New Insights into VILI

Cellular Response to Mechanical Strain

Growing interest has focused on the cellular response to mechanical strain, which has been comprehensively reviewed lately [80]. Parker and colleagues studied the different signal transduction pathways that may be involved in the microvascular permeability increases observed during experimental VILI [81]. They found that gadolinium (that blocks stretch-activated nonselective cation channels) annulled the increases in vascular permeability induced by high airway pressure [82]. Authors concluded that stretch-activated cation channels might initiate the increase in permeability induced by mechanical ventilation through increases in intracellular Ca2+ concentration. To further explore this hypothesis, the same team studied the effect of inhibitors of the Ca2+/calmodulin - myosin light chain kinase pathway on vascular permeability [83]. Using an isolated perfused rat model, they showed that kinase inhibitors, which may prevent Ca2+ entry, contraction of the actin-myosin filaments or release of adhesion proteins, could significantly attenuate the vascular permeability increase induced by high pressure mechanical ventilation [83]. Taken together, these results suggest that the increase in microvascular permeability may not be a simply passive physical phenomenon (a "stress failure" [84,85]), but the result ofbiochemical reactions. Maintenance ofplasma membrane integrity is essential in response to mechanical stress. Recently, Vlahakis and colleagues reported a heretofore-undescribed response of alveolar epithelial cells to deformation [86]. They labeled membrane lipids to study deformation-induced lipid trafficking and observed in a direct manner (laser confocal microscopy) epithelial cells of the alveolar basement membrane response to deforming forces. A 25% stretch deformation resulted in lipid transport to the plasma membrane to ensure its integrity and an increase in epithelial cell surface area. This lipid trafficking occurred in all cells, in contrast with plasma breaks which were seen in only a small percentage of cells. Authors concluded that deformation-induced lipid traf ficking serves, in part, to repair plasma breaks in order to maintain plasma membrane integrity and cell viability, and that this could be viewed as a cytopro-tective mechanism against plasma membrane stress failure seen during VILI [10, 85]. Other investigators have focused on the relative importance of deformation frequency, duration, and amplitude in deformation-induced cell injury [87]. Exposing rat primary alveolar epithelial cells to cyclic deformation (25, 37 and 60% increase in membrane surface area [ASA]) led to significantly greater cell death in comparison with static deformation. To investigate the relative importance of peak deformation magnitude a cyclic deformation amplitude on deformation-induced injury, cells were submitted to cyclic deformation amplitudes of 12% and 25% ASA superimposed on a static deformation of 25% ASA, thus resulting in a peak deformation magnitude of 37 and 50% ASA, respectively. Interestingly, authors found that limiting the deformation amplitude resulted in significant reductions in cell death at identical peak deformations. From these results, an analogy can be drawn with experiments that showed a decrease in lung injury when VT was reduced with a constant PEEP level, thus reducing end-inspiratory lung volume [47].

Influence of Capnia on VILI

Deleterious effects of hypocapnia have been extensively 287 reviewed recently [88] and are addressed in the chapter by Brian Kavanagh (page 287). However, it is important to note that in addition to detrimental effects of hypocapnia [89] or of hypercapnic acidosis buffering [90] on ischemia-reperfusion lung injury, experimental studies have shown that hypercapnic acidosis is protective of VILI [91,92].

Strategies to Reduce VILI: Use of the PV Curve

The ARDS network trial [6] has undisputedly shown that reducing Vt from 12 ml/kg to 6 ml/kg resulted in a 22% reduction of mortality. Due to protocol, the same reduction of VT was applied in all the patients allocated to the low VT group. However, it has repeatedly been shown that the pressure and the volume that are considered safe for some ARDS patients may cause lung overdistension in others [93-96]. Conversely, arbitrary settings may result in an unnecessary reduction in Vt, which a recent meta-analysis has suggested as being potentially harmful [7]. It has been suggested that information from the inspiratory PV curve of the respiratory system could be used to tailor ventilator settings. For instance, the presence of an opening pressure (lower inflection point) could be used to adjust the PEEP [27-29]. In addition to improving oxygenation, PEEP reduces the severity of VILI [10] and may lessen the damage produced by the repeated opening and closing of lung units in surfactant-depleted lungs [31,33]. However, PEEP may favor overinflation if Vt is not reduced [2, 97]. It has been proposed that the Vt be adjusted according to PV curve analysis by limiting end-inspiratory pressures to below the decrease in slope seen at high pressure/volume, called the upper inflection point (UIP) [3, 95, 96]. The UIP often seen in patients with ARDS has been ascribed to overinflation [95, 96], or to the end of recruitment [98, 99] during lung expansion. However, whether or not ventilator settings that would result in pressure/volume excursions above the UIP are deleterious remains unsettled, and has never been assessed experimentally. The impact of pulmonary edema and the resulting decrease in ventilatable lung volume on the inspiratory limb ofthe respiratory system PV curve has not yet been evaluated. A better understanding of its significance is required before the UIP can be used to set VT in patients. A recent experimental study was designed to examine several hypotheses [100]. The first was that the reduction in ventilatable lung volume (the baby-lung effect) not only decreases the compliance of the lung [93,101] but also affects the position of the UIP. The second was that the development of edema alters the PV curve essentially because of distal airway obstruction. And the third was that individual characteristics of the PV curve reflect the susceptibility of the lungs to the deleterious effects of high volume ventilation. The first two hypotheses were tested by obstructing the distal airways of rats by instilling a viscous liquid and by comparing the PV curves obtained to those obtained during hyperinflation ventilation of intact rats. Authors found that changes in the shape of the PV curve (gradual decrease in compliance and volume at which the UIP was seen, and progressive increase in end-inspiratory pressure) were very similar whether they were due to viscous instillation into the lungs or due to the development of overdistension pulmonary edema. To test the third hypothesis, PV curves prior to mechanical overinflation were examined with respect to the amount of pulmonary edema induced by overinflation in lungs injured by a-naphthylthiourea (ANTU). Authors found that the higher the compliance and the position of the UIP before overinflation, the less edema occurred after overinflation. Taken together, these results suggest that the position of the UIP is a marker of ventilatable lungvolume and is both influenced by and predictive of the development of edema during mechanical ventilation.

Conclusion and Clinical Applications

The experimental concept of VILI has recently received a resounding clinical relevance [6]. However, what might have been seen as the final step in ARDS ventilatory strategy knowledge (i.e., unilateral drastic Vt reduction for every ARDS patient) has very recently been shaken [7]. For the time being and until further evidence, one may put forward the following conclusions:

• drastic Vt reduction may not be justified for every ARDS patient.

• reasoned Vt reduction, designed to avoid volutrauma, may be guided by the state of lung mechanical properties as can be provided by the respiratory system PV curve, in order to avoid excessive or insufficient Vt reduction.

• use of high levels of PEEP is not to date justified.

• Evidence-based ventilatory management of ARDS is a difficult art; luckily basic physiology is still there to help clinicians [37, 62, 102,103].

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