Knee Osteoarthristis
Conditions
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
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.
Interventions
DEVICENeuromuscular 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.
Sponsors
National Institute on Aging (NIA)
University of Vermont
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cross-sectional Area (CSA) of Muscle Fibers | Baseline and 5-weeks post-TKA surgery | CSA of skeletal muscle fibers via myosin heavy chain (MHC) immunohistochemistry |
| Intermyofibrillar Mitochondrial Content | Baseline and 5-weeks post-TKA surgery | Fractional area of intermyofibrillar (IMF) mitochondria via electron microscopy |
| Maximal Calcium-activated Tension Single Muscle Fiber Tension | Baseline and 5-weeks post-TKA surgery | Tension (force per unit muscle fiber cross-sectional area) from segments of chemically-skinned single human muscle fibers assessed under maximal calcium-activated condition, with muscle fiber type determined post-measurement by gel electrophoresis |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Knee Extensor Muscle Strength | Baseline and 5-weeks post-TKA surgery | Knee extensor isometric peak torque assessed by dynamometry on the surgical leg. |
| Physical Activity Level | Baseline and 5-weeks post-TKA surgery | Physical activity will be assessed by accelerometry. |
| 30-second Sit-to-stand Test | Assessed at baseline and 5 weeks post-surgery | Number of repetitions that an individual can complete the sit-to-stand transition in 30 seconds |
| Quadriceps Muscle Cross-sectional Area | Baseline and 5-weeks post-TKA surgery | Quadriceps muscle cross-sectional area will be assessed by computed tomography at the mid-thigh on both surgical and non-surgical non-surgical legs. |
| Short Physical Performance Battery | Baseline and 5-weeks post-TKA surgery | Physical functional assessment based on 2 lower extremity activities (5-time sit-to-stand, 4-m gait speed) and standing balance (side-side, tandem, semi-tandem) based on time or repetitions (0-4 score) with a minimum score of 0 and a maximal score of 12. Each activity is scored from 0 to 4 based on the level of performance (with higher values indicating better physical function and lower values indicating increasing levels of disability). The scores from the 3 activities are summed to give the total score, which is what is reported. Higher total score values indicate higher levels of physical function (more healthy), whereas lower values indicate increasing levels of physical disability/frailty. |
Countries
United States
Participant flow
Recruitment details
Recruitment began on January 1, 2017, and ended on January 13, 2022. Volunteers undergoing assessment for TKA were screened from the Adult Reconstruction Service of our Department of Orthopedics and Rehabilitation and local private practices.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: NMES Volunteers randomized to this arm/group will receive neuromuscular electrical stimulation (NMES) for 5 weeks after total knee arthroplasty (TKA) | 11 |
| Experimental: Control Patients randomized to this arm/group will not receive any experimental intervention, but will receive standard of care. | 12 |
| Total | 23 |
Baseline characteristics
| Characteristic | Experimental: NMES | Experimental: Control | Total |
|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 7.1 | 64.8 Years STANDARD_DEVIATION 6.5 | 64.0 Years STANDARD_DEVIATION 6.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 12 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 |
| other Total, other adverse events | 1 / 10 | 2 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 |
Outcome results
Primary
Cross-sectional Area (CSA) of Muscle Fibers
CSA of skeletal muscle fibers via myosin heavy chain (MHC) immunohistochemistry
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Mixed model analysis statistically adjusted for baseline value and sex
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Cross-sectional Area (CSA) of Muscle Fibers | MHC I fiber cross-sectional area - Baseline | 2680 micron squared | Standard Error 113 |
| Experimental: NMES | Cross-sectional Area (CSA) of Muscle Fibers | MHC I fiber cross sectional area - 5-week post-surgery | 2028 micron squared | Standard Error 83 |
| Experimental: NMES | Cross-sectional Area (CSA) of Muscle Fibers | MHC IIA fiber cross sectional area - Baseline | 2039 micron squared | Standard Error 183 |
| Experimental: NMES | Cross-sectional Area (CSA) of Muscle Fibers | MHC IIA fiber cross sectional area - 5-week post-surgery | 1623 micron squared | Standard Error 145 |
| Experimental: Control | Cross-sectional Area (CSA) of Muscle Fibers | MHC IIA fiber cross sectional area - 5-week post-surgery | 1389 micron squared | Standard Error 109 |
| Experimental: Control | Cross-sectional Area (CSA) of Muscle Fibers | MHC I fiber cross-sectional area - Baseline | 2377 micron squared | Standard Error 86 |
| Experimental: Control | Cross-sectional Area (CSA) of Muscle Fibers | MHC IIA fiber cross sectional area - Baseline | 1971 micron squared | Standard Error 155 |
| Experimental: Control | Cross-sectional Area (CSA) of Muscle Fibers | MHC I fiber cross sectional area - 5-week post-surgery | 1882 micron squared | Standard Error 68 |
Primary
Intermyofibrillar Mitochondrial Content
Fractional area of intermyofibrillar (IMF) mitochondria via electron microscopy
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Mixed model analysis adjusting for baseline value and sex
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Intermyofibrillar Mitochondrial Content | IMF mitochondria fractional area - 5-week post-surgery | 2.1 percent area | Standard Error 0.2 |
| Experimental: NMES | Intermyofibrillar Mitochondrial Content | IMF mitochondria fractional area - Baseline | 2.36 percent area | Standard Error 0.2 |
| Experimental: Control | Intermyofibrillar Mitochondrial Content | IMF mitochondria fractional area - 5-week post-surgery | 1.7 percent area | Standard Error 0.2 |
| Experimental: Control | Intermyofibrillar Mitochondrial Content | IMF mitochondria fractional area - Baseline | 2.34 percent area | Standard Error 0.2 |
Primary
Maximal Calcium-activated Tension Single Muscle Fiber Tension
Tension (force per unit muscle fiber cross-sectional area) from segments of chemically-skinned single human muscle fibers assessed under maximal calcium-activated condition, with muscle fiber type determined post-measurement by gel electrophoresis
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Mixed model analysis adjusting for baseline value and sex.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC I tension - Baseline | 114 milliNewtons per millimiter squared | Standard Error 5 |
| Experimental: NMES | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC I tension - 5-week post-surgery | 112 milliNewtons per millimiter squared | Standard Error 5 |
| Experimental: NMES | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC IIA tension - 5-week post-surgery | 132 milliNewtons per millimiter squared | Standard Error 6 |
| Experimental: NMES | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC IIA tension - Baseline | 173 milliNewtons per millimiter squared | Standard Error 5 |
| Experimental: Control | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC IIA tension - 5-week post-surgery | 107 milliNewtons per millimiter squared | Standard Error 8 |
| Experimental: Control | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC I tension - 5-week post-surgery | 103 milliNewtons per millimiter squared | Standard Error 5 |
| Experimental: Control | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC IIA tension - Baseline | 175 milliNewtons per millimiter squared | Standard Error 6 |
| Experimental: Control | Maximal Calcium-activated Tension Single Muscle Fiber Tension | MHC I tension - Baseline | 111 milliNewtons per millimiter squared | Standard Error 5 |
Secondary
30-second Sit-to-stand Test
Number of repetitions that an individual can complete the sit-to-stand transition in 30 seconds
Time frame: Assessed at baseline and 5 weeks post-surgery
Population: Analysis of variance model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | 30-second Sit-to-stand Test | 30-s sit-to-stand - Baseline | 10.45 repetitions | Standard Error 0.97 |
| Experimental: NMES | 30-second Sit-to-stand Test | 30-s sit-to-stand - Post-surgery | 10.55 repetitions | Standard Error 0.59 |
| Experimental: Control | 30-second Sit-to-stand Test | 30-s sit-to-stand - Baseline | 11.78 repetitions | Standard Error 1.39 |
| Experimental: Control | 30-second Sit-to-stand Test | 30-s sit-to-stand - Post-surgery | 12.56 repetitions | Standard Error 1.22 |
Secondary
Knee Extensor Muscle Strength
Knee extensor isometric peak torque assessed by dynamometry on the surgical leg.
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Analysis of variance model. Note that n=9 for surgical leg isokinetic peak torque in one NMES volunteer because knee pain prevented completing of strength testing protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Knee Extensor Muscle Strength | Surgical Isometric peak torque - Baseline | 113.0 Newton meter | Standard Error 14.5 |
| Experimental: NMES | Knee Extensor Muscle Strength | Surgical Isokinetic peak torque - 5-week post-surgery | 53.3 Newton meter | Standard Error 4.2 |
| Experimental: NMES | Knee Extensor Muscle Strength | Surgical Isometric peak torque - 5-week post-surgery | 65.8 Newton meter | Standard Error 6.9 |
| Experimental: NMES | Knee Extensor Muscle Strength | Surgical Isokinetic peak torque - Baseline | 89.9 Newton meter | Standard Error 9.6 |
| Experimental: Control | Knee Extensor Muscle Strength | Surgical Isokinetic peak torque - Baseline | 58.9 Newton meter | Standard Error 9.6 |
| Experimental: Control | Knee Extensor Muscle Strength | Surgical Isometric peak torque - Baseline | 94.7 Newton meter | Standard Error 9.8 |
| Experimental: Control | Knee Extensor Muscle Strength | Surgical Isometric peak torque - 5-week post-surgery | 65.7 Newton meter | Standard Error 6.9 |
| Experimental: Control | Knee Extensor Muscle Strength | Surgical Isokinetic peak torque - 5-week post-surgery | 42.5 Newton meter | Standard Error 3.9 |
Secondary
Physical Activity Level
Physical activity will be assessed by accelerometry.
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Analysis of variance. Note that one patient in the control group did not complete accelerometry assessments.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Physical Activity Level | Step counts - Baseline | 4167 steps per day | Standard Error 688 |
| Experimental: NMES | Physical Activity Level | Step counts - 5-week post-surgery | 2088 steps per day | Standard Error 588 |
| Experimental: Control | Physical Activity Level | Step counts - Baseline | 4767 steps per day | Standard Error 691 |
| Experimental: Control | Physical Activity Level | Step counts - 5-week post-surgery | 2500 steps per day | Standard Error 587 |
Secondary
Quadriceps Muscle Cross-sectional Area
Quadriceps muscle cross-sectional area will be assessed by computed tomography at the mid-thigh on both surgical and non-surgical non-surgical legs.
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Mixed model analysis with control for baseline value and sex
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Quadriceps Muscle Cross-sectional Area | Surgical Quadriceps cross-sectional area - Baseline | 45.5 centimeters squared | Standard Error 3 |
| Experimental: NMES | Quadriceps Muscle Cross-sectional Area | Surgical Quadriceps cross-sectional area - 5-week post-surgery | 38.3 centimeters squared | Standard Error 3.3 |
| Experimental: NMES | Quadriceps Muscle Cross-sectional Area | Non-surgical Quadriceps cross-sectional area - 5-week post-surgery | 48.7 centimeters squared | Standard Error 3.6 |
| Experimental: NMES | Quadriceps Muscle Cross-sectional Area | Non-surgical Quadriceps cross-sectional area - Baseline | 52.0 centimeters squared | Standard Error 3.3 |
| Experimental: Control | Quadriceps Muscle Cross-sectional Area | Non-surgical Quadriceps cross-sectional area - 5-week post-surgery | 44.9 centimeters squared | Standard Error 3.9 |
| Experimental: Control | Quadriceps Muscle Cross-sectional Area | Surgical Quadriceps cross-sectional area - 5-week post-surgery | 33.8 centimeters squared | Standard Error 2.7 |
| Experimental: Control | Quadriceps Muscle Cross-sectional Area | Non-surgical Quadriceps cross-sectional area - Baseline | 46.0 centimeters squared | Standard Error 4.5 |
| Experimental: Control | Quadriceps Muscle Cross-sectional Area | Surgical Quadriceps cross-sectional area - Baseline | 38.8 centimeters squared | Standard Error 3.1 |
Secondary
Short Physical Performance Battery
Physical functional assessment based on 2 lower extremity activities (5-time sit-to-stand, 4-m gait speed) and standing balance (side-side, tandem, semi-tandem) based on time or repetitions (0-4 score) with a minimum score of 0 and a maximal score of 12. Each activity is scored from 0 to 4 based on the level of performance (with higher values indicating better physical function and lower values indicating increasing levels of disability). The scores from the 3 activities are summed to give the total score, which is what is reported. Higher total score values indicate higher levels of physical function (more healthy), whereas lower values indicate increasing levels of physical disability/frailty.
Time frame: Baseline and 5-weeks post-TKA surgery
Population: Analysis of variance.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: NMES | Short Physical Performance Battery | Short Physical Performance - Baseline | 9.36 Scores on a scale | Standard Error 0.56 |
| Experimental: NMES | Short Physical Performance Battery | Short Physical Performance Battery - 5-week post-surgery | 10.45 Scores on a scale | Standard Error 0.53 |
| Experimental: Control | Short Physical Performance Battery | Short Physical Performance - Baseline | 9.80 Scores on a scale | Standard Error 0.61 |
| Experimental: Control | Short Physical Performance Battery | Short Physical Performance Battery - 5-week post-surgery | 10.10 Scores on a scale | Standard Error 0.55 |