The role of pleural pressure in inducing pneumothorax and other adverse effects of positive pressure ventilation

Introduction

To better understand the adverse effects of mechanical ventilation, it is essential to first examine the differences between mechanical ventilation and natural respiration. Loring (1), and more recently Butler et al. (2), have argued that there is no significant difference between negative pressure ventilation (NPV), which mimics natural inspiration by pulling the thoracic wall outward, and positive pressure ventilation (PPV). Both modes indeed produce the same lung volume when the transpulmonary pressure is equivalent. However, positive airway pressure increases pleural pressure (P_pleural), whereas negative extra-thoracic pressure and natural inspiration decrease it. P_pleural plays a critical role, either pushing the lung toward the thoracic wall (positive P_pleural) or pulling it away (negative P_pleural). Consequently, it is expected that the side effects of PPV will be closely related to these differences in P_pleural behavior.

The structure of the respiratory system

In the discussion on development of pneumothorax and complications during artificial ventilation we emphasize the critical role of intra-pleural pressure.

In the Figure 1, the respiratory system can be interpreted as a two balloon combination: the lungs (balloon 1) enclosed by the thorax wall and diaphragm (balloon 2). Around the lung are the pleurae, the visceral (pulmonary) pleura as the outer shield/wall of the lung, bending back at the hilum as the parietal (costal) pleura, following and attached to the thorax wall and the diaphragm bordering the mediastinum back to the hilum. The intra-pleural space between the visceral and parietal pleurae is small in volume and filled with lubricating fluid. The intra-pleural pressure (also simply “pleural pressure”, P_pleural) is characteristic for the pressure within the thorax cavity. The least invasive method to measure P_pleural is by a balloon pressure sensor in the esophagus. Normally P_pleural is sub-atmospheric: in the end-expiratory state, when all respiratory muscles are relaxed the thorax tends to expand to a larger volume, but the lungs naturally recoil, resulting in a negative pressure of about −7 cmH₂O. At this point, lung volume equals the functional residual capacity (FRC). The negative P_pleural pulls the two pleurae apart and in combination with the lubricant, this facilitates smooth movement during respiration.

Figure 1 A transverse section of the thorax, showing the thorax wall, the pleural cavity, the lungs, and the mediastinum. The inner “balloon” lung, boarded by the visceral pulmonary pleura, is enclosed by the parietal costal pleura, attached to thorax wall, the outer “balloon”. The space between the pleurae, the pleural space has little volume and is filled with lubricant, facilitating mutual movements of the pleurae. The pressure in the pleural space, normally sub-atmospheric, is characteristic for the pressure in the thorax, and determines with the alveolar pressure the transpulmonary pressure. At equilibrium, in the absence of airway closure, the alveolar pressure equals the airway pressure (Adapted from Henry Gray, Anatomy of the Human Body, 1918, https://archive.org/details/anatomyofhumanbo1918gray/).

P_pleural, however is not uniform. Gravity creates a pressure gradient from top to bottom due to the lung’s weight. The lung, being highly flexible, behaves like a liquid transmitting pressure in all directions and experiencing the weight of the lung tissue above. This results in a gradient proportional to the product of lung height and specific weight of the air-filled lung, typically around 7 cmH₂O, with individual variations depending on factors such as body length, total lung capacity etc. (and, if present, edema!).

The lungs surrounded by pleural fluid

Casha et al. (3) describe how the balance between negative P_pleural and capillary forces enables the lungs (with a specific weight of approximately 0.3 g/cm³ at the FRC level) to be surrounded by a thin layer of much denser pleural fluid (with a specific weight of 1 g/cm³).

This fluid layer serves both as a lubricant and a spacer. According to Casha’s calculations, the thickness of this layer varies from about 20 to 200 microns, which is sufficient to prevent the numerous microvilli on the pleurae (3,4), each less than 5 microns long, from damaging one another during the respiratory cycle’s movements. Negative P_pleural is crucial in maintaining the balance with capillary forces. Positive pressure will result in removal of the pleural fluid from between the pleurae, causing the lung to “float” on the denser pleural fluid. Therefore, positive P_pleural might damage the microvilli as well as the pleurae themselves.

Behavior of P_pleural during natural respiration and mechanical ventilation

In this discussion, P_pleural refers to the mean P_pleural, averaged over the height of the lung.

Both the lung and thoracic wall can be modeled as balloons, following a linear pressure-volume (PV) relationship, where the volume is proportional to the transmural pressure (P_trans). P_trans is defined as the pressure inside the balloon minus the pressure outside it. For the lung, this is expressed as airway pressure (P_airway) minus P_pleural, and for the thoracic wall, as P_pleural minus the outside pressure (P_outside). Given that the volume of the pleural space is negligible, the volumes of the thoracic cavity and lungs can be considered equal (assuming there is no pneumothorax or other air leak). For a non-ventilated person at FRC, the following conditions apply (C = compliance and V = volume): FRC=Vthorax(Ptrans=0)+Cthorax×(Ppleural−Poutside), since (Ppleural−Poutside) is negative, it follows that Vthorax(Ptrans=0) is larger than FRC; the thorax indeed tends to expand. FRC=Vlung(Ptrans=0)+Clung×(Pairway−Ppleural), since (Pairway−Ppleural) is positive, it follows indeed that Vthorax(Ptrans=0) is smaller than FRC; the lung tends to shrink.

Starting from FRC, inspiration requires an increase in transpulmonary pressure, which can be achieved either by decreasing P_pleural or increasing P_airway. During natural breathing, P_pleural decreases as the respiratory muscles expand the thoracic cavity, drawing air into the lungs. NPV mimics this process by lowering the external pressure on the thorax (using a cuirass) or the entire body (using an iron lung). Alternatively, PPV increases lung volume by raising P_airway. However, as lung volume increases, thoracic volume must also increase, raising the transmural pressure of the thoracic wall. Since P_outside remains constant during PPV, P_pleural rises (becoming less negative or even positive). This is the key difference between natural inspiration (or inspiration using negative surrounding pressure) and PPV: P_pleural changes in the opposite direction.

An important consequence of higher P_pleural, besides its effect on the pleural fluid layer, is that the pleurae experience more friction and shear stress when the lung volume changes, especially when P_pleural is positive for then the pleurae are pressed together. Consequently, the likelihood of pneumothorax may be influenced by P_pleural and the extent of lung movement, i.e., the tidal volume.

In cases where lung compliance decreases, the driving pressure must be increased to achieve the same tidal volume. However, if thoracic wall compliance remains unchanged, the trans-thoracic pressure and P_pleural will also remain unchanged, with only transpulmonary pressure increasing. The additional driving pressure is entirely used to compensate for the reduced lung compliance.

In efforts to optimize positive end-expiratory pressure (PEEP) during mechanical ventilation of acute respiratory distress syndrome (ARDS) patients, researchers have measured P_pleural to account for the actual individual lung and thoracic wall compliances. Contrary to theoretical predictions, measured P_pleural is often positive and significantly elevated. This discrepancy likely arises from factors beyond just reduced lung compliance. In such cases, only a portion of the lung is involved in ventilation, with other parts collapsed or filled with edema, a condition often referred to as “baby lung”. Despite this, airway driving pressures must be substantially higher than measured P_pleural, as transpulmonary pressure must overcome lung elasticity even when airflow is zero. High P_pleural correlates with an increased thoracic cavity and lung volume, raising the risk of overstretching the ventilated alveoli. Therefore, limiting tidal volume is crucial to minimize this risk.

Atelectasis and airway closure

In 1963, Bendixen et al. (5) demonstrated that general anesthesia with mechanical ventilation results in worsening intra-operative oxygenation and compliance in patients with normal preoperative lung function. Brismar et al. (6) showed that these deteriorations were related to lung tissue density, detectable by computed tomography. Atelectasis directly impairs oxygenation and can lead to further lung injuries, such as pneumonia. The development of atelectasis is strongly associated with peripheral airway closure (7,8).

Peripheral airway closure (9,10) is a crucial property of the lung that protects against alveolar collapse. The airway closes at a higher transmural pressure than the alveolus collapses. This means that when the local trans-alveolar pressure is low, the alveolus has reached its minimum volume but still contains air. The volume of air remaining in the lungs when all airways are closed is the residual capacity (RC).

This process of airway closure as local transpulmonary pressure decreases is evident in the lower inflection curve of the PV relation: during deep expiration, compliance gradually reduces. In the linear part of the PV relation, when all alveoli are participating in the ventilation, compliance is maximal and equals the slope of the straight part of the PV curve. As more alveoli close, compliance decreases, reaching zero at RC, when all feeding airways are closed.

Airway closure will occur at the moment transpulmonary pressure drops, which is common in the obese patient (11). In the supine position, abdominal pressure against the diaphragm tends to increase P_pleural and reduce the lung volume. This pressure can be so high that total lung closure is observed, preventing any airflow into the lungs unless P_airway exceeds the Airway Opening Pressure. Standard procedures to counteract this include positioning the patient in an anti-Trendelenburg position and applying PEEP.

Interaction between mechanical ventilation and airway closure

The role played by airway closure during mechanical ventilation is not yet fully understood. Hedenstierna (12) showed that 50% of the standard patients at the operating room experience airway closure above the level of FRC, while Dollfuss’s (8) experiments showed that airway closure begins below FRC during deep exhalation. Hedenstierna’s group (6) also showed that PEEP can prevent airway closure and highlighted (13) the risk of high oxygen fractions in causing absorption atelectasis. Milic-Emili (9) explains that the surface area enclosed by the PV relation is a measure for airway closure.

Recent literature provides two examples of the clinical impact of airway closure. The PV curves registered with the Ventinova Evone (14) ventilator are notably narrow, likely due to the controlled airflow during both inspiration and expiration, which helps prevent airway closure. Similarly, the technique of FLow controlled EXpiration (FLEX) (15) improves ventilation/perfusion ratios by regulating expiratory flow.

PPV can also lead to cyclic closure and reopening of peripheral airways. Inspired air will first inflate proximal alveoli. The increased lung/thorax volume raises P_pleural throughout the lung. Some of the dependent airways will be closed by the decreased trans-alveolar pressure, but reopen when, after the inspiratory flow has stopped, the air redistributes from proximal to distal alveoli. It is known that cyclic closure and opening of airways contributes to ventilator induced lung injury (VILI).

VILI, ARDS, pneumothorax and mechanical ventilation

Positive pressure mechanical ventilation has been used to treat acutely ill patients for several decades. While clinicians recognize its life-saving potential, research dating back to the 1960s and 70s has highlighted several potential drawbacks and complications. A State of the Art review by Pingleton (16) discusses these complications in detail. For many years, VILI was synonymous with clinical barotrauma. In 1979, Johnson et al. (17) reported the radiographic detection was a key indicator of potential further complication in patients receiving PEEP therapy for severe respiratory failure. Of 17 patients who developed interstitial gas, 9 progressed to further barotrauma, pneumomediastinum, pneumothorax, and extra-thoracic dissection. Radiographically, interstitial gas appears as vesicular rarefactions (cystic changes), linear streaks along the bronchi and vessels, halos of gas around vessels, and sub-pleural gas. In 1944, Macklin and Macklin (18) proposed a similar mechanism for spontaneous pneumothorax, suggesting it is often preceded by interstitial emphysema. Damage of the parenchyma with cystic airspaces and inflammatory changes in chronic obstructive pulmonary disease (COPD) patients is the cause of their well-known increased risk of pneumothorax. Pichurov et al. (19) investigated 82 patients with pneumothorax, 14 of which were COPD patients, and confirmed that all patients showed interstitial pulmonary emphysema.

Amato (20) and Miller (21) demonstrated that reduction of mean and peak airway pressures as well as limiting tidal volume, leads to a significant reduction in the number of pneumothoraces and related mortality of artificial ventilation. Their proposed lung protective strategies (LPS) have been embraced worldwide.

During the COVID pandemic, it was observed that the incidence of pneumothorax and other air leaks was disproportionately high (22,23). However, pneumothorax is seldom seen during NPV (24). This further supports the idea that positive ventilation pressure is a key factor in the development of pneumothorax, as confirmed by its occurrence during “non-invasive” BiPAP ventilation (25,26).

A plausible explanation for this lies in the friction between the two pleura blades and the shear stress in the parenchyma caused by the force with which the two blades are pressed together during PPV. In natural breathing, or in ventilation with negative pressure (such as the iron lung), a negative pressure is maintained between the two pleura blades during the whole breathing cycle. The elasticity of the lungs continuously pulls the visceral pleura away from the parietal pleura. Additionally, the negative P_pleural, in cooperation with capillary forces, helps maintain a thin layer of pleural fluid around the lungs. This pleural fluid acts as a lubricant, effectively absorbing and facilitating the mutual movements of the pleurae during volume changes.

However, during PPV, particularly of ARDS patients, P_pleural proves to be very high and positive (27-29). This increased pressure forces the pleurae together with considerable force, complicating their movements and leading to friction and shear stress. This shear stress can damage the lung parenchyma, often resulting in interstitial emphysema, which has been shown to precede pneumothorax (17,30). The loss of support from the parenchyma to the visceral pleura contributes to the development of pneumothorax.

Summary of the side effects of PPV via the P_pleural

The key difference between natural respiration and PPV lies in the behavior of the P_pleural.

• Positive airway pressure increases P_pleural.
• This elevated P_pleural during PPV can lead to partial, repetitive, and cyclic airway closure.
• Positive P_pleural causes the lung to be pushed against the thorax wall, whereas during natural breathing, when P_pleural is negative throughout the entire cycle, the lung is pulled away from the thorax wall.
• Positive P_pleural increases friction between the two pleurae when lung volume is changing, leading to shear stress and damage in the parenchyma.
• Positive P_pleural disrupts the equilibrium between negative P_pleural and the capillary forces that maintain a lubricating layer of pleural fluid around the lungs. This disruption reduces the distance between the pleurae, increasing the risk of damage to the microvilli attached to them.

Therefore, any measure that limits P_pleural can help mitigate the effects of VILI. Practical measures include allowing and synchronizing with patients efforts, phrenic nerve stimulation and prone positioning as well as the application of PEEP and recruitment maneuvers.

Conclusions

PPV, while life-saving in critical care settings, introduces several challenges and risks primarily due to its effects on P_pleural. Unlike natural respiration, where P_pleural remains negative throughout the breathing cycle, PPV raises P_pleural, leading to several potential complications.

• P_pleural and lung mechanics: the elevation in P_pleural caused by positive airway pressure leads to the lung being pushed against the thoracic wall, contrasting with the pulling away of the lung during natural, negative pressure respiration. This change increases friction between the pleurae, leading to shear stress and potential damage to lung parenchyma.
• Airway closure and atelectasis: positive P_pleural can cause cyclic airway closure, particularly in dependent regions of the lung, contributing to atelectasis. This airway closure not only impairs oxygenation but also sets the stage for subsequent lung injury, including the risk of pneumonia.
• Impact on pleural fluid dynamics: the transition to positive P_pleural disrupts the delicate balance maintained by negative P_pleural and capillary forces, which normally keep a thin, lubricating layer of pleural fluid around the lungs. This disruption can reduce the effectiveness of the pleural fluid as a spacer and lubricant, increasing the likelihood of damage to the pleurae’s microvilli.
• Clinical implications and protective strategies: the increased risk of VILI associated with PPV highlights the importance of strategies that minimize P_pleural. Such strategies include synchronization with patient efforts, prone positioning, and the careful use of PEEP and recruitment maneuvers. These approaches aim to limit the harmful effects of elevated P_pleural and improve patient outcomes.

In summary, understanding the differences in P_pleural behavior between natural respiration and PPV is crucial in managing and mitigating the adverse effects associated with mechanical ventilation. By adopting lung protective strategies, clinicians can reduce the incidence of complications such as pneumothorax, atelectasis, and VILI, ultimately improving patient care in critical settings Since NPV inherently lowers P_pleural, it may help avoid many of the adverse side effects previously discussed. Therefore, reconsidering and reintroducing NPV in a modern context should be seriously explored.

Acknowledgments

The authors want to thank Prof. David Howard for his contributions in improving the formulations and text. J.v.E. is a team Member of the Exovent Development Group (Exovent.org). The Exovent Development Group is a UK registered charity no. 1189967:10 Queen St Pl, London EC4R 1BE, UK.

Funding: None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-497/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-497/coif). The authors have no conflicts of interest to declare.

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