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. Second- and 3rd-generation chemical agents include 2 types of nerve agents:
G-series agents, or G agents, include GA (tabun), GB (sarin), GD (soman), and GF (cyclosarin), which were developed by Nazi Germany before and during World War II. V-series agents include VX; these compounds were synthesized after World War II.
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.
At room temperature, G agents are watery liquids with high volatilities and pose both skin-contact and inhalational hazards. VX is a liquid with the consistency of motor oil and that evaporates relatively slowly. None of these agents has a pronounced odor or causes local skin irritation.
Fourth-generation agents are nerve agents created after the development of VX. Much information about them remains classified. They include the A-series agents, or Novichok compounds, which are low-volatility nerve agents even more persistent than VX. One of the A agents was used in a 2018 assassination attempt in the United Kingdom.
Nerve agents inhibit the enzyme acetylcholinesterase (AChE), which hydrolyzes the neurotransmitter acetylcholine (ACh) once ACh has finished activating receptors in neurons, muscles, and glands. Muscarinic ACh receptors are present in the 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. 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 central nervous (CNS) and in skeletal muscle by fatigue and failure of the tissue. Long-term neurologic and neurobehavioral effects include a syndrome that has been called chronic organophosphate-induced neuropsychiatric disorder and, more recently, organophosphorus-ester–induced chronic neuropathy.
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 a day or two.
Patients exhibit parts or all of the cholinergic toxidrome, or cholinergic crisis (see tables Common Toxic Syndrome (Toxidromes) 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.
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.
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.
Attention to Airway, Breathing, Circulation, Immediate Decontamination, and Drugs (the ABCDDs) is paramount. Bronchoconstriction may be so severe that ventilation may be impossible until atropine is given (see table Symptoms and Treatment of Specific Poisons).
In the US two drugs are given, atropine and 2-pyridine aldoxime methyl chloride (2-PAM—also called pralidoxime). Atropine blocks the action of acetylcholine (ACh) at muscarinic receptors. 2-PAM reactivates acetylcholinesterase (AChE) that has been phosphorylated by nerve agents (or organophosphate insecticides) but that has not yet undergone aging. Because atropine acts only at muscarinic ACh receptors, 2-PAM is also needed to reverse effects on skeletal muscles (eg, twitching, respiratory-muscle weakness and paralysis). The oxime 1,1′-methylenebis[4-[(hydroxyimino)methyl]-pyridinium dibromide, or MMB-4, appears to be more effective against a broader range of nerve agents than is 2-PAM and will replace 2-PAM for US military use in the next few years.
For prehospital care, autoinjectors for intramuscular use are typically used; each contains 2.1 mg of atropine and 600 mg of 2-PAM. The drugs are given into the belly of a large muscle (eg, thigh) before establishing IV access. Once IV access is obtained, subsequent doses are given IV.
Adult patients with significant difficulty breathing or with systemic effects should promptly receive three 2.0-mg or 2.1-mg doses of atropine and three 600-mg doses of 2-PAM followed immediately by 2 to 4 mg of diazepam (also available as 2-mg autoinjectors) or 1 to 2 mg of midazolam (which is better absorbed intramuscularly than diazepam). Patients with less severe signs and symptoms can be given one combination autoinjector repeated in 3 to 5 minutes if symptoms have not resolved; a benzodiazepine is not automatically given unless 3 autoinjectors are required to be given all at once. Additional 2-mg doses of atropine are given every 2 to 3 minutes until muscarinic effects (airway resistance, secretions) resolve. Additional 600-mg doses of 2-PAM may be given hourly as needed for the control of skeletal-muscle effects (twitching, fasciculations, weakness, paralysis). Additional doses of benzodiazepines are given as needed for seizures. Note that paralyzed patients may have seizures in the absence of visible convulsions. Transition to IV administration should be done at the first opportunity. Dosages are adjusted downward for children.
Decontaminate all suspicious liquid on skin as soon as possible using Reactive Skin Decontamination Lotion (RSDL®); a 0.5% hypochlorite solution may also 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.
A-series agents are difficult to treat once victims have gone into cholinergic crisis; aggressive treatment with atropine and an oxime is needed along with scopolamine 1 mg IV. During the latent period, victims need to be decontaminated thoroughly as soon as possible, although decontamination may be effective even an hour or two after exposure. Heart rate, core temperature, and acetylcholinesterase (AChE) levels should be monitored.
If exposure to a nerve agent is anticipated, pretreatment with pyridostigmine bromide 30 mg orally every 8 hours should be considered. This compound is a reversible carbamate anticholinesterase. Because pyridostigmine combines reversibly with acetylcholinesterase, it actually protects the enzyme from the essentially irreversible inhibition by subsequently delivered nerve agent; after the reversible bond is broken, the released cholinesterase can then help hydrolyze excess acetylcholine in target organs.
Pyridostigmine was originally intended for potential exposure to the fast-aging nerve agent soman (GD) but is now authorized as pretreatment for all G-, V-, and A-series nerve agents. Thus, it could also make sense to use pyridostigmine during the long latent period after suspected exposure to A-series agents. However, because pyridostigmine also is an acetylcholinesterase inhibitor, it should not be given after the onset of cholinergic crisis or even if the heart rate or core temperature decreases by > 25% from baseline; such patients should be treated for cholinergic crisis.
The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army, Department of Defense, or the US Government.