Clinical overview of the physiology and pathophysiology of pleural fluid movement: a narrative review

Physiology of PF movement

The pleural space is the system that couple the lung to the rib cage. Pressure in the pleural space (pleural surface pressure) plays an important role in cardiopulmonary physiology. Pleural surface pressure results from the opposing pressure of the outer surfaces of the lungs and heart and the pressure of the inner surface of the thoracic cavity. These structures are distensible; their volume depends on the pressure gradient between their inner and outer structures, as well as on their compliance. Hence, pleural surface pressure is useful for determining the volume of these organs.

Under normal conditions, the pleural space contains a small amount of fluid, with a low protein content [7]. This fluid originates from the pleural capillaries and reaches the pleural space via microvascular filtration [8]. To reach the pleural space, PF and the proteins it contains cross two barriers: the capillary endothelium (the main resistance to fluid and protein movement) and the pleural interstitium (or membrane). The filtration of PF and solutes from the circulation into the pleural space is governed by two equations. The first is Starling's equation, which considers the difference in hydrostatic and oncotic pressures between the pleural capillaries and the pleural space [9]. The second is the solute flux equation, based on the capacity of diffusion of each solute, which depends on the filtration coefficient, surface area (∼4000 cm² in a 70 kg man) and thickness of the membrane. The drag reflection coefficient of each solute is also considered in the solute flux equation [10]. In parallel to electrolyte absorption, there is also a small active transport by which the two mesothelial layers absorb fluid [11].where PFM, represents pleural fluid motion; K, pleural filtration coefficient; CapHP, capillary hydrostatic pressure; PLEhp, pleural hydrostatic pressure; CAPop, capillary oncotic pressure; and PLEop, pleural oncotic pressure.

Experimentally it has been observed that the physiological PF pressure is lower (more negative) than the pleural surface pressure. At the bottom of the thoracic cavity, PF pressure is only slightly lower than the surface pressure. This difference increases progressively as we ascend in the thoracic cavity. If PF behaved as a continuous system with homogeneous thickness and remained in static equilibrium, for a column of liquid with a gravimetric density of 1 g·mL⁻¹, the vertical difference in hydrostatic pressure should be 1 cmH₂O·cm⁻¹ height. However, the fluid pressure gradient has been found to range from 0.14 to 0.80 cmH₂O·cm⁻¹ height [12]. In contrast, the surface pressure gradient is −0.2 cmH₂O·cm⁻¹ height [13]. Hence, pleural surface pressure would vary with height in the pleural space according to PF pressure, regional deformation of pleural surface (at the contact points between the two pleural sheets) and weight of the lung, which is higher in the dependent regions of the lung [14]. Therefore, there must be a gravitational flow of fluid in the pleural cavity from the apex to the base of the lung. As a result, differences between PF and surface pressures will be greater at high lung volumes [15]. One theory to explain the difference between the surface pressure and the pressure of the PF would be that, at functional residual capacity, the thickness of the PF ranges between 6 and 15 µm and there are cells with a similar diameter in it. Therefore, at this lung volume, these cells will be trapped between both pleural surfaces and will produce local deforming forces in the pleura. If lung volume increases, the thickness of the PF will decrease, more cells will be trapped and more deforming forces will be created. Furthermore, it must be taken into account that the mesothelial cells on both pleural surfaces have abundant microvilli about 3 µm in length. When the thickness of the PF is less than this length, the microvilli will impact the opposite pleural leaf, creating more deforming forces and further reducing the pressure of the PF.

Under normal conditions, the volume of PF in the pleural space is the result of a dynamic equilibrium between fluid inflow and outflow. This equilibrium is maintained by the equations mentioned above and by lymphatic drainage. Drainage takes place through stomas (or openings) in the parietal pleura, which form lymphatic lacunae immediately beneath the mesothelial layer. The lacunae merge into collecting lymphatic vessels, which join the vessels of the intercostal trunk and direct the flow mainly to the mediastinal lymph nodes [11, 16]. The pleura is a thin membrane consisting of five layers, including an outer fibroelastic layer; a highly vascularised layer of loose subpleural connective tissue; an inner layer of elastic tissue; a submesothelial layer of loose connective tissue; and a mesothelial cell layer [17]. The structure of these cells is similar to that found in the serous membranes of a wide variety of animals [17]. In addition to providing a passive lining to serous cavities, the mesothelium of the inner lining of the pleural space, which is metabolically active, is involved in cellular and humoral immunity and plays an active role in the production and reabsorption of PF [18, 19].

The fluid in the pleural space is continuously exchanged and forms a small film about 10 µm thick between the parietal and the visceral pleura [17] that allows one membrane to slide over the other. This lubrication is provided by hyaluronic acid-rich glycoproteins trapped in the microvilli of the mesothelium and provides a low coefficient of friction [20]. Under physiological conditions, 1–2×10³ cells·mL⁻¹, usually macrophages, are found in this fluid. The PF filtered through the parietal pleura generates a higher pressure gradient than that coming from the visceral pleura. The reason for this difference is that the capillaries of the parietal pleura receive blood from the systemic circulation, whereas those of the visceral pleura receive it from the pulmonary circulation [21]. In other words, in a normal situation, the parietal pleura plays a more relevant role in the filtration of fluid into the pleural space than the visceral pleura [22].

The characteristics and volume of PF are subject to a number of dynamic phenomena that influence systemic and pulmonary circulation, lymphatic drainage, and rib cage and heart movements [23]. Studies in animal models have revealed that, under normal conditions, the net rate of PF formation is ≈0.01 mL·kg⁻¹·h⁻¹, hence, in a 60-kg person, about 15 mL·day⁻¹ would enter. In contrast, its reabsorption is ≈0.28 mL·kg⁻¹·h⁻¹ [24, 25]. In the healthy subject, as a result of the balance between hydrostatic and oncotic pressures between the pleural space and the visceral pleura, the net fluid flow through this membrane is virtually zero. It must be taken into account that the physiological PF in the pleural space also has oncotic and hydrostatic pressure. This hydrostatic pressure is negative at functional residual capacity due to balance between the elastic lung recoil force, which tends to retract the lung, and the rib cage, which tends to expand it (figure 1a). Therefore, fluid primarily filtrates through the parietal pleura, since, as described above, hydrostatic pressure is higher in the pleural capillaries than in the visceral pleura. Once in the pleural space, PF flows towards the lower parts for the aforementioned reasons and is reabsorbed by the lymphatics of the parietal pleura; lymphatics are located in the most dependent regions on this membrane, mainly in the diaphragmatic and mediastinal regions [10]. The lymphatics of the visceral pleura join the mediastinal lymphatics and only drain lymph from the lungs, as they have no contact or communication with the pleural space [26].

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1

Movement of fluid in the pleural space. Reproduced from [4] with permission of the Spanish Society of Pulmonology and Thoracic Surgery. a) Normal lung and pleura. The balance of the hydrostatic and oncotic pressure gradients of the pleural capillaries and pleural space favours the formation of pleural fluid, with a net flow of fluid from the parietal pleura and a balance in the visceral pleura (pressures in centimetres of H₂O). b) Heart failure. The pulmonary oedema that occurs in these cases increases the hydrostatic pressure in the capillaries of the visceral pleura and the fluid passes into the pleural space. c) Trapped lung. The visceral pleura is thick and fibrous due to a previous inflammatory process, which prevents expansion into the lung and leads to negative hydrostatic pleural pressure. This alteration of Starling forces leads to the formation of a transudative pleural fluid.

Pathophysiology of PF movement

For a PE to develop, one of the following situations must occur: the amount of fluid passing into the pleural space must be 30 times greater than normal to exceed the rate of lymphatic reabsorption; or lymphatic reabsorption is significantly decreased. Patients with heart failure are a typical case where the two situations occur simultaneously [27]. There are several mechanisms by which one of these situations may occur (table 1).

Decrease in hydrostatic pressure in the pleural space

This type of PE occurs in the trapped lung. The hydrostatic gradient between the pleural space and the parietal pleura rises due to the increased negative pressure in the pleural space; as a result, the net flow of fluid into the pleural space increases to reduce the hydrostatic gradient (figure 1c). In this type of PE, as fluid is removed by thoracentesis, intrapleural hydrostatic pressure becomes even more negative and fluid builds up again in the pleural space [32]. In this situation, pleural elastance (change in PF pressure in cmH₂O/litre of fluid removed) increases (figure 2) [4, 33, 34].

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 2

In the trapped lung, the visceral pleura has a thicker layer of fibrin, due to a previous disease, which will prevent lung re-expansion. For this reason, the initial pleural pressure will be negative. The withdrawal of fluid, on one hand, and the stiffness of the lung, on the other, will cause a rapid decrease in pleural pressure, leading to elevated pleural elastance. Pleural elastance=45.5, which is the difference between the initial intrapleural pressure and the final intrapleural pressure after withdrawal of 600 mL, either in a single extraction (red line) or after three consecutive extractions (blue line). Modified from [4] with permission of the Spanish Society of Pulmonology and Thoracic Surgery.

These three mechanisms involve a change in pressure (hydrostatic or oncotic), which causes an amount of fluid to pass into the pleural cavity, thereby exceeding the reabsorption capacity of the lymphatics. This type of effusion is called transudate, and pleural membranes remain intact.

Types of PE

In clinical practice, transudates are separated from exudates by measuring the amount of a given solute in the pleural space. There is evidence that the concentration of a solute in PF is solely determined by its concentration in blood and the permeability of the pleural capillaries. Hence, a solute concentration is not determined by the amount of solute extravasated by the leukocytes and erythrocytes into the pleural space after solute degeneration [52]. Therefore, exudates should contain higher concentrations of any solute than transudates [53, 54]. So far, no single parameter has been found to be superior to the others in separating transudates from exudates [55], especially considering that their concentration in PF may be influenced by different factors [56]. Although it is out of the scope of this review, it is necessary to determine which parameter differentiates exudates from transudates most effectively. Ideally, the most effective parameter would be one with such a high molecular weight that, in the absence of an increased vascular permeability, filtration through the endothelium of the pleural capillaries was difficult.

When performing a differential diagnosis and investigating the aetiology of a PE, whether a transudate, exudate, chylothorax or haemothorax, it is essential to be familiar with the predominant underlying pathophysiological mechanisms that cause the accumulation of fluid in the pleural space. Cellular mechanisms are of special interest, as their inflammatory and immunological reactions are reflected in the composition of PF and pleural tissue. Therefore, interpreting correctly the information obtained from the analysis of PF and pleural tissue is essential. Although it is not the aim of this review, measurement parameters such as pH, glucose, C-reactive protein, adenosine deaminase, interleukins, carcinoembryonic antigen and soluble urokinase plasminogen activator receptor (suPAR), to name a few, in PF may be useful for the differential diagnosis of PE and determine the need for invasive diagnostic or therapeutic procedures [57–59]. Table 2 shows the certain (or high probability) diagnoses that can be established by PF analysis and the pathophysiological mechanism involved [4, 30, 31, 58, 60, 61].

On another note, there are some considerations to be taken into account. Firstly, abnormal PF collections occur as a result of an insult to the pleura, which reacts differently according to the type of insult. The different PE etiologies are associated with different response patterns, with PF having specific analytical characteristics. However, a prospective study revealed that pleural response is heterogeneous, and the pleura may respond differently to the same aetiology or similarly to different etiologies, which makes diagnosis of PE difficult [62]. Secondly, in 30% of cases, PE is caused by several underlying diseases, with different mechanisms being simultaneously involved. Identifying these mechanisms may be crucial to determining the best therapeutic approach and ensuring clinical benefit [63]. Finally, PF may change biochemically over time. In the early stages of some malignant PEs, fluid may begin to accumulate due to lymphatic drainage obstruction rather than to direct infiltration through the pleura [64]. At that point, the fluid would behave as a transudate; the reason is that PF would be an ultrafiltrate of plasma with a low protein content, requiring several weeks for the accumulated protein to exceed 50% of serum concentration [65]; this would cause a non-negligible percentage of malignant PEs to behave biochemically as a transudate [66].

In summary, under physiological conditions, the fluid in the pleural space, which couples the lung to the rib cage, is constantly changing and maintains equilibrium between fluid inflow and outflow. Different pathophysiological mechanisms can lead to the accumulation of fluid in the pleural space. These mechanisms are activated by inflammatory and immunological reactions that take place in the mesothelial cells and the pleural space in response to a given insult (disease). For clinicians to understand the heterogeneity of pleural response and identify the aetiology of PE, it is necessary to be aware of the physiology and pathophysiology of PF movements and correctly interpret analytical findings in PF and pleural tissue.