE inhibitor*
Although this complication has not been reported in humans, atropine
should not be given intravenously until the hypoxia has been at least
partially corrected

GENERAL TREATMENT PRINCIPLES

     

The principles of treatment of nerve agent poisoning are the same as
they are for any toxic substance exposure: namely, terminate the
exposure; establish or maintain ventilation; administer an antidote, if
one is available; and correct cardiovascular abnormalities.\
     

Most importantly, medical care providers or rescuers must protect
themselves from contamination. If the caregiver becomes contaminated,
there will be one more casualty and one fewer rescuer. Protection of the
rescuer can be achieved by physical means, such as masks, gloves, and
aprons, or by ensuring that the casualty has been thoroughly
decontaminated. The importance of casualty decontamination should be
obvious, but, unfortunately, it is often forgotten or overlooked. There
were reports that in several instances during the Iran--Iraq War
(1981--1988), incompletely decontaminated mustard casualties who were
transported to European medical centers for further care caused
contamination of others, who then also became casualties.\
     

This section discusses the general principles of treating nerve agent
poisoning. The specific treatment of casualties in the six exposure
categories (suspected, minimal, mild, moderate, moderately severe, and
severe) is addressed in the next section.\
\
Terminating the Exposure

Decontamination is performed for two reasons:

to prevent further absorption of the agent by the casualty or further
spread of the agent on the casualty, and

to prevent spread of the agent to others, including medical personnel,
who must handle or who might come into contact with the casualty.

Because of the small amount of nerve agent needed to cause death and
because of the short time (10--15 min) in which a lethal amount will
cause severe effects in an untreated casualty, it is unlikely that a
living nerve agent--poisoned casualty with nerve agent on his skin will
be brought to a medical care facility. To successfully reduce damage to
the casualty, decontamination must be performed within minutes after
exposure. The only decontamination that prevents or significantly
reduces damage from a chemical agent, whether a nerve agent or another
agent, is that done within the first several minutes:
*self-decontamination*.\
     

The importance of rapid self-decontamination cannot be overemphasized
and must be clearly understood by anyone who might be exposed to
chemical agents. Because the skin absorbs most chemical agents rapidly
and because of evaporation (even "persistent" agents, such as VX and
mustard, evaporate from skin rather quickly), it is unlikely that there
will be a significant amount of agent on the skin by the time the
casualty reaches a medical treatment facility. However, agent may be in
areas, such as in hair or on clothing, where it will not be readily
absorbed percutaneously.  *Skin decontamination is not necessary after
exposure to nerve agent vapor*.\
     

If vapor is the only exposure source, the exposure can be terminated by
putting a protective mask on the casualty or by moving him to an
environment free of toxic vapor (eg, by moving the casualty outside and
sealing the doors if the vapor is in a room or building). Liquid agent
on the skin or clothing should be physically removed and detoxified by
chemical degradation or neutralization. Nerve agents penetrate clothing;
mere removal of contaminated apparel is not adequate since some agents
may reach the skin before the clothing is removed. If the contamination
is localized, cutting out the affected section of clothing (leaving very
wide margins) may be adequate. If there is doubt, however, all clothing
should be removed. The underlying skin should then be decontaminated
thoroughly.\
     

Military decontamination kits contain charcoal and sorptive resins; the
agent is physically removed and adsorbed. This kit (M258A1) is a
standard decontamination kit that contains two moistened towelettes. One
is intended for use with the G agents, and the other with VX and
mustard. Since the agent probably would not be identified at the time of
exposure in the field, both towelettes should be used to physically
remove the chemical agent by blotting, not wiping, it; the towelettes
also aid in decontamination by chemically neutralizing the agent,
although this chemical reaction is slow.

A solution that releases chlorine, such as household bleach (5% sodium
hypochlorite) or a solution that is sufficiently alkaline to neutralize
the agent, such as dilute hydroxide, can also be used for physical
removal and chemical neutralization of a chemical agent. Because of the
potential for skin damage from 5% hypochlorite, the current military
procedure is to use 0.5% hypochlorite for skin decontamination. Dilute
hydroxide and the contents of the M258A1 kit are damaging to the skin,
however, and should be thoroughly rinsed off.\
     

Water is also a decontaminant since, when used in large amounts, it
physically removes and dilutes chemical agents. (Most agents hydrolyze
to some degree in water, but hydrolysis usually takes hours to days.) If
used alone, water is not ideal; however, if nothing else is available,
flushing with large amounts of water to physically remove the chemical
agent is satisfactory. Water should be used to wash off the other
decontaminants. Commonly available products (such as tissue paper and
flour) that can help remove or adsorb the agent should be used if other
decontaminants are not available.

Ventilatory Support

Ventilatory support is a necessary aspect of therapy if a casualty with
severe respiratory compromise is to be saved. Antidotes alone may be
effective in restoring ventilation and saving lives in some instances;
in animal studies antidotes alone, given intramuscularly at the onset of
signs, were adequate to reverse the effects of agent doses of about 3
LD~50~ , but their effectiveness was greatly increased with the addition
of ventilation. Pyridostigmine, given as pretreatment and followed by
the current therapy after challenges with higher amounts of two agents,
appears to prevent apnea. Impairment of breathing is an early effect of
exposure to nerve agent vapor or aerosol. When the exposure is small,
the casualty may have mild to severe dyspnea, with corresponding
physical findings, and the impairment will be reversed by the
administration of atropine. If the distress is severe and the casualty
is elderly or has pulmonary or cardiac disease, the antidote may be
supplemented by providing oxygen by inhalation. In most other
circumstances, supplementation with oxygen is unnecessary.

Severely exposed casualties lose consciousness shortly after the onset
of effects, usually before any signs of respiratory compromise. They
have generalized muscular twitching or convulsive jerks and may
initially have spontaneous but impaired respiration. Breathing ceases
completely within several minutes after the onset of exposure in a
severely poisoned person who has not been pretreated with
pyridostigmine.

Assisted ventilation may be required to supplement gasping and
infrequent attempts at respiration, or it may be required because
spontaneous breathing has stopped. In addition to a decrease in central
respiratory drive, weakness or paralysis of thoracic and diaphragmatic
muscles, and bronchospasm or constriction, there are copious secretions
throughout the airways. These secretions tend to be thick, mucoid, and
"ropy," and may plug up the airways. Postural drainage can be used, and
frequent and thorough suctioning of the airways is necessary if
ventilation is to be successful. In one instance, efforts to ventilate a
severely apneic casualty were markedly hindered for 30 minutes until
adequate suction was applied to remove thick mucoid plugs. Initially,
because of the constriction or spasm of the bronchial musculature, there
is marked resistance to attempts to ventilate

Mouth-to-mouth ventilation might be considered by someone who wants to
assist an apneic buddy when no emergency aid is nearby. ***[A major
drawback is the likelihood of contamination.]{.underline}*** Before even
considering this method, the rescuer should be sure that there is no
vapor hazard, which is not always possible, and that there is no liquid
contamination on the individual to be ventilated. The expired breath of
the casualty is a lesser hazard. Studies involving sarin have shown that
only 10% or less of inspired nerve agent is expired, and that the
toxicant is expired immediately after inspiration of the agent.

ATROPINE THERAPY

Cholinergic blocking substances act by blocking the effects of excess
acetylcholine at muscarinic receptors. Acetylcholine accumulates at
these receptors because it is not hydrolyzed by ChE when the enzyme is
inactivated by an inhibitor. Thus, cholinergic blocking substances do
not block the direct effect of the agent (ChE inhibition); rather, they
block the effect of the resulting excess ACh. Many cholinergic blocking
substances have been tested for antidotal activity. Among the findings
are the following:

Almost any compound with cholinergic blocking activity has antidotal
activity.

Atropine and related substances reduce the effects of the ChE
inhibitors, primarily in those tissues with muscarinic receptor sites.

Antidotal substances with higher lipoid solubility, which penetrate the
CNS more readily, might be expected to have greater antidotal activity,
since some of the more severe effects of ChE inhibitor poisoning (such
as apnea and seizures) are mediated in the CNS.

***The dose of atropine which the individual serviceman in the field,
can be allowed to use must be a compromise between the dose which is
therapeutically desirable and that which can be safely administered to a
nonintoxicated person. Laboratory trials have shown that 2 mg of
atropine sulfate is a reasonable amount to be recommended for injection
by an individual and that higher doses may produce embarrassing effects
on troops with operational responsibilities***

When given to a normal individual (one without nerve agent
intoxication), a dose of 2 mg of atropine will cause an increase in
heart rate of about 35 beats per minute (which usually is not noticed by
the recipient), a dry mouth, dry skin, mydriasis, and some paralysis of
accommodation. Most of these effects will dissipate by 4 to 6 hours, but
near vision may be blurred for 24 hours, even in healthy young men. The
decrease in sweating caused by 2 mg of atropine is a major, potentially
harmful side effect that may cause some people who work in the heat to
become casualties.

The 6 mg of atropine contained in the three injectors given each soldier
may cause mild mental aberrations (such as drowsiness or forgetfulness)
in some individuals if administered in the absence of nerve agent
intoxication. Atropine given intravenously to healthy young people
causes a maximal increase in the heart rate in 3 to 5 minutes, but other
effects (such as drying of the mouth and change in pupil size) appear
later.

Thus, the autoinjector is not only more convenient to use than the
needle and syringe, but its use causes more rapid absorption of the
drug. Needle-and-syringe delivery produces a "glob" or puddle of liquid
in muscle. The AtroPen, on the other hand, sprays the liquid throughout
the muscle as the needle goes in. The greater dispersion of the AtroPen
deposit results in more rapid absorption. It has not been determined
whether the onset of beneficial effects in treating nerve agent
intoxication corresponds to the onset of bradycardia, the onset of
tachycardia, or to other factors

.\
 When administered in an adequate amount, atropine reverses the effects
of the nerve agent in tissues that have muscarinic receptor sites. It
decreases secretions and reverses the spasm or contraction of smooth
muscle. The mouth dries, secretions in the mouth and bronchi dry,
bronchoconstriction decreases, and gastrointestinal musculature will be
less hyperactive. However, unless given in very large doses, intravenous
or intramuscular atropine does not reverse miosis caused by nerve agent
vapor in the eyes. A casualty with miosis alone should not be given
atropine, therefore, and pupil size should not be used to judge the
adequacy of atropine dosage.

Whether atropine controls convulsions in humans is unclear.

\[[In the field of medical toxicology "atropinization" can often be
described by the following example. Once achieved, the patient will
be:"MAD AS A HATTER/ HOT AS A HEN/ DRY AS A BONE/ RED AS A BEET AND
BLIND AS A BAT"\]]{.underline}

.[\
]{.underline}The amount of atropine to administer is a matter of
judgment. In a conscious casualty with mild-to-moderate effects who is
not in severe distress, 2 mg of atropine should be given intramuscularly
at 5- to 10-minute intervals until dyspnea and secretions are minimized.
Usually no more than a total dose of 2 to 4 mg is needed. In an
unconscious casualty, atropine should be given (a) until secretions are
minimized (those in the mouth can be seen and those in the lungs can be
heard by auscultation) and (b) until resistance to ventilatory efforts
is minimized (atropine decreases constriction of the bronchial
musculature and airway secretions). If the casualty is conscious, he
will report less dyspnea, and if assisted ventilation is underway, a
decrease in airway resistance will be noted.

Secretions alone should not be the reason for administering more
atropine if the secretions are diminishing and are not clinically
significant. Mucus blocking the smaller airways may remain a hindrance
despite adequate amounts of atropine. In severe casualties (unconscious
and apneic), ***5 to 15 mg of atropine*** has been used before
spontaneous respiration resumed and the casualty regained consciousness
(which occurred 30 min to 3 h after exposure) Several recovering
casualties have had non--life-threatening adverse effects (such as
nausea and vomiting) 24 to 36 hours after exposure for which atropine
was administered (personal observation). However, there would appear to
be no reason to give atropine routinely in this period.\
     

In contrast, much larger amounts of atropine (500--1,000 mg) have been
required in the initial 24 hours of treatment of individuals severely
poisoned by organophosphorus pesticides ***Medical care providers must
recognize that the amount of atropine needed for treatment of
insecticide poisoning is different from the amount needed for treatment
of nerve agent poisoning***. Pesticides may be sequestered in the body
or metabolized at a slower rate than nerve agents; whatever the reason,
they continue to cause acute cholinergic crises for a much longer period
(days to weeks).\
     

The goal of therapy with atropine should be to minimize the effects of
the agent (ie, to remove the casualty from a life-threatening situation
and to make him comfortable), which may not require complete reversal of
all of the effects (such as miosis). However, in a casualty with severe
effects, ***[it is better to administer too much atropine than too
little.]{.underline}*** Too much atropine does far less harm than too
much unantagonized nerve agent in a casualty suffering severe effects.
However, a moderately dyspneic casualty given atropine 2 mg,
administered intramuscularly, will report improvement within 5 minutes.
A caregiver should resist the temptation to give too much atropine to a
walking, talking casualty with dyspnea. In general, the correct dose of
atropine for an individual exposed to a nerve agent is determined by the
casualty's signs and symptoms, the route of exposure (vapor or liquid),
and the amount of time elapsed since.

After vapor exposure, the effects of nerve agents appear very quickly
and reach their maximum activity within seconds or minutes after the
casualty is removed from or protected against the vapor. In what were
apparently high concentrations of nerve agent vapor, two individuals
collapsed, unconscious, almost immediately after taking one or two
breaths, and 4 to 5 minutes later they were flaccid and apneic.

Even at very low concentrations, maximal effects occur within minutes of
termination of exposure. Because effects develop so rapidly, antidotal
therapy should be more vigorous for a casualty seen during or
immediately after exposure than for a casualty seen 15 to 30 minutes
later.

As a general rule, if a patient is seen immediately after exposure from
vapor only, the contents of one MARK I kit should be given if miosis is
the only sign, the contents of two kits should be administered
immediately if there is any dyspnea, and the contents of three kits
should be given for severe dyspnea or any more-severe signs or symptoms.
When seen 15 to 30 minutes after an exposure to vapor alone, the patient
should receive no antidote if miosis is the only sign, the contents of
one MARK I kit for mild or moderate dyspnea, the contents of two kits
for severe dyspnea (obvious gasping), and the contents of three kits and
diazepam (with additional atropine, but no more oxime) if there are more
serious signs (such as collapse or loss of consciousness). If dyspnea is
the most severe symptom, relief should begin within 5 minutes, and the
drugs should not be repeated until this interval has passed. Remember
that the aggressive therapy given immediately after the onset of effects
is not for those early effects per se (eg, atropine is relatively
ineffective against miosis), but is in anticipation of more-severe
effects within the following minutes.

Atropine Therapy After Dermal Exposure to Liquid

The therapy for an individual whose skin has been exposed to nerve agent
is less clear. The onset of effects is rarely immediate; they may begin
within minutes of exposure or as long as 18 hours later. As a general
rule, the greater the exposure, the sooner the onset; and the longer the
interval between exposure and onset of effects, the less severe the
eventual effects will be. Effects can begin hours after thorough
decontamination; the time of onset may be related to the duration of
time the agent was in contact with the skin before decontamination. The
problem with treating dermal exposure is not so much *how* to treat a
symptomatic casualty as *whether* to treat an asymptomatic person who
has had agent on the skin.

In general, an asymptomatic person who has had skin contact with a nerve
agent should be kept under medical observation, because effects may
begin precipitately hours later. Caregivers should not administer the
contents of a MARK I kit to an asymptomatic person, but should wait for
evidence of agent absorption. However, if an individual is seen minutes
after a definite exposure to a large amount of nerve agent on the skin
("large" is relative; the LD~50~ for skin exposure to VX is only 6--10
mg, which is equivalent to a single drop 2--3 mm in diameter), there may
be some benefit in administering antidotes before the onset of effects.

Antidotes should be administered until ventilation is adequate and
secretions are minimal. In a mildly to moderately symptomatic individual
who is complaining of dyspnea, relief is usually obtained with 2 or 4 mg
of atropine (the amount of atropine in one or two MARK I kits).

In a severely exposed person who is unconscious and apneic or nearly
apneic, at least 6 mg of atropine (the amount in three MARK I kits), and
probably more, should be administered initially, and ventilatory support
should be started. Atropine should be continued at appropriate intervals
until the casualty is breathing adequately with a minimal amount of
secretions in the mouth and lungs. The initial 2 or 4 mg has proven
adequate in conscious casualties. Although 6 to 15 mg has been required
in apneic or nearly apneic casualties, the need for continuing atropine
has not extended beyond 2 to 3 hours (although distressing but not
life-threatening effects, such as nausea and vomiting, have necessitated
administering additional atropine in the following 6--36 h). This is in
contrast to the use of atropine to treat intoxication by
organophosphorus insecticides, which may cause cholinergic crises (such
as an increase in secretion and bronchospasm) for days to weeks after
the initial insult.

OXIME THERAPY

Oximes are nucleophilic substances that reactivate the
organophosphate-inhibited ChE (the phosphorylated enzyme) by removing
the organophosphoryl moiety. There are limitations to oxime therapy,
however.\
\
Mechanism of Action\
     

After the organophosphorus compound attaches to the enzyme to inhibit
it, one of the following processes may occur:

the enzyme may be spontaneously reactivated by hydrolytic cleavage,
which breaks the organophosphoryl--ChE bond, reactivating the enzyme; or

the organophosphoryl--ChE bond may "age," or become resistant to
reactivation by water or oxime.

Both of these processes are related to the size of the alkyl group
attached to the oxygen of the organo-phosphorus compound, the group
attached to the first carbon of this alkyl group, and other factors.
Once the organophosphoryl--enzyme complex ages, it cannot be broken by
an oxime. (Further discussion of the chemical process can be found
elsewhere; for a brief discussion, Oxime therapy is not effective after
aging occurs.\
     

Because the nerve agents differ in structure, their rates of spontaneous
reactivation and aging differ. For example, when complexed with VX,
RBC-ChE spontaneously reactivates at a rate of roughly 0.5% to 1% per
hour for about the first 48 hours; the VX-- enzyme complex ages very
little during this period. The soman--enzyme complex does not
spontaneously reactivate; the half-time for aging is about 2 minutes.
The half-time for aging of the sarin--RBC-ChE complex is about 5 hours,
and a small percentage (5%) of the enzyme undergoes spontaneous
reactivation. The half-time for aging of the tabun--enzyme complex is
somewhat longer.\
     

The oximes differ in their required doses, their toxicity, and their
effectiveness (for example, TMB4 is more effective against tabun
poisoning than is 2-PAM Cl). After thorough study of many of these
compounds, 2-PAM Cl was chosen for use in the United States. The choice
was made because of research in both the civilian and military sectors
and also because of the demonstrated efficacy of 2-PAM Cl in treating
organophosphorus insecticide poisoning. At present, the only oxime
approved by the Food and Drug Administration for use in the United
States is 2-PAM Cl.\
     

Since oximes reactivate the ChE inhibited by a nerve agent, they might
be expected to completely reverse the effects caused by nerve agents.
However, because nerve agents possibly produce biological activity by
mechanisms other than inhibition of ChE or because of reasons not
understood, oximes are relatively ineffective in reversing effects in
organs with muscarinic receptor sites. They are much more effective in
reversing nerve agent--induced changes in organs with nicotinic receptor
sites. In particular, when oximes are effective (ie, in the absence of
aging), they decrease the abnormality in skeletal muscle, improving
strength and decreasing fasciculations.

Dosage\
     

The therapeutic dosage of 2-PAM Cl has not been established, but
indirect evidence suggests that it is 15 to 25 mg/kg. The effective dose
depends on the nerve agent, the time between poisoning and oxime
administration, and other factors. The 2-PAM Cl administered with the
ComboPen autoinjector (600 mg) produces a maximal plasma concentration
of 6.5 µg/mL when injected intramuscularly in the average soldier (8.9
mg/kg in a 70-kg man).\
    

For optimal therapy, 2-PAM Cl should be given intravenously, but usually
this is not possible in the field. Even at small doses (2.5--5.0 mg/kg),
the drug, when given intravenously in the absence of nerve agent
poisoning, may cause transient effects, such as dizziness and blurred
vision, which increase as the dose increases. Transient diplopia may
occur at doses higher than 10 mg/kg. These effects, if they occur, are
insignificant in a casualty poisoned with a ChE-inhibiting substance.
Occasionally, nausea and vomiting may occur. The most serious side
effect is hypertension, which is usually slight and transient at
intravenous doses of 15 mg/kg or less, but may be marked and prolonged
at higher doses.^145^ 2-PAM Cl is commercially available as the
cryodesiccated form (Protopam Chloride, in vials containing 1 g, or
about 14 mg/kg for a 70-kg person. Blood pressure elevations greater
than 90 mm Hg systolic and 30 mm Hg diastolic may occur after
administration of 45 mg/kg, and the elevations may persist for several
hours.^145^ Giving the oxime slowly (over 30--40 min) may minimize the
hypertensive effect, and the hypertension can be quickly but transiently
reversed by phentolamine 5 mg, administered intravenously.  2-PAM Cl is
rapidly and almost completely excreted unchanged by the kidneys: 80% to
90% of an intramuscular or intravenous dose is excreted in 3 hours,
probably by an active tubular excretory mechanism (its renal clearance
is close to that of paminohippurate), with a half-time of about 90
minutes. Both clearance and amount excreted are decreased by heat,
exercise, or both.

Thiamine also decreases excretion (presumably by blocking tubular
excretion), prolongs the plasma half-life, and increases the plasma
concentration for the duration of thiamine activity, though some
question its therapeutic benefit.

Administration\
      

***Initially, an oxime should be administered with atropine***. In cases
of severe exposure, the contents of three MARK I kits should be
administered; if the kits are not available, then oxime 1 to 1.5 g
should be administered intravenously over a period of 20 to 30 minutes
or longer. Additional atropine should be given to minimize secretions
and to reduce ventilatory problems, thereby relieving the casualty's
distress and discomfort.\
     

Since an improvement in the skeletal muscle effects of the agent (ie, an
increase or decrease in muscle tone and reduced fasciculations) may be
seen after oxime administration, medical personnel may be tempted to
repeat the oxime along with atropine. Because of side effects, however,
no more than about 2.5 g of oxime should be given within 1 to 1.5 hours.
If the oxime is effective, it can be repeated once or twice at intervals
of 60 to 90 minutes. 

2-PAM Cl can be administered intravenously, intramuscularly, and orally.
Soon after it became commercially available, 2-PAM Cl was administered
orally both as therapy and as a pretreatment for those in constant
contact with organophosphorus compounds (eg, crop dusters).

At one time, the United Kingdom provided its military personnel with a
supply of oxime tablets for pretreatment use, but it no longer does so.
Enthusiasm for this practice waned for a number of reasons:

erratic absorption of the drug from the gastrointestinal tract, leading
to large differences (both between individuals and in the same person at
different times) in plasma concentration;

the large dose required (5 g to produce an average plasma concentration
of 4 µg/mL);

the unpopularity of the large, bitter 0.5-g or 1.0-g tablets; and

the relatively slow absorption compared with that for administration by
other routes.

In addition, the frequent administration (every 4--6 h) required by
workers at risk caused gastrointestinal irritation, including diarrhea.
It is also no longer common practice for crop workers to be given 2-PAM
Cl as a pretreatment, the rationale being that crop workers who take the
medication might have a false sense of security and therefore might tend
to be careless with safety measures.\
     

Despite these drawbacks, 2-PAM Cl tablets might be the best alternative
in certain cases, such as a depot worker exposed to a nerve agent who
shows no effects except for an inhibition of RBC-ChE activity. An oxime
might be given to restore his RBC-ChE activity to 80% of his baseline
value, which is necessary for his return to work. (See Blood
Cholinesterases section, above, for discussion of monitoring RBC-ChE
activity.) Administration by the oral route might be considered
preferable (although less reliable) to administration by a parenteral
route because tablets can be self-administered and taking tablets avoids
the pain of an injection.\
     

Intramuscular administration of 2-PAM Cl with the ComboPen results in a
plasma concentration of 4 µg/kg at 7 minutes versus 10 minutes for
conventional needle-and-syringe injection. (A maximal plasma
concentration of 6.9 µg/kg occurs at 19 min vs 6.5 µg/kg at 22 min for
the needle-and-syringe method.) About 80% to 90% of the intact drug is
excreted unmetabolized in the urine; the half-life is about 90 minutes.
When a 30% solution of 2-PAM Cl was injected intramuscularly at doses
ranging from 2.5 to 30 mg/kg, the drug caused no change in heart rate or
any signs or symptoms (except for pain at the injection site, as
expected after an injection of 2 mL of a hypertonic solution). When
given intramuscularly, 30 mg/kg caused an elevation in blood pressure
and minimal ECG changes, but no change in heart rate.\
     

Because of the very rapid aging of the soman--AChE complex, oximes are
often considered ineffective in treating soman poisoning..

Anticonvulsive Therapy\
     

Convulsions occur after severe nerve agent exposure. In reports of
severe cases, convulsions (or what were described as "convulsive jerks"
or "spasms") started within seconds after the casualty collapsed and
lost consciousness, and persisted for several minutes until the
individual became apneic and flaccid. The convulsions did not recur
after atropine and oxime therapy and ventilatory support were
administered. In these instances, no specific anticonvulsive therapy was
needed nor was it given.\
     

Diazepam has been used successfully to terminate convulsions caused by
organophosphate insecticide poisoning and has been fielded in the U.S.
military. As discussed earlier, each soldier is issued one autoinjector
(ComboPen) containing 10 mg of diazepam in 2 mL of diluent. When a
soldier exposed to a nerve agent is unable to help himself, a buddy
should administer diazepam as well as the contents of three MARK I
kits---whether or not there are indications of seizure activity. In
fact, it is preferable to administer diazepam ***before*** the onset of
seizure activity.

The medic carries additional diazepam injectors and is authorized to
administer two additional injectors to a convulsing casualty at
10-minute intervals. Current military doctrine is for the buddy to
administer the diazepam immediately following the administration of the
third MARK I when the three MARK I kits are given together. This is not
only military doctrine, it is sound medical advice, and this action
should be taken automatically when assisting a casualty with severe
exposure to organophosphate nerve agents.\
\
Therapy for Cardiac Arrhythmias

Minimal Exposure\
     

Miosis, with accompanying eye symptoms, and rhinorrhea are signs of a
minimal exposure to a nerve agent, either vapor or vapor and liquid.
This distinction is quite important in the management of this casualty.
There are many situations in which one can be reasonably certain that
exposure was by vapor alone (if the casualty was standing downwind from
a munition or container, for example, or standing across a laboratory or
storeroom from a spilled agent or leaking container). On the other hand,
if an unprotected individual is close to an agent splash or is walking
in areas where liquid agent is present, exposure may be by both routes.
Effects from vapor exposure occur quickly and are at their maximum
within minutes, whereas effects from liquid agent on the skin may not
occur until hours later.\
     

Atropine (and oxime) should not be given for miosis because it is
ineffective in the usual doses (2 or 4 mg). If eye pain (or head pain)
is severe, topical atropine or homatropine should be given. However, the
visual blurring caused by atropine versus the relatively small amount of
visual impairment caused by miosis must be considered. If the rhinorrhea
is severe and troublesome, atropine (the 2 mg contained in one MARK I
kit) may give some relief.\
     

If liquid exposure is suspected, the patient must be kept under
observation, as noted above. If liquid exposure can be excluded, there
is no reason for prolonged observation.

Mild Exposure\
     

An individual with mild or moderate dyspnea and possibly with miosis,
rhinorrhea, or both can be classified as having a mild exposure to nerve
agent. The symptoms indicate that the casualty has been exposed to a
nerve agent vapor and may or may not have been contaminated by a liquid
agent.  

If an exposed person in this category is seen within several minutes
after exposure, he should receive the contents of two MARK I kits
immediately. If 5 to 10 minutes have passed since exposure, the contents
of only one kit should be given immediately. If no improvement occurs
within 5 minutes under either circumstance, the casualty should receive
the contents of another MARK I kit. The contents of an additional kit
may be given if the casualty's condition worsens 5 to 10 minutes later,
but it is unlikely that it will be needed. Only three oxime
autoinjectors should be given; further therapy should be with atropine
alone.\
     

A person having mild exposure to a nerve agent should be thoroughly
decontaminated (exposure to vapor alone does not require
decontamination) and have blood drawn for measurement of RBC-AChE
activity prior to MARK I administration if facilities are available for
the assay. As noted above, if there is reason to suspect liquid
exposure, the casualty should be observed longer.

Moderate Exposure\
     

A casualty who has had moderate exposure to either a nerve agent vapor
alone or to vapor and liquid will have severe dyspnea, with accompanying
physical signs, and probably also miosis and rhinorrhea. The casualty
should be thoroughly decontaminated (REMEMBER: exposure to vapor alone
does not require decontamination) and blood should be drawn for assay of
RBC-ChE activity if assay facilities are available.

The contents of three MARK I kits and diazepam should be given if the
casualty is seen within minutes of exposure. If seen later than 10
minutes after exposure, the casualty should receive the contents of two
kits. Additional atropine should be given at 5- to 10-minute intervals
until the dyspnea subsides. No more than three MARK I kits should be
used; however, additional atropine alone should be administered if the
contents of three kits do not relieve the dyspnea after 10 to 15
minutes. If there is reason to suspect liquid contamination, the patient
should be kept under observation for 18 hours.\
     

Nausea and vomiting are frequently the first effects from liquid
contamination; the sooner after exposure they appear, the more ominous
the outlook. Therapy should be more aggressive when these symptoms occur
within an hour after exposure than when there is a longer delay in
onset. If the onset is about an hour or less from the known time of
liquid exposure, the contents of two MARK I kits should be administered
initially, and further therapy (the contents of MARK I kits to a total
of three, then atropine alone) given at 5- to 10-minute intervals, with
a maximum of three oxime injections. If the onset is several hours after
the time of known exposure, the contents of one MARK I kit should be
given initially, and additional MARK I kits as needed to a total of
three. Atropine alone should be used after the third MARK I. If the time
of exposure is unknown, the contents of two MARK I kits should be
administered.\
     

Nausea and vomiting that occur several hours after exposure have been
treated successfully with 2 or 4 mg of atropine, and the symptoms did
not recur. However, the exposure was single-site exposure (one drop at
one place). It is not certain that this treatment will be successful if
exposure is from a splash or from environmental contamination with
multiple sites of exposure on the skin. Therefore, casualties with this
degree of exposure should be observed closely for at least 18 hours
after the onset of signs and symptoms.\
\
Moderately Severe Exposure\
     

In cases of moderately severe exposure, the casualty will be conscious
and have one or more of the following signs and symptoms: severe
respiratory distress (marked dyspnea and objective signs of pulmonary
impairment such as wheezes and rales), marked secretions from the mouth
and nose, nausea and vomiting (or retching), and muscular fasciculations
and twitches. Miosis may be present if exposure was by vapor, but it is
a relatively insignificant sign as a guideline for therapy in this
context.\
     

The contents of three MARK I kits should be administered immediately.
Preferably, if the means are available, 2 or 4 mg of atropine should be
given intravenously, and the remainder of the total amount of 6 mg of
atropine, along with the three oxime injections, should be given
intramuscularly. The anticonvulsant diazepam should always be given when
the contents of three MARK I kits are administered together. The
casualty should be thoroughly decontaminated and have blood drawn for
AChE assay before oxime is given.\
     

Again, knowledge of the route of exposure is useful in planning further
treatment. If the exposure was by vapor only and the casualty is seen in
a vapor-free environment some minutes later, drug therapy should result
in improvement. If the casualty has not lost consciousness, has not
convulsed, and has not become apneic, he should improve. If the exposure
was the result of liquid agent or a combination of liquid and vapor,
there may be a reservoir of unabsorbed agent in the skin; despite the
initial therapy, the casualty's condition may worsen. In either case,
medical care providers should be prepared to provide ventilatory
assistance, including adequate suction, and additional drug therapy
(atropine alone) if there is no improvement within 5 minutes after
intravenous administration of atropine, or 5 to 10 minutes after
intramuscular administration of atropine.\
     

The triad of consciousness, lack of convulsive activity, and spontaneous
respiration is an indicator of a good outcome, provided adequate therapy
is given early.\
\
Severe Exposure\
     

A casualty who is severely exposed to a nerve agent will be unconscious.
He may be apneic or gasping for air with marked cyanosis, and may be
convulsing or postictal. The casualty will have copious secretions from
the mouth and nose and will have generalized fasciculations in addition
to convulsive or large-muscle twitching movements. If the casualty is
postictal, he may be flaccid and apneic.\
     

If the casualty shows no movement, including no signs of respiration,
the initial response should be to determine if the heart is beating.
This is not an easy task when the rescuer and the casualty are both in
full ***mission-oriented protective posture***, known in military terms
as MOPP 4 gear, but it must be accomplished because a nonmoving,
nonbreathing casualty without a heartbeat is not a candidate for further
attention on the battlefield in contrast to a medical treatment facility
where the medical personnel may be slightly more optimistic and proceed
with aggressive therapy. After the sarin release in the Tokyo, Japan,
subways, several casualties who were not breathing and who had no
cardiac activity were taken to a hospital emergency department. Because
of very vigorous and aggressive medical management, one or two of these
casualties were able to walk out of the hospital several days later.\
     

Despite the circumstances, self-protection from contamination from the
patient is important. Since decontamination of the patient may not be
the first priority, caregivers must wear appropriate protective
equipment until they have an opportunity to decontaminate the casualty
and to remove him and themselves from the contaminated area.\
     

The success of therapy under these circumstances is directly
proportional to the viability of the casualty's cardiovascular system.
If the heart rate is very slow or nonexistent or if there is severe
hypotension, the chances for success are poor, even in the best possible
circumstances.\
     

First, medical personnel must provide oxygenation and administer
atropine by a technique that ensures it will be carried to the heart and
lungs. If ventilatory assistance is not immediately available, the best
treatment is to administer the contents of three MARK I kits and
diazepam. If ventilatory assistance will be forthcoming within minutes,
the contents of the three MARK I kits should be administered whether the
circulation is intact or not. When there is no chance of rapid
ventilatory assistance, little is gained by MARK I therapy, but an
attempt at treatment should be made anyway.\
     

In the case of a failed or failing cardiovascular system, routes of
atropine administration other than intramuscular should be considered.
The intravenous route generally provides the fastest delivery of the
drug throughout the body, but it is not without danger in an apneic and
cyanotic patient. Whether or not concomitant ventilatory support can be
provided, military medical personnel might want to consider
administering atropine intratracheally by needle and syringe, if
available, or with the atropine autoinjector (the AtroPen). Even if the
casualty's systemic blood pressure is low, the peribronchial circulation
may still have adequate blood flow to carry the drug to vital areas. If
an endotracheal tube can be inserted, atropine could be injected into
the tube either by needle and syringe or with the injector.\
     

For severely exposed casualties, the initial dose of atropine should be
at least the 6 mg from the three autoinjectors, but an additional 2 mg
or 4 mg should also be given intravenously---if the capability is
available and if the casualty is not hypoxic (ventilatory support must
be started before intravenous atropine is given). If additional atropine
cannot be given intravenously, then the amount should be given
intramuscularly. The total initial dose of atropine can be as much as 10
mg, but this dose should not be exceeded without allowing at least
several minutes for a response. Further atropine administration depends
on the response. If secretions decrease or if there are attempts at
breathing, it might be prudent to wait even longer before administering
additional atropine. All three injectors of 2-PAM Cl should be given
with the initial 6 mg of atropine, but no more oxime should be given for
an hour.\
     

Possibly the most critical factor in treatment of severely exposed
casualties is restoration of oxygenation. Atropine alone might restore
spontaneous breathing in a small number of apneic individuals. Ideally,
an apparatus that delivers oxygen under positive pressure will be
available. Even an RDIC or a mask-valve-bag apparatus used with ambient
air will provide some assistance.\
     

When the contents of three MARK I kits are administered together to a
severely poisoned casualty, diazepam should be administered with the
contents of the third MARK I---whether or not there are indications of
seizure activity. The risk of respiratory depression from this amount of
diazepam given intramuscularly is negligible.\
     

Hypotension per se need not be treated, at least initially. Generally
the restoration of oxygenation and the increase in heart rate caused by
atropine, aided perhaps by the hypertensive effects of 2-PAM Cl, will
cause the blood pressure to increase to an acceptable level.\
     

Even with adequate oxygenation and large amounts of atropine, immediate
reversal of all of the effects of the nerve agent will not occur. The
casualty may remain unconscious, without spontaneous respiration and
with muscular flaccidity or twitching, for hours. Even after respiration
is at least partly spontaneous, secretions are minimized, and the
casualty is partly alert, close monitoring is necessary. Muscular
fasciculations may continue for hours after the casualty is alert enough
and has strength enough to get out of bed.

*RETURN TO WORK/DUTY*\
     

Various factors should be considered before an individual who has been a
nerve agent casualty is returned to work or duty. In an industrial
setting (depot or laboratory), the criteria for reactivation are that
the individual's RBC-ChE activity must have returned to within 80% of
its baseline value and that the individual is otherwise symptom- and
sign-free.

SUMMARY\
      

Nerve agents are the most toxic chemical warfare agents known. They
cause effects within seconds and death within minutes. These agents are
in the military stockpiles of several countries but have been used in
only one war. They can be manufactured by terrorist groups and have been
used in terrorist attacks.\
    

Nerve agents cause biological effects by inhibiting the enzyme AChE,
causing an excess of the neurotransmitter to accumulate. Hyperactivity
in those organs innervated by cholinergic nerves results, with increased
secretions from exocrine glands, hyperactivity of skeletal muscles
leading to fatigue and paralysis, hyperactivity of smooth muscles with
bronchoconstriction, and CNS changes, including seizure activity and
apnea.\
     

Therapy is based on the administration of atropine, which interferes
with receptor binding of acetylcholine at muscarinic but not nicotinic
receptors, and the oxime 2-PAM Cl, which breaks the agent--enzyme bond
formed by most agents. Assisted ventilation and other supportive
measures are also required in severe poisoning.

VESICANTS

INTRODUCTION\
     

A *vesicant* (ie, an agent that produces vesicles or blisters) was first
used as a chemical weapon on the battlefields of World War I; that same
vesicant---sulfur mustard---is still considered a major chemical agent.
In the intervening years between World War I and today, there have been
a number of recorded and suspected incidents of mustard use, culminating
with the Iran--Iraq War in the 1980s. During this conflict, Iraq made
extensive use of mustard against Iran. Popular magazines and television
brought the horrors of chemical warfare to the public's attention with
graphic images of badly burned Iranian casualties.

When, in the fall of 1990, the U.S. military joined the United Nations
forces in preparation to liberate Kuwait, one of the major concerns was
the threat that Iraq would again use mustard. Fortunately, chemical
agents were not used in the short ground phase of the Persian Gulf War;
however, the threat of an enemy's using chemical weapons against U.S.
forces is ever present. Although mustard is the most important vesicant
militarily, the vesicant category includes other agents, such as
Lewisite and phosgene oxime (See table below). The clinical differences
among the vesicants discussed in this chapter are shown in the table
below.

  ------------------------- ------------------------ ------------ ------------------------ --------------- ------------------------
  **CHEMICAL, PHYSICAL,                                                                                    
  ENVIRONMENTAL, AND                                                                                       
  BIOLOGICAL PROPERTIES OF                                                                                 
  VESICATING AGENTS**                                                                                      

  **Properties         **   **Impure Sulfur Mustard               **Distilled Sulfur       **Phosgene      **Lewisite(L)**
                            (H)**                                 Mustard (HD)**           Oxime (CX)**    

  **Chemical and Physical**                                                                                

     Boiling Point          Varies                                227°C                    128°C           190°C

     Vapor Pressure         Depends on purity                     0.072 mm Hg at 20°C      11.2 mm Hg at   0.39 mm Hg at 20°C
                                                                                           25°C (solid)\   
                                                                                           13 mm Hg at     
                                                                                           40°C (liquid)   

     Density:                                                                                              

       Vapor                approx 5.5                            5.4                      \<3.9?          7.1

       Liquid               approx 1.24 g/mL at 25°C              1.27 g/mL at 20°C        ND              1.89 g/mL at 20°C

       Solid                NA                                    Crystal: 1.37 g/mL at    NA              NA
                                                                  20°C                                     

     Volatility             approx 920 mg/m^3^ at                 610 mg/m^3^ at 20^o^C    1,800 mg/m^3^   4,480 mg/m^3^ at 20^o^C
                            25^o^C                                                         at 20^o^C       

     Appearance             Pale yellow to dark                   Pale yellow to dark      Colorless,      Pure: colorless, oily
                            brown liquid                          brown liquid             crystalline     liquid\
                                                                                           solid or a      As agent: amber to dark
                                                                                           liquid          brown liquid

     Odor                   Garlic or mustard                     Garlic or mustard        Intense,        Geranium
                                                                                           irritating      

     Solubility:                                                                                           

       In Water             0.092 g/100 g at 22°C                 0.092 g/100 g at 22°C    70%             Slight

       In Other\            Complete in CCl~4~,                   Complete in CCl~4~,      Very soluble in Soluble in all common
        Solvents            acetone, other organic                acetone, other organic   most organic    organic solvents
                            solvents                              solvents                 solvents        

  **Environmental and                                                                                      
  Biological**                                                                                             

     Detection              Liquid: M8 paper                      Liquid: M8 paper         M256A1 ticket   Vapor, M256A1 ticket or
                                                                                           or card         card, ICAD

                            Vapor: CAM                            Vapor: CAM, M256A1 kit,                   
                                                                  ICAD                                     

     Persistence:                                                                                          

       In Soil              Persistent                            2 wk--3 y                2 h             Days

       On Materiel          Temperature-dependent;                Temperature-dependent;   Nonpersistent   Temperature-dependent;
                            hours to days                         hours to days                            hours to days

     Skin                   M2581 kit\                            M258A1 kit\              Water           Dilute hypochlorite\
     Decontamination        Dilute hypochlorite\                  Dilute hypochlorite\                     M258A1 kit\
                            Water\                                Soap and water\                          Water\
                            M291 kit                              M291 kit                                 M291 kit

     Biologically Effective                                                                                
  Amount:                                                                                                  

       Vapor                LC*t*~50~: 1,500                      LC*t*~50~: 1,500         Minimum         Eye: \<30\
     (mg•min/m^3^)                                                (inhaled)\               effective Ct:   Skin: approx 200\
                                                                  10,000 (masked)          approx 300;\    LC*t*~50~: 1,200--1,500
                                                                                           LC*t* ~50~:     (inhaled)\
                                                                                           3,200           100,000 (masked)
                                                                                           (estimate)      

       Liquid               LD~50~ : approx 100                   LD~50~ : 100 mg/kg       No estimate     40--50 mg/kg
                            mg/kg                                                                          

  CAM: chemical agent                                                                                      
  monitor\                                                                                                 
  ICAD: individual chemical                                                                                
  agent detector\                                                                                          
  LD~50~: dose that is                                                                                     
  lethal to 50% of the                                                                                     
  exposed population                                                                                       
  (liquid, solid)\                                                                                         
  LC*t*~50~: (concentration                                                                                
  • time of exposure) that                                                                                 
  is lethal to 50% of the                                                                                  
  exposed population                                                                                       
  (vapor, aerosol)\                                                                                        
  NA: not applicable\                                                                                      
  ND: not determined                                                                                       

  CLINICAL DIFFERENCES                                                                                     
  AMONG VESICANTS                                                                                          

                            **Onset**                                                                      

  **Chemical Agent**        **Pain**                 **Tissue     **Blister**                              
                                                     Damage**                                              

                                                                                                           

  Mustard                   Hours later              Immediate;   Fluid filled                             
                                                     onset of                                              
                                                     clinical                                              
                                                     effects is                                            
                                                     hours later                                           

  Lewisite                  Immediate                Seconds to   Fluid filled                             
                                                     minutes                                               

  Phosgene Oxime            Immediate                Seconds      Solid wheal                              

                                                                                                           

                                                                                                           
  ------------------------- ------------------------ ------------ ------------------------ --------------- ------------------------

There are two types of mustard: sulfur mustard and nitrogen mustard

A second group of vesicants is the arsenicals. The major compound in
this group is Lewisite. It was synthesized and developed in the United
States during the late stages of World War I and was manufactured for
battlefield use. The shipment of Lewisite was on its way to Europe when
the war ended, so it was destroyed at sea. There are no data on Lewisite
from battlefield use. Lewisite has some advantages and disadvantages
over mustard that are discussed below.

The third compound considered to be a vesicant by the U.S. military is
phosgene oxime. This is not a true vesicant because, unlike mustard and
Lewisite, it does not produce fluid-filled blisters; rather, it produces
solid lesions resembling urticaria. There has been no verified
battlefield use of this compound, and there has been little study of it
in the western world.

MUSTARD

     

Mustard \[bis-(2-chloroethyl) sulfide; also called 2,2\'-dichlorethyl
sulfide; is one of the two most important known chemical agents (the
group of nerve agents is the other). Although mustard was introduced
late in World War I (July 1917), it caused more chemical casualties than
all the other agents combined: chlorine, phosgene, and cyanogen
chloride.

While lethality from mustard exposure was low, casualties filled the
medical facilities. Despite 75 years of research, there is still no
antidote for mustard. This fact is especially crucial when we consider
that probably at least a dozen countries have mustard in their arsenals
today. Allegedly, mustard received its name from its smell or taste
(onion, garlic, mustard) or its color (which varies from yellow, to
light tan, to dark brown).

Properties\
     

Mustard is an oily liquid and is generally regarded as a "persistent"
chemical agent because of its low volatility. In cool weather there is
little vapor; however, mustard's evaporation increases as the
temperature increases. At higher temperatures, such as those in the
Middle East during the hot season, 38°C to 49°C (100°F--120°F), mustard
vapor becomes a major hazard

Toxicity\
     

For liquid mustard on the skin, the dose that is lethal to 50% of the
exposed population (LD~50~) is about 100 mg/kg, or about 7.0 g for a
person weighing 70 kg. This is about 1.0 to 1.5 teaspoons of liquid;
this amount will cover about 25% of the body surface area. An area of
erythema with or without blisters caused by liquid mustard that covers
this or a larger area of skin suggests that the recipient has received a
lethal amount of mustard. A 10-µg droplet will produce vesication.\
     

On the other hand, exposure to a vapor or aerosol in air is usually
described as the product of the concentration (C, expressed as
milligrams per cubic meter) and the time the exposure lasted (*t*,
expressed as minutes):

C*t* = mg•min/m^3^

Thus, the effect produced by an aerosol or vapor exposure to 0.05
mg/m^3^ • 100 minutes is equal to the effect produced by an exposure to
5 mg/m^3^ • 1 minute; in either case, C*t* = 5 mg•min/m^3^. The
threshold for skin damage is highly dependent on skin site, heat,
sweating, and other factors (localized sweating will lower the threshold
on the portion of the skin that is sweating^30^); the threshold is
generally in the range of 200 to 2,000 mg•min/m^3^.

[Biochemical Mechanisms of Injury]{.underline}

Although mustard has been considered a major chemical weapon for 75
years, there is still no clear understanding of its biochemical
mechanism of action; therefore, no specific therapy for its effects
exists

Clinical Effects\
     

The organs most commonly affected by mustard are the skin, eyes, and
airways (see table): the organs with which mustard comes in direct
contact. After a significant amount of mustard has been absorbed through
the skin or inhaled, the hemopoietic system, gastrointestinal tract, and
CNS are also damaged. Mustard may also affect other organs but rarely do
these produce clinical effects.

Skin\
     

The threshold amount of mustard vapor required to produce a skin lesion
(erythema) is a C*t* of about 200 mg•min/m^3^ . This varies greatly
depending on a number of factors, including temperature, humidity,
moisture on the skin, and exposure site on the body. Warm, moist areas
with thin skin such as the perineum, external genitalia, axillae,
antecubital fossae, and neck are much more sensitive. The mildest and
earliest form of visible skin injury is erythema, which resembles
sunburn.

It is usually accompanied by pruritus, burning, or stinging. After a
small exposure, this might be the extent of the lesion. More commonly,
small vesicles will develop within or on the periphery of the
erythematous areas (like a string of pearls); these vesicles will later
coalesce to form larger blisters. Erythema begins to appear 1 to 24
hours after the skin is exposed to mustard, although onset can be later.
The effects from liquid mustard appear more rapidly than the effects
from mustard vapor. Characteristically, the onset of erythema is about 4
to 8 hours after mustard exposure. Vesication begins about 2 to 18 hours
later and may not be complete for several days.

The typical bulla is dome-shaped, thin-walled, superficial, translucent,
yellowish, and surrounded by erythema. Generally, it is 0.5 to 5.0 cm in
diameter, although it can be larger (Figure 7-4). The blister fluid is
initially thin and clear or slightly straw-colored; later it turns
yellowish and tends to coagulate. The blister fluid does not contain
mustard and is not itself a vesicant. Vapor injury is generally a first-
or second-degree burn; liquid mustard may produce deeper damage
comparable to a third-degree burn.\
     

After exposure to extremely high doses, such as those resulting from
exposure to liquid mustard, lesions may be characterized by a central
zone of coagulation necrosis, with blister formation at the periphery.
These lesions are more severe, take longer to heal, and are more prone
to secondary infection.^29^ Necrosis and secondary inflammation, which
were the expected prominent pathophysiological characteristics of a deep
burn in the preantibiotic era, are evident.

     

*EYE:*

The eye is the organ most sensitive to mustard. The C*t* required to
produce an eye lesion under field conditions is 12 to 70 mg•min/m^3^ .
The effective C*t* for conjunctivitis, or slightly more severe damage,
was just under 10 mg/m^3^ in 13 subjects; several subjects had lesions
at C*t*s of 4.8 to 5.8 mg•min/m . One subject had no symptoms after
several hours; however, by 12 hours after the exposure, marked
blepharospasm and irritation were apparent.\
     

Generally, the asymptomatic period varies with the concentration of
mustard vapor (or the amount of liquid) and individual sensitivity. The
latent period for eye damage is shorter than that for skin damage. Eye
irritation within minutes after exposure has been reported but some
reports speculate that the irritation might have been due to other
causes. Corneal damage consists of edema with clouding (which affects
vision), swelling, and infiltration of polymorphonuclear cells. Clinical
improvement occurs after approximately 7 days with subsiding edema.
Corneal vascularization (pannus development, which causes corneal
opacity) with secondary edema may last for weeks. Vision will be lost if
the pannus covers the visual axis. Severe effects from mustard exposure
may be followed by scarring between the iris and the lens, which
restricts pupillary motions.

The most severe eye damage is caused by liquid mustard, which may be
delivered by an airborne droplet or by self-contamination Symptoms may
become evident within minutes after exposure. Severe corneal damage with
possible perforation of the cornea can occur after extensive eye
exposure to liquid mustard. The patient may lose his vision or even his
eye from panophthalmitis, particularly if drainage of the infection is
blocked, such as by adherent lids. Miosis sometimes occurs, probably due
to the cholinergic activity of mustard and predisposes the individual to
glaucoma. Mustard initially causes vasodilation and increased vascular
permeability in the conjunctiva, which lead to progressive edema.
Secretion of mucus occurs within minutes of exposure

*Airways*:

Mustard produces dose-dependent damage to the mucosa of the respiratory
tract, beginning with the upper airways and descending to the lower
airways as the amount of mustard increases. The inflammatory reaction
varies from mild to severe, with necrosis of the epithelium. When fully
developed, the injury is characterized by an acute inflammation of the
upper and lower airways, with discharge in the upper airway,
inflammatory exudate, and pseudomembrane formation in the
tracheobronchial tree. The injury develops slowly, intensifying over a
period of days.

After a low-dose, single exposure, casualties might notice a variety of
catarrhal symptoms accompanied by a dry cough; on examination, they
might have pharyngeal and laryngeal erythema. Hoarseness is almost
always present, and the patient often presents with a barking cough.
Typically, this hoarseness may progress to a toneless voice, which
appears to be particularly characteristic of mustard exposure. Patients
characteristically note a sense of chest oppression. All of these
complaints typically commence approximately 4 to 6 hours after exposure,
with sinus tenderness appearing hours later. Vapor concentrations
sufficient to cause these symptoms typically produce reddened eyes,
photophobia, lacrimation, and blepharospasm. There may be loss of taste
and smell.

Patients occasionally experience mild epistaxis and sore throat. In
individuals with abnormal sensitivity (smokers and patients with
irritable airways or acute viral illness), prominent wheezing and
dyspnea may be present.\
     

Exposures to higher concentrations of vapor result in an earlier onset
and greater severity of the above effects. Hoarseness rapidly progresses
to aphonia. Severe tachypnea and early radiological infiltrates may
appear. More-intense respiratory exposures create necrotic changes in
the respiratory epithelium that result in epithelial sloughing and
pseudomembrane formation. There may be substantial airway occlusion from
the inflammatory debris or from pseudomembranes, which can obstruct the
upper airways as they form or can break off and obstruct lower airways.\
     

The initial bronchitis is nonbacterial. White blood cell elevation,
fever, pulmonary infiltrates seen on radiograph, and colored secretions
may all be present to mimic the changes of a bacterial process. This
process is sterile during the first 3 to 4 days; bacterial
superinfection occurs in about 4 to 6 days. Careful assessment of the
sputum by Gram's stain and culture should be done daily.

Gastrointestinal Tract\
     

Nausea and vomiting are common within the first few hours after mustard
exposure, beginning at about the time the initial lesions become
apparent. The early nausea and vomiting, which are generally transient
and not severe, may be caused by the cholinergic activity of mustard by
a general reaction to injury, or because of the unpleasant odor. Nausea
and vomiting that occur days later are probably due to the generalized
cytotoxic activity of mustard and damage to the mucosa of the
gastrointestinal tract.\
     

Diarrhea is not common, and gastrointestinal bleeding seems to be even
less common. Animals that were given approximately 1 LD~50~ of mustard
(administered either intravenously or subcutaneously) had profuse
diarrhea, which was frequently bloody; however, this was unusual when
mustard was administered percutaneously or by inhalation. (Diarrhea was
more common after nitrogen mustard)\
     

Diarrhea and gastrointestinal bleeding do not seem to be common in
humans. Of 107 autopsied cases, none had experienced diarrhea; and in
the 57 cases in which the gastrointestinal tract was thoroughly
examined, none had significant lesions. In several reported series of
Iranian casualties, totaling about 700 casualties, few had diarrhea and
only a very few who died had bloody diarrhea. Constipation was noted in
casualties with mild exposure.

Central Nervous System\
     

Although the effects are not usually prominent clinically, mustard
affects the CNS. Reports of World War I casualties described apathy,
depression, intellectual dullness, and languor. Of 233 Iranian
casualties sent to various western European hospitals for medical care
during the Iran--Iraq War, about 83% had CNS complaints; most
complaints, however, were mild and nonspecific.\
     

Large amounts of mustard administered to animals (via the inhalational,
intravenous, subcutaneous, or intramuscular routes) caused
hyperexcitability, abnormal muscular movements, convulsions, and other
neurological manifestations. Animals died a "neurological death" a few
hours after receiving a lethal amount of mustard.^9^ Autopsies of these
animals disclosed few abnormalities.\
     

After three children were accidentally exposed to a large amount of
mustard, two of them presented with abnormal muscular activity, and the
third alternated between coma and agitation. The first two children died
3 to 4 hours after exposure, possibly from neurological mechanisms.
Whether these CNS manifestations are from a cholinergic activity of
mustard or from other mechanisms is unknown

Death\
     

Most casualties die of massive pulmonary damage complicated by infection
(bronchopneumonia) and sepsis (resulting from loss of the immune
mechanism). When exposure is not by inhalation, the mechanism of death
is less clear. In studies with animals in which mustard was administered
via routes other than inhalational, the animals died from 3 to 7 days
after the exposure; they had no signs of pulmonary damage and often had
no signs of sepsis. The mechanism of death was not clear, but autopsy
findings resembled those seen after radiation^1^ (Mustard is considered
to be a radio-mimetic because it causes tissue damage similar to that
seen after radiation.)

Diagnosis\
     

The differential diagnosis of mustard casualties after a known chemical
attack is not difficult. The history of a chemical attack is useful,
particularly if the chemical agent is known. Simply questioning the
casualty about when the pain started---whether it started immediately
after the exposure or hours later---is very helpful. Whereas pain from
Lewisite (the other vesicant that causes blistering) begins seconds to
minutes after exposure, pain from mustard does not begin until the
lesion develops hours later.\
     

Blisters appearing simultaneously in a large number of people, in the
absence of a known chemical attack, should alert medical personnel to
search the area with a chemical agent detector. Because naturally
occurring organisms, both plants and insects, cause similar blisters,
the appearance of one or more blisters in only a single individual makes
exposure to a natural substance the more likely possibility

Laboratory Tests\
     

There is no specific laboratory test for mustard exposure. As
inflammation and infection occur, signs of these (eg, fever and
leukocytosis) will develop.

Patient Management\
     

[*Decontamination within 1 or 2 minutes after exposure is the only
effective means of preventing or decreasing tissue damage from
mustard*.]{.underline} This decontamination is not done by medical
personnel. In the military setting, It must be performed by the soldier
himself immediately after the exposure. Generally, the soldier/patient
will not seek medical help until the lesions develop, hours later. By
that time, skin decontamination will not help the soldier because
mustard fixes to the skin within minutes, and tissue damage will already
have occurred.\
     

If any mustard remains on the skin, late decontamination will prevent
its spreading to other areas of the skin; but after several hours,
spreading will probably already have occurred. Decontamination will,
however, prevent mustard from spreading to personnel who handle the
casualty.\
     

By the time a skin lesion has developed, most of the mustard will
already have been absorbed (and the chemical agent will have fixed to
tissue); and, unless the site was occluded, the remaining unabsorbed
agent will have evaporated. Mustard droplets disappear from the surface
of the eye very quickly, so late flushing of the eye will be of no
benefit, either.\
     

However, all chemical agent casualties must be thoroughly decontaminated
before they enter a clean medical facility. This should be done with the
realization that by the time a contaminated soldier reaches medical
treatment, this decontamination will rarely help the casualty; it does,
however, prevent exposure of medical personnel.\
     

Mustard casualties generally fall into three categories. The first is
the return to duty/work category. These individuals have a small area of
erythema or one or more small blisters on noncritical areas of their
skin; eye irritation or mild conjunctivitis; and/or late-onset, mild
upper respiratory symptoms such as hoarseness or throat irritation and a
hacking cough. If these casualties are seen long after exposure, so that
there is good reason to believe that the lesion will not progress
significantly, they can be given symptomatic therapy and returned to
duty.\
     

The second category includes casualties who appear to have
non--life-threatening injuries but who are unable to return to
work/duty. Casualties with the following conditions must be hospitalized
for further care:

A large area of erythema (with or without blisters),

An extremely painful eye lesion or an eye lesion that hinders vision,
and

A respiratory injury with moderate symptoms that include a productive
cough and dyspnea.

Some of these conditions may develop into life-threatening injuries, and
these categories, therefore, should be used only to assess a casualty's
*presenting* condition. For example, an area of erythema caused by
liquid mustard that covers 50% or more of the body surface area suggests
that the individual was exposed to 2 LD~50~ of the agent. Likewise,
dyspnea occurring within 4 to 6 hours after the exposure suggests
inhalation of a lethal amount of mustard.\
     

The third category comprises those casualties who appear to have
life-threatening injuries when they first present at an medical
treratment facility. Life-threatening injuries include large skin burns
caused by liquid mustard, and early onset of moderate-to-severe
pulmonary symptoms. Most of the casualties in this category will die
from their injuries.\
     

Many mustard casualties will fall into the first category, the majority
will fall into the second category, and only a very small percentage of
casualties will fall into the third category. Data from World War I, in
which only 3% of mustard injuries were lethal despite the
unsophisticated medical care at that time (eg, no antibiotics), suggest
that most mustard casualties are not severely injured and that most of
them will survive.\
     

Most casualties of mustard exposure will, however, require some form of
medical care---from a few days to many weeks. Eye care and airway care
will promote healing within weeks; skin lesions take the longest to heal
and may necessitate hospitalization for months.^16^ Casualties with
mild-to-moderate mustard damage will need supportive care. Pain control
is extremely important. Fluids and electrolytes should be carefully
monitored. Although there is not a great deal of fluid loss from mustard
burns (compared with thermal burns), a casualty will probably be
dehydrated when he enters the MTF; and a sick patient usually does not
eat or drink enough. Parenteral fluid supplements and vitamins may be of
benefit. Casualties who have lost their eyesight because of mustard
exposure should be reassured that they will recover their vision.\
     

Casualties who do become critically ill from their exposure to mustard
will present with large areas of burns, major pulmonary damage, and
immunosuppression. Some of the casualties may die from sepsis or from
overwhelming damage to the airways and lungs. Medical officers should
remember, however, that even with the limited medical care available in
World War I, very few deaths were caused by mustard exposure.\
     

Despite the attention given to mustard since World War I, research has
not produced an antidote. Because casualties have been managed in
different eras and, more recently, in different medical centers, there
have been no standard methods of casualty management, nor have there
been any controlled studies of one method compared to another. The
following advice describes care by organ system. Most casualties will
have more than one system involved, and many of these casualties will be
dehydrated and have other injuries as well.

Skin\
     

The general principles for managing a mustard skin lesion are to keep
the casualty comfortable, keep the lesion clean, and prevent infection.
The burning and itching associated with erythema can be relieved by
calamine or another soothing lotion or cream such as 0.25% camphor and
menthol. These lesions should heal without complication.\
     

Small blisters (\< 1 cm) should be left alone; however, the surrounding
area should be cleaned (irrigated) at least once daily. An application
of a topical antibiotic should immediately be applied to the blisters
and the surrounding area. The blisters and the surrounding area do not
need to be bandaged unless the casualty will be returning to duty.\
     

Larger blisters (\> 1 cm) should be unroofed and the underlying area
should be irrigated (2 to 4 times daily) with saline, sterile water, or
clean soapy water, and liberally covered (to a depth of 1 mm) with a
topical antibiotic cream or ointment (silver sulfadiazine, mafenide
acetate, bacitracin, or Neosporin. Dakin's solution (hypochlorite) was
used on patients in World War I and during the Iran--Iraq War as an
irrigating solution. It does not detoxify the chemical agent in the
skin, as was once thought; however, it is an adequate antiseptic and
keeps the area clean. Multiple or large areas of vesication necessitate
hospitalization for frequent and careful cleaning; a whirlpool bath is a
useful means of irrigation. In general, care of mustard skin lesions is
the same as that of second-degree thermal burns, although the
pathophysiology is different.\
     

Systemic analgesics should be given liberally, particularly before
manipulation of the burned area. Systemic antipruritics (eg,
trimeprazine) may be useful. Fluid balance and electrolytes should be
monitored. Fluids are lost into the edematous areas, but fluid
replacement is of less magnitude than that required for thermal burns.
Medical personnel accustomed to treating patients with thermal burns
must resist the temptation to overhydrate mustard burn patients, which
could lead to untoward consequences such as pulmonary edema.\
     

Skin healing can take weeks to months but usually is complete, although
pigment changes may persist. Scarring is proportional to the depth of
the burn. Skin grafting is rarely needed, but it was successful in one
person who had a deep burn.

*EYES:*

The basic principles of eye care are to prevent infection and to prevent
scarring. Although it is unlikely that mustard will still be in the eye
by the time the casualty is seen, the eye should be irrigated to remove
any possible chemical agent that might be on the lashes and to remove
any inflammatory debris that might be on the surface of the eye. Mild
lesions (eg, conjunctivitis) can be treated three to four times daily
with a soothing eye solution. Casualties with more-severe eye lesions
should be hospitalized. Care for these patients should consist of at
least one daily irrigation, preferably more, to remove inflammatory
debris; administration of a topical antibiotic three to four times
daily; and administration of a topical mydriatic (atropine or
homatropine) as needed to keep the pupil dilated (to prevent later
synechiae formation). Vaseline or a similar material should be applied
to the lid edges to prevent them from adhering to each other; this
reduces later scarring and also keeps a path open for possible infection
to drain. Topical analgesics may be used for the initial examination;
however, they should not be used routinely as they might cause corneal
damage. Pain should be controlled with systemic analgesics. The benefit
of topical steroids is unknown; however, some ophthalmologists feel that
topical steroids may be helpful if used within the first 48 hours after
the exposure (but not after that). In any case, an ophthalmologist
should be consulted as early as possible on this and other questions of
care. Keeping the casualty in a dim room or providing sunglasses will
reduce the discomfort from photophophobia. The transient loss of vision
is usually the result of edema of the lids and other structures and not
due to corneal damage. Medical personnel should assure the patient that
vision will return. Recovery may be within days for milder injuries,
while those with severe damage will take approximately a month or longer
to recover.

*Airways*:

The therapeutic goal in a casualty with mild airway effects (eg,
irritation of the throat, nonproductive cough) is to keep him
comfortable. In a casualty with severe effects, the goal is to maintain
adequate oxygenation. Antitussives and demulcents are helpful for
persistent, severe, nonproductive cough. Steam inhalation might also be
useful.\
     

Hypoxia is generally secondary to the abnormalities in the
ventilation--perfusion ratio caused by toxic bronchitis. Mucosal
sloughing further complicates this abnormality. Underlying irritable
airways disease (hyperreactive airways) is easily triggered;
consequently, therapy with bronchodilators may be necessary. Casualties
with hyperreactive airways may benefit from steroid treatment with
careful attention to the added risk of superinfection. Oxygen
supplementation may be necessary for prolonged periods; this will
depend, primarily, on the intensity of mustard exposure and the presence
of any underlying pulmonary disorder.\
     

Hypercarbia may result from a previously unrecognized hyperreactive
airways state or from abnormal central sensitivity to carbon dioxide,
complicated by increased work of respiration (this state may result from
bronchospasm). Bronchodilators are acceptable initial therapy.
Ventilatory support may be necessary to assist adequate carbon dioxide
clearance. The use of certain antibiotic skin creams (such as mafenide
acetate) to treat skin lesions may complicate the acid--base status of
the individual by inducing a metabolic acidosis. Steroids should be
considered if a prior history of asthma or hyperreactive airways disease
is obtained.\
     

Initially, the bronchitis resulting from mustard exposure is
nonbacterial. White blood cell elevation, fever, pulmonary infiltrates
on a chest radiograph, and colored sputum may all be present; however,
careful assessment of sputum by Gram's stain and culture demonstrates
that bacterial superinfection typically is not present during the first
3 to 4 days. Antibiotic therapy should be withheld until the identity of
a specific organism becomes available. Of particular importance is the
patient's immune status, which may be compromised by a progressive
leukopenia beginning about day 4 or 5. The development of leukopenia
signals severe immune system dysfunction; massive medical support may
become necessary for these patients. In these instances, sepsis
typically supervenes, and despite combination antibiotic therapy, death
commonly occurs.\
     

A casualty with severe pulmonary signs should be intubated early, before
laryngeal spasm makes it difficult or impossible. Intubation assists in
ventilation and also allows suction of necrotic and inflammatory debris.
Bronchoscopy may be necessary to remove intact pseudomembranes or
fragments of pseudomembranes; one of the Iranian casualties treated in
western European hospitals during the Iran--Iraq War died of tracheal
obstruction by a pseudomembrane. Early use of positive end-expiratory
pressure or continuous positive airway pressure may be beneficial. The
need for continuous ventilatory support suggests a bad prognosis; of the
Iranian casualties treated in western European hospitals who needed
assisted ventilation, 87% died.

Gastrointestinal Tract\
     

The initial nausea and vomiting are rarely severe and can usually be
relieved with atropine or common antiemetics. Later vomiting and
diarrhea are usually indicative of systemic cytotoxicity and require
fluid replacement.

Bone Marrow\
     

Suppression of the hemopoietic elements cannot be predicted from the
extent of skin lesions (eg, the lesions might be from vapor and
therefore superficial, but significant amounts of mustard may have been
absorbed by inhalation). Frequent counts of the formed blood elements
must be done on a casualty who has significant skin lesions or airway
damage. Mustard destroys the precursor cells, and cell elements in the
blood are depressed.

Because white blood cells have the shortest life span, their numbers
decrease first; the red blood cells and the thrombocytes soon follow if
the casualty lives long enough or does not start to recover. Typically,
leukopenia begins at day 3 through day 5 after the exposure, and reaches
a nadir in 3 to 6, or 7 to 9, days. Leukopenia with a cell count lower
than 200 cells/mm^3^ usually signifies a bad prognosis, as does a rapid
drop in the cell count; for example, from 30,000 to 15,000 cells/mm^3^
in a day. Medical personnel should institute therapy that sterilizes the
gut with nonabsorbable antibiotics at the onset of leukopenia. Cellular
replacement, either peripheral or marrow, may also be successful.

Other Treatment Modalities\
     

A variety of antiinflammatory and sulfhydryl-scavenging agents (such as
promethazine, vitamin E, heparin, and sodium thiosulfate) have been
suggested as therapeutic drugs. Activated charcoal, administered orally,
has been tried with unknown results; however, it may provide some
benefit if given immediately after mustard is ingested. Hemodialysis was
not only without benefit, it appeared to have deleterious effects. This
is not surprising because mustard becomes fixed to tissue within
minutes.

Long-Term Effects\
     

Mustard burns may leave areas of hypopigmentation or hyperpigmentation,
sometimes with scarring. Individuals who survive an acute, single
mustard exposure with few or no systemic or infectious complications
appear to recover fully. Previous cardiopulmonary disorders, severe or
inadequately treated bronchitis or pneumonitis, a prior history of
smoking, and advanced age all appear to contribute to long-term chronic
bronchitis; there is no definitive way to determine whether these
conditions are the result of aging, smoking, or a previous mustard
exposure. Casualties with severe airway lesions may later have
postrecovery scarring and stenosis, which predisposes the individual to
bronchiectasis and recurrent pneumonia. An important late sequela of
mustard inhalation is a tracheal/bronchial stenosis that necessitates
bronchoscopy and other procedures Mustard has been reported to create a
long-term sensitivity to smoke, dust, and similar airborne particles,
probably as a result of clinically inapparent broncho-spasm.

LEWISITE

Lewisite (ß-chlorovinyldichloroarsine) is an arsenical vesicant but of
only secondary importance in the vesicant group of agents. It was
synthesized in the early 20th century and has seen little or no
battlefield use. Lewisite is similar to mustard in that it damages the
skin, eyes, and airways; however, it differs from mustard because its
clinical effects appear within seconds of exposure. An antidote, British
anti-Lewisite (BAL), can ameliorate the effects of Lewisite if used soon
after exposure. Lewisite has some advantages over mustard but also some
disadvantages.

Properties\
     

Pure Lewisite is an oily, colorless liquid, and impure Lewisite is amber
to black. It has a characteristic odor of geraniums. Lewisite is much
more volatile and persistent in colder climates than mustard. Lewisite
remains fluid at lower temperatures, which makes it perfect for winter
dispersal. Lewisite hydrolyzes rapidly, and, on a humid day, maintaining
a biologically active concentration of vapor may be difficult.

Toxicity\
     

The toxicity of Lewisite vapor is very similar to that of mustard vapor;
the LC*t*~50~ (the concentration • time that is lethal to 50% of the
exposed population) by inhalation is estimated to be about 1,500
mg•min/m^3^, and the LC*t*~50~ for eye and airway damage are about 150
and 500 mg•min/m^3^, respectively. Vesication is caused by 14 µg of
liquid, and the LD~50~ of liquid on the skin is about 30 mg/kg. Blister
fluid from a Lewisite-caused blister is nonirritating, but it does
contain 0.8 to 1.3 mg/mL of arsenic.

Biochemical Mechanisms of Injury\
     

Lewisite shares many biochemical mechanisms of injury with the other
arsenical compounds. It inhibits many enzymes: in particular, those with
thiol groups, such as pyruvic oxidase, alcohol dehydrogenase, succinic
oxidase, hexokinase, and succinic dehydrogenase As is true with mustard,
the exact mechanism by which Lewisite damages cells has not been
completely defined. Inactivation of carbohydrate metabolism, primarily
because of inhibition of the pyruvate dehydrogenase complex, is thought
to be a key factor.

Clinical Effects\
     

Lewisite damages skin, eyes, and airways by direct contact and has
systemic effects after absorption. Unlike mustard, it does not produce
immunosuppression. Data on human exposure are few. Lewisite was applied
to human skin in a few studies; however, most information on its
clinical effects is based on animal studies.

Skin\
 

Lewisite liquid or vapor produces pain or irritation within seconds to
minutes after contact. Pain caused by a Lewisite lesion is much less
severe than that caused by mustard lesions, and it diminishes after
blisters form.\
     

Erythema is evident within 15 to 30 minutes after exposure to liquid
Lewisite, and blisters start within several hours; these times are
somewhat longer after vapor exposure. Lewisite is absorbed by the skin
within 3 to 5 minutes (compared with 20--30 min for an equal amount of
mustard) and spreads over a wider area than the same amount of mustard.
The Lewisite blister begins as a small blister in the center of the
erythematous area and expands to include the entire inflamed area,
whereas vesication from mustard begins as a "string of pearls" at the
periphery of the lesion, small blisters that eventually merge. Other
differences between the lesions produced by these two chemical agents
are

the inflammatory reaction from Lewisite generally occurs much faster,

the lesions from Lewisite heal much faster,

secondary infection is less common after Lewisite exposure, and

subsequent pigmentation is likewise less common.

Eyes     

A person is less likely to receive severe eye injury from Lewisite vapor
than from mustard vapor because the immediate irritation and pain caused
by Lewisite will produce blepharospasm, effectively preventing further
exposure. A small droplet of Lewisite (0.001 mL) can cause perforation
and loss of an eye.\
     

In tests performed on rabbits, Lewisite caused almost immediate edema of
the lids, conjunctiva, and cornea (which was maximal after the lid edema
had subsided) and early and severe involvement of the iris and ciliary
body, followed by gradual depigmentation and shrinkage of the iris
stroma. Miosis appeared early. In this same study, miosis was not noted
after mustard exposure. No long-term effects of Lewisite were noted,
such as the delayed keratitis seen after mustard.\
\
Airways\
     

Lewisite vapor is extremely irritating to the nose and lower airways,
causing individuals exposed to it to seek immediate protection, thus
limiting further exposure. The airway lesion of Lewisite is very similar
to the lesion caused by mustard exposure except that the Lewisite vapor
is extremely irritating to the mucous membranes. In large amounts,
Lewisite causes pulmonary edema.\
     

After exposure to Lewisite, dogs exhibited massive nasal secretions,
lacrimation, retching, vomiting, and labored respiration. These symptoms
worsened until death finally occurred. On autopsy, the lungs were
edematous, and a pseudomembrane often extended from the nostrils to the
bronchi. Tracheal and bronchial mucosa was destroyed and the submucosa
was congested and edematous. Bronchopneumonia was commonly mixed with
edema.\
\
**Other Effects**\
     

"Lewisite shock" is seen after exposure to large amounts of Lewisite.
This condition is the result of protein and plasma leakage from the
capillaries and subsequent hemoconcentration and hypotension.\
     

A small amount of Lewisite on the skin will cause local edema because of
the effects of this agent on local capillaries. With a large amount of
Lewisite, the pulmonary capillaries are also affected (because they are
more sensitive to Lewisite than other capillaries or because absorbed
Lewisite reaches the lungs before it reaches the systemic circulation);
there is edema at the site of exposure and pulmonary edema. With even
larger amounts of Lewisite, all capillaries are affected, and proteins
and plasma leak from the circulation into the periphery. Even after
small amounts of Lewisite, the fluid loss can be sufficient to cause
diminution of renal function and hypotension.\
     

Arsines are known to cause hemolytic anemia, but there is little mention
of this in reports on Lewisite exposure. A "true or hemolytic anemia"
was noted with Lewisite shock.

Diagnosis

Lewisite exposure can be distinguished from mustard exposure by the
history of pain on contact with the agent. Phosgene oxime also causes
pain on contact, but phosgene oxime does not produce a liquid-filled
blister. If a single individual has an isolated blister, other plant or
animal causes of vesication should be sought. There is no specific
laboratory test for Lewisite. Urinary arsenic excretion might be helpful
in identifying possible exposure to Lewisite, however.\
\
Patient Management\
     

Medical personnel should follow the same principles for managing
Lewisite skin, eye, and airway lesions that they follow for managing
mustard lesions. A specific antidote, BAL (dimercaprol), will prevent or
greatly decrease the severity of skin and eye lesions if applied
topically within minutes after the exposure and decontamination
(however, preparations of BAL for use in the eyes and on the skin are no
longer available). Given intramuscularly, BAL will reduce the severity
of systemic effects. BAL binds to the arsenic of Lewisite more strongly
than do tissue enzymes, thereby displacing Lewisite from the cellular
receptor sites.\
     

BAL reduced the mortality in dogs when it was given within 100 minutes
after they had inhaled a lethal amount of Lewisite. Burns of the eyes
from Lewisite can be prevented if BAL is applied within 2 to 5 minutes
of exposure; when it was applied within an hour after exposure, BAL
prevented vesication in humans. BAL has some unpleasant side effects,
including hypertension and tachycardia; the user should read the package
insert.\
\
Long-Term Effects\
     

There are no data on human exposure from which to predict the long-term
effects from Lewisite. There is no substantial evidence to suggest that
Lewisite is carcinogenic, teratogenic, or mutagenic. The committee
appointed by the National Academy of Science reported a causal
relationship between Lewisite exposure and chronic respiratory diseases,
and also that acute, severe injuries to the eye from Lewisite will
persist.

PHOSGENE OXIME

Phosgene oxime (CX) is not a true vesicant because it does not produce
vesicles. Instead, phosgene oxime is an urticant or nettle agent: it
causes erythema, wheals, and urticaria. Its lesions have been compared
with those caused by nettle stings. Because it causes extensive tissue
damage, phosgene oxime has been called a corrosive agent. Phosgene oxime
is not known to have been used on a battlefield, and there is very
little information regarding its effects on humans. This compound must
be distinguished from phosgene (CG), which exerts its effects on the
alveolar--capillary membrane.

Biochemical Mechanisms of Injury\
     

Phosgene oxime is the least well studied of the chemical agents
discussed in this volume, and its mechanism of action is unknown. It
might produce biological damage because of the necrotizing effects of
the chlorine, because of the direct effect of the oxime, or because of
the carbonyl group The skin lesions, in particular, are similar to those
caused by a strong acid. This agent seems to cause its greatest systemic
effects in the first capillary bed it encounters. For example, cutaneous
application or intravenous injection of phosgene oxime causes pulmonary
edema, while injection into the portal vein produces hepatic necrosis
but not pulmonary edema.\
\
Clinical Effects\
Phosgene oxime affects the skin, the eyes, and the lungs. The effects
are almost instantaneous, and it causes more severe tissue damage than
other vesicants. A characteristic of phosgene oxime is the immediate
pain or irritation it produces on the skin, in the eyes, and in the
airways. No other chemical agent produces such an immediately painful
onset that is followed by rapid tissue necrosis.\
\
***Skin***\
Pain occurs immediately on contact with the liquid or solid form of this
agent. Approximately 5 to 20 seconds after solutions containing 8% to
70% phosgene oxime were applied, pain and blanching occurred at the
application site. Following the initial exposure, the site became
grayish with a border of erythema. Within 5 to 30 minutes after the
exposure, edema formed around the edges of the tissue; the tissue later
became necrotic. During the next 30 minutes, a wheal formed but
disappeared overnight. The edema regressed over the following 24 hours
and the original blanched area became pigmented. A dark eschar formed
over the following 7 days; this gradually healed from below by
granulation. The lesion extended into the underlying panniculus and
muscle and was surrounded by an inflammatory reaction. In some subjects,
healing was incomplete 4 to 6 months after exposure. In both animal and
human subjects, the skin had completely absorbed the phosgene oxime
within seconds---by the time pallor appeared.\
\
***Eyes***\
The eye lesions from phosgene oxime are similar to those caused by
Lewisite; these lesions result in immediate pain, conjunctivitis, and
keratitis. An exact description of these effects, however, is not
available.\
\
***Airways***\
The main lesion of phosgene oxime in the lungs is pulmonary edema. This
effect occurs after either inhalation or systemic absorption of the
agent. The pulmonary edema may be accompanied by necrotizing
bronchiolitis and thrombosis of pulmonary venules. A ***large amount of
phosgene oxime on the skin may produce pulmonary edema after a
several-hour delay; pulmonary thromboses are prominent.\
***\
**Patient Management**\
There is no antidote for phosgene oxime, nor is there a recommended
therapeutic regimen. Medical personnel should treat necrotic areas of
the skin the same way other necrotic lesions are treated---by keeping
them clean and avoiding infection. The eye lesions require the same care
as one would supply for damage from a corrosive substance. The pulmonary
lesion, noncardiac pulmonary edema, should be managed as a toxic
inhalational injury.

Decontamination, or self-aid, must be accomplished immediately after
contact because the agent is absorbed from the skin within seconds.

SUMMARY;

The military has considered vesicants to be major chemical warfare
agents since 1917. Mustard, however, is the only vesicant known to have
been used on the battlefield. Mustard and Lewisite, in much smaller
amounts, are known to be in the stockpiles of other countries.

Mustard was used on a large scale in World War I, causing a great number
of casualties; it was also used during the Iran--Iraq War. Data from the
Iran--Iraq War are scanty; however, data from World War I indicate that
more than 95% of mustard casualties survived but most required lengthy
hospitalizations. If mustard is ever used again, military medical
personnel must be prepared to accept and care for large numbers of
casualties, who will require long-term hospitalization.

**CYANIDE POISONING**

Cyanide, long considered a toxic, deadly substance, has been used as a
poison for thousands of years. Although substances containing cyanide
had been used for centuries as poisons, it was not until 1782 that
cyanide itself was identified. It was first isolated by the Swedish
chemist Scheele, who later may have died from cyanide poisoning in a
laboratory accident.It was not highly successful as a chemical warfare
agent in World War I, possibly because of the way it was delivered. The
effects of a high dose of cyanide are quick, and death occurs within
minutes. Antidotes are effective if administered in time.

Cyanide is ubiquitous. It is present in some foods, in the products of
combustion of synthetic materials, and is widely used in industry. Much
of the cyanide used is in the form of salts, such as sodium, potassium,
or calcium cyanide. The cyanides of military interest are the volatile
liquids hydrocyanic acid (hydrogen cyanide, HCN; North American Treaty
Organization \[NATO\] designation: AC) and cyanogen chloride (NATO
designation).

  ------------------- --------------------------- --------------------------
  **CHEMICAL,                                     
  PHYSICAL,                                       
  ENVIRONMENTAL, AND                              
  BIOLOGICAL                                      
  PROPERTIES OF                                   
  CYANIDES**                                      

  **Properties**      **Hydrogen Cyanide (AC)**   **Cyanogen Chloride (CK)**

  Chemical and                                    
  Physical                                        

    Boiling Point     25.7°C                      12.9°C

    Vapor Pressure    740 mm Hg                   1,000 mg Hg

    Density:                                      

      Vapor           0.99 at 20°C                2.1

      Liquid          0.68 g/mL at 25°C           1.18 g/mL at 20°C

      Solid                                       Crystal: 0.93 g/mL at
                                                  -40°C

    Volatility        1.1 x 10^6^ mg/m^3^ at 25°C 2.6 x 10^6^ mg/m^3^ at
                                                  12.9°C

    Appearance\       Gas: Odor of bitter almonds Colorless gas or liquid
    and Odor          or peach kernels            

    Solubility:                                   

      In Water        Complete at 25°C            6.9 g/100 mL at 20°C

      In Other        Completely miscible in      Most organic solvents
  Solvents            almost all organic solvents (mixtures are unstable)

  Environmental and                               
  Biological                                      

    Detection         ICAD; M254A1 kit            M256A1 kit

    Persistency:                                  

      In Soil         \<1 h                       Nonpersistent

      On Materiel     Low                         Nonpersistent

  Skin                Water; soap and water       Water; soap and water
  Decontamination                                 

    Biologically                                  
  Effective Amount:                               

      Vapor\          LC*t*~50~: 2,500--5,000     LC*t*~50~: 11,000
      (mg•min/m^3^)   (time-dependent)            

      Liquid (mg/kg)  LD~50~ (skin): 100          --

  ICAD: individual                                
  chemical agent                                  
  detector\                                       
  LC*t*~50~: the                                  
  vapor or aerosol                                
  exposure                                        
  \[concentration •                               
  time\] that is                                  
  lethal to 50% of                                
  the exposed                                     
  population\                                     
  LD~50~: the dose                                
  that is lethal to                               
  50% of the exposed                              
  population                                      
  ------------------- --------------------------- --------------------------

**Nonmilitary Uses**

There has been little use of cyanide by the military; most of the
information on cyanide poisoning has been from civilian experience in
poisoning, fires, and industrial accidents. Most people probably contact
cyanide in some form almost every day. Hundreds of thousands of tons of
cyanide are manufactured annually in this country. Cyanide is used in
many chemical syntheses, electroplating, plastics processing, gold and
silver extraction, tanning, metallurgy, and as a fumigant. Cyanides are
in some foods, are pyrolysis products of many substances, and have
gained notoriety for their use in executions, homicides, and suicides.\
     

Cyanide poisoning has been reported^8^ from eating chokecherries, bitter
almonds, and apricot pits. In addition, cyanide is found in lima beans
and cassava beans and roots. Cassava is a staple in certain countries
and is blamed for the high incidence of tropical ataxic neuropathy in
those areas.\
     

Combustion of synthetic products that contain carbon and nitrogen, such
as plastics and synthetic fibers, releases cyanide. Cigarette smoke
contains cyanide; the nonsmoker averages 0.06 µg/mL of cyanide in blood,
whereas the smoker has 0.17 µg/mL. The effects of cyanide and of carbon
monoxide, also formed in fires, are additive because they both
contribute to tissue hypoxia by different mechanisms. The two gases are
major causes of combustion-related fatalities. In residential fires,
cyanide poisoning may be more significant than has previously been
appreciated. The short half-life of cyanide in blood contributes to the
low concentrations of cyanide found in fire victims when blood is drawn
after the victims reach the hospital.\
     

From April 1988 through April 1989, a team of French investigators
collected samples---on the scene---from 109 victims of residential fires
in and around Paris, France. The data they gathered were compared with
data from a control group (N = 114) of individuals whose injuries were
not caused by fire.

Blood cyanide concentrations were much higher in the fire victims than
in the control group (Table 10-2), and victims who died had
significantly higher levels (\> 5-fold) than victims who survived.
Contrary to what previous researchers have concluded, the results from
this study "suggest that cyanide poisoning may prevail over carbon
monoxide poisoning as the cause of death in some fire victims".
Therefore, military medical officers need to be aware that victims of
smoke inhalation from fires may be suffering the effects of cyanide
poisoning, and might benefit from early antidotal cyanide therapy.\
     

In addition, cyanide is used by governments, terrorists, corporations,
and individuals to achieve various economic, beneficial, humanitarian,
or harmful ends:

Cyanide is the agent used in "gas chambers," in which a cyanide salt is
dropped into an acid to produce HCN. (These chemicals---an acid and a
cyanide salt---were found in several subway restrooms in Tokyo, Japan,
in the weeks following the release of nerve agents in Tokyo in March
1995.)

It was illicitly placed in bottles of Tylenol in the Chicago area in
1982, killing seven people.

In 1978 near Port Kaituma, Guyana, the followers of the Reverend Jim
Jones drank a grape-flavored drink laced with cyanide, and more than 900
children and adult members of the People's Temple committed mass
suicide.

Furthermore, cyanide is a metabolic product of ingested Laetrile (an
alleged cancer chemotherapeutic compound not available in this country)
and may have been responsible for the deaths of some patients who took
this substance.

     

Chronic ingestion of cyanide in the form of organic cyanogens is a
public health problem in areas such as East Africa and Southeast Asia.
Several common plants contain cyanogenic glycosides; ingestion coupled
with improper processing of such cyanogenic glycosides can result in
death. Consumption of foodstuffs such as cassava result in tropical
neuropathies in Africa^17^ and in other diseases, such as tropical
thyroid disease and tobacco amblyopiopia.

**BIOCHEMICAL BASIS FOR POISONING**\
     

Although cyanide is known to bind and inactivate several enzymes, it is
thought to exert its ultimate lethal effect of histotoxic anoxia by
binding to the active site of cytochrome oxidase, thereby stopping
aerobic cell metabolism after an initial effect on excitable tissue. The
binding to the cytochrome oxidase can occur over minutes. A more rapid
effect appears to occur on neuronal transmission. No antagonists are
known for the latter reaction, although it appears to be feasible to
develop competitive antagonists for cyanide at a cytochrome
oxidase--binding site. Cyanide is readily diffusible through epithelium.
This property contributes to its lethal toxicity after inhalation of
hydrogen cyanide (HCN) gas (the usual route of military exposure),
ingestion of cyanide salts or cyanogens, or percutaneous absorption of
cyanide from high-concentration solutions. Because cyanides are present
at low concentrations in several naturally occurring environmental
sources, it is not surprising that most animals have intrinsic
biochemical pathways for detoxification of the cyanide ion.

The most important route of cyanide excretion is by formation of
thiocyanate (SCN^--^), which is subsequently excreted in the urine.
Thiocyanate possesses a less inherent toxicological hazard than cyanide,
cyanate, or isocyanate. Thiocyanate formation is catalyzed directly by
the enzyme rhodanese (EC 2.8.1.1) and indirectly via a spontaneous
reaction between cyanide and the persulfide sulfur products of the
enzymes 3-mercaptopyruvate sulfurtransferase (EC 2.8.1.2^1^ and
thiosulfate reductase (EC number unassigned) (see Figure 10-1). The
mechanisms of all three enzymes as well as the pharmacokinetics of
thiocyanate formation have been studied. Although 3-mercaptopyruvate
functions to convert cyanide to this cyanate, its instability and
sulf-auto-oxidation at a basic pH may mask this effect. The enzymatic
routes are efficient but have an insufficient capacity for
detoxification in acute poisoning because of lack of sulfur donors. The
mitochondrial sulfurtransferase reactions are exploited by the
administration of sodium thiosulfate (used in therapy and discussed
later in this chapter) in the treatment of acute poisonings. It is still
not known with any certainty, however, what specific endogenous sulfur
sources participate in the formation of thiocyanate from cyanide.\
     

A minor route of metabolism is the oxidation of cyanide to cyanate
(CNO^--^), which occurs via enzymatic and nonenzymatic pathways. The
interaction of cystine and cyanide to form 2-amino thiazoline
4-carboxylic acid and its tautomer accounts for approximately 20% of
cyanide metabolism. This increases with toxic doses of cyanide. However,
the protection conferred by forming cyanate derivatives is limited
because of the cell's inability to utilize oxygen during cyanide
intoxication.\
     

Combined, these metabolic routes detoxify 0.017 mg of cyanide per
kilogram of body weight per minute in the average human. Cyanide is one
of the few chemical agents that does not follow Haber's law, which
states that the C*t* (the product of concentration and time) necessary
to cause a given biological effect is constant over a range of
concentrations and times. ***For this reason, the LCt~50~ (the vapor or
aerosol exposure that is lethal to 50% of the exposed population) for a
short exposure to a high concentration is different from a long exposure
to a low concentration.***

**Cyanide Pharmacokinetics and Pharmacodynamics**\
     

Cyanide appears to display first-order kinetics during the period of
initial toxicity. The volume of distribution for cyanide appears to
change as the blood levels of the chemical change but these alterations
probably reflect the marked intracellular sequestration of the molecule.

**Toxicity**\
 

Although they are generally considered to be very toxic substances, when
compared with other lethal chemical warfare agents, cyanides are among
the least toxic. The LC*t*~50~ for hydrogen cyanide (hydrocyanic acid)
is generally stated to be 2,500--5,000 mg•min/m^3^; for cyanogen
chloride, about 11,000 mg•min/m^3^. (Comparable values for the nerve
agents are 10--200 mg•min/m^3^; for sulfur mustard, 1,500 mg•min/m^3^;
and for phosgene, 3,000 mg•min/m^3^.)\
     

The estimated intravenous dose that is lethal to 50% of the exposed
population (LD~50~) of hydrogen cyanide for man is 1.0 mg/kg, and the
estimated LD~50~ for liquid on the skin is about 100 mg/kg.

**CLINICAL PRESENTATION AND MANAGEMENT**\
     

The effects from cyanide poisoning are those of progressive histotoxic
tissue hypoxia (Figure 10-2). The symptoms, signs, and physical findings
are directly related to the dose of cyanide, the route of exposure, and
the type of cyanide compound. In addition to the effects described
below, cyanogen chloride also produces irritation of the eyes and mucous
membranes similar to that produced by riot control agents.

On a military battlefield, casualties will be from exposure to cyanide
gas; this can be fatal within minutes after exposure to high
concentrations. An initial hyperpnea (15 sec after exposure), due to the
effect of cyanide on the chemoreceptor bodies, is closely followed by a
loss of consciousness (30 sec after exposure). This progresses to apnea
(3--5 min after exposure), cessation of cardiac activity (5--8 min after
exposure), and death.\
     

After exposure to lower concentrations, or exposure to lethal amounts
via the oral or percutaneous routes, the effects are slower to develop.
For example, after ingestion of a lethal dose of a cyanide salt, the
casualty might have 15 to 30 minutes of survival time during which an
antidote could be administered.\
     

Prominent early signs and symptoms of cyanide poisoning include a
transient hyperpnea, headache, dyspnea, and findings of general central
nervous system (CNS) excitement, including anxiety, personality changes,
and agitation progressing to seizures.^33^ Diaphoresis, flushing,
weakness, and vertigo may also be present. Late-appearing indications of
CNS depression, such as coma and dilated, unresponsive pupils, are
prominent signs of cyanide intoxication These signs are not specific for
cyanide poisoning, which makes the distinction from other types of
poisoning very difficult without a history of exposure. The telltale
odor of bitter almonds cannot be used as a guide because 40% to 60% of
the population is unable to detect the odor.\
 

Because the toxic effect of cyanide is to block tissue uptake and
utilization of oxygen, the casualty is transiently flushed and may have
other, related signs of poor tissue oxygen extraction. For example,
funduscopic examination shows an equally bright red color for retinal
arteries and veins because of poor oxygen extraction. Increased
oxygenation of venous blood is also responsible for a "cherry-red" skin
color, but this sign may not always be present.

**Laboratory Findings**\
     

Relevant laboratory findings include an early decreased arteriovenous
difference in the partial pressure of oxygen (PO~2~) with progressive
lactic acidosis.\
     

Timely measurements of blood and urine concentrations for suspected
intoxicants are useful in guiding clinical therapy, especially when
there is toxicity associated with the treatment agents. Unfortunately,
analysis of cyanide in biological fluids is a difficult task for a
variety of reasons. Also, measurements of blood cyanide concentrations
are almost never available during the treatment phase. See blood
concentrations of cyanide and associated clinical effects are shown in
table below.

^Documentation\ of\ blood\ cyanide\ levels\ is\ useful\ in\ confirming\ the\ clinical\ diagnosis\ and\ in\ subsequent\ follow-up\ investigations.\ The\ red\ blood\ cells\ contain\ most\ of\ the\ cyanide\ in\ the\ blood,\ so\ an\ assay\ of\ whole\ blood\ is\ necessary.\ Furthermore,\ cyanide\ levels\ tend\ to\ fall\ in\ stored\ samples\ because\ of\ the\ compound's\ short\ half-life,\ and\ this\ process\ can\ only\ partially\ be\ limited\ by\ optimal\ storage\ conditions.\ Therefore,\ the\ time\ of\ sampling\ and\ the\ conditions\ of\ storage\ are\ very\ important\ factors\ to\ consider\ and\ record.\ Cyanide\ concentrations\ in\ tissue,\ such\ as\ liver,\ lung,\ spleen,\ and\ heart,\ may\ be\ more\ accurate\ indicators\ of\ the\ blood\ cyanide\ intoxication\ levels.\ Estimates\ of\ tissue\ levels\ are\ necessary\ adjunctive\ studies\ in\ forensic\ cases.^

  ------------------------------------------ ----------------------------
  **BLOOD CONCENTRATIONS OF CYANIDE AND      
  ASSOCIATED CLINICAL EFFECTS**              

  **Cyanide Concentration (µg/mL)**          **Signs and Symptoms**

  0.2--0.5                                   None

  0.5--1.0                                   Flushing, tachycardia

  1.0--2.5                                   Obtunded

  2.5--3.0                                   Coma

   3.0                                      Death

  Reprinted from Rumack BH. Cyanide          
  poisoning. In: Newball HH, ed. Respiratory 
  care of chemical casualties. In:           
  *Proceedings of the Symposium on           
  Respiratory Care of Chemical Casualties*.  
  Fort Detrick, Frederick, Md: US Army       
  Medical Research and Development Command;  
  28--30 November 1983: 186.                 
  ------------------------------------------ ----------------------------

SPECIFIC ANTIDOTES

     

The clinical use of most antidotes is based on animal experiments and on
extrapolations made from a small number of clinical cases. Comparing
results from animal studies has limitations because of the differences
in experimental design from one study to another as well as marked
interspecies differences in cyanide and drug metabolism. Moreover, the
studies were not designed to resemble the usual emergency medical or
battlefield scenario. The disparity of antidotes for cyanide is due to
the following factors::

the small number of patients;

the fact that most cyanide victims understandably receive several
treatment agents;

the lack of readily available, adequate analysis of blood and tissue
concentrations; and

the limited comparison studies that are available in animal models.

Antidotes are usually unnecessary if the casualty is conscious.\
\
**Nitrites**\
 

Amyl nitrite and sodium nitrite, with or without sodium thiosulfate, are
used as antidotes for cyanide. The antidotal action of amyl nitrite was
first noted as early as 1888.\
     

The oxidized form of heme iron (Fe^3+^) in methemoglobin has a higher
binding affinity for cyanide than does cytochrome oxidase. The
preferential binding of cyanide to methemoglobin to form
cyanomethemoglobin frees cytochrome oxidase to resume its role in
aerobic metabolism.^51^ In the United States and other countries, sodium
nitrite has been used as the methemoglobin-inducing drug of choice.\
      

In addition to methemoglobin formation, both sodium and amyl nitrite
cause significant vasodilation, which warrants careful monitoring of
blood pressure. Marked vasodilation with orthostatic hypotension,
dizziness, and headache, in addition to the unpredictable levels of
methemoglobin formed, limit the utility of amyl nitrite in an upright
casualty. Therefore, if a casualty is conscious and able to stand, he
should not receive any nitrite. These factors, together with other
concerns, have caused amyl nitrite to be removed from the cyanide
antidote kit in the U.S. Army formulary for field units.\
     

Sodium nitrite is available in the Lilly Cyanide Antidote Kit
(manufactured by Eli Lilly and Company, Indianapolis, Ind.) in 10-mL
ampules containing 300 mg for intravenous administration. (The kit also
contains amyl nitrite encased in glass "pearls," which are meant to be
broken so the drug can be inhaled.) The solution of sodium nitrite (30
mg/mL) should be given to an adult intravenously over 5 to 15 minutes,
with careful monitoring of blood pressure. A single dose is sufficient
to raise the methemoglobin level to 20% in an adult, and a second dose,
up to half as large as the initial one, can be given. Methemoglobin
levels should be monitored if possible and kept below 35% to 40%, the
range that is associated with oxygen-carrying deficits caused by
methemoglobin itself. In children, sodium nitrite can cause lethal
methemoglobin levels if the dose is too high. The recommended dose for
children is 0.33 mL of the 10% solution per kilogram of body weight.\
     

Because most automated clinical analyzers do not detect
cyanomethemoglobin, the residual normal hemoglobin capable of oxygen
transport can be overestimated by measuring total hemoglobin only.
Methemoglobin-inducing substances should not be given to fire victims,
even if cyanide intoxication is suspected, because neither methemoglobin
nor carboxyhemoglobin (formed by carbon monoxide) transport oxygen.
Alternative therapy in this situation consists of administering oxygen,
thiosulfate, and other standard supportive measures.\
          

Some data indicate that nitrites exert their action by a mechanism other
than methemoglobin formation. It has been suggested that the protective
effect is due to the vasodilating effect of nitrite. Several
-adrenergic antagonists (eg, chlorpromazine, promethazine, promazine,
and phenoxybenzamine) that cause vasodilation also antagonize cyanide
toxicity. Further information is needed to determine the mechanism or
mechanisms by which chlorpromazine and phenoxybenzamine reverse cyanide
intoxication.\
     

Several alternative methemoglobin-forming drugs that have different
pharmacological properties from sodium nitrite have been investigated
and used in other countries.\
**Other Methemoglobin-Forming Drugs**\
     

4-Dimethylaminophenol (4-DMAP), *p*-amino-propiophenone (PAPP),
*p*-aminoheptanoylphenone (PAHP), and *p*-aminooctanoylphenone (PAOP)
are also methemoglobin-forming compounds that have protective effects
against cyanide. 4-DMAP was proposed as a fast-acting antidote with low
toxicity. This German-developed compound is used in the German military
and by the civilian population. In humans, intravenous injection of
4-DMAP (3 mg/kg) can produce a level of 15% methemoglobin within 1
minute.

     

The disadvantages of 4-DMAP are (1) the appearance of necrosis in the
area of injection after intramuscular administration and (2) the
possibility that extremely high levels of methemoglobin may occasionally
result. Increases in pain, fever, and muscle enzymes also occur after
intramuscular administration of the drug. 4-DMAP has been reported to
produce positive results in the Ames test, which suggests that the
compound may be a mutagen. PAHP appears to be the safest phenone of the
series.

**Thiosulfate and Other Sulfur Donors**\
     

Thiosulfate has been used primarily with sodium nitrite in a fixed
antidotal regimen. The standard dose of sodium thiosulfate, which is
supplied in the Lilly Cyanide Antidote Kit in 50-mL ampules, is 50 mL of
the 250 mg/mL (12.5 g), given intravenously. A second treatment with
half of the initial dose may be given. The pediatric dose is 1.65 mL per
kilogram of body weight.\
     

The utility of thiosulfate is limited because of its short biological
half-life and its small volume of distribution. This combination of
pharmacological properties, in addition to the suggestion that the
presence of cyanide increases the intracellular availability of the
thiosulfate, indicates that this compound probably cannot be used as a
prophylactic but only as an antidote. Compounds containing the
more-lipophilic sulfane sulfur (R---S---S^--^) or compounds that can be
actively transported into the cells may be more beneficial as cyanide
antagonists, but none are commercially available.

**Cobalt Salts**\
     

Cobalt salts have been shown to be an effective means for binding
cyanide in vitro and in vivo. Kelocyanor, the cobalt salt of
ethylenediamine-tetraacetic acid (EDTA), which is commercially available
in Europe but not in the United States, is administered intravenously.
In comparison studies against nitrite and hyposulfite, the cobalt
chelate was thought to be superior; however, in other studies the
nitrite-thiosulfate combination was found to be superior.\
     

The drawback of cobalt compounds is their rather severe toxicity.
Cardiac effects such as angina pectoris and ventricular arrhythmias,
edema around the eyes, vomiting, and death have been observed. A
clinical caveat is that severe toxicity from cobalt can be seen even
after initial recovery from acute cyanide poisoning.

**Hydroxocobalamin**\
     

Hydroxocobalamin (vitamin B~12a~) is an effective antagonist of cyanide
intoxication that binds cyanide directly without forming methemoglobin.
It is useful under certain conditions such as in fire victims who may
already have a decreased concentration of functioning hemoglobin. It has
a low toxicity even at high doses. In addition, in vitro cyanide studies
have shown a greater affinity for hydroxocobalamin than for cytochrome
oxidase. Sodium thiosulfate can improve the protection provided by
hydroxocobalamin alone.\
     

There are several disadvantages in the clinical use of this drug. In
rare instances, urticaria can result from hydroxocobalamin
administration. More importantly, hydroxocobalamin has a relatively
short shelf life because it decomposes in light. It may cause
tachyphylaxis, which may limit its usefulness. The cost of the drug is
high, in part because so much is needed on a molar basis. At 1,346 grams
per mole of hydroxocobalamin, a dose of at least 4 g is needed to
neutralize a lethal amount of cyanide.

**Prophylactic Drugs**\
     

PAPP and PAOP are also aminophenol derivatives. PAPP may not be active
against cyanide intoxication; its metabolite,
*p*-hydroxylamino-propiophenone, may be the active compound. This could
account, in part, for the fact that cyanide toxicity *itself* changes
the pharmacokinetics of the antidote. PAPP reduces cyanide levels within
red blood cells, and its effect is greatly enhanced in the presence of
sodium thiosulfate. PAPP, PAHP, and PAOP all have pharmacokinetics that
may allow for prophylactic administration. Prophylactic methemoglobin
formation could present its own problems, however, for victims of smoke
inhalation or in other settings where high levels of carbon monoxide
occur.^0^\
     

A number of 8-aminoquinoline analogs of primaquine have also been
studied as potential prophylactic drugs because they create elevated
methemoglobin levels of long duration. Only preliminary information is
available regarding the methemoglobin- forming potential of these drugs
in humans.

**Cyanohydrin-Forming Drugs**\
     

Aldehydes and carbonyl-related compounds (such as pyruvate,
-ketoglutaric acid, glyoxal, and reducing sugars) form cyanohydrins
from cyanide. This action may be a mechanism for improving the
protection provided by nitrites. Steinberg and Thomas found that glyoxal
trimer may be the most effective compound of the group that they
examined. The relatively short half-lives of these reversible reactions
and the drug dose required^85^ may limit the clinical utility of this
class of compounds.

SUMMARY

     

Cyanide, an ancient compound, is often associated with murders and
assassinations. Because of the high amount needed to cause death and the
inefficient weapons in which it was used, cyanide was not an effective
chemical weapon in World War I; however, it was possibly used by Iraq
against the Kurds in the Iran--Iraq War during the late 1980s.\
     

Cyanide causes intracellular hypoxia by inhibiting the intracellular
electron transport mechanism, the cytochrome enzymes. After inhalation
of a large amount of cyanide---as either hydrocyanic acid or cyanogen
chloride---the onset of effects is within seconds, symptoms are few,
physical findings are scanty, and death occurs within minutes.\
     

The antidotes used in the United States, sodium nitrite and sodium
thiosulfate, are quite effective if given before cessation of cardiac
activity.

**RIOT-CONTROL AGENTS**

**OVERVIEW**

Riot-control agents, also called irritants, lacrimators, and \"tear
gas,\" produce transient discomfort and eye closure to render the
recipient temporarily incapable of fighting or resisting. Law
enforcement agencies use them for riot control, and military forces use
them for training and in combat (see below). They have a high LCt~50~
and a low effective Ct~50~, and therefore have a high safety ratio.
Their major activity is to cause pain, burning, or discomfort on exposed
mucous membranes and skin; these effects occur within seconds of
exposure but seldom persist more than a few minutes after exposure has
ended.

**Physicochemical Characteristics**

Unlike most agents, which are liquids under temperate conditions,
riot-control agents are solids with low vapor pressures and are
dispersed as fine particles or in solution. Dispersion devices include
small, hand-held spray cans, large spray tanks, grenades, and larger
weapons.

**MECHANISM OF TOXICITY**

The mechanism of biological activity is less well characterized for
riot-control agents than for most other agents. Fortunately, a detailed
knowledge of the mechanism of action is not necessary for appropriate
medical management.

CS and CN are SN~2~ alkylating agents (mustard, in contrast, is an SN~1~
alkylator) and react readily at nucleophilic sites. Prime targets
include sulfhydryl-containing enzymes such as lactic dehydrogenase. In
particular, CS reacts rapidly with the disulfhydryl form of lipoic acid,
a coenzyme in the pyruvate decarboxylase system. It has been suggested
that tissue injury may be related to inactivation of certain of these
enzyme systems.

Pain can occur without tissue injury and may be bradykinin mediated. CS
causes bradykinin release [in]{.underline} [vivo]{.underline} and
[in]{.underline} [vitro]{.underline}, and elimination of bradykininogen
[in]{.underline} [vivo]{.underline} abolishes the systemic response to
CS.

The initial response to aerosolized CS is an increase in blood pressure
and irregular respiration, suggestive of the Sherrington pseudo
affective response. Bypassing the pain receptors of the nose and upper
airway by endotracheal administration of CS leads to the same decrease
in blood pressure and in respiration seen after intravenous injection.
This suggests that the initial pressor effect and irregular respiration
are responses to a noxious stimulus rather than pharmacological effects
of CS.

**CLINICAL EFFECTS**

The main effects of riot-control agents are pain, burning and irritation
of exposed mucous membranes and skin. These effects do not differ
appreciably from one agent to another except in the case of DM, which
will be discussed in a separate section.

**[Eyes]{.underline}*:***

The eye is the organ most sensitive to riot-control agents. Contact with
agent produces a sensation of conjunctival and corneal burning and leads
to tearing, blepharospasm, and conjunctival injection. The severe
blepharospasm causes the lids to close tightly and produces transient
\"blindness,\" an effect that could inhibit the recipient\'s ability to
fight or resist. However, if the recipient opens his eyes, his vision is
near normal even if a significant concentration of the agent persists.

Because these compounds are solids, it is possible for a particle or
clump to become embedded in the cornea or conjunctiva to cause tissue
damage. With the caveat noted below, there is no evidence that this
complication has ever occurred; however, a recipient seeking medical
care for eye pain after exposure should have his eyes thoroughly
decontaminated and undergo thorough ophthalmic examination. It could be
necessary to pick out the particles of agent from tissue.

Reviewers examined the evidence for permanent eye damage from
riot-control agents. In each instance, the damage was from a weapon
fired from close range (about 50% were self-inflicted). The reviewers
concluded that the blast force driving the agent deep into tissue (with
or without the wadding of the weapon) was the major cause of permanent
injuries. This should not happen under normal use.

**[Nose and mouth]{.underline}*:***

Contact with the delicate mucous membranes of the nose produces a
burning sensation, rhinorrhea, and sneezing; a similar burning sensation
accompanied by increased salivation occurs after contact with the mouth.

**[Airways]{.underline}*:***

Inhalation causes burning and irritation of the airways with
bronchorrhea, coughing, and a perception of a \"tight chest\" or an
inability to breathe. However, pulmonary function studies done
immediately after exposure have shown minimal alterations.

An inhaled irritating compound might be expected to exacerbate a chronic
pulmonary disease such as asthma, emphysema, or bronchitis, but this
appears not to happen after CS or CN, even though these agents have been
used widely in mixed populations. The medical care provider should
nevertheless anticipate airway problems in individuals with lung
disease, particularly if they are exposed to higher than the average
field use concentrations.

There is no evidence that CS causes permanent lung damage after one or
several exposures to field concentrations. Following inhalation of
lethal amounts, animals died from severe airway damage 12 to 24 hours
post-exposure, but survivors from large exposures had minimal or no
pulmonary abnormalities. After multiple (50 or more) daily exposures to
smaller amounts, animals developed laryngitis and tracheitis.

**[Skin]{.underline}*:***

Contact with the skin causes a tingling or burning sensation and may
cause erythema, particularly if the skin is raw or freshly abraded
(e.g., shortly after shaving). The erythema begins several minutes after
exposure and generally subsides 45 to 60 minutes after termination of
exposure.

Under conditions of high temperature, high humidity, and high
concentration of agent, there may be more severe dermatitis starting
with erythema hours after exposure and followed byvesication. Generally
these are second-degree burns not unlike, but more severe than sunburn.
Firemen who entered contaminated buildings after summer riots several
decades ago developed these lesions. After stirring up the contaminating
particles, they later developed erythema and blisters on their exposed
skin. Hypersensitivity may develop. In one instance, an individual
developed generalized vesication and high fever after an uneventful
exposure to CS more than 20 years after his only and equally uneventful
previous exposure.

**[Gastrointestinal tract]{.underline}*:***

Gastrointestinal effects usually do not occur with most riot-control
agents (DM is an exception), although there may be retching or vomiting
if the agent concentration is high, exposure is prolonged, or the
individual is sensitive.

**[Cardiovascular]{.underline}:**

A transient increase in heart rate and blood pressure has occurred in
people immediately prior to an exposure to a riot-control agent or
immediately after onset of exposure. The heart rate and blood pressure
returned essentially to pre-test ranges while exposure continued and may
have been caused by the anxiety or the initial pain rather than to a
pharmacological effect of these agents. This \"alarm reaction\" may
cause adverse effects in one with pre-existing cardiovascular disease.

**[Oral ingestion]{.underline}*:***

Children occasionally eat CS, and several adults have swallowed CS
pellets. Aside from bouts of diarrhea and abdominal cramps (which might
have been from the cathartics and antacids used as therapy), their
courses have been uneventful. In animals, the LD~50~ is about 200 mg/kg
(which is about 14 grams/70-kg person), an amount unlikely to be
ingested, even deliberately. A few animals fed lethal amounts (or
greater) had gastric irritation or erosions, and several had signs of
intestinal perforation. Recommended therapy after ingestion consists of
cathartics, antacids, and surgical observation.

**[Lethality]{.underline}*:***

CN, occasionally in combination with DM, has caused deaths in people who
refused to exit a confined space. In each case the agent was used in
excess. Death generally occurred hours after initial exposure, and
post-mortem findings were those of severe airway damage similar to that
seen in animals.

**[Metabolism]{.underline}:**

Animals given lethal amounts of CS by intravenous or intraperitoneal
administration developed increased blood thiocyanate concentrations
hours later, indicating that the malononitrile portion of CS had been
metabolized to cyanide. Cyanide was not a factor in causing death (lung
damage was). A significant increase in blood concentration of
thiocyanate has not been noted after aerosol administration of CS.
Several popular databases mention this cyanogenic potential of CS and
suggest that treatment of a CS casualty might require therapy for
cyanide poisoning (this recommendation is apparently based on the i.v.
or i.p. administration data). After receiving lethal amounts of CS by
inhalation, animals died 12 to 24 hours later from severe airway damage;
cyanide was not implicated in their deaths.

**TIME COURSE OF EFFECTS**

Except for those produced by DM, the biological effects from these
agents begin seconds after exposure and continue for 15 minutes or so
after one exits the contamination to fresh, clean air. The effects from
DM begin two to four minutes after the onset of exposure and may last an
hour or two. (This is advantageous militarily, as an individual unaware
of the agent will continue to inhale it for several minutes and absorb a
larger dose. He may then vomit, requiring mask removal, which leads to
continued inhalation of agent.)

**LABORATORY FINDINGS**

There are no specific laboratory tests that will confirm the diagnosis.
Complications, e.g., infection of a skin lesion, will produce the
laboratory findings characteristic of the complication.

**MEDICAL MANAGEMENT**

The effects of exposure to these agents under the usual field conditions
generally are self-limiting and require no specific therapy. Most will
disappear in 15 to 30 minutes, although erythema may persist for an hour
or longer.

The following section discusses potential complications occurring only
under exceptional circumstances, such as exposure to a very large amount
of agent (as in an enclosed space), exposure in adverse weather, or
experimental studies in humans or animals. They are not to be expected
with normal use of these agents.

Less than 1% of exposed people will have effects severe or prolonged
enough to cause them to seek medical care. Those who do probably will
have eye, airway, or skin complaints. Because there is no antidote for
these agents, treatment consists of symptomatic management.

**[Eyes]{.underline}*:***

The eye should be carefully flushed with water or saline, and impacted
particles should be sought. General care consists of a topical solution
(many are available) to relieve the irritation and topical antibiotics.
An ophthalmologist should be consulted for further evaluation and care.

**[Pulmonary]{.underline}:**

These agents may exacerbate chronic disease or unmask latent disease
(although there is little evidence of this). Bronchospasm with wheezing
and mild distress continuing hours after exposure may occur in a latent
asthmatic. More severe effects and respiratory distress may occur in one
with chronic bronchitis or emphysema. Management includes oxygen
administration (with assisted ventilation, if necessary),
bronchodilators if bronchospasm is present, and specific antibiotics
dictated by the results of sputum studies (Gram stains of smears
followed by culture). A specialist skilled in the treatment of
inhalation injury should be consulted early. Animal studies and very
limited human data indicate that maximal effects occur 12 hours after
exposure.

 

***[Skin]{.underline}:***

The early erythema requires reassurance, but no specific therapy unless
severe and prolonged more than an hour or two. The later onset erythema
precipitated by a larger exposure in a hot and humid atmosphere is
usually more severe and less likely to resolve quickly. It may require
the use of soothing compounds such as calamine, camphor, and mentholated
creams. Small vesicles should be left intact, but larger ones will
ultimately break and should be drained. Irrigation of denuded areas
several times a day should be followed by the application of a topical
antibiotic. Large, oozing areas have responded to compresses containing
substances such as colloidal oatmeal, Burrow\'s solution, and other
dermatologic preparations.

**SUMMARY: CS, CN**

**[Signs and Symptoms]{.underline}*:*** burning and pain on exposed
mucous membranes and skin, eye pain and tearing, burning in the
nostrils, respiratory discomfort, and tingling of the exposed skin.

**[Detection*:*]{.underline}** no detector.

**[Decontamination]{.underline}*:*** **Eyes:** thoroughly flush with
water, saline, or similar substance. **Skin:** flush with copious
amounts of water, alkaline soap and water, or a mildly alkaline solution
(sodium bicarbonate or sodium carbonate). Generally, decontamination is
not needed if the wind is brisk. Hypochlorite exacerbates the skin
lesion and should [not be used]{.underline}.

**[Immediate management]{.underline}*:*** Usually none is necessary;
effects are self-limiting.