Oxidative stress mediates associations between preoperative psychosocial phenotype and pain-related outcomes at 6 months following total knee arthroplasty: a longitudinal cohort study.

OBJECTIVE: Greater preoperative depression, anxiety, and pain catastrophizing are associated with more severe long-term pain following total knee arthroplasty (TKA). In a secondary analysis of previously reported data, we tested the hypothesis that these associations are mediated by oxidative stress (OS). DESIGN: A mixed between/within-subjects longitudinal cohort design. SETTING: A single academic medical center. SUBJECTS: Osteoarthritis patients (n = 91; 62.6% female) undergoing unilateral TKA. METHODS: We assessed depression, anxiety, and catastrophizing, as well as markers of central sensitization (widespread pain, temporal summation of pain) preoperatively. Blood samples were then obtained immediately prior to intraoperative tourniquet placement for quantification of in vivo biomarkers of systemic OS, F2-isoprostanes and isofurans. Post-TKA pain intensity (numeric rating scale worst pain [NRS], McGill Pain Questionnaire-2 [MPQ-2]) and function (PROMIS Pain Interference) were assessed at 6 months following TKA. RESULTS: Greater preoperative depression, catastrophizing, and widespread pain were associated with higher intraoperative combined OS (F2-isoprostanes+isofurans/2), which was in turn associated with higher post-TKA pain intensity and worse function (P < .05). All preoperative phenotype predictors except anxiety were correlated positively with post-TKA pain and/or function (P < .05). Bootstrapped mediation analyses revealed significant (P < .05) indirect (mediated) effects of depression (NRS Worst Pain, MPQ-2, PROMIS Pain Interference), anxiety (MPQ-2, PROMIS Pain Interference), and catastrophizing (PROMIS Pain Interference) on adverse long-term post-TKA outcomes via elevated OS. Central sensitization-related predictors demonstrated only direct effects (P < .05) on post-TKA outcomes that were independent of OS mechanisms. CONCLUSIONS: Results suggest that the adverse impact of depression, anxiety, and pain catastrophizing on post-TKA pain and functional outcomes are mediated in part by elevated OS.

Central Sensitization: The Missing Link Between Psychological Distress and Poor Outcome Following Primary Total Knee Arthroplasty.

BACKGROUND: While preoperative psychological distress is known to predict risk for worse total knee arthroplasty (TKA) outcomes, distress may be too broad and nonspecific a predictor in isolation. We tested whether there are distinct preoperative TKA patient types based jointly on psychological status and measures of altered pain processing that predict adverse clinical outcomes. METHODS: In 112 TKA patients, we preoperatively assessed psychological status (depression, anxiety, and catastrophizing) and altered pain processing via a simple quantitative sensory testing protocol capturing peripheral and central pain sensitization. Outcomes (pain, function, opioid use) were prospectively evaluated at 6 weeks and 6 months after TKA. Cluster analyses were used to empirically identify TKA patient subgroups. RESULTS: There were 3 distinct preoperative TKA patient subgroups identified from the cluster analysis. A low-risk (LR) group was characterized by low psychological distress and low peripheral and central sensitization. In addition, 2 subgroups with similarly elevated preoperative psychological distress were identified, differing by pain processing alterations observed: high-risk centralized pain and high-risk peripheral pain. Relative to LR patients, high-risk centralized pain patients displayed significantly worse function and greater opioid use at 6 months after TKA (P values <.05). The LR and high-risk peripheral pain patient subgroups had similar 6-month outcomes (P values >.05). CONCLUSIONS: Among patients who have psychological comorbidity, only patients who have central sensitization were at elevated risk for poor functional outcomes and increased opioid use. Central sensitization may be the missing link between psychological comorbidity and poor TKA clinical outcomes. Preoperative testing for central sensitization may have clinical utility for improving risk stratification in TKA patients who have psychosocial risk factors.

Preoperative Predictors of Prolonged Opioid Use in the 6 Months After Total Knee Arthroplasty.

OBJECTIVES: Prolonged postoperative opioid use increases the risk for new postsurgical opioid use disorder. We evaluated preoperative phenotypic factors predicting prolonged postoperative opioid use. METHODS: We performed a secondary analysis of a prospective observational cohort (n=108) undergoing total knee arthroplasty (TKA) for osteoarthritis with 6-week and 6-month follow-up. Current opioid use and psychosocial, pain, and opioid-related characteristics were assessed at preoperative baseline. Primary outcomes were days/week of opioid use at follow-up. RESULTS: At 6 weeks, preoperative opioid use and greater cumulative opioid exposure, depression, catastrophizing, anxiety, pain interference, sleep disturbance, and central sensitization were significantly associated with more days/week of opioid use after controlling for contemporaneous pain intensity. Prior euphoric response to opioids were also significant predictors at 6 months. All 6-week predictors except anxiety remained significant after controlling for preoperative opioid use; at 6 months, cumulative opioid exposure, catastrophizing, pain interference, and sleep disturbance remained significant after this adjustment ( P <0.05). In multivariable models, a psychosocial factor reflecting negative affect, sleep, and pain accurately predicted 6-week opioid use (area under the curve=0.84). A combined model incorporating psychosocial factor scores, opioid-related factor scores, and preoperative opioid use showed near-perfect predictive accuracy at 6 months (area under the curve=0.97). DISCUSSION: Overall, preoperative psychosocial, pain-related, and opioid-related phenotypic characteristics predicted prolonged opioid use after total knee arthroplasty.

Is cement mantle thickness a primary cause of aseptic tibial loosening following primary total knee arthroplasty?

BACKGROUND: Aseptic tibial loosening following primary total knee replacement is one of the leading causes of long-term failure. Cement mantle thickness has been implicated as a source of aseptic tibial loosening. Therefore, the following study was designed to determine (1) what is the cement mantle thickness in patients that develop aseptic tibial loosening, and (2) is there a difference in cement mantle thickness based on the interface of failure? METHOD: This retrospective cohort included 216 patients revised for aseptic tibial loosening. Patient demographics, operative data, and clinical outcomes were recorded. A preoperative radiographic assessment was performed to determine the interface of failure and the thickness of the cement mantle using the Knee Society Radiographic Evaluation System zones. RESULTS: The average patient age was 65 years and body mass index was 33.7 kg/m2. 203 patients demonstrated radiographic failure at the implant-cement interface and 13 patients demonstrated failure at the cement-bone interface. The average cement mantle thickness of each radiographic zone for the entire cohort on the AP and lateral views was 4.4 and 4.5 mm, respectively. The average cement mantle thickness of patients that developed failure at the implant-cement interface was significantly greater than patients that failed at the cement-bone interface in each radiographic zone (p < 0.001). CONCLUSIONS: Patients that develop implant loosening at the cement-bone interface were noted to have a significantly decreased cement mantle compared to patients that failed at the implant-cement interface. Methods for decreasing tibial implant loosening should likely focus on improving the fixation at the implant-cement interface.

Perioperative oxidative stress predicts subsequent pain-related outcomes in the 6 months after total knee arthroplasty.

ABSTRACT: Total knee arthroplasty (TKA) is effective for pain reduction in most patients, but 15% or more report unsatisfactory long-term pain outcomes. We tested whether oxidative stress (OS) related to extended tourniquet application during TKA and subsequent ischemic reperfusion (IR) contributed to adverse post-TKA pain outcomes. Blood samples were obtained in 91 patients with osteoarthritis (63% female) undergoing TKA before tourniquet placement (T1), 45 minutes after tourniquet inflation (T2), and 15 minutes after tourniquet removal (T3). Plasma levels of F 2 -isoprostanes and isofurans, the most specific measures of in vivo OS, were quantified. Pain intensity and function were assessed at baseline and again at 6 weeks and 6 months after TKA. Results indicated that higher Combined OS (F 2 -isoprostanes + isofurans/2) at T1 baseline and larger increases in Combined OS from T1 to T2 were associated with higher baseline-corrected past 24-hour worst and average pain intensity (numeric rating scale) and higher past week McGill Pain Questionnaire-2 total scores at 6-month follow-up ( P 's < 0.05). Increases in Combined OS from T1 to T3, which should most directly capture OS and IR injury related to tourniquet use, were not associated with short-term or long-term post-TKA pain outcomes. Longer ischemia duration was unexpectedly associated with lower baseline-corrected pain intensity at 6-month follow-up. Combined OS was not linked to functional outcomes at either follow-up. Elevated perioperative OS seems to exert small but significant adverse effects on long-term post-TKA pain outcomes, although this OS seems unrelated to IR injury associated with extended tourniquet use.

Preoperative Predictors of Complex Regional Pain Syndrome Outcomes in the 6 Months Following Total Knee Arthroplasty.

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a "warm CRPS" phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P's < .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P's < .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P's < .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P's < .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PERSPECTIVE: This article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.

Oxidative stress is associated with characteristic features of the dysfunctional chronic pain phenotype.

ABSTRACT: The dysfunctional chronic pain (Dysfunctional CP) phenotype is an empirically identifiable CP subtype with unclear pathophysiological mechanisms that cuts across specific medical CP diagnoses. This study tested whether the multidimensional pain and psychosocial features that characterize the dysfunctional CP phenotype are associated broadly with elevated oxidative stress (OS). Measures of pain intensity, bodily extent of pain, catastrophizing cognitions, depression, anxiety, sleep disturbance, pain interference, and function were completed by 84 patients with chronic osteoarthritis before undergoing total knee arthroplasty. Blood samples were obtained at the initiation of surgery before incision or tourniquet placement. Plasma levels of F2-isoprostanes and isofurans, the most highly specific measures of in vivo OS, were quantified using gas chromatography/negative ion chemical ionization mass spectrometry. The results indicated that controlling for differences in age, sex, and body mass index, higher overall OS (mean of isoprostanes and isofurans) was associated with significantly (P < 0.05) greater pain intensity, more widespread pain, greater depressive symptoms and pain catastrophizing, higher pain interference, and lower function. OS measures were not significantly associated with sleep disturbance or anxiety levels (P >0.10). The results build on prior case-control findings suggesting that presence of a CP diagnosis is associated with elevated OS, highlighting that it may specifically be individuals displaying characteristics of the dysfunctional CP phenotype who are characterized by elevated OS. Clinical implications of these findings remain to be determined.

Is preoperative genicular radiofrequency ablation effective for reducing pain following total knee arthroplasty? A pilot randomized clinical trial.

BACKGROUND AND OBJECTIVE: Although total knee arthroplasty (TKA) is an effective treatment for severe knee osteoarthritis (OA), a subset of patients experience significant postoperative pain and dissatisfaction. Several clinical trials support the analgesic benefits of genicular nerve radiofrequency ablation (GN-RFA) for non-operative knee OA, but only one prior trial has examined the effects of this intervention given preoperatively on postoperative outcomes following TKA, showing no analgesic benefit of cooled GN-RFA. The current study evaluated whether conventional thermal GN-RFA performed preoperatively resulted in significant improvements in pain and function following TKA. METHODS: This was a single-center, prospective, randomized, sham-controlled, double-blinded pilot trial in which patients received either conventional GN-RFA (n=30) or sham (n=30) between 2 and 4 weeks prior to their TKA. Baseline measures were obtained preprocedurally on the day of intervention, with follow-up outcomes obtained preoperatively on the day of surgery, and at 2 and 6 weeks postoperatively. RESULTS: Patients receiving GN-RFA showed no significant improvements relative to sham controls in the primary outcome, pain intensity at rest at 6-week follow-up. Secondary outcomes, including pain with ambulation and physical function, also showed no significant differences between groups at any follow-up assessment. CONCLUSIONS: Conventional GN-RFA of the superior lateral, superior medial, and inferior medial genicular nerves when performed prior to TKA did not provide clinically significant pain relief or improvement in functional status at 2 or 6 weeks postoperatively. TRIAL REGISTRATION NUMBER: NCT02947321.

Inhibition of Wnt/ß-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. The canonical Wnt/ß-catenin pathway, which is activated in OA, is emerging as an important regulator of tissue repair and fibrosis. This study seeks to examine Wnt pathway effects on synovial fibroblasts and articular chondrocytes as well as the therapeutic effects of Wnt inhibition on OA disease severity. Mice underwent destabilization of the medial meniscus surgery and were treated by intra-articular injection with XAV-939, a small-molecule inhibitor of Wnt/ß-catenin signaling. Wnt/ß-catenin signaling was highly activated in murine synovial fibroblasts as well as in OA-derived human synovial fibroblasts. XAV-939 ameliorated OA severity associated with reduced cartilage degeneration and synovitis in vivo. Wnt inhibition using mechanistically distinct small-molecule inhibitors, XAV-939 and C113, attenuated the proliferation and type I collagen synthesis in synovial fibroblasts in vitro but did not affect human OA-derived chondrocyte proliferation. However, Wnt modulation increased COL2A1 and PRG4 transcripts, which are downregulated in chondrocytes in OA. In conclusion, therapeutic Wnt inhibition reduced disease severity in a model of traumatic OA via promoting anticatabolic effects on chondrocytes and antifibrotic effects on synovial fibroblasts and may be a promising class of drugs for the treatment of OA.

Risk of Periprosthetic Joint Infection in Patients With Multiple Arthroplasties.

BACKGROUND: Risk of subsequent periprosthetic joint infection (PJI) in a second prosthetic joint following initial PJI has been shown to be 19%-20%. We sought to identify (1) the risk of developing a second PJI for our patients with multiple prosthetic joints and (2) the effect of bacteremia on development of a subsequent PJI. METHODS: We retrospectively reviewed all patients treated surgically for PJI by a single surgeon from 2003 to 2014. Time between initial and subsequent infection, bacteremia, and risk factors for PJI were identified. RESULTS: Of 167 patients treated for PJI, 76 had multiple prosthetic joints. Thirteen percent (10/76) developed a PJI in a second location. Excluding simultaneous infections, the rate was 8.3% (6/72), despite having a 57% incidence of immunosuppression, diabetes, renal failure, smoking, or steroid use. Average follow-up for patients with 1 PJI was 4.6 years (range 0.03-13.6). Seventy percent (7/10) of patients with multiple infections were bacteremic at the time of initial infection compared to 18.1% (12/66) of patients with a single infection (P = .0004). Excluding the 4 simultaneous infections (all bacteremic), the risk of developing an infection in a second joint was 20% if bacteremic and 5.2% if not bacteremic. CONCLUSION: Our study identified the risk of developing a subsequent PJI to be one half of previous studies. Bacteremia at the time of PJI is an important factor for developing subsequent PJI. Multiple prosthetic joints may be less hazardous than previously thought for patients with PJI suggesting that suppressive antibiotics may only be necessary in cases with bacteremia.

Human mesenchymal stromal cells: identifying assays to predict potency for therapeutic selection.

Multipotent mesenchymal stromal cells (MSCs) have the potential to repair and regenerate damaged tissues, making them attractive candidates for cell-based therapies. To maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used. Our goal was to identify feasible and reproducible in vitro assays to predict MSC potency. We generated cell lines from 10 normal human bone marrow samples and used the International Society for Cellular Therapy's minimal criteria to define them as MSCs: plastic adherence, appropriate surface marker expression, and trilineage differentiation. Each MSC line was further characterized by its growth, proliferation, and viability as determined by cell count, bromodeoxyuridine incorporation, and cellular ATP levels, respectively. To determine whether these tests reliably predict the therapeutic aptitude of the MSCs, several lines were implanted in vivo to examine their capacity to engraft and form granulation tissue in a well-established murine wound model using polyvinyl alcohol sponges. Long-term engraftment of MSCs in the sponges was quantified through the presence of the human-specific Alu gene in sponge sections. Sections were also stained for proliferating cells, vascularity, and granulation tissue formation to determine successful engraftment and repair. We found that high performance in a combination of the in vitro tests accurately predicted which lines functioned well in vivo. These findings suggest that reliable and reproducible in vitro assays may be used to measure the functional potential of MSCs for therapeutic use.

Acute kidney injury after placement of an antibiotic-impregnated cement spacer during revision total knee arthroplasty.

We performed a retrospective cohort study of 84 patients to determine the incidence and predictors of acute kidney injury after antibiotic-impregnated cement spacer (ACS) placement for infected total knee arthroplasties. Acute kidney injury was defined as a more than 50% rise in serum creatinine from a preoperative baseline to a level greater than 1.4 mg/dL within 90 days postoperatively. Total incidence was 17% (n = 14; 95% confidence interval [CI], 10%-26%), and acute kidney injury was significantly associated with ACS tobramycin dose as both a dichotomous variable (>4.8 g; odds ratio, 5.87; 95% CI, 1.43-24.19; P = .01) and linear variable (odds ratio, 1.24 for every 1-g increase; 95% CI, 1.00-1.52; P = .049). Routine monitoring of serum creatinine and measurement of serum aminoglycoside levels in response to a threshold creatinine rise may be warranted after the placement of an aminoglycoside-containing ACS.

Innovative analyses support a role for DNA damage and an aberrant cell cycle in myelodysplastic syndrome pathogenesis.

We used flow cytometry to analyze the cell cycle, DNA damage, and apoptosis in hematopoietic subsets in MDS marrow. Subsets were assigned using CD45, side scatter, CD34, and CD71. Cell cycle fractions were analyzed using DRAQ 5 (DNA content) and MPM-2 (mitoses). DNA damage was assessed using p-H2A.X, and apoptosis using Annexin V. Compared to controls, MDS patients demonstrated no increased mitoses in erythroid, myeloid, or CD34+ cells. Myeloid progenitors demonstrated increased G2 cells, which with no increased mitoses suggested delayed passage through G2. Myeloid progenitors demonstrated increased p-H2A.X, consistent with DNA damage causing this delay. Annexin V reactivity was equivalent in MDS and controls. Results for each parameter varied among hematopoietic compartments, demonstrating the need to analyze compartments separately. Our results suggest that peripheral cytopenias in MDS are due to delayed cell cycle passage of marrow progenitors and that this delayed passage and leukemic progression derive from excessive DNA damage.

Quantitative assessment of myeloid nuclear differentiation antigen distinguishes myelodysplastic syndrome from normal bone marrow.

By using flow cytometry, we analyzed myeloid nuclear differentiation antigen (MNDA) expression in myeloid precursors in bone marrow from patients with myelodysplastic syndrome (MDS) and control samples from patients undergoing orthopedic procedures. The median percentage of MNDA-dim myeloid precursors in MDS cases was 67.4% (range, 0.7%-97.5%; interquartile range, 44.9%-82.7%) of myeloid cells, with bimodal MNDA expression in most MDS samples. Control samples demonstrated a median MNDA-dim percentage in myeloid precursors of 1.2% (range, 0.2%-13.7%; interquartile range, 0.6%-2.7%), with no bimodal pattern in most samples. The area under the receiver operating characteristic curve for MNDA-dim percentage in myeloid precursors was 0.96 (P = 9 × 10(-7)). Correlation of MNDA-dim levels with World Health Organization 2008 morphologic diagnoses was not significant (P = .21), but correlation with patient International Prognostic Scoring System scores suggested a trend (P = .07). Flow cytometric assessment of MNDA in myeloid precursors in bone marrow may be useful for the diagnosis of MDS.

Metal-backed versus all-polyethylene tibias in megaprostheses of the distal femur.

In megaprostheses, the tibial component is rarely a source of failure. The evolution of these implants has followed standard arthroplasty trends moving from majority use of all-polyethylene tibias (APT) to high volume use of metal-backed tibial (MBT) components. We report the results of 72 endoprostheses using either MBT (n = 42) or APT (n = 30) implanted between 1994 and 2006. Failures of the implant related to the tibial component were isolated, and 5-year survival of the tibial implant of the MBT cohort was 94%, and for the APT cohort, 87% (P = .39). The difference in tibial component failures between the 2 groups was not statistically significant (Pearson χ(2) = 0.1535, P = .6952). Revision rates for the entire implant and infection rates were not significantly different between the 2 groups.