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Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty

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ClinicalTrials.gov Identifier: NCT03051984
Recruitment Status : Recruiting
First Posted : February 14, 2017
Last Update Posted : November 4, 2020
Sponsor:
Information provided by (Responsible Party):
Michael J. Toth, Ph.D., University of Vermont

Brief Summary:
Total knee replacement, or arthroplasty, is the final clinical intervention available to relieve pain and functional limitations related to advanced stage knee osteoarthritis. Despite its beneficial effects, the early post-surgical period is characterized by the erosion of lower extremity muscle size and strength that cause further disability and slow functional recovery. While the detrimental effects of this period on muscle are widely recognized, the mechanisms underlying these adaptations are poorly understood and there are currently no widely-accepted clinical interventions to counter them

Condition or disease Intervention/treatment Phase
Knee Osteoarthritis Device: Neuromuscular electrical stimulation Not Applicable

Detailed Description:
Total knee arthroplasty (TKA) is currently the most common elective surgery in the US and will increase in frequency nearly five-fold by 2030 to 3.5 million surgeries annually. This surgery is most prevalent among older adults with advanced knee osteoarthritis (OA) and its increase is explained primarily by growth in this population. Although TKA reliably reduces joint pain, it fails to correct objectively-measured functional disability due, in part, to dramatic declines in lower-extremity neuromuscular function during the early, postsurgical period. These deficits are never fully remediated, remaining for years after surgery and contributing to persistent disability. Despite these detrimental effects of TKA, the fundamental skeletal muscle adaptations that occur in the early, post-surgical period are poorly defined and understudied and there is currently no widely-accepted, evidence-based intervention to counter these changes. To address this clinical problem, the investigators goals in this application are to define the skeletal muscle structural and functional adaptations following TKA at the whole body, tissue, cellular, organellar and molecular levels in humans in an effort to identify factors contributing to functional disability and to assess the utility of neuromuscular electrical stimulation (NMES) to counter post-surgical muscle adaptations at these same anatomic levels. We hypothesize that TKA fails to remediate physical disability in patients, in part, because of the profound skeletal muscle myofilament and mitochondrial loss and dysfunction that develops during the early, post-surgical period. Moreover, the investigators posit that NMES will improve functional recovery following TKA by countering these early skeletal muscle adaptations. To test this model, the investigators will evaluate participants with knee OA prior to and following TKA for skeletal muscle structure and function at multiple anatomic levels, with patients randomized to receive NMES or sham control intervention during the first 5 weeks post-surgery.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty
Actual Study Start Date : January 1, 2017
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Knee Replacement

Arm Intervention/treatment
Experimental: NMES
Neuromuscular electrical stimulation (NMES) will be administered for 5 weeks post-TKA in the quadriceps of the surgical leg. Treatment will occur 5 days per week, twice daily for 45 minutes on each occasion.
Device: Neuromuscular electrical stimulation
NMES will be conducted on the quadriceps of the operative leg using a portable stimulation device, starting within 48-72 hrs of surgery. The operative leg will be immobilized at a neutral angle (~30º), with electrodes affixed to the anterior surface of the thigh. Symmetrical, biphasic pulses (400 µs duration at 50 Hz) will be used, with a duty cycle of 25% (10 s on, 30 s off), with patient-selected stimulation intensity to cause visible contractions below pain threshold. NMES sessions will occur 5 d/week, twice daily for 45 min (5 min warm-up) for 5 wks.
Other Name: NMES

No Intervention: Control
No intervention will be administered during the 5 weeks post-TKA in the surgical leg.



Primary Outcome Measures :
  1. Cross-sectional area of muscle fibers [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Cross-sectional area of skeletal muscle fibers will be evaluated using immunohistochemistry, with specification of all relevant muscle fiber types

  2. Intermyofibrillar mitochondrial content [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Area fraction of intermyofibrillar mitochondria will be assessed by electron microscopy

  3. Maximal calcium-activated tension single muscle fiber tension and shortening velocity [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Tension (force per unit muscle fiber cross-sectional area) from segments of chemically-skinned single human muscle fibers will be assessed under maximal calcium-activated condition and shortening velocity will be evaluated from isotonic load clamps, with muscle fiber type determined post-measurement by gel electrophoresis

  4. Mitochondrial function [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Oxygen consumption rate of isolated muscle mitochondria under adenosine diphosphate stimulation and hydrogen peroxide production


Secondary Outcome Measures :
  1. Physical activity level [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Physical activity will be assessed by accelerometry.

  2. Quadriceps muscle cross-sectional area [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Quadriceps muscle cross-sectional area will be assessed by computed tomography at the mid-thigh.

  3. Physical functional measures [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Whole body physical function will be assessed.

  4. Whole muscle strength [ Time Frame: Change from baseline cross-sectional area at 5 weeks ]
    Knee extensor isometric and isokinetic strength will be assessed by dynamometry.



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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • symptomatic, primary knee osteoarthritis (OA)
  • being considered for total knee arthroplasty

Exclusion Criteria:

  • knee OA secondary to inflammatory/autoimmune disease
  • untreated/uncontrolled hypertension, diabetes or thyroid disease
  • chronic heart failure, actively-treated malignancy, exercise-limiting peripheral vascular disease, stroke or neuromuscular disease
  • body mass index >38 kg/m2
  • lower extremity blood clot or known coagulopathies
  • implanted pacemaker/ICD

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): NCT03051984


Contacts
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Contact: Michael J Toth, PhD 802-656-7989 michael.toth@uvm.edu
Contact: Patrick Savage 802-847-4545 patrick.savage@uvmhealth.org

Locations
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United States, Vermont
University of Vermont College of Medicine Recruiting
Burlington, Vermont, United States, 05405
Contact: Patrick Savage    802-847-4545    patrick.savage@uvmhealth.org   
Sponsors and Collaborators
University of Vermont
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Responsible Party: Michael J. Toth, Ph.D., Associate Professor of Medicine, University of Vermont
ClinicalTrials.gov Identifier: NCT03051984    
Other Study ID Numbers: M16-528
First Posted: February 14, 2017    Key Record Dates
Last Update Posted: November 4, 2020
Last Verified: November 2020
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: Yes
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Osteoarthritis, Knee
Muscular Atrophy
Atrophy
Osteoarthritis
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases