Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness

Wollersheim, Tobias; Woehlecke, Janine; Krebs, Michaël; Hamati, Jida; Lodka, Doerte; Luther-Schroeder, Anja; Langhans, Claudia; Haas, Kurt; Radtke, Theresa; Kleber, Christian; Spies, Claudia; Labeit, Siegfried; Schuelke, Markus; Spuler, Simone; Spranger, Joachim; Weber‐Carstens, Steffen; Fielitz, Jens

doi:10.1007/s00134-014-3224-9

Cited by 118 publications

(210 citation statements)

References 41 publications

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“…First, as an observational study, we cannot assess causality of the associations of ICU length of stay and corticosteroids with post-ALI physical impairments. However, our results are consistent with detailed ultrasound, histologic, and biochemical muscle evaluations in mechanically ventilated ICU patients, which demonstrate early and rapid muscle wasting that is progressive with increasing ICU length of stay (13,14), and with preclinical data on the effect of corticosteroids on muscles (74,75). Patient characteristics and the medical indications for administering corticosteroids may confound the association with physical complications.…”

Section: Discussionsupporting

confidence: 86%

“…Moreover, as further evidence of physical impairments being ICUacquired, a prior report on this cohort indicated that over 1-year follow-up, 56% of EDEN survivors required new institutionalization post-ALI and/or physical rehabilitation, with only 48% of previously employed survivors returning to work (20). In addition, in mechanically ventilated patients, there is clear evidence of early and rapid muscle wasting (13,14), especially in patients with more severe oxygenation impairment (e.g., ALI) and multiorgan failure (13). Existing cohort studies with prospective measurement of pre-ICU status also have clearly demonstrated the occurrence of important new post-ICU physical impairments (4-6).…”

Section: Discussionmentioning

confidence: 84%

“…However, there is uncertainty regarding this relationship because no association was observed between muscle weakness and duration or cumulative dose of corticosteroids in this study (11) or in subsequent research (1). Moreover, a systematic review demonstrated no consistent relationship between corticosteroids and neuromuscular abnormalities in critical illness (12), and recent detailed analyses of muscle wasting in mechanically ventilated patients also demonstrated no association (13,14). The nature of any association between corticosteroids and physical impairments may be complex and may vary with corticosteroid dose, the physical outcome evaluated, and the trajectory of patient recovery.…”

mentioning

confidence: 68%

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Risk Factors for Physical Impairment after Acute Lung Injury in a National, Multicenter Study

Needham

Wozniak

Hough

et al. 2014

Am J Respir Crit Care Med

168

133

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Rationale: Existing studies of risk factors for physical impairments in acute lung injury (ALI) survivors were potentially limited by single-center design or relatively small sample size.Objectives: To evaluate risk factors for three measures of physical impairments commonly experienced by survivors of ALI in the first year after hospitalization.Methods: A prospective, longitudinal study of 6-and 12-month physical outcomes (muscle strength, 6-minute-walk distance, and Short Form [SF]-36 Physical Function score) for 203 survivors of ALI enrolled from 12 hospitals participating in the ARDS Network randomized trials. Multivariable regression analyses evaluated the independent association of critical illness-related variables and intensive care interventions with impairments in each physical outcome measure, after adjusting for patient demographics, comorbidities, and baseline functional status.Measurements and Main Results: At 6 and 12 months, respectively, mean (6 SD) values for strength (presented as proportion of maximum strength score evaluated using manual muscle testing) was 92% (6 8%) and 93% (6 9%), 6-minute-walk distance (as percent-predicted) was 64% (6 22%) and 67% (6 26%), and SF-36 Physical Function score (as percent-predicted) was 61% (6 36%) and 67% (6 37%). After accounting for patient baseline status, there was significant association and statistical interaction of mean daily dose of corticosteroids and intensive care unit length of stay with impairments in physical outcomes.Conclusions: Patients had substantial impairments, from predicted values, for 6-minute-walk distance and SF-36 Physical Function outcome measures. Minimizing corticosteroid dose and implementing existing evidence-based methods to reduce duration of intensive care unit stay and associated patient immobilization may be important interventions for improving ALI survivors' physical outcomes.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 68%

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Risk Factors for Physical Impairment after Acute Lung Injury in a National, Multicenter Study

Needham

Wozniak

Hough

et al. 2014

Am J Respir Crit Care Med

168

133

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“…This weakness was caused by fiber atrophy, and by dysfunction of the sarcomeric proteins. Considering the magnitude of contractile weakness, we propose that these changes at the diaphragm muscle fiber level largely account for the 30-50% reduction in in vivo diaphragm strength in critically ill patients, as measured by bilateral phrenic nerve stimulation (11,13,14,(38)(39)(40).…”

Section: Contractile Weakness Of Individual Diaphragm Fibers In Critimentioning

confidence: 99%

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

Hooijman

Beishuizen²,

Witt³

et al. 2015

Am J Respir Crit Care Med

Self Cite

172

180

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Rationale: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.Objectives: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.Methods: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.Measurements and Main Results: Both slow-and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.Conclusions: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.

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“…The mechanisms of ICU-acquired weakness (ICUAW) are multiple but not fully elucidated, although an early decreased synthesis and increased degradation of myosin heavy chain has been implicated [11].…”

Section: Icu-acquired Weaknessmentioning

confidence: 99%

Focus on clinical neuroscience

Smith

Citerio

2016

Intensive Care Med

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Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness

Cited by 118 publications

References 41 publications

Risk Factors for Physical Impairment after Acute Lung Injury in a National, Multicenter Study

Risk Factors for Physical Impairment after Acute Lung Injury in a National, Multicenter Study

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

Focus on clinical neuroscience

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