Muscle Recovery After Critical Illness

Study Overview
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Brief Summary
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The overarching goal of the proposed study is to determine the trajectories of physical recovery and cellular markers involved with the underlying failure to recover muscle after critical illness, while exploring which characteristics are associated with sustained physical disability. This proposal will examine muscle pathophysiology carefully aligned with physical function outcomes in order to longitudinally assess the recovery, or failed recovery, of muscle function in participants after critical illness: to examine the recovery of muscle and physical function in ICU survivors through longitudinal assessments to investigate the underlying cellular markers and mechanisms of muscle recovery in ICU survivors to determine which cellular markers contribute to physical disability in ICU survivors up to 1 year after hospital admission

Detailed Description
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Patients surviving critical illness develop significant impairments in skeletal muscle, commonly referred to as ICU-acquired weakness (ICUAW)[8-10]. It is estimated that up to 70-80% of patients admitted to ICU will develop some degree of neuromuscular dysfunction, weakness, myopathy or atrophy [11,12]. ICUAW encompasses muscle impairments that develop as a direct result of admission for critical illness[13] and is an independent predictor of mortality and long-term functional impairments[14-19]. Interventions to mitigate muscle deficits and improve physical function are a critical area of rehabilitation because of the high prevalence of short- and long-term impairments. ICU survivorship is particularly important as roughly 6 million Americans will survive an acute admission to the ICU this year alone.[24-26] Survivors of critical illnesses such as sepsis, viral-illnesses including coronaviruses, and acute respiratory failure (ARF) have reduced quality of life, lost wages from inability to return to work and increased caregiver and healthcare burden for years after hospital discharge.[27-31] Impairments in skeletal muscle are known contributors to physical disability and specifically prevent the performance of simple daily life activities like standing up from a chair. However, very little is known about cellular mechanisms leading to muscle and physical dysfunction in patients surviving critical illness during recovery. These gaps in knowledge are significant because identifying the phenotypes and underlying cellular mechanisms that lead to impaired muscle and physical function will facilitate the development of pharmacologic and non-pharmacologic interventions to mitigate or reverse disability. From a scientific perspective, this proposal is noteworthy because it will be the first to assess muscle protein synthesis rates in combination with cellular phenotypes, muscle strength, and physical function in patients recovering from an ICU admission. Studying muscle at the cellular level and integrating that knowledge with physical function will help improve our understanding of why certain patients fail to recover. Elucidating cellular mechanisms during recovery phase will provide the framework to develop interventions in subsequent studies. We will assess measures of muscle and physical function in the first year of recovery to establish why some patients have restored function, yet others have sustained disability. Improved classification of muscle dysfunction and physical function enables future studies to employ a targeted approach instead of the historical rehabilitation approach of one-size-fits-all. Specifically, the cellular findings will lead to development of novel interventions specifically designed for the underlying mechanisms, while identification of the recovery trajectories will enhance clinicians' ability to implement interventions to patients with the greatest need.

Official Title
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Cellular and Physical Function Outcomes Leading to Failed Muscle Recovery After Critical Illness

Conditions
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ICU Acquired Weakness, Post Intensive Care Unit Syndrome, Muscle Weakness, Critical Illness

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult (>18 y/o) admission for sepsis or acute respiratory failure with at least 72 hour stay in ICU Exclusion Criteria: acute or chronic neurologic condition acute or chronic orthopedic condition preventing strength/functional testing patients who were not ambulatory prior to ICU admission patients not expected to survive  6months after admission

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Survivor<br>Patients (n = 206) surviving critical illness will be enrolled to longitudinal, observational study examining muscle strength, power, and fatigue as well as physical function at hospital discharge and repeated at 3-, 6-, and 12-month following. A subset of individuals (n =40) will undergo muscle biopsies and blood will be collected. | |
| Control<br>A group of healthy controls will be recruited to serve as comparator to measures of strength, power, physical function, and muscle tissue analyses. Controls will participate in a one-time assessment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical function | Short Physical Performance Battery | the change from baseline to 12-months | 
| Mitochondrial function | muscle mitochondrial respirometry | the change from baseline to 12-months | 
| Muscle strength | lower-extremity muscle strength | the change from baseline to 12-months | 
| Muscle power | lower-extremity muscle power (unilateral leg-press) | the change from baseline to 12-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical activity | actigraphy | the change from baseline to 12-months | 
| functional mobility | timed-up and go test | the change from baseline to 12-months | 
| Cardiopulmonary endurance / exercise capacity | 6-minute walk test | the change from baseline to 12-months | 
| self-reported health-related quality of life | EuroQol-5Domains (EQ-5D) visual analog scale is a self-report of quality of life (0-100) with higher scores indicating a better perception of quality of life | the change from baseline to 12-months | 
| Muscle morphology #1 | myofiber size | the change from baseline to 12-months | 
| Muscle morphology #2 | myofiber type | the change from baseline to 12-months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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skeletal muscle, physical function