Freeman III 
PULMONARY IRRITANTS: PHOSGENE, CHLORINE, CHLORPICRIN 
Smith Freeman, Ph, D,, M,D, 
Assistant Professor of Physiology and.Pharmacology 
Northwestern University Medical School, Chicago. 
Mr, Chairman, and members of the audience; The pulmonary 
irritants that I have been asked to c.iscuss be.ore you this after- 
noon include chlorine, chlorpicrin and phosgene. Vfhat one says 
about 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 gas 
with an irritating effect on the mucous membranes. This gas is 
approximately two and a half times as heavy as air. Chlorine re- 
acts readily with water to form hydrochloric acid and to liberate 
oxygen. Its toxicity we will designate as 1. 
Chlorpicrin is a light colorless liquid that has a boiling 
point of 112° Centrigrade• Its vapors are live and a half times as 
heav-.y as air and it has a sweetish'odor which has been described 
as resembling that of fresh fly-paper. The gas is quite volatile 
and it is stable. It doc-s not react readily with acids or alkalis 
or 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 three 
and a half times heavier than air-, In a dry atmosphere phosgene 
is fairly stable. In the presence of moisture it rapidly decom- 
poses to form hydrochloric acid and carbon dioxide. The toxicity 
of phosgene as compared to that of chlorine is 10. That is to 
say, it is approximately ten times as toxic, and the lethal dose 
ia one-tenth that of chlorine. 
Next we will take up some of the clinical manifestations of 
acute 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 come 
in contact with «hlorine, itch and burn and smart. The lachrymal, 
mucosal, and salivary glands all respond to chlorine with increased 
secretion. Coughing, choking, retching and dyspnoea are all among Freeman III 
the immediate effects following exposure to chlorine. Cyanosis, 
frothy sputum and pulmonary edema occur within a few hours sifter 
contact with a sufficiently high concentration of the gas. The 
edema is apt to reach a maximum between 10 and 15 hours after ex- 
posure to chlorine. In the early stages following exposure to the 
gas the pulse is full and alow and the blood pressure is well main- 
tained. as pulmonary edema and the anoxia which accompanies it 
progress the pulse and respiration become more rapid and the blood 
pressure falls. 
Death from pulmonary edema is likely to occur in the first 
2U hours. Otherwise, the exudate is absorbed rapidly, so that the 
chcsr will be relatively clear within IS to 72 hours, unless second- 
ary infection occurs. 
Bronchial pneumonia is a fairly common complication after 
chlorine poisoning, more so than for either of the other two gases. 
Phosgene: Unlike chlorine, phosgene causes relatively 
little irritation to the eyes and the mucosa of the mouth and to 
the upper respiratory tract. Consequently the immediate symptoms 
may be slight. The retching and paroxysms of coughing observed 
characteristically after chlorine and chlorpicrin may be almost 
entirely absent. The patient may merely complain of a sense of 
tightness in the chest and the symptoms may be so mild that the 
victim is deceived as to tho severity of the injury. There have 
been several examples of workers exposed to phosgene who felt 
better in a little while and even wanted to go back to work, but 
subsequent 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. Shortly 
afterwards the majority of the animals will vomit, defecate, uri- 
nate and may have diarrhea. Thereafter dyspnoea may be the only 
gross 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 had 
a nosebleed. Thereafter he felt well and no abnormal physical 
findings could be demonstrated* lie was rested s,nd transported to 
a hospital as a precautionary measure. Six hours later he complain- 
ed of feeling ill and presented the typical gray collapse that may 
occur after phosgene poisoning. His pulse became almost impercep- 
tible, the rate went up to 130 per minute. The heart sounds were 
essentially Inaudible, Fine crepitations were present throughout 
the chest. The face was pale, with a purple tinge to the tips of 
his ears; his skin was cold and clammy. There was extreme rest- 
lessness, coughing and gasping for breath; respiration was 66 per 
minute. There was a copious frothy, slightly yellow sputum,, 
Oxygen therapy was continued for five days. On the seventh day 
diaphragmatic pleurisy developed. There was dyspnea on exertion 
until the forty-second day. Freeman III 
Vedder reports the case of a chemist who inhaled a 
breath of phosgene, became pale and coughed slightly. He was 
removed to a hospital whore he remained comfortable and appar- 
ently normal for four and a half hours. Afterwards coughing 
and the expectoration of large quantities of frothy fluid 
began, his face became gray, and ho died five and a half hours 
after exposure to the gas. 
Phosgene cases have been divided into those with blue or 
with gray cyanosis. The former group is said to have distended 
veins and may possibly have an increased venous pressure. An 
increase 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 blood 
pressure low, the respiration shallow and rapid. Those indi- 
viduals arc likely to have received a higher dosage of gas and 
are generally considered in a terminal state. Patients with 
blue cyanosis may become gray prior to death. 
The pulmonary edema which accornpani.es the cyanosis is 
most likely to occur during the first 2U hours after exposure 
to the gas. The majority of fatalities occur' within the first 
two or throe days. The latent period between exposure and the 
gross 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 of 
edema may not bo demonstrable before 10 or 12 hours. 
Chiorpierin; Chlorpicrin, as you know, is also called 
vomiting gas, .It has a variety of actions. It resembles 
chlorine by causing irritation to the mucous membranes and it 
resembles phosgene in that it also injures the periphery of the 
lung. In symptomatic characteristics it is intermediate in its 
position between the two other gases. It causes lachrymation, 
coughing, nausea, vomiting, colic, diarrhea and all the acute 
and chronic sequelae which may result from exposure to cither 
of the two gasos previously described. These include pulmonary 
edema, 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 a 
rapid feeble pulse as the patient becomes worse. Circulatory 
collapse, anoxia, low blood pressure, and terminal acidosis are 
all part of the advanced findings following chlorine inhalation. Freeman III 
Typically phosgene causes a preliminary hemodilution which 
precedes 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 blood 
stream or an accumulation of rod blood cells in the lung cap- 
illaries, Some authors have failed to find any increase in blood 
volume 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 thpy 
were initially. The hemoconcontration will go to such a point that 
the cells may represent as much as CO per cent of the volume of the 
blood in the experimental animal. This period of hemoconcontration 
is part of the second stage iollowing phosgene poisoning. The 
hemoconcontration usually roaches a maximum 12 to 24 hours follow- 
ing exposure to the gas, but less frequently may roach a maximum 
from 24 to 4C hours following exposure, Experimentally, hcraocon- 
centration does not necessarily precede death. I have seen animals 
which died in the hemodilution stage. Both domodilution and hemo- 
conccntration are associated with the outpouring of fluid into the 
lungs, but the edema usually becomes apparent during the stage of 
homoconcentration. This fluid is a transudate containing the pro- 
tein constituents of the blood, plasma. Hardy does the pulmonary 
edema fluid contain many red blood colls. 
Following exposure to phosgene, manifestations of vagotonia 
occur and the heart rate decreases from around SO or 90 down to 
40 or 50 per minute. Retching and defecation are the rule rather 
than the exception in the gassed dog. These manifestations can 
bo abolished by vagotomy or sufficient atropine. As the pulmon- 
ary edema progresses the respiration and rate of the heart arc 
markedly increased. The percentage saturation of the arterial 
blood with oxygen decreases, Hemoconcentration occurs, cyanosis 
becomes 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 membranes 
and upper respiratory tract. There may be a necrosis of the lin- 
ing of the larynx, trachea, and the bronchij a fibrinous exudate 
forms over the injured area and sufficiently injured areas slough. 
The injury may extend to the smaller radicles of the lung and these 
may bo obstructed with exudate and necrotic epithelium. Leucocytes 
invade the injured areas, Hyalinization and necrosis may extend 
to the periphery of the lung. Injury to the alveolar wall results 
in 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 > Freeman III 
tho lesions become more local. Bronchial pneumonia and atelec- 
tasis may occur. There may bo some scarring of the lungs as 
tho foci of secondary infection heal. 
Phosgene: Soon after injury of the lungs with this gas a 
microscopic examination of tissues is very disappointing. One sees 
little that is abnormal except fluid and capillaries congested with 
blood. 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 is 
relatively 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 fills 
the periphery of the lung and extends from the periphery toward 
the main bronchi, limiting the respiratory movement of the lung. 
The movement of air in and out of tho lung churns the transudate 
into a stable foam, and forms a frothy bubbling fluid which is 
quite a stable emulsion and which eventually serves as an effective 
barrier to the free exchange of air. After a few days, necrosis 
of the bronchcol, r epithelium with cellular infiltration occurs. 
Bronchopneumonia, resulting in some fibrosis of the lung is less 
likely after phosgene than after chlorine poisoning. 
Ghloruicrin: Chlorpicrin causes changes intermediate be- 
tween those of chlorine and phosgene. There may be superficial 
necrosis of the upper respiratory tract epithelium and the nec- 
rosis rosy extend to the bronchcolar epithelium. Pulmonary edema 
and emphysema also occur after chlorpicrin with subsequent focal 
necrosis. 
Treatment 
It should be pointed out in the beginning that these pul- 
monary irritants and injurants react rapidly with the tissues of 
the body to do irreversible harm. Treatment must be instituted 
early 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 or 
minimize 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 leads 
to increased capillary permeability and hence to further exuda- 
tion. The exudation encroaches on whatever functional lung tissue 
may remain. Practically all authors agree that rest and moderate 
warmth are desirable. These conditions reduce the work of the 
body to a minimum so that the oxygen requirement and the carbon 
dioxide production may be reduced to a minimum. The subjett should 
not be warm enough to cause perspiration. The room temperature 
should not be above 75° Fahrenheit nor the relative humidity more 
than 60 per cent. Freeman III 
The question as to whether or not the gas patient should 
be considered a stretcher case is perhaps somewhat arbitrary. The 
aim is to minimize dyspnoea, coughing and spasm and whatever course 
of 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 authors 
in the treatment of gassed patients. These are not presented in 
the order of their relative merit. 
Venesection: The removal of 500 of blood soon after 
exposure to phosgene has boon recommended. This procedure may 
bo 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 gray 
cyanosis, Underhill advocated the introduction of small quanti- 
ties of saline in conjunction with venesection, He would blood 
them immediately and then give a little salt solution. It is 
questionable whether vonesection is ever of benefit to tho gassed 
patient. 
Oxygon Inhalation: Concentrations of oxygon varying from 
50 to 100 per cent have been recommended. The amount of oxygon to 
bo administered must be judged by the findings in the individual 
case. To minimize dyspnoea, anoxia, restlessness and anxiety and 
to promote rest, oxygen administration should be instituted as early 
as possible. Certainly one should not wait until the patient is 
cyanotic and edematous. 
Helium-oxygen Administration: Barach advocates tho use of 
a mixture of 2>% oxygon and. 65% helium in tho treatment of pulmon- 
ary edema. Ho recommends positive pressure respiration as an 
additional measure to reduce the formation of transudate in the 
lungs, Tho positive pressure recommended is in the neighborhood 
of 6 centimeters of water, A mask or hood is essential for ob- 
taining positive pressure in conjunction with helium and oxygen 
therapy; however, he states that some benefit can be derived from 
simply expressing the expired air through a cigarette holder or 
through pursed lips. There is thought to bo a disproportion be- 
tween tho function of tho two sides of tho heart, the left side 
not keeping pace. Increasing tho intrapulmonary pressure and dur- 
ation of expiration decreases the amount of blood entering tho 
right 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 exposed 
to those gases. Sedation is frequently necessary to reduce the 
respiratory effort and to promote rest. Morphine or its deriva- 
tives, by injection, arc probably the most effective drugs for Freeman III 
the purpose of promoting rest, reducing dyspnoea and making the 
respiration slow, regular and efficient. Those drugs should be 
given in small doses (l/6 to 1 /1+ gr,), and no more should be used 
than 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 symptoms 
may respond to increasing the oxygen content of the inspired air. 
Solomon suggests that one should avoid if possible the use 
of morphine in cyanotic patients, but further states that the veyy 
restless 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 reduce 
capillary tone and. therefore predispose to shock in the susceptible 
individual. The cough which so frequently occurs is unproductive 
in the early stages, only adds trauma to the already injured lungs 
and disturbs the rest of the individual. Codeine is probably the 
drug of choice for inhibiting the cough. 
Spasm of the bronchial tree and pulmonary vessels may be a 
factor in the events which follow inhalation of pulmonary irritants. 
Atropine has been shown capable of relieving the bronchial spasm 
duo to bromine inhalation. Many authors have condemned atropine 
as being without any value in the treatment of pulmonary edema. 
There is no unanimity of opinion concerning the importance of spasm 
as a factor in producing pulmonary edema or upon the most effective 
method for relieving whatever spasm does occur. Atropine will re- 
duce the manifestations of vagotonia which follow the inhalation of 
those gases. There is no adequate experimental proof one way or 
the other as to the value of atropine for other than symptomatic 
relief. Numerous other drugs that act on the circulatory and res- 
piratory systems have been recommended for treatment of pulmonary 
edema and its complications. These drugs include coraminc, caffeine 
sodium benzoate, papaverine, and preparations of digitalis. There 
is no adequate proof of the effectiveness of any of these drugs in 
pulmonary edema produced by these gases. Postural drainage has 
been suggested as an aid in draining off the edema fluid formed in 
the lungs. However, such a posture as would be necessary for drain- 
age of the lungs may have undesirable effects upon the circulation 
and respiration. 
Sulfanilamide and the other sulfa drugs arc of value for 
preventing or minimizing secondary infection following injury to 
the lungs by those gases. Instrumentation and general anesthetics 
ore not well tolerated by the gassed patient. If some surgical 
procedure has to bo carried out a local anesthetic probably should 
be used*