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Pathophysiology of pleural cavity disorders 

Pathophysiology of pleural cavity disorders
Pathophysiology of pleural cavity disorders

Davide Chiumello

and Cristina Mietto

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date: 03 December 2020

Key points

  • The pleural cavity is a virtual space. Negative (subatmospheric) pressure is essential to guarantee the mechanical coupling between the lung and the chest wall.

  • The three major determinants of this balance are the Starling forces, the lymphatic drainage, and the active transmembrane transport.

  • When fluid or air accumulates inside the pleural cavity, pleural pressure rises to atmospheric level. The consequence is that the lung and chest wall tend to their resting position—the lung collapses, while the chest wall tends to expand. The displacement is not equally distributed between lung and chest wall, because it depends upon the individual compliance.

  • Pneumothorax can be defined as primary if it is not associated with any lung disease. Otherwise, pneumothorax is usually referred as secondary and the most common causes are chronic obstructive pulmonary disease, cystic fibrosis, infectious diseases, and cancer. Traumatic pneumothorax can be consequence of chest injury or invasive medical procedures (mechanical ventilation, central venous catheter placement, thoracentesis).

  • Pleural effusion is classified as transudates or exudates, mainly based on protein content. Transudates are typically bilateral and the increase in systemic capillary pressure is due to increased filtered fluid in the presence of preserved endothelium. Exudates occur when a protein rich fluid is collected for an altered mesothelial barrier permeability.


The pleural cavity is a virtual space delimited by the pleura and contains a thin layer of fluid pivotal for the mechanical coupling of the respiratory system. Collection of air (pneumothorax) and excess fluid (pleural effusion) impair the function of the respiratory system and are common in critically-ill patients, occurring in up to 15 and 60% of patients admitted to intensive care unit, respectively [1,2].


The pleural cavity is a closed space bordered by the pleura, a serous membrane consisting of a parietal leaflet that covers the internal surface of the thoracic cage, the diaphragm and the mediastinum, and a visceral leaflet that coats the external surface of the lung. The upper limit of the pleural space, occupied by the dome of the lung, extends 2–3 cm above the first rib and behind the sternocleidomastoid muscle. The inferior limit follows the border between the diaphragm and the chest wall, corresponding to the sixth rib anteriorly and just below the twelfth rib posteriorly. The visceral pleura is adherent to the lung surface from which it is not separable, ensuring a homogenous transmission of the forces. Both pleura are constituted by a single line of mesothelial cells, that are joined by tight junctions, such as endothelial cells, and have intracellular synthesis capability and active trans-cellular transport [3]‌. Mesothelial cells are provided with microvilli on the luminal side, a major density characterizes the visceral pleura and caudal lung regions. The parietal pleura is distinguished by the presence of stomata, round holes opening between cells which provide communication between the pleural space and lymphatic vessels of submesothelial tissue [3]. Blood supply is from systemic circulation for both pleura, the visceral one drains into the pulmonary vein system. Regarding innervation, the parietal pleura is provided by the intercostal and phrenic nerves, which entail a mark sensibility to pain, while the visceral pleura has an autonomic innervation and it is insensible to painful stimuli. However, nerve terminals with neurochemical characteristics of mechanosensory/nociceptive terminals could be involved in the pathogenesis of dyspnoea associated to pleural diseases [4].

Pleural cavity and respiratory system mechanics

The two pleural leaflets are separate by a thin layer of liquid that must be kept at the minimum needed to ensure the mechanical coupling between the lung and the chest wall. Lung and chest wall resting positions are different, so that at functional residual capacity (FRC) lung inward recoil is counterbalanced by chest wall outward tendency. These opposite recoil forces, which tend to separate the visceral and parietal pleura, are the major determinants of pleural pressure (Ppl). Pleural surface is exposed to a negative (subatmospheric) pressure that prevents lung collapsing and allows the lung and chest wall to move together. In clinical practice the oesophageal pressure (Pes) is the only available surrogate of Ppl and Pes variations are reliable of Ppl changes [5]‌. Moreover, Ppl is not equal along the whole lung height, but there is a vertical gradient, roughly 0.25 cmH2O/cm, due to the lung weight [6]. Gravity exerts a uniform force on the lung, but its visco-elastic nature and the presence of the supporting chest wall determines an inhomogeneous distribution. Consequently, Ppl is more negative at the top and tends to keep the lung open, whereas the bottom is compressed against the chest wall and the resulting Ppl is relatively higher. Ppl gradient is lower than the hydrostatic (1 cmH2O/cm) because lung density is just one quarter the density of water. In the literature, two different models have been proposed for the pleural liquid pressure (Pliq). A theory proposes that Pliq is more negative than Ppl because of the presence of points of contact between the two pleural leaflets [7]. The other model states that lung and chest wall recoils are transmitted hydraulically through the pleural liquid, so that Pliq equals Ppl [8].

If air is collected into the pleural space, pleural pressure rises to atmospheric level causing the lung to collapse and the chest wall to expand, until a new equilibrium is reached. Pleural cavity has a high compliance, meaning that a large amount of fluid can be accumulated before Pliq begins to rise. Pleural effusion collects into the pleural cavity with a gravity distribution, altering Ppl. Above the pleural fluid Ppl gradient is normal, while below the gradient becomes hydrostatic with the consequence of a greater reduction of the transpulmonary pressure (Pl):

P L   =   P aw     P pl
[eqn 1]

where Paw is the airway pressure. The consequence is the loss of aeration of the dependent lung zones. The displacement is not equally distributed between lung and chest wall, but it depends upon their own compliance. Thus, the volume of lung and chest wall are different, leading to the uncoupling of the respiratory system—the more compliant the chest wall, the more it accomplishes and the more compliant the lung, the greater the reduction in lung volume. Studies showed that pleural effusion entails a decrease in FRC of about one-third of the added volume, while the remainder is accepted by chest wall displacement. Moreover, regional lung volumes changed accordingly and the reduction of lung volume is mostly accounted for by the dependent regions with minimal changes in the upper lobes [9,10]. This distribution is in accordance with an altered Ppl and consequently Pl gradient. In another study, lung recruitment manoeuvres partially reversed the reduction in respiratory system compliance primarily due to the lung component, which can suggest that airway collapse can be an important mechanism involved [11].

Consistently, humans studies showed a small increase in lung volume after pleural effusion drainage compared with the volume removed, but a significant dyspnoea relief and more negative Pes [12,13]. A possible explanation is that the chest wall outward displacement determines a decrease in the length of the inspiratory muscles reducing their effectiveness [13]. Thoracentesis can restore the normal length and improve muscles efficacy with dyspnoea relief.

Pleural fluid dynamics

Normal pleural liquid volume is roughly 0.2 mL/kg, with a composition typical of plasma filtrate through a biological sieving membrane—protein content is low, 1–2 g/100 mL, and albumin is the major fraction [14]. The volume of pleural liquid is determined by the equilibrium of fluid turnover between in- and outflow, being equal to 0.2 mL/Kg/hour under physiological conditions [14,15]. Pleural fluid filters through the capillary of the parietal pleura and then is reabsorbed, mainly from stomata lymphatic system of the parietal pleura and, to a less extent, by solute-coupled transport and absorption into the capillaries of the visceral pleura. The three major determinants of this balance are the Starling forces, the lymphatic drainage, and the active transmembrane transport. Starling equation describes filtration across biological barriers (i.e., endothelium, as well as mesothelium):

If   = Kf   [ ( P c     P liq )     σ ( π c     π liq ) ]
[eqn 2]

where If refers to the net fluid movement across the compartments, Kf is the filtration coefficient, P is the hydrostatic pressure, π‎c and π‎liq the colloid–osmotic pressure in the sub-pleural capillaries and pleural liquid, respectively, and σ‎ is the protein reflection coefficient of pleural mesothelium. If we consider as a whole the driving force between brackets, the eqn 2 simplifies to:

If   =   Kf     Δ Pf
[eqn 3]

the transpleural liquid flow is dependent on the overall driving force (Δ‎Pf) and on the Kf, that is equal to the product of the total surface (S) available for filtration and the water hydraulic permeability (Lp) (Kf = S·Lp). Lp (the coefficient defining water hydraulic permeability) is mostly dependent on the size and distribution of small aqueous channels, called pores, opening on the membrane. Studies suggests that mesothelial cells are also active in a solute-coupled liquid absorption and transcytosis based on morphological evidence of vesicular transport [14]. A similar equation can be written for the lymphatic drainage (Jl):

Jf = KI     ( P labs   =   P liq )
[eqn 4]

where Kl is the conductance of the lymphatics, which is proportional to extension and is 10-fold greater than Kf, Plabs and Pliq are the absorption and the pleural liquid pressures, respectively. Plabs is rather negative, thus promoting reabsorption of pleural liquid. Lymphatic drainage is the main pathway limiting liquid accumulation and is essential for removing molecules and cells from the pleural space [14,15]. Pleural liquid turnover is polarized, filtration being greater in the upper regions of the cavity, whereas drainage is predominant at the diaphragmatic and mediastinal side [15]. Lymphatic flow seems the only way for draining cells back to blood circulation. Pleural fluid contains approximately 1500–2500 cells/mm3, the majority are macrophages with fewer leucocytes, erythrocytes, and mesothelial cells [14].


Pneumothorax happens when air is introduced into the pleural cavity, causing chest wall displacement and lung collapse. Air can enter through the lung parenchyma or through chest wall injuries. Normally, air is not present into the pleural cavity, despite the negative pleural pressure, because the total of the partial pressure of gases dissolved in blood is less than one atmosphere (arterial blood 708 mmHg and venous blood 655 mmHg, breathing room air). This is essential for keeping the pleural cavity free of gases and reabsorption of collected air. Pneumothorax is classified in two groups based upon the aetiological mechanism–spontaneous and traumatic (Table 123.1). Spontaneous pneumothorax can be secondary, i.e. associated to pulmonary diseases (mainly chronic obstructive pulmonary disease (COPD), cystic fibrosis, tuberculosis, cancer, interstitial lung diseases, and others). If no lung disease can be identified as a triggering factor, the pneumothorax is usually referred to as being primarily spontaneous, and is more frequent in young, thin, tall males. The classical theory is that it derives from the rupture of a subpleural bleb or bulla. Evidence to support this theory is derived by CT studies finding that 80% of patients with primary spontaneous pneumothorax show emphysema-like changes of lung parenchyma [16]. These alterations are often bilateral and mainly represented in the upper lobes. Some studies found a correlation with atmospheric pressure changes, loud music, height and smoking that seem to be a major risk factor [17].

Table 123.1 Causes of pneumothorax

Type and causes of pneumothorax







Rheumatoid arthritis

Cystic fibrosis



Marfan’s syndrome

Pneumocistis carinii pneumonia

Ehlers–Danlos syndrome

Idiopatic pulmonary fibrosis

Lung cancer

Histocytosis X





Penetrating or non-penetrating chest injury


Transthoracic needle aspiration

Subclavian vein catheter


Internal jugular vein catheter

Transthoracic pleural biopsy

Mechanical ventilation

A different model has been proposed for those patients without sign of emphysema-like changes or broken bulla during surgery. Visceral pleura show lesions of the mesothelial layer that is replaced by an inflammatory fibrotic tissue, alteration referred as ‘pleural porosity,’ and that can sustain the air leakage [17]. Both bullae and pleural porosity may be related to airway chronic inflammation, anatomy anomalies, connective tissue diseases, local ischaemia or malnutrition. Another possible scenario is the development of a haemopneumothorax, where the cause of bleeding is often an ectopic vessel enveloped into the pleural bulla.

On the other hand, traumatic pneumothoraxes can result from both penetrating and non-penetrating chest injuries, and can be divided into two major groups—iatrogenic or non-iatrogenic. The latter can be due to air leakage directly through the chest wall or visceral pleura wounds. Instead, alveolar rupture is a consequence of lung contusion or blast injuries. Iatrogenic pneumothorax is common and can be a complication of different medical procedures, such as transthoracic needle aspiration, thoracentesis, and the insertion of central intravenous catheters. Another important iatrogenic cause of pneumothorax in critically-ill patients is mechanical ventilation, referred to as barotrauma, and it is due to ventilation with high positive airway pressure, which determines high transpulmonary pressure (Pl) leading to alveoli over inflation or even rupture. Air leakage can be not only into the pleural cavity, but may even extend to mediastinum and body surface.

Pleural effusion

Pleural effusion is defined as any increase in pleural liquid volume sustained by an altered fluid turnover, depending on an increased filtration rate exceeding absorption compensatory mechanisms or caused by a primarily impaired drainage system. Enhanced filtration can be a consequence of increased filtration pressure, or altered mesothelial and endothelial permeability. The increase in pleural liquid promotes a change in the balance of fluid turnover toward a reduced filtration and enhanced absorption—a decrease in the net hydrostatic filtration pressure, an increase in lymphatic flow, and if the fluid has a low protein content, the oncotic pressure is still in favour of reabsorption. Parietal pleura lymphatic drainage is the main adapting mechanism facing fluid retention and can increase to 20 times its basal value [7]‌. Pleural effusion is classified as transudates or exudates, mainly based on protein content (Table 123.2). A pleural effusion is defined as exudates when the protein concentration is greater than 30 g/L or when the fluid to serum total protein ratio (Cliq/Cp) is higher than 0.5. Relaying only on this parameter, 15% of transudates and 10% of exudates are misclassified, thus Light’s criteria can be used to better distinguish between the two types of pleural effusion with a sensibility of almost 100% for exudates [18,19]. Light’s criteria take into account liquid and serum lactic dehydrogenases (LDH): pleural fluid to serum LDH ratio (LDHliq/LDHp) greater than 0.6, LDHliq greater than two-thirds of the upper limit of serum reference and Cliq/Cp greater than 0.5 [20]. In the case of pleural effusion with a protein concentration between 25 and 35 g/L or in patients in therapy with diuretics, where Cliq can be misleading, a difference in serum and liquid protein greater than 31 g/L or an albumin concentration difference higher than 12 g/L suggest transudate [19]. This classification comprises different pathological mechanisms beneath the two kind of pleural effusion. In transudates, that are typically bilateral, the increase in systemic capillary pressure is due to the increased filtered fluid in the presence of preserved endothelium and mesothelium sieving properties, resulting in an acellular and low protein fluid. The most frequent conditions associated are heart diseases, chronic renal failure, hepatic cirrhosis, pleural fibrosis, and atelectasis. Isolated right heart failure rarely causes pleural effusion probably because the increased filtration can be matched by the enhanced lymphatic system. On the contrary, pleural effusion is common in case of biventricular or left ventricular failure where there is an increase in visceral pleura permeability leading to functional communication between the pleural and lung extravascular space (i.e., interstitial lung oedema) causing an excess of fluid filtration overwhelming compensatory mechanism. Systemic venous hypertension can be a rare cause of impaired lymphatic drainage. Then, renal and hepatic diseases may determine a decrease in protein content, with the result of a decreased colloid–osmotic pressure, as well as primary hypo-albuminaemia. Lastly, there may be direct transdiaphragmatic leak of ascitic fluid from the peritoneum. On the other hand, exudates occur when a protein rich fluid is collected for an altered mesothelial barrier permeability with cell and protein leak into the pleural space or for impaired lymphatic removal. The most common cause of exudates is inflammation; other conditions associated can be malignant neoplasms, primary of mesothelial cells or metastatic, tuberculosis, or asbestos-related diseases. The hallmark of pleural involvement in local or systemic inflammatory diseases is increased microvascular and mesothelial permeability, occurring with opening of new transcellular pathways and for direct mesothelial cell damage with loss of barrier selectivity [14,15]. One of the most frequent type of exudates is pleural effusion associated to pulmonary infection, parapneumonic effusion. Evidence shows that mesothelial cells are active elements in the immunity defence process—they can recognize the pathogens, and subsequently initiate and propagate the inflammatory response. Mesothelial cells have phagocytic properties and can release reactive oxygen species as first line defence mechanism. Mesothelial cells release also cytokines that are pivotal in the recruitment of native and acquired immunity cells [20]. Inflammation promotes a fibrin deposition upon damaged tissue and a fine balance between fibrin deposition and removal is essential to avoid the development of pleural fibrosis.

Table 123.2 Causes of pleural effusion



Congestive heart failure


Severe mitral stenosis

Neoplastic disease (lung, mesothelioma, metastatic)


Pulmonary thromboembolism

Nephrotic syndrome

Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus)


Asbestos exposure

Pulmonary thromboembolism

Post-coronary artery bypass

Superior vena cava syndrome


Peritoneal dialysis




Haemothorax is defined as any pleural effusion with a haematocrit greater than 50% of peripheral blood. It is to remember that a haematic pleural effusion with a haematocrit >5% is visually indistinguishable from blood. Most cases are the result of chest trauma or invasive procedures. Other causes can be vascular rupture (aortic dissection or pulmonary vessel malformation), tumours, inherited or acquired coagulopathy, and anticoagulation therapy.


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