chapter 9 toxic inhalational injury - dead-

Toxic Inhalational Injury

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Chapter 9

TOXIC INHALATIONAL INJURY

JOHN S. URBANETTI, M.D., FRCP(C), FACP, FCCP*

INTRODUCTION

TOXIC INHALATIONAL INJURYPhysical AspectsClinical EffectsPhysiologyEvaluation of Injury

GENERAL THERAPEUTIC CONSIDERATIONSFurther ExposureCritical Care ConceptsClinical AbnormalitiesSteroid Therapy

EXERTION AND TOXIC INHALATIONAL INJURYInteractions of Pulmonary Toxic Inhalants and ExerciseTherapy

HISTORICAL WAR GASESChlorinePhosgene

SMOKES AND OTHER SUBSTANCESZinc OxidePhosphorus SmokesSulfur Trioxide–Chlorosulfonic AcidTitanium TetrachlorideNitrogen OxidesOrganofluoride Polymers: Teflon and Perfluoroisobutylene

SUMMARY

*Clinical Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510

Medical Aspects of Chemical and Biological Warfare

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INTRODUCTION

Pulmonary toxic inhalants have been a militaryconcern since the Age of Fire. Thucydides, in 423BC, recorded the earliest belligerent use of a toxicinhalant. The Spartans used a burning mixture ofpitch, naphtha, and sulfur to produce sulfur diox-ide that was used in sieges of Athenian cities.1 Thereis scant reference in the literature to further mili-tary use of toxic inhalants until World War I. In early1914, both the French and Germans investigatedvarious tear gases, which were later employed. Byearly 1915, the German war effort expanded its gasresearch to include inhaled toxicants. As a result,

on 22 April 1915, at Ypres, Belgium, the Germansreleased about 150 tons of chlorine gas along a7,000-m battlefront within a 10-minute period. Al-though the exact number of injuries and deaths areunknown, this “new form” of warfare produced adegree of demoralization theretofore unseen.2 Al-though phosgene and chlorine have not been usedmilitarily since 1918, vast amounts are producedannually for use in the industrial sector. The poten-tial for accidental or deliberate exposure to a toxicinhalant exists, and military personnel should beprepared.

TOXIC INHALATIONAL INJURY

Physical Aspects

Airborne (and consequently inhaled) toxic ma-terial may be encountered in gaseous or particu-late form (Exhibit 9-1). Airway distribution of toxic

inhalants as a gas or vapor follows normal respira-tory gas flow patterns. The central airways ex-change gases with the environment as a result ofthe mechanical aspects of breathing. Each breathdilutes central airway gas with newly inhaled gas.

EXHIBIT 9-1

DEFINITIONS OF AIRBORNE TOXIC MATERIAL

Gas The molecular form of a substance, in which molecules are dispersedwidely enough to have little physical effect (attraction) on each other; there-fore, there is no definite shape or volume to gas.

Vapor A term used somewhat interchangeably with gas, vapor specifically refersto the gaseous state of a substance that at normal temperature and pres-sure would be liquid or solid (eg, mustard vapor or water vapor com-pared with oxygen gas). Vaporized substances often reliquefy and hencemay have a combined inhalational and topical effect.

Mist The particulate form of a liquid (ie, droplets) suspended in air, often as aresult of an explosion or mechanical generation of particles (eg, by a spin-ning disk generator or sprayer). Particle size is a primary factor in deter-mining the airborne persistence of a mist and the level of its deposition inthe respiratory tract.

Fumes, Smokes, and Dusts Solid particles of various sizes that are suspended in air. The particles maybe formed by explosion or mechanical generation or as a by-productof chemical reaction or combustion. Fumes, smokes, and dusts may them-selves be toxic or may carry, adsorbed to their surfaces, any of a varietyof toxic gaseous substances. As these particles and surfaces collide,adsorbed gases may be liberated and produce local or even systemic toxicinjury.

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


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Gas moves by convection into the peripheral air-ways (airways of ≤ 2-mm diameter) and then bydiffusion to the alveolar-capillary membranes. Con-sequently, there is a much slower dilution of gas atthis level. Therefore, toxic inhalants reaching thislevel may have a more profound effect due togreater relative duration of exposure.

Particles (such as those present in mists, and infumes, smokes, and dusts) present a more complexdistribution pattern because the particle size affectsits deposition at various levels of the airway. Suchfactors as sedimentation and impact rates also con-trol particle deposition. Therefore, heavier particlesmay settle in the nasopharynx or upper airways,whereas lighter or smaller particles may reachmore-peripheral airways. Once they have impacted,particles are susceptible to a variety of respiratorydefense mechanisms. These mechanisms deter-mine the efficiency with which particle removalprogresses, thereby determining the particle’s ulti-mate degree of adverse effects.

Clinical Effects

Toxic inhalants may cause damage in one or moreof the following ways:

• Asphyxiation may result from a lack of oxy-gen (eg, as in closed-space fires) or by in-terference with oxygen transport (eg, bycyanide, which compromises oxygen up-take by preventing its transport to cellularmetabolic sites).

• Topical damage to the respiratory tract mayoccur due to direct toxic inhalational injuryto the airways or alveoli. Cellular damagewith consequent airway obstruction, pul-monary interstitial damage, or alveolar-capillary damage ultimately compromisesadequate oxygen–carbon dioxide exchange.Some substances are relatively more toxicto the central airways, whereas others aremore toxic to the peripheral airways or al-veoli.

• Systemic damage may occur as a result ofsystemic absorption of a toxicant throughthe respiratory membranes (eg, leukopeniafollowing mustard inhalation) with conse-quent damage to other organ systems. Ef-fects on other organ systems may be moreobvious than the respiratory effects of ex-posure (as with mercury).

• Allergic response to an inhaled toxicantmay result in a pulmonary or systemic re-

action, which may be mediated by one ormore of a variety of immunoglobulins. Sec-ondary by-products of this reaction maycause cellular destruction or tissue swell-ing; consequently, oxygen–carbon dioxideexchange may be compromised, and theremay be systemic inflammatory damage.

Physiology

The ultimate effect of a particular toxic inhalanton the respiratory system or the whole organism isthe result of a complex interaction of multiple fac-tors, including the intensity of exposure, conditionof exposed tissues, and intrinsic protective and re-parative mechanisms.

Intensity of Exposure

The intensity of exposure variable is partiallyaffected by the physical state and properties of thetoxicant. Heavier-than-air gases are particularlyaffected by environmental conditions; for example,warm environments increase the vaporization ofsome substances (such as mustard), making inha-lational toxicity more likely. Increased humidityincreases particle size by hygroscopic effects. In-creased particle size may decrease the respiratoryexposure to a toxicant because larger particles mayprecipitate prior to inhalation, or they may be col-lected preferentially in the upper airways, whichhave better clearance mechanisms.

The intensity as well as the site of exposure ispartially affected by the toxic inhalant’s degree ofwater solubility: more soluble toxicants (such aschlorine) primarily affect the upper airways and themore central airways. Despite the relatively highrate of airflow in central airways, the more solubletoxic gases are almost entirely deposited there. Theless-soluble gases tend to produce effects in theperipheral airways or alveoli. In peripheral airways,air motion is relatively slow, occurring primarilyby molecular diffusion. Foreign substances (such ascigarette smoke and toxic gases) that have not beentrapped at more-central sites tend to remain longerin the peripheral airways. These substances mayinduce a surprising degree of damage due to theirprolonged effect.

The intensity of exposure is commonly measuredby multiplying the concentration (C, in milligramsper cubic meter) of a substance by the time of expo-sure (t, in minutes); the product is known as the Ct;the units of measurement as mg•min/m3. Precisemeasurement of the toxicant’s concentration at the


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site of topical effect is not possible. An inhaledbreath of toxic inhalant is mixed into a greater vol-ume of airway gas (containing oxygen, nitrogen,carbon dioxide, and water vapor). The distributionof that breath then depends on such variables asspeed of inhalation, depth of inhalation, and evenbody position during inhalation. Additionally, theduration of exposure, particularly in a combat set-ting, may be exceptionally difficult to assess. Finally,little attention is paid to the additional variable ofdepth and frequency of respiration (minute venti-lation). This variable is highly affected by the exer-cise state or metabolic rate of the soldier. Deeperand more frequent breathing during combat mayexpose the airways to a greater amount of toxic in-halants compared to the exposure of an individualat rest.

Because of difficulties in accurately measuringCt, the threshold limit value (TLV) of a substance isused more often; a thorough discussion of TLV canbe found in another volume in the Textbook of Mili-tary Medicine series, Occupational Health: The Soldierand the Industrial Base.3 Calculations are made of amaximum allowable exposure to a toxicant, typi-cally expressed for a 15-minute or an 8-hour period.This calculation makes the development of environ-mental standards and alarm detection systemssomewhat simpler. The TLV should not, however,be considered a definition of a safe level. The con-cept of safe level wrongly implies that exposure totoxicants below that level has no effect. Rather, theTLV should be considered an expedient method ofdefining the statistical risk of injury resulting froman exposure. As biological and medical testing tech-niques undergo revision, toxic inhalants are oftenfound to have histological or physiological effectsin experimental animals at levels well below theestablished TLV. Therefore, rather than defining a“safe” level of a toxicant, the TLV may simply de-scribe a level at which there is no recognized bio-logical effect.

Condition of Exposed Tissues

Preexisting airway damage (such as that causedby prior toxic inhalant exposure) may seriouslycompromise the respiratory system’s normal pro-tection and clearance mechanisms. Specifically,there may be depletion of critical enzyme systems.Cigarette smoking may severely compromise air-way function with respect to both airway patencyand clearance mechanisms. Hyperreactive airways(asthma in varying degrees) are seen in up to 15%of the adult population. Toxic inhalant exposures

may trigger bronchospasm in these individuals.This bronchospasm may delay the clearance of thetoxicant, interfering further with gas transport. Thedevelopment of an acute interstitial process (eg,phosgene-related pulmonary edema) may also trig-ger bronchospasm. Individuals with any of the fol-lowing characteristics should be considered likelyto develop bronchospasm as the result of a toxicinhalant exposure:

• prior history of asthma or hay fever (evenas a child),

• prior history of eczema, or• family history of asthma, hay fever, or ec-

zema.

Individuals with hyperreactive airways will ben-efit from bronchodilator therapy and possibly fromsteroids after exposure to a toxic inhalant. Thisstatement, however, does not constitute an endorse-ment for routine steroid use in all toxic inhalationalinjuries.

Evaluation of Injury

Individuals exposed to a toxic inhalant shouldbe carefully examined by medical personnel whoare well versed in military medicine in the area ofpulmonary injury. Obtaining a medical history andexamining an exposed individual require the exam-iner to have an extensive knowledge of militarytoxicology and a thorough background in the fun-damental aspects of medical practice. Casualtieswith toxic inhalational injuries present with a his-tory that is characteristically different from that ofmost injuries; the cause–effect relationship may beparticularly difficult to assess. The possibility ofdelayed effects caused by toxic inhalants cannot beoveremphasized. Evidence of physiological damagemay not become apparent for 4 to 6 hours after alethal exposure (eg, to mustard or phosgene). If suchan exposure is suspected, the patient must be ob-served for at least 4 to 6 hours. Even if there is noobvious injury noted during the observation period,the patient must be carefully reassessed before be-ing discharged from the medical system.

History

Collecting historical data from the casualty is acritical aspect of assessing and treating toxic inha-lational injury. Careful questioning of an exposedindividual will often greatly simplify the diagnosisand therapy of the injury.


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• Environment. Were explosions observed?Was there obvious smoke? If so, what colorwas it? Was the smoke heavier than air?What were the weather conditions (tem-perature, rain, wind, daylight, fog)? Werepools of liquid or a thickened substance inevidence?

• Protective Posture. What was the level ofmission-oriented protective posture (MOPP)?Was there face mask or suit damage? Didthe face mask fit adequately? When was thefilter changed? How well trained was thesoldier in using the appropriate protectiveposture, in making clinical observations,and in choosing appropriate therapy? Wereother factors present (eg, consumption ofalcoholic beverages, exposure to otherchemicals, psychiatric status)?

• Prior Exposure. Was there prior exposureto other chemical agents? Is the individuala cigarette smoker? (For how long? Howrecently? How many?)

• Pulmonary History. Is there a prior historyof chest trauma, hay fever, asthma, pneu-monia, tuberculosis, exposure to tubercu-losis, recurrent bronchitis, chronic cough orsputum production, or shortness of breathon exertion?

• Cardiac and Endocrine History. Is there ahistory of cardiac or endocrine disorder?

• Acute Exposure History. What were the ini-tial signs and symptoms?

° Eyes. Is there burning, itching, tearing,or pain? How long after exposure didsymptoms occur: minutes, hours, days?

° Nose and sinuses. Was a gas odor de-tected? Is there rhinorrhea, epistaxis, orpain? How long after exposure didsymptoms occur: minutes, hours, days?

° Mouth and throat. Is there pain, chok-ing, or cough? How long after exposuredid symptoms occur: minutes, hours,days?

° Pharynx and larynx. Are there swallow-ing difficulties, cough, stridor, hoarse-ness, or aphonia? How long after expo-sure did symptoms occur: minutes,hours, days?

° Trachea and mainstem bronchi. Is therecoughing, wheezing, substernal burn-ing, pain, or dyspnea? How long afterexposure did symptoms occur: minutes,hours, days?

° Peripheral airways and parenchyma. Is

there dyspnea or chest tightness? Howlong after exposure did symptoms occur:minutes, hours, days?

° Heart. Are there palpitations, angina, orsyncope? How long after exposure didsymptoms occur: minutes, hours, days?

° Central nervous system. Is there diffuseor focal neurological dysfunction?

Physical Examination

Physical examination may be particularly diffi-cult in the event of combined toxic and conventionalinjuries; therefore, it is essential that medical per-sonnel note the following conditions:

• Reliability. Is the casualty alert and ori-ented?

• Appearance. Is he anxious or tachypneic?• Vital Signs. What are his weight, blood pres-

sure, pulse, and temperature?• Trauma. Is there a head injury? Are there

burns in the region of the eyes, nose, ormouth?

• Skin. Are there signs of burns, erythema,sweating, or dryness?

• Eyes. Is there conjunctivitis, corneal burnsor abrasion, miosis, or mydriasis?

• Nose. Is there erythema, rhinorrhea, orepistaxis?

• Oropharynx. Is there evidence of perioralburns or erythema?

• Neck. Is there hoarseness, stridor, or sub-cutaneous emphysema?

• Chest. Is there superficial chest walltrauma, tenderness, crepitation, dullness, orhyperresonance? Are crackles present? Thismeasurement should be made by asking thepatient to hold a forced expiration at re-sidual volume for 30 seconds, then listen-ing carefully at the lung bases for inspira-tory crackles. Is wheezing present? Thisexamination should be undertaken by lis-tening for wheezes bilaterally in the chestboth posteriorly and anteriorly under cir-cumstances of forced expiration.

Laboratory Measurements

Sophisticated laboratory studies are of limitedvalue in the immediate care of an exposed, injuredindividual. The following studies are of some pre-dictive value in determining the severity of expo-sure and the likely outcome.


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Chest Radiograph. The presence of hyperinfla-tion suggests toxic injury of the smaller airways,which results in air being diffusely trapped in thealveoli (as occurs with phosgene exposure). Thepresence of “batwing” infiltrates suggests pulmo-nary edema secondary to toxic alveolar capillarymembrane damage (as occurs with phosgene expo-sure). Atelectasis is often seen with more-centraltoxic inhalant exposures (such as with chlorineexposure). As radiological changes may lag behindclinical changes by hours to days, the chest radiographmay be of limited value, particularly if normal.

Arterial Blood Gases. Hypoxia often results fromexposure to toxicants, such as occurs following ex-posure to chlorine. Measurement of the partial pres-sure of oxygen (PO2) is a sensitive but nonspecific toolin this setting; both the central and peripheral effectsof toxic inhalant exposure may produce hypoxia. At4 to 6 hours, normal arterial blood gas (ABG) val-ues are a strong indication that a particular expo-sure has little likelihood of producing a lethal ef-fect. Typically, carbon dioxide elevation is seen inindividuals with underlying hyperreactive airways;in this circumstance, it is thought that bronchospasmis triggered by exposure to the toxic inhalant.

Pulmonary Function Tests. A variety of airwayfunction measures and pulmonary parenchy-mal function measures can be performed in rear-echelon facilities. Initial and follow-up measure-ments of the flow-volume loop, lung volumes,and the lung diffusing capacity for carbon monox-ide (DLCO) are particularly useful in assessing andmanaging long-term effects of a toxic inhalantexposure. Although such laboratory studies areof minimal value in an acute-care setting, flow vol-ume loop measures may document a previously un-recognized degree of airway obstruction. A degreeof reversibility may also be demonstrated ifbronchodilators are tested at the same time. Sub-stantial airway obstruction may be present withlittle clinical evidence. In all cases of unexplaineddyspnea, regardless of clinical findings, carefulpulmonary function measurements should be un-dertaken. Ideally, these studies should be performedin an established pulmonary function laboratoryand would include DLCO and ABG measurements.These studies should also be performed during ex-ertion if dyspnea on exertion is noted that cannototherwise be explained by pulmonary functionstudies performed at rest.

GENERAL THERAPEUTIC CONSIDERATIONS

Further Exposure

A soldier’s exposure to toxic inhalants is limitedby removing him from the environment in which thetoxicant is present. Careful decontamination servesto limit reexposure to the toxicant from body surfacesor clothing. Furthermore, decontamination reducesthe risk of secondary exposure of other personnel.

Critical Care Concepts

Life-threatening pathophysiological processesarising from toxic inhalants usually develop in theupper airway, where laryngeal obstructions cancause death in a few minutes, and in the lower res-piratory tract, where bronchospasm can cause deathalmost as rapidly. Severe bronchospasm may indi-cate exposure to a nerve agent. If there is any pos-sibility that exposure to nerve agents has occurred,the use of one or more of the three Mark I Auto-Injector kits that are provided to all military mem-bers (see Chapter 5, Nerve Agents) should be con-sidered an urgent part of initial therapy. Like theairway and breathing, cardiac function must like-wise be assessed immediately.

Adequate control of the airway is important inall toxic inhalant exposures. Exposure to centrallyabsorbed toxic inhalants (such as chlorine) and tofires may be particularly dangerous, insofar aslaryngeal or glottal edema may rapidly compromiseupper airway patency. Evidence of perinasal orperioral inflammation indicates the need formore careful investigation of the oropharynx forerythema. Subsequent laryngoscopy or bronchos-copy may be of particular value and should be un-dertaken along with preparations for expedient in-tubation. The presence of stridor indicates the needfor immediate airway control.

Primary failure of respiration after exposure totoxicants other than nerve agents suggests a sever-ity of exposure that requires intensive medical sup-port; at this point, a triage decision may be needed.The presence of wheezing indicates severe broncho-spasm, which requires immediate therapy. The pres-ence of dyspnea necessitates careful observation ofthe patient for at least 4 to 6 hours, until severe,potentially lethal respiratory damage can be reason-ably excluded.

Primary failure of cardiac function, like respira-tion, is a grave sign after exposure to toxicants other


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than nerve agents. Cardiac rate and rhythm abnor-malities are often seen after toxicant exposure.These abnormalities are often transient and improveonce the casualty is removed from the toxic envi-ronment and is provided with supplemental oxy-gen. Hypotension is a grave prognostic sign if notimmediately reversed by fluid and volume resusci-tation and intensive medical care.

Clinical Abnormalities

Clinical abnormalities that may lead to respira-tory failure can also be observed after pulmonarytoxic inhalational injury. These include hypoxia,hypercarbia, pulmonary edema, which are all signsof possible toxic inhalant exposure; and infection,which is a frequent complication, particularly inintubated patients.

Oxygen supplementation should be provided tomaintain a PO2 greater than 60 mm Hg. Very earlyapplication of positive end-expiratory pressure(PEEP) is important, with progression to intubationand positive pressure ventilation if PEEP fails tonormalize the PO2. Note that PEEP application mayprecipitate hypotension in individuals with margin-ally adequate intravascular volume (such as thosewith conventional trauma or pulmonary edema) orin individuals previously treated with drugs thathave venodilating properties (such as morphine ordiazepam). Particular attention to anemia is neces-sary if hypoxia is present.

An elevation of the partial pressure of carbondioxide (PCO2) greater than 45 mm Hg suggests thatbronchospasm is the most likely cause of hyper-carbia; therefore, bronchodilators should be usedaggressively. If the patient has a prior history ofclinical bronchospasm, steroids should be addedimmediately; steroids should also be considered ifthe patient has a history of hay fever or eczema andobvious bronchospasm with the current exposure.Occasionally, positive pressure ventilation may alsobe necessary. Interstitial lung water (early pulmo-nary edema) may trigger bronchospasm in indi-viduals who are otherwise hyperreactive (such asthose with “cardiac” asthma). Steroids are not pri-marily useful in this circumstance.

Pulmonary edema noted after a toxic inhalantexposure should be treated similarly to adult res-piratory distress syndrome (ARDS) or “noncardiac”pulmonary edema. The early application of PEEPis desirable, possibly delaying or reducing the se-verity of pulmonary edema. Diuretics are of lim-ited value; however, if diuretics are used, it is use-

ful to monitor their effect by means of the pulmo-nary artery wedge pressure measurement becauseexcessive diuretics may predispose the patient tohypotension if PEEP or positive-pressure ventila-tion is applied.

Toxic inhalant exposures typically cause acutefever, hypoxia, elevated polymorphonuclearwhite cell count, and radiologically detectableinfiltrates. These changes should not be taken toindicate bacteriological infection during the first 3to 4 days postexposure. Thus, routine or prophy-lactic use of antibiotics is not appropriate duringthis period.

Infectious bronchitis or pneumonitis commonlysupervenes 3 or more days postexposure to a toxicinhalant, particularly in intubated patients. Closeobservation of secretions, along with daily sur-veillance bacterial culture, will permit the earlyidentification and specific treatment of identifiedorganisms.

Steroid Therapy

Systemic steroid therapy has been consideredfor use in certain toxic inhalational exposures.U.S. Army Field Manual 8-285, Treatment ofChemical Agent Casualties and Conventional MilitaryChemical Injuries,4 suggests a benefit in phosgeneexposure, but human data supporting this approachare scanty. There is some support in the literaturefor steroid use in exposure to zinc/zinc oxideand oxides of nitrogen. However, there is no otherstrong support in the literature for the treatmentof other specific toxic inhalations with systemicsteroids.

A significant percentage of the population has adegree of airway irritability or hypersensitivity, asexemplified by persons with asthma. These indi-viduals are likely to display heightened sensitivityor even bronchospasm, nonspecifically after aninhalational exposure. The use of systemic steroidswould be indicated in this population if their bron-chospasm were not readily controlled with moreroutine bronchodilators. Systemic steroids may,if used in this setting, be required for prolongedperiods, particularly if superinfection shouldsupervene.

Inhaled steroids may be less effective thansystemic steroids in circumstances of acute expo-sure—especially if later infected. Inhaled steroidsappear most useful as an adjunct to the gradual re-duction or weaning or both from a systemic steroiduse.


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EXERTION AND TOXIC INHALATIONAL INJURY

“The extra amount of oxygen needed in the ex-ertion could not be supplied and the results showedat once.… [M]en who had been comfortable whilelying became rapidly worse and sometimes diedsuddenly if they walked or sat about,”5(p424) wroteHerringham in his article describing gassed casu-alties in World War I.

There is scant, primarily anecdotal, informationrelating to the effects of exercise postexposureto toxic inhalants. During World War I, attemptsto assess the effects of toxic inhalant exposure onexercise tolerance were severely constrained bya limited understanding of basic exercise physiol-ogy and by limited technological capacity. Someearly observations in exercise-limited victimsof gassing included observations of limited “depthof respiration” and tachycardia after “mildestexercise”6(p3); and a heartbeat that “rises more thannormal for given exercise...returns to normal moreslowly after exercise [seen in 116 of 320 gassedpatients].”7(p10)

As a result of the World War I experience, itwas clear that cardiorespiratory damage resultingfrom toxic inhalant exposures could severely limitexercise capacity. Of primary concern, however,was whether exercise undertaken after a toxic in-halant exposure could, in some way, exacerbate theeffects of that exposure and thus increase the mor-bidity or mortality of exposed individuals. Thiswas a particularly practical concern in light of themilitary needs to return soldiers to active duty assoon as possible and to require soldiers to partici-pate (insofar as they appeared able) in their ownevacuation.

Toxic inhalant exposures may produce directpulmonary effects, indirect cardiac effects, andother systemic effects (eg, central nervous system[CNS] effects of mercury inhalation). Severe dam-age to those systems will be readily apparent; how-ever, identification of lesser damage may requireincreasingly sophisticated examination. Minor or-gan dysfunction is best identified during stress; thatis, an organ system that is functioning near its maxi-mum capacity is more likely to demonstrate physi-ological limitation than a system that is function-ing under conditions of rest. The principle of organstress as a method of functional assessment is wellrecognized. Both cardiologists and endocrinologistshave devised stress testing methods that allow ear-lier and more sensitive demonstration of cardiacand endocrine limitations. Systems with small de-

grees of physiological limitation are much morelikely to display such limitations during stress thanat rest. Conversely, an organ system that is impairedmay become so dysfunctional during stress that itexceeds its compensatory mechanisms (and thoseof other support systems) and fails, with resultingcatastrophic consequences for the organism as awhole.

The normal human body is designed to functionat a wide range of activity. Normal cardiopulmo-nary reserves permit a 25- to 30-fold increase inoxygen delivery to working muscles. Other com-pensatory mechanisms permit transient activitieseven beyond these limits. Ultimately, however, anyactivity requires adequate oxygen delivery and car-bon dioxide extraction for cell function. A damagedcardiorespiratory system that is unable to accom-plish normal oxygen–carbon dioxide exchange willfirst appear limited at the extreme of exertion. Maxi-mum exercise capacity will be restricted. With in-creasing damage to the cardiorespiratory system,exercise capacity becomes further limited untilsymptoms (eg, dyspnea or orthopnea) appear evenat rest.

Although oxygen–carbon dioxide exchange maybe adequate at rest (oxygen delivery of approxi-mately 250 mL/min), the requirements of oxygendelivery during exercise (up to 5,000 mL/min) cannot be met if there is cardiorespiratory damage:with cardiorespiratory damage, cellular hypox-ia results during exercise. Anaerobic mechanismsare transiently effective but are inadequate toprovide energy for extended periods of time, andmetabolic acidosis ensues. Ordinarily the metabolicacidosis (lactate-predominant) causes enough dis-comfort and discoordination of activity to limit theexertion. Lactate is then cleared from the circula-tion and excreted from the body as carbon dioxide.However, should respiratory limitation also bepresent, then excess carbon dioxide load is notreadily exchanged. A respiratory acidosis is super-imposed. Acidosis develops more rapidly than sys-temic buffer systems can accommodate it. The re-sulting hydrogen ion excess compromises myocardialcontractility, increases pulmonary artery resistance,and causes peripheral venous dilation. Cardiacoutput then diminishes relative to metabolicneeds.

Furthermore, a diminished intravascular bloodvolume—which is secondary to losses to the ex-travascular space, particularly to lung paren-


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chyma—and increased intrathoracic pressure (airtrapping secondary to bronchospasm) reducevenous return. This contributes to a further, severecompromise of cardiac output. Hypotension thenexceeds other compensatory mechanisms (suchas tachycardia), with further restriction of oxygendelivery to metabolizing tissue. Finally, moreintense acidosis occurs and, ultimately, death su-pervenes.

Interactions of Pulmonary Toxic Inhalants andExercise

Airway resistance may increase because of tox-ic inhalational injury, resulting in increasedwork of respiration. Air trapping secondary to in-creased airway resistance increases intrathoracicpressure. Increased work of respiration and de-creased venous return result in exercise limitation.Ventilation–perfusion abnormalities of disorderedairway function limit oxygen delivery and carbondioxide clearance, which also compromises exercisetolerance.

Acute, short-term changes in interstitial functionsecondary to pulmonary edema, or long-termchanges secondary to interstitial inflammation orfibrosis subsequently limit diffusing capacity, a par-ticularly exercise-sensitive portion of the gas ex-change system.

During exercise, the airways and the alveoli havegreater exposure to a toxicant because of increasedventilation. Hyperventilation may itself inducemild bronchospasm, delaying toxicant clearancefrom the lung periphery. Already limited oxygendelivery may be critically compromised by exercise,

resulting in systemic hypoxia (including cerebral,cardiac, renal, and hepatic systems).

With regard to interstitial mechanisms, incre-ments of pulmonary arterial pressure with in-creased cardiac output may aggravate capillaryleaks, increasing interstitial edema. Inflammatorycells may accumulate in the interstitium, creatinglocal toxicity as they degenerate.

Therapy

After a toxic inhalational exposure, exercise mayfurther compromise the patient. Hypoxia is a pri-mary factor. Oxygen supplementation is necessaryat rest and especially during exercise. Exercise mayaggravate the effects of toxicant exposure andshould be limited or restricted if possible.

Toxicant exposure may produce pulmonary ab-normalities which result in dyspnea. Clinical orlaboratory testing may fail to confirm this symp-tom in the early hours postexposure; hence exami-nation of the patient must also take place at 4 to 6hours postexposure, if no abnormalities are initiallyidentified.

Dyspnea may be present long after the chestradiograph, physical examination, and restingvalues for ABG return to normal. Exercise eval-uation of these individuals (with ABG readingsas a necessary part of that evaluation) must beundertaken to understand the exposed individ-ual’s complaints. Failure to make these meas-urements in a soldier complaining of exerciselimitation displays a lack of understanding ofboth toxic inhalant exposures and basic exercisephysiology.

HISTORICAL WAR GASES

A variety of chemical agents were used as toxicinhalants during World War I; of these, several areconsidered current threats. Some toxicants havecurrent military relevance either because of theirpresence in stockpiles or because of their currentor recent use in military operations in other coun-tries. Other toxicants exist in large quantities as aresult of their industrial use. Because of themilitary’s preparedness in managing large-scaleexposure to toxicants, such as poisonous gases,military assistance may be required in the event ofa major accident involving toxic inhalants.

The following section discusses chlorine andphosgene, the two war gases that were used dur-ing World War I. Although they are not considered

current threats, under the right conditions theycould pose a threat to military personnel.

Chlorine

Chlorine is a dense, acrid, pungent, greenish-yel-low gas that is easily recognized by both color andodor. Because of its density and tendency to settlein low-lying areas, this gas is hazardous in closedspaces. Because the gas has a characteristic odor andits odor threshold is well below acute TLVs, chlo-rine is said to have good warning properties. How-ever, chronic exposures are thought to lead to a pro-gressive degradation of the odor threshold. As aresult, workers with frequent or long-term occupa-


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tional exposures to chlorine are at greater risk ofinhalational damage in later years.8–10

Clinical Effects of Exposure

An almost characteristic initial complaint of chlo-rine exposure is that of suffocation: the inability toget enough air.11 Typically, low exposures produce arapid-onset ocular irritation with nasal irritation, fol-lowed shortly by spasmodic coughing and a rapidlyincreasing choking sensation. Substernal tightness isnoted early. Complaints are particularly evident inindividuals who have a history of hyperreactive air-ways (asthma). Minimal to mild cyanosis may be evi-dent during exertion, and complaints of exertionaldyspnea are prominent. Deep inspiration producesa typical persistent, hacking cough.

Moderate chlorine exposures result in an imme-diate cough and a choking sensation. Severe sub-sternal discomfort and a sense of suffocation de-velop early. Hoarseness or aphonia is often seen,and stridor may follow. Symptoms and signs ofpulmonary edema may appear within 2 to 4 hours;radiological changes typically lag behind the clini-cal symptoms. There may be retching and vomit-ing, and the gastric contents often have a distinc-tive odor of chlorine. Figure 9-1 shows the chestradiograph of a chemical worker 2 hours postex-posure to chlorine: note the diffuse pulmonaryedema without significant cardiomegaly. This pa-tient experienced severe resting dyspnea, diffusecrackles on auscultation, and had a PO2 of 32 mm

Fig. 9-1. The chest radiograph of a 36-year-old femalechemical worker 2 hours postexposure to chlorine inhal-ant. She had severe resting dyspnea during the secondhour, diffuse crackles/rhonchi on auscultation, and a PO2of 32 mm Hg breathing room air. The radiograph showsdiffuse pulmonary edema without significant cardiomegaly.

Fig. 9-2. A section from a lung biopsy (from the patientwhose chest radiograph is seen in Figure 9-1) taken 6weeks postexposure to chlorine. At that time, she had noclinical abnormalities and a PO2 of 80 mm Hg breathingroom air. The section shows normal lung tissues with-out evidence of interstitial fibrosis/inflammation. Hema-toxylin and eosin stain; original magnification x 100.

Hg breathing room air. Figure 9-2 is a section of lungbiopsy taken from the same worker 6 weekspostexposure. The section shows no residual injuryfrom the chlorine exposure. The patient’s PO2 was80 mm Hg breathing room air.

Intense toxic inhalant exposures may cause pul-monary edema within 30 to 60 minutes. Secretionsfrom both the nasopharynx and the tracheobron-chial tree are copious, with quantities of up to 1 L/h reported.12 Severe dyspnea is so prominent thatthe patient may refuse to move. On physical exami-nation, the chest may be hyperinflated. Mediastinalemphysema secondary to peripheral air trapping maydissect to the skin and present as subcutaneousemphysema. The sudden death that occurs withmassive toxic inhalant exposure is thought to besecondary to laryngeal spasm.13

Therapy

There is no chemically specific prophylactic orpostexposure therapy for chlorine inhalation; there-fore, postexposure therapy is directed toward treat-ing the observed physiological signs and symptoms.Most deaths occur within the first 24 hours and arecaused by respiratory failure.

Individuals who survive a single, acute exposuregenerally demonstrate little or no long-term patho-logical or physiological sequelae. Individuals withunderlying cardiopulmonary disease or those whosuffer complications (such as pneumonia) duringtherapy are at risk for developing chronic bronchi-


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tis or (rarely) a gradual and progressive bronchi-olitis obliterans. Chronic bronchitis was thought tobe common after World War I chlorine inhalant ex-posures. Current assessment of these gassed indi-viduals suggests that their chronic or progressiveillness is more likely to have resulted from a com-bination of inadequately treated complicating in-fections and cigarette smoking than from the de-structive effects of a single, acute exposure.14,15

Secretions are typically copious but generallythin; mucolytics are not required. Careful attentionto the appearance of secretions will assist in theearly identification of bacterial superinfection,which may be associated with secretions that areother than clear or white.

Bacterial superinfection is commonly noted 3 to5 days postexposure. Early, aggressive antibiotictherapy should be directed as specifically as pos-sible against identified organisms. Careful, frequentGram’s stains and cultures of sputum are used toidentify a predominant organism. Persistent fever,infiltrates, or elevated white blood cell count in thepresence of thickened, colored secretions shouldprompt the institution of a broad-spectrum antibi-otic (such as ampicillin or a cephalosporin). Thechoice of antibiotic should be based on local expe-rience with either community-acquired or nosoco-mial organisms. Antibiotics are not used prophy-lactically in this setting; such therapy would onlyserve to select a resistant bacterial population in theinjured individual.

Bronchospasm is an early and prominent com-plication of chlorine exposure. Aggressive bron-chodilator therapy (a combination of adrenergicagent and theophylline) is appropriate. Steroids areused if the patient has a history of hyperreactiveairways. Bronchodilators are used at least until theantibiotics are discontinued and there is no furtherevidence of clinical response (eg, as indicated bylaboratory testing). Steroid doses should be taperedas rapidly as clinical circumstances warrant afterthe first 3 to 4 days of (uncomplicated) recovery.Superinfection may complicate prolonged steroidtherapy.

Hypoxia improves as the bronchospasm im-proves, and long-term oxygen supplementation israrely required. If long-term oxygen supplementa-tion is needed, a search for other causes of hypoxiashould be undertaken. Early institution of positiveairway pressure (such as using a PEEP mask) maybe useful. Positive pressure ventilation may be nec-essary if PEEP is insufficient to maintain PO2 greaterthan 60 mm Hg. Occasional reports of subcutane-ous emphysema after chlorine exposure should not

be considered a contraindication to using PEEP orpositive pressure ventilation.16,17

Generally, the patient gradually recovers from hisacute injury in 36 to 72 hours, depending on thedegree of exposure. Delay in recovery may be theresult of superinfection. Pleural effusions of up to600 mL have been identified, generally in associa-tion with pulmonary edema. Areas of pneumonicconsolidation may be evident on the chest radio-graph.16 Follow-up studies of acute toxic inhalantexposures have generally demonstrated that pa-tients who had no acute complications developedno significant long-term effects.15 Pulmonary func-tion and respiratory symptoms in individuals withrepetitive, long-term, or low-dose toxic inhalantexposures have been reviewed in a number of re-ports.18 Although accurate records are difficult tomaintain and, consequently, the data may be some-what difficult to interpret, long-term or multiple,low-dose toxic inhalant exposures appear to pro-duce no significant physiological defects when theresults are corrected for smoking.18

Clinical Summary

Long-term complications from chlorine exposureare not found in those individuals who survive anacute exposure. There is little or no evidence thatsignificant long-term respiratory compromise oc-curs, unless there has been a superimposed bron-chitis or pneumonitis. The toxic effects of chlorinein the absence of superinfection are relatively shortlived. Bronchospasm may require prolongedtherapy, occasionally with steroids. There is littleevidence for significant long-term pathophysiologi-cal abnormalities with either acute, severe chlorineexposure or repetitive low-dose, long-term expo-sures. A patient’s failure to demonstrate substan-tial recovery within 3 to 4 days should prompt aninvestigation for the possible presence of bacterialsuperinfection or other complicating features.

Phosgene

Phosgene (military designation, CG) appears atusual battlefield temperatures as a white cloudwhose density is due, in part, to hydrolysis. The gasis heavier than air and at low concentrations has acharacteristic odor of newly mown hay. At higherconcentrations, a more acrid, pungent odor may benoted. An odor threshold of 1.5 ppm has been re-ported but does not apply to all observers. This odorthreshold is inadequate to protect against toxic in-halant exposures to this substance. Furthermore, a


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relatively rapid nasal adaptation limits the useful-ness of odor as a detection mechanism.19 Synonymsfor phosgene include carbonyl chloride, D-Stoff,and green cross.


In the first 30 minutes following exposure tophosgene, low concentrations may produce mildcough, a sense of chest discomfort, and dyspnea.Exposure to moderate concentrations triggers lac-rimation and the unique complaint that smokingtobacco produces an objectionable taste.20 High con-centrations may trigger a rapidly developing pul-monary edema with attendant severe cough, dysp-nea, and frothy sputum. Onset of pulmonary edemawithin 2 to 6 hours is predictive of severe injury.High concentrations may produce a severe coughwith laryngospasm that results in sudden death;this could possibly be due to phosgene hydrolysis,which releases free hydrochloric acid at the level ofthe larynx.21

In the first 12 hours after toxic inhalant exposure,depending on the intensity of exposure, a subster-nal tightness with moderate resting dyspnea and

Fig. 9-4. A lung section of the patient whose chest radio-graph is seen in Figure 9-3. This patient died 6 hours af-ter exposure to phosgene; the biopsy section was takenat postmortem examination. The section shows nonhemor-rhagic pulmonary edema with few scattered inflamma-tory cells. Hematoxylin and eosin stain; original magni-fication x 100.

Fig. 9-3. The chest radiograph of a 42-year-old femalechemical worker 2 hours postexposure to phosgene. Dys-pnea progressed rapidly over the second hour; PO2 was40 mm Hg breathing room air. This radiograph showsbilateral perihilar, fluffy, and diffuse interstitial infil-trates. The patient died 6 hours postexposure.

prominent exertional dyspnea become evident.These symptoms are often a prelude to the charac-teristic development of pulmonary edema. Initiallysmall, then greater, amounts of thin airway secre-tions may appear. The delayed and insidious onsetof severe pulmonary edema often has resulted in acasualty’s being medically evaluated and dis-charged from the medical facility, only to returnsome hours later with severe and occasionally le-thal pulmonary edema. The chest radiograph of afemale chemical worker 2 hours postexposure tophosgene (Figure 9-3) shows bilateral perihilar,fluffy, and diffuse interstitial infiltrates. A sectionof the lung (Figure 9-4) from the same patient showsnonhemorrhagic pulmonary edema with few scat-tered inflammatory cells.

An individual may remain relatively asymptom-atic for up to 72 hours after inhalant exposure. Dur-ing that time, dyspnea or pulmonary edema maybe triggered by exertion (see the preceding section,Exertion and Toxic Inhalational Injury).

Therapy

Pulmonary edema is the most serious clinicalaspect of phosgene exposure and begins with few,if any, clinical signs. Consequently, early diagnosisof pulmonary edema requires that careful attentionbe paid to the patient’s symptoms of dyspnea orchest tightness. The presence of these symptoms ina setting of possible inhalant exposure requires ex-


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peditious auscultation, chest radiograph, and ABGmeasurements.

If abnormal, these measurements mandate closeobservation and support at the intensive care level.If the measurements are normal, they all must berepeated 4 to 6 hours after the suspected exposure;only then can an individual be released to a lowermedical priority status. Abnormality of any one ofthose measures, in the absence of other explanation,should prompt institution of therapy for noncardiacpulmonary edema. At the early stages of treatment,therapy should include positive airway pressurewith early application of the PEEP mask. Later ap-plication of positive pressure ventilation throughintubation may be required if the PEEP mask failsto maintain adequate arterial PO2.

Figures 9-5 and 9-6 are the chest radiographsof a male chemical worker 2 hours and 7 hours,respectively, postexposure to phosgene. Thechest radiograph taken 2 hours postexposure wasnormal. The patient presented with mild restingdyspnea, but otherwise his physical examina-tion was normal. The same individual, 7 hourspostexposure, presented with moderate restingdyspnea and a few crackles on auscultation. Hischest radiograph showed mild interstitial edema.Figure 9-7 is a lung section from this patient, whodied 4 years later from unrelated causes. These tis-sues are normal, and there is no evidence of inter-stitial fibrosis.

Diuretics may be of minor value in reducing cap-illary pressure and consequently decreasing the rate

Fig. 9-5. The chest radiograph of a 40-year-old male chemi-cal worker 2 hours postexposure to phosgene. The patientexperienced mild resting dyspnea for the second hour; how-ever, his physical examination was normal with a PO2 of 88mm Hg breathing room air. This radiograph is normal.

Fig. 9-6. The same patient seen in Figure 9-5, now 7 hourspostexposure to phosgene. He had moderate resting dys-pnea, a few crackles on auscultation, and a PO2 of 64 mmHg breathing room air. This radiograph shows mild in-terstitial edema.

Fig. 9-7. A lung section from the patient whose chest ra-diographs are shown in Figures 9-5 and 9-6, who died 4years later from causes unrelated to his exposure to phos-gene. This section shows normal lung tissues withoutevidence of interstitial fibrosis or inflammation. Hema-toxylin and eosin stain; original magnification x 400.


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of fluid loss through a (presumptively) damagedalveolar–capillary membrane. It should be kept inmind that intravascular volume reduction (such asthat induced by diuretics) may lead to serioushypotension if positive pressure ventilation isrequired. Steroids have not been found to be clini-cally useful in treating phosgene-induced pneu-monitis. There has been some discussion in theliterature concerning the use of hexamethaminetetramine. However, reliable comparative datasupporting this therapeutic intervention are notavailable.22–24

Clinical Summary

The toxic effects of phosgene in the absence ofsuperinfection or other complications are relativelyshort-lived. There is little evidence of significantlong-term pathophysiological abnormalities witheither acute, severe phosgene exposures or repeti-tive, low-dose, long-term exposures. A patient’s fail-ure to demonstrate substantial recovery within 3 to4 days should prompt an investigation for the pos-sible presence of bacterial superinfection or othercomplicating features.25

SMOKES AND OTHER SUBSTANCES

Smokes and obscurants comprise a category ofmaterials that are not used militarily as directchemical agents. They may, however, produce toxicinjury to the airways. The particulate nature ofsmokes may lead to a mechanical irritation of theupper and lower airways—therefore inducing bron-chospasm in some hypersensitive individuals (eg,those with asthma). Certain smokes contain chemi-cals with a degree of tissue reactivity that results indamage to the airways. A discussion of obscurantsmokes is followed by a discussion of certain ex-plosion-related (oxides of nitrogen) or pyrolysis-related (perfluoroisobutylene) substances that areimportant in military practice.

Zinc Oxide

During World War I, the difficulties experiencedby the Allies in using white phosphorus as anobscurant smoke led both the French and theU.S. Chemical Warfare Service to search forother smokes; zinc oxide (military designation, HCor HC smoke) is an outgrowth of that search. HCcontains equal percentages of zinc oxide andhexachloroethane, with approximately 7% grainedaluminum. The material is currently formulated foruse in smoke pots, smoke grenades, and artilleryrounds.

On combustion, the reaction products are zincchloride and up to 10% chlorinated hydrocarbonssuch as phosgene, carbon tetrachloride, ethyl tet-rachloride, hexachloroethane, and hexachloro-benzene. In addition to these products, hydrogenchloride, chlorine, and carbon monoxide are alsoproduced. As the zinc chloride particles form, theyhydrolyze in ambient water vapor to produce adense white smoke. The toxicity of this chemicalagent is generally attributed to the topical toxic ef-fects of zinc chloride. However, carbon monoxide,

phosgene, hexachloroethane, and other combustionproducts may also contribute to the observed res-piratory effects, depending on the circumstances ofthe munitions ignition.26


Since World War I, there have been numerousreports of accidental exposures to the combus-tion products of HC. Depending on the intensityof the exposure, a wide range of clinical effects oc-curs; exposures as brief as 1 minute may lead todeath.

Low-dose toxic inhalant exposures are character-ized by sensations of dyspnea without subsequentradiological, auscultatory, or blood gas abnormali-ties. These patients should be watched carefully for4 to 6 hours postexposure (see the earlier discus-sion on phosgene); however, severe clinical sequelaeare uncommon.

Moderate exposures to HC are characterizedby severe dyspnea, which may show a relativelyrapid clinical improvement during the first 4 to 6hours. Because the chest radiograph is typically un-remarkable at this time, the patient is often inap-propriately discharged. These patients usually re-turn to the medical facility within 24 to 36 hourscomplaining of rapidly increasing shortness ofbreath. By that time, the chest radiograph typicallydemonstrates dense infiltrative processes, whichclear slowly with further care. Moderate to severehypoxia may persist during the period of radiologi-cal abnormality.

After exposure, the chest radiograph is charac-teristically unremarkable within the first hours de-spite severe clinical symptoms, which include rapidrespirations and severe dyspnea. An elevated tem-perature is often noted within the first 4 to 6 hoursand may remain over the ensuing days. At 4 to 6


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hours, the chest radiograph begins to show a denseinfiltrative process that is thought to representedema. However, bronchopneumonia may super-vene in the following days; a long-standing, diffuseinterstitial fibrosis may become evident, with onlyvery gradual recovery.27,28

Figure 9-8 is the chest radiograph of a 60-year-old male 8 hours postexposure to HC; it shows dif-fuse, dense, peripheral pulmonary infiltrates. Thepatient presented with moderately severe restingdyspnea and diffuse coarse crackles on ausculta-tion. Taken 14 weeks postexposure, Figure 9-9 is asection from an open lung biopsy from the samepatient. Diffuse interstitial fibrosis with inflamma-tory cells are evident. This patient presented with apersistent, moderate resting dyspnea. At this point,the patient had not been treated with steroids.

Exposures to very high doses of HC common-ly result in sudden, early collapse and death,which are thought to be due to rapid-onset laryn-geal edema and glottal spasm with consequentasphyxia. Exposures to high but nonlethal dosestypically produce very early, severe hemorrhagic ul-ceration of the upper airway. Such exposures mayalso produce a relatively rapid onset of pulmonaryedema.

Prolonged, severe exposures typically result inrelatively rapid onset of severe dyspnea, tachypnea,sore throat, and hoarseness. A characteristic parox-ysmal cough often produces bloody secretions. Anacute tracheobronchitis may lead to death withinhours.

Fig. 9-8. The chest radiograph of a 60-year-old male sailorwho inhaled zinc oxide (HC) in a closed space, taken 8hours postexposure. He had moderately severe restingdyspnea during the seventh and eighth hours, diffusecoarse crackles on auscultation, and a PO2 of 41 mm Hgbreathing room air. The radiograph shows diffuse denseperipheral pulmonary infiltrates.

Fig. 9-9. A section from an open lung biopsy of the pa-tient whose chest radiograph is shown in Figure 9-8, 14weeks postexposure to zinc oxide (HC). He had persis-tent moderate dyspnea at rest and a PO2 of 61 mm Hgbreathing room air. Steroids had not been used. The sec-tion shows diffuse interstitial fibrosis with few inflam-matory cells. Hematoxylin and eosin stain; original mag-nification x 400.

Therapy

There is no chemically specific prophylactic orpostexposure therapy for exposure to HC. Routineclinical support for specific complaints of acute tra-cheobronchitis and noncardiac pulmonary edemahas been detailed previously (see the section titledGeneral Therapeutic Considerations). Systemic ste-roid therapy is thought to be useful in treatment ofthe inflammatory fibrosis seen with this disorder.29–32

There are no reports of the clinical efficacy ofchelating agents; however, the use of such agentsas British anti-Lewisite (BAL) and calcium ethyl-enediaminetetraacetic acid (CaEDTA) has beensuggested because of their capacity to reduce se-rum zinc levels. After acute exposure, however,long-term pulmonary function testing is indicateduntil the patient’s condition is stable by that mea-surement. The continued presence of exertionaldyspnea 2 to 3 months postexposure implies fur-ther development of interstitial fibrotic changes.Exercise testing would be of value to obtain a moreaccurate assessment of the degree of oxygen trans-port limitation. There are no data evaluating the useof long-term steroid therapy in the treatment of in-terstitial disease secondary to HC inhalation.29–32

Clinical Summary

Although most patients with zinc chloride inha-lational injuries progress to complete recovery, a


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smaller group of approximately 10% to 20% of ex-posed individuals may go on to develop fibroticpulmonary changes. Both groups show early clini-cal recovery, making it difficult to distinguish pa-tients who are likely to recover from those who arelikely to develop more permanent changes. Earlysteroid use may modify the intensity of pulmonaryreaction and the resulting fibrosis; therefore, ste-roids appear indicated in the acute therapy of zincoxide exposure.

Phosphorus Smokes

Phosphorus occurs in three allotropic forms:white, red, and black. Of these, white phosphoruswas used most often during World War II in mili-tary formulations for smoke screens, marker shells,incendiaries, hand grenades, smoke markers, col-ored flares, and tracer bullets.

White phosphorus is a very active chemical thatwill readily combine with oxygen in the air, even atroom temperature. As oxidation occurs, white phos-phorus becomes luminous and bursts into flameswithin minutes. Complete submersion in water isthe only way to extinguish the flames. Vapors fromwhite phosphorus are toxic; however, because thesevapors quickly oxidize into phosphorus pentoxideand phosphoric acid, they are harmless to humansand animals at usual field concentrations.


At room temperature, white phosphorus is some-what volatile and may produce a toxic inhalationalinjury. Over a period of years, repetitive exposurescan result in systemic poisoning.33 At warmer tem-peratures, a slow oxidation to phosphorus trioxide(P2O3), which smells like garlic, can occur. At stillhigher temperatures (approximately 32°C [90°F])and with adequate air exposure, dense white cloudsof phosphorus pentoxide (P2O5) result from thecombustion of phosphorus.

In moist air, the phosphorus pentoxide producesphosphoric acid. This acid, depending on concen-tration and duration of exposure, may produce avariety of topically irritative injuries. Irritation ofthe eyes and irritation of the mucous membranesare the most commonly seen injuries. These com-plaints remit spontaneously with the soldier’s re-moval from the exposure site. With intense exposures,a very explosive cough may occur, which rendersgas mask adjustment difficult. There are no reporteddeaths resulting from exposure to phosphorussmokes.

Because of the toxicity associated with the manu-facture of white phosphorus and because of its fieldrisks, a gradual shift to red phosphorus (95% phos-phorus in a 5% butyl rubber base) was undertakenafter World War II. The British smoke grenade (L8-A1-3), which used red phosphorus, produced ad-equate field concentrations of smoke and func-tioned as an effective tank screen. Oxidation of redphosphorus produces a variety of phosphorus ac-ids that, on exposure to water vapor, producepolyphosphoric acids. These acids may producemild toxic injuries to the upper airways that resultin a cough and irritation. There are no reported deathsresulting from exposure to red phosphorus smokes.

Therapy

Phosphorus smokes are generated by a varietyof munitions. Some of these munitions (such as theMA25 155-mm round) may, on explosion, distrib-ute particles of incompletely oxidized white phos-phorus. Contact with these particles can cause lo-cal burns, and systemic toxicity may occur iftherapy is not administered. Therapy consists oftopical use of a bicarbonate solution to neutralizephosphoric acids and mechanical removal and de-bridement of particles. A Wood’s lamp in a dark-ened room may help to identify remaining lumi-nescent particles.

Clinical Summary

The principal form of toxicity of absorbed el-emental phosphorus, a destructive jaw process(phossy jaw), has been virtually eliminated by us-ing (a) less white phosphorus in all industrial settingsother than the military and (b) efficient adjunctivedental screening of exposed individuals for peri-ods of up to 2 years postexposure. Careful dentalscreening consists of regular radiological assess-ment of the mandible for characteristic lesions, earlyand aggressive treatment of those lesions, and ab-solute prohibition of further phosphorus exposure.33

Sulfur Trioxide–Chlorosulfonic Acid

Sulfur trioxide–chlorosulfonic acid (military des-ignation, FS smoke) consists of 50% (weight/weight) sulfur trioxide (SO3) and 50% (weight/weight) chlorosulfonic acid [SO2(OH)Cl]. FS smokeis typically dispersed by spray atomization. Thesulfur trioxide evaporates from spray particles, re-acts with moisture in the air, and forms sulfur acid,which condenses into droplets that produce a dense


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white cloud. The highly corrosive nature of FSsmoke in the presence of moisture resulted in thearmy’s abandoning its use.


Contact with liquid FS smoke produces a typicalmineral acid burn of exposed tissues. Exposure tothe smoke—which constitutes exposure to sulfuricacids—produces irritation of the eyes, nose, andexposed skin and complaints of cough, substernalache, and soreness. After a severe exposure to FSsmoke, a casualty demonstrates profuse salivationand an explosive cough, which could render respi-rator adjustment difficult. The highly irritative na-ture of the substance acts as an adequate warning,however, and prompts an immediate evacuationfrom the smoke cloud.

Therapy

Severe exposures (sufficient to give rise to therapid onset of symptoms) may require therapeuticintervention similar to that for chlorine exposure.Individuals with highly reactive airways are par-ticularly at risk. In the event of triggered broncho-spasm, these patients would benefit from aggres-sive bronchodilator use; consideration should alsobe given to the early use of steroids as well as posi-tive-pressure ventilation.4,29,34

Titanium Tetrachloride

Titanium tetrachloride (military designation, FMsmoke) is a corrosive substance typically dispersedby spray or explosive munitions. A dense, whitesmoke results from the decomposition of FM smokeinto hydrochloric acid, titanium oxychloride, andtitanium dioxide. Because titanium tetrachlorideis extremely irritating and corrosive in both liquidand smoke formulations, FM smoke is not com-monly used.

Exposure to the liquid may create burns similarto those of mineral acids on conjunctiva or skin.Exposure to the dense, white smoke in sufficientconcentration may produce conjunctivitis or cough.There are no reports of exposure-related humandeaths, nor are data available regarding pulmonaryfunction assessment in extensively exposed indi-viduals. Individuals with hyperreactive airwayswould be expected to develop bronchospasm withexposure to this substance.

Aggressive bronchodilator therapy and, possibly,steroid therapy should be considered.4

Nitrogen Oxides

The oxides of nitrogen (military designation,NOx), particularly nitrogen dioxide, are compo-nents of photochemical smog. Their concentrationsin smog are generally thought to be low enough tobe of no significant clinical concern for the normal,healthy individual.35

There are four forms of nitrogen oxide. The firstis nitrous oxide (N2O), which is commonly used asan anesthetic; however, in the absence of oxygen, itacts as an asphyxiant. The second is nitric oxide(NO), which rapidly decomposes to nitrogen diox-ide in the presence of moisture and air. Nitrogendioxide exists in two forms: NO2 and N2O4. At roomtemperatures, nitrogen dioxide is a reddish brownvapor consisting of approximately 70% N2O4 and30% NO2. Injuries from this toxic inhalant are seenmost often in nonmilitary settings of silage storage.36,37

In a military or industrial setting, nitrogen diox-ide occurs in the presence of electric arcs or otherhigh-temperature welding or burning processes,and particularly where nitrate-based explosives areused in enclosed environments (such as tanks andships). Diesel engine exhaust also contains substan-tial quantities of nitrogen dioxide.36–39


At NOx concentrations of 0.5 ppm or less, indi-viduals with preexisting airways disease show noclinical effects postexposure. At 0.5 ppm to approxi-mately 1.5 ppm, individuals with asthma may noteminor airway irritation. Concentrations of 1.5 ppmmay produce changes in pulmonary function mea-surements in normal individuals, including airwaynarrowing, reduction of diffusing capacity of thelung, and widening of the alveolar–arterial differ-ence in the partial pressure of oxygen (PAO2 – PaO2)gradient.

This level of toxic exposure may occur with littleinitial discomfort. The soldier may ignore the re-sultant mild coughing or choking. Because of rapidsymptomatic accommodation to this cough, contin-ued exposure may occur. A lethal exposure can oc-cur within 0.5 hour, with the soldier only experi-encing a minimal sense of discomfort.

The clinical response to NOx exposure is essen-tially triphasic. In phase 1, symptoms appear moreor less quickly, depending on the intensity of expo-sure. With a low dose, initial eye irritation, throattightness, chest tightness, cough, and mild nauseamay appear. Once the casualty is removed from thesource of exposure, these symptoms disappear


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spontaneously over the next 24 hours. However, at24 to 36 hours postexposure, a particularly severerespiratory symptom complex may appear sud-denly; exertion seems to be a prominent precipitat-ing factor. There may be severe cough, dyspnea, andrapid onset of pulmonary edema. If the patient sur-vives this stage, spontaneous remission occurswithin 48 to 72 hours postexposure. More intenseexposures produce a relatively rapid onset of acutebronchiolitis with severe cough, dyspnea, andweakness, without the above-mentioned latent pe-riod. Again, spontaneous remission occurs at ap-proximately 3 to 4 days postexposure.40

Phase 2 is a relatively asymptomatic period last-ing approximately 2 to 5 weeks. There may be a mildresidual cough with malaise and perhaps minimalshortness of breath, and there could be a sense ofweakness that may progress. The chest radiograph,however, typically is clear.

In phase 3, symptoms may recur 3 to 6 weeksafter the initial exposure. Severe cough, fever, chills,dyspnea, and cyanosis may develop. Crackles areidentified on physical examination of the lung. Thepolymorphonuclear white blood cell count is el-evated, and the partial pressure of carbon dioxide(PCO2) may be elevated as well.41 The chest radio-graph demonstrates diffuse, scattered, fluffy nod-ules of various sizes, which may become confluentprogressively, with a butterfly pulmonary edemapattern and a prominent acinar component. At thispoint, pathological study demonstrates classic bron-chiolitis fibrosa obliterans, which may clear spon-taneously or may progress to severe, occasionallylethal respiratory failure. The fluffy nodularchanges noted in the chest radiograph typicallyshow no clinical improvement. Pulmonary functiontesting may show long-term persistence of airwaysobstruction.37,42,43

Therapy

There is no chemically specific prophylactic orpostexposure therapy for NOx inhalational injury.Current therapy consists of intervention directed atspecific symptoms (see the earlier discussion titledGeneral Therapeutic Considerations). Pneumonitisappears to complicate the initial pulmonary edemarelatively early; nevertheless, the use of prophylac-tic antibiotics is not indicated.

The use of steroids early in phase 3 has been re-ported; and although controlled studies are notavailable, these reports strongly suggest the valueof steroid therapy in modifying the bronchiolitisobliterans that develops in the third stage.42 Despite

therapy, persistent limitation of airway function istypically seen, as demonstrated by long-term ab-normalities in pulmonary function.44

Clinical Summary

Exposure to NOx may produce a variety of de-layed and severe pulmonary sequelae that are notreadily predicted from early clinical or laboratorydata. Careful, long-term observation appears to beimportant. Steroid therapy may be a useful thera-peutic tool.

Organofluoride Polymers: Teflon andPerfluoroisobutylene

Teflon (polytetrafluoroethylene, manufacturedby Du Pont Polymers, Wilmington, Del.) and othersimilar highly polymerized organofluoride poly-mers (eg, perfluoroethylpropylene) enjoy wide-spread use in a variety of industrial and commer-cial settings. Because of their desirable chemical andphysical properties (eg, lubricity, high dielectricconstant, chemical inertness), organofluoride poly-mers are considered important and are used exten-sively in military vehicles such as tanks and aircraft.The occurrence of closed-space fires in such settingshas led to toxicity studies of the resultant by-prod-ucts created from incinerated organofluorines. In-halation of a mixture of pyrolysis by-products ofthese substances produces a constellation of symp-toms termed polymer fume fever.

A primary high-temperature pyrolysis by-prod-uct of these substances is perfluoroisobutylene(PFIB). Inhalation of this material may produce a“permeability” or “noncardiac” type of toxic pul-monary edema very much like that produced byphosgene.

General Description of Polymer Fume Fever

Teflon pyrolysis occurring at temperatures ofapproximately 450°C produces a mixture of particu-late and gaseous by-products; in 1951, Harris45 wasthe first to describe polymer fume fever, the clini-cal syndrome that resulted from inhaling this mix-ture. Within 1 to 2 hours postexposure, a syndromeknown as polymer fume fever appears. Often mis-taken for influenza, polymer fume fever causes mal-aise, chills, fever to 104°F (40°C), sore throat, sweat-ing, and chest tightness. Once the patient is removedfrom the site of exposure, the symptoms spontane-ously and gradually disappear over 24 to 48 hourswithout any specific treatment. The patient typically


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has no long-term complaints or sequelae.46 Muchof this symptomatology may be due to a millipore-filtrable particulate. Animal studies have shown analleviation of symptoms with filtration of the pyro-lyzed materials47 and restoration of symptoms withparenteral injection of the filtered material.48

Polymer fume fever may be induced by smok-ing Teflon-contaminated cigarettes (the burning tiptemperature reaches 884°C46). Smoking contami-nated cigarettes can also induce the signs and symp-toms of pulmonary edema. Onset of pulmonaryedema is typically rapid (2–4 h), mild in degree(rarely requiring oxygen supplementation as part oftreatment, and rapidly remits (clears within 48 h).49

As Teflon is pyrolyzed at a higher temperatures,more variety and higher concentrations of organo-fluoride by-products are noted.50 Among these, PFIBis found to be the most toxic (Exhibit 9-2), with anLCt50 (ie, the vapor or aerosol exposure [concen-tration • time] that is lethal to 50% of the exposedpopulation) of 1,500 mg•min/m3 (in comparison,the LCt50 of phosgene is 3,000 mg•min/m3).51

Clinical Effects of Exposure to Perfluoroisobutylene

Inhalation of PFIB is followed by a very rapidtoxic effect on the pulmonary tissues (see the sec-tion below titled Clinical Pathology), with micro-scopic changes of perivascular edema evidentwithin 5 minutes.52 Exposure to a very high con-centration of this colorless, odorless gas may pro-duce early conjunctivitis53; in animal studies, it hasproduced sudden death (“lightning death” reportedby Karpov, which occurred within 1 min).54 No suchsudden human deaths have been reported.

Less-intense exposures to PFIB are followed bya clinically asymptomatic period (clinical latentperiod) of a variable duration. During this period,normal biological compensatory mechanisms con-trol the developing pulmonary edema until thosecompensatory mechanisms are overwhelmed. Thelength of this interval depends on the intensity andduration of exposure and on the presence or absenceof postexposure exercise. Recent animal studies ofPFIB inhalation strongly support World War I an-ecdotal human observations (with phosgene) thatthe resulting toxic pulmonary edema appears ear-lier and with more intensity when the casualty isrequired to exercise postexposure. It may be thatincreased pulmonary blood flow increases the per-meability of the already damaged alveolar-capillarymembrane.55

The clinical latent period for PFIB injury is 1 to 4hours (compared with 1–24 h for phosgene). Sub-

sequent symptoms of pulmonary edema progres-sively appear: initially, dyspnea on exertion; thenorthopnea; and later dyspnea at rest. Radiologicalsigns and clinical findings of pulmonary edemaprogress for up to 12 hours, then gradually clearwith complete recovery by 72 hours. Typically, thereare no long-term sequelae49,56–59; however, twodeaths have been reported.53,60 The death reportedby Auclair et al53 occurred after very severe pulmo-nary edema (requiring intubation), hypotension,and ultimately, Gram-negative superinfection.

Four reports on the long-term effects of PFIB ex-posure are available. Brubaker56 reported a decre-ment in DLCO 2 months after a single exposure.Capodaglio et al61 reported that 3 of 4 exposed in-dividuals showed pulmonary function test (PFT)abnormalities 6 weeks to 6 months postexposure.Paulet and Bernard62 reported four workers withabnormal PFTs and DLCOs during the 4 months fol-lowing exposure. Williams et al63 reported an indi-vidual with pulmonary interstitial fibrosis aftermultiple episodes of polymer fume fever.

Clinical Pathology of PFIB Inhalation

PFIB primarily affects the pulmonary system.Although animal studies occasionally report dis-seminated intravascular coagulation and other or-gan involvement, these effects only occur with sub-

EXHIBIT 9-2

PROPERTIES OFPERFLUOROISOBUTYLENE (PFIB)

Chemical formula: (CF3)2C=CF2

Molecular weight: 200

Boiling point at 1 atm: 7.0°C

Gas density (dry air,at 15°C and 760mm Hg = 1.22 g/L): 8.2 g/L

Colorless

Odorless

Very slightly soluble

Data source: Smith W, Gardner RJ, Kennedy GL. Short-term inhalation toxicity of perfluoroisobutylene. Drugand Chemical Toxicology. 1982;5:295–303.


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stantial pulmonary injury, suggesting that systemichypoxia is a major factor.64 No human studies re-port organ involvement other than the respiratorysystem.

Pathological data on acute human exposure toPFIB are not available; however, pathological dataon animals show both histological and ultramicro-scopic changes occurring within 5 minutes of ex-posure.52 Interstitial edema with alveolar fibrindeposition progresses rapidly over the next 24hours, then gradually subsides until the patient isfully recovered. At 72 hours, a type II pneumocytehyperplasia is seen (interpreted as consistent withknown reparative processes). Although some long-term animal pathological changes have been re-ported,54 most animal studies do not identify suchlong-term changes.

Human long-term pathological data are availablein only one reported case: a 50-year-old femaleexperienced approximately 40 episodes of polymerfume fever—typically occurring from smokingcontaminated cigarettes. Eighteen months after herlast episode, progressive exercise dyspnea wasnoted. A cardiopulmonary physical examination,chest radiograph, and ABG were all normal. Pul-monary function testing supported a provisionaldiagnosis of alveolar capillary block syndrome (de-creased DLCO, increased exercise PAO2 – PaO2 gradi-ent, and minimal airway disease). Death occurredfrom an unrelated cause. The autopsy providedhistological evidence of moderate interstitial fibro-sis with minimal chronic inflammatory cell infil-trate.63 Only two human deaths from pyrolysisproducts of polymerized organofluorides have beenreported.53,60

Therapy

There is no recognized prophylactic therapy forhuman PFIB exposure. Animal studies suggest thatincreasing pulmonary concentrations of oxygenfree-radical scavengers containing thiol groups maybe of value; N-acetyl cysteine has been found effec-tive.65,66 No postexposure medical or chemicaltherapy that effectively impedes or reverses the ef-fects of this toxic inhalational injury is known.

Specific therapy for the observed “noncardiac”pulmonary edema symptoms has been derived fromclinical experience with ARDS. Pulmonary edemaresponds clinically to application of positive airwaypressure. PEEP/CPAP (continuous positive airwaypressure) masks are of initial value. Intubation maybe required.

Oxygen supplementation is provided for evidenthypoxia or cyanosis. Expeditious fluid replacementis mandatory when hypotension is present. Com-bined systemic hypotension and hypoxia may dam-age other organ systems. Bacterial superinfectionis sufficiently common to warrant careful surveil-lance cultures. There is no literature support, how-ever, for use of routine prophylactic antibiotics.

Steroid therapy for PFIB exposure has been re-ported in only two instances—both for the sameworker.49 The fact that recovery may be spontane-ous and rapid makes it difficult to decide whethersteroid use improves recovery.

Laboratory studies clearly support the observa-tion that rest subsequent to exposure is useful. Be-cause the intensity of injury and the duration of theclinically latent period are both affected by exer-cise, bed rest and litter transport are preferred.

SUMMARY

During World War I, the number and types ofpulmonary toxicants available to the military in-creased substantially. At least 14 different respira-tory agents were used, as well as obscurants(smokes), harassing agents (chloracetone), and vesi-cants (mustard) that could cause pulmonary injury.Today, only a handful of these toxicants still existin stockpiles around the world, but several, suchas chlorine and phosgene, are currently producedin large quantities for industrial purposes. Whetherproduced for military or industrial uses, thesechemical agents pose a very real threat to militarypersonnel.

Toxic inhalational injury poses a 2-fold problemfor military personnel:

1. No specific therapy exists for impeding orreversing toxic inhalant exposures.

2. Toxic inhalational injury can cause largenumbers of casualties that can significantlyburden medical facilities.

The pathophysiological processes that developin the upper and lower respiratory tract can greatlyincapacitate a casualty or result in death within min-utes of exposure. It is therefore imperative that ad-equate control of the casualty’s airways be main-tained. Medical personnel should look for hypoxia,hypercarbia, and pulmonary edema, all of whichare signs of possible toxic inhalant exposure. Infec-tious bronchitis or pneumonitis (particularly in in-


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tubated patients) is a frequent complication. Theimportance of chronic health problems that occurpostexposure to toxic inhalants is a contentious sub-

ject because of the nebulous signs and symptomsthat mimic degenerative diseases, such as emphy-sema, common to the general population.

REFERENCES

1. Thucydides; Crawley, trans. The Complete Writings of Thucydides: The Peloponnesian War. New York, NY: Ran-dom House; 1951. Unabridged.

2. Haber LF. The Poisonous Cloud. Oxford, England: Clarendon Press; 1986.

3. Weyandt TB, Ridgeley CD Jr. Carbon monoxide. In: Deeter DP, Gaydos JC. Occupational Health: The Soldier andthe Industrial Base. Part 3, Vol 2. In: Zajtchuk R, Jenkins DJ, Bellamy RF, eds. Textbook of Military Medicine. Wash-ington, DC: US Department of the Army, Office of The Surgeon General, and Borden Institute; 1993: 419.

4. US Department of the Army. Smokes. In: Treatment of Chemical Agent Casualties and Conventional Military Chemi-cal Injuries. Washington, DC: DA; 1990: 8-1–8-8. Field Manual 8-285.

5. Herringham WP. Gas poisoning. Lancet. 1920;1:423–424.

6. Haldane JS. The reflex restriction of respiration after gas poisoning. In: Reports of the Chemical Warfare Commit-tee, Medical Research Committee. London, England: Chemical Warfare Department, Army Medical Service; 1918: 3–4.

7. Hunt GH. Changes observed in the heart and circulation and the general after-effects of irritant gas poisoning.In: Reports of the Chemical Warfare Committee, Medical Research Committee. London, England: Chemical WarfareDepartment, Army Medical Service; 1918: 10.

8. Patil LRS, Smith RG, Worwald AJ, Mooney TF. The health of diaphragm cell workers exposed to chlorine. AmInd Hyg Assoc J. 1970;31:678–686.

9. Beck H. Experimentelle Ermittlung von Gerüchsschwelleneiniger wichtige Reizgare (Chlor, Schwefeldioxyd, Ozon,Nitrose) und Ersheimüngen bei Einwirkung geringer Konzentrationen auf deu Meuschen. Würzburg, Germany: Uni-versity of Würzburg; 1959: 1–69. PhD dissertation.

10. Laciak M, Sipa K. The importance of the sense of smelling, in workers of some branches of the chemical indus-try. Medycyna Pracy. 1958;9:85–90.

11. Berghoff S. The more common gasses: Their effect on the respiratory tract. Arch Int Med. 1919;24:678–684.

12. Bunting H. Clinical findings in acute chlorine poisoning. In: Respiratory Tract. Vol 2. In: Fasciculus on ChemicalWarfare Medicine. Washington, DC: Committee on Treatment of Gas Casualties, National Research Council;1945: 51–60.

13. Gilchrist HL, Matz RB. The residual effects of warfare gases: The use of phosgene gas, with report of cases. MedBull Veterans Admin. 1933;10:1–37.

14. Hoveid P. The chlorine accident in Mjondalen (Norway) 26 January 1940: An after investigation. Nord HygTidskr. 1956;37:59–66.

15. Weill HR, Schwarz GM, Ziskind M. Late evaluation of pulmonary function after acute exposure to chlorinegas. Am Rev Respir Dis. 1969;99:374–379.

16. Bunting H. The pathology of chlorine poisoning. In: Respiratory Tract. Vol 2. In: Fasciculus on Chemical WarfareMedicine. Washington, DC: Committee on Treatment of Gas Casualties, National Research Council; 1945: 24–36.

17. The acute lung irritant gases. In: History of the Great War. Vol 2. London, England: H. M. Statistical Office; 1923: 621.


268

18. Chester EH, Gillespie DG, Krause FD. The prevalence of chronic obstructive pulmonary disease in chlorine gasworkers. Am Rev Respir Dis. 1969;99:365–373.

19. Bunting H. Changes in the oxygen saturation of the blood in phosgene poisoning. In: Respiratory Tract. Vol 2.In: Fasciculus on Chemical Warfare Medicine. Washington, DC: Committee on Treatment of Gas Casualties, Na-tional Research Council. 1945: 484–491.

20. Underhill FP. The Lethal War Gases: Physiology and Experimental Treatment. New Haven, Conn: Yale UniversityPress; 1920.

21. Gilchrist HL. A Comparative Study of WWI Casualties from Gas and Other Weapons. Edgewood Arsenal, Edgewood,Md: US Chemical Warfare School; 1928: 1–51.

22. Cucinell SA. Review of the toxicity of long-term phosgene exposure. Arch Environ Health. 1974;28:272–275.

23. Galdston M, Leutscher JA Jr, Longcope WT, Ballich NL. A study of the residual effects of phosgene poisoningin human subjects, I: After acute exposure. J Clin Invest. 1947;26:145–168.

24. Brand P. Effect of a Local Inhalation Dexamethasone Isonicotinate Therapy on Toxic Pulmonary Edemas Caused byPhosgene Poisoning. Würzburg, Germany: University of Würzburg; 1971. Dissertation.

25. Diller WF. Medical phosgene problems and their possible solution. J Occup Med. 1978;20:189–193.

26. Wang Y, Lee LKH, Poh S. Phosgene poisoning from a smoke grenade. Eur J Respir Dis. 1987;70:126–128.

27. Pare CMB, Sandler M. Smoke-bomb pneumonitis: Description of a case. J R Army Med Corps. 1954;100:320–324.

28. Evans EH. Casualties following exposure to zinc chloride smoke. Lancet. 1945;2:368–370.

29. Cullumbine H. The toxicity of screening smokes. J R Army Med Corps. 1957;103:119–122.

30. Hjortso E, Qvist J, Bud MI, et al. ARDS after accidental inhalation of zinc chloride smoke. Intensive Care Med.1988;14:17–24.

31. Johnson FA, Stonehill RB. Chemical pneumonitis from inhalation of zinc chloride. Dis Chest. 1961;40:619–624.

32. Milliken JA, Waugh D, Kadish ME. Acute interstitial pulmonary fibrosis caused by a smoke bomb. Can MedAssoc J. 1963;88:36–39.

33. Hunter D. The Diseases of Occupations. London, England: Hodder and Stoughton; 1978.

34. Cameron GR. Toxicity of chlorsulphonic acid-sulphur trioxide mixture smoke clouds. J Pathol Bacteriol.1954;68:197–204.

35. Ozone in fog. Lancet. 1975;2:1077. Editorial.

36. Scott EG, Hunt WB Jr. Silo-filler’s disease. Chest. 1973;63:701–706.

37. Ramirez RJ, Dowell AR. Silo-filler’s disease: Nitrogen dioxide–induced lung injury. Ann Intern Med. 1961;74:569–576.

38. LaFleche LR, Boivin C, Leonard C. Nitrogen dioxide—A respiratory irritant. Can Med Assoc J. 1961;84:1438–1440.

39. Delaney LT Jr, Schmidt HW, Stroebel CF. Silo-filler’s disease. Mayo Clin Proc. 1956;31:189–194.

40. Ramirez RJ. The first death from nitrogen dioxide fumes. JAMA. 1974;229:1181–1182.

41. Lowry T, Schuman LM. Silo-filler’s disease. JAMA. 1956;162:153–155.


269

42. Becklake MR, Goldman HI, Bosman AR, Freed CC. The long-term effects of exposure to nitrous fumes. Am RevTuberc Pulm Dis. 1957;76:398–412.

43. Jones GR, Proudfoot AT, Hall JT. Pulmonary effects of acute exposure to nitrous fumes. Thorax. 1973;28:61–65.

44. Leib RMP, Davis WN, Brown T, McQuiggan N. Chronic pulmonary insufficiency secondary to silo-filler’s dis-ease. Am J Med. 1958;24:471–478.

45. Harris DK. Polymer-fume fever. Lancet. 1951;2:1008–1011.

46. Williams N, Smith FK. Polymer-fume fever, an elusive diagnosis. JAMA. 1972;219:1587–1589.

47. Smith W, Gardner RJ, Kennedy GL. Short-term inhalation toxicity of perfluoroisobutylene. Drug and ChemicalToxicology. 1982;5:295–303.

48. Cavagna G, Finulli M, Vigliani EC. Studio sperimentale sulla patogensi della febre da inalazione di fumi diTeflon (politetrafluoroetilene) [in Italian]. Med Lav. 1961;52:251–261.

49. Lewis CE, Kerby GR. An epidemic of polymer-fume fever. JAMA. 1965;191:103–106.

50. Waritz RS, Kwon BK. The inhalation toxicity of pyrolysis products of polytetrafluoroethylene heated below500 degrees Centigrade. Am Indust Hygiene Assoc J. 1968;19–26.

51. Clayton JW. Toxicology of the fluoroalkenes: Review and research needs. Environ Health Perspect. 1977;21:255–267.

52. Nold JB, Petrali JP, Wall HG, Moore DH. Progressive pulmonary pathology of two organofluorine compoundsin rats. Inhalation Toxicol. 1991;3:123–137.

53. Auclair F, Baudot P, Beiler D, Limasset JC. Accidents benins et mortels dus aux “traitements” du polytetra-fluoroethylène en milieu industriel: Observations cliniques et mesures physico-chimiques des atmosphèrespolluees. Toxicological European Reasearch. 1983;5(1):43–48.

54. Karpov BD. Establishment of upper and lower toxicity parameters of perfluroisobutylene toxicity. Tr LenigSanit-Gig Med Inst. 1977;111:30–33.

55. Moore DH. Effects of exercise on pulmonary injury induced by two organohalides in rats. In: Proceedings of theWorkshop on Acute Lung Injury and Pulmonary Edema, 4–5 May 1989. Aberdeen Proving Ground, Md: MedicalResearch Institute of Chemical Defense; 1993: 12–19.

56. Brubaker RE. Pulmonary problems associated with the use of polytetrafluoroethylene. J Occup Med. 1977;19:693–695.

57. Evans EA. Pulmonary edema after inhalation of fumes from polytetrafluoroethylene (PTFE). J Occup Med.1973;15:599–601.

58. Nuttall CJB, Kelly MJ, Smith CBS, Whiteside CCKJ. Inflight toxic reaction resulting from fluorocarbon resinpyrolysis. Aerospace Med. 1964;35:676–683.

59. Robbins JJ, Ware RL. Pulmonary edema from Teflon fumes. N Engl J Med. 1964;271:360–361.

60. Makulova ID. Clinical picture of acute poisoning with perflurosebutylene. Gig Tr Prof Zabol. 1965;9:20–23.

61. Capodaglio E, Monarca G, Divito VG. Respiratory syndrome by intermediate volatile products of polytetra-fluoroethylene. Rass Med Insusdr. 1961;30:124–139.

62. Paulet G, Bernard JP. Heavy products appearing during the fabrication of polytetrafluorethylene: Toxicity-physiopathologic action; therapy. Biol-Med (Paris). 1968;57:247–301.

63. Williams N, Atkinson GW, Patchefsky AS. Polymer-fume fever: Not so benign. J Occup Med. 1974;16:519–522.


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64. Zook BC, Malek DE, Kenney RA. Pathological findings in rats following inhalation of combustion products ofpolytetrafluoroethylene (PTFE). Toxicology. 1983;26:25–26.

65. Bridgeman MME, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations inplasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax. 1991;46:39–42.

66. Lailey AF, Hill L, Lawston IW, Stanton D, Upshall DG. Protection by cysteine esters against chemically in-duced pulmonary edema. Biochem Pharmacol. 1991;42:S47–S54.

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