Unifying Hypothesis of Ventilator-Induced Lung Injury

Acute Respiratory Distress Syndrome (ARDS) (The Acute Respiratory Distress Syndrome Network, N Engl J Med 342:1301–8, 2000) denotes a severe lung injury linked to an unacceptably high mortality rate. The primary treatment approach involves essential supportive measures, predominantly relying on mechanical ventilation. Despite decades of investigation, challenges such as the complexities of lung involvement, diverse responses to interventions, and population heterogeneity seem to impede progress, leading to stagnant outcomes. Ongoing debate and a lack of conclusive evidence constrain practical applications at the bedside, hindering the potential for further improvement (Bellani et al., JAMA 315:788–800, 2016). Recently, there has been a significant rise in cases of acute respiratory failure attributed to COVID-19-induced Acute Respiratory Distress Syndrome (CARDS), characterized by a notably high mortality rate resistant to standard treatments. This surge has underscored the limitations of traditionally accepted standards of care, highlighting the crucial need to deepen our understanding of ARDS pathophysiology. The urgency for personalized, protective mechanical ventilation strategies becomes paramount in managing respiratory failure within the complexities of these challenging circumstances. The pathophysiology of ARDS encompasses several key elements: (i) heightened alveolar-capillary permeability, (ii) the flooding of alveoli with protein-rich edema fluid, (iii) surfactant dysfunction, and (iv) altered alveolar and alveolar duct (acinar) mechanics. This includes the dynamic change in alveolar and alveolar duct size and shape, resulting in unstable and nonuniform inflation during tidal ventilation. In addition to its primary pathology, CARDS disrupts the matching of pulmonary perfusion with ventilation. This disruption leads to hyper-perfusion of collapsed or edema-filled tissue, significantly increasing the shunt fraction. Concurrently, there is hypoperfusion and ischemia in less involved lung regions, further complicating the respiratory dynamics associated with this syndrome (Herrmann Nat Commun 11:4883, 2020; Habashi et al., J Appl Physiol (1985) 130:877–91, 2021). The deactivation of surfactant and the presence of edema induce changes in the time constants associated with the opening and collapse of alveoli and alveolar ducts. This biophysical transformation fundamentally alters the mechanisms of dynamic acinar mechanics. The modified mechanics result in regional repetitive alveolar collapse and expansion (RACE) as well as regional alveolar instability and collapse. These changes introduce stress multipliers that predispose the lung to a secondary ventilator-induced injury (VILI). This process has the potential to escalate, encompass, and expand the pathology to involve larger areas of the lung, parenchyma creating a perpetual and persistent state of VILI. The progression from mechanical trauma to lung tissue serves as a catalyst, propelling the transition from early acute lung injury (ALI) to the full manifestation of ARDS. This chapter intricately interlaces these pathophysiologies, articulating a unified hypothesis on the mechanisms steering VILI. A thorough grasp of the sequential pathology of ARDS, with a specific focus on the consequences of alterations in alveolar mechanics that render the lung susceptible to secondary injury from mechanical ventilation, is of paramount importance. Without this comprehension, the capacity to effectively mitigate the morbidity and mortality induced by VILI remains significantly constrained.