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. 2012 Apr;40(4):1254-60.
doi: 10.1097/CCM.0b013e31823c8cc9.

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

Matthew B Hudson  1 , Ashley J Smuder, W Bradley Nelson, Christian S Bruells, Sanford Levine, Scott K Powers
Affiliations

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

Matthew B Hudson et al. Crit Care Med. 2012 Apr.

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.

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Conflict of interest statement

The authors have not disclosed any potential conflicts of interest.

Figures

Figure 1
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
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
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
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
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
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.
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References

    1. Jaber S, Petrof BJ, Jung B, et al. Rapidly Progressive Diaphragmatic Weakness and Injury during Mechanical Ventilation in Humans. Am J Respir Crit Care Med - PubMed
    1. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327–1335. - PubMed
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    1. Shanely RA, Zergeroglu MA, Lennon SL, et al. Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med. 2002;166(10):1369–1374. - PubMed

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