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PULMONARY IRRITANTS: PHOSGENE, CHLORINE, CHLORPICRIN

Smith Freeman, Ph, D,, M,D,

Assistant Professor of Physiology and.PharmacologyNorthwestern University Medical School, Chicago.

Mr, Chairman, and members of the audience; The pulmonaryirritants that I have been asked to c.iscuss be.ore you this after-noon include chlorine, chlorpicrin and phosgene. Vfhat one saysabout phosgene also applies to diphosgene, I will start by tell-ing you a few of the general characteristics of these gases.

General Characteristics

Chlorine, as you pobably all know, is a yellowish-green gaswith an irritating effect on the mucous membranes. This gas isapproximately two and a half times as heavy as air. Chlorine re-acts readily with water to form hydrochloric acid and to liberateoxygen. Its toxicity we will designate as 1.

Chlorpicrin is a light colorless liquid that has a boilingpoint of 112° Centrigrade• Its vapors are live and a half times asheav-.y as air and it has a sweetish'odor which has been describedas resembling that of fresh fly-paper. The gas is quite volatileand it is stable. It doc-s not react readily with acids or alkalisor with water. It has a toxicity of 1+ as compared to chlorine.

Phosgene has the odor of moldy hay. It is a musty odor.The bailing point of phosgene is o° Centrigrade, This gas is threeand a half times heavier than air-, In a dry atmosphere phosgeneis fairly stable. In the presence of moisture it rapidly decom-poses to form hydrochloric acid and carbon dioxide. The toxicityof phosgene as compared to that of chlorine is 10. That is tosay, it is approximately ten times as toxic, and the lethal doseia one-tenth that of chlorine.

Next we will take up some of the clinical manifestations ofacute poisoning by each of these three gases.

Clinical Manifestations

Chlorine; This gas is very irritating to the eyes, nose,mouth and respiratory tract. All moist parts, once they have comein contact with «hlorine, itch and burn and smart. The lachrymal,mucosal, and salivary glands all respond to chlorine with increasedsecretion. Coughing, choking, retching and dyspnoea are all among

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the immediate effects following exposure to chlorine. Cyanosis,frothy sputum and pulmonary edema occur within a few hours siftercontact with a sufficiently high concentration of the gas. Theedema is apt to reach a maximum between 10 and 15 hours after ex-posure to chlorine. In the early stages following exposure to thegas the pulse is full and alow and the blood pressure is well main-tained. as pulmonary edema and the anoxia which accompanies itprogress the pulse and respiration become more rapid and the bloodpressure falls.

Death from pulmonary edema is likely to occur in the first2U hours. Otherwise, the exudate is absorbed rapidly, so that thechcsr will be relatively clear within IS to 72 hours, unless second-ary infection occurs.

Bronchial pneumonia is a fairly common complication afterchlorine poisoning, more so than for either of the other two gases.

Phosgene: Unlike chlorine, phosgene causes relativelylittle irritation to the eyes and the mucosa of the mouth and tothe upper respiratory tract. Consequently the immediate symptomsmay be slight. The retching and paroxysms of coughing observedcharacteristically after chlorine and chlorpicrin may be almostentirely absent. The patient may merely complain of a sense oftightness in the chest and the symptoms may be so mild that thevictim is deceived as to tho severity of the injury. There havebeen several examples of workers exposed to phosgene who feltbetter in a little while and even wanted to go back to work, butsubsequent events indicated that they were in no shape to do so.Dogs that are exposed to phosgene do not lachryraate or show evi-dence of acute discomfort while in the gassing chamber. Shortlyafterwards the majority of the animals will vomit, defecate, uri-nate and may have diarrhea. Thereafter dyspnoea may be the onlygross symptom for some hours.

... T. Jones reports the case of a man splashed with phos-gene when a pipe broke. The patient coughed, became pale and hada nosebleed. Thereafter he felt well and no abnormal physicalfindings could be demonstrated* lie was rested s,nd transported toa hospital as a precautionary measure. Six hours later he complain-ed of feeling ill and presented the typical gray collapse that mayoccur after phosgene poisoning. His pulse became almost impercep-tible, the rate went up to 130 per minute. The heart sounds wereessentially Inaudible, Fine crepitations were present throughoutthe chest. The face was pale, with a purple tinge to the tips ofhis ears; his skin was cold and clammy. There was extreme rest-lessness, coughing and gasping for breath; respiration was 66 perminute. There was a copious frothy, slightly yellow sputum,,Oxygen therapy was continued for five days. On the seventh daydiaphragmatic pleurisy developed. There was dyspnea on exertionuntil the forty-second day.

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Vedder reports the case of a chemist who inhaled abreath of phosgene, became pale and coughed slightly. He wasremoved to a hospital whore he remained comfortable and appar-ently normal for four and a half hours. Afterwards coughingand the expectoration of large quantities of frothy fluidbegan, his face became gray, and ho died five and a half hoursafter exposure to the gas.

Phosgene cases have been divided into those with blue orwith gray cyanosis. The former group is said to have distendedveins and may possibly have an increased venous pressure. Anincrease in venous pressure has not been demonstrated experi-mentally, The cases with gray cyanosis show signs of a peri-pheral circulatory collapse. The pulse is rapid and the bloodpressure low, the respiration shallow and rapid. Those indi-viduals arc likely to have received a higher dosage of gas andare generally considered in a terminal state. Patients withblue cyanosis may become gray prior to death.

The pulmonary edema which accornpani.es the cyanosis ismost likely to occur during the first 2U hours after exposureto the gas. The majority of fatalities occur' within the firsttwo or throe days. The latent period between exposure and thegross manifestations of lung edema is variable, but will de-pend to some extent upon the amount of gas inhaled.

Dogs gassed with phosgene show beginning lung edema gross-ly on autopsy two hours after gassing, but physical signs ofedema may not bo demonstrable before 10 or 12 hours.

Chiorpierin; Chlorpicrin, as you know, is also calledvomiting gas, .It has a variety of actions. It resembleschlorine by causing irritation to the mucous membranes and itresembles phosgene in that it also injures the periphery of thelung. In symptomatic characteristics it is intermediate in itsposition between the two other gases. It causes lachrymation,coughing, nausea, vomiting, colic, diarrhea and all the acuteand chronic sequelae which may result from exposure to citherof the two gasos previously described. These include pulmonaryedema, bronchial pneumonia, lung abscesses, atelectasis, chron-ic bronchitis, bronchiectasis, asthma, and emphysema.

Pathological Physiology

The pulmonary edema which accompanies injury from a suff-icient dosage of chlorine is associated with hemoconccntration.The bradycardia observed soon after gassing is replaced by arapid feeble pulse as the patient becomes worse. Circulatorycollapse, anoxia, low blood pressure, and terminal acidosis areall part of the advanced findings following chlorine inhalation.

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Typically phosgene causes a preliminary hemodilution whichprecedes hemoconcontration. This period of hemodilution is call-ed the first stage. There is a question as to whether the hemo-dilution actually represents an increase of fluid in the bloodstream or an accumulation of rod blood cells in the lung cap-illaries, Some authors have failed to find any increase in bloodvolume during the early stages following phosgene poisoning, where-as others have reported that the volume of blood is increased.

After the preliminary dilution of the blood (apparent dilu-tion) the hematocrit readings will rapidly become higher than thpywere initially. The hemoconcontration will go to such a point thatthe cells may represent as much as CO per cent of the volume of theblood in the experimental animal. This period of hemoconcontrationis part of the second stage iollowing phosgene poisoning. Thehemoconcontration usually roaches a maximum 12 to 24 hours follow-ing exposure to the gas, but less frequently may roach a maximumfrom 24 to 4C hours following exposure, Experimentally, hcraocon-centration does not necessarily precede death. I have seen animalswhich died in the hemodilution stage. Both domodilution and hemo-conccntration are associated with the outpouring of fluid into thelungs, but the edema usually becomes apparent during the stage ofhomoconcentration. This fluid is a transudate containing the pro-tein constituents of the blood, plasma. Hardy does the pulmonaryedema fluid contain many red blood colls.

Following exposure to phosgene, manifestations of vagotoniaoccur and the heart rate decreases from around SO or 90 down to40 or 50 per minute. Retching and defecation are the rule ratherthan the exception in the gassed dog. These manifestations canbo abolished by vagotomy or sufficient atropine. As the pulmon-ary edema progresses the respiration and rate of the heart arcmarkedly increased. The percentage saturation of the arterialblood with oxygen decreases, Hemoconcentration occurs, cyanosisbecomes apparent, the body temperature falls, and the subject be-comes restless and apprehensive. There is a terminal acidosis.

Pathology

Chlorine: Chlorine gas injures the oral mucous membranesand upper respiratory tract. There may be a necrosis of the lin-ing of the larynx, trachea, and the bronchij a fibrinous exudateforms over the injured area and sufficiently injured areas slough.The injury may extend to the smaller radicles of the lung and thesemay bo obstructed with exudate and necrotic epithelium. Leucocytesinvade the injured areas, Hyalinization and necrosis may extendto the periphery of the lung. Injury to the alveolar wall resultsin an edema which fills the air spaces of both the injured and un-injured lung tissue with fluid. Areas of emphysema are inter-spersed between areas of consolidation. After a few days if >

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tho lesions become more local. Bronchial pneumonia and atelec-tasis may occur. There may bo some scarring of the lungs astho foci of secondary infection heal.

Phosgene: Soon after injury of the lungs with this gas amicroscopic examination of tissues is very disappointing. One seeslittle that is abnormal except fluid and capillaries congested withblood. The failure in function far outruns any microscopic mani-festations of injury to the lung tissue insofar as its cellular make-up is concerned, A mild hyperemia of the trachea may occur, but isrelatively inconsequential. The outpouring of fluid into the al-veolar spaces is by far the most outstanding manifestation of pul-monary injury. Patches of emphysema also occur. The fluid fillsthe periphery of the lung and extends from the periphery towardthe main bronchi, limiting the respiratory movement of the lung.The movement of air in and out of tho lung churns the transudateinto a stable foam, and forms a frothy bubbling fluid which isquite a stable emulsion and which eventually serves as an effectivebarrier to the free exchange of air. After a few days, necrosisof the bronchcol, r epithelium with cellular infiltration occurs.Bronchopneumonia, resulting in some fibrosis of the lung is lesslikely after phosgene than after chlorine poisoning.

Ghloruicrin: Chlorpicrin causes changes intermediate be-tween those of chlorine and phosgene. There may be superficialnecrosis of the upper respiratory tract epithelium and the nec-rosis rosy extend to the bronchcolar epithelium. Pulmonary edemaand emphysema also occur after chlorpicrin with subsequent focalnecrosis.

Treatment

It should be pointed out in the beginning that these pul-monary irritants and injurants react rapidly with the tissues ofthe body to do irreversible harm. Treatment must be institutedearly to bo most effective

The object of therapy is to minimize the constitutional re-action to the injury which has occurred, that is, to prevent orminimize the pulmonary edema that so frequently results.

Once an edema develops, a vicious cycle is sot up, Exuda-tion leads to impaired lung function and anoxia. Anoxia leadsto increased capillary permeability and hence to further exuda-tion. The exudation encroaches on whatever functional lung tissuemay remain. Practically all authors agree that rest and moderatewarmth are desirable. These conditions reduce the work of thebody to a minimum so that the oxygen requirement and the carbondioxide production may be reduced to a minimum. The subjett shouldnot be warm enough to cause perspiration. The room temperatureshould not be above 75° Fahrenheit nor the relative humidity morethan 60 per cent.

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The question as to whether or not the gas patient shouldbe considered a stretcher case is perhaps somewhat arbitrary. Theaim is to minimize dyspnoea, coughing and spasm and whatever courseof behavior will make the symptoms minimal probably is most de-sirable* Certainly there should bo no double-quick, nor any ex-cess of exercise which is likely to increase pulmonary trauma,

Various measures have been recommended by different authorsin the treatment of gassed patients. These are not presented inthe order of their relative merit.

Venesection: The removal of 500 of blood soon afterexposure to phosgene has boon recommended. This procedure maybo repeated at later intervals if there is evidence of an increas-ed venous pressure. Venesection is contraindicated in individ-uals who have circulatory collapse which may be indicated by graycyanosis, Underhill advocated the introduction of small quanti-ties of saline in conjunction with venesection, He would bloodthem immediately and then give a little salt solution. It isquestionable whether vonesection is ever of benefit to tho gassedpatient.

Oxygon Inhalation: Concentrations of oxygon varying from50 to 100 per cent have been recommended. The amount of oxygon tobo administered must be judged by the findings in the individualcase. To minimize dyspnoea, anoxia, restlessness and anxiety andto promote rest, oxygen administration should be instituted as earlyas possible. Certainly one should not wait until the patient iscyanotic and edematous.

Helium-oxygen Administration: Barach advocates tho use ofa mixture of 2>% oxygon and. 65% helium in tho treatment of pulmon-ary edema. Ho recommends positive pressure respiration as anadditional measure to reduce the formation of transudate in thelungs, Tho positive pressure recommended is in the neighborhoodof 6 centimeters of water, A mask or hood is essential for ob-taining positive pressure in conjunction with helium and oxygentherapy; however, he states that some benefit can be derived fromsimply expressing the expired air through a cigarette holder orthrough pursed lips. There is thought to bo a disproportion be-tween tho function of tho two sides of tho heart, the left sidenot keeping pace. Increasing tho intrapulmonary pressure and dur-ation of expiration decreases the amount of blood entering thoright heart and hence reduces the pulmonary congostion.

Drugs; Restlessness, anxiety, dyspnoea, coughing and de-lirium are symptoms ono is apt to encounter in a person exposedto those gases. Sedation is frequently necessary to reduce therespiratory effort and to promote rest. Morphine or its deriva-tives, by injection, arc probably the most effective drugs for

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the purpose of promoting rest, reducing dyspnoea and making therespiration slow, regular and efficient. Those drugs should begiven in small doses (l/6 to 1/ 1+ gr,), and no more should be usedthan is absolutely necessary, for fear of depressing the respira-tory center, One should remember that the symptoms of anoxia in-clude restlessness, anxiety and delirium and that these symptomsmay respond to increasing the oxygen content of the inspired air.

Solomon suggests that one should avoid if possible the useof morphine in cyanotic patients, but further states that the veyyrestless patient should receive morphine even if deeply cyanosed.It is his opinion that barbiturates may be used in moderate doses.However, they too depress the respiratory center and tend to reducecapillary tone and. therefore predispose to shock in the susceptibleindividual. The cough which so frequently occurs is unproductivein the early stages, only adds trauma to the already injured lungsand disturbs the rest of the individual. Codeine is probably thedrug of choice for inhibiting the cough.

Spasm of the bronchial tree and pulmonary vessels may be afactor in the events which follow inhalation of pulmonary irritants.Atropine has been shown capable of relieving the bronchial spasmduo to bromine inhalation. Many authors have condemned atropineas being without any value in the treatment of pulmonary edema.There is no unanimity of opinion concerning the importance of spasmas a factor in producing pulmonary edema or upon the most effectivemethod for relieving whatever spasm does occur. Atropine will re-duce the manifestations of vagotonia which follow the inhalation ofthose gases. There is no adequate experimental proof one way orthe other as to the value of atropine for other than symptomaticrelief. Numerous other drugs that act on the circulatory and res-piratory systems have been recommended for treatment of pulmonaryedema and its complications. These drugs include coraminc, caffeinesodium benzoate, papaverine, and preparations of digitalis. Thereis no adequate proof of the effectiveness of any of these drugs inpulmonary edema produced by these gases. Postural drainage hasbeen suggested as an aid in draining off the edema fluid formed inthe lungs. However, such a posture as would be necessary for drain-age of the lungs may have undesirable effects upon the circulationand respiration.

Sulfanilamide and the other sulfa drugs arc of value forpreventing or minimizing secondary infection following injury tothe lungs by those gases. Instrumentation and general anestheticsore not well tolerated by the gassed patient. If some surgicalprocedure has to bo carried out a local anesthetic probably shouldbe used*