Continuing Education Activity

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 knowledge of nerve agents. Some of the more recognizable nerve agents are sarin [(RS)-propan-2-yl methyphosphonofluoridate], also known as GB; soman (O-Pinacolyl methylphosphonofluoridate), also known as GD; and VX (ethyl ({2-[bis(propan-2yl)amino]ethyl}sulfanyl)(methyl)phosphinate). 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. This activity reviews some of the more common nerve agents used, their associated signs and symptoms, and recommendations for management. This activity reviews the importance of the interprofessional team in diagnosing and treating patients exposed to nerve agents.

Objectives:

• Describe the signs and symptoms that a patient with acetylcholinesterase inhibitor toxicity might exhibit.
• Identify the organ system most at risk of failing and thereby leading to mortality in patients with acetylcholinesterase inhibitor toxicity.
• Explain important treatment considerations for patients with acetylcholinesterase inhibitor toxicity.
• Identify the most likely setting in which the interprofessional team would be expected to deal with widespread acetylcholinesterase inhibitor toxicity. Describe how team members would communicate and collaborate to reduce the burden of the toxicity.

Introduction

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, although never used during the war. More recent examples of nerve agent use include the 1995 Tokyo subway attack with Sarin gas, the 2017 assassination of Kim Jong-Nam with a binary form of VX. More recently the has been the use of "Novichok", or newcomer agents, that are more potent than VX in the attempted assassinations of Sergei Skripal and Alexei Navalny. [1] All the G agents, V agents, and Novichok agents act by inhibition of acetylcholinesterase.

Etiology

The main chemicals used as nerve agents are:

• Tabun Ethyl dimethylamidocyanophosphate, also know as GA
• Sarin   (RS)-propan-2-yl methyphosphonofluoridate, also known as GB
• Soman (O-Pinacolyl methylphosphonofluoridate), also known as GD
•  VX      (ethyl ({2-[bis(propan-2yl)amino]ethyl}sulfanyl)(methyl)phosphinate)
•  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

Structurally similar to organophosphate insecticides, the G group compounds were first made in Germany around the 1930s for use as chemical weapons. The V group were made after World War II by England and the United States. All of these compounds cause the same signs and symptoms as organophosphate toxicity but are more potent, longer-lasting, sometimes irreversible in the case of Soman, and potentially more lethal.

Epidemiology

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 over 5000 civilians exposed and in nearly 640 people seeking treatment at a single hospital.[2] Twelve people died in that event. Additionally, there was a suspected Sarin attack during the Syrian civil war in 2013[3] that resulted in nearly 80 people being killed. VX was most recently suspected in the attack on Kim Jong-Nam in 2017.[4] Due to the sporadic and intentional nature of these attacks, the frequency is hard to define, but the overall incidence of exposure is low.

Pathophysiology

All nerve 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 systems. Because the main method of breakdown acetylcholine is inhibited, these effects are prolonged if not treated promptly.[5] The clinical effects include muscle paralysis, respiratory failure, increased respiratory secretions, seizures, coma, and death.

Toxicokinetics

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 ingestion, although inhalation has the most immediate and profound effects.[6] 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.[7] 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 that irreversibly binds them to the acetylcholinesterase enzyme.[8]

History and Physical

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, related to ciliary muscle dysfunction, and lacrimation. Respiratory symptoms are comprised of wheezing and chest tightness secondary to bronchoconstriction and increased nasal and pulmonary secretions causing cough.[9] Cardiac symptoms include initial tachycardia, followed by bradycardia. 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 the cholinergic crisis or hypoxia-related to respiratory compromise.[5]

Evaluation

Evaluation of patients exposed to nerve agents should be based on the environment in which they were exposed. Immediate decontamination with copious showering and removal of all clothes is critical to prevent further exposure to both the victim and health care providers. 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.

No laboratory test to identify these agents are available for use in real-time. 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.[10] 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.[11] 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.[12]

Treatment / Management

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.[13] Copious irrigation of the patient to remove any lingering liquids is also necessary. Further treatment of contaminated environmental 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.[14] 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 occur. 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 mostly at the muscarinic sites, 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 within minutes.[15]

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 muscarinic excess begin to disappear. Specifically titrating to dying of pulmonary secretions is the gaol of atropine therapy. Pralidoxime can be given at doses of 15 to 25 mg/kg via slow IV injection. Diazepam dosing follows typical seizure treatment doses of 5 to 10 mg or IV.[7]

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.

Differential Diagnosis

Before jumping to the conclusion of nerve agent exposure, one should consider other common diagnoses. For instance, organophosphate-based and carbamate pesticides still exist and can cause similar, though typically less pronounced effects. Type IV pyrethrins have some overlap symptoms. Other considerations should be for an overdose of either direct or indirect cholinergic drugs such as bethanechol, neostigmine, and pyridostigmine.

Prognosis

These agents are designed to be lethal. failure to recognize and treat these chemical attacks promptly will result in death.  Prognosis is largely determined by how quickly and efficiently the known toxic 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 even in the absence of immediately available antidotes.

Complications

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.[16]  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.[17][18]

Consultations

Consider early consultation with your regional poison control center.

Deterrence and Patient Education

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.

Pearls and Other Issues

• If nerve agent exposure is a concern, first protect yourself and your staff.
• Immediately decontaminate those exposed with copious water by showering and removing clothes.
• Do not wait for laboratory confirmation to begin treatment.
• Securing the airway and early medication administration are key.

Enhancing Healthcare Team Outcomes

The most likely setting where a healthcare team would be expected to deal with organophosphate poisoning is in the event of a terrorist attack. In this setting, communication with the police/security forces is imperative to contain the exposures and assist in decontaminating those exposed. Emergency departments with the possibility to receive a large number of patients should have well-established procedures and adequate stockpiles of antidotes to treat the potential victims. Hospitals who subscribe to the CHEMPACK program have a container with enough doses for 500 to 1000 pateints.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

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. [PMC free article: PMC6039123] [PubMed: 30003185]

2.

Okumura T, Hisaoka T, Yamada A, Naito T, Isonuma H, Okumura S, Miura K, Sakurada M, Maekawa H, Ishimatsu S, Takasu N, Suzuki K. The Tokyo subway sarin attack--lessons learned. Toxicol Appl Pharmacol. 2005 Sep 01;207(2 Suppl):471-6. [PubMed: 15979676]

3.

John H, van der Schans MJ, Koller M, Spruit HET, Worek F, Thiermann H, Noort D. Fatal sarin poisoning in Syria 2013: forensic verification within an international laboratory network. Forensic Toxicol. 2018;36(1):61-71. [PMC free article: PMC5754388] [PubMed: 29367863]

4.

Chai PR, Boyer EW, Al-Nahhas H, Erickson TB. Toxic chemical weapons of assassination and warfare: nerve agents VX and sarin. Toxicol Commun. 2017;1(1):21-23. [PMC free article: PMC6027656] [PubMed: 29974075]

5.

Moshiri M, Darchini-Maragheh E, Balali-Mood M. Advances in toxicology and medical treatment of chemical warfare nerve agents. Daru. 2012 Nov 28;20(1):81. [PMC free article: PMC3556041] [PubMed: 23351280]

6.

Read RW, Riches JR, Stevens JA, Stubbs SJ, Black RM. Biomarkers of organophosphorus nerve agent exposure: comparison of phosphylated butyrylcholinesterase and phosphylated albumin after oxime therapy. Arch Toxicol. 2010 Jan;84(1):25-36. [PubMed: 19862504]

7.

Balali-Mood M, Saber H. Recent advances in the treatment of organophosphorous poisonings. Iran J Med Sci. 2012 Jun;37(2):74-91. [PMC free article: PMC3470074] [PubMed: 23115436]

8.

Worek F, Koller M, Thiermann H, Szinicz L. Diagnostic aspects of organophosphate poisoning. Toxicology. 2005 Oct 30;214(3):182-9. [PubMed: 16051411]

9.

Sidell FR. Soman and sarin: clinical manifestations and treatment of accidental poisoning by organophosphates. Clin Toxicol. 1974;7(1):1-17. [PubMed: 4838227]

10.

Ajami D, Rebek J. Chemical approaches for detection and destruction of nerve agents. Org Biomol Chem. 2013 Jun 28;11(24):3936-42. [PubMed: 23604461]

11.

Ganesan K, Raza SK, Vijayaraghavan R. Chemical warfare agents. J Pharm Bioallied Sci. 2010 Jul;2(3):166-78. [PMC free article: PMC3148621] [PubMed: 21829312]

12.

Wang J, Timchalk C, Lin Y. Carbon nanotube-based electrochemical sensor for assay of salivary cholinesterase enzyme activity: an exposure biomarker of organophosphate pesticides and nerve agents. Environ Sci Technol. 2008 Apr 01;42(7):2688-93. [PubMed: 18505017]

13.

Balali-Mood M, Balali-Mood K. Neurotoxic disorders of organophosphorus compounds and their managements. Arch Iran Med. 2008 Jan;11(1):65-89. [PubMed: 18154426]

14.

Balali-Mood M, Ayati MH, Ali-Akbarian H. Effect of high doses of sodium bicarbonate in acute organophosphorous pesticide poisoning. Clin Toxicol (Phila). 2005;43(6):571-4. [PubMed: 16255339]

15.

Marrs TC, Rice P, Vale JA. The role of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev. 2006;25(4):297-323. [PubMed: 17288500]

16.

Emerick GL, Peccinini RG, de Oliveira GH. Organophosphorus-induced delayed neuropathy: a simple and efficient therapeutic strategy. Toxicol Lett. 2010 Feb 01;192(2):238-44. [PubMed: 19914363]

17.

Engel CC, Jaffer A, Adkins J, Riddle JR, Gibson R. Can we prevent a second 'Gulf War syndrome'? Population-based healthcare for chronic idiopathic pain and fatigue after war. Adv Psychosom Med. 2004;25:102-22. [PubMed: 15248370]

18.

Masson P. Evolution of and perspectives on therapeutic approaches to nerve agent poisoning. Toxicol Lett. 2011 Sep 25;206(1):5-13. [PubMed: 21524695]

Disclosure: Brian Greathouse declares no relevant financial relationships with ineligible companies.

Disclosure: Farah Zahra declares no relevant financial relationships with ineligible companies.

Disclosure: Mark Brady declares no relevant financial relationships with ineligible companies.