Respiratory Muscle Dysfunction in Mechanically Ventilated Critically Ill Patients

The general aim of this thesis is to provide better insights into the respiratory muscle dysfunction in mechanically ventilated critically ill patients. We measured the respiratory muscle effort during a spontaneous breathing trial (SBT) in patients with brain injury and evaluated their predictive ability for ventilator liberation failure in these patients. To establish the abnormalities of the diaphragm muscle and reveal the underlying mechanisms of diaphragm weakness, we extensively investigated the (ultra)structural changes of the diaphragm biopsies obtained from critically ill patients. We also investigated the efficacy of slow and fast skeletal troponin activators for restoring myofibers contractile ability. For the first time, we assessed the reproducibility of expiratory muscle ultrasound in mechanically ventilated critically ill patients, and then explored the time-dependent changes of expiratory muscle thickness in these patients. In a year amid the covid pandemic, we also explored SARS-CoV-2 viral infiltration and its associated pathological changes in the diaphragm of Covid- 19 non-survivors. Here, we highlight the most important findings and new insights from the Chapters 2 - 7. In chapter 2, We found that seventeen (37%) patients failed ventilator liberation within 48 h and 61% within 7 days after a successful spontaneous breathing trial. Indepth analysis of the respiratory muscle effort (e.g., respiratory pressure-time-product diaphragm electrical activity and neuromechanical efficiency of the diaphragm) measured during the successful spontaneous breathing trial, however, failed to predict ventilator liberation failure in these patients. In chapter 3, diaphragm biopsies from 54 critically ill patients and 25 control patients were analyzed in depth. We found that myofiber atrophy and contractile weakness developed in critically ill patients, which are in agreement with our previous findings in a small group of patients. Most importantly, we found that replacement fibrosis and myosin super-relaxed state may contribute to diaphragm weakness. In chapter 4, we summarized current knowledge on the physiology and pathophysiology of expiratory muscle in critically ill patients. The expiratory muscles, which include the abdominal wall muscles and some of the rib cage muscles, are an important component of the respiratory muscle pump and are recruited in the presence of high respiratory load or low inspiratory muscle capacity. Recruitment of the expiratory muscles may have beneficial effects, including reduction in end-expiratory lung volume, reduction in trans-pulmonary pressure and increased inspiratory muscle capacity. However, severe weakness of the expiratory muscles may develop in critically ill patients and is associated with adverse outcomes, including difficult ventilator weaning and impaired airway clearance. In chapter 5, our data showed that: 1) ultrasound is a highly reproducible tool to assess thickness of the expiratory muscles in mechanically ventilated critically ill patients; 2) lung volume in the range of tidal breathing has a significant but small effect on expiratory muscle thickness; 3) expiratory muscle thickness decreases in 22%, increases in 12% and remains stable in 66% of critically ill ventilated patients; 4) the observed increase in thickness of the expiratory muscles mainly result from an increase in thickness of the muscle fasciae; 5) changes in thickness of the expiratory muscles are not associated with changes in the thickness of the diaphragm. In chapter 6-7, we revealed that SARS-CoV-2 viral inflation in the diaphragm and may associated with distinct genes expression and pathological features in the diaphragm of Covid-19 non-survivors. These changes may lead to diaphragm weakness and might contribute to ventilator weaning failure, persistent dyspnea, and fatigue in patients who survived. But the mechanisms that cause these changes are remained to be established. Furthermore, it is also remained to be established whether these changes are SARS-CoV-2 specific or will develop in other viruses.