Investigating the Anabolic Response to Resistance Exercise After Critical Illness (ARTIST-2)

Study Overview
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Brief Summary
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ICU survivors often suffer from long-term functional disability. An attenuated response to physical exercise in skeletal muscle after critical illness may contribute to persisting weakness. The aim of this study is to investigate the effects of resistance exercise on muscle protein synthesis in former ICU patients. The investigators hypothesize that study subjects recovering from critical illness have an impaired anabolic response to resistance exercise after ICU stay as compared to non-critically ill controls.

Detailed Description
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Background The debilitating impact of critical illness has been recognized for several decades. Disability related to intensive care is now described as a syndrome called ICU-acquired weakness (ICUAW). ICUAW affects up to 70% of ICU patients and is most common with higher illness severity. Patients that develop ICUAW require longer hospitalization and have a higher risk of death. Weakness may persists for several years in ICU survivors. It has significant long-term consequences, and is associated with increased health care costs, delayed return to work, and overall poor quality of life. Muscle atrophy is a major contributor to ICUAW. Critical illness is associated with a rapid loss of skeletal muscle, induced by catabolic signals from proinflammatory cytokines and hormones. The ability to regain lost muscle mass during convalescence may also be impaired. In a small observational study, muscle atrophy resolved only in a minority of ICU survivors at six months after ICU discharge. Studies in exercise physiology have demonstrated that resistance training and amino acid ingestion have synergistic effects on muscle protein synthesis in healthy subjects. It is therefore an appealing therapy to reconstitute muscle mass after critical illness. Despite several clinical trials, there is equipoise regarding the efficacy of exercise in improving physical function in-ICU after ICU discharge. These mixed signals are unsurprising given the heterogeneous causes of ICUAW. Only a few studies in this field have examined muscle architecture or cellular signaling in response to training. However, the gold standard in determining the anabolic response to exercise is to directly measure the effects on protein synthesis and breakdown. There is still no published research using this methodology to assess the effects of exercise interventions in former ICU patients. To understand the role of physical exercise in regaining lost muscle mass, the investigators plan to investigate the anabolic effects to resistance training after critical illness. Aim and hypothesis The aim of this study is to determine the anabolic response to resistance exercise after critical illness. The investigators hypothesize that study subjects recovering from critical illness have an impaired anabolic response to resistance exercise after ICU stay as compared to non-critically ill controls.

Official Title
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Investigating the Anabolic Response to Resistance Exercise After Critical Illness: The ARTIST-2 Non-Randomized Controlled Trial

Conditions
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Critical Illness, Muscle Loss

Intervention / Treatment
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* Procedure: Resistance exercise
* Dietary Supplement: Oral protein supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years) previously admitted to an ICU at Karolinska University Hospital for ≥3 days and discharged alive from hospital OR Adult (≥18 years) without a history of ICU admission (control group) Exclusion Criteria: Not able to provide informed consent >6 months since ICU discharge* Warfarin or dual antiplatelet therapy Clinically significant inherited or acquired disorder of hemostasis Lower-limb amputee Lower-limb atherosclerotic disease with critical ischemia. Recent fracture in lower limbs or significant osteoarthritis limiting movement in knee or hip joint Metastatic cancer or active hematological malignancy Inherited disorder of amino acid metabolism. Chronic muscle, neuromuscular or neurologic disease with prior documentation of clinically significant lower-limb involvement Pregnancy Single organ failure not requiring invasive mechanical ventilation during ICU stay* Intubated only for airway protection with no other organ failure(s) during ICU stay* Planned postoperative care in ICU after elective cardiothoracic surgery* Exclusion criteria marked with asterisk only apply to former ICU patients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Former ICU patients<br>Research subjects with a prior history of ICU treatment within six months. | Procedure: Resistance exercise<br>* Knee extensions in flywheel inertia machine in four sets of 10 repetitions.<br>Dietary Supplement: Oral protein supplementation<br>* 24 grams of hydrolyzed whey protein.<br>|
| Active Comparator: Age- and sex-matched control group<br>Research subjects without a prior history of ICU treatment within the last 30 years, age- and sex-matched in a 1:2 ratio to the experimental arm. | Procedure: Resistance exercise<br>* Knee extensions in flywheel inertia machine in four sets of 10 repetitions.<br>Dietary Supplement: Oral protein supplementation<br>* 24 grams of hydrolyzed whey protein.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle protein fractional synthetic rate | The difference between the experimental and active comparator group in muscle protein fractional synthetic rate. | 150 minutes post-exercise. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gene expression | The difference between the experimental and active comparator group in gene expression (mRNA) in skeletal muscle, assessed by RNA sequencing. | 150 minutes post-exercise. | 
| Signaling pathways | The difference between the experimental and active comparator group in the activity of major anabolic/catabolic signalining pathways in skeletal muscle, assessed by western blot. | 150 minutes post-exercise. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resistance exercise, Muscle protein, Anabolic resistance