Effects of Acute Administration of Corticosteroids during Mechanical Ventilation on Rat Diaphragm

Maes, Karen; Testelmans, Dries; Cadot, Pascal; DeRuisseau, Keith C.; Powers, Scott K.; Decramer, Marc; Gayan‐Ramirez, Ghislaine

doi:10.1164/rccm.200702-296oc

Cited by 61 publications

(63 citation statements)

References 52 publications

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“…Interestingly, in this study the calpain-inhibiting effect of corticosteroids was shown to depend on the dose administered, being minimal at low concentrations. Recently our group showed that administration of a single high dose of methylprednisolone (80 mg/kg, corresponding ~13 mg/kg in humans) during controlled mechanical ventilation protected the diaphragm from the deleterious effects of prolonged mechanical ventilation through inhibition of the calpain system [9]. This study and a previous CMV study, in which we used a calpain inhibitor [9], confirm the important role of the calpain system in the development of VIDD.…”

Section: Introductionsupporting

confidence: 71%

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

et al. 2010

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BackgroundHigh dose of corticosteroids has been previously shown to protect against controlled mechanical ventilation (CMV)-induced diaphragmatic dysfunction while inhibiting calpain activation. Because literature suggests that the calpain inhibiting effect of corticosteroid depends on the dose administered, we determined whether lower doses of corticosteroids would also provide protection of the diaphragm during CMV. This may be important for patients undergoing mechanical ventilation and receiving corticosteroids.MethodsRats were assigned to controls or to 24 hours of CMV while being treated at the start of mechanical ventilation with a single intramuscular administration of either saline, or 5 mg/kg (low MP) or 30 mg/kg (high MP) of methylprednisolone.ResultsDiaphragmatic force was decreased after CMV and this was exacerbated in the low MP group while high MP rescued this diaphragmatic dysfunction. Atrophy was more severe in the low MP group than after CMV while no atrophy was observed in the high MP group. A significant and similar increase in calpain activity was observed in both the low MP and CMV groups whereas the high dose prevented calpain activation. Expression of calpastatin, the endogenous inhibitor of calpain, was decreased in the CMV and low MP groups but its level was preserved to controls in the high MP group. Caspase-3 activity increased in all CMV groups but to a lesser extent in the low and high MP groups. The 20S proteasome activity was increased in CMV only.ConclusionsAdministration of 30 mg/kg methylprednisolone during CMV protected against CMV-induced diaphragm dysfunction while 5 mg/kg was more deleterious. The protective effect is due mainly to an inhibition of the calpain system through preservation of calpastatin levels and to a lesser extent to a caspase-3 inhibition.

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Section: Introductionsupporting

confidence: 71%

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

et al. 2010

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“…Patients suffering from acute respiratory failure are often treated with corticosteroids for the underlying lung disease or other inflammatory conditions (62). This is significant because glucocorticoid treatment can promote steroid-induced myopathy of both respiratory and limb muscles (60,96).…”

Section: Impact Of Age and Drugs On Mv-induced Diaphragmatic Contractmentioning

confidence: 99%

“…This is significant because glucocorticoid treatment can promote steroid-induced myopathy of both respiratory and limb muscles (60,96). Recent reports have investigated the combined effects of high-dose corticosteroid treatment on diaphragm function in animals using both partial and full support MV (61,62). Unfortunately, these studies have yielded divergent results.…”

Section: Impact Of Age and Drugs On Mv-induced Diaphragmatic Contractmentioning

confidence: 99%

Ventilator-induced diaphragm dysfunction: cause and effect

Powers

Wiggs

Sollanek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Powers SK, Wiggs MP, Sollanek KJ, Smuder AJ. Ventilator-induced diaphragm dysfunction: cause and effect. Am J Physiol Regul Integr Comp Physiol 305: R464 -R477, 2013. First published July 10, 2013 doi:10.1152/ajpregu.00231.2013 is used clinically to maintain gas exchange in patients that require assistance in maintaining adequate alveolar ventilation. Common indications for MV include respiratory failure, heart failure, drug overdose, and surgery. Although MV can be a life-saving intervention for patients suffering from respiratory failure, prolonged MV can promote diaphragmatic atrophy and contractile dysfunction, which is referred to as ventilator-induced diaphragm dysfunction (VIDD). This is significant because VIDD is thought to contribute to problems in weaning patients from the ventilator. Extended time on the ventilator increases health care costs and greatly increases patient morbidity and mortality. Research reveals that only 18 -24 h of MV is sufficient to develop VIDD in both laboratory animals and humans. Studies using animal models reveal that MV-induced diaphragmatic atrophy occurs due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, autophagy, and the ubiquitin-proteasome system as key proteases that participate in MV-induced diaphragmatic proteolysis. The challenge for the future is to define the MV-induced signaling pathways that promote the loss of diaphragm protein and depress diaphragm contractility. Indeed, forthcoming studies that delineate the signaling mechanisms responsible for VIDD will provide the knowledge necessary for the development of a pharmacological approach that can prevent VIDD and reduce the incidence of weaning problems. respiratory muscle; atrophy; mechanical ventilation; weaning; muscle wasting MECHANICAL VENTILATION (MV) is used clinically to achieve sufficient pulmonary gas exchange in patients unable to sustain adequate alveolar ventilation on their own. Common indications for MV include respiratory failure due to chronic obstructive pulmonary disease, status asthmaticus, and/or heart failure. In addition, MV is often an essential intervention in patients suffering from acute drug overdose, neuromuscular diseases, sepsis, and during surgery along with postsurgical recovery.The number of patients receiving prolonged MV in the United States exceeds more than 300,000 each year in the intensive care unit (ICU) (20). Although MV can be a lifesaving measure, prolonged MV results in the rapid development of diaphragmatic weakness due to both atrophy and contractile dysfunction. This detrimental impact of prolonged MV on the diaphragm has been termed ventilator-induced diaphragmatic dysfunction (VIDD) and VIDD is predicted to be a major contributor to problems in weaning patients from the ventilator (26, 114). Although previous reports describing the impact of prolonged MV on the diaphragm have appeared in the literature, advances in our understanding of the mechanisms responsible for VIDD h...

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“…During prolonged MV, MV-induced diaphragmatic atrophy develops as a result of an increase in oxidative stress in the muscle fibers (1,31,47), which leads to a decrease in protein synthesis (36) and an increase in protein degradation during which all proteolytic pathways are activated (26,37,47). This is also the case in locomotor skeletal muscles after unloading (3,9), and, furthermore, it is well known that early recovery of these muscles is associated with enhanced oxidative stress (35), proteolysis, and protein synthesis (37) compared with the unloaded muscle.…”

Section: Reloading the Diaphragm Has No Effect On Proteolysismentioning

confidence: 99%

“…The latter because, in ventilator-induced diaphragm dysfunction, the Ca 2ϩ -dependent calpain system and the caspase-3 system have been shown to be one of the most important proteolytic systems, as they are necessary for the initial degradation of actomyosin complexes. In addition, their inhibition has been shown to result in a prevention of the deleterious effects of CMV on the diaphragm (1,26,27). However, no changes could be detected in these markers of protein degradation.…”

Section: Reloading the Diaphragm Has No Effect On Proteolysismentioning

confidence: 99%

Time course of diaphragm function recovery after controlled mechanical ventilation in rats

Thomas

Maes

Agten

et al. 2013

Journal of Applied Physiology

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Controlled mechanical ventilation (CMV) is known to result in rapid and severe diaphragmatic dysfunction, but the recovery response of the diaphragm to normal function after CMV is unknown. Therefore, we examined the time course of diaphragm function recovery in an animal model of CMV. Healthy rats were submitted to CMV for 24–27 h ( n = 16), or to 24-h CMV followed by either 1 h (CMV + 1 h SB, n = 9), 2 h (CMV + 2 h SB, n = 9), 3 h (CMV + 3 h SB, n = 9), or 4–7 h (CMV + 4–7 h SB, n = 9) of spontaneous breathing (SB). At the end of the experiment, the diaphragm muscle was excised for functional and biochemical analysis. The in vitro diaphragm force was significantly improved in the CMV + 3 h SB and CMV + 4–7 h SB groups compared with CMV (maximal tetanic force: +27%, P < 0.05, and +59%, P < 0.001, respectively). This was associated with an increase in the type IIx/b fiber dimensions ( P < 0.05). Neutrophil influx was increased in the CMV + 4–7 h SB group ( P < 0.05), while macrophage numbers remained unchanged. Markers of protein synthesis (phosphorylated Akt and eukaryotic initiation factor 4E binding protein 1) were significantly increased (±40%, P < 0.001, and ±52%, P < 0.01, respectively) in the CMV + 3 h SB and CMV + 4–7 h SB groups and were positively correlated with diaphragm force ( P < 0.05). Finally, also the maximal specific force generation of skinned single diaphragm fibers was increased in the CMV + 4–7 h SB group compared with CMV (+45%, P < 0.05). In rats, reloading the diaphragm for 3 h after CMV is sufficient to improve diaphragm function, while complete recovery occurs after longer periods of reloading. Enhanced muscle fiber dimensions, increased protein synthesis, and improved intrinsic contractile properties of diaphragm muscle fibers may have contributed to diaphragm function recovery.

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Effects of Acute Administration of Corticosteroids during Mechanical Ventilation on Rat Diaphragm

Cited by 61 publications

References 52 publications

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

Ventilator-induced diaphragm dysfunction: cause and effect

Time course of diaphragm function recovery after controlled mechanical ventilation in rats

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