Nerve agents are compounds that have the capacity to inactivate the enzyme acetylcholinesterase (AChE).[1, 2] The first compounds to be synthesized were known as the G-series agents ("G" stands for German): tabun (GA), sarin (GB), and soman (GD).[3] These compounds were discovered and synthesized by German scientists, led by Dr Gerhard Schrader, prior to and during World War II.
In 1954, the British first synthesized O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate, the most important agent in the V series and coded in the United States as "VX". The V-series weapons, including VX, are among the most highly toxic chemical warfare nerve agents ("V" stands for venomous). The V agents are approximately 10-fold more poisonous than sarin (GB).
The V-series 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 due to low volatility characteristics. 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 other agents in the V series are less known, and the information available about their characteristics is fairly limited in the open, unclassified literature. The other agents also have coded names, including VE, V-gas, VG, and VM (see Table 1 below). This article discusses VX as the prototype of the V-series nerve agents. Table 1. Code and Chemical Names for the V-Series Agents
The V-series 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-series 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, and 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.[4]
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).
No instances of intentional nerve agent poisoning have been reported in the United States. The However, these agents are still present in certain chemical weapons elimination sites on military facilities. Personnel in these facilities could come in contact with these agents in case of an accidental release. The US produced approximately 4400 tons of VX between 1961 and 1969; it began destruction of its VX stores in 1969 but has not yet completed destruction at all storage sites.[5]
International
No confirmed reports exist of the use of V-series nerve agents in chemical warfare. It is possible that VX or other nerve agents were used by the Iraqis in the 1981-1987 Iran-Iraq War.[6] In February 2017, Kim Jong-nam, the older, estranged brother of Kim Jong-un, the North Korean leader, was killed in the Kuala Lumpur (Malaysia) airport. Two women rubbed chemicals onto his face in very rapid succession. Within 20 minutes, he suffered from what was described as seizures, followed by death. VX was detected in forensic analysis.[7, 8]
The Chemical Weapons Convention (CWC) took effect in 1997 and bans the production, stockpiling, and use of chemical weapons, including VX.[9] 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 two 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). With an LCt50 of 10 mg ⋅ min/m3, VX is the most toxic of the G and V-series 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-series agents are more volaitle, and in addition to penetrating the skin, they are a significant inhalational hazard. Table 2. Toxicity and Half-Lives of Nerve Agents
The onset of symptoms after exposure to a V-series 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; however, symptoms may present rapidly if a large exposure occurs. Clinical manifestations may be delayed for several hours or longer 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 V agents may be deployed in their binary form, where two precursor agents are mixed to produce the active agent. In these cases, a slightly delayed onset of symptoms can occur.[7, 8]
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. Chemical demilitarization laborers and laboratory workers may be at particular risk for exposure.
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*
View Table
See Table
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-series 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.
Degrees of toxicity
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
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. Nerve agents have also been used as part of assasination attempts of high value targets, such as spies and government officials.[7, 8, 11]
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, measurement of acetylcholinesterase (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.
AChE can be measured in red blood cells or plasma. The red blood cell cholinesterase (RBC-AChE) level is believed to be the most reliable indicator of the tissue cholinesterase status. Plasma cholinesterase (butyrylcholinesterase) levels also are referred to as pseudocholinesterase levels, because they are less predictive of central nervous system (CNS) cholinesterase activity. This often is the earliest enzyme to be inhibited by organophosphates, but that is not true for some nerve agents, particularly VX and GB.
In 2016, Schulze and colleagues released findings that accurate and precise quantitation of nerve agent metabolites can be obtained from serum, plasma, whole blood, lysed blood and postmortem blood.[12]
Order basic laboratory tests for all but minimally symptomatic patients. Measurement of electrolytes and arterial blood gases may aid in the evaluation of the patient's fluid status and the acid/base balance.
A number of new tests for the detection and quantification of chemical warfare agents are being developed. These include an active capillary dielectric barrier discharge plasma ionization (DBDI) technique for mass spectrometry, which may be useful in combination with hand-held instruments for on-site monitoring[13, 14] and a highly accurate method for detecting G- and V-series organophosphorus nerve agent adducts to butyrylcholinesterase in filtered blood, serum, or plasma.[15]
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.
Typically, request a chest radiograph for dyspneic and intubated patients. A chest radiograph may also help in the diagnosis of noncardiogenic pulmonary edema.
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.
Prehospital management includes the following:
With a vapor exposure, removal of the victim from the area of contamination, disrobing, and provision of fresh air are the most important steps, and often the only ones 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. In general, agents are best removed with copious amounts of soap and water followed by a water rinse. However, avoid unnecessary delays of decontamination while looking for soap if water is readily available. Agent neutralization and use of dilute bleach are no longer recommended for decontamination.[16]
In a study conducted by Josse and colleagues, showering hair with water one-hour post exposure led to 72% reduction of contamination of agent VX. The addition of detergent slightly increased the decontamination effectiveness. Hair treatment with Fuller's Earth (FE) or the Reactive Skin Decontamination Lotion (RSDL) 30 min prior to showering also improved the decontamination rate. The combination of FE use and showering, which yielded a decontamination factor of 41, was demonstrated to be the most effective hair decontamination procedure. In addition, hair wiping after showering further contributed to hair decontamination. These results of highlight the importance of including hair decontamination as part of decontamination protocols.[17]
The military has developed Autoinjector kits (Mark 1 kits) that contain two antidotes, an oxime (an AChE reactivator) and atropine. Antidote Treatment Nerve Agent Autoinjector (ATNAA) kits combine both antidotes in a single autoinjector and are now available. 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 planning, decontamination facilities, training, and personnel at the ED, since most victims are likely to be contaminated upon their arrival at the hospital.
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 the A, B, or C 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.
Level C provides respiratory protection with Air Purifying Respirators (APR) using filters appropriate for chemical incident response. Not approriate for use at the incident site, they may be a safe and reasonable alternative to level A or B suits for hospital-based first receivers (ie, healthcare workers at a hospital receiving contaminated victims for treatment).
The Occupational Safety & Health Administration (OSHA) has developed a set of best practices for hospital-based first receivers of victims from mass casualty incidents involving the release of hazardous substances. These cover both PPE and training of first receivers. Also see CBRNE - Chemical Decontamination.
Medical management in the ED is discussed in the Medication section.
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.
All but the mildest exposures result in 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.
Clinical Context:
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.
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.
Clinical Context:
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. The military has a 10-mg autoinjector form available, known as the CANA kit. Unlike the atropine and pralidoxime autoinjectors, this device is not used for self-administration.
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.
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.
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.
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.
Daniel C Keyes, MD, MPH, Associate Chair, Academic Affairs, Department of Emergency Medicine, St Joseph Mercy Hospital; Clinical Faculty, Emergency Medicine Residency, University of Michigan Medical School; Clinical Associate Professor, Department of Surgery, Division of Emergency Medicine and Toxicology, University of Texas Southwestern School of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Fernando L Benitez, MD, Assistant Medical Director, Dallas Metropolitan BioTel (EMS) System; Associate Professor in Emergency Medicine, Department of Surgery, Division of Emergency Medicine, University of Texas Southwestern Medical Center and Parkland Health and Hospital
Disclosure: Nothing to disclose.
Larissa I Velez-Daubon, MD, Professor, Program Director, Department Emergency Medicine, University of Texas Southwestern Medical School, Parkland Memorial Hospital; Staff Toxicologist, Department of Emergency Medicine, North Texas Poison Center, Parkland Memorial Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Duane C Caneva, MD, MSc, Senior Medical Advisor to Customs and Border Protection, Department of Homeland Security (DHS) Office of Health Affairs; Federal Co-Chair, Health, Medical, Responder Safety Subgroup, Interagency Board (IAB)
Disclosure: Nothing to disclose.
Additional Contributors
Fred Henretig, MD, Director, Section of Clinical Toxicology, Professor, Medical Director, Delaware Valley Regional Poison Control Center, Departments of Emergency Medicine and Pediatrics, University of Pennsylvania School of Medicine, Children's Hospital
CMA Public Affairs. Last VX nerve agent eliminated from Army stockpile. www.army.mil. Available at http://www.army.mil/article/15572/last-vx-nerve-agent-eliminated-from-army-stockpile/. Accessed: February 5, 2015.
Centers for Disease Control and Prevention. Facts About VX. CDC. Available at http://www.bt.cdc.gov/agent/vx/basics/facts.asp. Accessed: February 5, 2015.
Nakagawa T, Tu AT. Murders with VX: Aum Shinrikyo in Japan and the assassination of Kim Jong-Nam in Malaysia. Forensic Toxicology. July 2018. 36;2:542-544.
Shah bin Mahmood M. Post-mortem examination report for the case of Kim Chol. Malaysia. Kuala Lumpur Hospital. February 15, 2017.
Marrs TC, Maynard RL, Sidell FR. Chemical Warfare Agents: Toxicology and Treatment. England: John Wiley and Sons; 1996.
Benjamin Kentish. "Poison used on Sergei and Yulia Skripal in Salisbury attack was novichok nerve agent, confirms chemical weapons watchdog". The Independent. April 12, 2018. Available at https://www.independent.co.uk/news/uk/politics/sergei-and-yulia-skripal-in-salisbury-attack-was-a-novichok-nerve-agent-confirms-chemical-weapons-a8301121.html
Cibulsky SM, Kirk MA, Ignacio JS, Leary AD, Schwartz MD. Patient Decontamination in a Mass Chemical Exposure Incident:National Planning Guidance for Communities. Department of Homeland Security, Department of Health and Human Services. December 2014. Available at http://www.dhs.gov/sites/default/files/publications/Patient%20Decon%20National%20Planning%20Guidance_Final_December%202014.pdf
Freeman G, Ludamann H, Cornblath M. Cardiovascular and respiratory effects of an acute parathion poisoning in dogs with particular regard to ventricular fibrillation. Medical Laboratory Research Report 303. AD042287. 1954.
Parker RM, Crowell JA, Bucci TJ. Negative delayed neuropathy study in chickens after treatment with isopropyl methylphosphonofluoridate (sarin, type 1). Toxicologist. 1988. 8:248.
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
Note: The other commonly used mnemonic "SLUDGE" is not used here, as it does not include an important sign and symptom: bronchorrhea and bronchoconstriction.
