Effects of lung-protective ventilation on microbial growth and inflammatory biomarkers in experimental sepsis

Sammanfattning: Sepsis is a severe disease state characterised by a dysregulated host response to infection. The need for mechanical ventilation is common in the sepsis population, for primarily pulmonary reasons or as a result of other organ dysfunction. Mechanical ventilation can be harmful to both the lungs and to extrapulmonary organs, particularly in association with an inflammatory insult. Great efforts has been made over the years in finding less injurious ventilator strategies aiming to reduce ventilator induced lung injury where focus has been on modulating tidal volume and positive end-expiratory pressure. A clear trend towards increased clinical use of this lung-protective ventilation has emerged. Consequently, investigation of the effects of mechanical ventilation on organs outside the lungs has earned growing scientific interest. We have used porcine experimental models to study the effects of different ventilator strategies. In an experimental Pseudomonas Aeruginosa pneumonia model the ventilatory differences on bacterial growth and lung injury were studied. Using an endotoxin challenge we aimed to study the effect of different ventilator regimens on systemic and organ-specific plasma levels of inflammatory cytokines and cell-free DNA. The effect of tidal volume on cerebral inflammation, metabolism and brain injury was studied during endotoxemia. Myostatin levels was studied in relation to anaesthesia, surgery, endotoxemia, pneumonia, inflammatory cytokines and different tidal volumes. The experiments were carried out for six hours or, to identify more long-term effects, for thirty hours.We found that ventilation with lower tidal volume and higher positive end-expiratory pressure reduce the bacterial burden and the development of lung injury in early pneumonia. Lung-protective ventilation suppresses systemic levels of cell free DNA and the liver is a significant contributor to systemic levels of cell free DNA, an effect that is attenuated by protective ventilation. Lower tidal volumes do not affect cerebral levels of cytokines but increase the cerebral perfusion, the cerebral metabolism and markers of brain injury in plasma and cerebral microdialysate. Plasma myostatin levels decrease in relation to surgery and anaesthesia where the decrease is decelerated by endotoxin. Myostatin levels in plasma were not affected by pneumonia or different tidal volumes.We conclude that lung-protective ventilation reduces pulmonary bacterial burden and lung injury in pneumonia and affects systemic and organ-specific levels of inflammatory markers in experimental sepsis with a potentially harmful effect on the brain.