Title: Ventilator-geïnduceerde diafragmadysfunctie in ratten: Tijdsduur van het herstel van de diafragmafunctie en impact van sepsis en hyperglycemie
Other Titles: Ventilator-induced diaphragm dysfunction in rats: Time course of diaphragm function recovery and impact of sepsis and hyperglycemia
Authors: Thomas, Debby
Issue Date: 15-Jan-2015
Abstract: Mechanical ventilation is an essential life-saving intervention used in critically ill patients with respiratory failure in the intensive care unit. However, difficulties in discontinuing ventilator support frequently remain a serious and time-consuming problem. A variety of factors may contribute to weaning failure in patients, but respiratory muscle weakness due to ventilator-induced diaphragm dysfunction probably plays an important role. Several studies in animal models have consistently shown that mechanical ventilation leads to a rapid time-dependent decrease in force-generating capacity of the diaphragm. These negative effects appear early in the course of mechanical ventilation and are associated with several alterations including increased oxidative stress, increased proteolysis and decreased protein synthesis, leading to diaphragm atrophy. Similar results have been obtained in mechanically ventilated critically ill patients, where twitch transdiaphragmatic pressure has been shown to be reduced, and the duration of mechanical ventilation to be associated with a progressive and logarithmic decline in diaphragm force. Furthermore, prolonged mechanical ventilation in humans also resulted in diaphragmatic atrophy, with an increase in oxidative stress and proteolysis biomarkers.It is not yet known whether ventilator-induced diaphragm dysfunction is reversible, and if so, the time course for the diaphragm to recover its normal function has not yet been determined, although it may play an important role in weaning from the ventilator. Therefore, the first aim of this thesis was to investigate the time course of diaphragm function recovery following controlled mechanical ventilation. On the other hand, in patients submitted to mechanical ventilation, diaphragm weakness may already be present due to underlying diseases or concomitant treatments. In this case, it is not known whether submission to mechanical ventilation would result in more severe diaphragm dysfunction. Therefore, in the second part of this thesis, the effects of controlled mechanical ventilation were examined on weak diaphragms at the start of mechanical ventilation, with diaphragm weakness due to underlying diseases or comorbidities that are very common in ventilated patients in the intensive care unit. First, we examined whether controlled mechanical ventilation would have an additional negative effect on diaphragm function in rats with sepsis. The last aim of this thesis was to examine the combined effect of controlled mechanical ventilation and hyperglycemia on the diaphragm.In healthy rats, 3 hours of diaphragm reloading by spontaneous breathing following 24 h of controlled mechanical ventilation was sufficient to improve mechanical ventilation-induced diaphragm contractile dysfunction, but full recovery occurred after 4-7 h of reloading. This was associated with an increase in the type IIx/b diaphragm muscle fiber dimensions, increased markers of protein synthesis and improved intrinsic contractile properties of skinned diaphragm muscle fibers. In rats with sepsis, 12 h of controlled mechanical ventilation resulted in an exacerbation of diaphragm contractile dysfunction associated with an augmentation of diaphragmatic IL-6 production, increased oxidative stress and increased autophagy. When controlled mechanical ventilation was applied to rats with hyperglycemia, diaphragm contractile dysfunction was exacerbated. This was not related to additional diaphragmatic atrophy nor to increased proteolysis by calpain and caspase-3, or autophagy. The exact mechanism behind this additional negative effect on diaphragm dysfunction was not yet unraveled and needs further investigation.In conclusion, this doctoral thesis showed that ventilator-induced diaphragm contractile dysfunction recovers very quickly following the inititaion of spontaneous breathing, at least in healthy animals. Further, it also showed that diaphragm contractile dysfunction was worsened when controlled mechanical ventilation was applied to rats with diaphragm weakness due to sepsis or hyperglycemia. Therefore, this doctoral thesis indicates that intensive care unit-acquired diaphragm weakness may be enhanced when mechanical ventilation is applied in critically ill patients suffering from sepsis or hyperglycemia, and this may further compromise the poor outcomes of these patients. This suggests that diaphragm function recovery may also be compromised in these patients and that they will experience more problems in weaning under these circumstances.
ISBN: 978 94 6165 150 1
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Gynaecological Oncology

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