© 2004 American Thoracic Society doi: 10.1164/rccm.2409004
Ventilator-induced Diaphragmatic DysfunctionToward a Better Treatment?Katholieke Universiteit Leuven Leuven, Belgium Ventilator-induced diaphragmatic dysfunction (VIDD) is characterized by a reduction in force-generating capacity by the diaphragm and was recently shown to occur in rats (1–3), rabbits (4), piglets (5), and baboons (6). In rats, VIDD is already present after as few as 12 hours of controlled mechanical ventilation, resulting in a reduction of specific force by 20% (2). Larger reductions (25–50%) were observed in rabbits after 1 day (4), piglets after 5 days (5), and baboons after 11 days (6). VIDD is likely to be one of the prime causes of weaning failure (7). The latter occurs in about 20 to 25% of mechanically ventilated patients, with an astonishing 59% of time in the ICU being devoted to weaning in patients with chronic obstructive pulmonary disease. VIDD is thus a major medical problem in ventilated patients. In recent years several groups have examined the occurrence and mechanisms of VIDD in animal models. These experiments have significantly enhanced our understanding of VIDD. It is clear that VIDD occurs after very short-term controlled mechanical ventilation, i.e., 12 hours in rats, and its magnitude increases with increasing time spent on the ventilator (2). This underlines the potential significance to humans as short periods of controlled mechanical ventilation are still applied frequently in the ICU. VIDD is due to mechanical ventilation itself and not to anesthesia (2), although recent evidence suggests that it might be enhanced by the administration of paralyzing agents (8). From a mechanistic point of view the following were demonstrated in the diaphragm after controlled mechanical ventilation: reduced muscle mass (1, 2, 9); diminished fiber dimensions of type I, IIa, and IIx/b fibers (3, 10, 11); myofibrillar damage (4); enhanced proteolysis due to enhanced calpain and 20S proteosome activity (10); increased reactive carbonyl derivatives and total lipid hydroperoxides as products of protein oxidation and lipid peroxidation (12); reduced expression of the growth factor IGF-I (3); decreased expression of the myogenic transcription factor MyoD associated with enhanced or unaltered expression of myogenin and hence, reduction of the MyoD to myogenin ratio (13); diminished sarcoplasmic-endoplasmic reticulum Ca ATPase (SERCA-1a) expression (13); and increased expression of muscle atrophy factor (MAF-box) (14). All of these factors contribute to or are the expression of muscle atrophy or myopathy. The prime physiologic trigger leading to these alterations in oxidative stress, proteolysis, and expression of proteins, growth, and transcription factors is not clear at present. Diaphragm unloading and inactivity, leading to disuse, may well be the prime cause. Other causes may include: rhythmic passive shortening (13), stretching, steroid use, and use of paralyzing agents. In a recent study, we demonstrated that unloading and immobilization of a peripheral muscle in rats produced changes in growth and transcription factor expression similar to those seen in the diaphragm with mechanical ventilation. Rhythmic passive shortening did not appear to add to these changes (13). However, the diaphragm may respond differently than other skeletal muscles, given differences in fiber composition and excitation–contraction coupling (15). Finally, recent experiments demonstrated that assisted mechanical ventilation preserved diaphragmatic force and expression of MAF-box protein in rabbits, indicating that intermittent diaphragmatic contraction protects against VIDD (14). Along the same lines, we recently found that intermittent spontaneous breathing attenuated the effect of controlled mechanical ventilation (16). The latter findings may provide us with approaches for preventing VIDD in patients. Understanding the mechanisms underlying VIDD should lead to better prevention or treatment of VIDD. In the present issue of the Journal (pp. 1179–1184), Betters and coworkers report interesting findings in this respect (17). This study confirmed the significance of enhanced diaphragmatic proteolysis and oxidative stress in the genesis of VIDD. The novel finding, however, was that in rats treatment with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) restored diaphragmatic force and improved fatigue properties after 12 hours of controlled mechanical ventilation. In addition, Trolox reduced elevated tyrosine levels and 20S proteasome activity, indicative of enhanced proteolysis in the diaphragm. Finally, Trolox failed to restore the total thiol and glutathione levels that were reduced due to mechanical ventilation, suggesting that such therapy apparently protected the diaphragm against oxidative modification of biomolecules without affecting these assays. The mechanism for this Trolox-induced effect, however, remains unclear. These data open up new potential therapeutic approaches for VIDD. However, further research is needed before such treatment may become applicable in the human situation of weaning failure. This research should most probably continue along two distinct lines: (1) although enhanced proteolysis and oxidative stress appear to be involved in VIDD, it will be important to determine the initiating triggers that lead to these changes. These triggers will provide us with clues for the underlying physiological mechanisms and hence, potential new preventive strategies; (2) human research is desperately needed. At present, it is unknown whether fast onset VIDD also develops in humans, whether it develops in the same time frame as in experimental animals, and whether similar underlying mechanisms are involved. As already suggested by Vassilakopoulos and Petrof (7) studies on donors for lung transplantation could be enlightening. Such human studies would be highly useful, as ways to prevent or treat VIDD and its clinical consequences in patients seem almost within reach. FOOTNOTES Conflict of Interest Statement: M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.G.-R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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