Are Three Doses of Intravenous Tranexamic Acid more Effective than Single Dose in Reducing Blood Loss During Bilateral Total Knee Arthroplasty?

Abstract

Purpose

Tranexamic acid (TXA) has shown to reduce perioperative blood loss after bilateral total knee arthroplasty (TKA). But dosage and schedule of administration are not clear in literature. This study was aimed to compare prospectively blood loss and transfusion requirement in bilateral TKA with 3-dose regimen versus a single intra-operative dose of intravenous TXA.

Methods

This prospective non-randomised controlled trial included 25 patients undergoing bilateral simultaneous TKA who received three doses of 1 g intravenous TXA (group 1). First dose was given prior to deflation of the tourniquet, followed by two more doses 6 h apart. The control group included 25 matched patients (group 2) receiving a single dose of 1 g intravenous TXA just prior to deflation of the tourniquet.

Results

Mean drop in haemoglobin was less in group 1 as compared to group 2, but this difference was not statistically significant (2.51 vs 2.93 g/dL, p = 0.210). Similarly mean drop in haematocrit was more in group 2 as compared to group 1, though it was not statistically significant (9.34 vs. 9.18, p = 0.868). The need for blood transfusions was more in group 2 compared to group 1, but this difference was not statistically significant (p = 0.601). Higher frequency of ecchymosis around the surgical site was noted in group 2 as compared to group 1, for which prophylactic low-molecular-weight heparin had to be stopped post-operatively, but this difference was not statistically significant (p = 0.065).

Conclusion

The study has failed to show any significant beneficial effect of three doses of TXA in TKA as compared to a single dose. Though a trend towards reduction in mean haemoglobin drop and decreased need for stopping LMWH in post-operative period was seen, the results were not statistically significant.

Level of Evidence

II, prospective non-randomised controlled trial

Introduction

Anaemia and blood transfusion in perioperative period are associated with increased morbidity, prolonged duration of hospital stay and increased mortality [1, 2]. Interventions to reduce perioperative blood loss are an important focus for improvement in surgical practices in total knee arthroplasty (TKA).

Intravenous tranexamic acid (TXA) is an evidence-based intervention to reduce blood loss and requirement for blood transfusion during TKA. TXA binds to plasminogen and prevents it from activating fibrin, thereby resulting in inhibition of fibrinolysis. Commonly, it is given during surgery, either at the time of skin incision or just prior to deflation of tourniquet. Numerous protocols of administration have been described in literature, such as intravenous, topical or oral [3, 4]. Though its efficacy is proven, dosage and schedule of administration are not clear in literature.

A single dose of tranexamic acid at the time of surgery has been used by most authors [5–8]. In an attempt to improve its efficacy, researchers have tried to extend use of intravenous TXA to post-operative period. It is based on assumption that blood loss occurs not only at the time of surgery, but also hidden blood loss continues to occur for a variable time in the post-operative period. This hidden blood loss might be decreased with the use of additional doses of TXA, without increasing the risk of venous thrombo-embolism [9].However, there is no consensus weather additional doses make any difference in outcomes. Several studies have shown that a single bolus of either 20 mg/kg or 30 mg/kg can be as effective as multiple doses [5, 7]. This study was aimed to compare prospectively blood loss and transfusion requirement in bilateral TKA with 3-dose regimen versus a single intra-operative dose of intravenous TXA.

Materials and Methods

Study design: prospective non-randomised controlled trial.

Study Groups

Study was conducted over a period of 6 months, from July 2019 to December 2019. All patients undergoing bilateral, simultaneous single-staged TKA were enrolled for the research. Written and informed consent was taken from each participant. The study included 25 patients undergoing bilateral TKA who received three doses of 1 g intravenous TXA (group 1).The first dose was administered following cementing of the knee prosthesis, prior to deflation of the tourniquet. Two more doses were given 6 h apart, after the first dose. The control group included 25 patients matched for age, gender and body mass index (group 2). They received single dose of 1 g intravenous TXA just prior to deflation of the tourniquet.

Inclusion and Exclusion Criteria

All patients undergoing bilateral TKA and having a varus deformity of less than 15° pre-operatively were included in the study. Patients were optimised to have haemoglobin of at least 11 g/dL prior to surgery; otherwise they were not included in the study. Patients with history of thrombo-embolic disease, recent history of cerebral vascular disease or myocardial infarction within last 1 year, unstable angina pectoris or a known thrombotic or bleeding disorder were excluded. Patients who were on any anti-platelet or anticoagulant medications prior to the surgery were also excluded.

Surgical Details

Standard mid-vastus approach was used in all the patients. Tourniquet was inflated prior to the skin incision and deflated after skin closure on both sides. Bilateral TKA was done in the same sitting, and the second knee was started after prosthesis of the first knee had been cemented. Same total knee prosthesis was used in all the patients (NexGen, Zimmer). No negative suction drains were used at the surgical site. All surgeries were performed under spinal and epidural anaesthesia by the same surgeon.

Post-operatively, cryo-packs were used in all the patients for reducing pain and swelling. Mobilisation was encouraged, and they were made to sit at the bedside preferably on the same day, and stand and walk using a walking frame the day after the surgery. Mechanical calf and ankle pumps were used in all the patients as a prophylaxis against deep venous thrombosis (DVT).

Outcomes

Estimation of mean intra-operative blood loss was done by measuring the quantity of blood recovered from suction machines in operating room (subtracting the amount of the saline used during the surgery), and by measuring increase in weight of surgical mops soaked in blood.

Preoperatively, a complete haemogram was done up to a week prior to the surgery. Post-operatively, complete hemogram was done at 48 h after the surgery, and mean drop in hematocrit and hemoglobin (g/dl) was noted by a blinded observer. Wound status of all patients was inspected during routine post-operative dressings after 48 h. Any local wound site complications like surgical site oozing, ecchymosis, or excessive soakage were also compared. All patients with haemoglobin of less than 8 g/dL were given packed red blood cell (PRBC) transfusion in the post-operative period.

DVT Prophylaxis

Low-molecular-weight heparin (LMWH) (enoxaparin 60 mg subcutaneous once a day) was used as prophylaxis against DVT. It was continued for 10 days after the surgery unless it had to be stopped in view of haematoma at the surgical site, oozing from the wound or increasing ecchymosis around the surgical site. In all cases where LMWH had to be stopped, the patients were started on oral anti-platelet drug, like aspirin (150 mg daily), as an anti-thrombotic prophylaxis. Following 10 days of LMWH therapy, anti-thrombotic prophylaxis was continued with oral aspirin (150 mg), once daily for one month.

Statistical Analysis

Continuous variables are presented as mean and standard deviation, and categorical variables as absolute numbers and percentages. Categorical variables were compared using chi-square test in both the groups. Continuous variables in the two group were compared using Student t test. Results were considered statistically significant when the P value was less 0.05. Test results were analysed using SPSS software version 23.0 (SPSS Inc., Chicago, IL, USA).

Sample size calculation was done on the basis of mean difference in post-operative haemoglobin between the 2 groups. Considering clinically significant difference of 2 g/dL, standard deviation of 2 g/dL, power of 0.80 and 95% confidence intervals, sample size was calculated as 16 in each group.

Results

Details of pre-operative mean age, gender and body mass index are presented in Table 1. There was no difference between the 2 groups in mean age, body mass index, gender, pre-operatively knee deformity and pre-operative range of motion of the knee joint.

Table 1.

Comparison of patient characteristics and perioperative details between the 2 groups

Variables	Group 1	Group 2	P value
Mean age (years), SD	64.08, 7.79	64.2, 6.91	0.95
Male/female	5/20	2/23	0.229
Body-mass index, SD	21.82, 2.08	22.51, 1.44	0.184
ASA Grade
Grade 1 (numbers, percentage)	20, 80%	19, 76%	0.739
Grade 2 (numbers, percentage)	4, 16%	5, 20%
Grade 3 (numbers, percentage)	1, 4%	1, 4%
Pre-operative tibial femoral angle (degrees), SD	13.72, 1.45	14.04, 1.39	0.432
Pre-operative range of motion in flexion and exension, SD	108.8, 10.53	108.4, 11.06	0.896
Pre-operative haemoglobin in g/dL, SD	12.8, 1.7	13.2, 1.9	0.437
Post-operative haemoglobin in g/dL, SD	10.3, 2.3	10.3, 2.5	1.000

SD standard deviation

Perioperative and postoperative comparisons between both the groups are tabulated in Table 2. Mean intra-operative blood loss was comparable in the two groups. Mean drop in haemoglobin was less in group 1 (2.51) as compared to group 2 (2.93), but this difference was not statistically significant (p = 0.210). Similarly, mean drop in haematocrit was more in group 2 (9.34), compared to group 1 (9.18), but this was not statistically significant (p = 0.868). Three patients needed PRBC transfusions in group 1 (4 units of PRBC), and four patients needed PRBC transfusions in group 2 (6 units of PRBC). This difference was not statistically significant (p = 0.601).

Table 2.

Comparison of perioperative and post-operative variables between the 2 groups

Variables	Group 1	Group 2	P value
Mean operative time (minutes), SD	80.64, 6.88	83.48, 5.91	0.124
Mean duration of tourniquet use (minutes), SD	75.72, 6.68	78.48, 5.89	0.128
Mean intraoperative estimation of blood loss (ml), SD	200, 20.41	208, 18.71	0.155
Mean Drop in haematocrit, SD	9.18, 4.06	9.34, 2.57	0.868
Mean drop in haemoglobin in g/dL, SD	2.51, 1.27	2.93, 1.06	0.210
Mean number of PRBCs transfused, SD	0.16, 0.47	0.24, 0.59	0.601
Mean length of hospital stay(days), SD	3.2, 0.76	3.68, 1.62	0.187
LMWH stoppage (number)	2	7	0.065

SD standard deviation, POD post-operative day

In group 1, LMWH had to be stopped in two patients on post-operative day 2 because of bruising or sanguineous ooze from the wound. In group 2, LMWH had to be stopped in 4 patients on day 2 and in 3 patients on day 3. This difference was not statistically significant (p = 0.065) (Table 2).

No episode of clinically evident DVT or pulmonary embolism was seen in any patient. Surgical site infection was seen in one patient from group 2, which required irrigation and debridement of the right knee joint. No significant difference was seen in the groups with respect to mean duration of surgery, mean duration of tourniquet use and length of hospital stay (Table 2).

Discussion

TXA is an anti-fibrinolytic drug. Surgical trauma during TKA causes hyper-fibrinolysis, and thus TXA is beneficial in these patients. Since a large part of the procedure is performed under tourniquet, major blood loss may be expected in the post-operative period. Most of this blood loss can be hidden blood loss, which seeps into the anatomical third compartment. This is exacerbated by hyper-fibrinolysis and release of inflammatory mediators, leading to post-operative swelling and inflammation. This hidden blood loss may account for about 50% of blood loss during knee and hip arthroplasty [10]. This hyper-fibrinolysis due to surgical trauma, may peak at 6 h after the surgery, and would last for about 18 h [11]. Elimination half-life of TXA is about 2 h. Thus, a single bolus of tranexamic acid given during the surgery may not be sufficient to reduce hidden blood loss after the surgery.

TXA has consistently shown to reduce blood loss and transfusion requirement after TKA. But, the dosing pattern and frequency of administration vary considerably amongst the studies [3, 4, 7, 8, 12–15]. Several studies have compared outcomes of single dose versus additional doses of TXA, but no conclusive results have been drawn. Xie et al. [16] conducted a randomised control trial comparing a single bolus of 20 mg/kg of intravenous TXA before the skin incision (group 1), to one additional bolus dose of 10 mg/kg 3 h after the surgery (group 2) and two additional doses of 10 mg/kg 3 h and 6 h after the surgery (group 3). Maximum drop in haemoglobin was significantly less in group 3 as compared to group 1. No difference was seen between group 1 and group 2 in haemoglobin drop. Total blood loss was significantly lesser in both group 2 and group 3. Iwai et al. [17] prospectively compared a group of 21 patients receiving single intra-operative course of 1 g TXA with 26 patients receiving two such doses with 3 h apart. Two-dose treatment regimen led to a significant reduction in blood loss after the surgery. Sun et al. [15] compared patients receiving single intra-operative dose with those receiving one additional post-operative dose and 2 additional post-operative doses. No significant difference in mean haemoglobin drop was seen between the groups. Though, a significant reduction in blood loss was seen with the addition of post-operative TXA. But this study was based on unilateral TKA. Total dose of drug received by each patient was same, though they were divided in different frequencies in each group.

Legnani et al. [18] retrospectively compared 2 groups of patients, those receiving a single dose of 15 mg/kg of TXA and those receiving 2 doses of 15 mg/kg of TXA. No statistically significant difference was seen in the amount of blood loss in post-operative drains or in drop in mean haemoglobin concentrations between the two groups. Several other authors have suggested that a single bolus dose of TXA can be as effective as multiple doses [7]. A randomised controlled trial conducted by Hourlier et al. [7] assigned patients into 2 groups, group 1 receiving intra-operative single dose of 30 mg/kg TXA and group 2 receiving a dose of 10 mg/kg followed by a continuous infusion of 2 mg/kg/hour for 20 h starting 2 h later. No significant difference was seen between the two groups in post-operative drain outputs, mean drop in haemoglobin level or number of patients developing post-operative haematoma. Maniar et al. [19] studied different dosing regimen of TXA in patients undergoing TKA. This randomised controlled trial concluded that a pre-operative dose in addition to standard intra-operative dose was more effective in reducing drain output and blood loss. But addition of a post-operative dose to standard intra-operative dose did not result in decreased blood loss. This study enrolled patients undergoing unilateral TKA, and also differed from our study in dose and frequency of administration of drug. Li et al. [9] in a prospective comparative study compared patients receiving two doses of 1 g of intravenous TXA, one before inflation of the tourniquet and another after release of tourniquet with patients receiving supplemental TXA 1 g twice a day for another two post-operative days. No difference in mean haemoglobin drop, total blood loss or post-operative drain output was seen between the groups.

TXA has a good safety profile. It has not shown incidence of increased complications like deep vein thrombosis or pulmonary embolism or worsening of previous cerebrovascular vascular accidents or ischaemic heart disease [20–22]. Much higher doses of TXA have been used in cardiac surgeries [23] without increased incidences of complications. Thus, there are no substantial safety concerns in use of additional doses of TXA. But at the same time, efficacy of additional doses is not supported by this study.

We did not do a separate calculation for total blood loss using formulae as used by Xie et al. [16]. This calculation was not absolutely relevant in our study as we did not use negative suction drains post-operatively to calculate measure blood loss. The entire surgery, starting from the skin incision to skin closure was performed under tourniquet.

Limitations of the study are a relatively smaller sample size and that the patients were not randomly allocated to the study groups. Any subclinical risk of thromboembolic events could also not be investigated. Patients stable for a major elective surgery were included and patients with severe comorbidities were excluded.

Conclusion

Our study has failed to show any significant effect of three-dose regimen versus single-dose regimen of TXA in TKA. Though a trend towards reduction in mean haemoglobin drop and decreased need for stopping LMWH in post-operative period was seen, the results were not statistically significant.

Funding

Nil.

Compliance with Ethical Standards

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical standard statement

The institutional ethics committee approved the study. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. The study was conducted in All India Institute of Medical Sciences, Rishikesh, India.

Informed consent

Informed consent was obtained from all patients for being included in the study.

Research involving human participants and/or animals

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).