AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The V-series weapons, including VX, are the most highly toxic chemical warfare nerve agents. Nerve agents are compounds that have the capacity to inactivate the enzyme acetylcholinesterase (AChE). The first compounds to be synthesized were known as the G agents ("G" stands for German): tabum (GA), sarin (GB), and soman (GD). These compounds were discovered and synthesized by German scientists, led by Dr Gerhard Schrader, during World War II.

The V agents are part of the group of persistent agents, which are nerve agents that can remain on skin, clothes, and other surfaces for long periods of time. The consistency of these agents is similar to oil; thus, the inhalation hazard is less than with the G agents. This consistency thus renders them toxic mainly by dermal exposures. 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 below). The V agents are approximately 10-fold more poisonous than sarin (GB). 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

Pathophysiology

The 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 ACh 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, where it binds to its receptor (muscarinic or nicotinic). This activates the ACh receptor and results in a new action potential, transmitting the signal down the neuron. Normally, after this interaction between ACh and its receptor, ACh detaches from its receptor and is degraded (hydrolyzed) 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 recycled to produce 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. Any 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. Thus, the clinical effects of nerve agent poisoning are the result of this persistent stimulation and subsequent fatigue at the muscarinic and nicotinic ACh receptors.

"Aging" and VX nerve agent

For all nerve agents, including the V agents, inactivation of AChE eventually becomes permanent (irreversible). This phenomenon of irreversible inactivation of AChE is known as aging. Aging represents the formation of a covalent bond between the nerve agent and the AChE. Once aging occurs, the AChE enzyme cannot be reactivated. After aging occurs, new AChE must be produced in order for the clinical effect of the nerve agent to be reversed. 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.

The amount of time (listed as aging half-life) required for aging by various nerve agents is listed in Table 2 in Mortality/Morbidity. The nerve agent VX has a very long aging half-life of more than 2 days. This means that certain antidotes will be effective much longer for this agent than for the others (see Treatment).

Frequency

United States

No instances of nerve agent poisoning have been reported in the United States. However, these agents are still present in certain military facilities. Military personnel in these facilities could come in contact with these agents in case of an accidental release.

International

Although G agents were synthesized during World War II, no evidence exists that they ever were actually deployed during this conflict. They were tested in concentration camps but not in the battlefield. The only confirmed wartime use of nerve agents was during the 1981-1987 Iran-Iraq War, where tabun and sarin were used by Iraq in an effort to gain advantage over Iran. Current literature does not indicate whether VX was used by the Iraqis, although they were found to have substantial stockpiles of the agent at the time of the first Gulf War. They were also reported to have used them against various Kurdish civilians in the north of Iraq.

The Chemical Weapons Convention (CWC) took effect in 1997 and bans the production, stockpiling, and use of chemical weapons. It also provides for the monitoring of their destruction through the Organisation for the Prohibition of Chemical Weapons.

Mortality/Morbidity

Toxicity of nerve agents is typically described in 2 ways: 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, which renders it hazardous mainly by the percutaneous and dermal routes. By contrast, G agents tend to volatilize instead of penetrating the skin, which makes them a significant inhalational hazard.

Table 2. Toxicity and Half-Lives of Nerve Agents

Race

Sensitivity to nerve agents varies with the individual, but no studies have addressed this differential in susceptibility.

Sex

No evidence exists of any differential susceptibility between the sexes.

Age

No evidence exists of a differential susceptibility based on age.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The onset of symptoms after exposure to a V agent varies according to the route and quantity of exposure.
• • After inhalation, onset is rapid due to the high vascularity of the lungs and because the lungs are primary target organs. However, it must be remembered that, due to the low volatility of the V agents, this is not the most common route of exposure.
  • After cutaneous exposure, systemic symptoms may be delayed for minutes to hours. The V agents may present rapidly if a large exposure occurs. However, clinical manifestations may be delayed for several hours after lesser exposures, as the agent diffuses slowly through the keratin layers of the skin. This is in contrast to the G (volatile) agents, which are expected to cause onset of symptoms in the first few minutes after exposure.
• 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 in cases of accidental releases. Military personnel, chemical demilitarization laborers, and laboratory workers may be at particular risk for exposure.

Physical

Clinical signs and symptoms are related to excessive stimulation at the nicotinic and muscarinic cholinergic 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*

* Adapted from Marrs, Maynard, and Sidell.¹

• Eyes
• • 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 most likely because the eye usually is not exposed directly to the agent, unlike with the 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.
• Lungs
• • Shortness of breath is an important 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 along with the fasciculations. Generalized diaphoresis can occur with larger exposures.
• Gastrointestinal: Abdominal cramping can be present. With larger exposures, nausea, vomiting, and diarrhea are more prominent.
• Heart
• • The patient may present with either bradycardia or tachycardia. Heart rate depends on the predominance of sympathetic stimulation (resulting in tachycardia) or of the parasympathetic tone (causing bradycardia via vagal stimulation). Hypoxemia also increases adrenergic tone, which also manifests itself with tachycardia. Heart rate is thus 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 are torsade des pointes and ventricular fibrillation.
• Central nervous system
• • 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 altered mentation, loss of consciousness, and seizures.
• Most signs and symptoms are related to the excessive activation and subsequent fatigue at the cholinergic receptors. Some authors have divided exposures into minimal, moderate, and severe toxicity. Signs and symptoms associated with each exposure are summarized in Table 4.

  Table 4. Severity of Toxicity from Liquid and Vapor Exposures

  Severity of Exposure	Signs and Symptoms - Liquid	Signs and Symptoms - Vapor
  Onset of symptoms	Possibly delayed toxicity	Rapidly manifesting toxicity
  Minimal	Localized sweating at site Localized fasciculations at site	Miosis Rhinorrhea Mild dyspnea
  Moderate	Fasciculations Diaphoresis Nausea, vomiting, and diarrhea Generalized weakness	Above symptoms and the following: Moderate-to-marked dyspnea (bronchorrhea and/or bronchoconstriction)
  Severe	Above symptoms and the following: Loss of consciousness Seizures Generalized fasciculations Flaccid paralysis and apnea	Above symptoms and the following: Loss of consciousness Seizures Generalized fasciculations Flaccid paralysis and apnea

Causes

The 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 and symptoms of cholinergic overstimulation. This presentation would be typical during a terrorist event, as seen in the 1995 Tokyo subway attack, in which sarin was released.

DIFFERENTIALS

Section 4 of 11  

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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.

WORKUP

Section 5 of 11  

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• Clinical
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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; however, sending AChE levels for documentation and ongoing treatment is nevertheless prudent. Since there is a wide variability in baseline levels, AChE testing is most useful in treating chronic exposures when the clinician is able to compare values to an individual's baseline. 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 radiography: Typically, request a chest radiograph for dyspneic and intubated patients. A chest radiograph may also help in the diagnosis of noncardiogenic pulmonary edema.

Other Tests

• Electrocardiography - For palpitations or for any dysrhythmias noted on monitor

Procedures

• Because a significant cause of morbidity and mortality of these patients relates to the airway and breathing, ensure that ventilation (which can be impaired from the respiratory muscle fatigue) and oxygenation (which can be impaired from the bronchorrhea and bronchoconstriction) are adequate. Endotracheal intubation may be needed for those with ventilatory and/or respiratory compromise.

TREATMENT

Section 6 of 11  

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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 any 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. Based on the Tokyo sarin attack and other mass casualty experiences, as many as 85% of victims may present directly to hospitals. This means that hospital personnel must also be trained in terrorism response, including self-protection, triage, treatment, and decontamination.
• • With a vapor exposure, removal of the victim and provision of fresh air is the most important step, and often the only one needed.
  • 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. However, avoid unnecessary delays of decontamination while looking for hypochlorite solution if simple soap and water is readily available.
• The military has developed Autoinjector kits (Mark 1 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 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 treatment advice (1-800-222-1222). In a multiple casualty incident, activate the hospital emergency plan and notify local authorities.

MEDICATION

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Table 5 summarizes different agents used to treat nerve agent–poisoned patients. Table 6 provides an overview of general treatment guidelines.

Table 5. Drugs Used to Treat Nerve Agent–Poisoned Patients*

Table 6. Summary of Treatment Modalities According to Severity of Exposure*

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, especially atropine. In the severely poisoned patient, respiratory muscle paralysis adds to the problem. Intubation and mechanical ventilation are required for these patients.

Drug Category: Anticholinergic

Antagonizes ACh at the muscarinic receptor.

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 is considered beneficial. Pralidoxime has a half-life of 1 hour. Pralidoxime and TMB-4 have similar characteristics and are widely used outside of the US.
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 widely available for use in the US.

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.

FOLLOW-UP

Section 8 of 11  

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• Medication
• Follow-up
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• Multimedia
• References

Further Inpatient Care

• Admit patients with liquid exposures for observation after completion of proper decontamination. Onset of symptoms with these exposures has been observed to be delayed as long as 18 hours. This differs from vapor exposures, in which the symptoms have an almost immediate onset. In a patient with a vapor exposure and only minimal symptoms, the patient usually can be discharged home.

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.

Patient Education

• For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Chemical Warfare and Personal Protective Equipment.

MISCELLANEOUS

Section 9 of 11  

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• Multimedia
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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.

MULTIMEDIA

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• Follow-up
• Miscellaneous
• Multimedia
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Media file 1:  Chemical Terrorism Agents and Syndromes. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/chemical.html.
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REFERENCES

Section 11 of 11

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• References

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Article Last Updated: Dec 19, 2007