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Previous Volume 358:1327-1335 March 27, 2008 Number 13 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Sieck, G. C. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm.

Methods We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects). Case subjects had diaphragmatic inactivity and underwent mechanical ventilation for 18 to 69 hours; among control subjects diaphragmatic inactivity and mechanical ventilation were limited to 2 to 3 hours. We carried out histologic, biochemical, and gene-expression studies on these specimens.

Results As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively, decreased glutathione concentration of 23% (P=0.01), increased active caspase-3 expression of 100% (P=0.05), a 200% higher ratio of atrogin-1 messenger RNA (mRNA) transcripts to MBD4 (a housekeeping gene) (P=0.002), and a 590% higher ratio of MuRF-1 mRNA transcripts to MBD4 (P=0.001).

Conclusions The combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibers. These findings are consistent with increased diaphragmatic proteolysis during inactivity.

Source Information

From the Department of Surgery (S.L., T.N., N.T., M.E.F., M.T.B., P.R., J.Z., S.S., L.R.K., J.B.S.), the Department of Cell and Developmental Biology (N.A.R.), and the Pennsylvania Muscle Institute (S.L., M.T.B., N.A.R., J.B.S.), University of Pennsylvania; the Gift of Life Donor Program (S.L.); Medical Research, Surgical, and Laboratory Medicine Services, Department of Veterans Affairs Medical Center (S.L., T.N., R.S., J.B.S.) — all in Philadelphia; and the Center for Exercise Science, University of Florida, Gainesville (S.K.P.).

Address reprint requests to Dr. Levine at 1495 Wesleys Run, Gladwyne, PA 19035, or at sdlevine{at}mail.med.upenn.edu.

Full Text of this Article

Related Letters:

Mechanical Ventilation and Disuse Atrophy of the Diaphragm
McCool D., Ayas N., Brown R., Loring S. H., Heunks L. M.A., Dekhuijzen R. P.N., Fan E., Needham D. M., Leo F., Spaggiari L., Levine S., Budak M. T., Shrager J. B.
Extract | Full Text | PDF  
N Engl J Med 2008; 359:89-92, Jul 3, 2008. Correspondence

This article has been cited by other articles:

• McCool, D., Ayas, N., Brown, R., Loring, S. H., Heunks, L. M.A., Dekhuijzen, R. P.N., Fan, E., Needham, D. M., Leo, F., Spaggiari, L., Levine, S., Budak, M. T., Shrager, J. B. (2008). Mechanical ventilation and disuse atrophy of the diaphragm.. NEJM 359: 89-90 [Full Text]  
• (2008). Diaphragm Shrinkage in Mechanically Ventilated Patients. JWatch Neurology 2008: 1-1 [Full Text]  
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• Sieck, G. C., Mantilla, C. B. (2008). Effect of Mechanical Ventilation on the Diaphragm. NEJM 358: 1392-1394 [Full Text]