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Investigating the Anabolic Response to Resistance Exercise During Critical Illness (ARTIST-1)

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ClinicalTrials.gov Identifier: NCT05197231
Recruitment Status : Recruiting
First Posted : January 19, 2022
Last Update Posted : June 6, 2022
Sponsor:
Information provided by (Responsible Party):
Martin Sundstrom Rehal, Karolinska University Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Critical Illness Muscle Loss Procedure: Resisted knee extension exercise Drug: IV amino acids Not Applicable

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Investigating the Anabolic Response to Resistance Exercise During Critical Illness: The ARTIST-1 Randomized Controlled Trial
Actual Study Start Date : April 25, 2022
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: IV amino acids + standardized physiotherapy with lower limb resistance exercise.
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
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.

Drug: IV amino acids
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.
Other Name: Glavamin (Fresenius Kabi)

Active Comparator: IV amino acids + standardized physiotherapy.
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
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.
Other Name: Glavamin (Fresenius Kabi)




Primary Outcome Measures :
  1. Between-group difference in change in lower limb protein balance [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.


Secondary Outcome Measures :
  1. Between-group difference in change in lower limb protein synthesis [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  2. Between-group difference in change in lower limb protein breakdown [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  3. Between-group difference in change in lower limb 3-methylhistidine rate of appearance [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  4. Within-group change in lower limb protein balance (experimental group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  5. Within-group change in lower limb protein balance (active comparator group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  6. Within-group change in lower limb protein synthesis (experimental group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  7. Within-group change in lower limb protein synthesis (active comparator group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  8. Within-group change in lower limb protein breakdown (experimental group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  9. Within-group change in lower limb protein breakdown (active comparator group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  10. Within-group change in lower limb 3-methylhistidine rate of appearance (experimental group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.

  11. Within-group change in lower limb 3-methylhistidine rate of appearance (active comparator group) [ Time Frame: Time = 165-180 minutes from start of study protocol to approximate Time = 315 minutes from start of study protocol. ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult (≥18 years) patient admitted to the ICU of the study site.
  2. Patient deemed suitable for active mobilization by the attending physician and physiotherapist.
  3. Not expected to be discharged or transferred from the unit within 24 h of enrollment.
  4. Functioning arterial catheter in situ.

Exclusion Criteria:

  1. Not able to provide informed consent.
  2. 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.
  3. Clinically significant inherited or acquired disorder of hemostasis.
  4. Morbid obesity that interferes with femoral cannulation or doppler measurements.
  5. Hemodynamic instability requiring ongoing volume resuscitation with crystalloid solutions or blood products.
  6. Lower-limb amputee.
  7. Lower-limb artherosclerotic disease with critical ischemia.
  8. Metastatic cancer or active hematological malignancy.
  9. Inherited disorder of amino acid metabolism.
  10. Chronic muscle, neuromuscular and neurologic disease with prior documentation of clinically significant lower-limb involvement.
  11. Pregnancy.
  12. CAM-ICU screening positive for delirium.
  13. Single organ failure not requiring invasive mechanical ventilation prior to enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05197231


Contacts
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Contact: Martin Sundström Rehal, MD PhD +46-8-58580000 martin.sundstrom@gmail.com
Contact: Arabella Fischer, MD PhD arabella.fischer@meduniwien.ac.at

Locations
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Sweden
Karolinska University Hospital Recruiting
Huddinge, Stockholm, Sweden, 14186
Contact: Martin Sundström Rehal, MD PhD    +46-8-58580000    martin.sundstrom@gmail.com   
Sponsors and Collaborators
Karolinska University Hospital
Investigators
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Principal Investigator: Martin Sundström Rehal, MD PhD Karolinska University Hospital
Study Chair: Olav Rooyackers, PhD Karolinska Institutet
  Study Documents (Full-Text)

Documents provided by Martin Sundstrom Rehal, Karolinska University Hospital:
Publications:

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Responsible Party: Martin Sundstrom Rehal, Principal Investigator, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT05197231    
Other Study ID Numbers: K 2021-10530
First Posted: January 19, 2022    Key Record Dates
Last Update Posted: June 6, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Martin Sundstrom Rehal, Karolinska University Hospital:
Physiotherapy
Resistance exercise
Amino acids
Muscle protein balance
Additional relevant MeSH terms:
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Critical Illness
Disease Attributes
Pathologic Processes