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Chemical Weapons Part 2
Nerve Agents, V-series:
Ve, Vg, Vm, Vx
Background: Nerve
agents are compounds that have the capacity to inactivate the enzyme
acetylcholinesterase (AChE). The first of these compounds are known as the
G agents ("G" stands for German). These compounds were discovered and
synthesized by German scientists during World War II, led by Dr Gerhard
Schrader.
V agents are part of the group of persistent agents, which are nerve
agents that can remain on clothes and other surfaces for long periods. The
British first synthesized O-ethyl S-(2-diisopropylaminoethyl)
methylphosphonothioate (VX) in 1954. The most important agent in the
series was coded in the US as VX. The other agents in the series are less
known, and the information available about them is fairly limited. The
other agents also have coded names, including VE, V-gas, VG, and VM (see Table
1). V agents are approximately 10-fold more poisonous than sarin (GB).
The consistency of these agents is similar to oil; thus the inhalation
hazard is less than with G agents. This consistency renders them toxic by
dermal exposures. Since many of the agents in this series have not been
studied extensively, this article discusses VX as the prototype of the
series.
Table 1. Code and Chemical Names for
the V-Series Agents
|
Code Name |
Chemical Name |
|
VX |
O-Ethyl-S-[2(diisopropylamino)ethyl]
methylphosphonothioate |
|
VE |
O-Ethyl-S-[2-(diethylamino)ethyl]
ethylphosphonothioate |
|
VG |
O,O-Diethyl-S-[2-(diethylamino)ethyl]
phosphorothioate |
|
VM |
O-Ethyl-S-[2-(diethylamino)ethyl]
methylphosphonothioate |
|
V-gas |
Russian equivalent of VX |
Pathophysiology: V agents bind to AChE much more
potently than the organophosphate and carbamate insecticides. AChE is the
enzyme that mediates the degradation of acetylcholine (ACh). ACh is an
important neurotransmitter of the peripheral nervous system. It activates
2 types of receptors, muscarinic and nicotinic. Nicotinic ACh receptors
are found at the skeletal muscle and at the preganglionic autonomic
fibers. Muscarinic receptors are found mainly in the postganglionic
parasympathetic fibers. In addition, ACh is believed to mediate
neurotransmission in the central nervous system (CNS).
ACh is released when an electrical impulse reaches the presynaptic
neuron. It travels in the synaptic cleft and reaches the postsynaptic
membrane. In the postsynaptic membrane, ACh binds to the receptor
(muscarinic or nicotinic). This interaction leads to activation of the ACh
receptor and signal transmission in the postsynaptic side of the cleft.
Normally, after this interaction between ACh and its receptor, ACh is
degraded into choline and acetic acid by AChE. This regenerates the
receptor and renders it active again. The choline moiety undergoes
reuptake into the presynaptic cell and is used to regenerate ACh.
Nerve agents act by inhibiting the hydrolysis of ACh by AChE. Nerve
agents bind to the active site of AChE, rendering it incapable of
deactivating ACh. ACh that is not hydrolyzed still can interact with the
receptor, resulting in persistent and uncontrolled stimulation of that
receptor. After persistent activation of the receptor, fatigue occurs.
This is the same principle used by the depolarizing neuromuscular blocker
succinylcholine. Clinical effects of nerve agents are the result of this
persistent stimulation and subsequent fatigue at the ACh receptor.
For nerve agents, including V agents, inactivation of AChE eventually
becomes permanent (irreversible). This phenomenon of irreversible
inactivation of AChE is known as aging. Once aging occurs, the AChE enzyme
cannot be reactivated. For the clinical effect to be reversed, new enzyme
has to be produced. This new enzyme production is a very slow process.
This irreversible binding is one important difference between
organophosphate compounds (including nerve agents) and carbamates. For
carbamates, AChE binding is always reversible. With VX, a small degree of
spontaneous enzyme reactivation occurs, which has been found to be
approximately 6% per day for the first 3-4 days and then 1% per day.
Frequency:
- Internationally: Although G agents were synthesized
during World War II, no evidence exists that they ever were used as part
of the chemical warfare arsenal. They were tested in concentration camps
but not in the battlefield. The only instance in which nerve agents were
used is believed to be during the Iran-Iraq war. The Iraqis also
allegedly used them in the war against the Kurds.
Mortality/Morbidity: Toxicity of nerve agents is
measured in 2 forms, the LCt50 and LD50. LCt50 refers to the inhalational
toxicity of the vapor form. "Ct" refers to the concentration of the vapor
or aerosol in the air (measured as mg/m3) multiplied by the
time the individual is exposed (measured in minutes). At 10
mg?min/m3, VX is the most toxic of the nerve agents (see Table
2). VX also is the least volatile of the nerve agents. This characteristic
makes VX a hazard by percutaneous and dermal routes. By contrast, G agents
tend to volatilize instead of penetrating the skin.
Table 2. Toxicity of Nerve Agents
|
Agent |
LCt50 (mg?min/m3) |
LD50 (mg) |
|
Tabun (GA) |
400 |
1000 |
|
Sarin (GB) |
100 |
1700 |
|
Soman (GD) |
50 |
100 |
|
VX |
10 |
10 |
Race: Sensitivity to nerve agents varies with the
individual, but no studies have addressed this differential in
susceptibility.
CLINICAL
History:
- The onset of symptoms after exposure to a nerve agent varies
according to the route of exposure.
- After inhalation, onset is rapid due to the high vascularity of
the lungs and because the lungs are primary target organs.
- After cutaneous exposure, systemic symptoms may be delayed for
minutes to hours.
- The onset of symptoms also depends on the area of the skin that is
exposed. In sites where the dermal layers are thin (eg, eyelids, ears),
penetration by the nerve agent is more rapid.
- In many situations, history of exposure to a nerve agent is absent.
In case of a terrorist attack, suspect the diagnosis when multiple
patients present with symptoms of cholinergic excess.
- Occupational history may aid in making the diagnosis. Military
personnel and laboratory workers may be at particular risk for
exposure.
Physical: Clinical signs and symptoms are related to
excessive stimulation at the cholinergic nicotinic and muscarinic
receptors. Central effects may be mediated by cholinergic receptors, as
well as by effects on N-methyl-D-aspartate-ergic and
GABA-ergic systems. See Table 3 for a summary of the clinical effects of
nerve agents.
Table 3. Pharmacologic Effects of Nerve Agents*
|
Receptor Involved |
Clinical Effect |
|
Acetylcholine, GABA, N-methyl-D-aspartate:
Central (CNS) |
Anxiety, restlessness, seizures, failure to concentrate,
depression, coma, apnea |
| Acetylcholine: Muscarinic
Postganglionic parasympathetic |
"DUMBELS" (commonly used
mnemonic)
D - Diarrhea
U - Urination
M - Miosis
B -
Bronchorrhea, bronchoconstriction
E - Emesis
L - Lacrimation
S - Salivation |
| Acetylcholine: Nicotinic
Motor endplate
Sympathetic and parasympathetic ganglia |
Pallor, tachycardia, hypertension, muscle weakness and/or
paralysis, fasciculations | * Adapted from Marrs, Maynard, and Sidell
- The most common effects of nerve agents on the eyes are
conjunctival injection and pupillary constriction, known as miosis.
The patient complains of eye pain, dim vision, and blurred vision.
This is most likely from direct contact between the agent and
eye.
- Miosis may persist for long periods and may be unilateral. Severe
miosis results in the complaint of dim vision. Ciliary spasm also may
cause eye pain.
- Patients exposed to VX may not have miosis. This is probably
because the eye usually is not exposed directly to the agent, unlike
with G agents. Miosis may be a delayed sign of VX exposure.
- Nose: Rhinorrhea is most common after a vapor exposure but also can
be observed with exposures by other routes.
- Shortness of breath is a common complaint. Patients may describe
chest tightness, respiratory distress, or gasping and even may present
in apnea. Bronchoconstriction and excessive bronchial secretions cause
these important life-threatening symptoms.
- With severe exposures, death may result from central respiratory
depression and/or complete paralysis of the muscles of respiration.
Respiratory failure is the major cause of death in nerve agent
poisoning.
- Skeletal muscle: Fasciculations are the most specific identifiable
manifestations of intoxication with these agents. Upon initial exposure
they can be localized, but they then spread to cause generalized
involvement of the entire musculature (after severe exposures).
Myoclonic jerks (twitches) may be observed. Eventually, muscles fatigue
and a flaccid paralysis ensues.
- Skin: With small liquid exposures, localized sweating can be
observed with the fasciculations. Generalized diaphoresis can be
observed with larger exposures.
- Gastrointestinal: Abdominal cramping can be observed. With larger
exposures, nausea, vomiting, and diarrhea are more prominent.
- The patient may present with either bradycardia or tachycardia.
Heart rate depends on the predominance of adrenergic stimulation
(resulting in tachycardia) or of the parasympathetic tone (causing
bradycardia via vagal stimulation). Heart rate is an unreliable sign
of nerve agent poisoning.
- Many disturbances in cardiac rhythm have been reported after both
organophosphate and nerve agent poisonings. Heart blocks and premature
ventricular contractions can be observed. The 2 arrhythmias of
greatest concern that have been reported include torsade de pointes
and ventricular fibrillation.
- Smaller exposures to nerve agents may result in behavioral changes
such as anxiety, psychomotor depression, intellectual impairment, and
unusual dreams.
- Large exposures to nerve agents result in loss of consciousness
and seizures.
Causes: Nerve agents are not readily available.
Suspect nerve agent exposures in military or research laboratory workers
who may have access to these substances. Also, suspect nerve agent
poisoning when several patients present with signs of cholinergic
overstimulation. This presentation would be typical during a terrorist
attack.
Other Problems to be Considered:
Diagnosis of toxicity from a nerve agent is suggested when several
persons present with the symptoms discussed in Clinical.
Differential
diagnosis mainly includes poisoning by organophosphate or carbamate
insecticides.
Lab Studies:
- Exposure to VX in both the vapor and liquid forms has been studied
since the 1950s. Laboratory tests do not aid in the acute treatment of
patients exposed to nerve agents. AChE testing is most useful in
treating chronic exposures when the clinician is able to compare values
to an individual?s baseline. If a clinician is caring for a single
patient or a small group of patients, sending AChE levels for
documentation and ongoing treatment is nevertheless prudent. Never
withhold treatment while waiting for laboratory results.
- Red blood cell cholinesterase (RBC-AChE) level: This is believed to
be the most reliable indicator of the tissue cholinesterase
status.
- Plasma cholinesterase (butyrylcholinesterase) levels: These also are
referred to as pseudocholinesterase levels, because they are less
predictive of CNS cholinesterase activity. This often is the earliest
enzyme to be inhibited by organophosphates, but this is not true for
some nerve agents, particularly VX and GB.
- Other laboratory studies: Order basic laboratory tests for all but
minimally symptomatic patients. Electrolytes and arterial blood gases
may aid in the evaluation of the fluid status and the acid/base
balance.
Imaging Studies:
- Chest x-ray: Typically, request a chest x-ray for dyspneic and
intubated patients.
Other Tests:
- Electrocardiogram - For palpitations, irregular rhythm, or
dysrhythmia noted on monitor
TREATMENT
Prehospital Care: An
important concept to keep in mind is that rescue personnel, if not
properly protected, can become victims. The cornerstones of prehospital
management are based on rapid termination of the exposure, treating the
life-threatening emergencies, and administration of antidotes whenever
indicated and available.
- Ideally, decontaminate prior to transportation of the victim. Move
decontaminated victims to a clean area to prevent cross-contamination of
patients and medical personnel. Decontamination techniques vary with the
extent and route of exposure.
- With a vapor, removal of the victim and provision of fresh air is
the most important step.
- If the exposure is dermal, undress the patient. If droplets can be
seen, blot them away without forceful wiping. Abrading the skin
increases absorption of the agent. Agents also can be neutralized with
alkaline solutions such as soap and water or 0.5% hypochlorite
solution, which releases chlorine, followed by a water rinse. Avoid
unnecessary delays of decontamination while looking for hypochlorite
solution if simple soap and water is available.
- The military has developed Autoinjector kits that contain 2
antidotes, an oxime (an AChE reactivator) and atropine. Some ambulance
systems and hazardous materials (HAZMAT) teams also have these kits
available to use in the prehospital setting. These kits also are now
available commercially.
- During a mass casualty incident, most patients arrive to the
emergency department (ED) without the benefit of emergency medical
services (EMS) or HAZMAT team treatment. In the Tokyo subway sarin
attack, 85% of patients arrived by private car. This emphasizes the
importance of proper decontamination facilities, training, and personnel
at the ED, since most victims are likely to be contaminated fully upon
their arrival at the hospital.
Emergency Department Care:
- If decontamination has not occurred, ED personnel should be able to
provide this intervention prior to the patient?s entrance to the
hospital. If weather permits, decontamination stations can be set up
outside.
- All hospital personnel in contact with contaminated individuals must
wear full personal protective equipment (PPE) at either the A or B
levels.
- Level A PPE refers to the highest level of respiratory protection
and protective clothing. It is a fully encapsulated,
chemical-resistant, vapor-protective suit that provides vapor
protection to the respiratory and mucous membranes and skin. A
self-contained breathing apparatus (SCBA) with a full face piece must
be worn inside the suit.
- Level B still provides the highest level of respiratory protection
with SCBA but with a lesser level of skin protection. Level B suits
are not encapsulated and do not protect the skin from vapor
exposures.
- Medical management in the ED is discussed in the Medication
section.
Consultations: Whenever the diagnosis of nerve agent
exposure is suspected, contact the regional poison center for advice. In a
multiple casualty incident, activate the hospital emergency plan and
notify local authorities.
MEDICATION
Table 5
summarizes different agents used to treat nerve agent poisoned patients. Table 6
provides an overview of general treatment guidelines.
Drug Category: Gases -- All but the
mildest exposures have some degree of respiratory compromise. For this
reason, oxygen should be readily available. Most of these symptoms result
from bronchorrhea and bronchoconstriction and improve after administration
of antidotes. In the severely poisoned patient, respiratory muscle
paralysis adds to the problem. Intubation and mechanical ventilation are
required for these patients.
Drug Name
|
Oxygen -- Assists patients with
respiratory compromise.
|
| Adult Dose |
Supplement as needed
|
| Pediatric Dose |
Supplement as needed
|
| Contraindications |
None reported
|
| Interactions |
None reported
|
| Pregnancy |
A - Safe in pregnancy
|
| Precautions |
Inspired oxygen concentrations of
50-100% carry a substantial risk of lung damage | Drug Category: Anticholinergic -- Antagonizes ACh
at the muscarinic receptor.
Drug Name
|
Atropine (Isopto, Atropair,
Atropisol) -- Antagonizes ACh at its receptor; acts only at
muscarinic receptor, leaving nicotinic receptors unaffected; in
contrast to organophosphate insecticides, nerve agents rarely
require >20 mg; administer until excess muscarinic symptoms
improve; this can be gauged by improved ease of breathing in
conscious patient or improvement in ease of ventilation of intubated
patient; airway patency is critical, life-saving endpoint in
treatment.
|
| Adult Dose |
Usual starting dose: 2 mg
IV/IM/ETT; dose can be repeated after 5-10 min in boluses of 2-4 mg
|
| Pediatric Dose |
Usual starting dose: 0.02 mg IV/ETT
(minimal dose 0.1 mg); dose can be repeated q5-10min, titrated to
clinical response
|
| Contraindications |
Documented hypersensitivity;
thyrotoxicosis; narrow-angle glaucoma; tachycardia
|
| Interactions |
Coadministration with other
anticholinergics has additive effects; pharmacologic effects of
atenolol and digoxin may increase with atropine; antipsychotic
effects of phenothiazines may decrease with this medication; TCAs
with anticholinergic activity may increase effects of atropine
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Caution in Down syndrome and/or
children with brain damage to prevent hyperreactive response;
caution also in coronary heart disease, tachycardia, congestive
heart failure, cardiac arrhythmias, hypertension, peritonitis,
ulcerative colitis, hepatic disease, and hiatal hernia with reflux
esophagitis; in prostatic hypertrophy, prostatism can have dysuria
and may require catheterization | Drug
Category: Oximes -- Reactivators of AChE; 2-PAM Cl, also
known as pralidoxime, is widely available in the US; administer
concomitantly with atropine. After aging (irreversible binding of agent
with AChE enzyme) occurs, usefulness of pralidoxime is negligible. VX has
a slow aging process (aging half-life has been calculated at 48 h or
more), so delayed treatment with oximes may be beneficial. Pralidoxime has
a half-life of 1 hour and is excreted renally. Another subset of oximes
termed the H oximes (H is for Hagedorn) include agents such as HI-6,
HGG-12, and HGG-42; studies exist using these antidotes in the military
setting, but the drugs currently are not available for use in the US.
Drug Name
|
Pralidoxime (2-PAM Cl, Protopam) --
Reactivators of AChE.
|
| Adult Dose |
Recommended dose: 15-25 mg/kg IV/IM
(military Autoinjectors are IM); infuse IV over 20 min to prevent
hypertension, one of the most common complications; can repeat in 1
h if needed
|
| Pediatric Dose |
Administer as in adults
|
| Contraindications |
Documented hypersensitivity
|
| Interactions |
Use barbiturates with caution
because action of barbiturates is potentiated by AChE inhibitors;
antagonism with neostigmine, pyridostigmine, and edrophonium;
morphine, theophylline, aminophylline, succinylcholine, reserpine,
and phenothiazines can worsen condition of patients poisoned by
organophosphate insecticides or nerve agents (do not administer)
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Infuse IV dose over 20 min to
prevent one of the most common complications, hypertension, which
usually is transient but can be treated with phentolamine (5 mg IV)
if severe; rapid injection can cause tachycardia, laryngospasm,
muscle rigidity, pain at injection site, blurred vision, diplopia,
impaired accommodation, dizziness, drowsiness, nausea, tachycardia,
hypertension, and hyperventilation; can precipitate myasthenia
crisis in patients with myasthenia gravis and muscle rigidity in
normal volunteers; decrease in renal function increases drug levels
in the blood because 2-PAM is excreted in urine; can produce
transient elevation in creatine phosphokinase; 1 of 6 patients has
an elevation in SGOT and/or SGPT | Drug
Category: Benzodiazepines -- Seizures can result from
severe nerve agent poisoning; for this reason, treatment with
benzodiazepines has been advocated as part of the antidotal armamentarium.
Experts advocate use in moderately-to-severely poisoned patients, even
prior to seizure onset, as well as in actively seizing patients.
Drug Name
|
Diazepam (Valium, Diazemuls) --
Belongs to benzodiazepine family, the members of which act by
stimulating GABA, the main inhibitory neurotransmitter in the CNS.
Stimulation of GABA results in sedation and increased seizure
threshold.
|
| Adult Dose |
2-5 mg IV or 10 mg IM
|
| Pediatric Dose |
0.2-0.4 mg/kg IV
|
| Contraindications |
Documented hypersensitivity;
narrow-angle glaucoma
|
| Interactions |
Increases toxicity of
benzodiazepines in CNS with coadministration of phenothiazines,
barbiturates, alcohols, and MAOIs
|
| Pregnancy |
A - Safe in pregnancy
|
| Precautions |
Large doses can result in excessive
sedation and potential airway compromise; caution with other CNS
depressants, low albumin levels, or hepatic disease (may increase
toxicity) | --
Table 5. Drugs Used to Treat Nerve Agent?Poisoned Patients*
|
Drug |
Dose |
Route |
Indications |
Contraindications |
|
Atropine |
2 mg q5-10min prn |
IV/IM/ETT |
Excessive muscarinic symptoms |
Relative - IV route in
hypoxia has been associated with ventricular
fibrillation |
|
2-PAM Cl (pralidoxime chloride, Protopam) |
15-25 mg/kg over 20 min; can be repeated after 1 h |
IV/IM |
Symptomatic nerve agent poisoning |
Rapid infusion may result in hypertension |
|
Diazepam (Valium) |
2-5 mg IV or 10 mg
IM |
IV/IM |
Active seizures;
administer as prophylaxis if moderate or severe signs of poisoning
are present |
None | *Adapted
from Sidell
Table 6. Summary of Treatment
Modalities According to Severity of Exposure*
|
Severity/Route of Exposure |
Atropine |
2-PAM Cl |
Diazepam |
Other |
|
Suspected |
No |
No |
No |
Decontamination and 18-h observation for liquid
exposures |
|
Mild |
2 mg for severe rhinorrhea or dyspnea; may repeat
prn |
Administer if patient has nonimproving dyspnea or GI
symptoms |
No |
Decontamination and 18-h observation for liquid exposures;
oxygen |
|
Moderate |
6 mg; may require repeat doses |
Administer with atropine |
Administer even in absence of seizures |
Decontamination, oxygen |
|
Severe |
Start with 6 mg; may need to repeat |
Administer with atropine; should repeat once or
twice |
Administer even in absence of seizures |
ABCs, decontamination | * Adapted from Sidell
FOLLOW-UP
FOLLOW-UP
Further Inpatient Care:
- Admit patients with liquid exposures for observation. Onset of
symptoms with these exposures has been observed to be delayed as long as
18 hours. After vapor exposure with only minimal symptoms, the patient
usually can be discharged home. Admit patients who are more than
minimally symptomatic for observation and further inpatient
care.
Further Outpatient Care:
- Patients who are discharged from the hospital generally do not
require further care. Nerve agents have not been associated with
organophosphate-induced delayed neuropathy. Advise patients with miosis
not to drive at night until this symptom resolves.
In/Out Patient Meds:
- Generally, none are needed.
Complications:
- Patients with status epilepticus may suffer from anoxic brain
injury.
Prognosis:
- If patients recover from the acute effects of exposure, chronic
effects should not occur. Subtle behavioral and cognitive changes have
been noted to persist for days to weeks after the initial exposure.
Patients may have permanent sequelae if they suffered from anoxia during
the acute phase of poisoning.
Medical/Legal Pitfalls:
- Careful documentation of physical findings, response to treatment,
and laboratory parameters is important.
- In a terrorist attack, any evidence collected can be used to
prosecute the perpetrators.
- In occupational accidents, data are needed to make recommendations
for follow-up care and for determining dates for possible return to
work. Documentation of an occupational exposure to a nerve agent such
as VX also helps to improve safety in the workplace.
Special Concerns:
- Special concerns (pregnant, pediatric, geriatric): Information from
nerve agents has been gathered mainly from accidental exposures or
volunteer studies in military personnel. Little information exists
regarding effects or outcome for children or other special
populations.
REFERENCES:
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