V-Series (Ve, Vg, Vm, Vx) Toxicity


Article Author:
Matthew Smith


Article Editor:
Henry Swoboda


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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Avais Raja
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Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
3/31/2019 11:22:08 PM

Introduction

V-Series nerve agents are organophosphate esters that are used as chemical weapons. They are extremely potent acetylcholinesterase inhibitors. Biological effects include seizures, salivation, lacrimation, urination, diaphoresis, diarrhea, vomiting, miosis, and muscles spasms. As little as a few milligrams of some V-series agents can be lethal to humans.

Etiology

The V-series nerve agents were first discovered in 1952 by scientists in the United Kingdom researching organophosphate esters as pesticides. The five most well-known V-series nerve agents are VX, VE, VG, VM, and VR. V-series nerve agents are highly viscous and have low volatility; thus, they can persist in the environment and are difficult to wash away. They are oily liquids at room temperature. Some V-series agents can be deployed as binary agents, in which two non-toxic chemicals react together inside the weapon before deployment to form the chemical weapon. For example, isopropyl aminomethyl ethyl phosphorite and elemental sulfur react to form VX. V-series agents can be deployed as liquids or aerosols.

Epidemiology

Thousands of tons of V-series nerve agents were stockpiled during the 1950s and 1960s in the form of rockets, bombs, artillery shells, aerosol sprays, and landmines. Remnants of VX were detected on warheads used by Saddam Hussein against Iraqi Kurds in Halabja in 1988. The Japanese cult Aum Shinrikyo used VX to attack three people in 1994 and 1995, one of whom died. Stockpiles of V-series nerve agents continue to be disposed of following the 1997 Chemical Weapons Convention. The remaining VX in the United States will be destroyed at the Blue Grass Chemical Agent Destruction Pilot Plant near Richmond, Kentucky.

Pathophysiology

V-series nerve agents inhibit acetylcholinesterase when the enzyme binds a phosphoryl group in the esteratic subsite. The role of the acetylcholinesterase enzyme is to break down acetylcholine in the synapse into acetate and choline, and the enzyme can degrade approximately 25,000 molecules of acetylcholine per second. When the acetylcholinesterase enzyme is inhibited, it causes acetylcholine to accumulate in the synapse and thus continue to stimulate the acetylcholine receptors. Salivation, lacrimation, urination, diarrhea, and vomiting are caused by the stimulation of muscarinic acetylcholine receptors in the parasympathetic nervous systems. Skeletal muscle symptoms are caused by the stimulation of nicotinic acetylcholine receptors. Nerve agents have also demonstrated the ability to inhibit other enzymes, including neurotoxic esterase (NTE). [1] [2]

Toxicokinetics

The median lethal dose of VX for humans is approximately 6 to 10 milligrams by dermal exposure. Absorption is rapid (seconds to minutes) by inhalation but is significantly slower (minutes to hours) by dermal exposure. V-series nerve agents are odorless and tasteless. Biologic half-lives of V-series agents in humans are dependent on the dose administered as well as numerous other factors. 

History and Physical

The only use of V-series nerve agents (other than for research) is a chemical weapon. Thus, patients exposed to these agents may present in large numbers and report a history consistent with a terrorist attack. Symptoms are identical to those of the organophosphate toxidrome and include seizures, salivation, rhinorrhea, lacrimation, urination, diaphoresis, diarrhea, vomiting, miosis, and muscles spasms. Other symptoms include bronchospasm, central apnea, and bradycardia. Most deaths occur because of respiratory failure from the combination of respiratory symptoms. Those who survive nerve agent exposure may experience insomnia, depression, anxiety, irritability, and impaired memory and judgment. Ocular symptoms such as miosis, dim vision, blurry vision, and eye pain may persist for several weeks following exposure. Long-term neurologic effects of nerve agents have been reported.[1]

Evaluation

Exposure to V-series nerve agents should be considered if there is a clinical history concerning for exposure to nerve agents or symptoms of nerve agent exposure. Decontamination and treatment should begin as soon as possible. Laboratory tests for the presence of V-series agents in the body are not readily available and are not used to guide management. Patients may demonstrate lab abnormalities consistent with metabolic acidosis and the breakdown of striated muscle. Decreased erythrocyte cholinesterase levels may be observed after exposure to nerve agents. V-series nerve agents can also be detected in patients or in the environment by M8 paper, M9 tape, the M256A1 Chemical Agent Detector Kit, or the Joint Chemical Agent Detector (JCAD). [3] [4] [5] [6] [7] [8]

Treatment / Management

The most important treatment is to terminate the patient's exposure by removing them from the contaminated environment and performing decontamination. Decontamination of the patient should be performed before further medical treatment if possible. Some nerve agents may remain in the skin and continue to cause symptoms via a depot effect. Patients can be decontaminated by washing the affected areas with a 0.5% hypochlorite solution or with soap and clean water. However, the most effective method of decontamination of patients exposed to nerve agents is Reactive Skin Decontamination Lotion (RSDL), which should be used if availabe. The ingredients of Reactive Skin Decontamination Lotion sequester, retain, and neutralize organophosphate chemical warfare agents. Patients with large areas of dermal exposure will require numerous Reactive Skin Decontamination Lotion sponges to be effectively decontaminated. Patients known to have been exposed to nerve agents or those exhibiting symptoms of nerve agent exposure should be given the antidote medications atropine and pralidoxime. Atropine works by binding and blocking muscarinic acetylcholine receptors, thus preventing the buildup of acetylcholine from continuing to affect the receptors. Because atropine does not act on nicotinic receptors, it will not improve skeletal muscle symptoms. Atropine should be administered until there is clinically evident recution of airway secretions and airway resistance; doses of atropine can be given every three to five minutes. When administered soon after exposure to nerve agents, pralidoxime (also known as 2-pyridine aldoxime methyl chloride or 2-PAM Cl) removes the phosphyl moiety from acetylcholinesterase, thus reactivating the enzyme. Dual-chamber auto-injectors have been developed containing atropine sulfate and pralidoxime; examples of these include the Mark I Nerve Agent Antidote Kit (NAAK) or the newer Antidote Treatment Nerve Agent Autoinjector (ATNAA). Each Antidote Treatment Nerve Agent Autoinjector contains 2.1 mg of atropine and 600mg of pralidoxime. Patients are also given diazepam or midazolam to prevent seizures and convulsions. When given intramuscularly, midazolam is absorbed faster than diazepam. The United States military uses a specialized diazepam auto-injector called the Convulsive Antidote Nerve Agent (CANA). Patients may be given up to three Antidote Treatment Nerve Agent Autoinjector autoinjectors. After three Antidote Treatment Nerve Agent Autoinjector have been given, patients may receive additional doses of atropine every three to five minutes as clinically indicated, however additional doses of pralidoxime should not be given for 60 to 90 minutes. Patients who receive three Antidote Treatment Nerve Agent Autoinjector autoinjectors should also receive a Convulsive Antidote Nerve Agent (or a dose of benzodiazepine) even if there is no visible evidence of seizures. Medication administration by autoinjector has been shown to cause plasma concentrations of these medications to each therapeutic levels faster than intramuscular administration using a needle and syringe. Scopolamine is effective at blocking muscarinic effects of acetylcholine in the central nervous system, and low doses of scopolamine can significantly reduce the amount of atropine needed for a patient. Opiates, phenothiazines, antihistamines, and succinylcholine should be avoided in patients that have been exposed to V-series nerve agents. [9] [10] [2] [11] [12] [13]

Enhancing Healthcare Team Outcomes

The assassination of Kim Jong-nam with VX in the Kuala Lumpur International Airport in February 2017 and the poisoning of Sergei and Yulia Skripal with a 'novichok' (Russian for 'newcomer') nerve agent in the United Kingdom in March 2018 serve as examples of how nerve agent attacks with even one or two victims will quickly become international news. Once a patient has been diagnosed with a V-series nerve agent exposure, healthcare providers will be responsible for communicating not only numerous colleagues and staff but also with public health officials, law enforcement agencies, members of the media, and elected officials. The marshaling of resources to respond will almost certainly reach the national and international levels. (Level V)

Important communication points early in the care of the patient among physicians, nurses, and pharmacists will include adequate decontamination of the patient and appropriate precautions for first responders and hospital staff to avoid additional casualties. Training and education prior to such an event will be more effective than just-in-time training after an event has occurred when emotions run high and resources may run low. In large-scale events, it will be essential for healthcare staff to have a clear understanding of their available resources, and continuously communicating with government officials to access medical supply stockpiles and resources for the capacity to treat large numbers of patients will be vital. (Level V)


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V-Series (Ve, Vg, Vm, Vx) Toxicity - Questions

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Which of the following enzymes are inhibited by V-series nerve agents?



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What are the symptoms of V-series nerve agent exposure?



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Paramedics report that a tasteless, odorless gas has been released at a large concert. The patients have been vomiting, urinating, sweating, drooling, coughing, seizing, and experiencing episodes of diarrhea. First responders who did not use appropriate personal protective equipment have begun to demonstrate similar symptoms as well. HAZMAT responders on scene then report that the gas is a V-series nerve agent. After appropriate decontamination has been performed on the incoming patients, what medications should be given?



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A mass casualty event has taken place in which a V-series nerve agent was used in a crowded area. Patients are being extricated from the scene, decontaminated, and treated with atropine and pralidoxime autoinjectors before arriving at the medical facility. Some patients have continued seizure-like activity despite having received three atropine and pralidoxime autoinjectors. Which medications would best help these patients?



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V-Series (Ve, Vg, Vm, Vx) Toxicity - References

References

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Developments in alternative treatments for organophosphate poisoning., Iyer R,Iken B,Leon A,, Toxicology letters, 2015 Mar 4     [PubMed]
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[Medical management in the chemical terrorism scene]., Krivoy A,Rotman E,Layish I,Goldberg A,Horvitz A,Yehezkelli Y,, Harefuah, 2005 Apr     [PubMed]
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Terrorist Event Training in US Medical Schools. A Survey of Chemical, Biologic, Radiologic, Nuclear, and High-Yield Explosives Training in US Medical Schools., Feeney JM,Ziegler K,Armstrong JM,Shapiro D,, Connecticut medicine, 2015 Nov-Dec     [PubMed]
Medical Countermeasures for Children in Public Health Emergencies, Disasters, or Terrorism.,, Pediatrics, 2016 Jan 4     [PubMed]
Current and emerging strategies for organophosphate decontamination: special focus on hyperstable enzymes., Jacquet P,Daudé D,Bzdrenga J,Masson P,Elias M,Chabrière E,, Environmental science and pollution research international, 2016 Feb 2     [PubMed]
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