Chemical Terrorism

Charles G. Hurst, Jonathan Newmark,

James A. Romano, Jr.

The use of chemical warfare agents (CWAs) in modern warfare dates

back to World War I (WWI). Sulfur mustard and nerve agents were
used by Iraq against the Iranian military and Kurdish civilians. Most
recently the nerve agent Sarin, GB, was used by the Syrian military
against their civilian population. Since the Japanese sarin attacks in
19941995 and the terrorist strikes of September 11, 2001, the alltooreal possibility of chemical or biological terrorism against civilian
populations anywhere in the world has attracted increased attention.
Military planners consider the WWI blistering agent sulfur mustard
and the organophosphorus nerve agents as the most likely agents
to be used on the battlefield. In a civilian or terrorist scenario, the
choice widens considerably. For example, many of the CWAs of
WWI, including chlorine, phosgene, and cyanide, are used today in
large amounts in industry. They are produced in chemical plants,
are stockpiled in large tanks, and travel up and down highways and
railways in large tanker cars. The rupture of any of these stores by
accident or on purpose could cause many injuries and deaths. In three
attacks in February 2007, for example, insurgents in Iraq used chlorine
gas released from tankers after explosions as a crude form of chemical
weaponry; these attacks killed 12 people and intoxicated more than
140 others. Countless hazardous materials (HAZMATs) that are not
used on the battlefield can be used as terrorist weapons. Some of them,
including insecticides and ammonia, could wreak as much damage
and injury as the weaponized chemical agents.

Many mistakenly believe that chemical attacks will always be so

severe that little can be done except to bury the dead. History proves
the opposite. Even in WWI, when IV fluids, endotracheal tubes, and
antibiotics were unavailable, the mortality rate among U.S. forces on
the battlefield from CWAschiefly sulfur mustard and the pulmonary
intoxicantswas only 1.9%. That figure was far lower than the 7%
mortality rate from conventional wounds. In the 1995 Tokyo subway
sarin incident, among the 5500 patients who sought medical attention
at hospitals, 80% were not actually symptomatic and only 12 died.
Recent events should prompt not a fatalistic attitude but a realistic
wish to understand the pathophysiology of the syndromes these agents
cause, with a view to treating expeditiously all patients who present
for care and an expectation of saving the vast majority. As we prepare
to defend our civilian population from the effects of chemical terrorism,
we also must consider the fact that terrorism itself can produce
sequelae such as physiologic or neurologic effects that may resemble
the effects of nonlethal exposures to CWAs. These effects are due to a
general fear of chemicals, fear of decontamination, fear of protective
ensembles, or other phobic reactions. The increased difficulty in differentiating
between stress reactions and nerve agentinduced organic
brain syndromes has been pointed out. Knowledge of the behavioral
effects of CWAs and their medical countermeasures is imperative to
ensure that military and civilian medical and mental health organizations
can deal with possible incidents involving weapons of mass
destruction.
For the readers benefit, the CWAs, their two-letter North Atlantic
Treaty Organization (NATO) codes (which were established by a
NATO international convention and convey no clinical implications),

their unique physical features, and their initial effects are listed in
Table 262e-1. Table 262e-2 provides guidelines for immediate treatment.
The focus of this chapter is on the blister and nerve CWAs,
which have been employed in battle and against civilians and have had
a significant public health impact.

Table 262e-1. Table 262e-2

Sulfur mustard has been a military threat since it first appeared on

the battlefield in Belgium during WWI. In modern times, it remains
a threat on the battlefield as well as a potential chemical terrorism
weapon because of the simplicity of its manufacture and its extreme
effectiveness. Sulfur mustard accounted for 70% of the 1.3 million
chemical casualties in WWI. Occasional cases of sulfur mustard intoxication
continue to occur in the United States among people exposed to
WWI- and WWII-era munitions.
Mechanism Sulfur mustard constitutes both a vapor and a liquid
threat to all exposed epithelial surfaces. The effects are delayed,
appearing hours after exposure. The organs most commonly affected
are the skin (with erythema and vesicles), the eyes (with manifestations
ranging from mild conjunctivitis to severe eye damage), and the airways
(with effects ranging from mild upper airway irritation to severe
bronchiolar damage). After exposure to large quantities of mustard,
precursor cells of the bone marrow are damaged, with consequent pancytopenia
and secondary infection. The gastrointestinal mucosa may
be damaged, and there are sometimes central nervous system (CNS)
signs of unknown mechanism. No specific antidotes exist; management
is entirely supportive. Immediate decontamination of the liquid

is the only way to reduce damage. Complete decontamination in 2 min

stops clinical injury; decontamination at 5 min reduces skin injury by
~50%. Table 262e-2 lists approaches to decontamination after exposure
to mustard and other CWAs.
Mustard dissolves slowly in aqueous media such as sweat, but, once
dissolved, it rapidly forms cyclic ethylene sulfonium ions that are
extremely reactive with cell proteins, cell membranes, and especially
DNA in rapidly dividing cells. The ability of mustard to react with and
alkylate DNA gives rise to the effects by which it has been characterized
as radiomimetii.e., similar to radiation injury. Mustard has
many biologic actions, but its actual mechanism of action is largely
unknown. Much of the biologic damage from mustard results from
DNA alkylation and cross-linking in rapidly dividing cells: corneal
epithelium, basal keratinocytes, bronchial mucosal epithelium, gastrointestinal
mucosal epithelium, and bone marrow precursor cells. This
damage may lead to cellular death and inflammatory reactions. In the
skin, proteolytic digestion of anchoring filaments at the epidermaldermal
junction may be the major mechanism of action resulting in
blister formation. Mustard also has mild cholinergic activity, which
may be responsible for effects such as early gastrointestinal and CNS
symptoms. Mustard reacts with tissue within minutes of entering the
body. Its circulating half-life in unaltered form is extremely brief.
Clinical Features Topical effects of mustard occur in the skin, airways,
and eyes; the eyes are most sensitive and the airways next most sensitive.
Absorbed mustard may produce effects in the bone marrow, gastrointestinal
tract, and CNS. Direct injury to the gastrointestinal tract
also may occur after ingestion of the compound through contamination
of water or food.

Erythema is the mildest and earliest form of mustard skin injury. It

resembles sunburn and is associated with pruritus, burning, or stinging
pain. Erythema begins to appear within 2 h to 2 days after vapor
exposure. Time of onset depends on severity of exposure, ambient
temperature and humidity, and type of skin. The most sensitive sites
are warm moist locations and areas of thin delicate skin, such as the
perineum, external genitalia, axillae, antecubital fossae, and neck.
Within the erythematous areas, small vesicles can develop, which
may later coalesce to form bullae (Fig. 262e-1). The typical bulla is
large, dome-shaped, flaccid, thin-walled, translucent, and surrounded
by erythema. The blister fluid, a transudate, is clear to straw-colored
and becomes yellow, tending to coagulate. The fluid does not contain
mustard and is not itself a vesicant. Lesions from high-dose liquid
exposure may develop a central zone of coagulation necrosis with blister
formation at the periphery. These lesions take longer to heal and are
more prone to secondary infection than are the uncomplicated lesions
seen at lower exposure levels. Severe lesions may require skin grafting.
The primary airway lesion is necrosis of the mucosa with possible
damage to underlying smooth muscle. The damage begins in the
upper airways and descends to the lower airways in a dose-dependent
manner. Usually the terminal airways and alveoli are affected only as
a terminal event. Pulmonary edema is not usually present unless the
damage is very severe, and then it becomes hemorrhagic.
The earliest effects of mustardand perhaps the only effects of a
low concentrationinvolve the nose, sinuses, and pharynx. There may
be irritation or burning of the nares, epistaxis, sinus pain, and pharyngeal
pain. As the concentration increases, laryngitis, voice changes, and
nonproductive cough develop. Damage to the trachea and upper bronchi

leads to a productive cough. Lower airway involvement causes dyspnea,

severe cough, and increasing quantities of sputum. Terminally,
there may be necrosis of the smaller airways with hemorrhagic edema
into surrounding alveoli. Hemorrhagic pulmonary edema is rare.
Necrosis of airway mucosa causes pseudomembrane formation.
These membranes may obstruct the bronchi. During WWI, high-dose
mustard exposure caused acute death via this mechanism in a small
minority of cases (Fig. 262e-2).
The eyes are the organs most sensitive to mustard vapor injury. The
latent period is shorter for eye injury than for skin injury and is also
dependent on exposure concentration. After low-dose vapor exposure,
irritation evidenced by reddening of the eyes may be the only effect.
As the dose increases, the injury includes progressively severe conjunctivitis,
photophobia, blepharospasm, pain, and corneal damage
About 90% of eye injuries related to mustard heal in
2 weeks to 2 months without sequelae. Scarring between the iris and
the lens may follow severe effects; this scarring may restrict pupillary
movements and predispose victims to glaucoma. The most severe
damage is caused by liquid mustard. Extensive eye exposure can be
followed by severe corneal damage with possible perforation of the
cornea and loss of the eye. In some individuals, latent chronic keratitis,
sometimes associated with corneal ulcerations, has been described as
early as 8 months and as late as 20 years after initial exposure.
The mucosa of the gastrointestinal tract is susceptible to mustard
damage from either systemic absorption or ingestion of the agent.
Mustard exposure in small amounts will cause nausea and vomiting
lasting up to 24 h. The mechanism of the nausea and vomiting
is not understood, but mustard does have a cholinergic-like effect.

The CNS effects of mustard also remain poorly defined. Exposure to

large amounts can cause seizures in animals. Reports from WWI and
from the IranIraq war described people exposed to small amounts of
mustard acting sluggish, apathetic, and lethargic. These reports suggest
that minor psychological problems could linger for 1 year.
The cause of death in the majority of mustard poisoning cases is
sepsis and respiratory failure. Mechanical obstruction via pseudomembrane
formation and agent-induced laryngospasm is important in the
first 24 h, but only in cases of severe exposure. From the third through
the fifth day after exposure, secondary pneumonia due to bacterial
invasion of denuded necrotic mucosa can be expected. The third wave
of death is caused by agent-induced bone marrow suppression, which
peaks 721 days after exposure and causes death via sepsis.

TREATMENTSulfur Mustard Intoxication

A patient severely ill from mustard poisoning requires the general
supportive care provided for any severely ill patient as well as the
specific care given to a burn patient. Liberal use of systemic analgesics,
maintenance of fluid and electrolyte balance, provision of nutrition,
administration of appropriate antibiotics, and other supportive
measures are necessary (Table 262e-2).
The management of a patient exposed to mustard may range
from simple (as in the provision of symptom-based care for a
sunburn-like erythema) to complex (as in total management of
a severely ill patient with burns, immunosuppression, and multisystem
involvement). Before raw denuded areas of skin develop,
especially with less severe exposures, topical cortisone creams or
lotions may be of benefit. Some very basic research data point

to the early use of anti-inflammatory preparations. Small blisters

(<12 cm) should be left intact. Because larger bullae eventually
will break, they should be unroofed carefully. Denuded areas
should be irrigated three or four times daily with saline, other sterile
solutions, or soapy water and then liberally covered with the topical
antibiotic of choice, such as silver sulfadiazine, mafenide acetate, or
triple antibiotic ointment to a thickness of 12 mm. Some physicians
advocate sterile needle drainage of large blisters, with collapsing of
the blister roof to form a sterile dressing. Mustard blister fluid does
not contain sulfur mustard but rather consists only of sterile tissue
fluid. Health care staff should not fear possible contamination. If an
antibiotic cream is not available, sterile petrolatum will be useful.
Modified Dakins solution (sodium hypochlorite, 0.5%) was used for
field-expedient irrigation and antisepsis both in WWI and for Iranian
casualties in the IranIraq war (19841987). Large areas of vesication
require hospitalization, IV therapy, and whirlpool bath irrigation.
Systemic analgesics should be used liberally, particularly before
manipulation of the patient. Monitoring of fluids and electrolytes is
important in any sick patient, but it must be recognized that fluid
loss is not of the magnitude seen with thermal burns. Overly rigorous
hydration seems to have precipitated pulmonary edema in a
few Iranian casualties sent to European hospitals.
Conjunctival irritation from a low-vapor exposure responds to
any of a number of available ophthalmic solutions after the eyes
are irrigated thoroughly. A topical antibiotic applied several times
a day reduces the incidence and severity of infection. Animal
laboratory data reflect remarkable results with early application
of commercially available topical antibiotic/glucocorticoid ophthalmologic

ointments. An ophthalmologist should be consulted.

Topical glucocorticoids are not of proven value, but their use during
the first few hours or days may significantly reduce inflammation
and subsequent damage. Further use should be relegated to an
ophthalmologist.
Petroleum jelly or a similar substance should be applied regularly
to the edges of the eyelids to prevent them from sticking together.
Topical analgesics, although of limited value, may be useful initially
if blepharospasm is too severe to permit an adequate examination.
A productive cough and dyspnea accompanied by fever and
leukocytosis occurring within 1224 h are indicative of chemical
pneumonitis. The clinician must resist the urge to use prophylactic
antibiotics for this process. Infection often occurs on the third to fifth
day and is signaled by increased fever, a pulmonary infiltrate, and
increased sputum production with a change in color. Appropriate
antibiotic therapy should await confirmation by Grams stain and,
later, by culture and sensitivity assessment.
Intubation may be necessary if laryngeal spasm or edema makes
breathing difficult or becomes life-threatening. Intubation permits
better ventilation and facilitates suctioning of necrotic and inflammatory
debris. Early use of positive end-expiratory pressure (PEEP)
or continuous positive airway pressure (CPAP) may be beneficial.
Pseudomembrane formation may require fiberoptic bronchoscopy
for suctioning of necrotic debris.
Bronchodilators are of benefit for bronchospasm. If additional
relief of bronchospasm is needed, glucocorticoids should be used.
There is little evidence that the routine use of glucocorticoids is
beneficial except for additional relief of bronchospasm.

Leukopenia begins around day 3 with major systemic absorption.

Marrow suppression peaks at 714 days. In the IranIraq war, a white
blood cell count of 200/L usually resulted in death of the patient.
Sterilization of the gut by nonabsorbable antibiotics should be considered
to reduce the possibility of sepsis from enteric organisms.
Cellular replacement (bone marrow transplants or transfusions)
may be successful. Granulocyte colony-stimulating factor produced
a 50% reduction in the time required for bone marrow recovery in
nonhuman primates exposed to sulfur mustard. Medication for nausea
and vomiting may be necessary for gastrointestinal side effects.
Lymphopenia precedes general leukopenia by a day or more and
may be a useful clinical tip-off to impending leukopenia.
Excellent experimental assessments of the contributions of DNA
alkylation, inflammation, activation of proteolytic enzymes, or lipid
peroxidation to the mustard injury have been developed in the past
1520 years. Some examples include (1) the demonstration of a
reduction by up to 75% of inflammation and tissue damage in the
mouse ear swelling test by vanilloid compounds and (2) the demonstration
of 5060% protection by N-acetylcysteine in the generation
of free radicals within guinea pig lung exposed to mustard. In
many cases, the demonstration of protection is dependent on the
availability of sufficient amounts of drugs with adequate half-lives.
Strategies to enhance bioavailability include attachment of polyethylene
glycol to the antioxidant drug/enzyme and/or delivery of the
drug/enzyme in a liposome.
NERVE AGENTS
The organophosphorus nerve agents are the deadliest of the CWAs.
They work by inhibition of tissue synaptic acetylcholinesterase, creating

an acute cholinergic crisis. Death ensues because of respiratory

depression and can occur within seconds to minutes.
The nerve agents tabun and sarin were first used on the battlefield
by Iraq against Iran during the first Persian Gulf War (19841987).
Estimates of casualties from these agents range from 20,000100,000.
In 1994 and 1995, the Japanese cult Aum Shinrikyo used sarin in two
terrorist attacks in Matsumoto and Tokyo. Two U.S. soldiers were
exposed to sarin while rendering safe an improvised explosive device
in Iraq in 2004.
The classic nerve agents include tabun (GA), sarin (GB), soman
(GD), cyclosarin (GF), and VX; VR, similar to VX, was manufactured
in the former Soviet Union (Table 262e-1). All the nerve agents are
organophosphorus compounds, which are liquid at standard temperature
and pressure. The G agents evaporate at about the rate of
water, except for cyclosarin, which is oily and thus probably will have
evaporated within 24 h after deposition on the ground. Their high
volatility thus makes a spill of any amount a serious vapor hazard. In
the Tokyo subway attack in which sarin was used, 100% of the symptomatic
patients inhaled sarin vapor that spilled out on the floor of
the subway cars. The low vapor pressure of VX, an oily liquid, makes
it much less of a vapor hazard but potentially a greater environmental
hazard because it persists in the environment far longer.
Mechanism Acetylcholinesterase inhibition accounts for the major
life-threatening effects of nerve agent poisoning. The efficacy of
antidotal therapy in the reversal of this inhibition proves that this is
the primary toxic action of these poisons. At cholinergic synapses,
acetylcholinesterase, bound to the postsynaptic membrane, functions
as a turn-off switch to regulate cholinergic transmission. Inhibition of

acetylcholinesterases causes the released neurotransmitter, acetylcholine,

to accumulate abnormally. End-organ overstimulation, which is
recognized by clinicians as a cholinergic crisis, ensues (Fig. 262e-4).
Clinical Features Clinical effects of nerve agent exposure are identical
for vapor and liquid exposure routes if the dose is sufficiently large.
The speed and order of symptom onset will differ (Table 262e-2).
Exposure of a patient to nerve agent vapor, by far the more likely
route of exposure in both battlefield and terrorist scenarios, will cause
cholinergic symptoms in the order in which the toxin encounters
cholinergic synapses. The most exposed synapses on the human
integument are in the pupillary muscles. Nerve agent vapor easily
crosses the cornea, interacts with these synapses, and produces miosis,
described by Tokyo subway victims as the world going black. Rarely,
this vapor also can cause eye pain and nausea. Exocrine glands in the
nose, mouth, and pharynx are next exposed to the vapor, and cholinergic
overload here causes increased secretions, rhinorrhea, excess
salivation, and drooling. Toxin then interacts with exocrine glands in
the upper airway, causing bronchorrhea, and with bronchial smooth
muscle, causing bronchospasm. This combination of events can result
in hypoxia.
Once the victim has inhaled, vapor can passively cross the alveolarcapillary
membrane, enter the bloodstream, and incidentally and
asymptomatically inhibit circulating cholinesterases, particularly free
butyrylcholinesterase and erythrocyte acetylcholinesterase, both of
which can be assayed. Unfortunately, the results of this assay may not
be easily interpretable without a baseline, since cholinesterase levels
vary enormously between individuals and over time in an individual,
healthy patient.

Usually the first organ system to become symptomatic from

bloodborne nerve agent exposure is the gastrointestinal tract, where
cholinergic overload causes abdominal cramping and pain, nausea,
vomiting, and diarrhea. After the gastrointestinal tract becomes
involved, nerve agents will affect the heart, distant exocrine glands,
muscles, and brain. Because there are cholinergic synapses on both the
vagal (parasympathetic) and sympathetic sides of the autonomic input
to the heart, one cannot predict how heart rate and blood pressure
will change once intoxication has occurred. Remote exocrine activity
will include oversecretion in the salivary, nasal, respiratory, and sweat
glandsthe patient will be wet all over. Bloodborne nerve agents
will overstimulate neuromuscular junctions in skeletal muscles, causing
fasciculations followed by frank twitching. If the process goes on
long enough, ATP in muscles will eventually be depleted and flaccid
paralysis will ensue.
In the brain, since the cholinergic system is so widely distributed,
bloodborne nerve agents will, in sufficient doses, cause rapid loss of
consciousness, seizures, and central apnea leading to death within
minutes. If respiration is supported, status epilepticus that does not
respond to usual anticonvulsants may ensue (Chap. 445). If status
epilepticus persists, neuronal death and permanent brain dysfunction
may occur. Even in mild nerve-agent intoxication, patients may
recover but may experience weeks of irritability, sleep disturbance, and
nonspecific neurobehavioral manifestations.
The time from exposure to development of the full-blown cholinergic
crisis after nerve agent vapor inhalation can be minutes or even
seconds, yet there is no depot effect. Since nerve agents have a short
circulating half-life, if the patient is supported and, ideally, treated

with antidotes, improvement should be rapid, without subsequent

deterioration.
Liquid exposure to nerve agents results in different speeds and
orders of symptom onset. A nerve agent on intact skin will partially
evaporate and partially begin to travel through the skin, causing localized
sweating and then, when it encounters neuromuscular junctions,
localized fasciculations. Once in muscle, the agent will cross into the
circulation and cause gastrointestinal discomfort, respiratory distress,
heart rate changes, generalized fasciculations and twitching, loss of
consciousness, seizures, and central apnea. The time course will be
much longer than with vapor inhalation; even a large, lethal droplet
can take up to 30 min to exert an effect, and a small, sublethal dose
could progressively take effect over 18 h. Clinical worsening that
occurs hours after treatment has started is far more likely with liquid
than with vapor exposure. In addition, miosis, which is practically
unavoidable with vapor exposure, is not always present with liquid
exposure and may be the last manifestation to develop in this situation;
such a delay is due to the relative insulation of the pupillary muscle
from the systemic circulation.
Unless the cholinesterase is reactivated by specific therapy (oximes),
its binding to the enzyme is essentially irreversible. Erythrocyte acetylcholinesterase
activity recovers at ~1% per day. Plasma butyrylcholinesterase
recovers more quickly and is a better guide to recovery of
tissue enzyme activity.
TREATMENT NERVE AGENT INTOXICATION
Acute nerve agent poisoning is treated by decontamination, respiratory
support, and three antidotes: an anticholinergic, an oxime, and
an anticonvulsant (Table 262e-3). In acute cases, all these forms of

therapy may be given simultaneously.

DECONTAMINATION
Decontamination of a vapor is formally unnecessary; however, in
the Tokyo subway attack, sarin vapor trapped in patients clothing
caused miosis in 10% of emergency personnel. Removal of clothing
would have prevented most of these instances. Expedient decontamination
methods for CWAs are available. For soap and water
decontamination, the skin surface and hair are washed in warm or
tepid water at least three times, or the exposed individual showers
for 2 min, washing with soap and rinsing. The rapid physical removal

Table 262e-3

of a chemical agent is essential. Scrubbing of exposed skin with a

stiff brush or bristles is discouraged, because skin damage may occur
and may increase absorption of agent. Gentle liquid dish soap and
copious amounts of water should be used, with mild to moderate
friction applied with a single-use sponge or washcloth in the first
and second washes. The third wash should be a rinse with copious
amounts of warm or tepid water. Shampoo can be used to wash the
hair. If only cold water is available, it should be used; decontamination
should not be delayed while warm water is sought. Spot (local)
decontamination with reactive skin decontamination lotion (RSDL),
followed by a soap and water wash/shower, is the method preferred
by the Department of Defense. RSDL is available for purchase by
civilians and has been shown to be superior across a broad spectrum
of nerve agents as well as sulfur mustard. RSDL is the only product
approved by the U.S. Food and Drug Administration (FDA) for initial

spot decontamination. An important caveat is that RSDL and 0.5%

sodium hypochlorite (dilute bleach military field expedient) should
not be used concurrently because of a potential exothermic reaction.
In any event, decontamination must be accomplished before
the patient enters the medical facility to avoid contaminating the
facility and its staff. In patients with contaminated wounds, potentially
contaminated clothing and other foreign material that may
serve as a depot for the liquid agent should be extracted.
RESPIRATORY SUPPORT
Death from nerve agent poisoning is almost always attributable
to respiratory causes. Ventilation will be complicated by increased
resistance and secretions. Atropine should be given before ventilation
or as it begins, since it will make ventilation far easier.
ANTIDOTAL THERAPY
Atropine In theory, any anticholinergic agent could be used to
treat nerve agent poisoning. Worldwide, however, the choice is
invariably atropine because of its wide temperature stability and
rapid effectiveness when administered either IM or IV and because
inadvertent administration of this drug usually causes little CNS
dysfunction (Table 262e-3). Atropine rapidly reverses cholinergic
overload at muscarinic synapses but has little effect at nicotinic
synapses. The practical implication is that atropine can quickly treat
the life-threatening respiratory effects of nerve agents but probably
will not help with neuromuscular (and possibly
sympathetic) effects. In the field, military
personnel are given a combined autoinjector
containing both 2.1 mg of atropine and
oxime (2-pralidoxime chloride [2-PAM Cl])a

product licensed by the FDA under the trade

name Duodote. Its miltary designation is the
Antidote Treatment Nerve Agent Autoinjector
(ATNAA) (Fig. 262e-5). Only fulland not
dividedautoinjector doses can be administered.
The field loading dose is 2, 4, or 6 mg,
with re-treatment every 510 min until the
patients breathing improves and secretions
diminish. The Iranian military initially used
larger doses during the IranIraq war, in which
oximes were in short supply. When the patient
reaches a level of medical care at which drugs
can be given IV, this is the preferred route.
In small children, the IV route may be the
initial avenue for atropine therapy; however,
pediatric autoinjectors of 0.5 mg and 1 mg are
manufactured. There is no upper limit to atropine
therapy (whether IM or IV), but the total
average dose for a severely afflicted adult is
usually 2030 mg.
In a mildly afflicted patient with miosis and
no other systemic symptoms, atropine or homatropine
eyedrops may suffice for therapy.
This treatment will result in ~24 h of mydriasis. Frank miosis or
imperfect accommodation may persist for weeks or even months
after all other signs and symptoms have resolved.
Oximes Oximes are nucleophiles that reactivate the cholinesterase
whose active site has been occupied and bound to nerve agent

(Table 262e-3). Therapy with oximes therefore restores normal

enzyme function. Oxime therapy is limited by a second side reaction,
called aging, in which a side chain on nerve agents falls off
the complex at a characteristic rate. Aged complexes are negatively
charged, and oximes cannot reactivate negatively charged
complexes. The practical effect of this limitation differs from one
nerve agent to another since each ages at a characteristic rate. For
example, sarin ages in 35 h, tabun ages over a longer period (1213
h), and VX ages much less rapidly (>48 h). All these intervals are so
much longer than the patients expected life span and expected
treatment time after acute nerve-agent toxicity that they are irrelevant.
Soman, in contrast, ages in 2 min; thus, only a few minutes
after exposure, oximes are useless in treating soman poisoning. The
oxime used varies by country; the United States has approved and
fielded 2-PAM Cl. MARK 1 kits and Duodotes (Fig. 262e-5A) both
contain autoinjectors holding 600 mg of 2-PAM Cl. Initial field loading
doses are 600, 1200, and 1800 mg. Since blood pressure may
become elevated after administration of 45 mg/kg in adults, field
use of 2-PAM Cl is restricted to 1800 mg/h IM. During the time when
more oxime cannot be given, atropine alone is recommended. In
the hospital setting, 2.525 mg/kg of 2-PAM Cl by the IV route has
been found to reactivate 50% of inhibited cholinesterase. The usual
recommendation is 1000 mg by slow IV drip over 2030 min, with
2500 mg over a period of 11.5 h. Active research aims to field a
more effective and broader-spectrum oxime than 2-PAM Cl.
Anticonvulsants Nerve agentinduced seizures do not respond to
the usual anticonvulsants used for status epilepticus, including phenytoin,
phenobarbital, carbamazepine, valproic acid, and lamotrigine

(Chap. 445). The only anticonvulsants that have been shown to stop
this form of status are the benzodiazepines. Diazepam is the only
benzodiazepine approved for seizures in humans, although other
FDA-approved benzodiazepines (notably midazolam) work well
against nerve agentinduced seizures in animal models. Diazepam
therefore is manufactured in 10-mg injectors for IM use and given to
U.S. forces for this purpose (Fig. 262e-5B). Civilian agencies are stockpiling
this field product (convulsive antidote for nerve agent, CANA),
which generally has not been used in hospital practice. Extrapolation
from animal studies indicates that adults will probably require 3040
mg of diazepam given IM to stop nerve agentinduced status epilepticus.
In the hospital or in a small child unable to receive the autoinjector,
IV diazepam may be used at similar doses. The clinician may
confuse seizures with the neuromuscular signs of nerve agent poisoning.
In the hospital, early electroencephalography is advised to
distinguish among nonconvulsive status epilepticus, actual seizures,
and postictal paralysis. Animal studies have shown that the most
effective benzodiazepine in this situation is midazolam, which is not
FDA-approved for seizures. At the time of this writing, a new drug
application for use of midazolam against seizures has been submitted
to the FDA. The superiority of IM midazolam to IV lorazepam in a
large community trial of status epilepticus suggests that emergency
personnel will soon incorporate autoinjectors into routine clinical
practice and that these field products will thus become integrated
into clinical medicine.
Peripheral neuropathy and the so-called intermediate syndrome,
which are prominent long-term effects of insecticide poisoning, are
not described in nerve agent survivors.

Recent research has explored approaches leading to transient

immunity and eventually to biologic products that will be protective
against lethal nerve agents yet be devoid of side effects. A novel
approach is to use enzymes to scavenge these highly toxic nerve
agents before they attack their intended targets. The accumulated
work has shown that if a scavenger is present at the time of nerve
agent exposure, toxicant levels are rapidly reduced. This reduction
is so rapid and profound that the need to administer a host of pharmacologically
active drugs as antidotes is, according to laboratory
studies, eliminated.

CYANIDE
Cyanide (CN) has become an agent of particular interest in terrorist
scenarios because of its applicability to indoor targets. In recent years,
for example, attacks with this agent have targeted the water supply of
the U.S. Embassy in Italy. The 1993 World Trade Center bombing in
New York may have been intended as a cyanide release as well.
Hydrogen cyanide and cyanogen chloride, the major forms of cyanide,
are either true gases or liquids very close to their boiling points at
standard room temperature. Hydrogen cyanide gas is lighter than air
and does not remain concentrated outdoors for long; thus it is a poor
military weapon but an effective weapon in an indoor space such as a
train station or a sports arena. Cyanide is also water-soluble and poses
a threat to the food and water supply from either accidents or malign
intent. It is well absorbed from the gastrointestinal tract, through the
skin, or via inhalationthe preferred terrorist route. Cyanide smells
like bitter almonds, but 50% of persons lack the ability to smell it.
Unique among CWAs, cyanide is a normal constituent of the

environment and actually is a required cofactor in many compounds

important in metabolism, including vitamin B12. Cyanide is present
in many plants, including tobacco; therefore, smokers, for instance,
chronically carry cyanide at three times the usual level. Humans have
evolved a detoxification mechanism for cyanide. Cyanide poisoning
results if a large challenge of CN overwhelms this mechanism, while
treatment of cyanide poisoning exploits it.
Mechanism Cyanide directly poisons the last step in the mitochondrial
electron transport chain, cytochrome a3, which results in a
shutdown of cellular energy production. Tissues are poisoned in direct
proportion to their metabolic rate, with the carotid baroreceptors and
the brainthe most metabolically active tissues in the bodyaffected
fastest and most severely. This poisoning results from cyanides high
affinity for certain metals, notably Co and Fe+++. Cytochrome a3
contains Fe+++, to which CN binds. Cyanide-poisoned tissues cannot
extract oxygen from the blood; even though pulmonary oxygen
exchange and cardiac function are preserved, cells die of hypoxiai.e.,
of histotoxic rather than cardiopulmonary cause.
Clinical Features Hyperpnea occurs ~15 s after inhalation of a high
concentration of cyanide and is followed within 1530 s by the onset of
convulsions and electrical status epilepticus. Respiratory activity stops
23 min later, and cardiac activity ceases several minutes after that.
Exposure, especially via inhalation, to a large challenge of CN can
cause death in as little as 8 min. Smaller challenges will cause symptom
spread over a longer period; very low doses may produce no effects at
all because of the bodys ability to detoxify small amounts. Cyanogen
chloride additionally produces mucous membrane irritation. Many
but not all patients have a cherry-red appearance because their venous

blood remains oxygenated.

Differential Diagnosis In a mass casualty incident caused by a chemical
agent, the primary differential diagnosis of cyanide poisoning will be
nerve agent poisoning. Cyanide-poisoned patients lack the prominent
cholinergic signs seen in nerve agent poisoning, such as miosis and
increased secretions. The cherry-red appearance often seen in cyanide
poisoning is never seen in nerve agent poisoning. Cyanosis, confusingly,
is not a prominent early sign in cyanide poisoning.
TREATMENTCyanide
Treatment of cyanide poisoning may require simply evacuation of
the patient from the source of contamination. Decontamination of a
true gas, other than clothing removal to avoid gas trapped in clothing
air cells, is probably not a major concern.
Oxygen, supplied via mask, nasal cannula, or endotracheal tube,
has been shown to benefit patients, although the benefit is not
explained by the known mechanism of action of CN.
Cyanide antidotes exploit the bodys innate detoxification mechanism,
the hepatic enzyme rhodanese. They also exploit cyanides
affinity for certain metal ions. Antidote recommendations are summarized
in Table 262e-4.
The classic two-step cyanide antidote kit includes two IV solutions:
sodium nitrite and sodium thiosulfate. It may also include
amyl nitrite perles for inhalation. Nitrites are methemoglobin formers;
when administered to a patient, nitrite converts a fraction of the
bodys hemoglobin into methemoglobin by converting heme iron
from Fe++ to Fe+++. CN has a greater affinity for methemoglobin Fe+++
than for cytochrome a3. As a result, administration of nitrite creates
a sink of cyanmethemoglobin; formation of methemoglobin pulls

CN off mitochondrial cytochrome a3, allowing cellular respiration

to resume. Recent work suggests that nitrites may also work via a
second mechanism involving the neurotransmitter nitrous oxide;
if so, this mechanism may explain why cyanide-poisoned patients
improve after nitrite administration faster than is explained by the
known rate of methemoglobin formation.
Nitrite administration may save the patient acutely but creates
an unstable pool of cyanmethemoglobin, the elimination of which
requires a sulfur donor: sodium thiosulfate. Sodium thiosulfate
donates sulfur to the reaction catalyzed by rhodanese; cyanide is
converted to thiocyanate, a compound the body eliminates harmlessly
in urine. Sodium thiosulfate alone may be administered to fire
victims, whose oxygen-carrying capacity is already reduced and in
whom the administration of nitrite may form so much methemoglobin
as to render the blood unable to carry oxygen at all.
Hydroxocobalamin, or vitamin B12a, has recently been approved
for use as an alternative cyanide antidote. Unlike sodium nitrite
and sodium thiosulfate, it must be reconstituted at the scene.
Hydroxocobalamin lacks the propensity of nitrites for hypotension,
but many cases in which it has been beneficial have also required
the use of sodium thiosulfate. Hydroxocobalamin causes an orange
discoloration of the skin that is of no functional significance.
All of these antidotes require the placement of an IV line. Amyl
nitrite is currently the only non-intravenous cyanide antidote available
and has never been formally approved by the FDA. Amyl nitrite
perles in cyanide antidote kits can be crushed and inhaled by a
patient who is still breathing. Amyl nitrite can also be given through
a respirator.

None of the cyanide antidotes is specifically approved for pediatric

use.
Prognosis Cyanide casualties tend to recover much more quickly than
casualties exposed to other chemical agents. Many patients with industrial
cases have returned to work within the same shift. If a patient
receives a large challenge and dies, death usually takes place within
minutes of exposure.

Table 262e-4