| Failure to wean from mechanical ventilation (MV) is a serious problem in acute medical care today. Approximately 5% of patients receiving MV experience difficult weaning, but these patients account for approximately 40--50% of all MV days. Numerous animal studies have documented that MV use leads to diaphragm atrophy, oxidative stress, reduced muscle strength and altered gene expression in as little as 6--24 hours, and this phenomenon has been termed ventilator induced diaphragm dysfunction (VIDD). Additionally, recent human work has documented severe VIDD (diaphragm muscle fibers atrophying ∼55%) following approximately 39 hours of MV, and clinical human studies have shown that patients experiencing difficulty weaning have impaired respiratory muscle performance, consistent with changes seen in VIDD models. However, it is unknown how soon the diaphragm begins to start the process of atrophy following the start of mechanical ventilation. We hypothesized that the genes responsible for maintaining diaphragmatic contractile function, stress response, energy transduction would be altered over the course of a 5 hour cardiothoracic surgery.;Two diaphragm biopsies were obtained from 5 male patients (67 +/- 11years) undergoing cardiothoracic surgery. The first biopsy was obtained as soon as the diaphragm was exposed; the second biopsy was obtained as late in the surgery as possible (4.9 +/- 1.8 hours). We profiled mRNA from the 5 pairs of muscle biopsies with a microarray (Affymetrix Hu U133 plus 2.0). Microarray analysis identified 763 differentially expressed (early vs. late samples) unique gene products (p< 0.005) after cardiothoracic surgical procedures. Post-operatively, the genes related to the generalized stress response and redox regulation were upregulated. We also found significantly upregulated expression of cathepsin C (2.7-fold), cathepsin L1 (2.0-fold), and various ubiquitin-conjugating enzymes (E2) (∼1.5-fold). Myocyte enhancer factor 2C (MEF2C), a key transcriptional factor for skeletal muscle development and regeneration, was significantly down-regulated (3.5-fold). We conclude that cardiothoracic surgery results in rapid changes in diaphragm gene expression, including genes related to generalized stress response, redox regulation, and proteolysis. This work provides the first data examining the changes of diaphragm gene expression following surgical procedures. These data will lead to future research examining intraoperative pharmacological interventions aimed at preventing VIDD in humans.;Meanwhile, most PMV patients require participating in unsupported, progressively lengthening, spontaneous breathing trials (SBT). Thirty-eight PMV (46+/-23 days) patients (male/female ratio: 16/22, Age 64+/-12yrs) were studied. Breathing pattern (BP) variables including exhaled minute ventilation (VE), breathing frequency (f), inspired tidal volume (VT), peak inspiratory flow (PIF), inspiration time (TI), expiration time (TE), and duty cycle were measured during the first 30 min of successful and failed SBT and the mean values and coefficients of variation (CV) of these BP variables were calulated. SBT failure was defined with standard criteria. Compared to successful SBT, the failed SBT displayed significantly high PIF and f (31.3+/-9.2 vs. 28.8+/-5.9 L/min and 29+/-11 vs. 26+/-7 breath/min, respectively). The CV of VE, f and PIF were higher during successful trials. We conclude that selected BP variables are different within subjects during the first 30 minute interval of failed and successful SBT in PMV patients, reflecting a higher drive to breathe in failed trials. BP CVs variables revealed more significant differences than the mean values. |
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