Blood Flow Restriction Therapy Following Acute Shoulder Injury Patients: Assessment of Efficacy in Return to Activity
Phase: NA
Conditions: Shoulder Injury
Sponsor: Wake Forest University Health Sciences

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Blood Flow Restriction Therapy Following Acute Shoulder Injury Patients: Assessment of Efficacy 
in Return to Activity 
 
 
 
IRB00103746 
 
 
NCT06223373 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Title: Blood Flow Restriction Therapy Following Acute Shoulder Injury Patients: 
Assessment of Efficacy in Return to Activity 
 
Principal Investigator, Co-investigator(s): Kristen Nicholson, Edward Beck, Brian Waterman 
 
Sponsor or funding source: None 
 
Background, Rationale and Context 
 
Upper extremity injuries are a detriment to the careers of overhead throwing athletes, including baseball 
players at all playing levels. Recent estimates suggest that professional Major League Baseball (MBL) 
players have lost 7 billion dollars in wages due to injuries,1 most of which are of the upper extremity.2, 3 
Atrophy and weakness of the shoulder are a common problem following treatment of a number of 
shoulder and elbow pathologies.4-6 Even with relatively short periods of reduced activity, the magnitude 
of muscle loss can be quite substantial. 7 In attempts to address this issue, researchers have investigated 
therapeutic modalities to both limit muscle atrophy during the rehabilitation period and accelerate the 
strengthening process. Blood flow restriction (BFR) therapy is one such therapeutic tool that has received 
increasing attention, which involves application of a pressurized tourniquet to the injured limb during 
rehabilitation that limits atrophy when performing strength training with weight that otherwise would not 
produce enough of a contraction to prevent muscular atrophy.8 To date, several studies have been 
performed on BFR therapy, however, the effect of therapy on ligamentous and tendinous injury in the 
upper extremity remain unclear as most studies have focused on muscular strengthening in healthy 
individuals and on lower extremity injuries distal to the tourniquet.9-12   
 
Also known as Kaatsu training, BFR therapy is an increasingly common practice employed during 
resistance exercise by healthy athletes attempting to increase muscle hypertrophy and strength.13-16 During 
BFR training, blood flow to the activated muscle is mechanically restricted by placing flexible 
pressurizing cuffs around the active limb proximal to the working muscle. This results in the 
accumulation of metabolites that are associated with muscle growth.17, 18 Furthermore, other studies have 
demonstrated that BFR training may cause changes in neuromuscular function such as depressed resting 
twitch torque and enhanced post-activation potential, suggesting that BFR may have a neurological 
component to its improvements in strength.15 Most recently, Bowman et al. conducted randomized control 
trial evaluating the effect of low-load BFR training on both the proximal and distal muscle groups in 
relation to the BFR tourniquet in healthy patients. The authors demonstrated that BFR training led to a 
greater increase in muscle strength and limb circumference when compared to patients undergoing similar 
excises without the BFR tourniquet.19 This is a critical point for patients with postsurgical or acute injury 
who cannot undergo heavy weight training during physical rehabilitation, as the drive for protein 
breakdown often surpasses the stimulus required for protein synthesis, resulting in muscle atrophy and 
loss of strength.  
 
Recent literature has described the use of BFR therapy as a parallel rehabilitation for injured patients. A 
number of studies have demonstrated that BFR therapy can increase limb usage and strength in military 
patients with traumatic lower limb salvage rehabilitation.20, 21 Other clinical outcome studies have 
identified that BFR therapy can have improved outcomes when used in postoperative rehabilitation after 
knee arthroscopy and Achilles tendon rupture.9, 10 However, there are very limited studies involving BFR 
on upper extremity both distal and proximal to the pressure cuff, representing a significant gap in 
knowledge in upper extremity treatment.22 Furthermore, while these studies demonstrated improvement in 
hypertrophy and strength, they did not evaluate the effect of rehabilitation in injured patients. 
 
BFR Mechanism of Action 
 

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While the mechanism of action of BFR therapy in injury rehabilitation is not well understood, one of the 
prevailing theories involves the cascade of metabolites as result of the BFR-induced localized anabolic 
state. In the anabolic state during exercise, muscles produce lactate, which results in growth hormone 
(GH) release.23, 24 Evidence in the literature shows that individuals undergoing low-weight strength 
training exercises with BFR  have significantly higher levels of both lactate and GH when compared to 
those at similar intensity levels without BFR.25, 17, 18, 24 The increase in these metabolites are similar to 
those measured in high intensity training and heavy-load exercise.24, 26 As lactate accumulates in muscle 
fibers, it decreases the ability to generate contractions with enough force, and therefore, results in 
recruitment of additional motor units, thus preventing atropy. More importantly however, the metabolite 
cascade is theorized to promote healing of injured tendons and muscle through collagen synthesis. GH 
stimulates the production of IGF-1, an important mediator during the inflammatory and proliferative 
phase of tendon, muscle, and bone healing.27, 28 Similar to the GH studies, IGF-1 concentrations have 
been observed to be higher when using BFR in low load exercise versus similar intensity exercise without 
BFR.29, 25, 30  Local IGF-1 directly increases the number of satellite cells and tendinous stem cells recruited 
to promote tissue healing.31  
 
Another theory of mechanism of action on BFR therapy is the activation of muscle protein synthesis 
through the mammalian target of rapamycin complex 1 (MTORC1) pathway cascade. The MTORC1 is 
protein complex that, in skeletal muscle, is activated through a number of pathways including IGF-1, 
resistance exercise, amino acids.32 Studies have indicated that phosphorylation of S6K1, a downstream 
markers of MTORC1, and protein synthesis was significantly higher in patients undergoing BFR plus 
exercise at 20% effort when compared to those undergoing similar intensity exercise without BFR.30 
Furthermore, other studies have demonstrated downregulation in myostatin, which is an inhibitor of 
protein synthesis in BFR users.33 
 
Other theories on the mechanism of BFR on tissue healing involves the acute inflammatory response 
during blood flow restriction. IL-6 is a cytokine released after exercise in response to muscle 
microdamage, and plays a role in skeletal muscle regeneration by recruitment of inflammatory cells.34 As 
with IGF-1, IL-6 also contributes to the activation and proliferation of satellite cells, as well as activating 
the mTORC-1 pathway.35, 36 It is important to note, however, that while the studies above have been 
performed in the setting of BFR use on healthy individuals, the mechanism of action in injured patients 
has not been evaluated. Furthermore, these studies have only measured blood markers prior to BFR cuff 
placement and immediately after, with none evaluating the trend in changes of markers over multiple 
sessions of BFR therapy. 
 
 
Objectives 
Aim 1: To determine whether patients with non-surgical rotator cuff and biceps tendinopathy 
undergoing BFR rehabilitation show increased improvements in shoulder function relative to 
patients undergoing routine therapy with a tourniquet that is not occluding arterial blood (i.e. sham 
BFR). We hypothesize that patients undergoing rehabilitation with BFR tourniquet pressurized to 
recommended therapeutic specifications will have increased muscle strength and CSA, as well as higher 
functional score averages compared to patients undergoing rehabilitation with sham BFR. We will be 
measuring shoulder strength in injured and non-injured arms for both study groups using a Biodex testing 
machine. Ultrasound will be used to measure the CSA of the rotator cuff muscles. Both strength testing 
and ultrasound measurements will be performed before and after the rehabilitation protocol has been 
completed. Patients will receive questionnaires evaluating shoulder function at baseline, once cleared by 
physical therapy, as well as 6 and 12 months after completing rehabilitation. 
  
Aim 2: To determine whether trends in blood biomarker concentration differ between both groups 
throughout the rehabilitation protocol. We hypothesize that patients undergoing BFR will have higher 

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trends in GH,IL-6, and IGF-1 over the 6 week rehabilitation protocol. Patients will receive the blood 
draws in clinic at the following time points: prior to 1st day of rehabilitation, half-way through the 
protocol (approximately 3 weeks), and after completing rehabilitation (approximately 6 weeks). ELISA 
will be used to quantify GH, IL-6, and IGF-1 plasma levels at the 6 time points. The trends in these 3 
blood markers will be compared between the two groups.  
 
Methods and Measures 
 
Design 
Describe the basic design of the study, use as many of the following terms as apply.  
• 
For intervention studies: randomized controlled trial; placebo-controlled; before-after 
trial; pilot study 
 
Setting 
Academic medical center 
 
Subjects selection criteria 
 
• 
Inclusion Criteria 
• 
Inclusion criteria will be any injured patient ages 18 to 55 years with clinical and magnetic 
resonance imaging (MRI) consistent with a formal diagnosis of  non-operative rotator cuff 
and/or biceps tendinopathy, no prior upper extremity ipsilateral procedures or history of deep 
vein thrombosis, and those willing to be part of the study.  
• 
Exclusion Criteria 
• 
Exclusion criteria includes patients younger than 18 or older than 55 years of age, a history of 
revision surgery or prior ipsilateral upper extremity surgery, concomitant ligamentous, 
tendinous, or cartilage injury that would alter postoperative rehabilitation protocol, inability 
to comply with the proposed follow-up clinic visits, and patients lacking decisional capacity.  
• 
Sample Size 
• 
Based on the literature review, there are no published studies that have evaluated the effect 
BFR therapy on shoulder injury rehabilitation. Some studies have taken a pilot study 
approach and used 12 patients in each limb based off what has been recommended in the 
previous literature.45, 46  However, others evaluating the effect of BFR therapy on quadriceps 
strength after ACL reconstruction have evaluated their sample size based on their own 
preliminary pilot studies and established sample sizes of 24 per group in order to achieve 
80% power.47 A previous study comparing  GH levels between healthy individuals 
undergoing BFR strength training vs those without was used to estimate the number of 
patients needed to achieve at least 80% power.48 Based of the difference in GH between the 
two groups, an effect size of 2.203 was calculated. An a priori power analysis demonstrated 
that 6 patients were required in each group in order to achieve a power of 90%. However, we 
feel that the standard deviation of the current study may be larger, and as such, for this pilot 
study we will recruit a minimum of 8 patients in each arm. However, we hope to recruit at 
least 12 in each arm by the time the study is completed in order to have 24 patients similar to 
established sample sizes in other BFR studies.47 
 
Interventions and Interactions 
Study Arms   
 
 
Once consented, patient will be enrolled in of the two study arms prior to beginning physical 
rehabilitation. Patients will be randomized to one of the study arms using Microsoft Excel (version 

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16.82). Prior to beginning therapy, patients will undergo a blood draw at the clinic to establish baseline 
blood biomarkers. The patient will also undergo upper extremity physical strength assessment, and 
functional evaluation prior to beginning therapy. Baseline patient reported functional status will also be 
evaluated though upper extremity-specific questionnaires. During physical therapy, participants will 
undergo blood draws, receive electronic questionnaires, and undergo assessment of biomechanical at 
specified time points outlined below. Patient questionnaire information will be de-identified and coded 
into an encrypted centralized database. The schematic in figure 1 provides the time points of each 
datapoint collected. 
 
Figure 1. Schematic of study workflow indicating timepoints for carrying out study aims 
 
BFR Protocol 
 
Patients assigned to the BFR group will undergo BFR therapy during each session throughout the 
entire rehabilitation protocol. The standard rehabilitation protocol recommended by the physical 
therapists at WFBH is 2 sessions a week for 6 weeks. The therapy will be performed by one of the WFBH 
physical therapists who is trained and certified in using BFR therapy. The standard BFR protocol that is 
implemented by the Wake Forest physical therapists and recommended by expert opinion involve 
performing 4 separate exercises during each session. Each exercise will be done 4 consecutive times, 
starting with 30 repetitions, followed by 15 repetitions performed 3 times. Each set will be separated by 
30 seconds break.  After the finishing the 4 sets for one specific exercise, the patient will rest for 2 
minutes prior to beginning the next 4 sets. In summary, the patient will perform 4 sets of 4 different 
exercises, perming the following repetitions: 30-15-15-15.  
 
In the BFR group, the tourniquet will be pressurized to 50% limb occlusion pressure (LOP), 
which is the pressure necessary for occluding 50% of arterial limb flow in the upper extremity. The 
amount of cuff inflation is personalized to each patient as a safety measure and for maximizing the acute 
physiological response.40 In the sham BFR group, the tourniquet will be pressurized to 0% occlusion 
pressure, while maintaining enough pressure to keep the tourniquet in place.  
 

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The tourniquet system (Delfi, Medial Innovations Inc) used in our physical rehabilitation clinic 
allows a patient specific LOP to be measured and automatically calculates the patient’s personalized 
tourniquet pressure (PTP) as percentage of LOP. As an additional safety measure, the cuff automatically 
shuts off after 8 minutes to prevent prolonged restriction, and is locked from turning back on for 2 
minutes. The sets for each exercise are structured so that the patient is able to finish 4 sets of one specific 
exercise within the 8 minute time limit.  
 
Shoulder Strength and Cross Sectional Area Measurement 
 
Isocentric shoulder strength will be measured for injured and non-injured arms for both groups at 
baseline, half-way through the strength training phase of rehabilitation, and once rehabilitation has 
completed. A biodex testing machine will be used to evaluate changes in strength over time. Shoulder 
strength measurements will include shoulder flexion, abduction, external rotation, and internal rotation, as 
well as elbow flexion. Strength testing will be performed prior to beginning the rehabilitation session. 
Each test will be performed 3 times and the measurement will be averaged.  
 
Ultrasound will be used to quantify the changes in rotator cuff muscle before and after therapy. 
As previously described, the supraspinatus and infraspinatus muscles will be measured in each patient 
using a standard technique.27 A multifrequency linear transducer (5-15 MHz) on a GE Logic S7 Expert 
will be used throughout the study. In order to measure the supraspinatus, the patient will sit in a chair, 
with the examiner standing behind the patient. The muscle belly of the supraspinatus and infraspinatus 
muscles will be evaluated while the patient had their hand placed on the anterior ipsilateral thigh for the 
examination. The muscle bellies of the supraspinatus and infraspinatus will be measured in the in the 
perpendicular plane to the long axis of their central tendon and muscle bellies to measure their respective 
cross sectional area and circumference. Landmark for obtaining measurement of the supraspinatus will be 
obtained by palpating the posterior corner of the acromion and measuring 8 cm medially along the spine 
of the scapula. From this position the transducer will be placed in the plane perpendicular to the spine of 
the scapula to visualize the cross section of the supraspinatus muscle belly and it’s central tendon. 
Landmark for obtaining measurement of the infraspinatus will be obtained by palpating the posterior 
corner of the acromion and measuring 5 cm medially along the spine of the scapula. From this position 
the transducer will be placed in the plane perpendicular to the spine of the scapula to visualize the cross 
section of the infraspinatus muscle belly and central tendon. Because the footprint of the transducer is 
smaller than the width of the muscle belly, panoramic images acquisition will be accomplished using 
LOGICView mode. The panoramic glide will be stopped once the full myofascial boarder between the 
infraspinatus and teres minor were in view. The difference between pre- and post-therapy cross sectional 
area of each muscle will be compared between both BFR and sham BFR groups. 
 
Blood Biomarkers 
 
 
Blood samples will be acquired at baseline prior to intervention and at specific time points 
throughout the rehabilitation process to evaluate the effect of BFR therapy on the recovery of muscle, 
tendon, and ligamentous damage. Samples will be collected prior to beginning physical therapy, half-way 
through the structured protocol, and once the patient has completed rehabilitation. These blood samples 
will be collected by a member of the research team, who is trained in phlebotomy and is someone other 
than the principal investigator, and stored in a locked freezer until all samples for all patients have been 
collected. The patients will receive the blood draws in the physical therapy clinic on the day of their 
rehabilitation appointment. Once completed, GH, IGF-1, and IL-6 will be quantified using ELISA assays 
performed in the Wake Forest orthopedic surgery department. Each sample will have 3 technical 
duplicates analyzed to avoid loss of data during sample processing.  
 
Patient Functional Status 

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Shoulder/Elbow functional status will be assessed using the following questionnaires that have 
been previously vetted for evaluation after upper extremity surgery: Quick Disabilities of the Arm, 
Shoulder, and Hand (DASH) survey, American Shoulder and Elbow Surgeons (ASES) standardized 
assessment form, visual analog scale for pain and satisfaction, and return to sport/daily activity 
questionnaires.42, 43 Patient reported outcomes will be captured prospectively over the course of one year 
using the PatientIQ, a web-based data collection healthcare platform. A blinded de-identified email and/or 
text message will be sent at baseline, and once cleared by therapy,  as well at 6 and 12 months after 
completing therapy. After three days, if a participant does not respond to the survey, a second email 
and/or text message will be sent. If the participant does not respond after three consecutive weeks, a 
phone call will be administered to encourage continued participation.44  
 
Outcome Measure(s) 
 
• 
Shoulder strength, and rotator cuff muscle cross sectional area,  
• 
Blood markers: GH, IGF-1, and IL-6 
• 
Patient reported outcome measures: DASH, ASES, visual analog scale for pain and satisfaction  
 
 
Analytical Plan 
 
Subject descriptive statistics will be analyzed using mean ± standard deviation for continuous variables, 
and frequencies and percentages for categorical variables. Normality analyses will be performed utilizing 
data visual inspection and parametric testing. Averages between the two groups will be compared using 
independent T-test and chi-square analysis were appropriate. Repeated measures ANOVA will be 
performed to evaluate statistical significance in blood biomarkers.  
 
 
Human Subjects Protection 
 
Subject Recruitment Methods 
Describe how and where subjects will be identified and recruited.  Indicate who will do the recruiting, and 
tell how subjects will be contacted.  Describe efforts to ensure equal access to participation among 
women and minorities.  Describe how you will protect the privacy of potential subjects during 
recruitment.   
 
• 
For studies using recruitment flyers and advertisements, please provide copies of these materials 
for IRB review. 
• 
For studies using PHI to identify subjects via medical records search or referral from a treating 
physician, who will then be contacted, you will need a limited waiver of HIPAA authorization,  If 
this applies to your study, please provide the following information: 
o Under this limited waiver, you are allowed to access and use only the minimum amount 
of PHI necessary to review eligibility criteria and contact potential subjects.  What 
information are you planning to collect for this purpose?  
 
o How will confidentiality/privacy be protected prior to ascertaining desire to participate?   
 
o When and how will you destroy the contact information if an individual declines 
participation?   
 

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Informed Consent 
 
Signed informed consent will be obtained from each subject. Informed consent will be gathered by the 
one of the study coordinators or study investigators in clinic after being screened with inclusion/exclusion 
criteria and prior to undergoing non-surgical treatment for the injury.  
 
 
Confidentiality and Privacy 
 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
linkage file, store separately from the data.  The linkage file will be kept secure, with access limited to 
designated study personnel.  Following data collection subject identifying information will be destroyed 
(state the anticipated time the data will be destroyed, e.g. three years after closure of the study, and the 
method of destruction), consistent with data validation and study design, producing an anonymous 
analytical data set.  Data access will be limited to study staff.  Data and records will be kept locked and 
secured, with any computer data password protected.  No reference to any individual participant will 
appear in reports, presentations, or publications that may arise from the study. 
 
 
Data and Safety Monitoring 
 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants.  The principal investigator will be assisted by other members of the study staff. 
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes will 
be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
There are potential risks in this study. Risks and side effects related to this study. Patients may 
experience discomfort, bruising and/or bleeding where the needle is inserted. Occasionally some 
people become dizzy lightheaded or feel faint. Infection may occur on rare occasions.  Risks of 
blood flow restriction tourniquet includes development of a blood clot, which could result in 
breathing complications if the clot travels to the lung. These risks have been minimized by 
excluding patients with risk factors for blood clots, as well as ensuring that the cuff is inflated to 
standard measurements that limit this risk. Other risks for tourniquet use include pain and 
discomfort at the site. However, the standard protocol limits the compression of the tourniquet to 
30 second intervals, and there are no reports of persistent pain after sessions. The benefit of BFR 
therapy in shoulder injury is unknown. It is possible that by being in the BFR rehabilitation 
group, rehabilitation process may be slower than undergoing rehabilitation with BFR included.  
 
 

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Appendix 
1. ASES survey 
2. DASH survey 
3. Consent form