Investigating the Anabolic Response to Resistance Exercise During Critical Illness

Study Overview
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Brief Summary
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ICU patients often suffer from rapid and severe muscle loss. It is not known if physical therapy can mitigate the muscle wasting associated with critical illness. The aim of this study is to investigate the effects of resistance exercise on muscle protein turnover in ICU patients. The investigators hypothesize that resistance exercise, in addition to amino acid supplementation and routine physiotherapy, results in an improved lower limb muscle protein balance compared to amino acid supplementation and routine physiotherapy alone.

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 also has significant long-term consequences, and is associated with significant health care costs, delayed return to work, and overall poor quality of life. Preventing or reducing muscle atrophy is a potential way to counteract weakness. Critical illness is associated with a rapid loss of skeletal muscle. 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 counteract muscle wasting in the ICU. Despite several clinical trials, there is equipoise regarding the efficacy of exercise in improving physical function in-ICU or after discharge. These mixed signals are unsurprising given the heterogeneous causes of ICUAW. Only a few studies in this field assess 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 effect on protein synthesis and breakdown. To our knowledge there is still no published research using this methodology to assess the effects of exercise interventions in critically ill patients. Aim and hypothesis The overall aim of this project is to determine the anabolic response to resistance exercise during critical illness. The investigators hypothesize that resistance exercise, in addition to amino acid supplementation and routine physiotherapy, results in an improved muscle protein balance in ICU patients compared to amino acid supplementation and routine physiotherapy alone (primary outcome). The effect of the intervention on other parameters of muscle protein kinetics and within-group differences in protein kinetics before and after physiotherapy will be assessed as secondary outcome measures.

Official Title
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Investigating the Anabolic Response to Resistance Exercise During Critical Illness: The ARTIST-1 Randomized Controlled Trial

Conditions
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Critical Illness, Muscle Loss

Intervention / Treatment
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* Procedure: Resisted knee extension exercise
* Drug: IV amino acids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years) patient admitted to the ICU of the study site. Patient deemed suitable for active mobilization by the attending physician and physiotherapist. Not expected to be discharged or transferred from the unit within 24 h of enrollment. Functioning arterial catheter in situ. Exclusion Criteria: Not able to provide informed consent. Systemic anticoagulation with LMWH/UFH/DOAC in therapeutic dose range for deep vein thrombosis or pulmonary embolism, or dual antiplatelet therapy. If LMWH is administered twice daily, the patient is eligible for participation provided that vascular access is performed at nadir prior to the first daily dose. Clinically significant inherited or acquired disorder of hemostasis. Morbid obesity that interferes with femoral cannulation or doppler measurements. Hemodynamic instability requiring ongoing volume resuscitation with crystalloid solutions or blood products. Lower-limb amputee. Lower-limb artherosclerotic disease with critical ischemia. Metastatic cancer or active hematological malignancy. Inherited disorder of amino acid metabolism. Chronic muscle, neuromuscular and neurologic disease with prior documentation of clinically significant lower-limb involvement. Pregnancy. CAM-ICU screening positive for delirium. Single organ failure not requiring invasive mechanical ventilation prior to enrollment.

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV amino acids + standardized physiotherapy with lower limb resistance exercise.<br>Research subjects randomized to the intervention group will receive an infusion of IV amino acids during a session of protocolized physiotherapy that includes a knee extension resistance exercise targeting the thigh muscles. The supplemental amino acid infusion will continue up until 90 minutes after the subject has returned to bed rest. | Procedure: Resisted knee extension exercise<br>* Patients in the intervention group will perform a seated knee extension exercise in three sets. Resistance will be adjusted using ankle weights, targeting 8-12 repetitions per set.<br>Drug: IV amino acids<br>* IV amino acids (Glavamin, Fresenius Kabi) delivered by continuous infusion at a rate of 0.1 g/kg/h. The infusion is started immediately prior to physiotherapy and continued until all blood samples required for outcome assessment are collected during a 90-minute resting period after the exercise session.<br>* Other names: Glavamin (Fresenius Kabi);|
| Active Comparator: IV amino acids + standardized physiotherapy.<br>Research subjects randomized to the control group will receive an infusion of IV amino acids during a session of protocolized physiotherapy NOT including lower limb resistance exercise. The supplemental amino acid infusion will continue up until 90 minutes after the subject has returned to bed rest. | Drug: IV amino acids<br>* IV amino acids (Glavamin, Fresenius Kabi) delivered by continuous infusion at a rate of 0.1 g/kg/h. The infusion is started immediately prior to physiotherapy and continued until all blood samples required for outcome assessment are collected during a 90-minute resting period after the exercise session.<br>* Other names: Glavamin (Fresenius Kabi);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between-group difference in change in lower limb protein balance | The difference between the experimental and active comparator group in change in lower limb protein balance (nmol Phenylalanine/min) from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between-group difference in change in lower limb protein synthesis | The difference between the experimental and active comparator group in change in lower limb protein synthesis (nmol Phenylalanine/min) from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Between-group difference in change in lower limb protein breakdown | The difference between the experimental and active comparator group in change in lower limb protein breakdown (nmol Phenylalanine/min) from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Between-group difference in change in lower limb 3-methylhistidine rate of appearance | The difference between the experimental and active comparator group in change in lower limb 3-methylhistidine rate of appearance (nmol 3-methylhistidine/min) from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb protein balance (experimental group) | The change in lower limb protein balance (nmol Phenylalanine/min) in the experimental group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb protein balance (active comparator group) | The change in lower limb protein balance (nmol Phenylalanine/min) in the active comparator group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb protein synthesis (experimental group) | The change in lower limb protein synthesis (nmol Phenylalanine/min) in the experimental group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb protein synthesis (active comparator group) | The change in lower limb protein synthesis (nmol Phenylalanine/min) in the active comparator group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb protein breakdown (experimental group) | The change in lower limb protein breakdown (nmol Phenylalanine/min) in the experimental group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb protein breakdown (active comparator group) | The change in lower limb protein breakdown (nmol Phenylalanine/min) in the active comparator group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb 3-methylhistidine rate of appearance (experimental group) | The change in lower limb 3-methylhistidine rate of appearance (nmol 3-methylhistidine/min) in the experimental group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 
| Within-group change in lower limb 3-methylhistidine rate of appearance (active comparator group) | The change in lower limb 3-methylhistidine rate of appearance (nmol 3-methylhistidine/min) in the active comparator group, from baseline to post-physiotherapy. Blood samples and lower limb blood flow measurements to determine protein kinetics are performed at baseline (before IV amino acids and physiotherapy) and at 30, 60, and 90 minutes during bed rest after the physiotherapy session. | Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Physiotherapy, Resistance exercise, Amino acids, Muscle protein balance