Nerve Agents

Etiology

The etiology of nerve agent toxicity is primarily environmental exposure. Patients can be exposed to nerve agents via occupational exposure or bioterrorism. Organophosphates and carbamates found in many insecticides occasionally cause toxicity in agricultural and industrial workers. Synthetic nerve agents like soman, tabun, sarin, and V-series have been used in bioterrorism in the past and present.

Soman

A volatile liquid nerve agent, soman was originally developed in Germany during World War II but was never used in warfare.

Tabun

Tabun is an organophosphorus compound, first synthesized in Germany. During the Nuremberg trials, a military officer admitted to conspiring to assassinate Adolf Hitler in his bunker with Tabun.

Sarin

Sarin is highly volatile. Death from respiratory paralysis can occur in as little as 1 to 10 minutes. Sarin was used in the 1995 Tokyo subway attack, killing 12 people.[1] 

V-Series

The V-series nerve agents were first discovered in 1952 by scientists researching organophosphate esters as pesticides in the United Kingdom. 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 2 nontoxic 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.

The following are the 5 most well-known V-series nerve agents:

• VX: O-Ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate 
  • A synthetic, nonvolatile liquid nerve agent
  • Used in the assassination of North Korea's Kim Jong Un's half-brother, Kim Jong Nam, in February 2017
• VE: O-Ethyl-S-[2-(diethylamino)ethyl] ethylphosphonothioate
• VG: O,O-Diethyl-S-[2-(diethylamino)ethyl] phosphorothioate
• VM: O-Ethyl-S-[2-(diethylamino)ethyl] methylphosphonothioate
• VR: N-diethyl-2-(methyl-(2-methylpropoxy)phosphoryl)sulfanylethanamine
  • The compound from which Soviet newcomer agents (Novichok), Novichok 5, and Novichok 7 are derived [2]

Novichok ("Newcomer") Agents

Primarily developed between the 1970s and 1990s, the Novichok agents exist in either solid or liquid form and are thought to be significantly more toxic than other nerve agents, likely due to rapid aging, which results in irreversible binding to the acetylcholinesterase enzyme and resistance to oxime antidotes. A Novichok agent is thought to be responsible for the poisoning of Alexei Navalny in 2020.[3][4]

• A-230: N-2-diethylaminomethylacetoamidido-methylphosphonofluoridate
  • First of the A-series Novichok agents, can crystallize at low temperatures
• A-232: methoxy-(1-(diethylamino)ethylidene)phosphoramidofluoridate
  • Resistant to colder temperatures, distinct from prior nerve agents because it is not a phosphonate [5]
• A-234: N-2-diethylaminomethylacetamido-ethoxyphosphonofluoridate
  • Thought to be the agent responsible for the poisonings of Sergei and Yulia Skripal in 2018 [6]

Epidemiology

While chemical weapon or bioterror nerve agent poisoning is relatively rare, organophosphate and carbamate toxicity affects over 10,000 people in the United States and over 3,000,000 worldwide each year. Up to 300,000 deaths per year are attributable to insecticides, herbicides, rodenticides, and, more rarely, chemical warfare agents like soman, sarin, tabun, and V-series.[7] Clinical situations in which nerve agent toxicities include agricultural accidents, bioterrorism, and industry.

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. VX warheads were used by Saddam Hussein against Iraqi Kurds in Halabja in 1988.[8] The Japanese cult Aum Shinrikyo used VX to attack 3 people in 1994 and 1995, of which 1 died.[9] Stockpiles of V-series nerve agents continue to be disposed of following the 1997 Chemical Weapons Convention. The remaining VX in the United States was destroyed at the Blue Grass Chemical Agent Destruction Pilot Plant near Richmond, Kentucky. Russia has developed a series of Novichok agents that are more potent than the first generation of V agents, which have been implicated in several assassinations.

Pathophysiology

Nerve agents like organophosphates are primarily absorbed in the body through the lungs, skin, and gastrointestinal tract. In general, nerve agents bind and phosphorylate acetylcholinesterase (AChE), leading to the inactivation of the enzyme and excess amounts of acetylcholine (ACh) at autonomic synaptic clefts and at the neuromuscular junction. The pathophysiologic mechanism of this process occurs when the phosphorus moiety binds to the serine hydroxyl group in the esteratic subsite of AchE. The role of the AChE enzyme is to break down ACh in the synapse into acetate and choline; the enzyme can degrade approximately 25,000 ACh molecules per second. However, when the AChE is inhibited, acetylcholine accumulates in the synapse and thus continues to stimulate the ACh receptors.

Excessive ACh leads to constant depolarization of the postsynaptic neurons, which causes the symptoms of nicotinic and muscarinic toxicity. Until new AChE is synthesized or an oxime like pralidoxime is used to displace the organophosphate from AChE, ACh persists in the neuromuscular junction, constantly binding the muscarinic and nicotinic receptors, leading to the signs and symptoms of cholinergic excess. The stimulation of muscarinic acetylcholine receptors in the parasympathetic nervous system causes salivation, lacrimation, bronchorrhea, bronchospasm, urination, diarrhea, and vomiting. Stimulation of nicotinic acetylcholine receptors causes skeletal muscle symptoms of fasciculation and paralysis. Nerve agents have also demonstrated the ability to inhibit other enzymes, including neurotoxic esterase.[10][11]

After the initial phosphorylation of AChE by a nerve agent, a conformational change known as "aging" can occur, during which an alkoxy group is lost from the phosphorylated enzyme. Aging is clinically significant because it renders AChE permanently inactive and prevents reactivation by oximes. The rate of aging varies between nerve agents. For example, soman ages rapidly, within 5 to 8 minutes, whereas VX has a much slower aging process, requiring as much as 24 hours.[12] Early recognition of symptoms and prompt treatment with oximes are critical before aging occurs; once aging has occurred, the patient will no longer respond to oxime treatment and may continue to experience symptoms until AChE is spontaneously regenerated.[13]

Toxicokinetics

The toxicokinetics of nerve agents vary significantly depending on the specific agent and route of exposure. 

Absorption

Nerve agents are rapidly absorbed through inhalation, dermal exposure, ingestion, and ocular absorption:

• Inhalation: Absorption occurs within seconds to minutes via the respiratory epithelium and is the primary clinical route of exposure.[14] G-series agents, such as sarin, pose a greater inhalation risk than V-series agents. 
• Dermal exposure: Dermal absorption is thought to be slower but significant, especially for the lipophilic V-series agents, such as VX, which can penetrate intact skin.[15]
• Ocular absorption: Eye exposure can in rapid absorption. Miosis is an early sign of exposure.
• Ingestion: Ingestion is rare but effective for absorption.

Distribution

Once absorbed, nerve agents rapidly distribute to tissues, particularly those rich in cholinergic activity, including the central nervous system, skeletal muscles, and autonomic nervous system. G-series agents (eg, sarin) cross the blood-brain barrier more readily than VX, resulting in earlier and more profound central effects. Lipophilic agents, particularly VX, tend to accumulate in adipose tissues, contributing to prolonged effects.

Metabolism

Metabolism of nerve agents primarily involves enzymatic hydrolysis by paraoxonase-1 (PON1) and other nonspecific esterases. The rate of metabolism differs among agents.[16]

• Sarin (G-series, B) is rapidly metabolized in the plasma and liver.[17]
• Soman (G-series, D) undergoes very rapid aging after binding to AChE, making oxime therapy ineffective shortly after exposure.
• VX is metabolized more slowly than G-series agents, with a significant portion excreted unchanged, and its active metabolite, EA 2192, exhibits significant toxicity.[18]

Elimination

Nerve agents are eliminated through renal excretion of both the parent compound and its metabolites. Biological half-lives vary by agent. Due to irreversible binding to AchE, the duration of their effect may be prolonged beyond elimination.

Aging and Recovery

The phenomenon of aging—a conformational change in the AChE-phosphorylated complex that renders it irreversibly inactive—is among the factors most predictive of toxicity of the nerve agents:

• Soman (G-series, D) ages rapidly, within 5 to 8 minutes, leaving a very short window after exposure for effective oxime therapy.
• Sarin (G-series, B) ages more slowly, allowing more time for oxime intervention.
• Cyclosarin (G-series, F) and VX age more slowly, with VX taking as much as 24 hours to age, providing an extended opportunity for antidotal therapy.
• The Novichok agents are thought to age very rapidly, similar to Soman.[19]

Recovery of AChE activity occurs only via spontaneous enzyme regeneration or de novo synthesis, processes that can take days to weeks. During this time, clinical symptoms may persist.

History and Physical

Acute Clinical Features of Nerve Agent Toxicity

Nerve agent toxicity causes excessive cholinergic stimulation, which is summarized by the classic symptomatology acronym DUMMBBELS: defecation, urination, muscle weakness, miosis, bradycardia, bronchospasm, bronchorrhea, emesis, lacrimation, and salivation. Other symptoms include central apnea and bradycardia. ACh binding at nicotinic receptors results in muscle fasciculations, cramps, weakness, paralysis, and areflexia. Excess ACh can also affect the central nervous system, where it can induce seizures and coma. Nerve agent toxicity affects nearly all organ systems, leading to a multitude of signs and symptoms often clouding the clinical picture, and patients frequently present in extremis quickly after exposure.

The only known application of many nerve agents, such as V-series nerve agents and Novichok agents, is chemical warfare. Thus, patients exposed to these agents may present as part of a mass casualty incident and report a history consistent with a terrorist attack. Most deaths occur because of respiratory failure from the combination of bronchospasm, bronchorrhea, and respiratory muscle weakness. Those who survive nerve agent exposure may experience insomnia, depression, anxiety, irritability, and impaired memory and judgment. Ocular symptoms, eg, miosis, dim vision, blurry vision, and eye pain, may persist for several weeks following exposure.

Intermediate and Delayed Symptoms of Nerve Agent Toxicity

Following the resolution of the cholinergic crisis, 2 syndromes are well described following organophosphate poisoning: the intermediate syndrome and organophosphate-induced delayed neuropathy (OPIDN). Both of these syndromes are thought to be rare after V series and other chemical weapon nerve agent poisoning; only 1 victim of the Tokyo subway sarin gas attack.[20]

Intermediate syndrome

Approximately 24 to 96 hours after organophosphate exposure, typically during or after recovery of acute cholinergic symptoms, some patients may develop a syndrome characterized by proximal muscle weakness, particularly of the neck flexors, and may also include hyporeflexia, cranial nerve palsies, and respiratory muscle weakness. Some believe the intermediate syndrome may be more likely in cases of inadequate oxime therapy, but this is not certain. The intermediate syndrome is reversible and self-limited.[21]

Organophosphate-induce delayed neuropathy

OPIDN typically develops several weeks after organophosphate exposure and typically affects distal muscle groups, characterized by painful stocking-glove paraesthesia and lower extremity weakness. Typical clinical symptoms may include gait ataxia or foot drop. Axonal degeneration with greater motor than sensory fiber involvement is typical.[22] A pathophysiological overlap between OPIDN and historical reports of neuropathy is likely due to chronic exposure to chemicals, eg, tri-ortho-cresyl phosphate, which caused an epidemic known as "Ginger Jake Paralysis" in the early 1930s.[23] Neurology and medical toxicology consultation and follow-up are recommended if clinicians suspect OPIDN.[24] The clinical symptoms undergo variable recovery over months to years.

Evaluation

Exposure to nerve agents should be considered if a clinical history is consistent with exposure or if symptoms of nerve agent exposure are noted. The diagnosis of nerve agent toxicity is primarily clinical, as specific assays and reference laboratory testing take time and often lack the sensitivity and specificity necessary for an accurate assessment. Therefore, as laboratory studies are being performed, decontamination and treatment should begin as soon as possible.

Cholinesterase levels can help support a diagnosis and may inform prognosis. Assays of red blood cell (RBC)-AChE, which is thought to best reflect cholinesterase activity at the synapse, can give more information about the degree of toxicity. This assay is often not readily available. Testing of plasma cholinesterase is more common but is less predictive of toxicity. Follow-up measurements of RBC-AChE can demonstrate the reactivation of the enzyme over time and the effectiveness of treatment.[1][25] Additionally, patients may demonstrate laboratory abnormalities consistent with metabolic acidosis and the breakdown of striated muscle. Decreased erythrocyte cholinesterase levels may also be observed after exposure to nerve agents.

Routine laboratory analysis is often low-yield but can help exclude differential diagnoses and guide care. If clinically suspected, a trial of atropine 1 mg in adults or 0.01 mg/kg in children can be used to assess for clinical improvement, though true organophosphate poisoning may require extremely large doses of atropine to counteract cholinergic symptoms.[26][27][28] V-series nerve agents can also be detected in patients or the environment by M8 paper, M9 tape, the M256A1 Chemical Agent Detector Kit, or the Joint Chemical Agent Detector (JCAD). 

Treatment / Management

The management of nerve agent toxicity follows typical emergency care, including early assessment and management of the airway, respiratory status, circulation, and decontamination. Antidote administration is the cornerstone of management in treating acute nerve agent exposures.

Decontamination and Supportive Therapies

The most essential initial treatment is to terminate the patient's exposure by removing them from the contaminated environment and performing decontamination. If possible, decontamination should always be performed before further medical treatment, as some nerve agents may remain on the skin or clothing and continue to cause symptoms via a depot effect. Moreover, all healthcare personnel should don personal protective equipment, as dermal exposure is a significant route of toxicity. If the agent is unknown or persistent vapors are of concern, level B HAZMAT may be appropriate and should be dictated by the clinician's emergency management authorities.

Patients can be decontaminated by washing the affected areas with a 0.5% hypochlorite solution or soap and clean water. If available, reactive skin decontamination lotion (RSDL) is another effective method of decontaminating patients exposed to nerve agents. RSDL's ingredients sequester, retain, and neutralize organophosphate chemical warfare agents. Patients with large areas of dermal exposure will require numerous RSDL sponges to be effectively decontaminated.

Death from nerve agents primarily occurs from respiratory failure secondary to pulmonary secretions, bronchospasm, and paralysis. Thus supportive care with definitive airway control and mechanical ventilation when necessary is key. Patients and their respiratory status should be continually and closely monitored. Patients with excessive secretions may require intubation in addition to antidotal therapy. In the case of intubation, succinylcholine should not be used; AChE metabolizes succinylcholine, and its inhibition will lead to an extended duration of drug action. Rocuronium or other nondepolarizing paralytics are preferred for rapid sequence intubation.[29][30][11][31][32][33](B3)

Excessive AChE stimulation can cause bradycardia, and QT interval prolongation can lead to ventricular dysrhythmias, particularly torsades de points. If QT interval prolongation is seen, intravenous (IV) magnesium should be administered.[24][34] (A1)

Antidote Medications

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 is a competitive antagonist of ACh at the neuromuscular junction and is the primary antidote in nerve agent poisoning. Atropine, a readily available antidote in many clinical settings, works by binding and blocking muscarinic ACh receptors, thus preventing the buildup of ACh from continuing to affect the receptors. However, because atropine does not act on nicotinic receptors, skeletal muscle symptoms will not improve. Atropine should be administered until a clinically evident reduction of airway secretions and airway resistance is noted. The standard dose for atropine is 1 to 3 mg intravenously every 3 to 5 minutes until tracheobronchial secretions attenuate. Very large doses of atropine, on the order of hundreds of milligrams, may be required in cases of severe poisoning.

Oximes like pralidoxime remove the organophosphate phosphoryl moiety from AChE, thus reactivating the enzyme. When administered soon after exposure to nerve agents, pralidoxime (also known as 2-pyridine aldoxime methyl chloride or 2-PAM Cl) can prevent aging. Thus, oxime therapy should be initiated as soon as possible. The recommended dosage is 30 mg/kg IV bolus followed by an infusion of 8 mg/kg per hour and continued for 24 to 48 hours. 

Dual-chamber autoinjectors 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). Medication administration by autoinjector has been shown to cause plasma concentrations of these medications to reach therapeutic levels faster than intramuscular administration using a needle and syringe. Each ATNAA contains 2.1 mg of atropine and 600 mg of pralidoxime. Patients may be given up to 3 ATNAA, after which they may receive additional doses of atropine every 3 to 5 minutes as clinically indicated. However, additional doses of pralidoxime should not be given for 60 to 90 minutes.

Scopolamine also effectively blocks the muscarinic effects of ACh in the central nervous system. 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 exposed to nerve agents.[29][30][11][31][32][33](B3)

Antiseizure Medications

Seizures are also commonly seen with nerve agent poisoning. The first-line treatment for seizures in organophosphate poisoning is benzodiazepines (eg, diazepam or midazolam). When given intramuscularly, midazolam is absorbed faster than diazepam. Ativan 2 mg push is also an appropriate choice, though it has been less studied. The United States military uses a specialized diazepam autoinjector called the convulsive antidote nerve agent (CANA). Patients who receive 3 ATNAA can also be given a CANA or a dose of benzodiazepine, even if no visible evidence of seizures is noted. Antiepileptics like levetiracetam and fosphenytoin are generally less effective but can be considered when high doses of benzodiazepines are not abating seizures.[29][30][11][31][32][33](B3)

Differential Diagnosis

The diagnosis of nerve agent poisoning can be challenging without a history of known exposure to an agent. Prompt recognition of muscarinic and nicotinic symptoms is critical. Differential diagnosis could include exposure to other substances, eg, physostigmine or other carbamate, nicotine, edrophonium, or other acetylcholinesterase inhibitors. Infectious sources could present with signs and symptoms similar to cholinergic toxicity, particularly vomiting and diarrhea.

Treatment Planning

The United States has stockpiles of all 3 antidotes (atropine, pralidoxime, and benzodiazepine) in the CHEMPACK program. Prehospital CHEMPACKS and hospital-based CHEMPACKs are available, containing variable amounts of antidotes. They must be kept in a climate-controlled location and linked by secure phone connections to a central location that monitors whether they are opened.

Prognosis

Nerve agents can result in significant morbidity and mortality. Immediate decontamination and administration of antidotes as soon as nerve agent poisoning is suspected will improve the chances of survival. The prognosis depends on the specific nerve agent exposure, amount, route, and duration of contact with the agent. A Glasgow coma score (GCS) of less than 13 portends a poor prognosis. The poisoning severity scale was originally used to determine prognosis. However, other scoring systems like Acute Physiology and Chronic Health Evaluation II (APACHE-II), Simplified Acute Physiology Score II (SAPS-II), and Mortality Prediction Model II (MPM-II) outperformed poisoning severity scale in predicting death in multiple studies.[24]

Complications

In addition to complications associated with cholinergic crisis, patients poisoned by nerve agents are at risk for 2 syndromes. The intermediate syndrome occurs 24 to 96 hours after exposure and can include hyporeflexia, respiratory muscle weakness, weakness of neck flexion and of other proximal muscle groups, and cranial nerve palsies. The OPIDN syndrome occurs several weeks after recovery from the cholinergic syndrome and affects mainly distal muscle groups. It is characterized by painful stocking-glove paraesthesia and lower extremity weakness. Gait ataxia and foot drop are described, and axonal degeneration is characteristic. OPIDN is independent of the severity of initial cholinergic toxicity. Neurology and medical toxicology consultation and follow-up are recommended if clinicians suspect OPIDN.[24]