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According to the current literature, the pathogenesis of ventilator-induced lung injury is exclusively caused by overdistension or forced opening and collapse of the alveoli, while stretch of the upper airways is generally not taken into consideration. In the present thesis we hypothesized that mechanical ventilation may lead to a distension of the upper airways that may contribute relevantly to the characteristic pathophysiologic symptoms of ventilator-induced lung injury.
Experiments were performed on anesthetized adult C57Bl/6J mice that were ventilated with tidal volumes of 6, 10 or 15 ml/kg body weight (bw), respectively. Flat-panel volume CT (vCT) scans were performed and central airways were segmented and rendered to 3D to analyse quantitatively the volume of the upper airways. By intravital microscopy, distension of the isolated trachea as well as of the subpleural alveoli in vivo was imaged. Functional dead space was evaluated by capnographic studies. Compliance of the upper airways and of the functional dead space were calculated by appropriate pressure-volume-curves. In isolated and mechanically ventilated tracheae early response cytokine release was measured. Histological analyses of lung tissue after ventilation allowed for assessment of tissue damage subsequent to mechanical ventilation. To compare the mechanical properties between mice and larger mammals, murine trachea and porcine segmental bronchi of equal diameter were analysed in an organ bath by computer-assisted pressure-volume-slopes.
vCT studies revealed a significant up to 2.5-fold increase of upper airway volume under mechanical ventilation, which was reversible upon return to spontaneous breathing. The most significant distension was detected in the main bronchi already under moderate tidal volumes of 10 ml/kg bw, whereas trachea, segmental bronchi and functional dead space showed a linear volume increase with higher tidal volumes. Alveoli as the most distal part of the bronchial tree even showed disproportional distension under mechanical ventilation when VT was increased from 10 ml/kg bw to 15 ml/kg bw. In isolated tracheae mechanical ventilation caused a significant release of the proinflammatory cytokines TNF-α and IL-1β. Comparison of murine tracheae and porcine segmental bronchi revealed similar anatomical structures and comparable values of airway compliance.
Mechanical ventilation causes a rapid, pronounced and reversible distension of the upper airways, accompanied by an increase of functional dead space. Upper airways distend mostly under moderate tidal volumes, associated with a proinflammatory reaction and tissue injury of the surrounding blood vessels. Hence, mechanical ventilation causes upper airway distension that may contribute critically to the pathological features of ventilator-induced lung injury. On the other hand, upper airways seem to act as a buffer system to protect the sensitive alveoli from overdistension by excessive tidal volumes. This protective function is lost as soon as a certain volume threshold is exceeded. In that case, the damaging volume is passed undiminished to the distal airways and alveoli and causes the common clinical pattern of ventilator-induced lung injury, as emphysema or edema formation, loss of function of the blood-air-barrier and reduced gas exchange in the lungs.
Preliminary interspecies comparison between murine tracheae and porcine segmental bronchi allows for the transfer of our findings in terms of a potential distal airway distension with the associated inflammatory reaction and protective function to larger mammals such as pigs and men. Hence, upper airway distension should be taken into consideration in the pathophysiological concept of ventilator-induced lung injury.