Science review: Mechanisms of ventilator-induced injury

Since the first description of acute respiratory distress syndrome (ARDS) in 1967 [1] and the first description of the treatment of ARDS with mechanical ventilation in 1971 [2], the only therapeutic invention to convincingly demonstrate a significant reduction in mortality in patients with ARDS and acute lung injury is a lung-protective strategy of mechanical ventilation. No pharmacologic intervention has significantly reduced mortality in a large-scale trial [3]. In the recent National Institutes of Health-sponsored Acute Respiratory Distress Syndrome Network study of 861 patients [4], ventilation with 6 ml/kg (predicted body weight) and a plateau airway pressure limit of 30 cmH2O reduced mortality from 40 to 31% compared with a conventional tidal volume of 12 ml/kg and similar levels of positive end expiratory pressure (PEEP). These data confirm a long-held suspicion of many clinicians that mechanical ventilation has a double role in ARDS: life saving, but also potentially magnifying the severity of lung injury.Despite the demonstrated benefits of tidal volume reduction, the mechanisms of the protective effect are incompletely understood. Lung injury related to mechanical ventilation ranges from macroscopic air leaks to intracellular changes in protein phosphorylation signaling cascades and gene expression [5]. The focus of the present article is to review these more subtle changes and their roles in the release of proinflammatory mediators, in changes in permeability, and in changes in ion and solute transport in ventilator-induced lung injury (VILI). Because the precise contribution of mechanical ventilation to lung injury can be difficult to discern in patients with pre-existing acute lung injury, the term ventilator-associated lung injury (VALI) is often used in place of VILI, especially in clinical studies [5].The incidence of ARDS has been estimated at 5–15/100,000 per year [6,7,8,9], but recent data suggest the incidence may be higher [10]. ARDS is a syndro