Evidence of Detrimental Effects of Air Space Collapse

Putting aside the practical problems related to the clinical implementation of lung recruitment, there is experimental evidence of a beneficial effect associated to the maintenance of end-expiratory volume at every level of observation.

On the cellular level, the consequences of controlled deformation on the alveolar epithelial viability were assessed in an in vitro model [34]. In this model, repetitive stretching of alveolar epithelial cells was more damaging than tonically held deformations. For the same maximum deformation, any reduction of the amplitude of cell deformation (obtained by increasing the tonic or sustained deformation during the relaxation phase) significantly reduced damage as compared with full range or large-amplitude deformations. These data suggest that prevention of cyclic air space deflation to low volumes followed by re-expansion by means of enough end-expiratory pressure might reduce injury.

The reopening of a collapsed airway was modeled experimentally and computationally by means of the progression of a bubble in a narrow fluid-occluded channel with a lining of viable pulmonary epithelial cells, as mentioned above [22]. This model was valid both for collapsible or rigid-fluid-filled airways and demonstrated that the mechanical stresses during airway reopening causes injury to epithelial cells, ultimately resulting in cell death and epithelial detachment. High surface tension forces at the lining layer seemed to amplify those phenomena. However, even when considering healthy airways and normal lungs, recent studies have suggested that, during airway reopening, there is enough stress to cause problems along periods as short as 6 hours of mechanical ventilation [35]. The airway collapse in this study was simply promoted by muscle paralysis, increasing the pleural pressures preferentially at the dependent zones.

In vivo microscopy demonstrated that PEEP stabilized alveoli in the model of surfactant deactivation with tween [36]. After enough PEEP, tidal ventilation resembled an almost normal pattern of alveolar inflation. A study to determine if this nearly normal appearance is also related to less release of inflammatory cytokines is currently under way (Gary Nieman, personal communication).

At a broader level of observation ofthe lung function, which includes pulmonary mechanics, oxygenation, pressure-volume curves, histology and production of inflammatory cytokines, a protective effect of PEEP was demonstrated in all the studies thatkept a similarend-inspiratory pressure inthe comparison group. Webb and Tierney first demonstrated that 10 cmH2O PEEP was protective when applied during ventilation with 45 cmH2O peak pressure. They showed better oxygenation, compliance and absence of alveolar edema in comparison with the huge alterations observed in the group ventilated with 45 cmH2O peak pressure and zero PEEP [37]. This finding was consistent with the subsequent work of Dreyfuss et al., who also demonstrated that the ultra structure of the alveolar epithelium was preserved in a group of rats ventilated with 45 cmH2O peak pressure and 10 cmH2O PEEP [38]

However, in all these in vivo experiments it was difficult to isolate the effect of PEEP in preventing injurybecauseofthe impossibility ofmaintainingsimilarblood flow and oxygenation between the comparison groups. To overcome this problem, Muscedere and colleagues developed an ex vivo non-perfused model of lung injury induced by lung lavage [39]. They demonstrated that low volume ventilation could worsen previous lung injury and that PEEP above the LIP of the pressure volume curve did prevent damage. In a subsequent study with a similar ex vivo model, Tremblay showed that a group of rats ventilated with tidal volume (Vt) of 15 ml/kg and PEEP of 10 cmH2O (peak pressure around 56 cmH2O) suffered less injury than both a group ventilated with Vt 40 ml/kg and zero PEEP (peak pressure around 46 cmH2O) and a group with Vt 15 ml/kg and zero PEEP (peak pressure around 30 cmH2O). The static compliance curves of the moderate volume/ high PEEP group were not shifted to the right after two hours of ventilation, which markedly occurred in both zero PEEP groups. The final concentrations of tumor necrosis factor (TNF)-a, interleukin (IL)-1p, IL-6, macrophage inflammatory protein (MIP)-2, interferon (IFN)-y and IL-10 in the lung lavage were also lower in the PEEP group [40]. This finding, although criticized [41], was consistent with subsequent investigation in a sheep model of lung injury induced by repeated lavage [42]. Takeuchi et al. [42] demonstrated higher levels of messenger RNA for IL-1P and IL-8 in lung lavage sheep ventilated with PEEP titrated according to oxygenation (around 16 cmH2O) when compared to two other PEEP-titration strategies based on the pressure-volume curve, in which PEEP was around 22 and 26 cmH2O. The plateau pressure was slightly higher in the two latter groups, implying that the prevention of lung collapse played a pivotal role in lung protection, even at the cost of a somewhat higher plateau pressure.

Nonetheless, in our opinion, comparisons between high frequency oscillation ventilation (HFOV) and conventional ventilation provide the most compelling histological evidence of lung protection through a strategy aiming at the maintenance of a high expiratory lung volume. In an in vivo rabbit model of lung lavage, Hamilton demonstrated that HFOV after a sustained inflation of 25-30 cmH2O was associated with a PaO2 around 400 mmHg during 5 and 20 hours. The conventional ventilation group also received the same sustained inflation, but was later submitted to lower mean airway pressures and progressed with deterioration on oxygenation and death within 20 hours. On histological examination, the lungs ventilated with HFOV showed less prominent epithelial sloughing and necrosis and much less hyaline membrane formation [43]. In a complementary study, the same group compared two strategies ofHFOV. The HFOV strategy aiming at a high lungvolume applied whatever airway pressure necessary to achieve a PaO2 > 350 mmHg. This strategy was associated with less epithelial damage than both HFOV employing lower mean airway pressures and conventional ventilation [44].

Extending further these results, Rimensberger ventilated surfactant-depleted rabbits, demonstrating that a volume recruitment strategy during small Vt venti lation (using conventional frequencies) plus lung volumes above a critical closing pressure is as protective as HFOV at similar lung volumes [45]. These findings strongly suggest that the mainstay of a comprehensive protective ventilation is the maintenance of the alveolar volume.

Obviously, when the maintenance of end-expiratory lung volumes results in unavoidable increment of end-inspiratory pressures because of the constraints of CO2 removal the net result of such a strategy will depend on the range of pressures applied, and the peculiarities of the animal model studied. However, two consistent findings in the literature should be noted:

a) When considering studies comparing animals submitted to equivalent end-in-spiratory pressures, there is almost no exception for the protective effects of PEEP, b) Even in studies where PEEP caused some increment in end-inspiratory pressures (compared to the control group), a beneficial net effect was still demonstrated by several of them, depending on the range of pressures applied and on the animal preparation.

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