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Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm

Authors:
Emmanuel Futier at Centre Hospitalier Universitaire de Clermont-Ferrand
Emmanuel Futier
jean-michel Constantin at Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
jean-michel Constantin
Lydie Combaret at French National Institute for Agriculture, Food, and Environment (INRAE)
Lydie Combaret
Laurent Mosoni at French National Institute for Agriculture, Food, and Environment (INRAE)
Laurent Mosoni
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Controlled mechanical ventilation (CMV) induces profound modifications of diaphragm protein metabolism, including muscle atrophy and severe ventilator-induced diaphragmatic dysfunction. Diaphragmatic modifications could be decreased by spontaneous breathing. We hypothesized that mechanical ventilation in pressure support ventilation (PSV), which preserves diaphragm muscle activity, would limit diaphragmatic protein catabolism. Forty-two adult Sprague-Dawley rats were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive 6 or 18 hours of CMV or PSV. After sacrifice and incubation with 14C-phenylalanine, in vitro proteolysis and protein synthesis were measured on the costal region of the diaphragm. We also measured myofibrillar protein carbonyl levels and the activity of 20S proteasome and tripeptidylpeptidase II. Compared with control animals, diaphragmatic protein catabolism was significantly increased after 18 hours of CMV (33%, P = 0.0001) but not after 6 hours. CMV also decreased protein synthesis by 50% (P = 0.0012) after 6 hours and by 65% (P < 0.0001) after 18 hours of mechanical ventilation. Both 20S proteasome activity levels were increased by CMV. Compared with CMV, 6 and 18 hours of PSV showed no significant increase in proteolysis. PSV did not significantly increase protein synthesis versus controls. Both CMV and PSV increased protein carbonyl levels after 18 hours of mechanical ventilation from +63% (P < 0.001) and +82% (P < 0.0005), respectively. PSV is efficient at reducing mechanical ventilation-induced proteolysis and inhibition of protein synthesis without modifications in the level of oxidative injury compared with continuous mechanical ventilation. PSV could be an interesting alternative to limit ventilator-induced diaphragmatic dysfunction.
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Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphra
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... Baseline demographic data are shown in Table 1. Median baseline t di at end expiration (mm) and at end inspiration (mm) were 22 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and 37 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), respectively. On day 3 of MV, a significant decrease in t di was observed at end expiration and t di at end inspiration by approximately 27.2 and 17%, respectively, versus baseline recordings [16 (11-22) vs. 22 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), P=0.023; 29 (23-36) vs. 37 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), P<0.001, respectively], as shown in Fig. 3a. ...
... Median baseline t di at end expiration (mm) and at end inspiration (mm) were 22 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and 37 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), respectively. On day 3 of MV, a significant decrease in t di was observed at end expiration and t di at end inspiration by approximately 27.2 and 17%, respectively, versus baseline recordings [16 (11-22) vs. 22 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), P=0.023; 29 (23-36) vs. 37 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), P<0.001, respectively], as shown in Fig. 3a. On fifth day of MV, continuous diaphragm ultrasound parameters were recorded in 22 patients. ...
... Another study observed 15% decrease in diaphragm force within 72 h of assistcontrol mechanical ventilation [35]. Diaphragmatic oxidative stress is induced by partial support ventilation as much as controlled ventilation [36]. Trying to find the effect of MV on diaphragm activity, we applied t di at end inspiration as an ultrasound parameter of diaphragm activity. ...
Assessment of ventilator-induced diaphragmatic dysfunction in patients with chronic obstructive pulmonary disease using transthoracic ultrasonography
Article
Full-text available
  • May 2018
Background Mechanical ventilation (MV) can cause progressive thinning of diaphragm muscle and hence progressive decrease in diaphragmatic function. We aimed to assess the rate at which diaphragm thickness ( t di ) changed during MV and its effect on weaning outcome using transthoracic ultrasound (TUS) evaluation in patients with chronic obstructive pulmonary disease (COPD). Patients and methods Thirty mechanically ventilated patients with COPD were enrolled in this cohort study. Baseline t di was recorded within 24 h of MV after stoppage of sedation using TUS. The subsequent measurements were recorded on the third, fifth, and seventh day of MV and at the time of initiation of weaning. Results There was a significant decrease in t di at end expiration and at end inspiration by approximately 27.2 and 17% at third day of MV, respectively, and 35.5 and 18.5% at fifth day of MV, respectively, compared with baseline parameters. In the 10 patients who were still on ventilator till the seventh day, t di were significantly lower compared with baseline recordings. Percentage of decrease of t di at end inspiration from baseline recordings was significantly higher in patients with difficult weaning than in those with simple weaning. The optimum cutoff value of % of decline of t di at end inspiration associated with difficult weaning was at least 10.6% giving 88.9% sensitivity and 83.3% specificity. Conclusion MV is associated with gradual diaphragmatic atrophy which can be detected by TUS and could predict weaning outcome in mechanically ventilated patients with COPD.
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... Ventilator-induced diaphragm dysfunction may be attenuated, but not prevented, by maintaining active diaphragm contraction with partial unloading using pressure support ventilation in place of controlled ventilation. In an animal model comparing the two modes, diaphragm proteolysis was demonstrated after 18 h of controlled ventilation and was reduced in the group receiving pressure support ventilation [23]. ...
The ReInvigorate Study—phrenic nerve-to-diaphragm stimulation for weaning from mechanical ventilation: a protocol for a randomized pivotal clinical trial
Article
Full-text available
  • Aug 2024
  • TRIALS
Background In the United States in 2017, there were an estimated 903,745 hospitalizations involving mechanical ventilation (MV). Complications from ventilation can result in longer hospital stays, increased risk of disability, and increased healthcare costs. It has been hypothesized that electrically pacing the diaphragm by phrenic nerve stimulation during mechanical ventilation may minimize or reverse diaphragm dysfunction, resulting in faster weaning. Methods The ReInvigorate Trial is a prospective, multicenter, randomized, controlled clinical trial evaluating the safety and efficacy of Stimdia’s pdSTIM System for facilitating weaning from MV. The pdSTIM system employs percutaneously placed multipolar electrodes to stimulate the cervical phrenic nerves and activate contraction of the diaphragm bilaterally. Patients who were on mechanical ventilation for at least 96 h and who failed at least one weaning attempt were considered for enrollment in the study. The primary efficacy endpoint was the time to successful liberation from mechanical ventilation (treatment vs. control). Secondary endpoints will include the rapid shallow breathing index and other physiological and system characteristics. Safety will be summarized for both primary and additional analyses. All endpoints will be evaluated at 30 days or at the time of removal of mechanical ventilation, whichever is first. Discussion This pivotal study is being conducted under an investigational device exception with the U.S. Food and Drug Administration. The technology being studied could provide a first-of-kind therapy for difficult-to-wean patients on mechanical ventilation in an intensive care unit setting. Trial registration Clinicaltrials.gov, NCT05998018, registered August 2023.
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... 2 Although VIDD has received considerable attention in critically ill patients in general ICU, it has not attracted sufficient diligence in the moderate to severe TBI patient population despite their requirement for prolonged mechanical ventilation. 3 The diaphragm thickness decreases rapidly during the initial several days of mechanical ventilation in 40% of patients, and lower levels of inspiratory effort and higher levels of ventilatory support predict this decrease. Diaphragmatic thickness has been shown to reduce by 6 to 7.5% per day in mechanically ventilated patients. ...
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... Ventilator-induced diaphragm dysfunction may be attenuated, but not prevented, by maintaining active diaphragm contraction with partial unloading using pressure support ventilation in place of controlled ventilation. In an animal model comparing the two modes, diaphragm proteolysis was demonstrated after 18 hours of controlled ventilation and was reduced in the group receiving pressure support ventilation [19]. ...
The ReInvigorate Study - Phrenic Nerve-to-Diaphragm Stimulation for Weaning from Mechanical Ventilation: A Protocol for a Randomized Pivotal Clinical Trial
Preprint
Full-text available
  • Feb 2024
Background In the United States in 2017, there were an estimated 903,745 hospitalizations involving mechanical ventilation (MV). Complications from ventilation can result in longer hospital stays, increased risk of disability and increased healthcare costs. It has been hypothesized that electrically pacing the diaphragm by phrenic nerve stimulation during mechanical ventilation may minimize or reverse diaphragm dysfunction, resulting in faster weaning. Methods The ReInvigorate Trial is a prospective, multicenter, randomized, controlled clinical trial evaluating the safety and efficacy of Stimdia’s pdSTIM System for facilitating weaning from MV. The pdSTIM system employs percutaneously placed multipolar electrodes to stimulate the cervical phrenic nerves and activate contraction of the diaphragm bilaterally. Patients who were on mechanical ventilation for at least 96 hours and who failed at least one weaning attempt were considered for enrollment in the study. The primary efficacy endpoint was the time to successful liberation from mechanical ventilation (treatment vs. control). Secondary endpoints will include maximal inspiratory pressure, the rapid shallow breathing index, and other physiological and system characteristics. Safety will be summarized for both primary and additional analyses. All endpoints will be evaluated at 30 days or at the time of removal of mechanical ventilation, whichever is first. Discussion This pivotal study is being conducted under an investigational device exception with the U.S. Food and Drug Administration. The technology being studied could provide a first-of-kind therapy for difficult-to-wean patients on mechanical ventilation in an intensive care unit setting. Trial Registration Clinicaltrials.gov, NCT05998018, registered August 2023.
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... [1][2][3] Compared with fully controlled ventilation, benefits of spontaneous breathing include gas exchange and hemodynamics improvement, 1 better ventilationperfusion matching, 4 and decreased ventilatorinduced diaphragmatic dysfunction. 5 However, vigorous spontaneous effort can worsen lung injury through several mechanisms including global and local overdistension, increased lung perfusion, and negative-pressure pulmonary edema due to increases in transmural vascular pressure. [6][7][8][9] Moreover, although muscle pressure is uniformly distributed in healthy lungs, [10][11][12] diaphragmatic contraction may be transmitted heterogeneously in injured lungs: this causes a shift of gas from nondependent to dependent lung regions (pendelluft phenomenon), which generates local overstretch aggravating lung injury. ...
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... In this regard, maintaining appropriate diaphragm activity during MV could prevent diaphragmatic injury. According to research, providing assisted MV rather than controlled MV could reduce muscle protein hydrolysis and weakness [71,72]. Furthermore, transitioning a clinically stable patient to spontaneous breathing using assisted ventilation modes with reduced or interrupted sedation might preserve diaphragm activity and prevent the occurrence of disuse atrophy [73]. ...
Perioperative Diaphragm Dysfunction
Article
Full-text available
  • Jan 2024
Diaphragm Dysfunction (DD) is a respiratory disorder with multiple causes. Although both unilateral and bilateral DD could ultimately lead to respiratory failure, the former is more common. Increasing research has recently delved into perioperative diaphragm protection. It has been established that DD promotes atelectasis development by affecting lung and chest wall mechanics. Diaphragm function must be specifically assessed for clinicians to optimally select an anesthetic approach, prepare for adequate monitoring, and implement the perioperative plan. Recent technological advancements, including dynamic MRI, ultrasound, and esophageal manometry, have critically aided disease diagnosis and management. In this context, it is noteworthy that therapeutic approaches for DD vary depending on its etiology and include various interventions, either noninvasive or invasive, aimed at promoting diaphragm recruitment. This review aims to unravel alternative anesthetic and operative strategies that minimize postoperative dysfunction by elucidating the identification of patients at a higher risk of DD and procedures that could cause postoperative DD, facilitating the recognition and avoidance of anesthetic and surgical interventions likely to impair diaphragmatic function.
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... Protective mechanical ventilation of the diaphragm has been advocated in recent years, and various studies have been conducted in this regard [6][7][8]. According to this view, which is also supported by experimental studies, pressure-support ventilation preserves diaphragm protein content and causes less reduction in the cross-sectional area of diaphragmatic muscle fibers compared to controlled mechanical ventilation [9][10][11]. ...
Evaluation of IntelliVent-ASV® and PS-SIMV Mode Using Ultrasound (US) Measurements in Terms of Diaphragm Atrophy
Article
Full-text available
  • Jun 2023
Background: Mechanical ventilation is a life-saving intervention for critically ill patients, but it can also lead to diaphragm atrophy, which may prolong the duration of mechanical ventilation and the length of stay in the intensive care unit. IntelliVent-ASV® (Hamilton Medical, Rhäzüns, Switzerland) is a new mode of ventilation that has been developed to reduce diaphragm atrophy by promoting spontaneous breathing efforts. In this study, we aimed to evaluate the effectiveness of IntelliVent-ASV® and pressure support-synchronized intermittent mandatory ventilation (PS-SIMV) mode in reducing diaphragm atrophy by measuring diaphragm thickness using ultrasound (US) imaging. Methods: We enrolled 60 patients who required mechanical ventilation due to respiratory failure and were randomized into two groups: IntelliVent-ASV® and PS-SIMV. We measured the diaphragm thickness using US imaging at admission and on the seventh day of mechanical ventilation. Results: Our results showed that diaphragm thickness decreased significantly in the PS-SIMV group but remained unchanged in the IntelliVent-ASV® group. The difference in diaphragm thickness between the two groups was statistically significant on the seventh day of mechanical ventilation. Conclusions: IntelliVent-ASV® may reduce diaphragm atrophy by promoting spontaneous breathing efforts. Our study suggests that this new mode of ventilation may be a promising approach to preventing diaphragm atrophy in mechanically ventilated patients. Further studies using invasive measures of diaphragm function are warranted to confirm these findings.
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... (24) MV is associated with increased oxidative stress in the diaphragm. (25) This finding may suggest the growing role of pharmacologic agents such as antioxidants to lower oxidative stress and theophylline to reverse the reduction of transdiaphragmatic pressure resulting from resistive loaded breathing. (26) To this date, few studies have reported management of ventilator-induced DD. ...
Diaphragm Dysfunction and Weaning Failure in the Ventilated Critically Ill Patient: a Systematic Review and Meta-analysis
Article
Full-text available
  • Jun 2022
Introduction: Diaphragm dysfunction following mechanical ventilation is associated with weaning failure from ventilator in critically ill patients, resulting in bad prognosis and increased mortality. We conducted a systematic review and meta-analysis to measure the risk of diaphragm dysfunction on weaning failure. Methods: We searched PUBMED, Embase, Cochrane, and Scopus databases without restriction to publication date. Clinical question was “is diaphragm dysfunction associated with weaning failure and increased weaning time in patient with >24 hours positive pressure mechanical ventilation?” The primary outcome was weaning failure and the secondary outcome was weaning time. ROBINS-I was used to assess study quality and GRADE approach was used to assess the certainty of evidence. Results: The search string yielded 164 studies. Twenty-one studies were collected for full text and appraised thoroughly following PRISMA guideline. Four studies with similar clinical question were included in systematic reviewing. ROBINS-I showed the studies have low to medium risk of bias. GRADE showed moderate to high level of certainty evidence. Pooled odds ratio showed diaphragm dysfunction is closely associated with weaning failure (156 patients), OR 3.27 (CI95% 1.34-8.02) but loosely associated with weaning time (188 patients), mean weaning time difference of 3.12 (CI95% -0.09-6.33) hours. Conclusion: Diaphragm dysfunction as a complication of mechanical ventilation should be addressed carefully in critically ill patients since it is associated with weaning failure.
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Ventilator‐induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis
Article
Full-text available
Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life‐saving intervention for patients in respiratory failure, an unintended side‐effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV‐induced diaphragmatic weakness is labelled as ‘ventilator‐induced diaphragm dysfunction’ (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox‐regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV‐induced changes in the structure/function of diaphragm muscle and discusses the cell‐signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field. image
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Diaphragm Ultrasound in Critically Ill Patients on Mechanical Ventilation—Evolving Concepts
Article
Full-text available
  • Mar 2023
Mechanical ventilation (MV) is a life-saving respiratory support therapy, but MV can lead to diaphragm muscle injury (myotrauma) and induce diaphragmatic dysfunction (DD). DD is relevant because it is highly prevalent and associated with significant adverse outcomes, including prolonged ventilation, weaning failures, and mortality. The main mechanisms involved in the occurrence of myotrauma are associated with inadequate MV support in adapting to the patient’s respiratory effort (over- and under-assistance) and as a result of patient-ventilator asynchrony (PVA). The recognition of these mechanisms associated with myotrauma forced the development of myotrauma prevention strategies (MV with diaphragm protection), mainly based on titration of appropriate levels of inspiratory effort (to avoid over- and under-assistance) and to avoid PVA. Protecting the diaphragm during MV therefore requires the use of tools to monitor diaphragmatic effort and detect PVA. Diaphragm ultrasound is a non-invasive technique that can be used to monitor diaphragm function, to assess PVA, and potentially help to define diaphragmatic effort with protective ventilation. This review aims to provide clinicians with an overview of the relevance of DD and the main mechanisms underlying myotrauma, as well as the most current strategies aimed at minimizing the occurrence of myotrauma with special emphasis on the role of ultrasound in monitoring diaphragm function.
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Mechanisms of ubiquitination and proteasome-dependent proteolysis in skeletal muscle
Chapter
Full-text available
  • Aug 2003
This book contains 24 chapters covering a broad range of research in molecular nutrition. The first 2 chapters by J. Zhang and H. Daniel cover technical advances that have been made in genomics and post-genomics, and the promise that these technologies hold for future nutrition research. Next, H. Daniel, D.B. McCormick and J. Zempleni tell us how nutrients enter cells, how they are being targeted to their sites of action in cells and how physiological processes such as cell proliferation affect nutrient transport. This section is completed by a chapter by J.C. Mathers in which he reviews the roles for nutrients in apoptosis. A series of fine chapters by F. Foufelle and P. Ferracute˜e, M.S. Kilberg et al ., U. Beisiegel et al ., D.R. Soprano and K.J. Soprano, K. Dakshinamurti, A. Fischer et al ., E.M. Schmelz, T. Badger et al ., and D. Attaix et al . provides examples for roles of macro- and micronutrients in signal transduction, gene expression and proteolysis. J.K. Christman, J. Zempleni, and J. Kirkland and J.C. Spronck contributed reviews of nutrient-dependent modifications of nucleic acids and nucleic acid-binding proteins. Chapters on regulation of lipoprotein assembly (J.A. Higgins), cellular cholesterol metabolism (J.-Y. Lee et al .), oxidative stress (A. Taylor and M. Siegal) and immune function (P. Yaqoob and P.C. Calder) were selected to demonstrate how events at the molecular level can be integrated into multiorgan and whole-body metabolic pathways. Finally, J.S. Stanley and G. Bannon, and S.L. Taylor share their thoughts in the fields of genetically modified foods and molecular mechanisms of food allergy.
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Ventilator-induced diaphragm dysfunction: The clinical relevance of animal models
Article
  • Jan 2009
Experimental evidence suggests that controlled mechanical ventilation (CMV) can induce dysfunction of the diaphragm, resulting in an early-onset and progressive decrease in diaphragmatic forcegenerating capacity, called ventilatorinduced diaphragmatic dysfunction (VIDD). The mechanisms of VIDD are not fully elucidated, but include muscle atrophy (resulting from lysosomal, calpain, caspase and proteasome activation), oxidative stress, structural injury (disrupted myofibrils, increased numbers of lipid vacuoles, and abnormally small and disrupted mitochondria), myofiber remodeling and mitochondrial dysfunction. The major clinical implication of the VIDD is to limit the use of CMV to the extent possible. Partial (assisted) modes of ventilatory support should be used whenever feasible, since these modes attenuate the deleterious effects of mechanical ventilation on respiratory muscles.
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Measurements of protein using Bicinchoninic acid
Article
  • Oct 1985
Bicinchoninic acid, sodium salt, is a stable, water-soluble compound capable of forming an intense purple complex with cuprous ion (Cu1+) in an alkaline environment. This reagent forms the basis of an analytical method capable of monitoring cuprous ion produced in the reaction of protein with alkaline Cu2+ (biuret reaction). The color produced from this reaction is stable and increases in a proportional fashion over a broad range of increasing protein concentrations. When compared to the method of Lowry et al., the results reported here demonstrate a greater tolerance of the bicinchoninate reagent toward such commonly encountered interferences as nonionic detergents and simple buffer salts. The stability of the reagent and resulting chromophore also allows for a simplified, one-step analysis and an enhanced flexibility in protocol selection. This new method maintains the high sensitivity and low protein-to-protein variation associated with the Lowry technique.
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Ventilator-induced diaphragmatic dysfunction
Article
  • Nov 2009
  • CURR OPIN CRIT CARE
Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation. There is increasing recognition of a condition termed ventilator-induced diaphragmatic dysfunction. The purpose of the present review is to present evidence that mechanical ventilation can itself be a cause of diaphragmatic dysfunction, to outline our current understanding of the cellular mechanisms responsible for this phenomenon, and to discuss the implications of recent research for future therapeutic strategies. Many critically ill patients demonstrate diaphragmatic weakness. A large body of evidence from animal models, and more limited data from humans, indicates that mechanical ventilation can cause muscle fiber injury and atrophy within the diaphragm. Current data support a complex underlying pathophysiology involving oxidative stress and the activation of several intracellular proteolytic pathways involved in degradation of the contractile apparatus. This includes the calpain, caspase, and ubiquitin-proteasome systems. In addition, there is a simultaneous downregulation of protein synthesis pathways. Studies in animal models suggest that future therapies may be able to specifically target these processes, whereas for the time being current preventive measures in humans are primarily based upon allowing persistent diaphragmatic activation during mechanical ventilation. Diaphragmatic dysfunction is common in mechanically ventilated patients and is a likely cause of weaning failure. Recently, there has been a great expansion in our knowledge of how mechanical ventilation can adversely affect diaphragmatic structure and function. Future studies need to better define the evolution and mechanistic basis for ventilator-induced diaphragmatic dysfunction in humans, in order to allow the development of mechanical ventilation strategies and pharmacologic agents that will decrease the incidence of ventilator-induced diaphragmatic dysfunction.
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The effect of denervation and dystrophy on the adaptation of sarcomere number to the function length of the muscle in young and adult mice
Article
  • Dec 1976
In young animals the elongation of the limb bones increases the functional lengths of the muscles. In adult animals the functional length of a muscle can be increased by immobilizing it in the lengthened position. In both cases the muscle adapts by adding on more sarcomeres in series. The role of the nerve supply in this adaptation has been investigated using denervated muscles and muscles from dystrophic animals where there is thought to be an abnormality of the nerve supply. Postnatal sarcomere addition in denervated muscles falls short of that of controls. Although this might mean that the nerve supply is necessary for normal addition of sarcomeres, it is just as likely that there is a change in gait resulting from denervation, which affects the sarcomere number. Sarcomere number in fully grown mice is not affected by denervation, nor is the ability of the muscle to adapt to immobilization in the lengthened position. This is true for fast-twitch as well as slow-twitch muscles. In dystrophic muscles postnatal sarcomere addition is normal, although the presence of a few short fibres in the muscle may mean that some muscle fibres cannot adapt to an increase in the functional length of the muscle accompanying bone growth. Adult dystrophic muscle is capable of adapting to immobilization in the lengthened position. However, although the total number of additional sarcomeres is the same as in normal immobilized muscle, they are added on at a slower rate. The experiments show that although denervated and dystrophic muscle fibres are in a state of atrophy they are still capable of adding on sarcomeres in series when the functional length of the muscle is increased. It would appear that the mechanism which enables the muscle to respond in this way to an increased functional length does not involve the nerve supply. This work was supported by a grant from the National Fund for Research into Crippling Diseases.
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Uncomplicated Surgery, but not General Anesthesia, Decreases Muscle Protein Synthesis
Article
  • Apr 1992
  • Am J Physiol
The impact of anesthesia and surgery on protein metabolism is not well characterized. The single effect of general anesthesia and the combined effects of surgery and general anesthesia on protein synthesis in skeletal muscle were studied in metabolically healthy patients (n = 14) undergoing elective abdominal surgery. The rate of muscle protein synthesis was calculated from the increase in enrichment of [1-13C]leucine in protein during 90 min after an intravenous infusion of [1-13C]leucine (0.05 g/kg, 20 atom percent excess). The 1-13C enrichments of plasma leucine and plasma alpha-ketoisocaproate were used to indicate the enrichment of muscle free leucine. The protein synthesis rate was unaffected by general anesthesia; however, at the end of surgery, a 31.5% decline was seen from 2.19(2.13,2.33)%/24 h before anesthesia to 1.50(1.21,1.77)%/24 h (P less than 0.05) immediately after cholecystectomy while the patients were still under general anesthesia.
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Trace element movement and oxidative stress in skeletal muscle atrophied by immobilization
Article
  • Jun 1992
  • Am J Physiol
The movements of trace elements and the level of oxidative stress in the soleus, a typical slow red muscle which, atrophied by immobilization, were investigated in designated intervals. Male Wistar rats (14 wk old) whose one ankle joints were immobilized in the extended position were killed after 4, 8, and 12 days. Fe, Zn, Mn, and Cu concentrations and the levels of thiobarbituric acid-reactive substance (TBARS) and glutathione were measured. The rate of atrophy increased rapidly until the 8th day and slowly after that. In whole muscle, Fe concentration kept increasing, and Zn and Mn increased temporarily. Their subcellular distributions also changed; especially, the Fe level of the microsomal fraction kept increasing and reached threefold at 12 days. Increased TBARS and glutathione disulfide and decreased total glutathione indicated the increased oxidative stress in atrophy, which might result from an increased Fe level, especially that of the microsomal fraction. Vitamin E injection lessened the rate of atrophy, which showed that oxidative stress accelerated muscle atrophy. This might be mediated by increased intracellular Ca. Also metallothionein was induced in muscle atrophy.
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