The Concept of VILI

VILI arises from repeated application of high mechanical forces that either directly tear a weak tissue or initiate a signaling process that culminates in a pro-inflammatory state [3], in the context of an altered lung and in the presence of extrapulmonary factors which may potentially increase the damage. Soon after the times in which invasive mechanical ventilation was effectively introduced as a supportive therapy, i.e., the 1952 polio epidemic in Denmark, the potential harm from mechanical ventilation was noted and started to raise concerns, as the term “respirator lung syndrome” [4] was used to label the injury observed in ventilated patients. It was then discovered how mechanical ventilation itself could cause a structural damage to the lung, characterized by diffuse alveolar infiltrates and hyaline membranes that were found on postmortem examination [5], although the major factor causing injury was thought to be the high fractional concentrations of oxygen used in many ventilated patients.

Webb and Tierney [6] conducted one of the first comprehensive studies in intact animals, unambiguously demonstrating that mechanical ventilation can cause pulmonary edema. In their seminal investigation, the authors ventilated rats with very high peak airway pressures (and therefore overdistention) and zero positive end- expiratory pressure (PEEP). Hypoxemia developed in the animals, and postmortem examination revealed perivascular and alveolar edema. Edema did not develop in animals that underwent ventilation with the same peak airway pressure but with the addition of a PEEP of 10 cm of water, showing an interaction between overdistention and low end-expiratory lung volume with respect to lung injury.

Although the term used throughout this chapter is VILI, the mechanisms of injury are related to factors which can also occur during spontaneous ventilation. Indeed, in their proof-of-concept investigation, Mascheroni et al. [7] injected sodium salicylate into the cisterna magna of spontaneously breathing, otherwise healthy sheep, causing a marked increase in minute ventilation and alveolar overdistention with each breath. All the animals developed hypoxemia, along with an increased respiratory elastance and severe morphologic pulmonary alterations at postmortem examination, consistent with lung injury commonly observed during mechanical ventilation. Indeed, such effects did not develop in animals that were similarly treated with sodium salicylate, but underwent controlled ventilation which prevented unsafe lung stretching. Hence, a better term than VILI might be ventilation-induced lung injury. Nevertheless, experimental evidence provides consistent laboratory observations and clinical trials regarding the factors which, alone or in conjunction, lead to the development of VILI. As a consequence of adverse patterns of ventilation, both airway and alveolar injury occur, causing a damage that prevails in anatomically dependent zones. Indeed, VILI can resemble ARDS itself, and it is often difficult to diagnose in humans because its appearance can be similar to the underlying disease for which MV was instituted [8].

The consequences of our better understanding of the mechanisms related to VILI are significant in terms of lives saved. Indeed, the incidence and mortality of ARDS have declined steadily over the past decades. A pivotal study by Li et al. [9] found that the decline in the incidence was primarily due to a decrease in nosocomial

ARDS. Moreover, as documented by the first trial of extracorporeal membrane oxygenation, the mortality rate of patients with ARDS was close to 90% in the late 1970s [10]. Mortality in studies of ARDS has then fallen impressively from 48 to 59% between 1983 and 1991 to 25-26% since 2000 [11], and data from patients enrolled in the ARDS Network randomized controlled trials document a further significant trend toward improvement in mortality during the following period [12]. It is tempting to believe that, among the several major advances in critical care practice, the widespread use of lung-protective ventilation and a reduced incidence of VILI may significantly have contributed to this trend. Indeed, although it still remains unclear how inflammatory mediators exert their detrimental effects on distal organs, experimental studies and clinical trials in ARDS have shown that the application of protective ventilator strategies is associated with decreased serum cytokine levels [13], decreased extrapulmonary organ dysfunction [14], and decreased mortality [15].