Nerve agents are some of the most deadly and easily employed chemical warfare agents. Given the global threat of terrorism, it is prudent to have a baseline understanding of nerve agents. Some of the more recognizable nerve agents are Sarin (also known as GB), Soman (also known as GD), and VX. Initially developed in the early-to-mid 1900s from chemically similar insecticides, their volatility and potential to be weaponized was exploited during World War II. More recent examples of nerve agent use include the 1995 Tokyo subway attack with Sarin gas and the 2017 assassination of Kim Jong-Nam with VX gas.
Structurally similar to organophosphate insecticides, these compounds were first made in Germany around the 1930s for use as chemical weapons. Staying true to their roots, they cause the same signs and symptoms as organophosphate toxicity but are more potent, longer lasting, sometimes irreversible, and more lethal.
Due to the Geneva Convention ban, exposures are uncommon; however, they do still occur. Notably, the confirmed Sarin attacks in the 1995 Tokyo subway incident resulted in nearly 640 people seeking treatment. Additionally, there was a suspected Sarin attack during the Syrian civil war in 2013 that resulted in nearly 80 people being killed. VX gas was most recently suspected in the attack on Kim Jong-Nam in 2017. Due to the sporadic and intentional nature of these attacks, the frequency is hard to define, but the overall incidence of exposure is low.
All 3 agents exert their predominant effect by inhibiting acetylcholinesterase at the nerve junction. A phosphorus group on the agent covalently binds to the cholinesterase-active site which prevents the enzyme from hydrolyzing acetylcholine at the nerve junction. This leads to an accumulation of acetylcholine and overstimulation of both the muscarinic and nicotinic acetylcholine receptors in the central and peripheral nervous system. Because the main method of breakdown acetylcholine is inhibited, these effects are prolonged if not treated promptly. The clinical effects include muscle paralysis, respiratory failure, increased respiratory secretions, seizures, coma, and death.
Usually created in a liquid form, their volatility enables aerosolization to make mass dispersion of the agent possible. The agents can enter the body through inhalation, ocular, dermal, or gastric transmission, although inhalation has the most immediate and profound effects. Once inside the body, these agents are inherently active and will exert their effects until they are spontaneously reversed via hydrolysis (Sarin and Soman) or oxidation (VX). These agents can also be reversed through several pharmacologic agents which will be discussed later. After these agents are broken down, they are typically cleared by the kidneys and excreted in the urine. There is a period during which oximes can also reverse these agents. The period varies with the specific agent but ranges from seconds to hours. At the conclusion of this timeframe called "aging," the agents undergo a chemical transformation which irreversibly binds them to the acetylcholinesterase enzyme.
Patients exposed to organophosphate nerve agents will exhibit signs of cholinergic crisis. The rapidity of onset and severity of symptoms is dependent on both the dose and method of exposure. Due to the dose-dependent nature of the effects and the varying rates of onset from the various absorption pathways, a good history covering potential exposures over the previous 24 to 48 hours is essential. These agents are absorbed through various mechanisms, and their immediate effects will be specific to the muscarinic and nicotinic structures at the site of absorption. When these agents contact the skin, absorption begins, and local reactions such as muscle twitching and sweating may occur. Ocular symptoms consist of miosis, lacrimation, and headache related to ciliary muscle dysfunction. Respiratory symptoms are comprised of wheezing and chest tightness secondary to bronchoconstriction and increased nasal and pulmonary secretions causing cough. Gastrointestinal effects generally result in nonspecific findings such as nausea, vomiting, and diarrhea. Systemic central nervous system (CNS) effects are typically seen after prolonged or significant exposures and consist of bradycardia, fatigue, weakness, paralysis, and central apnea. Seizures can also occur from cholinergic crisis or hypoxia related to respiratory compromise.
Evaluation of patients exposed to nerve agents should be centric to the environment in which they were exposed. For patients coming from a known or highly probable terrorist incident, identifying the specific nerve agent should not delay treating the symptoms. The general treatment for all organophosphate agents is the same and staying vigilant for the signs of cholinergic crisis can help steer your diagnosis and management. Evaluation and treatment should follow the standard airway, breathing, circulation priorities after precautions to protect self and staff from secondary exposure are taken. Special attention should be paid to the respiratory system as its failure is most likely to lead to the mortality of the patient.
There are several tests used to detect exposure to nerve agents. For quick non-specific detection in the field, the military and similar institutions utilize M8 or M9 paper. However, to identify the specific nerve agents GC-MS or Ion Spectrum Mobility are used. However, neither of these methods are useful for determining the amount of agent to which someone was exposed. For this purpose, the most commonly employed method is to measure the level of acetylcholinesterase inhibition within red blood cells (RBC) through the use of colorimetric assays. Due to the drawbacks with the specificity of measuring RBC acetylcholinesterase inhibition, newer methods such as carbon nanotube-based sensors are currently being developed as a more sensitive, non-invasive method of measurement.
When concerned for exposure to nerve agents, the first line of treatment is the protection of the provider and decontamination of the patient. Don personal protective equipment (PPE) following local institutional guidelines; rubber suits and charcoal filtered respirators will provide general protection. Copious irrigation of the patient to remove any lingering liquids is also necessary. Further treatment of contaminated surfaces with hot water and basic solutions (pH greater than 8) will assist in the breakdown of the nerve agents by promoting hydrolysis and oxidation. Treatment of exposure to organophosphorus nerve agents revolves around preserving respiratory function. As acetylcholinesterase is inhibited, the effects on the respiratory system are pronounced as bronchoconstriction, increased secretions, and decreased respiratory drive develop. Supplemental oxygen and consideration of early intubation to secure the airway and manage secretions is necessary.
The pharmacological mainstays of treatment are atropine, oxime-derivatives (pralidoxime and obidoxime), and potentially diazepam. Atropine acts by competitively inhibiting the acetylcholine receptor thus decreasing the downstream effects of excess acetylcholine at the receptor site. Oxime-derivatives, such as pralidoxime, displace the nerve agents from the acetylcholinesterase enzyme thus enabling it to begin hydrolyzing acetylcholine again. However, as mentioned previously, as time after exposure increases, the enzymes run the risk of becoming irreversibly inhibited. This is particularly noticeable with Soman where pralidoxime is ineffective due to the rapid rate of aging.
In severe cases, the CNS effects of acetylcholine excess can cause seizures, which require treatment with intravenous (IV) benzodiazepines.
Autoinjectors are available for atropine and pralidoxime and are carried by agencies with a high risk of exposure, for example, the military. However, should an autoinjector not be available, both medications can be given intramuscularly (IM) or intravenously, noting that they should be given together or in close succession. The dose for atropine is 2 mg and should be repeated until the signs of cholinergic excess begin to disappear. Pralidoxime can be given at doses of 15 to 25 mg/kg via slow injection. Diazepam dosing follows typical seizure treatment doses of 5 to 10 mg IM.
Additionally, for agents such as Soman where aging occurs nearly instantaneously, prophylactic agents such as pyridostigmine can be used. These agents competitively inhibit the nerve agent from binding to acetylcholinesterase. Prophylactic treatment does not remove the necessity to receive treatment with atropine and oxime derivatives.
Before jumping to the conclusion of nerve agent exposure, one should consider other common diagnoses. For instance, organophosphate-based pesticides still exist and can cause similar, though typically less pronounced effects. Other considerations should be for an overdose of either direct or indirect cholinergic drugs such as bethanechol or neostigmine and pyridostigmine, respectively.
As discussed below, there are no well-documented effects of the toxin on the tissue itself. Rather, the effects are related to the cholinergic overload. As such, the prognosis is largely determined by how quickly and efficiently the side effects are managed. Most deaths from organophosphate nerve agent exposure are related to respiratory failure, so supporting respiratory function is key to good long-term outcomes.
Short-term effects relating to organophosphate nerve agent exposure are related to the effects of acetylcholine excess at local sites and the downstream effects associated with them. There are some delayed complications such as weakness, paresthesia, and generalized neuropathy that have been noted to exist for several days to weeks; however, these typically resolve. Likewise, there is no direct evidence for long-term complications following exposure to low levels of nerve agents. However, studies looking at patients thought to be exposed to nerve agents in the Gulf War and from patients exposed to Sarin following the Tokyo subway incident have shown non-specific symptoms such as fatigue, neuropathy, and various mental health complaints like depression, chronic pain, and post-traumatic stress disorder (PTSD), but causation is hard to prove.
Consider early consultation with your local poison control center.
Deterrence is achieved by avoiding areas where the risk of nerve agent use is high. For most people, this should not be an issue. However, for those in the military this may be unavoidable. For civilian patients, if there is a concern for potential exposure to an organophosphate nerve agent, they should proceed directly to an emergency room. For those who are at higher risk, such as paramedics or military personnel, these members should carry proper PPE, atropine and pralidoxime auto-injectors, and consider prophylactic treatment when the risk of exposure is very high.
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