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Clinical Aspects of Large-Scale

Chemical Events

John S. Urbanetti and Jonathan Newmark

INTRODUCTION

Since the dawn of civilization, chemical materials have been a part of human life. Today nearly 100,000 different commercial chemicals are known. Several thousand new chemicals are devel- oped yearly. Of these new chemicals, nearly a thousand reach the commercial market. Annual worldwide chemical production is estimated at 400 million tons. Of this production, most is bulk stored and bulk transported. Hence there is a risk of large-scale release with resulting environmental and health effects. Human toxicity from chemical exposure has been well recorded since the beginning of the industrial age. Recognition and investi- gation of those effects have allowed the development of thera- peutic interventions. Toxic effects of chemicals may result from exposures to small amounts such as present in foods or medica- tions, or larger amounts resulting from accidental or intentional releases from storage or transportation facilities. The human toxic effects of smaller chemical exposure events have generally been well managed because there are rarely more than one or two patients requiring care at a time. Large-scale exposures vastly complicate the medical response to a toxic chemical event, princi- pally because of overwhelming logistical difficulties. This chapter explores various clinical aspects of large-scale exposures to chem- ical agents. Several examples of both intentional (e.g., warfare or terrorist) and accidental events will be presented. Accompanying commentary will support the following central principles.

PRINCIPLES OF CHEMICAL EVENTS

1) The degree and speed of symptom onset results primarily from the amount of chemical incorporated (“dose response”) and secondarily, from the speed of chemical incorporation.

2) Much of the clinical information about toxic (warfare) chem- ical effects has been collected from studies of young, healthy military men. Extrapolation of those data to other subsets of the population (old, female, and persons with complicating medical illness, or concomitant use of medications) can be very difficult.

3) Medical investigation of human chemical effects is hindered by: a) The extraordinary and rapidly increasing number of

chemicals that seemingly warrant study; b) Concurrent use of multiple chemicals, which creates inter-

actions that further complicate medical investigations; c) Research in nonhuman systems that may correlate poorly

with human systems. 4) Medical investigation of clinical toxicity, particularly when

occurring during a large-scale chemical event, must include study of both immediate and near-term effects, as well as associated illness and longer-term effects. Careful analysis of these events is critical to validation of current medical practice and development of novel approaches. This type of investigation is generally successful in commercial drug stud- ies. The precision and attention to detail practiced in drug investigations should be applied equally to medical studies of toxic effects in a chemical event.

5) Immediate and near-term lethal sequelae of chemical events, even those intentionally orchestrated, rarely occur in more than 3%–5% of exposed individuals.

6) Large-scale chemical events trigger public anxiety and fear to a degree that is strikingly disproportionate to the number of deaths. The media appears to be a primary contributor to this public anxiety, largely as a result of its presentation format. The medical community must assist the media with both its presentation of content and methods.

7) Lethal sequelae of chemical events, in the immediate or near term, are primarily respiratory in nature. Thus, disaster pre- paredness for chemical events should emphasize respiratory illness as a principal focus.

8) Technology for rapid identification and intervention in chemical event–related respiratory illness is well developed and advancing rapidly on many research fronts. Therefore, the prospect of successful intervention in chemical event– related severe respiratory illness is high, particularly if early assistance is provided.

9) Traditionally, the medical community has focused primarily on immediate response to a chemical event. It must now

430 Koenig and Schultz's Disaster Medicine : Comprehensive Principles and Practices, edited by Kristi L. Koenig, and Carl H. Schultz, Cambridge University Press, 2009. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/apus/detail.action?docID=564432. Created from apus on 2018-03-08 08:56:29.

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begin to focus on the broader aspects of an event. During the time period termed “recovery,” the medical community has two unique responsibilities: a) Critical assessment of the long-term clinical aspects of

the event should include both medical and psycholog- ical sequelae. Careful long-term evaluations of all the victims from an exposure should be undertaken in a fashion similar to the September 11, 2001 U.S. terror- ist attacks follow-up programs underway in New York City. Carefully documented clinical and laboratory vic- tim data should be collected in a medically accessible database for future review and use. This long-term clin- ical/medical review should be undertaken independent of legal, political, or commercial interests in the event;

b) Critical assessment must be made of the medical aspects of mitigation, preparedness, and response in the event. This assessment must be compiled and produced as a referenced document, available for immediate and later review. This is a disaster preparedness review with a med- ical focus. It should also be produced independent of legal, political or commercial interest in the event.

10) The aforementioned two types of review should begin as soon as possible after a chemical release.

11) The clinical review mentioned should be undertaken by a national organization equipped to undertake epidemiologi- cal, medical, and psychiatric evaluations of all involved indi- viduals from the beginning of the event through long-term assessment. There is no national organization that currently performs this type of function within the United States.

The disaster preparedness review should be undertaken by a team of trained medical observers who would respond to an event with full access to medical and first respon- der facilities. The U.S. Department of Homeland Security, Federal Emergency Management Agency’s (FEMA’s) Chem- ical Stockpile Emergency Preparedness Program (CSEPP) (detailed later) has demonstrated, for the past 15 years, an exceptional ability to perform this function for large-scale chemical exercises throughout the United States. Shifting this CSEPP expertise from exercise observation alone to involve- ment in a real chemical event would be an immensely prac- tical use of a well-established organization.

12) Many of the long-term medical evaluations that have been attempted in large-scale chemical events have been hindered by limitations placed on both medical data collection and reporting. Political and commercial interests often appear to interfere with and even degrade the quality of medical assess- ment of an event. Legal interests often appear to restrain an openness of medical evaluation and discussion. As a result of legal involvement, medical evaluators have become hesitant to perform critical assessments and their ability to discuss or publish their observations has been compromised.

13) The medical community has been complicit in accepting scant and poorly undertaken investigations of medical disas- ter preparedness (mitigation, preparedness, response, and recovery) in large-scale chemical events. As has been so well demonstrated by the U.S. National Traffic Safety Board and certain other federal organizations, critical investigation, independent of political, commercial, and legal influences is possible. This type of critical event investigation, performed with a specific medical focus, should become a routine aspect of any large-scale event.

The following text includes a historical presentation of chem- ical use and events, progressing to examples of large-scale events with commentary on disaster preparedness issues. Finally, sug- gestions for future medical system planning will be presented.

STATE OF THE AR T

Chemical History

Since at least 1000 bc, chemicals in some form have been used as weapons. Initially those chemicals were found as natural mate- rials that could be used to produce a particular desired effect when extracted from geological deposits. For example, in approx- imately 670 ad, the Byzantine Greeks in Constantinople devel- oped a combination of materials that when ignited became an effective weapon. Greek Fire was a combination of uncertain composition that probably contained naphtha, sulfur, saltpeter, and pitch. When used against enemy ships, this “wet, dark, sticky fire” would float on water, stick to ships and even continue to burn under water. It was almost impossible to extinguish and hence was particularly effective against enemy wooden ships. Greek Fire not only produced substantial physical damage, but also, perhaps much more importantly, spread extraordinary fear among the enemy. That fear was the result of

1) Failure to anticipate the use of the material as a weapon (mitigation)

2) Failure to develop adequate weapon protection (prepared- ness)

3) Inability to control the immediate effects of the weapon (response)

4) Inability to learn the method of manufacture of Greek fire and develop plans for its future use (recovery)

Substantial effort was expended in attempting to educate sailors about the methods of use and effects of Greek Fire. Fear that this was a weapon “of the devil” was mollified. Training in methods of flame control helped ease anxiety as well. These early forms of “disaster preparedness” helped overcome the advantage of fear that Greek Fire carried.

By the 18th century, the discovery of unique chemicals such as cyanide and chlorine was quickly followed by recognition of their harmful effects. Shortly thereafter, various military groups around the world proposed use of these materials, specifically for their toxic properties. During WW I, large-scale production and use of chemical agents as toxic weapons became common.

French riot control agents were perhaps the first chemical weaponry of WW I. Riot control agents were relatively ineffec- tive, however, because highly motivated soldiers could easily tolerate their irritant effects. On April 22, 1915, after exten- sive preliminary preparation and some false starts, the Germans released approximately 150 tons of chlorine from approximately 6,000 cylinders over a 7-km front line. Large clouds of a yellow- green, intensely irritating gas spread in the direction of the oppos- ing French. Chlorine gas is heavier than air. As a result, the clouds settled into the very trenches that the soldiers thought would protect them. Choking and gasping, those soldiers ran from a fearful unknown substance, perhaps inhaling greater quantities simply as a result of their physical activity. The effects of that first attack, by some accounts, included 2,000 deaths and up to 20,000 wounded.1 The Allies quickly identified the chemical agent used

Koenig and Schultz's Disaster Medicine : Comprehensive Principles and Practices, edited by Kristi L. Koenig, and Carl H. Schultz, Cambridge University Press, 2009. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/apus/detail.action?docID=564432. Created from apus on 2018-03-08 08:56:29.

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432 ■ JO H N S. UR BA N E T T I A N D JO NAT H A N NEW M A RK

and shortly retaliated in kind. Within months, chlorine (and later phosgene) was produced, weaponized, and used in large quan- tities by both the Axis and the Allies. These agents are primarily toxic by inhalation. Accordingly, the development of increas- ingly effective gas masks diminished the “value” of these agents. Of course, gas masks were useful only if the soldiers had adequate education and training and were highly motivated. Use of the gas mask for any period of time was exceptionally uncomfortable. As a result, the soldiers often used them only when their noses provided an alarm. Chlorine, with its intensely irritating aroma, prompted immediate mask use and thus could be avoided. Phos- gene, a later weapon development, had a more pleasant smell (likened to newly mown hay). As a result, inhalation of toxic amounts of phosgene easily occurred prior to donning of the mask. A delayed physiological effect, with (frequently lethal) pul- monary edema, occurred in 4–12 hours. Victims, appearing and feeling normal during the first few hours after exposure, would often continue full military activities. Later, it was learned that exercise during the “latent period” prior to development of pul- monary edema resulted in more rapid onset of more intense dis- ease. This delayed onset of a sometimes-lethal respiratory failure was commonly seen in an individual who initially appeared and felt well. Extreme fear and anxiety resulted among the troops who never knew where or when they would become affected. Inten- sive efforts to provide the soldiers with a better understanding of chemical weapons and the circumstances/likelihood of their use were combined with improved mask protection. There was a resulting decrease in medical aid station visits for both real and imagined gas exposures.

Because improved Allied education, training, and equipment led to a decrease of effectiveness of the German chemical attacks, the Germans introduced a novel chemical material. On Decem- ber 17, 1917, sulfur mustard, active either as a liquid (below 14◦C) or as a vapor, was first released. Sulfur mustard damaged any topical/epithelial surface of contact. Unprotected eyes, skin, and respiratory tract suffered inflammatory damage to a degree related to the “dose” to which the individual was exposed. Sul- fur mustard had a unique aroma, often characterized as similar to garlic or horseradish; however, severe exposure, particularly to the liquid, could occur with a minimal warning aroma. The primary molecular effect of the chemical agent, alkylation of nucleic acids, occurred within the first few minutes of contact. An intense, irritating, inflammatory biological response to that con- tact would typically occur after a latent period of some hours to days depending on the exposure dose. As a direct result, soldiers would often develop clinical symptoms distant in time and place from their original exposure. There was no available technology to permit identification of sulfur mustard–contaminated areas. As a result, soldiers were unable to identify contaminated places or even people. Fear of cross-contamination seriously compro- mised their daily activities. Blindness, painful skin blisters, and respiratory symptoms including cough, wheezing, and substan- tial shortness of breath occurred in soldiers without obvious sulfur mustard contact. An overwhelming sense of fear of chem- icals resulted. Soldiers would avoid any areas that had unusual smells suspecting that mustard might be present. Certainly this fear was one of the most important effects of the use of chemical weapons.

Sulfur mustard rapidly became an important adjunct to WW I weaponry. By the end of the war more than one-half of all shells fired were filled with a chemical agent, often sul- fur mustard. Approximately 25% of all WW I casualties were

chemically related. The ease of chemical weapon manufacture attracted the attention of many countries after WW I. This resulted in substantial research, manufacture, weaponization, and stockpiling of chemical agents, particularly including mus- tard, in anticipation of possible future needs.

Since the discovery of mustard in 1850 by Guthrie, the intense inflammatory effects of mustard have been recognized. There has been substantial research regarding its cellular and systemic tox- icity; however no specific antidote has been identified to date. Each instance of its use subsequent to WW I has been associ- ated with production of large numbers of debilitated and dis- abled individuals. Medical statistical assessment of these injuries during WW I has documented the frequency, distribution, and duration of illness of each of the bodily systems involved. Of per- haps greatest interest is the documentation of a 3%–5% death rate, largely respiratory. An important comparison is the WW I Allies’ 25% death rate from conventional weapons. This, sta- tistically and perhaps surprisingly low death rate, appears con- sistently throughout records of subsequent large-scale chemical events, whether accidental or terrorist related.2

Despite the (relatively) low death rate that has historically occurred from chemical events, both military and public percep- tion is that chemical events, whether accidental or intentional, are to be greatly feared. The degree of fear surrounding chemi- cal events appears to be disproportionate to the degree of actual illness and death. Similar degrees of seemingly excessive public fear are evident in nearly every report of a chemical event. Fear of a chemical event, in fact, seems to create much more pub- lic distress than the actual morbidity and mortality created by the release itself. For this reason disaster preparedness profes- sionals have expressed concern about possible terrorist use of easily available toxic industrial chemicals (TICs).1 In theory, the difficulty of acquiring or manufacturing a military-style agent could be bypassed and an equally large-scale public effect could be achieved by making use of commercially available chemicals. In the public mind, chemicals are “all cut from the same cloth” and hence reports of any release are likely to provoke substantial public reaction: fear and terror. It appears that even the threat of TIC use may be enough to trigger intense public anxiety and terror (see Improvised Explosive Devices).

The majority of deaths that occur after a large-scale chemi- cal release occur within the first few hours following the event. Salvage of severely ill individuals within this time window is obvi- ously highly desirable but presents a daunting logistical problem. For the two common chemical agents that have available anti- dotes (organophosphates and cyanide), stockpiling and training in the use of those antidotes is valuable. Deaths that occur with organophosphates and cyanide are due principally to respiratory causes and immediately available antidotes can be of great value. In the case of large-scale events with other agents, the major- ity of deaths are also from respiratory effects. Most of those deaths occur in the immediate or near term. Useful immedi- ate interventions include oxygen supplementation, intubation, and ventilatory support. In the event of a large-scale chemical disaster with high numbers of exposed and sickened victims, the logistics of providing oxygen supplementation, intubation, and mechanical ventilation may at first appear overwhelmingly difficult. The numbers of individuals suffering acute (and treat- able) respiratory failure, however, are relatively few. Rapid iden- tification of those individuals with acute respiratory failure is actually the principal logistical problem. Even if specific anti- dotes are not available, the character of the acute respiratory

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failure includes abnormalities of airway and alveolar function for which a variety of increasingly useful interventions are becoming available. The logistics of delivery of those novel interventions will have to be further studied. Much of the following discus- sion will be directed toward demonstrating the importance of rapid identification and treatment of those individuals with early acute respiratory failure. Several examples of events will be fol- lowed by commentaries that will include perspectives on the mitigation, preparedness, response, or recovery efforts for each event.

EXAMPLES OF CHEMICAL EVENTS: IMPLICATIONS FOR DISASTER PREPAREDNESS

Intentional (Nonstate Sponsored) Chemical Events

Arsenic Use in 1946 at Stalag 13 Shortly after the end of WW II, in April of 1946, a small

group of Holocaust survivors undertook a chemical poisoning attack on a large group of Nazi SS soldiers held in an Amer- ican prisoner of war camp. Desiring to avenge the deaths of 6 million Jews, an organization known as “DIN” (an acronym for “Avenging Israel’s Blood”-Dahm Y’Israel Nokeam) planned to poison and kill hundreds of thousands of German civilians. Arsenic poisoning of the water systems of several major German cities was first considered. When a British investigation threat- ened to reveal the plan, it was discarded. An alternate plan to poison the food of Nazi inmates in prisoner of war camps was developed. An American prisoner of war camp (Stalag 13, just outside of Nuremberg, Germany) that contained approximately 15,000 former Nazi SS soldiers was selected. A plan to poison the black bread supply was developed because the perpetrators had noted that the prisoners preferred black rye whereas the Ameri- can guards and local workers preferred white bread. On the night of April 13th, access was obtained to the bakery. There, an odor- less mixture of arsenic and glue was painted on the bottom of up to 3,000 loaves of bread, poisoning a number of the prisoners. The perpetrators escaped. Large numbers of ill prisoners were treated at local medical facilities. Specific data concerning the arsenic effects and numbers of dead and injured are not avail- able. News articles appeared in both the New York Times and the Munich newspaper Suddeutsche Zeitung. The Munich news of April 24, 1946 reported, “tests taken immediately following the event showed that the bread contained the poison arsenic. Four bottles filled with poison and two empty ones were found in the bakery. Out of 15,000 inmates, 2,283 fell ill from the poisoning, with 207 hospitalized. According to the hospital’s records, there were no fatalities.” DIN sources report 4,300 sickened, 1,000 hos- pitalized and 700–800 either paralyzed or dead within weeks of the event. An American official investigation was apparently con- ducted but casualty numbers were withheld for “fear of causing mass panic.”3,4

GENERAL COMMENTAR Y

This attack, despite creating a large number of ill and hospi- talized victims, received very little notoriety in the contemporary press. Available records are scant. There is no evidence that any specific action was taken by the U.S. military or German civil- ian organizations to mitigate any subsequent chemical attacks. Evaluation of the medical response to this event would be of

extraordinary value; however, there are no available records of the medical response.

MITIGATION

In Germany, during and immediately after WW II, medical facilities nearby to prison camps maintained minimal if any rela- tionship with those camps. At the end of the war, with the Allied discovery of the prison camps, there was immediate need for nutritional evaluation and medical care of recently released pris- oners. Local medical facilities were already overwhelmed with other local needs. Allied medical teams provided most of the medical support for the newly released prisoners. There was no consideration given to the possibility of a large-scale prison illness event.

PREPAREDNESS

There are few available records that detail the type or extent of medical support available to the WW II Allied prison camps. Some “subcontracting” of medical care was arranged with local physicians and hospitals. These resources, however, had few supplies and still fewer personnel. There was no con- sideration given to the possibility of a large-scale prison illness event.

RESPONSE

In the absence of specific medical records, few conclusions can be drawn from the reports of numbers hospitalized and ill or dead. At that time, British anti-Lewisite (BAL – Dimercaprol) was known to be effective in arsenical poisonings. It is unlikely, however, that any substantial supply of BAL would have been available within the local civilian community. Quantities of BAL might have been available within the (Allied) military medical structure in anticipation of possible German use of the chemical weapon Lewisite. There is no record of BAL use in this event. Res- piratory failure, sometimes seen with arsenic poisoning, might have prompted use of ventilator support. An early mechanical ventilator was available in the U.S. at the time (Drinker “iron lung”). There is no record of such ventilator availability or use during this event. Even if some ventilators had been available in Germany, they would have been cumbersome, effort-intensive, and ineffective for the management of pulmonary edema (adult respiratory distress syndrome [ARDS]) associated with arsenic poisoning. There are no specific data regarding the medical facilities within Stalag 13. There is no available record of their response to the arsenic poisoning. The scarcity of public news may have been the result of a concerted attempt to avoid both public fear of the (suspected Jewish) attack and to avoid spread of fear within other prison compounds maintained by the Allied forces.

RECOVER Y

There is no available report specifically concerning any (Allied) investigation of the event. No records are available from any of the local hospitals that dealt with the arsenic poisonings.

Thus, no data exist that could be used as a basis for review and planning for similar large-scale events. As a result, an opportunity to review a large-scale arsenic event has been lost.

Nerve Agent Plans in 1974 by Alphabet Bomber

Muharem Kurbegovic was a Yugoslav immigrant to the U.S. Through the years of 1967–1974, he worked in a variety of

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engineering jobs where he presumably acquired enough training and education to manufacture explosives and chemical agents. He developed a personal terror network that he called “Aliens of America.” A series of bomb threats and attacks followed. Three deaths and 35 injuries followed an explosion at the Los Angeles International Airport. His nickname “Alphabet Bomber” came from threats using alphabet letters to designate the next site of attack. His audiotaped threats were sent to the local media and were subsequently widely reported. One of these threats led to particularly widespread public anxiety in Los Angeles dur- ing the summer of 1974. In 1974, his attention also focused on nerve agent production and use. By audiotape, he informed the news media of his production of four different nerve agents. He reported his placement of time-release containers of “AA4S nerve gas” in several cities around the world including New York, Miami Beach, London, Paris, Tokyo, and Hong Kong. There was no subsequent evidence, however, that nerve agent actually existed in any of the threatened cities. Other chemical dispersals were threatened including injection of chemical warfare agents into the air conditioning systems of Los Angeles skyscrapers. Ultimately, after his capture, search of his apartment revealed 11 kg of sodium cyanide, and bottles labeled nitric acid and car- bon tetrachloride. There was speculation that these substances might have been intended for the production of tabun or hydro- gen cyanide gas as lethal agents.5–7

GENERAL COMMENTAR Y

It appears that most of Kurbegovic’s knowledge and abilities were acquired through a combination of personal contacts dur- ing his work experience (engineering/aerospace industry) and research in numerous books and articles on the subjects of nerve agent and explosives. These resources are much more easily avail- able by Internet search today than they were in the 1970s. The public anxiety that resulted from widespread reporting of Kurbe- govic’s threats was apparently difficult to control. Kurbegovic presented most of his threats by audiotape delivered directly to the news media. The media, interested in rapid dissemination of their “breaking news,” did not appear to interact with the public officials who were interested in controlling public anxi- ety. As a result, “news” of impending Alphabet Bomber attacks seemed to balloon public anxiety. Public concerns about possible widespread effects of a “lethal” material were the forerunner of similar concerns that sprang up around the U.S. anthrax event of 2001.

MITIGATION

During the time that Kurbegovic was active, U.S. med- ical establishments had not developed an organized process of risk assessment and analysis. Chemical materials associated with explosive devices were a principal part of the weaponry of WW I and were in fact so “successful” that they have been manu- factured, stockpiled, and used by many countries since that time. Despite clear demonstration of the effects of chemical weapons since WW I, U.S. federal, state, and local emergency response organizations generally did not consider that intentional use of chemicals was a significant risk. As a result, the politicians and particularly the medical structure did not anticipate and were unable to control substantial public anxiety about a chemical attack within the U.S. It was only with the advent of the CSEPP that an organized medical preparation for possible large-scale chemical events was developed.

PREPAREDNESS

Substantial public anxiety resulted from the extensive media coverage of Kurbegovic’s audiotaped warnings and threats of planned chemical attacks on major U.S. cities. This anxiety was exceptionally difficult to control. Local, state, and federal medical systems were not prepared to provide a coherent and organized presentation to the public about the (medical) validity of the threats or to offer any useful suggestions for medical preparation. News media reports that occur during and shortly after an event of this sort typically contain erroneous and conflicting infor- mation, opinions, and suggestions from a variety of often self- proclaimed “experts.” The medical community must prepare in advance to provide useful, media-based information to the public (see Chapter 22). A single, well-credentialed spokesperson must be available to the media for public comment. This spokesper- son should clearly represent a respected medical organization. This spokesperson should have substantial experience in public relations, and, perhaps most importantly, this spokesperson should be familiar to the public before an event.

RESPONSE

There is no evidence that any local hospital had undertaken specific preparations for a large-scale chemical event.

RECOVER Y

There was no chemical event. As was the case during the 2001 U.S. anthrax letter event, the medical established was ineffective in managing a great degree of public anxiety. There was no medical review that assessed the adequacy of public information dissemination. There has been no prepared report that would provide insight into the media-related difficulties experienced by both the political and medical systems involved.

Chemical Weapons Threat in 1975 by Baader-Meinhof Gang

The Baader-Meinhof gang was a revolutionary West German left- wing organization originating from German student movements in the 1950s. By the early 1970s, the group, then calling itself the Red Army Faction (RAF), focused on the U.S. military presence in Germany.

In May 1975, the Times of London and a German newspa- per Bild Zeitung reported that the Baader-Meinhof/RAF gang had stolen chemical munitions. A mustard agent attack, using bombs and SAM-7 missiles, was threatened against the population of Stuttgart, Germany. The attack would occur unless “all political prisoners” (including leaders of the Baader-Meinhof gang) were granted immunity in a pending trial in Stuttgart. There are vari- ous accounts of how much and in what form “mustard gas” had gone missing from a depot in Münster. Numerous subsequent investigations revealed scant specifics of this event. There was no subsequent proof that the Baader-Meinhof gang had physi- cal possession of mustard agent or any specific plan for its use. Nevertheless, intense media coverage resulted in the need for substantial military and civilian investigation.8,9

GENERAL COMMENTAR Y

This event stimulated public anxiety that was apparently fueled by media coverage in what has been described as “journal- istic sensationalism.” It is presented as an example of public fear of the unknown. Despite valiant attempts by chemical warfare

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and terrorism experts to control public anxiety with rational and scientific reviews of the event, there appeared to be no publicly trusted spokesperson who could effectively assuage public anxi- ety (see also Alphabet Bomber).

MITIGATION

Chemical weapons storage in Europe during the 1950s was a part of the extensive North Atlantic Treaty Organization plan- ning for possible European Theater warfare. Because public awareness of the European storage of chemical weapons was limited, revelation of this information coincided with the inter- ests of various student and militant groups wishing to disturb the military stability in the country. Although European mili- tary medical personnel were extensively trained and prepared for chemical weapon use, civilian hospital personnel had little awareness and even less training. This lack of education was likely a primary contributor to much of the medical confusion that arose from the threatened mustard event.

RESPONSE

Media reports of the threatened combined missile and chem- ical attack on Stuttgart triggered a public hysteria that was par- ticularly difficult to control despite substantial effort by govern- mental agencies. As suggested in the Alphabet Bomber example, the medical community must prepare in advance to provide useful, media-based information to the public. A single, well- credentialed spokesperson must be available to the media for public comment. This spokesperson should clearly represent a fully respected medical organization. This spokesperson should have substantial experience in public relations, and, perhaps most importantly, this spokesperson should be familiar to the public before an event.

Cyanide Poisoning of Water Supply in 1985 – The Covenant, the Sword, and the Arm of the Lord

The Covenant, the Sword, and the Arm of the Lord (CSA) was a survivalist group that appears to have been primarily interested in large-scale murder to “hasten the return of the Messiah by car- rying out God’s judgments.” The group was conceived in 1971 by a fundamentalist preacher, James Ellison. The group planned and prepared for Armageddon, which would result in the destruc- tion of the American economic system. On April 22, 1985, an FBI raid of the CSA compound revealed a stockpile of machine guns, ammunition, an antitank rocket and an armored car. The FBI found 114 L of potassium cyanide. The CSA initially explained that the cyanide was to be used for pest poisoning. Further FBI analysis revealed there had been extensive discussions and plan- ning with intent to use the cyanide to poison water supplies in New York, Chicago, and Washington.10

GENERAL COMMENTAR Y

The toxicity of a chemical agent is principally dependent on the quantity delivered. Therefore, cyanide, or other more toxic materials such as organophosphates, if placed in a large community water supply, would be sufficiently diluted as to ren- der the biological effect negligible.

To intentionally achieve an effect through a water system, either extraordinary quantities of agent would be required or the agent would need to be delivered within the system, closer to the victim. Cyanide has often been used in small quantities in

criminal tampering with drugs and food products. The Chicago contaminated Tylenol R© event in 1982 was the first documented U.S. incident of food tampering with cyanide. Seven deaths resulted from distribution of the poisoned capsules to six stores in the city. A number of subsequent “copycat” events occurred over the next several years with additional deaths. Despite a $100,000 reward offered by Tylenol R© manufacturer Johnson & Johnson, the perpetrator has not been caught. Prior to 1982, tamper-proof capsules and packaging were virtually unknown. Subsequent to the tampering events, public anxiety mushroomed. Manufac- turers of packaged foods and medicines promptly responded with development and application of an extraordinary variety of complex and protective packaging. It appears that this extra level of “public protection” consumes many millions of dollars yearly. The cost/benefit of the extra packaging has yet to be mea- sured. On such occasions, public anxiety, often fueled by media speculation, may present a far greater problem than the medical issues.

MITIGATION

Communities with public water suppliers routinely partici- pate in a risk assessment and vulnerability analysis concerning possible compromise of their water supplies. Normally problems of environmental disaster or drought are a primary focus. As a result of such notorious industrial poisonings as the Minimata mercury-poisoning event in Japan (resulting in ∼400 deaths and 1,000 permanent injuries), many cities have also become con- cerned about environmental “pollutant” contamination. Risk assessment and vulnerability studies for possible environmental pollution are, in fact, just the type of action that would be use- ful for mitigation of possible chemical, biological or radiation contamination.

PREPAREDNESS

Specific medical preparations for possible water supply con- tamination have long been an accepted part of military pre- paredness. Civilian medical systems, however, rarely have ade- quate detection equipment or response technology to respond to an intentional water supply contamination. By federal regu- lation, U.S. communities have developed an interactive disaster preparedness committee, the Local Emergency Planning Com- mittee. Primarily through this type of community-wide orga- nizational structure, such issues as water supply risks can be addressed in a cooperative fashion with appropriate assistance requested from organizations such as the Environmental Protec- tion Agency (EPA) at the state and federal levels.

RESPONSE

Despite threats by many organizations and individuals, at the time of this writing, no such large-scale intentional water supply contamination has occurred. The U.S. EPA has undertaken an extensive public information, planning, and preparation effort to assist in the understanding of the scope of this concern. This is a fine example of national governmental mitigation and pre- paredness for a perceived risk.

Cyanide at the U.S. World Trade Tower Bombing in 1993

The February 1993 New York City World Trade Center (WTC) bombing killed six people, injured approximately 1,000 and caused nearly $300 million in damage. At the time, there was

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no clinical evidence that victim illness or death was in any way related to a cyanide exposure. By mid-1994, a mistaken belief that cyanide was a component of the attack began to circulate among medical and law enforcement professionals and others interested in such events. Suspicion that cyanide was an intentional com- ponent of the bomb appears to derive from the following

1) Discovery of a single sealed bottle of aqueous sodium cyanide in the bombers’ chemical storage shed

2) Discussions with the bombing conspirators revealed that they had considered incorporating sodium cyanide in the bomb but had decided against it because it was “going to be too expensive to implement”

3) Prosecutor questioning during the four bombers’ trial raised awareness of the consequences of mixing sodium cyanide with either nitric or sulfuric acid (both of which were known to be in the bomb). There was, however, no specific allegation of such use

During sentencing of four convicted bombers, Judge Kevin T. Duffy stated, “You had sodium cyanide around, and I’m sure it was in the bomb. Thank God the sodium cyanide burned instead of vaporizing. If the sodium cyanide had vaporized, it is clear what would have happened is the cyanide gas would have been sucked into the north tower and everybody in the north tower would have been killed. That to my mind is exactly what was intended.”

During the trial, however, the prosecutor’s summary state- ment did not mention sodium cyanide as present in the bomb. Finally, there were no forensic data presented during the trial sug- gesting that the FBI had found any evidence of sodium cyanide.11

GENERAL COMMENTAR Y

It appears that there was no substantial evidence for use of cyanide as part of the 1993 WTC bombing; however, public anxiety was unduly heightened as a result of the rumor. Per- haps more importantly, much subsequent scholarly and political effort resulted from what appears to be inaccurate “informa- tion.” Conversely, however, the apparent willingness of terrorists to utilize a chemical weapon should certainly be acknowledged in community defensive planning.

MITIGATION

Prior to the 1993 WTC attack, there was little international concern regarding the possibility that an explosion could be con- taminated with chemical, biological, or radiological materials. Environmental disasters have historically and characteristically been associated with both chemical and biological contamina- tion. Hence, first responders and medical personnel have experi- ence working in such contaminated environments. The general public, however, does not seem to appreciate this depth of expe- rience and hence seems more fearful of the prospect of inten- tional/terrorist chemical contamination of an explosive event. This fear is particularly difficult to dispel. Control of this fear is necessary to mount a successful response to an event. Control of this fear will be best achieved with education. The U.S. Cen- ters for Disease Control and Prevention (www.cdc.gov) provides extensive data regarding mitigation and preparedness for such an event.

Evaluation of the risk of a biologically contaminated terrorist explosion has been incorporated into the routine medical prac-

tice policies and procedures of at least one country (Israel).12

Israeli hospitals’ Emergency Department personnel consider the possibility that victims of an explosion may be contaminated with chemical, biological, or nuclear material. Appropriate pre- cautions are taken.

PREPAREDNESS

In 1993, New York City medical systems did not have specific plans to evaluate or respond to intentional use of a chemical contaminant in an explosion. There is no available record of specific preparation for an intentional chemical attack involving the WTC. Although routine firefighting preparations using a self-contained breathing apparatus (SCBA) would be considered adequate for fire department personnel, ambulance and medical personnel were not trained or equipped for such an event.

RESPONSE

Immediately after the bombing, there was no clinical indi- cation of chemical contaminants. Firefighters responding to the scene quickly assessed the possible need for SCBA. While there was no evidence of cyanide at the time, specific testing for cyanide may not have been accomplished. Local hospitals mounted an excellent response within their Emergency Departments; how- ever, this was a trauma response that did not incorporate consid- eration of possible chemical, biological, or nuclear contamina- tion. Some months subsequent to the bombing, the (mistaken) thought that cyanide was an intended part of the bombing became newsworthy. The cyanide story was quickly embraced by many professional “Disaster Preparedness” consultants and lecturers and incorporated into their public presentations. There was no apparent effort to assess the accuracy of the story. Dis- closure of the inaccuracy of the story, as so often happens when media-driven excitement is later found to be unwarranted, was accomplished in a halting and poorly documented fashion, leav- ing much of the public recalling the erroneous story (if they remembered at all). Accurate, trustworthy information must be expeditiously provided after an event.

RECOVER Y

Careful postevent investigation of the 1993 WTC event resulted in a remarkable assessment of evacuation problems. The well-established and experienced U.S. National Institute of Standards and Technology (www.nist.gov) undertook an inten- sive investigation of the 1993 event. Specific attention was paid to issues of employee evacuation. Severe problems were identi- fied, showing confusion, anxiety, and poor supervision to have contributed to an extremely slow response to the alarm system. A number of changes were introduced in the evacuation pro- cess. Designating Evacuation Monitors, each responsible for the supervised evacuation of a particular floor, proved to be an excep- tionally innovative and useful change. It has been said that tens of thousands of employees were successfully evacuated during the September 11th event who would not otherwise have escaped if the “old” 1993 plan had still been in effect. A WTC Research & Development Program evolved from this investigation, provid- ing much innovative planning and direction for intervention in future high-rise building fires. There has not been a comprehen- sive review of the immediate or near-term medical community actions. A critical review of those actions, particularly in com- parison to existing emergency operations plans, would be of immense value. Equally desirable would be a review of how the

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changes enacted in medical emergency operations plans after the 1993 WTC event affected the response to the September 11, 2001 U.S. terrorist attacks.

Nerve Agent Use in 1995 – Aum Shinrikyo

On June 27, 1994, a successful chemical attack was undertaken in Matsumoto, a city (population 200,000) situated in the northern Japanese Alps, 201 km northwest of Tokyo. Aum Shinrikyo, a 40,000 member, well-funded “doomsday” cult perpetrated the attack. The use of sarin, a military organophosphate poison, resulted in seven deaths among nearly 600 victims. Five victims were found dead, two were transported to the hospital in full cardiac arrest, dying within 4 hours, and one victim survived in a vegetative state due to (presumed) hypoxic encephalopa- thy and died of respiratory failure in August 2008. There were 56 hospitalizations distributed among six hospitals. Several vic- tims required intubation and mechanical ventilation. General- ized seizures were noted in many of the severely affected victims. There were 208 additional outpatient clinic medical evaluations and 277 symptomatic victims who did not seek medical care. The first report of the event came as a telephoned request for an ambulance 2 hours after the exposure. Eight of the 52 rescuers and one doctor providing care showed symptoms of poisoning as a result of (presumed) cross-contamination. One rescuer required hospitalization. Ten years later, a long-term questionnaire-based survey of local residents showed 73% of exposed and 44% of nonexposed residents reporting psychological problems.13 The intent of the attack, prevention of a legal decision in a local civil suit, was achieved by poisoning the three judges involved. Sarin was specifically identified as the toxic agent in a sample taken from a local pond on July 4, 1994. Those data and other related law enforcement concerns provided sufficient evidence for a police raid of the principle Aum Shinrikyo facilities, planned for March 1995. The Tokyo subway sarin attack, however, occurred first.14

On March 20, 1995, Aum Shinrikyo cult members released an estimated 24 L of sarin of approximately 30% purity. The perpetrators may have had atropine sulfate injections available for personal use if necessary.15 The sarin was distributed into 11 polyethylene bags, although probably fewer bags were actu- ally opened. Five different subway trains were involved, all of which were scheduled to arrive within 4 minutes of each other between 8:00 and 8:10 am at the Kasumigaseki Station. The station was selected for proximity to Tokyo’s National Police Agency and Finance Ministry as part of the cult’s plan to signal the beginning of Armageddon and to specifically attack mem- bers of a chemically trained police squad. Ultimately, 15 subway stations were involved. The first notification of a medical emer- gency was directed to the city fire department within minutes of the attack. Some 15 subway stations called within the next several minutes. Area hospitals were notified at 8:16 am, but the initial report was of a gas explosion. Therefore, the hospitals prepared to receive patients with burns and carbon monoxide poisoning. It was more than an hour before emergency dispatch recognized the disaster as a single event. Ultimately 131 ambu- lances and 1,364 emergency medical technicians (EMTs) were dispatched to the affected subway stations. Poor communica- tion with the Emergency Operations Center resulted in EMT transport of all nearby victims directly to St. Luke’s International Hospital (SLIH). Even though SLIH had a mutual aid agree-

ment with another nearby hospital to take less ill patients, this agreement could not be implemented because all available trans- portation was otherwise occupied. SLIH saw 649 victims within the first 24 hours. The EMTs attempted on-site triage at the scene of the release and some medical support; however, there was no on-scene clothing removal, decontamination, antidote administration, or intubation of victims with severe respiratory distress. The EMTs had no personal protective equipment. Of the 1,364 EMTs who worked to transport victims to hospitals, 135 developed clinical evidence of sarin poisoning requiring some medical therapy, including at least 25 hospitalizations. SLIH had three entrances, each of which remained open, allowing patients, relatives, television crews, and various onlookers full access. Not all victims arriving at the hospital were directed to disrobe or shower. As a result, 110 hospital staff members at SLIH (23% of the staff) themselves experienced some symptoms of (cross- contamination) sarin exposure. There were 12 deaths as a result of the attack. Six deaths occurred within 2 hours of the event and the remaining six deaths occurred from 20 to 80 days later. Some deaths were among the subway station personnel, who apparently cleared sarin-contaminated waste with bare hands and no respiratory protection. From available medical reports at SLIH (two deaths of 1,000 patients seen), it appears that the two deaths resulted from cardiac arrest. One victim, in full arrest upon arrival, was immediately intubated and provided ventila- tory support. She survived to be discharged 5 days later. Of partic- ular interest, this 21-year-old woman apparently received no spe- cific antidote until approximately 90 minutes after her exposure. Notification that sarin was the offending agent did not occur until approximately 10:30 am, 2.5 hours after the event. Reportedly, a military physician recognized the clinical signs and symptoms as indicative of a nerve agent exposure. Beginning at that time, oxime therapy was provided for those severely affected. SLIH quickly devised a treatment protocol that enabled the victims to be more rapidly treated. An official prosecutor’s report puts the number of injuries at 3,938. Of a total of 4,973 people reportedly seen at Tokyo hospitals within the first 24 hours, approximately 1,100 were hospitalized. Of all patients reporting to Tokyo hospi- tals complaining of chemical agent exposure, some 74% showed no clinical signs or symptoms. These patients apparently pre- sented largely because of media announcements reporting the event and suggesting that civilians who “felt unwell” should immediately go to the hospital. SLIH conducted a postevent questionnaire-based evaluation of 610 victims. At 1 month after the event nearly 60% reported symptoms interpreted as indica- tive of posttraumatic stress disorder. Repeated studies at 3 and 6 months showed similar percentages of individuals with such symptoms. People reported flashbacks, insomnia, depression, and nightmares. Some individuals’ very high anxiety prevented their subsequent use of the subway. Long-term (10 years) follow- up has been reported and shows persistence of long-lasting psy- chological problems and posttraumatic stress disorder in some victims.13,16

On two separate occasions later in 1995, the Aum Shinrikyo undertook a hydrogen cyanide attack in the Tokyo Rail system. On May 5, 1995 an incendiary device intended to release cyanide was placed in a busy train station. On July 4, 1995 similar devices were placed in four different subway stations. Both these attacks were unsuccessful.

Despite legal and political action and subsequent intense investigation of the Aum cult, there is evidence of more recent

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Aum activity in the Ukraine, Belarus, Kazakhstan, and Russia. In March 1998, a reported Aum member telephoned the Russian newspaper Itar-Tass with a threatened plan to spread a toxic gas throughout the Moscow subway system.17

GENERAL COMMENTAR Y

The Aum Shinrikyo has produced the greatest number of nonstate-sponsored chemical (and biological) attacks on record. Between April 1990 and March 1995, the Aum undertook 10 biological attacks. There were no recorded casualties. Between November 1993 and 4 July 1995 the Aum undertook a total of 12 chemical attacks (one phosgene, two cyanide, five VX, and four sarin) with 20 deaths and approximately 1,300 injured.18

Reports from various medical facilities in Tokyo have expanded knowledge of the time course and clinical response to sarin vapor. Sarin vapor inhalational exposure produces clinical effects very rapidly, within seconds to minutes. Individuals exposed to sarin, provided the exposure ceases (i.e., removal from the site), typi- cally demonstrate their peak of disease within the first 30 minutes after exposure.19 Individuals who survive to reach a medical care facility will likely survive even without specific antidotal therapy unless other complications supervene. At SLIH, one individual arrived in full cardiac arrest. Specific antidotal therapy (atropine and pralidoxime chloride) was not provided until more than 90 minutes after exposure. The victim nevertheless survived without complications. Two other victims suffered respiratory arrest in the setting of seizures after hospital arrival. Immediate provision of diazepam and mechanical ventilation were effective preventing their deaths.

Of the more than 5,500 individuals reported to have been involved in the Tokyo event, some 1,100 were hospitalized, mostly with recognized nerve agent–related signs and symp- toms. Assuming that this cohort of 1,100 was “truly” exposed, the death of “only” 12 individuals among this group represents an important detail in terms of disaster preparedness for this and in fact many other chemical events. In a large-scale chem- ical event, sizeable numbers of patients may be transported or self-present to nearby facilities. As was seen in the Tokyo event, likely only a very small number of these individuals suffer imme- diately life-threatening illness. Importantly, that illness in Tokyo was primarily respiratory. In all cases, immediate identification of severely affected victims with immediate application of respi- ratory support was sufficient to stabilize the victims even without immediate use of antidote. Certainly, later provision of atropine and oxime appeared to ameliorate the degree and shorten the time of the illness. The rapid application of basic and advanced life support principles appears to have been of critical impor- tance. This observation further suggests that first responders and first receivers should be fully qualified and prepared to pro- vide respiratory support, including ventilation and intubation, possibly even at the scene of the event.

MITIGATION

The medical structure in Tokyo had a complex, well- organized and well-trained disaster preparedness organization in place prior to the nerve agent attacks. The principal threat to the city was considered to be an earthquake. Much of the plan- ning and training therefore was focused on aspects of medical care of large numbers of trauma victims. As is often the case, the nerve agent event was unexpected in size and scope. There had been no education or training for a large-scale chemical con- tamination event outside of the military structure. Despite the

experiences of WW II, there was no repository of medical knowl- edge or experience of large events upon which civilian disaster planners could draw. Therefore there was no hazard analysis or vulnerability assessment undertaken.

PREPAREDNESS

Equipment designed for deployment in a contaminated environment was scarce and first responders were not well trained in its use. Contamination of a very large percentage of the first responders emphasized the importance of such prepa- ration.

RESPONSE

The local hospitals managed a very large number of indi- viduals within a short period of time. Presumably due to lack of training, further complicated by an overwhelming influx of vapor-contaminated patients, there was little or no attention paid to patient decontamination or to health professional self- protection. Consequently, in some areas of the hospitals, up to 25% of the hospital staff members suffered clinical effects of cross-contamination. Nevertheless, the most severely ill victims were identified expeditiously and treated with appropriate focus on critical components of their illness. Respiratory failure and seizure with associated respiratory failure were the principal life- threatening illnesses. These were handled very competently. Of note was the absence of early specific antidotal therapy. Although the victims presented with evidence of cholinergic excess, the possibility of organophosphate toxicity was not considered for about 2 hours. By this time, individuals with severe illness had either already expired or were significantly improved having been intubated and ventilated.

RECOVER Y

The medical structure in Tokyo has, in the years after the event, carefully reviewed the medical response, found associated difficulties and proposed and enacted realistic improvements in the city’s disaster preparedness plans. Yanagisawa makes a particularly invaluable recommendation for organized medical evaluation and follow up of such a large-scale event by using an integrated team including epidemiological, neurological, and psychiatric disciplines. Perhaps the most important result of the event has been the development of a National Disaster Center in Tokyo. This facility is a day-to-day resource and training facility for disaster preparedness. In the event of a large-scale disaster, the facility can be converted to provide medical care for disaster victims.13

Commercial Production and Sale of Toxic Chemicals in 1997 by Russian Chemist

On August 6, 1997, a Russian chemist, Valery Borzov was arrested in Moscow for the attempted sale of mustard. A former chemist at the Moscow Scientific Research Institute of Reagents, Borzov had branched into the private production and sale of various poisons. In a secret laboratory in Moscow, he reportedly manufactured and sold a variety of poisonous materials to criminals including the Russian mafia. An undercover policeman paid $1,500 US for 2 mL of mustard, subsequently arresting Borzov. Search of his residence revealed 50 L of toxic chemicals including 400 mL of synthesized mustard agent as well as detailed production notes. He has reportedly been incarcerated in a psychiatric treatment facility with a diagnosis of schizophrenia.20

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GENERAL COMMENTAR Y

Chemical warfare agent production is often said to be eas- ily accomplished with a high school chemistry background and Internet access for the recipes. Actual production of chemical warfare agent (mustard in this case) is difficult, requiring a sub- stantial investment in equipment and training. Even with the extensive training evident in this case, risks in manufacture are considerable. As “meth labs” across the U.S. have shown, possible dangers associated with chemical production are easily neglected in the face of prospects for wealth. There are no specific data sug- gesting that Borzov’s products were used intentionally, and the quantities involved were not sufficiently great to have created a large-scale event. Public anxiety appears to have been controlled in this setting, possibly due to some degree of media control existing within Moscow at the time.

According to a database compiled by the Monterey Institute’s Center for Nonproliferation Studies, 263 incidents were reported worldwide between January 1960 and April 2007 involving crim- inal, politically, or ideologically motivated use of toxic chemicals.

Of the 263 chemical attacks, the toxic weapon was identi- fied in 183 cases. Of this total, only 13 incidents, most of them linked to Aum Shinrikyo, involved the use of a military chemical warfare agent. Instead, the majority of attacks were conducted with household or industrial chemicals, such as cyanides (41 incidents), butyric acid (35 incidents), tear gas (21 incidents), insecticide or pesticide (14 incidents), sulfuric acid (two inci- dents), weed killer (three incidents), and more recently, chlorine associated with improvised explosive devices ([IEDs] eight inci- dents). The delivery system, when known, was often equally low-tech: direct contact with the target (32 incidents), spray or aerosol (13 incidents), contamination of food or drink (36 inci- dents), consumer product tampering (26 incidents), explosive device (16 incidents), contamination of the water supply (14 incidents), canister/container release (five incidents), letter or package (25 incidents), and insertion into a building ventila- tion system (three incidents). Importantly, 85 of the 263 attacks occurred in the United States and Canada. Of particular interest, 35 of the 85 North American attacks were specifically directed against medical facilities.

Intentional (nonstate) production of military chemical war- fare chemicals is possible and has been accomplished as noted previously. Only the Aum Shinrikyo has accomplished both the production and use of chemical warfare agents. This effort required the extensive resources of a highly expensive and com- plex laboratory. The actual number of short-term deaths result- ing from a total of 12 Aum Shinrikyo chemical attacks was 20. Therefore, the total numbers of events and associated deaths and illness have been relatively small compared with deaths and illness associated with accidental releases of TICs. Perhaps this is due to a small degree to the relative difficulty in the manufacture of military chemical warfare chemicals. The widespread availability of and easy accessibility to TICs, combined with their demon- strated effectiveness as “fear-inducing” entities makes their use as a terrorist weapon much more likely. Perhaps more importantly, however, is the fact that whether intentional or accidental, such chemical events have been occurring with increasing regularity. Many more deaths and associated illness have occurred world- wide as a result of accidental chemical events than have occurred as a result of intentional use of chemical substances in warfare or terrorist attacks. A discussion of the use of cyanide and carbon monoxide as lethal agents during WW I is beyond the scope of this chapter.

Improvised Explosive Devices as Chemical Weapons – Iraq 2004–2007

In 2007, IEDs in various forms became the single greatest cause of death among the U.S. troops in Iraq. Nearly 57% of the 327 U.S. deaths during the first 6 months of 2007 were the result of IEDs. Increasing complexity of the IEDs has been associated with greater difficulty in detecting and defending against them, resulting in an increasing mortality rate. Recent escalation of their complexity has resulted from incorporation of chemicals into the device. Both military (sarin and mustard) and industrial chemicals (chlorine) have been incorporated into the devices, resulting in substantially increased anxiety regarding their danger.

Modern history of the use of IEDs dates to the 1936–1939 Spanish Civil War when General Franco ordered the use of petrol bombs against Spanish Republican Tanks near Toledo, Spain. The burning gasoline often set off secondary fires in the tank’s petrol fuel supply or within the turret where ammunition was stored. With the addition of tar to the petrol bombs, thick smoke aug- mented their effect. Molotov’s name (Stalin’s Minister of Foreign Affairs) was added to the device during the Soviet incursion into Finland in 1939.

Explosive powder-based IEDs came to be used in an orga- nized fashion during WW II when Belarusian Guerillas used command-detonated and delayed-fuse IEDs to derail thousands of German trains during 1943–1944. The Viet Cong used explo- sive devices during the Vietnam War. These were typically constructed from scavenged/unexploded American ordnance. Nearly one third of all U.S. Vietnam casualties resulted from “mine injuries” (military statistical reports combined both IEDs and commercial mine casualties). Use of explosive devices by the Provisional Irish Republican Army was widespread during their campaign against the British Army. These explosives initially included classic fuel bombs (Molotov cocktails) and homemade explosives. Later, there was a progression from homemade explo- sives to use of commercial explosives and eventually sophisticated plastic explosives such as Semtex. The Afghani Mujahideen, uti- lizing military materials originally from various Muslim states and the U.S., constructed explosive devices principally from anti- tank mines. Combining the explosives of several mines would result in a more powerful device. Remote-controlled explosion was favored over the pressure-fuse triggers of the original mines. At the time of this writing, these devices are increasingly used in Afghanistan against U.S. troops.

Iraqi IEDs have become more common. Larger sizes, trans- ported by car or truck are known as Vehicle-borne Improvised Explosive Devices (VBIED) and when delivered by a suicide bomber are termed suicide VBIED (SVBIED). These IED explo- sions have been responsible for an increasing percentage of U.S. deaths – averaging nearly 43% of all U.S. deaths (1545 of 3628) since 2003, with a gradually increasing percentage to 57% over the first 6 months of 2007.21

Iraqi IEDS have developed over the years. IEDs were initially placed at the roadside to explode underneath or at the side of vehicles. Improved vehicle armor has resulted in more sophis- ticated IED placement and further development of the type of IED. Shaped charges were developed to permit a more focused explosion. A refinement of the shaped charge, known as the Explosively Formed Penetrator, produced a fast-moving “bolt” of metal that was particularly effective in penetrating heavier armor. These Explosively Formed Penetrators could be placed at

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great distances of 40 m or more, rendering their detection and defense difficult.

In May 2004, an IED rigged from a 155-mm artillery round (possibly left from a Saddam Hussein stockpile) was found to contain the military nerve agent sarin. The round exploded before it could be disarmed. Two individuals required treat- ment for “minor exposure.” During that same month, an IED containing military mustard agent was also found.22

In early February 2007 some VBIEDs were found to contain liquefied chlorine canisters. Explosion of these devices produced some victims of chemical exposure and associated illness. The addition of chemicals to the IEDs, in effect produced a weapon similar to the chemical weapons of WW I. Most of the injuries related to the IED were from associated physical trauma. The effects of the chemical component achieved in WW I resulted from much larger quantities of chemicals delivered by muni- tions specially designed for that purpose. IEDs “accompanied” by chemicals are unlikely to achieve a WW I–equivalent toxic effect. The military/public reaction and associated psychological distress to announced use of a “chemical warfare agent” may have as much effect as the physical damage itself.23 As has been noted before, the best defense against such public (and med- ical responder) anxiety derives from education and training. Accordingly, concerns regarding a chemical release associated with IEDs have prompted training responses within the U.S. Of note is the annual Golden Guardian Exercise undertaken in the State of California. There, focus on the traumatic/explosive effects of an IED has been broadened to incorporate concern about the appropriate response to other materials (e.g., nerve agents), which might possibly be incorporated with the IED.24

The military response to incorporation of chemical (and possi- bly biological and radiological/nuclear – CBRN) materials with an IED has led to development of various remotely operated robotic devices with detectors capable of identifying chemi- cal, biological, and radiological/nuclear materials (e.g., Talon R©

Robots).

EXAMPLES OF UNINTENTIONAL CHEMICAL EVENTS

Ammonia Release in 2002 – Minot, North Dakota

At 1:37 am on January 18, 2002, 31 railroad cars (of 112) derailed in an incident 0.8 km west of Minot, ND, population 36,567. Five cars carrying anhydrous ammonia suddenly ruptured, releasing an estimated 555,300 L of anhydrous ammonia. This vaporized immediately into a large plume. An estimated 11,600 people were resident in the plume-involved area. There were 12 seri- ous injuries, including one traumatic death and 320 additional individuals sustained minor injuries.

The derailment damaged local power lines at the site. Elec- trical supply to 2,820 residences was disrupted. The conductor notified the central emergency dispatch number (911) in Minot by personal cell phone. The violent rupture of the tank cars caused some sections to be propelled as far as 356 m from the site. Temperature was −21◦C and winds were 10–12 km/hour from the west. Very low ambient temperature and slow winds kept the plume from rising. Deleterious health and medical effects were minimized because most residents were indoors asleep at the time. The plume that formed was an estimated 91 m high and 4 km wide as it ultimately drifted downwind to cover 8 km

of the valley containing Minot City. Within 10 minutes the local fire department chief, responding to notification by the 911 emer- gency dispatch operator, arrived on scene and established a com- mand post.

In the involved area, one couple attempted to flee their home. Their truck crashed into a house across the street from their res- idence. The female passenger returned to their house but the 38- year-old male driver collapsed outside. Ammonia vapors were described as so intense as to severely limit visibility in the imme- diate area. The Incident Commander prohibited first respon- ders from entering the site due to a substantial risk to personal safety. Approximately 3 hours after the event first responders were allowed entry to begin rescue of victims in the immediate area; 60–65 persons were ultimately evacuated. An attempted rescue of the collapsed driver failed due to rescuers not wearing SCBAs. All other residents were instructed to “shelter-in-place” with notification provided by warning siren, cable television inter- rupts, and radio notification. Many residents did not hear the siren due to its location, and residents without power did not receive the media notification. The collapsed driver was ulti- mately rescued approximately 3.5 hours after the event and found to be unresponsive. The 911 system handled over 2,800 calls, instructing people to “stay in their homes and shut down their furnaces and air handling systems, go into their bathrooms and use large amounts of water – turn on their showers and breathe through a wet cloth.” Residents with wells, whose power was interrupted, were unable to operate their showers. At 4:15 am the plume reached the nearest (Trinity) hospital. The hospital was not evacuated. Closing down the heating, ventilation and air-conditioning system was effective in preventing infiltration of much of the ammonia.

In emergency responders, seven minor injuries requiring hospital evaluation occurred in the 122 firefighters and 11 police personnel, including several dispatchers. These injuries were mostly eye irritation, chest discomfort, respiratory distress, and headaches.

At 2:15 am, the first casualty reached Trinity Hospital. The hospital disaster plan was activated at 2:30 am. Ultimately more than 370 persons were evaluated. Eleven individuals required hospitalization, three as the direct result of chemical burns to the eyes and face. Two individuals required mechanical ventila- tion. The Minnesota National Guard Civil Support Team arrived later that day. The railroad corporation rapidly established a claims and assistance center. The rapidity of this action may have reduced much of the public distress after the event.25,26

The National Transportation Safety Board (NTSB) began its activities early that morning, with inspection personnel fully active that same day. Town public meetings were conducted to assure residents that recovery efforts were in full progress. Much of the public commentary, however, focused on the belief that 911 and other portions of the emergency response system appeared to have failed the community. An informal review of public perception was undertaken in September 2004 during a Department of Justice Disaster Preparedness Program in North Dakota. Many residents spontaneously reported their continued dissatisfaction with the Minot emergency response, reflecting, “they just abandoned us.”27 The NTSB Report noted that Minot had undertaken a Disaster Preparedness drill the prior September that had enhanced the effectiveness of the emergency response and that a three hour restriction of emergency responders from the involved area was appropriate to their personal safety.28,29

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GENERAL COMMENTAR Y

An evaluation of the event, conducted per federal regulation by the NTSB, was completed and reported on March 9, 2004. This was a comprehensive evaluation that also included a brief assessment of disaster preparedness within the first responder and medical community. Although the originators of this partic- ular portion of the report were not identified and their medical review qualifications are therefore uncertain, there appears no other publicly available comprehensive evaluation of the medi- cal (hospital and first responders) response to the event. Public anxiety is typically very difficult to control during a large-scale event. In this case, postevent efforts to explain the sheltering-in- place process and address other public concerns regarding feel- ings of abandonment were not entirely effective. Two years later, there was persistent public perception of inadequate emergency response. Such perceptions can continue to erode necessary public confidence in the emergency response systems of the com- munity. This is an important public relations issue.

MITIGATION

Minot has, for a number of years, performed high-quality hazard analysis and risk assessment in regards to dangers associ- ated with rail transportation of toxic materials.

PREPAREDNESS

A citywide exercise of response capabilities was conducted 4 months prior to the event. Details of the after-action of that exercise are not readily accessible; hence specific identified weak- nesses are not available for comment. It does appear that first responder equipment and training issues may have contributed to some travel and work difficulties of first responders within the ammonia cloud.

RESPONSE

Specific details of first responder and hospital response are not readily available. The NTSB Report provides some insight into the disaster response of the first responder and medical system. Although a more complete first response/medical review would be highly desirable, the NTSB Report stands as an example of an available document that allows some degree of retrospective review of the event.

RECOVER Y

The city review of the event apparently identified several problems with communications. These reportedly have been addressed; however, important issues of public confidence in Minot’s emergency response system still seem to exist.

Methyl Isocyanate Release in 1984, Bhopal, India

On the evening of December 2–3, 1984, at a Union Carbide of India industrial plant in Bhopal (population 900,000), an approximately 27-ton leak of methyl isocyanate (MIC) occurred. Atmospheric conditions included a relatively low wind speed and a nocturnal temperature inversion. These conditions resulted in a gas cloud that moved slowly, primarily close to the ground, ulti- mately covering approximately 40 km2 of the surrounding city. The cloud rapidly engulfed the homes of a large number of pri- marily poor and uneducated residents. The cloud may have con- tained additional contaminants and decomposition by-products such as phosgene, mono methylamine, hydrogen cyanide, vari-

ous oxides of nitrogen, and carbon monoxide, although specific data are unavailable. An estimated 500,000 people were exposed and an estimated 3,000–15,000 deaths occurred. Accurate statis- tics are unavailable for a variety of reasons, but a 2%–3% death rate seems consistent with available information.

Most immediate and near-term MIC deaths appear to have occurred due to respiratory effects of the chemical. MIC produces airway inflammatory changes, contributing to airway obstruc- tion. MIC also appears to produce a delayed pulmonary edema, much like phosgene. This effect may have contributed to the impression that phosgene was also released during the event. Additional concern was expressed about the possibility of cyanide or various decomposition products of MIC acting as contribut- ing factors. There was no direct evidence to support that concern.

On the evening of the event an estimated 400,000 people fled the city in an uncontrolled evacuation. Nearly half of those who lived more than 10 km away from the event site left, reacting out of fear. Approximately 2 weeks later, during attempts to neutralize the remaining MIC at the Union Carbide plant, pub- lic fear resulted in a second wave of mass evacuation involving approximately 200,000 people. The local medical system, which consisted of approximately 300 doctors and 1,800 hospital beds, was entirely overwhelmed. An estimated additional 1,500 people are reported to have died in subsequent months due to injuries caused by the release.30

Near-term medical care was provided, insofar as possible, by local facilities that were later assisted by Indian government aid. Additional support was provided by a number of non- governmental organizations. Long-term evaluation of medical health and consequences of exposure have been conducted by a variety of individuals and organizations, both private and pub- lic. Their data, albeit somewhat compromised by both ongoing legal/political difficulties and substantial difficulty with estab- lishing and reliably following a cohort of exposed individuals, suggest a variety of possible long-term MIC effects that will require further investigation.

GENERAL COMMENTAR Y

The Bhopal event occurred in a country with limited and poorly developed resources. The sudden release of a large toxic vapor cloud, whether accidental or (as suggested by a Union Car- bide evaluation) intentional, resulted in the world’s single most catastrophic chemical event to date at the time of this publica- tion. A more careful analysis of the event from a perspective of disaster preparedness is warranted.

MITIGATION

The city of Bhopal at the time of the release had a popu- lation of 900,000 people. Nearly 200,000 lived within 10 km of the Union Carbide plant. The majority of these individuals were poor, living in housing that often consisted of no more than tin shacks. Recognizing some risks of residence close to a chem- ical plant, the provincial government attempted to encourage residents to move away. It appeared, however, that individuals actually preferred to live close to a business that might offer many new, well paying jobs to the local residents. The local government maintained few records of the identities or even the numbers of these individuals. There was no record maintained of any indi- viduals with special needs. No governmental or local political organization existed that collectively represented these individu- als. The few city organizations responsible for the health or safety

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of the local population received no effective citizen input. In the absence of a specific citizen action group, there was no organi- zation able to collect information regarding the potential risks of a disaster in the neighborhood of the chemical plant. Thus, no hazard assessment or vulnerability analysis was performed. The nearby first responder community (fire and police) had little awareness or understanding of the possibility of a large toxic leak. Accordingly, there was little education, training, or equipment acquired for that possibility. The local medical facilities and per- sonnel were equally limited in their awareness or understanding of the possibility of a large toxic leak.

PREPAREDNESS

The nearby residents were unaware of the risks posed to their community by industrial facilities in the area (specifically the Union Carbide Plant). In the absence of an organization like the U.S. model of a Local Emergency Planning Committee, there was no evident effort directed toward preparing for an industrial chemical event. No evidence exists that local hospi- tals had become aware of the dangers or risks of the industrial plants in their immediate area or had made efforts to understand and prepare for those risks. Union Carbide had established a small clinic at the entrance to the facility. A physician was hired 8 months prior to the event to act as occupational physician for the facility. Evidence is lacking that the physician either initially had or subsequently acquired particular expertise with respect to MIC. Furthermore, there is no evidence that the company physi- cian was active in preparing either the local medical or civilian community for possible chemical exposures.

RESPONSE

Immediately after the incident, notification of the surround- ing population was ineffective. There had been no community education or training of appropriate response to the alarm sirens. Accordingly, the neighboring residents did not react to the emer- gency alarm. Arrival of irritating fumes drove many individuals to escape on foot. Running resulted in the need for deeper respira- tions – likely causing inhalation of greater amounts of MIC with each labored breath. Some individuals, unable or unwilling to run away, effectively sheltered in place and survived the toxic event. Emergency communications between the Union Carbide Plant, local government, first responders, and local medical facilities and personnel were poor or nonexistent. Confusion with respect to what particular substance was released appeared to play a major role in complicating both medical and logistical response to the event. There was much criticism of the lack of “correct” medical information and training and appropriate equipment. Although there was no specific antidote known, that criticism reflects the deeper problem of failure of education and training. Although MIC has since come to be recognized as an irritating substance with pulmonary edema effects similar to phosgene, this information was not available to the local medical commu- nity at the time. Accordingly, life-saving efforts were directed toward immediate symptomatic therapy – principally the con- trol of obvious respiratory failure. Most near-term deaths were clearly respiratory. The actual number of deaths can only be esti- mated. With the data available, it is not possible to determine the relative importance of the following factors in relationship to those deaths.

1) Inadequate/insufficient medical equipment: although there is no evidence that specific preparations had been made for

large numbers of respiratorily compromised individuals – even had hundreds of ventilators been available, appropri- ately trained personnel would not have been available.

2) Inadequate medical knowledge/experience: some basic edu- cation and training of local medical personnel would have been useful. Details of the risks/toxic effects of MIC and other large-quantity chemicals stored at the Union Carbide facility could have been easily provided. This should have been the responsibility of the occupational physician of the facility. As noted, however, the number of victims with respiratory failure would likely have far exceeded even the best prepara- tion with large numbers of ventilators, given the absence of personnel to manage them.

3) Inadequate numbers of medical practitioners: additional numbers of trained medical personnel were needed, but were not immediately available. In some countries such as the U.S., chemical facilities have provided groups of their on-site industrial workers with basic life-saving training. In case of a chemical event, these on-site workers can act as an imme- diately available group of first responders.

RECOVER Y

Subsequent to the event, both the Bhopal government and various private organizations have maintained a roster of exposed individuals. Some of these victims have been compensated. Some private and university medical groups have undertaken “cohort” follow-up assessment of some of the victims. These group stud- ies have revealed some very important medical observations regarding the long-term effects of MIC exposure; however, there appears to be no centralized repository for this accumulated medical information. There is little evidence that information gleaned from such cohort studies has been incorporated into routine medical practice in the local area.

Exposure site clean-up is of concern to local medical facili- ties. Site clean-up has not been completed, and a variety of toxic materials have been recognized as remaining in residual solid wastes. Local medical personnel and hospitals have been pro- vided little if any information regarding the medical aspects of these materials.

The Bhopal event has prompted international discussion that may ultimately lead to an improved nationally coordinated med- ical recovery response in India. Similar to the practices of the U.S. NTSB, the following thoughts are proposed.

Shortly after the incident, as part of the recovery, a data collection team (best sponsored by the national government) should undertake responsibility for

1) Victim demographics – immediate recording (names/ identifiers) of deaths, injuries, and individuals resident in the area of exposure

2) Clinical demographics – recording of any clinical records established for the individuals noted above

3) Establishment of epidemiological studies for near- and long- term follow-up of victims

4) Establishment of specialty treatment centers for both medical and psychiatric aspects of near- and long-term victim illness

5) Preparation of a report evaluating the quality of pre-event mitigation and preparedness within the local (and perhaps provincial) medical community. The quality of the response should be also evaluated with specific attention to the adher- ence of the medical system to previously established local emergency plans

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MEDICAL RESPONSE TO LARGE-SCALE CHEMICAL EVENTS

In circumstances of large-scale chemical events, early knowl- edge of the specific materials involved is an ideal medical goal. This is, however, an illusory target. Specific antidotes are avail- able for only two significant types of toxic chemical exposures: organophosphates and cyanide. Commercial/industrial formu- lations of cyanide and organophosphates typically present as dermal or ingestion exposures. There is a slower onset and progression of the clinical illness, often affording ample time to deliver appropriate antidotal therapy. Military/chemical war- fare organophosphates, and cyanide, when presenting as inhaled agents, act very rapidly, often within seconds to minutes. Conse- quently, antidotal therapy of both organophosphate and cyanide inhalational exposures must be delivered immediately on-site. This implies the necessity of establishing stockpiles of anti- dote as “far forward” as possible, in locations of actual or sus- pected risk. Just such a “far forward” deployment of organophos- phate (nerve agent) antidote has been accomplished for specific issues by both U.S. Department of Defense and FEMA/CSEPP (see later). An equivalent “far-forward” deployment of cyanide antidote has not been undertaken. In part this is due to issues of cost and effectiveness of the currently available antidote “kits.” A hydroxocobalamin-based antidote has been successfully used in Europe since the early 1960s. It appears to have a better risk/benefit ratio than the current U.S. antidote kit, particularly for use in pediatric patients. The U.S. Food and Drug Administra- tion has reviewed and cleared this antidote for use in the United States. Believing that cyanide exposures are not very likely, many U.S. hospitals currently maintain little or no antidote supply, however, the availability of hydroxocobalamin may change this.

Aside from antidotal therapy, medical management of a large-scale chemical event is generally accomplished by syn- dromic/symptomatic assessment. An extensive medical litera- ture has been produced on the subject of rapid assessment of injured individuals. A large body of medical responders has been educated and trained in a systematic approach to the rapid assessment and categorization of exposed individuals. The Sim- ple Triage and Rapid Treatment system allows very rapid iden- tification of those victims needing immediate, life-saving care. Assessment of three major bodily systems (airway/respiration, circulation, and neurological) can be quickly and consistently accomplished even by nonmedical personnel with minimal train- ing. Cone and Koenig have proposed a modification of this triage system for use for mass casualties exposed to a chemical agent.31

A pediatric format (JumpSTART) has been developed as well, however, none of these systems have been adequately validated (see Chapter 12). As suggested by the examples herein, the major- ity of immediate and near-term chemical event-related illness is respiratory. Immediate and near-term toxic respiratory illness caused by a chemical event is very amenable to intervention with relatively simple and inexpensive technology. Thus rapid identi- fication and intervention in these respiratory “Immediates” is of the highest value.

MANAGEMENT OF RESPIRATORY COMPROMISE FROM LARGE-SCALE CHEMICAL EVENTS

1) Identification of immediate (life-threatening) airway/ respiratory victims can be very rapidly accomplished (sec- onds) by individuals with minimal training.

a) Individuals with apnea may be considered for immediate intubation only if other evidence of viability is apparent. Use of newer technology esophageal obturator intuba- tion devices and portable ventilators is appropriate.

b) Individuals with upper airway obstruction (hoarse- ness/stridor/inspiratory wheezes) should be considered for elective intubation. Upper airway inflammatory dis- order typically results from exposure to a highly solu- ble inflammatory chemical with resulting laryngeal/vocal cord edema and rapidly progressive obstruction. Direct vision intubation (or video laryngoscopy) is preferred in this situation. Emergency tracheostomy is often required when failed attempts at direct vision intubation/video laryngoscopy result in further laryngeal edema. Use of a portable ventilator is appropriate.

c) Individuals with rapid respiratory rates in the range of 30 or higher and other evidence of primary respiratory abnormality (hypoxia or pulmonary edema) should be considered for application of continuous positive air- way pressure (CPAP) if available. Otherwise immediate intubation is appropriate. Rapid transition to a volume- controlled ventilator would be appropriate.

2) Medical care (ventilation or intubation) of the identified “immediate airway/respiratory” victim can be very rapidly achieved by individuals with basic medical skills. Using newer technology equipment, intubation should be within the purview of paramedics or the equivalent. Ventilatory sup- port equipment has also become simpler and less expensive. Many U.S. CSEPP community hospitals have stockpiled large numbers of “disposable-portable,” pressure-controlled ven- tilators in preparedness for a possible large-scale chemical event.

3) After airway control has been achieved, additional medical care of chemically induced respiratory illness can then pro- ceed at a more measured pace with attention to the following categories. a) Airway bronchospastic disorder. A large percentage of the

human population has been shown to possess “hyperir- ritable airways.” Inhalation of irritant or inflammatory chemical materials may trigger bronchospasm in these individuals. Therapy of that bronchospasm should follow normal practice. Use of inhaled and/or systemic bron- chodilators is immediately indicated. Systemic steroid supplementation is appropriate for moderately severe levels of bronchospasm. Prolonged use of bronchodila- tors and steroids may be necessary. Some substances have been shown to engender bronchospasm on an immuno- genic basis. Isocyanates found in various industrial set- tings may act in this way. For this reason, further studies investigating possible methyl isocyanate immunogenic effects are underway in the Bhopal population.

b) Lower airway inflammatory disorder. Lower airway expo- sure to toxic/inflammatory chemicals typically results in endobronchial tissue swelling and inflammation. Obstructive signs and symptoms may develop rapidly and be of substantial severity to necessitate long- term volume-controlled ventilator assistance. Under- lying bronchospastic disorder further complicates the care of these patients. Exposure to some toxic agents may result in progressive development of increased pul- monary interstitial water (pulmonary edema) as a result of capillary leakage. This produces the radiological and

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physiological equivalent of ARDS. ARDS has been observed as a common sequelae of phosgene expo- sure and also appears as a common complication of high-dose hydrochloric acid, chlorine, ammonia, per- fluoroisobutylene, and MIC inhalations. Possible devel- opment of ARDS after such chemical inhalational exposure should be anticipated. Symptoms of dyspnea and chest tightness, especially if unexplained by other obvious abnormalities, are a typical early indication of progressive pulmonary edema. Such symptoms often appear 1–2 hours before signs of abnormal physical examination (crackles), or abnormal arterial blood gas levels or abnormal chest x-ray results are noted. Although bronchoalveolar lavage may provide an early and sensi- tive indication of impending pulmonary edema, use of the technique is impractical in large-scale events.32 Mod- ern laboratory investigation has suggested that a vari- ety of medical interventions, when applied within 30–90 minutes after exposure, minimize or block the devel- opment of toxic chemical–induced pulmonary edema. Specifically, ibuprofen, n-acetylcysteine, aminophylline, salmeterol, and steroid therapy all seem very effective in various animal studies. Human studies have not been performed to confirm a wide variety of excellent animal data.33–36 Early application of CPAP may be of value. Early intubation is indicated in the event of deteriorat- ing oxygenation. First responders should be trained and equipped for possible on-site intubation. Intubation may be most easily accomplished with the use of newer tech- nology esophageal obturator devices.37,38

AGENT-SPECIFIC CLINICAL CONSIDERATIONS AND TREATMENT RECOMMENDATIONS

Health care personnel should suspect an exogenous chemical attack whenever there are multiple patients with similar acute symptoms, especially after exposure to air with an odd smell or color. Chemical agents likely to be used in a large-scale terrorist attack overwhelmingly fall into four categories of compounds: pulmonary intoxicants, cyanides, vesicants, and nerve agents. Two categories, cyanides and nerve agents, have specific anti- dotes that must be administered in a time-sensitive manner. For the other two categories of agents, only supportive care is available.

Of the four categories, pulmonary intoxicants and vesicants tend to produce delayed effects. Unlike biological agents with incubation periods typically lasting days, the latent period before symptoms appear for these chemical agents tends to be on the order of hours to a day. For cyanides and nerve agents, symptoms are more likely to be immediate or to appear with a latent period of only seconds to minutes.

Certain general principles apply for any suspected mass casu- alty event involving chemical agents. Decontamination is the most important. Although decontamination of patients exposed to chemical agents may be useful for the patients, it is even more important in order to avoid contamination of other patients, health care providers, and treatment facilities. During the Tokyo sarin attack in 1995, an estimated 10% of the emergency depart- ment staff developed miosis, the first sign of vapor sarin poison- ing. This was because they had not removed patients’ clothes before they entered the emergency department. Sarin vapor,

trapped in air cells in those clothes, caused symptoms in the health care workers. A useful concept for chemical agent expo- sures is to consider patients as contagious without being infec- tious. This concept will remind properly trained emergency staffs to remove clothing and do at least a brief decontamination of patients suspected of chemical exposure before they enter the facility.

The specific physical state of the agent is an important consid- eration in determining efficacious decontamination procedures. True vapors or gases require much less attention to full-body decontamination, since clothing removal will eliminate 90% or more of the risk to health care workers. Cyanides and pulmonary intoxicants are likely to be only vapor or gas hazards because they are all vapors at standard temperature and pressure. Mustards and nerve agents, on the other hand, are liquids at standard temperature and pressure. Liquid chemical agent requires full- body decontamination. Thus, it is critical to obtain the exposure history. Even though mustards and nerve agents are liquids at standard temperature and pressure, in many likely scenarios, exposure to patients will be in only the vapor phase. In this case, agents such as the nerve agent sarin, which evaporates rapidly from the liquid phase at standard temperatures, can overwhelm- ingly cause vapor hazards rather than liquid hazards. In the Tokyo subway attack, 30% sarin solution was spilled out onto the floor and seats of subway cars. Although the agent causing intoxica- tion was liquid, essentially none of the roughly 5,500 people who presented for care were directly touched by the liquid. Instead, they inhaled sarin vapor, which evaporated from the floor of the subway car and was carried throughout the subway system by the movement of the train.

Physical removal of contaminants is superior to all known catalytic or chemical decontaminants. Water or soap and water, if applied quickly and in sufficient quantities, is an appropri- ate decontaminant for liquid chemical agent on the skin. The U.S. military developed doctrine for tactical situations in which water was not available in sufficient quantities and for decades has fielded 0.5% bleach. This solution is 10-fold diluted from commercially available bleach bottles, which are 5% bleach in concentration, a concentration that is damaging to normal skin. Reactive Skin Decontamination Lotion (RSDL, E-Z-Em Corpo- ration) has been licensed by the U.S. Food and Drug Adminis- tration as a skin decontaminant for all chemical agents. It is not approved in wounds. Therefore, if the skin is broken, providers should use sterile saline or sterile water as a rinse. Work done in the 1950’s in the Netherlands, however, shows that many house- hold products such as corn oil are equally effective as decontam- inants as 0.5% bleach. The key concept is to decontaminate as quickly as possible, using some physical agent that will wash the skin of the patient. Verification of decontamination in a large civilian attack involves confirmation that the patient has been washed. In military settings, detector papers (M8 and M9 paper) that turn specific colors if liquid chemical agent is still present have been applied to patients’ skin.

Another general principle revolves around logistics. For pul- monary intoxicants and mustards, which have no specific anti- dotes, proper management to improve survival requires that severely exposed patients be transported to intensive care set- tings. In these cases, evacuation to a higher level of care may be more valuable than actual emergency treatment. By contrast, for the more rapidly acting cyanides and nerve agents, immediate care may need to be given even before the patient is properly decontaminated, possibly even in the “hot zone.”

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For more detailed information on specific agents the reader is directed to the Medical Aspects of Chemical Warfare portion of the Textbook of Military Medicine, published by the Borden Institute and Walter Reed Army Medical Center, 2008.39 This volume, as well as the shorter handbook of treatment published by the Chemical Casualty Care Division of the U.S. Army Med- ical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (Chemical Casualty Care Division) are avail- able on the Division’s web site at http://ccc.apgea.army.mil.40

Non-military organizations must register for the web site in advance, a process that usually takes 2–3 business days. Emer- gency personnel who may need to care for chemical casualties should therefore register their organizations during the planning phase so that they can access current data during an event.

The following discussion primarily emphasizes the mustards and nerve agents, which do not generally cause casualties outside of military or terrorist scenarios. Pulmonary intoxicants and cyanides have the potential to result in casualties after industrial accidents in many communities.

Pulmonary Intoxicants

A large variety of agents cause pulmonary toxicity by the inhala- tion route. Many of these are toxic industrial chemicals or mate- rials. A few have been used in warfare or in terrorist attacks. Space does not permit detailed discussion of the entire list.

Most pulmonary intoxicants primarily affect only the respi- ratory tree and do not cause systemic or multi-organ toxicity. This generalization allows a further categorization. Highly reac- tive or water-soluble pulmonary intoxicants cause toxicity in the central compartment of the respiratory tract, the trachea, large bronchi, and larynx. Typical examples of these include hydrochloric acid and ammonia. Among the weaponized agents, sulfur mustard is another good example, although its primary use in terrorism or warfare is as a skin vesicant. By contrast, pulmonary intoxicants which are less reactive or water-soluble do not react with the structures of the central component, and thus are able to reach the alveoli. They exert primary effects upon the peripheral pulmonary compartment, alveoli in the lung parenchyma. Classic examples of this category include phos- gene, oxides of nitrogen (the major component of photochemi- cal smog), and perfluoroisobutylene, the combustion product of Teflon. Central agents cause irritation, local edema, and, in severe cases, pseudomembrane formation through sloughing in large airways. Peripheral agents tend to disrupt the alveolar-capillary membrane, causing leakage; this will produce non-cardiogenic, toxic pulmonary edema. Agents differ, but in phosgene intoxica- tion, this occurs due to acylation at the alveolar-capillary mem- brane. This distinction between primarily centrally and peripher- ally acting agents, while useful, is inconsistent; a severe exposure to any intoxicant can cause both central and peripheral toxicity. Certain agents, such as chlorine, have mixed effects.

The common industrial and military pulmonary agents are gases at standard temperatures and pressures. While they may be mucous membrane irritants – chlorine is a good example – and thus cause transient tearing and salivation, only their pulmonary effects are life-threatening. Because they are gases, decontami- nation is a relatively minor issue. Clothing removal and a quick wash-down of the patient should suffice to protect both provider and emergency treatment facilities.

While all pulmonary intoxicants can produce shortness of breath, the peripheral and central syndromes clinically differ.

Central pulmonary agent toxicity manifests as stridor, laryn- gospasm, and dyspnea, often with a latent period which varies according to the specific intoxicant and the amount inhaled but which is typically on the order of several hours. A severe toxic exposure to a centrally acting agent can cause sudden complete airway obstruction either from edema or by the sloughing of pseudomembranes; these patients can deteriorate rapidly.

By contrast, peripheral toxicity manifests first as dyspnea, with or without chest tightness, but without coughing and with- out any signs of pulmonary compromise, either on direct aus- cultation or even on X-ray. This is because the initial phase of pulmonary edema involves leakage of fluid from the capillaries only into the interstitial space. Until fluid has penetrated into the alveoli themselves, there will only be symptoms without signs. After that point, there will be rales and crackles, with clear signs of edema on X-ray. As the syndrome intensifies, arterial blood gases will show hypoxemia, and sequestration of up to 1 L/h of fluid in the lungs may lead to hypovolemia and hypotension – very unlike cardiogenic pulmonary edema. Patients die of respiratory failure due to hypoxia, hypovolemia, or a combination. World War I data clearly show that exertion during the latent period of peripheral pulmonary toxicity can exacerbate the situation and turn a minor illness into a life-threatening emergency.

Although the latent period may be long enough that the patient is no longer being exposed at the time of medical evalua- tion, it is important to confirm that the patient has been removed from the source of agent. The development of symptoms and signs of pulmonary intoxicant toxicity within four hours of expo- sure is a poor prognostic sign regardless of therapy. This is true for both the central and peripheral syndromes. There is no spe- cific therapy for pulmonary agent toxicity. Therapy is entirely supportive.

For central pulmonary toxicity, the key principle is to main- tain the integrity of the airway. In severe cases, where pseu- domembranes can form and block off the airway, endotracheal intubation or even emergency tracheostomy may be required. For primarily peripheral difficulties, intubation with positive end- expiratory pressure may be needed. Fluid management should be judicious; these patients, unlike cardiogenic edema patients, are actually hypovolemic, and thus diuretics are relatively con- traindicated and intravenous fluids may be required in multi-liter quantities. Treat hypoxia directly as warranted by monitoring blood gas results in expectation that supportive care will allow the respiratory system to recover.

Most patients with isolated toxicity from inhaled pulmonary intoxicants recover if supportive care is provided in a timely manner. A few peripheral pulmonary intoxicants are associated with interstitial fibrosis post-crisis, including oxides of nitrogen. Phosgene and chlorine, the two most common agents in terror- ist scenarios, cause acute syndromes from which patients recover with no apparent lasting structural damage on subsequent patho- logical examination. This implies that management of patients with these intoxications may become more of a logistic challenge than a medical one.

Cyanides

Cyanides are not considered to be useful battlefield agents, but are a high threat for use as a terrorist weapon due to their rapid action. The commonly cited cyanide products, hydrogen cyanide and cyanogen chloride, are close to their boiling points at stan- dard temperatures and pressures. They are occasionally used in

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criminal scenarios for small-scale attacks – usually against spe- cific individuals – to poison water and food supplies close to the point of consumption.

As a method of large-scale attack against a population, cyanides are not well adapted because the gaseous phase of cyanide ion is lighter than air. Hence, in an outdoor attack, cya- nide dissipates rapidly. The reason for the high interest in cyanides as terrorist weapons lies in the possibility of using them in an indoor environment against a large crowd, such as in a sports arena, legislative building, railroad station or airport ter- minal.

Cyanide, or CN− ion, is a normal part of the environment; there is even a normal human cyanide level. It is present in all organic media; tobacco smokers, for example, average three times the normal human baseline cyanide level in blood. Cyanide ion is also a required cofactor for many human enzymes, including Vitamin B12. Because humans evolved in an environment con- taining cyanide – unlike any of the other chemical agent classes – people also evolved a mechanism to detoxify small quantities of this ion, based upon the hepatic enzyme rhodanese. This mech- anism underpins antidotal therapy for cyanide poisoning.

The mode of action of cyanide is to poison the electron transport chain in mitochondria, at the level of the last enzyme in the chain, cytochrome oxidase or cytochrome A3. Cyanide ion has a high binding affinity for various metals, including iron, which is the central atom in this enzyme. Once cyanide binds to the iron in this enzyme, it shuts down aerobic metabolism; cells can only continue metabolism by switching to the inefficient anaerobic metabolic pathway. With poisoned electron transport chains, cells cannot utilize oxygen to make glucose and carry out other metabolic functions. As a consequence, venous blood is no longer turned blue, and this explains the classic “cherry red” appearance associated with cyanide victims – an ironic twist, since cyanide victims are NOT cyanotic. The term “cyanide” (Greek for blue) comes not from cyanosis but from Prussian blue, from which Von Scheele originally isolated the compound in 1782.

Cyanide causes a primary histotoxic anoxia. It affects cells in direct proportion to their metabolic rate, or to their concen- tration of mitochondria. Inhaled cyanide crosses the alveolar- capillary barrier and circulates via the blood, giving rise to the old misnomer “blood agent” for cyanide. This term is still in use despite the fact that the blood is only a passive carrier for cyanide. Blood is essentially unaffected by the passage of cyanide, since most blood cells have very few mitochondria. In humans, the most actively metabolic cells are those in the carotid bodies which serve as baroreceptors. Thus, inhalation of a sizable cyanide chal- lenge causes initial hyperpnea, hypotension and syncope. The second most highly metabolic cells are those of the brain. There- fore the next symptom of cyanide poisoning, which in large challenges will be almost instantaneous, is loss of consciousness, followed shortly by seizures, probably caused by hypoxia. Within seconds to minutes, central apnea affects the medullary breath- ing centers. Cardiac tissue will become affected next, causing vascular instability leading to cardiopulmonary arrest and death within about 8 minutes if there is no treatment.

Via the inhalation route, cyanide is one of two chemical agent classes that can cause a virtually instantaneous loss of conscious- ness and seizures. The other is nerve agents. Key concepts for the differential diagnosis are detailed later.

Removal of the patient from the source of contamination is crucial and may be life-saving. Because the body has its own

detoxification mechanism, humans can metabolize a small chal- lenge of cyanide. Clinical experience has shown that simple removal from the source of cyanide can revive mild cases of poisoning.41

Although the mechanism is not well understood, nasal or mask oxygen therapy is helpful acutely in cyanide poisoning. While theoretically implausible since mitochondrial electron transport chains are poisoned rendering cells unable to use oxy- gen, oxygen therapy should be instituted rapidly as it has been proven clinically effective. In addition to oxygen, specific antido- tal therapy is valuable for acute cyanide poisoning, but only if it can be instituted in a timely manner. There are two major forms of antidotal therapy, the multi-component cyanide antidote kit and hydroxocobalamin.

The cyanide antidote kit is based upon beagle dog experi- ments performed in the 1930s that showed that the components of the kit were capable of saving animals exposed to up to 20 lethal doses of cyanide gas. Conceptually, it consists of two types of anti- dotes used sequentially. The first antidote is a methemoglobin former, a nitrite (not nitrate). Methemoglobin, with its iron in the Fe+3 (ferric) state rather than the Fe+2 (ferrous) state of nor- mal hemoglobin, binds to cyanide ion with even greater affinity than does cytochrome a3. Hence, creation of a methemoglobin pool, which results from therapy with nitrite, will pull cyanide off cytochrome a3 and rapidly restore normal cell function. Nitrite is given either via inhalation of an amyl nitrite ampule or via intravenous administration of sodium nitrite. The dose in the vial provided in the cyanide antidote kit is 10 ml and if an initial dose requires repeating, half of the second vial (5 ml) should be administered. For children, the U.S. military recommends 0.33 ml/kg of the standard 3% nitrite solution given slowly over 5–10 minutes. Nitrite will cause hypotension, and so patients should be lying down when they receive it, whether inhaled amyl or intravenous sodium nitrite. Additionally, in situations where patients may have reduced oxygen carrying capacity – such as fire victims – the use of nitrite, which will form methemoglobin from the already depleted stores of hemoglobin, may cause hypoxia. In these cases, experts recommend considering omitting the nitrite step and proceeding directly to the second antidote in the kit. The use of nitrite alone, however, will create a pool of cyan- methemoglobin in the blood. This is unstable, and unless the second antidote is given, cyanide will eventually come unbound from methemoglobin and cause subsequent toxicity.

The second antidote, sodium thiosulfate, is necessary because the body cannot tolerate a large pool of cyan-methemoglobin indefinitely. In order to permanently eliminate the cyanide ion from the body, sodium thiosulfate, a sulfur donor, is adminis- tered as a cofactor to activate the liver stores of rhodanese, the body’s natural cyanide detoxifier. The result of this reaction is that rhodanese forms sodium thiocyanate. Sodium thiocyanate is excreted harmlessly in the urine. Sodium thiosulfate is given via the intravenous route only; the kit contains two 50-ml vials, and if after one is given the patient requires more, half of the second vial (25 ml) should be administered. The U.S. military recommends a pediatric dose of 1.65 ml/kg of the standard 25% solution.

Hydroxocobalamin is commonly used in Europe and in 2007 was licensed by the U.S. Food and Drug Administration as an alternate cyanide antidote. It binds stoichiometrically (1:1) to circulating cyanide and forms cyanocobalamin (Vitamin B12) which the body tolerates well. One disadvantage is that hydrox- ocobalamin is a huge molecule and 1:1 binding means that large

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volumes of hydroxocobalamin must be used via the intravenous route. Additionally, unlike the nitrite and thiosulfate solutions in the antidote kit, hydroxocobalamin must be reconstituted from powder. Extensive clinical experience from the Paris Fire Brigade has demonstrated that hydroxocobalamin can be used as on-scene treatment by trained first responders. The adult dose is two 2.5 g vials administered intravenously over 15 min- utes after reconstitution, with a second dose of two 2.5 g vials given as needed. The most common side effect of hydroxocobal- amin is chromaturia; urine tends to turn purple, although this in itself is harmless. In many of the published cases in which hydroxocobalamin has been used, sodium thiosulfate was also given; these treatments are, therefore, not mutually exclusive. Hydroxocobalamin has advantages over nitrite. It does not cause methemoglobinemia (diminishing oxygen carrying capacity) or hypotension. However, it takes longer to administer and requires the infusion of large volumes.

Vesicants

Sulfur mustard, the prototypical vesicant agent, has been a mil- itary threat since it first appeared on the battlefield in Belgium during World War I. In modern times it remains a threat on the battlefield as well as a potential terrorist threat because of sim- plicity of manufacture and extreme effectiveness. Sulfur mustard accounted for 70% of the 1.3 million chemical casualties in World War I and an estimated 45,000 Iranian casualties during the Iran- Iraq War. Other vesicants of lesser military importance include nitrogen mustard (still used in cancer chemotherapy), Lewisite and phosgene oxime, which will not be discussed in detail.

Sulfur mustard constitutes both a vapor and a liquid threat to all exposed epithelial surfaces. Like peripheral pulmonary agents, mustard’s effects are delayed, appearing hours after exposure. Organs most commonly affected are the skin (erythema and vesicles), eyes (ranging from mild conjunctivitis to severe eye damage), and airways (ranging from mild upper airway irri- tation to severe bronchiolar damage). Following exposure to large quantities of mustard, precursor cells of the bone mar- row are damaged, leading to pancytopenia and secondary infec- tion. The gastrointestinal mucosa may be damaged, and there are sometimes central nervous system (CNS) signs of unknown mechanism. No specific antidotes exist; management is entirely supportive.42

Mustard dissolves slowly in aqueous media, such as sweat, but once dissolved, it rapidly forms extremely reactive cyclic ethylene sulfonium ions, which react with cell proteins, cell membranes, and especially DNA in rapidly dividing cells. Mustard’s ability to react with and alkylate DNA gives rise to the effects characterized as “radiomimetic,” i.e., similar to radiation injury. Mustard has many biological effects, but the actual mechanism of action is largely unknown. Mustard reacts with tissue within minutes of entering the body. Its circulating half-life in unaltered form is extremely brief.

Topical effects of mustard occur in the eyes, airways, and skin, in that order of sensitivity. Absorbed mustard may pro- duce effects in the bone marrow, gastrointestinal tract, and CNS. Direct injury to the gastrointestinal tract may also occur follow- ing ingestion of the compound through contamination of water or food.

Erythema is the mildest and earliest form of mustard skin injury. It resembles sunburn and is associated with pruritus, burning, or stinging pain. Erythema begins to appear within

2 h to 2 days after vapor exposure. Time of onset depends on the severity of exposure, ambient temperature and humidity, and type of skin. The most sensitive sites are the warm moist locations and thin delicate skin, such as the perineum, external genitalia, axillae, antecubital fossae, and neck.

Within erythematous areas, small vesicles can develop, which may later coalesce to form bullae. The typical bulla is large, dome- shaped, flaccid, thin-walled, translucent, and surrounded by ery- thema. The blister fluid, a transudate, is clear to straw-colored, which becomes yellow, tending to coagulate. The fluid does not contain mustard and is not itself a vesicant. Lesions from high- dose liquid exposure may develop a central zone of coagulation necrosis with blister formation at the periphery. These lesions take longer to heal and are more prone to secondary infection than the uncomplicated lesions seen at lower exposure levels. Severe lesions may require skin grafting.

Sulfur mustard vapor is a centrally acting pulmonary intox- icant. The primary airway lesion is necrosis of the mucosa with possible damage to underlying smooth muscle. The damage begins in the upper airways and descends to the lower airways in a dose-dependent manner. Usually, the terminal airways and alveoli are affected when death is imminent.

Necrosis of airway mucosa causes exfoliation of epithelial debris, or “pseudomembrane“ formation, as with any centrally acting pulmonary agent. These membranes may cause obstruc- tion of the bronchi. During World War I, high-dose mustard exposure caused acute death via this mechanism in a small minority of cases.

The eyes are the organs most sensitive to mustard vapor injury. The latent period is shorter for eye injury than for skin injury and is also exposure concentration–dependent. After low- dose vapor exposure, irritation evidenced by reddening of the eyes may be the only effect. As the dose increases, the injury includes progressively more severe conjunctivitis, photophobia, blepharospasm, pain, and corneal damage, which may lead to severe visual impairment.

Ninety percent of eye casualties heal in 2 weeks to 2 months without sequelae. Scarring between the iris and lens may follow severe effects; this scarring may restrict pupillary movements and may predispose victims to glaucoma. The most severe damage is caused by liquid mustard. After extensive eye exposure, severe corneal damage with possible perforation of the cornea and loss of the eye can occur. In some individuals, chronic eye irrita- tion, sometimes associated with corneal ulcerations, has been described 10 to 20 years after exposure.

The mucosa of the gastrointestinal tract is susceptible to mustard damage, either from systemic absorption or ingestion of the agent. Mustard exposure in small amounts will cause nau- sea and possible vomiting lasting up to 24 h. The mechanism of the nausea and vomiting is not understood, but mustard does have a cholinergic-like effect. The CNS effects of mustard, like- wise, remain poorly defined. Large exposures can cause seizures in animals. Reports from WWI and Iran described the behavior of persons exposed to small amounts of mustard as sluggish, apathetic, and lethargic. These reports suggest that minor psy- chological problems could linger for a year or longer.

The causes of death in the majority of mustard poisoning cases are sepsis and respiratory failure. Mechanical obstruc- tion via pseudomembrane formation and agent-induced laryn- gospasm is important in the first 24 h, but only in cases of severe exposure. From the third through the fifth day after exposure, a secondary bacterial pneumonia can be expected due to invasion

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of denuded necrotic mucosa. The third wave of death is caused by agent-induced bone marrow suppression, which peaks 7 to 21 days after exposure and causes death via sepsis. Early warning of impending marrow suppression is a drop in the lymphocyte count beginning as early as 24 hours. Polymorphonuclear cells may actually rise at first and begin falling at 3–5 days.

A patient severely ill from mustard poisoning requires the general supportive care provided for any severely ill patient as well as the specific care given to a burn patient. Liberal use of systemic analgesics, maintenance of fluid and electrolyte balance and nutrition, use of appropriate antibiotics, and other support- ive measures are necessary.

The management of a patient exposed to mustard may range from simple, as in the provision of symptomatic care for a sunburn-like erythema, to complex, as in the provision of total management for a severely ill patient with burns, immunosup- pression, and multisystem involvement. Before raw denuded areas of skin develop, especially with less severe exposures, topical cortisone creams or lotions may be of benefit. Some basic research data suggest benefit from the early use of anti-inflammatory preparations. Small blisters (<1 to 2 cm) should be left intact. Because larger bullae will eventually break, they should be care- fully unroofed. Denuded areas should be irrigated three to four times daily with saline, other sterile solutions, or soapy water and then liberally covered with a topical antibiotic, such as silver sulfadiazine or mafenide acetate, to a thickness of 1 to 2 mm. Some experts advocate sterile needle drainage of large blisters, collapsing the blister roof to form a sterile dressing. Mustard blister fluid does not contain sulfur mustard, only sterile tissue fluid. Health care staff should not fear contamination.

Systemic analgesics should be used liberally, particularly before patient manipulation. Monitoring of fluids and elec- trolytes is important in any sick patient, however fluid loss after mustard exposure is not of the magnitude seen with deeper ther- mal burns. Overly rigorous hydration seems to have precipitated pulmonary edema in a few Iranian casualties sent to European hospitals.

Conjunctival irritation from a low vapor exposure will respond to any of a number of available ophthalmic solutions after the eyes are thoroughly irrigated. A topical antibiotic applied several times a day will reduce the incidence and severity of infec- tion. Animal laboratory data have shown remarkable results with commercially available topical antibiotic/glucocorticoid oph- thalmologic ointments applied early. Topical glucocorticoids alone are not of proven value, but their use during the first few hours or days may significantly reduce inflammation and sub- sequent damage. Ophthalmologic consultation is indicated and further use of glucocorticoids should be at the specialist’s discre- tion. Vaseline or a similar substance should be applied regularly to the edges of the lids to prevent them from sticking together.

A productive cough and dyspnea accompanied by fever and leukocytosis occurring within 12 to 24 h is indicative of a chem- ical pneumonitis. The clinician must avoid use of prophylactic antibiotics to manage this process. Infection often occurs on the third to fifth day and is signaled by fever, pulmonary infiltrates, and an increase in sputum production with a change in color. Initial antibiotic therapy should await evidence of infection from Gram stain of sputum; regimens can then be tailored according to the results of sputum culture and sensitivity. Studies suggest that Iran-Iraq War veterans may develop a chemical pneumoni- tis responsive to erythromycin, 400–600 mg/day for 6 months following mustard exposure.

Intubation may be necessary for laryngeal spasm or edema, permitting better ventilation and facilitating suction of the necrotic inflammatory debris. Early use of positive end- expiratory pressure (PEEP) or continuous positive airway pres- sure (CPAP) may be beneficial. Pseudomembrane formation may require fiberoptic bronchoscopy for suctioning of the necrotic debris. Bronchodilators are of benefit for bronchospasm. If addi- tional relief of bronchospasm is needed, glucocorticoids should be used. There is little evidence that the routine use of gluco- corticoids is beneficial, except for additional relief of broncho- spasm.

Leukopenia begins around day 3 with major systemic absorp- tion. Marrow suppression peaks at 7 to 14 days. In the Iran–Iraq war, a white blood count of ≤ 200/µL usually resulted in death of the patient. Sterilization of the gut by nonabsorbable antibiotics should be considered to reduce the possibility of sepsis from enteric organisms. Cellular replacement (bone marrow trans- plants or transfusions) may be successful. In one study, granulo- cyte colony-stimulating factor produced a 50% reduction in the time for the bone marrow to recover in non-human primates exposed to sulfur mustard and should be considered in human exposure. Antiemetics may be necessary for gastrointestinal side effects.

Lewisite, a chemically unrelated compound, causes a remark- ably similar clinical syndrome to sulfur mustard. There are two important clinically differences between Lewisite and sulfur mus- tard. Lewisite is a direct skin irritant so early detection of expo- sure is more likely. This means that decontamination is likely to be more effective in preventing systemic damage and the agent is less likely to be used for either a military or civilian terrorist attack. An additional difference is that Lewisite is an arsenical compound so it can be treated with a chelating agent that binds arsenic. The antidote, British anti-Lewisite or dimercaprol, was developed in the 1930’s and remains available as a chelating agent. The only U.S. FDA-approved formulation is an intramus- cular injection dissolved in peanut oil, to which some patients are allergic.

Nerve Agents

The organophosphorus nerve agents are the deadliest of the chemical warfare agents. They work by inhibition of tissue synaptic acetylcholinesterase, creating an acute cholinergic crisis. Death ensues because of respiratory depression and can occur within seconds to minutes.

The classic nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX. VR, similar to VX, was manufactured in the former Soviet Union. The two-letter codes are a NATO international convention and convey no clinical implications. All of the nerve agents are organophosphorus com- pounds, which are liquids at standard temperatures and pres- sures. The “G” agents evaporate at about the rate of water, except for GF, which is oily, usually evaporating within 24 h after depo- sition on the ground. Their high volatility makes a spill of any amount a serious vapor hazard. In the Tokyo subway attack 100% of the symptomatic patients inhaled sarin vapor that spilled out on the floor of the subway cars. VX, an oily liquid, is the excep- tion. Its low vapor pressure makes it much less of a vapor hazard but potentially a greater environmental hazard. The nerve agents tabun and sarin were first used on the battlefield by Iraq against Iran during the first Persian Gulf war, 1984–1987. Estimates of casualties from these agents range from 20,000 to 100,000.

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Acetylcholinesterase inhibition accounts for the major life- threatening effects of nerve agent poisoning. Reversal of this inhibition by antidotal therapy is effective, proving that this is the primary toxic action of these poisons. At cholinergic synapses, acetylcholinesterase, bound to the postsynaptic mem- brane, functions as a turn-off switch to regulate cholinergic trans- mission. Inhibition of acetylcholinesterases causes the released neurotransmitter acetylcholine to accumulate abnormally. End- organ overstimulation, manifesting as cholinergic crisis, ensues. Clinical effects of nerve agent exposure are identical for vapor and liquid exposure routes if the dose is sufficiently large. The speed and order of symptom onset however, will differ.

Nerve agent vapor exposure is overwhelmingly the more likely exposure route in both battlefield and terrorist scenarios. Vapor exposure will cause cholinergic symptoms in the order that the toxin encounters cholinergic synapses. The most exposed synapses on the human integument are in the pupillary muscles. Nerve agent vapor easily crosses the cornea, interacts with these synapses, and produces miosis, described by Tokyo subway vic- tims as “the world going black.” Rarely, this can also cause eye pain and nausea. Exocrine glands located in the nose, mouth, and pharynx are exposed to the vapor next, and cholinergic overload here causes increased secretions, rhinorrhea, excess salivation, and drooling. Finally, toxin interacts with exocrine glands in the upper airway, causing bronchorrhea, and with bronchial smooth muscle, causing bronchospasm, the combination of which can cause hypoxia.

Once the victim has inhaled, vapor can passively cross the alveolar-capillary membrane, enter the bloodstream, and, inci- dentally and asymptomatically, inhibit circulating cholinester- ases, particularly free butyrylcholinesterase and erythrocyte ace- tylcholinesterase, both of which can be assayed. The assay may not be easily interpreted without a baseline, however, since cholinesterase levels vary enormously between persons and over time in an individual healthy patient.

The gastrointestinal tract is usually the first organ system to become symptomatic from bloodborne nerve agent exposure. Cholinergic overload causes abdominal cramping and pain, nau- sea, vomiting, and diarrhea. After the gastrointestinal tract is involved, nerve agents affect the heart, distant exocrine glands, muscles, and brain. Because there are cholinergic synapses on both the vagal (parasympathetic) and sympathetic sides of the autonomic input to the heart, changes in heart rate and blood pressure are unpredictable. Remote exocrine activity will include oversecretion in the salivary, nasal, respiratory, and sweat glands – the patient will be “wet all over.” Bloodborne nerve agents overstimulate neuromuscular junctions in skeletal mus- cles, causing fasciculations followed by frank twitching. If the process continues, ATP in muscle will eventually be depleted and flaccid paralysis will ensue.

Due to the wide distribution of the cholinergic system in the brain, sufficient doses of bloodborne nerve agents cause rapid loss of consciousness, seizures, and central apnea, lead- ing to death within minutes. If respiration is supported, status epilepticus may manifest. If status persists, neuronal death and permanent brain dysfunction may occur. Even in mild nerve agent intoxication, patients may recover but experience weeks of irritability, sleep disturbances, and other nonspecific neurobe- havioral symptoms.

The time from exposure to development of full-blown cholinergic crisis after nerve agent vapor inhalation can be min- utes or even seconds; however, there is no depot effect. Since nerve

agents have a short circulating half-life, improvement should be rapid with no subsequent deterioration if the patient is treated with antidotes and supportive care.

Liquid exposure to nerve agents differs in speed and order of symptom onset. A nerve agent on intact skin will partially evaporate and partially begin to travel through the skin, caus- ing localized sweating and then localized fasciculations when it encounters neuromuscular junctions. Once in muscle, it will cross into the circulation and cause gastrointestinal discomfort, respiratory distress, heart rate changes, generalized fasciculations and twitching, loss of consciousness, seizures, and central apnea. The time course will be much longer than with vapor inhalation; even a large, lethal droplet can take up to 30 minutes to have effect, and a small, sublethal dose could continue to take effect over 18 h. Clinical worsening that occurs hours after treatment has started is far more likely with liquid than with vapor expo- sure. Additionally, miosis, practically unavoidable with vapor exposure, is not always present with liquid exposure and may be the last symptom to present. This is due to the relative insulation of the pupillary muscle from the systemic circulation.

Unless a nerve agent is removed by specific therapy (oximes), its binding to cholinesterase is essentially irreversible. Erythro- cyte acetylcholinesterase activity recovers at about 1% per day. Plasma butyrylcholinesterase recovers more quickly and is a bet- ter guide to recovery of tissue enzyme activity.

Acute nerve agent poisoning is treated by decontamination, respiratory support, and three antidotes – an anticholinergic, an oxime, and an anticonvulsant. In acute cases, all of these forms of therapy may be given simultaneously. Death from nerve agent poisoning is almost always due to respiratory failure. Ventila- tion will be complicated by increased resistance and secretions. Atropine should be given before ventilation or as it begins, as it will facilitate ventilation.

In theory, any anticholinergic could be used to treat nerve agent poisoning, but worldwide the choice is invariably atropine because of its wide temperature stability and rapid effectiveness. Atropine can be administered either intramuscularly or intra- venously. It rapidly reverses cholinergic overload at muscarinic synapses but has little effect at nicotinic synapses. Practically, this implies that atropine can quickly treat the life-threatening respiratory effects of nerve agents but will probably not reverse neuromuscular and possibly sympathetic effects. In the field, military personnel in some countries are given MARK I kits, which contain 2 mg atropine in autoinjector form for intramus- cular use. In addition, some civilian agencies are now stockpiling this product (FDA-approved in the U.S.). One can only give full autoinjector doses and not divide them. The field-loading dose is 2, 4, or 6 mg, with retreatment every 5 to 10 min until the patient’s breathing and secretions improve. The Iranians initially used larger doses during the Iran–Iraq war where oximes were in short supply. Pediatric autoinjectors are now available at dosages of 0.5 and 1.0 mg for rapid intramuscular injection, however intravenous drug administration is the preferred route when this is logistically feasible, especially in small children. There is no upper bound to atropine therapy in a patient either intramus- cularly or intravenously. A total average adult dose for a severely afflicted patient usually ranges from 20 to 30 mg.

In a mildly affected patient with miosis and no other systemic symptoms, atropine or homatropine eye drops may suffice for therapy. This will produce roughly 24 h of mydriasis. Frank miosis or imperfect accommodation may persist for weeks or even months after all other signs and symptoms have resolved.

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Oximes are nucleophiles that reactivate the cholinesterase whose active site has been occupied and bound to nerve agent. Therapy with oximes therefore restores normal enzyme function. Oxime therapy is limited by a second side reaction, called aging, in which a side chain on nerve agents falls off the complex at a characteristic rate. “Aged” complexes are negatively charged, and oximes cannot reactivate negatively charged complexes, so oxime cannot reactivate “aged” complexes. The practical effect of this differs from one nerve agent to another, since each ages at a char- acteristic rate. VX, for practical purposes, never ages, sarin ages in 3 to 5 h, and tabun ages over a longer period. All of these are so much longer than the patient’s expected lifespan after untreated acute nerve agent toxicity that they may be ignored from a clini- cal standpoint. Soman, on the other hand, ages in 2 min. Thus, after only a few minutes following exposure, oximes are useless in treating soman poisoning. The oxime used varies by country; the United States has approved and fielded 2-pralidoxime chlo- ride (2-PAM Cl). MARK I kits contain autoinjectors of 600 mg of 2-PAM Cl. Initial field loading doses are 600, 1200, or 1800 mg. Since blood pressure elevation may occur after administra- tion of 45 mg/kg in adults, field use of 2-PAM Cl is restricted to 1800 mg/hr intramuscularly. During the time when more oxime cannot be given, atropine alone is recommended. In the hospital setting, 2.5 to 25 mg/kg of 2-PAM Cl intravenously has been found to reactivate 50% of inhibited cholinesterase. The usual recommendation is 1000 mg through slow intravenous drip over 20 to 30 min, with no more than 2500 mg over a period of 1 to 1.5 h.

Dosage recommendations for children are less certain than for adults and are based upon extrapolations from adults; fur- ther studies are needed in children.43 In small children (<25 pounds), autoinjectors, even the pediatric doses, may not be practical. Additionally, the clinical syndromes in children may be harder to recognize; in particular, seizures in children often manifest without tonic-clonic movements and may be missed. The U.S. FDA has approved a dual-dose autoinjector (ATNAA, Autoinjector Treatment Nerve Agent Antidote), containing 2.1 mg atropine and 600 mg 2-PAM Cl. This was shown bioequiva- lent to the MARK 1 kit, but requires only half as long to admin- ister.

Nerve agent–induced seizures do not respond to all of the usual anticonvulsants used for status epilepticus. The only class of anticonvulsants that has been shown to stop this form of status are the benzodiazepines. Diazepam is the only benzodiazepine approved for seizures in the U.S. in humans, although other benzodiazepines, especially midazolam, work well against nerve agent–induced seizures in animal models. Diazepam is manufac- tured in 10-mg injectors for intramuscular use and given to U.S. military forces for this purpose. Civilian agencies stockpile this fielded product (convulsive antidote for nerve agent, “CANA”), which is not generally used in hospital practice. Extrapolation from animal studies indicates that adults will probably require 30 to 40 mg diazepam, intramuscularly, to stop nerve agent– induced status epilepticus. In the hospital, or in a child too small to tolerate the autoinjector, intravenous diazepam may be used at similar doses. The clinician may confuse seizures with the neuromuscular signs of nerve agent poisoning. In the hospital, early electroencephalography is recommended in order to distinguish between nonconvulsive status epilepticus, actual seizures, and postictal paralysis. Intravenous lorazepam is also effective.

MEDICAL REVIEW OF LARGE-SCALE CHEMICAL EVENTS

Medical review of large-scale chemical events is necessary for pur- poses of “quality improvement” and to provide a database record to assist in validation of current medical practice and develop- ment of novel medical interventions. Within the U.S., there is no federal structure that provides this type of unified medical review independent of modifying influences of the legal, polit- ical, and commercial communities. There is, however, a federal program that has extensive depth of personnel, long-standing experience, and great competence and experience in evaluation of large-scale chemical event exercises. This FEMA-directed pro- gram, the CSEPP could easily furnish the building blocks of a national chemical event assessment program.

CSEPP HISTORY

At the time of this writing, there are seven chemical weapons stockpile sites within the United States. In 1986, Congress man- dated chemical weapon destruction, at that time also mandating maximum protection for the public, environment, and workers involved in destroying the chemical munitions.

In 1988, FEMA, in cooperation with the U.S. Army, devel- oped an assistance program to enhance the abilities of commu- nities surrounding the seven stockpile sites to respond to the unlikely event of a chemical agent emergency. FEMA is respon- sible for developing preparedness plans, upgrading response capabilities, and conducting training for these civilian commu- nities. These obligations were integrated into a program called the CSEPP. With the help of FEMA and the Army, the com- munities surrounding the seven sites have expanded their emer- gency plans and capabilities to meet the slight but real threat of an emergency involving chemical agents. These communi- ties have plans and procedures in place to manage a stockpile incident. Moreover, they are constantly striving to enhance pre- paredness. CSEPP has provided funding and technical assis- tance to

■ Improve public warning capabilities ■ Build and upgrade state-of-the-art emergency operations

centers ■ Train emergency managers and first responders ■ Hold functional exercises that improve readiness ■ Increase public knowledge and understanding of protective

actions ■ Overpressurize schools to ensure the safety of children (over-

pressurize = provision of higher than ambient air pressure within classrooms to preclude infiltration of outside toxic fumes/vapors; this is typically accomplished through the use of high-volume, high-flow air to the rooms that has been filtered through chemical [charcoal] filtration systems)

■ Study emergency response options to determine the best way to protect communities

■ Train doctors and nurses to treat victims of chemical agent exposure

Under CSEPP, federally managed exercises (FMEs) began in 1991. These exercises demonstrated the ability of the communi- ties to respond to a chemical incident. Representatives from the

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Department of the Army, FEMA, other federal agencies, state and local governments, the Army installations, and civilian volunteer agencies participated in these exercises. Under the Department of Homeland Security, FEMA administers CSEPP activities occur- ring outside military installations. There are annual exercises of the community response to a large-scale chemical event. Dur- ing these exercises, trained and experienced medical observers carefully evaluate the medical response capabilities of local med- ical facilities. A thorough assessment of the medical response is recorded, and then that response is compared with the existing emergency operations plan of the involved medical structure. Discrepancies are evaluated and new plans are developed. A final report becomes available to medical reviewers for purposes of quality improvement and as a database record to assist in val- idation of current medical practice and development of novel medical interventions.

The CSEPP program functions in a remarkable fashion. CSEPP observers dispassionately record and then critically review the medical aspects of a community response to a large- scale chemical event. This critical review becomes the basis for future revisions in local emergency operations plans. This pro- gram, in existence since 1991, is the sole medical/first responder evaluation system for chemical events within the United States. As a consequence of the CSEPP program, the surrounding com- munities have developed an extraordinary capability to respond to a large-scale chemical event. These communities represent the U.S. national best in mitigation, preparedness, and (exer- cised) response. Their “recovery, and after action process” con- tains exactly the type of critical medical review that is detailed herein. This type of structure should be emulated for intra- and postchemical event evaluations. Direct incorporation of the FEMA/CSEPP program into a national medical review system should be considered.

SUMMARY

The following key points are synthesized from the examples and attached commentaries detailed in this chapter.

1) Chemical events, whether intentional or accidental, often tax the capabilities of the local medical response system. During the early stages of those events, first responders must recognize a) There are typically very few individuals who require

immediate (life-saving) intervention. Therefore, rapid identification and treatment of those individuals is of highest priority

b) Most individuals who suffer acute respiratory failure have a type and extent of pulmonary physiological limitation that is amenable to current therapeutic interventions

c) Best medical care of those individuals involves their very rapid identification among a larger population of exposed and “less ill” victims. “Far-forward” placement of appropriately trained and equipped first responders would allow efficient identification and care of those vic- tims within the first 1–2 hours after an event

d) Technologies for rapid and successful intubation and ventilation exist. More recent research has demonstrated therapeutic interventions that may minimize or block some aspects of the pulmonary toxicity of certain chem-

ical agents. These specific interventions will be most useful if also placed in the hands of the “far-forward” responders.

2) The release of toxic chemicals typically create a degree of public anxiety and fear that is vastly disproportionate to the medical illness and death involved. Media involvement in reporting chemical events often appears to be a source of further anxiety and fear. Mitigation of that fear can be approached by the following a) Public education regarding disaster preparedness and

“weapons of mass effect” should commence during ele- mentary school education

b) Media sensationalism must be modified. Techniques must be developed to ensure that media presentations utilize credible sources and are accurately presented

c) Public medical information should be principally pro- vided by a single, consistent, publicly recognized, and experienced spokesperson. Much like the presence pro- vided by the Mayor of New York after the September 11, 2001 terrorist attacks, a “parental figure” would have the most success in ameliorating public anxiety and fear

3) Chemical events, particularly those of large-scale, are often reviewed by any (or all) of a number of U.S. federal agencies including the U.S. Chemical Safety and Hazard Investiga- tion Board; the Bureau of Alcohol Tobacco, Firearms and Explosives; the NTSB; the EPA; the Occupational Safety and Health Administration (OSHA); and Agency for Toxic Sub- stances and Disease Registry. Most of these agencies focus to some extent (but not primarily) on medical and first respon- der disaster response. A large-scale event that involves sig- nificant illness or death should be critically reviewed from a medical perspective. Medical review has two principal obliga- tions a) The immediate, near- and long-term medical health of

exposed individuals should be reviewed by a team of medical professionals. This team should at minimum include specialists in epidemiology, emergency and inter- nal medicine and psychiatry. Careful clinical and labo- ratory documentation of the medical effects of the event should be collected and reviewed on a regular basis over a long term

b) The quality of medical response to the event should be reviewed by a team of experienced “disaster review personnel,” supplemented by medical professionals with similar experience. Much like the investigations taken by the FEMA/CSEPP structure (see previous mentions), careful review of each of the medical steps surrounding an event should be undertaken and reported. Mitiga- tion, preparedness, response, and recovery should each be reviewed with particular attention to the design of and compliance with already existing local emergency operation plans

4) The importance of such medical review cannot be overem- phasized. Careful medical investigation of chemical events is critical to validation of current medical disaster preparedness and to the development of novel approaches to future chal- lenges. Medical reviews of this sort are typically begun with every large-scale chemical event. In the same way, the reviews are typically delayed, diminished, criticized, and sometimes discarded because of direct involvement of legal, political, and/or commercial entities whose goals may be different

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from those of the medical community. For this reason the medical reviews suggested must be undertaken outside of the influence of these entities. To a substantial extent, many federal agencies are able to accomplish this; however, the agencies noted previously (e.g., U.S. Chemical Safety and Hazard Investigation Board; the Bureau of Alcohol Tobacco, Firearms and Explosives; and NTSB) do not focus primarily on the medical aspects of the event

5) The medical community must, collectively, assert the impor- tance of such reviews and encourage the development of a single organization to undertake such studies

RECOMMENDATIONS FOR FURTHER RESEARCH

1) Disaster/terrorism-related events must undergo an immedi- ate and careful review of related medical aspects a) Individual medical illness referable to the event should

be recorded and reviewed b) First responder actions should be recorded and reviewed c) First provider actions should be recorded and reviewed d) The U.S. CSEPP provides an excellent example of a

well-trained and thoroughly practiced evaluation system. This existing infrastructure should serve as an exam- ple for a proposed national medical incident evaluation team

2) Recognized difficulties that impede expeditious and thor- ough evaluation of medically related aspects of the event must be mitigated a) Corporate responsibility for event-related expenses

should include reimbursement of expenses of medical investigation (see 1 above)

b) Legal entanglements that impede expeditious evaluation and reporting of medical aspects of the event must be bypassed i) Any (large-scale/chemical) event should be consid-

ered (U.S. OSHA or equivalent) reportable and sub- sequent investigations should include medical assess- ment undertaken by trained medical investigators

ii) Medical evaluators should be free of (current) legal entanglements to offer their written assessments of the event

c) Peer review of the these evaluations should be followed by proposals for corrective actions (if any)

d) Corrective actions should be incorporated into first provider (hospitals) system policies and protocols – pos- sibly through Joint Commission regulatory structures

e) Corrective actions should be incorporated into first responder system policies and protocols – this may require the development of a national/international evaluation/accreditation program for first responders.

3) Disaster/terrorism-related stress is thought to adversely impact the public a) Much of this stress appears to derive from the number,

quality, and content of media presentations. Recommen- dations include to i) Undertake education of the media regarding the

importance of the psychological effects of their work product

ii) Incorporate local media personnel into training and exercise programs designed to deal with large-scale events

b) Methods for mitigation of this stress must be investigated i) The value of a single, consistent, recognizable public

information resource (person) should be emphasized ii) This person(s) must be competent in public presen-

tations, competent in the field of knowledge, and recognizable to the public prior to the event

3) Other real-time accessible information resources should be explored and developed (e.g., Inter- net/telephone sites)

4) Recognition of respiratory failure as the principal medical issue in large-scale chemical events should prompt national study a) First responder use of ventilator support in a large-scale

chemical event must be considered from a variety of logistical and ethical perspectives

b) Alternative initial support tools (including CPAP and dis- posable ventilators) should be evaluated for their practi- cality in addition to their associated logistical and ethical perspectives

5) Material safety data sheets have been used as a resource for assessment and therapy of chemical exposures. OSHA man- dates their availability in the U.S. There is, however, a need for national or subject matter expert review of the data sheets for consistency of content throughout the United States. An area of future research would be to explore the development of a universal standardized resource with up-to-date information about the assessment and therapy of chemical exposures that could be deployed and maintained globally, perhaps under the auspices of the World Health Organization.

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