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To survey the causes of ventilator-induced lung injury focusing on its mechanical determinants, lung stress and strain.Tidal volume per ideal body weight (tidal volume/IBW) and airway pressure (PAW) are poor surrogates of strain and stress, which are respectively defined as the ratio of volume variation to lung resting volume and transpulmonary pressure. In healthy lungs, ventilation becomes lethal with strain reaching total lung capacity (tidal volume/IBW around 30–40 ml/kg) and with its related stress (roughly 24 cmH2O). The striking discrepancy between experimental data and clinical scenarios (harm at tidal volume/IBW of 12 ml/kg) may be explained by lung dishomogeneity, locally generating ‘stress risers’ or ‘pressure multipliers’. When mechanical ventilation becomes unsafe, as inferred from computed tomography-scan evaluation of dishomogeneity and stress/strain values, lung protective strategies can be maximized by further reducing tidal volume and increasing PAW (e.g. high frequency oscillatory ventilation). In alternative, artificial lungs may provide adequate gas exchange while reducing the load of mechanical ventilation. Recently, outcome benefit was shown with the use of this technique in H1N1 patients.When lung protective strategy is considered unsafe, various techniques of extracorporeal respiratory support may be applied, which by decreasing the load of mechanical ventilation, allow partial to total lung rest.