Organism and Environment as Illustrated by the Physiology of Breathing

To understand the oxygen supply to the body, and the connection between oxygen supply and breathing, it is evidently necessary to understand the circumstances under which oxygen is taken up or given off by the haemoglobin of the blood. These circumstances can Fig. 1. Thick line — dissociation curve of oxy haemoglobin in blood in the presence of 40 mm. pressure of CO2. Thin line — the dissociation curve of oxyhaemoglobin in blood within the body. be investigated outside the body, provided that we are able to reproduce outside the body the conditions which obtain within it. Until recently, failure to appreciate the importance of this led to great error.

The dissociation of oxyhaemoglobin with fall in the pressure of oxygen can best be represented graphically by a curve; and Figure 1 represents the law of dis- sociation of human oxyhaemoglobin under the condi- tions so far known to exist in circulating human blood, including the rise of COg pressure as the blood passes the capillaries. It will be seen that the curve has a very peculiar shape, with a double bend, which is of great physiological significance. At the steep part of the curve oxygen will evidently come off freely with a comparatively slight fall in oxygen pressure. The haemoglobin is thus admirably adapted for maintain- ing the oxygen pressure approximately constant within the pressures corresponding to the steep part as the blood passes through the capillary vessels of the body. So far as we know the circulation is never, under normal conditions, so slow that the oxygen pressure in the body capillaries falls below the steep part of the curve, and is seldom so rapid as to bring the oxygen pressure above the steep part. The oxygen pressure in the alveolar air is normally about 100 mm., or 13 per cent of an atmosphere, which corresponds to the flat upper part of the curve.

The general form of the dissociation curve of the oxyhaemoglobin in blood was discovered a few years ago by Bohr of Copenhagen. He and his pupils also found that the curve is much afifected, not only by temperature, but by the pressure of CO2 in the blood. In the absence of CO2 the curve (as represented in the figure) shifts to the left, so that oxygen is given off much less readily. For a specified amount of oxygen to be given off in the absence of the COo normally present in circulating blood, the pressure of oxygen would require to be lowered to about half the pressure

otherwise needed. Excess of CO2, on the other hand, facilitates the dissociation, so that the giving off of CO2 to the blood in the body capillaries helps to make the curve steeper and so facilitates the oxygen supply to the tissues. The curve is not at all of the shape which would be expected on purely chemical grounds from what is known of other substances which dissociate in a similar manner. It was discovered by Barcroft and his pupils that the inorganic salts present along with the haemo- globin in the red corpuscles determine this peculiar form. When the haemoglobin is freed from these salts its dissociation curve has the form which would have been expected on chemical grounds — namely, that of a rectangular hyperbola. With this form of curve the oxyhaemoglobin would be wholly unsuited for performing the work which it actually performs in the body. The action of the salts is almost certainly connected with their power of causing the haemoglo- bin molecules to become aggregated into groups. Bar- croft also found that it is in virtue of its action as an acid when in solution that CO2 affects the dissocia- tion curve. Alkalies shift the curve to the left, while acids shift it to the right ; and the changing position of the curve is an extraordinarily delicate index of small changes in the reaction of the blood.

Both the plasma and the corpuscles of blood contain substances which enter into chemical combination with CO2 ; and these combinations dissociate with fall in the pressure of CO2, and re-form with rise, just as oxyhaemoglobin dissociates and re-forms. The whole of the combined CO2 can be removed from blood by exposing it to a vacuum, just as the whole of the loosely combined oxygen can be removed. A strong acid does not liberate any more. This is a very remarkable fact; for we cannot remove the CO2 from a sodium carbonate solution by means of a vacuum, and sodium is certainly combined with CO2 in blood. Blood con- tains an excess of alkali which is not combined with any strong acid, and must be in part combined with CO2. The explanation lies in the fact that haemoglo- bin and other albuminous substances present in the blood are capable of acting as very weak acids and so partially preventing the CO, from combining with the available alkali. When the pressure of CO2, and therefore its "mass influence" is reduced, more and more of it is driven out of combination, until with the CO2 pressure at zero none is left.

From 100 volumes of human arterial blood about 50 volumes of CO2 as gas are given off to a vacuum, and average venous blood contains only about 4 vol- umes more. The relations between pressure of CO2 and the volume of CO2 absorbed by human blood were recently investigated by Christiansen, Douglas and myself, and Figure 2 represents the results graphically. We found that blood takes up considerably more CO2 at a given pressure of the gas when the oxy haemoglo- bin is dissociated than when it is present as oxyhaemo- globin. The oxyhaemoglobin thus acts as if it were a more acid substance than dissociated or reduced haemoglobin. The relation between pressure of CO2 and its absorption by the blood in the living body is

Fig. 2. Lower curve — absorption of CO2 by blood in pres- ence of air and CO2. Upper curve — absorption of CO2 by blood in presence of hydrogen and CO2. The line A-B represents the absorption of CO2 within the body. therefore represented by the thick line starting at 40 mm. which is the pressure of CO2 in arterial blood. This line rises steeply, so that far more CO2 can be taken up by the blood with a given rise of CO2 pres- sure than would be the case if oxyhaemoglobin and reduced haemoglobin had the same effect on the ab- sorption of CO2. It follows also that when the venous blood reaches the lungs and suddenly becomes oxy- genated, the pressure of CO2 in the blood suddenly rises. In this way much more CO2 is given off than would otherwise be the case considering the existing

pressure of 40 mm. in the alveolar air. In other words the oxygenation of the venous blood in the lungs helps to turn out the CO2 — a fact long ago suspected by Ludwig, but of which the only evidence that could be obtained was negative until new and rapid methods of blood-gas analysis were introduced by Barcroft and myself. As regards the carriage of both oxygen and CO2 it is thus the case that the blood is of such a nature that the pressures of these gases in the blood leaving the tissues may vary but little in spite of the varying amounts of gas carried. With respect to oxygen, a glance at the dissociation curve of oxyhaemoglobin shows that it matters but little to the saturation of the blood with oxygen whether the oxygen pressure in the alveolar air is a little higher or a little lower. With respect to CO2, however, variations in the alveolar CO2 pressure will make a distinct difference to the CO2 pressure in the blood leaving the tissues, so that it is intelligible that what governs the breathing is normally the CO2 pressure, and not the oxygen pres- sure in the arterial blood.

A further point about the curves for both oxygen and CO2 is that for any one individual they are ex- traordinarily constant from day to day and month to month. Under normal conditions no difference can be detected in them, just as with the gas pressures in the alveolar air. The significance of this constancy is unmistakable; and to a mechanist who pointed out that the taking up and giving off of gases by the blood is a purely chemical and physical matter, a vitalist

might well retort by asking what regulates all the complex conditions concerned in the process — the for- mation and marshalling of haemoglobin and salts in the corpuscles, and the astoundingly delicate balance of the various substances which are concerned in the carriage of CO2. Nevertheless the regulation of both the breathing and the carriage of gas by the blood can be disturbed, either temporarily or for long periods ; and it is only by studying these disturbances that we can get further insight into the regulation. It has already been men- tioned that when mineral acids are administered the breathing increases, so that the alveolar CO2 pressure necessarily falls, while the amount of CO2 in the arterial blood may be diminished in acid poisoning to a small fraction of what it normally is. The administration of alkalies has a similar effect in the opposite direction. Slighter effects of a similar kind can be brought about, at least temporarily, by mere changes in diet. In diabetes a condition sometimes occurs in which a great excess of organic acid is formed in the body ; and this also is accompanied by great increase in the breathing and fall in the alveolar CO2 percentage. A temporary effect in the same direction follows exposure to want of oxygen, or excessive muscular exertion. It was known that expo- sure to great want of oxygen leads to the production of lactic acid in the body, and that excessive muscular exertion must have the same effect, since the amount of work done excludes the possibility of the circula- tion being able to supply the muscles with the oxygen

required to keep up the work. These considerations led me to the conclusion that it is probably in virtue of its acidity that dissolved CO2 (H2CO3 or carbonic acid) affects the respiratory centre, and that other acids will therefore have a similar effect, and will thus help CO2 to excite the centre. This theory explains why less CO2 in the alveolar air is sufficient to excite breathing under the various conditions just referred to. At the time, however, there was no means available of accurately measuring the slight alkalinity of the blood. The old method of adding standard acid till an indicator changed colour was not only very rough, but also fallacious in principle. The blood is only very slightly alkaline, yet quite a large quantity of acid can be added to it before it becomes acid. It is full of so- called "buffer substances," which are capable of com- bining with acids or alkalies, but are not themselves very definitely acid or alkaline. Thus the amount of acid which has to be added to blood to change its reaction is a measure of the buffer substances rather than of the alkalinity of the blood. According to modern ideas the acidity or alkalinity of a solution depends on the relative concentrations in it of hydro- gen and hydroxyl "ions." This concentration can be measured directly by the electrometric method, but the difficulties in applying the method to blood were very great.

In 1912, however, Hasselbalch of Copenhagen suc- ceeded in obtaining reliable results ; and he and Lunds- gaard published curves showing graphically the rela- tlons between hydrogen ion concentrations and CO2 pressure in blood. A difference in CO2 pressure which would be sufficient to double the breathing, or to cause apnoea, produced a difference in hydrogen ion concen- tration which was just measurable by the method, so the method is very rough as compared with the deli- cacy of discrimination by the respiratory centre. By varying the diet from alkaline to acid-producing Hasselbalch succeeded in producing a variation of several millimetres in the alveolar COg pressure. He then found that with the blood saturated with CO2 at the existing alveolar CO2 pressure the hydrogen ion concentration as measured was sensibly the same on either diet ; whereas if the blood was saturated in both cases at the same CO2 pressure the hydrogen ion con- centration was markedly different on the two diets. The difference in alveolar CO2 pressure was thus just sufficient to keep the hydrogen ion concentration, in so far as it could be measured by the electrometric method, constant in the two samples of blood, although there was presumably a slight difference as indicated by the difference in the breathing. Other similar ex- periments had a similar result, and there seems now to be no doubt that it is true that what the respiratory centre responds to is hydrogen ion concentration, and not mere COo pressure.

The delicacy of the response of the respiratory centre to change in the reaction of the blood is very extraordinary ; but what is still more marvellous is the fact that in spite of this delicacy the alveolar CO2 pressure is so steady during rest. The respiratory recired to keep up the work. These considerations ledne to the conchision that it is probably in virtue of s acidity that dissolved COo (H2CO3 or carbonic aci) affects the respiratory centre, and that other acis will therefore have a similar effect, and will tb he^ CO2 to excite the centre. This theory ^^" ' wb less COo in the alveolar air is sufficient bnthing under the various conditions ji

X the time, however, there was no n ofLCCurately measuring the slight : bled. The old method of adding anndicator changed colour wa? '^ bualso fallacious in principle, sliatly alkaline, yet quite a lar bedded to it before it beconi caid "buft'er substances," wl bing with acids or alkalic ve' definitely acid or alk: aci which has to be ad rertion is a measure of tha of the alkalinity mcern ideas the acif^ detnds on the relativ geiand hydroxyl "ic mtsured directly by diiculties in apply] grit.

neys. Human urine is usually acid in reaction, though it is separated from the alkaline liquid, the blood. As shown clearly by L. J. Henderson of Harvard, the urine, like the blood, contains "buffer" substances, so that the slight acidity of the urine is an index of the separation of much acid from the blood. But the reaction of the urine, and therefore the separation of acid by the kidneys, varies from hour to hour, and depends on whether the diet is more or less acid forming or alkali forming. In herbivorous animals, which live on an alkali- forming diet, the reaction of the urine is normally alkaline ; and in man the urine also becomes alkaline when alkalies are administered. It seems evident, therefore, that the kidneys, as well as the liver, are constantly regulating the alkalinity of the blood, and doing so with an accuracy which no means of direct physical or chemical measurement enables us to measure, but which is shown by the great constancy of the alveolar COg percentage. Neverthe- less, we can be quite certain that it is in response to the stimulus of very slightly altered reaction in the blood that the regulating activity of the liver and kidneys comes into play : for by such means as acid poisoning we can make the stimulus so strong that direct measurements can detect it.

It has been rightly pointed out by L. J. Henderson that the blood, and the body as a whole, are so full of so-called buffer substances that a considerable amount of acid or alkali might be added without any measur- able disturbance of the blood alkalinity being produced. This is certainly true, and very important, but the disturbances which physiology has to deal with are far more minute than those which are appreciable by chemical methods, so that exact regulation of the reaction of the blood is indispensable.

We have seen above that the composition of the blood is so regulated that not only is its reaction practically constant, but the volume of CO 2 taken up by a given volume of blood at a given pressure of CO, remains also the same under ordinary normal condi- tions. It is easy, however, to disturb this regulation temporarily. One means of doing so is by violent muscular exertion. Douglas and I found that a few minutes after violent exertion the volume of CO2 taken up by a given volume of human arterial blood was reduced to about half. An hour later, however, the blood was again normal. The reduction was probably due to excessive discharge of lactic acid into the blood: for not only was the resting alveolar CO2 pressure diminished, but Ryffel succeeded in showing that after similar violent exertion the proportion of lactic acid in the blood and urine is greatly increased. Ryffel showed also that this excess disappears in about an hour, which is the same time, as we had observed, that the alveolar CO2 pressure requires to rise again to normal after a violent exertion. It is clear, however, that the capacity of the blood for taking up CO2 can- not depend merely on its reaction, and must depend on the presence in regulated amount of all the various sub- stances including albuminous substances, which enter into chemical reaction when COo is present. Their amount must therefore be regulated — probably by the

endothelial cells which line the capillary blood-vessels. Here, then, we have another delicate regulation con- nected with breathing. We must now turn to the respiratory regulation of oxygen supply. Normally, as we have seen, it is the CO2 pressure in the blood, and ultimately the reaction of the blood, which seems to regulate the breathing. Under normal conditions there is always a sufficient reserve of oxygen in the alveolar air to saturate the haemoglobin of the blood to about the full normal extent, even if, from any cause, the oxygen percent- age falls distinctly below normal. We can thus under- stand how it is that even if the oxygen percentage in the air breathed is reduced from 20.9 per cent, as in pure air, to as little as 14 or 15 per cent, which instantly extinguishes any ordinary flame, the breath- ing is not sensibly affected at the time, and the alveolar CO2 percentage is undisturbed although the alveolar oxygen percentage has fallen from 14 to 7 or 8. When, however, there is a further reduction in the oxygen percentage the breathing begins to increase, and the alveolar CO2 pressure consequently falls. The face and lips also begin to have a bluish or lead- coloured tinge, showing that the blood is not properly oxygenated in the lungs ; and if such air is breathed for a considerable time headache and nausea come on. If there is only 6 or 8 per cent of oxygen in the air breathed intense panting is at once produced, accom- panied by rapidly increasing dizziness, mental fail- ure, and other alarming symptoms, as well as marked blueness or leaden colour of the face.

On studying more closely the effects of breathing air very deficient in oxygen we found that the alveolar CO2 pressure still regulates the breathing; but the regulation is, as it were, set at a lower level. The great panting produced at first by want of oxygen is due to the fact that owing to the large reserve of CO2 in the blood and lymph the alveolar CO2 cannot be set at once to the new level without evident panting. When once the reserve of CO2 has been got rid of, the breathing diminishes, while the blueness and other symptoms increase. If the oxygen percentage or pres- sure in the air is only diminished gradually there is no evident panting, although there is still some increase in the breathing, as shown by the lower alveolar CO2 pressure. The formidable symptoms come on without the warning given by panting. Nevertheless apnoea can still be produced easily enough by forced breathing sufficient to reduce the alveolar CO2 pressure further, even though the face is blue all the time, and con- sciousness fails before there is any desire to breathe. It was through attending too exclusively to want of oxygen as a cause of the "venosity" of the blood that so many mistakes were made by physiologists as to the causes of apnoea, and the general physiology of breathing.

The action of gradually developing want of oxygen is very insidious, until dangerous effects develop with dramatic suddenness. These effects have been repeatedly observed by balloonists, as well as in mines. Nothing illustrates the effects better than the experi- ences of the well-known meteorologist Glaisher and his assistant Coxwell in a famous ascent from Wolver- hampton in 1862. The balloon gradually reached a height of 26,000 feet, at which the oxygen pressure in the air was reduced to two fifths of the normal. Glaisher then first noticed that he could not read his instruments properly. Shortly afterwards his legs were paralysed, and then his arms, though he could still move his head. Then his sight failed entirely, and afterwards his hearing, and he became unconscious. Coxwell meanwhile endeavoured to pull the rope of the valve, but found that not only his legs, but also his arms were paralysed. He succeeded, however, in seizing the rope with his teeth, thus opening the valve. As the balloon descended Glaisher, about seven minutes after he lost consciousness, began to hear Coxwell's voice again, and then to see him, after which he quickly recovered. The balloon had probably reached a height of about 30,000 feet.

In another famous high ascent from Paris the three observers, Tissandier, Sivel and Croce-Spinelli, were provided under Paul Bert's direction with bags of oxygen to breathe from if they felt any ill effects. Though the oxygen would have saved them they were all paralysed before they realised their danger; and only Tissandier survived. The balloon, as shown by a self-registering barometer, had reached a barometric pressure of 263 millimetres, corresponding to a height of 30,000 feet, so that the pressure was reduced to nearly a third of the normal.

The insidious effects of want of oxygen are per- haps still more strikingly illustrated in the case of carbon monoxide poisoning. This gas (CO) is the poisonous constituent of ordinary lighting gas ; and poisoning with it is extremely common in America on account of the high percentage of carbon monoxide in the carburetted water gas used extensively as a substitute for the old-fashioned coal gas still supplied in England. I discovered about twenty years ago that CO poisoning is also the cause of nearly all the deaths in great colliery explosions and fires, and a source of extreme danger to rescuers.

Claude Bernard found that CO enters into combina- tion with haemoglobin, just as oxygen does, but forms a far more stable compound. In presence, therefore, of sufficient CO the oxygen-carrying power of the haemoglobin is suspended, and death must result from want of oxygen. It was supposed that CO has also a direct poisonous action on the nervous system. That this is not so I succeeded in showing by placing ani- mals in compressed oxygen before giving them CO. In the compressed oxygen sufficient oxygen goes into ordinary physical solution in the blood to enable the animal to dispense with oxyhaemoglobin as an oxygen carrier; and the animal remains unharmed although its blood and tissues are saturated with CO. Animals which do not employ haemoglobin as an oxygen carrier live for weeks quite comfortably in an artificial air composed of 80 per cent of CO and 20 per cent of oxygen. CO is not oxidised in the living body, and apart from its one fatal property of combining with haemoglobin it is a physiologically indiflferent gas.

In CO poisoning there is usually only a small per- centage of CO in the air, and as the haemoglobin of the blood has a large capacity for CO it takes a con- siderable time for enough CO to accumulate in the blood to cause dangerous symptoms. These symp- toms, however,, come on in exactly the same insidious manner as those from oxygen want arising in any other way. The headache, nausea, etc., of CO poison- ing are the same as those of mountain sickness, and the more remote nervous, cardiac, and other after- symptoms of CO poisoning or serious oxygen want produced in any other way are due to damage result- ing from oxygen want, and to no other cause. The oxygen want produces not merely temporary func- tional effects, but structural changes in the cells of nervous and other tissues.

As CO in small but extremely dangerous propor- tions in air cannot be detected by smell or by a lamp, I introduced, as a test for it, the use of a small warm- blooded animal, such as a mouse or canary. A small animal has an enormously greater respiratory ex- change and circulation rate than a man ; and in con- sequence its blood becomes saturated with CO far more quickly. By watching the animal a miner can tell in good time whether he is in a dangerous atmos- phere, though in the long run the animal is not more sensitive to CO than the man. The provision of small animals for testing purposes at mines in Great Britain was made obligatory by recent legislation.

Yandell Henderson discovered that after excessive artificial respiration on animals the breathing does not return. The animal dies of want of oxygen, or failure of the circulation, without making any effort to breathe. Hence if we reduce the CO2 pressure of the blood low enough no amount of oxygen want will excite the respiratory centre. Oxygen want is thus not by itself an adequate stimulus to the respira- tory centre ; but it helps the action of COg, or if we like to put it otherwise, causes the respiratory centre to react in presence of a degree of blood alkalinity which would be too high to excite it under normal conditions.

Although a slight, or even a considerable, deficiency in the oxygen pressure of the air breathed produces no immediate effect on the breathing, yet a long-con- tinued deficiency has a very distinct effect ; and the study of the effects of a long-continued deficiency has furnished, I think, one of the most interesting chap- ters in recent physiology. To observe the effects of long-continued deficiency it is only necessary to go to places at high altitudes, where the barometric pres- sure is low, but where men nevertheless live under perfectly healthy conditions. The Anglo-American expedition to Pike's Peak in 1911 had for its object the careful study of these effects.

On going to a very high altitude the breathing is increased at once, and the alveolar CO2 pressure falls correspondingly ; but if the altitude is only very mod- erate there is at first no effect on the breathing, just as happens when air containing a moderately reduced percentage of oxygen is breathed in the laboratory for a short time. After some days, however, it will be found that the alveolar COg pressure has fallen, which shows that the breathing is deeper. This fall reaches a certain amount, depending on the altitude, and then ceases. On the subject's return to sea level the alveolar CO2 pressure does not at once return to normal again, but may take many days, or even some weeks, to do so. Figure 3 shows graphically the aver-

Fig. 3. Alveolar pressures of oxygen and CO2 and per- centages of haemoglobin in the blood of persons ac- climatised to altitudes from sea level to 14,000 feet, — barometric pressures from 760 to 45 0 mm. of mercury. age results of measurements of alveolar CO2 pressure made by Miss Fitz Gerald, in connection with the Pike's Peak Expedition, on persons residing perma- nently at different altitudes. It will be seen that the alveolar CO2 pressure diminishes regularly with alti- tude, starting from sea level. That this diminution is a response to the diminished alveolar oxygen pres- sure there can be no doubt. If the barometric pres- sure is kept steady, and the oxygen pressure is dimin- ished by lowering the percentage of oxygen, the re- sults are precisely the same, so far as can be judged by the available observations; and, as was first clearly pointed out by Paul Bert, practically all the physiologi- cal disturbances produced by low barometric pressures, or high altitudes, are due to lowering of the oxygen pressure.

From Figure 3 it is pretty evident that if the oxygen pressure is raised above the normal value at sea level, the alveolar CO2 pressure will rise still higher. That this is actually the case has recently been shown by Hasselbalch and Lindhard, who have confirmed in a steel chamber many of the Pike's Peak results, and have added further observations of their own. It appears from their results that the alveolar COg pressure does not rise much higher after the normal oxygen alveolar oxygen percentage has been exceeded ; but the fact that there is a rise is of great interest, as showing that even the "normal" alveolar COo pressure depends on the existing alveolar oxygen pressure.