Abstract
BackgroundMechanical ventilation can lead to ventilator-induced lung injury (VILI). In addition to the well-known mechanical forces of volutrauma, barotrauma, and atelectrauma, non-mechanical mechanisms have recently been discussed as contributing to the pathogenesis of VILI. One such mechanism is oscillations in partial pressure of oxygen (PO2) which originate in lung tissue in the presence of within-breath recruitment and derecruitment of alveoli. The purpose of this study was to investigate this mechanism’s possible independent effects on lung tissue and inflammation in a porcine model.MethodsTo separately study the impact of PO2 oscillations on the lungs, an in vivo model was set up that allowed for generating mixed-venous PO2 oscillations by the use of veno-venous extracorporeal membrane oxygenation (vvECMO) in a state of minimal mechanical stress. While applying the identical minimal-invasive ventilator settings, 16 healthy female piglets (weight 50 ± 4 kg) were either exposed for 6 h to a constant mixed-venous hemoglobin saturation (SmvO2) of 65% (which equals a PmvO2 of 41 Torr) (control group), or an oscillating SmvO2 (intervention group) of 40–90% (which equals PmvO2 oscillations of 30–68 Torr)—while systemic normoxia in both groups was maintained. The primary endpoint of histologic lung damage was assessed by ex vivo histologic lung injury scoring (LIS), the secondary endpoint of pulmonary inflammation by qRT-PCR of lung tissue. Cytokine concentration of plasma was carried out by ELISA. A bioinformatic microarray analysis of lung samples was performed to generate hypotheses about underlying pathomechanisms.ResultsThe LIS showed significantly more severe damage of lung tissue after exposure to PO2 oscillations compared to controls (0.53 [0.51; 0.58] vs. 0.27 [0.23; 0.28]; P = 0.0025). Likewise, a higher expression of TNF-α (P = 0.0127), IL-1β (P = 0.0013), IL-6 (P = 0.0007), and iNOS (P = 0.0013) in lung tissue was determined after exposure to PO2 oscillations. Cytokines in plasma showed a similar trend between the groups, however, without significant differences. Results of the microarray analysis suggest that inflammatory (IL-6) and oxidative stress (NO/ROS) signaling pathways are involved in the pathology linked to PO2 oscillations.ConclusionsArtificial mixed-venous PO2 oscillations induced lung damage and pulmonary inflammation in healthy animals during lung protective ventilation. These findings suggest that PO2 oscillations represent an independent mechanism of VILI.
Highlights
Mechanical ventilation can lead to ventilator-induced lung injury (VILI)
A constant mean Mixed-venous hemoglobin saturation (SmvO2) of 66 ± 2.8% with less than 3% of fluctuation was achieved that resulted in a constant mean Arterial partial pressure of oxygen (PaO2) of 104.3 ± 3.7 Torr, with less than 5 Torr of fluctuation
The present study investigated the effects of Partial pressure of oxygen (PO2) oscillations on lung damage and pulmonary inflammation in a state of minimal mechanical stress
Summary
In addition to the well-known mechanical forces of volutrauma, barotrauma, and atelectrauma, non-mechanical mechanisms have recently been discussed as contributing to the pathogenesis of VILI One such mechanism is oscillations in partial pressure of oxygen (PO2) which originate in lung tissue in the presence of within-breath recruitment and derecruitment of alveoli. In different animal models of acute respiratory distress syndrome (ARDS), several studies have described the phenomenon of within-breath fluctuations in arterial PO2 during mechanical ventilation [19,20,21,22,23] As these PO2 oscillations that originate in lungs by repetitive collapse and reopening of alveoli are dependent on the presence of recruitable atelectasis, they have been investigated primarily in diseased lungs. A first attempt to compare the progression of lung injury in different functional lung compartments in a surfactant depletion model combined with injurious ventilation in rabbits was presented by Otto et al, who concluded that cyclical recruitment seems more damaging than stretch injury [24]
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