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    Additional benefits of multiple-dose tranexamic acid to anti-fibrinolysis and anti-inflammation in total knee arthroplasty: a randomized controlled trial. Lei Yiting,Xie Jinwei,Huang Qiang,Huang Wei,Pei Fuxing Archives of orthopaedic and trauma surgery BACKGROUND:Consensus is lacking regarding the dose and timing of tranexamic acid (TXA). The aim of this study was to determine whether multiple-dose intravenous TXA further reduced blood loss and attenuated inflammation after total knee arthroplasty (TKA). MATERIALS AND METHODS:We prospectively studied four regimens on TXA: no TXA (A), before incision, 3, 6, and 12 h later (B), before incision, 3, 6, 12, and 18 h later (C) and before incision, 3, 6, 12, 18, and 24 h later (D). The primary outcome was hidden blood loss (HBL). Other outcome measurements such as total blood loss (TBL), intraoperative blood loss (IBL), fibrinolysis parameters [fibrin(-ogen) degradation products, D-dimer], inflammatory factors (C-reactive protein, interleukin-6), visual analog scale (VAS) score, transfusion rate, length of stay (LOS) and complications were also compared. RESULTS:The mean HBL and TBL were significantly lower in Group D than in Groups C, B and A. The level of inflammatory factors and fibrinolysis parameters were significantly lower in Group D than in Groups C, B and A at 24 and 72 h postoperatively. The VAS score on postoperative days 1 and 3 (POD1 and POD3) was significantly lower in Group D than in Groups C, B and A. There was no significant difference in LOS among groups. No patient underwent blood transfusion. No episodes of deep venous thrombosis or pulmonary embolism occurred in all the groups. CONCLUSION:The repeated doses of TXA up to 24 h can further diminish HBL, provide additional fibrinolysis and inflammation control and ameliorate postoperative pain following TKA. LEVEL OF EVIDENCE:I. 10.1007/s00402-020-03442-2
    Intra-Articular Tranexamic Acid Mitigates Blood Loss and Morphine Use After Total Knee Arthroplasty. A Randomized Controlled Trial. Laoruengthana Artit,Rattanaprichavej Piti,Rasamimongkol Supachok,Galassi Monton,Weerakul Santi,Pongpirul Krit The Journal of arthroplasty BACKGROUND:Tranexamic acid (TXA) has been widely used in total knee arthroplasty (TKA) for blood loss reduction. Given limited evidence on potential relationship between the TXA and improvement of pain control and functional outcome after TKA, this study aimed at comparing the blood loss, pain scores, morphine consumption, and knee flexion across the TXA administration routes. METHODS:The 228 primary TKA were randomized into no TXA use (No-TXA), intra-articular TXA (15 mg/kg) use (IA-TXA), and intravenous TXA (10 mg/kg) use (IV-TXA). A multivariate regression analysis was used for comparing perioperative blood loss (PBL), drain output, average number of units of blood transfused (ANUBT), visual analogue scales (VAS) for pain, amount of morphine consumption, and knee flexion angle. RESULTS:The IA-TXA and IV-TXA group had 193.26 (P < .01) and 160.30 mL (P < .01) less PBL than No-TXA, respectively. No-TXA significantly required higher ANUBT than IA-TXA and IV-TXA (P = .03). The IA-TXA group had lower VAS at 6 (P = .04), 12 (P = .03), and 24 hours (P = .02) postoperative when compared to No-TXA, while IV-TXA had no effect. The IA-TXA required 18.26 mg less total morphine at 48 hours than No-TXA (P = .02), whereas IV-TXA used insignificantly (5.31 mg; P = .31) less total morphine at 48 hours than No-TXA. Both TXA routes tended to improve knee flexion, but not statistically significant. CONCLUSION:Both IA-TXA and IV-TXA could significantly reduce PBL and ANUBT. The IA-TXA could significantly mitigate VAS and morphine use after TKA. Hence, IA-TXA could minimize blood loss and may be considered as an adjunct to pain control following TKA. 10.1016/j.arth.2019.01.030
    The efficacy and safety of combined administration of intravenous and topical tranexamic acid in primary total knee arthroplasty: a meta-analysis of randomized controlled trials. Xiong Huazhang,Liu Yi,Zeng Yi,Wu Yuangang,Shen Bin BMC musculoskeletal disorders BACKGROUND:The combined administration of intravenous (IV) and topical tranexamic acid (TXA) in primary total knee (TKA) knee remains controversial. The purpose of this meta-analysis was to assess the efficacy and safety of combined administration of IV and topical TXA in primary TKA. METHODS:PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Google Search Engine and China National Knowledge Infrastructure databases were searched for randomized controlled trials (RCTs) were comparing the combined administration of IV and topical TXA following primary TKA. The primary outcomes were total blood loss, maximum hemoglobin drop, and deep venous thrombosis (DVT) and/or pulmonary embolism (PE). The second outcomes were drainage volume and transfusion requirements. Data were analyzed using RevMan 5.3. RESULTS:A total of 6 RCTs involving 701 patients were included in the meta-analysis. The combined group provided lower total blood loss (MD - 156.34 mL, 95% CI, - 241.51 to - 71.18; P = 0.0003), drainage volume (MD - 43.54 mL, 95% CI, - 67.59 to - 19.48; P = 0.0004), maximum hemoglobin drop (MD - 0.56 g/dl, 95% CI, - 0.93 to - 0.19; P = 0.003) than IV TXA alone. No significant difference were found in terms of transfusion requirements (RR 0.48, 95% CI, 0.16 to 1.44; P = 0.19), DVT (RR 1.01, 95% CI, 0.14 to 7.12; P = 0.99) and PE (RR 0.33, 95% CI, 0.01 to 7.91; P = 0.49) between the two group. Subgroup analyses shows that the combined group was less total blood loss in non-tourniquet (P = 0.0008), topical TXA dose > 1.5 g (P <  0.00001) and number of IV TXA ≥ 2 doses (P = 0.005) of TXA compared with the IV group alone. CONCLUSIONS:The available evidence indicates combined group were associated with lower total blood loss, drainage volume, and maximum hemoglobin drop. A similar transfusion requirement was found in both groups. Subgroup analyses demonstrates that total blood loss was less in patients with non-tourniquet, topical TXA dose > 1.5 g and number of IV TXA ≥ 2 doses of TXA. There was no increase the rates of DVT and PE. 10.1186/s12891-018-2181-9
    Intra-articular tranexamic acid as an adjunct to intravenous tranexamic acid for simultaneous bilateral total knee arthroplasty: a randomized double-blind, placebo-controlled trial. Tsukada Sachiyuki,Kurosaka Kenji,Nishino Masahiro,Maeda Tetsuyuki,Yonekawa Yoshiharu,Hirasawa Naoyuki BMC musculoskeletal disorders BACKGROUND:Intra-articular tranexamic acid (TXA) as an adjunct to intravenous TXA was reported to decrease perioperative blood loss during unilateral total knee arthroplasty (TKA). However, there have been no randomized controlled trials comparing intravenous versus combined intravenous and intra-articular TXA administration in patients undergoing simultaneous bilateral TKA. METHODS:We randomly assigned 77 patients with 154 involved knees undergoing simultaneous bilateral TKA to the intravenous TXA group (intra-articular placebo for each knee) or combined TXA group (1000 mg of intra-articular TXA for each knee) with 1:1 treatment allocation. In both groups, 1000 mg of TXA was given intravenously twice, just before surgery and 6 h after the initial administration. Other perioperative medications, surgical procedures, and blood management strategies were the same for all patients. The primary outcome was perioperative blood loss calculated from blood volume and change in hemoglobin from preoperative to postoperative day 3. RESULTS:Intention-to-treat analysis showed no statistically significant differences in perioperative blood loss until postoperative day 3 (1067 ± 403 mL in the intravenous TXA group vs. 997 ± 345 mL in the combined TXA group [95% CI, - 240 to 100 mL], P = 0.42). No patients required allogenic blood transfusion. The incidence of thrombotic events did not differ between groups (12% in the intravenous TXA group vs. 9% in the combined TXA group; P = 0.73). CONCLUSIONS:The addition of intra-articular TXA did not reduce perioperative blood loss in patients undergoing simultaneous bilateral TKA compared with placebo. TRIAL REGISTRATION:University Hospital Medical Information Network UMIN000026137 . Registered 14 February 2017. 10.1186/s12891-019-2890-8
    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. Gomez-Barrena Enrique,Ortega-Andreu Miguel,Padilla-Eguiluz Norma G,Pérez-Chrzanowska Hanna,Figueredo-Zalve Reyes The Journal of bone and joint surgery. American volume 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. 10.2106/JBJS.N.00060
    Intraoperative Intravenous and Intra-Articular Plus Postoperative Intravenous Tranexamic Acid in Total Knee Arthroplasty: A Placebo-Controlled Randomized Controlled Trial. Tsukada Sachiyuki,Kurosaka Kenji,Nishino Masahiro,Maeda Tetsuyuki,Hirasawa Naoyuki,Matsue Yuya The Journal of bone and joint surgery. American volume BACKGROUND:Combined intraoperative intravenous and intra-articular tranexamic acid (TXA) is 1 of the most effective administration routes to decrease the amount of perioperative blood loss during total knee arthroplasty (TKA). However, the additive effect of postoperative intravenous TXA administration remains unclear. We hypothesized that the postoperative repeated-dose intravenous administration of TXA would provide lower perioperative blood loss. METHODS:We performed a double-blinded, placebo-controlled trial involving patients undergoing primary TKA. A total of 100 patients who were managed with combined intraoperative intravenous and intra-articular TXA were randomly assigned to receive 3 postoperative 1,000-mg doses of intravenous TXA (TXA group) or 3 postoperative doses of intravenous normal saline solution (placebo group) in a 1:1 ratio. The prespecified primary outcome was perioperative blood loss calculated from patient blood volume and the difference in hemoglobin from preoperatively to postoperative day 3. A post hoc power analysis showed that the number of patients allocated to either the TXA group (n = 46) or the placebo group (n = 54) possessed >80% power to detect a 200-mL difference in perioperative blood loss. RESULTS:In the intention-to-treat analysis, we found no significant differences in perioperative blood loss between the TXA group and the placebo group through postoperative day 3 (578 ± 229 compared with 640 ± 276 mL, respectively; 95% confidence interval for the difference, -40 to 163 mL; p = 0.23). The prevalence of postoperative thrombotic events did not differ between the 2 groups (4.3% compared with 3.7%, respectively; p > 0.99). CONCLUSIONS:Postoperative intravenous TXA had no additive effect in reducing perioperative blood loss in patients receiving intraoperative combined intravenous and intra-articular TXA. LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. 10.2106/JBJS.19.01083
    Combined Intra-Articular and Intravenous Tranexamic Acid Reduces Blood Loss in Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial. Nielsen Christian Skovgaard,Jans Øivind,Ørsnes Thue,Foss Nicolai Bang,Troelsen Anders,Husted Henrik The Journal of bone and joint surgery. American volume BACKGROUND:In total knee arthroplasty, both intravenous (IV) and intra-articular (IA) administration of tranexamic acid (TXA) have been shown to reduce blood loss in several randomized controlled trials, although routine use of systemic TXA is considerably more common. However, to our knowledge, the additional benefit of IA administration of TXA when combined with IV administration, without the use of a tourniquet, has not been previously investigated. Thus, the aim of this study was to evaluate whether combined IV and IA administration of TXA reduced total blood loss compared with IV-only administration of TXA. METHODS:In this randomized, double-blind, placebo-controlled trial, 60 patients scheduled for total knee arthroplasty were randomized to one of two interventions. The TXA IV and IA group received combined administration of TXA consisting of 1 g administered intravenously preoperatively and 3 g diluted in 100 mL of saline solution administered intra-articularly after closure of the capsule. The TXA IV and placebo group received 1 g of TXA administered intravenously only and 100 mL of saline solution administered intra-articularly. IA TXA was administrated through a needle. The primary outcome was the 24-hour calculated blood loss. Secondary outcomes were blood loss on postoperative day 2, thromboembolic complications, and transfusion rate. Blood loss was calculated by hemoglobin differences using the Gross formula. RESULTS:Data on the primary outcome were available for all 60 included patients. Baseline characteristics were comparable between the allocation groups. The mean 24-hour blood loss (and standard deviation) was 466 ± 313 mL in the TXA IV and IA group compared with 743 ± 358 mL in the TXA IV and placebo group; treatment effect (difference), 277 mL (95% confidence interval [CI], 103 to 451 mL) (p = 0.002). Second-day blood loss was 644 ± 382 mL in the TXA IV and IA group compared with 1017 ± 519 mL in the TXA IV and placebo group; treatment effect, 373 mL (95% CI, 132 to 614 mL) (p = 0.003). No thromboembolic complications were observed within 90 days postoperatively. CONCLUSIONS:The combined administration of IV and IA TXA resulted in a clinically relevant reduction in blood loss of 37% compared with IV TXA alone both at 24 hours postoperatively and on postoperative day 2. No thromboembolic complications were observed. LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. 10.2106/JBJS.15.00810
    Intravenous Versus Topical Tranexamic Acid in Total Knee Arthroplasty: Both Effective in a Randomized Clinical Trial of 640 Patients. Abdel Matthew P,Chalmers Brian P,Taunton Michael J,Pagnano Mark W,Trousdale Robert T,Sierra Rafael J,Lee Yuo-Yu,Boettner Friedrich,Su Edwin P,Haas Steven B,Figgie Mark P,Mayman David J The Journal of bone and joint surgery. American volume BACKGROUND:Tranexamic acid (TXA) reduces bleeding and the need for transfusion after total knee arthroplasty. Most literature has focused on intravenous (IV) administration of TXA, with less data available on the efficacy of topically administered TXA. This multicenter randomized clinical trial specifically assessed the efficacy of topical TXA compared with IV TXA as measured by calculated blood loss, drain output, and transfusion rates. Complications, including venous thromboembolism (VTE), were reported. METHODS:A total of 640 patients who underwent primary unilateral total knee arthroplasty for osteoarthritis at 2 large academic centers were randomized to receive 1 g of IV TXA prior to tourniquet inflation and 1 g at closure, or 3 g of TXA diluted in 45 mL of normal saline solution (total volume of 75 mL) and topically applied after cementation. Age, sex, body mass index, American Society of Anesthesiologists (ASA) score, and preoperative hemoglobin level were similar between the groups. Univariate, multiple linear regression, and multiple logistic regression analyses were performed. RESULTS:Patients who received topical TXA had significantly greater calculated blood loss compared with those who received IV TXA (mean of 324 compared with 271 mL; p = 0.005). Drain output was significantly higher in the topical TXA group compared with the IV TXA group (mean of 560 compared with 456 mL; p < 0.0001). The rate of transfusion was low in the topical and IV groups, with no significant difference on univariate analysis (1.6% compared with 0.6%, respectively; p = 0.45); however, on multiple logistic regression analysis, patients who received topical TXA were 2.2-fold more likely to receive a transfusion (p < 0.0001). The topical and IV TXA groups did not differ significantly with respect to the rate of thrombotic events (0.6% compared with 1.6%, respectively; p = 0.45). CONCLUSIONS:In this large, randomized clinical trial involving patients undergoing total knee arthroplasty, both IV and topical TXA were associated with a low rate of transfusion. While IV TXA was associated with less calculated blood loss, lower drain output, and fewer transfusions, the small differences between the groups may not be clinically important. Given the low prevalence of thrombotic complications, the relative safety of one formulation of TXA over the other cannot be definitely established. LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. 10.2106/JBJS.17.00908
    Comparison of Topical and Intravenous Tranexamic Acid for Total Knee Replacement: A Randomized Double-Blinded Controlled Study of Effects on Tranexamic Acid Levels and Thrombogenic and Inflammatory Marker Levels. Jules-Elysee Kethy M,Tseng Audrey,Sculco Thomas P,Baaklini Lila R,McLawhorn Alexander S,Pickard Amanda J,Qin WeiGe,Cross Justin R,Su Edwin P,Fields Kara G,Mayman David J The Journal of bone and joint surgery. American volume BACKGROUND:Tranexamic acid (TXA) is an antifibrinolytic drug. Topical administration of TXA during total knee arthroplasty (TKA) is favored for certain patients because of concerns about thrombotic complications, despite a lack of supporting literature. We compared local and systemic levels of thrombogenic markers, interleukin (IL)-6, and TXA between patients who received intravenous (IV) TXA and those who received topical TXA. METHODS:Seventy-six patients scheduled for TKA were enrolled in this randomized double-blinded study. The IV group received 1.0 g of IV TXA before tourniquet inflation and again 3 hours later; a topical placebo was administered 5 minutes before final tourniquet release. The topical group received an IV placebo before tourniquet inflation and again 3 hours later; 3.0 g of TXA was administered topically 5 minutes before final tourniquet release. Peripheral and wound blood samples were collected to measure levels of plasmin-anti-plasmin (PAP, a measure of fibrinolysis), prothrombin fragment 1.2 (PF1.2, a marker of thrombin generation), IL-6, and TXA. RESULTS:At 1 hour after tourniquet release, systemic PAP levels were comparable between the IV group (after a single dose of IV TXA) and the topical group. At 4 hours after tourniquet release, the IV group had lower systemic PAP levels than the topical group (mean and standard deviation, 1,117.8 ± 478.9 µg/L versus 1,280.7 ± 646.5 µg/L; p = 0.049), indicative of higher antifibrinolytic activity after the second dose. There was no difference in PF1.2 levels between groups, indicating that there was no increase in thrombin generation. The IV group had higher TXA levels at all time points (p < 0.001). Four hours after tourniquet release, wound blood IL-6 and TXA levels were higher than systemic levels in both groups (p < 0.001). Therapeutic systemic TXA levels (mean, 7.2 ± 7.4 mg/L) were noted in the topical group. Calculated blood loss and the length of the hospital stay were lower in the IV group (p = 0.026 and p = 0.025). CONCLUSIONS:Given that therapeutic levels were reached with topical TXA and the lack of a major difference in the mechanism of action, coagulation, and fibrinolytic profile between topical TXA and a single dose of IV TXA, it may be a simpler protocol for institutions to adopt the use of a single dose of IV TXA when safety is a concern. LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. 10.2106/JBJS.19.00258