Skeletal Muscle Regeneration in Survivors of Critical Illness: How to Prevent Satellite Cell Failure?

NCT05671614 | Recruiting

• 1 other identifier: NU21J-06-00078
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Modern intensive care enables patients to survive insults that in the past would have been supralethal. Nonetheless, increased number of survivors suffer from failed functional outcomes associated with prolonged muscle weakness and fatiguability. Whilst alterations of skeletal muscle biology that occur during critical illness slowly disappear over the period of months, muscle weakness remains. Recent pilot studies have shown that muscle weakness is associated with loss and alteration of satellite skeletal muscle cells, which are supposed to proliferate and repair damaged muscle tissue. The pathogenesis of this phenomenon has not been fully understood. In this grant project, we will study function and structure of satellite cells and their organelles (particularly mitochondria) using both classical bioenergetics and advanced microscopic techniques. Satellite cells will be isolated from biopsies taken from critically ill patients with developed muscle weakness in the acute and protracted phase of a disease and after 6 months. In time points, an ultrasound examination of muscle mass will be performed, and metabolism will be assessed using insulin clamps. In an in vitro experiments, we will test also effect of nutritional and anabolic factors and drugs, commonly used in ICU, on satellite cells. In a control branch, cells will be isolated from skeletal muscle of volunteers undergoing elective hip replacement surgery. Results of this study could significantly contribute to understanding of mechanisms leading to ICU acquired muscle weakness and to identify therapeutic strategy in future.

Conditions

Intensive Care Unit-acquired Weakness

Keywords

intensive care unit-acquired weakness; critically ill; skeletal muscle regeneration; satellite cells

Outcome Measures

Primary Outcomes (5)

• Quality of life as per 36-Item Short Form Health Survey (SF-36)

  A set of quality-of-life measures. A questionnaire includes questions about: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. The minimum and maximum scores are 0 and 100. A higher score defines a more favorable health state.

  on day 180

• Changes of muscle mass between baseline, day 7 and day 180

  By measurement of musculus rectus femoris cross-sectional area by diagnostic ultrasound.

  Changes between days 0, 7 and 180

• A measurement of muscle power by Medical Research Council Score

  A standardized testing of muscle power \[0-5\] on 12 muscle groups on all 4 limbs using Medical Research Council Score, giving the score from minimum 0 to maximum 60. A higher score defines a more favorable health state, 60 points suggest a normal muscle power.

  on day 180 (eventually on day 7 if the patient is conscious)

• Changes of mitochondrial function of satellite cells between baseline, day 7 and day 180

  Mitochondrial functional parameters will be assessed by Extracellular XF24 Seahorse Analyzer or high-resolution respirometry which enables continous real-time measurement of oxygen consumption in living cells at the baseline and after addition of various substrates, uncouplers and inhibitors of the respiratory chain. This allow to estimate parameters as ATP production, maximal respiratory capacity, respiration in baseline etc. The techniques measure oxygen consumption rate of living cells in pmol/min.

  Changes between days 0, 7 and 180

• Changes of mitochondrial structure of satellite cells between baseline, day 7 and day 180

  A mitochondrial structure and architecture of its network (mitochondrial density and a length of its branches etc.) will be assessed after staining of mitochondria by fluorescent probes and imaging on confocal laser scanning microscopy. The length/density will be measured in microns/microns 2.

  Changes between days 0, 7 and 180

Secondary Outcomes (5)

• Nitrogen balance measured in g/m2 of body surface area

  on first 7 days

• 6-minutes walking test to measure aerobic performance

  on day 180

• Changes of insulin sensitivity between days 7 and 180

  Changes between days 7 and 180

• Length of ICU stay in days

  on day 28

• Number of ventilator-free days

  on day 28

Study Arms (2)

Critically ill patients

Critically ill patients with sudden onset of disease receiving mechanical ventilation, to be enrolled within 72 hours of admission, who are likely to need 7 days or more of ICU stay.

Volunteers with a very good to excellent performance status

Elective hip surgery patients with a very good to excellent performance status, only limited to joint pain (ECOG 0)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Critically ill patients with sudden onset of disease receiving mechanical ventilation, to be enrolled within 72 hours of admission, who are likely to need 7 days or more of ICU stay. Study population will be compared with control group consisting of patients undergoing hip replacement surgery with a very good to excellent performance status.

You may qualify if:

• Critically ill patients receiving mechanical ventilation, to be enrolled within 72 hours of admission, who are likely to need 7 days or more of ICU stay
• Sudden onset of disease, which can be determined in time (such as trauma, stroke, sudden cardiac arrest etc.)
• Informed consent signed by patient or patient's representative

You may not qualify if:

• Unlikely to survive 6 months
• Premorbid downslope functional trajectory or poor performance status (ECOG Gr. 3 or worse) or baseline functional status unknown
• Bleeding disorder (INR≥1.5 or PLT\< that would preclude muscle biopsies)
• Known mitochondrial disease
• Endocrine crisis as a reason for admission
• Pregnant women
• Eligibility Criteria for a control group:
• Elective hip surgery patients with a very good to excellent performance status, only limited to joint pain (ECOG 0)

Sponsors & Collaborators

• Charles University, Czech Republic: lead
• Faculty Hospital Kralovske Vinohrady: collaborator

Study Sites (1)

Charles University

Prague, Czech Republic, Czechia

RECRUITING

Related Publications (25)

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• Ziak J, Krajcova A, Jiroutkova K, Nemcova V, Dzupa V, Duska F. Assessing the function of mitochondria in cytosolic context in human skeletal muscle: adopting high-resolution respirometry to homogenate of needle biopsy tissue samples. Mitochondrion. 2015 Mar;21:106-12. doi: 10.1016/j.mito.2015.02.002. Epub 2015 Feb 17.

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• Genserova L, Duska F, Krajcova A. beta-hydroxybutyrate exposure restores mitochondrial function in skeletal muscle satellite cells of critically ill patients. Clin Nutr. 2024 Jun;43(6):1250-1260. doi: 10.1016/j.clnu.2024.04.009. Epub 2024 Apr 9.

  PMID: 38653008 DERIVED

MeSH Terms

Conditions

Critical Illness

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Adéla Krajčová, MD, PhD

CONTACT

00420774732499; adela.krajcova@lf3.cuni.cz

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 16, 2022
• First Posted: January 4, 2023
• Study Start: August 17, 2022
• Primary Completion: March 31, 2025
• Study Completion: June 30, 2025
• Last Updated: January 1, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

CZ (1)