Changes in Quadriceps Muscular Activity in Patients After Total Knee Arthroplasty Compared to Healty Subjects
Conditions: Arthroplasty, Knee Replacement, Musculoskeletal Disorder
Sponsor: Istituto Clinico Humanitas

PROTOCOL NAME: Changes in quadriceps muscular activity in patients after 
total knee arthroplasty compared to healthy subjects 
 
 
PROTOCOL IDENTIFYING NUMBER: CLF19/03 
 
 
PROTOCOL VERSION DATE: 17/04/19 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
Glossary of abbreviations: 
 
TKA                              Total Knee Arthroplasty 
AMI                               Arthrogenic Muscle Inhibition 
QAB                              Quadriceps Activation Battery 
TUG                              Timed Up and Go Test 
NRS                               Numeric Rating Scale 
sEMG                            Surface Electromyography 
 
              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Coordinator: 
Roberto Gatti 
Phone: +39 0282246929 
Fax: / 
e-mail: roberto.gatti@hunimed.eu 

INDICE 
 
1 ABSTRACT ............................................ ERRORE. IL SEGNALIBRO NON È DEFINITO. 
2 BACKGROUND AND INTRODUCTION .......................................................................... 8 
3 RATIONALE ..................................................................................................................... 8 
4 AIMS ................................................................................................................................. 8 
4.1 General aims ................................................................................................................................. 8 
4.2 End-points ..................................................................................................................................... 8 
4.2.1 Primary endpoint .................................................................................................................. 8 
4.2.2 Secondary endpoint............................................................................................................... 9 
5 SELECTION CRITERIA ......................... ERRORE. IL SEGNALIBRO NON È DEFINITO. 
5.1 Inclusion criteria .......................................................................................................................... 9 
5.2 Exclusion criteria ......................................................................................................................... 9 
6 DESIGN ............................................................................................................................ 9 
6.1 General design .............................................................................................................................. 9 
7 STATISTICAL CONSIDERATIONS ............................................................................... 10 
7.1 Sample size .................................................................................................................................. 10 
7.2 Analysis ....................................................................................................................................... 10 
8 WITHDRAWAL FROM THE STUDY .............................................................................. 10 
9 FORMS AND PROCEDURES FOR THE DATA COLLECTION AND MANAGEMENT 11 
10 ETHICAL CONSIDERATIONS ..................................................................................... 11 
10.1 Patients protection ................................................................................................................... 11 
10.2 Patient identification – Data protection ................................................................................. 11 
10.3 Informed consent...................................................................................................................... 11 
11 CONFLICT OF INTEREST ........................................................................................... 11 
12 DATA OWNERSHIP ..................................................................................................... 11 

13 PUBLICATION POLICY ....................... ERRORE. IL SEGNALIBRO NON È DEFINITO. 
14 TIMING OF THE STUDY .............................................................................................. 12 
15 BIBLIOGRAPHY .......................................................................................................... 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1 Abstract   
 
 
Title 
Changes in quadriceps muscular activity in patients after total 
knee arthroplasty compared to healthy subjects 
 
Coordinator of the study 
Roberto Gatti  
 
Protocol number  
CLF19/03 
 
Protocol version date 
26/02/19 
Introduction and rationale 
 
During Total Knee Arthroplasty (TKA), the joint is subjected 
to considerable stress, which has been shown to be related to a 
recruitment and activation deficit of the quadriceps femoris 
muscle. The explanation for this correlation lies in a complex 
mechanism called Arthrogenic Muscle Inhibition (AMI). So 
far, AMI has been directly studied only in sub-acute and 
chronic phase after TKA because of the invasive procedures 
employed in order to evaluate it; However, clinical observation 
and some experimental studies also suggest the presence of 
this phenomenon in the initial postoperative days. The aim of 
the study is to investigate possible differences in quadriceps 
muscular activity, which could be associated with AMI and 
which may be investigated in the acute phase; data acquisition 
will be made on the first and third days after surgery.  
Population and selection criteria 
 
15 healthy subjects and 15 patients on hold for TKA will be 
recruited between July and September 2019. The inclusion 
criteria will be: age greater than 18 years old and a recent TKA 
or revision of TKA. Those patients with arthrogenic muscle 
inhibition before TKA with QAB<6 and the subjects with 
conditions (other than those which led to the TKA) that could 
interfere with quadriceps muscle activation or with motor 
performance will be excluded from the study.  
Design and duration  
 
Prospective observational study. It will start in July 2019 and 
the recruitment period should last until September 2019.  
Aims 
 
The primary aim of this study is the evaluation of possible 
differences in quadriceps muscular activation after TKA. 
Subjects will be asked to perform different tasks in isometric 
contraction, keeping the biomechanical context constant. 
Secondly, the correlation between the primary aim and the pain 
referred by the patient, registered using the NRS scale, will be 
investigated along with the patient’s functional ability, 
assessed by means of the Timed Up and Go Test (TUG). There 
will be three assessment sessions: the day prior to the TKA 
procedure and at one and three days postoperatively. 
 

 
 
Statistical methods and data 
analysis 
 
At the end of data acquisition, the normality and homogeneity 
of the demographic variables will be assessed, as will the 
outcome measures at baseline. Differences in the outcome 
measures will be investigated with the t student test (or with 
the related non-parametric tests) and by means of the mixed 
models repeated measures ANOVA test. Linear regression will 
be applied so as to evaluate the correlation between outcomes. 
 
 
Ethical considerations 
The study population will comprise subjects who have 
undergone TKA; they will be assessed in isometric 
contractions of quadriceps femoris in the acute phase after 
surgery. It is assumed that this type of evaluation does not lead 
to adverse events, since in terms of demands made on muscle 
and joints, it is comparable with the physiotherapeutic 
treatment administered to all patients twice a day after TKA. 
The aim of this study is to understand how the quadriceps 
activates in acute phase after TKA in order to identify the best 
physiotherapeutic approach for the initial postoperative days. 
Data acquisitions will be made so as to allow the patients to 
participate in both physiotherapy sessions. 
For the study, the materials supplied to the Movement Analysis 
Laboratory of the Humanitas Clinic will be used. Each 
assessment session will last about 20 minutes. 
 
Timing of the study 
 
 
Recruitment of subjects: July– September 2019  
Data analysis: September - October 2019 
Report presentation: November 2019 
 
 
 
 
 
 
 
 
 
 

2 Background and introduction 
Total Knee Arthroplasty is currently considered an effective treatment in reducing pain, improving 
functional abilities and quality of life in patients with advanced-stage knee osteoarthritis and in 
other diseases affecting the knee joint [1] [2]. However, considering that TKA is recognised as 
major surgery, the knee joint is subjected to considerable stress. This has been shown to be related 
to a recruitment and activation deficit of the quadriceps femoris muscle, both in sub-acute phase 
(starting from two weeks after surgery) and chronic phase (up to one year if compared with the 
contralateral limb) [3] [4] [5] [6]. This complex mechanism is termed arthrogenic muscle inhibition 
(AMI), properly defined as the long-lasting inability to fully activate the quadriceps muscle in the 
absence of nerve damage, following surgery and/or traumatic injury of the knee joint [7]. Although  
AMI has to date been described only in sub-acute and chronic phase after TKA because of the 
invasive procedures employed in order to evaluate it, some researchers have investigated this 
phenomenon by inducing in healthy subjects the same symptoms which are characteristic of the 
immediate postoperative period following knee surgery. These studies report a positive correlation; 
in particular they have shown how, inducing inflammation, pain and increasing intra-articular 
pressure, a recruitment deficit of the quadriceps muscle arises [8] [9] [10]. Clinical practice and 
published scientific research indicate the presence of AMI also in the acute phase after TKA. 
 
3 Rationale  
For ethical reasons, there are no studies currently published that directly investigate the presence 
and the size of AMI in the initial postoperative days following TKA. Clinical practice, and the study 
of AMI in sub-acute patients and in experimental clinical conditions, indicate an activation deficit 
of the quadriceps from the first day following surgery. This study aims to evaluate the role that AMI 
could play in the postoperative acute phase after TKA, examining possible differences in the 
activation patterns of the quadriceps muscle between patients and healthy subjects. 
The results could be useful to better manage the treatment of patients affected by a recruitment 
deficit of quadriceps muscle, by reducing motor impairment and by improving the quality and 
precision of the physiotherapy in the acute phase after TKA. 
 
4 Aims 
4.1 General aims 
The objective of the study is to evaluate possible differences in quadriceps muscular activation after 
TKA during the acute phase, with a comparison with healthy subjects. Moreover, it will be 
investigated whether any correlation exists between the outcomes obtained, the pain reported by the 
patient and his or her functional ability. 
 
4.2 Endpoints  
4.2.1 Primary endpoint 
The primary aim is to observe possible activation alterations of the quadriceps femoris, more 
specifically of the vastus medialis, lateralis and rectus femoris muscles, by means of 
electromyographic signal acquisition. The subject will be asked to perform different tasks in 
isometric contractions, without changing the biomechanical context. The subjects will be asked to 
perform a homolateral knee extension, a homolateral hip flexion, a contralateral hip extension with 

a contemporary homolateral hip flexion. The activation of the three muscles will be recorded 
through surface electromyography (sEMG) with four channels (FREEEEMG 1000, BTS SpA). The 
electromyographic surface sensors will be positioned following the European SENIAM guidelines 
regarding vastus medialis, lateralis and rectus femoris of quadriceps femoris homolateral in terms of 
surgery access, in order to evaluate the activation intensity during the different tasks [11]. 
 
4.2.2 Secondary endpoint 
The secondary aim is to understand whether there is a correlation between the acquired surface 
EMG data and the pain referred by the patient and the patient’s functional ability. The secondary 
outcomes will be the pain referred by the patient and the patient’s functional ability. The referred 
pain will be assessed through the Numeric Rating Scale (NRS) at the beginning of every session. 
The functional ability will be assessed with the Timed Up and Go Test (TUG) on the third day post-
surgery and via a descriptive analysis on the patient’s deambulation autonomy, considering the 
following characteristics: ambulatory aids, need for supervision or assistance, and maximum 
distance covered. 
 
5.1 Inclusion criteria  
- age: over 18 years. 
- subjects eligible for TKA. 
 
5.2 Exclusion criteria 
- QAB (quadriceps activation battery) < 6 the day before the operation [12]. 
- neurological or musculoskeletal diseases (different from the causes that which led the patient to 
the TKA), which may interfere with the quadriceps muscle activation or with motor performance of 
the subject. 
- Uncooperative subjects. 
 
6 Design 
Prospective observational study. See Attachment A. 
 
6.1 General design 
The patients scheduled for TKA will be recruited through the criteria mentioned above; moreover, 
healthy subjects will be recruited as control group. The patients will be assessed through a motor 
ability test (TUG), a referred pain scale, and a quadriceps isometric contractions session recorded 
with surface electromyography. The assessment sessions will be conducted the day before the 
operation and on the first and third postoperative day. The control group will be exposed once to the 
same assessments, with the EMG applied on the quadriceps muscle of the dominant limb. 
The sEMG data will be acquired by asking the subjects to perform the following tasks: 
“homolateral knee extension”, “homolateral hip flexion” and “contralateral hip extension with a 
contemporary homolateral hip flexion”. Each task will be repeated twice and the execution order 
will be randomized. The subject will be placed in the supine position and three bands will be 
positioned respectively at the level of the malleolus and the inferior margin of the patella in order to 
immobilise the inferior limb and ensure an isometric contraction of the quadriceps, while keeping 

the biomechanical context unchanged. For each subject belonging to the two study groups, the same 
setting will be used. During the data acquisitions, every subject will be encouraged to perform each 
contraction with the maximum strength. The performance of tasks will be video recorded in order to 
monitor the correct execution. 
The NRS scale will be administered to the patients after each quadriceps evaluation session, while 
the TUG test will be conducted the day before the operation and on the third day after surgery. 
In the first and third day after surgery, the session will take place after 3pm in order to allow the 
patients to participate in both of the physiotherapeutic treatments provided by the Humanitas Clinic 
Institute. 
The TUG test consists in asking the patient to stand up from a chair, walk at spontaneous speed, 
turn back at a cone placed at a distance of 3 metres and sit back down on the chair. The patient will 
be timed starting from the operator mark and stopping when the patient has resumed the seated 
position on the chair. The test will be performed once in a session, with a mock test before. 
The NRS scale consists of one 10cm segment, numbered from 0 to 10 on which the subject has to 
quantify their pain perception where 0 equals “no pain” and 10 equals “the worse pain ever 
perceived”. 
Every assessment session will be conducted by one expert operator. 
 
7 Statistical considerations 
7.1 Sample Size 
The primary outcome of this study is the EMG signal detected during different isometric 
contractions of the quadriceps muscle. In the published scientific literature, there is insufficient data 
to define the minimal statistically significant difference for this outcome. Therefore, it is not 
possible to calculate the sample size. Some studies exist which compare the muscular activation in 
the inferior limb between healthy subjects and patients who have undergone PTG, with 10 subjects 
for each group [13]. In this study, 15 healthy subjects and 15 patients will be recruited; it is 
estimated that this sample will be enough to obtain a preliminary valuation of the differences 
between groups. 
 
7.2 Analysis 
The statistical analysis will be carried out at the end of the data collection, using the SPSS 20.0 
software. The categorical variables will be described via mean and standard deviation or median 
and interquartile range. The normality of the demographic variables and the outcome measures will 
be evaluated through the Kolmogorov-Smirnov test.  
The t Student test (with normal variables) or the Mann-Whitney test (with non-normal variables) 
will be used to verify the pre-intervention homogeneity of the demographic variables. The mixed 
models ANOVA test for repeated measures will be used to analyse possible differences inter-groups 
and intra-groups. A post hoc analysis will be conducted in the eventuality of significant outcomes. 
Linear regression will be used to investigate the correlation between the EMG outcomes and the 
secondary outcomes (NRS and TUG).  
The threshold value for the statistical significance will be fixed at 0.05.  
 

8 Withdrawal from the study 
Subjects who decide to leave the study for any reason will be immediately excluded from it. The 
subjects will be also informed about the possibility of withdrawal from the study at every session 
provided for by the protocol, including during the planned follow-up period, giving prior 
notification to any of the experimenters. Data acquired from those subjects who do not complete the 
study will be excluded from the analysis. 
 
9 Forms and procedures for the data collection and management  
The demographic and outcome data will be input into an anonymous form within an Excel sheet 
(Attachment B). This data will be collected by two experimenters in order to minimise any errors 
and will be saved in password-protected electronic format. 
 
10 Ethical considerations 
10.1 Patient protection 
 The coordinators of the study guarantee that this work will be conducted following the criteria laid 
out in the Helsinki Declaration (Attachment C) and in accordance with the law and the regulations 
of the country in order to ensure the utmost protection for each person included in the study. The 
study will be conducted in accordance with the ICH guidelines for Good Clinical Practice. The 
protocol and the documents attached will be inspected and approved by the authorised Independent 
Ethics Committee (IEC).   
 
10.2 Subject identification – Data protection 
All data related to data acquisition and analysis and all the information related to each individual 
subject shall be handled in the strictest confidence and to the fullest extent of the applicable law. 
Privacy shall thus be safeguarded, and no information shall be made public. Each subject will be 
identified with an ID (Attachment B). The name and surname of the subject will not be required. 
The data required will pertain to sex and age. Only those personnel actively involved in the study 
will have access to the database. Each subject will be informed about data protection by means of 
an appropriate form in this regard (attachment D) and will be asked to sign an informed consent 
form in order to participate in the study.  
 
10.3 Informed consent 
All subjects will receive information regarding the manner in which the study is to be carried out, 
and the study aims. They will also be informed about the rigorous manner in which their data will 
be handled and protected. It will be underlined that participation is voluntary and that the subject 
can withdraw from the study at any time. Each subject will complete the informed consent form, 
and only after it is collected will the data be inserted into the Excel sheet (attachment E). 
 
11 Conflict of interest 
Each member of this study declares that he or she has no conflict of interest. 
  
12 Data ownership 
In accordance with the ICH guidelines for Good Clinical Practice, and taking into consideration that 
this study is monocentric, the owner of all the data is ICH.  
 
13 Publication policy 
On completion of the study, the coordinator will prepare a draft manuscript containing the final 
results of the study based on the statistical analysis. This manuscript will be submitted to an 

appropriate peer-reviewed scientific journal for publication. Any publications, abstracts, slides and 
data arising from this study will be subject to revision by the study coordinator.  
 
14 Timing of the study 
 
1. Subject recruitment: 2019, July - September 
2. Data analysis: 2019, September - October 
3. Report Presentation: 2019, November 
  
15 Scheme of the study 
See Attachment A. 
 
16 References 
 
1. Carr AJ, Robertsson O, Graves S, Price AJ, Arden NK, Judge A, Beard DJ. Knee replacement. 
Lancet. 2012 Apr 7;379(9823):1331-40 
 
2. Skou ST1, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L, Simonsen O, Rasmussen S. 
A Randomized, Controlled Trial of Total Knee Replacement. N Engl J Med. 2015 Oct 
22;373(17):1597-606. 
 
3. Moon YW, Kim HJ, Ahn HS, Lee DH. Serial Changes of Quadriceps and Hamstring Muscle 
Strength Following Total Knee Arthroplasty: A Meta-Analysis. PLoS One. 2016 Feb 5;11(2): 
e0148193. 
 
4. Schache MB, McClelland JA, Webster KE. Lower limb strength following total knee 
arthroplasty: a systematic review. Knee. 2014 Jan;21(1):12-20. 
 
5. Stevens-Lapsley JE, Balter JE, Kohrt WM, Eckhoff DG. Quadriceps and hamstrings muscle 
dysfunction after total knee arthroplasty. Clin Orthop Relat Res. 2010 Sep;468(9):2460-8. 
 
6. Mizner RL, Petterson SC, Stevens JE, Vandenborne K, Snyder-Mackler L. Early quadriceps 
strength loss after total knee arthroplasty. The contributions of muscle atrophy and failure of 
voluntary muscle activation. J Bone Joint Surg Am. 2005 May;87(5):1047-53. 
 
7. Rice DA, McNair PJ. Quadriceps arthrogenic muscle inhibition: neural mechanisms and 
treatment perspectives. Semin Arthritis Rheum. 2010 Dec;40(3):250-66. 
 

8. Rice DA, Graven-Nielsen T, Lewis GN, McNair PJ, Dalbeth N. The effects of experimental 
knee pain on lower limb corticospinal and motor cortex excitability. Arthritis Res Ther. 2015 
Aug 12; 17:204.  
9. Pietrosimone B, Lepley AS, Murray AM, Thomas AC, Bahhur NO, Schwartz TA. Changes in 
voluntary quadriceps activation predict changes in muscle strength and gait biomechanics 
following knee joint effusion. Clin Biomech (Bristol, Avon). 2014 Sep;29(8):923-9. 
 
10. Rice D, McNair PJ, Dalbeth N. Effects of cryotherapy on arthrogenic muscle inhibition using 
an experimental model of knee swelling. Arthritis Rheum. 2009 Jan 15;61(1):78-83.  
 
11. Freriks B, Hermens H, Disselhorst-Klug C, Rau G. European Recommendations for Surface 
Electromyography, SENIAM. 2000. 
12. Bade M, Struessel T, Paxton R, Winters J, Baym C, Stevens-Lapsley J. Performance on a 
Clinical Quadriceps Activation Battery Is Related to a Laboratory Measure of Activation and 
Recovery After Total Knee Arthroplasty. Arch Phys Med Rehabil. 2018 Jan;99(1):99-106. 
 
13. Abbey C. Thomas, Dana L. Judd, Bradley S. Davidson, Donald G. Eckhoff, and Jennifer E. 
Stevens-Lapsley. Quadriceps/Hamstrings Co-Activation Increases Early After Total Knee 
Arthroplasty. Knee. 2014 December; 21(6): 1115–1119. 
 
 
 
 
***  ***   *** 
 
List of the attached documents 
Attachment A_ Scheme of the study  
Attachment B_ Data collection form 
Attachment C_ Helsinki Declaration  
Attachment D_ Informed consent form 
Attachment E_ Privacy report 
Attachment F_ Equipment CEE trademark 
Attachment G_ Equipment technical report 
Attachment H_ Curriculum vitae of Roberto Gatti