Principles of General Physiology

where p2 is the higher pressure and, of course, the integral has to be taken along the particular limits of the dissociation curve corresponding to the respective tensions. In man, the amount of energy per minute works out at about one gram calorie. This might be done by epithelial cells of 0'5 p. in thickness, if their efficiency were 20 per cent., that is, no greater than that of the body as a whole. Another criticism made by K*rogh is that the histological structure of the pulmonary

epithelium is not at all what would be expected in a secreting organ. The cells are quite thin, and very unlike those of the gas gland of the fish, where, as we have seen (page 361), there is an obvious reason why oxygen should be actively secreted. A gas must be produced and absorbed in adaptation to the pressure at different •depths. It has been said indeed that, in the bird, where the need of extra supply of oxygen would be supposed to be greater than in the mammal, the pulmonary alveoli are devoid of epithelial lining altogether. If the exchange were by diffusion alone, the direct contact of the walls of the blood capillaries with the alveolar air would be of advantage. Again, unlike a secreting gland, oxygen passes with equal facility in either direction. Breathing fire damp, for example, causes instantaneous unconsciousness through loss of oxygen from the blood to the gas in the alveoli.

Hartridge (1912, I) introduced an improvement in the carbon monoxide method of Douglas and Haldane, by substituting observation of the change of position of the absorption bands, which is produced by carbon monoxide, instead of the mere visual comparison of the colour of two solutions. Using 'his new method, Hartridge (1912, 2) investigated the effects of producing oxygen want in the tissues in three ways, by breathing mixtures containing carbon monoxide, by lowering the oxygen tension of the air breathed, and by doing work. He was unable to find any evidence of crxygen secretion by the lungs in any case, but, as was stated above, Douglas and Haldane now hold that it is not to be detected until acclimatisation has been developed.

Bohr introduced the consideration of the rate at which oxygen could pass through the pulmonary epithelium and capillary wall, and calculated, entirely from theoretical data, what he called "invasion" and "evasion" coefficients. The conclusion to which he came was that the diS'erence between the tension of oxygen in the arterial blood and that in the alveolar air could only be accounted for by secretion on the part of the cells. Krogh, however (1910, 1), made direct experiments on the rate at which oxygen passed from water into a gas bubble, and found that the "invasion coefficient" is really nearly seven times that calculated by Bohr. It seems possible that the solubility of oxygen in water, which enters into the formula, is altered at the contact surface between the epithelium and the alveolar air, owing to the action of surface forces, a fact neglected by Bohr. We saw above that the solubility of gases depends on the surface tension of the liquid solvent (page 54), and that a low surface tension increases the solubility (Christov). It is quite possible that the surface tension of the liquid covering the membrane of the lung alveoli may have a very low surface tension, owing to presence of lipoid. If this were so, the solubility of oxygen in it might be much greater than that reckoned by Bohr. From the invasion coefficient it can be calculated how much oxygen can pass into the blood in a given time, and, although it appears that it is sufficient to satisfy the conditions of rest on the diffusion theory, it is held by Barcroft (1914, p. 216) that diffusion will not account for the large amount of oxygen used in exercise, or under the conditions of low oxygen tension as in rarefied air. It is to be remembered that the calculation requires knowledge of the quantity of blood passing through the lungs.

Krogh and Lindhard (1912) determined this experimentally in man, and found that, in muscular work, it might rise to as much as 21 '6 litres per minute, instead of the much smaller number taken by Bohr (1909) as the basis of his calculation. On p. 228 we find the following calculation. In a particular experiment it was found that 162 c.c. of oxygen per litre of blood passing through the lungs was taken up and utilised ; that is, 85 per cent, of the difference between arterial and venous blood. In muscular work, 2,700 c.c. of oxygen were consumed per minute. Hence, if we take 21 litres per minute as the cardiac output, according to the measurements of Krogh, we find that 162 x 21 =3,400 c.c. of oxygen per minute can be taken up by the lungs — more than enough to satisfy requirements. Similarly, the work of Patterson and Starling (1914) shows that the amount of blood sent out by the heart, when working under optimal conditions, is very much larger than previously assumed. Taking the data available, it can be shown that the amount of oxygen which the blood can carry from the .alveolar air by diffusion is considerably in excess of that found to be consumed under any muscular work hitherto determined. Marie Krogh (1915) has made further experiments and finds that diffusion is quite capable of explaining the maximum amount of oxygen consumed in muscular work.

At the same time, it must be admitted that we have no explanation for the results of Douglas and Haldane on Pike's Peak. It seems very desirable that the experiments should be repeated on lower animals by the aerotonometer method of Krogh. The difficulty is that the animals must be kept for some time under reduced oxygen pressure and the experiments made under anaesthesia. As regards the latter factor, the adherents of the secretion theory may make the objection that the narcosis paralyses the secretory power of the cells ; but it has no such effect on other glands. There is one fact in the data given by

Douglas, Haldane, Henderson, and Schneider which seems a little strange, although it may have no significance. Notwithstanding that the arterial oxygen tension was always higher than that given for the alveolar air, it was never as high as that of the atmosphere at the time, although occasionally not much below it. Why should the secretory power fail just at this level and not raise the oxygen tension above that of the atmosphere ? Is it possible that the blood had como into equilibrium with oxygen tension somewhere which was not given correctly by the measurement of that of the alveolar air?

Might it not also be possible that the carbon monoxide method gives different values when the haemoglobin content of the blood is increased, as in the case of acclimatisation to high altitudes? Hasselbalch (1912) shows that the hydrogen ion concentration is increased under these circumstances. This question of secretion by the lungs is instructive from the point of view of " vitalism." When first proposed, it was held to apply to the ordinary state of affairs ; but, as improvements were made in experimental methods, the absorption was shown to follow physical laws ; it was then held to apply to cases of muscular exercise, and now only to acclimatisation to high altitudes. One might venture to say that the more accurate the methods of investigation, the better is it found that chemical and physical laws are capable of explaining physiological phenomena.

By Hydrogen Ion Concentration of the Blood. — The renewal of the air with which the blood interchanges its gaseous constituents is effected by muscular movements, and it is plain that the rate of change of the air in the lungs needs to be varied in order to provide for the different rates at which oxygen is consumed and carbon dioxide evolved in states of rest and of activity. We have to inquire how this regulation is effected. The co-ordination of the muscular movements required is effected by the " respiratory centre " in the bulb, which sends out periodic discharges to the motor neurones of the spinal segments in which the muscles concerned are represented. Like other nerve centres, this centre is capable of being influenced by afferent impulses, especially from the lungs themselves. The function of these will be seen later.

It is the great merit of Haldane and Priestley (1905) to have shown that the regulation of respiration, meaning by that the amount of ventilation per unit of time, or the total volume of air sent in and out of the lungs, is effected by the carbon dioxide tension of the arterial blood, which is the same as that of the alveolar air of the lungs. Later work showed that the hydrogen ion concentration, due to the dissolved carbon dioxide, is the actual exciting agent. The cells or synapses of the respiratory centre must, therefore, be very sensitive to changes in the concentration of the hydrogen ions of the blood.

Now, the venous blood from the organs does not pass directly to the centre, but only after having interchanged with the alveolar air. The carbonic acid tension of the arterial blood is then the determining factor of the ventilation. It is thus of some importance to know how this value is related to that of the alveolar air, and this again to that of the venous blood. Bohr thought it necessary to assume, along with oxygen secretion, an active excretion of carbon dioxide on the part of the pulmonary epithelium. Krogh's experiments, already mentioned, showed the carbon dioxide tension of the arterial blood to be equal to that of the alveolar air, not less, as it would be if actively excreted. He points out that the remarkable sensibility of the respiratory centre to a slight increase of the carbon dioxide tension of the alveolar air would be upset by interference with the relation between that of the alveolar air and that of the arterial blood, such as would result from an excretory process. Haldane and Priestley, in fact, showed that a rise of the carbon dioxide tension in the lung alveoli of only 1'6 mm. of mercury, or of 0'22 per cent, of its content in carbon dioxide, increases the ventilation of the lungs to double its previous value. If the carbon dioxide tension of the venous blood rises by a very small amount, that of the alveolar air will also rise by diffusion, so tTiat the arterial blood leaving the lungs will have

slightly higher tension in carbon dioxide. At once the respiratory centre is stimulated, and more copious ventilation rapidly washes away the excess of carbon dioxide from the .alveoli, and thus from the venous blood. That it is to changes in the hydrogen ion concentration that the respiratory centre reacts is, perhaps, most definitely shown by the experiments of Hasselbalch (1912), although previous workers had found that the centre responds to acids other than carbon dioxide. Reference to these results will be found in the paper by Hasselbalch. Those of Winterstein (1911, p. 179) maybe mentioned. He found that respiratory movements could be induced in rabbits, four days old, which were perfused with oxygenated Ringer's solution from the aorta, when O'OOl molar hydrochloric acid was added to the solution, although no carbon dioxide was present. The nature of one kind of proof brought by Hasselbalch will be clear from the following consideration. Since a particular carbon dioxide tension in the alveoli corresponds to a definite ventilation, when other things are unaltered, it follows that, if we find this same ventilation along with a lower carbon dioxide alveolar tension, some other cause must be adding its influence on the centre. Hasselbalch found that, by altering the diet, he could alter the hydrogen ion concentration of the urine, hence that of the blood, which he also measured by the hydrogen electrode described / above (page 192). The carbon dioxide of the alveolar air always varied inversely! with this hydrogen ion concentration; hence the lung ventilation is always1 adjusted in such a way as to maintain the hydrogen ion concentration of the blood constant. Incidentally, we may note also that since, normally, the alveolar carbon dioxide tension varies only in very narrow limits, the sensibility of the kidney to acid in the blood must be such as to keep the concentration of hydrogen ion in the blood, other than that due to carbon dioxide, at a constant level.

It may, perhaps, seem surprising that it is to carbon dioxide rather than to oxygen tension that the respiratory centre is adjusted. Carbon dioxide is not very harmful to tissue processes, and it is a supply of oxygen that is the chief requirement. This consideration has led various observers to seek for a sensibility of the centre to a fall of oxygen tension ; the conclusion arrived at in the most accurate experiments has been that, until the oxygen tension falls very low, and the products of tissue activity are not completely oxidised, no increase of ventilation takes place, provided that increase of carbon dioxide tension is prevented. Although the centre is not sensitive to fall in oxygen tension in the sense of being excited by it, it is possible that its excitability might be raised so that the same carbon dioxide tension which excited it normally under normal oxygen tension might, under reduced oxygen tension, excite greater activity. Careful experiments by Campbell, Douglas, Haldani and Hobson (1913) showed that the alveolar oxygen pressure can be varieA within wide limits without sensibly affecting the excitability of the respiratorya centre to carbon dioxide.

This want of response to lowered oxygen tension may, under certain conditions, lead to serious consequences, such as mountain sickness, which will be referred to in a later paragraph. It is the increase in carbon dioxide tension that produces the increase of pulmonary ventilation in asphyxia, so that, if increase in carbon dioxide be prevented, as by respiration of pure nitrogen, a man may become unconscious before experiencing any unpleasant symptoms. Similarly, by forced breathing, the carbon dioxide tension may be reduced to such an extent, that so long a period of absence of stimulus to the respiratory centre may ensue, that severe signs of want of oxygen show themselves. Krogh points out that, if the carbon dioxide is excreted by the activity of the alveolar epithelium, this mechanism ought to be inhibited when the organism is threatened with death because the blood has parted with too much carbon dioxide.

It was mentioned above that, when the oxygen supply to the tissues is considerably below their requirements, acid products are formed, especially in the muscles ; these products naturally play a part in the stimulation of respiration by their hydrogen ion content. Thus Ryffel (1909) has shown that lactic acid is to be found in the urine after vigorous muscular exercise. When the oxygen tension in the blood has fallen below about 60 mm., the nerve centres are excited and convulsions ensue. This result is due to the formation of asphyxial products, probably of an acid nature, in the centres themselves. Mathison (1910, 1911) studied the stimulation of the spinal and bulbar centres by deprivation of oxygen without increase of carbon dioxide, that is, by respiration of nitrogen, and came to the conclusion that it is acid formed in the centres themselves which excites them. The bulbar (vasomotor) centre is more easily excited than the spinal

FIG. 194. RESPIRATORY REFLEXES PRODUCED BY INFLATING THE LUXUS. A, The dotted line is the tracing of a mercury manometer connected with the trachea, a rise indicatingdistension of the lungs. The curve below it is that of a lever attached to the diaphragm slips of the rabbit, and represents the movement of the diaphragm as a whole. Thus inspiration is The tracing at the top is from a control lever attached to the walls of the chest. Note that distension inhibits inspiration.

B, Similar effect of short inflation with pure hydrogen. To show that the result of the preceding experiment was not due to cessation of respiration owing to increased supply of air. centres. Thus, the former reacts to thirty seconds' deprivation of oxygen, to 5 per cent, carbon dioxide, or to 2 c.c. — lactic acid. The spinal centres require two minutes' deprivation of oxygen, 30 per cent, of carbon dioxide or 5 c.c. - lactic acid. The production of acids other than carbon dioxide is a sudden one and occurs at the point when the cell mechanisms are beginning to be disorganised ; hence the process is not of use to the organism, as far as the centres referred to are concerned, although the acids formed are very potent stimuli.

For further details with regard to the chemical regulation of respiration, the essay by Douglas (1914) may be consulted. The Nervous Mechanism. — From what we have seen above (pages 500, 511, and 540) as to the importance of afferent impulses from contracting muscles (proprioceptive impulses) in the regulation of their activity, it would be surprising if the respiratory mechanism were devoid of similar control. In the present case the receptors are mainly in the lungs and in connection

with the respiratory centre by means of the vagus nerves. They have been referred to above (page 387) in the discussion of the meaning of the electrical changes in the peripheral ends of the vagus nerves, as photographed by Einthoven (see Fig. 106, p. 386). The relative parts played by the nervous and the chemical factors were the subject of investigations by F. H. Scott (1908). Although expiration, under normal conditions, is almost entirely a passive movement, due to return of the mechanism to its equilibrium position, it is well known that, in dyspnoea, co-ordinated action of muscles antagonistic to those of inspiration takes place in the expiratory phase. We must, therefore, suppose that the respiratory centre is double, inspiratory and expiratory, and each of these will be capable of excitation and of inhibition, forming a system subject to double reciprocal innervation of the kind described above (page 498) with reference to the flexors and extensors of the limbs.

fluenced reflexly by stimulation of various afferent nerves, and especially of the vagus, the first clear and systematic results were obtained by Head (1889), using a slip of the diaphragm, which is so attached in the rabbit as to allow FIG. 195. EFFECT OF SHORT SUCTION. — As above in regard to meaning of tracings. tion of automatic movements. Diaphragm in mean state of tonus. a tracing lever to be connected without interference of the nervous supply to it or disturbance of the normal respiratory movements. The original paper must be consulted for numerous points to which we cannot refer here. The main question is as to what happens when the vagus endings in the lungs are stimulated by expansion and collapse of these organs. Hering and Breuer (1868) had already made experiments of this kind with a less perfect method, and founded a theory of self-regulation by the vagus nerves. Head showed definitely that the effect of increase in the volume of the lungs is to inhibit all inspiratory movements, and that decrease of volume has the opposite effect of exciting inspiration (see Figs. 194 and 195). Of course, as we should expect from what is known now of the part played by carbon dioxide, either inflation or suction, repeated periodically, produces stoppage of spontaneous respiration, owing to removal of carbon dioxide, but, with the vagi intact, the stoppage is in the position of inspiration ( = excitation of inspiratory centre), with suction, and the opposite with inflation (see Head's diagram, Fig. 196).

Scott's experiments (1908) showed that the increased respiratory activity produced by inhalation of carbon dioxide differs in form when the vagi are cut from that when they are intact. In the former case the respirations are increased in depth, without increase in rate, whereas there is an increase in both rate and depth when the vagi are intact. It would appear, then, that the inspirations excited by carbon dioxide in the normal state are cut short by the vagi inhibiting the discharge of the centre ; collapse of the lungs follows rapidly, the inhibition ceases, and the centre is again accessible to excitation by carbon dioxide. In this way we have the advantage of an increased rate in addition to the increased depth. It is interesting that the excitatory effect of carbon dioxide does not cause the centre to discharge more frequently, but with increased strength of discharge. The function of the nervous regulation is thus to moderate the discharge, which tends to be "all or none," in the absence of inhibitory impulses.

Apncea. — Since the stimulus to the respiratory centre depends on the tension of carbon dioxide in the alveolar air, it is plain that a diminution of this tension causes cessation of respiratory movements. This is true apnoea. Considerable discussion took place at one time as to whether a summation of the inhibitory vagus impulses, described in the preceding paragraph, could produce stoppage of respiration. Campbell, Douglas, Haldane, and Hobson (1913) have shown that no apmea can be produced, at least in man, unless the alveolar carbon dioxide tension is reduced.

Some aspects of this question have been referred to, incidentally, in previous pages. A few words may be added here with respect to "mountain sickness." In a low atmospheric pressure, not only is the oxygen tension below normal, but the alveolar carbon dioxide is also naturally at diminished pressure. Consequently, the stimulus to the respiratory centre is absent or very weak, although increased supply of air is necessary. The organism suffers, therefore, from want of oxygen. The symptoms observed on Pike's Peak are described thus by Douglas, Haldane, Henderson, and Schneider (1913, p. 308): constant blueness of lips and face, loss of appetite, nausea and vomiting, intestinal disturbance, headache, sometimes fainting, periodic breathing, and great hypernoea on exertion. Difficulty in mental effort is also experienced. All of these symptoms are such as are produced by want of oxygen. The view of Mosso that "acapnia" or diminution of carbon dioxide is the directly responsible factor can no longer be held (see especially the book by Zuntz, Loewy, Miiller, and Caspari, 1906). The symptoms are almost identical with those of carbon monoxide poisoning, " which have been shown to be due to want of oxygen and to nothing else." The psychical disturbances are often like those of alcoholic intoxication ; unreasonable behaviour on the part of visitors required the presence of a deputy sheriff on Pike's Peak. Perhaps unreasonable people met with under ordinary circumstances are really suffering from want of oxygen.

The first proof that the symptoms and dangers of low barometric pressure depend on diminished oxygen pressure, and consequent insufficient oxygen content in the blood, was given by Paul Bert (1878). In acclimatisation, the acidity of the blood due to non-volatile acids is increased, so that the respiratory centre becomes properly excited, although the alveolar carbon dioxide tension is low. It will be obvious that the danger from lack of oxygen is much greater in balloon ascents, where no time for acclimatisation is given. The tragic ascent of Tissandier with two companions in 1875 will be remembered (see Paul Bert, 1878, p. 1063). Some of the words used by Tissandier are worth quoting, as typical of the state of oxygen deficiency. " At about 7,500 m. (3UO mm. barometric pressure) the condition of torpor which comes over one is extraordinary. There is no suffering — one rises and is glad to be rising. This state of exhilaration continues to fche last moment, and immediately precedes loss of

consciousness, sudden, unexpected, and irresistible." When Tissandier recovered consciousness, both of his companions were dead. Although all were provided with oxygen to inhale, they were paralysed before they were aware of the fact, and therefore unable to take hold of the tubes. The object of the respiratory mechanism is to provide for a supply of oxygen to the tissues of the larger animals, where direct access is impossible, and for the escape of the carbon dioxide formed, in combustion.

The oxygen has to be taken up from the air and conveyed to the tissues in solution in a liquid, the blood. In the tracheate bisects, the gas is supplied directly to the tissues by means of fine tubes containing air. The necessity of continued supply of fresh air was proved by Robert Hooke in 1667, and the essential constituent, oxygen, was discovered by John Mayow in 1674. Black, in 1755, showed that the product of combustion in animals is different from common air and called it " fixed air " ; its nature as an oxide of carbon was discovered by Lavoisier in 1775.

There is no evidence that oxygen is stored in the cells in an " intra-molecular " or other form available for oxidation, with the exception of the very minute amount present as peroxide. Such conceptions as that of " biogen molecules " are not in agreement with experimental facts. The phenomena of narcosis are not due to inhibition of oxidation, but to changes in the properties of the cell membrane. Consideration of " life without oxygen " leads to the view that the actual source of the free energy required by a living organism is a secondary matter. If it cannot be •obtained by oxidation, other chemical reactions, although of a less efficient kind, are made use of.

Data of the actual consumption of oxygen by various tissues are given in the text. The heart is found to use oxygen in direct proportion to the tension energy developed. There is no more consumption of oxygen by the lungs themselves than by other organs in rest ; that is, there is no evidence of oxidation of metabolic products from other organs and contained in the blood. The actual amount of oxygen consumed in the lung tissue is only about half that consumed by the salivary gland at rest. The blood itself in mammals only consumes minimal amounts of oxygen, except when large numbers of young cells are present, as after anaemia. Nucleated red blood corpuscles consume considerable amounts of oxygen.

Since the supply 'of oxygen required is much greater than could be carried in ordinary solution, there is a special substance, haemoglobin, in the red corpuscles, which has the remarkable property of taking up oxygen in amount proportional to the pressure of the gas. Thus it takes up oxygen in the lungs and passes it on to the tissues where the oxygen tension is low. Haemoglobin contains iron, and it is held by many that the oxygen taken up is, in some way, in combination with the iron, since it appears to be in molecular proportion to it.

There is no chemical system known which has properties like those of the oxygen-haemoglobin system. Hence it seems probable that surface phenomena act as controlling factors in the amount of the " compound " present at a given oxygen tension. But no satisfactory explanation has been as yet suggested. The amount of oxygen which haemoglobin can take up at a given tension is lowered by rise of temperature and by the presence of neutral salts or acid. The importance of these facts with regard to its function is pointed out in the text.