The Impact of Blood Flow Restriction Training in Adolescents After ACL Reconstruction: A Randomized Controlled Trial
Phase: NA
Conditions: Anterior Cruciate Ligament Injuries, Knee Injuries, Quadriceps Muscle Atrophy
Sponsor: Connecticut Children's Medical Center

Version 1.2_.1.8.2023 
 
The Impact of Blood Flow Restriction Training on Lower Extremity Strength after ACL Reconstruction in Adolescents: A 
Randomized Controlled Trial 
IRB# :22-139 
Clinical Trial#: XXX   
January 8, 2023 
 
 
 
 
PRINICPAL INVESTIGATOR: Adam Weaver 
DEPARTMENT: Farmington Sports PT 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: aweaver@connecticutchildrens.org 
CO-INVESTIGATOR: Dylan Roman 
DEPARTMENT: Farmington Sports PT 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: droman@connecticutchildrens.org 
 
CO-INVESTIGATOR: Art Fredericks 
DEPARTMENT: Farmington Sports PT 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: Afredericks@connecticutchildrens.org 
 
CO-INVESTIGATOR: Nicholas Giampetruzzi 
DEPARTMENT: Farmington Sports PT 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: ngiampetruzzi@connecticutchildrens.org 
 
CO-INVESTIGATOR: Julie Burland, PhD, ATC, CSCS 
DEPARTMENT: Department of Kinesiology 
INSTITUTION: UCONN Institute for Sports Medicine 
PHONE: 860-488-3623 
EMAIL: julie.burland@uconn.edu 
 
CO-INVESTIGATOR: Allison Crepeau, MD 
DEPARTMENT: Department of Orthopaedics 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: acrepeau@connecticutchildrens.org 
 
CO-INVESTIGATOR Matthew Brown, MD 
DEPARTMENT: Department of Orthopaedics 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-545-9100 
EMAIL: mbrown05@connecticutchildrens.org 
 
CO-INVESTIGATOR: Donna Pacicca, MD 
DEPARTMENT: Department of Orthopaedics 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE:  860-545-9100 
EMAIL: dpacicca@connecticutchildrens.org 
CO-INVESTIGATOR: Jennifer Prue 
DEPARTMENT: Sports Medicine 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: JPrue@connecticutchildrens.org 
 
 
RESEARCH ASSISTANT: Megan Ranchinsky 
DEPARTMENT: Farmington Sports PT 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: mranchinsky@connecticutchildrens.org 
 
RESEARCH ASSISTANT: Adel Lolic 
DEPARTMENT: Farmington Sports PT 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: alolic01@connecticutchildrens.org 
STUDY COORDINATOR Jennifer Prue 
DEPARTMENT: Sports Medicine 
INSTITUTION: Connecticut Children’s Medical Center 
PHONE: 860-837-9220 
EMAIL: JPrue@connecticutchildrens.org 
 
 
 
 
 
 
 
 

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IF YES, INDICATE LEVEL: 
 
___ Medical/Dental Student 
 
 
 
 
 
 
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Note:  Student researchers are required to attend the Scientific Review Committee meeting when 
           their protocol is discussed.                                                                                                                                          
 
 
 

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Contents  
Introduction  
Purpose of Research, Specific Aims and Hypotheses 
Background  
Previous Work or Preliminary Studies 
Methods 
 
Target population 
 
Inclusion Criteria 
 
Exclusion Criteria 
 
Identification, recruitment, consent and retention of subjects  
 
Screening procedures 
Sample size justification 
Accrual and Expected Duration of Accrual 
Materials and Methods 
 
Setting 
 
Pre-testing 
 
Roles and responsibilities 
Administrative Organization 
Data Collection and Management 
Data Analysis 
Human Subjects Protection and Ethical Conduct of Study 
 
Risks and Benefits of Study 
Use of Study Results 
Budget 
Budget Justification 
Appendices 
 
 
References Cited 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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INTRODUCTION 
 
Each year approximately 200,000 adolescents and young adults sustain a traumatic anterior cruciate 
ligament (ACL) injury, and develop long-term persistent weakness in their quadriceps. Half of these individuals 
will be diagnosed with posttraumatic knee osteoarthritis within 10-15 years.1,2  Despite extensive research into 
optimal surgical and rehabilitative techniques, persistent quadriceps weakness is rampant, and nearly 1 in 3 
young athletes suffer a second ACL injury. Quadriceps weakness negatively impacts gait and lower extremity 
biomechanics,3,4 and is associated with higher risk for osteoarthritis development.5-7 Quadriceps strength is 
modifiable, however, current rehabilitative therapies often fail to address the underlying mechanism driving this 
persistent dysfunction.8,9 ACL injury induces a cascade of physiologic events10 that produces a unique muscle 
atrophy profile11 and creates an environment ripe for quadriceps muscle inhibition.12-14 The current standard of 
care in the immediate stages after ACL reconstruction (ACLR) is as follows: exercise prescription for passive 
range of motion, pain and swelling control, gait training, and neuromuscular electrical stimulation for 
quadriceps muscle recruitment. This early post-operative window is also a critical period for restoring 
quadriceps strength. 
 
BACKGROUND 
Prevalence and impact of quadriceps weakness after ACL injury.  Although there have been 
improvements and advances in surgical techniques, quadriceps weakness continues to be evident long after 
ACLR.  Best evidence suggests that return to sports occurs at approximately 9 months after ACLR. Despite 
extensive rehabilitation, deficits in quadriceps strength still vary widely after ACLR, ranging from 3-40% at 6 
months, and 3-38% at 12 months.8  Further, there is evidence that these deficits can exist up to 4 years after 
surgery.15 Unfortunately, these deficits often lead to post-traumatic osteoarthritis,5 and future re-injury.16   This 
is significant in that only 60% of these athletes return to sports at the same competitive level pre-injury.  
Therefore, it is imperative to seek new ways to address these limitations and overcome persistent quadriceps 
weakness. 
 
Quadriceps atrophy resulting from joint injury.  Atrophy is commonly seen in muscle tissue in the presence 
of disuse or inactivity. Recent evidence continues to demonstrate that the mechanisms of atrophy after 
traumatic ACL and joint injury are mechanistically and physiologically different.  After ACL injury, the 
quadriceps experiences significant decreases in muscle volume, and this may be in large part due to neural 
signaling alternations both spinally and cortically.17,18 These alterations directly impact the ability for the 
quadriceps to generate a muscle contraction.11 Alterations in neural activation to the quadriceps also lead to 
changes in muscle fiber type, which contributes to difficulty in normalizing strength. At a cellular level, there are 
a number of negative factors influencing the quadriceps after ACL injury.  Satellite cells, which are responsible 
for new muscle growth and regeneration, are often limited and fibrogenic cell expansion is seen within the 
quadriceps.19  Further, levels of myostatin are elevated after ACL injury, and this is thought to negatively affect 
muscle mass and fiber size.19  Myostatin directly influences satellite cell function, increases cytokine and other 
inflammatory components, and has a significant role in fibrotic pathways.  Clinically, this creates an 
environment not conducive for muscle growth, making traditional physical therapy challenging.  
 
Mechanisms of BFRT addressing quadriceps weakness. To date, rehabilitation strategies utilizing 
traditional strength training protocols targeting the quadriceps musculature have proven largely ineffective at 
fully restoring muscle function. This is in large part due to lack of consideration towards the underlying 
physiologic changes occurring in the muscle after ACLR. Clinical approaches that target specific cellular 
pathways should prove effective in combating muscle atrophy and inhibition and restore quadriceps function, 
and the most effective of such emerging therapies in adults is blood flow restriction training (BFRT). BFRT 
works by restricting venous outflow and partially restricting arterial outflow to the targeted tissue. While 
exercising, a pool of blood is created distal to the tourniquet that creates an environment of cellular swelling 
and local metabolic stress. The critical components of this environment is the stimulation of protein synthesis 
pathways and the local hypoxic environment, which: 1) increases type 2 fiber recruitment and 2) stimulates 
growth hormone production.20-22 Recent studies have shown the use of BFRT positively impacts muscle protein 
synthesis, muscle size, and gene expression, as well as reducing myostatin levels22-25. Kakehi et al reported 

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that the use of BFRT (14-day mobilization) resulted in preservation of the quadriceps cross sectional area, as 
well as increased MuRF1 gene expression, a marker for muscle protein synthesis.26  Further, after completion 
of an 8 week BFRT strength training program, improvements were observed in 1RM knee extension strength 
and decreased myostatin expression.23 
 
Relationship between BFRT and ACLR.  One of the earliest studies using BFRT 2x/day for 14 days after 
ACLR demonstrated an improved ability to limit post-operative muscle atrophy as compared to a control 
group.27  More recent work has shown improvements in quadriceps peak torque of greater than 10% after 9 
sessions of BFRT.28  Other recent studies have shown similar improvements in cross sectional area, 
preservation of muscle mass, and similar changes in strength.29,30 The use of BFRT after ACLR shows promise 
impacting muscle hypertrophy and knee extension strength in young adults, but has yet to be studied in 
adolescents.  Our recent work from our pilot study has demonstrated significant improvements in quadriceps 
peak torque at 3 months post-ACLR,31 and our future work will continue to build on this foundational evidence. 
 
PREVIOUS WORK 
Based on emerging work, and preliminary data from our research group,31 the implementation of blood 
flow restriction training (BFRT) may be an advantageous tool to implement in the early post-operative period to 
combat quadriceps muscle weakness.32  BFRT has been shown to be an effective alternative to high load 
resistance training (HL-RT) with comparable muscular and physiological benefits.33,34 Previous work in young 
adults demonstrated that the use of BFRT mitigates quadriceps atrophy after ACLR.27 Similarly, in adult 
patients, the use of BFRT in the early post-operative stages after ACLR has shown comparable improvements 
in quadriceps strength to HL-RT, and greater improvements in functional strength measures and self-reported 
function.29 Together, these results are promising. However, there is limited knowledge pertaining to the impact 
of BFRT on quadriceps strength and function after ACLR in an adolescent age group.  
 
The overall objective of this study is to investigate the impact of BFRT on isometric and isokinetic knee 
extension strength, quadriceps hypertrophy, and patient reported outcomes after ACLR at 5 different time 
points in the rehabilitation process. Adolescents and young adult patients undergoing ACLR at our institution 
and will be recruited to use BFRT for 8 weeks as part of their treatment compared to a standard ACL 
rehabilitation group at our institution 
 
RESEARCH QUESTION 
 
The purpose of this study is to compare the addition of a BFRT based exercise protocol to a standard 
ACL rehabilitation protocol in adolescents.   Does the addition of BFRT-based exercise improve strength, 
hypertrophy, and patient reported outcomes after ACL reconstruction in the adolescent population?   
 
PURPOSE OF THE RESEARCH, AIMS AND HYPOTHESES 
 
The specific aims of this study are as follows. 
 
Primary Aim 1: Determine if adjunct BFRT during ACLR post-surgical rehabilitation impacts isometric and 
isokinetic strength lower extremity strength, when compared to a control group receiving the standard of care 
rehabilitation. 
Hypothesis 1a: We hypothesize that isometric knee extension peak torque and limb symmetry will be greater in 
the BFRT group compared to the control group at 8 and 12 weeks after ACLR. 
Hypothesis 1b: We hypothesize that isokinetic knee extension peak torque and limb symmetry will be greater 
in the BFRT group compared to the control group at 6 months and time of return to sport after ACLR. 
Hypothesis 1c: We hypothesize that the BFRT group will show a greater change in strength from pre-operative 
testing to 8 weeks post-operative from the control group. 
 
Primary Aim 2: Determine if BFRT during ACLR post-surgical rehabilitation improves patient-reported 
outcomes (IKDC, KOOS, ACL-RSI) compared to the control group. We hypothesize that the BFRT group will 
show greater self-reported function and confidence as compared to the control group at all study time points. 
 
Secondary Aim 1:  Determine if the use of BFRT during ACLR post-surgical rehabilitation increases mid-thigh 

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circumference when compared to a control group. We hypothesize that the BFRT group will demonstrate five 
percent or greater difference in mid-thigh circumference than the control  at all study time points. 
 
OUTCOMES DEFINITIONS / DATA POINTS COLLECTED 
 
1) Demographic information: 
a. Age 
b. Medical record number 
c. Date of ACL surgery and related surgeries 
d. Date of Injury 
e. Sex 
f. Graft Type 
g. Concomitant pathology/Meniscal tear type, laterality 
h. Surgeon 
h. Surgeon 
i.  Sport 
j.  Level of competition in sport 
k. Weight, Height and BMI 
l.  Race 
m. Insurance status (Public/Private) 
n. Weight bearing status (number of weeks) 
 
 
Primary Outcomes Definitions  
Active knee range of motion: Knee AROM will be measured in supine position using a goniometer and 
standardized procedures reported by Norkin and White.35   
Mid-thigh circumference will be used to measure and track muscle hypertrophy.  
10 Repetition Max Test:  The 10 repetition max test will be used to determine an estimate 1 rep maximum on 
the Shuttle Leg Press machine, as this is a safe and reliable alternative to predicting a 1 rep maximum.   
Isometric thigh strength: Preoperative, 8 week and 12 weeks, 6 months and return to play assessments will 
measure maximum isometric muscle torque using an isokinetic dynamometer (Humac CSMi USA, Stoughton, 
MA, USA).  Return to play assessments will occur at approximately 9 months post-operative. 
Isokinetic thigh strength: For assessments at 6 months and time of return to play, maximum muscle torque will 
be assessed using an isokinetic dynamometer (Humac CSMi USA, Stoughton, MA, USA).  
 
Patient Reported Outcomes: 
1) Pediatric International Knee Documentation Committee Subjective Knee Evaluation form (Pedi-IKDC) 
2)  Knee Injury and Osteoarthritis Outcome Score (KOOS) 
3) Tegner Activity Scale 
4) Anterior Cruciate Ligament Return to Sport Index (ACL-RSI) scale.  
 
These 4 outcome measures will be collected at Pre-op, 3months, 6months, return to play, and 2 years. The 
Pedi-IKDC form is a validated knee-specific questionnaire36 that measures pain, symptoms, and functioning in 
daily and sport activities.37,38  The KOOS form is a validated questionnaire that measures patient-reported pain, 
symptoms, activities of daily living, sport and recreation and quality of life.39,40 The Tegner Activity Scale is a 2-
item outcome measure on which participants are asked to describe the peak physical activity intensity prior to 
ACL injury and at the time of study enrollment. The ACL-RSI is a validated scale that is used to evaluate 
psychological readiness to return to sport,41,42 and includes items that describe an individual’s emotions, 
confidence in performance, and risk appraisal related to re-engagement in sport after ACLR.  
 
 
STUDY DESIGN 
A single randomized control trial will compare the use of exercises augmented with BFRT with quantitative 
measurements of strength and patient-reported outcomes. A total of 40 youth and adolescent patients 
undergoing a surgical procedure for ACLR and subsequent physical therapy at our institution will be recruited 
for this study. Patients will be randomized into one of two groups using computer randomization for allocation: 

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the intervention group receiving BFRT as part of physical therapy, and the control group will follow the 
institution’s standard ACLR rehabilitation protocol. Both groups will follow a time- and criterion-based 
standardized rehabilitation protocol. The primary outcomes will be isometric and isokinetic knee peak torque 
and limb symmetry indices. Secondary outcomes will be quadriceps hypertrophy via mid-thigh circumference 
and patient-reported outcomes.  
 
Target Population 
Adolescent patients between the ages of 12 and 18 will be recruited at the time of surgery, specifically, those 
that participate in sports who are undergoing primary ACLR reconstruction at Connecticut Children’s 
 
Study Group and Control Group Inclusion Criteria 
1) Prior to surgery participated in > 50 hours/year of level I or II sports as defined by Noyes et al43 and planned 
to return to prior level. 
Level I  Sports (4-7 days/week) 
Jumping, hard pivoting, cutting (basketball, volleyball, 
football, soccer, gymnastics, skiing. wrestling) 
Running, twisting, turning (racquet sports, baseball, hockey) 
Level II sports (1-3 days/week) 
Jumping, hard pivoting, cutting (basketball, volleyball, 
football, soccer, gymnastics, skiing. wrestling) 
Running, twisting, turning (racquet sports, baseball, hockey) 
 
2) Completion of postoperative rehabilitation following standard protocols 
3) Orthopedic surgical intervention and physical therapy completed at Connecticut Children’s. 
 
Study Group and Control Group Exclusion Criteria 
 
1) An additional lower extremity injury at time of knee injury or previous surgical intervention on the knee 
(ipsilateral and contralateral) 
2) Multiple ligament ruptures or trauma 
3) Weight bearing restrictions for greater than 4 weeks after surgery due to concomitant pathology such as 
meniscal root/radial repair, chondral pathology, or multi-ligament pathology 
4) Follow-up surgical procedures including, but not limited to, post-operative arthrofibrosis 
6) Inability to attend regular physical therapy sessions (≥80% of patient treatment sessions and all assessment 
visits 
7) Contraindications to performing BFRT including known history of central or peripheral neurologic 
impairments, cardiac or metabolic condition or history of deep vein thrombosis (DVT).  
The exclusion of age is to ensure that the study population is old enough to complete testing on the HUMAC 
isokinetic dynamometer and young enough to be treated by one of our Sports Medicine physicians. 
The secondary diagnosis and previous knee injury exclusions are to limit the influence of other diagnoses or 
injuries on measured knee strength, as well as provide a more homogeneous group for comparison to past 
data.  
Identification, recruitment, consent and retention of subjects  
 
Patient Screening and Determination of Eligibility 
 
Pre-Screening 
All potential patients undergoing ACL reconstruction at Connecticut Children’s Sports Medicine will be 
approached for participation for this study.  Patients scheduled to undergo ACL reconstruction will be screened 
by the individuals listed on this protocol using our pre-screening documentation form.  All patients undergoing 
ACL reconstruction undergo a pre-operative appointment.   
 
Identification and Recruitment:  

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Once identified as a potential candidate, the study purpose and protocol will be explained and a brief summary 
of the study will be provided at the conclusion of the pre-operative appointment.  Patients must meet all the 
requirements of inclusion and exclusion criteria to be eligible for consent. 
 
 
 
 
Consent:  Consenting will take place at the pre-operative visit.  The patient/parent will be given a detailed 
description of the purpose and methodology for this study.  They will have the opportunity to read the consent 
forms and ask any questions they may have about the research.  If they agree to participate, they will be asked 
to sign the consent form and a copy will be provided to the patient and family. All consenting documents will be 
stored in REDCap 
 
If patients agree to enroll, all demographics and information listed in the protocol will be stored in REDCap on a 
data collection sheet that is listed in the attachments.  This sheet will be used to record all pertinent information 
for all active participants on the study and will be stored in REDCap   
.  
Retention:  Eligible patients will be required to be seen for a minimum of 80% of patient visits to be included in 
this study.  
 
Data Collection:  
Prior to completing enrollment measures, patients will provide written informed consent to participate in the 
study. Data collection will occur at five different time points during the rehabilitation process: preoperatively, 8 
weeks, 12 weeks, 6 months, and time of return to play.  Return to play assessments will be completed at 
approximately 9 months post-operatively.  The schedule of study assessments is listed in Table 1 below. 
 
Table 1.  Schedule of Study Procedures and Assessments 
Procedure 
Pre-operative 
Screen 
8 
weeks 
12 
weeks 
6 
months 
Return 
to Play 
2 year 
follow-up 
Informed Consent 
x 
 
 
 
 
 
Background Information  
x 
 
 
 
 
 
Patient Reported Outcomes 
x 
x 
x 
x 
x 
x 
Estimated 1 rep Max 
x 
 
 
 
 
 
Mid-thigh circumference 
x 
x 
x 
x 
x 
 
Isometric thigh strength 
x 
x 
x 
x 
x 
 
Isokinetic thigh strength 
 
 
 
x 
x 
 
Range of motion (ROM) 
x 
x*** 
x 
x 
x 
 
***ROM will be assessed and collected at each treatment visit for the first 8 weeks after surgery 
 
Primary Outcomes (See table below):  
Active knee range of motion: Knee AROM will be measured in supine position using a goniometer and 
standardized procedures reported by Norkin and White.35   
Mid-thigh circumference will be used to measure and track muscle hypertrophy. Circumferential measurements 
has been shown to be valid and is often used after ACLR to assess quadriceps hypertrophy.44 All subjects will 
be supine with the knee in full extension.  The average of 3 measurements will be recorded with the starting 
point 10cm superior to the superior pole of the patella.   
10 Repetition Max Test:  The 10 repetition max test will be used to determine an estimate 1 rep maximum on 
the Shuttle Leg Press machine, as this is a safe and reliable alternative to predicting a 1 rep maximum.  This 
will allow for exercise prescription.45  All participants will complete a double leg and single leg Shuttle leg press 
10 repetition maximum.   The test will follow the protocol as recommended by the National Strength and 
Conditioning Association.46    

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Isometric thigh strength: Preoperative, 8 week, 12 week, 6 month, and return to play assessments will measure 
maximum isometric muscle torque using an isokinetic dynamometer (Humac CSMi USA, Stoughton, MA, 
USA).  Patients will complete 3 trials with each knee in 60° of flexion and will be allowed a 5-second rest period 
between trials.  The uninvolved limb's quadriceps and hamstring strength will be tested first, followed by the 
involved limb. Patients will be given verbal encouragement throughout the test to provide maximal effort. The 
highest peak torque measurement of the five trials will be collected and recorded in newton-meters (Nm). 
These peak torque values will be used to calculate the Limb Symmetry Index (LSI), or the ratio between the 
involved limb and uninvolved limb and expressed as a percentage. Peak torque will subsequently be 
normalized to the patient's body mass (kilogram) and recorded for analysis (Nm/kg). 
Isokinetic thigh strength: For assessments at 6 months and time of return to play, maximum muscle torque will 
be assessed using an isokinetic dynamometer (Humac CSMi USA, Stoughton, MA, USA). Patients will be 
positioned in short sitting with 90 degrees of hip flexion, their trunk and thigh supported with straps, and 
dynamometer arm secured proximal to the ankle joint. The uninvolved limb's quadriceps and hamstring 
strength will be tested first, followed by the involved limb. Patients will be given verbal encouragement 
throughout the test to provide maximal effort. Using an isokinetic dynamometer in this manner has been shown 
to be a reliable method to quantify quadriceps and hamstring peak torque in adults47,48 and children.49  All 
administrators of the isokinetic testing are trained per HUMAC NORM standardized guidelines. Isokinetic 
quadriceps and hamstring torque was assessed through a knee range of motion from 0 to 90°, with gravity 
correction applied.50 Three practice trials will be completed, followed by ten test trails (completed at 180°/sec) 
and two practice trials paired with five test trials (completed at 60°/sec).  The highest peak torque 
measurement of the five trials will be collected and recorded in newton-meters (Nm). These peak torque values 
will be used to calculate the Limb Symmetry Index (LSI), or, the ratio between the involved limb and uninvolved 
limb and expressed as a percentage. Peak torque will subsequently be normalized to the patient's body mass 
and recorded for analysis (Nm/kg). 
 
Patient Reported Outcomes: 
1) Pediatric International Knee Documentation Committee Subjective Knee Evaluation form (Pedi-IKDC) 
2)  Knee Injury and Osteoarthritis Outcome Score (KOOS) 
3) Tegner Activity Scale 
4) Anterior Cruciate Ligament Return to Sport Index (ACL-RSI) scale.   
 
Data will be collected at five different time points during the rehabilitation process.  Additionally, we will collect 
data at 2 year phone/email follow up to record patient outcomes.  These assessments are completed in 
conjunction with the surgeon’s follow up visit.  The physical therapist completing the assessment will record all 
outcomes in a REDcap database.    
Assessment 
time point 
Data Points Collected 
Pre-op 
8 weeks 
12 weeks  
Range of motion (Involved/Uninvolved) 
    1) Flexion and Extension(º) 
HUMAC isometric knee extension at 60º (Involved/Uninvolved) 
     2) Involved/Uninvolved Peak Torque (Nm) 
     3) Involved/Uninvolved Peak Torque normalized to bodyweight (Peak torque/bodyweight) (Nm-Kg) 
     4) Quadriceps Limb Symmetry Index (LSI)=Knee extension peak torque involved/knee extension peak        
torque uninvolved*100 

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HUMAC isometric knee flexion at 60º (Involved/Uninvolved) 
      5) Involved/Uninvolved Peak Torque (Nm) 
      6) Hamstring deficit=Knee extension peak torque involved/knee extension peak torque uninvolved*100 
      7) Involved/Uninvolved Peak Torque normalized to bodyweight (Peak torque/bodyweight) (Nm-Kg) 
Quadriceps hypertrophy thigh circumference (Involved/Uninvolved)  
     8) Measured at 10cm above the superior pole of the patella bilaterally 
Patient Reported Outcome Measures 
      9) Pedi-IKDC 
      10) ACL-RSI 
      11) KOOS 
6 months 
9 months 
Range of motion (Involved/Uninvolved) 
     1) Flexion and Extension(º) 
HUMAC isometric knee extension at 60º (Involved/Uninvolved) 
     2) Involved/Uninvolved Peak Torque (Nm) 
     3) Involved/Uninvolved Peak Torque normalized to bodyweight (Peak torque/bodyweight) (Nm-Kg) 
     4) Quadriceps LSI= Knee extension peak torque involved/knee extension peak torque uninvolved*100 
HUMAC isometric knee flexion at 60º (Involved/Uninvolved) 
      5) Involved/Uninvolved Peak Torque (Nm) 
      6) Hamstring deficit=Knee extension peak torque involved/knee extension peak torque uninvolved*100 
      7) Involved/Uninvolved Peak Torque normalized to bodyweight (Peak torque/bodyweight) (Nm-Kg) 
Isokinetic knee extension at 180º/sec, and 60º/sec 
       8)  Involved/Uninvolved Peak Torque (Nm) 
       9) Quadriceps deficit=Knee extension peak torque involved/knee extension peak torque uninvolved*100 
       10)  Involved/Uninvolved Peak Torque normalized to bodyweight (Peak torque/bodyweight) (Nm-Kg) 
Isokinetic knee flexion at 180º/sec, and 60º/sec 
       11) Involved/Uninvolved Peak Torque (Nm) 
       12)  Hamstring deficit=Knee extension peak torque involved/knee extension peak torque uninvolved*100 
       13)  Involved/Uninvolved Peak Torque normalized to bodyweight (Peak torque/bodyweight) (Nm-Kg) 
Quadriceps hypertrophy thigh circumference (Involved/Uninvolved)  

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       14) Measured at 10cm above the superior pole of the patella bilaterally 
Patient Reported Outcome Measures 
        15) Pedi-IKDC 
        16) ACL-RSI 
        17) KOOS 
2 years 
Patient Reported Outcome Measures 
  1)  Pedi-IKDC 
  2) ACL-RSI 
  3) KOOS 
 
1. Control Group: All control group participants will follow the ACL reconstruction rehabilitation protocol  
These patients will complete outcome measures, and standardized strength assessments consistent 
with the standard current standard of care listed above. The same data points will be collected.  
2. All data collected all time points will be stored in a custom built REDcap database built specifically for 
this study. 
 
Recruitment and Retention: We will track recruitment and retention as outcomes.  Connecticut Children’s 
sports medicine surgeons and physical therapists care for approximately 100-150 ACL tears per year on 
average. Our expertise in pediatric sports medicine positions us well to treat these patients after ACLR. Our 
physical therapists will care for approximately half of these patients on an annual basis. In our recent pilot 
study, we enrolled approximately 40 patients and had 0% attrition in our BFRT group throughout the study 
period. Our close relationship and adjoined clinic with our sports medicine providers allows us to target and 
recruit potential patients for enrollment. Our team has been able to identify and establish formal procedures for 
the recruitment and consenting process.  We anticipate to enroll 2-4 patients/month, and at this rate we would 
finish enrollment within approximately 10 months.   
 
Study Procedures: All patients that undergo ACLR at Connecticut Children’s begin physical therapy within 5-7 
days of surgery.  The implementation of BFRT will begin at the second post-operative visit to account for 
differences in post-operative pain and recovery.   
 
BFRT Intervention Group:  
In addition to the standard ACL rehabilitation protocol, the experimental group will complete 2 exercises using 
the Delfi BFR cuff 2x/week for 8 weeks during their treatment session at Connecticut Children’s Sports 
Physical Therapy on the second post-operative visit.   Exercise selection is listed in Table 2.  All patients will 
use the Delfi BFR unit and will complete exercises at 80% limb occlusion pressure.  Cuff size will be 
determined by patient thigh circumference as described in Delfi BFR unit manual.  Limb occlusion pressure will 
be determined in supine position and all exercises will be completed at 80% occlusion.    
 
Control Group: In addition to the standard ACL rehabilitation protocol, the control group will complete the 
same exercises as the experimental group starting on the second post-operative visit. 
 
Table 2. Exercise Progression 
 
Long Arc Quadriceps (LAQ) progression 
Shuttle progression 

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Post-op visit 2- 2 weeks 
Quadriceps Set 
Standing Straight Leg Raise 
2 weeks-4 weeks 
Available range LAQ 
Standing terminal knee extension 
4 weeks-8 weeks 
LAQ  (0-90°) 
Single Limb Shuttle/Leg Press  
 
Exercise volume and progression guidelines 
 
BFR equipment: All participants in the intervention group will use an automatic personalized tourniquet 
system (Delfi Medical, Vancouver, BC).  This is an FDA-approved device that automatically calculates limb 
occlusion pressure (LOP), which is defined as the minimum pressure required for full arterial occlusion.51  The 
device increases cuff pressure in small increments, while analyzing pressure in the cuff, to help determine 
LOP.  Additionally, the system uses a nylon and contoured cuff that is sized to the patient for comfort.  All 
patients will have the LOP set while lying in the supine position, with the cuff in the most proximal portion of the 
involved limb.  BFR pressure will be set to 80% LOP prior to initiating the exercise protocol.   
 
BFRT Group:  
a. Exercise volume:  All patients in this study will complete 4 sets of an exercise, with goal repetitions of 
30 in the first set, and 15 repetitions in sets 2-4, for a total of 75 repetitions. This method has been 
demonstrated to be effective in increasing muscle strength.52-55  Upon completion of exercise, there will 
be a 30 second rest break between sets.  Patients will be provided with a minimum of 1 minute rest and 
a maximum of 3 minutes between exercises to allow for adequate rest time and setup between 
exercises. To insure a controlled pace of completion, all patients will be encouraged to complete 
exercises with a 1 second concentric phase, 1 second isometric phase, and 1 second eccentric phase 
with the use of a metronome. 
 
b. Exercise progression: Load progression of exercises will be based on the patient’s ability to complete 
the prescribed number of total repetitions (75) as follows.   
o 75 Repetitions = Increase weight after 2 sessions 
o 60-74 Repetitions = Continue with training, but extend rest period between sets 3 and 4 
to 45 second until 75 repetitions is completed. 
o 45-59 Repetitions = Stay at same weight until 75 repetitions are completed. 
o <44 Repetitions = Reduce load by approximately 10% until 75 repetitions is achieved 
 
c. For the long arc quadriceps (LAQ) progression, all exercises will start with no external resistance and 
after every 2 sessions weight will be increased by 1 pound.  For the Shuttle progression, exercises will 
start at 30% of patients 1RM.  An estimated single leg and double leg 1 repetition max will be 
determined at pre-operative visit.  Patients unable to complete the prescribed dosage will complete the 
exercise using both limbs on the Shuttle and will use a ratings of perceived exertion (RPE) scale to 
determine intensity.  RPE has been shown to be an effective tool to individualize exercise prescription 
and load progression.56 
d. The standing straight leg raise exercise will be completed from week 0-2 unless the patient is able to 
demonstrate 10 straight leg raise repetitions with minimal extensor lag.  All standing exercises will be 
standardized to complete in the same position to have minimal compensation. 
e. Discontinuation or stoppage of exercise: Patients will be instructed to attempt to complete all exercises.  
Should the patient be unable to tolerate 80% limb occlusion or report lower extremity paresthesia, the 
therapist will reduce occlusion by 5mmHg between exercise sets.  Should the patient reach less than 
60% limb occlusion, the exercise will be stopped.  
 
f. 
At the completion of both exercises, patients will be asked to rate RPE, pain on a visual analog scale, 
and report from a list of documented adverse events.   
 
Control Group:  All exercises will be completed in the manner described above without the use of the Delfi 
BFR device.  Exercise volume, progression, and discontinuation will be determined in the same manner. 
 
Sample Size/Power Analysis: Based on our preliminary work evaluating differences between isometric 
quadriceps strength at 3 and 6 months after ACLR in adolescents, an a priori power analysis for a two-way 

Version 1.2_.1.8.2023 
 
repeated measures analysis of variance (within-between interaction) was conducted using an alpha level of 
0.05, power of 0.80 and moderate effect size (0.6). The projected sample size needed to determine differences 
between groups was determined to be 14 total individuals. Thus, we have increased the sample size to 40 (20 
per group) to allow for even group numbers and to account for possible attrition. 
 
Data analysis 
Data will be collected on all patients enrolled into the study.  Descriptive statistics will be generated on the 
demographic characteristics of both treatment groups. We will use a two-way repeated measures analysis of 
variance to determine the effect of treatment groups, BFRT compared to standard of care therapy, over time 
on subjective and objective outcomes. Exact analysis for each test will depend on variance and 
distribution/normality of data set. This will be achieved using the Statistical Package for the Social Sciences 
(SPSS) software version 27.0 (IBM Corp., Armonk, NY, USA).  We will address each aim in the following 
manner. 
 
Accrual and Expected Duration of Accrual    
Once approved, we expect that this study can be accomplished within two to three years. The open 
period for this study will be between February 2022 and February 2025. 
 
Study Limitations:  
There are several limitations anticipated with this study that will impact its power and external validity. These 
limitations include an inherent sampling bias with our recruitment strategy, lack of patient or participant 
blinding, and small sample size.  
Attempts will be made to reduce any potential bias by having standardized educational scripts regarding BFR 
training that each treating therapist will read to subjects prior to their first BFR session.  
Subjects in our study will likely come from the same surgeons and the same type of ACL graft (QT). This could 
be a potential limitation in the generalizability of our results to other surgeons and graft types.  
 
 
 
 
Administrative Organization 
Roles and responsibilities:   
Adam Weaver, PT, DPT: Will serve as the study’s primary investigator.  Adam will provide primary support for 
the SRC and IRB study protocol development and submission, as well as maintaining updates and compliance 
with clinicaltrials.gov. He will review the required databases and pull the relevant data required to complete this 
study.  He will also aid in data interpretation and manuscript preparation.  
All MDs listed: The MDs listed on this proposal will be responsible for recruitment of patients, data 
interpretation and manuscript preparation.   
All physical therapists listed:  The PT’s listed on this proposal will serve as the study’s co-investigator.  They 
will provide support in development of SRC and IRB documents (review of literature).  They will help with data 
collection, recruitment, consenting patients.    
Jennifer Prue: Jennifer is ATC in Sports Medicine who will assist with relcruitment, consenting, and data 
collection.  She also will serve as the study coordinator. 
Adel Lolic, Megan Ranchinsky: Our exercise technologists listed will assist with consenting, as well as data 
collection during testing times, and organizing tabulated results.  

Version 1.2_.1.8.2023 
 
Julie Burland, ATC, PhD: Julie is a researcher at UCONN Sports Medicine Institute.  She will be assisting in 
study design, data interpretation and preparation, statistical analysis and manuscript preparation:  
Data Collection and Management   
 
a. Data collection forms: All data points and outcome measures will be completed and entered into a 
 
REDcap database to facilitate data analysis. 
 
 
b. Data collection software: The Research Operations and Development team assisted with the 
development of this REDCap project. Connecticut Children’s has licensed this software toolset and 
workflow methodology for electronic collection and management of research data. REDCap (Research 
Electronic Data Capture) data collection projects rely on a thorough study. The development and 
testing process results in a well–planned data collection strategy for studies. This project will use 
REDCap data transactions due to the web–based information transmission being encrypted. REDCap 
was developed specifically around HIPAA–Security guidelines. REDCap has been disseminated for use 
locally at other institutions and currently supports over 5854 academic/non-profit consortium partners 
and over 2.1 million research end–users (www.project-redcap.org)Adam Weaver will oversee data 
management.  The data will be collected by investigators, and it will be entered into REDCap by Adam 
Weaver and Jennifer Prue to insure data accuracy.  Statistics will be run using Microsoft Excel and 
SPSS. 
 
 d. Adam Weaver will oversee data management. The data will be collected by investigators, and 
 
it will be stored only in REDcap.  The database will only be accessible to those individuals included 
 
in this study.   
 
e. Information will be reviewed prior to de-identification to insure there are no errors with 
 
transcription. 
 
f. Data quality assurance: Data that is collected will be manually verified to ensure that no information 
 
has been entered into REDcap incorrectly. Additionally, we will randomly check 10% of data in the 
 
REDcap database for accuracy after initial entry to insure accuracy 
 
g. Record retention and confidentiality will be dictated by the current procedures in place here at 
 
Connecticut Children’s. All information will be stored in a private office and on a 
 
single password protected computer. No access to information is possible from an outside source. 
Human Subjects Protections and Ethical Conduct of the Study 
Patient confidentiality statement  
Strict measures will be required for respecting and maintaining patient confidentiality. Application for IRB 
approval is currently being created for submission, and once IRB evaluation has occurred we will make any 
changes required to ensure HIPPA compliance. Collection of a patient identifier including medical record 
numbers and the patients name is necessary to ensure comprehensive inclusion of eligible subjects and 
accurate linking of data from different data sets. The database used for the study will be password protected 
and stored in REDcap.  Once we have collected all the data, the data set will be frozen for analysis. At this 
time, we will completely de-identify all subjects. Medical record numbers as well as the patient’s names will be 
removed and patients will be referred to by study number only. De-identification will take place once we have 
collected all data. In the event that further time is needed prior to de-identification of the data set, we will 
request a continuation through the IRB at the time of annual review of the protocol. We expect that these 
measures will minimize any risk to confidentiality very effectively, and that any unavoidable residual risk will be 
balanced generously by the potential benefit to society of the knowledge that will be obtained through this 
research. 
Financial:  There are no financial burdens for the subjects. There are no extra costs due to travel to extra 
appointments or therapy sessions as the subjects will follow standard of care protocols for timing and quantity 
of physical therapy and follow-up appointments with their surgeon.   

Version 1.2_.1.8.2023 
 
Benefits:  The results of this study would benefit patients, surgeons, rehabilitation specialists, and of course 
future patients and their families by possibly providing a method of determining the patient’s progress at an 
earlier stage and allow for early interventions to improve the patient’s outcome. 
 
Risk: The risk to patients using BFR is anticipated to be minimal overall.  Several studies on adults after ACLR 
has shown that BFR is well tolerated, and our recently published study on BFR in adolescent showed similar 
findings. 57-59  To monitor patient tolerance, patients will rate pain levels using a visual analog scale,60 RPE, 
and our team will screen for adverse responses.  Though these response are rare, we will monitor for pain, 
bruising, dizziness, and nausea. At subsequent follow up PT visits, we will monitor for any potential delayed 
events.   
Use of results of study 
The results of this study would provide the Connecticut Children’s Sports Medicine surgeons and physical 
therapists here at Connecticut Children’s information to determine the effectiveness and application of the use 
of BFR in conjunction with exercise.  
Study Budget 
 
Equipment and Supplies:  There will be no equipment costs associated with this study.  The BFR Delfi units 
that are necessary for completion of BFR exercise by the intervention group are already owned by Connecticut 
Children’s Sports Physical Therapy 
  
Travel:  There will be no travel costs associated with this study.  
 
 
All personnel will provide effort that is in kind, and there will be no stipends provided to the patients.  These 
follow up assessment visits currently already occur as the standard of care for all patients undergoing ACLR at 
Connecticut Children’s 
Budget Justification 
 
All treatment visits and follow up visits will be covered by patient insurance 97110 and 97140 CPT code will 
cover the costs of all physical therapist treatment visits. 
The 97530 codes will cover all assessment visits (12 weeks, 6 months, and return to play) 
Note:  The sports physical therapists who will guide the patient in performing the functional assessment skills 
and follow the standard of care in grading these skills will bill their services to the patient’s insurance.   
Appendices (as needed) 
The attached data collection from in MS excel will serve as a template initially.  Upon IRB approval, a full RED 
cap data base will be built to include all data points mentioned above.   
 
 
 
 
 
 
 

Version 1.2_.1.8.2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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