Letter to the Editor

With great interest we read the paper by Corpeno and colleagues that reports the time course of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat (Corpeno et al. 2014). In their study, rats were mechanically ventilated for up to 14 days and a time-resolved analysis of the diaphragm structure and function was performed. In the first 4 days of controlled mechanical ventilation, specific force generation of muscle fibres was significantly decreased in the presence of protein modifications associated with oxidative stress. Surpri-singly, cross sectional area (CSA) of these muscle fibres was not affected in the first 4 days of mechanical ventilation. This led the authors to conclude that a reduction of muscle fibre size is not a dominating factor underlying the early decline in diaphragm muscle function in response to controlled mechanical ventilation. In our opinion, two important issues potentially confound their findings on diaphragm muscle fibre size. Firstly, rapid induced atrophy of the diaphragm due to controlled mechanical ventilation has consistently been established in animals (Shanely et al. 2002; Maes et al. 2007; Schellekens et al. 2014). In all these studies, diaphragm atrophy was assessed by CSA measurement of the specific fibre types (fast and slow), whereas this was not done in the paper by Corpeno et al. (Fig.1). Since CSA differs significantly among fibre types (Eddinger & Moss, 1987; Shanely et al. 2002; Maes et al. 2007), this may have underestimated the degree of diaphragm atrophy in their study. Accordingly, to establish the presence of diaphragm atrophy muscle fibre size should be reported per fibre type. Secondly, for unexplained reasons the authors applied high inspiratory fractions of CO2 () in their experimental setup. This may have had important unnoticed effects on diaphragm fibre size. Recently, we demonstrated that hypercapnia protected against the development of diaphragm atrophy during 18 h of mechanical ventilation in rats (Schellekens et al. 2014). In that study we induced hypercapnia by applying an of 0.05. Corpeno et al. 2014report an of 0.03 in their mechanical ventilation model. It is therefore likely that their animals developed hypercapnia, which consequently attenuated ventilator-induced diaphragm atrophy. It must be emphasized that Corpeno and colleagues have conducted a challenging and important study that adds to our understanding of the pathophysiology of ventilator-induced diaphragm dysfunction. However, the authors need to be more careful in their conclusion that diaphragm fibre atrophy does not develop early in ventilated rats, as this cannot be concluded with certainty from their results. Understanding the mechanisms resulting in diaphragm dysfunction in ventilated animals and ultimately critically ill patients is of major importance in order to develop effective strategies to combat the development of respiratory muscle dysfunction in these patients. Insight in early and late responses is important and may affect treatment strategies.