throughout. The constant-flow respiration was administered through a intravenously at appropriate intervals (in addition to the general

414 6I2.22I:6I2.2I5.5 GASEOUS INTERCHANGES THROUGH THE VISCERAL PLEURA OF THE CAT. By M. KREMER, A. T. WILSON AND SAMSON WRIGHT. (Department of Physiology, Middlesex Hospital Medical School.) (Received July 9, 1934.) THIS study arose out of an examination of a method of artificial respiration which may be called "constant flow positive pressure" respiration. It is not uncommonly employed in the human subject when operations have to be carried out which involve opening the pleural cavity [T i e g e l, 1909; Davies, 1911]. The method consists essentially in passing a steady current of oxygen through the lungs under slight positive pressure without any rhythmic movement being imparted to it. Such a procedure might perhaps be expected to oxygenate the blood sufficiently, but it did not appear to us probable that it could prove effective in eliminating carbon dioxide from the lungs. A study of the blood gases confirmed our anticipations, but we found that when the method was used with the chest widely opened, CO2 was given off in much larger amounts than when the chest was closed. We were thus led to study the passage of CO2 and oxygen across the visceral pleura. METHODS. Cats lightly anmesthetized with nembutal or chloralose were used throughout. The constant-flow respiration was administered through a tracheal cannula; the general arrangement used is indicated in Fig. 1. Experiments were carried out with the chest closed wbile natural breathing also took place, with the chest partially opened by removal of a few ribs, and with the lungs widely exposed to the outside air by removal of the greater part of the chest wall. In some instances curare was injected intravenously at appropriate intervals (in addition to the general

GASEOUS EXCHANGE THROUGH PLEURA. 415 anmesthetic) to paralyse natural respiratory movements. Arterial blood was collected from the femoral or carotid artery and the gas contents determined with the van Slyke apparatus in the usual way. :To D.B. Water resistance Fig. 1. Arrangement of constant-flow positive pressure respiration. Tr =trachea; 02 cyl. = oxygen cylinder; To D.B. = To Douglas bag. RESULTS. Experiments with chest wall intact. If natural breathing is taking place and constant-flow respiration is commenced it is always found to hamper considerably the elimination of carbon dioxide. During expiration the air which is expelled from the chest obviously cannot flow back into the cylinder whence it is issuing under positive pressure and so passes out through the water valve. During inspiration air enters the lungs partly from the oxygen cylinder and partly from the water-valve side of the tracheal tube. The latter contains partially diluted expired air with raised CO2 content, with the result that the functional dead space is considerably increased. Under these conditions of the experiment the rate of outflow from the cylinder and the level of positive pressure used within wide limits made little difference to the efficacy of CO2 elimination; the range employed for flow and pressure was 05-2-0 litres per minute and 2 5-10 cm. water respectively. With the same conditions of artificial respiration considerable

416 M. KREMER, A. T. WILSON AND S. WRIGHT. variation in C02 output took place in different animals; it was highest usually when the natural breathing was vigorous and deep. The colour of the blood remained bright red and its percentage saturation with oxygen was normal. The two protocols given below indicate the range of efficacy of CO2 elimination noted. Cat A. Normal breathing. C02 output in 12 min. 204 c.c. Blood C02 36 p.c. 12 min. constant-flow respiration. C02 output 108 c.c. Blood C02 rose to 42 p.c. Next 12 min. C02 output 150 c.c. (Blood CO2 ultimately rose to 64 p.c. When constant-flow respiration was stopped the unimpeded natural breathing restored the blood CO2 to normal level in 10 min.) Cat B. Normal breathing 15 min. CO2 output 290 c.c. Blood C02 42 p.c. Constant-flow respiration 18 min. CO2 output 27 c.c. Blood C02 62 p.c. When the animal with chest intact is thoroughly curarized to paralyse natural breathing, constant-flow respiration is more regularly and strikingly ineffective. The blood C02 rose in one instance from 42 to 75 p.c. in 30 min., and to 87 p.c. in 90 min.; in another from 36 to 50 p.c. in 25 min. and to 72 p.c. in 45 min. According to Irving, Foster and Ferguson [1932] the amount of C02 in the muscles per kg. body weight is five times as great as in the blood. If the body weight is 3*5 kg., a rise of 36 c.c. vol. p.c. C02 in the blood (such as occurred in the latter experiment) means a retention of 100 c.c. C02 in the blood and of about 500 c.c. in the muscles in 45 min. or of practically the whole of C02 formed during that time. The rate of C02 output via the trachea shows erratic variations, but is commonly reduced to a small fraction (e.g. 10 p.c.) of its normal value. Experiments with chest opened. If the chest is opened C02 elimination under constant-flow respiration takes place more effectively than with the chest closed. This is indicated by the following observations: (i) The blood C02 does not rise so rapidly or to such high levels, e.g.: Cat C. Initial blood C02 44 p.c. Chest opened and constant-flow respiration started. Blood C02 after 25, 35, 65, 80 and 105 min. was 56, 56-5, 56, 57.5, 59, 59 p.c.

GASEOUS EXCHANGE THROUGH PLEURA. Cat D. Initial blood CO2 43 p.c. Chest opened and constant-flow respiration started. Blood CO2 after 30, 60, 120 and 195 min. was 45, 54, 53, 55 p.c. (ii) If the blood CO2 has previously been allowed to accumulate under constant-flow respiration with the chest closed, opening the chest usually leads to a fall which may be considerable. Exp. 12. ii. 34. CO2 output via trachea Time Blood CO2 p.c. (for 15 min.) Notes c.c. 1.30 Curarized; chest intact 1.45 59-2.0 74 36 2.15 75 36 2.30-116 2.20-2.30 chest 2.35 57 2-45 - 32 2.55 50 opened wide 417 The manipulations which take place while the chest is opened are equivalent to manual artificial respiration and temporarily increase the CO2 output. The amount given off as shown in the above protocol does not account for the fall in blood C02, as the rate of CO2 elimination via the trachea was under 150 c.c. during the period of 10 min. In any case the blood CO2 further declined in the succeeding 20 min. from 57 to 50 p.c. There can be no doubt that the CO2 was eliminated almost wholly via the visceral pleura. (iii) If only a small part of the chest wall is removed the decrease in blood CO2 may be very slight. Exp. 22. ii. 34. Curare. Chest intact, constant-flow respiration. Blood CO2 rose to 75 p.c. Three ribs were then removed on each side. 20 min. later the blood CO2 was 73 p.c. The rest of the chest wall was then removed. (Only 5 c.c. CO2 were given off via the trachea during the manipulations.) 20 min. later the blood CO2 was 63 p.c.; 40 min. later 59 p.c. (iv) A series of experiments were performed to demonstrate directly the relative extent of the elimination of CO2 that took place via the trachea and visceral pleura respectively when the chest was wide open. The degree of positive pressure employed was adjusted in a way that was thought to favour the passage of CO2 outwards; it was always sufficient to produce moderate distension of the lungs, so as to expose as large a surface as possible without, however, being so great as to compress the

418 M. KREMER, A. T. WILSON AND S. WRIGHT. pulmonary capillaries and so hamper the blood flow. The animal was then placed in an airtight box provided with several outlets: one for the tube from the tracheal cannula which connected with the artificial respiration, one for sampling the air in the box, and two to enable a current of air to be blown through the box. The air from the lungs (tracheal perfusate) and from the box (box perfusate) was collected in separate D o u g 1 a s bags. Preliminary experiments showed that if no air current was blown through the box (which had a volume of 9 litres) the C02 percentage in it rose rapidly, going up (in a representative experiment) in 20, 40 and 63 min. to 1'0, 2x1 and 2-6 respectively. In this instance 250 c.c. C02 were given off in an hour via the pleura against a normal C02 output of 900 c.c., and the blood CO2 rose from 43 to 52 p.c. The results of three typical double perfusion experiments were as follows: 2. ii. 34. In 105 min., tracheal C02 output, less than 25 c.c.; C02 output vta pleura 730 c.c. 6. ii. 34. Tracheal perfusate C02 output, 15 c.c. in 110 min. C02 output via pleura: 220 c.c. in first 40 min., 760 c.c. in next 70 min. 2. ii. 34. Tracheal perfusate C02 output, 25 c.c. in 105 min. C02 output via pleura, 714 c.c. in 105 min. These experiments show that the changes in the CO2 of the blood which occur when constant-flow respiration is given with the chest wide open will depend almost entirely on the rate at which C02 can diffuse out through the visceral pleura. It should be remembered that on an average every 1 c.c. p.c. rise or fall in the C02 concentration in the blood corresponds (in an animal weighing 4 0 kg.) to a change of 3 c.c. total C02 in the blood and of 15 c.c. in the muscles, making 18 c.c. in all. With the chest wide open and constant-flow respiration in use, when the blood C02 is about 70 p.c. corresponding to a tension of over 80 mm. on the oxygenerated blood curve, our results show that enough C02 can be given off under favourable conditions to cope not only with current C02 production but also with a considerable proportion of the previous C02 accumulation. When the C02 content falls to about 50 p.c. corresponding to about 40 mm. C02 pressure it becomes only just possible to deal with current C02 formation. In other words, when C02 elimination is taking place predominantly via the visceral pleura, a gradient between the blood and the outside air of at least 40 mm. C02 pressure is necessary to deal with about 800 c.c. per hour C02 which are usually formed, as compared with a difference of a few millimetres which suffices under normal conditions when the gaseous interchanges are taking place between the blood and the normally ventilated alveolar air.

GASEOUS EXCHANGE THROUGH PLEURA. 419 Oxygen diffusion through the visceral pleura. To study oxygen interchanges through the visceral pleura the following method was adopted. Artificial respiration was carried out with low oxygen mixtures for periods of 10 min.-first with the chest closed and later with the chest widely opened, and the percentage oxygen saturation of the arterial blood determined under both circumstances. When the chest is open the blood in the lungs is exposed simultaneously to the low oxygen pressure in the alveoli and to the higher oxygen in the room air. If the oxygen saturation were bigher in the blood in this latter case it would be indicative of oxygen diffusion from the outside air through the visceral pleura into the blood. The Palmer ideal pump was employed using a fixed rate and stroke. Preliminary experiments showed that with the level of ventilation employed 10 min. was a long enough period to establish a constant oxygen pressure in the alveolar air. A sufficiently large stroke was employed to ensure good distension of the lungs, so that when the chest wall was removed a considerable surface was exposed to the outside air. The carotid sinuses were denervated because (as shown by Selladurai and Wright [1932]) oxygen lack under these conditions rapidlyparalyses respiration; the cessation of active respiratory movements causes the chest to follow the pump movements passively and makes the ventilation with the chest open and closed strictly comparable. It is unlikely that th e resistance of the inactive chest wall makes any significant difference to the degree of distension of the lungs as the pump employed is a powerful one. The oxygen mixtures employed were selected to fall on the steep part of the dissociation curve so that a small rise of blood oxygen tension would produce a readily determinable change in percentage saturation. When the chest is open the lungs often collapse more during expiration than they probably do with the chest closed; this varied with the degree of elasticity of the lungs. To make conditions more closely comparable a TABLE I. Artificial Chest closed Chest open Oxygen respiration, mixture rate and stroke p.c. 02 02 tension p.c. 02 02 tension Exp. p.c. c.c. saturation calculated saturation calculated 5. iii 6-4 30 x 100 48 29 73 41 5. iii 5-5 12 x 100 31 22 44 27 7. iii 6-0 12 x 100 34 23 59 34 12 x150 59 34 79 49 7.iii 60 12 x100 48 29 58 34 12 x100 46 28 70 40 8. iii 5-7 12 x 100 41 25 62 35 12x150 62 35 79 49

420 M. KREMER, A. T. WILSON AND S. WRIGHT. small amount of expiratory resistance was employed when the chest was open. The results obtained are shown in Table I. The oxygen tensions were determined from the standard haemoglobin dissociation curve. No allowance was made for possible changes in C02 tension. The results as given show quite regularly a higher percentage saturation in the arterial blood with the open chest. The calculated 02 tensions with the chest open are, however, undoubtedly incorrect, because direct experiment shows that the amount of artificial respiration employed produces considerable acapnia which shifts the dissociation curve to the left, so that the higher percentage saturation obtained does not necessarily indicate a correspondingly raised oxygen tension. The experiments were, therefore, repeated, adding percentages of C02 varying from 3-6 to 5-6 p.c. to the low oxygen mixture used. The results are given in Table II and now show a very slight rise of oxygen pressure (average 3 mm.) when the chest was opened. TABLE II. Artificial Chest closed Chest open Mixture p.c. respiration - ---A A, rate and stroke P.C. 02 02 tension P.C. 02 02 tension Exp. 02 C02 C.C. saturation calculated saturation calculated 9. iii 6 0 3-6 12 x 100 29 20 34 23 12 x 150 37 24 36 24 11. iii 6-3 4.4 12 x 100 32 22 54 31 12 x 150 46 28 59 34 13. iii 5.9 5-8 12 x 100 28 19 33 22 12 x 150 35 23 35 23 14. iii 7 0 5-6 12 x 100 35 23 42 25 12x150 48 29 52 30 Average 36 23-5 43 26.5 If the experiment of 11. iii is excluded the difference in the two sets of observations becomes only 2 mm. Furthermore (as pointed out to us by Prof. B arcroft) it is impossible to say how uniform is the degree of distension of different parts of the lungs with the chest opened and closed. Minor variations in this respect could easily account for the trivial differences in arterial oxygen pressure obtained. To get still more decisive results some experiments were finally performed in which, after the chest was opened, the animal was placed in a box through which a stream of pure oxygen was passed so that the pulmonary blood vessels were exposed to a very high oxygen pressure on the outside of the visceral pleura. The most favourable conditions were thus provided for oxygen diffusion inwards. Artificial respiration was carried out as before. In two representative experiments the arterial oxygen

GASEOUS EXCHANGE THROUGH PLEURA. pressures with the chest closed were 23 and 30 mm., and with the chest open and the lungs exposed to pure oxygen the results were 25 and 34 mm. respectively. DIsCUSSION AND CONCLUSIONS. 421 The relative sizes of the surface of the alveoli and of the visceral pleura in the cat are not known, but some approximate data are available for the human subject. According to Zuntz and Loewy the area of the alveoli in man is 90 sq. metres. The area of the surface of the moderately distended human lungs is about 0-2 sq. metre, or about five hundred times smaller. The thickness of the visceral pleura relative to that of the alveolar epithelium is about ten to one. The velocity of gaseous exchanges varies directly as the area and inversely as the thickness of the membrane. Gaseous interchange through the visceral pleura should, therefore, be several thousand times less efficient than through the alveolar epithelium Ṫhese theoretical data can be compared with the experimental results. Evans calculated that a C02 pressure difference of 0-03 mm. is sufficient to eliminate the C02 formed in the resting body. In our experiments it was found that a pressure difference of 40 or 50 mm. 002 was needed between the blood and the outside air to dispose of concurrent C02 production via the pleura; this figure is on an average about 1500 times as large as the normal. This gives an index of inefficiency of interchange of approximately the same order as that theoretically deduced. In the case of the experiments with oxygen an allowance has to be made for the fact that oxygen diffuses twenty-five times less rapidly than C02. On the basis of our data and those of Zuntz and Loewy a pressure gradient between the outside air and the blood of several thousand millimetres oxygen pressure would be necessary for normal arterial oxygen saturation to be brought about by this route. Our observations show, in agreement with this, that when the lungs are exposed to outside air (02 pressure gradient of about 100 mm.) the uptake of oxygen is almost negligible. It is somewhat surprising that more definite improvement in the oxygenation of the blood was not observed when the pressure gradient was raised higher by replacing the atmospheric air by means of oxygen. It is clear that under the most favourable circumstances the diffusion of oxygen through the visceral pleura is very slow. Our results suggest that the value of constant-flow positive pressure respiration in man depends principally on the following considerations:

422 M. KREMER, A. T. WILSON AND S. WRIGHT. (i) the blood is adequately oxygenated; (ii) the presence of active respiratory movements produces partial elimination of C02 via the trachea; (iii) as the chest wall is opened some C02 loss takes place through the visceral pleura; (iv) in operations of comparatively short duration there is no time for the blood C02 to rise excessively when one takes the C02 binding powers of the tissues into account; (v) C02 excess may not produce the same degree of permanent injury to tissues, especially to the brain, as does anoxia. SUMMARY. 1. A study of constant flow positive pressure respiration led to an examination of gaseous interchange through the visceral pleura in the cat. 2. The passage of C02 outwards from the blood through the visceral pleura takes place about 1500 times as slowly as into the normally ventilated alveoli. To eliminate all the C02 which is being concurrently made, a pressure gradient between the blood and outside air of 40-50 mm. is necessary. 3. The passage inwards of oxygen from the outside air through the visceral pleura takes place far more slowly than is the case with C02. A pressure gradient of several hundred millimetres only produces doubtful or just perceptible effects on the degree of oxygen saturation of the blood. 4. On the basis of the results obtained the merits of constant-flow respiration in man are discussed. The expenses of the above research were partially defrayed by a grant through the Government Grants Committee of the Royal Society. REFERENCES. Davies, H. M. (1911). Brit. med. J. ii, 61. Irving, L., Foster, H. C. and Ferguson, J. K. W. (1932). J. biol. Chem. 95, 95. Selladurai, S. and Wright, S. (1932). Quart. J. exp. Phy8iol. 22, 233. Tiegel, M. (1909). Beitr. klin. Chirurg. 64, 356.