VENTILAZIONE MECCANICA E VOLUTRAUMA: STUDIO IN VIVO IN UN MODELLO SUINO
Creators: name: PASTORE, CAMILLA VALERIA
Publisher: name: Universit� degli Studi di Milano
Year: 2010

description: Mechanical ventilation is an essential support for patients with acute lung pathologies, such as acute respiratory distress syndrome and acute lung injury, and it is generally applied in chirurgical practice. Specialists are however aware that, despite of its ?life saving? role, this practice presents several negative side effects. Recently one of the most serious negative effects of mechanical ventilation, called Ventilatory Induced Lung Injury (VILI), has been detected and better analysed. This syndrome, initially associated with barotrauma, has been recently defined as volutrauma, meaning a damage of lung parenchyma caused by mechanical stress deriving from overdistension induced by high tidal volumes (VT). 
The aim of the present study was to evaluate the onset of ventilatory induced lung injury in a clinically relevant, validated and well-studied model, which closely mimics the human physiology and the ventilator setting currently used in the clinical arena. The study was performed using 18 pigs were involved, divided into three groups (n=6): two groups were mechanically ventilated (VT 20 ml/kg and 8 ml/kg), and one group was spontaneously breathing (SB). The duration of the experiments was 240 minutes. Hemogasanalysis and all main respiratory and circulatory parameters were detected every 30 minutes. Metalloproteinases 2 and 9 expression and activation and ET-1 levels were observed in the bronchoalveolar lavage fluid. At the end of the experiment, the animals were sacrificed and autoptic samples of lung, kidney and liver for histological and zymographic analysis were obtained. The results showed serious alterations of lung mechanics and structure induced by high VT, although the protective strategies as low VT were not immune from negative side effects. Respiratory function worsening was observed in spontaneously breathing subjects, too. Therefore, our study demonstrates that, both animals undergoing mechanical ventilation with high volumes and non-assisted breathing animals develop a massive lung edema, as revealed by extra-vascular lung water values. As expected, the alveolar over-distension induced ultrastructural cellular abnormalities only in animals subjected to high VT and not in those where lung distension was limited, as in our VT8 group, or absent, as in SB group. 
Our data show irrefutably that the severe edema formation noticed in spontaneously breathing animals was clearly related to the increase in pulmonary arterial pressure, which induced the extravasation of fluid into lung parenchyma.
Moreover, we have evaluated the changes in lung mechanics and metalloproteinases production and activation in three different types of lung damages evoked by mechanical, hypoxic and septic stress. Under that, 24 pigs were studied, randomly divided into four groups (n=6): control group (pigs spontaneously breathing), mechanical stress group (pigs ventilated with high VT), hypoxic group (pigs inhaled with an hypoxic gas mixture), septic group (pigs i.v. infused with E.coli LPS). All the animals were studied for 240 minutes. Hemogasanalysis and main respiratory and circulatory parameters were detected every 20 minutes. At the end of the experiment, subjects were sacrificed and autoptic samples of lung for histological and zymographic analysis were obtained. The changes in physiological parameters were in line with morphological lung alterations. Zymographic analysis showed a strong activation of MMP-2 but no activation of MMP-9 in control, mechanical and hypoxic stress groups. The septic stress group has reflected a specular situation with activation of MMP-9 and low levels of MMP-2, which was present only in the inactivated form. The present study has underlined an acute modulation of MMPs in lung tissues and MMPs different behaviour facing different stimulations.
In conclusion, it is clear that mechanical ventilation strategies profoundly affects lung parenchyma integrity and functionality, and the choice of a ventilation strategy that avoids these damages, ensuring at the same time an appropriate exchange of gases, is strongly encouraged.