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

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

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.

Study Overview

• Status: Suspended
• Conditions: Critical Illness; Muscle Loss
• Intervention / Treatment: Procedure: Resisted knee extension exercise; Drug: IV amino acids

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Stockholm
    • Huddinge, Stockholm, Sweden, 14186
      • Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Glavamin (Fresenius Kabi)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Investigators: Principal Investigator: Martin Sundström Rehal, MD PhD, Karolinska University Hospital; Study Chair: Olav Rooyackers, PhD, Karolinska Institutet

Publications and helpful links

General Publications

• Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, Chan P, Hopkinson NS, Phadke R, Dew T, Sidhu PS, Velloso C, Seymour J, Agley CC, Selby A, Limb M, Edwards LM, Smith K, Rowlerson A, Rennie MJ, Moxham J, Harridge SD, Hart N, Montgomery HE. Acute skeletal muscle wasting in critical illness. JAMA. 2013 Oct 16;310(15):1591-600. doi: 10.1001/jama.2013.278481. Erratum In: JAMA. 2014 Feb 12;311(6):625. Padhke, Rahul [corrected to Phadke, Rahul].
• Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. doi: 10.1056/NEJMoa1011802.
• 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.
• Batt J, Herridge MS, Dos Santos CC. From skeletal muscle weakness to functional outcomes following critical illness: a translational biology perspective. Thorax. 2019 Nov;74(11):1091-1098. doi: 10.1136/thoraxjnl-2016-208312. Epub 2019 Aug 20.
• Plank LD, Connolly AB, Hill GL. Sequential changes in the metabolic response in severely septic patients during the first 23 days after the onset of peritonitis. Ann Surg. 1998 Aug;228(2):146-58. doi: 10.1097/00000658-199808000-00002.
• Wolfe RR. Skeletal muscle protein metabolism and resistance exercise. J Nutr. 2006 Feb;136(2):525S-528S. doi: 10.1093/jn/136.2.525S.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 25, 2022
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 5, 2022
• First Submitted That Met QC Criteria: January 5, 2022
• First Posted (Actual): January 19, 2022

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Physiotherapy; Resistance exercise; Amino acids; Muscle protein balance
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: K 2021-10530

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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