YANDELL HENDERSON
INHALATIONAL TREATMENT OF ANGINA PECTORIS AND
INTERMITTENT CLAUDICAT1ON”
YANDELL HENDERSON, PH.D.
NEW HAVEN, CONN.
INHALATION of carbon oxide is now administered for various thera-
peutic and prophylactic purposes. The benefits afforded depend
chiefly on the part which carbon dioxide plays in the control of respi-
ration. Resuscitation from asphyxia of the newborn,1 prevention of
postoperative atelectasis and pneumonia,2 elimination of ethyl ether,2
of carbon monoxide,4 and of other anesthetic and toxic gases3 from the
lungs and blood, all alike depend upon the increase of pulmonary
ventilation under stimulation of the respiratory center by inhalation
of carbon dioxide.
INFLUENCE OF CARBON DIOXIDE UPON TIIE HEART AND BLOOD VESSELS
The equally marked influence of carbon dioxide upon the circulation
has not as yet, or to an equal degree, been exploited for therapeutic
purposes. Yet, simultaneously with the modern development of res-
piration, physiology has produced also observations indicating a pow-
erful influence of carbon dioxide upon the heart. In a long series of
experiments,6 from fifteen to twenty-five years ago, my collaborators
and I demonstrated on dogs, under artificial respiration or breathing
naturally under a slight pressure of air after the opening of the tho-
rax, a condition verging on tetanus of the heart-in the physiological
sense of the word tetanus, that, is a fusion of successive beats.
This state was effectively counteracted and heartbeats of full
amplitude were restored as a consequence of the restoration of a normal,or per-
haps slightly excessive, carbon dioxide content in the blood. The les-
son of these observations is now generally applied in experiments upon
the isolated heart in the Starling7 heart-lung preparation. It is rec-
ognized that the blood for perfusion, in addition to being oxygenated,
must also be supplied with a sufficient amount of carbon dioxide to
overcome the tendency of an exposed or excised heart to develop an
inadequate diastolic relaxation. Otherwise it passes into a continuous
systolic state, an incomplete tetanus or cramp of the heart.
Following these observations upon the heart, it was shown in an-
other series of experiments” that carbon dioxide may exert an equally
strong influence upon the peripheral circulation, and particularly upon
the volume of the venous return to the right heart. Clinically this
*From the Laboratory of Applied Physiology, Sheffield Scientific School, Yale
University,
effect is best seen as a result of the inhalation of carbon dioxide after
a prolonged and extensive surgical operation under open ether anes-
thesia. The return of blood to the cutaneous vessels, the flushing of
the skin, the refilling of the veins previously collapsed, bear at least a
superficial similarity to the effects induced by inhalation of amyl
nitrite. But the effects, like those of a hot bath and in contrast to
amyl nitrite, are more physiological than pharmacological; they are
lasting and are accompanied by a restoration of a full strong heart
action and a recovery of normal arterial pressure. Never in my expe-
rience have there been any symptoms suggesting an overloading of the
heart.
Among the various treatments of heart disease, that at Nauheim is
the most celebrated. It consists in baths in carbonated water. The
good effects, which the treatment, is claimed to have, have never really
been explained. There is a stimulating action upon the skin, but there
is little ground for believing that a slight cutaneous hyperemia can by
itself be of much benefit. It is at least possible that the greater part
of the benefit sometimes derived from the Nauheim treatment is due
rather to inhalation of the carbon dioxide volatilizing from the surface
of the bath.
DECREASE OF ANGINA UNDER INHALATION
With these considerations as a physiological background, it has
seemed to me justifiable to try, with all due caution at first, the influ-
ence of carbon dioxide inhalation upon cases of angina pectoris which
are as yet in their earlier stages, but in which moderately severe suf-
fering on exertion is already developing. This is not an emergency
treatment, but a therapy for prolonged application. The inhalations
are not given during an attack of pain, but at regular times every
day, usually before the midday and evening meals, and at bedtime.
The patient lies quietly on his back for a few minutes holding over his
own face a mask which has a sufficiently large opening to the outside
air to offer no resistance to breathing. He is told to keep his mouth
open and to breathe deeply rather than rapidly. Then a stream of
carbon dioxide gas through a small rubber tube from a cylinder of the
pure liquefied substance is fed to the mask. At first the flow is kept
small, but as respiration gradually deepens the amount of the gas is
increased until at the end of two or three minutes a maximal or nearly
maximal depth of breathing is developed. The stimulation is not,
however, pushed to the point of increase of rate. This condition is
maintained for fifteen or twenty minutes continuously. Then the gas
is shut off, and the patient is directed to lie quiet for ten minutes more,
so as to avoid the slight giddiness which occurs if he gets up immedi-
ately.
THE AMERICAN HEART JOURNAL
It is to be noted that the technic of this inhalation differs markedly
from the use of a mixture of oxygen and 7 per cent carbon dioxide.
which is best employed for resuscitation from asphyxia. The inhala-
tion used on these heart eases is on the contrary essentially like that
applied by Henderson, Haggard and Coburn, and by White after anes-
thesia and operation.3 A mixture of oxygen and carbon dioxide is
rather expensive, and a cylinder of it, is exhausted in a single inhala-
tion; while on the contrary even a small cylinder of liquid carbon
dioxide lasts for several weeks of this treatment.. so that its cost,
aside from the control apparatus, is slight. But of course pure carbon
dioxide should be used only with such an open mask that the small
volume of the gas supplied is diluted by the patient’s breathing in the
relatively large volume of the inspired air.
The essentials of the control apparatus employed are (a) an open
mask, as above described, and (b) a device for the control of the flow
of the gas to the mask, so that by no possibility can the patient receive
an excess ; it must be fool proof.
For this purpose a water manometer only 100 to 120 mm. long is so
arranged that it not only serves as a gauge but also as a safety valve,
through which any excess supply of the gas blows off into the air
without going to the mask. It is merely a straight glass tube, 5 mm.
bore, which extends down for this distance below the surface of water
in a bottle, flask or test tube. Between this manometer and the tube
leading to the mask is a hole of not more than 1 mm. diameter. Thus
the maximum volume of gas that can go to the mask is that which
under a pressure of 100 to 120 mm. of water column will pass through
a 1 mm. hole. The supply of gas to the manometer and to this milli-
HENDERSON : INHALATIONAL TREATMENT OF ANGINA PECTORIS
meter hole is controlled either by a finely adjustable needle valve, or
better by a McCaa reducing valve and a needle valve, as shown in
Fig. 1.* If only the needle valve is used, it has to be frequently re-
adjusted by the person administering the inhalation. If the reducing
valve is used also, the flow is so steady that an intelligent patient may
manage the entire procedure for himself. This is a distinct. advan-
tage in a treatment which the patient may find it necessary to con-
tinue one or more times a day for the remainder of his life. For the
utmost that can be expected, or even hoped, in regard to such a dis-
order as angina pectoris is not absolute cure, but, a check upon the
fundamental conditions, prevention of suffering and prolongation of
life.
The effects of this inhalation on the patients thus far treated, as yet
only three in number and none with high arterial pressure, have been,
in addition to the deeper respiration, as follows: There is a distinct
improvement in the color and temperature of the lips and skin, previ-
ously rather bloodless or bluish and cold, but becoming warm and pink
under the influence of carbon dioxide upon the peripheral circulation.
Arterial pressure and the pulse rate are not in appreciable degree in-
creased, although a markedly fuller circulation is evident. The sen-
sation of oppression in the chest, and the pain or “pins and needles”
in the shoulder and arm is considerably decreased, and may cease alto-
gether for some hours after the inhalation. After some weeks of daily
inhalations the capacity to take such exercise as walking uphill is
markedly increased, and the chief difficulty is to prevent the patient
from overexerting his partially restored physical capacity.
This is all that it seems justifiable to report in an initial communi-
cation on a treatment which will certainly need far more evidence
before it can be regarded as of proved general therapeutic value. The
cases thus far treated have, however, appeared so much benefited and
the technic here described appears to be so safe, that it seems best to
put the matter on record, in order that others also may try it for a
class of patients for whom there is otherwise little that can be done to
relieve or even to delay the development of a peculiarly painful, anx-
ious and hopeless form of invalidism, with an ever-present risk of
sudden death from coronary thrombosis.
Mention may also be made here of the effects of this inhalation
upon two cases of intermittent claudication in the lower extremities.
In both of these cases a marked improvement in the circulation of the
ischemic limb was observed under the inhalation. and in one in which
the treatment was continued for some weeks there was a distinct
cumulative beneficial effect. These cases were studied particularly in
the belief that, if the pain in angina pectoris and that in intermittent.
*An apparatus of this type without the McCaa reducing valve may be obtained
from the Foregger Company, 47 West 42nd Street, New York City. An apparatus
with the reducing valve from the Mine Safety Appliances Company, Pittsburgh. Pa.
THE AMERICAN HEART JOURNAL
claudication are due to similar local reactions, improvement in both
types of cases would tend to support the probability that in both the
results are real and not imaginary, either in the patient, or in the mind
of him who has applied the treatment.
THEORETICAL CONSIDERATIONS
The general conception under which these observations were made
was as follows: In a normal person muscular exertion induces no
pain either in a limb or in the heart, for the reason that the blood sup-
ply is sufficient to afford all the oxygen needed initially in the working
parts. This supply of oxygen quickly converts a large part of the
fatigue products, especially lactic acid, into carbon dioxide. The car-
bon dioxide then induces a relaxation of the blood vessels and thus
increases the blood supply to the working parts, both heart and limbs.
This is the normal reaction to exercise. The healthy man takes a walk
or plays an athletic game to improve the oxygenation of his tissues.
Thus as Miescher” said forty-five years ago : “Carbon dioxide spreads
its protecting wings over the oxygen supply of the body.”
Quite different, is the reaction in a person in whose heart or limbs
the blood vessels are sclerotic or constantly contracted. The blood
supply and therefore the oxygen supply are insufficient for the initial
requirements of exertion. Lactic acid and other fatigue products ac-
cumulate; for in the absence of a large supply of oxygen they cannot
be burned to carbon dioxide. They tend to induce a cramp of the
musculature, cardiac or striated, in contrast to the influence of carbon
dioxide which, as I long ago demonstrated experimentally on the
heart, promotes relaxation.6 To do effective work a muscle must be
able to relax as well as to contract. From excess of lactic acid and
local deficiency of carbon dioxide come the abnormal reaction to exer-
cise, the ischemia and the cramp.
If now a patient who is liable to such an abnormal reaction receives
an inhalation of carbon dioxide, still a third form of reaction devel-
ops. He experiences the benefits, without the disadvantages, of physi-
cal exercise. He makes no exertion. His muscles are at rest, and his
heart is put, under no additional strain. There is no decrease of the
oxygen supply to any part, but rather an increase, for the carbon di-
oxide inhaled induces a relaxation of the finer blood vessels, a more
ample heartbeat, and a fuller circulation. The balance of supply and
demand for oxygen in the tissues is thus distinctly improved and the
tendency to cramp is diminished. Furthermore as the treatment is
repeated day after day the blood vessels and the heart muscle, under
the influence of an essentially normal physiological agent and an essen-
tially normal reaction, gradually acquire and retain a state of de-
creased habitual strain and more normal behavior. Along these lines
HENDERSON : INHALATIONAL TREATMENT OF ANGINA PECTORIS
we may figure to ourselves why and how inhalations of carbon diox-
ide may exert a beneficial effect both immediate and to some degree
lasting.
In support of this general conception mention may here be made
also of the extraordinary observations which were reported by the late
Dr. A. S. Loevenhart10 in which he found that inhalation of carbon
dioxide administered to cases of catatonia caused a temporary resto-
ration of mental responsiveness. The simplest explanation of the
results in these cases is to postulate an habitual contraction of blood
vessels in the brain of the catatonic patient and to assume that the
influence of carbon dioxide upon these vessels is similar to that upon
the peripheral circulation elsewhere in the body. The effects of over-
breathing in inducing, and of oxygen and carbon dioxide in tempo-
rarily inhibiting, fits in epilepties11 are also suggestive of a similar
conception.
Finally I have pleasure in acknowledging my indebtedness to my
colleague, Dr. George Blumer, for the opportunity to work on one of
the cases here reported, and to Dr. Samuel C. Harvey for two of the
others. Investigations on the experimental side of this general prob-
lem are now being published from Dr. Harvey’s laboratory, and fur-
ther investigations upon patients are to be conducted in the clinic
here.
CONCLUSION
Daily inhalations of carbon dioxide appear to offer a possibility of
considerable amelioration of the crippling effects and suffering in cases
of angina pectoris and also of intermittent claudication.
REFERENCES
- Henderson, Y.: The Prevention and Treatment of Asphyxia in the New-
Born, J. A. M. A. 90: 583, 1928.
Incomplete Dilatation of the Lungs as a Factor in Neonatal Mortality, J. A. M. A. 96: 495, 1931.
- Henderson, Y.: Acapnia as a Factor in Postoperative Shock, Atelectasis and
Pneumonia, J. A. M. A. 95: 572, 1930.
- Henderson, Y., Haggard, H. W., and Coburn, R. C.: The Therapeutic Use of
Carbon Dioxide After Anesthesia and Operation, J. A. M. A. 74: 783, 1920.
White, J. C.: Deetherization by Means of Carbon Dioxide Inhalations, Arch.
Surg. 7: 347, 1923.
- Henderson, Y.: The Dangers of Carbon Monoxide Poisoning and Measures to
Lessen These Dangers, J. A. M. A. 94: 179, 1930.
- Henderson, Y., and Haggard, H. W.: Respiration Influencing Their Action. Noxious Gases and the Principles of
American Chemical Society Monograph Series, New York City, 1927, The Chemical Catalog Company.
- Henderson, Y.: Acapnia and Shock. I. Carbon Dioxide as a Factor in the Regulation of the
Heart Rate, Am. J. Physiol. 21: 126, 1908.
- Starling, E. H.: Linacre Lecture on the Heart, London, 1918. Also Knowlton,
- P., and Starling, E. H.: The Influence of Variations in Temperature and
Blood Pressure on the Performance of the Isolated Mammalian Heart, J.
Physiol. 44: 206. 1912. Also Patterson, S. W., and Starling. E. H.: On
the Mechanical Factors Which Determine the Ouput of the Ventricles, J.
Physiol. 48: 357, 1914; with Piper, H. : The Regulation of the Heartbeat, J. Physiol. 48: 465, 1914.
- Henderson, Y., and Harvey, S. C.: VIII. The Venopressor Mechanism, Am. J.
Physiol. 46: 363, 1918.
Bryant, J., and Henderson, Y. : Closed Ether and a Color Sign, J. A. M. A.
65: 1, 1915.
- Miescher, F.: Bemerkungen zur Lehrc van den Athembewegungen, Archiv. f.
Anat. u. Physiol. 1885. Physiol. Abtheilung, p. 355. Republished in Die
Histochemischen u. physiologischen. Arbeiten von Friedrich Miescher. Verlag
- C. W. Vogel, Leipzig, 1897.
- Loevenhart, A. S., Lorenz, W. F., and Walter, R. M.: Cerebral Stimulation,
- A. M. A. 92: 880, 1929.
- Lennox, W. G., and Cobb, S.: Epilepsy, Medicine 7: 162, 1928.
