Management of Stiffness Following Total Knee Arthroplasty

 COPYRIGHT © 2006 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED Management of Stiffness Following Total Knee Arthroplasty BY JAVAD PARVIZI, MD, FRCS, T. DAVID TARITY, BS, MARLA J. STEINBECK, PHD, ROMAN G. POLITI, BS, ASHISH JOSHI, MD, MPH, JAMES J. PURTILL, MD, AND PETER F. SHARKEY, MD Introduction tiffness following total knee arthroplasty is a disabling complication1-7. Although some predisposing factors have been identified, in most cases the exact etiology of the stiffness cannot be discerned. The reported prevalence of this complication has ranged widely from 1.3% to 12%1,8-10. The difference in rate may be due in part to varied definitions of stiffness11. Several factors affecting the postoperative range of motion that have been identified include the preoperative range of motion, contracture of the extensor mechanism and capsular structure, the preoperative diagnosis, personality of the patient, lack of patient compliance with the rehabilitation protocol, and the patient’s threshold for pain12-18. Technical factors, such as overstuffing the patellofemoral joint, mismatch of the flexion and extension gaps, inac- S curate ligament balancing, component malpositioning, use of oversized components, joint-line elevation, excessive tightening of the extensor mechanism, and underresection of the patella have also been implicated1,19. Various management protocols have been proposed to address this complication. This exhibit presents our institutional experience with the management of stiffness following total knee arthroplasty. We report the findings of a case-control study that was designed to predict the factors responsible for stiffness after total knee arthroplasty. In addition, the results of an ongoing basic-science study attempting to unravel the molecular mechanism of arthrofibrosis following total knee arthroplasty are presented. We also provide the outline of our current treatment strategy for the management of stiffness following total knee arthroplasty. Fig. 1 Demographic distribution of patients in the study and control groups. TKA = total knee arthroplasty, and BMI = body-mass index.  THE JOURNAL BONE & JOINT SURGER Y · JBJS.ORG VO L U M E 88-A · S U P P L E M E N T 4 · 2006 OF Materials and Methods Case-Control Study he purpose of this study was to identify factors that predispose patients to stiffness following total knee arthroplasty. With use of an institutional computerized database, the outcome of primary total knee arthroplasty performed in T M A N A G E M E N T O F S T I F F N E S S F O L L OW I N G TO T A L K N E E A R T H RO P L A S T Y nearly 10,000 patients from 1995 to 2004 was evaluated. Patients with stiffness following total knee arthroplasty, defined as an arc of motion of <90°, or patients requiring a manipulation of a prosthetic knee, were identified. The cohort comprised 112 knees (ninety-eight patients). These knees were matched for the year of surgery and surgeon with a control Fig. 2 Analysis of preoperative and surgical parameters. ROM = range of motion. Fig. 3 Analysis of radiographic parameters. IS = Insall-Salvati ratio.  THE JOURNAL BONE & JOINT SURGER Y · JBJS.ORG VO L U M E 88-A · S U P P L E M E N T 4 · 2006 OF M A N A G E M E N T O F S T I F F N E S S F O L L OW I N G TO T A L K N E E A R T H RO P L A S T Y Fig. 4 COX-2 and Bcl-2 immunohistochemistry and TUNEL analysis of tissue from stiff knees (A, D, and G), knees with aseptic loosening (B, E, and H), and knees with periprosthetic infection (C, F, and I). (Top row [A, B, and C] shows COX-2 staining; middle row [D, E, and F] shows apoptosis by means of TUNEL analysis; and bottom row [G, H, and I] shows fluorescently labeled Bcl-2 cells). Note the absence of apoptotic cells and the corresponding increase in COX-2 and Bcl-2 in the arthrofibrotic samples. group in a 1:2 ratio. The control group consisted of 224 knees in 186 patients, all of which were confirmed to have an arc of motion of >90° at least one year following a total knee arthroplasty (Fig. 1). Sixteen knees (fifteen patients) from the control group were then excluded on the basis of the lack of sufficient information, leaving 208 knees in 171 patients for the final analysis. The clinical and radiographic records of all patients were examined in detail (Figs. 2 and 3). Demographic, surgical, and radiographic etiological factors were evaluated. These included age, race, sex, bodymass index, preoperative range of motion, preoperative diagnosis, intraoperative complications, total operative time, and estimated blood loss. Radiographic variables included patellar tilt, Insall-Salvati ratio20, patellar thickness, femoral flexion angle, tibial slope, femorotibial angle, and joint-line measurements. The results of all interventions, both surgical and nonsurgical, for the treatment of stiffness were also evaluated. Descriptive statistical correlation with use of univariate analysis was performed with SAS software (version 9.1; SAS Institute, Cary, North Carolina) to determine the mean, standard deviations, medians, 25% and 95% interquartile range, and the frequency distribution for the demographic variables. Multivariate analysis was performed with use of stepwise logistic regression after adjusting for the potential confounders to determine the variables that would predict stiffness after total knee arthroplasty. Results Of the ninety-eight patients comprising the study group, a manipulation under anesthesia was performed once for ninety-three patients and twice for five patients. Fourteen patients underwent revision total knee arthroplasty for stiffness. The etiology of the stiffness following total knee arthroplasty in those patients was deemed to be arthrofibrosis (thirteen patients) and technical error (one patient). Demographics: Analysis was performed on 320 knees, with 112 knees (35%) in the study group and 208 (65%) in the control group. The average age of the patients was fifty-eight years (range, forty-seven to sixty-nine years) in the study group and sixty-four years (range, fifty-three to seventy-five years) in the control group; the difference was not significant. A majority of the patients in both the study and control groups were white and female (Fig. 1). The patients in the study group had a slightly lower body weight (p = 0.05) compared with the control group, whereas the body-mass index was significantly less (p = 0.003) compared with the controls. No significant differences were seen with respect to patient height. A significantly higher proportion of individuals who  THE JOURNAL BONE & JOINT SURGER Y · JBJS.ORG VO L U M E 88-A · S U P P L E M E N T 4 · 2006 OF TABLE I Predisposing Factors for Stiffness Following Total Knee Arthroplasty Parameter P Value Odds Ratio Young age at time of total knee arthroplasty 0.0009 0.87 Low body-mass index 0.01 0.97 High femoral flexion 0.02 0.78 Patella baja 0.0003 3.50 had stiffness were younger compared with the controls (p < 0.0001). There was no significant difference in the prevalence of stiffness between the genders or between races (white and black) after adjusting for potential confounders. Clinical History: The diagnosis was degenerative joint disease for all patients in both groups. With the numbers studied, no significant difference was detected between the groups with respect to the preoperative range of motion or other postoperative complications (p > 0.05). Moreover, no significant difference was found between the groups with respect to total operative time (p = 0.52) or estimated blood loss (p = 0.86) (Fig. 2). Radiographic Findings: The patients with stiffness had a significantly lower patellar length (p = 0.02), increased patellar tendon length (p < 0.0001), a lower Insall-Salvati ratio (p < 0.0001), decreased femoral component width (p = 0.007), and a decreased femoral-tibial component ratio (defined as the ratio between the widths of the femoral and tibial components as determined on anteroposterior radiographs) (p = 0.03). No significant difference was identified in other radiographic variables. Adjusted Analysis: After adjusting for potential confounders, we performed stepwise logistic regression analysis to determine the factors predicting stiffness after total knee arthroplasty. It was found that the age at the time of the total knee arthroplasty, body-mass index, a higher femoral flexion angle, and the position of the patella were significant predictors of stiffness. The odds of developing stiffness increased in individuals who had total knee arthroplasty performed at a younger age (odds ratio = 0.87; p = 0.0009), had a lower bodymass index (odds ratio = 0.97; p = 0.01), had an increased femoral flexion angle (odds ratio = 0.78; p = 0.02), and had patella baja (odds ratio = 3.50; p = 0.0003) prior to or after arthroplasty (Table I). Stratification Analysis: Gender-based stratified analysis was performed to determine the predictors of stiffness in males and females. We found that age at the time of the index operation, body-mass index, femoral flexion, and patella baja were significant predictors of stiffness in females, whereas patella baja was the only significant predictor for stiffness in males. The odds of developing stiffness increased in females when total knee arthroplasty was performed at a younger age (odds ratio = 0.91; p = 0.02) and in those with a lower bodymass index (odds ratio = 0.85; p = 0.02), an increased femoral flexion angle (odds ratio = 0.78; p = 0.04), and patella baja M A N A G E M E N T O F S T I F F N E S S F O L L OW I N G TO T A L K N E E A R T H RO P L A S T Y (odds ratio = 2.87; p = 0.006). The only significant predictor for stiffness in males was patella baja (odds ratio =0.11; p = 0.04). Basic Science Study Tissue Collection This multicenter study utilized a standardized tissue-retrieval protocol allowing collection and analysis of periarticular tissues from the knee of patients with arthrofibrosis who were undergoing revision arthroplasty. Tissues from the same region of the knee from patients with osteoarthritis undergoing primary knee arthroplasty, or revision arthroplasty for infection, as well as an aseptic indication were used as controls. Tissue samples measuring 2 cm3 from ten affected or control knees were retrieved. Tissue samples were taken from the periarticular area, which included the suprapatellar, medial gutter, lateral gutter, and infrapatellar regions. The tissue was placed in sterile saline solution and was transferred immediately to our laboratory for detailed analyses. Tissue samples from other centers were placed on ice and transferred overnight. Immunohistochemistry: Tissues were fixed in Tissue-Tek OCT (Fisher Scientific, Hampton, New Hampshire) freeze medium and sectioned (6 µm), and they were fixed in 4% paraformaldehyde, dehydrated, embedded in paraffin, and sectioned (6 µm). The paraffin sections were dewaxed and rehydrated. Endogenous peroxidase activity was blocked with 3% H2O2 in methanol. Prior to incubation with primary antibodies, tissue sections were treated with one of the following: Triton X-100, antigen-retrieval reagent, or proteinase K (0.01 U/mL). Immunohistochemistry was performed with the antibodies to NF-κB (nuclear transcription factor-kappaB), COX-2 (cyclooxygenase-2), Bcl-2, PCNA (proliferating cell nuclear antigen), FGF (fibroblast growth factor), TGF-β (transforming growth factor-beta), chymase, and type-I collagen. As a negative control for immunohistochemistry, the sections were incubated with no primary antibodies. Immunohistochemistry experiments utilized the DAB Detection Kit (Vector Laboratories, Burlingame, California) with biotinylated horse antimouse IgG or goat anti-rabbit IgG as secondary antibodies. Histochemical Staining: Sections were stained with alcian blue to determine proteoglycan content; alizarin red to determine tissue calcification; hematoxylin and eosin to determine cellularity, vascularization, and inflammatory cell infiltration; and toluidine blue to determine mast cell numbers. Image Acquisition and Analysis Images of the stained tissue were observed with use of confocal laser scanning microscopy (FluoView, Olympus, Tokyo, Japan), equipped with a krypton-argon laser. Three randomly selected areas of the slices were imaged in red and green, with fluorescence excitations at 488 and 568 nm and fluorescence emissions at 530 and 590 nm, respectively. Images were analyzed with use of Image-Pro Plus software (Media Cybernetics, Silver Spring, Maryland), and the mean fluorescence intensity of the three randomly chosen areas in each slice was determined. At least three slices per sample were used. Background autofluorescence was subtracted from the green and red signal.  THE JOURNAL BONE & JOINT SURGER Y · JBJS.ORG VO L U M E 88-A · S U P P L E M E N T 4 · 2006 OF M A N A G E M E N T O F S T I F F N E S S F O L L OW I N G TO T A L K N E E A R T H RO P L A S T Y Fig. 5 Immunohistochemical and cellular stains of tissue retrieved from stiff knees (A through E) and control tissues from knees without stiffness (F through J).Various staining protocols were performed: PCNA (proliferating cell nuclear antigen)-labeled proliferative cells (A and F), FGF (fibroblast growth factor)-labeled cells (B and G), collagen type-I deposition (C and H), Prussian blue-hemosiderin (D and I), and hematoxylin and eosin (E and J). The images are representative of staining differences between affected and control samples (×10). Apoptosis Assay TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay was used to measure the index of apoptosis. The TUNEL assay takes advantage of the fact that, during apoptosis, nucleosomes and endonucleases digest genomic DNA into multiple fragments of approximately 200 bp. To measure the fragmented DNA, the nucleotide ends were labeled with use of the Klenow FragEL Kit (Oncogene Research Products, Cambridge, Massachusetts), according to the manufacturer’s instructions, and the oxidized diaminobenzidine (brown precipitate) product was visualized by light microscopy. To improve detection of TUNEL-positive cells, the cells were not counterstained. Measurement of Lipofuscin and Nitrosylated Proteins Direct measurement of reactive oxygen and nitrogen species (RONS) production in surgical tissues is difficult because of inadequate assay sensitivity and reproducibility. Moreover, the quantity of RONS detected represents only the amount produced at that specific time-point. To overcome these limitations, we measured oxidative products of RONS reactions, namely, nitrosylated proteins and lipofuscin in the tissue samples. Lipofuscin is a highly polymerized molecule that is generated by the oxidation of lipids. It acts as a proinflammatory mediator, and its presence indicates abnormal tissue production of RONS. The amount of lipofuscin in tissue samples was determined by autofluorescence and by the Schmorl dye lipofuscin detection method. Localization, microscopy, and analy- sis to detect lipofuscin were performed. Immunolocalization, microscopy, and analysis to detect nitrosylated proteins were also performed. The immunohistochemistry was performed as described above. Results The tissue samples from the knees of individuals with arthrofibrosis demonstrated an increased number of cells expressing the pro-survival factors COX-2 and Bcl-2 and a very low number of TUNEL-positive or apoptotic cells (Fig. 4). In addition, these samples demonstrated an aggressive fibroblastic proliferation (Fig. 5, A and B), deposition of type-I collagen (Fig. 5, C), and accumulation of abnormal matrix proteins (Fig. 5, D). Furthermore, microvascular hemorrhage (Fig. 5, E), hypervascularity, and excessive numbers of myofibroblasts and inflammatory cells, in particular mast cells, were found in the arthrofibrotic tissues. The most compelling observation was that arthrofibrotic tissue contained a number of RONS products that were not present in the control tissue samples. The products were localized to regions near ruptured blood vessels and regions of high fibroblast density. Discussion tiffness following total knee arthroplasty, although fortunately rare, can be challenging. In this study, individuals undergoing total knee arthroplasty at an earlier age were significantly more likely to have stiffness develop compared with the control group (p < 0.0009). After adjustment for potential S  THE JOURNAL BONE & JOINT SURGER Y · JBJS.ORG VO L U M E 88-A · S U P P L E M E N T 4 · 2006 OF M A N A G E M E N T O F S T I F F N E S S F O L L OW I N G TO T A L K N E E A R T H RO P L A S T Y Fig. 6 An overview of the findings of the study. ROS = reactive oxygen species, and FGF = fibroblast growth factor. confounders, a gender-based stratified analysis was performed. Factors predisposing women to stiffness following total knee arthroplasty included a young age at the time of total knee arthroplasty, a lower body-mass index, a high femoral flexion angle, and the presence of patella baja. Only patella baja was a significant predictor in males (Table I). An acute awareness of these factors during the rehabilitation period may serve to reduce the development of stiffness following total knee arthroplasty in selected patients. The exact pathoetiology of stiffness secondary to arthrofibrosis following total knee arthroplasty remains elusive. However, aggressive fibroblast proliferation and tissue metaplasia is known to be the trademark of this condition6,21. Alterations in normal tissue composition, the replacement of matrix with disordered collagen fibrils, and cellular damage leading to dysfunctional repair are observed in other fibrotic tissues22-26. The healing response is initiated by the clotting cascade resulting in the migration of inflammatory cells to the site of injury23-25,27-30. Both the migration of inflammatory cells into the injured tissue and the proliferation of fibroblasts result in the release of cytokines, growth factors, and reactive oxygen and nitrogen species (RONS)28,31,32. An excessive accumulation of RONS then drives inflammatory infiltration and aggressive fibroblast and mast cell proliferation that result in the oxidative modification of periarticular tissue, the release of cytokines and growth factors, and the induction of pro-apoptotic genes, all of which are central to the pathogenesis of stiffness33-35. Patients with a genetic predisposition to this process demonstrate a deficiency in RONS removal (antioxidants) and/or exaggerated RONS production. The production of RONS and its byproducts may be responsible for vascular hemorrhaging and the release of the iron oxidation product hemosiderin (Fig. 5, D) as well as fibroblast and mast cell proliferation. The accumulation of hemosiderin in turn fuels further release of RONS products (oxidized lipids and nitrosylated proteins). The most reactive of the RONS products are singlet oxygen, hypochlorous acid, chlorine gas, hydroxyl radicals, and peroxynitrite. Our in vitro studies have revealed that both ma- ture type-I and type-II collagen are modified by RONS36. These changes may affect the organization of the tissue matrix, altering its mechanical properties as well as preventing normal remodeling and resolution of the injury response. The expression of COX-2 activates Bcl-2, a key regulator of the antiapoptotic machinery, and strongly suggests that cells are not undergoing apoptosis and thereby attenuating the wound-healing response. These observations strongly suggest an imbalance in the chemical mediators regulating the normal resolution of the inflammatory and fibroblastic proliferative phases of healing. We conclude that aggressive periarticular fibrosis and the unresolved healing process in patients with arthrofibrosis are results of an excessive accumulation of RONS and RONS-modified lipids and proteins (Fig. 6). Furthermore, we suggest that periarticular arthrofibrosis initiated and propagated by RONS will most likely occur in patients with a genetic predisposition to this process, that is, individuals with a genetic makeup that results in a deficiency in RONS removal (antioxidants) and/or exaggerated RONS production. Treatment modalities with use of antioxidant treatment are being studied and may have a role in the management of this challenging condition. „ Corresponding author: Javad Parvizi, MD, FRCS 925 Chestnut Street, Philadelphia, PA 19107. E-mail address: [email protected] The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. 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