Both high level pressure support ventilation and controlled mechanical ventilation induce diaphragm dysfunction and atrophy

Abstract

Objectives: Previous workers have demonstrated that controlled mechanical ventilation results in diaphragm inactivity and elicits a rapid development of diaphragm weakness as a result of both contractile dysfunction and fiber atrophy. Limited data exist regarding the impact of pressure support ventilation, a commonly used mode of mechanical ventilation-that permits partial mechanical activity of the diaphragm-on diaphragm structure and function. We carried out the present study to test the hypothesis that high-level pressure support ventilation decreases the diaphragm pathology associated with CMV.

Methods: Sprague-Dawley rats were randomly assigned to one of the following five groups:1) control (no mechanical ventilation); 2) 12 hrs of controlled mechanical ventilation (12CMV); 3) 18 hrs of controlled mechanical ventilation (18CMV); 4) 12 hrs of pressure support ventilation (12PSV); or 5) 18 hrs of pressure support ventilation (18PSV).

Measurements and main results: We carried out the following measurements on diaphragm specimens: 4-hydroxynonenal-a marker of oxidative stress, active caspase-3 (casp-3), active calpain-1 (calp-1), fiber type cross-sectional area, and specific force (sp F). Compared with the control, both 12PSV and 18PSV promoted a significant decrement in diaphragmatic specific force production, but to a lesser degree than 12CMV and 18CMV. Furthermore, 12CMV, 18PSV, and 18CMV resulted in significant atrophy in all diaphragm fiber types as well as significant increases in a biomarker of oxidative stress (4-hydroxynonenal) and increased proteolytic activity (20S proteasome, calpain-1, and caspase-3). Furthermore, although no inspiratory effort occurs during controlled mechanical ventilation, it was observed that pressure support ventilation resulted in large decrement, approximately 96%, in inspiratory effort compared with spontaneously breathing animals.

Conclusions: High levels of prolonged pressure support ventilation promote diaphragmatic atrophy and contractile dysfunction. Furthermore, similar to controlled mechanical ventilation, pressure support ventilation-induced diaphragmatic atrophy and weakness are associated with both diaphragmatic oxidative stress and protease activation.

Conflict of interest statement

The authors have not disclosed any potential conflicts of interest.

Figures

Figure 1

4-HNE accumulation (percentage of control) in diaphragm samples. Values are means ± SE. *Significantly different vs. CON (P < 0.05). #Significantly different vs. 12PSV (P < 0.05).

Figure 2

Chymotryspin-like 20S proteasome activity in diaphragm samples. Values are means ± SE. *Significantly different vs. CON (P < 0.05). #Significantly different vs. 12PSV (P < 0.05).

Figure 3

Active calpain 1 protein levels in diaphragm muscle expressed as percentage of control. Values are means ± SE. *Significantly different vs. CON (P < 0.05).

Figure 4

Active caspase-3 protein levels in diaphragm muscle expressed as percentage of control. Values are means ± SE. *Significantly different vs. CON (P < 0.05). #Significantly different vs. 12PSV (P < 0.05). δSignificantly different vs. 12CMV.

Figure 5

Fiber cross-sectional area (CSA) in diaphragm skeletal muscle myofibers expressing myosin heavy chain (MHC) I (type I), MHC IIa (type IIa), and MHC IIx/IIb (type IIx/IIb). A: representative fluorescent staining of MHC I (DAPI filter/blue), MHC IIa (FITC filter/green), and dystrophin (rhodamine filter/red) proteins in diaphragm samples from CON, 12PSV, 12CMV, 18PSV, and 18CMV. B: type I, type IIa, and type IIx/IIb fiber CSA. Values are means ± SE. *Significantly decreased vs. CON (P < 0.05). #Significantly decreased vs. 12PSV (P < 0.05).

Figure 6

Diaphragmatic force-frequency response (in vitro) of diaphragm samples. Values are mean ± SE. *12PSV, 18PSV, 12CMV, and 18CMV significantly decreased vs. CON (P < 0.05). #12CMV and 18CMV significantly decreased vs. 12PSV and 18PSV (P<0.05). δ18PSV, 12CMV, 18CMV significantly decreased vs. control and 12PSV (P<0.05). Δ18PSV significantly decreased vs. 12PSV.