Mechanical ventilation results in progressive contractile dysfunction in the diaphragm

Abstract

These experiments tested the hypothesis that a relatively short duration of controlled mechanical ventilation (MV) will impair diaphragmatic maximal specific force generation (specific P(o)) and that this force deficit will be exacerbated with increased time on the ventilator. To test this postulate, adult Sprague-Dawley rats were randomly divided into one of six experimental groups: 1) control (n = 12); 2) 12 h of MV (n = 4); 3) 18 h of MV (n = 4); 4) 18 h of anesthesia and spontaneous breathing (n = 4); 5) 24 h of MV (n = 7); and 6) 24 h of anesthesia and spontaneous breathing (n = 4). MV animals were anesthetized, tracheostomized, and ventilated with room air. Animals in the control group were acutely anesthetized but were not exposed to MV. Animals in two spontaneous breathing groups were anesthetized and breathed spontaneously for either 18 or 24 h. No differences (P > 0.05) existed in diaphragmatic specific P(o) between control and the two spontaneous breathing groups. In contrast, compared with control, all durations of MV resulted in a reduction (P < 0.05) in diaphragmatic specific tension at stimulation frequencies ranging from 15 to 160 Hz. Furthermore, the MV-induced decrease in diaphragmatic specific P(o) was time dependent, with specific P(o) being approximately 18 and approximately 46% lower (P < 0.05) in animals mechanically ventilated for 12 and 24 h, respectively. These data support the hypothesis that relatively short-term MV impairs diaphragmatic contractile function and that the magnitude of MV-induced force deficit increases with time on the ventilator.

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy

“…Heart rate (365 Ϯ 9 beats/min) and mean blood pressure (90 Ϯ 4 mm Hg) homeostasis were maintained during MV across all treatment groups. Blood gas homeostasis and pH (data not shown) were maintained within physiologic levels during the experiment as reported previously (1,4,6,18). Because sepsis is associated with diaphragmatic contractile dysfunction, strict aseptic techniques were followed throughout the experiments (1,4,6,18).…”

“…To characterize the response of diaphragm myofibers and myonuclei to MV, we chose a 12-h treatment period because we have previously demonstrated this duration as the early occurrence of contractile dysfunction in this model (4). Diaphragmatic myofiber cross-sectional area was determined for individual fiber types in cross sections obtained from 12 h MV and 12 h MV with caspase-3 inhibition via DEVD-CHO.…”

Effects of controlled and pressure support mechanical ventilation on rat diaphragm muscle

“…This ventilatorinduced diaphragmatic dysfunction (VIDD), analyzed in many studies, may be due to: muscle disuse atrophy, reduced protein synthesis, increased proteolytic activity, oxidative stress, intrinsic abnormalities (ultrastructural level) of muscle fibers, problems with the excitation-contraction coupling and myonuclear loss 2,7,8,12,16,23,24 .…”

“…is characterized by a reduction in diaphragm force generation capacity due to controlled mechanical ventilation (CMV) and was recently shown to occur in humans 1 , being well-recognized in animal models as well, like rats 2,3 , rabbits 4 , piglets 5 , and baboons 6 .…”

“…Studies demonstrated the following alterations in the diaphragm after controlled mechanical ventilation: reduced muscle mass 2,10,11 ; diminished type I, IIa, and IIx/b fiber dimensions 3,12,13 ; myofibrillar damage 4 ; enhanced proteolysis 12 ; increased protein oxidation and lipid peroxidation 14 ; reduced expression of the insulin-like growth factor (IGF-I) 3 ; decreased sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA-1a) expression 15 ; increased expression of muscle atrophy factor (MAF-box) 16 ; and a decrease in myonuclear content 17 . All of these factors seem to contribute to the development of VIDD, but the precise contribution of each factor and their apparition kinetics has yet to be defined.…”