caused by the forcible application of a hard object to the organ in question.

The only direct effects of changes of pressure are those which are felt in the ears, and occasionally in the sinuses connected with the nose. The ear drums are connected with the throat and contain air at the prevailing pressure. If the pressure is lowered this air expands, and forces its way out through the Eustachian tubes into the throat. If the outside pressure is increased, it sometimes happens, particularly when the subject has a cold and the Eustachian tubes are inflamed, that air does not pass readily into the middle ear. Accordingly the tympanic membranes are forced inward by the pressure; and this may cause acute pain. Workers in compressed air are accustomed, while going "into the air," i. e., into pressure, to hold their noses and blow at frequent intervals as a means for expanding the ear drums. Aviators even during very rapid descents are generally relieved by merely swallowing.

To sum up all that has been said thus far, the influence of low barometric pressure is not mechanical but chemical. Life is often compared to a flame; but there are marked differences, depending upon the peculiar affinity of the blood for oxygen. A man may breathe quite comfortably in an atmosphere in which a candle is extinguished. The candle will burn with only slightly diminished brightness at an altitude at which a man collapses. The candle is affected by the proportions of oxygen and nitrogen. The living organism depends solely upon the absolute amount of oxygen-its so-called partial pressure.

Unlike the flame, a man may become acclimatized to a change of atmosphere in the course of a few days or weeks. He is thus adjusted to the mean barometric pressure under which he lives. Every healthy person is so adjusted, New Yorkers to a mean

barometric pressure of 760 mm. no less than the inhabitants of Denver or Cripple Creek to their altitudes. Even your tall buildings could probably be shown to exert a slight climatic effect upon the tenants of the upper stories. The study of the processes involved in such acclimatization affords us one of the most promising means of analyzing some of the fundamental problems of life. In fact, is not the gaseous interchange of protoplasm, the carbon and oxygen metabolism of the cell, the central fact of life? Is not the mode of regulation of the interior environment of the body-the constants of the "humours" -the prime problem of the "vegetative" side of physiology.

Among the ill effects of lack of oxygen we may distinguish three more or less distinct conditions. They are comparable, in terms of more common disorders, to acute disease in contrast with chronic conditions of various degrees. Thus any one suddenly exposed to acute deprivation of oxygen, as is the balloonist or the aviator in very lofty ascents, shows one set of symptoms. If the exposure is less acute, as in the case of one taking up residence on a high mountain, the effects develop gradually; he passes through the stages of mountain sickness, a condition much like sea sickness, to a state of acclimatization and renewed health. If however the ascent or the flight is for only two or three hours, a period too short for any degree of acclimatization to develop, and this strain on the oxygen-needing organs is repeated daily, as is the case with the aviator of the upper air, the condition of "air staleness" is likely sooner or later to result. It is the effect of repeated slight oxygen deficiency on an individual who does not become acclimatized. It is, I believe, closely related to those effects of repeated over-exertion

and oxygen shortage which appear in the over-trained athlete.

The classic description of collapse from oxygen deficiency is that written by Tissandier, the sole survivor of a fatal balloon ascent in 1875.

I now come to the fateful moments when we were overcome by the terrible action of reduced pressure. At 7,000 meters (Bar. 320 mm.) we were all below in the car.... Torpor had seized me. My hands were cold and I wished to put on my fur gloves; but without my being aware of it, the action of taking them from my pocket required an effort which I was unable to make. At this height I wrote, nevertheless, in my notebook almost mechanically, and reproduce literally the following words, though I have no very clear recollection of writing them. They are written very illegibly by a hand rendered very shaky by the cold. My hands are frozen. I am well. We are well. Haze on the horizon, with small rounded cirrus. We are raising. Crocé is panting. We breathe oxygen. Sivel shuts his eyes. Croce also shuts his eyes. I empty aspirator. 1.20 P.M.,11°, Bar. 320. Sivel is dozing. 1.25-11°, Bar. = 300. Sivel throws ballast. Sivel throws ballast. (The last words are scarcely legible.) . . . I had taken care to keep absolutely still, without suspecting that I had already perhaps lost the use of my limbs. At about 7,500 meters (Bar. 300 mm.) the condition of torpor which comes over one is extraordinary. Body and mind become feebler little by little, gradually and insensibly. There is no suffering. On the contrary one feels an inward joy. There is no thought of the dangerous position; one rises and is glad to be rising. The vertigo of high altitudes is not an empty word; but so far as I can judge from my own impressions this vertigo appears at the last moment, and immediately precedes extinction, sudden, unexpected and irresistible. . . . I soon felt myself so weak that I could not even turn my head to look at my companions. I wished to take hold of the oxygen tube, but found that I could not move my arms. My mind was still clear, however, and I watched the aneroid with my eyes fixed on the needle, which soon pointed to 290 mm. and then to 280. I wished to call out that we were now at 8,000 meters; but my tongue was paralyzed. All at once I shut my eyes and fell down powerless, and lost all further memory. It was about 1.30.

3 Quoted from Paul Bert, op. cit., p. 1061.

In this ascent the balloon continued to rise until a minimum pressure, registered automatically, of 263 mm. was reached. When Tissandier recovered consciousness Sivel and Crocé-Spinelli were dead. They were all provided with oxygen, ready to breath; but all were paralyzed before they could raise the tubes to their lips. Tissandier's notes are characteristic of the mental condition when oxygen-want is becoming dangerous.

In marked contrast to this condition is that of men who, gradually ascending into the mountains, day by day become acclimatized without realizing that any change has occurred. The record for the greatest altitude attained by mountaineers is held by the Duke of Abruzzi and his party in the Himalayas. They reached an altitude of 24,000 feet, where the atmospheric pressure is only two fifths of that at sea level, or practically the same as that at which Tissandier's companions lost consciousness. At this tremendous altitude the Duke and his Swiss guides were not only free from discomfort, but were able to perform the exertion of cutting steps in ice and climbing. Dr. Filippi, the physician who accompanied them, in discussing this matter says that the fact of their immunity admits of but one interpretation:

Rarefaction of the air under ordinary conditions of the high mountains to the limits reached by man at the present day (307 mm.) does not produce mountain sickness.4

In this statement, however, he is certainly mistaken, for the observations of others show conclusively that the sudden exposure of unacclimatized men to an altitude considerably less than that reached by this party would either produce collapse like that of Tissandier's companions, or if long

4 Quoted from Douglas, Haldane, Henderson and Schneider, "Physiological Observations on Pikes Peak," Phil. Trans., 1913, B. 203, p. 310.

continued would result in mountain sickness. The latter effect especially is one which was the subject of careful study by an expedition of which I was a member, and which during the summer of 1911 spent five weeks at the summit of Pike's Peak, Colorado, altitude, 14,100 feet, Bar. 450 mm. We were there enabled to make observations upon hundreds of tourists who ascended the Peak, and who were acclimatized at most to the altitude of Colorado Springs or Manitou at the foot of the mountain. We saw a number of cases of collapse fainting-from oxygen deficiency as shown by the striking cyanosis.

In the majority of cases, however, tourists who spent no more than the regulation half hour at the summit of the Peak, and then descended, experienced no acute ill effects. Headache and some degree of nausea were common even among these persons, however-often developing slowly for some hours after their descent. On the other hand, among persons who remained over night, and were thus exposed for several hours to deficiency of oxygen, the classic symptoms of mountain sickness occurred; and few escaped. Their second day at the summit was marked usually by extreme discomfort-headache, nausea, vomiting, dizziness and extraordinary instability of temper-symptoms which were strikingly exacerbated by even the smallest use of alcohol.

Our immediate party passed through these conditions and after two or three days, or in one case nearly a week, re-attained practically normal health. A definite functional readjustment had occurred. To illustrate and emphasize the nature of this readjustment I will quote a recent experiment of my friend the leader of the Pike's Peak expedition, Dr. J. S. Haldane. He has equipped his laboratory at Ox

5 Personal communication.

ford with a small lead-lined chamber in which a man can be hermetically closed. The carbonic acid which he exhales is continually absorbed by alkali, so that no accumulation occurs, while the oxygen is progressively decreased by the breathing of the man himself. Dr. Haldane found that after a day or two in this chamber he had reduced the oxygen to an extent comparable to Pike's Peak. At the same time there had evidently occurred in himself a gradual process of adjustment, for he felt quite well. At this stage he invited another person to come into the chamber with him, and he had the satisfaction of observing the immediate development of blueness and the other symptoms of oxygen collapse in his companion.

Evidently acclimatization is a very real phenomenon and of the utmost importance to any one exposed to a lowered tension of oxygen.

As we observed it in ourselves during our stay on Pike's Peak acclimatization consists in three chief alterations: (1) increased number of red corpuscles in the blood; (2) some change in the lungs or blood (Haldane considers it the secretion of oxygen inward by the pulmonary tissue) which aids the absorption of oxygen, and (3) a lowering of the CO2 in the alveolar air of the lungs. This lowering of the CO, in the lungs is bound up with increased volume of breathing. It is the concomitant of a decreased alkaline reserve in the blood just as in nephritis and diabetes. Acclimatization in this respect consists therefore in the development of a condition which would nowadays be called acidosis.

All of these changes are of a quantitative character. Miss FitzGerald has supplemented the results obtained on Pike's Peak by an extensive series of careful observa

6 FitzGerald, M. P., Phil. Trans., 1913, B. 203, p. 351, and Proc. Royal Soc., 1914, B. 88, 248.

I shall not discuss pulmonary oxygen secretion now, because the problem is still extremely obscure; nor the increased production of red blood corpuscles, which is a slow process requiring weeks for completion, and playing no considerable part in the matter particularly before us.

We will fix our attention upon the fact that both the alveolar CO2 of the pulmonary air and the alkaline reserve of the blood are reduced in accurate adjustment to any altitude, or oxygen tension, to which a man is subjected for a few days or even a few hours. This functional readjustment is, I believe, of great significance in relation to aviation, since it involves a larger volume of breathing per unit mass CO, eliminated: it thus compensates in part for the rarefaction of the air.

But how is it brought about? And why are the changes of breathing gradual, when the changes of altitude and oxygen tension are abrupt? The answer lies in part at least in the mode of development, and the nature of that acidosis of altitude to which I have referred. It is scarcely necessary to remind you that, as L. J. Henderson has shown, the balance of acids and bases in the blood, its Сн, depends upon the maintenance of a certain ratio between the dissolved carbonic acid, H2CO, and sodium bicarbonate, NaHCO2, or as Van Slyke terms it, the alkaline reserve. On the basis of this conception the prevalent view of acidosis is that, when acids other than carbonic are produced in the body, the bicarbonate is in part neutralized. The alkaline

reserve is thus lowered, and the carbonic acid of the blood being now in relative excess, an increased volume of breathing is caused as an effort at compensation.

Recent investigations' by Dr. H. W. Haggard and myself show that an exactly opposite process is likewise possible. We find that whenever respiration is excited to more than ordinary activity, and the carbonic acid of the blood is thus reduced below the normal amount, a compensatory fall of the alkaline reserve occurs. The body is evidently endowed with the ability to keep the ratio of H,CO, to NaHCO, normal, not only by eliminating CO2 when the alkali is neutralized, but also by the passage of sodium out of the blood into the tissue fluid (or by some equivalent process) to reduce the alkaline reserve. A loss of CO2 during over-active breathing is thus balanced. If it were not balanced a state of alkalosis would occur, which would inhibit and induce a fatal apnoea.

3

2

It is really in this way I believe that some of those conditions arise which nowadays are called "acidosis." If so they are not truly acidosis, or rather the process producing them is not acidosis, although the resultant condition gives some of the most characteristic tests of this condition. It is on the contrary a state, or rather a process, which Mosso was the first to recognize, although obscurely, and which he termed "acapnia" an excessive elimination of CO2. Recent papers from my laboratory have shown that a sudden and acute acapnia induces profound functional disturbances, including circulatory failure.

It is one of the well-known facts in physi

7 Henderson and Haggard, Jour. Biol. Chem., 1918, 33, pp. 333, 345, 355, 365.

8 Henderson and Harvey, Amer. Jour. Physiol., 1918, 46, p. 533, and Henderson, Prince and Haggard, Jour. Pharmac. Exper. Therap., 1918, 11, p. 189.

ology that deficiency of oxygen, or anoxemia, causes an "acidosis.” Recent and as yet unpublished work of Dr. Haggard and myself indicates that the process involved is almost diametrically the opposite of that which has heretofore been supposed to occur, and that the result is not a true acidosis. Under low oxygen, instead of the blood becoming at first more acid with a compensatory blowing off of CO2, what actually occurs is that, as the first step, the anoxemia induces excessive breathing. This lowers the CO2 of the blood, rendering it abnormally alkaline; and alkali passes out of the blood to compensate what would otherwise be a condition of alkalosis.

We regard the current explanation, based on the production of lactic acid, as needing

reversal.

The application of this idea to the changes of breathing and of the blood alkali in acclimatization clears up some of the points which heretofore have been obscure. Thus on Pike's Peak we saw that persons whose breathing under the stimulant of oxygen deficiency increased quickly to the amount normal for the altitude suffered correspondingly little, while those whose respiratory center was relatively insensitive to this influence suffered severely. The one type readily developed the acapnia and in consequence the pseudo-acidosis which the altitude requires. The other did not.

Here let me pause a moment to bring these conceptions into some degree of harmony with fundamental doctrines regarding respiration. For more than a century, in fact ever since the days of Lavoisier, the argument has been active whether our breathing is controlled by oxygen need or by the output of CO2. For the past thirty years, and especially during the last ten or twelve, the theory of regulation by CO2, or in its later form by C, has held the field. Indeed it is established now-almost beyond

the possibility of contradiction, it would seem that during any brief period of time, and under conditions to which the individual is accustomed, the amount of CO2 produced in the tissues of the body, through its influence on the CH of the blood, is the factor controlling the volume of air breathed. Its effects are immediate.

But when we view the matter more broadly it is clear that this is by no means the whole story. The oxygen tension of the air is the influence which determines just how sensitive the respiratory center is to excitement by CO2. But the effects of any change of oxygen tension are slow in developing, requiring in some persons, as we saw on Pike's Peak, hours to begin and several days to become complete. In fact there are many perfectly healthy persons who, if caused to breathe progressively lowered tensions of oxygen down to 6 or 7 per cent. in the course of half an hour, feel nothing. Their breathing shows no considerable augmentation. They simply lose consciousness, and if left alone they would die, without any apparent effort on the part of respiration to compensate for the deficiency of oxygen. In such persons the stimulant of oxygen deficiency exerts only a slowly developing influence upon the sensitiveness of the respiratory center to the stimulus of CO2. They can become acclimatized to great altitude only at the cost of prolonged mountain sickness. Evidently they are not suited to be aviators.

In very sensitive subjects, on the contrary, the period of readjustment is much shorter. It is a matter not of days but of hours, and the functional alterations begin to develop almost immediately even under slight oxygen deficiency. The upper air is for those men whose organization readily responds with vigorous compensatory reacgen.