Effects of single high dose topical tranexamic acid administration on bleeding and complicatıons after total knee arthroplasty surgery:A retrospective clinical study

Amac: Literaturde ortopedik cerrahide Traneksamik asit (TA) kullaniminin optimal yontemi konusunda fikir birligi yoktur. Bu calismanin amaci, total diz artroplastisi (TDA) cerrahisinde tek yuksek doz (3g) topikal TA uygulamasinin postoperatif kanama ve komplikasyonlar uzerine etkilerini degerlendirmektir. Gerec ve Yontemler: Ocak 2016 - Haziran 2018 tarihleri arasinda klinigimizde TDA uygulanan hastalar retrospektif olarak degerlendirildi. Hastalar TA uygulamasina gore iki gruba ayrildi: Grup 1 (topikal TA, n = 105/242) ve Grup 2 (TA olmayan, n = 137/242). Demografik parametreler, komorbiditeler, yuksek risk faktorleri, preoperatif hemoglobin (Hb) duzeyi, postoperatif en dusuk Hb duzeyi, Hb'deki toplam degisiklik, toplam dren cikisi, transfuzyon varligi veya yoklugu, transfuzyon yapilan kan miktari, hastanede kalis suresi ve komplikasyonlar degerlendirildi. Bulgular: Grup 1'de postoperatif birinci ve ikinci gun Hb seviyeleri grup 2'ye gore anlamli olarak yuksekti. Grup 1'de ameliyat gunu kan kaybi, ameliyat sonrasi ilk gun kan kaybi ve toplam dren kan kaybi anlamli olarak daha dusuktu. Grup 2'deki hastalarin anlamli olarak daha fazla kan transfuzyonuna ihtiyac duyduklari ve hastanede kalis surelerinin daha uzun oldugu belirlendi. Iki grup arasindaki komplikasyonlarda istatistiksel olarak anlamli fark saptanmadi. Sonuc: Bu calismada, TA'nin yara kapatildiktan sonra diz eklemine topikal uygulamasi; primer TDA yapilan hastalarda tromboembolik riskte bir artis yaratmadan, postoperatif Hb kaybini ve kan kaybini onemli olcude azaltmistir. Bu durum hastanede kalis suresini de azaltmaktadir.


Introduction
Osteoarthritis (OA), also known as degenerative joint disease, is a cartilage disease characterised by the progressive loss of the structure and function of articular cartilage, where the synovial joints are involved. The treatment of OA is multifaceted and includes patient education, lifestyle changes, rehabilitation, painkillers, intra-articular injections, needle lavage, and surgical treatment.
Total knee arthroplasty (TKA) is the most common method in the surgical treatment of OA in orthopaedic practice. [1] Trauma during TKA surgery triggers the coagulation cascade and local fibrinolysis. The deflating of the tourniquet, which is used to prevent bleeding during surgery, increases the fibrinolysis and increases the bleeding. Thus, bleeding can increase after surgery, and 10-38% of patients require a blood transfusion. The average blood loss per patient can be 1,450-2,000 ml. [2] Anaemia causes hypovolemic shock, renal failure, cardiac problems, and wound healing problems. Complications, such as allergic reactions, bacterial/viral infections, transfusionrelated acute lung injury, blood type incompatibility, hemolysis, and impaired metabolic balance due to blood transfusion for the treatment of acute anaemia, significantly increase mortality and morbidity. Medical expenses also increase as a result of blood transfusion and prolonged hospital stay, which is caused by these morbidities. For this reason, in the literature, the number of studies has been increasing recently to find ways to minimise blood loss and the need for blood transfusion. [3] Tranexamic acid (TA), a synthetic anti-fibrinolytic agent, prevents fibrinolysis by blocking plasmin formation from plasminogen.
The clot becomes stabilised due to reduced numbers of fibrin monomers and decreasing fibrinogen degradation. [4] Although TA has been used in cardiothoracic surgery, gynecologic bleeding and acute trauma for more than 40 years, its use in orthopaedic surgery has become widespread only in recent years. TA has intravenous, oral, and topical administration routes. [5] In the literature, it is reported that TA, which is applied after TKA, decreases the bleeding significantly without increasing the thromboembolic risk. However, patients with a history of renal failure, thromboembolic disorder, previous stroke, myocardial infarction, deep vein thrombosis, or pulmonary embolism are considered to be at high risk, and intravenous administration is considered to be contraindicated. Topical TA application is an alternative in these patients. [6] Although many studies have compared the efficacy of intravenous and topical administration of TA, there is no consensus on the optimal method of administration in the literature.
The purpose of this study is to evaluate the effects of single high dose topical TA application on postoperative bleeding and identify possible complications in healthy and high-risk patients.

Material and Methods
Topical TA has been routinely applied with TKA in our clinic since 2017. Patients who underwent TKA in our clinic between January 2016 and June 2018 were retrospectively analysed.  Following bleeding control, the joint was irrigated with normal saline and suctioned out. Intra-articular suction drains were routinely applied. Then the wound was closed, and, for group 1 (topical TA), 3g of TA was applied via the suction drain without any dilution with saline. The negative suction drain was clamped for 30 minutes to obtain the full effect of topical TA application and then opened in group 1. The same procedure was applied to Group 2 without TA administration. Total drain output, haemoglobin, and hematocrit levels were recorded daily postoperatively. The criteria for blood transfusion were a haemoglobin concentration of <8 g/dl or a haemoglobin level of <10 g/dl if the patient had any signs of anaemia (e.g.,

Demographics
A total of 242 patient results were evaluated. Table 1 shows the demographic characteristics of the patients. There were no statistically significant differences in demographics.
Hemoglobin levels were recorded postoperatively on the day of surgery and for the following 3 days. In group 1, postoperative first-and second-day Hb levels were significantly higher than those in group 2 (p<0,001). The difference between the highest and lowest Hb values obtained after surgery was termed as the maximum Hb decrease and it was significantly higher in group 2 (3,33 ± 0,90 mg/dl) than group 1(3,89 ± 1,19 mg/dl) (p<0,001). When the records of the amount of blood loss through the drain were examined, it was determined that both the blood loss on the day of surgery (p<0,001), the blood loss on the first postoperative day (p=0,033) and total drain blood loss (p<0,001) were significantly lower in group 1( Table 2).  (Table 3).

Hospital Stay
Patients in group 1 had a mean hospital stay of 4,94 days compared with 5,27 days for patients in group 2, and there were statistically significant differences between the two groups (p=0,034) ( Table 2).

Complications
There were 6 complications in group 1 (2 wound healing problems, 3 cases of articular effusion, and 1 case of pneumonia) and 12 in group 2 (3 wound healing problems, 6 cases of articular effusion, 2 cases of pneumonia, and 1 acute arterial thrombosis of the lower extremity resulting in amputation) (Table 1). No coagulation-related complications were found in any patient included in the study. There was no statistical difference in complications between the two groups.

Discussion
In our clinic, as indicated in the literature, a topical administration is preferred to minimize systemic absorption of TA and thus prevent thromboembolic side effects. [6,7] In previous studies, both low-dose (500 mg) and high-dose (3 g) TA administration has been shown to be effective in reducing blood loss after surgery. [8,9] Recent studies have shown that high-dose topical TA administration is more effective. [4,10] For this reason, we preferred high-dose TA application in our clinical practice.
In this study, topical administration of TA via suction drain to the knee joint after wound closure significantly reduced postoperative Hb loss and blood loss in patients having a primary TKA. In the topical TA group, Hb values were significantly higher than in the non-TA group on the first and second post-operative days, which is consistent with reports in the literature [11,12]. However, no significant difference was found between the post-operative Hb values obtained on the day of surgery. Hemodilution due to intravenous fluid and drug administration, which is applied more intensively during and soon after surgery, may cause this result. Similar to the results obtained in previous studies, the blood loss through the drain on the day of surgery and the first post-operative day and the total drain blood loss in the topical TA group were significantly lower than in the non-TA group. [4,13] After primary TKA surgery, bolus blood loss occurs due to tourniquet use. [14] In the topical TA group, both TA administration and closure of the suction drain for 30 minutes after application may prevent bolus blood loss and result in decreased total drain output.
Previous studies have shown that intravenous TA protocols, both during and after surgery [11,14,15] and topical TA applications, including periarticular injections. [5,9,16] reduce blood transfusion rates compared with a placebo after primary TKA surgery. However, in the studies, different topical doses of TA (1g, 1,5g, 2g, and 3g) were not superior to each other. [4,9,10] In this study, 3g of TA was applied topically and there was a statistically significant decrease in blood transfusion rates compared with the non-TA group, which isconsistent with reports in the literature. [9] We encountered thromboembolic disorder in only 1 of the 242 patients included in our study, and this patient was in group 2 (non-TA group). In addition, we did not find any statistically significant difference between the groups when all the complications were evaluated.
The present study had several limitations. First, our study is a retrospective study and no power analysis was performed to determine the size of the study population. Second, in our clinic, we only administer a single high dose (3g) of topical TA after primary TKA. Therefore, we could not compare the results to other reported results using different administration procedures. Third, our data reflect short-term results and therefore we could not evaluate the effects of TA application in the long-term follow-up period.

Conclusions
In conclusion,our clinical practice and results support that topical TA application effectively and significantly reduces blood loss and transfusion rates after surgery,without serious side effects, in patients undergoing primary TKA. This reduces the length of the hospital stay.In addition, further studies are needed to determine the optimal dose range and route of administration of TA and thus establish "gold standard" treatment protocols.

Declaration of conflict of interest
The authors received no financial support for the research and/or authorship of this article. There is no conflict of interest.