The new england journal of medicine Review Article Dan L. Longo, M.D., Editor Toxidrome Recognition in Chemical- Weapons Attacks Gregory R. Ciottone, M.D.​​ errorist attacks are increasing in both frequency and com- From Beth Israel Deaconess Medical plexity around the world. In 2016 alone, there were more than 13,400 ter- Center, Harvard Medical School, Boston. 1 Address reprint requests to Dr. Ciottone rorist attacks globally, killing more than 34,000 people. Of equal concern, at Beth Israel Deaconess Medical Center, T Dept. of Emergency Medicine, Rosenberg chemical-warfare agents that were developed for the battlefield are being used on civilians in major cities and conflict zones. The recent sarin attacks in Syria,2,3 the Building, 1 Deaconess Rd., Boston, MA 02215, or at gciotton@ bidmc . harvard . edu. latest in a series of chemical attacks in that region,3,4 along with the use of the nerve agent VX in the assassination of Kim Jong-nam in Malaysia and the Soviet- N Engl J Med 2018;378:1611-20. 5 DOI: 10.1056/NEJMra1705224 era agent Novichok in the poisoning of Sergei Skripal in the United Kingdom, all Copyright © 2018 Massachusetts Medical Society. represent a worrisome trend in the use of deadly chemical agents by various rogue groups in civilian settings. In light of the rise in coordinated, multimodal terrorist attacks in Western urban centers,6,7 concern has been expressed about an increase in the use of chemical agents by terrorists on civilian targets around the world. Such attacks entail unique issues in on-the-scene safety8,9 and also require a rapid medical response.10 As health care providers, we must be proactive in how we prepare for and respond to this new threat. This article reviews the toxidromes (constellations of signs and symptoms that are characteristic of a given class of agents) for known and suspected chemical- warfare agents that have properties that are well suited for terrorist attacks — namely, high volatility and rapid onset of incapacitating or lethal effects.11 Poison- control procedures currently use toxidromes to identify specific classes of agents. Although symptoms such as eye irritation and coughing are common to a number of classes, specific clinical findings, including fasciculations, hypersecretions, early seizure, and miosis or mydriasis, can be rapidly identified as part of an acute- phase triage system and used to differentiate among classes of agents. This should lead to reduced morbidity and mortality while also decreasing the risk to respond- ing health care workers.12 The combined group of chemical-warfare agents exam- ined here includes nerve agents, asphyxiants (blood agents), opioid agents, anes- thetic agents, anticholinergic (antimuscarinic) agents, botulinum toxin, pulmonary agents, caustic agents (acids), riot-control agents, T-2 toxin, and vesicants (Table 1). History Chemical warfare is not new. As early as 10,000 B.C., rival tribes used various poi- sons derived from plants and animals to coat their spear tips before battle.13 The modern world witnessed the first large-scale use of chemical weapons on the battlefields of World War I, where chlorine,14 phosgene,15,16 and sulfur mustard17,18 were deployed, with devastating effects.19 During World War II, the Nazi regime developed new and much more lethal nerve agents, such as sarin,20 tabun,21 and soman,22 though they were never deployed on the battlefield against the Allied n engl j med 378;17 nejm.org April 26, 2018 1611 The New England Journal of Medicine Downloaded from nejm.org at EMORY UNIVERSITY on June 14, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 1. Classes of Chemical-Warfare Agents (CWAs) Likely to Be Used in a Civilian Attack. Last Known Use or Attempted Use Class Representative Agents as a CWA* Nerve agents (cholinesterase G-series (sarin, soman, cyclosarin, tabun), Syria, 2017: sarin; Malaysia, 2017: VX inhibitors) V-series (VE, VG, VM, VX), organo- phosphates Asphyxiants (blood agents) Hydrogen cyanide, cyanogen chloride New York City subway, 2003: cyanide Opioid agents Fentanyl, carfentanil, remifentanil Moscow theater, 2002: fentanyl or carfentanil (used to subdue terrorists) Anesthetic agents Chloroform, halothane, nitrous oxide No known use as CWA Anticholinergic 3-Quinuclidinyl benzilate (BZ), Agent 15 (chemi- Syria, 2012: Agent 15 (antimuscarinic) agents cally the same as or related to BZ), atropine Vesicant agents Mustards (nitrogen and sulfur), lewisite, Syria and Iraq, 2016: mustard gas phosgene oxime Caustic agents (acids) Hydrochloric acid, hydrofluoric acid, sulfuric acid London, 2017: sulfuric acid Riot-control agents Chloroacetophenone (CN), chlorobenzy- Falkland Islands, 1982: “tear gas” lidenemalononitrile (CS), bromobenzyl- used on British troops cyanide (CA) Trichothecene mycotoxins T-2 toxin Possible use in Vietnam War, 1970: T-2 Pulmonary agents Chlorine, phosgene, diphosgene Syria, 2017: chlorine Botulinum toxin Botulinum toxin Tokyo, 1995: botulinum toxin used by Aum Shinrikyo * Information on previous use of CWAs is from the Global Terrorism Database, University of Maryland,1 and other sources.3,9,10 troops.23,24 The Nazis did, however, combine hy- rately; however, when combined, they become a drogen cyanide with an absorbent to form Zyk- lethal chemical agent. VX is an example of a lon B, which was then used to kill millions of chemical-warfare agent that has two nontoxic people in gas chambers.25 Chemical weapons binary precursors, and there has been some have also been used in the Iran–Iraq war and speculation that the assassination of Kim Jong- present-day Syria.26-28 As a response to the devel- nam may have involved the application of two opment and use of such agents, the Chemical such binary agents.5 Nontraditional agents such Weapons Convention, essentially an arms-con- as Novichok are next-generation chemical com- trol agreement put into effect on April 29, 1997, pounds with varying effects, levels of detection, prohibits the development, stockpiling, transfer, and mechanisms of action. These newly devel- and use of chemical weapons by state entities.29 oped chemicals are considered classified by the Late in the 20th century, terrorist groups be- United States, so little is known about them gan to obtain chemical-warfare agents and use outside of the government. them on civilian targets. The most extensively documented case was the use of sarin in the Agents of Concern subways of Tokyo by the Aum Shinrikyo group in 1995.30,31 During the same period, a number Chemical weapons vary in their onset of action, of countries clandestinely developed more ad- toxicity, and symptomatology.34-36 The character- vanced and more lethal chemical weapons that istics most suitable for use in a terrorist attack were safer to handle and transport yet harder to include high volatility, fast and effective absorp- detect.32,33 Such agents include binary agents and tion through the respiratory tract or skin, and lesser known, nontraditional agents. Binary for- rapid onset of lethal or incapacitating effects.37 mulations are two chemically stable and non- Some toxins (i.e., poisons produced by living lethal precursors that are safe to carry sepa- organisms) can behave like chemical weapons. 1612 n engl j med 378;17 nejm.org April 26, 2018 The New England Journal of Medicine Downloaded from nejm.org at EMORY UNIVERSITY on June 14, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Toxidrome Recognition in Chemical-Weapons Attacks In World War II, botulinum toxin was produced nation is a medical countermeasure that miti- and used by the Japanese; after the war, it was gates the conversion of an external dose to an produced by some other countries, which main- internal dose. tained large stockpiles.38 The two lethal toxins included in this review, botulinum toxin and T-2 The Problem toxin (a trichothecene mycotoxin), can be ab- sorbed through the respiratory system or skin Chemical-weapons attacks occur without warn- and are relatively fast-acting.38,39 ing and create chaotic scenes, resulting in con- The effects of nerve agents such as sarin and fusion on the part of emergency medical re- VX, asphyxiants such as cyanide, and opioids sponders and hospital-based personnel, most of such as fentanyl and carfentanil, can be coun- whom are unprepared40,41 and have very little tered by the emergency administration of spe- training in the recognition of a chemical attack42 cific antidotes. Nerve agents inhibit cholines- or in the donning and doffing of personal pro- terase at the synapse, leading to a build-up of tective equipment.43,44 In addition, the initial acetylcholine and requiring atropine and prali- scene of a chemical attack may look very similar doxime as antidotes. Asphyxiants block cellular to other incidents involving mass casualties, respiration, requiring urgent administration of particularly if release of the agent is combined hydroxocobalamin or sodium thiosulfate and with use of conventional weapons as part of a sodium nitrite as antidotes, and opioids cause multimodal attack. The chaos of the early phase respiratory depression, requiring rapid adminis- of such an event may lead to further delay in tration of naloxone. All other agents are inca- identifying the chemical agent, placing respond- pacitating and potentially lethal but have no ers at risk while also delaying potentially life- specific lifesaving antidote, therefore requiring saving treatment for the victims. An understand- urgent decontamination and supportive care ing of the patterns of signs and symptoms initially. Anesthetic agents may cause sedation (toxidromes) that characterize the classes of and bradypnea, whereas pulmonary agents cause known agents, as well as familiarity with the pat- eye and throat irritation, coughing, chest pain, terns of injuries caused by conventional weapons, and shortness of breath.