Organism and Environment as Illustrated by the Physiology of Breathing

To most persons it must come as a surprise that the breathing is so exactly regulated. Common observa- tion shows us that the breathing is often more or less interrupted temporarily, and varies in frequency or depth at different times, as if the regulation were only rough. We also know that breathing is under volun- tary control, and there is a popular idea that by spe- cial forms of training in breathing we can improve the aeration of the blood and the supply of oxygen to the body.

If samples of the alveolar air are taken it is found that they only give a constant percentage of CO2 if the breathing is quite regular at the time, and they are taken at the same phase of the respiratory act — say at the end of inspiration or of expiration. Ac- tually the percentage is varying distinctly from moment to moment round the average ; and it is only the average that is constant. If, moreover, the per- centage of COo in the air inspired is suddenly increased, it takes some little time before the breath- ing increases to the new average. There is thus a considerable lag between changes in the alveolar CO2 percentage and the response of the respiratory centre. This lag may be in either direction. If, for instance, the breathing is voluntarily held for a short time.

there follows excessive breathing; and if the alveolar air be then analysed it will be found that the COg percentage has fallen below normal. The breathing is, as it were, making up for lost time. This is easy to understand. Not only does it take an appreciable time for the blood to flow from the lungs to the respiratory centre, but both the blood and the lymph surrounding the tissue elements in the respiratory centre have a large capacity for absorbing CO2. They saturate and desaturate somewhat slowly when brought into connection with varying concen- trations of CO2 in the alveolar air. Consequently the respiratory centre only responds gradually to these variations. Were it not so the breathing would be very jerky, and it would be difficult to interrupt it in speaking or singing or swallowing. Momentary varia- tions in the alveolar CO2 percentage have thus no appreciable influence on the breathing, and it is only the average that counts. But this average is regu- lated with an accuracy which is extraordinary.

It is evident that the average percentage of CO2 in the alveolar air can be kept constant either by shallow and frequent or by deep and infrequent breathing. We can voluntarily set the breathing to very different frequencies, letting the depth take care of itself. For instance we can breathe three times or fifty times a minute. If, however, samples are taken of the alveolar air when once these different rates have been properly established, it is found that the average percentage of CO2 is sensibly the same. Increased frequency is compensated for by diminished

depth, and vice versa. It is an entire mistake to judge of the amount of air breathed by the mere frequency of the breathing. With very rapid and shallow breathing only a little of the pure inspired air clears the air-passages and enters the lungs. The very rapid and shallow breathing of a dog in hot weather does not over-ventilate its lungs, and is only designed to promote evaporation from its tongue, and consequent cooling, since a dog sweats with its tongue, and not with its skin.

If the breathing is obstructed, so that considerable effort is needed to draw in and expel air, as in breath- ing through a partially closed tap, there is still no appreciable rise in the alveolar CO2 percentage. The breathing is less frequent ; but it is also deeper, and the fundamental regulation is practically undisturbed. It was shown by Paul Bert that the physiological actions of CO2 and various other gases depend upon the pressure which they exercise. This pressure de- pends on the number of molecules of the gas present in a given volume. For instance, 5 per cent of CO2 present in dry air at the normal sea-level pressure of 760 millimetres of mercury has a pressure of 760 X %Q0 nr 38 mm., and exercises the same pressure as 10 per cent of CO2 in air at 380 mm. barometric pressure. It also contains the same number of molecules in a cubic centimetre. The air in the lung alveoli is satu- rated with aqueous vapour at the body temperature, and this vapour has a pressure of 47 mm., which must be allowed for in calculating from an analysis the pressure of CO2 in alveolar air. As already seen the

average percentage of CO2 in the alveolar air of adult men is 5.6. This is calculated for dry air. Allowing for the moisture present the pressure of CO2 with normal barometric pressure is (760 — 47) X ^-/loo == 39.9, or, in round numbers, 40 mm. On observing the alveolar COg percentage at increased or moderately diminished atmospheric pres- sure we found, just as might be expected from Paul Bert's experiments, that it is the pressure, and not the percentage, of CO2 which remains constant. The percentage is only constant if the barometric pressure remains the same. At five atmospheres* pressure the percentage of CO2 in moist alveolar air during rest is only a fifth of what it is at normal pressure. At any one position on the earth's surface the changes in barometric pressure from day to day are so slight that the corresponding changes in the alveolar CO, percentage are not very noticeable ; but with con- siderable changes in altitude, or in the case of workers in compressed air, these changes may of course be very great.

We thus reach the provisional conclusion that the breathing is so regulated as to keep the pressure or concentration of CO2 in the alveolar air constant within narrow limits. The slightest increase in con- centration of COo causes an increase in the breathing which almost completely neutralises the increase in concentration. The slightest decrease in the con- centration of alveolar CO2 causes a compensating diminution in breathing. To put the matter some- what differently, the respiratory centre reacts with

enormous delicacy towards the slightest changes, up- wards or downwards, in the concentration of CO2 in the alveolar air in contact with the arterial blood which supplies the centre. It is of the highest significance that a slight change in the downwards direction is sufficient to suspend natural or involuntary breathing. CO2 was formerly regarded as merely a "waste product," the getting rid of which as rapidly and completely as possible could only be a physiological advantage. It has turned out, however, that the presence of a certain concentration of CO2 is essential to the continuance of breathing. This brings us at once into connection with a series of investigations independently initiated by Professor Yandell Henderson of Yale, and afterwards carried on side by side with the Oxford investigations. His work was at first concerned mainly with the effects of concentration of CO2 on the circulation, and he found that undue removal of CO2 from the blood has the most disastrous effects on the circulation, producing symptoms similar to those observed in the surgical condition known as "shock." He found that when CO2 is removed from the body in undue quantity by excessive artificial ventilation of the lungs, the heart and circulation gradually fail, and death results. To this subject I will return later; but I am referring to it now in order to emphasise the point that the pres- ence of CO2 in a certain concentration in the arterial blood is just as necessary to life as, say, the presence of oxygen. An environment of CO2 is apparently as essential as an environment of oxygen.

The effects in man of undue deficiency or undue excess of CO2 can easily be observed. By forced breathing we can greatly reduce the alveolar CO2 percentage and also the quantity of CO2 in the arte- rial blood. The effects of continued forced breathing are very marked. These are ''swimming" of the head, abnormal sensations of "pins and needles," loss of sensibility, contractions of various groups of muscles, and gradual loss of consciousness. By breathing dur- ing rest air containing 6 per cent or more of CO2, or a less percentage during exertion, we can observe the effects of undue excess of CO2 — headache, giddiness, and often rapid loss of consciousness. Breathing is so regulated as to avoid these and other ill effects of excess or deficiency of COg. In other words the main- tenance of breathing is but one manifestation of the co-ordinated bodily activities of which the outcome is the maintenance of bodily activity and structure as a whole. Breathing is a manifestation of life and there- fore possesses its characteristic features.

It is evident that the mechanistic school of physi- ologists can point to the new facts with regard to the regulation of breathing as a confirmation of their principles. For the respiratory centre may be re- garded as a mechanism which reacts in a very sensi- tive manner to slight changes in the concentration of CO2. There is thus no mystery about the regulation of breathing — no need to invoke the presence of factors which are not physical or chemical. The respiratory centre is, in fact, typical of other bodily mechanisms. The delicacy of their reaction is due

to the delicacy of their mechanism, and not to the interference of some mysterious guiding influence such as the so-called "vital principle." But the vitalists can equally find confirmation m the new facts. They can lay stress on the extreme delicacy of the regulation, and the fact that in man this delicate regulation is maintained, day after day, and year after year, in spite of all kinds of changes in the external environment, and in spite of the metabolic changes constantly occurring in all living tissues. These facts preclude the hypothesis that the respiratory centre is a permanent structure so stable that it is unaffected by changes in environment. The regulation, if it be a mechanism, is utterly mys- terious from the physical and chemical standpoint, and necessitates the assumption that a special guiding influence is present, such as does not exist, so far as we. know, in the inorganic world. The more delicate and definite the physiological regulations which the advance of experimental physiology is constantly dis- covering, the stronger the case for vitalism.

I have tried to put the case fairly on both sides ; for both sides have always appealed to me strongly, and I have been utterly unable to accept the one- sided mechanistic arguments which have been put for- ward by many leading physiologists in recent times,^ or the equally onesided vitalism of the vitalistic minority. 1 As an example of these I may perhaps refer to Sir Edward Schafer's Presidential address to the British Asso- ciation in 1911. Some of the immediate practical applications of the new knowledge with regard to the regulation of breathing are perhaps of sufficient interest to be men- tioned shortly. The air of all sorts of confined spaces is apt to be vitiated by the presence of CO2 ; and along with the excess of CO2 there is usually a deficiency of oxygen, since the vitiation is due to processes of oxi- dation, in which oxygen is used up in proportion as CO2 is formed. In the air of ordinary rooms CO2 is formed and oxygen used up by respiration and by the burning of illuminants. The natural ventilation of an ordinary room is, however, so considerable that it is very seldom that the percentage of CO2 in the air exceeds 0.5 per cent. What effects will the gaseous impurity in such air have? Clearly none that are appreciable. The breathing will be very slightly deeper, so as to keep the alveolar CO2 percentage con- stant ; but the increase in breathing will be less than a tenth, and such an increase is totally unappreciable subjectively. The slightly increased breathing will also keep the oxygen percentage in the alveolar air from falling, so that the diminished oxygen percent- age in the air will be of no account. We must thus seek elsewhere than in the gaseous impurities of the air of rooms for the causes of the discomfort felt in crowded rooms.

In mines and other underground spaces the propor- tion of CO2 often goes much higher, and may reach about 3 per cent in places where a light will still burn. With 3 per cent of COo in the air the breathing is doubled. This effect becomes just noticeable during rest; but during any exertion the effect is not merely- noticeable, but very trying. During moderate work in pure air the breathing is three or four times what it is during rest ; but when air containing 3 per cent of CO2 is breathed the increase is to 6 or 8 times the amount of air breathed during rest in pure air. Pant- ing is thus very severe, and hinders all hard work. Constant employment on hard work such as mining in air of this composition is apt to produce in the lungs the condition known as emphysema, and thus to cause premature disablement. The ventilation of a mine ought, therefore, to be at least sufficient to prevent the CO2 percentage from exceeding about 1 per cent, where no other gaseous impurities than CO2 are to be found.

One of the most interesting examples of the effects of CO2 is that which occurs in diving with the ordi- nary diver's equipment. The diver is supplied with air by a pipe through which air is pumped down to him. The air passes into his helmet, and escapes into the water by a valve situated at the side of the helmet. The deeper he goes the greater is of course the pres- sure at which this air must be supplied ; and the com- position of the air which he breathes in the helmet will of course depend on the amount of air supplied to him and on the rate at which he vitiates this air. During work, for instance, he may produce four or five times as much CO2 as during rest, so that he will need correspondingly more air during work.

Supposing that the diver is working at a depth of 22 fathoms, or 132 feet, the air supplied to him will have a total barometric pressure of five atmospheres. If, now, the rate of supply, as measured by the strokes of the pump, is such as would keep the percentage of CO2 in the air of the helmet at not more than 2 per cent during work, this quantity of air would suffice to keep him comfortable if he were at or near the sur- face. But if the same quantity of air is supplied to him at 22 fathoms, or five atmospheres' pressure, the effect of 2 per cent of CO2 will, as we have seen, be the same as that of 5 X ^ = 10 per cent of COg at surface. Hence if the diver exerts himself he will not merely pant excessively, but rapidly lose conscious- ness. It used to be a common occurrence for divers to lose consciousness in this way; and the fact that British naval divers were so commonly unable to do any work at considerable depths led to an investiga- tion of the whole subject in the light of the new knowl- edge available, and to the laying down of regulations which now make work quite easy at the greatest depths required. The air supply to a diver ought evidently to be increased in direct proportion to the increase in the atmospheric pressure at which he works.

A diver is in no danger from want of oxygen, since the pressure of oxygen in his helmet and in his alveo- lar air is always far higher than in pure air at surface. It is almost always from oxygen want that a man dies who is asphyxiated by vitiated air in mines ; but a diver may die from CO2 poisoning in the presence of abundance of oxygen. I must now turn to another line of investigation in relation to the regulation of breathing. In 1868 Hering and Breuer discovered that if expiration is prevented by blocking the outlet of air at the end of an inspiration, particularly if the lungs are well dis- tended, rhythmic breathing efforts are interrupted. There is a long pause, during w^hich there is nothing but expiratory effort ; and only after this long pause is there an effort at inspiration. Similarly if inspira- tion is blocked at the end of expiration there is a long interval in v^hich only inspiratory effort is observed. The rhythmic activity of the respiratory centre is interrupted in either case.

They also discovered that if the vagus nerves, which proceed from the medulla oblongata in the brain, and supply branches to the lungs, are cut, these effects are no longer produced. Rhythmic inspiratory and expi- ratory efforts continue, quite regardless of whether the lungs are inflated or deflated. Clearly, therefore, impulses proceeding up the vagus nerves from the lungs are concerned in the regulation of breathing. When these nerves are cut or frozen across the breathing immediately becomes less frequent, but deeper, and acquires a well-marked dragging char- acter.

Hering and Breuer interpreted their observations as signifying that with the vagus nerves intact disten- tion of the lungs excites the nerve-endings with the result that impulses which stop or inhibit inspiration, and excite expiration, pass up the nerves. On de- flation of the lungs to a certain point during expira- tion a corresponding process occurs which inhibits expiration and excites inspiration. Thus the disten- tion of the lungs during inspiration is the immediate cause of expiration, and the deflation on expiration is the immediate cause of inspiration. Subsequent inves- tigation by various other observers confirmed in the main these conclusions. The regulation of breathing thus appeared to be an automatic process dependent, so long as the vagus nerves are intact, on the effects of alternate distention and deflation of the lungs. Until recently, also, many observers concluded from their experiments that apnoea is the summed effect of frequently repeated over-distention of the lungs, and has nothing to do with chemical changes in the blood. The majority believed that there is both a "chemical" and a "vagus" apnoea. The continued in- spiratory or expiratory effort which accompanies con- tinuous deflation or inflation of the lungs cannot properly be called apnoea, however.

I have already referred to the evidence showing that there is certainly no such thing as an apnoea due to the mere summed effects of repeated distention of the lungs, such as occurs in panting. The apnoea which follows forced breathing or excessive artificial ventila- tion of the lungs is due to reduction in the amount of CO2 in the alveolar air and arterial blood, and to no other cause. Were it the case that repeated unusual distention of the lungs tends to cause apnoea we should have a physiological arrangement exactly suited to defeat the whole physiological end of increased breath- ing. It seems extraordinary that the extreme improba- bility of this should not have weighed more heavily with the authors of the "vagus" theory of apnoea.

The theory that the breathing is regulated merely by the effects of alternate distention and collapse of the lungs is also quite plainly absurd in view of what is now known about the part played by the carbon dioxide pressure in the alveolar air and arterial blood. The observations of Hering and Breuer and of others who have made experiments along the same lines are none the less significant, however. Mr. Mavrogorato and I have found that the main facts, apart from the effects of section of the vagus nerves, can best be observed and analysed in man. The subject breathes through a wide bored tap which can be opened or closed at any moment ; the nose is clipped ; and a pres- sure-gauge is connected between the mouth and the tap so as to show the inspiratory or expiratory pres- sure.

When the tap is closed at the end of inspiration it will be noticed on the gauge that there is expiratory pressure, slight at first, but afterwards increasing more and more rapidly, till at last, after an interval occupy- ing the time of several normal respirations, there is a sudden inspiratory effort. The natural tendency of the respiratory centre to discharge alternate inspiratory and expiratory impulses thus breaks through the prolonged expiratory effort. Similarly, if the tap is closed at the end of inspiration there is a prolonged and increasing expiratory effort. If, now, apnoea is produced by forced breathing before the experiment, there is inspiratory or expiratory pressure as before; but it is a very long time before this pressure begins to increase. On the other hand if air containing COg

has been breathed before, so that the breathing is naturally increased, the inspiratory or expiratory pres- sure mounts up very rapidly, and is soon broken by an inspiratory effort. If the tap is closed midway in inspiration, long-continued inspiratory pressure, gradually increasing, is shown on the gauge, just as if the interruption had been at the end of expiration ; and similarly there is long-continued expiratory pres- sure if expiration has been interrupted midway.

If we put together the human observations and the results obtained in animals with the vagus nerves intact and divided, it appears that the effect of disten- tion of the lungs is to stop inspiratory and initiate expiratory discharge of the respiratory centre, while deflation of the lungs stops expiratory and initiates inspiratory discharge. Both inspiratory and expira- tory discharges continue until they are again stopped by distention or deflation. The result is that the dis- charges from the centre are directly co-ordinated with actual inflation or deflation of the lungs. This is brought about through the vagus nerves. The degree of energy of the inspiratory or expiratory discharges depends, however, on the action of COg in the blood upon the centre.

The degree of inflation or deflation necessary to inhibit mspiration or expiration and initiate expiration or inspiration depends quite clearly also on the chemi- cal stimuli acting on the centre through the blood : for the breathing is far deeper when the pressure of CO2 in the alveolar air and arterial blood is higher. We can thus understand how it is that when the fre- quency of breathing is varied voluntarily or involun- tarily, the depth naturally adjusts itself in such a way that the average alveolar CO2 pressure remains sensi- bly constant: for the least lowering of alveolar CO2 pressure enables the Hering-Breuer inhibitory effect to become effective within narrower limits of inflation and deflation, while the least raising of alveolar CO2 pressure has the opposite effect. We can also explain a very interesting phenomenon recently discovered independently by Yandell Henderson in America and Liljestrand, Wollin and Nilsson in Sweden. When artificial respiration is performed on a conscious sub- ject by Schafer's or any of the other usual methods, air enters and leaves the chest in just about the normal amount, although the subject carefully refrains from himself making any breathing efforts. If the rate of artificial respiration is increased there is no increase in the air entering the chest per minute : for the breaths become shallower. If, finally, apnoea is produced by previous forced breathing, and artificial respiration is then applied, hardly any air enters the chest. The Hering-Breuer inhibition comes into play with the slightest inflation or deflation of the lungs, and the breathing is, as it were, jammed.

When the vagi are cut, an animal can still regulate its breathing so as to keep the alveolar CO2 pressure constant ; for the depth of the drawn-out respirations depends on the alveolar COo pressure. But, as might be expected, the regulation breaks down easily under any strain, as was recently shown by Scott. The breaths cannot follow quickly enough the requirements which are easily met by an animal with intact vagi. In the regulation of breathing we have thus a strik- ing instance of the co-ordination between the actions of two different nervous stimuli. The influence of the peripheral stimuli acting through the vagus nerves is dependent upon the action of the central stimuli, and vice versa. This interdependence is characteristic of the effects of nervous stimuli and indeed of all phys- iological stimuli. As an outcome of the interdepend- ence in the present case, the breathing organs work as a whole, the discharges from the respiratory centre being correlated with the actual movements of the lungs.

Even after the vagi and nearly all other nervous connections to the respiratory centre are severed, alter- nate inspiratory and expiratory discharges from the centre continue in their proper order. The inspiratory discharge seems during its continuance to inhibit ex- piratory discharge, and vice versa. Here, also, we see the co-ordination which is inherent in all physiological activity, and which manifests itself even in the be- haviour of an isolated heart or strip of muscle, but far more strikingly in the case of the nervous system, even after great mutilation, or in the case of the chemical activities of any living part of the body.

We have seen that under ordinary conditions the regulation of breathing is dependent on very small variations in the degree to which the arterial blood leaving the lungs is saturated with CO2, and that a normal CO2 pressure of about 40 mm. is maintained in the alveolar air of the lungs during rest. Never- theless this normal pressure may become altered. Thus if the oxygen percentage or pressure in the lung air becomes very low in consequence of great deficiency in the oxygen percentage of the air breathed, or from the barometric pressure being very low, as at great altitudes, the breathing is increased and the alveolar CO2 pressure falls. A similar fall occurs after mineral acids have been taken, or in diseases in which abnor- mal quantities of acid are discharged into the blood, or after severe muscular exertion. To understand how the breathing is affected under these various con- ditions, and on what the normal conditions of breath- ing ultimately depend, it is necessary to consider the blood, and particularly the gases contained in it.

When a liquid is brought into intimate contact with a gas the liquid takes up the gas in solution until a point is reached at which equilibrium or saturation occurs. At this point as many molecules of gas are being given off from the liquid as enter it, and the pressure of the gas leaving the liquid is thus equal to the gas pressure outside. If, as in the lungs, a mixture of gases is in contact with the liquid, the pressure of each of the gases in the liquid becomes, if no interference to their passage inwards or out- wards occurs, equal to the pressure of the correspond- ing gas in the gas-mixture. This holds good even if the liquid contains substances which form well- defined compounds with the gas ; but in the latter case the amount of gas which the liquid has to take up before equilibrium occurs may be very large. If no such chemical combinations occur the volume of gas taken up by the liquid is in ordinary cases directly proportional to the pressure of the gas.

As we have already seen, the red corpuscles of the blood contain a coloured albuminous substance, haemoglobin, which enters into chemical combination with oxygen. The compound, oxyhaemoglobin, has the remarkable property of dissociating freely as the pressure of oxygen in the surrounding liquid falls, and re-forming as it rises. The oxyhaemoglobin thus acts as a reservoir of oxygen, enabling the blood to take up or give off far more oxygen with varying pres- sures of oxygen than water would take up or give off, and thus to act as a very efficient carrier of oxygen from the lungs, where the oxygen pressure is high, to the capillary vessels of the body tissues, where it is low in consequence of the constant consumption of oxygen. Human blood saturated in the lungs is capa- ble of giving off about 18 cc. of oxygen per 100 cc. of blood, whereas water would only give off about 0.3 cc.