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

Overview

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.

Full Title of Study: “Investigating the Anabolic Response to Resistance Exercise After Critical Illness: The ARTIST-2 Non-Randomized Controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2023

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 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.

Interventions

  • Procedure: Resistance exercise
    • Weighted knee extensions in four sets targeting 8-12 repetitions to failure.
  • Dietary Supplement: Oral protein supplementation
    • 24 grams of hydrolyzed whey protein.

Arms, Groups and Cohorts

  • Experimental: Former ICU patients
    • Research subjects with a prior history of ICU treatment within six months.
  • Active Comparator: Age- and sex-matched control group
    • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Gene expression
    • Time Frame: 150 minutes post-exercise.
    • The difference between the experimental and active comparator group in gene expression (mRNA) in skeletal muscle, assessed by RNA sequencing.
  • Signaling pathways
    • Time Frame: 150 minutes post-exercise.
    • 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.

Participating in This Clinical Trial

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 within the last 30 years Exclusion Criteria:

1. Not able to provide informed consent 2. >6 months since ICU discharge* 3. Warfarin or dual antiplatelet therapy 4. Clinically significant inherited or acquired disorder of hemostasis 5. Lower-limb amputee 6. Lower-limb atherosclerotic disease with critical ischemia. 7. Recent fracture in lower limbs or significant osteoarthritis limiting movement in knee or hip joint 8. Metastatic cancer or active hematological malignancy 9. Inherited disorder of amino acid metabolism. 10. Chronic muscle, neuromuscular or neurologic disease with prior documentation of clinically significant lower-limb involvement 11. Pregnancy 12. Single organ failure not requiring invasive mechanical ventilation during ICU stay* Exclusion criteria marked with asterisk only apply to former ICU patients.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Karolinska University Hospital
  • Provider of Information About this Clinical Study
    • Principal Investigator: Martin Sundstrom Rehal, Principal Investigator – Karolinska University Hospital
  • Overall Official(s)
    • Martin Sundström Rehal, MD PhD, Principal Investigator, Karolinska University Hospital
    • Olav Rooyackers, PhD, Study Chair, Karolinska University Hospital
  • Overall Contact(s)
    • Martin Sundström Rehal, MD PhD, +48-8-58580000, martin.sundstrom@gmail.com

References

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Doiron KA, Hoffmann TC, Beller EM. Early intervention (mobilization or active exercise) for critically ill adults in the intensive care unit. Cochrane Database Syst Rev. 2018 Mar 27;3(3):CD010754. doi: 10.1002/14651858.CD010754.pub2.

Connolly B, Salisbury L, O'Neill B, Geneen L, Douiri A, Grocott MP, Hart N, Walsh TS, Blackwood B; ERACIP Group. Exercise rehabilitation following intensive care unit discharge for recovery from critical illness. Cochrane Database Syst Rev. 2015 Jun 22;2015(6):CD008632. doi: 10.1002/14651858.CD008632.pub2.

Fossat G, Baudin F, Courtes L, Bobet S, Dupont A, Bretagnol A, Benzekri-Lefevre D, Kamel T, Muller G, Bercault N, Barbier F, Runge I, Nay MA, Skarzynski M, Mathonnet A, Boulain T. Effect of In-Bed Leg Cycling and Electrical Stimulation of the Quadriceps on Global Muscle Strength in Critically Ill Adults: A Randomized Clinical Trial. JAMA. 2018 Jul 24;320(4):368-378. doi: 10.1001/jama.2018.9592.

Hickmann CE, Castanares-Zapatero D, Deldicque L, Van den Bergh P, Caty G, Robert A, Roeseler J, Francaux M, Laterre PF. Impact of Very Early Physical Therapy During Septic Shock on Skeletal Muscle: A Randomized Controlled Trial. Crit Care Med. 2018 Sep;46(9):1436-1443. doi: 10.1097/CCM.0000000000003263.

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