Fatih Durgut  ( Cihanbeyli State Hospital )
Omer Faruk Erkocak  ( Orthopedics and Traumatology Department, Selcuk University Medicine Faculty )
Bahattin Kerem Aydin  ( Orthopedics and Traumatology Department, Selcuk University Medicine Faculty )
Ali Ozdemir  ( Orthopedics and Traumatology Department, Selcuk University Medicine Faculty )
Ali Gulec  ( Orthopedics and Traumatology Department, Selcuk University Medicine Faculty )
Ali Ihsan Tugrul  ( Beyhekim State Hospital, Konya, Turkey )

Objective: To compare the efficacies of intra-articular applications of tranexamic acid and adrenaline on postoperative bleeding after total knee arthroplasty.
Methods: The single-center, retrospective, controlled study was conducted at Selcuk University , department of orthopedic surgery and comprised data of patients who underwent primary, unilateral, cemented total knee arthroplasty between July 2012 and December 2014. Group 1 had received tranexamic acid 1g after closure of articular capsule. Group 2 had received adrenalin. Group 3, the control group, received no medication intraarticularly after total knee arthroplasty. The amount of blood collected in the drain and postoperative alterations in haemoglobin and haematocrit values were compared.
Results: Of the total 90 subjects, there were 30(33.33%) in each of the three groups. The decrease of haemoglobin and haematocrit values in Group 1 was statistically significant compared to both Group 2 and Group 3 (p<0.05). The amount of blood collected in the drains was remarkably lower in Groups I and 2 compared to Group III (p<0.05). No deep venous thrombosis or pulmonary emboli were encountered across the sample.
Conclusion: Intra-articular administration of tranexamic acid was found to be beneficial and safe for the achievement of effective haemostasis after total knee arthroplasty.
Keywords: Tranexamic acid, Adrenaline, Haemostasis, Blood loss, Total knee arthroplasty. (JPMA 69: 325; 2019)

Introduction

Currently, total knee arthroplasty (TKA) is considered the treatment of choice in advanced stages of knee osteoarthritis. Despite advances in surgical and anaesthetic techniques, TKA is still associated with considerable amount of perioperative blood loss. Postoperatively, blood continues to ooze from the cut-ends of bone, open intramedullary canal and dissected soft tissues. Increased fibrinolytic activity, which is stimulated by surgical trauma, may also increase blood loss after TKA, at least during the early postoperative hours. Anaemia due to surgical blood loss is not infrequent in patients undergoing TKA and is associated with high rate of allogenic blood transfusion in approximately 40% of cases.¹ In addition to the potential complications of blood transfusion, including transmission of infectious disease and transfusion-related reactions, it has been shown that blood transfusion compromises the outcome of TKA patients, prolongs hospital stay, and increases the risk of surgical site infection.^1,2 Although various measures and strategies, such as autologous blood transfusion and use of cell salvage systems, have been introduced, the safest and the most efficient perioperative blood conservation method has yet to be found.^3-5 Additionally, these strategies have limitations and are not cost-effective.^6,7 Using algorithmic approaches and determining predictors of perioperative bleeding and transfusion appear to be the main strategies which can lead to reduction in allogeneic blood use after joint arthroplasty.^8,9 Tranexamic acid (TXA) is an antifibrinolytic agent, which can effectively decrease postoperative bleeding by inhibiting the fibrinolytic activity. Intravenous (IV) or intra-articular (IA) administration of TXA have been proposed to reduce perioperative blood loss in TKA. .^10,12 Recent literature has demonstrated the effectiveness of TXA on blood loss and transfusion rates without increasing rate of thromboembolism after TKA. .^13,14 Similarly, IA adrenaline infusion during surgical closure is another method which has been recommended for the reduction of surgical bleeding and postoperative blood loss following TKA. Nevertheless, adrenaline can be associated with delayed wound healing, skin necrosis, haematoma, elevated blood pressure (BP) and deep venous thrombosis (DVT).^15,16 However, little information is available regarding the comparative efficacies of these two agents on postoperative bleeding following TKA. Thus, the current study was planned to determine if the use of TXA reduces perioperative blood loss and need for allogenic blood transfusion in patients undergoing TKA, to compare the effectiveness of intra-articularly administered TXA and adrenaline on perioperative blood loss, and evaluate the rate of complications, including the rate of thromboembolic  events, in patients receiving TXA and adrenaline.

Material and Method

The single-center, retrospective, controlled study was conducted at Selcuk University, department of orthopedics surgery and comprised data of patients who underwent primary, unilateral, cemented total knee arthroplasty between July 2012 and December 2014. After approval was obtained from the institutional review board, the sample size was determined which was equal to the anticipated population according to result of our statistical power analyses. The power analysis are performed for testing the mean difference in haemoglobin and haematocrit and draninage and it is detected that the observed power as 0,971, 0,863 and 1 respectively. In this case our anova results are trustworthy with high power. Three groups were formed. Group 1 had received TXA 1g after closure of articular capsule. Group 2 had received adrenalin. Group 3, the control group, had received no medication intra-articularly after TKA. Exclusion criteria consisted of American Society of Anaesthesiologists grade IV (ASA-IV) or higher physical status, severe ischaemia and/or cardiac valvular disease, revision cases, collagen vascular disease, bilateral knee joint arthroplasty, hypersensitivity to TXA or adrenaline, coagulopathy, history of the thromboembolic disease and renal dysfunction (serum creatinine level >1.5 g/dl). TXA and adrenalin were applied as retrograde via haemovac drain when the wound entirely closed. Haemovac drain was kept closed for 30 minutes after application. Group I received IA 4 ampul TXA (1 amp %5lik 5ml 250 mg TXA), while 1 ampul adrenaline (0,5mg/ml) diluted with 20ml of physiological saline was applied to Group 2. A standard surgical procedure was carried out by the same surgical team and same cemented prostheses design (Vanguard-posterior stabilised type, Biomet USA) was utilized for all patients. First dose antibiotic prophylaxis (IV cefazolin 1 or 2g according to body weight) was administered one hour before the surgical procedure, and continued for 24 hours postoperatively. All surgical procedures were performed under spinal anaesthesia with the use of a thigh tourniquet and knee joint was accessed through a medial parapatellar arhtrotomy. Pharmacological DVT prophylaxis with low molecularweight heparin, (40-60 mg/daily, s.c) was given 12 hours before the procedure and continued for six weeks starting from 6th hour postoperatively. Anti-embolic stockings were administered and cryotheraphy was started in early postoperative period. Lower limb muscle contraction exercises were initiated as soon as possible after the spinal anaesthesia dissolved and muscular function recovered. Patients were mobilised day after the surgery and, and ambulation with assistive devices was encouraged for two or three weeks postoperatively. The same rehabilitation regimen was applied to all patients. Haemoglobin (Hb) and haematocrit (Hct) levels were assessed preoperatively, and on 6th and 24th hours postoperatively. After surgery, drains were maintained for 24 hours. Blood volume collected in drains was recorded in all groups. Red blood cell (RBC) transfusion was not made if Hb level was >10 g/dl. In case of Hb level was between 8- 10 g/dl, patients were assessed regarding clinical findings such as tachycardia, palpitation, dizziness and fatigue, and autologous blood transfusion was initiated accordingly.  Routine RBC transfusion was, however, reserved for cases with Hb<8 g/dl. The amount of RBC suspension transfusion was noted for every patient. Clinical examination data, including haemodynamic alterations and complications, were noted. Two staff members blinded to patients evaluated the data. The incidence of symptomatic DVT and pulmonary embolism was assessed until the 90th day. Pain, swelling of the limb, calf tenderness, superficial venous engorgement, and Homan's sign were assessed daily until the patient was discharged. In case of any pain or swelling at the calf or thigh, an initial evaluation for DVT was made with vascular doppler ultrasonography. Dyspnoea and chest pain, which may indicate pulmonary embolism, were also evaluated. Patients were followed up on the 30th and 90th days postoperatively and instructed to report any signs of DVT. Baseline descriptive data, volume collected in the drain, preand postoperative Hb and Hct levels, changes in Hb and Hct levels on 24th hour, and the amount of RBC suspension transfused were noted and compared among the groups. Comparison of groups was made using a parametric test, analysis of variance (ANOVA). Normality and homogeneity of variance were tested with Kolmogorov-Smirnov and Levene tests to check the assumption of ANOVA, respectively. Tukey honestly significant difference (HSD) test was used for multiple comparisons. For all tests, the possibility for type 1 error was assumed as α=0.05. Differences in groups regarding discrete data were evaluated with Cochran's test. Quantitative variables were expressed as mean, standard deviation (SD), median, interquartile range (IQR), and minmax range. The confidence interval was 95%, and level of significance was set at p<0.05.

Result?

Of the total 90 subjects, there were 30(33.33%) in each of the three groups. Mean age in Group 1, was 65.66}6.91 years, Group 2, 65.83}4.94 years, and Group 3, 68.30}6.51 years. Overall, 52(58%) patients were operated on the right side, while 38(42%) cases underwent TKA for the left knee. Among the groups, there was no significant difference in demographic characteristics (p>0.05) (Table-1)



No remarkable difference was observed in groups regarding Hb and Hct levels preoperatively or on 6th and 24th hours postoperatively. But when all the groups were compared in terms of preoperative Hb and Hct with postoperative values, the decrease was significantly lower in Group 1 compared to Group 2 and Group 3 (p<0.05). The decrease of Hb and Hct values were lower in Group 2 compared to Group 3 but it was not statistically significant (p>0.05) (Table-4, 5).





 When the groups were compared for amount of blood in drains, the amount was significantly lower in Group 1 and 2 compared to Group 3 (p<0.05), and also the amount of blood was significantly lower in Group 1 compared to Group 2 (p<0.05). The volumes collected in the drain were significantly different for all groups (Table- 2).



 Group 1 had the lowest volume collected in the drain, while Group 3 had the highest volume (Table-3).



After surgery, 9 units of RBC suspensions were administered to 5(17%) patients in Group 3. Three (10%) patients received a total of 4 units of RBC suspensions in Group 2, while no transfusion was needed for any patient in Group 1 (Figure).

No complications, such as infection, pulmonary emboli and DVT, were detected in any patient.

Discussion

TKA is an effective treatment for osteoarthritis of the knee, but this surgery is frequently accompanied by severe blood loss. The amount of blood loss for TKA varies between 500 and 1.500ml17 In spite of the development in surgical techniques and perioperative care, TKA is still associated with substantial bleeding. Since considerablebleeding can increase morbidity, many methods have been proposed to reduce perioperative blood loss and preserve haemodynamic stability in patients undergoing TKA. In this regard, topical agents such as TXA, adrenaline and other haemostatic gels and powders have been recommended. Even though these methods have reduced the need for allogeneic blood transfusion (ABT), none of them alone has been enough. ¹⁸  The most obvious finding of the current study is that topical TXA can be effective in managing postoperative blood loss and may avoid the need for ABT after TKA. A study demonstrated that topical TXA can be very effective in managing postoperative blood loss, and avoiding ABT in  primary TKA. When adrenaline was added to the TXA saline solution, there was a greater haemostatic effect compared to the TXA saline solution alone. ¹¹  In the present study, we compared the haemostatic effects of adrenaline and TXA separately and noted that TXA had a more prominent  impact on controlling blood loss after TKA. TXA is an inhibitor of fibrinolysis and an activator of  plasminogen and is known to inhibit blood loss after TKA. ¹⁹  Since TKA is mostly performed under tourniquet, veins of the lower extremity are in a hypoxic state, and this may lead to the release of tissue plasminogen activator from the vascular endothelium. Tourniquet deflation results in venous expansion and increased haemorrhage in the lower extremity. Fibrinolysisis temporarily activated after surgery and bleeding will be aggravated. TXA strongly blocks the fibrinolysis and promotes the stability and deposition of blood clots in the tissue space. ¹¹  The haemostatic effect of adrenaline is linked with the peak of blood flow which persists for 20-30 minutes following the release of tourniquet release. Local adrenaline infusion prior to the release of the  tourniquet not only triggers contraction of peripheral vessels,but also induces platelet aggregation. Therefore, adrenaline  can be useful for peripheral vessels and haemostatic effect of reducing perioperative and postoperative blood loss. ¹⁵ In accordance with the results of a previous publication, ¹¹ we observed that IA use of TXA and adrenaline solutions with drainage started 30 minutes after surgical closure of the wound were safe without any apparent postoperative complications such as DVT and pulmonary emboli. Notably, there was no need for transfusion of RBC suspension for patients receiving TXA. In conjunction with data from the relevant literature^20,21  our results support that use of TXA in the articular cavity provided the satisfactory haemostatic effect. Metaanalyses indicated that TXA remarkably reduced both the number of patients requiring transfusion and volume of blood products transfused. ²²  Even though it has been suggested that intra-articular adrenaline injection was effective for decreasing blood loss in TKA²³  a study reported that it was not useful. ²⁴  Our results indicated that even though TXA had a more  obvious effect than adrenaline for haemostasis after TKA. However, we think that adrenaline may be used as an adjunctive measure to enhance the activity of TXA. Main limitation of the current study is its retrospective design and single-institution orientation. Possible complications and adverse events can be investigated  more accurately in larger series. Lack of analysis of the synergistic effects of TXA and adrenaline is another significant limitation. Moreover, we recruited only patients with osteoarthritis of the knee alone, without other inflammatory disorders such as rheumatoid arthritis. Hence, interpretation and extrapolation of our results must be made with caution. Our data may be restricted since there is no long-term follow-up and diagnosis of DVT was based on clinical presentation only. Depending on the selection of the surgeon and characteristics of the patient, TXA may be administered intravenously or topically in the surgical wound. ¹⁸  The optimal treatment protocol for TXA remains to be determined in further studies. A study stated that IV TXA was more effective than local application due to the decreased absorption. ²⁵   However, IA administration after surgical closure of the capsule can be a method to overcome this problem.

Conclusion

TXA was beneficial for the reduction of total blood loss, postoperative blood loss, Hb loss, the units of blood products transfused per patient and the number of patients receiving blood transfusions after TKA. Both TXA and adrenaline did not seem to increase the risk of thromboembolic complications and other adverse events.

Disclaimer:None.
Conflict Interest:None.
Source of Funding:None.

References

1. Spahn DR. Anemia and patient blood management in hip and knee surgery: a systematic review of the literature. Anesthesiology. 2010; 113:482-95.
2. Rasouli MR, Gomes LS, Parsley B, Barsoum W, Bezwada H, Cashman J, et al. Blood conservation. J Arthroplasty. 2014; 29:65- 70.
3. Parvizi J, Chaudhry S, Rasouli MR, Pulido L, Joshi A, Herman JH, et al. Who needs autologous blood donation in joint replacement? J Knee Surg. 2011; 24:25-31.
4. Greenky M, Shaner J, Rasouli MR, Han SB, Parvizi J, Hozack WJ. Intra operative blood salvage in revision total hip arthroplasty: who benefits most? J Arthroplasty. 2014; 29:1298-300.
5. Perazzo P, Vigano M, De Girolamo L, Verde F, Vinci A, BanfiG, et al. Blood management and transfusion trategies in 600 patients undergoing total joint arthroplasty: an analysis of pre-operative autologou blood donation. Blood Transfus. 2013; 11:370-6.
6. Amin A, Watson A, Mangwani J, Nawabi DH, Ahluwalia R, Loeffler M. A prospective randomised controlled trial of autologous retransfusion in total knee replacement. J Bone Joint Surg Br. 2008; 90:451-4.
7. Rao VK, Dyga R, Bartels C, Waters JH. A cost study of postoperative cell salvage in the setting of elective primary hip and knee arthroplasty. Transfusion. 2012; 52:1750-60.
8. RosencherN, Kerkkamp HE, Macheras G, Munuera LM, Menichella G, Barton DM, et al. Orthopedic Surgery Transfusion Hemoglobin European Overview(OSTHEO) study: blood management in elective knee and hiparthroplasty in Europe. Transfusion. 2003; 43:459-69.
9. Slappendel R, Dirksen R, Weber EW, van der Schaaf DB. An algorithm to reduce allogenic red blood cell transfusions formaj or orthopedic surgery. Acta Orthop Scand. 2003; 74:569-75.
10. Benoni G, Fredin H. Fibrinolytic inhibition with tranexamic acid reduces blood loss and blood transfusion after knee arthroplasty: a prospective, randomised, double-blind study of 86 patients. J Bone Joint Surg Br. 1996; 78: 434-440.
11. Gao F, Sun W, Guo W, Li Z, Wang W, Cheng L. Topical administration of tranexamic acid plus diluted-epinephrine in primary total knee arthroplasty: a randomized double-blinded controlled trial. J Arthroplasty. 2015; 30: 1354-1358.
12. Georgiadis AG, Muh SJ, Silverton CD, Weir RM, Laker MW. A prospective double-blind placebo controlled trial of topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013; 28:78-82.
13. Gandhi R, Evans HM, Mahomed SR, Mahomed NN. Tranexamic acid and the reduction of blood loss in total knee and hip arthroplasty: a meta-analysis. BMC Res Notes. 2013; 6:184.
14. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in reducing blood loss in total knee arthroplasty: a metaanalysis. J Bone Joint Surg Am. 2012; 94:1153-9.
15. Gasparini G, Papaleo P, Pola P, Cerciello S, Pola E, Fabbriciani C. Local infusion of norepinephrine reduces blood losses and need of transfusion in total knee arthroplasty. IntOrthop. 2006; 30: 253-6.
16. Zhaohui L, Wanshou G, Qidong Z, Guangduo Z. Topical hemostatic procedures control blood loss in bilateral cemented single-stage total knee arthroplasty. J Orthop Sci. 2014; 19:948-53.
17. Park JH, Rasouli MR, Mortazavi SM, Tokarski AT, Maltenfort MG, Parvizi J.Predictors of perioperative blood loss in total joint arthroplasty. J Bone Joint Surg Am. 2013; 95:1777-83.
18. Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. Eur J Orthop Surg Traumatol. 2015; 25:525-41.
19. Yamada K, Imaizumi T, Uemura M, Takada N, Kim Y. Comparison between 1-hour and 24-hour drain clamping using diluted epinephrine solution after total knee arthroplasty. J Arthroplasty. 2001; 16: 458-62.
20. Chimento GF, Huff T, Ochsner JL Jr, Meyer M, Brandner L, Babin S. An evaluation of the use of topical tranexamic acid in total knee arthroplasty. J Arthroplasty. 2013; 28: 74-7.
21. Tan J, Chen H, Liu Q, Chen C, Huang W. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. J Surg Res. 2013; 184:880-7.
22. Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta-analysis of randomized controlled trials. Transfusion. 2005; 45: 1302-7.
23. Anderson LA, Engel GM, Bruckner JD, Stoddard GJ, Peters CL. Reduced blood loss after total knee arthroplasty with local injection of bupivacaine and epinephrine. J Knee Surg. 2009; 22:130-6.
24. Malone KJ, Matuszak S, Mayo D, Greene P. The effect of intraarticular epinephrine lavage on blood loss following total knee arthroplasty.Orthopedics. 2009; 32: 100.
25. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on blood loss and transfusion rate in primary total knee arthroplasty. J Arthroplasty. 2013; 28:1080-3.