Current concepts in the management of biologicand chemical warfare causalities

Bellal Joseph, MD, Carlos V. Brown, MD, Conrad Diven, MD, Eric Bui, MD,Hassan Aziz, MD, and Peter Rhee, MD, Tucson, Arizona

B iologic warfare, also known as germ warfare, is the use ofbiologic toxins, infectious agents, or insects as an act of

war.1 Biologic weapons or ‘‘bioagents’’ are living organismsthat can replicate within their host victims. Such weapons arecharacterized by low visibility, high potency, and relativelyeasy delivery.2

Chemical warfare is the use of chemicals formulated toinflict death or harm to human beings.3 They are separate frombiologic weapons (which cause diseases), nuclear weapons(which use subnuclear fission), and radiologic weapons (whichuse radioactive decay of elements).4 Chemical weapons can bewidely dispersed in gas, liquid, and solid formsVand can easilyafflict others beyond the intended targets. Civilian physicianshave rarely seen the effects of either biologic or chemicalwarfare, but the threat in the modern era is ever present andmost likely increasing. 2Y4

In this article, we briefly review the major forms of bi-ologic and chemical warfare, their clinical effects, and currenttreatment options.

BIOLOGIC WEAPONS

Bioterrorism is the deliberate release of viruses, bacteria,or other biologic agents to cause illness or death.2 The use ofbiologic agents is not a new concept. As far back as 400 BC,nomadic archers in Scythia infected their arrows by dippingthem in decomposing bodies or in blood mixed with manure.5

The ancient Romans were known to throw feces in the faces oftheir enemies as a form of biologic terrorism.3 In the middleages, animals infected with diseases such as smallpox werethrown over the walls of fortresses.

These agents are explained later.

Communicable AgentsCommunicable biologic warfare agents that remain

highly relevant today include Yersinia pestis, the causative

agent of the plague that killed an estimated 70 million people inthe 14th century; smallpox; and viral hemorrhagic fevers(VHFs).1,6Y8

YersiniaA gram-negative bacterium, Y. pestis killed up to 60% of

the European population in the 14th century.1 In the 19thcentury, outbreaks of Yersinia were prevalent throughout theIndian subcontinent and Hong Kong and, because of fleas,transported on infected rats that had stowed away on Chinesesteamships.6 More recently, Yersinia was used during WorldWar II as a biologic weapon.7 Every year, the World HealthOrganization (WHO) reports 1,000 to 3,000 new cases ofplague, although only 5 to 15 cases occur in the United States.8

Transmitted to fleas by rodents and then to humans withsubsequent bites, Yersinia proliferates in lymph nodes, where itis able to avoid the immune system. There exist two forms ofplague: (1) bubonic form and (2) pneumonic form.9 The bu-bonic form of plague is not communicable. Symptoms usuallymanifest 2 days to 5 days after exposure to Yersinia. The mainsymptom is swollen lymph nodes (buboes), which are com-monly found in the armpits, groin, or neck. In contrast, thepneumonic form of plague is communicable.10 It can occurwhen a person breathes in Yersinia particles, although suchnaturally occurring pneumonic plague is uncommon; usually, itis the sequel of untreated bubonic plague. Symptoms includeshortness of breath, chest pain, and hemoptysis.

To isolate Yersinia, advanced knowledge and technologyare needed. For individual patients, identification of the bac-terium is from culture analysis. In addition, a rapid dipstick testcan identify the Yersinia antigen.11

Currently, no vaccine is available, although a recombi-nant protein vaccine is now undergoing trials in a murinemodel.12 The standard antibiotic therapy for bubonic orpneumonic plague is Streptomycin.13 Therapeutic effect maybe expected with 30 mg/kg per day (up to a total of 2 g/d) individed doses given intramuscularly, to be continued for a totalof 10 days or until 3 days after the temperature has returned tonormal.13 Successful treatment reduces the mortality rate to 1%to 15%.9

SmallpoxThere is long history of smallpox and its devastation

to mankind.14 More recently, in the 18th century, it was usedby the United States against the French and their NativeAmerican Indian allies at the Siege of Fort Pitt in southwesternPennsylvania.15 Smallpox is a highly contagious virus that cancause variola major (severe form of the disease) and variola

REVIEW ARTICLE

J Trauma Acute Care SurgVolume 75, Number 4582

Submitted: May 21, 2013, Revised: June 16, 2013, Accepted: June 18, 2013.From the Division of Trauma, Critical Care, and Emergency Surgery (B.J., C.D.,

H.A., P.R.), Department of Surgery, University of Arizona, Tucson, Arizona;Division of Trauma, Critical Care, and Emergency Surgery (C.V.B., E.B.),Department of Surgery, Brackenridge Hospital, University of Texas MedicalBranch-Austin, Austin, Texas. Division of Acute Care Surgery, Department ofSurgery,University Medical Center Brackenridge,University of Texas South-western - Austin, Austin, TX

Address for reprints: Bellal Joseph, MD, University of Arizona, Department ofSurgery, Division of Trauma, Critical Care, and Emergency Surgery, 1501 N.Campbell Ave, Room 5411, PO Box 245063, Tucson, AZ 85727; email:bjoseph@surgery.arizona.edu.

DOI: 10.1097/TA.0b013e3182a11175

Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

minor (a mild form). Smallpox was so named to distinguish itfrom the ‘‘great pox,’’ that is, syphilis.16,17 Transmitted easilythrough the atmosphere, smallpox has a high mortality rate(20Y40%).17 As recent as 1967, according to WHO, an esti-mated 15 million people contracted smallpox, 2 million ofwhomdied that year.17 The last smallpox outbreakwas reportedin Merca, Somalia, on October 26, 1977.18

Smallpox occurs only in humans; it has no external hostsor vectors. Symptoms sometimes do not manifest for 12 daysafter infection. The overall case-fatality rate in patients withvariola major is approximately 30% but varies by pock dis-tribution.19 In patients with ordinary-type confluent, the dis-ease is fatal approximately 50% to 75% of the time; withordinary-type semiconfluent, the disease is fatal approxi-mately 25% to 50% of the time; with a discrete rash, the diseaseis fatal less than 10% of the time. The overall case-fatality ratein patients with variola minor is 1% or less. Although this formof smallpox is highly contagious, US Presidents GeorgeWashington, Andrew Jackson, and Abraham Lincoln allcontracted it and recovered.

People born before 1970 were vaccinated for smallpoxunder theWHO program, but the effectiveness of vaccination islimited: the vaccine provides a high level of immunity for only3 years to 5 years. Revaccination protection lasts longer. As abiologic weapon, smallpox is particularly dangerous because ofits highly contagious nature. The infrequency with whichvaccines are administered in the general population (especiallysince the eradication of the disease in 1979) has left mostpeople unprotected from any future outbreak. In the vast ma-jority of people, smallpox vaccination within 3 days after ex-posure will prevent or significantly lessen the severity ofsmallpox symptoms. Vaccination 4 days to 7 days after ex-posure likely offers some protection from the disease or mightat least modify its severity.

No drug is currently approved for the treatment of pa-tients with smallpox. However, antiviral treatments have im-proved since the last large smallpox epidemics; recent studiessuggest that the antiviral drug cidofovir might be useful as atherapeutic agent.20 However, cidofovir must be administeredintravenously and can cause serious renal toxicity. Tecovirimat(ST-246) is another treatment option available for smallpoxand, in recent studies, has shown not to be nephrotoxic.21

According to the Centers for Disease Control and Prevention(CDC), enough smallpox vaccine is available to vaccinateeveryone who would need it in the event of an emergency.

VHFsVHFs refer to a group of illnesses caused by several

distinct families of viruses. Characteristically, the overallvascular system is damaged, resulting in fever and bleedingdisorders, which may be life threatening.22 Culprits includethe Bunyaviridae (hantaviruses), Flaviviridae, Reoviridae,Togaviridae, Filoviridae (Marburg and Ebola viruses), and theArenaviridae (Lassa, Machupo, and Sabia viruses, amongothers). Filoviridae and Arenaviridae are different from othersin that they are nonarbovirsuses, that is, they do not have anarthropod vector.

The overall case-fatality rate in patients with Ebola virusdisease ranges from 50% to 90%.22 No cure currently exists,

although vaccines are in development. In years past, both theUnited States and the thenYSoviet Union investigated the use ofEbola for biologic warfare. Death from Ebola virus disease iscommonly caused by multiple-organ failure and hypovolemicshock.

Marburg was first discovered in Marburg, Germany, in1967.23 No treatments currently exist aside from supportivecare. The arena viruses have a greatly reduced case-fatality rate,as compared with the that of the filoviruses, but a largerpresence, chiefly in central Africa and South America. They aretransmitted mainly by contact with feces or by aerosolization ofrodent urine or saliva. In addition, Machupo and Lassa virusescan be transmitted via secondary human-to-human transmis-sion by contact with an infected person’s blood, by contact withcontaminated surfaces, or by aerosolization.22,23

The survival of the viruses that cause VHFs typicallydepend on an animal or insect host, called the natural reservoir.The viruses are geographically restricted to the areas wheretheir host species live. Humans are not natural reservoirs forany of these viruses. For the most part, rodents and arthropodsare the main reservoirs for these viruses. The hosts of Ebola andMarburg viruses remain unknown.

With a few noteworthy exceptions, no cure or establisheddrug treatment exists at this time for patients with VHFs. Ri-bavirin has been effective in treating some patients with Lassafever or with hemorrhagic fever with renal syndrome.Convalescent-phase plasma has been also been used as asuccessful option in some patients with Argentine hemorrhagicfever.23 Convalescent-phase plasma is obtained from patientswho recently recovered from the disease. It contains a highconcentration of protective antibodies against the culprit agent.

With the exception of yellow fever and Argentinehemorrhagic fever, for which vaccines have been developed, novaccines exist that can protect against VHFs.24 Therefore,prevention efforts must concentrate on avoiding contact withhost species. For hemorrhagic fever viruses that can be trans-mitted from one person to another, avoiding close physicalcontact with infected patients and their body fluids is the mostimportant way to control the spread of disease. Evidence islacking for a history of ‘‘weaponization’’ for many VHFs, butall of them are considered by military medical planners to havea potential for aerosolization, weaponization, or confusion withsimilar agents that might be weaponized.25

Noncommunicable AgentsTularemia

The case-fatality rate in patients with tularemia (alsocalled rabbit fever, if treated, is very low). Streptomycin is thedrug of choice, but tularemia can be severely incapacitating.The disease is caused by the Francisella tularensis bacterium, agram-negative intracellular bacterium. In North America, theprincipal reservoir is the tick. Naturally occurring tularemia canalso be acquired when infected body fluid or tissue comes intocontact with broken skin or mucous membranes.

F. tularensis is very infectious. A small number (10Y50organisms) can cause disease; they have the ability to invadeand replicate within macrophages.26 If these bacteria were usedas a weapon, they would likely be made airborne for expo-sure by inhalation. People who inhale an infectious aerosol

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generally experience severe respiratory illness; if they are nottreated, they can develop life-threatening pneumonia andsystemic infection.27

The bacteria that cause tularemia occur widely in natureand could be isolatedVand grown in quantityVin a laboratory,although manufacturing an effective aerosol weapon wouldrequire considerable sophistication. The CDC regards F.tularensis as a viable bioweapons agent; at various times, it hasbeen included in the biologic warfare programs of the UnitedStates, the Soviet Union, and Japan.27 It was viewed as anattractive bioweapons agent because it is easily aerosolized,highly infective, nonpersistent, easily decontaminated, andhighly incapacitatingVall with a relatively low lethality, ascompared with other agents. In 1969, aWHO expert committeeestimated that an aerosol dispersal of 50 kg of virulent F.tularensis over a metropolitan area of 5 million would inca-pacitate 250,000 people, 19,000 of whom would die.28

An attenuated, live vaccine against tularemia is availablefor high-risk groups such as laboratory workers but not for thegeneral public. The vaccine’s use as postexposure prophylaxisis not recommended. The best ways to prevent tularemia in-fection are to wear rubber gloves when handling or skinninglagomorphs (e.g., rabbits), to avoid ingesting uncooked wildgame, to avoid drinking from untreated water sources, towear long-sleeved clothes, and to use insect repellent to preventtick bites.

BotulismBotulism is one of the most potent and deadliest toxins

known to humankind. The development and use of botulinumtoxin as a possible bioweapon began at least 60 years ago.29

Nowadays, the toxin is readily available worldwide as thetrademarked Botox, owing to it its cosmetic applications ininjections.

The word botulism comes from the Latin for ‘‘sausage’’:it was first described as a ‘‘sausage poison.’’ The causativeagent isClostridium botulinum. Usually, botulism is contractedby eating food contaminated with the spores in an anaerobicenvironment, resulting in wound infections. The toxin reducesthe body’s ability to release acetylcholine, thereby interferingwith nerve impulses and causing flaccid paralysis (as opposedto spastic paralysis, which is seen with tetanus).

If botulism is diagnosed early, treatment consists of anequine antitoxin, enemas, and extracorporeal removal of thegut contents. Severe wound infections can be treated surgically.Adequate cooking kills the toxin. Information regarding safecanning methods and public education about the disease are thebest ways to prevent it.

Tests to detect botulism include a brain scan, nerveconduction test, and Tensilon test (to differentiate botulismfrom myasthenia gravis, which manifests in a similar way). Inaddition, electromyography can be used to differentiate botu-lism not only from myasthenia gravis but also from Guillain-Barre syndrome, both of which botulism often mimics.

The best method to definitively identify botulism is atoxicity test of serum specimens, of stool specimen cultures, orof wound tissue culturesVwhich are then injected into micebecause the standard laboratory diagnostic test for clinicalspecimens and foods is the mouse bioassay.30,31 Alternatively,

mass spectrometry technology can be used; it reduces testingtime to just 3 hours or 4 hours and can identify the seven typesof the botulinum toxin.

Between 1950 and 1996, the case-fatality rate in patientswith botulinum poisoning was 15.5%, down from approxi-mately 60% during the first half of the 20th century. Death isgenerally secondary to respiratory failure due to paralysis of therespiratory muscles, so treatment consists of antitoxin ad-ministration and artificial ventilation until the neurotoxins areexcreted or metabolized. Occasionally, functional recovery cantake several weeks to months or more.

AnthraxAnthrax was first tested by the Japanese Army in the

1930s. Weaponized anthrax was part of the US stockpile before1972, when the United States signed the Biologic WeaponsConvention.32 Anthrax has been used in a variety of conflicts asa weapon. In 1916, the Scandinavian freedom fighters used itagainst the Imperial Russian Army in Finland. In 1978, theRhodesian government used it against cattle and humansduring its war with black nationalists. In April and May 1979,an unusual anthrax epidemic occurred in Sverdlovsk, SovietUnion, leading to the deaths of 105 or more Soviet citizens.33

Even more recently, in September 2011, anthrax spores weresent to several locations via the US Postal Service; 5 in-dividuals died, and 11 developed cutaneous lesions.32

Bacillus anthracis is unicellular and can exist as a spore,which is highly resistant to changes in temperature or inavailability of nutrients. The spore form becomes activatedunder favorable conditions. Anthrax is a naturally occurringdisease of animals, which acquire the spore in the soil. Animalscan be vaccinated to prevent the disease, but doing so is lo-gistically difficult in many parts of the world, such as Africa,Asia, and the Middle East. Anthrax occurs much less fre-quently in the United States, where there are animal health andinspection programs to help prevent people from coming incontact with infected animals or their products. Anthrax is notknown to be spreadable from one person to another, buthumans can be infected by inhaling spores or by handlingproducts, or eating undercooked meat, from infected animals.In 2001, worldwide, 21 cases of naturally occurring anthraxwere reported in humans.32

The three types of anthrax are cutaneous, gastrointesti-nal, and inhalation.34,35 Cutaneous anthrax usually begins as ablister that progresses to an ulcer and subsequent black area;gastrointestinal anthrax, with nausea and anorexia that progressto bloody diarrhea, fever, and stomach pain; inhalation anthrax,with flu-type symptoms.35

Symptoms of anthrax often do not show up for 7 days to6 weeks after initial infection. Penicillin and doxycycline areboth approved by the US Food and Drug Administration foranthrax. Treatment with antibiotics can be for up to 2 months.

Patients with cutaneous anthrax can be treated with an-tibiotics (ciprofloxacin, levofloxacin, doxycycline, penicillin),but even if untreated, 80% will survive. However, gastroin-testinal anthrax is more serious; 25% to 50% of patients willdie.25 Most worrisome of the three types is inhalation anthrax,which kills 50% of patients. An anthrax vaccine is available butnot for the general public. The available vaccine for prevention

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is an aluminum hydroxide-absorbed preparation derived fromculture fluid supernatant taken from an attenuated strain. Thecurrent vaccination series consists of six subcutaneous dosesfollowed by annual boosters. However, insufficient evidenceexists regarding its efficacy against inhalation anthrax inhumans.

CHEMICAL WEAPONS

A toxic chemical, as defined by the Chemical WarfareConvention, is any chemical that, through its chemical actionon life processes, can cause death, temporary incapacitation, orpermanent harm to humans or animals.15,36,37 Various classi-fication systems exist for chemical agents, but the CDC usesthese categories: biotoxins, blister agents (vesicants), bloodagents, caustics (acids), choking or pulmonary agents, inca-pacitating agents, long-acting anticoagulants, metals, nerveagents, organic solvents, riot control agents (tear gas), toxicalcohols, and vomiting agents.38 However, the US militaryofficially designates chemical warfare agents as thosechemicals intended to cause death or serious injury (toxicagents). The North Atlantic Treaty Organization uses codes ofone to three letters for chemical warfare agents, to providestandard terminology across multiple languages (given, whenpertinent, in parentheses later). General principles in pre-hospital care are given in Table 1.

Blister Agents (Vesicants)The CDC classifies blister agents (vesicants) as

chemicals that severely blister the eyes, respiratory tract, orskin. Blister agents are typically categorized as either mustardsor lewisites (L, L-1, L-2, L-3), in addition to the combination ofmustard/lewisite (HL); phosgene oxime (CX) is classifiedalone. Mustards include distilled mustard (HD), mustard gas orsulfur mustard (H), mustard/T, nitrogen mustard (HN-1, HN-2,HN-3), and sesqui-mustard.39 The most likely blister agent tobe involved in large-scale chemical exposures is mustard gas(H). Dating back to World War I, it is the only blister agent tohave been used on the battlefield.40 It was first introduced byGermany in July 1917 before the Third Battle of Ypres.41

Blister agents have low volatility and persist as liquids,leading to toxic exposure via direct contact with the skin, eyes,or respiratory mucosa. Most blister agents produce immediatesymptoms, but mustard gas (H) usually has a latent period of

many hours before producing clinical effects. Casualties ex-posed to blister agents initially experience dermal signs andsymptoms (e.g., itching, pain, erythema, and blistering of theskin), which, over the ensuing days, can progress to necrosisand eschar formation. Ocular manifestations can include pain,lacrimation, conjunctivitis, ulceration, blurry vision, or evenblindness.

Respiratory effects of blister agents can be as mild asrhinorrhea, sore throat, and cough but as severe as dyspnea,tachypnea, and hemoptysis. High-dose exposure can lead tocardiovascular complications (e.g., hypotension, atrioventric-ular block) and neurologic symptoms (e.g., tremors, seizures,and coma). Direct ingestion can cause gastrointestinal irritation(e.g., abdominal pain, nausea, vomiting, and diarrhea).

Blister agents can sometimes be identified by an odor ofgarlic, onions, or mustard, but odor alone should not be reliedon for detection.42 A variety of military and commerciallyavailable field detection kits and chemical detection papers areavailable, which can quickly and definitively detect the pres-ence of blister agents.42

Rescue personnel should wear personal protectiveequipment (PPE). Decontamination measures include remov-ing the casualty from the contaminated area, removing all of thecasualty’s clothing, and thoroughly washing the contaminatedskin with a solution of soap and water. Other topical decon-tamination options include use of dilute sodium hypochlorite(bleach solution) and the M291decontamination kit.43 No an-tidote exists for blister agents, so rapid and thorough decon-tamination is the only method of minimizing tissue damage.

Treatment is largely supportive and tailored towardsymptom relief but can include some specific interventions,depending on organ system involvement. Patients with skininvolvement are typically treated with cleansing, topical anti-biotics, and symptom relief for pain and itching. Eyes shouldbe irrigated thoroughly, and ophthalmic antibiotic ointmentshould be applied. Respiratory effects might require onlysymptom relief with humidified air, cough suppression, andsupplemental oxygen; however, if respiratory failure develops,patients might require early endotracheal intubation, mechan-ical ventilation, bronchoscopy, and systemic antibiotics forsecondary infections. Gastrointestinal symptoms can be treatedwith antiemetics and intravenous volume resuscitation, avoidinggastric lavage and catharsis.

Blood AgentsBlood agents comprise a group of toxic chemicals that

exert their poisonous effect after being absorbed into the blood.The CDC lists specific blood agents: arsine (SA), carbonmonoxide, saxitoxin, cyanide, and sodium monofluoroacetate(compound 1080).42 Table 2 highlights the clinical propertiesand therapeutic options for blood agents.

Cyanide, the most studied of the blood agents, is a nat-urally occurring substance present in four forms as follows: acolorless gas, such as hydrogen cyanide (HCN) or cyanogenchloride (CNCl), or a crystal, such as sodium cyanide (NaCN)or potassium cyanide (KCN).38 Cyanide exposure can oc-cur via ingestion, via absorption through the eyes or skin(not usually clinically significant), and via wounds directly intothe circulation. Most often and most efficiently, exposure

TABLE 1. Prehospital Care

1. Recognition of the chemical attack

2. Isolation and security at the scene of attack

3. Implementation of the incident command and control system

4. Provision of PPE for rescue personnel

5. Decontamination of casualties

6. Identification of the chemical agent

7. Communication and coordination of security, rescue, and medical personnel

8. Triage of victims

9. Initiation of treatment

10. Transportation to hospital

11. Recovery activities

12. Fatality management

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occurs through inhalation, followed by rapid absorption andwidespread dissemination throughout the body. A highlyvolatile gas that evaporates and disperses quickly in openspaces, cyanide is most dangerous in enclosed places.

Once cyanide is absorbed by the body, it exerts its toxiceffects on the cellular level. It has a high affinity for transitionalmetals, particularly the trivalent form of iron (Fe3+).37,38 Thecyanide ion interrupts oxidative phosphorylation by binding tocytochrome a3 in the mitochondrial cytochrome oxidase sys-tem, thus preventing use of intracellular oxygen, and eventualcell death.

Clinical manifestations, which occur seconds to minutesafter cyanide exposure, are primarily due to central nervoussystem and cardiovascular sequelae. Signs and symptoms in-clude tachycardia, hyperapnea, restlessness, headache, anddizziness, which can progress to bradycardia, hypotension,and loss of consciousness, seizures, apnea, respiratory failure,and death. Patients can have a cherry-red skin color secondaryto high venous oxygen content.

Like blister agents, cyanide can emit a distinctive odor,namely, a ‘‘bitter almond’’ odor, but not always.38 Moreover,not everyone can detect the odor. The presence of cyanide canalso be detected by using a field detection kit.

Furthermore, several laboratory evaluations can indicatethe presence of cyanide toxicity. Nonspecific laboratory ab-normalities after cyanide exposure include a high-anion-gapmetabolic acidosis due to lactate accumulation and to the el-evated oxygen content of venous blood. An even more specifictoxicity test assesses for an elevated concentration of cyanide inthe blood.

Decontamination does not play a critical role in the careof a cyanide casualty. Inhalation and ingestion do not requirespecific decontamination, other than prevention of ongoingexposure. If liquid contamination is a possibility, any wetclothes the casualty might have been wearing should be re-moved, and the skin should be cleansed with soap and water. Aswith any other patient exposed to a toxic chemical, medicalcare of a cyanide casualty centers on general supportive

measures directed at derangements with airway, breathing, andcirculation. However, a cyanide-specific treatment option ex-ists, administered in two parts.38 First, hemoglobin is oxidizedto methemoglobin by administering a nitrite compound (e.g.,amyl nitrite or sodium nitrite). The trivalent ferric ion (Fe3+) hasmore affinity for methemoglobin than for cytochrome a3,resulting in the removal of the bound cyanide from cytochromea3 and allowing normal use of mitochondrial oxygen. Second,after nitrite therapy, the patient is given sodium thiosulfate,which in turn reacts with the cyanomethemoglobin complex.38

The end result of this reaction is the formation of thiocyanateand sulfite, both of which are cleared and excreted in the urine.Intravenous hydroxocobalamin and epinephrine have alsoshown to improve survival in swine model of cyanide-inducedcardiac arrest.41,42,44

Pulmonary AgentsPulmonary agents cause severe irritation or swelling of

the upper or lower respiratory tract. Thousands of substancesare capable of such harm; some of the more common chemicalsinvolved in chemical warfare or unintentional exposure includeammonia, chlorine (CL), methyl isocyanate, and phosgene(CG). Pulmonary agents are typically encountered in the gas-eous state; after inhalation, they lead to severe inflammationand damage of the upper and lower airways. On contact withthe moisture of the upper or lower airways, pulmonary agentsform strong acids (chlorine Y hydrochloric acid) or bases(ammonia, NH3+ Y NH4+), leading to the destruction of theunderlying airway mucosa.

Generally, upper airway symptoms develop shortly(within 30 minutes) after contact with the offending pulmonaryagent; during the ensuing 24 hours to 72 hours, lower airwaysymptoms progress and worsen. Clinical manifestations ofupper airway exposure can be relatively mild, includingburning pain in the nose and throat, sneezing, coughing,dysphagia, and hoarseness.

However, after large exposure, patients can have life-threatening laryngospasm secondary to upper airway edema.

TABLE 2. Blood Agents

Agent Properties Exposure Clinical Symptoms Treatment

Sodium monofluoroacetate(compound 1080)

White powder Ingestion Nonspecific No specific antidote

Odorless and tasteless Inhalation Muscarinic blockade symptoms Activated charcoal

LD50, 2Y5 mg/kg

Arsine Colorless crystals Aerosols Vomiting No specific antidotes

Odorless Irritation Antiemetic

Garlic taste Mental status changes Supportive treatment

Saxitoxin Naturally occurring toxin Ingestion Paralytic shellfish poisoning No specific antidotes

Heat resistant Inhalation Dizziness Supportive therapy

Paralysis

Cardiopulmonary arrest

Carbon monoxide Colorless Inhalation Neurotoxic 100% oxygen

Odorless Hypoxia hyperbaric oxygen

Present in gas form Seizures

The data have been derived from Kenar and Karayilanoglu49 and Staudenmayer and Schecter.48

LD, lethal dose.

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Their lower airway symptoms include coughing and shortnessof breath but can rapidly progress to lethal hypoxia due tosevere pulmonary edema.

Detecting pulmonary agents can be difficult, given theirrapid dispersion and the lack of an agent-specific field detectionkit. Odor cannot be relied on independently, although somepulmonary agents can display a distinctive odor. For example,phosgene has an odor similar to that of freshly mown hay orgrass; white phosphorus smells like garlic. The odor of hy-drogen chloride is pungent; that of ammonia is sharp and in-tensely irritating.

Decontamination after exposure to a pulmonary agentprimarily consists of termination of the exposure. To preventsecondary exposure to health care providers, the patient’sclothing, especially if damp, should be removed, and the skincleansed with soap and water.

No antidote or neutralizing agent for pulmonary agentsexists, so treatment is largely supportive, with measures di-rected at the damaged airways. In patients with hoarseness,stridor, or any evidence of upper airway edema, a definitiveairway (endotracheal or surgical) should be established. Inpatients with hypoxia, supplemental oxygen and/or mechanicalpositive-pressure ventilation will be necessary. Significantairway secretions and bronchospasm should be expected;treatment is with regular suctioning and bronchodilators.Secondary pulmonary infection is a major concern, but pro-phylactic antibiotics should not be administered. Severalstudies have suggested the use of inhaled or parenteral steroidsand bicarbonate therapy (4 mL of a 3.75% solution made bydiluting 2 mL of a standard 7.5% solution with 2-mL normalsaline [NS] inhaled via nebulizer) for decreasing respiratorycomplications after chlorine exposure.45

Nerve AgentsThe most dangerous class of chemical warfare agents,

nerve agents can cause death within minutes after exposure.Nerve agents are classified with either a G or Vas the first letterof their North Atlantic Treaty Organization code. G agentsinclude sarin (GB), soman (GD), tabun (GA), and GF; the onlyV agent is VX. Nerve agents are liquids, but the more volatileagents (GB) can exist in a vapor form.39 Although G and Vagents vary slightly in their chemical structure, they are similarto organophosphate pesticides and exert their biologic effectswith the same end result, inhibiting acetylcholinesterase en-zymes. In 1995, Aum Shinrikyo sect released an impure formof sarin in the Tokyo Metro, killing 13 people. Recent reportshave also suggested the use of sarin gas in the Syrian war.

Nerve agent exposure occurs through either vapor in-halation or direct contact of the liquid form with the skin oreyes. Either route of exposure rapidly (within seconds to mi-nutes) leads to the same mechanism of action, efficient andirreversible binding and inhibition of the acetylcholinesteraseenzyme. Inhibition of this enzyme leads to the body’s inabilityto degrade acetylcholine and to an ongoing accumulation ofacetylcholine at the cholinergic receptor site. Unrelentingcholinergic stimulation results in pathophysiologic effects atboth the nicotinic and muscarinic receptor sites, manifesting asa cholinergic crisis.46,47

Nicotinic effects, seen in the cardiovascular and mus-culoskeletal systems, include tachycardia or bradycardia, ar-rhythmias, hypertension, and the muscular effects of weakness,fasciculations, and flaccid paralysis. Muscarinic receptors,which affect most other systems in the body, can manifest assigns or symptoms in the skin (sweating), eyes (miosis, blurredvision), nose (rhinorrhea), mouth (salivation), lungs (bron-chospasm, bronchorrhea, dyspnea), gastrointestinal tract (ab-dominal pain, nausea, vomiting, diarrhea), and, most seriously,central nervous system (coma, apnea, seizures).47

After nerve agent exposure, decontamination is criticalVnot only to halt ongoing exposure to patients but also to preventsecondary exposure to health care providers. Exposure to aliquid nerve agent requires decontamination in the samefashion as exposure to a blister agent. Rescue personnel shouldwear PPE. Decontamination measures include removingthe casualty from the contaminated area, removing all of thecasualty’s clothing, and thoroughly washing the contaminatedskin with a solution of soap and water. Other topical decon-tamination options include use of dilute sodium hypochlorite(bleach solution) and the M291skin-decontamination kit. Ex-posure to a vapor nerve agent requires similar decontaminationmeasures, especially to avoid secondary exposure to health careproviders via direct contact or off-gassing of the vapor.48,49

Treatment of patients exposed to a nerve agent includesgeneral support of the airway, breathing, and circulation.Specific treatment is available in the form of pralidoximechloride (i.e., Protopam, 2-PAM) and atropine. Pralidoximechloride (15Y25 mg/kg, intramuscularly or intravenously) is anantidote to nerve agent effects on the cholinergic nicotinicreceptors, counteracting the cardiovascular and musculoskel-etal effects. It binds to the nerve agent that is inhibitingacetylcholinesterase, thereby breaking this otherwise irre-versible bond and restoring normal enzyme activity. Theoxime-organophosphate complex is then excreted in thepatient’s urine. The timing of pralidoxime chloride therapy iscritical, to afford the greatest antidote effect. The agent-acetylcholinesterase complex ages over a matter of hours,and pralidoxime chloride’s capacity to disassociate the com-plex decreases over time. Therefore, pralidoxime chlorideshould be given as soon as possible after exposure, preferablywithin a few hours.

Simultaneously, atropine (2 mg/kg, intramuscularly or,preferably, intravenously) should be administered, to offset themuscarinic manifestations of the nerve agent. Atropine directlycompetes with acetylcholine within the synapse, thereby de-creasing the cholinergic response from muscarinic stimulation.If the patient is unconscious, the initial dose of atropine can beincreased (to 6Y10 mg/kg). Atropine should be redosed untilmuscarinic symptoms resolve.

In addition to pralidoxime chloride and atropine, diaz-epam can be given to patients with evidence of severe toxicity,in an attempt to prevent and/or treat seizure activity. Table 3highlights the treatment options for some of the chemicalagents.

CONCLUSION

Biologic and chemical weapons are important causes ofmass causalities. There exist deficiencies and disparities in

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literature regarding the initial triage and definitive care of theseinjuries. Adequate information and prevention are two of thekey issues that we must address if we are to make meaningfulprogress in preventing, or containing, this disturbing andpotentially catastrophic danger. Effective communication isalso of great significance in managing a mass biologic andchemical biowarfare catastrophe and requires repetitive full-scale rehearsal.

AUTHORSHIP

B.J., C.V.B., and P.R. designed this study. B.J., H.A., C.D., and E.B.searched the literature and collected the data, which were analyzed byB.J, C.V.R. and P.R. All other authors participated in manuscriptpreparation.

DISCLOSURE

The authors declare no conflicts of interest.

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TABLE 3. Treatment options for Blister Agents, Blood Agents,and Nerve Agents

Agent Treatment

Mustard Steroid and antibiotic Ointment

Ophthalmologic ointments containing 5% boric acid

Cycloplegic eye drops (atropine or homatropine)3 times a day

Debride ruptured vesicles or bullae

Nebulized N-acetylcysteine (NAC) may possibly reducelung injury.

Hydroxocobalamin

Cyanide 4-Dimethylaminophenol, intravenous injection of 3 mg/kg

Sulfanegen TEA, intramuscular/intravenous/intraperitoneal,single or divided dose based on weight

Chlorine gas Sodium bicarbonate 4 mL of a 3.75% solution made bydiluting 2 mL of a standard 7.5% solution with 2-mLNS inhaled via nebulizer

Albuterol, 5 mg in 2.5-mL NS for nebulization

Phosgene gas Methylprednisolone: usual dosing range, 2Y60 mg/d peros divided every 6Y24 h

Dopamine, 5Y15 Hg/kg/min intravenously administeredmay increase renal blood flow,cardiac output, heart rate, and cardiac contractility

Zafirlukast, 20 mg per os twice daily

Pralidoxime chloride (15Y25 mg/kg, intramuscularlyor intravenously)

Sarin gas Biperidin

Atropine (2 mg/kg)

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