Manipulation Under Anesthesia (MUA) to Treat Postoperative Stiffness After Total Knee Arthroplasty: A Multicenter Randomized Clinical Trial
Phase: PHASE4
Conditions: Stiffness Following Total Knee Arthroplasty
Sponsor: Mayo Clinic

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Manipulation Under Anesthesia (MUA) to Treat Postoperative 
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Stiffness after Total Knee Arthroplasty: 
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A Multicenter Randomized Clinical Trial 
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Matthew P. Abdel, M.D.  
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Paul Sousa, M.D., M.B.A.  
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Mark W. Pagnano, M.D. 
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Daniel J. Berry, M.D.  
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Principal Site:  Mayo Clinic, Rochester, Minnesota 
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INTRODUCTION 
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Stiffness after total knee arthroplasty (TKA) occurs when patients have difficulty flexing and 
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extending their knee for routine activities of daily living. Patients require 67 degrees of knee 
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flexion during the swing phase of gait, 83 degrees to ascend stairs, 90 degrees to descend stairs 
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and 93 degrees to rise from a standard chair.1 When less than 90 degrees of motion is reached 
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after TKA, the quality of life for patients is substantially decreased since simple activities like 
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walking can become difficult.2 3 
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Despite advancements in surgical technique, implant design and pain management, arthrofibrosis 
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(i.e., malignant stiffness) remains one of the top five reasons for revision TKA. At the upcoming 
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2016 American Academy of Orthopaedic Surgeons annual meeting, Matthew P. Abdel, M.D., 
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and colleagues will present their data indicating a contemporary arthrofibrosis rate of 5.8 percent 
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after primary TKA at Mayo Clinic. In addition, 2.8 percent of patients require a manipulation 
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under anesthesia (MUA). While there are alternatives to MUA, physical therapy shows only 
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modest gains and surgery is reserved for patients that fail non-operative management. With 
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MUA, mean flexion improved 35 degrees.  However, 5 percent of patients failed to maintain at 
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least 90 degrees of flexion after the MUA at our institution. More concerning, these results were 
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similar to the previous decade, where the rate of arthrofibrosis was 5.4 percent, with 2.9 percent 
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requiring MUA. The only identifiable risk factor for MUA was previous knee operation.  Lastly, 
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a manipulation under anesthesia significantly increased the risk for revision.  As one can see, the 
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incidence of arthrofibrosis following primary TKA has remained unchanged over the past two 
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decades. With the exponential increase in primary TKAs, arthrofibrosis is a large burden to the 
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patient, surgeon and entire U.S. health care system ($8.75 billion annually). 
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Preliminary clinical and translational research has indicated that an inflammatory disorder of the 
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musculoskeletal system may be responsible for post-operative stiffness in some patients.4-8 
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Although evidence remains limited to animal models, the inflammatory cascade plays a central 
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role in the formation, and recurrence, of arthrofibrosis, particularly at the time of insult (i.e. time 
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of index arthroplasty and/or MUA).7,9,10 This is essential as some insurance companies have 
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stopped covering this procedure. The purpose of this study was to determine the efficacy of 
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manipulation under anesthesia (MUA), with and without perioperative oral celecoxib and 
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intravenous (IV) corticosteroid. 
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PATIENTS AND METHODS 
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Study Design 
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This study is a prospective, multicenter, randomized clinical trial (RCT) designed to evaluate the 
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use of anti-inflammatory medications for the management of arthrofibrosis following primary 
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TKA. Patients will be randomly assigned to either the control or experimental group. Both groups 
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will receive a manipulation under anesthesia (MUA) if flexion is < 90 degrees at 4 –12 weeks 
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postoperatively.  Manipulation under anesthesia is the international standard of care for early 
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arthrofibrosis.  The control group will not receive any IV corticosteroids or PO non-steroidal anti-
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inflammatory medications (NSAIDs).  The experimental group will receive a single dose of IV 
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corticosteroids (8 mg IV dexamethasone immediately prior to MUA) and 2 weeks of PO celecoxib 
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at a dose of 200 mg daily.  Many surgeons, including several at the Mayo Clinic, consider the use 
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of IV corticosteroids and PO celecoxib the standard of care with a MUA.   
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Patients 
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Patients will be recruited from sixteen high-volume, academic, tertiary-care referral centers 
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(Table 1).  All enrolling centers have been vetted, as only surgeons that are members of the 
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prestigious closed Knee Society (representing the top 100 knee surgeons in the world) are 
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participating.  Patients approached for enrollment will have received a primary unilateral TKA 
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for a diagnosis of osteoarthritis. All primary TKA constructs will have constraint that is less than 
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that of varus-valgus constraint (VVC).  All VVC and hinged TKAs will be excluded.  Only 
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MUAs scheduled between 4 –12weeks postoperatively will be included.   
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Institutional Review Board (IRB) approval will be obtained from all respective institutions prior 
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to initiation of the study.  The Mayo Clinic will serve as the coordinating site. Patients will be 
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excluded from the study if any of the following exist:  (1) intolerance to NSAIDs, (2) renal 
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dysfunction, (3) age < 18 or > 90 years,  (4) primary diagnosis of rheumatoid arthritis and (5) 
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patients with GFR <60 as the cut off for CKD (stage 3 CKD).  Use of non-steroidal anti-
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inflammatory medications during the first two weeks after manipulation under anesthesia will 
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exclude patients from participation in this study. However, celecoxib (a non-steroidal anti-
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inflamatory medication) will be provided for those patients randomized to the experimental 
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group, once daily for fourteen days following the manipulation under anesthesia. Aspirin, used 
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routinely for DVT prophylaxis post-operatively, did not restrict patients from participation in this 
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study. Patients who are on NSAIDs prior to MUA, is ok to enroll. Patient demographics were 
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noted, including age at index arthroplasty, sex, body mass index (BMI), ASA score, and 
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Charlson Index. 
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Randomization 
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Patients will be randomized into one of 2 groups: (1) MUA only (i.e. control group) or (2) MUA 
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plus 8 mg of IV dexamethasone immediately before MUA, followed by 2 weeks of PO celecoxib 
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(200 mg daily) (experimental group). Assignment of patients into either group will be made prior 
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to the initiation of enrollment for the study. Patients will be randomized using a computer 
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generated (SAS PROC) block randomization schedule to ensure equivalent numbers of patients 
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in each group over the course of the study in case early stopping is required. The randomization 
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schedule will be generated by the Mayo Clinic Department of Epidemiology and Biostatistics 
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with the randomization list provided to the investigators prior to initiation of patient recruitment. 
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Neither the patient nor the treating physician were blinded the randomization group.   
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Manipulation Under Anesthesia 
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Patients will undergo MUA per their institutional protocol.  As previously noted, these will be 
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completed between 4 and 10 weeks postoperatively for flexion < 90 degrees.  Patients will 
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receive sedation per their institutional protocol.  Physical therapy (either supervised or 
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unsupervised) will be prescribed 2 -3 times per week for 4 – 6 weeks thereafter.   
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Outcome Measures 
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The primary outcome measure will be knee range of motion, including both passive and active 
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flexion and extension 6 weeks after the manipulation and 1 year from the date of the TKA. 
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Secondary outcomes will include comparison of Knee Society Scores (KSS), 12-item Short 
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Form Survey (SF-12v2), Knee Injury and Osteoarthritis Outcome Score (KOOS), and the 
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Promise-29 outcome form (Appendices 1-4). Outcomes will be documented pre-MUA, 6 weeks 
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after the MUA, and 1 year after the TKA. A standardize evaluation form will be shared amongst 
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all participating sites, and will be used consistently for all patients (Appendix 1-4). 
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Power Analysis 
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The mean and standard deviation for sample size calculation were derived from a study by 
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Yercan et al. In that study, the authors found that the mean ROM following MUA was 114° ± 
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16°.11  We hypothesized that a 10° difference in total range of motion would constitute a 
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clinically significant difference. With a type I error rate of 5%, 108 total patients (54 per arm) are 
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required to have 90% power to detect this difference. Accounting for a dropout rate of 20%, 65 
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patients per arm (130 total patients) will be recruited. 
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Statistical Analysis 
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All data will be summarized and reported descriptively using appropriate summary statistics, 
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including mean and standard deviation (SD) for continuous variables, and count and percentage 
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for categorical variables.  The analysis was focused on the two primary study outcomes: range of 
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motion (total arc of motion as well as angle of terminal knee flexion, measured in degrees), and 
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subjective outcome (KSS, SF-12v2, KOOS, and PROMIS).  Outcomes were compared between 
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the two study groups using two-sample t-tests if the data are approximately normally distributed; 
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if the data are not sufficiently normally distributed, non-parametric Wilcoxon rank sum tests was 
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used.  Since the subjects were assigned to the study groups in a randomized manner, no 
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significant differences between the subjects in the two groups were expected.  However, 
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apparent differences in subject demographics or baseline clinical data were evaluated, and 
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further analysis was undertaken using multivariable modeling to compare the two groups while 
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adjusting for other important variables.  When necessary and appropriate, the analysis was 
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adjusted for enrolling center.  Categorical outcomes were analyzed using chi-square tests and 
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logistic regression.  Separate analyses were performed for the 6-week and 1-year outcomes. All 
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statistical tests were two-sided and p-values less than 0.05 will be considered significant. 
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Sources of Funding 
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This study is partially supported by the Knee Society Branded Multi-Center Randomized Clinical 
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Trial Grant. 
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TABLES 
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Table 1. List of participating institutions included  
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Aria 3B Orthopaedic Specialists 
 
Colorado Joint Replacement  
 
Duke University Medical Center 
 
HipKnee Arkansas Foundation 
 
Hospital for Joint Diseases 
 
Hospital for Special Surgery 
 
Houston Methodist 
 
Joint Implant Surgeons 
 
Mayo Clinic 
 
New York-Presbyterian at Columbia University 
 
OrthoCarolina 
 
Rothman Institute 
 
Rush University Medical Center 
 
 
 
Cleveland Clinic 
 
University of Nebraska Medical Center 
 
University of Utah Orthopaedic Center 
 
 
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Table 2. Baseline demographics and clinical characteristics  
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Demographic and Clinical 
Characteristics 
MUA 
(N = X) 
MUA + AI 
(N = X) 
Demographic Characteristics 
     Age (year) 
     Sex (female/male) (no. of patients) 
     Weight (kg) 
     Height (cm) 
     BMI (kg/m2) 
     ASA Status (no. of patients) 
 
 
Implant Type 
 
 
Range of Motion 
     Total 
     Flexion Contracture 
     Extension Deficit 
 
 
 
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Table 3. Outcome following manipulation under anesthesia for stiffness after total knee 
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arthroplasty  
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Blood Loss, Drain Output, and Rate of 
Blood Transfusions 
MUA 
(N = X) 
MUA + AI 
(N = X) 
p value 
Six Week ROM 
     Total Pre-Manipulation 
     Flexion 
     Total 6 weeks Post-MUA 
     Flexion 
     < 90 degrees 
     < 80 degrees 
    Total 6 weeks Post-MUA 
     Flexion 
     < 90 degrees 
     < 80 degrees 
 
 
 
Six Week Subjective Outcome 
     KSS 
     SF-12v2 
     KOOS  
     Promis 29 
 
 
 

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Blood Loss, Drain Output, and Rate of 
Blood Transfusions 
MUA 
(N = X) 
MUA + AI 
(N = X) 
p value 
One Year ROM 
     Total Pre-Manipulation 
     Flexion 
     Total 6 weeks Post-MUA 
     Flexion 
     < 90 degrees 
     < 80 degrees 
    Total 6 weeks Post-MUA 
     Flexion 
     < 90 degrees 
     < 80 degrees 
 
 
 
One Year Subjective Outcome 
     KSS 
     SF-12v2 
     KOOS  
     Promis 29 
 
 
 
 
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