Office of Emergency Coordination (OEC)

OEC Update: June 2017 Nerve Agents

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Nerve Agents

Recent reports of the use of nerve agents in Syria, including by ISIS, have again focused attention on this particular class of chemical weapons. Nerve agents – the best known are sarin, soman, tabun, cyclosarin, and VX – can be extremely lethal, even at small doses. While antidotes are available, they must be administered quickly to prevent death in severely poisoned individuals.

Given the events of recent years, it seems reasonable to believe that certain terrorist organizations would be willing to use these agents against civilian populations in western countries. Consequently, nerve agents should be seen by Americans as a legitimate threat.

Nerve agents are the most toxic and rapidly acting of the known chemical warfare agents.

Sarin Attack on the Tokyo Subway System, 1995

– For a very brief history of the development of nerve agents, and examples of their use by militaries and by terrorists, see Appendix A.

– Nerve agents are similar to organophosphate insecticides in terms of their mechanism of action and the signs and symptoms they produce. However, nerve agents are much more potent.

Nerve agents (and other chemical warfare agents) have a number of characteristics that would make them attractive to terrorists.

– “Chemical agents . . . . are appealing to terrorists because compared to biologicals, chemicals are ubiquitous, inexpensive, and more stable. . . . the technology required to produce a nerve agent like sarin is readily accessible to any moderately experienced chemist. Additionally, chemical agents used as weapons, especially nerve agents, are more dramatic [in their effects] than biological weapons. As history has shown, chemical agents can wreak havoc in urban settings; onlookers bear witness to the convulsive sequelae of an insidious chemical poisoning that needs no heralding of an exploding shell.” (Medical Aspects of Chemical Warfare – USAMRICD 2008, p.126.)

– “The general tendency of many terrorism experts is to declare ‘it’s not a question of if, but when terrorists will use chemical agents against noncombatants [and this has already occurred – see Appendix A]. This view is focused primarily on the vulnerability of unprotected civilians, increased access to education sources, and increased availability of technology with hazardous materials in a global economy. Additionally, pound for pound, chemicals are much more potent than conventional explosives, causing many experts to speculate that terrorists would naturally be interested in weapons that could cause the most casualties.” (Medical Aspects of Chemical Warfare – USAMRICD 2008, p.126.)

Nerve agents can be dispersed from spray tanks, and from bombs, rockets, artillery shells, and other large munitions.

Nerve agents, as their name implies, affect the nervous system, and the result is an overstimulation of muscles and glands. Among the muscles and glands that are overstimulated are those in the walls of the small airways of the lungs, resulting in difficulty breathing because of constriction of these airways and the presence of copious secreations. In addition, large doses of a nerve agent cause seizures and apnea (cessation of breathing) due to effects on the central nervous system. A more detailed description of the mechanism of action of these agents is shown in Appendix B.

Signs and symptoms, which will vary depending on the type and extent of exposure (see table below), can appear quickly: as short as a few seconds after inhalation of the vapor form of the agent, and within a few

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minutes to hours after skin exposure to the liquid form. With severe poisoning, death may occur within approximately 10 minutes unless the individual receives appropriate medical management, including the use of antidotes. Causes of death are respiratory failure and depression of the central nervous system.

Onset and Signs/Symptoms of Nerve Agent Exposure

Nerve Agents (UPMC Center for Health Security, 2013)

Transdermal = through the skin. Miosis = excessive smallness or contraction of the pupil of the eye. Rhinorrhea = excessive mucous secretion from the nose.

Dyspnea = shorthess of breath; labored or difficult breathing. Apnea = cessation of breathing.

Diagnosis (and the initiation of treatment) will generally be based on history and on signs and symptoms. Miosis (constriction of the pupils) will usually be present except in some persons who have experienced transdermal exposure (i.e., exposure through the skin). Although laboratory tests are available, the results will not be received soon enough to be useful in making emergency clinical decisions.

Treatment consists of supportive care and the use of the drugs atropine and pralidoxime chloride as antidotes.

– Supportive care can include suctioning of airway secretions (which can be massive) and, with severe poisoning, intubation and the provision of supplemental oxygen.

– Atropine and pralidoxime chloride can be given intramuscularly (IM, including by auto-injector) and intravenously (IV). Appendix B contains a brief description of the mechanism of action of these antidote drugs.

– In addition to the antidotes, diazepam or similar injectable benzodiazepine drugs can be used to

Atropine Autoinjector and

Pralidoxime Chloride Autoinjector

Diazepam Autoinjector

mitigate the seizures that can be associated with nerve agent exposure.

Full recovery from severe poisoning can take months. Also, survivors of severe poisoning are at risk for significant residual disability if hypoxia-causing events occurred, such as cardio-respiratory arrest. (Hypoxia is a deficiency in the amount of oxygen reaching the tissues.)

Following an attack with a nerve agent, first responders and emergency medical personnel can be at risk for secondary exposure and possible toxicity from direct contact with contaminated skin or clothing, or from vapors trapped in clothing. Appropriate personal protective equipment (PPE) should be utilized, and all patients must be decontaminated as necessary before transfer to the treatment area in a medical facility.

Sources:

Nerve Agents (UPMC Center for Health Security, 2013) http://www.upmchealthsecurity.org/our-work/pubs_archive/pubs-pdfs/fact_sheets/nerve_agents.pdf

Organophosphorus Pesticides and Nerve Agents - Tabun [GA], Sarin [GB], Soman [GD], and VX (CDC) https://chemm.nlm.nih.gov/nerveagents.htm

Nerve Agents (DHSS) http://health.mo.gov/emergencies/ert/med/nerveagents.php

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Appendix A

Very Brief History of Nerve Agent Development and Use

Nerve agents were developed in Germany prior to World War II. During the war, the Nazis reportedly produced, and put into munitions, 10,000-30,000 tons of tabun and smaller quantities of sarin. However, these weapons were never used.

During the Iran-Iraq War in the 1980s, Iraq used large quantities of tabun and sarin against Iranian forces, causing tens of thousands of casualties. There have also been unconfirmed reports that Iran may have developed nerve agents and used them against Iraq.

A House Armed Services report in 1993 mentioned 31 nations as possessing or having the ability to develop offensive chemical weapons. It has been noted that because chemical weapons are less expensive and easier to acquire than nuclear weapons, they are a credible threat from developing nations.

In the mid-1990s, the Japanese cult group Aum Shinrikyo carried out two successful nerve agent attacks on civilian populations, resulting in the deaths of 19 people and significant illness in many others.

– In June 1994 cult members released sarin from the back of a van in Matsumoto, Japan, resulting in a cloud of agent being spread over a 500 by 100-yard area. Seven people were killed and over 140 were injured.

– In March 1995, the group released sarin in the Tokyo subway during the morning commute. The sarin, which was contained in polyethylene bags, was brought onto several trains by group members, and then once on board, the bags were punctured with umbrellas. Passengers at multiple subway stations were subsequently exposed to the agent. Twelve people died, and approximately 900 individuals required hospitalization, with 54 in “critical condition.” Among the hospitalized were 135 emergency responders. Also, over 5,500 persons who apparently did not have actual exposure to sarin presented to hospitals and demanded screening and treatment.

– In addition to these attacks, the cultists may have discussed plans to use sarin in attacks within the United States. Also notable is the fact that the group’s “chemical agent facility” in Japan, at the time it was raided by police, reportedly had on hand enough precursor materials to produce 50 tons of sarin.

Medical Aspects of Chemical Warfare (USAMRICD, 2008) http://www.cs.amedd.army.mil/borden/Portlet.aspx?id=d3d11f5a-f2ef-4b4e-b75b-6ba4b64e4fb2

Nerve Agents Tabun (GA) Sarin (GB) Soman (GD) GF VX

Summary: Nerve agents inhibit the enzyme acetylcholinesterase (AChE), which can then no longer break down its substrate, the neurotransmitter chemical acetylcholine (ACh). As a result, excess amounts of ACh accumulate, resulting in over-stimulation of certain nerves, muscles, and glands, thus causing the specific signs/symptoms of nerve agent poisoning. Antidotes are atropine (an ACh inhibi-tor) and 2-PAM Cl (which breaks the nerve agent-AChE bond and hydrolyzes the nerve agent to restore the normal activity of AChE).

Enzyme: A protein (or protein-based molecule) that speeds up a chemical reaction which converts one substance (called the substrate) into another

substance(s).

Neurotransmitter: A chemical that is released from a nerve cell and stimulates the adjacent nerve to fire, the adjacent muscle to contract, or the adjacent

gland to secrete.

Normal functioning of ACh and AChE, and the effects of exposure to a nerve agent:

Nerve cells are electrically conducting cells

(although from one cell to another, the signal is

no longer electrical, but chemical).

The connection between cell and cell is called

the synapse, and the space between the cells,

the synaptic cleft.

When a nerve cell fires, an electrical impulse

travels down the nerve, causing release of the

neurotransmitter chemical, ACh (there are

other neurotransmitters, but only ACh is being

discussed here).

ACh diffuses across the synaptic cleft to the

post-synaptic nerve.

When ACh reaches the post-synaptic nerve

cell, it attaches to post-synaptic cholinergic

receptors located on the cell. The result is that

the cell is stimulated to fire (i.e., stimulated to

initiate an electrical impulse that then proceeds

down the cell).

The enzyme AChE (which is actually located

on the post-synaptic membrane) is the turn-off

switch to this system. It destroys (hydrolyzes)

the neurotransmitter Ach, which ends the

reaction and keeps it regulated. Put simply, no

more transmitter, no more impulse, no more

end-organ activity.

An acetylcholinesterase inhibitor, such as a

nerve agent, inhibits AChE and consequently

it does not destroy ACh. As a result, excess

ACh accumulates and continues to stimulate

the post-synaptic nerve.

In the above diagrams, the nerve cell on the left interacts with another nerve cell

(the post-synaptic nerve) located on the right. However, the nerve cell on the left

could also interact with smooth or skeletal muscle, or with a gland. Regardless, the

functioning of ACh and AChE is essentially the same, and the presence of an

acetylcholinesterase inhibitor (e.g., nerve agent) will result in excess ACh and

over-stimulation of the end organ, whether this end organ is a nerve, a muscle, or a

gland – over-stimulation will lead to repeated firing of the post-synaptic nerve,

excessive contraction of the muscle, or excessive secretion of the gland.

Appendix B

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Types of cholinergic receptors/organ systems affected: 2 major types of post-synaptic cholinergic receptors: 1) muscarinic, and 2)

nicotinic. The following table shows the location of these receptors and the actions that result from excessive stimulation by ACh.

Muscarinic Receptors

Smooth (non-voluntary) muscles

Small airways – constrict difficulty breathing

GI tract – constrict peristalsis, bowel sounds, and possibly nausea, vomiting, and diarrhea

Pupils - constrict miosis

Exocrine glands Eyes, nose, mouth, sweat glands,

airways, GI tract - secrete

Certain cranial nerves

Vagus nerve heart rate

Nicotinic Receptors

Skeletal muscles – contract fasciculations, twitching, fatigue, flaccid paralysis

Pre-ganglionic nerves in the sympathetic

nervous system heart rate, possible blood pressure

Both Muscarinic and Nicotinic Receptors

Central Nervous System (CNS)

(with large dose of nerve agent) loss of consciousness, seizures, apnea (because of loss of central respiratory drive), and death.

(with small, acute dose of nerve agent)

slowness in thinking and decision-making, sleep disturbances, poor concentration, emotional problems.

The most life-threatening problem will be to the airways, not just from the smooth muscle hyperactivity but also from the increased

secretions from exocrine glands in these airways. Also, large doses of nerve agent cause seizures and apnea due to effects on the CNS.

Signs/Symptoms:

Nerve Agent Effects - Vapor Exposure Nerve Agent Effects - Liquid on Skin

Mark I Kit: Contains Atropine and 2-PAM Cl autoinjectors

DuoDote: A single autoinjector containing both Atropine and 2-PAM Cl

General management principles:

Airway, Breathing, Circulation

Drugs (nerve agent antidotes)

Decontamination - can be done with soap

and water. Must decon skin within 1-2

minutes of exposure to liquid nerve agent

to ensure no lasting effects; little benefit to

patient after 30 minutes. But even after this

time, decon is necessary to protect persons

providing care to the patient (if the

patients’s skin or clothing is contaminated

with liquid nerve agent, care givers can be

contaminated by direct contact or through

off-gassing vapor). Skin decon is not

necessary after exposure to vapor alone,

but clothing should be removed as it may

contain "trapped" vapor.

Supportive care of the airway

Anticonvulsant therapy (such as diazepam,

lorazepam, or other benzodiazepines)

Nerve agent antidotes:

Atropine - competitive inhibitor of ACh. Atropine has extremely fast action at

muscarinic receptors, preventing ACh from interacting with them. Because it can

quickly restore patients’ ability to breathe, it can be life-saving. Does not bind to

nicotinic receptors, so nicotinic effects of nerve agents are not affected by atropine.

Pralidoxime chloride (Protopam chloride,

2-PAM Cl) – an oxime which attaches to the

nerve agent that is inhibiting the AChE, breaks

the AChE-nerve agent bond, and then hydrolyzes

the nerve agent to restore the normal activity of

the AChE. Effect at nicotinic sites is to skeletal

muscle strength; however, when used in

combination with atropine, one does not see much

additional clinical effect at muscarinic sites.

Within a certain period of time after the nerve

agent binds to AChE, a second reaction (called

“aging”) occurs. Once the AChE-nerve agent

complex has “aged”, an oxime is no longer

effective. Aging times: Soman (GD) 2 minutes;

Sarin (GB) 3-4 hours; other agents take longer.

Slides and text were taken from a USAMRICD CD-ROM entitled Medical Management of Chemical Casualties: MMCC Supplemental Training Materials, v. 4.00. Additional text was taken from USAMRICD. Medical Management of Chemical Casualties (3rd Ed), July 2000.

Effects from nerve agent vapor begin within seconds to several minutes after exposure. Loss of consciousness and seizure onset have occurred within a minute of exposure to a high concentration. Effects may continue to progress for a period of time, but maximal effects usually occur within minutes after exposure stops.

A large amount of liquid on the skin causes effects within minutes. Commonly see an asymptomatic period of 1-30 min, and then sudden onset of a cascade of events, including loss of consciousness, seizures, apnea, and muscular flaccidity. After small amounts of liquid agent on the skin, onset of effects has been delayed for up to 18 hrs after contact. Initially these effects are GI.

June 2017 For additional information on nerve agents, go to:

http://health.mo.gov/emergencies/ert/med/nerveagents.php