chapter 10 - toxic inhalational injury and toxix industrial chemicals - pg. 339 - 370

8/3/2019 Chapter 10 - Toxic Inhalational Injury and Toxix Industrial Chemicals - Pg. 339 - 370

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Toxic Inhalational Injury and Toxic Industrial Chemicals

Chapter 10

TOXIC INHALATIONAL INJURY ANDTOXIC INDUSTRIAL CHEMICALS

SHIRLEY D. TUORINSKY, MSN,*ANDALFRED M. SCIUTO, PHD

INTRODUCTION

HISTORY AND USE

Military UsesNonmilitary Uses

MECHANISMS OF TOXICITYMechanistic Effects of Inhaled Pulmonary AgentsBiochemical Responses

SPECIFIC INHALED TOXIC-GASINDUCED EFFECTS AND THEIR TREATMENTAmmoniaChlorineHydrogen CyanidePerfluoroisobutylenePhosgene

CLINICAL PRESENTATION AND DIAGNOSISCentrally Acting Toxic Industrial ChemicalsPeripherally Acting Toxic Industrial ChemicalsChemicals That Act on Both the Central and Peripheral AirwaysClinical EffectsDiagnostic Tests

MEDICAL MANAGEMENTPatient HistoryPhysical ExaminationAcute Medical ManagementClinical CarePatient TransportLong-Term Effects

SUMMARY

*Lieutenant Colonel, AN, US Army; Executive Officer, Combat Casualty Care Division, US Army Medical Research Institute of Chemical Defense, 3100Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400

Research Physiologist, Analytical Toxicology Division, Medical Toxicology Branch, US Army Medical Research Institute of Chemical Defense, 3100Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010-5400


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Medical Aspects of Chemical Warfare

INTRODUCTION

Clinical recognition of damage to the central compart-ment or the peripheral compartment or both should beenough to guide medical management in the absenceof identification of specific chemicals.

Determining the damaged compartment is done onthe basis of the chemicals aqueous solubility, chemicalreactivity, and dose received. Lung-damaging TICs cancause damage to central or peripheral compartmentsof the respiratory system. The central compartmentof the respiratory system consists of the conductingairways, larynx, trachea, and bronchi. The peripheralcompartment consists of the smaller airway, in whichgas exchange takes place. Effects of agents that act onthe peripheral airway are found in the bronchioles tothe alveoli of the respiratory system. Centrally act-ing TICs normally form strong acids or bases (alkali)with the water in the central airway tissues, which

leads to the destruction of these tissues. The dam-aged tissue swells and may slough into the airway,restricting breathing. Ammonia and sulfur mustard areexamples of centrally acting TICs. Peripherally actingchemicals cause life-threatening pulmonary edema.However, both centrally and peripherally acting TICscause damage in the lungs by inhalation. TICs do notaffect the lungs when they are absorbed through theskin, injected, or orally ingested. This chapter will berestricted to those chemical agents with acute localpulmonary effects.

Toxic industrial chemicals (TICs) are a wide varietyof lung-damaging chemical agents used in manufac-turing. TICs are commonly found in communities ofindustrialized nations that manufacture petroleum,

textiles, plastics, fertilizers, paper, pesticides, and manyother products. These extensively used chemicals areinexpensive; easily acquired; and transported by ship,train, pipeline, and truck, making them an obviouschoice for terrorists. The list of these chemicals is ex-tremely long. According to the North Atlantic TreatyOrganization, TICs are chemicals at least as poisonousas ammonia that are produced in large quantities. Bythis definition, TICs could be released in sufficientquantities to produce mass casualties on or off thebattlefield.

The toxicity of TICs varies greatly: some are acutelytoxic, whereas others have little toxicity. They come in

liquid, vapor, and solid form (Table 10-1); the liquid andvapor forms generally lead to the greatest intensity ofexposure. A crucial aspect of the medical managementof acute toxic inhalational casualties is determining therespiratory system compartment or compartments af-fected, then treating the compartmental damage, ratherthan adhering to a specific treatment protocol for eachagent. Knowing the identity of the specific TIC releasedis helpful but not necessary in the medical evaluationof the pulmonary agent casualty, which should con-centrate on the location of lung compartment damage.

TABLE 10-1

DEFINITIONS OF AIRBORNE TOXIC MATERIAL

Gas The molecular form of a substance, in which molecules are dispersed widely enough to havelittle physical effect (attraction) on each other; therefore, there is no definite shape or volumeto gas.

Vapor A term used somewhat interchangeably with gas, vapor specifically refers to the gaseous stateof a substance that at normal temperature and pressure would be liquid or solid (mustardvapor or water vapor compared with oxygen gas). Vaporized substances often reliquefy andhence may have a combined inhalational and topical effect.

Mist The particulate form of a liquid (droplets) suspended in air, often as a result of an explosion or

mechanical generation of particles (by a spinning disk generator or sprayer). Particle size is aprimary factor in determining the airborne persistence of a mist and the level of its depositionin the respiratory tract.

Fumes, Smokes, and Dusts Solid particles of various sizes that are suspended in air. The particles may be formed by explo-sion or mechanical generation or as a by-product of chemical reaction or combustion. Fumes,smokes, and dusts may themselves be toxic or may carry, adsorbed to their surfaces, any ofa variety of toxic gaseous substances. As these particles and surfaces collide, adsorbed gasesmay be liberated and produce local or even systemic toxic injury.

Aerosol Particles, either liquid or solid, suspended in air. Mists, fumes, smokes, and dusts are all aerosols.


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The potential for accidental or deliberate exposureto lung-damaging TICs exists for the military and ci-vilian populations. These industrial chemicals provideeffective and readily accessible materials to developimprovised explosives, incendiaries, and poisons.1On April 30, 2007, newspapers around the world re-

ported an incident in Ramadi, Iraq, in which insurgentsexploded a tanker loaded with chlorine gas, causingmany civilian deaths and injuries. This chapter willhelp to prepare the military medical community torecognize the symptoms of lung-damaging TICs andprovide treatment.

HISTORY AND USE

Military Uses

The use of chemical or even biological warfareagents goes back to antiquity. Early agents of choicewere smokes, which could be generated from a com-bustible source and serve as a formidable offensiveweapon in favorable wind conditions. The Greeks wereknown to expose their enemies to concoctions of smokeand flame mixed with sulfur.2In 1456 arsenical smokeswere used defensively in Belgrade against the Turks.3

During World War I chemical agents such as phosgene,chlorine, sulfur mustard, diphosgene (trichloromethyl-chlorformate), diphenylarsine, chloropicrin, and di-phenylchloroarsine were used offensively by both theAllies and the Axis to produce mass casualties.

These agents were largely used in some combinationfor ease of use and to maintain the persistence of thegas on the battlefield to attain the greatest exposureeffects. For example, phosgene, the principal nonper-sistent gas, had to be cooled in salt brine during themixing process because of its low boiling point (8C),so it was combined with either chlorine or diphosgenefor more efficient weaponization.4Phosgene was the

gas of choice because of its well-known toxicity andcapacity to produce the most casualties. Battlefieldexposure to gas mixtures such as chlorine-phosgenewas responsible for approximately 71,000 casualties orabout 33% of all casualties entering the hospital; how-ever, phosgene was reportedly directly responsible foronly 6,834 casualties and 66 deaths4(this contradictssome reports that suggest phosgene alone was respon-sible for nearly 80% of all gas casualty deaths during191419185). Although the number of fatalities was low,phosgene gassing during the war caused men to lose311,000 days to hospitalization, equal to 852 person-years.4Because chemical warfare agents are used notsolely to exterminate the opposition, but also to takesoldiers off the battlefield, phosgene was an effectiveagent. France first weaponized phosgene in 1916,and Germany quickly followed, choosing to combinephosgene with diphosgene because its higher boilingpoint (128C) made the concoction easier to pour intoshells. Also, diphosgene was believed to break downto phosgene under proper conditions, especially whenit reached the lung.6

During the latter course of the war, thousands ofchemical agent shells were fired by both sides. Thelargest number of American casualties from one artil-lery attack occurred at the Battle of the Marne on June1415, 1918, when 1,559 soldiers were gassed.6Laterthat year, on August 2, the Germans fired 20,000 shells,which produced 349 casualties, and on August 7 and8, they used 8,000 to 10,000 gas-filled shells, producingover 800 casualties and 47 deaths.6Table 10-2 gives anoverview of the chronological use of chemical warfare

agents in World War I.Because of the massive battlefield casualties and

the long-term postwar health effects from the chemi-cal weapons in World War I, the Geneva Protocol wasestablished to ban the use of offensive chemicals in war.The ban was neither generally accepted nor adhered toby all countries, and it was not ratified by the UnitedStates until 1975. Egypt reportedly used chemicalagents in Yemen between 1963 and 1967, and evidencecites the use of CS (tear gas [2-chlorobenzylidene ma-lonitrile]) and Agent Orange (a plant defoliant) by USforces in Vietnam in the late 1960s and early 1970s.7

Nonmilitary Uses

The chemical agents discussed above, used as in-capacitating agents or weapons of mass casualty, alsohave important uses as industrial chemical interme-diates or are the end products of nonweapons manu-facturing processes. The large number of potentiallytoxic gases described below and listed in Table 10-3are limited to those that have been studied under ex-perimental conditions and have an associated humanexposure/treatment database.8

Ammonia, a naturally occurring soluble alkalinegas, is a colorless irritant with a sharp odor. It is widelyused in industrial processes, including oil refiningas well as the production of explosives, refrigerants,fertilizers, and plastics. Ammonia is also used as afixative in photographic, blueprinting, and duplicat-ing processes. It is a particularly significant airborneenvironmental hazard in swine and poultry confine-ment areas. Another source of exposure can be fromwell-known ammonium-based cleaning agents. Am-monia is transported daily by rail and road across the


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TABLE 10-2

CHEMICAL AGENTS USED IN WORLD WAR I (IN CHRONOLOGICAL ORDER)

Agent Type First Use Agent Type First Use

Ethyl bromoacetate I Aug 1914 Trichloromethyl chloroformate R May 1916

o-Dianisidine chlorosulfonate I Oct 1914 Hydrogen cyanide R Jul 1916Chloroacetone I Nov 1914 Hydrogen sulfide R Jul 1916Xylyl bromide I Jan 1915 Chloropicrin R Aug 1916Xylylene bromide I Jan 1915 Cyanogen bromide R Sept 1916Benzyl bromide I Mar 1915 Cyanogen chloride R Oct 1916Chlorine R Apr 1915 Phenylcarbylamine chloride May 1917Bromine R May 1915 Diphenylchlorarsine I Jul 1917Methyl chlorosulfonate I Jun 1915 Bis(2-chloroethyl) sulfide S Jul 1917Ethyl chlorosulfonate I Jun 1915 Phenyldichloroarsine I Sept 1917Chloromethyl chloroformate I Jun 1915 Bis(chloromethyl) ether R Jan 1918Dichloromethyl chloroformate I Jun 1915 Bis(bromomethyl) ether R Jan 1918Bromoacetone I Jun 1915 Thiophosgene I Mar 1918Bromomethylethylketone I Jul 1915 Ethyldichloroarsine S Mar 1918Iodoacetone I Aug 1915 Methyldichloroarsine S Mar 1918

Dimethyl sulfate I Aug 1915 Diphenylcyanoarsine I May 1918Perchloromethyl mercaptan R Sep 1915 N-ethylcarbazole I Jul 1918Ethyl iodoacetate I Sep 1915 -Bromobenzylcyanide I Jul 1918Benzyl iodide I Nov 1915 10-Chloro-5,10-dihydro-phenarsazine I Sep 1918Phosgene R Dec 1915 Phenyldibromoarsine I Sep 1918o-Nitrobenzyl chloride I 1915 Ethyldibromoarsine S Sep 1918Benzyl chloride I 1915 Cyanoformate esters 1918Acrolein I Jan 1916

I: primary irritant; R: lethal via respiratory route; S: mainly skin effects; : no data.Data source: Beswick FW. Chemical agents used in riot control and warfare. Hum Toxicol. 1983;2:247-256.

country. Industrial exposure of approximately 1,700

parts per million (ppm) of ammonia has been shownto cause severe airway obstruction.9

Chlorine, a greenish to yellowish compound, isanother irritant gas. Chlorine was used as a chemi-cal warfare agent during World War I because of itsheavier-than-air capacity to occupy low-lying areassuch as trenches. Chlorine is widely used in the paperand pulp mill production industries; over 10 milliontons of chlorine are manufactured in the United Statesand Europe each year.10Accidental exposure to chlo-rine can occur in the household or anywhere bleach ismixed with acidic cleansers in an unventilated room.Other common sources of exposure are swimmingpools, where an imbalance in mixing or dilution canresult in increased release of chlorine gas. Since WorldWar I over 200 major incidents involving mild to toxicchlorine exposure have occurred worldwide.11

Intentional exposures are not limited to the battle-field. Irritating, poorly water-soluble smokes such asCS, CN (chloroacetophenone), and CR (dibenz[b,f]-1,4-oxazepine), commonly referred to as riot controlagents or tear gas, have been used for many years to

quell social disturbances. CS was first introduced in

Britain by Corson and Stoughton in 1958 to replaceCN for riot control because it was safer and more ef-fective.12These gases effect the sensory nerves of theskin and mucosa in the nose, eyes, and mouth, causinguncomfortable irritation at the sites of exposures. Theoverall effects of CS and CN inhalation are respiratoryand ventilatory depression. CS has also been linkedto reactive airways dysfunction syndrome (RADS)resulting from a single intentional exposure.13Theseagents have no practical use in the chemical and manu-facturing industries. Olajos and Salem have provideda review of the tear gases.14

Hydrogen cyanide (HCN) is one of the gases mosttoxic to humans. It may be encountered in industrialprocesses as sodium or potassium cyanate or as acry-lonitrile. Exposures to the salts may occur during theextraction of gold, in electroplating, or in photographicprocesses. HCN can be manufactured as a byproductduring the synthesis of acrylonitrile, which is a morecommon industrial hazard used in the production ofsynthetic rubber and as a fumigant. Mixtures of so-dium cyanide, magnesium carbonate, and magnesium


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TABLE 10-3

US ARMY CENTER FOR HEALTH PROMOTION AND PREVENTIVE MEDICINE TOXICINDUSTRIAL CHEMICALS

(Table 10-3continues)

sulfate are used as rodenticides. Exposure to cyanidecan result from the release of HCN gas when the solidmixture comes into contact with water. Exposure toHCN gas, which is lighter than air, can also result fromfires because many organic compounds release HCNduring combustion or pyrolysis processes.15Cyanide,a metabolic poison that smells like almonds, is a po-

tent inhibitor of cytochrome-c-oxidase, the terminalenzyme in the mitochondrial electron transport chainrequired for cellular respiration.16Chapter 11, CyanidePosoning, contains more details on HCN.

Hydrogen sulfide (H2S), or sour gas, has a well-known pungent and irritating odor that smells likerotten eggs. A heavier-than-air and colorless gas, H2S


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may occur in industrial processes associated with min-ing, crude oil refining, tanning, farming, paper pulpmills, sewage treatment, and rubber production. It isalso a component of natural gas, a major component ofvolcanic eruptions, and a major airborne hazard in ani-mal confinement areas. H2S is nearly as toxic as HCNand acts almost as rapidly. It is responsible for moredeaths than any other gas.17Case reports indicate thatexposure can cause neurological symptoms, with focalnecrosis of the brain implicated in a fatal outcome.18Environmental release of H2S can cause breathlessnessand eye and nasopharyngeal irritation.19Reiffensteinet al20 have provided an early review of H2S reportingthat the typical rotten-egg odor is inadequate warn-

ing of short-term exposures to high levels, which cancause an inability to smell the gas (olfactory paralysis),among other adverse health effects.

Oxides of nitrogen come in four stable forms: (1)nitrogen oxide (N

2O), an anesthetic compound, and

(2) nitric oxide (NO), an important byproduct of in-tracellular biochemical nitrogen metabolism, whichalso forms (3) nitrogen dioxide (NO2) and (4) nitro-gen tetroxide (N2O4) when oxidized in air. Oxides ofnitrogen are important reactive end products of airpollution. The reactive dioxide form is a pulmonary ir-ritant that can be found in fresh silage from agriculturalprocesses preserving green crops such as alfalfa andcorn (silo-fillers disease), in unventilated areas with

Table 10-3continued

Reproduced from: US Army Center for Health Promotion and Preventive Medicine. Industrial Chemical Prioritization and Determination ofCritical Hazards of Concern.Aberdeen Proving Ground, Md: USACHPPM; 2003: Appendix B. USACHPPM Report 47-EM-6154-03.


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high temperature arc welding, and the production andtransport of nitric acid. N2O may also be produced inthe dipping of aluminum, brass, and copper and incombustion and pyrolysis processes.21

Polytetrafluoroethylene (Teflon [Dupont, Wilm-ington, Del]) can form toxic gases when heated to

temperatures above 400C. Combustion and pyrolysisbyproducts of Teflon, which have been known for sometime, have been implicated in pulmonary injury andeven deaths following a single exposure.22 Illnessescaused by the inhalation of combustion byproductshave been given the label polymer fume fever. One ofthe more common byproducts is perfluoroisobutylene(PFIB), which is reportedly 10 times more toxic thanphosgene.23

Phosgene has been used extensively for the past 60years in the production of pharmaceuticals, anilinedyes, polyfoam rubber, isocyanates, and plastic prod-ucts in the United States and worldwide. In 1998 the

United States used 4.3 million pounds of phosgenein manufacturing processes.24 Phosgene is used ina phosgenation reaction to help supply chlorinegroups to reaction products. Babad and Zeiler25havereviewed phosgene chemical reactions, finding thatphosgene rapidly reacts with water to form carbondioxide and hydrochloric acid, and it also reacts withmacromolecules containing sulfhydryl, amine, andhydroxyl groups in aqueous solutions. Phosgene canbe formed by the thermal decomposition of chlori-nated hydrocarbons and poses a threat for welders,refrigeration mechanics, and automobile mechanics.26Commonly used industrial degreasers contain chlori-

nated hydrocarbons, such as perchloroethylene, which

can form phosgene when heated. Therefore, industrialworkers, fire fighters, military personnel, and othersare at risk for accidental or occupational exposure tophosgene. In Poland, for example, because of heavyindustrialization in proximity to densely populatedareas, phosgene, along with chlorine, ammonia, and

sulfur dioxide, has been identified as one of the mostsignificant threats to the environment.27

Smoke is a general classification of a complexmixture of particulate/gaseous emissions. Smokesare products of the combustion process of burning orsmoldering. The major cause of death from fire-relatedevents is smoke inhalation. Smoke can include manyof the chemicals mentioned earlier. Particulate mattersuch as carbon soot particles can make up a significantproportion of toxic smoke, as can carbon monoxide,HCN, phosgene, aldehydes such as formaldehyde,ammonia, and PFIB.

Sulfur dioxide is a major air pollutant and a prin-

cipal source of photochemical smog and acid rain. Acolorless, water-soluble gas 2.26 times heavier thanwater, sulfur dioxide is used in a number of industrialprocesses such as the smelting production of copper,iron, lead, and zinc ores. When it comes into contactwith moist surfaces, sulfur dioxide is hydrolyzed andoxidized to form sulfuric acid. It is extremely corrosiveto the nasopharynx region, eyes, and upper airways.Inhalation exposure may progress to acute respiratorydistress syndrome (ARDS) and has been implicated incausing RADS.28Prolonged exposure causes inflamma-tion of the airways and impairs the immune systemand lung resistance.29Table 10-4 provides a very lim-

ited overview of some well-known gaseous irritants.

MECHANISMS OF TOXICITY

Numerous studies have been undertaken to deter-mine the mechanisms of toxicity and the basis for lunginjury from exposure to toxic gases. These investiga-tions have historically involved animal models. Asearly as 1919 the progression and intensity of exposureto agents such as phosgene was demonstrated in dogs.In later decades, animal models included mice, rats,guinea pigs, swine, and monkeys to more accuratelypredict the temporal effects of injury progression andscope in humans. Many of these models involvedthe use of inhalation techniques, focused essentiallyon the establishment of a fundamental relationship:lethal concentration (C), in ppm, times the duration(T), in minutes, of exposure (also known as Haberslaw).30The product of C T corresponds to a standardresponse measure describing a biological endpoint ofedema formation, death, or any other consistent physi-ological parameter. Conceptually, this product simply

meant that the same biological endpoint would occurwhether the animals were exposed to 100 ppm of gasfor 10 minutes, 50 ppm for 20 minutes, or 20 ppm for50 minutes (all resulting in a C T of 1,000 ppmmin).However, later experiments showed that for a gas suchas phosgene and other irritants, Habers law was ap-plicable only over short exposure times.31,32It is nowgenerally agreed that concentration rather than dura-tion of exposure determines the gass effect.

As implied by this discussion of Habers law, theuse of such a general quantitative assessment forexposure-response effects includes inherent problems.Many fundamental physiological, toxicological, histo-pathological, and biochemical effects are lost in suchan evaluation, especially when death is the endpoint.As shown in Table 104,many of these compoundshave varying solubility ranges, resulting in a rangeof effects within the pulmonary tree. For example,


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inhalation of compounds that have limited solubilityresults in lower lung injury, whereas compounds thatare miscible in water affect the upper regions of therespiratory tree. Compounds discussed earlier, such asphosgene, chlorine, oxides of nitrogen, and PFIB, areconsidered lower airway (peripheral compartment)irritants based on their solubility characteristics. Gasessuch as ammonia, sulfur dioxide, and hydrochloricacid are generally considered upper airway (central

compartment) irritants but can affect the lower lungregions if exposure concentration and duration aresufficient. Carbon monoxide, H2S, and HCN are clas-sified as systemic chemical asphyxiants.

Rational and effective medical countermeasuresagainst the inhalational injury caused by gases,smokes, fumes, and mists depend on mechanisticevidence of exposure responses at the tissue and cel-lular levels. The investigation required to determinethe correct treatment route, therapeutic window, anddosing levels is costly and time consuming. Study ofrepresentative compounds from a class of gases canprovide general insight into the mechanisms respon-sible for tissue and cellular injury and the subsequentrepair processes. In recent years extensive data on themechanisms of phosgene, chlorine, H2S, and oxides ofnitrogen gas exposure have been published.3234Thesestudies evaluated the following range of effects overtime and at various exposures:

histopathology of exposed lung tissue; biochemical pathway assessment of lung

tissue markers of exposure such as a simpledetermination of wet/dry weight ratio forpulmonary edema estimates;

inflammation pathways; metabolic markers of exposure such as arachi-

donate mediators; physiological assessment of blood gas and

hemodynamic status; cell differential counts;

pulmonary function as measured by plethys-mography;

tissue and bronchoalveolar lavage fluid redoxand antioxidant status;

behavioral effects; genomic expression markers; immunosuppression effects; and

mortality as determined by survival rate studies.

Mechanistic Effects of Inhaled Pulmonary Agents

Exposure to inhaled agents can compromise theentire pulmonary tree through a range of altered physi-ological, biochemical, and pathophysiological processes.The general mechanisms of toxic gas exposure are shownin Figure 10-1. Researchers have used animal models toexamine these dysfunctional pathways in many ways.In an obligate nose-breathing experimental animal likethe rodent, the basic mammalian life processes are ex-trapolated to humans, allowing for reasonable estimatesof potential human exposure responses. This chapterwill cover studies of prominent pathways through which

TABLE 10-4

MECHANISMS OF LUNG INJURY OF GASEOUS RESPIRATORY IRRITANTS

Irritant Gas Mechanism of Injury

Ammonia (NH2) Alkali burns

Source: Agriculture, rain, plastic, explosivesHydrogen chloride (HCl) Acid burnsSource: Dyes, fertilizers, textiles, rubber, thermal degradation of polyvinyl chloride

Sulfur dioxide (SO2) Acid burnsSource: Smelting, combustion of coal/oil, paper manufacturing, food preparation

Chlorine (Cl2) Acid burns, free radical formationSource: Paper, textile manufacturing, sewage treatment

Oxides of nitrogen (NO, NO2, N2O4) Acid burns, free radical formationSource: Agriculture, mining, welding, manufacturing of dyes/lacquers

Phosgene (COCl2) Acid burnsSource: Firefighters, welders, paint strippers, chemical intermediates (isocyanate,

pesticides, dyes, pharmaceuticals)

Colors indicate water solubility. Red: high; yellow: intermediate; green: low.Data source: Schwartz DA. Acute inhalational injury. Occup Med. 1987;2:298.


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inhaled compounds affect basic life processes.It should be kept in mind that the effects of an inhala-

tional event are related to the chemical reactivity of thetoxicant, its concentration, and the duration of exposure.In accidental exposure scenarios, there is generally poorquantifiable information on concentration and exposureduration; in some cases the identity of the agent may beuncertain. Also, the possibility of multiple simultaneouschemical exposures, which can occur in a chemical plantexplosion, must be considered. In Bhopal, India, an ac-cidental release of methylisocyanate used in the produc-tion of the pesticide carbaryl was responsible for over

60,000 casualties and nearly 5,000 deaths in December1984.35Inhalation of the toxic gas resulted in a range ofpulmonary symptoms that included irritation and cough-ing. Pulmonary edema and atelectasis were the eventualcauses of death. Long-term survivors were diagnosedwith lung inflammation, fibrosis, and compromised lungfunction. Survivors continue to have health issues relatedto catastrophe event after nearly 25 years.36

Physiological Responses

Many studies have shown that the adverse effects

Inhalation of chlorine gas

Cl2+ H2O 2HCl + [Or] Cl2+ H2OHOCl + HCl

Hydrochloric and hypochlorious acids as well as nascent oxygen

Toxic to the mucosa from the upper respiratory tract to the alveoli

Irritation of the airway mucosa leads to local oedema,perhaps direct stimulation of the smooth muscleof the bronchioles with resulting contraction

Direct injury to the epithelialand endothelial membranes

Release of mediators

Hypoxaemia

Airwayobstruction

Grossshuntingof blood

Increasedpermeability ofthe pulmonarycapillary walls

Flooding

of alveoli

Increasedtransport of fluidand protein intothe alveolus

Pulmonary

oedema

Sieving ofplasma to theinterstitium

Haemoconcentration

Increased

expiratory

resistance

Decreased

lung

compliance

Endothelins

Pulmonary

hypertension

Proinflammatorycytokines,

(TNF, IL-1, IL-6)

Systemicinflammatoryresponse

Increasedright heartwork

Right heart failure

Vaso-constriction

Increased interstitial hydration

Imbalancein V/Qmatching

Air trappinghyperinflation

Hypoxicpulmonaryvasoconstriction

Fig. 101.General mechanisms of toxic gas exposure.IL: interleukinTNF: tumor necrosis factorV/Q: ventilation profusion ratioReproduced with permission from: Wang J. Pathophysiology and Treatment of Chlorine Gas-Induced Lung Injury: An ExperimentalStudy in Pigs[dissertation]. Linkping, Sweden: Linkping University; 2004: 36.


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of toxic gas inhalation can easily be assessed by mea-suring basic pulmonary function. Several irritantssuch as phosgene, chlorine, and PFIB initiate reactionsthat result in problems with physiological breathingprocesses. Cranial nerve input in the nasopharyngealregion is mainly responsible for initiating changes in

respiratory function, as evidenced by altered breathingmechanics. Experiments in mice exposed to phosgeneshow that minute ventilation is increased followingexposure,37caused by an increase in respiratory ratein response to local irritation from the gas. Inspiratoryand expiratory flow rates are also compromised bylocal sensory irritation because of formation of hydro-chloric acid in the mucous membranes in the upperairway of the central airway compartment. Severalstudies found decreased dynamic compliance andincreases in both airway resistance and tracheal pres-sure to be predictable patterns of response followingirritant gas exposure.3841Phosgene exerts much of its

toxic effect in the peripheral compartment of the lung,and histopathologic specimens show a significant al-teration of the acinar type I and II epithelial cell layersof the airblood barrier. Exposure causes significantpulmonary edema and respiratory acidosis throughincreased PCO2 saturation, decreased PaO2saturation,and decreased arterial pH.4244Similar responses havebeen observed in animal models using chlorine, PFIB,and ammonia. Studies involving PFIB have demon-strated that rats made to exercise following exposureexhibited an enhancement of transcellular transport ofblood proteins to the alveolar surface.45,46These datasuggest that although the lung may be injured and

edematous, fleeing from the site of exposure may notin itself contribute to the edematous effect.

Decreased body weight is a useful indicator ofexposure and systemic toxicity. Pulmonary edemaformation can be estimated by the lung wet weightto dry weight ratio, which increases over time as theinjury progresses . Although the wet/dry weight ratiois an important measure of edema, it may not showsubtle effects that preexist fulminant alveolar edema.A valuable indicator of what is actually occurring inthe deep lung environment is bronchoalveolar lavagefluid (BALF). BALF tests provide a wealth of informa-tion. Lavage fluid protein levels give a good indica-tion of subtle changes in the integrity of the airbloodbarrier. Increased protein levels can be measured insome cases hours prior to gross alveolar edema for-mation. This may indicate that interstitial edema isoccurring. Much use has been made of the electrolytehomeostatic responses to toxic gas exposure. Sciuto etal have shown that phosgene exposure can producea possibly deleterious effect on lung homeostaticprocess by altering ionized Ca++, Na+, and K+levels

indirectly, thus indicating possible compromisedNa+, K+, or Ca++-adenosine triphosphatase pumpfunction.47Inhalation of irritants such as phosgene isknown to eventually result in immunosuppression,which may increase mortality via infection in thecompromised lung.48,49

Genomic studies have provided insight into the ef-fects of toxic gas exposure on gene expression levels. Inphosgene-exposed mice, it was demonstrated that theearliest changes (occurring within 1 to 4 hours) in lungtissue involved increased expression levels of antioxi-dant enzymes of the glutathione redox cycle.50Thesedata strongly suggest that free-radicalmediated injuryprocesses are active well before gross pathophysiologicchanges become manifest. It has been shown that invitro exposure of epithelial cells to nitrogen dioxidecan cause a range of problems in the entire length ofthe respiratory tract. Many of these detrimental effectsare the result of activated reactive nitrogen species

free radicals such as the peroxy radical OONO - or thenitrogen dioxide radical NO2itself.

51Riot control agents, also called incapacitants, can

cause ocular and cutaneous as well as acute pulmo-nary responses during exposure. Although generallynonlethal, incapacitants may have magnified contactproblems if exposure occurs within a confined space.Symptoms resulting from a single exposure can lastfor years.8

Pathophysiological Effects of Exposure

Examination of histopathological effects on chemi-

cally exposed lung tissue provides critical informationon the effects of a C T response. The mechanisms oflung injury and repair are summarized in Figure 10-2.52Evaluation of phosgene-induced pulmonary injuryto the peripheral compartment revealed characteristictemporal acute toxicity lesions. Early lesions of atoxic gas exposure can be characterized by leakage ofedema, fibrin, and erythrocytes from the pulmonarymicrovasculature into the alveolar spaces and intersti-tial tissues. In general, alveolar and interstitial edemacan characterize the earliest and most significant pul-monary changes. Epithelial damage in the terminalbronchioles and alveoli as well as mild inflammatorycell infiltrates can accompany increasing pulmonaryedema. The repair and regeneration of epithelialdamage centered on the terminal bronchioles maycomplement the resolution of edema.53In this studyearly indicators of phosgene-induced pulmonary in-jury were identified by comparing acute pulmonaryhistopathologic changes to bronchoalveolar lavage andlung wet-weight gravimetric measurements. Of theBALF parameters studied, lactate dehydrogenase and


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protein levels were the most sensitive early indicatorsof pulmonary edema. In experiments in rats exposed toPFIB, as the mass exposure concentration increased, theearlier tissue injury occurred. Epithelial and endothe-lial cell blebbing occurred, which progressed overtime to endothelial swelling and fenestrations of theepithelial barrier, denudement of the alveolar surface,and interstitial edema.45PFIB and phosgene exposure

also caused alteration of the production of specificsurfactant phospholipids, which can have importantimplications for reduced lung compliance and the sub-sequent treatment of this injury.54In rats exposed to thepyrolysis products of Teflon at 450C, ultrastructuralchanges in the lung consisted of pulmonary edema,hemorrhage, and necrotic tracheobronchial epithelium,accompanied by pneumocyte bleb formation, denuda-

Mechanism of lung injury and repair.

Initiationof injury

Repair Progression of injury

Chronic lungdisease

Altered lungstructure

Persistent/chronicinflammation

Environmentand toxins

Ventilation

Oxygen

Edema, inflammation

Disruption epithelial and/orendothelial barrier

Lunginjury

Susceptibility

Altered lungstructure

Cellulardifferentiation

Cellularproliferation

Fibroblastproliferation

Matrixdegradation

Apoptosis

Tissue

remodeling

Normallung

Epi/endotproliferation

Matrixaccumulation

Nutritionhormones

GeneticsPrematurity

Disrupted alveolargenesisImmature defenseImmature structure

Fig. 10-2.Pathophysiology of toxic gas inhalation.Epi/Endot: epithelial and/or endothelialAdapted with permission from: Copland I, Tanswell K, Post M. Principals of lung development, growth, and repair. In:Notter RH, Finkelstein JN, Holm BA, eds. Lung Injury: Mechanisms, Pathophysiology, and Therapy.Boca Raton, Fla: Taylor &Francis Group; 2005: 1966.


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tion, and fragmentation.55

Lung tissue and cellular responses to inhalationexposure can also be manifested in the form of cellmembrane destruction. This can be measured to somedegree by determining the extent of lipid peroxida-tion, an indicator of oxidative stress caused by the

abundance of free radicals. Lipid peroxidation is aprocess whereby the rigid lipid bilayer of the mem-brane becomes more fluid, resulting in the activationof intracellular metabolic pathways regulated byaltered enzyme function. One of the more importantpathways is the arachidonic acid (AA) pathway, whichleads to the production of mediators of inflamma-tion and edema such as the leukotrienes. The othermetabolic arm of the AA pathway leads to vasoactivecompounds such as prostaglandins, which are in partresponsible for vascular tone. Both leukotrienes andprostaglandins have been implicated in toxic-gasin-duced acute lung injury.5659Adenlyate cyclase is yet

another injury-activated enzyme system responsiblefor the cleavage of adenosine triphosphate to formadenosine 3,5-cyclic monophosphate (cAMP), whichis required for endothelial and epithelial tight-junctionformation. The initial step in this process is damage tomembrane surface-adrenergic receptors, which aid inthe regulation of cAMP formation. With the deactiva-tion of cAMP formation, tight junctions become morepermeable and allow the passage of fluid or waterinto intracellular and extracellular spaces. DecreasedcAMP production and the resultant pulmonary edemahave been implicated in toxic-gasinduced acute lunginjury.39

Acute exposure to nitrogen dioxide causes a rangeof pathological effects characterized by increasedepithelial permeability and the proliferation of Claraand type II epithelial cells.60Chronic exposure inducesbronchiolit is, alveolar bronchiolarization, ciliatedcysts, and emphysema. Exposure effects may be morepronounced in those with preexisting compromisedlung function such as asthma. In experiments in anasthmatic population exposed to 1 ppm nitrogen diox-ide, increased levels of mediators of inflammation andvasoactive compounds were measured in the BALF.61Metabolites of the cyclooxygenase pathway of the AAcascade, such as 6-keto-prostaglandin F

1-(responsible

for bronchodilation) were decreased; however, bothprostaglandin D2 and thromboxane B2 (responsible forbronchoconstriction) were increased. Elevated levels ofleukotrienes such as C4, D4, and E4, which are productsof the lipoxygenase pathway of the AA cascade relatedto bronchial hyperresponsiveness, were also involvedin the inflammatory response.

Exposure to smoke has been shown to cause suf-ficiently severe acute lung injury to ultimately result

in death. In human smoke-related fatalities, the lungswere shown to exhibit soot staining in the tracheobron-chial mucosa, and they were heavy (edematous) andhyperemic. Light microscopy indicated pulmonarycongestion, and electron microscopy revealed car-bon particles as well as interstitial and intraalveolar

edema.62

Inflammatory Pathways

Inflammation is a critical result of toxic-gasinhalation injury. Many studies have demonstrateda decrease in the number of macrophages, which areimportant in clearance mechanisms, and an increasein neutrophils, which aid in detoxification of toxicmediators and metabolites. These shifts in cell popu-lations generally occur over time and are usually afunction of the gas involved, the depth of inhalation,the concentration, and the duration of exposure. In

the case of some inhaled gases, the chemical reactionin the tissue can produce deleterious amounts of freeradicals. These radicals in turn can damage migrat-ing cells such as neutrophils, causing them to dumptheir toxic proteases, proinflammatory cytokines andchemokines, and additional toxic free radicals suchas the hydroxyl species OH and superoxide anionO2

-into the intracellular environment, causing greaterdamage. This additive effect may account for some ofthe latent injury responses seen following inhalationof gases such as phosgene and possibly other irritants,some of which have well-described latency (124hours) effects.

Markers of inflammation and the timing of theirrelease after exposure can provide useful informationabout the potential therapeutic window for eventualand successful treatment. Many studies have focusedon cytokines, which are produced by a variety of whitecells, fibroblasts, and epithelial and endothelial cells,to assess the inflammatory response. Cytokines canhave a wide range of proinflammatory and antiin-flammatory effects in tissue injury responses. Thesecompounds serve as important mediators of tissue andinjury repair processes and as such represent suitablemarkers of inflammation injury and signal transduc-tion pathways (Table 10-5).63

For example, in phosgene-exposed mice, BALF cy-tokine and chemokine analysis over 72 hours clearlydemonstrated that the cytokine interleukin-6 and thechemokine macrophage inflammatory protein-2, theanalog in mice for human interleukin-8, were both sig-nificantly increased within 4 to 8 hours of exposure.64Both interleukin-1and tumor necrosis factor-weresignificantly increased 24 to 72 hours after exposure.The data support the postulation that tumor necrosis


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factor-may aid in fluid clearance in this injury model.The nature of lung injury in response to an inhalationalevent can be extremely complex. Figure 10-3 providesa visual representation of the alveolar region of the pe-ripheral lung compartment following exposure to toxicgas. The difficulty in treating an injury with a large ar-

ray of metabolic chaos is that many of these pathwaysare activated and on-going simultaneously.

Biochemical Responses

Understanding the biochemical responses to inha-

TABLE 10-5

MAIN INFLAMMATORY AGENTS INVOLVED IN ACUTE LUNG INJURY, THEIR SOURCE AND ACTION

Agent Source Actions

Cytokines (Proteins)

IL-1 In response to infection/injury Regulates systemic inflammatory response, causes from activated macrophage. increase in blood neutrophils; causes fever. Induces Induced by TNF from other cytokines. Stimulates NO production, produces mononuclear and endothelial PLA2, PAF, releases histamine. cells.

IL-6 Induced by IL-1 from epithelial Creates pyrogen, activates stromal bone marrow tocells. produce CSF.

IL-8 Secreted by macrophages, Chemotactic for neutrophils and activates macrophages. endothelial cells, T cells and

fibroblasts in response to LPS,IL-1 or TNF stimulation.

TNF- Large amounts from endotoxin- Induces arachidonic metabolites and synthesis of cytok- stimulated macrophages. ines. Chemotactic for neutrophils and macrophages.

Synergistic with IL-1. Causes fever.

Lipids (Arachidonic Acid Metabolites)

Leukotrienes (B4, C4, D4, E4) Enzymatic pathway from Causes vasoconstriction, bronchoconstriction, enhance- membrane phospholipid. ment of capillary leakage.

Prostaglandin E2 Enzymatic pathway from A vasodilator, has proinflammaotry and antiinflamma- membrane phospholipid. tory potential.

Thromboxane A2 Enzymatic pathway from Potent vasodilator, causes platelet sequestration. membrane phospholipid.

PAF Epithelial cells via the Causes platelet aggregation. Recruits eosinophils, causes arachidonic acid pathway, also vasodilation, increases vascular permeability, causes neutrophils, basophils and degranulation of neutrophils. Spasmogenic on bronchial

platelets. smooth muscle.Reduced Oxygen Species (Free Radicals)

OH, H2O2, superoxide anion LPS stimulated macrophage/ Very reactive, responsible for lung tissue injury. Interacts monocyte cell. with arachidonic acid pathway to increase levels of

eicosanoids.

CSF: colony-stimulating factorH2O2: hydrogen peroxideIL: interleukinLPS: lipopolysaccharideNO: nitric oxideOH: hydroxyl radicalPAF: platelet-aggregating factor

PLA2: phospholypase A2TNF: tumor necrosis factor


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lation exposure can provide a wealth of informationabout pathways that may lead to successful treatmentstrategies. One of the most important pathways is theglutathione (GSH) cycle. GSH is an important andubiquitous intracellular antioxidant. The GSH redoxcycle is activated in response to free-radicalmediatedtissue and cellular injury. GSH also aids in maintain-ing the proper balance between naturally occurringfree radical metabolism processes and antioxidantdetoxification. Basically, it helps to create equilibriumin the antioxidant/oxidant ratio. Exposure to inhaled

chemical toxins can elicit a response that favors theliberation of extremely toxic free radicals. Exposure tophosgene has been demonstrated to cause a significantdecrease in lung tissue GSH across a range of species.65Concurrent with decreased GSH protection in the lungtissue, BALF shows a marked increase in GSH levels.65Increased BALF GSH is believed to be a response ofdamaged lung tissue for the purpose of transportingGSH to critical areas in the alveolar regions. This oc-curs to protect the surfactant and epithelial integrityof the gas-exchanging units in response to free radi-

Fig. 103. General schema for the study of acute and chronic lung injury.HOCI: hypochlorous acid

INF: interferonH2O2: hydrogenperoxideH2O3: dihydrogen trioxideIL: interleukinLT: leukotrienePAF: platelet-aggregating factorRBC: red blood cellTNF: tumor necrosis factorCourtesy of: US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Md.

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SPECIFIC INHALED TOXIC-GASINDUCED EFFECTS AND THEIR TREATMENTS

following ammonia inhalation and ingestion exposure

in humans.

Chlorine

Affecting both the central and peripheral airwaycompartments, chlorine inhalation leads to abruptbronchoconstriction, increased airway resistance,and decreased compliance. In humans who have diedfrom chlorine poisoning, severe pulmonary edema,pneumonia, and ulcerative tracheobronchitis havebeen seen.71Recently, epithelial cell necrosis, smallairway dilation, and microvascular permeability havebeen found.44Efficacious therapeutic treatments have

been tested in experimental models using large swine.Aerosolized terbutaline or the corticosteroid budes-onide reduced acute lung injury when administered30 minutes after a 400 ppm 20-minute exposure.72Lung function was improved even more when bothcompounds were administered in combination. Theeffect of terbutaline or budesonide corroborates thebiochemical response mentioned earlier: terbutalinehelps increase cAMP levels through the stimulationof -adrenergic signaling pathways and adenylate cy-clase, thereby increasing tight junction strength and theintegrity of the airblood barrier, which reduces fluidtransport through compromised basement membranes.

Budesonide can work by reducing proinflammatorycytokines and by stabilizing membranes by limitingthe effects of membrane lipid peroxidative processesand the subsequent release of reactive mediators.

Hydrogen Cyanide

As a metabolic poison, HCN presents a challenge foreffective postexposure treatment. It is also considered tobe a cardiotoxin. Acute exposure to HCN rarely causesspecific changes in histopathological or pathologi-cal changes.73Many people believe that the slightestcontact with HCN means instant death, but studies ofexperimental animals have disproven this belief. Sub-lethal concentrations can produce incapacitation, withdizziness and nausea reported in some exposed peo-ple.74However, treatment should always be provided asrapidly as possible. Supportive and antidote treatmentsagainst HCN include the use of sodium thiosulfate,which hastens the detoxification of CN; sodium nitrite,a methemoglobin former; and rhodanese, an enzyme

Defining treatment strategies and clinical medical

management for toxic gas exposure is problematic.In most cases the chemical inhalant is unknown. Inother cases there may be multiple chemical exposure,patients may be too confused to accurately recall theduration of inhalation, and the patients health andage may affect the outcome. Many chemicals can causehyposmia or even anosmia following inhalation, mak-ing the assessment of duration and type of chemicalagent inhaled all the more difficult. Some individualsare known to be much more chemically sensitized thanothers, especially if, for example, asthma, smoking, oran acquired sensitivity is present. Many of the chemi-cals discussed thus far are listed as causing RADS or

occupationally-induced asthma.67,68

Currently, mostdoctrines describe management, including ventilationsupport, pulmonary function tests, chest radiographs,supportive fluid replacement, and antiinflammatorytreatment. The mechanisms of toxicity in acute lunginjury processes are largely consistent from chemicalto chemical, and injuries detected early will respondmore readily to supportive or specialized treatment.Several compounds for which experimental or evenclinical supportive therapy has been successfully usedare detailed below.

Ammonia

Inhalation exposure to ammonia, generally consid-ered a central airway compartment irritant, can causedamage to the airway epithelium and the alveolar-capillary membrane. Acute signs and symptoms ofinhalation, typical of irritant gases, include coughing,bronchospasm, difficulty in breathing, pulmonaryedema, hypoxemia, and respiratory failure.69At death,hemorrhagic pulmonary edema can be a hallmark ofexposure. Interstitial fibrosis has been observed in pa-tients following accidental exposure to ammonia.70

In rabbits exposed to nebulized ammonia at anestimated accidental exposure level (35,00039,000ppm over 4 minutes), acute and severe lung injuryoccurred. Decreased PaO2 and increases in airwaypressure and PaCO2were evident from 1 to 6 hoursafter exposure.69In this experimental model, the useof inhaled corticosteroids such as budesonide admin-istered 30 minutes after exposure was not effective inimproving gas exchange or reducing elevated airwaypressure. Corticosteroids are controversial for therapy

cal activity. This same response mechanism has beendemonstrated in smokers.66It is well established that

the toxic effect of smoking is largely a free radical-mediated process.


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currently used in experimental trials. In some instances100% oxygen supportive therapy in conjunction withsodium thiosulfate and sodium nitrite may be synergis-tically beneficial. Treatment with sodium bicarbonatecan be used to reverse lactate acidosis. Ballantyne andSalem75provide an in-depth review of HCN exposure

effects, mechanisms of action, antidotes, and sources ofexposure, and Chapter 11, Cyanide Poisoning, providesadditional information.

Perfluoroisobutylene

A significant exposure hazard from fires and chemi-cal industrial accidents, PFIB causes severe pulmonaryedema in the peripheral airway compartment. In micePFIB exposure caused a significant reduction in protec-tive sulfhydryl concentrations and myeloperoxidaseactivity, as well as enhancement of the influx of poly-morphonuclear leukocytes into the lung.76Exposure

can disrupt the airblood barrier, cause hemorrhagicpulmonary edema, and increase BALF protein leak.Treatment with cholinolytic 3-quinuclidinyl benzilate30 minutes before or 10 hours after exposure resultedin reduced indices of acute lung injury as measured bylung wet weight to body weight ratio, reduced bloodviscosity and reduced mortality.

Phosgene

Because of phosgenes extensive industrial use andextreme toxicity, a great deal of experimental modeldevelopment, mechanistic toxicology, and therapeutic

testing has taken place over the past 25 years. Phosgeneis very chemically reactive, especially with importantcellular components of biomolecules, such as sulfhy-dryl, amine, and hydroxyl groups.25 This chemicalreactivity occurs primarily in the distal lung peripheralairway compartment, and exposure has been foundto directly affect type I pneumocytes,77,78 increase la-vage polymorphonuclear phagocytes,79decrease bothcytochrome-c-oxidase and adenosine triphosphataseactivity,80 and significantly reduce lung adenosinetriphosphate concentrations.81Some limited and ques-tionable evidence suggests that phosgene inhalationmay be involved in toxic encephalopathy in humans82;however, this study involved long-term exposure tomany chemical solvents in an industrial environment,which may have confounded the role of phosgene asa single causative agent of neurotoxicity.

Recent experimental work with phosgene in ani-mals has shown that bronchoconstriction, enhancedpulmonary edema formation, elevated leukotriene pro-duction, increased lipid peroxidation byproducts, anddecreases in both dynamic compliance and lung tissuecAMP are several of the major responses of the lung

to phosgene inhalation.59,83,84Phosgene has been foundto be toxic through normal metabolic detoxificationmechanisms unrelated to direct inhalation exposure.In hepatocytes, phosgene binds with phospholipidssuch as phosphatidylcholine and ethanolamine underhypoxic or normoxic conditions.8587These bonds could

be mechanistically important during the injury processbecause alveolar surfactant is largely phospholipid incontent and alveolar edema causes a locally hypoxicenvironment. Experimental evidence has shown thatphosgene exposure has a significant effect on lungsurfactant levels.88

Based on these detrimental effects, postexposuretherapeutic efforts have succeeded in reducing lunginjury in exposed animals. Studies involving rodentsand rabbits have shown that the effects of increasedpulmonary edema, airway pressure, and pulmonaryartery pressure, as well as the inhibition of the releaseof reactive metabolites (such as the permeability-

enhancing leukotrienes, vasoactive prostaglandins,and free radicals) can all be reduced following treat-ment after exposure. Compounds approved by the USFood and Drug Administration such as isoproterenol,ibuprofen, aminophylline, and N-acetylcysteine canprotect the lung from further damage.33,83,89,90In somecases, treatment can enhance survival rates.89No datasupports the use of steroids to treat human exposure.However, medical management guidelines from theCenters for Disease Control and Prevention recom-mend starting intravenous corticosteroids in cases ofsevere exposure even if the patient is asymptomatic.Steroids administrated intravenously seem to be more

beneficial when administered before exposure,59 al-though this finding has yet to be tested clinically ona large scale. Not all effective treatment against phos-gene-induced lung injury involves the use of drugs.In large swine exposed to phosgene, effective therapyinvolved the modification of ventilation parametersafter exposure. Lower tidal volume, decreased ven-tilation rates, and decreased positive end-expiratorypressure, in addition to intravenous saline and glucosesupport, reduced cardiovascular effects, lung damage(reduced edema formation), and the histopathologicalresponse of the lung tissue.40

In addition to producing acute lung injury to thecentral and peripheral compartments, phosgene, chlo-rine, riot control agents, smokes, and ammonia canhave long-term effects. Fibrosis, bronchiolitis obliterans,chronic obstructive pulmonary disease, RADS, pulmo-nary function abnormalities, alveolitis, and bronchiecta-sis are some of the sequela of exposure. The exposurecould have been a one-time event, chronic exposureover years, or a multiple chemical exposure. In addition,gases such as PFIB, phosgene, and chlorine may give riseto ARDS in the days to weeks after exposure, especially


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if the exposure requires intensive care intervention. Bothlong-term effects and the potential for developing an

ARDS-like response must be taken into account in theadministration of therapeutic countermeasures.

CLINICAL PRESENTATION AND DIAGNOSIS

This section considers only TICs that pose a poten-

tial threat to military personnel. Although this list isnot complete, casualties from other lung-damagingagents are managed in the same way as these ex-amples. In low doses, highly reactive TICs have agreater effect on the central airway; some TICs acton both the central and peripheral airways; and stillothers that are not as reactive in the central airwaycan defuse deeper into the respiratory tract and de-stroy the tissues of the alveoli-capillary membranein the peripheral airways, leading to noncardiacpulmonary edema. Any large inhaled dose of a TICcauses both central and peripheral airway damage(Figure 10-4).

Centrally Acting Toxic Industrial Chemicals

Centrally acting chemicals affect the respiratory sys-tem from the nasopharynx to the bronchioles. Centrallyacting TICs normally form strong acids or bases (alkali)with the water in the central airway tissues, whichleads to the destruction of these tissues. The damagedtissue swells, causing sloughing of the epitheliumlining into the airway and reactive smooth musclecontraction, causing restriction of breathing.

Levels of exposure to toxic gases are defined by theshort-term exposure limit (STEL), time-weighted aver-

age (TWA), and concentrations at which toxic gassesare immediately dangerous to life or health (IDLH).STEL is the concentration of exposure that after 15

minutes may cause immediate or chronic compromise

to health. TWA is the concentration for an 8-hour work-day of a 40-hour workweek that most workers can beexposed to without adverse effects.91

Ammonia

This highly caustic and reactive gas has not beenused in warfare but may be encountered in industrialaccidents. Ammonia has a TWA of 25 ppm, an STEL of35 ppm and an IDLH of 500 ppm. Most injuries fromammonia are caused by inhalation. In low doses it isprimarily a centrally acting TIC (Table 10-6). Ammoniagas usually causes damage when it contacts the moist,

watery tissues of the central airway, which results inthe formation of a strongly alkaline solution. This re-action is exothermiccapable of causing significantthermal burns and destruction to tissues which couldlead to the victims presenting with a laryngospasmand airway collapse.

In 1941 Caplin classified accidental ammonia inha-lation as mild, moderate, and severe. Casualties withmild exposure present with pain and conjunctival andupper respiratory inflammation but no signs of respi-

Fig. 10-4. Airway compartments: central and peripheral.Courtesy of: US Army Medical Research Institute of Chemi-cal Defense, Aberdeen Proving Ground, Md.

TABLE 10-6GASEOUS AMMONIA EFFECTS AT VARIOUSCONCENTRATIONS

Amount (ppm) Effects

2550 Detectable odor; adverse effects unlikely

50100 Mild eye, nose, and throat irritation

140 Moderate eye irritation

400 Moderate throat irritation

700 Immediate eye injury

1,000 Directly caustic to airway 1,700 Laryngospasm

2,500 Fatal (after half-hour exposure)

2,5006,500 Sloughing and necrosis of airway mucosa,chest pain, pulmonary edema and

bronchospasm

5,000 Rapidly fatal

Data source: Issley S. Toxicity, ammonia. eMedicine from WebMD.Available at: http://www.emedicine.com/EMERG/topic846.htm.Accessed August 6, 2007.

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ratory distress. Casualties with moderate exposurepresent with the same signs but more exaggeratedsymptoms. Casualties with a severe exposure presentwith frank respiratory distress, productive cough, pul-monary edema, and dysphagia. After a brief exposuredamage is usually limited to the upper airway mucosa.

However, a brief exposure at a very high concentra-tion can be overwhelming to the victim and the entirerespiratory system.

Ammonia inhalation injuries also lead to pain of theoroharyngeal and retrosternal areas. Symptoms of dys-pnea, hemoptysis, hoarseness, and loss of conscious-ness could be noted. Tissues of the airway becomeswollen, and, longer term, scar tissue may form alongthe airway. Frequently, damaged tissue in the airwaywill die, slough off, and lead to obstruction. Individualswith reactive airway disease are particularly sensitiveto ammonia inhalation.

Ammonia can also be absorbed by dust particles

that travel to the small airways. Respiratory symptomscan develop after the ingestion of ammonia productsif aspiration pneumonia or pneumonitis complicatesingestion. Most casualties who survive the first 24hours will recover. Patients show improvement within48 to 72 hours, and patients with mild exposure couldrecover fully in this time. For patients with more se-vere respiratory symptoms, recovery can be expectedwithin several weeks to months.91

Sulfur Mustards

Produced solely for warfare, sulfur mustards are

vesicants and alkylating agents that act on the centralairway if inhaled. Sulfur mustards cause a dose-dependent inflammatory reaction in the upper andlower airways that develops several hours after ex-posure and progresses. Burning of the nasal pathwayresults in pain, epistaxis, larynigitis, loss of taste andsmell, coughing, wheezing, and possible dyspnea.Necrosis of the respiratory epithelium causes tissueto slough off in large sheets, known as pseudomem-branes, causing local airway obstruction.92Prolongedor repeated acute exposure to sulfur mustards couldlead to chronic respiratory disease. Repeated expo-sures result in cumulative effects because mustardsare not detoxified naturally in the body.93 Chapter8, Vesicants, provides more information on themedical management of sulfur mustards agents.

Peripherally Acting Toxic Industrial Chemicals

Air moves in the peripheral compartment of theairways only by diffusion. When peripherally actinglung-damaging TICs are inhaled, they travel to the

smallest segments of the respiratory system, the termi-nal and respiratory bronchioles, the alveolar ducts, thealveolar sacs, and the alveoli. These agents also causeinflammation and necrosis to the thin membrane thatseparates the capillaries from the alveoli by reactingwith the proteins and enzymes in the membranes. The

function of these membranes is to separate the bloodin the capillaries from the air in the alveoli, but whenthe membranes become damaged, this process cannotoccur. When the normal elimination of plasma serumfrom the respiratory system is interrupted becauseof this damage, the plasma leaks into the alveolarsepta, causing the air sacs to fill with fluid, blockingoxygen exchange. The casualty then suffers oxygendeprivation leading to hypoxia and apnea. The pul-monary tissue fills with massive amounts of fluid (up

Fig. 105.The chest radiograph of a male chemical worker2 hours postexposure to phosgene with mild resting dysp-nea for the 2nd hour. His physical examination was normalwith a PO2of 88 mm Hg breathing room air. The radiographis normal.


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to 1 L/h), which leads to noncardiogenic pulmonaryedema (Figures 10-5 10-8). For this reason, peripher-ally acting TIC poisoning is sometimes referred to asdry land drowning. The damage following acuteexposure to peripherally acting lung-damaging TICsis proportionate to the product of the concentrationand duration of exposure (Habers law); however,with chronic exposure Habers law does not apply.1

Perfluoroisobutylene

Produced as a common by-product in the fluoropo-lymer industry, PFIB is used for long-term protectionagainst high temperatures and corrosive chemicalsin automobiles, jet aircraft, and other products. Tef-lons lubricity, high dielectric constant, and chemi-cal inertness make it a desirable component for theinterior of many military vehicles, such as tanks andaircraft. PFIB smoke is given off when Teflon burns attemperatures above 400C, such as in a vehicle fire.Closed-space fires in military vehicles have promptedresearch on the toxicity of exposure to the by-products

Fig. 10-6. The same patient seen in Figure 10-5 now 7 hourspostexposure to phosgene with moderate resting dyspnea,a few crackles on auscultation, and a PO2 of 64 mm Hg

breathing room air. The radiograph shows mild interstitialedema.

Fig. 107.A lung section from the patient whose chest ra-diographs are shown in Figures 10-5 and 10-6. This sectionshows normal lung tissues without evidence of interstitialfibrosis or inflammation. Hematoxylin and eosin stain;original magnification 400.

Fig. 108. The chest radiograph of a female chemical worker2 hours postexposure to phosgene. Dyspnea progressedrapidly over the 2nd hour; PO2was 40 mm Hg breathingroom air. This radiograph shows bilateral perihilar, fluffy,and diffuse interstitial infiltrates. The patient died 6 hourspostexposure.

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created from incinerated organofluorines released byPFIB. The pyrolysis of PFIB produces a particulatesmoke, which produces symptoms termed polymerfume fever when inhaled. Polymer fume fever is aninflunza-like, self-limited symptom complex with alatent period of some hours followed by fever, chills,

and myalgias (which could lead to the misdiagnosis ofan acute viral illness). Typically, polymer fume feverepisodes resolve within 24 hours; however, some caseshave been reported to last longer. Only supportivecare including antipyretics and hydration is recom-mended. If wheezing or other obstructive respiratorychanges occur, inhaled bronchodilators are indicated.With bronchospasms or productive cough, inhaledsteroids may be indicated. Patients with polymerfume fever should be observed for at least 24 to 48hours for other lung consolidation changes such aschemical pneumonitis or noncardiogenic pulmonaryedema. Oxygen therapy including intubation with

positive end-expiratory pressure may be necessaryif respiratory distress is severe. Use of antibiotic andsystemic steroids should be considered, dependingon the patients condition. Survivors of vehicle fireswho are short of breath should be questioned carefullyabout smoke exposure and should be observed overa period of time.94

Oxides of Nitrogen

Oxides of nitrogen, or NOx, are components of pho-tochemical smog, which can be produced by the deto-nation of nitrate-based explosives or by electric or arc

welding. Significant quantities of nitrogen dioxide arefound in the exhaust of diesel engines. These danger-ous nitrous fumes can build to high concentrations onthe battlefield where artillery is fired and in enclosedspaces with inadequate ventilation, such as gun pits,ship magazines, armored vehicles, and turrets, as wellas in mining and tunneling operations. Inhalation ofNOx leads to the formation of nitrite, the productionof methemoglobin, and cellular hypoxia. Inhalation ofhigh concentrations could cause rapid death withoutthe formation of pulmonary edema; however, a severeexposure may result in death with the production ofyellow frothy fluid in the nasal passages, mouth, andtrachea, as well as with marked pulmonary edema.Symptoms following inhalation of NOx are mostly dueto nitrogen dioxide. The diagnosis is made from thehistory, from symptoms described by the patient, andpossibly by the yellowish discoloration of the exposedmembranes. NOx exposure should be suspected insoldiers who experience shortness of breath after heavyartillery firing in an enclosed space (tanks, ships).95

Fig. 10-9.Chest radiograph taken 8 hours postexposure ofa 60-year-old male sailor who inhaled zinc oxide in an en-closed space. He showed symptoms of moderately severeresting dyspnea during the 7th and 8th hours, diffuse coarsecrackles on auscultation, and a PO2of 41 mm Hg breathingroom air. The radiograph confirms diffuse dense peripheralpulmonary infiltrates.

Hexachloroethane Smoke

Hexachloroethane (HC) smoke, a mixture of equalamounts of HC and zinc oxide with approximately 7%grained aluminum or aluminum powder, is used in themilitary for obscuration. HC smoke is probably the most

acutely toxic of the military smokes and obscurants. Itstoxicity is due mainly to the irritating effects of the zincchloride. The more humid the air, the denser HC smokewill be. HC smoke is dispersed by grenades, candles,pots, artillery shells, and special air bombs.95

Zinc oxide cause upper respiratory tract (centralcompartment) damage from its irritant and corrosiveaction. In severe exposures, chemical pneumonia withpulmonary edema can appear. A chest radiograph of a60-year-old sailor 8 hours after exposure to HC whilein an enclosed space onboard ship shows diffuse denseperipheral pulmonary infiltrates (Figure 10-9). He hadsymptoms of moderately severe resting dyspnea dur-

ing the 7th and 8th hours, with diffuse coarse cracklesnoted on auscultation.96Metal fume fever, which hasbeen documented with an intense inhalation of metaloxides such as zinc oxide, has a delayed onset of 4 to48 hours after exposure, with symptoms includingdryness of the throat, coughing, substernal chest painor tightness, and fever. Respiratory symptoms gener-ally resolve in 1 to 4 days with supportive care. Mostindividuals with HC inhalation injuries progress tocomplete recovery; however, 10% to 20% develop fi-


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brotic pulmonary changes. Appropriate precautions,such as wearing protective masks, must be taken whenHC smoke is used.95

Chemicals That Act on Both the Central andPeripheral Airways

Chlorine

Chlorine is a good example of a combinationagent, one that acts on both airway compartments inlow doses because of its intermediate water solubil-ity. Chlorines effectiveness as a warfare agent wasgreatly reduced once protective masks became widelyavailable in World War I, but it continues to be seenin industrial accidents. The Occupational Safety andHealth Administrations permissible exposure levelof chlorine is 1 ppm. The National Institute for Oc-cupational Safety and Health has determined that

the IDLH concentration is 25 ppm. Chlorine turns tohydrochloric acid when it contacts the moisture ofthe airway; the hydrochloric acid then causes tissueburns to the epithelia of the conjunctivae and upperrespiratory mucus membranes.97Chlorine producessigns and symptoms similar to those associated withexposure to both centrally and peripherally actingagents. A chest radiograph of a chemical worker 2hours after exposure to chlorine shows diffuse pul-monary edema without considerable cardiomegaly(Figure 10-10). This person also experienced severeresting dyspnea and diffuse crackles on auscultation.Although the central lung damage of chlorine injury

may seem to be the primary concern in some patients(ie, they are coughing and wheezing), the healthcareprovider must anticipate treatment for potentialdevelopment of peripheral symptoms and take seri-ously any patient complaints about chest tightnessor breathing difficulty.96

Clinical Effects

Centrally Acting Agents

Almost immediately after exposure to these gassesor vapors, the casualty can develop a laryngospasm,which could cause sudden death. As the airways areirritated and damaged, the individual may experiencea wide variety of symptoms including sneezing; devel-opment of rhinorrhea; tachypea; pain in the nasophar-ynx, indicating early inflammation; dysphagia fromthe pain of swallowing; oropharyngeal inflammation;hoarseness; a feeling of choking; noise with exhalationcaused by laryngeal edema (the hallmark sign of cen-

Fig. 10-10.The chest radiograph of a female chemical worker2 hours postexposure to chlorine inhalant. On medical ex-amination she had severe resting dyspnea during the 2ndhour, diffuse crackles/rhonchi on auscultation, and a PO2of32 mm Hg breathing room air. The radiograph shows diffuse

pulmonary edema without significant cardiomegaly.

trally acting agents); chest pain or retrosternal burning;coughing, which could be violent at times; wheezingduring breathing from the trachea and bronchi inflam-mation; and edema. If the exposure is severe enoughand the TIC has penetrated into the peripheral airway,the casualty may experience peripheral effects. Later,scarring of the central airway can cause permanentairway narrowing, depending on the agent involvedand the dose received.

Peripherally Acting Agents

Peripherally acting agents exert a direct toxic effecton the peripheral compartment of the respiratory tract,leading to damage of the alveolar-capillary membraneand the hallmark clinical effectdyspnea. The time toonset of clinical effects from peripherally acting agentsdepends on dose, duration, and concentration. Shortlyafter low concentration exposure to phosgene or otheragents affecting the peripheral airway, the casualtiesare typically asymptomatic for 30 minutes to 72 hours(although they may notice irritation of the eyes, nose,and throat). However, symptoms may progress tocomplaints of coughing and dyspnea on exertion. Themajor effects do not occur until hours later. More sig-nificant exposures have a latency period of less than 24hours. Chlorine, which can affect both compartmentsbut primarily affects the central compartment of therespiratory tract, can also exhibit delayed effects in theperipheral compartment.

Approximately 2 to 24 hours after exposure, the ca-


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sualty with peripheral damage will notice shortness ofbreath and tightness in the chest, which are symptomsof the development of noncardiogenic pulmonaryedema. These symptoms may initially be mild, butas the damage progresses, dyspnea on exertion willbecome resting dyspnea. Coughing is at first nonpro-

ductive with chest tightness or discomfort describedas retrosternal burning, but if the damage is severe,the casualty will start producing clear to yellow frothysputum. This is caused by necrosis and inflammationof the lower airway and alveolar tissue and subsequentleakage of serum into the alveolar septa.

The eventual severity of dyspnea is related to dose,concentration, and duration of the exposure. A casu-alty with a very mild exposure will develop dyspnea6 to 24 hours after exposure, first noticed after heavyexertion. Later, however, the casualty becomes shortof breath after any activity. With proper care, completerecovery is expected. A casualty with a severe exposure

will notice shortness of breath within 4 to 6 hours afterexposure. Dyspnea, even at rest, results from inabilityof the pulmonary lymph system to eliminate the largeamount of fluid produced from the necrosis of the al-veolar-capillary membrane. This leads to the clinicalpresentation of noncardiogenic pulmonary edema,causing hypoxia and apnea. These casualties, evenwith intensive pulmonary care, may not survive.

Many of the casualties exposed to lung-damag-ing agents are between these two extreme situations.When the onset of dyspnea is more than 6 hours afterexposure, there may be progression to dyspnea at rest.However, with good pulmonary care beginning early

after the onset of effects, the casualty should recovercompletely. Failure to consider the asymptomatic pe-riod and delayed onset of peripherally acting lung-damaging agents may lead to early discharge fromthe emergency room, without an adequate period ofobservation, and possibly to a poor outcome.1

Diagnostic Tests

No commonly available laboratory tests exist forthe specific identification or quantification of exposureto lung-damaging agents; however, an increase in thehematocrit may reflect the hemoconcentration inducedby transudation of fluid into the pulmonary paren-chyma from the peripherally acting agents. Arterialblood gases may show a low PaO2or PaCO2, which isan early, nonspecific warning of increased interstitialfluid in the lung. Peak expiratory flow rate may de-crease early after a massive exposure to peripherallyacting agents. This nonspecific test helps assess the

degree of airway damage and the effect of bronchodi-lator therapy. Decreased lung compliance and carbonmonoxide diffusing capacity are particularly sensitiveindicators of interstitial fluid volume in the lung, butbecause of their complexity, these tests are usuallyperformed only in hospitals.

Chest Radiograph

Initial findings on a chest radiograph may be nor-mal; as the disease process progresses, the radiographmay demonstrate bilateral diffuse interstitial infiltrates.The early finding on a chest radiograph is hyperinfla-tion, which suggests toxic injury of the smaller airwaythat results in air being diffusely trapped in the alveoli.The appearance of batwing infiltrates is caused bypulmonary edema secondary to the alveolar capillarymembrane damage. Pulmonary edema develops laterand without cardiovascular changes of redistribution

or cardiomegaly. Radiological changes from centrallyacting lung-damaging agents may occur for hoursto days, so the use of a chest radiograph may be oflimited value.

Arterial Blood Gases

Measuring carboxyhemoglobin and methemoglo-bin levels can help determine whether the casualtieshave been exposed to methylene chloride or confirmsuspected carbon monoxide exposure; methemoglo-binemia may suggest other causes. Serial arterial bloodgases in cases of significant respiratory distress dem-

onstrate the degree of hypoxemia. Hypoxia is often theresult of exposure to both centrally and peripherallyacting lung-damaging agents. The measurement ofthe partial pressure of oxygen (PO2) can give insightinto the treatment of hypoxia, but it is a nonspecifictool in the diagnosis of exposure to a lung-damagingagent.1

Pulmonary Function Tests

A variety of airway and pulmonary parenchymalfunction measures can be performed in rear-medicaltreatment facilities. Initial and follow-up measure-ments of the flow-volume loop, lung volumes, andlung diffusing capacity for carbon monoxide are par-ticularly useful in assessing and managing long-termeffects of a lung-damaging TIC exposure. Althoughsuch laboratory studies are of minimal value in anacute-care setting, flow-volume loop measures maydocument a previously unrecognized degree of air-way obstruction. A degree of reversibility may also


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be demonstrated if bronchodilators are tested at thesame time. Substantial airway obstruction may bepresent with little clinical evidence. In all cases ofunexplained dyspnea, regardless of clinical findings,careful pulmonary function measurements should beundertaken. Ideally, these studies should be performed

in an established pulmonary function laboratory andwould include lung diffusing capacity for carbonmonoxide and arterial blood gas measurements. Thesestudies should also be performed during exertion ifthe patient has dyspnea on exertion that cannot oth-erwise be explained by pulmonary function studiesperformed at rest.1

Bronchoalveolar Lavage

Bronchoalveolar lavage is a diagnostic procedurethat involves washing a sample of cells and secretionsfrom the alveolar and bronchial airspaces. An inflam-

matory response can be detected by polymorpho-nuclear leukocytes and an increase in protein contentin the lung washings. Cell death or membrane damagecan be indicated by the release of cytoplasmic enzymesand lactate dehydrogenase into the acellular portionof the lavage fluid. Animals chronically exposed to

insoluble particles show a large increase in some ly-sosomal enzymes found in the bronchoalveolar lavagefluid. Also, angiotensin-converting enzymes have beenfound to be elevated with endothelial cell damage inthe pulmonary capillaries. Although bronchoalveolarlavage has been used to validate the presence of acute

lung injury from TICs, the method is limited by thelarge range of normal values for each parameter.53

Other Tests

Pulmonary capillary wedge pressure shouldbe monitored in cases of severe pulmonaryedema or ARDS.

Ventilation/perfusion scans can show abnor-mal air trapping in the setting of lower airwayobstruction and may be useful to help gaugeseverity or progress of respiratory disease;however, these findings are unlikely to change

acute medical management. Carbon dioxide levels should be monitored in

patients with prior lung disease such as asthmaand chronic obstructive pulmonary disease;these patients may be affected more severely andare at greater risk of retaining carbon dioxide.

MEDICAL MANAGEMENT

Lung-damaging TIC casualties may have minimalsigns and symptoms during the acute phase, and theprognosis should be guarded. Ongoing reassessmentis an essential component of the early medical manage-

ment of these casualties, for they could rapidly developsevere noncardigenic pulmonary edema. However,many of the casualties who survive for more than 48hours recover without sequelae. A complete medicalhistory is one of the most important aspects in themedical management of these casualties. In contrastto most occupational inhalational exposures, lung-damaging chemical warfare agents need specific im-mediate treatment in addition to the usual supportivecare (the suspicion of exposure to lung-damagingchemical warfare agents is of course higher in timesof war or terrorist activity).

Patient History

Collecting historical data from the casualty is acritical aspect of assessing and treating individualsexposed to lung-damaging agents. No specific state-ment can determine the correct diagnosis and ultimatetreatment, but careful questioning of an exposed in-dividual will often greatly simplify the diagnosis and

medical therapy. Different approaches to collectinga history may be needed depending on the circum-stances of the events involved (see Exhibit 10-1 for alist of example questions). If a casualty is unable to

provide a history of the incident, an observation ofthe scene can be helpful in determining treatment,the amount of time needed for observation, and thelikely prognosis. Other personnel on the scene of theincident, who may have conducted reconnaissance orany atmospheric monitoring, may be able to assist inthe clinical decision making.

Physical Examination

Physical examination may be particularly difficult inthe event of combined lung-damaging TICs and con-ventional injuries; therefore, it is essential that medicalpersonnel note the patients physical condition (spe-cific conditions to look for are listed in Exhibit 10-2).Symptoms of lung-damaging TIC inhalation injuriescan be delayed in onset, but some conditions that mayprecede the onset of delayed symptoms include facialburns, inflamed nares, wheezing, altered mental status,and productive cough. Coughing will more than likelybe the first symptom noted (although an occasional


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EXHIBIT 101

HISTORY ASSESSMENT FOR CASUALTIES EXPOSED TO LUNG-DAMAGING AGENTS

Environment: Were the explosions observed? Was there obvious smoke? If so, what color was it? Was thesmoke heavier than air or close to the ground? What was the weather condition (temperature, rain, wind,daylight, fog)? Were there pools of liquid or a thickened substance in evidence?

Protective posture:What was the level of mission-oriented protective posture (MOPP)? Was there face maskor suit damage? Did the face mask fit adequately? When was the filter last changed? How well trained wasthe indivual in using the appropriate protective posture? Were other factors present (eg, consumption ofalcoholic beverages, exposure to other chemicals, psychiatric status)?

Prior exposure:Was there prior exposure to other chemical agents? Is the individual a cigarette smoker? (Forhow many years? How recently did he or she last smoke? How many cigarettes smoked a day?)

Pulmonary history:Is there a prior history of chest trauma, hay fever, asthma, pneumonia, tuberculosis,exposure to tuberculosis, recurrent bronchitis, chronic cough or sputum production, or shortness of breathon exertion?

Cardiac and endocrine history:Is there a history of cardiac or endocrine disorder? Acute exposure history:What were the initial signs and symptoms?

Eyes:Is there burning, itching, tearing, or pain? How long after exposure did symptoms occur: minutes,hours, days?

Nose and sinuses:Was a gas odor detected? Is there rhinorrhea, epistaxis, or pain? How long after expo-sure did symptoms occur: minutes, hours, days?

Mouth and throat: Is there pain, choking, or cough? How long after exposure did symptoms occur: min-utes, hours, days?

Pharynx and larynx:Are there swallowing difficulties, cough, stridor, hoarseness, or aphonia? How longafter exposure did symptoms occur: minutes, hours, days?

Trachea and mainstem bronchi:Is there coughing, wheezing, substernal burning, pain, or dyspnea? Howlong a

chapter 10 - toxic inhalational injury and toxix industrial chemicals - pg. 339 - 370

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