Introduction
Answering the question set in our title comes as no easy task if we consider that the lung suffers from non-linear deformation even during normal breathing1. This becomes even harder when we consider the biomechanic factors that mechanical ventilation (MV) imposes on the lung. Such insults such as barotrauma (alveolar air leak due to excessive ventilation pressures), volutrauma (alveolar distention due to high tidal volume [TV]), atelectrauma (cyclic recruiting/derecruiting of alveolar units), biotrauma (inflammatory mediator liberation due to lung distention), ergotrauma (mechanical energy delivered through high stress respiratory cycle), vascular trauma (endothelial damage due to alveolar distention) and hemodynamic trauma (endothelial damage secondary to an increase in hydrostatic pressure in lung capillaries and due to shear forces)2. Finding alveolar stability amidst the previously described insult mechanisms might seem hard; however, studies in the field of alveolar micromechanics have recognized that high ventilator pressures are not harmful for the lung when statically applied (static deformation), but become harmful when dynamically applied (dynamic deformation). Another finding that points out that stability is attainable is the fact that isotropic alveolar expansion and contraction are responsible of the mayor shifts in lung volume. Studies in which rapid freezing of lung volume during different stages of lung expansion and deflation, confirm that alveolar shape remains unmodified even with changes in lung volume. This proves alveoli expand isometrically in every direction (Fig. 1)3,4. This might explain two mechanisms as responsible for alveolar stability: (1) pressure stability and (2) isotropy.
Figure 1. A: normal alveoli. B: isotropically expanded alveolus (adapted from: Cercos Pita J, et al. 20224).
Objectives
The study aimed to describe the mechanisms that favor alveolar stability, isotropy, and pressure stability.
Materials and methods
A search for papers published between 2000 and 2023 was made on PUBMED, Journal (Critical Care, Respiratory Care, Intensive Care Medicine) y and tertiary sources as Essential Graduate Physics-Classical Mechanics that included the following key words: inhomogeneity, alveolar stability, acute respiratory distress syndrome, isotropy, lung elasticity, and baby lung. An extensive review on alveolar and lung injury mechanisms associated to pressure-volume variations and their implications in an anatomical and clinical level. Mechanisms responsible for diminishing the damage were also searched for. The relation between mathematical formulations with alveolar anatomy and how they might explain mechanisms through which alveolar stability might be achieved were also analyzed.
Results
Investigations in the field of alveolar micromechanics and engineering have demonstrated that pressure stability brings lung protection by diminishing alveolar structural damage. Pressure variability destabilizes the alveoli through increased energy strain bringing histologic damage seen as thickening of alveolar wall and pulmonary edema. On the other hand, isotropy refers to the uniform propagation of stable pressure, which favors serial alveolar recruitment.
Discussion
Pressure stability
Pressure is defined as the force applied in an area unit, which is proportional to molecule collision among themselves and an inner wall. This force acts as a vector with direction and magnitude which when applied to a body, changes its shape3. In engineering, this alveolar deformation (strain) happens when positive end expiratory pressure (PEEP) or TV are applied. When alveoli are deformed by end expiratory pressure, it is known as static strain, and when its deformation comes from TV, it is known as dynamic strain.
Keeping deformation globally constant or static in the lung reduces cell death, therefore being less harmful than its dynamic counterpart, which has translated to mortality. Present day mortality of acute respiratory distress syndrome (ARDS) remains around 40% in spite of lung protection ventilatory strategies, which has proven to reduce relative risk of death to 22%, which according to reports should have been around 9-10%5. This difference might be explained by the different levels of airway pressure reached in different studies. Protti et al. evaluated through engineering the impact of MV on lung tissue, finding dynamic strain to be more harmful than static strain to the lung6. At the alveolar level, the recruitment/derecruitment (R/D) process causes instability, with histologic damage that has been observed in autopsies in the form of: (1) thickening of alveolar wall, (2) alveolar edema, and (3) neutrophil influx inside the alveoli7. Steinberg et al. determined through in vivo electric microscopy evaluated alveolar instability caused by MV and determined that alveolar wall thickening is secondary to wall folding, mechanism that causes alveolar instability that leads to collapse. In this study in order to induce alveolar instability large pressure variations were used. In addition, R/D amplifies tissular tension, stimulating inflammatory response8.
These sudden changes in the internal pressure of an alveolar unit amidst a uniform lung parenchyma, changes alveolar configuration, augmenting strain in the alveolar wall of neighboring units, which defines lung inhomogeneity9. Not only pressure variations damage alveoli, but large variations in lung volume may also deactivate surfactant through direct inhibition raising surface tension (sT) causing alveolar collapse10.
How can a biologic structure such as the alveoli maintain its mechanical integrity in the context of lung disease where there is high variation in alveolar circumstances and interconnection? Can there be a solution for lung inhomogeneity?11. The answer may lay in the absence of structure alteration (structure stability) and its interconnections. Mostly, the lung is seen as a dynamic system, and we can define stability within a dynamic system in various ways. Liapunov’s definition, which establishes a system as stable if there is no perturbation that affects it or if there its perturbation, it is buffered at any moment. For example, a dynamic system in which its vectorial trajectory depends on a single parameter, is shall be stable in relation to it if no change comes to it or if does not induce changes on its nature or number of attractors12. An attractor is a structure generated in space during the cycle of a system. For example, in a healthy lung, with cyclic regular behavior, vector trajectory (pressure) remains the same, making its behavior predictable.
An attractor may be defined as the state generated during a systems behavior toward where the system tends to evolve. In a regular cyclic system such as a healthy lung, the vector’s trajectory (pressure) is constant, making its behavior predictable (limit cycle attractor). An example of this might be fractal structures; Mandelbrot, in 1982, was the first to propose the lung as a structure with fractal geometry, and the coexistence of attractors defining its multistability13. The opposite is true for a chaotic behavior system, (sick lung with inhomogeneity), where vector trajectory is unpredictable locally, but seeing that it is circumscribed to a specific space, it might present global stability, this type of attractors is called “strange attractors”14. Therefore, to attain stability in a complex fractal organ it is necessary to know the behavior if a linear system to understand a non-linear system to attain stability of the nonlinear system to combat inhomogeneity that characterizes sick lungs15.
A linear system can be described as: X’ = F(X,t), where X’ is the variable’s instant variation, X represents the variable, t is time and F(X,t) a straight line function. As such, its behavior may be graphed, representing change of the variable through time16. In non-linear systems, vector trajectory may cross generating new points, behaving as a mined field in which vectorial trajectory depends on the closeness of these points. Therefore, in a healthy lung physiologic behavior X’ reflects the instant yet constant variation of pressure, X is the pressure and F(X,t) represents the constant linear pressure that stabilizes the system during spontaneous breathing17. In the context of MV, X’ corresponds to changes in pressure during MV, X represents the pressure set on the ventilator and t the time during which the system is under such pressure. Finally, F(X,t) corresponds to pressure propagation (vector trajectory) in a non-linear fashion in an inhomogeneous system. It represents pressure trajectory through that mined field, such as the one seen in a sick lung, where the pressure generated moves to different points, each with different milieu18.
As previously discussed, it would be ideal to be able to combat inhomogeneity and nonlinear behavior of a sick system in which healthy alveoli are found immerse in a heterogeneous structure. Fortunately, in non-linear systems, a phenomenon occurs, in which the existence of multiple isolated equilibrium points exists. An equilibrium point is stable if its variables originate near it, which requires a continuous vector19. This suggests that to reach equilibrium, pressure must remain constant and propagate to nearby areas. For propagation and closeness to exist, interconnection of the system is necessary. Fortunately, the lung is a highly interconnected tissue, firstly through small interalveolar channels known as Kohn pores (Fig. 2)20, covered in epithelium and which cross interalveolar septums, joining adjacent alveoli. Humans possess up to 7 pores per alveoli with measures from 2 to 13 micra, serving the main role of collateral ventilation. Along with Lambert Bronchioalveolar channels and Martin interbronchial channels; collateral ventilation routes area attained21.
Figure 2. Kohn’s pores (adapted from Pastor LM, et al. 200620).
Knowing that the lung is an interconnected system, generating and maintaining a pressure that moves and spreads the gas through the collateral system might attain global system stability. This is attained through spiral rings that irradiate toward the periphery, making diffusion a process that tends to erase local differences22. In the lungs, pressure and external forces of the alveolar elastic membrane drive the movement and diffusion of air on every point of the lung, which determines its direction through high to low pressure gradients. This movement is described by the Navier–Stokes equation, written in a vectorial manner, as pressure is a vectorial force. When the power over a membrane can be measured, it is observed that it propagates multiplying to the surrounding membrane curve23. As Stokes equation is linear, it states that a gas trajectory is proportional to power exercised over it, and thus, a constant force might better describe a uniform gas diffusion and recruitment of non-ventilated lung areas24. Vector propagation of pressure will extend spirally from less affected alveoli to more affected areas, creating lineal recruitment in midst of a nonlinear25.
Although difficult, it might be possible. Cressoni et al., through a lethal MV model, showed damage during MV comes from damage of the extracellular matrix which leads to alveolar collapse rather than to consolidation; and furthermore, that these areas are recruitable. This is due to the fact that there is increased lung weight in patients with ARDS, due to edema (Fig. 3), that also contributes to the diminished thoracic expansion along the sternum–vertebrae axis.
Figure 3. Transverse cut of an alveoli en ARDS. AC: alveolar consolidation; AT: atelectasis; HM: hialine membrane; M: macrofage (taken from:
Edematous lung tissue in patients ARDS is localized mainly in dorsal and inferior zones (Fig. 4)26 and as alveoli are mechanically interdependent, a constant pressure such as PEEP may redistribute edematous fluid from flooded alveoli to the interstitium promoting more uniform mechanics27.
Figure 4. CT of a patient with ARDS. Bilateral consolidation with opacities and normal lung in dependent zone (A) (adapted from Sheard S, et al. 201226).
It might seem that it is possible to recruit alveoli from non-dependent zones to dependent ones. This is supported in a series of studies that have found an average ratio of pulmonary elastance (PE)/Respiratory system (Res) of 0.7 in supine position in ARDS patients. PE is greater than the one in the respiratory system supporting the fact that vectorial collapse force comes from outside the lung and therefore, it is needed to counter alveolar collapse from the inside, here is where the second mechanism that may promote alveolar stability: isotropy28.
Isotropy
In the beginning, we stated alveoli expand evenly in every direction despite variations in its volume and that collapse is due to increased lung weight secondary to edema. However, and despite collapse forces, it is predicted that alveoli inside a net of interconnected of alveolar walls might stabilize with balanced pressures29. Animal studies have proved that through vector transport of sodium (Na+) and chloride (Cl–) from air space up to the interstitium accelerate the process of fluid elimination. This is secondary to the creation of an osmotic gradient that promotes fluid elimination30. It is known that accumulation of fluid in the interstitial space, increases lung weight, causing alveolar collapse, mainly in dependent zones31. It is reasonable to think that the objective is to recruit through the application of static pressures with vector trajectories directed to collapsed healthy zones. Marini y Gatinonni recently described the progression of ARDS lung injury as a contraction of healthy lung tissue (baby lung) to atelectasic one, (Fig. 5)32,33 which suggests that lung tissue in ARDS is not rigid, but small with distensibility proportionally related with lung dimensions and an almost normal intrinsic elasticity, this allows for redistribution of density, providing the scientific base for “gentile pulmonary treatment” translating the fact that pressure variations remain unreasonable. In fact, air movement is always from an open segment to the atelectasic one in a phenomenon called “VILI vortex34, which agrees with the Le-Chatelier. Equilibrium principle, that establishes that a system will be submitted to changing conditions to counter the effect that initially altered it, seeking return to its original position or to a new one that allows the restoration to equilibrium, meaning that vectors would move from high distensibility to low distensibility zones35.
Figure 5. Typical CT of ARDS, non homogenous distribution. Lung area with no consolidation known as “Baby lung” (adapted from Zompatori M, et al. 201433).
In non-linearity thresholds of elastic media, even isotropic ones (edematous alveoli) tension forces (strength) might generate small changes in volume to resist deformation. This explains how in alveolus internal and external tension (deformation) are correlated through Hooke constitutive equations36. According to them, in order to beat elastic forces acting parallel to superficial tension, it is needed a constant pressure that surpasses elasticity (even with mild but constant deformation of the alveoli) without surpassing elasticity limits to allow a de-collapsed proximal alveolus to serially neighboring distal alveolus37. Recruiting route would then be possible by generating an internal alveolar pressure vector that equals or surpasses the tension generated by alveolar recoiling (Fig. 6)38, that is able to flow through Kohn pores toward collapsed alveoli, freeing collapsed alveolus and thus atelectasis39. Within an inhomogeneous, constant pressure and therefore isotropic vectorial pressure directed outwards might be the tools needed to combat lung inhomogenity40.
Figure 6. Spiral location patterns observed on apliation experiments on black holes (adapted from Hu MM, et al. 201838).
Conclusion
Dynamic equilibrium seen in a healthy pulmonary system can be mimicked in a sick environment if isotropism and stability are preserved. Lung alveolar microstructure has the necessary mechanisms to overcome challenges presented by lung inhomogeneity, which altogether can be accomplished as the sum of small individual stabilities created and maintained through time.
Acknowledgments
The authors would like to thank at the Centro Médico ABC for allowing the dissemination of relevant medical information.
Funding
The authors declare that they have not received funding.
Conflicts of interest
The authors declare no conflicts of interest.
Ethical disclosures
Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this study.
Confidentiality of data. The authors declare that no patient data appear in this article.
Right to privacy and informed consent. The authors declare that no patient data appear in this article.
Use of artificial intelligence for generating text. The authors declare that they have not used any type of generative artificial intelligence for the writing of this manuscript, nor for the creation of images, graphics, tables, or their corresponding captions.
