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Trial registered on ANZCTR


Registration number
ACTRN12616001012460
Ethics application status
Approved
Date submitted
8/07/2016
Date registered
1/08/2016
Date last updated
1/08/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Skeletal muscle protein turnover in long-stayers in the ICU.
Scientific title
Skeletal muscle protein turnover in long-stayers in the ICU.
Secondary ID [1] 289643 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 299439 0
Condition category
Condition code
Diet and Nutrition 299419 299419 0 0
Other diet and nutrition disorders
Metabolic and Endocrine 299420 299420 0 0
Other metabolic disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Skeletal muscle protein and amino acid kinetics will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Skeletal muscle protein and amino acid kinetics will be assessed measuring the fluxes of labelled and unlabelled amino acids over the leg of the patient. For this the patients receive an infusion of [2H5]phenylalanine (0.5 mg/kg/h) and [2H2]3-methylhistidine (0.01 mg/kg/h) for 2.5 hours in a vein. After 2 hours and 15 minutes, 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. After 2 hours and 30 minutes a muscle biopsy is taken by a Bergstrom needle. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Steady state kinetics are used to assess muscle protein kinetics (protein synthesis, protein breakdown and protein balance) using the labelled amino acids. In addition amino acid fluxes are assessed by multiplying the arterial-venous difference of the amino acids times the plasma flow.

If a patient that has been studied and is still in the ICU 8-12 days later, and this patient still meets the inclusion criteria and if research staff is available, the patient will be studied again. Patients will be studied for a maximum of 3 times. For every study the same protocol, as described above, is used.
Intervention code [1] 295260 0
Not applicable
Comparator / control treatment
n/a
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298887 0
Skeletal muscle protein synthesis.
Timepoint [1] 298887 0
Skeletal muscle protein synthesis will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Skeletal muscle protein synthesis will be assessed measuring the fluxes of labelled and unlabelled amino acids over the leg of the patient. For this the patients receive an infusion of [2H5]phenylalanine (0.5 mg/kg/h) for 2.5 hours in a vein. After 2 hours and 15 minutes, 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. After 2 hours and 30 minutes a muscle biopsy is taken by a Bergstrom needle. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Steady state kinetics (3-pool model) are used to assess muscle protein synthesis using the labelled amino acids.
Primary outcome [2] 298935 0
Skeletal muscle protein breakdown.
Timepoint [2] 298935 0
Skeletal muscle protein breakdown will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Skeletal muscle protein breakdown will be assessed measuring the fluxes of labelled and unlabelled amino acids over the leg of the patient. For this the patients receive an infusion of [2H5]phenylalanine (0.5 mg/kg/h) and [2H2]3-methylhistidine (0.01 mg/kg/h) for 2.5 hours in a vein. After 2 hours and 15 minutes, 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. After 2 hours and 30 minutes a muscle biopsy is taken by a Bergstrom needle. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Steady state kinetics (3-pool model) are used to assess muscle protein kinetics protein breakdown using the labelled amino acids.
Primary outcome [3] 298936 0
Skeletal muscle protein balance. Skeletal muscle protein balance will be calculated by the difference between protein synthesis and protein breakdown at the same time points these are measured.

Skeletal muscle protein breakdown and synthesis will be assessed measuring the fluxes of labelled and unlabelled amino acids over the leg of the patient. For this the patients receive an infusion of [2H5]phenylalanine (0.5 mg/kg/h) and [2H2]3-methylhistidine (0.01 mg/kg/h) for 2.5 hours in a vein. After 2 hours and 15 minutes, 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. After 2 hours and 30 minutes a muscle biopsy is taken by a Bergstrom needle. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Steady state kinetics (3-pool model) are used to assess muscle protein synthesis and breakdown using the labelled amino acids.
Timepoint [3] 298936 0
Skeletal muscle protein balance will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.
Secondary outcome [1] 325546 0
Rate of appearance of phenylalanine in skeletal muscle.
Timepoint [1] 325546 0
Skeletal muscle rate of appearance will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Skeletal muscle rate of appearance will be assessed measuring the fluxes of labelled and unlabelled amino acids over the leg of the patient. For this the patients receive an infusion of [2H5]phenylalanine (0.5 mg/kg/h) for 2.5 hours in a vein. After 2 hours and 15 minutes, 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Steady state kinetics (2-pool model) are used to assess muscle rate of appearance of phenylalanine using the labelled amino acids.
Secondary outcome [2] 325547 0
Rate of disappearance of phenylalanine in skeletal muscle
Timepoint [2] 325547 0
Skeletal muscle rate of disappearance will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Skeletal muscle rate of disappearance will be assessed measuring the fluxes of labelled and unlabelled amino acids over the leg of the patient. For this the patients receive an infusion of [2H5]phenylalanine (0.5 mg/kg/h) for 2.5 hours in a vein. After 2 hours and 15 minutes, 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Steady state kinetics (2-pool model) are used to assess muscle rate of disappearance of phenylalanine using the labelled amino acids.
Secondary outcome [3] 325548 0
Skeletal muscle blood flow
Timepoint [3] 325548 0
Skeletal muscle blood flow will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the blood sampling period.
Secondary outcome [4] 325675 0
Skeletal muscle amino acid fluxes
Timepoint [4] 325675 0
Skeletal muscle amino acid fluxes will be measured in critically ill patients treated in the ICU for more then 10 days. Assessments are made 1-3 times 8-12 days apart in patients in the ICU between treatment day 10-40 after admission to the ICU.

Fluxes of amino acids will be measured over the leg of the patient. For this 4 samples (5 minutes apart) will be taken simultaneously from an artery and the femoral vein. Blood flow to the leg is measured with non-invasive venous occlusion plethysmography with 10 measurement at least 10 minutes before and 10 minutes after the sampling period. Amino acid fluxes will be calculated by multiplying the arterial-venous difference in the amino acid concentration time the blood flow.

Eligibility
Key inclusion criteria
An ICU stay of > 10 days after admission to the ICU. Patients are recruited and enrolled after day 10 in the ICU.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Withhold of treatment,
Contraindication to insertion of a catheter in the femoral vein and to a percutaneous muscle biopsy in the lateral portion the quadriceps femoralis muscle,
No informed consent.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Convenience sample
Timing
Prospective
Statistical methods / analysis
The study was powered to detect a 50% reduction (effect size 1) in the negative skeletal muscle protein balance between days 30-40 compared with 10-20 with 80% power and a p<0.05 from previous data (Klaude et al. Clin Sci, 2012: 122: 133-142). For this, a minimum of 8 patients are needed in each group. From clinical experience we calculated we needed to recruit 30 patients past day 10, to have 8-10 left in the unit at about day 40.

Values obtained between days 10 and 20 will be compared to those obtained between days 30 to 40 using Student's t-test or Mann Whitney test
Regression analysis related to the time of ICU stay.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8019 0
Sweden
State/province [1] 8019 0

Funding & Sponsors
Funding source category [1] 294025 0
Government body
Name [1] 294025 0
Stockholm County Council
Address [1] 294025 0
Stockholm County Council
Stockholms lans landsting
Box 22550
10420 Stockholm
Country [1] 294025 0
Sweden
Primary sponsor type
Individual
Name
Olav Rooyackers
Address
Department of Anesthesiology and Intensive Care
Clintec. Karolinska Institutet.
Karolinska University Hospital.
14186 Huddinge
Country
Sweden
Secondary sponsor category [1] 292844 0
None
Name [1] 292844 0
Address [1] 292844 0
Country [1] 292844 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295435 0
Regional etikprovningsnamnden i Stockholm
Ethics committee address [1] 295435 0
Box 289 (Nobel vag 12 A)
171 77 Stockholm
Ethics committee country [1] 295435 0
Sweden
Date submitted for ethics approval [1] 295435 0
Approval date [1] 295435 0
18/05/2009
Ethics approval number [1] 295435 0
2009/779-31

Summary
Brief summary
Critical ill patients treated in the ICU loose muscle mass at about 10% week. This is mainly due to a dramatic increase in muscle protein breakdown whereas muscle protein synthesis is, on average, normal. However this has only been measured in the early ICU treatment (up to 10 days) before. Since the loss of muscle mass sees to decrease when patients are treated for long periods (>10 days) the aim of this study is to measure skeletal muscle protein turnover between days 10-40 of ICU treatment. Skeletal muscle protein turnover is measured by infusing labelled amino acids (2H2-pheylalanine and 2H2-3-methylhistidine) and measuring their flux over the leg of patients. For this, following an 2 hours infusion of the amino acids, 3 samples from the femoral vein and a artery are taken with 5 minutes space; at the end a muscle biopsy is taken; and just before and after the sampling blood flow to the leg is measured using non invasive venous occlusion plethysmography. Samples are analyses for labelled and unlabelled amino acids and the protein kinetics are calculating using steady state 3 and 2 pool models. All details have been described before (Klaude et al, Clin Sci. 2007; 112:899-506). Patients will be measured when in the unit for 10 days or more. In some patients measurements will be repeated 8-12 days later, when possible. We hypothesize that the protein balance will be less negative with longer ICU stay.
Trial website
Trial related presentations / publications
Abstract "An attenuated rate of leg muscle protein depletion over time is seen in ICU longstayers." to be presented at ESICM annual meeting in Milan, Italy in October 2016.
Public notes

Contacts
Principal investigator
Name 67310 0
Prof Olav Rooyackers
Address 67310 0
Department of Anesthesiology and Intensive Care,
Clintec, Karolinska Institutet,
Karolinska University Hospital,
14186 Huddinge
Country 67310 0
Sweden
Phone 67310 0
+46 8 58586182
Fax 67310 0
Email 67310 0
olav.rooyackers@ki.se
Contact person for public queries
Name 67311 0
Prof Olav Rooyackers
Address 67311 0
Department of Anesthesiology and Intensive Care,
Clintec, Karolinska Institutet,
Karolinska University Hospital,
14186 Huddinge
Country 67311 0
Sweden
Phone 67311 0
+46 8 58586182
Fax 67311 0
Email 67311 0
olav.rooyackers@ki.se
Contact person for scientific queries
Name 67312 0
Prof Olav Rooyackers
Address 67312 0
Department of Anesthesiology and Intensive Care,
Clintec, Karolinska Institutet,
Karolinska University Hospital,
14186 Huddinge
Country 67312 0
Sweden
Phone 67312 0
+46 8 58586182
Fax 67312 0
Email 67312 0
olav.rooyackers@ki.se

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary