The Journal of Arthroplasty xxx (2014) xxx–xxx
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The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org
Original Article
Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial Chen Yue, MD, Pengde Kang, MD, Peiqing Yang, MD, Jinwei Xie, MD, Fuxing Pei, MD Department of Orthopedic Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
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Article history: Received 10 February 2014 Accepted 24 March 2014 Available online xxxx Keywords: topical tranexamic acid transfusions blood loss DVT THA
a b s t r a c t So far, studies of topical tranexamic acid (TXA) in total hip arthroplasty (THA) were still lacking and controversial. We conducted this randomized double-blind controlled trial which included 101 patients to assess the effect of a high-dose 3 g topical TXA in THA. The results showed that 3 g topical TXA could significantly reduce transfusions from 22.4% to 5.7% (P b 0.05) without increasing the risk of deep vein thrombosis (DVT), pulmonary embolism (PE) and other complications. In addition, topical TXA significantly reduced total blood loss, reduced drain blood loss, and the drops of HB and HCT in topical TXA group were lower than control group. We concluded that 3 g topical TXA was effective and safe in reducing bleeding and transfusions in THA. © 2014 Elsevier Inc. All rights reserved.
Total hip arthroplasty (THA) is one of the most common orthopedic operations which used for end-stage osteoarthritis and other hip diseases such as osteonecrosis of the femoral head (ONFH). However, THA was associated with a significant amount of blood loss in some cases and required allogenic blood transfusions subsequently. As reported before, the transfusion rate of THA was 16%–37% [1], which might carry the risks of immunological reactions, volume overload, infection, intravascular hemolysis, renal failure and even death [2,3]. Therefore, how to reduce bleeding and transfusions of THA has become an important and urgent problem to be resolved for orthopedist. So far, a large number of methods for controlling bleeding transfusions were successfully used following THA, which included autologous blood transfusion, intraoperative blood saving, hypotensive anesthesia and so on [3–5]. As a kind of antifibrinolytic agent, tranexamic acid (TXA) is a synthetic amino acid, which is able to prevent plasminogen activation and delay fibrinolysis [6,7] by blocking the lysine-binding sites of plasminogen. It has been used successfully to reduce bleeding in dental extraction, tonsillectomy, prostate surgery, heavy menstrual bleeding, cardiac surgery and in patients with hemophilia [8–10]. For THA, although there were still controversial, numerous studies have confirmed that intravenous tranexamic acid (IV-TXA) could effectively reduce blood loss and transfusions in THA without increasing the risk of DVT [11–16]. However, comparing with IVTXA, a topical application has the advantages of easy to administer, The Conflict of Interest statement associated with this article can be found at http://dx.doi.org/10.1016/j.arth.2014.03.032. Reprint request: Fuxing Pei, MD, Department of Orthopedics, West China hospital, Sichuan University, 37# Guoxue Road, 610041, People’s Republic of China.
providing a maximum concentration of TXA at the bleeding site, and was associated with little or no systemic absorption of the TXA [17], and so far, there were only several studies [17–20] that been reported to evaluate the effect of topical application in THA and the highquality randomized controlled trials were especially lacking, the effect of topical TXA in THA was unclear and controversial. Therefore, we conducted this randomized double-blind controlled trial in order to clarify the efficacy and safety of topical TXA in total hip arthroplasty.
Materials and Methods This was a randomized, double-blind, placebo-controlled trail which was registered and approved by the Institutional Review Board of Sichuan University, West China Medical Center (No. 201302007). Patients undergoing primary unilateral total hip arthroplasty for OA or ONFH were considered appropriate for the study. The exclusion criteria included patients who were receiving anticoagulant therapy, patients with a history of hemophilia, deep venous thrombosis, pulmonary embolism or ischemic heart disease and patients who were allergic to tranexamic acid. From September 2013 to October 2013, a total of 174 patients were scheduled to have a primary unilateral total hip arthroplasty in West China hospital, Sichuan University. 137 were eligibility for our study after prescreening by inclusion and exclusion criteria, but 34 patients rejected to participate. Then all the remaining 103 patients gave consent for the study and were randomized into two study groups (52 patients in topical TXA group and 51 patients in control group) by the method of opaque, sealed envelopes. The patients, surgeons and nurses were blinded and another non-related-research staff handed out the medications. Flow
http://dx.doi.org/10.1016/j.arth.2014.03.032 0883-5403/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
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C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
diagram of patients involved was listed in Fig. 1. (The detailed description of withdrawals and drop-outs were listed in “Result”.) All the operations were completed by one experienced orthopedic surgeon and the whole operations were performed through the posterolateral approach, the prosthesis was a cementless acetabular cup and a cementless femoral stem. The method of anesthesia was decided by anesthetists. We referred to and improved the methods described by Konig et al [20]: In topical TXA group, 3 g TXA in 150 mL saline was used at three points during the whole procedure of THA. First, after the acetabular preparation, we used an gauze (25 cm × 25 cm, monolayer) which was full of 50 mL of the TXA solution to soak the acetabulum for three minutes, an cementless acetabular component was then impacted. Then, after femoral canal broach preparation, another gauze (25 cm × 25 cm, monolayer) with 50 mL of the same concentration TXA was inserted in the femoral canal for three minutes, and then the cementless femoral stem was impacted. At last, the remaining 50 mL TXA fluid was injected to the hip joint after fascia closure. A drain was used and clamped for 30 minutes. In the control group, the same method was used with the same dose of saline and clamped for 30 minutes too. The drainage was removed in the next morning after the operation. All patients are given chemical thromboprophylaxis by low-molecular-weight heparin (LMWH) combined with mechanical thromboprophylaxis by a leg pump. The primary outcomes were the transfusion rate, the DVT and PE events. Blood Transfusion Protocol indicated when the hemoglobin was less than 70 g/L or when the hemoglobin of a patient was more than 70 g/L but with a bad mental status, palpitation or pallor. Every patient was given ultrasound examination routinely for screening DVT before they were discharged by senior ultrasound doctors and symptomatic DVT and PE were observed by follow-up for three months after the operation. The secondary outcomes were total blood loss, drain blood loss, hemoglobin and hematocrit drop, postoperative hospitalization days and other complications.
The total blood loss was calculated according to the Gross formula [21,22]: Total blood loss ¼ PBV Hctpre −Hctpost =Hctave Hctpre ¼ the initial preoperative Hct level Hctpost ¼ the Hct on the morning of the third postoperative day Hctave ¼ the average of the Hctpre and Hctpost
PBV = the patient's blood volume (PBV, mL). It was assessed according to the formula of Nadler et al [23]: PBV = k1 × height (m) + k2 × weight (kg) + k3; k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for men; and k1 = 0.3561, k2 = 0.03308, and k3 = 0.1833 for women. If either reinfusion or allogenic transfusion was performed, the total blood loss is equal to the loss calculated from the change in Hct plus the volume transfused [22]. We removed the drainage in the next morning after the operation, and then the postoperative blood loss in the vacuum collectors was recorded by nurses. Hemoglobin and hematocrit levels were tested before the operation and on postoperative day one and day three routinely. The postoperative hospitalization days and other complications were recorded carefully too. Statistical Analysis All the data were analyzed by using SPSS version 19.0(SPSS Inc. USA), Student-t test was used to analyze the normal distributed numerical variable, such as total blood loss. If the numerical variable was non-normal distribution or unequal variance, Wilcoxon MannWhitney U test would be used; Pearson chi-square test or Fisher exact test was used to analyze the qualitative variable. A P-value ≤0.05 was considered to be statistically significant. Results
Patients scheduled for THA (N=174) Excluded by inclusion and exclusion criteria (N=37) Eligible patients (N=137)
From September 2013, all the 103 patients included were observed and followed-up, two patients in control group were out of touch and were excluded for withdrawals and drop-outs. Thus, the data of 101 patients were analyzed at last. The baseline characteristics included: age, gender, height, weight, BMI, hip disease composition, basic diseases, anesthesia method, the level of preoperative hemoglobin and hematocrit. The baseline characteristics between the two groups were listed in Table 1. There were no statistically significant difference between the two groups except the height and BMI (P b 0.05).
Rejected to participate (N=34) Table 1 Baseline Characteristics of the Two Groups.
Included and randomized (N=103)
Topical TXA group (N=52)
Control group (N=51)
Excluded for withdrawals (N=2)
Analyzed (N=52)
Analyzed (N=49)
Fig. 1. Flow diagram of patients involved.
Year Gender(male/female) Height (m)⁎ Weight (kg) BMI⁎ Hip disease composition (OA/ONFH) Hypertension Diabetes mellitus COPD Anesthesia method (general/spinal) Preoperative HB(g/L) Preoperative HCT (L/L)
Topical TXA Group
Control Group
P
60.9 ± 13.2 21/31 1.63 ± 0.072 64.53 ± 9.33 24.4 ± 3.1 37/15 12/52 5 5 43/9 134.27 ± 9.26 0.400 ± 0.033
63.7 ± 10.0 18/31 1.66 ± 0.072 63.49 ± 9.10 23.1 ± 2.7 39/10 8/49 9 5 44/5 135.47 ± 11.16 0.410 ± 0.038
0.239 0.707 0.030 0.573 0.025 0.326 0.395 0.203 0.921 0.302 0.557 0.378
BMI: Body mass index = Weight/Height2; OA: Osteoarthritis; ONFH: Necrosis of femoral head; COPD: Chronic obstructive pulmonary disease; HB: Hemoglobin; HCT: Hematocrit The value was presented as mean ± SD. Year, height, weight, BMI, preoperative HB and preoperative HCT were analyzed by Student-t test. Gender, hip disease composition, hypertension, diabetes mellitus, COPD and anesthesia method were analyzed by Pearson chi-square test. ⁎ Significant difference.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
Drain blood loss of two groups
Table 2 The Primary Outcomes of Two Groups.
0.021 1 1
DVT: Deep vein thrombosis; PE: Pulmonary embolism. Transfusions, DVT, PE were analyzed by Fisher’s exact test. ⁎ Significant difference.
The Primary Outcomes The primary outcomes including transfusion rate, DVT and PE events. A total of 5.5 units red cells were given to three patients in topical TXA group versus 11 patients who received 24.5 units red cells in control group. The transfusion rate was significantly lower in topical TXA group than control group. One asymptomatic DVT was found by routine ultrasound examination in topical TXA group at the third day after the operation and was cured finally, the difference between study groups were not significant. No symptomatic PE event was found in both groups. The primary outcomes were showed in Table 2. The Secondary Outcomes The mean total blood loss was (945.5 ± 331.7) mL in tranexamic acid group versus (1255.5 ± 193.5) mL in control group, there was statistical significant difference between the two groups (P b 0.001). The postoperative drain blood loss was significantly less in the patients who received topical TXA [(217.5 ± 89.9) mL in TXA group versus (296.9 ± 109.0) mL in control group, P b 0.001]. The hemoglobin and hematocrit drop in postoperative day one and day three were significantly lower in topical TXA group than in control group. The difference of postoperative hospitalization days and other complications between the two groups was not significant. The secondary outcomes were listed in Figs. 2–3 and Table 3. Discussion This was a high-quality randomized double-blind controlled trial, the results revealed that a high-dose of 3 g topical application of TXA could effectively reduce transfusions from 22.4% to 5.7% without
Total blood loss of two groups
Total blood loss(ml)
1500
300
200
100
0 gr ou p
22.4% (11/49) 0 0
on tr ol
5.7% (3/52) 1 0
400
C
P
gr ou p
Control Group
TX A
TXA Group
Drain blood loss(ml)
Transfusions⁎ DVT PE
3
Fig. 3. Drain blood loss. The histogram showed that drain blood loss in topical TXA group was significantly less than control group (Student-t test).
increasing the risk of DVT, PE and other complications in THA, in addition, topical TXA was able to significantly reduce total blood loss by about 300 mL, reduce drain blood loss by about 80 mL and significantly reduce HB drop and HCT drop in postoperative day one and day three, topical TXA was effective and safe for THA. So far, studies on topical TXA in THA were still deficient, therefore the methods and effect of topical TXA application were unclear and controversial. The main characteristics of current RCTs were reviewed and listed in Table 4. We could see that 2 g of TXA application reported by Joseph G. Martin et al [19] could improve but nonsignificant reduce the units of blood transfused compared to placebo, however a total of 3 g topical TXA [20] could significantly reduce transfusions. In addition, a meta-analysis of topical TXA in total knee arthroplasty (TKA) [24] concluded that a high dose of topical TXA (N2 g) significantly reduced transfusion requirements, which might provide a reference of topical application in THA, and these were the reasons that we used a total of 3 g topical TXA. We topically used TXA at three different points, which was found effective in a prior study [20] and at the same time, we also improved the method: we used gauzes which were full of high-concentration TXA solution to soak the acetabulum and femoral canal rather than the mentioned method of bathing. The reason we referred to and improved this method was that for THA, a large number of blood loss came from the steps of acetabulum preparation and femoral canal broach preparation, and thus this method we improved could make topical TXA be more
Table 3 The Postoperative Hospitalization Days and Other Complications of the Two Groups.
1000
500
tr on C
TX
A
ol g
gr
ro
ou
p
up
0
Fig. 2. Total blood loss. The histogram showed that total blood loss in topical TXA group was significantly less than control group (Wilcoxon Mann-Whitney U test).
HB drop in postoperative day 1 (g/L)⁎ HB drop in postoperative day 3 (g/L)⁎ HCT drop in postoperative day 1 (L/L)⁎ HCT drop in postoperative day 3 (L/L)⁎ Superficial infection Deep infection Hematoma Wound secretion Postoperative hospitalization days
TXA Group
Control Group
P
28.29 ± 8.85 40.02 ± 9.74 0.080 ± 0.032 0.112 ± 0.031 1 0 0 5 5.1 ± 0.5
41.5 ± 6.39 53.27 ± 4.79 0.101 ± 0.026 0.144 ± 0.019 0 0 0 7 4.9 ± 0.7
b0.001 b0.001 b0.001 b0.001 1 1 1 0.468 0.742
HB: Hemoglobin; HCT: Hematocrit. HB and HCT drop in postoperative day 1 and day 3 were analyzed by Wilcoxon MannWhitney U test. Postoperative hospitalization day was analyzed by Student-t test. Wound secretion was analyzed by Pearson chi-square test. Superficial infection, deep infection, hematoma were analyzed by Fisher’s exact test. ⁎ Significant difference.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
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C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
Table 4 The Main Characteristics of Related Topical TXA in THA RCTs.
Author
Time
Number (TA/Control)
Dose of TXA
Intervention
Drainage
Blood Transfusion Protocol
DVT Prophylaxis
Primary Outcomes
Joseph [20]
2013
50(25/25)
2gTXA/ 100 mL NS
No drains
Symptomatic hypotension + HB b7 g/dL
2013
131(91/40)
Sattar [18]
2013
161(80/81)
3 g TXA/ 100 mL NS Not mentioned
clamping for 1 h Not mentioned
Hb b8 g/L + clinical symptoms HB b7 g/dL; HB b8 g/dL + tolerated anemia poorly; 7 g/dl b HB b 10 g/dL + clinical symptoms
Mechanical + warfarin (in hospital) and aspirin (out of the hospital) Not mentioned
Improve but non-significant reduce transfusions
Konig [21]
Intra-articular injection before joint closure Topically used at three points Not mentioned
targeted and make TXA play a role of anticoagulant and stopping bleeding in acetabulum and femoral canal more sufficiently and effectively. Through our study, we could see that the effect of 3 g topical TXA used in three points during the operation was satisfactory, the method we used could effectively reduce bleeding by about 300 mL (24.7%) and significantly reduce transfusions from 22.4% to 5.7%. Therefore, we could conclude that 3 g topical TXA used in three points was effective in THA. Comparing with application of intravenous tranexamic acid (IVTXA) in THA, topical TXA was considered with little or no systemic absorption of the TXA, therefore, topical TXA could avoid the potential complications of intravenous tranexamic acid administration [17]. However, we were not sure if topical TXA could carry the similarly good results in reducing bleeding and transfusions with intravenous tranexamic acid as related studies were too lacking. Only one study reported by Wind et al [18] compared the effect between topical TXA and IV-TXA, and they concluded that IV-TXA was a more predictable route of administration for maximum efficacy than topical TXA, but Wind’s study was retrospective, so the strength of evidence was not satisfactory and the conclusion might have bias. The results of this study showed that the risk difference of transfusions was about 17%, and a high-quality meta-analysis, which included 11 RCTs reported by Sukeik [10] showed the risk difference of transfusions was about 20% when IV-TXA was used in THA. So a topical dose of 3 g topical TXA might have the similar effect with IV-TXA for transfusions. In addition, the reduction of total blood loss was also similar between our RCT and Sukeik’s meta-analysis (about 300 mL of total blood loss reduction in our study versus 289 mL in Sukeik’s study). So these results gave us a reference that a high-dose topical TXA might be as effective as IV-TXA in THA. We thought the safety was very important and should be focused on when we used TXA in THA, therefore the primary outcomes we chose included DVT and PE events. So far TXA has been used in THA for more than 10 years, large clinical studies [10–20] and several metaanalyses [10,28] on TXA in THA had confirmed the safety of TXA, that TXA would not increase the risk of thrombo-embolism and mortality. In our study, the results also showed that there were no significant difference of thrombo-embolism events and other complications between topical TXA group and control group. Therefore, we trusted that topical TXA was safe in THA. However, some potential dangerousness of TXA may exist and just has not been clarified yet, more articles were needed to evaluate the safety of TXA. Several studies [22,25,26] have proved that the hidden blood loss was always huge in surgery and thus the total blood loss was always underestimated by clinical methods of calculating blood-soaked gauzes, suction bottles and the vacuum drain [17,26]. Therefore, we used Gross formula to evaluate the amount of total blood loss which was based on the hematocrit level and we thought the result we got was more accurate than clinical methods. The strengths of this study were obvious. First, this was a randomized controlled trial which was designed and performed carefully and strictly, the level of evidence was the highest Level I. So
Mechanical and mechanical + LMWH when BMI N30 kg/m2
Transfusions decreased dramatically from 15% to 1% Significantly reduced the risk of transfusions by 19.6%
the bias was miniature. Second, the transfusion protocol was explicit which made the primary result of transfusion rate convincing. Third, ultrasound examination was routine for every patient, we trusted our result of detecting DVT by using ultrasound was accurate for two reasons: (1) So far the literatures [29–31] had confirmed the accuracy of ultrasound to detect DVT, for example Barnes et al [29] showed that duplex scanning had an accuracy of 97% when venography was considered as the gold standard. (2) Our hospital was the largest medical center in West China, our ultrasound doctors were experienced and all the patients in our study were detected by senior ultrasound doctors, so the result was credible. In addition, the threemonth follow-up period was thought to be adequate to identify known adverse events [18]. At last, we improved the method of topical TXA application, and it was proved effective in reducing bleeding and transfusions. The main limitation of this study was that a large number of blood clots formed in local area after TXA gauze was used to soak the acetabulum whereas there were no obvious blood clots formed in control group, this might be found by surgeon and nurses. So although the surgeon and nurses were blinded, the strength of blinding might weaken. In addition, our method increased the duration of surgery by about six minutes, which might theoretically make the risk of infection higher [27]. However, in fact, the results of our study showed the rate of infection and other complications were very low. We didn’t think these limitations would affect the results seriously.
Conclusions In conclusion, a dose of 3 g topical TXA could significantly reduce bleeding and transfusions in primary THA without increasing the risk of DVT and PE, it was effective and safe in THA. However, as the related reports on topical TXA in THA are still lacking and some potential dangerousness of TXA may exist, more high-quality randomized controlled trials are needed to establish the efficacy and safety of topical TXA in THA.
References 1. Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am 1999;81(1):2. 2. Kumar A. Perioperative management of anemia: limits of blood transfusion and alternatives to it. Cleve Clin J Med 2009;76(4):112. 3. Cardone D, Klein AA. Perioperative blood conservation. Eur J Anaesthesiol 2009;26:722. 4. Lemaire R. Strategies for blood management in orthopaedic and trauma surgery [J]. J Bone Joint Surg (Br) 2008;90:1128. 5. Claeys MA, Vermeersch N, Haentjens P. Reduction of Blood Loss with Tranexamic Acid in Primary Total Hip Replacement Surgery. Acta Chir Belg 2007;107:397. 6. Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta 1981;673(1):75. 7. Singh J, Ballal MS, Mitchell P, et al. Effects of tranexamic acid on blood loss during total hip arthroplasty. J Orthop Surg 2010;18(3):282. 8. Dahl OE. The role of the pulmonary circulation in the regulation of coagulation and fibrinolysis in relation to major surgery. J Cardiothorac Vasc Anesth 1997;11:322.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx 9. Reid RW, Zimmerman AA, Laussen PC, et al. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 1997;84:990. 10. Sukeik M, Alshryda S, Haddad FS, et al. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. J Bone Joint Surg 2011;21:869. 11. Benoni G, Fredin H, Knebel R, et al. Blood conservation with tranexamic acid in total hip arthroplasty: a randomized, double-blind study in 40 primary operations. Acta Orthop Scand 2001;72:442. 12. Husted H, Blønd L, Sonne-Holm S, et al. Tranexamic acid reduces blood loss and blood transfusions in primary total hip arthroplasty: a prospective randomized double-blind study in 40 patients. Acta Orthop Scand 2003;74:665. 13. Lemay E, Guay J, Côté C, et al. Tranexamic acid reduces the need for allogenic red blood cell transfusions in patients undergoing total hip replacement. Can J Anaesth 2004;51:31. 14. Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double-blind study in 100 patients. Acta Orthop 2005;76:314. 15. Yamasaki S, Masuhara K, Fuji T. Tranexamic acid reduces blood loss after cementless total hip arthroplasty—prospective randomized study in 40 cases. Int Orthop 2004;28:69. 16. Ido K, Neo M, Asada Y, et al. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. Arch Orthop Trauma Surg 2000;120:518. 17. Alshryda S, Mason J, Sarda P, et al. Topical (Intra-Articular) Tranexamic Acid Reduces Blood Loss and Transfusion Rates Following Total Hip Replacement A Randomized Controlled Trial (TRANX-H). J Bone Joint Surg Am 2013;95:1969. 18. Wind TC, Barfield WR, Moskal JT. The Effect of Tranexamic Acid on Transfusion Rate in Primary Total Hip Arthroplasty. J Arthroplasty 2014;29(2):387–9. 19. Martin JG, Cassatt KB, Kincaid-Cinnamon KA, et al. Topical Administration of Tranexamic Acid in Primary Total Hip and Total Knee Arthroplasty. J Arthroplasty 2013. http://dx.doi.org/10.1016/j.arth.2013.10.005.
5
20. Konig G, Hamlin BR, Waters JH. Topical Tranexamic Acid Reduces Blood Loss and Transfusion Rates in Total Hip and Total Knee Arthroplasty. J Arthroplasty 2013;28:1473. 21. Gross JB. Estimating allowable blood loss: corrected for dilution. Anaesthesiology 1983;58:277. 22. Liu X, Zhang X, Chen Y, et al. Hidden Blood Loss After Total Hip Arthroplasty. J Arthroplasty 2011;26(7):1100–5.e.1. 23. Nadler SB, Hidalgo JU, Bloch T. Prediction of blood volume in normal human adults. Surgery 1962;51:224. 24. Panteli M, Papakostidis C, Dahabreh Z, et al. Topical tranexamic acid in total knee replacement: A systematic review and meta-analysis. Knee 2013;20:300. 25. Sehat KR, Evans RL, Newman JH. Hidden blood loss following hip and knee arthroplasty. J Bone Joint Surg (Br) 2004;86-B:561. 26. Eipe NP, Ponniah M. Perioperative blood loss assessment—how accurate? Indian J Anaesth 2006;50(1):35. 27. Urguhart DM, Hanna FS, Brennan SL, et al. Incidence and risk factors for deep surgical site infection after primary total hip arthroplasty: a systemic review. J Arthroplasty 2010;25(8):1216. 28. Zhou XD, Tao LJ, Li J, et al. Do we really need tranexamic acid in total hip arthroplasty? A meta-analysis of nineteen randomized controlled trials. Arch Orthop Trauma Surg 2013;133:1017. 29. Barnes CL, Nelson CL, Nix ML, et al. Duplex scanning versus venography as a screening examination in total hip arthroplasty patients. Clin Orthop Relat Res 1991(271):180. 30. Grady-Benson JC, Oishi CS, Hanson PB, et al. Routine postoperative duplex ultrosonography screening and monitoring for the detection of deep vein thrombosis. Clin Orthop Relat Res 1994;307:130. 31. Tremaine DM, Choroszy CJ, Menking SA. Deep vein thrombosis in the total hip arthroplasty patient after hospital discharge. J Vase Tech 1992;16:23.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
Contents lists available at ScienceDirect
The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org
Original Article
Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial Chen Yue, MD, Pengde Kang, MD, Peiqing Yang, MD, Jinwei Xie, MD, Fuxing Pei, MD Department of Orthopedic Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
a r t i c l e
i n f o
Article history: Received 10 February 2014 Accepted 24 March 2014 Available online xxxx Keywords: topical tranexamic acid transfusions blood loss DVT THA
a b s t r a c t So far, studies of topical tranexamic acid (TXA) in total hip arthroplasty (THA) were still lacking and controversial. We conducted this randomized double-blind controlled trial which included 101 patients to assess the effect of a high-dose 3 g topical TXA in THA. The results showed that 3 g topical TXA could significantly reduce transfusions from 22.4% to 5.7% (P b 0.05) without increasing the risk of deep vein thrombosis (DVT), pulmonary embolism (PE) and other complications. In addition, topical TXA significantly reduced total blood loss, reduced drain blood loss, and the drops of HB and HCT in topical TXA group were lower than control group. We concluded that 3 g topical TXA was effective and safe in reducing bleeding and transfusions in THA. © 2014 Elsevier Inc. All rights reserved.
Total hip arthroplasty (THA) is one of the most common orthopedic operations which used for end-stage osteoarthritis and other hip diseases such as osteonecrosis of the femoral head (ONFH). However, THA was associated with a significant amount of blood loss in some cases and required allogenic blood transfusions subsequently. As reported before, the transfusion rate of THA was 16%–37% [1], which might carry the risks of immunological reactions, volume overload, infection, intravascular hemolysis, renal failure and even death [2,3]. Therefore, how to reduce bleeding and transfusions of THA has become an important and urgent problem to be resolved for orthopedist. So far, a large number of methods for controlling bleeding transfusions were successfully used following THA, which included autologous blood transfusion, intraoperative blood saving, hypotensive anesthesia and so on [3–5]. As a kind of antifibrinolytic agent, tranexamic acid (TXA) is a synthetic amino acid, which is able to prevent plasminogen activation and delay fibrinolysis [6,7] by blocking the lysine-binding sites of plasminogen. It has been used successfully to reduce bleeding in dental extraction, tonsillectomy, prostate surgery, heavy menstrual bleeding, cardiac surgery and in patients with hemophilia [8–10]. For THA, although there were still controversial, numerous studies have confirmed that intravenous tranexamic acid (IV-TXA) could effectively reduce blood loss and transfusions in THA without increasing the risk of DVT [11–16]. However, comparing with IVTXA, a topical application has the advantages of easy to administer, The Conflict of Interest statement associated with this article can be found at http://dx.doi.org/10.1016/j.arth.2014.03.032. Reprint request: Fuxing Pei, MD, Department of Orthopedics, West China hospital, Sichuan University, 37# Guoxue Road, 610041, People’s Republic of China.
providing a maximum concentration of TXA at the bleeding site, and was associated with little or no systemic absorption of the TXA [17], and so far, there were only several studies [17–20] that been reported to evaluate the effect of topical application in THA and the highquality randomized controlled trials were especially lacking, the effect of topical TXA in THA was unclear and controversial. Therefore, we conducted this randomized double-blind controlled trial in order to clarify the efficacy and safety of topical TXA in total hip arthroplasty.
Materials and Methods This was a randomized, double-blind, placebo-controlled trail which was registered and approved by the Institutional Review Board of Sichuan University, West China Medical Center (No. 201302007). Patients undergoing primary unilateral total hip arthroplasty for OA or ONFH were considered appropriate for the study. The exclusion criteria included patients who were receiving anticoagulant therapy, patients with a history of hemophilia, deep venous thrombosis, pulmonary embolism or ischemic heart disease and patients who were allergic to tranexamic acid. From September 2013 to October 2013, a total of 174 patients were scheduled to have a primary unilateral total hip arthroplasty in West China hospital, Sichuan University. 137 were eligibility for our study after prescreening by inclusion and exclusion criteria, but 34 patients rejected to participate. Then all the remaining 103 patients gave consent for the study and were randomized into two study groups (52 patients in topical TXA group and 51 patients in control group) by the method of opaque, sealed envelopes. The patients, surgeons and nurses were blinded and another non-related-research staff handed out the medications. Flow
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Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
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C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
diagram of patients involved was listed in Fig. 1. (The detailed description of withdrawals and drop-outs were listed in “Result”.) All the operations were completed by one experienced orthopedic surgeon and the whole operations were performed through the posterolateral approach, the prosthesis was a cementless acetabular cup and a cementless femoral stem. The method of anesthesia was decided by anesthetists. We referred to and improved the methods described by Konig et al [20]: In topical TXA group, 3 g TXA in 150 mL saline was used at three points during the whole procedure of THA. First, after the acetabular preparation, we used an gauze (25 cm × 25 cm, monolayer) which was full of 50 mL of the TXA solution to soak the acetabulum for three minutes, an cementless acetabular component was then impacted. Then, after femoral canal broach preparation, another gauze (25 cm × 25 cm, monolayer) with 50 mL of the same concentration TXA was inserted in the femoral canal for three minutes, and then the cementless femoral stem was impacted. At last, the remaining 50 mL TXA fluid was injected to the hip joint after fascia closure. A drain was used and clamped for 30 minutes. In the control group, the same method was used with the same dose of saline and clamped for 30 minutes too. The drainage was removed in the next morning after the operation. All patients are given chemical thromboprophylaxis by low-molecular-weight heparin (LMWH) combined with mechanical thromboprophylaxis by a leg pump. The primary outcomes were the transfusion rate, the DVT and PE events. Blood Transfusion Protocol indicated when the hemoglobin was less than 70 g/L or when the hemoglobin of a patient was more than 70 g/L but with a bad mental status, palpitation or pallor. Every patient was given ultrasound examination routinely for screening DVT before they were discharged by senior ultrasound doctors and symptomatic DVT and PE were observed by follow-up for three months after the operation. The secondary outcomes were total blood loss, drain blood loss, hemoglobin and hematocrit drop, postoperative hospitalization days and other complications.
The total blood loss was calculated according to the Gross formula [21,22]: Total blood loss ¼ PBV Hctpre −Hctpost =Hctave Hctpre ¼ the initial preoperative Hct level Hctpost ¼ the Hct on the morning of the third postoperative day Hctave ¼ the average of the Hctpre and Hctpost
PBV = the patient's blood volume (PBV, mL). It was assessed according to the formula of Nadler et al [23]: PBV = k1 × height (m) + k2 × weight (kg) + k3; k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for men; and k1 = 0.3561, k2 = 0.03308, and k3 = 0.1833 for women. If either reinfusion or allogenic transfusion was performed, the total blood loss is equal to the loss calculated from the change in Hct plus the volume transfused [22]. We removed the drainage in the next morning after the operation, and then the postoperative blood loss in the vacuum collectors was recorded by nurses. Hemoglobin and hematocrit levels were tested before the operation and on postoperative day one and day three routinely. The postoperative hospitalization days and other complications were recorded carefully too. Statistical Analysis All the data were analyzed by using SPSS version 19.0(SPSS Inc. USA), Student-t test was used to analyze the normal distributed numerical variable, such as total blood loss. If the numerical variable was non-normal distribution or unequal variance, Wilcoxon MannWhitney U test would be used; Pearson chi-square test or Fisher exact test was used to analyze the qualitative variable. A P-value ≤0.05 was considered to be statistically significant. Results
Patients scheduled for THA (N=174) Excluded by inclusion and exclusion criteria (N=37) Eligible patients (N=137)
From September 2013, all the 103 patients included were observed and followed-up, two patients in control group were out of touch and were excluded for withdrawals and drop-outs. Thus, the data of 101 patients were analyzed at last. The baseline characteristics included: age, gender, height, weight, BMI, hip disease composition, basic diseases, anesthesia method, the level of preoperative hemoglobin and hematocrit. The baseline characteristics between the two groups were listed in Table 1. There were no statistically significant difference between the two groups except the height and BMI (P b 0.05).
Rejected to participate (N=34) Table 1 Baseline Characteristics of the Two Groups.
Included and randomized (N=103)
Topical TXA group (N=52)
Control group (N=51)
Excluded for withdrawals (N=2)
Analyzed (N=52)
Analyzed (N=49)
Fig. 1. Flow diagram of patients involved.
Year Gender(male/female) Height (m)⁎ Weight (kg) BMI⁎ Hip disease composition (OA/ONFH) Hypertension Diabetes mellitus COPD Anesthesia method (general/spinal) Preoperative HB(g/L) Preoperative HCT (L/L)
Topical TXA Group
Control Group
P
60.9 ± 13.2 21/31 1.63 ± 0.072 64.53 ± 9.33 24.4 ± 3.1 37/15 12/52 5 5 43/9 134.27 ± 9.26 0.400 ± 0.033
63.7 ± 10.0 18/31 1.66 ± 0.072 63.49 ± 9.10 23.1 ± 2.7 39/10 8/49 9 5 44/5 135.47 ± 11.16 0.410 ± 0.038
0.239 0.707 0.030 0.573 0.025 0.326 0.395 0.203 0.921 0.302 0.557 0.378
BMI: Body mass index = Weight/Height2; OA: Osteoarthritis; ONFH: Necrosis of femoral head; COPD: Chronic obstructive pulmonary disease; HB: Hemoglobin; HCT: Hematocrit The value was presented as mean ± SD. Year, height, weight, BMI, preoperative HB and preoperative HCT were analyzed by Student-t test. Gender, hip disease composition, hypertension, diabetes mellitus, COPD and anesthesia method were analyzed by Pearson chi-square test. ⁎ Significant difference.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
Drain blood loss of two groups
Table 2 The Primary Outcomes of Two Groups.
0.021 1 1
DVT: Deep vein thrombosis; PE: Pulmonary embolism. Transfusions, DVT, PE were analyzed by Fisher’s exact test. ⁎ Significant difference.
The Primary Outcomes The primary outcomes including transfusion rate, DVT and PE events. A total of 5.5 units red cells were given to three patients in topical TXA group versus 11 patients who received 24.5 units red cells in control group. The transfusion rate was significantly lower in topical TXA group than control group. One asymptomatic DVT was found by routine ultrasound examination in topical TXA group at the third day after the operation and was cured finally, the difference between study groups were not significant. No symptomatic PE event was found in both groups. The primary outcomes were showed in Table 2. The Secondary Outcomes The mean total blood loss was (945.5 ± 331.7) mL in tranexamic acid group versus (1255.5 ± 193.5) mL in control group, there was statistical significant difference between the two groups (P b 0.001). The postoperative drain blood loss was significantly less in the patients who received topical TXA [(217.5 ± 89.9) mL in TXA group versus (296.9 ± 109.0) mL in control group, P b 0.001]. The hemoglobin and hematocrit drop in postoperative day one and day three were significantly lower in topical TXA group than in control group. The difference of postoperative hospitalization days and other complications between the two groups was not significant. The secondary outcomes were listed in Figs. 2–3 and Table 3. Discussion This was a high-quality randomized double-blind controlled trial, the results revealed that a high-dose of 3 g topical application of TXA could effectively reduce transfusions from 22.4% to 5.7% without
Total blood loss of two groups
Total blood loss(ml)
1500
300
200
100
0 gr ou p
22.4% (11/49) 0 0
on tr ol
5.7% (3/52) 1 0
400
C
P
gr ou p
Control Group
TX A
TXA Group
Drain blood loss(ml)
Transfusions⁎ DVT PE
3
Fig. 3. Drain blood loss. The histogram showed that drain blood loss in topical TXA group was significantly less than control group (Student-t test).
increasing the risk of DVT, PE and other complications in THA, in addition, topical TXA was able to significantly reduce total blood loss by about 300 mL, reduce drain blood loss by about 80 mL and significantly reduce HB drop and HCT drop in postoperative day one and day three, topical TXA was effective and safe for THA. So far, studies on topical TXA in THA were still deficient, therefore the methods and effect of topical TXA application were unclear and controversial. The main characteristics of current RCTs were reviewed and listed in Table 4. We could see that 2 g of TXA application reported by Joseph G. Martin et al [19] could improve but nonsignificant reduce the units of blood transfused compared to placebo, however a total of 3 g topical TXA [20] could significantly reduce transfusions. In addition, a meta-analysis of topical TXA in total knee arthroplasty (TKA) [24] concluded that a high dose of topical TXA (N2 g) significantly reduced transfusion requirements, which might provide a reference of topical application in THA, and these were the reasons that we used a total of 3 g topical TXA. We topically used TXA at three different points, which was found effective in a prior study [20] and at the same time, we also improved the method: we used gauzes which were full of high-concentration TXA solution to soak the acetabulum and femoral canal rather than the mentioned method of bathing. The reason we referred to and improved this method was that for THA, a large number of blood loss came from the steps of acetabulum preparation and femoral canal broach preparation, and thus this method we improved could make topical TXA be more
Table 3 The Postoperative Hospitalization Days and Other Complications of the Two Groups.
1000
500
tr on C
TX
A
ol g
gr
ro
ou
p
up
0
Fig. 2. Total blood loss. The histogram showed that total blood loss in topical TXA group was significantly less than control group (Wilcoxon Mann-Whitney U test).
HB drop in postoperative day 1 (g/L)⁎ HB drop in postoperative day 3 (g/L)⁎ HCT drop in postoperative day 1 (L/L)⁎ HCT drop in postoperative day 3 (L/L)⁎ Superficial infection Deep infection Hematoma Wound secretion Postoperative hospitalization days
TXA Group
Control Group
P
28.29 ± 8.85 40.02 ± 9.74 0.080 ± 0.032 0.112 ± 0.031 1 0 0 5 5.1 ± 0.5
41.5 ± 6.39 53.27 ± 4.79 0.101 ± 0.026 0.144 ± 0.019 0 0 0 7 4.9 ± 0.7
b0.001 b0.001 b0.001 b0.001 1 1 1 0.468 0.742
HB: Hemoglobin; HCT: Hematocrit. HB and HCT drop in postoperative day 1 and day 3 were analyzed by Wilcoxon MannWhitney U test. Postoperative hospitalization day was analyzed by Student-t test. Wound secretion was analyzed by Pearson chi-square test. Superficial infection, deep infection, hematoma were analyzed by Fisher’s exact test. ⁎ Significant difference.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
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C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx
Table 4 The Main Characteristics of Related Topical TXA in THA RCTs.
Author
Time
Number (TA/Control)
Dose of TXA
Intervention
Drainage
Blood Transfusion Protocol
DVT Prophylaxis
Primary Outcomes
Joseph [20]
2013
50(25/25)
2gTXA/ 100 mL NS
No drains
Symptomatic hypotension + HB b7 g/dL
2013
131(91/40)
Sattar [18]
2013
161(80/81)
3 g TXA/ 100 mL NS Not mentioned
clamping for 1 h Not mentioned
Hb b8 g/L + clinical symptoms HB b7 g/dL; HB b8 g/dL + tolerated anemia poorly; 7 g/dl b HB b 10 g/dL + clinical symptoms
Mechanical + warfarin (in hospital) and aspirin (out of the hospital) Not mentioned
Improve but non-significant reduce transfusions
Konig [21]
Intra-articular injection before joint closure Topically used at three points Not mentioned
targeted and make TXA play a role of anticoagulant and stopping bleeding in acetabulum and femoral canal more sufficiently and effectively. Through our study, we could see that the effect of 3 g topical TXA used in three points during the operation was satisfactory, the method we used could effectively reduce bleeding by about 300 mL (24.7%) and significantly reduce transfusions from 22.4% to 5.7%. Therefore, we could conclude that 3 g topical TXA used in three points was effective in THA. Comparing with application of intravenous tranexamic acid (IVTXA) in THA, topical TXA was considered with little or no systemic absorption of the TXA, therefore, topical TXA could avoid the potential complications of intravenous tranexamic acid administration [17]. However, we were not sure if topical TXA could carry the similarly good results in reducing bleeding and transfusions with intravenous tranexamic acid as related studies were too lacking. Only one study reported by Wind et al [18] compared the effect between topical TXA and IV-TXA, and they concluded that IV-TXA was a more predictable route of administration for maximum efficacy than topical TXA, but Wind’s study was retrospective, so the strength of evidence was not satisfactory and the conclusion might have bias. The results of this study showed that the risk difference of transfusions was about 17%, and a high-quality meta-analysis, which included 11 RCTs reported by Sukeik [10] showed the risk difference of transfusions was about 20% when IV-TXA was used in THA. So a topical dose of 3 g topical TXA might have the similar effect with IV-TXA for transfusions. In addition, the reduction of total blood loss was also similar between our RCT and Sukeik’s meta-analysis (about 300 mL of total blood loss reduction in our study versus 289 mL in Sukeik’s study). So these results gave us a reference that a high-dose topical TXA might be as effective as IV-TXA in THA. We thought the safety was very important and should be focused on when we used TXA in THA, therefore the primary outcomes we chose included DVT and PE events. So far TXA has been used in THA for more than 10 years, large clinical studies [10–20] and several metaanalyses [10,28] on TXA in THA had confirmed the safety of TXA, that TXA would not increase the risk of thrombo-embolism and mortality. In our study, the results also showed that there were no significant difference of thrombo-embolism events and other complications between topical TXA group and control group. Therefore, we trusted that topical TXA was safe in THA. However, some potential dangerousness of TXA may exist and just has not been clarified yet, more articles were needed to evaluate the safety of TXA. Several studies [22,25,26] have proved that the hidden blood loss was always huge in surgery and thus the total blood loss was always underestimated by clinical methods of calculating blood-soaked gauzes, suction bottles and the vacuum drain [17,26]. Therefore, we used Gross formula to evaluate the amount of total blood loss which was based on the hematocrit level and we thought the result we got was more accurate than clinical methods. The strengths of this study were obvious. First, this was a randomized controlled trial which was designed and performed carefully and strictly, the level of evidence was the highest Level I. So
Mechanical and mechanical + LMWH when BMI N30 kg/m2
Transfusions decreased dramatically from 15% to 1% Significantly reduced the risk of transfusions by 19.6%
the bias was miniature. Second, the transfusion protocol was explicit which made the primary result of transfusion rate convincing. Third, ultrasound examination was routine for every patient, we trusted our result of detecting DVT by using ultrasound was accurate for two reasons: (1) So far the literatures [29–31] had confirmed the accuracy of ultrasound to detect DVT, for example Barnes et al [29] showed that duplex scanning had an accuracy of 97% when venography was considered as the gold standard. (2) Our hospital was the largest medical center in West China, our ultrasound doctors were experienced and all the patients in our study were detected by senior ultrasound doctors, so the result was credible. In addition, the threemonth follow-up period was thought to be adequate to identify known adverse events [18]. At last, we improved the method of topical TXA application, and it was proved effective in reducing bleeding and transfusions. The main limitation of this study was that a large number of blood clots formed in local area after TXA gauze was used to soak the acetabulum whereas there were no obvious blood clots formed in control group, this might be found by surgeon and nurses. So although the surgeon and nurses were blinded, the strength of blinding might weaken. In addition, our method increased the duration of surgery by about six minutes, which might theoretically make the risk of infection higher [27]. However, in fact, the results of our study showed the rate of infection and other complications were very low. We didn’t think these limitations would affect the results seriously.
Conclusions In conclusion, a dose of 3 g topical TXA could significantly reduce bleeding and transfusions in primary THA without increasing the risk of DVT and PE, it was effective and safe in THA. However, as the related reports on topical TXA in THA are still lacking and some potential dangerousness of TXA may exist, more high-quality randomized controlled trials are needed to establish the efficacy and safety of topical TXA in THA.
References 1. Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am 1999;81(1):2. 2. Kumar A. Perioperative management of anemia: limits of blood transfusion and alternatives to it. Cleve Clin J Med 2009;76(4):112. 3. Cardone D, Klein AA. Perioperative blood conservation. Eur J Anaesthesiol 2009;26:722. 4. Lemaire R. Strategies for blood management in orthopaedic and trauma surgery [J]. J Bone Joint Surg (Br) 2008;90:1128. 5. Claeys MA, Vermeersch N, Haentjens P. Reduction of Blood Loss with Tranexamic Acid in Primary Total Hip Replacement Surgery. Acta Chir Belg 2007;107:397. 6. Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta 1981;673(1):75. 7. Singh J, Ballal MS, Mitchell P, et al. Effects of tranexamic acid on blood loss during total hip arthroplasty. J Orthop Surg 2010;18(3):282. 8. Dahl OE. The role of the pulmonary circulation in the regulation of coagulation and fibrinolysis in relation to major surgery. J Cardiothorac Vasc Anesth 1997;11:322.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
C. Yue et al. / The Journal of Arthroplasty xxx (2014) xxx–xxx 9. Reid RW, Zimmerman AA, Laussen PC, et al. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 1997;84:990. 10. Sukeik M, Alshryda S, Haddad FS, et al. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. J Bone Joint Surg 2011;21:869. 11. Benoni G, Fredin H, Knebel R, et al. Blood conservation with tranexamic acid in total hip arthroplasty: a randomized, double-blind study in 40 primary operations. Acta Orthop Scand 2001;72:442. 12. Husted H, Blønd L, Sonne-Holm S, et al. Tranexamic acid reduces blood loss and blood transfusions in primary total hip arthroplasty: a prospective randomized double-blind study in 40 patients. Acta Orthop Scand 2003;74:665. 13. Lemay E, Guay J, Côté C, et al. Tranexamic acid reduces the need for allogenic red blood cell transfusions in patients undergoing total hip replacement. Can J Anaesth 2004;51:31. 14. Johansson T, Pettersson LG, Lisander B. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double-blind study in 100 patients. Acta Orthop 2005;76:314. 15. Yamasaki S, Masuhara K, Fuji T. Tranexamic acid reduces blood loss after cementless total hip arthroplasty—prospective randomized study in 40 cases. Int Orthop 2004;28:69. 16. Ido K, Neo M, Asada Y, et al. Reduction of blood loss using tranexamic acid in total knee and hip arthroplasties. Arch Orthop Trauma Surg 2000;120:518. 17. Alshryda S, Mason J, Sarda P, et al. Topical (Intra-Articular) Tranexamic Acid Reduces Blood Loss and Transfusion Rates Following Total Hip Replacement A Randomized Controlled Trial (TRANX-H). J Bone Joint Surg Am 2013;95:1969. 18. Wind TC, Barfield WR, Moskal JT. The Effect of Tranexamic Acid on Transfusion Rate in Primary Total Hip Arthroplasty. J Arthroplasty 2014;29(2):387–9. 19. Martin JG, Cassatt KB, Kincaid-Cinnamon KA, et al. Topical Administration of Tranexamic Acid in Primary Total Hip and Total Knee Arthroplasty. J Arthroplasty 2013. http://dx.doi.org/10.1016/j.arth.2013.10.005.
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20. Konig G, Hamlin BR, Waters JH. Topical Tranexamic Acid Reduces Blood Loss and Transfusion Rates in Total Hip and Total Knee Arthroplasty. J Arthroplasty 2013;28:1473. 21. Gross JB. Estimating allowable blood loss: corrected for dilution. Anaesthesiology 1983;58:277. 22. Liu X, Zhang X, Chen Y, et al. Hidden Blood Loss After Total Hip Arthroplasty. J Arthroplasty 2011;26(7):1100–5.e.1. 23. Nadler SB, Hidalgo JU, Bloch T. Prediction of blood volume in normal human adults. Surgery 1962;51:224. 24. Panteli M, Papakostidis C, Dahabreh Z, et al. Topical tranexamic acid in total knee replacement: A systematic review and meta-analysis. Knee 2013;20:300. 25. Sehat KR, Evans RL, Newman JH. Hidden blood loss following hip and knee arthroplasty. J Bone Joint Surg (Br) 2004;86-B:561. 26. Eipe NP, Ponniah M. Perioperative blood loss assessment—how accurate? Indian J Anaesth 2006;50(1):35. 27. Urguhart DM, Hanna FS, Brennan SL, et al. Incidence and risk factors for deep surgical site infection after primary total hip arthroplasty: a systemic review. J Arthroplasty 2010;25(8):1216. 28. Zhou XD, Tao LJ, Li J, et al. Do we really need tranexamic acid in total hip arthroplasty? A meta-analysis of nineteen randomized controlled trials. Arch Orthop Trauma Surg 2013;133:1017. 29. Barnes CL, Nelson CL, Nix ML, et al. Duplex scanning versus venography as a screening examination in total hip arthroplasty patients. Clin Orthop Relat Res 1991(271):180. 30. Grady-Benson JC, Oishi CS, Hanson PB, et al. Routine postoperative duplex ultrosonography screening and monitoring for the detection of deep vein thrombosis. Clin Orthop Relat Res 1994;307:130. 31. Tremaine DM, Choroszy CJ, Menking SA. Deep vein thrombosis in the total hip arthroplasty patient after hospital discharge. J Vase Tech 1992;16:23.
Please cite this article as: Yue C, et al, Topical Application of Tranexamic Acid in Primary Total Hip Arthroplasty: A Randomized Double-Blind Controlled Trial, J Arthroplasty (2014), http://dx.doi.org/10.1016/j.arth.2014.03.032
