6I2.2I6:6I alveolar pressure. It follows that the evident alteration in the respiratory rhythm is an alteration in amplitude.

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6I2.2I6:6I2.223.11 SOME EFFECTS OF CARBONIC ACID ON THE CHARACTER OF HUMAN RESPIRATION. BY J. BARCROFT AND R. MARGARIA' (Turin). (From the Physiological Laboratory, Cambridge.

1 6I2.2I6:6I SOME EFFECTS OF CARBONIC ACID ON THE CHARACTER OF HUMAN RESPIRATION. BY J. BARCROFT AND R. MARGARIA' (Turin). (From the Physiological Laboratory, Cambridge.) THE following facts concerning the effect of inhalation of C2 on the respiratory rhythm have been known since the work of Haldane and Priestley [195]: (1) that inhalation of C2 increases the total ventilation, (2) that no very simple statement can be made as to this as regards the frequency. Short of breathing 6 p.c. C2 the alteration in frequency due to that gas is no greater than the range of frequency at a given alveolar pressure. It follows that the evident alteration in the respiratory rhythm is an alteration in amplitude. We have failed to discover any detailed statement as to the effect of C2 inhalation upon (1) the duration of the phases of respiration, namely, inspiration, expiration and the pause (if any), (2) upon the rates at which air is taken in and given out during the various phases. In the hibernating marmot, in which the respirations are very slow, and in which the phases can be followed very easily, the rate at which air is taken into the lung during inspiration is practically uninfluenced by carbonic acid. The incteased depth of respiration is attained by extension of the time occupied by the inhalation of air at a given rate [Endres and Taylor, 193]. In man the possibilities of increasing the total ventilation on this principle are limited, seeing that the inspiration in quiet breathing already occupies a third (less or more) of the whole period of one respiration. In the marmot the period of expiration is quickened by C2, so that even though twice the normal quantity of air may leave the lung, the time reckoned from the height of inspiration to the depth of expiration is only about half the normal. A view of the action of C2 on respiration put forward by one of us [B arcroft, 1919] differed from the conception based on the respiration of the marmot, in that it stipulated for increase in the rate of inhalation 1 Fellow of the Rockefeller Foundation.

176 J. BARCROFT AND R. MARGARIA. of air during the inspiration as well as of the exhalation of air during the expiration. It seemed desirable to ascertain the facts in the human subject. METHOD.

2 176 J. BARCROFT AND R. MARGARIA. of air during the inspiration as well as of the exhalation of air during the expiration. It seemed desirable to ascertain the facts in the human subject. METHOD. Experiments were carried out on two persons. The experimenters and the apparatus were in a glass room of 1 cubic metres capacity; this room was approximately air-tight as regards diffusion, but not so tight that addition of gas to the atmosphere therein caused a permanent rise in the barometric pressure. In the calculation of the alveolar airs given below the barometric readings used are those outside the chamber. In the room was a large CO2 cylinder fitted with a meter, a table with a Sandstrom drum, and a spirometer of the Krogh type. To the spirometer was fitted a well-fitting rubber mask; between the two was a three-way aluminium tap such as is used for a Douglas bag. With the handle of this tap "across" the subject breathed into and out of the open air whilst the spirometer was sealed; with the handle " up and down" he rebreathed the air from the spirometer. The dead spaces in the system were cut down to the minimum. Valves were not used as it was found in preliminary experiments that, especially during hyperpnuea, the resistance of the valves affected the curve of respiration more than did the small extra dead space entailed by their absence. For the "collection" of alveolar air the mask was modified in the following way. The orifice to which normally an expiratory valve is fitted was plugged, and through the plug was inserted a piece of rubber pressure tubing-this went into the mouth of the subject. The orifice outside the mask was fitted with a vacuous gas sampling tube. The routine was as follows: (1) The chamber door being closed, CO2 in the required quantity was liberated in the chamber, through the meter. The air of the chamber was kept mixed with a fan. The subject breathed the air of the chamber for at least 1 minutes. (2) He then put on the mask, taking care that the harness was properly adjusted. (3) The upper tap of the gas sampling tube being open to the air, the subject blew out expired air, thus filling the dead space of the tubing between the mask and the sampling tube with what is as nearly alveolar air as can be obtained by blowing down so fine a tube. The volume of this dead space was roughly 2 c.c. and the sampling tubes 5 c.c., so that if the air in the tubing differed from alveolar air by, say, I p.c., this would show as an error of 1/25 part of that in the final analysis, or 1l mm. The tap is now shut. (4) The

3 C2 ON HUMAN RESPIRATION. 177 operator starts the drum; he then turns the aluminiuum tap so that the subject, who hitherto has been breathing from the open air, rebreathes the spirometer air for three or perhaps four respirations. (5) The aluminium tap is turned back and the subject takes a sample of his alveolar air. (6) A sample of the air of the chamber is taken. (7) The subject Fig. 1. Spirometer tracings of the respiration. Subject, Barcroft. C2 in inspired air: (i) -2 p.c. (ii) 1FO p.c. (iii) 2-2 p.c. (iv) 4-2 p.c. (v) 5.3 p.c. (vi) 7-5 p.c. Inspiration downwards, expiration upwards. Tracing read from left -to right. Time, 1 sec. and the opeirator change places and the routine from number 2 onwards is repeated. In each case the first subject was Barcroft, the second Margaria, so that Margaria had been breathin'g the 'air of the chamber about 15 minutes before hiis records w'ere'taken. In the experiment described, six sets of records were taken with increasing quantities of CO2. The samples taken were analysed after

4 178 J. BARCROFT AND R. MARGARIA. the second, fourth and sixth records for which purpose the experimenters came out of the chamber. RESULTS. Figs. 1 and 2 show the results obtained of the last experiment. In reading them it must be noted that the drum was not going at the same velocity in each record. I R Fig. 2. Subject Margaria. Othierwise legend as in Fig. 1. (1) As regards frequency our results are the same as those of other authors, there is no certain relation between amount of CO2 in the inspired or alveolar air and rate of respiration. Fig. 3, A and B, shows the relation of the total ventilation in the two subjects to the frequency of respiration. In Margaria the frequency rises from the start in an almost linear relation to the total ventilation, in B arcroft there is little change in the frequency till the ventilation has trebled. After that point the frequency rises, if anything more rapidly in the case of B arcroft than that of Margaria.

5 C2 ON HUMAN RESPIRATION F > 3 * x x## X OX I I I * Total ventilation Fig. 3 A. 3 2?22~ * ~ > ( * 1, l li I A Total ventilation Fig. 3B. Figs. 3 A and 3 B. Relations of frequency of respiration and total ventilation., during inhalation of C2; *, during exercise. A, Margaria; B, Barcroft.

18 J. BARCROFT AND R. MARGARIA. Fig. 4. Spirometer tracing showing the method of drawing the tangent. Total ventilation: 67 litres per min. Inspiration downwards. C&' ) CD lv 2.8 2'6 2.4 2*2 2.

6 18 J. BARCROFT AND R. MARGARIA. Fig. 4. Spirometer tracing showing the method of drawing the tangent. Total ventilation: 67 litres per min. Inspiration downwards. C&' ) CD lv 2.8 2' *2 2. 1* '.8.6 '4.2 4 Fig Total ventilation, litres per min. 6 7 Relation of tangent (rate of inspiration in litres per sec.) and total ventilation in litres per min. during inhalation of C2. * Barcroft; ( Margaria.

C2 ON HUMAN RESPIRATION. (2) As regards the primary object of the research, a rise in the carbonic acid in the inspired and alveolar airs causes a rise in the rate at which air' is inhaled.

7 C2 ON HUMAN RESPIRATION. (2) As regards the primary object of the research, a rise in the carbonic acid in the inspired and alveolar airs causes a rise in the rate at which air' is inhaled. The greatest deviation from a uniform rate of inspiration is shown in the curves where the ventilation is greatest, such as Fig. 4. Even in these it is possible to draw a tangent to the curve which (with suitable corrections) gives the rate of inspiration at the middle of the inspiratory phase. The necessary corrections are (a) for the fact that the lever is describing an arc, and (b) for alterations in the velocity of the drum. When these have been made and the tangent of the angle is expressed in terms of litres inspired divided by time, it gives the most constant relation which we have been able to obtain, namely that the tangent of the angle is nearly proportional to the total ventilation-see Fig. 5. The ratio of the tangent to the ventilation is not the same in the two persons observed. The maximum total ventilation obtained with C2. We found it impracticable to breathe 1 p.c. of CO2 for more than a few minutes. The inspiration of 7-5 p.c. CO2 which is the highest quantity that could be endured over a period of a quarter of an hour produced in Margaria a total ventilation of 71 litres per minute and in Barcroft 6 litres per minute. TABLE I. Alveolar CO2 Total ventilation p.c. C2in,- A-----_, inspired air B. M. B. M * X * *2 5* *5 6' The above points are in general agreement with "Peabody's Curve" [1915], relating the CO2 in the inspired air to the total ventilation. There is, however, a limit set to the ventilation to be obtained by CO2 inhalation, which is due to the fact that unlimited concentration of CO2 cannot be tolerated. In practice we believe that the limit was attained in our experiments; it gave an alveolar CO2 in the case of Margaria of 6 mm. Hg. 181

'III N. Ir Fig. 6. Spirometer tracings of Margaria before and after exercise. (i) before, (ii) after 3 sec. from the end of the exercise, (iii) after 14 min., (iv) after 2i min., (v) after 34 min.

8 'III N. Ir Fig. 6. Spirometer tracings of Margaria before and after exercise. (i) before, (ii) after 3 sec. from the end of the exercise, (iii) after 14 min., (iv) after 2i min., (v) after 34 min., (vi) after 5 min., (vii) after 7 min. Inspiration downwards. 4 3 ) Co ea 2 I II I I Total ventilation, litres per min. Fig. 7. Relation of tangent (rate of inspiration in litres per sec.) and total ventilation, Margaria. Breathing C2. After exercise.

9 C2 ON HUMAN RESPIRATION. Comparison of increase in total ventilation wrought by C2 and by exercise. Evidently the maximal total ventilation caused by CO2 as given above is much less than what can be obtained by exercise. This fact may be deduced from the writings of previous workers, but as it is not definitely set forth, we determined to compare the increments in total ventilation brought about by the two methods. In the experiment given below, the subject ran down and up the laboratory stairs. The following data were obtained: TABLE II. Ventilation Tangent Frequency (litres per min.) (litres per sec.) BarCrOft. Before 13* After 3 sec min min. 19* P29 5 mi. 19* P7 Margaria. Before 16* After 3 sec min k mi min min. 17* *87 7 mi. 18* Both in the case of Margaria and of Barcroft, a very moderate amount of exercise produced a greater frequency of respiration and a greater total ventilation than the limit produced by CO2. Yet from the literature we have no reason to suppose that this alveolar C2 rose to anything approaching 61 mm. In the case of Barcroft the rate at which air was inspired (the tangent) was also much greater in the case of exercise. It is probable that in a young athletic man such as Margaria the upper limit of ventilation on exercise might be double that obtainable with C2. On the other hand such moderate exercise as was taken in the above experiment produced no unpleasant ef$ects either at the time of the exercise or afterwards. The breathing of 7-5 p.c. of C2 for 2 minutes produces a shock from which the system does not wholly escape for some hours or perhaps even a longer time. It seems clear that C2 can only be one contributory factor to the dyspncea of exercise. In this connection it seemed desirable to rule out the possibility of

10 184 J. BARCROFT AND R. MARGARIA. peripheral stimulation by the carbonic acid. We therefore made an experiment on a cat to ascertain whether the same total ventilation was produced with CO2 (1) when no nerves were cut, (2) when the vagi were cut, (3) when both vagi and sympathetics were cut. Since the CO2 was inhaled through a tracheal tube the cutting of the vagi and sympathetics abolish the possibility of sensory fibres from the lung. 1 1 I X 1 1 X 1 r I I I I I I I I I _ o o 1~~ Fig. 8. Chloralosed cat. The total ventilation, c.c. per min. (ordinata) is plotted against the time in minutes (abscissa) during the administration of a 9*4 p.c. C2 mixture in air, or during the administration of air. a-a', administration of C2 mixture; b-b', administration of air; X, normal cat; *, after vagi cut; x, after vagi and sympathetics cut. The results are shown in Fig. 8, namely that although during air inhalation the total ventilation was increased by section of the vagi, yet after the administration of 9-4 p.c. CO2 the total ventilation was the same with the vagi cut as it had been with 9-4 p.c. CO2 and the vagi uncut. When the -C2 effect had worn off, the ventilation returned approximately to the original values both with the vagi cut and intact. Whilst under the influence of considerable concentrations of CO2 the total ventilation is the same whether or not the vagi be cut, the type of respiration is different, being slower and deeper with the cut vagi.

11 C2 ON HUMAN RESPIRATION. Vagi intact Vagi cut Total ventilation 93 c.c. per mim. 913 Frequency Depth General correspondence between the measuredfactors in dyspncea caused by C2 and by exercise. In general the relations between the total ventilation, the tangent of the angle of inspiration and the frequency, bear the same general relations whether the dyspncea is produced by C2 inhalation or by exercise. These relations also show the same differences between the two individuals (see Figs. 3 A and 3 B). Presumably the mechanisms for CO2 and for exercise have much in common. SUMMARY. 1. The inhalation of C2 quickens both the rate of air inhalation and of air exhalation and shortens the time occupied by each phase of respiration. 2. The rate of inhalation of air at the middle of inspiration varies almost exactly with the total ventilation. 3. The above relation and indeed all others which we have measured are the same for an individual whether the hyperpnoea is produced by C2 inhalation or by exercise. 4. The maximal total ventilation produced by exercise is much greater (nearly but not quite twice as great) than that produced by the highest concentration of C2 which could be breathed for a quarter of an hour. 5. It would seem probable from 3 and 4 above that 2 inhalation and exercise act in a similar way, but that the maximal effect of C2 falls short of that of exercise. 185 REFERENCES. Barcroft, J. (1919). J. Phy8iol. 53, Proc. p. xlviii. Endres, G. and Taylor, H. (193). Proc. Roy. Soc. B, 17, 231. Haldane, J. S. and Priestley, J. G. (195). J. Physiol. 32, 223. Peabody, F. W. (1915). Arch. Intern. Med. 16, 846. Quoted by van Slyke, D. D.,, Factors affecting the distribution of electrolytes, water and gases in the animal body. Lippincott, Philadelphia. PH. LXXII. 13

Douglas and Haldane(2) has shown that the oxygen determinations. since it forms the basis of the "Coefficient of Utilisation" (Krrogh) and

Douglas and Haldane(2) has shown that the oxygen determinations. since it forms the basis of the Coefficient of Utilisation (Krrogh) and THE MEASUREMENT OF THE OXYGEN CONTENT OF THE MIXED VENOUS BLOOD, AND OF THE VOLUME OF BLOOD CIRCULATING PER MINUTE. BY J. BARCROFT, F. J. W. ROUGHTON AND R. SHOJI. (From the Physiological Laboratory, Cambridge.)