Physiology and Pathophysiology of Pleural Fluid Turnover

SERIES 'THE PLEURA' Edited by H. Hamm and R.W. Light Number 1 in this Series Physiology and pathophysiology of pleural fluid turnover

G. Miserocchi

Physiology and pathophysiology of pleural fluid turnover. G. Miserocchi. ©ERS Journals Istituto di Fisiologia Umana, Università Ltd 1997. degli Studi, Milano, Italy ABSTRACT: The pleural space contains a tiny amount (≈0.3 mLákg-1) of hypo- oncotic fluid (≈1 gádL-1 protein). Pleural fluid turnover is estimated to be ≈0.15 Correspondence: G. Miserocchi -1 -1 Istituto di Fisiologia Umana mLákg áh . Pleural fluid is produced at parietal pleural level, mainly in the less Via Mangiagalli 32 dependent regions of the cavity. Reabsorption is accomplished by parietal pleur- 20133 Milano al lymphatics in the most dependent part of the cavity, on the diaphragmatic sur- Italy face and in the mediastinal regions. The flow rate in pleural lymphatics can increase in response to an increase in pleural fluid filtration, acting as a negative feedback Keywords: Fluid dynamics mechanism to control pleural liquid volume. Such control is very efficient, as a 10 lung interstitium fold increase in filtration rate would only result in a 15% increase in pleural liq- lung microvessels uid volume. When filtration exceeds maximum pleural lymphatic flow, pleural effu- lymphatics sion occurs: as an estimate, in man, maximum pleural lymph flow could attain 30 micropuncture -1 ≈ -1 ≈ mLáh , equivalent to 700 mLáday ( 40% of overall lymph flow). Received: November 2 1995 Under physiological conditions, the lung interstitium and the pleural space behave Accepted after revision July 31 1996 as functionally independent compartments, due to the low water and solute permeability of the visceral pleura. Pleural fluid circulates in the pleural cavity and intrapleural fluid dynamics may be represented by a porous flow model. Lubrication between lung and chest wall is assured by oligolamellar surfactant molecules stratified on mesothelial cells of the opposing pleurae. These molecules carry a charge of similar sign and, therefore, repulse each other, assuring a graphite-like lubrication. Eur Respir J., 1997; 10: 219Ð225.

A review on pleural space is certainly most welcome, the visceral pleura [1] would imply that pleural liquid for the simple reason that on opening a textbook of phy- protein concentration would keep increasing with age, siology the concepts concerning pleural fluid turnover but again there are no indications that this occurs. The date back to 1927 [1]. The same comment, in fact, applies existence of partial restriction to the movement of large in general to microvascular water and solute exchange. solutes, compared to that of water molecules, posed sci- This appears particularly misleading, considering the entists the major problem of explaining how interstitial major advances achieved in the field over the last 70 volume and protein concentration are kept fairly steady. yrs. Around the turn of the 19th century, STARLING and Ideologically, this led to re-evaluation of lymphatics as TUBBY [2] interpreted microvascular fluid and solute the major route for interstitial fluid drainage. In fact, exchange as resulting from the balance between hydraulic since lymphatics do not sieve proteins, they leave the and colloidosmotic pressures. This concept is still valid interstitial protein concentration unaltered the latter dep- today, but the complete formulation of transmicrovas- ending only upon the sieving properties of the filtering cular exchange has become much more complex because membrane. Accordingly, the description of interstitial water crosses biological membranes more easily than fluid homeostasis under steady state conditions is now large solutes (namely, plasma proteins) do [3]. In fact, dif- being explained as a balance between capillary filtra- ferent equations describe water and solute fluxes [4]. tion and lymphatic absorption. Major validation of this As a result, the general model of transcapillary fluid model has come from the accumulating experimental exchange still taught to students, based on fluid filtra- data over the past 30 yrs concerning interstitial tissues tion at the arteriolar end of the capillary bed and reab- [4] and serous spaces [5]. Interestingly, since the pio- sorption at the venular end, appears rather simplistic. neering, work of STARLING and TUBBY [2] the pleural Due to the different permeability to water and solutes, space has been used as a useful experimental model to one could predict on a mathematical basis that such a study the interaction between microvascular filtration model would lead to a progressive increase in intersti- and lymphatic drainage. tial protein concentration over time [3, 4], a condition This article presents an integrated view of pleural fluid that cannot be confirmed experimentally. turnover, based on data gathered from experimental stud- Similarly, the old hypothesis claiming that pleural ies on animals over the last 15 yrs. The situation in man fluid filters at parietal level and is reabsorbed through is, unfortunately, still poorly defined; yet, where possible, 220 G. MISEROCCHI extrapolations will be made in an attempt to relate the surface to 8,000ácm-2 on the diaphragm and their diam- present state of knowledge to human pleural patho- eter averages 1 µm (range <1–~40 µm) in size. A sim- physiology. ilar anatomical disposition was seen for the peritoneal cavity. Lacunae in man have not been definitely demonstrated, although their existence is probable. Furthermore, The pleural compartments they were found in mammals as large as sheep [13]. Mesothelial cells are only about 4 µm thick [11], and The pleural space, like other serous cavities of the connect to each other by tight junctions on the luminal body, may be considered an enlarged tissue space. In side and by desmosomes on the basal portion of the inter- fact, unlike a common interstitial space, it presents a cellular junction [11]. higher ratio of free fluid to solid tissue volume. Solid Microvilli 1–3 µm long are seen on mesothelial cells, volume may be represented by cells being present in varying in density from 2 to 30 per µm2, and trap high the pleural fluid and microvilli of mesothelial cells. The concentrations of glycoproteins and hyaluronic acid [11, pleural space actually contains a tiny amount of fluid, 14]. The thickness of the pleurae is quite variable among (≈0.3 mLákg-1 body mass, with a low protein concen- species: in animals with thin pleurae (dogs, rabbits and tration (≈1 gádL-1, [6, 7]); the latter appears a peculiar cats [15]), the thickness of the submesothelial intersti- feature considering that, in physiological conditions, the tium is equal for parietal and visceral pleura, averaging pressure of the pleural fluid is subatmospheric. In fact, 20 µm; however, in animals with thick pleurae (sheep, when a subatmospheric pressure is found in other tis- pig, horses and humans), it is about five times thinner sues, like the lung interstitium for example, protein con- in the parietal compared to the visceral pleura, where it centration increases and, furthermore, it is well-known can attain about 100 µm [13, 14, 16]. that an opposite condition, namely tissue hyperhydra- It might be useful to recall briefly the concepts con- tion, causes a decrease in interstitial protein concentra- cerning fluid and plasma protein flux across biological tion. membranes. All acceptable description of water flux Figure 1 is a simplified schema of pleuropulmonary (normally indicated as Jv) between two compartments compartments. Considering the anatomical arrangements, labelled 1 and 2 is given by the revised Starling law: it appears that five compartments are involved: the parietal systemic microcirculation; the parietal interstitial Jv = Kf [(PH - PH ) - σ (π1 −π2)] space; the pleural cavity itself; the lung interstitium; and 1 2 the visceral microcirculation (either systemic from bronchial artery or pulmonary). The membranes separating where Kf is the filtration coefficient, PH and π are the such compartments are: the capillary endothelium (on hydraulic and colloidosmotic pressures, and σ is the parietal and visceral side); and the parietal and the vis- solute reflection coefficient of the membrane. The coef- ceral mesothelia. The lymphatics provide drainage of ficient, σ, is a number varying from 0 to 1. For σ=1, the interstitial spaces but also of the pleural cavity, as the radius of the solute (we consider plasma proteins) they open directly on the parietal pleura (lymphatic sto- is larger than that of the pores of the membrane and, mata). Stomata, in rabbits and sheep [8Ð11], are fre- therefore, no solute flux can occur through the mem- quently grouped in clusters and connect to an extensive brane. For σ=0, the radius of the pores of the membrane network of submesothelial lacunae [11, 12]. They range is large enough to allow solute to cross the membrane. in density from 100 stomataácm-2 on the intercostal For 0 <σ < 1, there is partial restriction to solute movement. The description of solute flux is rather difficult, as it occurs partly via the water flux and partly down a Parietal Visceral diffusion concentration gradient [3]. pleura pleura Basal lamina Pleural space Pulmonary The old hypothesis on pleural fluid turnover Extrapleural s.c. interstitium In 1927, based on the Starling hypothesis of fluid parietal p.c. interstitium p.c. exchange, NEERGARD [1] proposed the hypothesis that pleural fluid turnover is entirely dependent upon the dif- Parietal Alveolus ference between hydraulic and colloidosmotic pressure. lymphatic Although provocative and relatively unchallenged for over half a century, this model appears today simplistic and untenable, as it neglects the existence of interstital Stoma Pulmonary lymphatic spaces, the permselectivity to water and solutes, and the existence of pleural lymphatics. NEERGARD [1] reasoned that pleural fluid filters at parietal level because hydraulic Microvilli pressure in systemic microcirculation exceeds colloidosmotic pressure; conversely, fluid is reabsorbed at vis- Unidirectional ceral level because in the pulmonary microcirculation valve the opposite is true. This hypothesis was developed by AGOSTONI et al. [17], who found that the difference Fig. 1. Ð Schema of the morphofunctional design of pleural space; between hydraulic and colloidosmotic pressure in the s.c.: systemic capillary; p.c.: pulmonary capillary. pulmonary capillaries was large enough to account for PLEURAL FLUID TURNOVER 221

a) Parietal Visceral a relatively small pressure gradient (fig. 2b). The aver- pleura pleura age filtration rate decreases with increasing animal size Systematic Pulmonary and ranges ~0.1Ð0.02 mLákg-1áh-1, from rabbits to dogs. capillary capillary It is important to recall that, in order to derive indications on pleural fluid turnover, one must carry out expe- Pleural riments in conditions close to the physiological one that liquid is characterized by two main features: namely, a small pleural liquid volume and subatmospheric pleural liquid pressures, such as those occurring during spontaneous breathing. In experimental models implying large pleural effusions and mechanical ventilation [24, 25], the database is difficult to interpret as it does not reflect a steady state situation. b) Parietal Visceral Comparative studies (with animals ranging from a few pleura pleura gram to 50 kg body mass) reveal that pleural fluid turn- Systemic capillary Pulmonary capillary over (normalized to body mass) decreases with increas- Jv=0.153 ing size [5]. In fact, it was found that with increasing Parietal mass: 1) pleural liquid pressure (considered at the level interstitium of the right atrium) becomes more negative; and 2) pleur- Pleural Lung Jv=0.194 Jv=0.05 liquid interstitium al fluid volume (normalized to body mass) and protein Jv=0.041 concentration decrease. Thus, it appears that, with increas- Lung ing body mass, the tendency develops for a greater "dehy- lymphatics dration" of the pleural space. At the extreme of this scale, anatomical records indicate that in animals as large as Lymphatics elephants, the pleural cavity is obliterated. From the biophysical standpoint, the parietal mesothe- [Jv]=mL·kg-1·h-1 lium can be modelled as a membrane with few but large Fig. 2. Ð a) Neergard's hypothesis (1927) [1]. The old hypothesis pores: this is reflected by a low σ value (≈0.3) but also concerning pleural fluid turnover, which neglects the existence of by a low solute permeability coefficient [7]. This fea- interstitial spaces and pleural lymphatics. b) the present view of pleur- ture makes it possible to sieve proteins efficiently, so al fluid turnover, based on the available experimental database gath- that the protein concentration of pleural fluid is rather ered with minimally invasive techniques in the rabbit. The pleural -1 space and the pulmonary interstitium are, under normal conditions, low (about 1 gádL ), smaller than the protein concen- two functionally separate compartments, fluid filters from the micro- tration in the extrapleural parietal interstitium (about 2.5 circulation and is drained by the lymphatics. Subatmospheric hydraulic gádL-1 [7]). Extrapolation to humans is difficult. Further- pressures are set by the action of the lymphatic pump. The figure more, in humans, there is the suggestion that some fil- shows water flux under steady state conditions. Solute (plasma protein) flux has been omitted. Although figures will vary in man, the tration may occur from the visceral pleura, as its blood overall situation is unlikely to be qualitatively different based on supply stems from the systemic circulation where func- anotomofunctional considerations. tional hydrostatic pressure is higher compared to pul- the subatmospheric pressure of the pleural liquid. This monary circulation; this fact however, may be of no old hypothesis (fig. 2a) is no longer valid today based relevance as the key variable in this respect is pulmonary on the present state of knowledge. In fact, a thorough interstitial pressure. The latter was directly measured in analysis of fluid (and solute) flux has required the devel- rabbits, by using the micropuncture technique through the pleural window approach, and was found to be rather opment of sophisticated techniques to measure hydraulic ≈ and colloidosmotic pressures in the various pleural com- subatmospheric ( -10 cmH2O [26]). The same technique partments [18, 19], to estimate water and solute per- made it possible to describe the pulmonary microvas- meability coefficients [7] of the membranes separating cular pressure profile [27]. Based on these findings, it the compartments, and, finally, to measure pleural lym- appears that fluid normally filters from pulmonary micro- phatic flow in conditions very close to the physiologi- vessels to the lung interstitium. If pulmonary intersti- cal ones [20Ð23]. The whole mosaic of knowledge is tial and microvascular pressures in humans were similar fairly complete in rabbits, where most of the techniques to those measured in rabbits, no gradient should be pre- were developed by preserving the integrity of the pleural sent to cause fluid filtration through the visceral pleura. space, and the available information has made it possible to develop a model of pleural fluid turnover that can be extended to animals as large as sheep and is com- Pleural fluid drainage patible with pathophysiological observations in man. Absorption flows through the visceral pleura are normally negligible, so that, under normal conditions, the Pleural fluid filtration pleural space and the pulmonary interstitium are two functionally separate compartments. This should also be From experimental determination of variables and true in man, given the great thickness of the visceral coefficients shown in the Starling equation [5, 7], it pleura, implying a low water and solute permeability. appears that pleural fluid is filtered at parietal pleural Most pleural fluid drainage (≈75%), estimated from clear- level from systemic microvessels to the extrapleural ance of labelled proteins in rabbits and dogs, occurs thr- interstitium and from there into the pleural space down ough parietal pleural lymphatics [22, 23]. Controversial 222 G. MISEROCCHI data on pleural lymph flow were gathered in sheep, nevertheless, although numbers may vary somewhat rel- where the same group of investigators found on differ- ative to other species, the situation is unlikely to be ent occasions that pleural lymphatics would drain either qualitatively different based on anatomofunctional con- <1% [25] or ≈70% of pleural fluid [24]. siderations and on data gathered in large mammals. Pleural lymphatics are able to generate a subatmospheric pressure [21] of about -10 cmH2O. Furthermore, they can increase the flow rate by about 20 fold in res- Control and pathophysiology ponse to an increase in pleural liquid volume following an increase in pleural fluid filtration [20]. Lymphatic Another implication of the original hypothesis of activity is pulsatile in nature, due partly to myogenic NEERGARD [1] was that pleural liquid volume and pro- rhythmic contraction of the smooth muscles of the tein concentration should vary on changing the Starling lymphatic walls (intrinsic activity), and partly to tissue balance of pressure across the pleurae. However, both pressure oscillations related to respiratory movements experimental evidence and medical practice indicate that (extrinsic mechanism). The two mechanisms account for pleural fluid volume and composition are highly stable about 40 and 60%, respectively, of total pleural lym- and, in fact, pleural effusions develop when dramatic phatic flow under physiological conditions, the stroke changes in fluid and solute homeostasis occur. Therefore, volume for each initial lymphatic stoma being of the order this suggests that some sort of mechanism ought to exist of 1×10-6 µLástoma [22]. Some features of the drainage to guarantee a tight control on pleural fluid volume and are peculiar, as a greater lymphatic drainage occurs in protein concentration. The same happens, of course, in the lowermost parts of the cavity [28], over the diaphrag- other tissues, although the features of the control vary. matic surface and in the mediastinal regions [18]. Since In the lung parenchyma, for example, a very tight filtration and absorption sites are different, this implies control exists to guarantee a minimum amount of inter- that pleural fluid circulates within the pleural space (see stitial fluid [26, 29] which is crucial to assure gas dif- below under "Intrapleural fluid dynamics"). fusion. The comparison between pleural space and lung Figure 2a presents the old hypothesis of pleural fluid interstitium offers, in fact, an important clue to the under- turnover, whilst the present model based on experimental standing of how a condition of minimum interstitial vol- results is shown in figure 2b. Fluid filters from the pari- ume is achieved. The pulmonary interstitium has a very etal microcirculation into the pleural space and is drained low mechanical compliance; accordingly, when facing by lymphatics: the new feature is that flows, rather than a condition of increased filtration, this leads to a marked pressure gradients, are presented in this figure in order increase in pulmonary interstitial pressure [29]. This rep- to describe the pleural fluid turnover rate. The figure resents the so-called "tissue safety factor" against the also shows that liquid filters from the pulmonary capil- development of pulmonary oedema, as it opposes, based laries into the lung interstitium, from where it is removed on the Starling balance of pressures, a further filtration. by the lymphatics. The latter point also represents a new However, due to its high compliance, the pleural space piece of knowledge [26], based strongly on interstitial has no "tissue safety factor"; therefore, the only mech- pressure measurements performed with lungs physiolo- anism assuring a control on minimum pleural liquid vol- gically expanded in the pleural space. The important ume is represented by lymphatic drainage. Since pleural concept to grasp here is that the lymphatics represent a lymphatics can increase the flow in response to an drainage mechanism, able to generate a subatmospheric increase in pleural liquid volume, they represent a neg- pressure (like a vacuum cleaner). From a mechanistic ative feedback mechanism controlling pleural liquid vol- standpoint, the lymphatics set the pressure in the compart- ume, as they tend to offset the induced perturbation ment to be drained; therefore, they establish an impor- Such a system seems to be highly efficient. In fact, tant variable appearing in the Starling pressure balance relatively wide variations in pleural filtration rate result equation, namely interstitial hydraulic pressure. As mentioned previously, similar concepts for fluid Power turnover are now also being shared for other interstitia Lymphatic and serous cavities [4], in fact, such a system allows a pump close control on interstitial volume and protein concen- Filtration tration. It is worth recalling here that when lungs are physiologically expanded in the chest, alveolar pressure is equal to atmospheric and pleural pressure is subat- Parietal pleura mospheric, so that, from the mechanical standpoint, the Buoy lung interstitium is subject to a tensile stress. Note that, if pulmonary interstital pressure were to be measured in isolated lungs passively inflated at positive alveolar pressure, a compressive stress would be applied to the lung tissue and this may raise interstitial pressure above atmospheric; clearly, such data bear little relationship Visceral to the physiological situation. Finally, as can be appre- pleura ciated from the available database, it is clear that no reabsorption of pleural fluid can occur into the pulmonary Fig. 3. Ð Simple schema to depict the features of lymphatic control. Lymphatics act as a pump controlled by a rheostat that can increase capillaries, as hypothesized by NEERGARD [1] in 1927. flow rate in response to an increase in pleural liquid volume. When In man no database is available to attempt an analysis the level of the buoy rises, the power to the pump increases and, cor- of fluid turnover in the pleuropulmonary compartments; respondingly, the lymph flow increases also. PLEURAL FLUID TURNOVER 223 in minor deviations from steady state pleural liquid vol- maximum lymph flow, transudate would then form. Exu- ume [30], the latter being maintained at a minimum va- date would mostly form when protein permeability of lue. Figure 3 shows a simple functional schema of the the systemic capillaries is increased; a comparable in- pleural space and of pleural lymphatics. The visceral crease in mesothelial protein permeability would only pleura is shown as a high resistance pathway as opposed cause a modest increase in pleural liquid protein concen- to the parietal pleura and to the parietal lymphatics. tration because interstitial protein concentration is low Parietal lymphatics act as a pump controlled by a rheo- already. Again, pleural effusion of exudate type would stat; when the level of the buoy rises (as a consequence occur when filtration rate exceeds maximum lymph flow. of an increased filtration), the power to the pump increa- It must be remembered that on biophysical grounds an ses and, correspondingly, lymph flow increases also. increase in solute, compared to water permeability, ref- To give an idea of such a regulatory mechanism, one lects a more severe lesion of the membrane. Finally, it may consider that for a 10 fold increase in filtration rate, must be noted that the extrapleural interstitium exerts a the steady state pleural liquid volume would only increase potent buffer action against the increase in pleural fil- by 15Ð20% [30], undetectable by common X-rays. The tration rate; indeed, due to its low compliance, an increased same regulatory capacity is retained even if the maxi- capillary filtration leads to a marked increase in inter- mum lymph flow rate is decreased 10 fold. It must be stitial pressure, thus opposing further capillary filtration. emphasized, however, that the increase in lymph flow to attain its maximum (about 20 fold) is smaller than the potential increase in Starling dependent filtration Pleural space and lung pathophysiology flows. In fact, an increase in filtration rate by two orders of magnitude may result from pathological conditions Some controversies should be reported concerning the (e.g. inflammation, right heart failure); clearly, an incre- permeability of the visceral pleura. Results from stud- ase in pleural filtration rate beyond the maximum pleu- ies on stripped specimens of the visceral pleura [33] ral lymph flow results in pleural effusion. Thus, although suggest that permeability of the visceral pleura to water lymph flow may increase substantially, lymphatics can- and solutes is fairly high. Contrary to these conclusions not cope with a massive increase in filtration rate. It are the results from experiments where the integrity of appears, therefore, more appropriate to regard lympha- the pleural space and spontaneous respiration were pre- tics as a system mostly effective in controlling pleural served; in these conditions, it was found that albumin liquid volume close to steady state conditions. transport from pleural space to pulmonary interstitium These conclusions may be valid in humans too, although accounted for less than 20% (an overestimate) of total some reservation is due because of the extrapolation. albumin removal from the pleural space with close to Let us consider a basal pleural lymph flow rate equal normal pleural liquid volume [23]. Thus, the finding of to that measured in dogs (0.02 mLákg-1áh-1: for a 70 kg a high permeability of the visceral pleura may suggest man this would correspond to 1.4 mL-1 or about 34 that experimental damage was induced. In line with the mLáday-1, about 2% of the overall daily lymphatic flow hypothesis of a highly permeable visceral pleura, other (1 mLákg-1áh-1 or 1,680 mLáday-1)). Maximum pleural data [34] suggest that the visceral pleura may represent lymph flow would amount to ≈30 mLáh-1, ≈700 mLáday-1 a pathway for fluid removal during pulmonary oedema; (about 40% of overall lymph flow), a remarkable increase, these data are based on the observation that protein rich and yet, still not enough to counteract the formation of liquid leaks through the visceral pleura of isolated, infla- large pleural effusions. Beyond maximum lymph flow ted, perfused lungs made oedematous in an artificial saturation, fluid exchanges depend upon hydraulic and pleural space. Again, the finding, of a protein-rich liquid osmotic pressure gradients, whilst below saturation level, suggests a marked alteration in membrane permability lymph flow represents the main drainage pathway. It both of capillaries and visceral pleura, because normal seems appropriate to recall here the long overlooked hy- pleural fluid is hypo-oncotic. pothesis proposed by Starling 100 yrs ago concerning Extrapolation of such findings to human pathology the fluid reabsorption from experimental pleural effu- may be difficult, as protein-rich pleural effusion is a sion, namely, that after hydraulic and osmotic equili- rather uncommon finding in pulmonary oedema. In fact, brium is accomplished, "...the absorption of fluid from it was also found that during lung interstitial oedema in the pleural cavity is extremely slow, so that it might rabbits (that have a thin visceral pleura), pulmonary perhaps be affected by the lymphatics alone" [31]. interstitial pressure rose well above atmospheric [29], Based on the fact that pleural fluid is filtered and creating a gradient for liquid filtration from the lung mostly reabsorbed via lymphatics at parietal level, an parenchyma into the pleural space. However, this did attempt was made to model pleural fluid turnover [32], not result (at least up to 3 h of observation) in any appre- as occurring between three compartments in series (sys- ciable increase in pleural liquid volume, indicating that temic capillaries, extrapleural parietal interstitium and the permeability of the visceral pleura is physiological- pleural cavity), separated by two resistances in series ly fairly low. Human clinical experience reveals that (capillary endothelium and parietal mesothelium), and transudative pleural effusion may develop several hours two draining pathways (extrapleural and pleural lym- after pulmonary oedema. To explain an increase in micro- phatics). As already mentioned, the visceral pleura does vascular filtration through the visceral pleura, two hypo- not appreciably account for pleural fluid egress under theses may be put forward: 1) on biophysical grounds, normal conditions. The model is useful to discuss some pulmonary vascular congestion implies an increase in important determinants of pleural effusion. A simul- surface area for microvascular exchanges (this may taneous increase of capillary and mesothelial water perm- involve not only the pulmonary circulation but also the eability leads to hypo-oncotic fluid; if filtration exceeds bronchial circulation that supplies the visceral pleura); 224 G. MISEROCCHI and 2) water permeability of the visceral pleura increas- References es as a general result of inflammation. 1. Neergard K. Zur Frage des Drukes in Pleuraspalt. Beitr Intrapleural fluid dynamics Klin Erforsch Tuberk Lungenkr 1927; 65; 476Ð485. 2. Starling EH, Tubby AH. On absorption from and sec- Intrapleural fluid movements were demonstrated by retion into the serous cavities. J Physiol 1894; 16: 140Ð following the intrapleural distribution of radioactive albu- 155. min with a gamma camera [18, 23, 38, 35]. Intrapleural 3. Kedem O, Katchalsky A. 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