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PTJ 99 8 1010

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Protocols

L.N. Erickson, PT, DPT, Department of


Rehabilitation Sciences, University of
Kentucky, Lexington, Kentucky.
Effect of Blood Flow Restriction
K.C. Hickey Lucas, PT, DPT, Department
of Rehabilitation Sciences, University of
Training on Quadriceps Muscle
Kentucky.
K.A. Davis, MS, Department of Rehabil-
Strength, Morphology, Physiology,
itation Sciences, University of Kentucky.
C.A. Jacobs, PhD, Department of Re- and Knee Biomechanics Before and
habilitation Sciences and Department
of Orthopaedic Surgery & Sports
Medicine, University of Kentucky.
After Anterior Cruciate Ligament

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K.L. Thompson, PhD, Department of
Statistics, University of Kentucky.
Reconstruction: Protocol for a
P.A. Hardy, PhD, Department of Radiol-
ogy and Magnetic Resonance Imaging Randomized Clinical Trial
and Spectroscopy Center, University of
Kentucky. Lauren N. Erickson, Kathryn C. Hickey Lucas, Kylie A. Davis, Cale A. Jacobs,
A.H. Andersen, PhD, Department of Katherine L. Thompson, Peter A. Hardy, Anders H. Andersen, Christopher S. Fry,
Neuroscience and Magnetic Resonance Brian W. Noehren
Imaging and Spectroscopy Center, Uni-
versity of Kentucky.
C.S. Fry, PhD, Department of Nutri-
Background. Despite best practice, quadriceps strength deficits often persist for years
tion & Metabolism, University of Texas
after anterior cruciate ligament reconstruction. Blood flow restriction training (BFRT) is
Medical Branch, Galveston, Texas. a possible new intervention that applies a pressurized cuff to the proximal thigh that
partially occludes blood flow as the patient exercises, which enables patients to train at
B.W. Noehren, PT, PhD, FACSM,
Department of Rehabilitation Sciences,
reduced loads. This training is believed to result in the same benefits as if the patients
University of Kentucky, 900 S. Lime- were training under high loads.
stone, Room 204D, Lexington, KY
40536-0200 (USA); and Department Objective. The objective is to evaluate the effect of BFRT on quadriceps strength and
of Orthopaedic Surgery & Sports knee biomechanics and to identify the potential mechanism(s) of action of BFRT at the
Medicine, University of Kentucky. cellular and morphological levels of the quadriceps.
Address all correspondence to Dr
Noehren at: b.noehren@uky.edu. Design. This will be a randomized, double-blind, placebo-controlled clinical trial.
[Erickson LN, Lucas KCH, Davis KA,
et al. Effect of blood flow restric- Setting. The study will take place at the University of Kentucky and University of Texas
tion training on quadriceps muscle
Medical Branch.
strength, morphology, physiology, and
knee biomechanics before and after an-
terior cruciate ligament reconstruction:
Participants. Sixty participants between the ages of 15 to 40 years with an ACL tear
protocol for a randomized clinical trial. will be included.
Phys Ther. 2019;99:1010–1019.]

C 2019 American Physical Therapy As- Intervention. Participants will be randomly assigned to (1) physical therapy plus active
sociation BFRT (BFRT group) or (2) physical therapy plus placebo BFRT (standard of care group).
Published Ahead of Print:
Presurgical BFRT will involve sessions 3 times per week for 4 weeks, and postsurgical
April 05, 2019 BFRT will involve sessions 3 times per week for 4 to 5 months.
Accepted: December 12, 2018
Submitted: May 15, 2018 Measurements. The primary outcome measure was quadriceps strength (peak quadri-
ceps torque, rate of torque development). Secondary outcome measures included knee
biomechanics (knee extensor moment, knee flexion excursion, knee flexion angle), quadri-
ceps muscle morphology (physiological cross-sectional area, fibrosis), and quadriceps mus-
cle physiology (muscle fiber type, muscle fiber size, muscle pennation angle, satellite cell
proliferation, fibrogenic/adipogenic progenitor cells, extracellular matrix composition).

Limitations. Therapists will not be blinded.


Conclusions. The results of this study may contribute to an improved targeted treatment
for the protracted quadriceps strength loss associated with anterior cruciate ligament injury
and reconstruction.

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Blood Flow Restriction Training: ACL Reconstruction

O
ver 200,000 individuals sustain an anterior The purpose of this study is to evaluate the effect of BFRT
cruciate ligament (ACL) tear in the United States on quadriceps strength and knee biomechanics and to
annually.1–3 Impairments in quadriceps strength identify the potential mechanism(s) of action of BFRT at
following ACL reconstruction are common4–14 and are the cellular and morphological levels of the quadriceps.
related to altered knee biomechanics.15–20 Additionally, The primary objective is to evaluate the effect of BFRT
quadriceps weakness has been associated with negative training on quadriceps strength, assessed via peak
short- and long-term outcomes, such as low quadriceps torque and rate of torque development, in
return-to-sport rate,21,22 reduced quality of life,13,23 and patients who have had an ACL reconstruction. The
early-onset osteoarthritis.24 Thus, an emphasis on secondary objectives are measuring changes in (1) knee
interventions to address impairments in quadriceps biomechanics, (2) quadriceps muscle morphology, and (3)
strength is needed to limit these negative consequences. quadriceps muscle physiology after using BFRT in patients
who have had an ACL reconstruction. Our hypothesis is

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A growing body of literature shows that peripheral that BFRT will restore quadriceps strength, knee
changes (morphologic and cellular) in the quadriceps biomechanics, and quadriceps morphology and cellular
occur following ACL injury and reconstruction that result composition in patients who have had an ACL tear and
in protracted quadriceps weakness.8,25–28 Traditional reconstruction to a greater extent than standard of care.
physical therapy techniques have had limited effectiveness
on mitigating these alterations in the composition of the
quadriceps muscle.8,25–27 However, blood flow restriction Methods
training (BFRT) has been suggested as a potential method Trial Design
to improve these deficits.29–31 With BFRT, a pressurized This is a randomized, double-blind, placebo-controlled
cuff is applied to the proximal thigh that partially occludes clinical trial that began in Fall 2017 and will continue for 5
blood flow as the patient exercises. It is believed that the years. All components of the study will be completed at
accumulated effects of fatigue, mechanical tension, the University of Kentucky except for the
metabolic stress, and reactive hyperemia contribute to immunohistochemical assays of the muscle biopsies,
promoting adaptation of the quadriceps with minimal which will be performed at the University of Texas
strain.32–39 Therefore, patients are able to train at reduced Medical Branch. The trial will be reported according to
loads and may receive the same training benefits as if they SPIRIT, TIDieR, and CONSORT guidelines. Figure 1
were training under high loads. outlines the trial phases.

BFRT has been successfully used in healthy populations,


Participants
demonstrating equivalent and/or greater strength gains
Participants will be recruited from the University of
than traditional forms of exercise.32,40–42 Additionally,
Kentucky Sports Medicine Clinic. We will enroll up to 60
BFRT has been shown to preferentially improve muscle
participants in the study, with each participant providing
fiber cross-sectional area and increase satellite cell
their written consent prior to enrollment. With a potential
abundance in healthy patients.33,35,43–46 These properties
attrition rate of up to 20%, we expect at least 48
of the quadriceps are negatively impacted after ACL injury
participants to complete the study, with approximately 24
and persist despite reconstruction and rehabilitation.47
participants per treatment group. Specific inclusion and
Whether BFRT is able to address these identified cellular
exclusion criteria for entrance into the study are detailed
properties is poorly understood.33,35,43–46 Establishing the
in Table 1.
efficacy of BFRT to positively alter these cellular
properties, when detrimentally affected by injury,
is crucial to translate the rehabilitative potential Randomization/Allocation/Blinding
of BFRT. Upon enrollment into the study, participants will be
randomly assigned to receive physical therapy plus active
To date, very few studies have tested BFRT following an BFRT (BFRT group) or physical therapy plus placebo
ACL reconstruction.48–50 The results of these studies have BFRT (standard of care group). All assessments will be
been conflicting in regards to quadriceps strength and done by the outcome assessors who are separate from the
cross-sectional area, and there have been no comparisons physical therapists applying BFRT to further maintain
of cellular alterations and movement mechanics. Previous blinding and control for bias. The randomization schedule
work is also limited by inconsistent experimental will be created by the study biostatistician, viewed and
procedures, including length of total occlusion time, updated by the physical therapists, and implemented in
intermittent versus continuous occlusion, and length of permuted blocks of 4 for each sex using R (version 3.4.0
rehabilitation. Therefore, further investigation is needed to or above) to ensure adequate distribution of all groups
determine if BFRT is able to mitigate strength loss in across the collection period. The physical therapists
injured populations for whom high-load strengthening cannot be blinded to the treatment, because they will
exercises are contraindicated. administer the BFRT session and will be responsible for
all discussions with the participants pertaining to BFRT.

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Figure 1.
Flowchart of the clinical trial. ACL = anterior cruciate ligament; BFRT = blood flow restriction training; MRI = magnetic resonance imaging.

Interventions shows the interventions for both groups throughout the


plan of care.
Physical therapy. Both groups will receive standard pre-
and postsurgical physical therapy, which will focus on
Presurgical physical therapy will involve visits 3 times per
range of motion, muscle activation, functional mobility,
week for 4 weeks. This phase will focus on effusion
hip strengthening, core stability, balance, and gait training.
management, range of motion, strength, and gait
eAppendix 1 (available at https://academic.oup.com/ptj)
(eAppendix 1, Part A).

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Blood Flow Restriction Training: ACL Reconstruction

Table 1.
Inclusion and Exclusion Criteria for Entrance Into the BFRT Clinical Trial for Patients With ACL Injurya

Inclusion Criteria
Male or female (15–40 years of age); must be skeletally mature with closed physes

Diagnosis of ACL tear with planned surgery confirmed via clinical examination and MRI within the past 8–10 weeks

No previous ACL injury or reconstruction on either the involved limb or noninvolved limb

At least a 5/10 on the Tegner Activity Scale

Pass the PARQ questionnaire with the exception of question 5, “Do you have a bone or joint problem?”, because the participant pool
being recruited for this study will have an ACL tear and having this injury does not change the risk for the participant

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Exclusion Criteria
Complete knee dislocation

Surgical management requiring repair of other structures within the knee other than the ACL and menisci (such as PCL, MCL, LCL)

Any current or previous conditions or surgeries that might affect gait

Body mass index ≥35

Pregnant

Spinal fusion

Any implanted medical device or other contraindication for MRI

History of deep vein thrombosis and/or varicose veins or family history of deep vein thrombosis

Taking Warfarin/Coumadin, Clopidogrel/Plavix, Rivaroxabn/Xarelto, Dabigatran/Pradaxa, Apixaban/Eliguis, Edoxaban/Savaysa,


Betrixaban, or any other anti-coagulant that may cause excess bleeding

Allergic to Betadine or Xylocaine HCl

Recent inflammation, bleeding disorders, active bleeding, or infection within the lower limbs

Diabetic or have uncontrolled hypertension

Diminished capacity to provide informed consent

Unfeasible to attend regular physical therapy and study visits


a
ACL = anterior cruciate ligament; BFRT = blood flow restriction training; HCl = hydrochloride; LCL = lateral collateral ligament; MCL = medial
collateral ligament; MRI = magnetic resonance imaging; PARQ = physical activity readiness questionnaire; PCL = posterior cruciate ligament.

Postsurgical physical therapy will involve visits 3 times per standard of care group with minimal restriction pressure
week for 6 to 7 months. This phase will be divided into 3 (less than 20 mmHg). For both groups, the band will be
stages. Stage 1 will be initiated within 3 days postsurgery placed proximally on the thigh as per manufacturer’s
and will continue for 2 to 6 weeks postsurgery. This stage instructions and will be controlled by a central unit that
will involve effusion management, muscle activation, continuously monitors the pressure in the leg. The central
range of motion, and returning to walking without the use unit will be shrouded from the participants; therefore, the
of crutches (eAppendix 1, Part B). Stage 2 will be initiated participants will not be able to see what the restriction
once all goals of Stage 1 have been achieved, typically 4 to pressure is set to. All participants will perform the same
6 weeks postsurgery. This stage will involve progression exercises with an emphasis on quadriceps strengthening.
of strengthening, proprioception exercises, and functional This step will control for the potential effect of differing
movement patterns (eAppendix 1, Part C). Stage 3 will be exercise programs and allow us to more accurately
initiated once all goals of Stage 2 have been achieved, determine the efficacy of BFRT.
typically 3 to 5 months after surgery. This stage will
involve introduction to dynamic agility, running, and Each BFRT session will last for approximately 20 minutes.
impact training in preparation for return to activity and Participants will receive BFRT for 4 weeks presurgery.
sport (eAppendix 1, Part D). BFRT will resume 2 weeks postsurgery and finish 4 to 5
months postsurgery at the time of Visit 4 (Fig. 1).
Participants with an isolated ACL reconstruction will finish
Blood flow restriction training. BFRT will use 1 of 2 at 4 months postsurgery, whereas participants with an ACL
systems (Brand 1 and Brand 2). Brand 1 will be utilized as reconstruction and meniscus repair will finish at 5 months
the active unit for the BFRT group with the restriction postsurgery due to initial weight-bearing and ROM
pressure set per manufacturer’s instructions, whereas restrictions.
Brand 2 will be utilized as the placebo unit for the

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Blood Flow Restriction Training: ACL Reconstruction

Physical Therapist Training and Treatment Fidelity


The physical therapists underwent a structured period of
training for 1 month, which involved instruction on the
theory and application of BFRT, practice trials of the BFRT
protocol with healthy individuals, and co-treating while
following the standard rehabilitation program to ensure
consistency among the physical therapists. Strict
adherence and compliance with the study’s manual of
operations will be maintained with any protocol
deviations being recorded and reviewed to assist in
research adherence to study protocols. All potential
adverse events will be reported within 24 hours to the

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Institutional Review Board and the Data and Safety
Monitoring Board. An adverse event form will be
completed, collected, and analyzed for all adverse events.
Subsequent follow-up will then follow standard operating
procedures as outlined in Figure 3. The physical therapists
will complete standardized treatment notes for each visit,
Figure 2.
and treatment fidelity will be assessed using a treatment
Rating of perceived effort. The scale begins at 0, which is defined as
no physical effort is taking place. This can be likened to the percep- checklist and audits.
tion of effort sitting on an exercise machine but not having to exert
any effort to complete the activity. The scale ends at 10, which is
described as the maximum perceivable effort. This can be likened to Outcome Measures
the perception of effort when, despite putting forth as much exer- The primary outcome measure will be peak quadriceps
tion as you can, you cannot physically complete the activity being strength and rate of torque development measured both
attempted. isometrically and isokinetically. For the isometric
measurements, each participant will perform 5 maximal
isometric contractions at 90 degrees of knee flexion with
Presurgery exercises and later stage postsurgery exercises 30 seconds of rest in between each contraction. For the
will consist of the seated knee extension machine, seated isokinetic measurements, each participant will perform 10
leg press machine, box step ups and step downs, and wall repetitions of knee flexion and extension at 150 degrees
squats with exercise ball (eAppendix 2, Part A, available at per second. Quadriceps strength will be assessed with a
https://academic.oup.com/ptj). Early stage postsurgery Biodex Multi-Joint System 4 Isokinetic Dynamometer
exercises will be non-weight–bearing exercises consisting (Biodex Medical Systems, Shirley, NY, USA) at Visits 2, 3, 4,
of quadriceps sets, short arc quads, long arc quads, prone and 5 (Fig. 1).
terminal knee extensions, and straight leg raises
(eAppendix 2, Part B). Exercise intensity will be The secondary outcome measures will include knee
progressively increased if the participant reports less than biomechanics as well as quadriceps muscle morphology
a 7 on the rating of perceived effort scale (Fig. 2). All and physiology. The participant’s knee biomechanics,
exercises will be performed at the end of each physical including knee extensor moment, knee flexion excursion,
therapist visit to minimize the effect of quadriceps fatigue and knee flexion angle, will be assessed via 3-dimensional
on the other exercises that the participants will be motion analysis. Participants will perform walking (Visits
performing as part of their visit. 2, 3, 4, and 5), step downs (Visits 2, 3, 4, and 5), running
(Visit 5), and drop vertical jumps (Visit 5). To evaluate
Treatment Adherence quadriceps muscle morphology, we will assess
Participants must attend 80% of their physical therapist physiological cross-sectional area (PCSA) and T1 rho
visits and cannot have more than 12 consecutive days relaxation times with magnetic resonance imaging (MRI)
between visits up until the time point of Visit 4. at Visits 2 and 4. Lastly, we will evaluate quadriceps
Participants with an isolated ACL reconstruction must muscle physiology through assessments of muscle fiber
attend 48 of 60 visits during this timeframe (1 month type, muscle fiber size, satellite cell proliferation,
presurgery and 4 months postsurgery), and participants fibrogenic/adipogenic progenitor cells, and extracellular
with an ACL reconstruction and meniscus repair must matrix composition from muscle biopsies collected at
attend 58 of 72 visits during this timeframe (1 month Visits 2 and 4 (Fig. 1). A variety of immunohistochemical
presurgery and 5 months postsurgery). Any participant not and histochemical assays will be used to evaluate these
meeting this requirement will be withdrawn from the cellular features in muscle.47,51,52 Assessing quadriceps
study and omitted from the analysis. Participants will muscle morphology and physiology will assist in
continue with standard physical therapy visits until understanding the mechanisms underlying the effects of
conclusion of the study at 6 to 7 months. BFRT.

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Figure 3.
Flow of adverse event reporting.

Data Analysis With a conservative estimate of a potential attrition rate of


up to 20%, a total of 60 participants will be recruited (30
Power calculations. Based on data from our preliminary
per group).
pilot study, a sample size of 48 participants (24 per group)
was calculated to detect a between-group difference of 39
± 47 Nm in quadriceps strength, with 80% power, at a Statistical analysis. Continuous variables will be
2-tailed significance level of .05. The power analyses for summarized with descriptive statistics (eg, sample size,
additional outcome measures are provided in Table 2. mean, standard error). Analysis of variance, analysis of
covariance (ANCOVA), and multivariate analysis of

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Blood Flow Restriction Training: ACL Reconstruction

Table 2.
Power Analysis for Primary and Secondary Outcome Measuresa

Difference to
Outcome Measure Estimated SD Powerb
Detect
Peak quadriceps torque (Nm) 47 39 80%

Knee extensor moment (Nm/kg) 0.50 0.42 81%

Knee flexion angle (degrees) 4.7 4 82%

PCSA (cm2 ) 32 27 82%

T1 rho relaxation time (s) 0.004 0.005 >90%

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Muscle fiber type (type 2A fiber relative frequency) 0.09 0.08 85%

Satellite cell abundance (Pax7 + satellite cells/fiber) 0.05 0.05 >90%

Fibroblasts (Tcf4 + fibroblasts/mm2 ) 21 18 83%

FAPs (PDGFRα + FAPs/mm ) 2


1.3 1.1 82%
a
FAPs = fibrogenic/adipogenic progenitors; Pax7 = paired box 7; PCSA = physiological cross-sectional area;
PDGFRα = platelet-derived growth factor receptor alpha; Tcf4 = transcription factor 4.
b
Power analyses performed with a sample size of 48 participants and an α = .05

variance will be used as appropriate depending on the Despite the growing use of BFRT, few studies have
outcome under analysis. Categorical variables will be assessed its use following an ACL reconstruction.48–50 For
summarized with inferential statistics (eg, counts, example, Takrada et al48 reported a significant increase in
percentages) and will be analyzed with appropriate knee extensor cross-sectional area in individuals receiving
statistical methods, such as logistic regression models. We BFRT. However, the study followed an outdated
will include potential confounders (eg, age, sex, race, time rehabilitation protocol in which no exercise stimulus was
to surgery) as covariates during analysis. For example, for provided with the BFRT. More recently, Iverson et al50
the primary outcome, quadriceps strength, we plan to followed a near identical protocol; however, they
perform an ANCOVA on quadriceps strength change performed quadriceps exercises concurrently with BFRT.
scores for all participants in the study, including In contrast to Takrada et al,48 they found no significant
explanatory variables such as age, sex, and treatment differences in cross-sectional area in participants receiving
group. Next, if the ANCOVA shows significance, posthoc BFRT compared with a matched control group. Lastly,
tests will be performed to identify differences over Ohta et al49 reported a significant increase in muscular
combinations of treatment group and/or sex. However, if strength and cross-sectional area in individuals receiving
model assumptions are not satisfied, remedial measures BFRT after an ACL reconstruction compared with a
(eg, variable transformations, nonparametric methods) will matched control group. In contrast to the other studies,
be employed. All data will be analyzed using SAS or R, Ohta et al49 used a standardized occlusion pressure (180
and data with P values of ≤ .05 will be considered mmHg) for all participants. Further, none of the studies to
statistically significant. Multiple testing corrections will be date have examined whether the improved cross-sectional
made as appropriate. area or strength transfers to improved movement
mechanics during common tasks such as walking,
Role of the Funding Source running, and jumping. The equivocal results and lack of
The funder (National Institutes of Health, ref. no. detailed assessments of mechanics among these studies
AR071398–01A1) played no role in the design, suggest a continued need to assess BFRT in individuals
implementation, analysis, interpretation of results, or the who have had an ACL reconstruction.
decision as to if and where to publish papers.
The combined use of 2 MRI techniques to evaluate PCSA
Discussion and the percentage of contractile and noncontractile tissue
To date, little is known of the effects of BFRT within could provide new insights on the effect of BFRT.
injured populations. To address this limitation, we will Previously, PCSA has been shown to be strongly related to
evaluate the effect of BFRT across scales from whole joint maximum muscle strength.53 Although important insights
mechanics and strength to morphological features of the have already been gained through assessment of muscle
muscle as well as cellular alterations within the cross-sectional area and muscle volume,54,55 these
quadriceps. We expect to identify potential mechanisms of techniques do not consider the overall architecture of the
action of this intervention within an injured population. muscle, such as the pennation angle and muscle fiber tract
This would in turn provide foundational evidence for length. Additionally, through the use of T1 rho, we will
using this treatment in physical therapy. delineate the change that is due to the addition of

1016  Physical Therapy Volume 99 Number 8 2019


Blood Flow Restriction Training: ACL Reconstruction

contractile tissues vs noncontractile tissue.53 These Providing facilities/equipment: P.A. Hardy, A.H. Andersen, C.S. Fry,
sequences will provide additional insight on whole muscle B.W. Noehren
morphology not previously known in the study of the Consultation (including review of manuscript before submitting):
effects of BFRT. L.N. Erickson, K.C. Hickey Lucas, C.A. Jacobs, P.A. Hardy, B.W. Noehren
Sponsor Contact Information: National Institutes of Health (NIH), 9000
Rockville Pike, Bethesda, MD 20892; Phone: 301–496-4000; Email:
The effects of BFRT after an ACL tear will be evaluated at
NIHinfo@od.nih.gov.
the cellular level through pre- and postassessment of
muscle biopsies taken from the vastus lateralis muscle. Executive Committee: primary investigator (Dr Brian Noehren), site directors
Negative alterations such as muscle fiber type switching, (Dr Brian Noehren, University of Kentucky; Dr Christopher Fry, University of
expansion of the extracellular matrix, and reduction of Texas Medical Branch), biostatistician (Dr Katherine Thompson), compliance
and subject recruitment leader (Dr Cale Jacobs), and medical officer (Dr
muscle satellite cell abundance impede skeletal muscle
Darren Johnson).
plasticity.56–59 We have, in our preliminary studies,

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Steering Committee: primary investigator (Dr Brian Noehren), site directors
reported that many of these alterations occur after the (Dr Brian Noehren, University of Kentucky; Dr Christopher Fry, University of
injury and before surgery.47,51 The administration of BFRT Texas Medical Branch), biostatistician (Dr Katherine Thompson), compliance
before surgery will allow us to assess the potential it has and subject recruitment leader (Dr Cale Jacobs), study coordinator (Ms
to reverse or even stop previously reported negative Jessica Newton), research assessors (Dr Peter Hardy, Dr Anders Andersen, Ms
alterations. Kylie Davis), research assistants (Dr Lauren Erickson, Dr Kathryn Hickey
Lucas), and medical officer (Dr Darren Johnson).
We recognize that there are several limitations and design
Ethics Approval
constraints in this study. For example, the physical
therapists are not blinded to the treatment groups. We This study was approved by the University of Kentucky’s Institutional Review
have attempted to minimize potential bias by using Board (15–0750-F6A).
standardized scripts for explaining the BFRT intervention
Funding
and all assessments are performed by the outcome
assessors who are blinded to group allocation. Another The funding for this study was provided by a National Institutes of Health
limitation is that if sample sizes are not large enough, it (NIH) research grant (ref. no. AR071398–01A1).
may not be feasible to conduct an intent-to-treat analysis Clinical Trial Registration
or missing data imputation for participants who drop out
of the study. However, based on our prior studies, dropout This study was registered at ClinicalTrials.gov (ref. no. NCT03364647).
is anticipated to be low, and this has been accounted for Protocol modifications will be reported to the University of Kentucky’s
Institutional Review Board and to the trial registry. Participants are assigned a
in our power analyses. We will investigate the effect of
numeric code for all documentation. The electronic data are stored on
omitting these participants in our future publications. In
password-protected computers and server. Limited study personnel will have
addition, we recognize that there are many potential administrative rights to access the data via password-protected files.
settings of BFRT and that we are able to assess only 1 set
of BFRT treatment parameters. Therefore, there is the Disclosures
potential that more effective criteria exist than those we The authors completed the ICJME Form for Disclosure of Potential Conflicts
have chosen. of Interest. They reported no conflicts of interest.

DOI: 10.1093/ptj/pzz062
To ensure that the results of our study will inform physical
therapists and have an impact on patient care, results will
References
be presented at scientific conferences and published in
academic journals. We also will disseminate the results of 1 Griffin LY, Albohm MJ, Arendt EA et al. Understanding and
preventing noncontact anterior cruciate ligament injuries: a
this clinical trial to professional groups, including the review of the Hunt Valley II meeting, January 2005. Am J
American Physical Therapy Association (APTA), American Sports Med. 2006;34:1512–1532.
College of Sports Medicine (ACSM), and National Institutes 2 McLean SG, Beaulieu ML. Complex integrative morphological
of Health (NIH). and mechanical contributions to ACL injury risk. Exerc Sport
Sci Rev. 2010;38:192–200.
3 Mather RC, III, Koenig L, Kocher MS et al. Societal and
economic impact of anterior cruciate ligament tears. J Bone
Joint Surg Am. 2013;95:1751–1759.
Author Contributions and Acknowledgments
4 Palmieri-Smith RM, Thomas AC, Wojtys EM. Maximizing
Concept/idea/research design: L.N. Erickson, K.C. Hickey Lucas, K.A. Davis, quadriceps strength after ACL reconstruction. Clin Sports Med.
C.A. Jacobs, K.L. Thompson, C.S. Fry, B.W. Noehren 2008;27:405–424, VII–IX.
Writing: L.N. Erickson, K.C. Hickey Lucas, K.A. Davis, C.S. Fry, B.W. Noehren 5 Maletis GB, Cameron SL, Tengan JJ, Burchette RJ. A
Data collection: L.N. Erickson, K.C. Hickey Lucas, K.A. Davis, P.A. Hardy, prospective randomized study of anterior cruciate ligament
A.H. Andersen, B.W. Noehren
reconstruction: a comparison of patellar tendon and
quadruple-strand semitendinosus/gracilis tendons fixed with
Data analysis: L.N. Erickson, K.C. Hickey Lucas, K.A. Davis, K.L. Thompson, bioabsorbable interference screws. Am J Sports Med.
P.A. Hardy, A.H. Andersen, B.W. Noehren 2007;35:384–394.
Project management: C.A. Jacobs, P.A. Hardy, B.W. Noehren 6 Jansson KA, Linko E, Sandelin J, Harilainen A. A prospective
Fund procurement: A.H. Andersen, B.W. Noehren randomized study of patellar versus hamstring tendon

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Blood Flow Restriction Training: ACL Reconstruction

autografts for anterior cruciate ligament reconstruction. Am J 23 Tengman E, Brax Olofsson L, Stensdotter AK, Nilsson KG,
Sports Med. 2003;31:12–18. Hager CK. Anterior cruciate ligament injury after more than
7 Feller JA, Webster KE. A randomized comparison of patellar 20 years. II. Concentric and eccentric knee muscle strength.
tendon and hamstring tendon anterior cruciate ligament Scand J Med Sci Sports. 2014;24:e501–e509.
reconstruction. Am J Sports Med. 2003;31:564–573. 24 Tourville TW, Jarrell KM, Naud S, Slauterbeck JR, Johnson RJ,
8 Snyder-Mackler L, Delitto A, Bailey SL, Stralka SW. Strength of Beynnon BD. Relationship between isokinetic strength and
the quadriceps femoris muscle and functional recovery after tibiofemoral joint space width changes after anterior cruciate
reconstruction of the anterior cruciate ligament. A ligament reconstruction. Am J Sports Med. 2014;42:302–311.
prospective, randomized clinical trial of electrical stimulation. 25 Krishnan C, Williams GN. Factors explaining chronic knee
J Bone Joint Surg Am. 1995;77:1166–1173. extensor strength deficits after ACL reconstruction. J Orthop
9 Witvrouw E, Bellemans J, Verdonk R, Cambier D, Coorevits P, Res. 2010;29:633–640.
Almqvist F. Patellar tendon vs. doubled semitendinosus and 26 Snyder-Mackler L, De Luca PF, Williams PR, Eastlack ME,
gracilis tendon for anterior cruciate ligament reconstruction. Bartolozzi AR , 3rd. Reflex inhibition of the quadriceps
Int Orthop. 2001;25:308–311. femoris muscle after injury or reconstruction of the anterior

Downloaded from https://academic.oup.com/ptj/article/99/8/1010/5429468 by guest on 20 September 2023


10 Natri A, Jarvinen M, Latvala K, Kannus P. Isokinetic muscle cruciate ligament. J Bone Joint Surg Am. 1994;76:
performance after anterior cruciate ligament surgery. 555–560.
Long-term results and outcome predicting factors after 27 Chmielewski TL, Wilk KE, Snyder-Mackler L. Changes in
primary surgery and late-phase reconstruction. Int J Sports weight-bearing following injury or surgical reconstruction of
Med. 1996;17:223–228. the ACL: relationship to quadriceps strength and function.
11 Hiemstra LA, Webber S, MacDonald PB, Kriellaars DJ. Knee Gait Posture. 2002;16:87–95.
strength deficits after hamstring tendon and patellar tendon 28 Noehren B, Andersen A, Hardy P et al. Cellular and
anterior cruciate ligament reconstruction. Med Sci Sports morphological alterations in the vastus lateralis muscle as the
Exerc. 2000;32:1472–1479. result of ACL injury and reconstruction. J Bone Joint Surg Am.
12 Lewek M, Rudolph K, Axe M, Snyder-Mackler L. The effect of 2016;98:1541–1547.
insufficient quadriceps strength on gait after anterior cruciate 29 Martin-Hernandez J, Marin PJ, Menendez H et al. Changes in
ligament reconstruction. Clin Biomech (Bristol, Avon). muscle architecture induced by low load blood flow restricted
2002;17:56–63. training. Acta Physiol Hung. 2013;100:411–418.
13 Lepley LK. Deficits in quadriceps strength and 30 Scott BR, Loenneke JP, Slattery KM, Dascombe BJ. Exercise
patient-oriented outcomes at return to activity after ACL with blood flow restriction: an updated evidence-based
reconstruction: a review of the current literature. Sports approach for enhanced muscular development. Sports Med.
Health. 2015;7:231–238. 2015;45:313–325.
14 Palmieri-Smith RM, Lepley LK. Quadriceps strength 31 Scott BR, Loenneke JP, Slattery KM, Dascombe BJ. Blood flow
asymmetry after anterior cruciate ligament reconstruction restricted exercise for athletes: a review of available evidence.
alters knee joint biomechanics and functional performance at J Sci Med Sport. 2016;19:360–367.
time of return to activity. Am J Sports Med. 2015;43:
32 Slysz J, Stultz J, Burr JF. The efficacy of blood flow restricted
1662–1669. exercise: a systematic review & meta-analysis. J Sci Med Sport.
15 Angelozzi M, Madama M, Corsica C et al. Rate of force 2015;19:669–675.
development as an adjunctive outcome measure for 33 Pearson SJ, Hussain SR. A review on the mechanisms of
return-to-sport decisions after anterior cruciate ligament
blood-flow restriction resistance training-induced muscle
reconstruction. J Orthop Sports Phys Ther. 2012;42:
772–780. hypertrophy. Sports Med. 2015;45:187–200.
34 Shoenfeld BJ. Potential mechanisms for a role of metabolic
16 Aagaard P, Simonsen EB, Andersen JL, Magnusson P, stress in hypertrophic adaptations to resistance training.
Dyhre-Poulsen P. Increased rate of force development and
Sports Med. 2013;43:179–194.
neural drive of human skeletal muscle following resistance
training. J Appl Physiol (1985). 2002;93:1318–1326. 35 Nielsen JL, Aagaard P, Bech RD et al. Proliferation of
myogenic stem cells in human skeletal muscle in response to
17 Jordan MJ, Aagaard P, Herzog W. Rapid low-load resistance training with blood flow restriction. J
hamstrings/quadriceps strength in ACL-reconstructed elite
Physiol. 2012;590:4351–4361.
Alpine ski racers. Med Sci Sports Exerc. 2015;47:109–119.
36 Thiebaud RS, Yasuda T, Loenneke JP, Abe T. Effects of
18 Kline PW, Morgan KD, Johnson DL, Ireland ML, Noehren B.
low-intensity concentric and eccentric exercise combined
Impaired quadriceps rate of torque development and knee
mechanics after anterior cruciate ligament reconstruction with blood flow restriction on indices of exercise-induced
muscle damage. Interv Med Appl Sci. 2103;5:53–59.
with patellar tendon autograft. Am J Sports Med.
2015;43:2553–2558. 37 Scott BR, Slattery KM, Sculley DV, Dascombe BJ. Hypoxia and
resistance exercise: a comparison of localized and systemic
19 Hart JM, Ko JW, Konold T, Pietrosimione B. Sagittal plane methods. Sports Med. 2014;44:1037–1054.
knee joint moments following anterior cruciate ligament
injury and reconstruction: a systematic review. Clin Biomech 38 Suga T, Okita K, Takada S et al. Effect of multiple set on
(Bristol, Avon). 2010;25:277–283. intramuscular metabolic stress during low-intensity resistance
exercise with blood flow restriction. Eur J Appl Physiol.
20 Paterno MV, Ford KR, Myer GD, Heyl R, Hewett TE. Limb 2012;112:3915–3920.
asymmetries in landing and jumping 2 years following
anterior cruciate ligament reconstruction. Clin J Sport Med. 39 Kacin A, Strazar K. Frequent low-load ischemic resistance
2007;17:258–262. exercise to failure enhances muscle oxygen delivery and
endurance capacity. Scand J Med Sci Sports.
21 Ardern CL, Taylor NF, Feller JA, Webster KE. Fifty-five per
2011;21:e231–e241.
cent return to competitive sport following anterior cruciate
ligament reconstruction surgery: an updated systematic 40 Abe T, Loenneke JP, Fahs CA, Rossow LM, Thiebaud RS,
review and meta-analysis including aspects of physical Bemben MG. Exercise intensity and muscle hypertrophy in
functioning and contextual factors. Br J Sports Med. blood flow-restricted limbs and non-restricted muscles: a brief
2014;48:1543–1552. review. Clin Physiol Funct Imaging. 2012;32:247–252.
22 Ardern CL, Webster KE, Taylor NF, Feller JA. Return to sport 41 Loenneke JP, Thiebaud RS, Fahs CA, Rossow LM. Blood
following anterior cruciate ligament reconstruction surgery: a flow-restricted resistance exercise: rapidly affecting the
systematic review and meta-analysis of the state of play. Br J myofibre and the myonuclei. J Physiol. 2012;590:5271.
Sports Med. 2011;45:596–606.

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Blood Flow Restriction Training: ACL Reconstruction

42 Loenneke JP, Wilson JM, Marin PJ, Zourdos MC, Bemben MG. 51 Fry CS, Johnson DL, Ireland ML, Noehren B. ACL Injury
Low intensity blood flow restriction training: a meta-analysis. reduces satellite cell abundance and promotes fibrogenic cell
Eur J Appl Physiol. 2012;112:1849–1859. expansion within skeletal muscle. J Orthop Res.
43 Wernbom M, Apro W, Paulsen G, Nilsen TS, Blomstrand E, 2017;35:1876–1885.
Raastad T. Acute low-load resistance exercise with and 52 Fry CS, Noehren B, Mula J et al. Fibre type-specific satellite
without blood flow restriction increased protein signalling cell response to aerobic training in sedentary adults. J Physiol.
and number of satellite cells in human skeletal muscle. Eur J 2014;592:2625–2635.
Appl Physiol. 2013;113:2953–2965.
53 Powell PL, Roy RR, Kanim P, Bello MA, Edgerton VR.
44 Moritani T, Sherman WM, Shibata M, Matsumoto T, Shinohara Predictability of skeletal muscle tension from architectural
M. Oxygen availability and motor unit activity in humans. Eur determinations in guinea pig hindlimbs. J Appl Physiol Respir
J Appl Physiol Occup Physiol. 1992;64:552–556. Environ Exerc Physiol. 1984;57:1715–1721.
45 Takarada Y, Sato Y, Ishii N. Effects of resistance exercise 54 Thomas AC, Wojtys EM, Brandon C, Palmieri-Smith RM.
combined with vascular occlusion on muscle function in Muscle atrophy contributes to quadriceps weakness after
athletes. Eur J Appl Physiol. 2002;86:308–314. anterior cruciate ligament reconstruction. J Sci Med Sport.

Downloaded from https://academic.oup.com/ptj/article/99/8/1010/5429468 by guest on 20 September 2023


46 Takarada Y, Takazawa H, Sato Y, Takebayashi S, Tanaka Y, 2016;19:7–11.
Ishii N. Effects of resistance exercise combined with moderate 55 Williams GN, Snyder-Mackler L, Barrance PJ, Buchanan TS.
vascular occlusion on muscular function in humans. J Appl Quadriceps femoris muscle morphology and function after
Physiol (1985). 2000;88:2097–2106. ACL injury: a differential response in copers versus
47 Noehren B, Andersen A, Hardy P et al. Cellular and non-copers. J Biomech. 2005;38:685–693.
morphological alterations in the vastus lateralis muscle as the 56 Fry CS, Lee JD, Jackson JR et al. Regulation of the muscle
result of ACL injury and reconstruction. J Bone Joint Surg Am. fiber microenvironment by activated satellite cells during
2016;98:1541–1547. hypertrophy. FASEB J. 2014;28:1654–1665.
48 Takarada Y, Takazawa H, Ishii N. Applications of vascular 57 Sato K, Li Y, Foster W et al. Improvement of muscle healing
occlusion diminish disuse atrophy of knee extensor muscles. through enhancement of muscle regeneration and prevention
Med Sci Sports Exerc. 2000;32:2035–2039. of fibrosis. Muscle Nerve. 2003;28:365–372.
49 Ohta H, Kurosawa H, Ikeda H, Iwase Y, Satou N, Nakamura S. 58 Fry CS, Kirby TJ, Kosmac K, McCarthy JJ, Peterson CA.
Low-load resistance muscular training with moderate Myogenic progenitor cells control extracellular matrix
restriction of blood flow after anterior cruciate ligament production by fibroblasts during skeletal muscle hypertrophy.
reconstruction. Acta Orthop Scand. 2003;74:62–68. Cell Stem Cell. 2017;20:56–69.
50 Iversen E, Røstad V, Larmo A. Intermittent blood flow 59 Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur
restriction does not reduce atrophy following anterior NK, Yan Z, Spiegelman BM. Skeletal muscle fiber-type
cruciate ligament reconstruction. J Sport Health Sci. 2016;5: switching, exercise intolerance, and myopathy in PGC-1alpha
115–118. muscle-specific knock-out animals. J Biol Chem.
2007;282:30014–30021.

2019 Volume 99 Number 8 Physical Therapy  1019

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