Volume and location of bone regeneration after autologous expanded mesenchymal stromal cells in hip osteonecrosis : a pilot study.

AIMS: Successful cell therapy in hip osteonecrosis (ON) may help to avoid ON progression or total hip arthroplasty (THA), but the achieved bone regeneration is unclear. The aim of this study was to evaluate amount and location of bone regeneration obtained after surgical injection of expanded autologous mesenchymal stromal cells from the bone marrow (BM-hMSCs). METHODS: A total of 20 patients with small and medium-size symptomatic stage II femoral head ON treated with 140 million BM-hMSCs through percutaneous forage in the EudraCT 2012-002010-39 clinical trial were retrospectively evaluated through preoperative and postoperative (three and 12 months) MRI. Then, 3D reconstruction of the original lesion and the observed postoperative residual damage after bone regeneration were analyzed and compared per group based on treatment efficacy. RESULTS: The mean preoperative lesion volume was 18.7% (SD 10.2%) of the femoral head. This reduced to 11.6% (SD 7.5%) after three months (p = 0.015) and 3.7% (SD 3%) after one year (p < 0.001). Bone regeneration in healed cases represented a mean 81.2% (SD 13.8%) of the initial lesion volume at one year. Non-healed cases (n = 1 stage progression; n = 3 THAs) still showed bone regeneration but this did not effectively decrease the ON volume. A lesion size under mean 10% (SD 6%) of the femoral head at three months predicted no ON stage progression at one year. Regeneration in the lateral femoral head (C2 under Japanese Investigation Committee (JCI) classification) and in the central and posterior regions of the head was predominant in cases without ON progression. CONCLUSION: Bone regeneration was observed in osteonecrotic femoral heads three months after expanded autologous BM-hMSC injection, and the volume and location of regeneration indicated the success of the therapy.Cite this article: Bone Joint Res 2022;11(12):881-889.

Both younger and elderly patients in pain are willing to undergo knee replacement despite the COVID-19 pandemic: a study on surgical waiting lists.

PURPOSE: To identify factors influencing patient's availability to re-schedule primary total knee replacement (TKR) or revision (RKR) surgery after the lockdown (March-May 2020) during the COVID-19 pandemic. METHODS: A prospective cohort study through a telephone survey was performed in 156 patients (143 for primary and 13 for revision) included in the TKR and RKR surgical waiting list before March 2020. Contact of each patient with COVID-19, stress and anxiety, perceived pain, and function were obtained in the interviews, and also the preference of each patient to have re-scheduled surgery (early or late). Finally, we registered their response (acceptance or refusal) when surgery was effectively re-scheduled. RESULTS: 88 out of 156 patients waiting for knee replacement (76/143 of those waiting for TKR, 12/13 of those waiting for RKR) declared themselves ready for surgery in less than 1 month. When re-scheduled, 115 patients underwent surgery and 41 refused. Significantly different preferences were found for age (more prone to surgery if under 65), revision surgery (more readily available), pain (7.9 ± 1.7/10 in NRS in those undergoing surgery, 5.6 ± 2.3/10 in those refusing, p = 0.000), or COVID-19 diagnosis, but not other close contact with COVID-19, comorbidities, stress, or anxiety. A logistic regression model confirmed that revision surgery (OR 9.33), perceived severe pain (OR 5.21), and age under 65 years (OR 5.82) were significantly associated with patient preference. The probability of patients over 65 to prefer early surgery reached 60% only with pain at or above 9/10. CONCLUSIONS: Surgical timing preferences for knee replacement vary between patients older than 65 years (immediate surgery only when pain is intense) and younger patients (immediate surgery no matter the amount of pain). Even if COVID-19 severely stroke our population, the need for knee replacement stood in the young population and even in the aged population at risk for COVID when pain was important.

Implantation of autologous Expanded Mesenchymal Stromal Cells in Hip Osteonecrosis through Percutaneous Forage: Evaluation of the Operative Technique.

Bone forage to treat early osteonecrosis of the femoral head (ONFH) has evolved as the channel to percutaneously deliver cell therapy into the femoral head. However, its efficacy is variable and the drivers towards higher efficacy are currently unknown. The aim of this study was to evaluate the forage technique and correlate it with the efficacy to heal ONFH in a multicentric, multinational clinical trial to implant autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSCs). METHODS: In the context of EudraCT 2012-002010-39, patients with small and medium-sized (mean volume = 13.3%, range: 5.4 to 32.2) ONFH stage II (Ficat, ARCO, Steinberg) C1 and C2 (Japanese Investigation Committee (JIC)) were treated with percutaneous forage and implantation of 140 million BM-hMSCs in a standardized manner. Postoperative hip radiographs (AP-anteroposterior and lateral), and MRI sections (coronal and transverse) were retrospectively evaluated in 22 patients to assess the femoral head drilling orientation in both planes, and its relation to the necrotic area. RESULTS: Treatment efficacy was similar in C1 and C2 (coronal plane) and in anterior to posterior (transverse plane) osteonecrotic lesions. The drill crossed the sclerotic rim in all cases. The forage was placed slightly valgus, at 139.3 ± 8.4 grades (range, 125.5-159.3) with higher dispersion (f = 2.6; p = 0.034) than the anatomical cervicodiaphyseal angle. Bonferroni's correlation between both angles was 0.50 (p = 0.028). More failures were seen with a varus drill positioning, aiming at the central area of the femoral head, outside the weight-bearing area (WBA) (p = 0.049). In the transverse plane, the anterior positioning of the drill did not result in better outcomes (p = 0.477). CONCLUSION: The forage drilling to deliver cells should be positioned within the WBA in the coronal plane, avoiding varus positioning, and central to anterior in the transverse plane. The efficacy of delivered MSCs to regenerate bone in ONFH could be influenced by the drilling direction. Standardization of this surgical technique is desirable.

Epidemiology of long bone non-unions in Spain.

Epidemiological and ecological studies on long bone non-unions (NU) are scarce, based on different populations and methodologies. The aim of this study was to produce a descriptive analysis of the femur, tibia, and humerus non-union epidemiology in Spain. Methods Data were obtained from the Minimum Basic Data (Conjunto Mínimo Básico de Datos, CMBD) Hospital Discharge Database of the Spanish Ministry of Health, according to the ICD9-CM coding for diagnoses and procedures, and from the National Institute of Statistics for population, generating secondary databases with the reported cases that included the code 733.82 in a disaggregated manner, by age (categorized in 5 intervals), gender, Spanish region, and calendar year (1997-2015). Percentage of non-unions related to fractures in the previous year, annual prevalence (expressed per 100,000 person-years) and period prevalence (expressed per 100,000 person-period) were calculated by age, gender, and Spanish regions. The Odds ratio (OR) was estimated with a confidence of 95% using a logistic regression model per anatomical site. Results A mean of 235,446 fractures in all locations were annually reported in Spain from 1997 to 2015. Regarding non-union of long bones (femur, tibia and humerus), a total of 37,053 cases were found, representing a yearly mean of 1,950 cases. The proportion of long bone fractures that evolved into a non-union was 4% (1.4% femur, 1.5% tibia, and 1% humerus). The mean annual prevalence rate of NU in Spain was estimated in 4.5 (3.7-4.9) cases per 100,000 persons-year. The overall NU prevalence in Spain was estimated in 86 cases per 100,000 persons. By the type of bone, the period prevalence (per 100,000 persons-period) of the femur NU was 31, of the tibia 33, and of the humerus 22. Conclusions This description of the epidemiology of long bone non-unions in Spain confirms that the overall non-union rate has been stable from 2000 to 2015, higher in the tibia and in the femur compared to the humerus. NU occurred more frequently in aged females than in males in the femur and the humerus, while the tibia non-unions were more frequent in males and younger age.

Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up.

Background: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first year.

Frontiers in non-union research.

Multifactorial aetiology defines non-unions, with a biological and a mechanical distortion of the timeline of bone healing.Research on new advances to increase osteogenesis and promote non-union healing is strongly directed towards new forms of cell products.Basic science and research on non-union treatments is needed to compile preclinical data on new treatments.Bone marrow concentration and expanded mesenchymal stromal cells still require extensive clinical research to confirm efficacy in non-union treatment.Solid preclinical studies, precise cell product definition and preparation, and appropriate ethical and regulatory approvals are needed to assess new advanced therapy medicinal products. Cite this article: EFORT Open Rev 2020;5:574-583. DOI: 10.1302/2058-5241.5.190062.

Defining the Most Effective Patient Blood Management Combined with Tranexamic Acid Regime in Primary Uncemented Total Hip Replacement Surgery.

The application of patient blood management (PBM) combined with tranexamic acid administration (TXA) results in decreased total blood loss volume (TVB) and transfusions in total hip replacements (THRs). Dosages, timing, and routes of administration of TXA are still under debate as all these aspects, as well as interpatient variations, may affect the efficacy of the protocol. This study aims to examine the effectiveness of timing and route of administration of TXA in combination with PBM by reducing the TBV following THR surgery. Consecutive primary uncemented THRs operated by a single surgical and anaesthetic team had the data prospectively collected and then retrospectively studied. Five treatment groups were formed, reflecting the progressive evolution of our protocol. Group 1 included patients managed with PBM alone (preoperative erythrocyte mass optimisation to at least 14 g/dL haemoglobin (Hb), hypotensive spinal anaesthesia and restrictive red blood cell transfusion criteria). Group 2 included patients with PBM and topical 3 g TXA diluted in normal saline to a total volume of 50 mL. Group 3 were patients with PBM and an IV dose of 20 mg/kg TXA at induction, followed by 20 mg/kg TXA as a continuous infusion for the duration of the operation. Group 4 consisted of patients managed as per Group 3 plus another 20 mg/kg TXA at three-hour post-procedure. Group 5 (combined): PBM and IV TXA as per Group 4 and topical TXA as per Group 2. A generalised linear model with the treatment group as an independent variable was modelled, using TBV as the dependent variable. The transfusion rate for all groups was 0%. TBV at 24 h, oscillated from 613.5 ± 337.63 mL in Group 1 to 376.29 ± 135.0 mL in Group 5. TBV at 48 h oscillated from 738.3 ± 367.3 mL (PBM group) to 434 ± 155.2 mL (PBM + combined group). The multivariate regression model confirmed a significant decrease of TBV in all groups with TXA compared with the PBM-only group. Overweight and preoperative Hb were confirmed to significantly influence TBV. The optimal regime to achieve the least TBV and a transfusion rate of 0% requires PBM and one loading 20 mg/kg dose of TXA, followed by continuous infusion of 20 mg/kg for the duration of the operation in uncemented THRs. Additional doses of TXA did not add a clear benefit.

Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions.

BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture. PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni). RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation. CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.

Validation of a long bone fracture non-union healing score after treatment with mesenchymal stromal cells combined to biomaterials.

The available scores to clinically evaluate fracture consolidation encounter difficulties to interpret progression towards consolidation in long-bone non-union, particularly when incorporating biomaterials in the surgical treatment. The aims of this study were to validate the REBORNE bone healing scale in tibia, humerus and femur non-unions treated by a combination of mesenchymal stromal cells (MSCs) and biomaterials, through the interclass correlation (ICC) among raters, and to define reliability and concordance in anteroposterior and lateral radiographs, compared to computed tomography (CT). METHODS: Twenty-six cases from the EudraCT 2011-005441-13 clinical trial underwent bone healing evaluation, if at least 3 out of 4 cortical views clearly identified. Three senior orthopaedic surgeons evaluated radiographs and CTs at 3 and 6 months FU. All cases included preoperative imaging and radiographs at 12 months. The 4-stage scale score was obtained from each cortical view in orthogonal radiographs or CTs. A score of 0.6875 (11/16) was set as a threshold for bone healing. Statistically, ICC evaluated agreement among raters. Cronbach's alpha coefficient tested reliability. Lin's concordance correlation coefficients (CCC) were estimated between mean CT scores and mean radiographic scores. Bland and Altman graphs provided the limits of agreement between both imaging techniques. Sensitivity and specificity were assessed in radiographs (against CT), and the Area Under the Receiver Operating Characteristics (ROC) Curve was estimated. The probability to predict bone consolidation with REBORNE scores obtained from radiographs was modelled. RESULTS: An ICC of 0.88 and 0.91 (CT and radiographs) confirmed agreement in the REBORNE score for non-union bone healing, with an inter-rater reliability of 0.92 and 0.95. Scores through the radiographic evaluation were found equivalent to the CTs at 6 months FU. A CCC of 0.79 was detected against CT. The radiographic scores in the REBORNE bone healing scale correctly classified bone consolidation in 77%, with an accuracy of 83% based on ROC curves. CONCLUSIONS: The REBORNE score measured with CT or radiographic images was reliable among raters at a follow-up time above 6 months for long bone non-union fractures. The REBORNE scale measured with radiographs proved valid to assess consolidation against CT measurements.

Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial.

BACKGROUND: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).

Arthroscopic Partial Meniscectomy for Painful Degenerative Meniscal Tears in the Presence of Knee Osteoarthritis in Patients Older than 50 Years of Age: Predictors of an Early (1 to 5 Years) Total Knee Replacement.

BACKGROUND: The role of arthroscopic partial meniscectomy (APM) for painful degenerative meniscal tears (PDMT) is currently controversial.To define the rate of early (1 to 5 years) conversion to total knee replacement (TKR) and their predictors after APM for PDMT in patients with knee osteoarthritis and more than 50 years of age. METHODS: Retrospective cohort study of patients more than 50 years of age with the diagnosis of PDMT, treated by means of APM. Patients were classified in two groups: Patients that required an early (between 1 and 5 years after APM) TKR (TKR group) after its failure and patients that did not require a TKR (non-TKR group). Patient demographics, general characteristics, Kellgren & Lawrence (KL) classification, Outerbridge classification, and other characteristics were analyzed. Postoperative variables were also analyzed: pain, use of walking aids and use of intra-articular injections (hyaluronic acid or corticosteroids) at 3, 6, and 12 months of follow-up. RESULTS: A total of 356 patients (356 APMs) were included. Forty-nine patients (13.7%) required an early (1.8 years on average) TKR and 307 did not. The main predictor of early TKR was the grade of the KL classification. After APM, the presence of pain and the need of walking aids also were predictors of an early TKR. CONCLUSION: In patients older than 50 years with PDMT, APM should be cautiously indicated in case of KL grade of 1 or more. Postoperative pain and prolonged need of walking aids were also predictors of an early (mean 1.8 years) TKR.

A Multicentric, Open-Label, Randomized, Comparative Clinical Trial of Two Different Doses of Expanded hBM-MSCs Plus Biomaterial versus Iliac Crest Autograft, for Bone Healing in Nonunions after Long Bone Fractures: Study Protocol.

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n = 108) will be randomly assigned to either the experimental low dose (n = 36), the experimental high dose (n = 36), or the comparator arm (n = 36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use.

Tranexamic Acid in a Multimodal Blood Loss Prevention Protocol to Decrease Blood Loss in Revision Total Knee Arthroplasty: A Cohort Study.

PURPOSE: To clarify if blood loss and transfusion requirements can be decreased in revision knee surgery through a multimodal blood loss approach with tranexamic acid (TXA). PATIENTS AND METHODS: A retrospective study was designed in 87 knees (79 patients) that received a knee revision between 2007 and 2013. To avoid heterogeneity in the surgical technique, only revisions with one single implant system were included. A treatment series of 44 knees that received TXA and other techniques in a multimodal blood loss protocol was compared to a control series of 43 knees that received neither TXA nor the rest of the multimodal blood loss protocol. No differences in the complexity of surgeries or case severity were detected. RESULTS: A significant decrease was observed from 58% transfusion rate in the control group to 5% in the treated group. The postoperative haemoglobin drop was also significantly different. Although the use of a blood loss prevention approach including TXA was the most relevant factor in the transfusion risk (OR=15), longer surgical time also associated an increased risk of transfusion (OR=1.15). CONCLUSION: This study supports the use of a two-dose intravenous TXA under a multimodal blood loss prevention approach in revision knee replacement with significant reduction in the transfusion rate, postoperative blood loss and haemoglobin drop.

Low-volume formulation of intra-articular tranexamic acid, 25-ml tranexamic acid (2.5 g) plus 20-ml saline, is effective in decreasing blood transfusion rate in primary total knee replacement even without preoperative haemoglobin optimization.

UNLABELLED: The efficacy of intra-articular tranexamic acid (TXA) to decrease blood loss after total knee replacement (TKR) has been confirmed in randomised clinical trials (RCTs) and meta-analysis. However, insufficient data are still available about the efficacy in clinical practice of intra-articular TXA administration in reducing the rate of postoperative blood transfusion. To prove the efficacy of a low-volume formulation of intra-articular TXA in current clinical practice, and the role of preoperative variables to influence the transfusion risk after primary TKR. We performed a retrospective study (using data that were gathered concurrently with the treatments but without a specific protocol to address the research question) in patients undergoing cemented TKR and receiving a low-volume formulation (2.5 g-25 ml TXA plus 20-ml saline) of intra-articular TXA (group B, study group, N = 85), and compared it with a cohort of high volume (3 g-30 ml TXA plus 70-ml saline) half topical half intra-articular TXA (group A, N = 39). Lower volume may diffuse less into the knee joint, and effectiveness assessment is required. To further confirm the effectiveness of the strategy, we compared this cohort with the historical cohort in our centre without TXA (group C, N = 393). End-point variables were compared and a multiple regression model was adjusted to obtain the odds ratio for confounding preoperative variables. Transfusion rates significantly differed between groups B (7%) and C (30%), but not between group A and group B, proving effectiveness of the low-volume formulation of intra-articular administration of TXA, despite in group B 18% of patients has less than 13 g/dl haemoglobin (Hb) vs. 0% in group A. The effectiveness of intra-articular TXA after TKR has been confirmed for a low-volume formulation (2.5 g-25 ml TXA plus 20 ml saline) even if Hb is less than 13 g/dl. Preoperative HB optimization (>13 g/dl) is also important. LEVEL OF EVIDENCE: Level IV.

Topical intra-articular compared with intravenous tranexamic acid to reduce blood loss in primary total knee replacement: a double-blind, randomized, controlled, noninferiority clinical trial.

BACKGROUND: Abundant literature regarding the use of intravenous tranexamic acid (TXA) in primary total knee replacement is available. Randomized controlled trials have confirmed the efficacy of topical TXA compared with placebo, but the comparison between topical and intravenous TXA is unclear. The present study was designed to verify noninferior efficacy and safety of topical intra-articular TXA compared with intravenous TXA in primary total knee replacement with cemented implants. METHODS: A Phase-III, single-center, double-blind, randomized, controlled clinical trial was performed to compare topical intra-articular TXA (3 g of TXA in 100 mL of physiological saline solution) with two intravenous doses of TXA (15 mg/kg in 100 mL of physiological saline solution, one dose before tourniquet release and another three hours after surgery) in a multimodal protocol for blood loss prevention. The primary outcome was the blood transfusion rate, and the secondary outcomes included visible blood loss (as measured in the drain) at twenty-four hours postoperatively and invisible blood loss (as estimated from the Nadler formula) at forty-eight hours postoperatively. The sample size of seventy-eight patients was calculated to give a statistical power of 99% for demonstrating noninferiority. Thirty-nine patients each were allocated to receive topical intra-articular TXA (the experimental group) and intravenous TXA (the control group); there were no significant differences in demographics or preoperative laboratory values between the groups. Noninferiority was estimated by comparing the confidence intervals with a delta of 10%. Student t and Mann-Whitney tests were used to assess the significance of any differences. RESULTS: The transfusion rate was zero in both groups; thus, noninferiority was demonstrated for the primary efficacy end point, suggesting equivalence. Noninferiority was also demonstrated for the secondary efficacy end points. Drain blood loss at twenty-four hours was 315.6 mL (95% confidence interval [CI], 248.5 to 382.7 mL) in the experimental group and 308.1 mL (95% CI, 247.6 to 368.5 mL) in the control group (p = 0.948, Mann-Whitney). Also, estimated blood loss at forty-eight hours was 1259.0 mL (95% CI, 1115.6 to 1402.3 mL) in the experimental group and 1317.9 mL (95% CI, 1175.4 to 1460.4 mL) in the control group (p = 0.837, Mann-Whitney). No significant safety differences were seen between groups. CONCLUSIONS: Topical administration of TXA according to the described protocol demonstrated noninferiority compared with intravenous TXA, with no safety concerns. This randomized controlled trial supports the topical intra-articular administration of TXA in primary total knee replacement with cemented implants. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Regional variability in the rates of total hip replacement in Spain.

The role of economic resources, distribution of providers, and demography may explain part of the variability found in hip arthroplasty in international surveys. We aimed to investigate the influence of ageing index, health budget, and density of orthopaedic surgeons in the regional variability of the primary and revision THR rate in Spain, where regions decide on the allocation of their health budget.Inpatient database of hip procedures for years 1997 to 2011 was obtained from the Spanish Ministry of Health, segregated for each of the 17 regional health services in Spain. Crude and adjusted rates (direct method with total Spanish population per year) were calculated and used as dependent variables. Ageing index, Health Expenditure of Gross Domestic Product (GDP), and number of orthopaedic surgeons per region were used as independent variables. Negative binomial regression analysis model and Poisson regression were calculated to estimate the risk contribution of the ecological variables.A total of 425,914 hip procedures, with 367,489 primary (mean crude rate = 124 × 105 inhabitants/year) and 58,425 revision hips (21 × 105 inhabitants/year) were included in the analysis. Regional variability was higher than expected in THR in Spain, despite a universal coverage health system in which equity may be challenged in the administration of hip arthroplasty. This was found particularly for primary THR. When hip replacement rates were adjusted for sex and age, the regional ageing index, the density of orthopaedic surgeons and the regional health budget could only partially explain risk ratio changes.

Blood transfusion after primary total knee arthroplasty can be significantly minimised through a multimodal blood-loss prevention approach.

PURPOSE: Our aim was to clarify the effective decrease in blood transfusion after primary total knee arthroplasty (TKA) from a multimodal blood-loss prevention approach (MBLPA) and the related risk factors of blood transfusion. METHODS: We retrospectively compared the rate of postoperative blood transfusion in 418 cases of primary TKA during 2010 from a single institution with two different groups of patients, allocating cases to the group with MBLPA (group 1, study group, N = 71) and controls to the group without MBLPA (group 2, standard group, N = 347). MBLPA procedure included pre-operative haemoglobin (Hb) optimisation; femoral canal obturation; limited incision and release; peri- and intra-articular use of saline with adrenalin, morpheic chloride, tobramycin, betamethasone and ropivacaine; tourniquet release after skin closure; 24 hour drain under atmospheric pressure; and two doses of tranexamic acid (TXA) i.v.. In the control group, surgeons followed the standard procedure without blood-saving techniques. Case-control comparison and blood transfusion risk factors were analysed. RESULTS: Group 1 had a zero transfusion rate (0/71), whereas 27.4% of patients (95/347) in group 2 received allogenic blood transfusion. Significant transfusion risk factors were pre-operative Hb <12 g/dl), American Society of Anesthesiologists (ASA) status III and nonobese body mass index (BMI); Age and gender were not significant risk factors. CONCLUSIONS: MBLPA in primary TKA was highly effective, with a zero transfusion rate. Risk factors for transfusion were determined, and eliminating them contributed to the avoidance of allogeneic blood transfusion in our study series.