THE ELIMINATION OF CARBON MONOXIDE FROM

THE BLOOD AFTER A DANGEROUS DEGREE OF

ASPHYXIATION, AND A THERAPY FOR ACCELER-
ATING THE ELIMINATION

YANDELL HENDERSON AND HOWARD W. HAGGARD

Investigations performed for the United States Bureau of Mines, in the Physiological
Laboratory of the Yale University School of Medicine

Received for publication June 4, 1920

Within a few hours after profound but not fatal poisoning with
carbon monoxide no trace of the gas is found in the blood (1).
It has been eliminated through a reversal of the process through
which it was absorbed. And yet for days, months, or even for
life, structural degenerations, and functional derangement, usu-
ally either nervous or cardiac, may continue.
No therapeutic measures (2) as yet suggested have proved of
value, or promise much, in relieving these effects. They are the
sequelae of the injury wrought by oxygen deficiency and its con-
comitants while the gas was still in the victim’s blood.
Our attention happened to be directed to the question of the
rate at which the gas is eliminated. We thus came upon a point
which has been overlooked, although it is obvious enough when
once seen. It suggests a therapy-or perhaps rather a prophy-
laxis.
So far s we are aware, no one has devoted particular attention
to the rate at which carbon monoxide is eliminated during the
first hour or two after a gassing which has produced a saturation
or the blood of considerably more than fifty per cent, with coma
and its accompaniments.
We have recently studied among other questions concerning
carbon monoxide the rate of elimination in men who have reached
saturations of 20 or 30 per cent (3). Haldane (4) has recorded
the rate of elimination after saturations of 40 or even 50 per cent.
11
12 YANDELL HENDERSON AND HOWARD W. HAGGARD

All of these data indicate an elimination during the first hour

of about one-half of the amount previously absorbed.
But these observations do not touch the matter to which we
have here to call attention; for the subjects in all of these experi-
ments were breathing practically normal volumes of air, and
their metabolism-oxygen consumption and CO2 production-was
at most only slightly impaired. It should be mentioned however
that Haldane (4) noted that when carbon monoxide asphyxiation
becomes acute over-breathing occurs; and that in coma the body
rapidly becomes cold, indicating depressed oxidation. He has
demonstrated also in numerous papers the close dependence of
volume of breathing upon the amount of CO2 requiring elimina-
tion from the body.
No one however has made the obvious inference from these
facts. The observations which we have to report came to us as
a purely experimental and unanticipated discovery.

DEPRESSED BREATHING AND CONTINUED ASPHYXIA

In brief, our observations indicate that during the develop-

ment of asphyxia under carbon monoxide there is excessive
breathing which markedly reduces the body’s store of CO2. Un-
der asphyxia the oxidative metabolism and production of CO2
are apparently greatly depressed. When the victim is removed
from the poisonous atmosphere the breathing, lacking its normal
stimulus, remains at a very low level for an hour or more. The
body lacks the CO2 needed to maintain an efficient ventilation of
the lungs. The elimination of carbon monoxide during this time
is therefore very slight. Although the body is surrounded by
fresh air the condition of asphyxiation continues within the tis-
sues. Even the administration of oxygen has no great effect,
for it is not adequately inhaled. Until a sufficient amount of
CO2 is reaccumulated in the blood, and a sufficient oxidative
metabolism recovered, so that efficient breathing is restored, the
injurious conditions within the living cells of the nervous system
and heart are only very graduaily abated. When, as ‘in our
experiments, the period of gassing is brief b’ut acute, most of the
 ELIMINATION OF CARBON MONOXIDE FROM BLOOD 13

asphyxia during which the harm is wrought may occur after the
subject is removed from the poisonous atmosphere. It may be
largely during this time that the autolytic and necrotic processes
are so intensified as to be thereafter irreversible.
This is probably what happens sometimes, for example, in the
case of city firemen overcome by smoke. It is likely to occur
also in acute industrial poisoning around gas plants and blast
furnaces. Even in the common sleeping room accident in which
the gassing progresses over night, the period of most profound
asphyxia comes at the end and is continued by the depressed
breathing for a considerable time after the victim is removed to
fresh air. In such cases the abbreviation of the post-gassing
period of depressed breathing and its continued asphyxia may be
of critical importance in preventing permanent damage.
The treatment which, as we shall show, achieves the rapid
termination of asphyxia is the inhalation of a mixture of oxygen
and CO2. The CO2 induces active respiration which affords the
oxygen an opportunity to displace carbon monoxide rapidly. It
is probably of value also in replacing in the blood and tissues the
CO2 lost by the previous over breathing (5).

EXPERIMENTAL PROCEDURES

Our experiments were performed upon dogs. A sample of

blood was obtained from the femoral artery under local anesthesia
with cocaine. The animal was then placed in one of the gassing
chambers developed here for the experiments done under the
Bureau of Mines and the Chemical Warfare Service (6). A suf-
ficient amount of city illuminating gas was added to the air in a
large gasometer to produce a concentration of 0.3 to 0.4 per cent
of carbon monoxide. This mixture was then passed into the
chamber by a motor driven air blower.
During the gassing the manifestations presented by the ani-
mals were almost identical in every instance. Up to unconscious-
ness the picture presented resembled closely that of slow anes-
thesia with ether. At first the animal moved about restlessly
and scratched at the glass sides. A stage of excitement followed;
14 YANDELL HENDERSON AND HOWARD W. HAGGARD

then muscular weakness. The animal’s hind legs relaxed, and

it supported itself with wide spread front legs. At about this
time the respiration became more and more vigorous, culminat-
ing in violent and prolonged hyperpnea. Saliva dripped from
the jaw’s and vomiting usually occurred. The animal then lay
down, and there was thereafter only an occasional feeble move-
ment. The breathing became of the Cheyne-Stokes type, and
unconsciousness followed.
After five or ten minutes of unconsciousness the animal was
removed from the gas chamber. A sample of arterial blood was
at once taken. In this the percentage saturation of the blood
with carbon monoxide was determined by the Haldane method
(7); a dilution of the original normal blood was titrated with a
dilute solution of carmine until equality of tint with the blood
containing carbon monoxide was obtained. At suitable intervals
thereafter additional blood samples were taken from the animal
and the percentage saturation with carbon monoxide determined.
At the same time the general physiological condition of the ani-
mal was recorded.
Although we here speak of these as experiments on carbon
monoxide poisoning, it should be noted that illuminating gas
was used. In some experiments performed to determine the rela-
tive toxicity of iiluminating gas and of pure carbon monoxide,
made from formic acid, we found that with the former death oc-
curred when the concentration of carbon monoxide in the blood
reached about 65 per cent saturation, while with the pure gas in
equal dilution death occurred at blood saturations of about 85
per cent. Evidently the illuminating gas used owes about 25
per cent of its toxicity to some substance other than carbon mon-
oxide. But as this substance appears to be likewise directly or
indirectly a powerful respiratory stimulant, and as illuminating
gas therefore indues even more marked over breathing than is
the case with pure carbon monoxide in corresponding dilutions,
the validity of the conclusions to be drawn from the experiments
is not affected.
 ELIMINATION OF CARBON MONOXIDE FROM BLOOD 15

THE ELIMINATION OF CARBON MONOXIDE IN UNTREATED ANIMALS

Three experiments were performed in which, after a gassing of

about half an hour, the animal was merely removed from the
chamber, and the course of events observed. One died in thirty
minutes. Owing to the inefficient breathing, there was a scarcely
measurable decrease in the concentration of carbon monoxide in
its blood. The other two exhibited during the first half hour or
more a markedly depressed respiration; and there was a corre-
spondingly slight decrease in the concentration of carbon monox-
ide in the blood. Thereafter the volume of breathing gradually

“1;.’,,,

FIG. 1. PLOTTED FROM THE DATA OF EXPERIMENTS 1, 2, AND 3

Showing the rate of elimination of carbon monoxide from the blood of pro-
foundly asphyxiated but thereafter untreated animals.

increased, and the elimination of carbon monoxide progressed

correspondingly. Consciousness returned slowly after about an
hour; but even after several hours the animals were still sick and
unsteady.
The analytical data are plotted in figure 1 from the following
protocols:

Experiment 1. Dog, male, 7.5 kilos. Gassed for thirty minutes.

Completely unconscious on removal from gassing chamber.
The times at which blood samples were taken and the percentage
saturation with carbon monoxide found were as follows:
Time, minutes 0 20 60 80 100 120
Percent CO 41 39 28 20 12 4
 16 YANDELL HENDERSON AND HOWARD W. HAGGARD

Experinza.t 2. Dog, male, 10 kilos. Gassed for thirty-five minutes.

Completely unconscious.’ Bloo) samples and analyses as in previous
experiment.
Time, minutes 0 20 40 60 80 100 120 140
Percent CO 62 58 55 52 45 33 16 0
Experiment 3. Dog. Female, 6 kilos. Gassed for thirty minutes.
Completely unconscious. Death thirty minutes later.
Time, minutes 0 20 30

Percent CO 64 62 62

THE ELIMINATION OF CARBON MONOXIDE UNDER INHALATION OF

OXYGEN

The procedure in these experiments was similar to that in the

preceding experiments except that the animals were made to
inspire pure oxygen by means of a mask and valves with as little
rebreathing as possible.

5 - - - - -

t I
‘: I 1,
I I I I
FIG. 2. PLOTTED FROM THE DATA OF EXPERIMENTS 4 AND 5

Showing the rate of elimination of carbon monoxide from the blood of animals
under inhalation of oxygen.

It will be seen from the protocols and from figure 2, in which

the results are plotted, that during the first forty minutes the
rate of elimination of carbon monoxide was only slightly more
rapid than in the case of animals breathing merely air. This
was manifestly due to the marked depression of breathing during
 ELIMINATION OF CARBON MONOXIDE FROM BLOOD 17

this time. During the next forty minutes, however, the rate of
elimination of carbon monoxide was markedly accelerted by oxy-
gen inhalation. The subsequent condition of the animals was
distinctly better than was the case with untreated animals.

Experiment 4. Dog, male, 9 kilos. Gassed thirty-four minutes.

Completely unconscious. Blood samples and analyses as in previous
experiments.

Time, minutes 0 20 40 60 80
Percent CO 58 55 50 33 12
Experiment 5. Dog, female, 7 kilos. Gassed thirty-eight minutes.
Completely unconscious.
Time, minutes 0 20 40 80

Percent CO 55 53 57 10
The third figure, 57, involves probably some degree of analytical
error, but it is given as found.

THE ELIMINATION OP CARBON MONOXIDE UNDER INHALATION OF

MODERATE PERCENTAGES OF CO2 IN AIR

The procedures in these experiments were similar to the pre-

ceding except that a mixture of CO2 and air was supplied under a
very slight pressure to a funnel fitting loosely over the animal’s
nose. The expired air passed out around the sides of the mask.
The air was delivered by a blower. The CO2 came from a tank
of compressed gas. The rate of flow of the air and the concen-
tration of CO2 were regulated by means of a double overflow flow
meter (8). The percentage of CO2 was determined by analysis.
The results of these experiments are shown in the following
protocols and are plotted in figure 3. They indicate that the
marked stimulation of breathing induced by the inspired CO2
resulted in a very much more rapid rate of elimination of carbon
monoxide from the blood and return of consciousness than in
either of the previous two sets of experiments. The subsequent
condition of the animals was correspondingly better.
18 YANDELL HENDERSON AND HOWARD W. HAGGARD

Experiment 6. Dog,
male, 10 kilos. Gassed for thirty minutes.
Completely unconscious.
After removal from the chamber the animal
was allowed to breathe air containing 10 per cent CO2. The volume of
breathing was very greatly augmented. Blood samples were taken
and analyses made as in previous experiments.

Time, minutes 0 15 30
Percent CO 49 36 8

0L\

:IIIII
rj... .
4 so 100

FIG. 3. PLOTTED FROM THE DATA OF EXPERIMENTS 6 AND 7

Showing the rate of elimination of carbon monoxide from the blood of animals
while breathing air plus CO2.

Experiment 7. Dog, female, 6.5 kilos. Gassed for thirty minutes.

Completely unconscious. After removal from the chamber the animal
was allowed to breathe air containing 6 per cent CO2. Respiration
moderately augmented.
Time. minutes 0 15 40 60 80
Percent. CO 61 54 36 24 4

THE ELIMINATION OF CARBON MONOXIDE UNDER OXYGEN PLUS

CO2

In these experiments the animals were gassed fully as deeply

as in any of the preceding. They were completely comatose on
removal from the chamber. After the usual blood sample had
been taken, they were made to inhale oxygen to which 10 per
 ELIMINATION OF CARBON MONOXIDE FROM BLOOD 19

cent of CO2 had been added. The inhalation was administered

through a mask and double valves so as to avoid any rebreathing.
A vigorous respiratory response occurred almost at once.
Within five minutes the animals were conscious and struggling.
When the inhalations were terminated at the end of twenty-two
and thirty minutes respectively, the subjects exhibited almost
complete restoration to normal condition. The data of the ex-
periments are given in the following protocols and are plotted in
figure 4.

77...;. n..,,,.

Fia. 4. PLOTTED FROM THE DATA OF EXPERIMENTS 8 AND 9

Showing the rate of elimination of carbon monoxide from the blood of animals
under inhalation of oxygen plus 002.

Experiment 8. Dog, male,14 kilos. Gassed for thirty-seven min-

utes. Completely unconscious. After removal from the chamber the
animal was allowed to breathe oxygen and 10 per cent CO2. The
volume of breathing was immediately very greatly augmented and
consciousness rapidly returned.

Time, minutes 0 15 30
Percent CO 55 15 2

Experiment 9. Dog, male, 12 kilos. Gassed for forty minutes.

Completely unconscious. Treated as in previous experiment with
Limilar results.

Time, minutes 0 8 15 22
Percent CO 60 55 28 .4
20 YANDELL HENDERSON AND HOWARD W. HAGGARD

CONCLUSIONS

It is here shown that during the development of carbon inonox-

ide asphyxia there is vigorous hyperpnea, and that thereafter,
probably owing to deficient oxygenation and other causes, there
is a diminished production of CO2. As a result of deficiency of
CO2 in the blood, asphyxiated animals when restored to pure air
exhibit for half an hour or more a very marked depression of
breathing. The rate of elimination of carbon monoxide is cor-
respondingly slow. The condition of tissue asphyxia is thus con-
tinued, although the body is surrounded by fresh air.
It is suggested that this post-gassing period of continued as-
phyxia may be of critical importance in inducing subsequent
structural degenerations and functional impairments. Its ab-
breviation is therefore an important object both for therapy and
prophylaxis.
Oxygen inhalation during this period has only a slight effect; it
is not adequately inspired.
Inhalation of CO2 diluted with air has an immediate effect.
It augments breathing and thus hastens the elimination of car-
bon monoxide.
Inhalation of oxygen plus CO2 is far more effective than either
gas alone; for the augmented breathing allows the oxygen to ef-
fect a rapid displacement of carbon monoxide from the blood.
Functional restoration is correspondingly accelerated.
We hope to carry this matter on into practical application.

REFERENCES

(1) HENDERSON, Y.: J. Amer.

Med. Assn., August 19, 1916, lxvii, 580-583.
(2) HENDERSON, Y.: J. Amer.
Med. Assn., July 1, 1918, lxvii, 1-5.
(3) HENDRRSON, Y., HAGGARD, H. W., TEAGUE, M. C., PRINCE, A. L., AND WUN-
DERLICH, R. M.: Report of Tunnel Gas Investigations, etc. To be
published by U. S. Bureau of Mines.
(4) HALDANE, J. S.: J. Physiol., 1895, xviii, 430.
(5) HAGGARD, H. W., HENDERSON, Y.: J. Biol. Chem., 1920 (in press).
(6) MARSHALL, E. K.: J. Pharm. & Exper. Therap., March, 1919, xii, 385.
(7) HALDANE, J. S.,: Methods of Gas Analysis.
(8) HENDERSON, Y., HAGGARD, H. W., AND COBURN, R. C.: J. Amer. Med. Assn.,
March 20, 1920, lxxiv, 783-786.