➢ Tranexamic acid is the prototypical antifibrinolytic and is becoming more prevalent as an adjunctive prophylactic measure against blood loss for patients undergoing primary total knee and hip arthroplasty.
➢ Tranexamic acid administration must be timed to counteract the fibrinolytic response to surgical trauma. During total knee arthroplasty, this response occurs after tourniquet release. For total hip arthroplasty, the timing of fibrinolysis has yet to be elucidated but is thought to begin at the time of skin incision and to peak before final prosthetic implantation.
➢ Level-I evidence supports the use of intravenous tranexamic acid during both primary total knee and hip arthroplasty for the reduction of perioperative blood loss and transfusion.
➢ Level-I evidence supports the use of topical or intra-articular tranexamic acid in total knee arthroplasty for the reduction of perioperative blood loss, with evidence of decreased systemic absorption of topical tranexamic acid when compared with the use of intravenous tranexamic acid. Comparative studies of patients undergoing total knee arthroplasty have suggested an equivalent role for intravenous and topical tranexamic acid.
➢ Systematic reviews and meta-analyses have not demonstrated an increased risk of postoperative thromboembolic events when antifibrinolytics are administered locally or systemically during lower-extremity total joint arthroplasty. However, no current clinical trial in arthroplasty research is adequately powered to detect a meaningful difference in this important outcome variable.
Total joint arthroplasty is considered to be a reliable method for the treatment of end-stage osteoarthritis of the hip and knee. Arthroplasty is, however, a major orthopaedic surgical intervention during which blood loss occurs as a result of soft-tissue dissection, reaming, and osteotomy of the long bones in the involved extremity. During total knee arthroplasty, tourniquet control aids in visualization of important anatomy, but perioperative hemostasis is unduly influenced by an accelerated fibrinolytic reaction at the time of tourniquet release1. Bleeding from vessels in synovial tissue as well as from the proximal tibial and femoral osteotomy sites often becomes apparent only after tourniquet release at the end of the procedure. During total hip arthroplasty, perforating intramuscular branches from the femoral and obturator vascular systems are at risk of injury in association with the use of the transmuscular surgical approach. As tourniquet application is of no benefit during total hip arthroplasty, exposed cancellous bone at the femoral neck osteotomy site and reamed acetabular surfaces are sources of continued blood loss in the postoperative period. Furthermore, a substantial amount of blood can collect in the soft tissues of the thigh, another potential source of unrecognized blood loss. Thromboembolic prophylaxis, widely considered the standard of care after total knee arthroplasty and total hip arthroplasty, is also a contributing factor to blood loss after major orthopaedic surgery.
The typical patient undergoing an arthroplasty also has a multitude of medical comorbidities that can impact the delivery of oxygen to vital organs. Blood loss resulting from total knee arthroplasty and total hip arthroplasty can potentiate these downstream effects. Transfusion of allogeneic blood products, traditionally considered the first-line treatment for postoperative anemia, should be avoided when possible. In addition to cost and resource constraints, there is evidence to support an increased risk of surgical site, urinary tract, and respiratory tract infections in patients who receive allogeneic blood at the time of arthroplasty2-5. Preoperative planning and implementation of blood-conservation modalities is of critical importance to patients undergoing total hip or knee arthroplasty.
Antifibrinolytic drugs are now considered to be valuable adjuncts to traditional blood-conservation protocols for patients undergoing arthroplasty. Administration of intravenous tranexamic acid in particular is viewed as a cost-effective way to reduce blood loss during and after high-risk surgical procedures6. Tranexamic acid has been used not only for total joint arthroplasty but also for cardiovascular interventions, with numerous investigators having made important contributions to the current pharmacologic and clinical outcomes research supporting the perioperative use of this antifibrinolytic agent7-10.
Despite the proposed clinical benefits, there is concern among many orthopaedic surgeons regarding intravenous administration of a clot-stabilizing drug for interventions that carry an elevated baseline risk of thromboembolism, such as total knee arthroplasty or total hip arthroplasty, even when thromboprophylactic agents are used in the postoperative period. This concern has prompted investigation into alternative routes of tranexamic acid delivery, resulting in the recent publication of studies touting similar benefits with regard to blood loss for intra-articular and topical administration of tranexamic acid. As a result, there is considerable heterogeneity in dosing strategies for tranexamic acid in total joint arthroplasty, with little consensus in the literature. In order to clarify the existing body of evidence, this review provides an overview of important studies outlining the role of antifibrinolytic therapy as an important modality for blood conservation for patients undergoing arthroplasty.
Lysine Analogs: Tranexamic Acid and Epsilon-Aminocaproic Acid
Tranexamic acid and epsilon-aminocaproic acid (EACA) constitute the lysine analog class of antifibrinolytic agents. They have identical mechanisms of action, with tranexamic acid displaying a sixfold to tenfold increased affinity in binding plasminogen when compared with EACA11. Because of its high affinity and comparatively low cost, tranexamic acid has largely replaced EACA as the predominant lysine analog used for major orthopaedic procedures.
Hemostasis in a surgical wound relies on the dynamic interplay of pro-coagulant and anti-coagulant processes, with the goal of promoting local clotting of injured tissues while maintaining blood vessel patency. Lysine analogs prevent fibrinolysis. The structural similarity to the amino acid lysine allows the drug to bind to the lysine-binding site on plasminogen. Under normal circumstances, plasminogen is a promoter of fibrinolysis when combined with a tissue plasminogen activator released from the surrounding tissues. Plasminogen subsequently gets converted to plasmin upon binding of fibrin, breaking down the cross-linked fibrin and dissolving the formed clot. Fibrin degradation products are formed as a byproduct of this reaction. By binding the active site of this proteolytic enzyme, tranexamic acid and EACA act as competitive inhibitors of plasminogen. As a consequence, fibrin molecules remain cross-linked, stabilizing the formed clot and promoting hemostasis (Fig. 1).
The pharmacokinetic properties of the lysine analogs make them ideal for decreasing the short-lived intra-articular fibrinolytic response after lower-extremity joint replacement surgery. Both molecules rapidly diffuse across tissue planes and are able to reach effective intra-articular concentrations shortly after intravenous administration. It has been shown that the absorption and elimination of tranexamic acid follows first-order kinetics, in a two-compartment model of distribution, with a half-life of roughly two hours11-13. Tranexamic acid is not bound to proteins in the systemic circulation and is rapidly excreted in urine, largely unchanged in chemical structure. A serum concentration of 10 to 15 μg/mL decreases fibrinolytic activity of plasmin by approximately 80%12. In addition, when administered via the topical or intra-articular routes, systemic absorption of tranexamic acid is reduced by approximately 70% of the equivalent intravenous dose14. Because of renal elimination, dose adjustments are necessary in those with decreased kidney function but not in those with hepatic impairment11,13. Local and systemic allergic reactions are rare complications of antifibrinolytic administration. Although there is evidence to suggest that high-dose tranexamic acid can potentiate seizures in patients who have undergone cardiopulmonary bypass surgery, an important inducer of fibrinolysis15, there is no evidence to suggest that there is a risk for seizure activity in association with the lower doses of tranexamic acid that are used for blood conservation in patients undergoing total knee arthroplasty or total hip arthroplasty.
Plasmin Inhibitors: Aprotinin
Aprotinin is a thrombin inhibitor, derived from bovine lung tissue, which was previously used as a valuable but costly blood-conservation adjunct for patients undergoing lower-extremity total joint arthroplasty. Its activity on the fibrinolytic cascade has yet to be fully elucidated, although it is postulated to exert most of its clinical effect indirectly by decreasing the activation of factor XII through an inhibitory effect on the kallikrein pathway16. The proteolytic activity of plasmin is also inhibited by aprotinin directly, although the mechanism is unclear17.
In recent years, the use of aprotinin has been restricted as a result of the increased mortality that has been observed when aprotinin is used during cardiac surgery18. Health Canada and the United States Food and Drug Administration have therefore suspended marketing of aprotinin in North America. These same findings were not observed in the groups that received tranexamic acid or EACA in the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study19. Recently, the European Medicines Agency and Health Canada have reinstated aprotinin for use during cardiac surgery when an excessive amount of blood loss is expected. Given the increased cost as well as safety concerns related to the use of aprotinin, it is unlikely that this antifibrinolytic agent will have a role in the reduction of blood loss in patients undergoing total joint arthroplasty.
Tranexamic Acid in Total Knee Arthroplasty
Use of the thigh tourniquet during total knee arthroplasty, although helpful for creating a bloodless surgical field, promotes a vigorous fibrinolytic response during the tourniquet-induced reperfusion reaction that occurs after deflation. Increased local levels of plasminogen activator inhibitors and antiplasmin result in a period of hyperfibrinolysis11,20. In the absence of any procedure to counter this phenomenon, blood loss into the soft tissues and knee joint ensues postoperatively, increasing the risk of local wound complications and the need for perioperative transfusion. Effective therapeutic regimens of tranexamic acid result in peak levels of drug within the joint prior to release of the tourniquet in order to effectively blunt this accelerated fibrinolytic reaction. To our knowledge, there are no available studies examining the efficacy of tranexamic acid as adjunctive therapy in total knee arthroplasty when a tourniquet is not inflated. As described in the following section, however, promising therapeutic outcomes have been reported following the timely administration of tranexamic acid via both the intravenous and intra-articular routes when a tourniquet is used for intraoperative hemostatic control of the surgical field.
Intravenous Tranexamic Acid in Total Knee Arthroplasty
A number of systematic reviews and meta-analyses have supported the use of tranexamic acid as a valuable adjunct for reducing blood loss and the need for transfusion of red blood cells (Table I). Ease of use and ability to administer serial doses of tranexamic acid are advantages associated with intravenous administration of this drug. Early evidence from small clinical studies questioned the efficacy of tranexamic acid in knee replacement surgery. Good et al. assessed the effect of tranexamic acid on hidden blood loss in total knee arthroplasty in a study in which a 10-mg/kg dose of intravenous tranexamic acid was given just before tourniquet release21. The authors concluded that the hemostatic agent reduced total blood loss and drain volume but showed no discernable effect in terms of the reduction of hidden blood loss. However, the validity of hidden blood loss as a primary outcome measure is poor. A number of recent studies have since refuted these early results. The clinical trial by Oremus et al. provided Level-I evidence supporting the clinical and economic benefits of intravenous tranexamic acid in total knee arthroplasty, with the authors stating that the use of tranexamic acid in the perioperative setting reduced blood loss by approximately 600 mL compared with placebo, making postoperative autologous reinfusion unnecessary and cost-prohibitive when a restrictive transfusion protocol was enforced concurrently22. In the recent clinical trial by Aguilera et al., in which two separate formulations of fibrin glue were compared with intravenous administration of tranexamic acid, only tranexamic acid was deemed to be effective for decreasing drain output and calculated blood loss23. Importantly, none of the aforementioned studies controlled for the extent of synovectomy, which is an important contributor to postoperative blood loss.
Although the general consensus is that intravenous tranexamic acid is beneficial in the setting of total knee arthroplasty, there is substantial heterogeneity among studies in terms of treatment regimens and outcome measures. It is therefore difficult to reliably assess the true clinical effect of adjunctive antifibrinolytic therapy in total knee arthroplasty (Table II). The ideal protocol with regard to dosing and timing of administration has yet to be fully elucidated, although recent evidence suggests that serial administration of tranexamic acid during the perioperative period results in improved control of postoperative blood loss. Maniar and colleagues, in a recent trial comparing four separate modes of tranexamic acid administration, showed that patients who received preoperative, intraoperative, and postoperative bolus administration of intravenous tranexamic acid at 10 mg/kg/bolus had the least drain output and total blood loss compared with those who received either one or two boluses of the drug perioperatively24. The prospective study by Alvarez and colleagues also showed that a cohort of patients undergoing total knee arthroplasty who received intravenous tranexamic acid as a bolus prior to tourniquet release, supplemented by a 1-mg/hr infusion for six hours postoperatively, had decreased levels of drain and total calculated blood loss in addition to a reduction in the rate of transfusion. In that study, the quoted number needed to treat to avoid one unit of blood transfused (autologous or allogeneic) was 9.2, further highlighting the efficacy of intravenous tranexamic acid in decreasing blood loss and transfusion for patients having total knee arthroplasty25.
Logistical barriers do, however, make timed serial dosing strategies and continuous bolus infusion difficult to administer, especially as the patient transitions to the postoperative recovery phase. A number of single-bolus dosing regimens have been shown to be effective. Ralley et al., in a large-scale retrospective review of total knee arthroplasty procedures that were performed before and after the implementation of a perioperative tranexamic acid protocol consisting of a single intravenous bolus dose of 20 mg/kg prior to tourniquet release, showed reductions in the decrease in hemoglobin and the need for blood transfusion postoperatively in the group that had received intravenous tranexamic acid prior to tourniquet release26.
Topical or Intra-Articular Tranexamic Acid in Total Knee Arthroplasty
Concerns about the systemic load of tranexamic acid when infused parenterally and the concomitant risk of inducing a prothrombotic state have made intra-articular administration of tranexamic acid an appealing option as a result of decreased systemic absorption of this antifibrinolytic. During total knee arthroplasty, tranexamic acid can be administered prior to closure of the arthrotomy site while a tranexamic acid solution is used to bathe the exposed joint (topical administration) or, alternatively, the solution can be infiltrated into the knee through a needle or drain once the arthrotomy site is closed (intra-articular administration). Either option provides intra-articular antifibrinolytic activity at the time of tourniquet-related hyperfibrinolysis.
There is Level-I evidence in support of the use of intra-articular tranexamic acid for the reduction of blood loss after total knee arthroplasty (Table II). A recent clinical trial by Wong et al. showed that 1.5 and 3-g tranexamic acid solutions were equally effective for reducing calculated blood loss by approximately 25% when compared with placebo14. In that study, a valuable addition to the clinical trial protocol was the biochemical analysis of plasma levels of tranexamic acid, measured one hour after administration in all treatment groups. The group that received the 1.5-g topical dose had lower systemic tranexamic acid load than the group that received the 3.0-g topical dose, with no meaningful difference in the desired clinical effect. Seo et al. performed a three-armed prospective cohort study of 150 patients in an attempt to contrast the effect of different routes of administration on postoperative blood loss and reported modest improvements in hemostasis and decreased drain output when intra-articular tranexamic acid was compared with both intravenous tranexamic acid and placebo27. Although the latter group only received intravenous tranexamic acid after the surgical site was closed, that study provides further evidence in support of intra-articular administration of tranexamic acid in total knee arthroplasty.
Tranexamic Acid in Total Hip Arthroplasty
Similar principles guide the use of tranexamic acid as an effective blood-conservation adjunct in total hip arthroplasty. The dosage and timing of tranexamic acid administration should allow for the drug to have optimal activity when the rate of intra-articular fibrinolysis reaction is elevated. In comparison with total knee arthroplasty, during which a predictable fibrinolytic reaction occurs after tourniquet release, blood loss during total hip arthroplasty has different considerations. First and foremost, the inability to use a tourniquet during total hip arthroplasty indicates that the hyperfibrinolytic reaction has a proposed onset at the time of skin incision and arthrotomy. Moreover, continued blood loss ensues after the femoral neck osteotomy and acetabular reaming. During the operative approach, there is also a potential for blood loss when transmuscular approaches to the hip are used for exposure of the hip joint. Perforation of intramuscular branches off the obturator and femoral circulatory systems can also cause continued postoperative bleeding. Prior to the advent of perioperative blood-conservation protocols, the estimated transfusion rate after total hip arthroplasty was approximately 35%28.
Intravenous Tranexamic Acid in Total Hip Arthroplasty
As is the case for total knee arthroplasty, intravenous tranexamic acid has been shown to be effective, safe, and relatively easy to administer to patients having primary total hip arthroplasty (Table III). One of the first studies on the subject was the small double-blind trial by Benoni et al., who did not ascertain any clinical benefit with regard to blood loss when the drug was infused after implantation of the prosthesis29. In a similar study by Ekbäck et al., however, the administration of intravenous tranexamic acid prior to the start of the procedure was associated with reductions in both intraoperative and postoperative blood loss in the group receiving tranexamic acid30. Although the sample sizes in these clinical trials were small, the contrasting results highlight the importance of appropriate dosage and timing of administration. On the basis of the results of this latter study, the majority of recently published studies on the topic have favored intravenous tranexamic acid administered prior to skin incision in primary total hip arthroplasty, as described in the following section.
Aggregate data from high-quality systematic reviews and meta-analyses have continued to show beneficial clinical outcomes, without an increase in complications, when intravenous tranexamic acid has been compared with placebo in patients undergoing primary total hip arthroplasty31-34. Often, however, studies contributing to the aggregate data are retrospective, are underpowered, and make use of suboptimal outcome measures. To a certain extent, this is true in both the total knee arthroplasty and total hip arthroplasty literature assessing blood loss and antifibrinolytic use. One of the higher-quality studies, the 2005 study by Johansson et al., demonstrated that a single weight-based dose of 15 mg/kg, given at the start of the procedure, is effective for decreasing calculated blood loss and the need for transfusion in the postoperative period35. The study by Ralley et al. also demonstrated a benefit with regard to transfusion, without an increase in complications, when a single bolus dose of 20 mg/kg was administered at the same time point26. Contrary to the total knee arthroplasty literature, there is a paucity of evidence supporting either a single-dose or multi-dose regimen of intravenous tranexamic acid in total hip arthroplasty. Imai et al., in a retrospective review of five separate regimens of intravenous tranexamic acid that were used for total hip arthroplasty, showed a benefit in terms of decreasing drain output when tranexamic acid was administered prior to skin incision and again six hours later, suggesting a role for serial dosing36. Much like in the literature supporting intravenous tranexamic acid use in total knee arthroplasty, heterogeneity in reported dosing strategies prevents the conclusive determination of the most effective treatment strategy.
Topical Tranexamic Acid in Total Hip Arthroplasty
Recent evidence suggests that the administration of topical tranexamic acid in primary total hip arthroplasty is an effective way to reduce perioperative blood loss. By direct infiltration into the periarticular area at the time of the operation, direct antifibrinolytic action on tissues can stabilize fibrin clots on bleeding tissues in order to effectively reduce local blood loss. However, to our knowledge, the time of peak fibrinolysis in primary total hip arthroplasty has never been formally studied. Peak fibrinolysis may occur during the operative approach, after preparation of the acetabular and femoral cut surfaces, or prior to implantation of the final components. The downside of topical tranexamic acid is the potential intraoperative delay as the solution bathes the periarticular area, which is not always acceptable. However, administering the drug when most convenient for the surgical team, at the time of closure of the arthrotomy site, allows fibrinolysis to continue throughout the majority of the procedure, providing a suboptimal effect on intraoperative blood loss. More research into the timing of fibrinolysis will inevitably help to elucidate the most effective timing of administration of topical tranexamic acid in total hip arthroplasty.
Despite these limitations, evidence supporting the use of topical tranexamic acid in primary total hip arthroplasty continues to grow (Table III). Preliminary evidence from a randomized controlled trial by Konig et al. demonstrated that a protocol of topical tranexamic acid administered at three intraoperative time points during primary total hip arthroplasty—after acetabular preparation, after femoral broaching, and at the time of closure of the arthrotomy site—reduced blood loss compared with placebo, with a negligible decrease in transfusion rate37. The European TRANX-H study, a prospective randomized controlled trial, also provided Level-I evidence for the use of topical tranexamic acid in primary total hip arthroplasty38. A drop in the transfusion rate was noted when the treatment arm that received 1 g of topical tranexamic acid infiltrated into the joint prior to closure of the arthrotomy site was compared with the placebo group. The evidence related to the use of topical tranexamic acid in total hip arthroplasty, however, lags behind the literature related to the use of intra-articular tranexamic acid in total knee arthroplasty. To our knowledge, no studies have assessed the absorption of topical tranexamic acid in the setting of total hip arthroplasty, although it is thought to result in less systemic load when compared with intravenous tranexamic acid, much like in the setting of total knee arthroplasty. Topical administration potentially represents a safer alternative for tranexamic acid delivery. Additional studies into the pharmacology of tranexamic acid, along with more high-powered prospective clinical trials, will help to evaluate the efficacy and safety of administering topical tranexamic acid in total hip arthroplasty.
Thromboembolic Risk After Tranexamic Acid Administration
The predominant concern associated with the use of tranexamic acid during lower-extremity total joint arthroplasty is the increased risk of thromboembolic events when intravenous tranexamic acid is used as a blood-conservation modality. It is well documented that both total knee arthroplasty and total hip arthroplasty carry an increased risk of venous thromboembolic events. To that effect, the American College of Chest Physicians and the American Academy of Orthopaedic Surgeons both strongly endorse thromboembolic prophylaxis as the standard of care after lower-extremity total joint arthroplasty39,40. Systemic administration of tranexamic acid is postulated to potentiate clot formation and to stabilize formed venous thromboemboli. There is a lack of randomized clinical trials powered to detect a difference in the rates of venous thromboembolic events related to tranexamic acid use. The lack of evidence for this important postoperative complication has led to reluctance in the widespread acceptance of tranexamic acid as adjunctive therapy for patients having hip or knee arthroplasty despite the documented efficacy in decreasing surgical blood loss.
To date, no study has demonstrated an increased risk of thromboembolic events when tranexamic acid is used during primary total knee arthroplasty or total hip arthroplasty. The most convincing evidence stems from the recent systematic review by Kagoma et al., which showed no significant difference in the rates of reported thromboembolic events in 949 patients receiving antifibrinolytic therapy as adjunctive therapy prior to total knee or hip arthroplasty when compared with a similar placebo group31. In truth, no prospective study that was included in that analysis had the statistical power to detect a difference in the rate of thromboembolic events when intravenous tranexamic acid was compared with placebo. Caution therefore must be exercised when interpreting aggregate data from a collection of individual studies in which the outcome measure in question is consistently underpowered. Moreover, loss to follow-up, often poorly documented in individual studies, can also bias results. Careful patient selection therefore remains a critically important step when considering the use of tranexamic acid. A thorough review of pertinent medical history and risk-benefit analysis is therefore an essential part of the preoperative work-up for patients having elective arthroplasty, especially if tranexamic acid use is being considered as part of the perioperative blood-conservation protocol.
Although not always clearly stated, most published studies of total knee arthroplasty and total hip arthroplasty exclude potential subjects with a medical history of coagulopathy, cerebrovascular events, or thromboembolic events as this patient population at high risk of thromboembolic events often acts as a confounder in the determination of postoperative complication rates. To our knowledge, no studies examining the application of topical or intra-articular tranexamic acid in high-risk patients undergoing lower-extremity arthroplasty are currently available. However, the results of the aforementioned study by Wong et al. demonstrated minimal systemic load when tranexamic acid was applied topically during primary total knee arthroplasty. Additional study into the pharmacokinetic and pharmacodynamic properties of intra-articular and intravenous tranexamic acid would be of great benefit for determining optimal tranexamic acid dosing regimens for this specific patient population undergoing either total knee arthroplasty or total hip arthroplasty.
There is growing support for the use of antifibrinolytic drugs as adjunctive therapy in total hip and total knee arthroplasty. A number of recent studies have suggested that substantial reductions in perioperative blood loss and transfusion rates can be achieved when tranexamic acid is administered intravenously or topically during both total knee arthroplasty and total hip arthroplasty. However, caution must be taken when interpreting the results of earlier studies, as these studies are often underpowered and lack reproducibility in terms of the reported outcome measures. When considering the clinical impact of the use of tranexamic acid during arthroplasty, the benefit of administering this antifibrinolytic must outweigh the risk. Multiple studies have touted reduction in perioperative blood loss, but no currently available prospective study is powered to detect clinically meaningful differences in transfusion or venous thromboembolic event-related complication rates. This is true even for robust Level-I studies in the total knee arthroplasty and total hip arthroplasty literature. Similarly, the increase in thromboembolic risk has never been shown in large-scale systematic reviews and meta-analyses, but no prospective clinical trial has been appropriately designed to answer this specific research question.
The advent of perioperative blood-conservation protocols dramatically decreases the need for transfusion of blood products in the perioperative setting, and the routine use of thromboprophylactic agents reduces the risk of deep-vein thrombosis and pulmonary embolism in the postoperative period. Completing a study assessing these now-infrequent outcomes would be costly, time-consuming, and labor-intensive but would provide a means of ensuring safety in administering a drug that is gaining in popularity worldwide for these two important surgical interventions. Appropriately powered clinical trials examining clinically relevant outcomes are needed to further elucidate definitive drug-safety profiles and effective dosing protocols for the use of tranexamic acid in primary total knee and hip arthroplasty. If tranexamic acid is to be utilized, optimal antifibrinolytic effect requires appropriate timing of administration in order to counteract the fibrinolytic response that is seen as a response to surgical trauma. Careful patient selection and completion of a thorough preoperative evaluation is essential to ensure that these hemostatic drugs are administered safely to patients undergoing arthroplasty.
Source of Funding: No external funds were received in support of this study.
Investigation performed at the Department of Surgery, Division of Orthopaedics, Schulich School of Medicine, Western University, London Health Sciences Center, University Hospital, London, Ontario, Canada
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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