Prolonged mechanical ventilation alters diaphragmatic structure and function

Abstract

Objective: To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology.

Measurements: Systematic literature review.

Conclusions: Prolonged mechanical ventilation can promote diaphragmatic atrophy and contractile dysfunction. As few as 18 hrs of mechanical ventilation results in diaphragmatic atrophy in both laboratory animals and humans. Prolonged mechanical ventilation is also associated with diaphragmatic contractile dysfunction. Studies using animal models revealed that mechanical ventilation-induced diaphragmatic atrophy is due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, and the ubiquitin-proteasome system as key proteases that contribute to mechanical ventilation-induced diaphragmatic proteolysis. The scientific challenge for the future is to delineate the mechanical ventilation-induced signaling pathways that activate these proteases and depress protein synthesis in the diaphragm. Future investigations that define the signaling mechanisms responsible for mechanical ventilation-induced diaphragmatic weakness will provide the knowledge required for the development of new medicines that can maintain diaphragmatic mass and function during prolonged mechanical ventilation.

Conflict of interest statement

The authors have not disclosed any potential conflicts of interest.

Figures

Figure 1

Prolonged (18 hrs) mechanical ventilation (MV) in rats results in significant atrophy of all diaphragm muscle fiber types. Values represent mean ± standard error of the mean; *indicates different from control. Data are redrawn from Shanely et al (13). CSA, cross-sectional area.

Figure 2

Microscopic photographs of diaphragm muscle fibers from control and mechanically ventilated patients (case) (18 hrs to 69 hrs of controlled mechanical ventilation [CMV]). Note that the slow-twitch (type I) and fast-twitch (type II) fibers in the CMV diaphragm samples (panels A, C, and E) are smaller than those in the control diaphragms (panels B, D, and F). Panels A and B (hematoxylin and eosin stain) show that neither inflammatory infiltrate nor necrosis is present in case or control specimens. The sections in panels C and D were preincubated with an antibody that is specific for the slow myosin heavy chain, whereas sections in panels E and F were preincubated with an antibody that reacts with all fast myosin heavy chains. In each of the sections, fibers reacting with the antibody appear orange-red, whereas fibers not reacting with the antibody appear black. In panels C, D, E, and F, a representative slow-twitch fiber is indicated by an open circle and a fast-twitch fiber by an open square. Reproduced with permission from Levine et al (20).

Figure 3

Prolonged (18 hrs to 69 hrs) controlled mechanical ventilation (MV) in humans results in significant atrophy within slow and fast diaphragm muscle fiber types. Values represent mean ± standard error of the mean; *indicates different from control. Data are redrawn from Levine et al (20). CSA, cross-sectional area.

Figure 4

Effects of prolonged mechanical ventilation (MV) on diaphragmatic-specific force production (in vitro) in young adult rats. Values represent mean ± standard error of the mean. Compared with diaphragms from control animals, prolonged MV resulted in a significant reduction in diaphragmatic-specific force production at all MV time points and stimulation frequencies. Data are redrawn from Powers et al (35).

Figure 5

Effects of prolonged mechanical ventilation (MV) on diaphragmatic specific force production (in vitro) in both young adult (4 mos old) and senescent (30 mos old) rats. Values represent means ± standard error of the mean; *indicates significantly different (p < .05) from young adult control animals; #indicates different (p < .05) from senescent control animals. Redrawn from Criswell et al (37).

Figure 6

Prolonged controlled mechanical ventilation results in numerous biochemical, structural, and functional effects on the diaphragm. ROS, reactive oxygen species.