Nerve agents are chemical-warfare agents that act directly at nerve synapses, typically increasing the activity of acetylcholine.
Other chemical agents were used in combat before World War II and are sometimes called first-generation chemical agents. Subsequent-generation chemical agents include 3 types of nerve agents:
G-series agents (second-generation)
V-series agents (third-generation)
A-series agents (fourth-generation)
G-series agents, or G agents, include tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), which were developed by Nazi Germany before and during World War II. At ambient temperatures, they are watery liquids with high volatility that pose both skin-contact and inhalational hazards.
V-series agents include VX; these compounds were synthesized after World War II. They are persistent liquids with the consistency of motor oil. They evaporate very slowly, and the main hazard is from contact with liquid. They are also much more potent than the G-series agents.
A-series agents are nerve agents developed by the Soviet Union beginning in the 1970s. They are also called Novichok agents, and representative compounds are A-230, A-232, and A-234, which are liquids that are even more persistent than V-series agents and are just as potent (1, 2). An A-series agent was used in a 2018 assassination attempt in the United Kingdom (3), and another A-series agent was used in the 2020 assassination attempt on Russian activist Alexei Navalny (4).
None of these agents has a pronounced odor or causes local skin irritation. All nerve agents are organophosphorus esters, as are organophosphate pesticides. However, nerve agents are far more potent; the LD50 (the amount required to cause death in half of people receiving that dose) of VX is approximately 3 mg.
General references
1. Chai PR, Hayes BD, Erickson TB, Boyer EW. Novichok agents: a historical, current, and toxicological perspective. Toxicol Commun. 2018;2(1):45-48. doi:10.1080/24734306.2018.1475151
2. Charejoo A, Arabfard M, Jafari A, Nourian YH. A complete, evidence-based review on Novichok poisoning based on epidemiological aspects and clinical management. Front Toxicol. 2023;4:1004705. Published 2023 Jan 25. doi:10.3389/ftox.2022.1004705
3. Vale JA, Marrs TC OBE, Maynard RL CBE. Novichok: a murderous nerve agent attack in the UK. Clin Toxicol (Phila). 2018;56(11):1093-1097. doi:10.1080/15563650.2018.1469759
4. Steindl D, Boehmerle W, Körner R, et al. Novichok nerve agent poisoning. Lancet. 2021;397(10270):249-252. doi:10.1016/S0140-6736(20)32644-1
Pathophysiology of Nerve Chemical-Warfare Injuries
Nerve agents inhibit the enzyme acetylcholinesterase (AChE), which hydrolyzes the neurotransmitter acetylcholine (ACh) once ACh has finished activating receptors in neurons, muscles, and glands. Inhibition of AChE leads to an excess of ACh at all of its receptors (cholinergic crisis), first causing increased activity of the affected tissue, followed eventually in the CNS and in skeletal muscle by fatigue and failure of the tissue. Nerve agents inhibit both muscarinic and nicotinic ACh receptors. Muscarinic ACh receptors are present in the central nervous system (CNS), autonomic ganglia, smooth-muscle fibers, and exocrine glands; nicotinic ACh receptors are present in skeletal muscle.
The binding of nerve agent to AChE is essentially irreversible without treatment; treatment with an oxime can regenerate the enzyme as long as the bond has not been further stabilized (a process termed aging) over time. Most nerve agents, like organophosphate insecticides, take hours to age fully, but GD (soman) can age essentially completely within 10 minutes of binding.
Symptoms and Signs of Nerve Chemical-Warfare Injuries
The clinical manifestations depend on the state of the agent, route of exposure, and dose.
Vapor exposure to the face causes local effects such as miosis, rhinorrhea, and bronchoconstriction within seconds, progressing to the full range of systemic manifestations of cholinergic excess.
However, inhaled vapor causes collapse within seconds.
Liquid exposure to the skin first causes local effects (local twitching, fasciculations, sweating). Systemic effects occur after a latent period that can be as long as 18 hours after exposure to a very small droplet of a G- or V-series nerve agent; even fatal doses usually take up to 20 to 30 minutes to cause symptoms and signs, which may include sudden collapse and convulsions without warning. Skin exposure to a liquid A-series agent has a latent period ranging from hours to 1 or 2 days.
Patients exhibit parts or all of the cholinergic toxidrome, or cholinergic crisis (see tables Common Toxic Syndrome and Symptoms and Treatment of Specific Poisons). Overstimulation and eventual fatigue of the CNS lead to agitation, confusion, unconsciousness, and seizures, progressing to failure of the respiratory center in the medulla. Overstimulation and eventual fatigue of skeletal muscles cause twitching and fasciculations that progress to weakness and paralysis. Overstimulation of cholinergically activated smooth muscle leads to miosis, bronchospasm, and hyperperistalsis (with nausea, vomiting, and cramping), and overstimulation of exocrine glands causes excessive tearing, nasal secretions, salivation, bronchial secretions, digestive secretions, and sweating. Death is usually due to central apnea, but direct paralysis of the diaphragm, bronchospasm, and bronchorrhea can also contribute.
Long-term neurologic and neurobehavioral effects also may occur and include a syndrome that has been called chronic organophosphate-induced neuropsychiatric disorder and organophosphorus-ester–induced chronic neuropathy.
Diagnosis of Nerve Chemical-Warfare Injuries
Clinical evaluation
Diagnosis is made clinically, although laboratory analysis of erythrocyte cholinesterase or plasma cholinesterase levels as well as more specialized laboratory tests can confirm nerve-agent exposure.
Triage
All people with suspicious liquid on their skin need to be prioritized for immediate decontamination of the affected area. Patients can then be triaged for medical treatment based on their symptoms and signs. All patients exposed to nerve agents who have significant difficulty breathing or systemic effects should be triaged as immediate for medical treatment.
Treatment of Nerve Chemical-Warfare Injuries
Oxime reactivators (eg, 2-PAM, MMB-4)
Benzodiazepines
Respiratory support as needed
Attention to Airway, Breathing, Circulation, immediate Decontamination, and DSymptoms and Treatment of Specific Poisons). Airway, breathing, and circulation are addressed in standard fashion, as discussed in Cardiopulmonary Resuscitation (CPR) in Adults.
Decontamination
Decontaminate all suspicious liquid on skin as soon as possible. A 0.5% hypochlorite solution may be used, as may soap and water. Possibly contaminated wounds require inspection, removal of all debris, and copious flushing with water or saline. Severe symptoms and death may occur after skin decontamination because decontamination may not completely remove nerve agents that are passing through the skin.
Pharmacotherapy
In the United States, 2 medications are given:
11, 2). (See also Fourth Generation Agents at Chemical Hazard Emergency Medical Management [CHEMM].)
Treatment references
1. Charejoo A, Arabfard M, Jafari A, Nourian YH. A complete, evidence-based review on Novichok poisoning based on epidemiological aspects and clinical management. Front Toxicol. 2023;4:1004705. Published 2023 Jan 25. doi:10.3389/ftox.2022.1004705
2. Vale JA, Marrs TC OBE, Maynard RL CBE. Novichok: a murderous nerve agent attack in the UK. Clin Toxicol (Phila). 2018;56(11):1093-1097. doi:10.1080/15563650.2018.1469759
3. Steindl D, Boehmerle W, Körner R, et al. Novichok nerve agent poisoning. Lancet. 2021;397(10270):249-252. doi:10.1016/S0140-6736(20)32644-1
