STRATEGIC CLINICAL DECISION-MAKING AFTER ACL INJURY …

STRATEGIC CLINICAL DECISION-MAKING AFTER

ACL INJURY AND RECONSTRUCTION:

PATIENT REPORTED OUTCOME MEASURES,

RETURN TO SPORT, SECOND INJURY PREVENTION,

AND PREDICTORS OF OSTEOARTHRITIS

by

Jessica L Johnson

A dissertation submitted to the Faculty of the University of Delaware in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomechanics and Movement Science

Spring 2020

© 2020 Jessica L Johnson All Rights Reserved

STRATEGIC CLINICAL DECISION-MAKING AFTER

ACL INJURY AND RECONSTRUCTION:

PATIENT REPORTED OUTCOME MEASURES,

RETURN TO SPORT, SECOND INJURY PREVENTION,

AND PREDICTORS OF OSTEOARTHRITIS

by

Jessica L Johnson

Approved: __________________________________________________________ Samuel C.K. Lee, Ph.D. Director of the Interdisciplinary Graduate Program in Biomechanics and

Movement Science Approved: __________________________________________________________ Kathleen S Matt, Ph.D. Dean of the College of Health Sciences Approved: __________________________________________________________ Douglas J. Doren, Ph.D. Interim Vice Provost for Graduate and Professional Education and

Dean of the Graduate College

I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy.

Signed: __________________________________________________________ Lynn Snyder-Mackler, Sc.D., FAPTA Professor in charge of dissertation I certify that I have read this dissertation and that in my opinion it meets

the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy.

Signed: __________________________________________________________ May Arna Risberg, Ph.D. Member of dissertation committee I certify that I have read this dissertation and that in my opinion it meets


Signed: __________________________________________________________ Thomas S Buchanan, Ph.D. Member of dissertation committee I certify that I have read this dissertation and that in my opinion it meets


Signed: __________________________________________________________ Elizabeth Wellsandt, Ph.D. Member of dissertation committee

I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy.

Signed: __________________________________________________________ James J Irrgang, Ph.D., FAPTA Member of dissertation committee

Trials teach us what we are; they dig up the soil and let us see what we are made of. -Charles Spurgeon You can’t do anything about the length of your life, but you can do something about

it’s width and depth. -Evan Esar

vi

To my advisor, Lynn Snyder-Mackler. From our first meeting in the

Wilmington Amtrak Station, your absolute no-nonsense, get-to-the-point attitude

convinced me that I could get this done. I would not be languishing in my sixth year of

writing with no dissertation in sight. Your commitment to my growth as a researcher

and scientist is invaluable and I will carry the lessons with me forever. Thank you.

To my committee. Thank you for your passion and excellence. Thank you for

your willingness to read, edit, and debate this work. Your combined expertise has

made me a better researcher, writer, and scientist.

To Martha Callahan and the staff at the Delaware Research Institute. Thank

you for taking care of our participants and all of your assistance with scheduling and

data management.

To the SmackLab, both past and present, I could not have managed this

without your support and guidance. To Jessica Galgiani, thank you for the listening ear

and the Trader Joe’s runs. To my fellow PhD students, which is too many to possibly

list, thank you. And lunch is still at noon.

And always, always, to my family. To my sister, Liz, your cards, letters, late

night texts, and constant cheering have made all the difference. To my brother-in-law,

Adam, your crazy questions and curiosity are always appreciated. To Mira, Malachi,

and Vivienne. I started this journey two weeks before Malachi was born and defended

three weeks after Vivienne. Your funny stories and smiling faces have been a bright

light in the rough times. And to my parents. Your unwavering faith in my abilities and

ACKNOWLEDGMENTS

vii

your constant encouragement has been my sustaining force. I could not ask for better

parents. Thank you.

This work is dedicated to all of the participants who volunteered for these

studies. This work would not be possible without all 380 of you. Thank you for your

time and willingness to participate.

This research was supported by the National Institutes of Health and the

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-

AR048242) and the Eunice Kennedy Shriver National Institute of Child Health and

human Development (937-HD037985). Thank you to the University of Delaware for

the support of a summer Dissertation Award.

viii

LIST OF TABLES ....................................................................................................... xii LIST OF FIGURES ..................................................................................................... xiii ABSTRACT ................................................................................................................ xiv Chapter

1 INTRODUCTION, RATIONAL, AND SPECIFIC AIMS ............................... 1

1.1 Introduction ............................................................................................... 1 1.2 Overall Scientific Premise ......................................................................... 2

1.2.1 Scientific Premise for Aim 1: Can we stop asking so many questions? Selection of patient reported outcome measures. ........ 3

1.2.2 Scientific premise for Aim 2: Secondary injury prevention for female athletes. .............................................................................. 4

1.2.3 Scientific premise of Aim 3: Timing of specialized intervention and the impact on rates of return to sport, competitive level, and second ACL injuries. ................................ 6

1.2.4 Scientific premise of Aim 4: Using gait biomechanics five years after ACL injury/reconstruction to predict joint space width 10 years after injury. ........................................................... 7

1.3 Significance ............................................................................................... 8 1.4 Innovation ................................................................................................. 9 1.5 Specific Aims .......................................................................................... 10 1.6 Summary ................................................................................................. 11

2 CAN WE STOP ASKING SO MANY QUESTIONS? COMPARING THE RESPONSIVENESS OF THE GLOBAL RATING SCALE TO LEGACY KNEE OUTCOME SCORES: A DELAWARE-OSLO COHORT STUDY .. 13

2.1 Introduction ............................................................................................. 13 2.2 Methods ................................................................................................... 16

2.2.1 Participants .................................................................................. 17 2.2.2 Study design ................................................................................ 17

TABLE OF CONTENTS

ix

2.2.3 Global Rating Score .................................................................... 18 2.2.4 Knee Outcome Survey-Activities of Daily Living Scale ............ 18 2.2.5 International Knee Documentation Committee-Subjective

Knee Form ................................................................................... 18 2.2.6 Knee injury and Osteoarthritis Outcome Score .......................... 19 2.2.7 Statistics ...................................................................................... 19

2.3 Results ..................................................................................................... 20

2.3.1 Effect Sizes .................................................................................. 20 2.3.2 Ceiling Effect .............................................................................. 21 2.3.3 Validity ........................................................................................ 21 2.3.4 Minimally Important Change ...................................................... 21

2.4 Discussion ............................................................................................... 23 2.5 Strengths and Limitations ....................................................................... 26 2.6 Conclusions ............................................................................................. 28

3 SECONDARY INJURY PREVENTION PROGRAM MAY DECREASE CONTRALATERAL ACL INJURIES IN FEMALE ATHLETES: 2-YEAR INJURY RATES IN THE ACL-SPORTS RANDOMIZED CONTROL TRIAL .............................................................................................................. 31


3.2.1 Participants .................................................................................. 34 3.2.2 Training ....................................................................................... 35 3.2.3 Age .............................................................................................. 36 3.2.4 Statistics ...................................................................................... 36

3.3 Results ..................................................................................................... 37

3.3.1 Second ACL injury ..................................................................... 38 3.3.2 Age .............................................................................................. 39

3.4 Discussion ............................................................................................... 41

3.4.1 Graft Rupture .............................................................................. 41 3.4.2 Contralateral ACL Injury ............................................................ 42 3.4.3 Return to Sport ............................................................................ 43 3.4.4 Post-surgical follow-up ............................................................... 43 3.4.5 RTS criteria ................................................................................. 44

x

3.5 Clinical Implications ............................................................................... 44 3.6 Strengths and Limitations ....................................................................... 45 3.7 Conclusions ............................................................................................. 46

4 HIGH RATES OF RETURN TO SPORT AND COMPETITIVE LEVEL WITH A SPECIALIZED INTERVENTION REGARDLESS OF TIMING OF INTERVENTION ...................................................................................... 48


4.2.1 Participants .................................................................................. 50 4.2.2 Intervention ................................................................................. 51 4.2.3 Surveys ........................................................................................ 52

4.3 Results ..................................................................................................... 52 4.4 Discussion ............................................................................................... 55 4.5 Strengths and Limitations ....................................................................... 58 4.6 Conclusion ............................................................................................... 58

5 LOW LOADING OF THE MEDIAL TIBIOFEMORAL COMPARTMENT DURING GAIT FIVE YEARS AFTER ACL INJURY IS PREDICTIVE OF SMALLER JOINT SPACE WIDTH AT TEN YEARS ............................ 59


5.2.1 Subjects ....................................................................................... 61 5.2.2 Modeling ..................................................................................... 61 5.2.3 Radiographs ................................................................................. 62 5.2.4 Statistics ...................................................................................... 63

5.3 Results ..................................................................................................... 63 5.4 Discussion ............................................................................................... 66 5.5 Conclusions ............................................................................................. 69

6 SUMMARY ..................................................................................................... 70

6.1 Overview of the aims .............................................................................. 70 6.2 Aim 1 Purpose ......................................................................................... 70

6.2.1 Hypothesis 1.1: ............................................................................ 70 6.2.2 Hypothesis 1.2: ............................................................................ 71 6.2.3 Conclusion ................................................................................... 71

xi

6.3 Aim 2 Purpose: ........................................................................................ 71

6.3.1 Hypothesis 2.1: ............................................................................ 71 6.3.2 Conclusion ................................................................................... 71

6.4 Aim 3 Purpose: ........................................................................................ 72

6.4.1 Hypothesis 3.1: ............................................................................ 72 6.4.2 Hypothesis 3.2: ............................................................................ 72 6.4.3 Hypothesis 3.3: ............................................................................ 72 6.4.4 Conclusion ................................................................................... 72

6.5 Aim 4 Purpose: ........................................................................................ 73

6.5.1 Hypothesis 4.1: ............................................................................ 73 6.5.2 Hypothesis 4.2: ............................................................................ 73 6.5.3 Conclusion ................................................................................... 73

6.6 Summary of Work ................................................................................... 74

REFERENCES ............................................................................................................. 75 Appendix

A IRB DOCUMENTATION ............................................................................... 93 B LIST OF ABBREVIATIONS .......................................................................... 95 C PROGNOSTIC FACTORS FOR PATIENT-REPORTED OUTCOME

MEASURES AND PHYSICAL ACTIVITY TWO TO TEN YEARS AFTER ACL INJURY OR RECONSTRUCTION: SYSTEMATIC REVIEW .......................................................................................................... 96

xii

Table 2.1: Demographics of participants at enrollment ............................................... 20

Table 2.2: Means, standard deviations, and percentage at ceiling for each PROM by time-point. ............................................................................................... 29

Table 3.1 Demographics of participants at enrollment by group. ................................ 37

Table 3.2 By group comparisons for SAPP versus SAPP+PERT ............................... 39

Table 3.3 Rates of second ACL injury by age. ............................................................ 40

Table 3.4: Comparison between rates of second injury for female athletes of the ACL-SPORTS trial matched by age to previous literature ..................... 40

Table 4.1: Demographics at enrollment ....................................................................... 53

Table 4.2: Rates of same sport and same competitive level 2 years after ACLR ........ 53

Table 4.3: Rates and side of second ACL injury two years after ACLR ..................... 55

TABLE C.1. PubMed search ..................................................................................... 130

TABLE C.2: Characteristics of included studies (n=20) ........................................... 131

TABLE C.3: Risk of bias assessment (n=20) ............................................................ 136

LIST OF TABLES

xiii

Figure 2.1 Effect sizes. ................................................................................................. 22

Figure 2.2 Ceiling effects. ............................................................................................ 23

Figure 3.1 Perturbation exercises performed by the SAPP+PERT group ................... 36

Figure 3.2 CONSORT flow diagram for ACL-SPORTS female athletes ................... 47

Figure 4.1: Rates of return to pre-injury sport ............................................................. 54

Figure 4.2: Rates of return to pre-injury competitive level .......................................... 54

Figure 4.3: Rates and sides of second ACL injuries .................................................... 55

Figure 5.1: Predicting medial compartment JSW at ten years with loading at ten years ........................................................................................................ 64

Figure 5.2: Predicting medial compartment JSW at ten years with loading symmetry at five years ............................................................................ 65

Figure 5.3 Predicting medial compartment JSW at ten years with loading at five year by surgical status ............................................................................. 66

Figure C.1. Flow chart ............................................................................................... 138

LIST OF FIGURES

xiv

Anterior cruciate ligament (ACL) reconstruction (ACLR) is the common treatment

recommendation after ACL injury,102 however, outcomes after surgery are not

uniformly good. Only about 55% of athletes return to previous levels of competition

after ACLR8 and among those who do return, up to 30% have a second ACL injury.58

Additionally, patients with ACL injury have higher rates of osteoarthritis,84,14 some as

early as one year after injury.32,74 ACL injury is a common sport injury2 with

increasing incidence,80,81,126 and a peak age between 15-25 years old,16,117,126,162 so

these injuries have devastating consequences to both activities of daily living and

sports participation in young active individuals.104,105,135

The long-term objective of this work is to improve clinical decision-making to

increase return to sport rate, reduce second injuries, and reduce incidence of early OA

after ACL injury. This project will measure responsiveness of four commonly used

PROMs (Aim 1), identify biomechanical risk factors for loss of medial compartment

tibiofemoral joint space width (Aim 2), evaluate the effect of a specialized

intervention on second injury rate (Aim 3), and the timing of intervention on second

injury and return to sport rates (Aim 4) to achieve this goal,. The goal of this work is

to inform clinical decision-making regarding outcome measures, timing of visits,

ABSTRACT

xv

second injury risk, and identification for progression of radiographic knee

osteoarthritis in patients after an ACL injury/reconstruction.

1

INTRODUCTION, RATIONAL, AND SPECIFIC AIMS

1.1 Introduction

The rates of primary anterior cruciate ligament (ACL) injury are on the rise,22 with the

highest incidence of ACL injury occurring between the ages of 15 and 25 years

old.117,126,162 These young athletes have very high expectations after ACL injury and

reconstruction that are not currently being met. While 91% expect to return to their

previous sports,44 a recent systematic review found only about 55% actually return to

their previous competitive levels, with younger age, male sex, and elite sport

participation all increasing the odds of returning to sport.8

Athletes who successfully return to a level I sport (jumping, hard cutting, and

pivoting)33 are approximately 15 times more likely to sustain a second injury than

matched uninjured controls,109 nearly half of the injuries occur within two months of

returning to sport.58 Again, age is important, with younger athletes at higher risk for

second ACL injuries,130,148,150 most in the first year after return to sport.150 However,

with a strong association between age and returning to cutting/pivoting sports,19,130,150

Chapter 1

2

younger age may be a proxy for returning to high risk sports and not an independent

risk.57

Long-term, 98% of patients expect no or only slightly higher risk of osteoarthritis

(OA) after their injury and ACL reconstruction (ACLR),44 but most have signs of

radiographic knee OA ten to twenty years after ACLR.84,85

Taken together, the impact of not returning to a sport, returning only to have a second

ACL injury, and the high rate of OA, suggest we are not meeting the expectations of

our patients. There are considerable and devastating effects of ACL injury on both

activities of daily living and sports participation104,105,135 we need to address.

1.2 Overall Scientific Premise

This dissertation aimed to improve clinical decision-making regarding outcome

measures, timing of visits, second injury risk, rate of return to sport, and identification

of potentially modifiable risk factors of radiographic knee OA in patients after an ACL

injury/reconstruction.

3

1.2.1 Scientific Premise for Aim 1: Can we stop asking so many questions? Selection of patient reported outcome measures.

Patient reported outcome measures (PROMs) are designed to measure the patient’s

perspective on symptoms, function, and health related quality of life.17 The selection

of PROMs is essential for obtaining meaningful information to determine a plan of

care37 and make clinical decisions,145 but even within a specific diagnosis such as

ACL injury and reconstruction, there are multiple recommended outcome

measures,68,88,92,93 and no consensus among providers.87 Surveys are often

administered concurrently,87 which may burden providers and patients leading to

mistakes and missing data.63 While the number of questions or length of time to

complete PROMs that patients will accept varies,121 longer PROMs place more strain

on respondents and administrators and may lead to errors in responding to items and

missing data,63 as well as lower response rates.121 Additionally, there may be higher

burden if multiple surveys with similar concepts are administered at the same time.121

In a survey of health care providers regarding markers of successful outcomes after

ACL injury and reconstruction, Lynch et al reported the highest scoring PROM was

the Global Rating Scale (GRS) with 45% of respondents reporting it as an important

measure; the Knee Outcome Survey-Activities of Daily Living (KOS-ADLS ),

International Knee Documentation Committee-Subjective Knee Form (IKDC-SKF),

and the Knee injury and Osteoarthritis Outcome Score (KOOS) were rated as

4

important by 41%, 38%, and 37% of healthcare providers respectively, none reaching

consensus.87

A valid measure must be able to detect a clinically-important change136 and construct

validity may be accessed with correlations to other measures of the construct.70,138

Responsiveness is an instrument’s ability to detect real changes in the construct that it

is intended to measure136 and may be measured with effect size,137 a standardized

measure of change in a group72 and the presence of a ceiling effect, the percentage of

patients with the maximum score.144 With no consensus, and the most frequently used

PROMs appropriate at different stages of recovery, having one simple measure that

can be used effectively throughout the rehabilitation timeline would improve plan of

care decision-making as well as monitor progress across the continuum of care.

We assessed the construct validity of the single-item GRS with the IKCD-SKF as well

as determined the minimal important difference for the GRS. We also assessed the

responsiveness of the four highest rated PROMs (GRS, IKDC-SKF, KOS-ADLs, and

the KOOS) in the 5 years after ACL injury and reconstruction

1.2.2 Scientific premise for Aim 2: Secondary injury prevention for female athletes.

Athletes who return to Level I sport (jumping, hard cutting, and pivoting)33 after an

ACLR are approximately 15 times more likely to sustain a second injury than matched

controls,109 most in the first year after return to sport150 and nearly half of those within

5

the first two months.58 The risks are highest for female athletes,90 with reported risk of

a second injury as high as six times that of male athletes.109 The type of second injury

is also different between sexes, with a higher contralateral injury rate in females

compared to males.109,113,149

And while the use of and enforcement of stringent RTS criteria have been shown to

reduce second injury risk,58 specialized secondary injury prevention programs are also

effective in reducing this risk, and current recommendations include quadriceps

strengthening and neuromuscular training for 9-12 months after ACLR.54,77,98 One

specific type of neuromuscular training, perturbation training, improves knee stability

through adaptations in neuromuscular control with potential destabilizing activities

about the knee.48 Perturbation training is designed to induce compensatory changes in

muscle activation patterns and facilitate dynamic joint stability.119 Perturbation

training improved self-reported knee function more than strength training alone in the

first six months after ACLR118.

Arundale et al. found a 2.5% second injury rate in the male participants of the ACL-

SPORTS randomized control trial using progressive strengthening, agilities,

plyometrics and prevention exercises; the injury rate was so low they were unable to

analyze the impact of perturbation training in these athletes.12 In this aim we assessed

how female athletes responded to this intervention and its effectiveness in reducing the

6

rate of second injuries. Specifically, this work determined the effectiveness of

reducing second ACL injuries with the addition of perturbation training to a secondary

injury prevention compared to the prevention program alone.

1.2.3 Scientific premise of Aim 3: Timing of specialized intervention and the impact on rates of return to sport, competitive level, and second ACL injuries.

Current recommendations after ACL injury include a phase of pre-operative

rehabilitation, with a systematic review finding pre-operative rehabilitation was

effective in improving post-operative outcomes in patients waiting for ACLR.4 A

clinical practice guideline update in 2016 also recommended a phase of pre-operative

rehabilitation.98 Additionally, the most effective post-operative training programs for

returning to pre-injury level of function and reducing the risk of reinjury include

quadriceps strengthening and neuromuscular training for 9-12 months.54,77,98

Limited resources and increasing healthcare costs may render extended pre-operative

and post-operative interventions difficult to implement. Currently, we do not know

how the timing of specialized interventions may impact risk factors and patient goals

if there are a limited number of visits available.

This work analyzed the impact of the timing of a specialized intervention (either pre-

operatively or in the return to sports phase of rehabilitation) on rates of return to sport,

competitive level, and rates of second ACL injury.

7

1.2.4 Scientific premise of Aim 4: Using gait biomechanics five years after ACL injury/reconstruction to predict joint space width 10 years after injury.

Athletes with ACL injuries experience high rates of radiographic OA 14,107 within a

decade of injury.96 Current best recommendations for the treatment of OA include

physical therapy, education, pain control, and surgery.106,163 These secondary and

tertiary level treatments address symptoms but are unable to reverse the damage to the

joint.106,122 With peak age of ACL injury at between 15-25 years old16,117,126,162 and

roughly 50% developing radiographic OA within twenty years of ACL

injury/reconstruction,84 identification of modifiable risk factors to intervene before the

initiation of cartilage degradation are critical.

One possible risk factor is gait biomechanics, which vary after ACL

injury.40,51,60,61,124,131,135 Even small changes in the load bearing position of the

tibiofemoral joint may be significant contributors to the development of premature

OA,39 and under-loading of the medial tibiofemoral compartment was associated with

ROA changes 5 years after ACLR.153 Since healthy cartilage responds positively to

load,5 this under-loading of normally loaded tissue may be responsible for the high

rate of radiographic knee OA in ACL injured athletes.

We assessed medial compartment tibiofemoral joint contact forces during gait 5 years

after injury/reconstruction with a previously validated EMG driven musculoskeletal

8

model20 to predict fixed location medial compartment tibiofemoral joint space width

using the International Knee Documentation Committee (IKDC) objective criteria to

classify narrowing of the tibiofemoral compartment64,97 10 years after ACL


1.3 Significance

While anterior cruciate ligament (ACL) reconstruction (ACLR) is the common

recommendation after ACL injury,102 outcomes after surgery are not uniformly good.

Only an average of 55% return to previous level of competition,8 up to 30% have a

second ACL injury after returning,58 and as many as 90% develop signs and symptoms

of OA after ACLR.14 Since ACL injury is a common sport injury2 with increasing

incidence,80,81,126 these injuries have devastating consequences to both activities of

daily living and sports participation.104,105,135 The long-term objective of this work is to

improve clinical decision-making to increase return to sport rate, reduce second

injuries, and reduce incidence of early OA after ACL injury. To achieve this goal, this

project measured responsiveness of four commonly used PROMs (Aim 1), evaluated

the effect of a specialized intervention on second injury rate (Aim 2) and timing of

specialized intervention on second injury and return to sport rates (Aim 3), and

identified risk factors for loss of JSW (Aim 4), and Thus, this work will inform future

work in developing interventions to reduce provider and patient burden with a valid

and responsive single-item PROMs used across time-points by any provider, identify

9

modifiable risk factors of for radiographic OA, reduce second injury rates, and

improve rates of return to sport and competitive level.

1.4 Innovation

This work is the first to assess responsiveness of PROMs through five years of ACLR

recovery. This work will decrease provider and patient burden, as well as improve

continuity of care among providers and ensure patient and provider goals are being

met. Additionally, this work is the first to assess the effect of perturbation training on

female athletes after ACLR. If effective, this intervention could reduce the rate of

second ACL injuries in female athletes. This work assessed the impact of the timing of

ten sessions of specialized training on rate of return to sports and competitive level

and rate of second ACL injuries. Lastly, we are the first to assess change in joint space

width as a marker of radiographic OA along with predictive factors of that change.

This assessment of long-term outcomes after ACL injury may inform future clinical

interventions and decision-making. These combined aims inform clinical decision

making to the best utilization of rehabilitation resources, improving outcomes and

decreasing costs associated with ACL injury.

Together, these innovations allow for the development of targeted treatments and

recommendations for prevention of second injuries, prevention of OA, and improved

sports participation.

10

1.5 Specific Aims

• Aim 1 Purpose: Determine the construct validity of the GRS and determine the

responsiveness of the GRS, the IKDC-SKF, the KOS-ADLS, and the KOOS

subscales with effect sizes and ceiling effects after ACL injury and reconstruction.

o Hypothesis 1.1: We hypothesized that the GRS would have good construct

validity when compared with the IKDC-SKF.

o Hypothesis 1.2: We hypothesized there would be no difference in

responsiveness between the GRS, the IKDC-SKF, the KOS-ADLS, and the

KOOS subscales as measured by effect size and ceiling effects.

• Aim 2 Purpose: We compared the rate and side of second ACL injuries in female

athletes who received post-operative strength, agility, plyometric and prevention

training (SAPP) compared to those who receive post-operative training plus

specialized perturbation (SAAP+PERT) training.

o Hypothesis 2.1: We hypothesized that SAPP+PERT athletes would have

fewer second ACL injuries than those who received SAPP training alone.

• Aim 3 Purpose: We analyzed the impact of timing of a specialized intervention (pre-

operatively versus return to sport phase) on rates of return to sport and competitive

level and rates of second ACL injury.

o Hypothesis 3.1 We hypothesized that those who received post-operative

training would have a higher rate of return to their pre-injury sports than

those who had pre-operative training.

11

o Hypothesis 3.2: We hypothesized that those who received post-operative

training would have a higher rate of return to their pre-injury competitive

levels of sport than those who had pre-operative training.

o Hypothesis 3.3: We hypothesized that there would be no difference in rates

of second ACL injury between those who received pre-operative training

and those who had post-operative training.

• Aim 4 Purpose: Using medial compartment joint contact forces collected during

gait at 5 years and tibiofemoral JSW from radiographs at five and ten years, we

will analyze predictive factors of joint space narrowing.

o Hypothesis 4.1: We hypothesized that under-loading in the medial

compartment of the knee during gait five years after ACL

injury/reconstruction would predict smaller JSW in the medial tibiofemoral

compartment ten years after ACL injury/reconstruction.

o Hypothesis 4.2: We hypothesized that lower loading in the medial

compartment of the knee during gait five years after ACL

injury/reconstruction would predict smaller JSW in the medial tibiofemoral

compartment ten years after ACL injury/reconstruction.

1.6 Summary Clinicians are faced with high patient expectations, low rates of return to sport, and

high rates of second injury and OA for patients after ACL injury and reconstruction.

12

This work improves clinical decision making by identifying the validity and

responsiveness of a single-item patient reported outcome measure to improve provider

communication and decrease provider and patient burden, by identifying possibly

modifiable risk factors for development of radiographic knee OA, by analyzing the

impact of specialized intervention on second ACL injury rates in female athletes, and

evaluating the impact of the timing of that intervention on rates of return to

sport/competitive level and second injury.

Taken together, these aims address the unmet high expectations of our patients and our

clinical decision-making to address common limitations and risks after ACL injury

and reconstruction.

13

CAN WE STOP ASKING SO MANY QUESTIONS? COMPARING THE RESPONSIVENESS OF THE GLOBAL RATING SCALE TO LEGACY KNEE

OUTCOME SCORES: A DELAWARE-OSLO COHORT STUDY

2.1 Introduction While originally designed for use in research, patient-reported outcome measures

(PROMs) are now also used by healthcare providers to assess the effects of clinical

care and are designed to measure the patient’s perspective on their symptoms,

function, and health-related quality of life.17 The selection of PROMs is essential for

obtaining meaningful information to manage a patient, determine a plan of care37 and

make clinical decisions,145 however, the process for selection of PROMs for clinical

care is not easy. The relevance to the patient, psychometric properties, including

reliability, validity, and responsiveness, as well as provider and patient burden are all

important factors to consider in selection of a PROM.

A 2010 systematic review by Wang et al. identified and evaluated 24 separate PROMs

for the knee and recommended different measures depending on diagnosis; while the

International Knee Documentation Committee-Subjective Knee Form (IKDC-SKF)

was the most generalizable, no measure was applicable across the spectrum of

Chapter 2

14

diagnoses or patient group.146 Even within a diagnosis such as anterior cruciate

ligament (ACL) injury and reconstruction, there are multiple recommended outcome

measures.68,88,92,93 While having multiple PROMs allows clinicians and researchers

flexibility in selecting the appropriate measure for their patient, this variation makes it

difficult to compare data across providers and studies.68

While the number of questions or length of time to complete PROMs that patients will

accept varies,121 longer PROMs place more strain on respondents and administrators

and may lead to errors in responding to items and missing data,63 as well as lower

response rates.121 Additionally, there may be higher burden if multiple surveys with

similar concepts are administered at the same time,121 as is often the case in research

studies and at initial clinical visits.

Previous work on other single-item scales has found they are valid in those with knee

injuries.129,157 The single assessment numeric evaluation (SANE) asks respondents: On

a scale from zero to 100, how would you rate your knee today (with 100 being

normal)? In comparison, the Global Rating Scale (GRS) asks respondents: Rate your

current knee function from 0% to 100%, with 100% equaling preinjury function.

The critical properties of outcome measures are patient-relevancy, user-friendliness,

reliability, validity, and responsiveness to clinical change.59 Kirshner & Guyatt

15

describe three applications of patient-reported measures; discriminative, used to

distinguish between individuals on an underlying dimension, predictive, used as a

screening or diagnostic instrument, and evaluative, used to quantitate treatment benefit

and must be able to detect a clinically meaningful difference over time.75 This work

falls into the last category, assessing the ability to detect real changes in functional

impairments and quality of life. Within the context of assessing change, a valid

measure must be able to detect a clinically-important change136 and responsiveness is

an instrument’s ability to detect real changes in the construct that it is intended to

measure.136 Construct validity may be accessed with correlations other measures of the

construct.70.138 Responsiveness may be measured with effect size,137 a standardized

measure of change in a group,72 (mean change score in baseline standard deviation

units; with pre-training as baseline)72 and the presence of a ceiling effect (percentage

of patients with the maximum score).144 A measure that has a ceiling effect is unable

to identify a further improvement in a high functioning individual.144

In a survey of health care providers regarding markers of a successful outcome after

ACL injury and reconstruction, Lynch et al. found a consensus (≥80%) that PROMs

are an important marker of success, but they did not find a consensus for the preferred

use of any individual measure.87 The highest consensus PROM was for the Global

Rating Scale (GRS) with 45% of respondents reporting it as an important measure.

The Knee Outcome Survey-Activities of Daily Living Scale (KOS-ADLS), the IKDC-

16

SKF, and the Knee injury and Osteoarthritis Outcome Score (KOOS) were rated as

important by 41%, 38%, and 37% of respondents respectively.87 This lack of

consensus among providers makes the selection of an appropriate outcome measure

increasingly difficult.

Regardless, having one simple measure that can be used effectively throughout the

rehabilitation timeline could improve plan of care decision-making as well as monitor

progress across the continuum of care. If GRS has similar effect size and ceiling effect

to longer measures, its use in isolation could decrease burden on patients and

providers.

The objective of this study was to assess the validity of the GRS compared to the

IKDC, determine the minimally important change (MIC) for the GRS, and to

determine the responsiveness of four PROMs as identified by Lynch et al87 via effect

size and the presence of a ceiling effect in a prospective cohort of ACL reconstructed

followed for 5 years. We hypothesized that the GRS would have similar effect size

and ceiling effect to the most commonly use legacy PROMs.

2.2 Methods This is a secondary analysis of an ongoing prospective observational study.36,56 The

study was approved by the ethical/human subjects committees at the Regional Ethics

17

Committee for South-Eastern Norway and the University of Delaware and all patients

provided written informed consent, or parental consent with written assent if under 18

years old at enrollment. Participants were enrolled at both centers between 2007 and

2012. The Delaware-Oslo ACL Cohort Study is supported by grant R37 HD037985

from the National Institutes of Health.

2.2.1 Participants

At enrollment, all participants had a complete unilateral ACL rupture confirmed by 3-

mm or greater difference in anterior tibial excursion with instrumented arthrometry33

(KT1000; MEDmetric Corporation, San Diego, CO) within the previous seven

months. Patients were athletes 13 to 55 years of age and regular participants in cutting

and pivoting activities for at least 50 hours per year before their injury. Exclusion

criteria included a repairable meniscus, symptomatic grade III injury to other knee

ligaments, or greater than 1-cm2 full-thickness articular cartilage lesion.

2.2.2 Study design

Following study enrollment, participants completed ten pre-operative rehabilitation

sessions. Of the 300 participants, 218 chose to have an ACLR, completed post-

operative progressive criterion-based rehabilitation early after surgery, and were

followed for five years. We collected the GRS, KOS-ADLS, IKDC-SKF, and KOOS

at pre- and post-training, and at 6, 12, 24, and 60 months after ACLR.

18

2.2.3 Global Rating Score

The GRS is a single item designed to assess current knee functional performance;

patients are asked to rate their current knee function from 0% to 100%, with 100%

equaling preinjury function.

2.2.4 Knee Outcome Survey-Activities of Daily Living Scale

The KOS-ADLS consists of 14 questions and was designed to determine symptoms

and functional limitations in usual daily activities caused by various knee

pathologies.68 The KOS contains activities such as walking, stair climbing, and

kneeling, and symptoms rated on their impact on these activities. It has questions

related to recreational or sporting activities. Scores range between 0-100%, a greater

symptoms and lower level of function resulting in a lower score.68

2.2.5 International Knee Documentation Committee-Subjective Knee Form

The IKDC-SKF has 18 items and was designed to detect improvement or deterioration

in symptoms, function, and sports activities in a variety of knee conditions.69 It is

reliable and valid for use in ligament and meniscal injuries, articular cartilage lesions,

arthritis, and patellofemoral populations.69 Scores range between 0-100%, with higher

19

scores representing lower levels of symptoms and higher levels of function and sports

activity.69

2.2.6 Knee injury and Osteoarthritis Outcome Score

The KOOS has 42 questions arranged in five subscales: Symptoms, Pain, Activities of

Daily Living (KOOS-ADL), Sport and Recreation function (Sport/Rec), and knee-

related Quality of Life (KOOS-QOL) with scores ranging between 0-100%, with

100% equaling no difficulties.123

2.2.7 Statistics

We used Excel (Microsoft, Seattle WA) to calculate effect sizes as: (mean score at

time-point minus the mean score at baseline, divided by baseline standard deviation;

pre-training as baseline)72 and the presence of a ceiling effect as a percentage of

patients with the maximum score. Effect size and ceiling effects cut-offs were set a

priori: 0.5 for medium effect size and 0.8 for large effect size,30 and ≥15% of

participants having a maximum score for the presence of a ceiling effect.95 We

correlated with GRS with the IKDC-SKF with a Pearson correlation. We calculated

the MDC for the GRS, IKDC-SKF, KOS-ADLS, and KOOS subscales as the values

associated with 20%125 and 33%160 of the standard deviation of the measure at

baseline. Power for the clinical trial was calculated a priori.

20

2.3 Results Of the 300 total participants, 218 (100 women) completed training and chose to have

an ACLR (106 hamstring grafts, 42 patellar tendon grafts, and 62 allografts);

demographics at enrollment are in Table 2.1. Results shown are for all available data

(Table 2.2); there was no change when the analysis used only those participants with a

complete data set (n=114). We did not begin collecting KOOS responses from study

participants until midway through enrollment, thus the analysis of the KOOS

subscales included only the 69 participants with baseline KOOS scores.

Table 2.1: Demographics of participants at enrollment

Mean (range) Age (years) 25.0 (13-52) Height (cm) 174.5 (148-195) Weight (kg) 75.7 (43.3-139) Body Mass Index (BMI) (kg/m2) 24.7 (18.6-40.2) Time from injury to enrollment (weeks)

8.3 (1-38)

2.3.1 Effect Sizes

Effect sizes for all PROMs peaked at the 24-month time-point, with minimal

differences observed between 12m, 24m, and 60m (Figure 2.1, Table 2.2). The IKDC-

SKF had the largest effect sizes at all time-points (Figure 2.1). The GRS had a similar

effect size and change in effect size compared to the longer PROMs.

21

2.3.2 Ceiling Effect

The KOOS-QOL subscale did not demonstrate a ceiling effect at any time-point and

the IKDC-SKF only showed a ceiling effect at the 24m time-point (Figure 2.2, Table

2.2). All other measures had a ceiling effect at at least one time-point (most at 12m,

24m, and 60m) while the KOOS-ADL subscale had a ceiling effect at all time-points,

and the KOOS-Pain subscale had ceiling effects at all but pre-training. The GRS had a

similar effect size and change in ceiling effect compared to the longer PROMs.

2.3.3 Validity

The Pearson correlation coefficient between the GRS and the IKDC-SKF was 0.72

(p<0.001) when data were pooled across all time-points.

2.3.4 Minimally Important Change

The MDC for the GRS was 2.9 when using an 20%125 and 4.9 at 30%160 of the

standard deviation of the scores, which correspond to a small and small to medium

effect. The MDC for the IKDC-SKF was 2.5 and 4.1 respectively.

22

Figure 2.1 Effect sizes. Medium effect size ≥0.5 (dashed line), large effect size ≥0.8 (dotted line). Post=post-training time-point

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

post 6m 12m 24m 60m

Effe

ct S

ize

Effect Size

KOS-ADLS GRS IKDC-SKF Pain Symptom ADL Sport_Rec QOL

23

Figure 2.2 Ceiling effects. The dashed line is the 15% cutoff for ceiling effect. Pre=pre-training time-point. Post=post-training time-point

2.4 Discussion In the current study, we examined the effect sizes and ceiling effects of four PROMs

after an ACL injury and reconstruction. The IKDC-SKF, GRS, KOS-ADLS, and the

KOOS-QOL subscale demonstrated large effect sizes at 12m, 24m, and 60m after

ACL reconstruction. These values indicated that these PROMs are sensitive to

detecting clinical change.72 While the GRS had a small effect size post-training and at

6m, the overall trajectory of change is similar among all PROMs.

0

10

20

30

40

50

60

70

80

pre post 6m 12m 24m 60m

Perc

enta

ge a

t Cei

ling

Ceiling Effect

KOS-ADLS GRS IKDC-SKF Pain Symptom ADL Sport/Rec QOL

24

Gangel et al. correlated the SANE with the Lysholm knee score in 130 college-age

patients after ACL reconstruction and found a good correlation (0.75, p<0.001).157

Shelbourne et al. correlated the same SANE to the IKDC-SKF after ACL

reconstruction and found an ICC of 0.66 and that the precision of agreement

(calculated as the mean difference ±1 standard deviation), was met for 81% of

respondents and limits of agreement (calculated as the mean difference ±2 SD) met for

94%.129 In this study, the correlation between GRS and IKDC-SKF was 0.72 (0.69-

0.75), p<0.001, which is a moderately strong relationship that provides some evidence

of construct validity for the GRS in this population.

As may be expected, the large effect sizes at the later time-points correspond to the

time-points with ceiling effects. All measures except the KOOS QOL had a ceiling

effect at at least one time-point (most at 12m, 24m, and 60m) while the KOOS-ADL

subscale had a ceiling effect at all time-points, and the KOOS-Pain subscale had

ceiling effects at all but pre-training. The GRS had a similar size and change in ceiling

effect compared to the longer PROMs. However, it is worth debating if the GRS can

truly have a ceiling effect. The GRS asks a respondent to rate their current knee

functional performance compared to pre-injury performance, so a score of 100%

indicates the full resolution of any impairments or limitations relevant to that

respondent. This may mean that, regardless of the percentage of respondents with a

score of 100%, the GRS does not have a ceiling effect, but a performance asymptote,

25

or the greatest true value that can be demonstrated147. In a measure with a ceiling

effect, a true score can only be observed if it is less than or equal to the ceiling

threshold. So a patient may score 100% on the IKDC-SKF or the KOOS but still have

functional limitations because not every activity or symptoms is covered on those

PROM. In contrast, we would not expect there to be a score above the 100% scored on

the GRS, this is an asymptote and not a ceiling, which differentiates it from the other

measures.

Clinical decision making requires that health care providers choose the best tool for

patient evaluation121 and previous authors have suggested a combination of PROMs

may be necessary to assess functional success.37,87 In practice, a clinician could

administer the GRS frequently, with the IKDC-SKF (or other measure as desired)

given at the initial visit, then at 3 month (initiation of running116/return to

participation)6 6 months (return to sport activities)6, 9 months (return to sport58/return

to performance)6, and at 12 and 24 months after ACLR. Based on our estimation of the

MDC of 2.8/4.9, if a participant reports GRS scores of 60, 65, 65, and 70, a therapist

should continue to progress treatment as indicated by stage of healing and objective

criteria. If, however, a patient reports weekly scores of 60, 65, 65, and then 40, it

would be appropriate to administer other tests/measures to identify causes for an

unexpected change in status. While single-item measures are reliable and valid,129,157

their simplicity comes at the cost of detail.132 To gain this detail, clinicians could use

26

outcome measures related to ADLs and functional limitations (KOS-ADLS68 or

IKDC-SKF69), fear (Tampa Scale of Kinesiophobia159 or the ACL-Return to Sports

after Injury151) or activity participation (Tegner143 or Marx94) as appropriate for the

stage of recovery and goals of rehabilitation. Additionally, no PROM alone is

sufficient to base all clinical decisions upon. Quadriceps strength, performance

measures, and biological healing are all important factors to consider after an ACL

injury.6,37,45,58

Additionally, when a patient is nearing return to sport/performance, current

recommendations suggest both objective and subjective criteria for clearance to

return.45,58 At the 12m time-point, the GRS had a large effect size, indicating it is

responsive to a clinically meaningful change from baseline to the time of return-to-

sport decision-making. Achieving a GRS of 9058 may indicate that the patient is ready

for objective criteria testing.45,58 As previously discussed, no one PROM is applicable

to all patients at all time-points.146 Clinicians can use the GRS for repeated, frequent

assessment of change and reserve longer, more burdensome PROM for significant

milestones during recovery.

2.5 Strengths and Limitations The study population was active athletes after ACL injury and subsequent ACLR.

These patients were not enrolled immediately after their ACL injury, but at a “quiet

27

knee” stage of recovery (8.3±5 weeks, range 1-38 weeks after injury). We, therefore,

do not have data from the patient’s initial encounter with a health professional, nor do

we have immediate post-operative data and so are unable to assess effect sizes with an

early post-operative baseline. Additionally, previous research comparing this cohort to

a comparable subgroup of the MOON cohort found our participants had statistically

and clinically significantly higher baseline and two-year IKDC-SKF and KOOS

scores42.

We assessed validity, responsiveness, and determined the MDC of the GRS in this

study. Future research should establish test-retest reliability, standard error of the

measurement. Also, while none of our measures are ACL specific, we only analyzed

patients with ACL rupture and subsequent ACLR. We do not know the validity,

responsiveness or MDC in patients with other knee injuries/surgeries.

Also, because we did not begin using the KOOS until midway through enrollment,

analysis of the KOOS was only done in the 69 participants who had baseline KOOS

scores.

We were unable to directly assess response burden in our participants. The difference

in the length and thus the time needed to complete each PROMs is however much

shorter in the GRS than the other three measures. The simplicity of administering the

28

GRS may decrease burden on respondents and administrators while still providing

responsive and valid information regarding patient status.

2.6 Conclusions

The IKDC-SKF has the largest effects sizes while the KOOS-QOL had the

smallest ceiling effects. The GRS, however, responds similarly to the IKDC-SKF,

KOS-ADLS, and KOOS measures and is responsive to patient change, with evidence

of construct validity and a small MDC. The ease of use and patient-specific nature of

the question means that, for clinical practice, it may be appropriate to use the GRS as a

frequent measure throughout the course of rehabilitation, with different measures used

at the beginning of treatment and other measures used at the later stages, or specific

scales based on patient’s deficits or goals.

29

Table 2.2: Means, standard deviations, and percentage at ceiling for each PROM by time-point.

Time- point Outcome N Mean Std.

Deviation Effect size

Percentage at ceiling

Pre

KOS-ADLS 216 84.5 10.3 n/a 3% GRS 216 77.6 14.7 n/a 6% IKDC-SKF 210 69.6 12.6 n/a 0% KOOS-Pain 69 84.0 10.8 n/a 6% KOOS-Symptom 69 75.8 13.5 n/a 7% KOOS-ADL 69 93.5 7.4 n/a 23% KOOS-Sport/Rec 69 66.5 18.7 n/a 1% KOOS-QOL 69 51.0 19.1 n/a 0%

Post

KOS-ADLS 202 89.5 8.6 0.49 8% GRS 202 83.3 14.3 0.39 8% IKDC-SKF 188 76.8 12.8 0.57 1% KOOS-Pain 67 89.0 8.9 0.46 15% KOOS-Symptom 67 83.7 12.1 0.59 4% KOOS-ADL 67 97.1 3.7 0.48 39% KOOS-Sport/Rec 67 74.4 16.1 0.42 4% KOOS-QOL 67 54.7 18.8 0.20 0%

6m


12m

KOS-ADLS 184 93.4 8.7 0.86 20% GRS 184 92.1 10.5 1 21% IKDC-SKF 181 89.2 11.8 1.54 11% KOOS-Pain 66 92.6 8.7 0.80 27% KOOS-Symptom 66 86.1 14.7 0.77 17% KOOS-ADL 66 98.0 4.8 0.60 59% KOOS-Sport/Rec 66 80.6 20.0 0.76 14% KOOS-QOL 66 70.8 19.7 1.04 6%

24m KOS-ADLS 166 94.0 8.1 0.92 28%

30

GRS 166 93.8 8.2 1.11 31% IKDC-SKF 166 90.7 11.1 1.66 22% KOOS-Pain 63 93.9 9.6 0.92 43% KOOS-Symptom 63 90.0 11.7 1.05 21% KOOS-ADL 63 98.2 5.1 0.63 68% KOOS-Sport/Rec 63 84.2 17.7 0.95 30% KOOS-QOL 63 75.2 20.9 1.26 13%

60m


31

SECONDARY INJURY PREVENTION PROGRAM MAY DECREASE CONTRALATERAL ACL INJURIES IN FEMALE ATHLETES: 2-YEAR

INJURY RATES IN THE ACL-SPORTS RANDOMIZED CONTROL TRIAL

3.1 Introduction The incidence of primary ACL reconstruction (ACLR) is on the rise, with a 77%

increase for women and 19% increase for men over a twelve year period.22 Female

athletes have a higher incidence of ACL injuries in the comparable sports of

basketball, soccer, and lacrosse2 compared to male athletes. Athletes who return to

cutting and pivoting sports after ACLR have increased odds of graft rupture and

contralateral injury compared to those who return to less strenuous sports.150 Up to one

in three athletes who return to sport may sustain a second ACL injury, nearly half of

those within two months of returning to sport58. Female athletes have a higher

contralateral injury rate compared to males109,113,149, with the reported risk of a

contralateral ACL injury as high as six times more likely compared to male athletes

(26% versus 5% respectively)109.

While younger athletes are more likely to return to their pre-injury levels of

sport8,71,150, athletes under 20 years-old have six times increased odds for a graft

Chapter 3

32

rupture and three times increased odds for a contralateral tear compared to older

athletes.150 A systematic review of athletes aged 6-19 years undergoing ACLR found

an overall second ACL injury rate of 27%71. Young female athletes have an even

higher rate of second ACL injury130, up to 32%149.

When an important marker of success (return to their previous level of sport) is also a

key risk factor for second ACL injury, clearly there is a need for targeted secondary

ACL injury prevention and return to sport (RTS) training. Current clinical practice

guidelines for primary prevention of knee and ACL injuries10 recommend preventative

training programs include a combination of neuromuscular training, strengthening,

balance, and proximal control exercises141. The most effective post-operative training

programs for returning to pre-injury level of function and reducing the risk of reinjury

include quadriceps strengthening and neuromuscular training for 9-12 months54,77,98.

Neuromuscular training techniques, such as perturbation training, designed to induce

compensatory changes in muscle activation patterns and facilitate dynamic joint

stability119, improve self-reported knee function more than strength training alone in

the first six months after ACLR118. Perturbation training improves knee stability

through adaptations in neuromuscular control with potential destabilizing activities

about the knee48. It is unclear how female athletes respond to post-operative

perturbation training.

33

The Anterior Cruciate Ligament-Specialized Post-Operative Return to Sports (ACL-

SPORTS) training program is a sport-specific secondary ACL injury prevention

program.155 ACL-SPORTS included progressive strengthening, agility, plyometric,

and prevention (SAPP) exercises. The program is effective for preventing secondary

ACL injury in men, with only one graft rupture in 40 male athletes12. However, the

second ACL injury prevention effects in women have yet to be explored.

The purpose of this study was to determine if adding perturbation training to a second

injury prevention program was more effective than the prevention program alone in

reducing second ACL injury rates in female athletes after ACLR. We hypothesized

that female athletes who received perturbation training in addition to the second injury

prevention program would have fewer graft ruptures and fewer contralateral ACL

injuries compared to those who received the prevention program alone.

3.2 Methods White et al155 previously published the methods of the ACL-SPORTS single-blinded

randomized controlled trial which was approved by the University of Delaware

Institutional Review Board and registered at clinicaltrials.gov (NCT01773317), with

funding provided by the National Institute of Child Health and Human Development

(NICHD) AR048212. This analysis is part of the a priori secondary outcomes for this

trial. Prior to enrollment, all athletes gave written consent (assent if under 18 years

34

with parent/guardian consent). The CONSORT diagram is in Figure 3.2. This analysis

achieves objective (a) in patient/athlete/public partner involvement in the research:

addressing outcomes deemed important by patients.

3.2.1 Participants

Participants were recruited from the local community through physician and physical

therapist referral, newspaper and flyer advertisements, and word of mouth, with 40

female athletes enrolled from December 2011 through January 2017 from 17

surgeons. Selection criteria were: age 13-55 years, participated in and planning to

return to a cutting/pivoting/jumping sport more than 50 hours per year, no previous

ACL injury, and no history of other major lower extremity injury/surgery. Participants

must have had a unilateral ACLR with no grade III concomitant ligament injuries or

cartilage defects larger than 1cm2.

Surgical technique, graft choice, and rehabilitation prior to enrollment were not

controlled. At enrollment, participants were screened by a physical therapist, and had

no knee pain, minimal to no knee effusion, and full knee range of motion. They were

less than nine months after ACLR, had ≥80% quadriceps index (QI), initiated a

running progression, and not yet returned to Level I/II sport. Athletes were

randomized to SAPP or SAPP plus perturbation (SAPP+PERT) using a random

35

number generator by a research coordinator (MC). All researchers performing data

collection were blinded.

All participants completed training. However, the researchers received information

that one athlete (SAPP+PERT group) may not have had an intact ACL graft at

enrollment. Therefore, we excluded her data from all analyses. All participants were

required to pass objective return to sport criteria58,154. Participants returned to the

clinic at 1- and 2-years after surgery for functional and clinical testing and patient

reported outcomes. Those who were unable to return in person at two years (n=3)

were contacted by phone. Self-reported second ACL injury status was collected for all

39 participants, as well as time from surgery to RTS, time from surgery to second

ACL injury, and time from RTS to second ACL injury. Additionally, 100% of

participants returned to sport by two years, 87% at their pre-injury level of sport.24

3.2.2 Training

Training occurred twice a week for five weeks under the supervision of a physical

therapist at the University of Delaware Physical Therapy Clinic. Perturbation exercises

used a platform/roller board combination, unilateral stance on a roller board, and

unilateral stance on a tilt board, each with therapist perturbations in multiple planes

(Figure 3.1); a full list and description of all training exercises can be found in White

et al155. Training also included education and cuing for correct technique of all

36

exercises especially avoiding valgus collapse during landings; progression was

determined according to soreness and effusion guidelines1,43,155. All participants were

required to pass the following RTS criteria before beginning return to sport: ≥90% QI

and four single legged hop limb symmetry index (LSI), ≥90% scores on the Knee

Outcomes Survey-Activities of Daily Living Subscale (KOS-ADLS) and a single item

global gating of perceived knee function (GRS), and obtain surgeon approval.

Figure 3.1 Perturbation exercises performed by the SAPP+PERT group A: Platform and roller board, B: Unilateral roller board, C: Unilateral tilt board

3.2.3 Age

Since younger age at primary ACL injury increases the risk of a second

injury71,130,149,150, we divided our athletes as those under 25, those under 20, and those

under 18.

3.2.4 Statistics

We compared rate and side of second ACL injury between the two groups using chi-

square tests of proportions and time from primary surgery to second ACL injury using

37

independent t-tests (alpha = 0.05) with SPSS (IBM Corp, Armonk NY). To compare

to previously published literature, we categorized the rate and side of second ACL

injury by age, independent of group assignment and calculated chi-squared tests of

proportions for each age category. Power was calculated a priori for the primary

outcomes of the trial (biomechanical and clinical and functional outcomes), and the

study was adequately powered155.

3.3 Results Thirty-nine female athletes were enrolled between December 2011 and January 2017.

There were no differences in demographics between groups at enrollment (Table 3.1).

Table 3.1 Demographics of participants at enrollment by group. No comparisons were significant at the p≤0.05. **Subject was 13.5 years at enrollment

Demographic SAPP (n=20) SAPP+PERT (n=19) p value Age at primary surgery Mean ± SD, range (years)

18.9 ± 5.8 (14.0-53.7)

19.0 ± 8.8 (12.7**-54.0)

0.99

Height at enrollment (m) 1.65 ± 0.06 1.65 ± 0.08 0.82 Weight at enrollment (kg) 68.8 ± 10.9 67.9 ± 14.3 0.83 Graft type 8 patellar tendon

autografts 8 hamstring autografts 4 allografts

8 patellar tendon autografts 10 hamstring autografts 1 allografts

0.32

Time from surgery to passing RTS criteria (weeks) mean ± SD (range)

37.0 ± 11.4 (18.4-63.0)

37.0 ± 12.1 (20.3-54.0)

0.99

38

3.3.1 Second ACL injury

There were 9 second ACL injuries within two years of ACLR in the women of the

ACL-SPORTS trial: 4 graft ruptures and 5 contralateral injuries, for an overall second

ACL injury rate of 23% (Table 3.2). All second ACL injuries occurred in athletes with

a hamstring autograft. There were no group differences in rate (p=0.77) or side

(p=0.25) of second ACL injury, thus the groups were collapsed for additional

comparisons. Post-hoc analysis revealed an effect size of w=0.047 for power of (1-

β)=0.059.

39

Table 3.2 By group comparisons for SAPP versus SAPP+PERT

SAPP (n=20) SAPP+PERT (n=19) p value Second ACL injuries 5 (25%) 4 (21%) 0.77 Side of second ACL injury

4 contralateral (20%) 1 graft rupture (5%)

1 contralateral (5%) 3 graft ruptures (16%)

0.25

Mechanism of second ACL injury

3 non-contact (2 contralateral, 1 graft rupture) 1 direct contact (contralateral injury) 1 contact to body (contralateral injury)

4 non-contact (1 contralateral, 3 graft ruptures)

Time from surgery to second ACL injury (weeks) mean ± SD (range)

50.3 ± 6.6 (42.3-56.6)

69.9 ± 24.8 (34.7-87.7)

0.13

Time from passing RTS criteria to second ACL injury (weeks) mean ± SD (range)

19.4 ± 4.45 (14.14-21.72)

40.9±24.7 (14.14-62.14)

0.09

3.3.2 Age

The second ACL injuries by age are in Table 3.3. Eight of the second ACL injuries

occurred in women under 18 at primary surgery; all 9 occurred in those under 20 years

at primary surgery. However, there was not a statistically significant difference in rate

of second ACL injury by age category. Results by age, with comparison to previous

literature, are in Table 3.4.

40

Table 3.3 Rates of second ACL injury by age.

Age group Graft ruptures Contralateral ACL Overall p value <25 (n=35) 4 (11.4%) 5 (14.2%) 9 (25.7%) 0.25 <20 (n=32) 4 (12.5%) 5 (15.6%) 9 (28.1%) 0.11 <18 (n=26) 3 (11.5%) 5 (19.2%) 8 (30.8%) 0.11

Table 3.4: Comparison between rates of second injury for female athletes of the ACL-SPORTS trial matched by age to previous literature

ACL-SPORTS

Paterno 2012

Paterno 2014

ACL-SPORTS

Webster 2016

ACL-SPORTS

Webster 2016

Age category

<25 years old <20 years old <18 years old

Sample size (female only)

35 42 59 32 116 26 85ǂ

Overall Second injury

22.8% 33.3% 32.2% 28.1% 35% 30.8% 31.8%

Graft rupture

11.4% 7.1% 8.5% 12.5% 12% 11.5% 12.9%

Contralateral rupture

14.2% (11.4% without contact injuries)

26.2% 23.7% 15.6% 17% 19.2% 18.8%

Surgeon/PT clearance for RTS?

YES YES YES YES Not reported

YES Not reported

Objective RTS criteria?

YES NO NO YES Variable YES Variable

Follow-up time

2 years after ACLR

1 year after RTS

2 year after RTS (approx. 32.3 months)

2 years after ACLR

Mean 5 years after ACLR (3-10 years)

2 years after ACLR

Mean 5 years after ACLR (3-10 years)

Surgery to RTS (mean)

8.8±2.6 months

Not reported

8.3±2.0 months

8.8±2.6 months

Not reported

8.7±2.7 months

Not reported

41

3.4 Discussion The purpose of this secondary outcomes analysis was to determine if adding

perturbation training to a second injury prevention program was more effective than

the prevention program alone in reducing second ACL injury rates in female athletes

after ACLR. There was not a statistically significant difference in rate or side of

second ACL injury between those who received SAPP+PERT and those who received

SAPP alone, so we collapsed the groups to determine any differences in outcomes

with our injury prevention program compared to the existing literature.

3.4.1 Graft Rupture

The graft rupture rate in our study is comparable, or slightly higher than previous

research (see Table 3.4 for comparisons). There are many risk factors for graft rupture,

including younger age at primary injury71,130,149,150, return to a

cutting/pivoting/jumping sport142,150, and graft type89,103,114. Almost half the athletes in

our study had a hamstring autograft, and all graft ruptures occurred in those with a

hamstring graft; Paterno et al did not report graft types109,113. Hamstring grafts have

slightly higher rates of failure than bone-patellar tendon-bone (BPTB) grafts114,115,128.

Athletes who had ACLR with hamstring autografts achieved impairment resolution

earlier and returned to sports on average 4 months earlier than those with BPTB

autografts. Therefore, biological healing may have played a role in the graft failure133.

42

Because age, time to return to sport, and rate of return to cutting/pivoting sports were

comparable, possible differences in graft selection may account for the differences

between our athletes and those reported by Paterno et al.

3.4.2 Contralateral ACL Injury

The contralateral ACL injury rate in our study is lower or comparable to previous

research (see Table 3.4 for comparisons). The lower rates of contralateral ACL

injuries may be due to the bilateral training in the ACL-SPORTS training program: all

agility drills and a majority of the plyometric and strengthening activities were

performed in both limbs. With similar altered movement patterns and impairments

predicting primary and secondary ACL injuries18,66,110, if poor mechanics and

movement patterns were at fault in primary ACL injury, similar mechanics and

movement patterns may exist in the contralateral limb. Additionally, the uninvolved

limb may also develop altered mechanics as compensation for the injured limb23,111,156.

Neuromuscular training can improve impairments15,119 and movement patterns28,101.

The ACL-SPORTS training emphasis on proper landing technique and movement

patterns during agilities, plyometric and performance activities bilaterally155 may

explain the lower contralateral injury rate in our study.

43

3.4.3 Return to Sport

Because athletes in our study had the highest rate of return to sport (100% returned to

sport, 87% to preinjury level24) reported in the literature8,150, they also had greater

sports exposure and subsequently, higher risk of any second ACL injury142,150. Yet, the

rate of second ACL injury in our study was not higher than previous research149,150.

Webster et al did not report the rate of returning to cutting/pivoting sports149,150 and

neither Paterno et al109,113 nor Webster et al149,150 reported any control of their

participants’ rehabilitation. Thus, the similarities in injury rates across different studies

may reflect a positive effect of our intervention.

3.4.4 Post-surgical follow-up

We registered new injuries in the first 2 years after ACL reconstruction. Over half of

all second injuries occur in the first year after ACLR149,150, and more than three

quarters occur within 2 years of surgery149. There were minimal differences in rates of

second injuries from 1- to 2-years after return to sport109,113, with a mean time from

RTS to second injury of 7.0 months113. In the female athletes of the ACL-SPORTS

trial, average time from surgery to RTS was 8.5 months, giving an average follow-up

of 15.5 months after RTS. Therefore, our 2-year registration period should be

sufficient to capture most second ACL injuries in our cohort.

44

3.4.5 RTS criteria

Passing RTS criteria can reduce risk of second ACL injuries47,58,79, but there is

conflicting evidence about the efficacy and impact of these criteria86,108. All athletes in

the ACL-SPORTS trial were required to pass objective criteria and have surgeon

approval for RTS: ≥90% QI and four single legged hop limb symmetry index (LSI),

≥90% scores on the Knee Outcomes Survey-Activities of Daily Living Subscale

(KOS-ADLS) and a single item global gating of perceived knee function (GRS). In the

cohorts reported by Paterno et al, athletes were required to have surgeon and physical

therapist approval for RTS but did not have to meet any objective criteria before

release109,113. The study cohort by Webster et al reported criteria including running and

squatting, but did not provide objective thresholds for passing149.

While we cannot separate the impact of our RTS criteria on rate of second ACL injury

from the impact of the training program, these findings suggest that the ACL-SPORTS

training program with objective RTS criteria may reduce risk of second ACL injury in

female athletes, however, it is not enough to reduce the risk of second ACL injury in

our youngest female athletes.

3.5 Clinical Implications The reduction in contralateral ACL injury rate in our female athletes compared to

other published research is promising, especially with an easy to implement training

45

program. However, our overall second injury rate of 26% is still much too high to

believe we have addressed the needs of our athletes. While the ACL-SPORTS training

was highly effective in reducing second ACL injury rates in male athletes (1 second

injury in 40 athletes)12, it was not as effective in female athletes. Current rehabilitation

programs are not meeting all the needs of female athletes, particularly those under 18

years. High compliance to a neuromuscular training program is associated with a

lower rate of ACL injuries in female athletes139. Higher volume and more frequent,

longer duration sessions are effective for primary knee injury prevention140. However,

ten sessions over five weeks, as in our study, may not maximize the benefits of

training for female athletes. Additional, research on longer, higher intensity, more

frequent secondary prevention programs for female athletes are needed, as well as

research on the influence of types of feedback52,53 and psychological readiness to

return to sport7,78,151.

3.6 Strengths and Limitations A strength of this study is our sample. We recruited from a variety of surgeons and

participants had post-operative rehabilitation at multiple physical therapy clinics,

making our results generalizable. Reasonable enrollment criteria ensured that all

participants entered the study at an appropriate point to begin the return to sport

progression but were not overly burdensome.

46

Athletes self-reported return to sport and level of participation and we did not assess

number of athletic exposures (practice/games). Because all athletes were required to

meet RTS criteria, we are unable to separate the effects of the training program from

the RTS criteria. Additionally, while a majority of second ACL injuries occur within

two years of ACLR, 2 years may not be sufficient follow-up to capture the true rate of

contralateral ACL injuries, which may occur later after ACLR.

While our sample of n=39 is small, Type II error is unlikely. Post-hoc analysis

revealed an effect size of w=0.047 for power of (1-β)=0.059. We would have needed

more than 3000 participants to be adequately powered to detect a between group

difference.

3.7 Conclusions While the addition of perturbation training to a secondary injury prevention program

does not seem to have benefits for female athletes, the participants in the ACL-

SPORTS training program report fewer contralateral injuries compared to previously

published results.

47

Figure 3.2 CONSORT flow diagram for ACL-SPORTS female athletes

48

HIGH RATES OF RETURN TO SPORT AND COMPETITIVE LEVEL WITH A SPECIALIZED INTERVENTION REGARDLESS OF TIMING OF

INTERVENTION

4.1 Introduction Anterior cruciate ligament (ACL) injury is a common sports injury2 with considerable

lasting effects on both activities of daily living and sports participation.104,105,135 While

91% of athletes expect to return to their previous levels of sport participation after an

anterior cruciate ligament reconstruction (ACLR), a 2014 meta-analysis found only

55% are able to return to their pre-injury levels of competition and only 80% return to

any sport activity after their ACLR.8

A successful return to sport is not the end of the journey. Athletes who do successfully

return to cutting and pivoting sports have a higher risk for a second ACL injury (both

graft rupture and contralateral ACL injury) compared to those who return to less

strenuous sports.150 Approximately one-third experience an second ACL injury, with

nearly half of those second injuries occurring within two months of their return.58

Objective return to sport (RTS) criteria can reduce these rates,12,58 with quadriceps

strength and performance measure symmetry currently recommended.1,6,58,79,112

Chapter 4

49

A recent clinical practice guideline recommends a phase of pre-operative

rehabilitation, with a systematic review of eight studies finding pre-operative

rehabilitation was effective in improving post-operative outcomes in patients waiting

for ACLR.4 Current post-operative recommendations include 9-12 months of

quadriceps strengthening and neuromuscular retraining.10,54,77,98,141 Previous work

from our lab has shown improved patient-reported outcomes, improved quadriceps

strength symmetry, and improved hop performance symmetry after a ten-session

progressive intervention in both ACL-deficient and reconstructed athletes.11,83,134 It

may not be possible, however, to have both extended pre-operative and post-operative

intervention due to financial limitations or insurance visit restrictions. We do not

currently know if the timing of this intervention impacts the rates of second injuries or

return to sport/competitive level, nor do we know the best recommendation for an

athlete if there are a limited number of physical therapy visits available.

The purpose of this work is to compare the rates of return to sport, return to

competitive level, and second ACL injuries in the two years after ACLR between a

group who received a ten-session intervention before reconstruction and a group who

received the intervention in the return to sports phase of rehabilitation after ACLR.

50

4.2 Methods This is a secondary analysis of an ongoing longitudinal prospective cohort study and a

randomized control trial.

4.2.1 Participants

The Delaware-Oslo Cohort (DOC) is a prospective cohort study of 13- to 55-year-

olds, participated in and planning to return to a cutting/pivoting/jumping sport more

than 50 hours per year. They were enrolled with a complete unilateral ACL rupture,

confirmed by 3-mm or greater difference in anterior tibial excursion with instrumented

arthrometry33 (KT1000; MEDmetric Corporation, San Diego, CO). They had a ten-

session intervention and then self-selected operative or non-operative management.

Exclusion criteria included a repairable meniscus, symptomatic grade III injury to

other knee ligaments, or greater than 1-cm2 full-thickness articular cartilage lesion.

This analysis uses only those in Delaware who self-selected ACLR (n=62). The study

was approved by the University of Delaware Institutional Review Board and all

patients provided written informed consent, or parental consent with written assent if

under 18 years old at enrollment. The Delaware-Oslo Cohort Study is supported by

grant R37-HD037985 from the National Institutes of Health.

The Anterior Cruciate Ligament-Specialized Post-Operative Return to Sports (ACL-

SPORTS) randomized control trial enrolled athletes 13-55 years old, who participated

51

in and planned to return to a cutting/pivoting/jumping sport for more than 50 hours per

year (n=70). Patients were enrolled 3-9 months after ACLR and had a ten-session

intervention. Exclusion criteria included a repairable meniscus, symptomatic grade III

injury to other knee ligaments, or greater than 1-cm2 full-thickness articular cartilage

lesion. The study was approved by the University of Delaware Institutional Review

Board and all patients provided written informed consent, or parental consent with

written assent if under 18 years old at enrollment. The ACL-SPORTS trial is

registered at clinicaltrials.gov (NCT01773317) and is supported by grant R01-

AR048212 from the Eunice Kennedy Shriver National Institute of Child Health and

Human Development.

4.2.2 Intervention

All participants in the DOC had ten sessions of progressive strengthening, agilities,

plyometrics, performance, and perturbation training.38 The athletes in the ACL-

SPORTS study were randomized, with all athletes receiving progressive strength,

agilities, plyometrics, and performance training and half also participating in the

perturbation exercises.154 However, no differences in strength, performance, return to

sport,11,13,24 or second injury12 were found between those who did and did not have

perturbation training, so the groups for ACL-SPORTS have been collapsed for this

analysis.

52

4.2.3 Surveys

We used the Tampa Scale of Kinseophobia (TSK-11) to assess fear of movement after

both surgery and intervention (6 months after ACLR for the DOC and post-

intervention for ACL-SPORTS). We administered the TSK-11 again two years after

ACLR. Also at the two-year time-point, participants were asked if they had had a

second ACL injury (yes/no, and if yes, side), returned to their pre-injury sport (yes/no,

if no was it because of knee related issues or lifestyle reasons), and if they had

returned to their pre-injury level of competition (yes/no, if no was it because of knee

related issues or lifestyle reasons). We used independent t-tests to compare age,

height, weight, TSK-11 and time to second ACL injury, and a Pearson chi-square to

compare sex, rate of returning to the same sport, rate of returning to the previous

competitive level, and rate of second injury.

4.3 Results Demographics for the two groups at enrollment are presented in Table 4.1. Only age

was statistically different between groups.

Rates of return to the same sport, competitive level are shown in Table 4.2 and Figures

4.1 and 4.2. There were no statistically significant differences between groups.

Rates of second injury are shown in Table 4.3 and Figure 4.3. We had two subjects

from the DOC cohort with missing second injury data (n=60). There was no

53

statistically significant difference between groups with either rate or timing of second

ACL injuries.

Table 4.1: Demographics at enrollment

Demographic DOC (n=62) ACL-SPORTS (n=70)

Significance

Age (years) 26.2±10.5 21.9±7.9 0.008 Height (cm) 174.7±9.3 171.8±9.5 0.140 Weight (kg) 75.2±16.6 76.6±14.9 0.613 Male/female 40/25 35/35 0.255 TSK-11 at 6 months/post-intervention

17.3±5.5 18.2±4.7 0.339

TSK-11 at 2-year time-point

15.8±4.6 16.11±4.2 0.707

Table 4.2: Rates of same sport and same competitive level 2 years after ACLR

Variable DOC (n=62) ACL-SPORTS (n=70) Significance Same sport Yes/No lifestyle/No knee related

47/9/6

59/3/8

0.124

Same competitive level Yes/No lifestyle/No knee related

47/8/7

59/3/8

0.199

54

Figure 4.1: Rates of return to pre-injury sport

Figure 4.2: Rates of return to pre-injury competitive level

76%

14%

10%

Same SportDOC

yes no (lifestyle) no (knee)

84%

4%12%

Same SportACL-SPORTS


76%

13%

11%

Same LevelDOC


84%

4%12%

Same LevelACL-SPORTS


55

Table 4.3: Rates and side of second ACL injury two years after ACLR

Variable DOC (n=60)

ACL-SPORTS (n=70)

Significance

Second injuries No/graft/contralateral

52/6/2

63/5/2

0.829

Time to injury (weeks from ACLR)

77.5±27.16 (29.3-114.7)

62.9±25.8 (34.7-104.1)

0.306

Figure 4.3: Rates and sides of second ACL injuries

4.4 Discussion Participants from both groups returned to pre-injury sport and competitive level at the

highest range compared to existing literature,8,9 with 76% of the DOC and 83% of the

ACL-SPORTS athletes returning to their pre-injury sports. Furthermore, our rates of

return to pre-injury competitive level in the DOC (76%) and the ACL-SPORTS (83%)

87%

10%3%

Second InjuryDOC

No Ipsilateral Contralateral

90%

7%3%

Second InjuryACL-SPORTS

No Ipsilateral Contralateral

56

were higher than the rates reported by Ardern et al (55%)8 and comparable to athletes

under 19 years old reported by Kay et al (79%).71 Previous work from our lab

demonstrated improved quadriceps strength, hop performance, and patient reported

outcomes with this ten-session intervention.11,83,134 Our intervention seems to prepare

athletes for a successful return to their pre-injury sports regardless of the timing of that

intervention. There was very low fear in both groups as shown by the low TSK-11

scores that were not different between groups at either time-point. The intervention

appears to successfully prepare athletes for return to previous activities.

We found no difference in the number of second ACL injuries between groups (DOC:

11%, ACL-SPORTS: 10%); these rates are among the lowest reported rates of second

ACL injury rates (9.6130 to 49%34). Since the intervention successfully prepared these

athletes to meet RTS criteria and we know that objective return to sport criteria can

reduce rates of second ACL injury,12,58 our intervention may reduce the risk of second

ACL injuries in athletes who do return to their pre-injury sports.

Only 53% of those over 20 years old returning to strenuous sports compared to 88% of

those under 20.150 There is a similar association with younger age and increased rates

of second ACL injury,31,148,150 with 29% of those under 20 going on to a second ACL

injury compared to only 8% of those over 20.150 Since the average age was 22 years

for ACL-SPORTS and 26 years for DOC, we expected to find lower rates of return to

57

sport and second ACL injuries in the DOC group.31,148,150 While there is a strong

association between age and returning to cutting/pivoting sports,19,130,150 , recent work

from our cohort showed that activity and functional readiness, not age, were the

critical factors for second anterior cruciate ligament injury and that age is a proxy for

returning to high risk sports.57 The similar rate of return to sport and competitive level

for the DOC group compared to the younger ACL-SPORTS group may therefore

explain why there was not a difference in second ACL injury rates between groups.

Our neuromuscular and strength training intervention may be addressing the needs of

older athletes, increasing their rate of return to pre-injury sports/competitive level.

Since the group who had the intervention pre-operatively showed excellent post-

surgical outcomes, both in this analysis and in other studies,28,38,62,100 it is further

evidence that delaying surgery for pre-operative rehabilitation positively impacts long

term clinical outcomes41 and that individualized decision-making regarding timing of

ACLR is appropriate.46,55 Since previous studies found no extra benefit from the

addition of perturbation training,11,13,24,27 progressive pre-operative rehabilitation that

addresses strength, range of motion, and control of swelling may not need multiple

visits of skilled physical therapy intervention. For patients with limited resources

(financial or insurance-based), participating a progressive pre-operative home program

to save physical therapy visits for the end of rehabilitation may be beneficial to

address patient-specific impairments and sport-specific return to sports training.

58

4.5 Strengths and Limitations While there were obvious differences in part of the enrollment criteria (ACL-deficient

versus return to sports phase after reconstruction), age range, sport participation,

intention to return, and all exclusion criteria were the identical for both groups. All

interventions for both DOC and ACL-SPORTS were provided by physical therapists

at the University of Delaware Physical Therapy Clinic. The participants in the DOC

were not asked about a return to any sport (versus return to pre-injury sport), so we

cannot assess that rate in the DOC; athletes in the ACL-SPORTS study had a 97%

return to any sport rate (95% for men12, 100% for women24).

4.6 Conclusion Both those who received the intervention pre-operatively and those who received the

intervention in the return to sports phase of rehabilitation after ACLR reported among

the highest rates of return to their pre-injury sport and competitive level compared to

previously published literature, while timing of intervention did not have a statistically

significant impact on rates of return to sport, competitive level, or second ACL injury.

A ten-session intervention may prepare athletes for a successful return to their pre-

injury sport and level of competition and reduce the rate of second ACL injuries.

59

LOW LOADING OF THE MEDIAL TIBIOFEMORAL COMPARTMENT DURING GAIT FIVE YEARS AFTER ACL INJURY IS PREDICTIVE OF

SMALLER JOINT SPACE WIDTH AT TEN YEARS

5.1 Introduction Anterior cruciate ligament (ACL) injuries have devastating consequences to both

activities of daily living and sport participation.104,105,135 Patient expectations do not

match actual outcomes. 98% of patients expect no or only a slightly higher risk of

osteoarthritis (OA) after injury and ACL reconstruction (ACLR),44 yet up to 50% of

ACL injured individuals develop radiographic OA within 20 years.14,32,74,84

Current best recommendations for the treatment of OA include physical therapy,

education, pain control, medication, and surgery.106,163 These secondary and tertiary

level treatments address symptoms but are unable to reverse extant joint damage.106,122

The peak age of ACL injury between 15-25 years old16,117,126,162 and roughly 50%

developing radiographic OA within ten to twenty years of ACL

injury/reconstruction.84 Thus, identification of modifiable risk factors for primary level

treatment before the initiation of cartilage degradation is critical.

Chapter 5

60

One possible risk factor for the development of OA is gait biomechanics, which are

altered after ACL injury/reconstruction.29,51,60–62,110,111,120,124,131 Gait biomechanics

continue to normalized from up to eight years after ACLR,40,51 suggesting a continued

long-term recovery of function and joint loading. These gait changes shift loading to

regions of cartilage not adapted to joint loading39 which may result in cartilage

degradation. The medial compart of the tibiofemoral joint carries the majority of the

tibiofemoral load127,158 and under-loading of the medial tibiofemoral compartment was

associated with radiographic OA changes five years after ACLR.152 Since healthy

cartilage responds positively to cyclic load,5 unloading normally loaded cartilage may

result in “deconditioned” cartilage, which if reloaded as gait biomechanics improve,

may account for the higher rates of radiographic knee OA after ACLR.

The purpose of this study was to analyze gait biomechanics five years after ACL

injury/reconstruction and to quantify its effect on medial tibiofemoral compartment

joint space width (JSW) five and ten years after ACL injury/reconstruction. We

hypothesized that low loading in the medial tibiofemoral compartment five years after

ACL injury would predict smaller medial compartment JSW at ten years. We

hypothesized that under-loading in the medial tibiofemoral compartment five years

after ACL injury/reconstruction would predict smaller JSW and a larger change in

JSW from five to ten years.

61

5.2 Methods This is a secondary analysis of an ongoing prospective observational study.55,82 The

study was approved by the human subjects committee at the University of Delaware,

and all patients provided written informed consent, or parental consent with written

assent if under 18 years old, at enrollment. Participants were enrolled between 2007

and 2012 and this analysis uses only those enrolled in Delaware. The Delaware-Oslo

ACL Cohort Study is supported by grant R37-HD037985 from the National Institutes

of Health.

5.2.1 Subjects At enrollment, participants were 13- to 55 years old with a complete unilateral ACL

rupture verified by ≥3mm difference in anterior laxity33 (KT1000; MEDmetric

Corporation, San Diego, CO) who participated in Level I/II cutting/jumping/pivoting

sports64 for 50 or more hours per year before their injury. Following study enrollment,

participants completed ten pre-operative intervention sessions38 then self-selected non-

operative management or ACLR. Dates for follow-up visits were five- and ten years

post-training for non-operative participants or post-ACLR if managed operatively.

5.2.2 Modeling We collected gait data 5 years after ACL injury/reconstruction using an 8-camera

motion capture system at 120Hz (VICON, Oxford UK), an embedded force plate at

62

1020 Hz (Bertec, Columbus OH), and thirty-nine retroreflective markers on both

lower extremities. Participants walked at a self-selected gait speed ±5%. Kinetics and

kinematics were calculated via inverse-dynamics (Visual3D, C-Motion, Germantown,

MD). Surface electromyography (EMG) data were collected from seven lower

extremity muscles bilaterally at 1080 Hz (MA-300 EMG System, Motion Lab

Systems, Baton Rouge, LA). Maximal isometric voluntary contractions were used to

normalize EMG data, which were high pass filtered (2nd order Butterworth), rectified,

and low-pass-filtered (6 Hz) to create a linear envelope. We calculated medial

tibiofemoral compartment contact forces using a previous validated91 EMG-driven

musculoskeletal model20 normalized by body weight (BW). We used the peak medial

compartment contact force in the first half of the stance phase averaged over trials. We

also calculated peak medial compartment loading symmetry (involved-uninvolved).

5.2.3 Radiographs We obtained bilateral weight-bearing posterio-anterior bent knee (30°) radiographs

using the Lyon-Schuss protocol (pelvis, thighs, and patellae flush against the film

cassette and coplanar with the tips of the great toes and the x-ray beam adjusted for

each image to align with the medial tibial plateau)65,67 at five- and ten-year follow-ups.

Angle was confirmed with a universal goniometer. We assessed each image for fixed

location joint space width in the medial compartment35 as a surrogate for cartilage

loss.21 While Kellgren and Lawrence (KL) grades are also used to assess radiographic

63

OA,73 tibiofemoral joint space width (JSW) may be measured on plain film

radiographs as a surrogate for cartilage loss.21 The International Knee Documentation

Committee (IKDC) has published objective criteria for JSW to classify narrowing of

the tibiofemoral compartment.64,97 JSW was measured by a single rater (JLJ,

ICC=0.959) (SigmaView, AGFA HealthCare, Mortsel, Belgium).

5.2.4 Statistics We used linear regression to assess effect of medial compartment loading five years

after ACL injury/reconstruction on medial compartment JSW at ten years, loading

symmetry five years after ACL injury/reconstruction. on medial compartment JSW at

ten years and loading symmetry five years after ACL injury/reconstruction on change

in JSW from five to ten years. Statistical significance was set at p ≤0.05 a priori.

5.3 Results Sixteen participants (6 female) had complete data sets, 6 had self-selected to manage

non-operatively (3 female), 1 subject had a medial meniscus repair at ACLR. The

average age was 38.0±11.8 years (range 21.5-58.6 years) and body mass index (BMI)

was 28.1±4.8 kg/m2 at the time of the five-year follow-up. None of our participants

had medial compartment radiographic OA five years after ACL injury/reconstruction

based on IKDC objective criteria of <4mm of JSW.64,97

64

Involved medial compartment loading at five years predicted involved medial

compartment JSW at ten years (R2=0.61, p<0.001, Figure 5.1). Loading symmetry

(involved-uninvolved) predicted JSW at ten years (R2=0.32, p=0.024, Figure 5.2).

Loading symmetry did not predict change in JSW from five- to ten years (R2=0.06,

p=0.379, no figure). Results varied by surgical status; all participants with

radiographic OA at ten years had chosen ACLR as their management (Figure 5.3).

Figure 5.1: Predicting medial compartment JSW at ten years with loading at ten years The black dashed line represents R2=0.61. The red vertical dashed line represents the mean compartment loading, 2.7 BW. The red horizontal dashed line represents 4.0mm, the IKDC cut-off for the presence of radiographic OA.

0.01.02.03.04.05.06.07.08.09.0

10.0

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5

Invo

lved

med

ial J

SW (m

m)

Involved medial compartment joint loading (BW)

Predicting medial JSW at 10 years from medial compartment loading at 5 years

65

Figure 5.2: Predicting medial compartment JSW at ten years with loading symmetry at five years

The black dashed line represents R2=0.32. The red vertical dashed lines represent 0.3 BW, the MDC for contact force, used to define symmetry and under- and over-loading. The red horizontal dashed line represents 4.0mm, the IKDC cut-off for the presence of radiographic OA.

0.01.02.03.04.05.06.07.08.09.0

10.0

-1.5 -1 -0.5 0 0.5 1 1.5 2

Invo

lved

med

ial J

SW (m

m)

loading symmetry (BW)

Predicting medial JSW at 10 years from loading symmetry at 5 years

66

Figure 5.3 Predicting medial compartment JSW at ten years with loading at five year by surgical status

Non-operative participants are designated with hollow circles with dotted line R2=0.850 and ACLR participants with “x”, dashed line R2=0.355. The red horizontal dashed line represents 4.0mm, the IKDC cut-off for the presence of radiographic OA.

5.4 Discussion The purpose of this study was to analyze gait biomechanics five years after ACL

injury/reconstruction and to quantify its effect on medial tibiofemoral compartment

JSW five and ten years after ACL injury/reconstruction. Medial compartment loading

during gait five years after ACL injury/reconstruction explained 61% of the variance

in JSW ten years after ACL injury/reconstruction. Symmetry of loading in the medial

compartment explained 32% of the variance in JSW ten years after ACL

injury/reconstruction; this was not predictive of change in JSW from five to ten years

0.01.02.03.04.05.06.07.08.09.0

10.0

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5

Med

ial J

SW (m

m)

Medial compartment joing loading (BW)

Predicting JSW at 10 years with loading at five yearsby surgical status

ACLR non-op

67

after ACL injury/reconstruction. Additionally, all participants with radiographic OA

changes ten years after ACL injury/reconstruction chose ACLR.

None of our participants had medial compartment radiographic OA five years after

ACL injury/reconstruction based on the IKDC objective criteria of >4mm. Ten years

after ACL injury/reconstruction, five participants had JSW between 3.0 and 3.9mm,

indicating mild radiographic OA.64,97 When we compare symmetry of medial

compartment loading using the previously established minimal detectable change

(MDC) of 0.3 BW50 in those classified with radiographic OA at ten years, three were

under-loaders, one was symmetrical, and one was an over-loader. For the eleven

participants without radiographic OA at ten years, one was an under-loader, five were

symmetrical, and five were over-loaders. When we analyze totally medial tibiofemoral

compartment load, four of the participants with radiographic OA at ten years were

below the mean compartment load of 2.7 BW with one just above; for those without

radiographic OA, four loaded below the mean of 2.7 BW, and seven were above.

Previous research has suggested that under-loading, and not overloading, of the

tibiofemoral joint may be the underlying cause of degenerative changes after ACL

injury.5,76,153,161 We found not only the symmetry of loading but the amount of load

was predictive of JSW at ten years after ACL injury/reconstruction. Gait biomechanics

are modifiable with a ten-session pre-operative intervention,62,111,153 but did not change

when the intervention was in the return to sports phase of rehabilitation after ACLR.25–

68

27 Thus, rehabilitation and intervention to restore both normal symmetry and quantity

of medial tibiofemoral compartment loading early after ACL injury/reconstruction

may be a primary treatment for those at high risk for developing OA after ACL


Even though ACLR is the most common recommendation after an ACL injury,102

there is growing evidence that non-operative management of ACL injuries is

successful, with no difference in patient reported function49,55,99 clinical outcomes,56,99

or OA progression49 between non-operative and operative managed participants. A

2014 meta-analysis of six studies found a higher relative risk for developing any

radiographic OA in the non-operatively managed patients but a lower relative risk of

moderate or severe radiographic OA compared to the operatively managed patients3,

however, all five of the participants with radiographic OA changes in this analysis

were operatively managed. The results of this study add to the evidence that those who

choose to manage non-operatively after ACL injury should not assume poorer

outcomes than those who select reconstruction.

In our participants, those who demonstrated low loading in the medial tibiofemoral

compartment during gait at five years had less joint space at ten years after ACL

injury/reconstruction. Since healthy cartilage responds positively to cyclic load,5 not

only the symmetry of loading but the amount of load may influence the maintenance

69

of JSW after ACL injury/ACLR. Additionally, only those who chose ACLR went on

to develop radiographic OA. The identification of these potentially modifiable risk

factors may drive future research into rehabilitation interventions to address low and

asymmetrical loading of the medial compartment of the tibiofemoral joint which may

reduce the rates of radiographic knee OA after ACL injury/reconstruction.

5.5 Conclusions We were able to predict 61% of the variance in JSW at ten years with medial

compartment loading at five years: the more loading that occurred in the medial

compartment at five years, the more JSW at ten years. Loading symmetry was

predictive of JSW at ten years but not predictive of change in joint space width from

five- to ten years after ACLR. All participants with radiographic OA changes were

operatively managed. These potentially modifiable risk factors may allow for the

development of interventions to target those at high risk of developing radiographic

OA before measurable joint degradation occurs.

70

SUMMARY

6.1 Overview of the aims

This dissertation aimed to improve clinical decision-making regarding patient-reported

outcome measures, second ACL injury risk, rate of return to sport and competitive

level, the timing of intervention, and identification of potentially modifiable risk

factors of radiographic knee OA in patients after an ACL injury/reconstruction.

This work aimed to address the high, unmet expectations of our patients and improve

our clinical decision-making to address common limitations and risks after ACL injury

and reconstruction.

6.2 Aim 1 Purpose

We determined the construct validity of the GRS and assessed the responsiveness of

the GRS, the IKDC-SKF, the KOS-ADLS, and the KOOS subscales with effect sizes

and ceiling effects in the five years after ACL injury and reconstruction.

6.2.1 Hypothesis 1.1:

We hypothesized that the GRS would have good construct validity when compared

with the IKDC-SKF.

Chapter 6

71


We hypothesized there would be no difference in responsiveness between the GRS,

the IKDC-SKF, the KOS-ADLS, and the KOOS subscales as measured by effect size

and ceiling effects.

6.2.3 Conclusion

The GRS had good construct validity, a small MDC, and responded similarly to the

IKDC-SKF, KOS-ADLS, and KOOS measures and was responsive to patient change.

The ease of use and patient-specific nature of the single item GRS means that, for

clinical practice, it may be appropriate to use as a frequent measure throughout

rehabilitation with other measures used as needed at specific milestones or for

additional details.

6.3 Aim 2 Purpose:

We compared the rate and side of second ACL injuries in female athletes who

received post-operative strength, agility, plyometrics, and prevention training (SAPP)

compared to those who received post-operative training plus specialized perturbation

(SAAP+PERT) training.


We hypothesized that SAPP+PERT athletes would have fewer second ACL injuries

than those who received SAPP training alone.

6.3.2 Conclusion

The addition of perturbation training to a secondary injury prevention program did not

have additional preventative benefits for female athletes. However, the participants in

72

the ACL-SPORTS training program reported fewer contralateral ACL injuries

compared to previously published results.

6.4 Aim 3 Purpose:

We analyzed the impact of the timing of a specialized intervention (pre-operatively

versus the return to sport phase) on rates of return to sport and competitive level and

rates of second ACL injury.


We hypothesized that those who received post-operative training would have a higher

rate of return to their pre-injury sports than those who had pre-operative training.


We hypothesized that those who received post-operative training would have a higher

rate of return to their pre-injury competitive levels of sport than those who had pre-

operative training.


We hypothesized that there would be no difference in rates of second ACL injury

between those who received pre-operative training and those who had post-operative

training.

6.4.4 Conclusion

Both the group that received the intervention pre-operatively and the group that

received the intervention in the return to sports phase of rehabilitation reported among

the highest rates of return to the same sport and competitive level reported in

73

published literature, but the timing of the intervention did not have a statistically

significant impact on rates of return to sport, competitive level, or second ACL injury.

6.5 Aim 4 Purpose:

Using medial compartment joint contact forces collected during gait at five years and

tibiofemoral JSW from radiographs at five and ten years after ACL

injury/reconstruction, we analyzed predictive factors of joint space narrowing.


We hypothesized that under-loading in the medial compartment of the knee during

gait five years after ACL injury/reconstruction would predict smaller JSW in the

medial tibiofemoral compartment ten years after ACL injury/reconstruction.


We hypothesized that lower loading in the medial compartment of the knee during gait

five years after ACL injury/reconstruction would predict smaller JSW in the medial

tibiofemoral compartment ten years after ACL injury/reconstruction.

6.5.3 Conclusion

We were able to predict 60% of the variance in JSW at ten years with medial

compartment loading at five years: the more loading that occurred in the medial

compartment at five years, the more JSW at ten years. Loading symmetry was

predictive of JSW at ten years but not predictive of change in joint space width from

five- to ten years after ACL injury/ reconstruction. The five participants with

radiographic OA at ten years were all operatively managed. These potentially

modifiable risk factors may allow for the development of interventions to target those

74

at high risk of developing radiographic OA before measurable joint degradation

occurs.

6.6 Summary of Work

Clinicians are faced with high patient expectations and low rates of return to sport and

high rates of second injury and OA. This work aimed to inform clinical decision-

making by analyzing the validity and responsiveness of a single-item patient-reported

outcome measure to improve provider communication and decrease provider and

patient burden, by analyzing the impact of specialized intervention on second ACL

injury rates in female athletes, by evaluating the impact of the timing of that

intervention on rates of return to sport/competitive level and second ACL injury, and

by identifying possibly modifiable risk factors for development of radiographic knee

OA.

75

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IRB DOCUMENTATION

Appendix A

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LIST OF ABBREVIATIONS

ACL Anterior Cruciate Ligament ACLR Anterior Cruciate Ligament Reconstruction ACL-SPORTS Anterior Cruciate Ligament-Specialized Post-Operative Return

To Sports ADL Activities of Daily Living BMI Body Mass Index BPTB Bone-Patellar Tendon-Bone Graft BW Body Weight DOC Delaware-Oslo Cohort EMG Electromyography ES Effect Size GRS Global Rating Scale IKDC International Knee Documentation Committee IKDC-SKF International Knee Documentation Committee-Subjective Knee

Form JSW Joint Space Width Kg Kilogram KOOS Knee injury and Osteoarthritis Outcome Score KOS-ADLS Knee Outcome Survey-Activities of Daily Living Scale LSI Limb Symmetry Index MIC Minimal Important Change mm Millimeter OA Osteoarthritis PERT Perturbation PROMs Patient Reported Outcome Measures QI Quadriceps Index QOL Quality Of Life RTS Return To Sports SANE Single Assessment Numeric Evaluation SAPP Strength, Agility, Plyometric, and Performance SAPP+PERT Strength, Agility, Plyometric, and Performance + Perturbation TSK-11 Tampa Scale of Kinesiophobia

Appendix B

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PROGNOSTIC FACTORS FOR PATIENT-REPORTED OUTCOME MEASURES AND PHYSICAL ACTIVITY TWO TO TEN YEARS AFTER

ACL INJURY OR RECONSTRUCTION: SYSTEMATIC REVIEW

Marie Pedersen, PT, MS1, Jessica L. Johnson, PT, DPT2, Hege Grindem, PT, PhD1, Karin Magnusson PT, PhD3,4, Lynn Snyder-Mackler, PT, ScD2,5, May Arna Risberg, PT, PhD1,6 1 Department of Sports Medicine, Norwegian School of Sport Sciences, Oslo, Norway 2 Graduate Program in Biomechanics and Movement Science, University of Delaware, Newark, DE, United States 3 Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Orthopaedics, Clinical Epidemiology Unit, Lund, Sweden 4 Diakonhjemmet Hospital, Department of Rheumatology, National Advisory Unit on Rehabilitation in Rheumatology, Oslo, Norway 5 Department of Physical Therapy, University of Delaware, Newark, DE, United States 6 Division of Orthopedic Surgery, Oslo University Hospital, Oslo, Norway Corresponding author: Marie Pedersen Department of Sports Medicine Norwegian School of Sport Sciences PB 4014 Ullevaal stadion 0806 Oslo Norway [email protected]

Appendix C

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Word count (excluding title page, abstract, references, figures and tables): 4845. Funding: The project is funded by the National Institutes of Health through grant R37HD37985. Public trials registry: Our study protocol was published in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018095602) on June 7th 2018.

AKNOWLEDGEMENTS We would like to acknowledge librarians Anne Grethe Gabrielsen, Karianne

Hasledalen and Elin Hecker at the Norwegian School of Sport Sciences and Marte

Ødegaard at the University of Oslo for assistance and reviewing of systematic

searches.

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ABSTRACT

OBJECTIVE: (1) Assess prognostic factors for patient-reported outcome measures

(PROMs) and physical activity (PA) two to ten years after anterior cruciate ligament

reconstruction (ACLR) or injury. (2) Assess differences in prognostic factors between

patients treated with ACLR and with rehabilitation alone.

DESIGN: Prognosis systematic review.

LITERATURE SEARCH: Systematic searches in PubMed, Web of science and

SPORTDiscus.

STUDY SELECTION CRITERIA: We selected prospective cohort studies and

randomised clinical trials that included adults/adolescents undergoing either ACLR or

rehabilitation alone after ACL rupture. Studies had to assess for a statistical

association between potential prognostic factors (factors related to patient

characteristics, injury or knee symptoms/function measured at baseline or within one

year) and outcomes (PROMS and PA).

DATA SYNTHESIS: Our search yielded 1008 references. Twenty studies met

inclusion criteria. Seven studies with low or moderate risk of bias remained for data

synthesis.

RESULTS: Concomitant meniscus and cartilage injuries were prognostic factors

with moderate certainty for worse PROMs two to ten years after ACLR, while BMI,

smoking and baseline PROMs were factors with very low certainty. Female sex and

worse baseline Marx Activity Rating Scale (Marx) were prognostic factors for worse

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Marx two to ten years after ACLR with very low certainty. There was a lack of studies

on prognostic factors after rehabilitation alone.

CONCLUSION: Concomitant meniscus and cartilage injuries are prognostic factors

for worse long-term PROMs after ACLR. The certainty is low/very low for other

prognostic factors. We were unable to assess differences in prognostic factors between

treatment groups.

KEY WORDS: Prognosis, Ligament, Knee surgery, Sporting injuries

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INTRODUCTION

Anterior cruciate ligament (ACL) injuries have serious negative long-term

consequences such as lower extremity dysfunction, low levels of physical activity

(PA), poor quality of life, and early development of knee osteoarthritis (OA) (1-7).

Resolving impairments and returning to sport are often the main short-term goals for

patients (1, 8). But as clinicians, we need to incorporate long-term consequences of

ACL injury into our patient education and allow them to inform our interventions

early after injury or reconstruction (9). Hence, high quality studies on prognostic

factors for important long-term outcomes such as patient reported outcome measures

(PROMs), levels of PA and OA are valuable.

A prognostic study can aim to predict the total individual risk given all available

information in a prediction model, or to estimate a population average causal effect of

an exposure or treatment on an outcome given adjustment for relevant confounders.

Both approaches may provide important information on prognostic factors, as a

prognostic factor can be either causally or non-causally related to an outcome variable

(10-12). Many systematic reviews have evaluated prognostic factors for developing

knee OA after ACL injury (5, 13-17). A few systematic reviews have reported

prognostic factors for long-term PROMs and level of PA (15, 16, 18-21), but most of

them are of poor quality due to lack of risk of bias assessments (15, 16, 18). Also,

patients treated with rehabilitation alone have not been included in these previous

systematic reviews.

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Consequently, we need a high-quality systematic review on prognostic factors for

PROMs and level of PA two to ten years after ACL injury or ACLR, with an

appropriate and thorough risk of bias assessment. Such a study may provide

information about prognostic factors that can be targeted with early treatment, and can

thereby help to improve outcomes for patients with ACL injury.

Current evidence suggests similar clinical courses following rehabilitation alone and

ACLR (3, 22-26), but we do not know if prognostic factors differ in the two treatment

groups. There is great clinical interest to identify early prognostic factors associated

with better outcome after both ACLR and rehabilitation alone. This knowledge can

help inform treatment choices. No systematic review has previously addressed this

topic.

Therefore, the aims of our systematic review were (1) To assess prognostic factors for

patient-reported outcome measures (PROMs) and physical activity (PA) two to ten

years after anterior cruciate ligament reconstruction (ACLR) or injury. (2) To assess

differences in prognostic factors between patients treated with ACLR and with

rehabilitation alone.

METHODS

This systematic review was conducted in accordance with the Preferred Reporting

Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (27). Our

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study protocol was published in the International Prospective Register of Systematic

Reviews (PROSPERO: CRD42018095602) on June 7th 2018.

Eligibility criteria

Studies were included using the following criteria: (1) Prospective cohort studies and

randomised clinical trials (RCT), that (2) report prognostic factors for PROMs or level

of PA, at (3) a mean of ≥ two and <10 years, in (4) adults and adolescents (mean

age > 13 years), (5) undergoing either ACLR or rehabilitation alone after complete

ACL rupture. (6) Studies had to assess the association between exposure and outcome

with regression analyses. Studies only on revision ACLR, knee dislocations, partial

tears or bilateral injury were excluded. We included studies where a subset of patients

had these conditions. Prognostic factors were defined as either patient characteristics

(all factors that describes a patient, eg age, sex, psychological factors), factors related

to the injury (eg concomitant injury) or knee symptoms and function (eg functional

performance, patient reported outcome measures) that were assessed ≤ one year after

injury or ACLR.

The following PROMs were selected; Knee injury and Osteoarthritis Outcome Score

(KOOS), International Knee Documentation Committee Subjective Knee Form

(IKDC-SKF) and Knee Outcome Survey Activities of Daily Living Scale (KOS-

ADLS). These PROMs were chosen based on their frequent use as stand-alone

PROMs for long-term outcomes during the last decade and because they have good

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measurement properties (28-34). The KOOS consists of five subscales: pain, other

symptoms, function in daily living (ADL), function in sport and recreation (S/R), and

knee-related quality of life (QoL) (32). KOOS can be reported as individual subscales

or as KOOS4 which is an average score of four subscales (ADL excluded). The IKDC-

SKF measures symptoms, function and sports activity in patients with different types

of knee problems (34). The KOS-ADLS assesses the impact of symptoms on subjects'

ability to perform daily activities (28). All three questionnaires are scored from 0

(worst) to 100 (best). We included all outcomes that reflect type and level of PA,

including the three components defining physical activity: frequency, intensity and

duration (35) (eg objective measures such as accelerometers, patient-reported PA

questionnaires and return to sports). An example of a patient-reported outcome

measure of PA for ACL injured individuals is The Marx Activity Rating Scale (Marx).

Marx is a brief survey on the frequency of participation in sports involving running,

pivoting, cutting, and deceleration (36).

Data sources and searches

We systematically searched PubMed, Web of science and SPORTDiscus for articles

published from database inception to 20th September 2018. See search strategy for

PubMed in TABLE 1. Filters on “Humans” and “English language” were used and all

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free text words/terms were searched on "Title/abstract". Relevant systematic reviews

were identified with the same search terms in PubMed. Reference lists from

systematic reviews and included studies were hand searched for relevant material to

supplement electronic database searches. To identify additional literature, the

following simplified search was performed in Google Scholar: "Anterior cruciate

ligament"|ACL Prognosis|"Prognostic factors"|Predict|Associations "Return to

sports"|Participation|"Activity level"|"Physical activity"|Tegner|Marx|KOOS

|IKDC|KOS "Prospective study"|"Observational study"|"Cohort study"|RCT”. The 100

first (and most relevant) results from Google Scholar were screened. The searches

were performed with assistance from and reviewed by librarians at the Norwegian

School of Sport Sciences and the University of Oslo.

Study selection and data extraction

Two independent researchers (MP and JLJ) screened for eligibility and extracted data

with customized data extraction forms. Covidence systematic review software (Veritas

Health Innovation, Melbourne, Australia, available at www.covidence.org) was used

to assist this process. Calibration exercises were performed to ensure consistency

between reviewers, but without testing agreement. Discrepancies were resolved by

discussion or a third reviewer (HG or MAR). We contacted study authors to resolve

uncertainties when necessary. Titles and abstracts were screened to identify potentially

relevant studies for full text eligibility assessment. The reasons for exclusion were

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recorded. When several exclusion criteria were fulfilled, the first reason on a

predefined list was chosen.

Risk of bias assessment

Risk of bias was assessed with the Quality in Prognosis Study (QUIPS) risk of bias

tool (37). We chose this tool because it is developed specifically for the

methodological assessment of prognostic studies. QUIPS is a reliable tool for

systematically assessing risk of bias in the following six domains: study participation,

study attrition, prognostic factor measurement, outcome measurement, study

confounding and statistical analysis and reporting (37). Three independent reviewers

(MP, JLJ and KM) performed the scoring of the different domains. Our

operationalization of the QUIPS items is described in APPENDIX 1. For studies

where the objective was prediction and not etiology, the confounding domain was

classified as irrelevant (because the goal of a prediction model is to predict the total

individual risk given all information, for example independent of the covariates’

influence on each other) (11, 12). The overall risk of bias for each study was

classified: (1) low, if there was low risk of bias in all domains, (2) moderate, if there

was moderate risk of bias for ≥one domain and (3) high, if there was high risk of bias

for ≥one domain (38). For all domains, high risk of bias was defined as a level where

the results of the study should not be trusted, and/or it was impossible to interpret due

to research methodology and/or inadequate description of methodology. This was an

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overall assessment and decision, hence, no study was classified as high risk of bias in

any domain based on only one question.

Data synthesis and analysis

Results from all included studies (n=20) are presented in APPENDIX 2 and 3. We

included only studies with low or moderate risk of bias in the data synthesis. The

purpose was to ensure conclusions and recommendations to clinicians and patients

were not based on results that should not be trusted, and to make the results easier to

interpret and, hence, easier to translate into practice. When data from the same patients

were used in publications on the same prognostic factors and outcomes at different

time points, we included the most recent publication. Results were presented

separately for the outcomes PROMs and level of PA and for patients undergoing

ACLR and rehabilitation alone. When possible, results from studies on each treatment

group were extracted separately. Results from adjusted analyses were preferred. It was

not possible to perform a meta-analysis due to methodological diversity in outcome

measures and follow-up time.

Quality of evidence for each prognostic factor was judged as high, moderate, low or

very low with the "Grading of Recommendations Assessment, Development and

Evaluation" (GRADE) approach. The GRADEpro software (39) was applied and

adjusted according to recommendations for prognostic factor research (40, 41).

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RESULTS

Search results

A total of 974 references were identified through database searching. Additional 23

references were identified through bibliographies (n=2), Google Scholar (n=3) and

reference lists (n=18). After removing duplicates, 561 references remained. All were

screened for eligibility and 431 were ineligible due to objectives, outcome or follow-

up time. The remaining 130 articles were read in full text and 20 met all eligibility

criteria (FIGURE 1). Seventeen of the included studies were identified through the

systematic search, while three were identified through other sources. Due to more

recent publications on the same prognostic factors and outcomes, we excluded the

results on concomitant cartilage lesions, but not meniscus lesions from Røtterud et al.

(42) and all results from the study by Magnussen et al. (43) from 2016. Seven studies

with low or moderate risk of bias remained for data synthesis (42, 44-49).

Study characteristics

Characteristics of the included studies (n=20) are presented in TABLE 2. Most of the

cohort studies were based on data from the Multicenter Orthopedic Outcomes

Network (MOON) cohort (n= 8) (43, 47, 48, 50-54) and the Swedish and/or

Norwegian Knee Ligament Registries (SKLR/NKLR) (n= 5) (42, 44, 46, 49, 55). In

the included RCTs, both treatment groups were treated as one cohort for the

assessment of prognostic factors (45, 56-58). Three of the RCT publications were

based on the Knee Anterior Cruciate Ligament, Nonsurgical versus Surgical

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Treatment (KANON) trial (45, 57, 58). The studies included median (Q1-Q3) 495

(121-2333) patients. Due to several publications on the same patients in the large

registry studies, it was challenging to estimate the total number of unique patients

included in this systematic review. Most studies included patients undergoing primary

ACLR only, and no study included only patients treated with rehabilitation alone.

Patients with substantial concomitant injuries (43, 45-47, 51, 53, 55-61) and/or

contralateral ACL injury (42, 46, 48, 49, 51-54, 56) were frequently excluded from the

included studies. The median age at inclusion was 26 years (range 18-27). The median

percentage of females was 44% (range 26-77%). Preinjury activity level was reported

in seven studies, where four (52, 59-61) included patients active in pivoting sports

preinjury and three (45, 57, 58) included patients with Tegner Activity Scale between

6 and 9 (6=recreational pivoting sports, 9=competitive sports).

Sixteen studies were etiological (42-47, 49-53, 56-59, 61) and four were predictive

(48, 54, 55, 60). Among the studies included in our data synthesis, only Spindler et al.

(48) was a predictive study.

Risk of bias

Risk of bias for the six QUIPS-domains and an overall rating is shown in TABLE 3.

Studies generally received poor scores on the domains "Study confounding" and

"Analysis and reporting" because they did not explicitly state what covariates were

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adjusted for and why, did not separate between confounders, mediators and colliders

(and subsequently did not treat these covariates in accordance with existing rules for

adjustment), or had mixed predictive and etiological statistical approaches, which led

to uninterpretable results (10, 12, 62).

Data synthesis of studies with low or moderate risk of bias (n=7)

Prognostic factors for PROMs in patients treated with ACLR

Prognostic factors for PROMs in patients treated with ACLR were assessed in seven

studies from four cohorts. The IKDC-SKF was an outcome in two studies (47, 48) and

the KOOS was an outcome in seven studies (42, 44-49). The following 13 factors

were assessed by ≥1 study with low or moderate risk of bias: sex, age, body mass

index (BMI), smoking, ethnicity, type of sport, concomitant injury on medial or lateral

concomitant ligaments (MCL/LCL), meniscus or cartilage, hearing a pop at injury,

knee laxity, extension range of motion deficit and baseline PROMs. These factors

were measured at baseline, preoperatively or during ACLR.

Patient characteristics

One predictive study reported higher baseline BMI as a prognostic factor for worse

six-year IKDC-SKF and KOOS S/R outcomes and smoking for worse IKDC-SKF

(48). The same study found no association between higher BMI and KOOS QoL, or

between smoking and KOOS QoL and KOOS S/R.

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There were no statistically significant association between the factors sex, age,

ethnicity and type of sport and the outcomes two- and six-year IKDC-SKF and KOOS

(44, 48).

Factors related to the injury

Concomitant meniscus injury was reported as a prognostic factor in some studies, but

not in others. Three studies (two etiological and one predictive) of three different

cohorts, found a statistically significant negative association between concomitant

meniscus injury and two-year patient-reported success (KOOS4 ≥80th percentile) (46)

and five- and six-year KOOS S/R and QoL outcomes (45, 48). The mean difference

between those with and without concomitant meniscus injury was 10-14.4 points for

KOOS S/R (45, 48) and 8.9 points for KOOS QoL (48). These values are of

questionable clinical relevance as the minimal perceptible clinical

improvement/minimal important difference are 8-12,1 points for KOOS S/R and 8-

18,3 points for KOOS QoL (63, 64). The same studies found, however, no statistically

significant associations between meniscus injury and the other KOOS subscales and

IKDC-SKF (45, 48). In one etiological study, concomitant meniscus injury was not a

prognostic factor for any two-year KOOS subscale (42).

Concomitant cartilage injury was assessed in four studies from four different cohorts

(45, 46, 48, 49). Two etiological studies found a statistically significant association

between concomitant cartilage lesions and five-year KOOS (all subscales),

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particularly for the full-thickness lesions (45, 49). The mean difference between those

with and without concomitant cartilage injury was 8.1 points for KOOS S/R (49) and

8-12.3 points for KOOS QoL (45, 49). These values are also of questionable clinical

relevance (63, 64). The results of Filbay et al. (45) applied only for the five-year

KOOS QoL in patients with early (not delayed) ACLR. In a third etiological study, the

absence of concomitant cartilage injury predicted two-year patient-reported success

(as previously defined) while having a concomitant cartilage injury predicted failure

(KOOS4 ≤ 20th percentile) (46). One predictive study found no association between

concomitant cartilage injury and six-year KOOS S/R and QoL and IKDC-SKF (48).

There were no statistically significant associations between concomitant MCL/LCL

injury or hearing a pop at injury and the outcomes two-year patient-reported success or

failure (46) and six-year IKDC-SKF, KOOS QoL and KOOS S/R (48).

Knee symptoms/function

In one etiological study, baseline KOOS4 predicted five-year KOOS Symptoms,

KOOS S/R and KOOS QoL, but not KOOS pain, in patients with early ACLR (45). In

those with delayed ACLR, KOOS4 did not predict any of the five-year KOOS

subscales (45). A predictive study found conflicting results for the association between

baseline and five-year KOOS scores (48).

Preoperative knee laxity, defined as severely abnormal either Lachman, anterior

drawer or pivot-shift test, was assessed in one etiological study (47). There was a

statistically significant association between preoperative knee laxity and six-year

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IKDC-SKF and KOOS QoL. The mean difference in IKDC-SKF and KOOS QoL

between those with and without preoperative laxity was small (2.3 and 2.7 points) and

therefore not clinically relevant (47).

There were no statistically significant associations between baseline Short-Form 36

and knee extension deficit >10 degrees and five-year KOOS outcomes (45).

GRADE evaluation for prognostic factors for PROMs in patients treated with ACLR

TABLE 4 shows the quality of evidence for each potential prognostic factor. The

evidence for concomitant meniscus and cartilage injuries was moderate, while for the

other factors it was low or very low. Our conclusions did not differ when all 20

eligible studies were included in a GRADE evaluation (APPENDIX 4)

Prognostic factors for PA in patients treated with ACLR

Prognostic factors for level of PA in patients treated with ACLR was assessed in two

studies from the same cohort, both using the Marx questionnaire as the outcome (47,

48). The following 13 factors were assessed by ≥1 study with moderate risk of bias:

sex, age, BMI, smoking, marital status, ethnicity, type of preinjury sport, baseline

PROMs, concomitant injury to the LCL/ MCL, meniscus or cartilage, knee laxity and

hearing a pop at injury (TABLE 2).

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Patient characteristics

One predictive study assessed several demographic factors as possible prognostic

factors for six-year Marx (48). Female sex and worse baseline Marx were prognostic

factors for worse six-year Marx, while age, BMI, smoking, marital status, ethnicity

and type of preinjury sport were not (48).

Factors related to the injury

None of the following factors were prognostic factors for six-year Marx score:

concomitant MCL/LCL, meniscus or cartilage injuries and hearing a pop at injury

(48). One etiological study found a statistically significant association between

preoperative laxity (as previously defined) and six-year Marx (47). The mean

difference between those with and without preoperative laxity was small (0.5 points)

and not clinically relevant (47).

GRADE evaluation for prognostic factors for level of PA in patients treated with

ACLR

Quality of evidence was judged as very low for all the prognostic factors for level of

PA in patients treated with ACLR. Serious limitations in several GRADE domains

occurred because evidence for all factors was based on only one study with moderate

risk of bias.

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Prognostic factors for PROMs and PA in patients treated with rehabilitation

alone

One etiological study assessed prognostic factors for five-year KOOS4 for a group of

patients treated with rehabilitation alone separately (45). None of the following factors

were prognostic factors: baseline cartilage defect, meniscus damage, osteochondral

lesion, extension deficit, SF-36 and KOOS4 (45). Quality of evidence was judged as

very low due to few studies. No study assessed prognostic factors for PA in this

patient group.

Differences in prognostic factors between treatment groups

One etiological study with low risk of bias assessed differences in prognostic factors

between those treated with rehabilitation alone and with ACLR (45). Based on

differences in prognostic factors for five-year KOOS4 between the treatment groups,

the authors suggested that patients with concomitant meniscus injury and those with

worse KOOS symptoms, S/R and QoL in the early phase may benefit most from

exercise therapy before choosing treatment (45).

DISCUSSION

Concomitant meniscus and cartilage injuries were, with moderate degree of certainty,

prognostic factors for worse PROMs two to ten years after ACLR. Smoking, BMI and

baseline PROMs were prognostic factors for two to ten-year PROMs with very low

certainty. For level of PA two to ten years after ACLR, we concluded with very low

certainty that female sex and worse baseline Marx were prognostic factors for worse

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long-term Marx. The other factors assessed in this systematic review were not

associated with the outcomes. No studies included only patients treated with

rehabilitation alone. One study assessed differences in prognostic factors between

patients treated with rehabilitation alone and with ACLR. They suggested that patients

with certain concomitant injuries and lower KOOS scores in the acute phase may

benefit most from an initial non-surgical treatment choice, but further research on the

topic is needed to draw conclusions. Hence, we could not answer the second aim of

this systematic review.

Comparison with other studies

To our knowledge, the current study is the first systematic review to assess prognostic

factors for PROMs and level of PA after ACL injury both in patients treated with

ACLR and with rehabilitation alone. Although the paucity of studies on patients

treated with rehabilitation alone made it impossible to answer our review questions

regarding prognostic factors for PROMs and level of PAs for this treatment group, or

to assess differences in prognostic factors between treatment groups. We used a high-

quality search strategy, a well-suited tool for risk of bias assessment and included only

studies with low or moderate risk of bias in the data synthesis which ensured that

conclusions and recommendations to clinicians and patients were not based on results

that should not be trusted.

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Our results highlighted the importance of risk of bias assessments in systematic

reviews as 12 of 20 included studies (60%) were rated as having high risk of bias. Bias

was suspected especially in the domains "Study confounding" and "Statistical analysis

and reporting". Lack of clarity in aims and methods about whether studies were

predictive or etiological was a recurring limitation. Effect estimates calculated from

one model, often a prediction model, which is presented in one table may give a wrong

interpretation because the underlying associations between covariates are not taken

into account (table 2 fallacy) (10). Even when study aims were clearly of an

etiological nature, because of a statistically driven rather than theoretically driven

approach, it was unclear in many of the papers if the estimate of the effect was

adjusted for all relevant confounders and whether it should have been interpreted as a

total or direct causal effect (11). Epidemiological research methodology has developed

over time, and the distinction between explanatory and predictive aims was less clear

at the time when the included studies were performed. As an example, our systematic

review included relatively recent articles (median publication year 2015, range 2005 to

2018), while studies excluded due to statistical analysis had a median publishing year

of 2007 (range 1999-2018).

Because of the systematic risk of bias assessment and inclusion of only studies with

low or moderate risk of bias in the data synthesis, our study could not reproduce some

of the conclusions of previous systematic reviews. For example, de Valk et al. (19)

concluded that male patients and patients aged <30 years had better functional

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outcomes after ACLR and that quadriceps weakness and range-of-motion deficits have

a negative effect on outcomes.

Also, the systematic review of Everhart et al. (21) drew conclusions based on studies

that found an association between psychological factors and the outcomes KOOS and

return to sport (65-67). These studies were not included in our review due to a longer

follow-up time and exclusion of studies with inappropriate statistical analysis.

We found that concomitant meniscus and cartilage injuries were negative prognostic

factors for outcomes (PROMs) which is supported by two previous systematic reviews

(16, 18). We also found similar results as Tan et al. (15) that there were no sex

differences in IKDC-SKF and KOOS after ACLR, while women had worse Tegner

scores and return to sport rates.

Limitations

As significant findings from observational studies are more likely to be published (68),

publication bias may be a serious limitation in our GRADE evidence profile, and

limits the ability to draw conclusions. We found no information about published study

protocols for the included studies, limiting our ability to assess this factor.

An important limitation in the literature was the likely between-study overlap of

patients within the different publications from the MOON cohort and the

SKLR/NKLR. This overlap can possibly have led to a correlation between study

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results that we could not account for. To minimize this problem, we only included the

most recent publication of data from the same patients and on the same prognostic

factors. Further, our strict inclusion criteria might have led us to miss high quality

research where other PROMs than IKDC-SKF, KOOS and KOS-ADLS were used,

such as Lysholm, ACL Return to Sport after Injury scale (ACL-RSI) and Short Form-

36 (SF-36). The included studies did not differentiate between types of meniscus

injuries, and we therefore lack knowledge on the prognosis after different injury types

(eg. dislocated bucket-handle tears versus stable, horizontal tears).

It is also important to bear in mind that the etiological and predictive studies in our

review should be interpreted differently. From the one prediction study in our data

synthesis (48), a prognostic factor cannot be interpreted as independent from the other

prognostic factors that are included in the prediction model, because the total risk

given all included prognostic factors is estimated (12).

Our results apply to individuals with first time complete unilateral ACL-injury, not

including knee dislocations. The prognostic factors are also only applicable to the

outcomes PROMs and level of PAs ≥ two and <10 years after ACLR. Important

outcomes such as psychological, overall health or quality of life outcomes was not

assessed in our study.

Implications for clinical practice

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Our work has important implications for future clinical practice. When planning future

physical activities and discussing patient expectations, it is useful for both patients,

physical therapists, orthopaedic surgeons and athletic trainers to be aware that

concomitant meniscus or cartilage injuries may lead to worse knee function two to ten

years after ACLR. As concomitant meniscus injuries are also the most frequently

reported prognostic factor for knee OA after ACL injury (5, 13), these patients should

be informed about preventive measures for knee OA such as optimal knee extensor

muscle strength and maintaining a healthy body weight (69-75). Although with very

low certainty, higher BMI was a prognostic factor for worse PROMs after ACLR. Due

to the relation to both knee function and development of knee OA, BMI as a

prognostic factor is important and needs to be incorporated in the early patient

education. We also found that smoking is a negative prognostic factor for PROMs. As

this factor is modifiable, patients should be informed that avoiding smoking might

contribute to better long-term outcomes.

Implications for future research on prognostic factors after ACL injury and

ACLR

The current study has several implications for future research. Future studies should

better clarify whether their aims and methods are mainly predictive or etiological. If

the aim is etiological, they should carefully state their hypothesis with background and

run an informed causal effect analysis, ensuring that rules for adjustment for different

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types of covariates (confounders, mediators and colliders) are followed (11, 76). If the

aim is predictive, studies should systematically build a prediction model based on all

available predictors and study the model’s discriminative ability and calibration and

subsequently internally and externally validate findings (77, 78). Pre-registration of

study protocols for observational studies on prognostic factors might enable

researchers to assess if selective reporting and publication bias occur within this field.

Future high-quality prognosis studies should include patients treated with

rehabilitation alone. This patient group is important as it represents between 26% and

77% of the ACL-injured population (79-81). New studies should also compare

prognostic factors between patients treated with rehabilitation alone and with ACLR in

order to help clinicians determine who will have the best prognosis with ACLR and

who will succeed with rehabilitation alone.

Our systematic review also uncovered a lack of studies on level of PAs long-term after

ACL injury. Most studies had high risk of bias and the study outcomes were only

activity rating scale (Marx) and the prevalence of return to sport, neither of which are

fully in line with the most common definition of level of PA (35) as they only measure

participation in specific type of sports. Future studies should therefore include more

general level of PA as outcomes (eg accelerometery, International Physical Activity

Questionnaire).

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Future studies should also assess modifiable prognostic factors which can be targeted

in early rehabilitation, such as muscle strength, range of motion and hop performance.

CONCLUSION

Concomitant meniscus and cartilage injuries were prognostic factors for worse

PROMs two to ten years after ACLR. In addition, prognostic factors with very low

certainty included BMI, smoking and baseline PROMs. Marx score was the only

outcome measure used for physical activity. Female sex and worse baseline Marx

score were prognostic factors with very low certainty for worse Marx score two to ten

years after ACLR. A high proportion of the included studies had a high risk of bias.

Due to a lack of studies on prognostic factors in patients treated with rehabilitation

alone, we were unable to assess differences in prognostic factors between treatment

groups.

KEY POINTS

FINDINGS: We have moderate confidence that concomitant meniscus and cartilage

injuries are prognostic factors for worse long-term PROMs after ACLR. The certainty

is low/very low for other prognostic factors.

IMPLICATIONS: When planning future activities and discussing patient

expectations, it is useful for both patients, physical therapists, orthopaedic surgeons

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and athletic trainers to consider that concomitant meniscus or cartilage injuries may

lead to worse knee function two to ten years after ACLR.

CAUTION: A large proportion (60%) of included studies in this systematic review

had high risk of bias and there is a lack of studies on prognostic factors in patients

treated with rehabilitation alone.

123

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Double-Bundle and Single-Bundle Anterior Cruciate Ligament Reconstruction. The American journal of sports medicine. 2016;44(4):855-64. 57. Ericsson YB, Roos EM, Frobell RB. Lower extremity performance following ACL rehabilitation in the KANON-trial: impact of reconstruction and predictive value at 2 and 5 years. British journal of sports medicine. 2013;47(15):980-5. 58. Roessler KK, Andersen TE, Lohmander S, Roos EM. Motives for sports participation as predictions of self-reported outcomes after anterior cruciate ligament injury of the knee. Scandinavian Journal of Medicine & Science in Sports. 2015;25(3):435-40. 59. Ithurburn MP, Paterno MV, Ford KR, Hewett TE, Schmitt LC. Young Athletes After Anterior Cruciate Ligament Reconstruction With Single-Leg Landing Asymmetries at the Time of Return to Sport Demonstrate Decreased Knee Function 2 Years Later. The American journal of sports medicine. 2017;45(11):2604-13. 60. Nawasreh Z, Logerstedt D, Cummer K, Axe M, Risberg MA, Snyder-Mackler L. Functional performance 6 months after ACL reconstruction can predict return to participation in the same preinjury activity level 12 and 24 months after surgery. British journal of sports medicine. 2018;52(6):375. 61. Sonnery-Cottet B, Saithna A, Cavalier M, Kajetanek C, Temponi EF, Daggett M, et al. Anterolateral Ligament Reconstruction Is Associated With Significantly Reduced ACL Graft Rupture Rates at a Minimum Follow-up of 2 Years: A Prospective Comparative Study of 502 Patients From the SANTI Study Group. The American journal of sports medicine. 2017;45(7):1547-57. 62. Hernán M, Robins J. Causal Inference: Boca Raton: Chapman & Hall/CRC, forthcoming; 2019. 63. Ingelsrud LH, Terwee CB, Terluin B, Granan LP, Engebretsen L, Mills KAG, et al. Meaningful Change Scores in the Knee Injury and Osteoarthritis Outcome Score in Patients Undergoing Anterior Cruciate Ligament Reconstruction. The American journal of sports medicine. 2018;46(5):1120-8. 64. Roos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health and quality of life outcomes. 2003;1:64. 65. Swirtun LR, Renstrom P. Factors affecting outcome after anterior cruciate ligament injury: a prospective study with a six-year follow-up. Scandinavian journal of medicine & science in sports. 2008;18(3):318-24. 66. Gobbi A, Francisco R. Factors affecting return to sports after anterior cruciate ligament reconstruction with patellar tendon and hamstring graft: a prospective clinical investigation. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2006;14(10):1021-8. 67. Thomee P, Wahrborg P, Borjesson M, Thomee R, Eriksson BI, Karlsson J. Self-efficacy of knee function as a pre-operative predictor of outcome 1 year after anterior cruciate ligament reconstruction. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 2008;16(2):118-27.

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TABLE C.1. PubMed search

1) Anterior cruciate ligament[mesh terms] OR Anterior cruciate ligament injury[mesh terms] OR Anterior cruciate ligament reconstruction[mesh terms]

2) Anterior cruciate ligament OR ACL 3) Prognosis[mesh terms] 4) Prognosis OR Prognostic factors OR Prognostic factor OR Predictor OR

Predictors OR Predict OR Prediction OR Predictive OR Effect modifiers OR Effect modifier OR Risk factors OR Risk factor OR Factor OR Factors OR Associated OR Association OR Associations

5) Return to sport[mesh terms] 6) Return to sport OR Return to sports OR Participation OR Activity level OR

Physical activity OR "Tegner activity scale" OR "Marx activity rating scale" OR Return to play OR KOOS OR "Knee injury and Osteoarthritis Outcome score" OR "International Knee Documentation Committee subjective knee form" OR "IKDC-SKF 2000" OR IKDC-SKF2000 OR "International Knee Documentation Committee Subjective Knee Evaluation Form" OR "IKDC-SKF" OR "Knee Outcome Survey" OR KOS

7) Prospective studies[mesh terms] 8) Prospective studies OR Prospective study OR Observational study OR Cohort

study OR Randomized controlled trial OR Randomized clinical trial OR Randomised controlled trial OR Randomised clinical trial OR RCT OR Randomised trial OR Randomized trial

9) 1 OR 2 10) 3 OR 4 11) 5 OR 6 12) 7 OR 8 13) 9 AND 10 AND 11 AND 12

131

TABLE C.2: Characteristics of included studies (n=20)

Study characteristics Patients' characteristics

Study

n Treatment

FU Years

Prognostic factors assessed

Outcome

Included in data synthesis

Sex % female

Median/ mean age Years

Ageberg et al. (2010) (44)

SKLR

10164

Primary ACLR

2 Age KOOS

ü 42%

27

Barenius et al. (2013) (55)

SKLR

8584

Primary ACLR

2 Sex, age, baseline PROMs, concomitant meniscus/ cartilage, knee laxity, previous knee surgery

KOOS

49%

NR

Brophy et al. (2016) (50)

MOON

2198

Primary or revision ACLR

2 Diabetes IKDC-SKF KOOS Level of PA

44%

24

132

Cox et al. (2014) (51)

MOON

1512


6 Sex, age, BMI, smoking, education, ethnicity, type of sport, competition level, baseline PROM, concomitant meniscus/ cartilage

IKDC-SKF KOOS Level of PA

44%

23

Dunn et al. (2010) (52)

MOON

446


2 Sex, age, BMI, smoking, education, marital status, ethnicity, type of sport, competition level, baseline PROM, concomitant meniscus/ cartilage, hearing a pop at injury

Level of PA

44%

23

Ericsson et al. (2013) (57)

KANON

121

ACLR or non-surgical

2 + 5

Early physical performance

KOOS

26%

26

Filbay et al. (2017) (45)

KANON

121

ACLR or non-

5 Baseline PROM, concomitant meniscus/

KOOS

ü 26%

26

133

surgical

cartilage, knee extension deficit

Hamrin Senorski et al. (2018) (46)

SKLR

15204

Primary ACLR

2 Concomitant MCL/LCL/ meniscus/ cartilage

KOOS

ü 50%

NR

Ithurburn et al. (2017) (59)

Cohort

48 Primary ACLR

2 Early physical performance

KOOS

77%

18

Magnussen et al. (2016) (43)

MOON

2333

Primary ACLR

2 Knee laxity IKDC-SKF KOOS

44%

27

Magnussen et al. (2018) (47)

MOON

2333

Primary ACLR

6 Knee laxity IKDC-SKF KOOS Level of PA

ü 44%

27

Nawasreh et al. (2018) (60)

Cohort

107

Primary ACLR

2 Sex, age, baseline PROM, early physical performance

Level of PA

34%

27

Roessler et al. (2015) (58)

KANON

121

ACLR or non-surgical

2 Psychological factors

KOOS

26%

26

Rotterud et al. (2013) (42)

S/N KLR

15783

Primary ACLR

2 Concomitant meniscus/ cartilage

KOOS

ü 42%

26

134

Sasaki et al. (2016) (56)

RCT

150

Primary ACLR

2 Sex, age, BMI, baseline PROM, concomitant meniscus

KOOS

58%

26

Sonnery-Cottet et al. (2017) (61)

Cohort

541

Primary ACLR

3 Sex, age, type of sport, concomitant meniscus

Level of PA

27%

22

Spindler et al. (2005) (53)

MOON

314

Primary ACLR

5 Sex, age, type of sport, concomitant meniscus/ cartilage, hearing a pop at injury, onset of swelling after injury

IKDC-SKF KOOS

45%

27

Spindler et al. (2011) (48)

MOON

448


6 Sex, age, BMI, smoking, ethnicity, marital status, type of sport, baseline PROM, concomitant MCL/LCL/ meniscus/ cartilage, hearing a pop at injury

IKDC-SKF KOOS Level of PA

ü 43%

23

135

Ulstein et al. (2018) (49)

S/N KLR

15783

Primary ACLR

5 Concomitant cartilage

KOOS

ü 42%

27

Wasserstein (2015) (54)

MOON

1761

Primary ACLR

2 + 6

Sex, age, BMI, smoking, education, baseline PROM, concomitant meniscus/ cartilage, previous knee pathology

KOOS

44%

23

FU, follow-up; NR, not reported; SKLR/NKLR, Swedish/Norwegian Knee Ligament Registry; MOON, Multicenter Orthopedic Outcomes Network; KANON, Knee Anterior Cruciate Ligament, Nonsurgical versus Surgical Treatment

136

TABLE C.3: Risk of bias assessment (n=20)

Stud

y Pa

rtic

ipat

ion

Stu

dy

Att

ritio

n Pr

ogno

stic

Fa

ctor

M

easu

rem

ent O

utco

me

Mea

sure

men

t Stud

y C

onfo

undi

ng

Ana

lysi

s and

re

port

ing

OV

ER

AL

L

Ageberg (2010) ☺ 😐 ☺ ☺ 😐 ☺ 😐 Barenius (2013) ☺ 😐 ☺ 😐 Irrelevant ☹ ☹

Brophy (2016) ☺ ☺ ☺ ☺ ☹ ☹ ☹ Cox (2014) ☺ ☺ ☺ ☺ ☹ ☹ ☹

Dunn (2010) ☺ ☺ ☺ ☺ ☹ ☹ ☹ Ericsson (2013) ☺ 😐 😐 ☺ ☹ ☹ ☹

Filbay (2017) ☺ ☺ ☺ ☺ ☺ ☺ ☺ Hamrin Senorski

(2018) ☺ 😐 😐 ☺ ☺ ☺ 😐 Itherburn (2017) 😐 ☹ ☺ ☺ ☹ ☹ ☹

Magnussen (2016) ☺ ☺ ☺ ☺ 😐 😐 😐

Magnussen (2018) ☺ ☺ ☺ ☺ 😐 😐 😐

Nawasreh (2018) ☺ ☹ ☺ ☺ Irrelevant ☺ ☹ Roessler (2015) ☺ ☺ ☺ ☺ ☹ 😐 ☹ Røtterud (2013) ☺ 😐 ☺ ☺ ☺ ☺ 😐

Sasaki (2016) ☺ ☺ ☺ ☺ ☹ ☹ ☹ Sonnery-Cottet

(2017) ☺ ☺ ☺ ☺ ☹ ☹ ☹ Spindler (2005) ☺ ☹ ☺ ☺ ☹ ☹ ☹ Spindler (2011) ☺ ☺ ☺ ☺ Irrelevant 😐 😐 Ulstein (2018) ☺ 😐 ☺ ☺ 😐 ☺ 😐

Wasserstein (2015) ☺ ☺ ☺ ☺ Irrelevant ☹ ☹

Low risk of bias= white � Moderate risk of bias= pale grey � High risk of bias= dark grey �

137

Concomitant meniscus injuries (4)

31556 ✓ ✕

e ✓ ✓ ✕

h ✕ ✕ 1 3 ⨁⨁⨁◯

MODERATE

Concomitant cartilage injuries (4)

31556 ✓ ✕

e ✓ ✓ ✕

h ✓ ✓ 1 4 ⨁⨁⨁◯

MODERATE

Hearing pop at injury (1)

448 ✕

c ✓ ✓ ✕ ✕

h ✕ ✕ 1 ⨁◯◯

◯ VERY LOW

Preoperative knee laxity (1)

2333 ✕

c ✓ ✓ ✕ ✕

h ✕ ✕ 1 ⨁◯◯

◯ VERY LOW

Preoperative extension deficit (1)

121 ✕

f ✓ ✓ ✕ ✕

h ✕ ✕ 1 ⨁◯◯

◯ VERY LOW

Higher baseline PROMs (2)

569 ✕

d ✕

e ✓ ✕ ✕

h ✕ ✕ 2 ⨁◯◯

◯ VERY LOW

For uni- and multivariable analyses: +, number of significant effects with a positive value; 0, number of non-significant effects; -, number of significant effects with a negative value. For GRADE factors: ✓, no serious limitations; ✕, serious limitations (or not present for moderate/large effect size, dose effect) a) Grading of Recommendations Assessment, Development and Evaluation b) Anterior Cruciate Ligament c) Evidence is based on only one study with moderate risk of bias d) Evidence is based on only two studies with moderate risk of bias e) Inconsistency within/between study/studies f) Evidence is based on only one study with low risk of bias g) Summary of authors conclusions when several outcomes for each factor were

assessed

138

Figure C.1. Flow chart

h) Due to a small number of included studies, we could not assess small study biases with a funnel plot. We therefore cannot rule out publication bias

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