Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty

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

Study Description

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.

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Contacts

Contact: Michael J Toth, PhD; 802-656-7989; michael.toth@uvm.edu

Contact: Patrick Savage; 802-847-4545; patrick.savage@uvmhealth.org

Locations

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

More Information

• 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
• Last Update Posted: November 4, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Osteoarthritis, Knee; Muscular Atrophy; Atrophy; Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases