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CLINICAL INVESTIGATIONS
Year : 2009  |  Volume : 53  |  Issue : 6  |  Page : 667-671 Table of Contents     

Efficacy and Safety of Tranexamic Acid in Control of Bleeding Following TKR: A Randomized Clinical Trial


1 Head of the Department of Anesthesia, Fortis Hospital, Shalimar Bagh, New Delhi, India
2 Attending Consultant, Department of Anesthesiology and Pain Management, Max Super specialty Hospital, Saket, New Delhi. 110017, India
3 Associate consultant, Department of Anesthesiology and Pain Management, Max Super specialty Hospital, Saket, New Delhi. 110017, India
4 Ex Senior resident, Department of Anesthesiology and Pain Management, Max Super specialty Hospital, Saket, New Delhi. 110017, India

Date of Web Publication3-Mar-2010

Correspondence Address:
P N Kakar
B - 8, Sushant Lok, Phase II, Golf Course Road, Sector - 56, Gurgaon
India
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Source of Support: None, Conflict of Interest: None


PMID: 20640094

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Total knee arthroplasty (TKA) is generally carried out using a tourniquet and blood loss occurring mainly post operatively is collected in drains. Tranexamic acid is an antifibrinolytic agent which decreases the total blood loss. Patients had unilateral / bilateral cemented TKA using combined spinal and epidural anaesthesia. In a double-blind fashion, they received either placebo (n=25) or tranexamic acid (n=25)10 mg.kg -1 i.v., just before tourniquet inflation, followed by 1 mg kg -1 h -1 i.v. till closure of the wound. The postoperative blood loss, transfusion requirement, cost effectiveness and complications were noted. The groups had similar characteristics. The mean volume of drainage fluid was 270 ml and 620 ml for unilateral(U/L) and bilateral(B/L) TKR patients in placebo group. Whereas it was 160ml and 286 ml respectively in unilateral(U/L) and bilateral(B/L) TKR patients who received tranexamic acid. This was considered statistically significant. Control group patients received 26 units of PRBC as compared to 4 units in tranexamic acid groups (p<0.001). This was again statistically significant. None of the patients in any of the groups developed deep vein thrombosis. Tranexamic acid decreased total blood loss by nearly 54% in B/L TKR and 40% in U/L TKR and drastically reduced (> 80%) blood transfusion.

Keywords: Tranexamic acid, TKR, blood loss


How to cite this article:
Kakar P N, Gupta N, Govil P, Shah V. Efficacy and Safety of Tranexamic Acid in Control of Bleeding Following TKR: A Randomized Clinical Trial. Indian J Anaesth 2009;53:667-71

How to cite this URL:
Kakar P N, Gupta N, Govil P, Shah V. Efficacy and Safety of Tranexamic Acid in Control of Bleeding Following TKR: A Randomized Clinical Trial. Indian J Anaesth [serial online] 2009 [cited 2019 Dec 7];53:667-71. Available from: http://www.ijaweb.org/text.asp?2009/53/6/667/60241


   Introduction Top


Major orthopedic procedures including hip and knee replacement and spine surgery, are associated with severe bleeding because of extensive dissections through bony and fibrotic tissue, increased fibrinolysis due to tourniquet application and surgery and inability to cauterize bleeding bony surfaces. [1],[2]

Tissue and vascular damage during surgery or trauma, stimulates cascade of coagulation leading to clot formation to prevent blood loss. However during surgery and trauma the fibrinolytic system is also acti­vated which leads to premature breakdown of the clot and excessive blood loss. [3], [4]

The activation of plasminogen, the plasma pre­cursor of the proteolytic enzyme plasmin mediates fi­brinolysis. Plasminogen binds to lysine residues on the surface of fibrin and is converted to plasmin by an ac­tivator released from endothelial cells [tissue plasmino­gen activator (t-PA)] that simultaneously binds to fi­brin. Plasmin then degrades fibrin into soluble fibrin degradation products. [3] Tranexamic acid is a synthetic derivative of the amino acid-lysine, which exerts antifibrinolytic effect through reversible blockade of lysine binding sites on plasminogen molecules. By block­ing lysine-binding sites on plasminogen molecules and thereby inhibiting the interaction of plasmin fibrin, it ex­erts its antifibrinolytic effect. [5],[6]

So, this study was designed to evaluate the effi­cacy of tranexamic acid (TAX) in reducing blood loss and postoperative blood transfusions following TKR.


   Methods Top


After Institutional, review board approval, a double blinded, prospective, randomized, placebo­controlled study was performed in 50 patients under­going primary cemented total knee arthoplasties (both unilateral(U/L) and bilateral(B/L).Written consent was obtained from all patients.

Patients were excluded if they had one of the fol­lowing criteria: known or suspected allergy to medica­tions used (TAX, local anaesthetics, midazolam, pethi­dine, propofol), inherited or acquired hemostatic dis­eases, abnormal coagulation screening tests (platelet count, prothrombin time, activated partial thromboplas­tin time), ingestion of aspirin or other nonsteroidal anti­inflammatory drugs within seven days of surgery, renal or hepatic insufficiency, pregnancy, history of deep venous thrombosis (DVT) or pulmonary embolism or history of ocular pathology or ophthalmological proce­dure other than corrective lenses.

Patients were randomly allocated, into four groups as follows:

Group TU (n = 12): U/L TKR patients received TAX

Group TB (n = 13): B/L TKR patients received TAX

Group CU (n = 12): U/L TKR patients received NS

Group CB (n = 13): B/L TKR patients received NS

All patients underwent a pre anaesthetic check up and were premedicated with oral ranitidine 150 mg, alprazolam 0.25 mg and metoclopramide 10 mg HS and in morning of surgery. All patients were moni­tored with five-lead electrocardiography (ECG), pulse oximetry; end tidal carbon dioxide, core temperature through nasal probe and non invasive blood pressure monitoring.

The anaesthetist, surgeon and the observer were blinded to the study drug. A person not further involved in the study prepared and started the test/placebo drug before tourniquet inflation. In Group TU and TB, Tranexamic acid was given immediately before infla­tion of the tourniquet. After a test dose of 1mL, pa­tients received a dose of 10 mg.kg -1 IV followed by an infusion of 1 mg.kg -1 hr -1 until skin closure. Patients in Group CU and CB received an equivalent volume of physiologic saline. Pneumatic tourniquet around the upper thigh was inflated to a pressure of 250-300 mm Hg in all patients before incision and deflated at the end of surgery. Before the surgery, Hb transfusion trigger point was determined for each patient according to the following criteria: for patients over 60 yr and associ­ated cardiopulmonary disease the transfusion trigger was 10 g dL -1 whereas for other patients, the transfu­sion trigger was 8 g dL -1 .

Intraoperative blood losses were negligible be­cause of tourniquet. Postoperative blood losses were assessed by measuring wound drainage until drains withdrawal (± 24 hr). During surgery and in postop­erative period, measured blood losses were replaced with Ringer's lactate in a 3:1 ratio and/or with pentastarch 10% (maximum dose 1500 mL) in a 1:1 ratio until Hb concentration fell below the transfusion trigger point. Thereafter, patients received leuco de­pleted allogenic packed red blood cells. Factors known to influence intraoperative and postoperative blood losses were noted. These included tourniquet time and pressure, length of surgery, mean arterial blood pres­sure maintained during surgery and minimal core tem­perature achieved.

After surgery patients were shifted to post anaes­thesia care unit for further management. Post opera­tive pain was managed with epidural infusion of 0.125% bupivacaine with clonidine 1.5 mcg.ml @ 4-6 ml/hr. Hemoglobin concentration, platelet count; coagulation profile and renal function tests were measured in the immediate postoperative period, after 4 hours and on postoperative day one. Drains were removed after 24 hours in the postoperative period.

Statistical analysis

For tests of differences between quantitative data, two-sided t-tests were used. In the text, data are pre­sented as mean ± standard deviation (SD) and p val­ues of <0.05 are considered significant.


   Results Top


There were no significant differences between the patients with respect to age, sex, weight, duration of surgery and fall in core temperature. [Table 1](p > 0.05)

The mean total blood loss was 270 ±88 ml and 620± 75 ml in U/L and B/L TKR patients in control groups. Whereas, in groups TU and TB (Those who received TAX), blood loss was 160 ± 87 ml and 286 ± 83 ml respectively. (P< 0.05) [Figure 1] This was statis­tically significant.

Altogether, the control group was given 26 units, compared with 4 units in the tranexamic acid group [Figure 2] Fall in hemoglobin concentration was consid­erably higher in the control group. [Figure 3] (p >0.05) This again was statistically significant.

None of the patients in any of the groups had clini­cal evidence of deep vein thrombosis observed daily for seven days or biochemical evidence of coagulation abnormality. Intraoperative hypotension requiring treat­ ment was comparable in the two groups.


   Discussion Top


We have investigated the effect of intraoperative tranexamic acid on blood loss and reduction of blood transfusion required after total knee arthoplasties.

Tranexamic acid (1, 4- amino- carboxylic acid) is an antifibrinolytic agent which is seven to 10 times as potent as epsilon aminocaproic acid (EACA). The vol­ume of distribution is 1.0 litre kg -1 and the plasma half­life approximately 80 min. The therapeutic concentra­tion is 5-10 mg.lit -1 . The therapeutic effect of tranexamic acid is apparent when the haemostatic system has pro­duced a fibrin clot which is prematurely dissolved by the proteolytic action of plasmin. 7

We had given tranexamic acid before inflation of tourniquet because fibrinolytic activation is a cascade process that is most easily inhibited in its earlier phases.

Moreover, previous research on tranexamic acid and thrombosis has failed to show any thrombogenic effect, even in patients who were treated for several days or even weeks. [4], [8] This may be due to the fact that fibrinolytic activity in vein walls is not affected by tranexamic acid. [4], [8] We did not do routine screening for thrombosis in our study because all the patients received LMWH in the postoperative period.

As shown in numerous studies, the fibrinolytic re­sponse after trauma is biphasic with an increased ac­tivity during the first hours, followed by a shutdown that peaks at about 24 hours. [9] After knee arthroplasty the early post-traumatic fibrinolysis is further augmented by that induced by the tourniquet. [10] The dosage regi­men adopted by us seems to be an adequate compro­mise between fibrinolytic inhibition and the risk of in­ducing an augmented fibrinolytic response.

In our study there was reduction in blood loss by 40% in Group TU and 54% in Group TB (patients receiving tranexamic acid). [Figure 1] This reduction in blood loss was statistically significant. This also reduced the postoperative blood transfusions by > 80%. [Figure 2] which again was statistically significant. The higher effectiveness in B/L TKR patients can be explained by the fact that in B/L TKR patients the bleeding is more as fibrinolytic system is already activated when second joint is operated.

The results are comparable to Cochrane review on "antifibrinolytic use for minimizing perioperative blood transfusion". It included 21 trials of tranexamic acid vs. control (hip and knee replacement), and reviewed 993 patients in orthopedic surgery. It showed that tranexamic acid, significantly reduced allogenic blood transfusion (56% ) and total amount of blood lost dur­ing perioperative period (avg. 440 ml) in orthopedic surgery. [11]

Beoni et al also showed a 48% reduction in blood loss and 70 % reduction in postoperative blood trans­fusion with the use of tranexamic acid. The total num­ber of transfused units was 12 in the prophylactic group of 43 patients as against 40 in the placebo group of 43 (p = 0.002). [4]

Patients in the tranexamic acid group were given 4 units of blood in total, compared with 26 units in the control group. In our hospital the dose of tranexamic acid given would cost Rs. 166, compared with Rs. 6000 for a unit of leucodepleted banked blood. Thus, the immediate saving in the patients given tranexamic acid would have been about Rs. 5000. (Cost calculation in appendix)

Appendix

  • Cost of 1 unit leuco depleted PRBC = Rs. 6000
  • Total cost of blood in Control patients ( 26 units) = Rs 1,56,000
  • Total cost of blood in TAX patients ( 4 units) = Rs 24, 000
  • Cost of 1 ampoule of TXA = Rs 166
  • Cost of TXA ( 25 patients) = Rs 8,300
  • Cost of blood saved by giving TXA= Rs 1,23,700
  • Cost saved per patient = Rs 4958
  • Potential savings per year ( 500 patients) = Rs 25,00,000


To our knowledge, giving tranexamic acid is the only blood saving method that is cheaper, per saved unit, than banked blood in this type of surgery. This estimate does not include potential adverse effects from banked blood such as immediate transfusion reactions, transmission of infectious agents and disturbances of the immune system.

In conclusion, TXA reduces perioperative bleed­ing by almost a half in patients undergoing TKR, and reducing blood transfusion requirement in these patients by almost 80%.It is also tempting to determine if addi­tional benefit could be achieved by repeating the Tranexamic acid in the post operative period.



 
   References Top

1.Pier Mannuccio Mannuccio and Marcel Levi. Preven­tion and treatment of major blood loss. N Engl J Med 2007; 356:2301-11.  Back to cited text no. 1      
2.Sculco TP, Adams GL, et al. Global blood management in orthopedic surgery. Clin Orthop Relat Res 1998;357:43­49.  Back to cited text no. 2      
3.Lisa Hall Zimmerman Causes and consequences of criti­cal bleeding and mechanism of blood coagulation. Phar­macotherapy 2007:27:45 S - 56 S.  Back to cited text no. 3      
4.Benoni G and 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-B:434-440  Back to cited text no. 4      
5.Montserrat Vera-Llonch. Clinical and economic conse­quences of bleeding following major orthopedic sur­gery. Thrombosis Research 2006;117: 569-577.  Back to cited text no. 5      
6.Cid and Lozano. Tranexamic acid reduces allogenic red cell transfusions in patients undergoing total knee ar­throplasty: results of a meta-analysis of randomized controlled trials. Transfusion 2005;45:1302-07.  Back to cited text no. 6      
7.Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999; 57:1005-32.  Back to cited text no. 7      
8.Bekassy Z, Astedt B. Treatment with fibrinolytic inhibi­tor tranexamic acid - risk for thrombosis? Acta Obstet Gynecol Scand 1990; 69: 353-54.  Back to cited text no. 8      
9.Eriksson BI, Eriksson E, Risberg B. Impaired fibrinoly­sis and postoperative thromboembolism in orthopedic patients. Thromb Res 1991; 62: 55-64.  Back to cited text no. 9      
10.Malone PC, Morris CJ. The sequestration and margin­ation of platelets and leucocytes in veins during condi­tions of hypokinetic and anemic hypoxia. Potential sig­nificance in clinical postoperative venous thrombosis. J Pathol 1978; 125: 119-29.  Back to cited text no. 10      
11.Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, et al. Anti-fibrinolytic use for minimiz­ing perioperative allogenic blood transfusion (Review). Cochrane Database of Systematic Reviews 2007, Issue 4.  Back to cited text no. 11      


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

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