Cellular and morphological changes with EAA supplementation before and after total knee arthroplasty.

Investigate the underlying cellular basis of muscle atrophy (Placebo) and atrophy reduction (essential amino acid supplementation, EAAs) in total knee arthroplasty (TKA) patients by examining satellite cells and other key histological markers of inflammation, recovery, and fibrosis. Forty-one subjects (53-76 yr) scheduled for TKA were randomized into two groups, ingesting 20 g of EAAs or placebo, twice-daily, for 7 days before TKA and for 6 wk after surgery. A first set of muscle biopsies was obtained from both legs before surgery in the operating room, and patients were randomly assigned and equally allocated to have two additional biopsies at either 1 or 2 wk after surgery. Biopsies were processed for gene expression and immunohistochemistry. Satellite cells were significantly higher in patients ingesting 20 g of essential amino acids twice daily for the 7 days leading up to surgery compared with Placebo (operative leg P = 0.03 for satellite cells/fiber and P = 0.05 for satellite cell proportions for Type I-associated cells and P = 0.05 for satellite cells/fiber for Type II-associated cells.) Myogenic regulatory factor gene expression was different between groups, with the Placebo Group having elevated MyoD expression at 1 wk and EAAs having elevated myogenin expression at 1 wk. M1 macrophages were more prevalent in Placebo than the EAAs Group. IL-6 and TNF-α transcripts were elevated postsurgery in both groups; however, TNF-α declined by 2 wk in the EAAs Group. EAAs starting 7 days before surgery increased satellite cells on the day of surgery and promoted a more favorable inflammatory environment postsurgery.NEW & NOTEWORTHY Clinical studies by our group indicate that the majority of muscle atrophy after total knee arthroplasty (TKA) in older adults occurs rapidly, within the first 2 wks. We have also shown that essential amino acid supplementation (EAAs) before and after TKA mitigates muscle atrophy; however, the mechanisms are unknown. These results suggest that satellite cell numbers are elevated with EAA ingestion before surgery, and after surgery, EAA ingestion positively influences markers of inflammation. Combined, these data may help inform further studies designed to address the accelerated sarcopenia that occurs in older adults after major surgery.

Essential Amino Acid Supplementation Mitigates Muscle Atrophy After Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Substantial muscle atrophy occurs after total knee arthroplasty (TKA), resulting in decreased strength and impaired mobility. We sought to determine whether perioperative supplementation with essential amino acids (EAA) would attenuate muscle atrophy following TKA and whether the supplements were safe for ingestion in an older surgical population. METHODS: We performed a double-blind, placebo-controlled, randomized trial of 39 adults (age range, 53 to 76 years) undergoing primary unilateral TKA who ingested 20 g of EAA (n = 19) or placebo (n = 20) twice daily for 7 days preoperatively and for 6 weeks postoperatively. At baseline and 6 weeks postoperatively, magnetic resonance imaging (MRI) scans were obtained to measure quadriceps and hamstrings muscle volume. Secondary outcomes included functional mobility and strength. Data on physical activity, diet, and patient-reported outcomes (Veterans RAND 12-Item Health Survey and Knee injury and Osteoarthritis Outcome Score) were collected. Safety was determined through blood tests evaluating blood urea nitrogen, creatinine, creatinine clearance, homocysteine, and renal and liver function. Laboratory values at baseline, on the day of surgery, and at 2 days, 2 weeks, and 6 weeks postoperatively were compared between treatment groups. Analysis of covariance models, with baseline values as covariates, were used to evaluate outcomes between treatment groups. P values were adjusted for multiple tests. RESULTS: Compared with baseline, the EAA group had significantly less decrease in mean quadriceps muscle volume compared with the placebo group in the involved leg (-8.5% ± 2.5% compared with -13.4% ± 1.9%; p = 0.033) and the contralateral leg (-1.5% ± 1.6% compared with -7.2% ± 1.4%; p = 0.014). The hamstrings also demonstrated a greater muscle-volume-sparing effect for the EAA group than for the placebo group in the involved leg (-7.4% ± 2.0% compared with -12.2% ± 1.4%; p = 0.036) and contralateral leg (-2.1% ± 1.3% compared with -7.5% ± 1.5%; p = 0.005). There were no differences between the groups in terms of functional measures or strength. Blood chemistry values varied significantly between assessments periods but did not statistically differ between groups. CONCLUSIONS: The results of the present study suggest that EAA supplementation is safe and reduces the loss of muscle volume in older adults recovering from TKA. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Transcriptional profiling and muscle cross-section analysis reveal signs of ischemia reperfusion injury following total knee arthroplasty with tourniquet.

Total knee arthroplasty (TKA) is the most common and cost-effective treatment for older adults with long-standing osteoarthritis. Projections indicate that nearly 3.5 million older adults will undergo this procedure annually by the year 2030. Thus, understanding the factors that lead to optimal outcomes is of great clinical interest. In the majority of cases, tourniquet is applied during surgery to maintain a clear surgical field, however, there is debate as to whether this intervention is completely benign. In particular, muscle atrophy is a significant factor in preventing full functional recovery following surgery, and some evidence suggests that tourniquet application and the associated ischemia-reperfusion injury that results contributes to muscle atrophy. For this reason, we examined tissue level changes in muscle in TKA patients following surgery and found that there was a significant increase in cross-sectional area of muscle fibers of all types. Furthermore, to detect changes not evident at the tissue level, we performed NextSeq analysis to assess the transcriptional landscape of quadriceps muscle cells following TKA with tourniquet and found 72 genes that were significantly upregulated. A large proportion of those genes regulate cell stress pathways, suggesting that muscle cells in our cohort of older adults were capable of mounting a significant response to cell stress. Furthermore, factors related to complement were upregulated, suggesting tourniquet may play a role in priming cells to ischemia reperfusion injury. Therefore, our analysis reveals potential harms of tourniquet during TKA, thus suggesting that surgeons should consider limiting its use.

Endoplasmic Reticulum Stress Activation during Total Knee Arthroplasty.

Total knee arthroplasty (TKA) is the most common remediation for knee pain from osteoarthritis (OA) and is performed 650,000 annually in the U.S. A tourniquet is commonly used during TKA which causes ischemia and reperfusion (I/R) to the lower limb but the effects of I/R on muscle are not fully understood. Previous reports suggest upregulation of cell-stress and catabolism and downregulation of markers of cap-dependent translation during and after TKA. I/R has also been shown to cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). We hypothesized that the UPR would be activated in response to ER stress during TKA. We obtained muscle biopsies from the vastus lateralis at baseline, before TKA; at maximal ischemia, prior to tourniquet deflation; and during reperfusion in the operating room. Phosphorylation of 4E-BP1 and AKT decreased during ischemia (-28%, p < .05; -20%, p < .05 respectively) along with an increase in eIF2α phosphorylation (64%, p < .05) suggesting decreased translation initiation. Cleaved ATF6 protein increased in ischemia (39%, p = .056) but returned to baseline during reperfusion. CASP3 activation increased during reperfusion compared to baseline (23%, p < .05). XBP1 splicing assays revealed an increase in spliced transcript during ischemia (31%, p < .05) which diminished during reperfusion. These results suggest that in response to I/R during TKA all three branches of the ER stress response are activated.

Essential amino acid supplementation in patients following total knee arthroplasty.

BACKGROUND: By the year 2030, 3.48 million older U.S. adults are projected to undergo total knee arthroplasty (TKA). Following this surgery, considerable muscle atrophy occurs, resulting in decreased strength and impaired functional mobility. Essential amino acids (EAAs) have been shown to attenuate muscle loss during periods of reduced activity and may be beneficial for TKA patients. METHODS: We used a double-blind, placebo-controlled, randomized clinical trial with 28 older adults undergoing TKA. Patients were randomized to ingest either 20 g of EAAs (n = 16) or placebo (n = 12) twice daily between meals for 1 week before and 2 weeks after TKA. At baseline, 2 weeks, and 6 weeks after TKA, an MRI was performed to determine mid-thigh muscle and adipose tissue volume. Muscle strength and functional mobility were also measured at these times. RESULTS: TKA patients receiving placebo exhibited greater quadriceps muscle atrophy, with a -14.3 ± 3.6% change from baseline to 2 weeks after surgery compared with -3.4 ± 3.1% for the EAA group (F = 5.16, P = 0.036) and a -18.4 ± 2.3% change from baseline to 6 weeks after surgery for placebo versus -6.2 ± 2.2% for the EAA group (F = 14.14, P = 0.001). EAAs also attenuated atrophy in the nonoperated quadriceps and in the hamstring and adductor muscles of both extremities. The EAA group performed better at 2 and 6 weeks after surgery on functional mobility tests (all P < 0.05). Change in quadriceps muscle atrophy was significantly associated with change in functional mobility (F = 5.78, P = 0.021). CONCLUSION: EAA treatment attenuated muscle atrophy and accelerated the return of functional mobility in older adults following TKA. TRIAL REGISTRATION: Clinicaltrials.gov NCT00760383.

MAFbx, MuRF1, and the stress-activated protein kinases are upregulated in muscle cells during total knee arthroplasty.

Total knee arthroplasty (TKA) is the most common and a cost-effective surgical remediation for older adults with long-standing osteoarthritis. In parallel with the expanding population of older adults, the number of TKAs performed annually is projected to be 3.48 million by 2030. During this surgery, a tourniquet is used to stop blood flow to the operative leg. However, the molecular pathways that are affected by tourniquet use during TKA continue to be elucidated. We hypothesized that components of the catabolic FoxO3a (i.e., MuRF1, MAFbx, and Bnip3) pathway, as well as the cellular stress pathways [i.e., stress-activated protein kinase (SAPK)/JNK and MAPKs], are upregulated during TKA. The purpose of this study was to measure changes in transcripts and proteins involved in muscle cell catabolic and stress-activated pathways. We obtained muscle biopsies from subjects, 70 ± 1.3 yr, during TKA, from the vastus lateralis at baseline (before tourniquet inflation), during maximal ischemia (just before tourniquet release), and during reperfusion. Total tourniquet time was 43 ± 2 min and reperfusion time was 16 ± 1. Significant increases in FoxO3a downstream targets, MAFbx and MuRF1, were present for mRNA levels during ischemia (MAFbx, P = 0.04; MuRF1, P = 0.04), and protein expression during ischemia (MAFbx, P = 0.002; MuRF1, P = 0.001) and reperfusion (MuRF1, P = 0.002). Additionally, stress-activated JNK gene expression (P = 0.01) and protein were elevated during ischemia (P = 0.001). The results of this study support our hypothesis that protein degradation pathways are stimulated during TKA. Muscle protein catabolism is likely to play a role in the rapid loss of muscle volume measured within 2 wk of this surgery.

Proteins regulating cap-dependent translation are downregulated during total knee arthroplasty.

Total knee arthroplasty (TKA) utilizes a tourniquet to reduce blood loss, maintain a clear surgical "bloodless" field, and to ensure proper bone-implant cementing. In 2007, over 600,000 TKAs were performed in the United States, and this number is projected to increase to 3.48 million procedures performed annually by 2030. The acute effects of tourniquet-induced ischemia-reperfusion (I/R) on human skeletal muscle cells are poorly understood and require critical investigation, as muscle atrophy following this surgery is rapid and represents the most significant clinical barrier to long-term normalization of physical function. To determine the acute effects of I/R on skeletal muscle cells, biopsies were obtained at baseline, maximal ischemia (prior to tourniquet release), and reperfusion (following tourniquet release). Quadriceps volume was determined before and 2 wk post-TKA by MRI. We measured a 36% decrease in phosphorylation of Akt Ser(473) during ischemia and 37% during reperfusion (P < 0.05). 4E-BP1 Thr(37/46) phosphorylation decreased 29% during ischemia and 22% during reperfusion (P < 0.05). eEF2 Thr(56) phosphorylation increased 25% during ischemia and 43% during reperfusion (P < 0.05). Quadriceps volume decreased 12% in the TKA leg (P < 0.05) and tended to decrease (6%) in the contralateral leg (P = 0.1). These data suggest cap-dependent translation initiation, and elongation may be inhibited during and after TKA surgery. We propose that cap-dependent translational events occurring during surgery may precipitate postoperative changes in muscle cells that contribute to the etiology of muscle atrophy following TKA.

High complication rate with anterior total hip arthroplasties on a fracture table.

BACKGROUND: Recent attention in THA has focused on minimally invasive techniques and their short-term outcomes. Despite much debate over the outcomes and complications of the two-incision and the mini-lateral and mini-posterior approaches, complications arising from use of the anterior THA on a fracture table are not well documented. QUESTIONS/PURPOSES: We determined the intraoperative and postoperative complications with the anterior approach to THA through an extended single-surgeon patient series. METHODS: We reviewed 800 primary THAs performed anteriorly with the aid of a fracture table over 5 years and recorded all intraoperative and postoperative complications up to latest followup (average, 1.8 years; range, 0-5 years). Patients with severe acetabular deformity or severe flexion contractures were excluded and those surgeries were performed with a lateral approach during the time period of this study. RESULTS: Intraoperative complications included 19 trochanteric fractures, three femoral perforations, one femoral fracture, one acetabular fracture, one bleeding complication, and one case of cardiovascular collapse. There were no ankle fractures. Postoperative complications included seven patients with dislocations; seven with deep infections; one with delayed femur fracture; 37 with wound complications, among which 13 had reoperation for local débridement; 14 with deep venous thrombosis; and two with pulmonary embolism; and 31 other nonfatal medical complications. CONCLUSIONS: The main intraoperative complications of trochanteric fractures and perforations occurred mostly early in the series, while the main postoperative complications related to wound healing were prevalent throughout the entire series. Despite potential advantages of use of a fracture table, surgeons should be aware of the potential complications of trochanteric fractures, perforations, and wound-healing problems associated with this technique. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Is there faster recovery with an anterior or anterolateral THA? A pilot study.

Surgical technique is an important factor affecting recovery of hip function after total hip arthroplasty (THA). We therefore asked whether short-term recovery of hip strength and motion would differ between the anterior and anterolateral THA approaches. We presumed that although both approaches would improve hip function by 16 weeks postsurgery when compared with presurgery, a slower recovery would be demonstrated by the anterolateral group at 6 weeks when compared with the anterior group as a result of division and reattachment of the abductor muscles. We observed hip kinematics and kinetics during walking and isometric hip abductor strength for the involved limb. Hip abductor strength of all patients was lower than controls at all three testing times. Compared with presurgery, all patients demonstrated improved abductor strength at 16 weeks postsurgery. At 6 weeks, the patients with an anterior approach had improved late stance peak abductor moment postsurgery and reached the level of controls, but those with an anterolateral approach did not. Although the anterior approach was associated with improved gait velocity and peak flexor moments at 6 weeks compared to before surgery, we observed no differences between the two approaches for most of the isometric strength and dynamic gait measures at 6 or 16 weeks. Neither approach provided faster recovery.

Radiographic failure patterns of polished cemented stems.

Changes in cemented femoral component geometry and surface finish have been made to improve predicted results. We studied the failure rates and radiographic failure patterns of four polished femoral stems with different geometries to determine if design changes over time improved our results. We retrospectively reviewed 910 patients with 1031 total hip arthroplasties performed from 1993 to 2003 with a minimum 2-year followup. All arthroplasties used the same cementing technique with polished femoral stems with a surface roughness of 4 microinches but with differing geometries. By 2005, seven stems (0.6%) were revised for aseptic loosening. All loosening started at the cement-bone interface. The time from the onset of loosening to revision averaged 3.3 years. In all but one patient the bone damage was minimal and amenable to simple revision femoral techniques. We found no obvious difference in loosening rates or radiographic failure patterns among the four stem geometries. The patients showed less bone damage and progressed slower than previous reports of failed rough femoral stems.

Sequential bilateral total hip replacement during the same hospitalization.

UNLABELLED: Numerous authors describe the efficacy and relative safety of simultaneous bilateral total hip replacement or bilateral surgeries separated by more than 6 weeks. We compare those reported results with our 32-year experience using a unique timing protocol: doing sequential bilateral total hip replacements during the same hospitalization separated by 5 to 7 days. From 1972 to 2004, 112 patients were selected for bilateral total hip replacement surgery during the same hospitalization. All surgeries were done using a direct lateral approach to the hip with a variety of cemented and cementless implants. Of the 112 patients, 96 charts were available for review. The average length of stay was 13.8 days. With an average of 6.3 years (range, 1-23 years) followup, Iowa hip scores improved from an average of 42 points to an average of 94 points. Implant survivorship compared favorably with other reports of similar implants, and there were no acute deep infections and two delayed infections. Sixteen patients developed medical complications, two had pulmonary emboli (one fatal) and two died (one of pulmonary embolism and one cerebral bleed not related to the surgery). Sequential bilateral total hip arthroplasty offers surgeons an alternative to simultaneous or staged surgery for the appropriately selected patient. LEVEL OF EVIDENCE: Therapeutic study, Level IV (case series). See the Guidelines for Authors for a complete description of levels of evidence.

Clinical assessment of tibial polyethylene thickness: comparison of radiographic measurements with as-implanted and as-retrieved thicknesses.

Sixty-six posterior cruciate-retaining inserts of one fixed-bearing design were revised because of wear or osteolysis. Tibial polyethylene thickness was estimated from standard anteroposterior radiographs and compared with the original or final minimum thicknesses. The most accurate method involved measuring the shortest distance from each femoral condyle to a transverse line through the middle of the baseplate's superior surface. On radiographs acquired 6 weeks after arthroplasty, the mean error was -0.1 mm (underestimate) +/- 0.6 mm (standard deviation), with 72% of the measurements within 0.5 mm of the original minimum thickness and 87% within 1.0 mm. The method was less accurate for radiographs made before revision, for which the mean error was 0.6 mm (overestimate) +/- 1.0 mm. In this study, 41% and 70% of the prerevision measurements were accurate to within 0.5 and 1.0 mm, respectively.