Ventilator-induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis

Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life-saving intervention for patients in respiratory failure, an unintended side-effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is labelled as 'ventilator-induced diaphragm dysfunction' (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox-regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV-induced changes in the structure/function of diaphragm muscle and discusses the cell-signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field. image Abstract figure legend Prolonged mechanical ventilation results in diaphragmatic inactivity and a rapid increase in the production of reactive oxygen species (ROS) in mitochondria within diaphragm fibres. This rapid increase in mitochondrial ROS production results in disrupted redox signalling, leading to increased proteolysis and depressed protein synthesis. Together, these changes promote diaphragmatic atrophy and contractile dysfunction leading to diaphragmatic weakness. Notably, diaphragmatic weakness is a risk factor for difficulties in weaning patients from the ventilator. image