Title: How Effective is Intra-Articular Tranexamic Acid in Reducing Blood Loss in Total Knee Arthroplasty; Prospective, Randomised, Double-Blind Study
Author(s): Robin G MacGillivray FCA(SA)1, Samih B Tarabichi MD2, Nayzak T Raoof FRCA1, Marwan F Hawari MD1, Usama H Saleh MD2*
Affiliattion(s): 1 The American Hospital Dubai 2 Tarabichi Joint Replacement Institute
* Corresponding Author
Vol 1, Num 2, October 2014
The effect of intra-articular tranexamic acid on blood loss in concurrent bilateral total knee arthroplasty was studied in 60 patients in double blind fashion; one knee receiving tranexamic acid, the other knee receiving physiological saline acting as control. A single surgeon performed all operations utilising the same surgical technique and prosthesis. Mean blood loss from intra-articular drains was not significantly different, being 141ml in the tranexamic acid group and 163ml in the control group.
Circumferential leg measurements at levels above, through and below the knees were not significantly different between groups on day two post-operatively compared to pre-operatively. Intra-articular tranexamic acid instillation did not lead to a significant reduction in blood loss in these patients.
Keywords: Bilateral total knee arthroplasty, Blood loss, Intra-articular tranexamic acid
Tranexamic acid (TA) is a synthetic amino acid that inhibits fibrinolysis by preventing plasmin binding with fibrinogen and fibrin structures after clot formation.(1) Intravenous TA has been shown to diffuse rapidly into the synovial fluid (2), and has been shown in meta-analysis to reduce blood loss and requirement for allogenic blood transfusion in total knee arthroplasty (TKA).(3)
In TKA post-operative blood loss is attributed to diffuse microvascular bleeding as a consequence of increased fibrinolytic activity after release of the tourniquet. Following evidence that local application of TA can reduce blood loss in orthopaedic surgery (4), recent attention has turned to the intra-articular application of TA in TKA (5-9), with demonstrated success in reduction of blood loss versus placebo. Concurrent bilateral total knee arthroplasty (BTKA) would be expected to be associated with a higher blood loss and transfusion requirement.
In a previous study utilising intravenous TA, we demonstrated a modest reduction in transfusion requirement with the higher of two recommended doses of intravenous TA 10. However there is an associated risk of systemic thromboembolic events such as deep vein thrombosis (DVT) and pulmonary embolus (PE) with intravenous administration. As minimal systemic absorption of TA has been observed with local application (5), we studied the effect of intra-articular TA on blood loss in one knee of patients undergoing BTKA, the other knee of the patient acting as his/her own control. A single surgeon performed all operations utilising the same surgical technique and prosthesis.
Materials and Methods
Following approval from the institutional ethics and research committee, written consent was obtained from 60 patients presenting for BTKA. The patients were randomly allocated to one of two groups:
Group 1 received a solution of 3g TA (Cyklocapron 100mg/ml; Pharmacia, Uppsala, Sweden) up to 50 ml with normal saline into the right knee joint; and 50 ml normal saline into the left knee joint. The solution was prepared under sterile conditions and coded in the pharmacy, supplied to the scrub nurse who emptied the contents into a sterile bowl. The solution was applied by bulb syringe to the open joint prior to closure and placement of a surgical suction drain.
Group 2 received the same solutions but with the TA applied to the left knee, and the saline to the right knee.
All surgeries were performed under spinal anesthesia by the same surgeon using a standard sub-vastus approach, with the same design prosthesis (NexGen, Zimmer, Warsaw, Ind). The right knee was operated on first in all cases. The intra-articular drains (Hemovac, Zimmer) were left closed for one hour following deflation of the tourniquet.
The contents of the drains had the volumes collected from the two sides recorded independently, up to the time of their removal, with reinfusion of autologous blood according to standard protocol.
Patients were not eligible for the study if they had a history of: allergy to TA, anaemia, any bleeding diathesis, recent anticoagulant therapy, acute intracranial disease or haemorrhagic stroke, myocardial infarction within three months, gastrointestinal or urogenital bleeding within six months, severe renal or liver disease or active malignancy.
Preoperative investigations included haemoglobin (Hb), haematocrit (Hct), platelet count, Prothrombin Time (PT), International Normalised ratio (INR), activated partial thromboplastin Time (aPTT), liver and renal function tests. The haematology (Hb, Hct, platelets, PT, INR, aPTT) were repeated on days 1 and 3 postoperatively and before discharge. Postoperative Hb values less than 80g/dl acted as trigger for transfusion of allogenic packed red blood cells.
Leg circumference at levels of 6cm above midpoint of the knee, at midpoint and 6cm below were measured pre-operatively and on day 2 post-operatively, to investigate whether TA has an influence on leg swelling after surgery 6. Venous thrombo-embolism prophylaxis was started post-operatively with 10mg rivaroxaban (Xarelto, Johnson & Johnson), any thrombotic or other complication occurring during the hospital stay was recorded.
It was calculated that a sample size of 30 in each group would have a 90% power to detect a mean blood loss difference of 300ml (assuming a SD of 280) using 2 group t- test with 0.050 2-sided significance level.
Details of 59 patients are shown in Table 1 (one patient from Group 2 was excluded from the study as the volume of blood loss from the drains was not recorded). There were no significant differences between them as far as the data presented. While the duration of surgery and tourniquet times were no different between groups, the times between right leg and left leg were different, Table 2.
Blood loss as measured from the drains did not differ between those receiving TA (mean 141ml +/- 107) and NS (mean 164ml +/- 112), Table 3. There was also no significant difference between right and left leg drainage in either the TA or the NS patients, or in overall drainage between right and left sides, Table 3.
In terms of leg swelling as evidenced by circumferential measurements, there was no significant difference between TA and NS groups at any of the three levels, Table 4.
Haematology values are shown in Table 5. Haemoglobin and haematocrit values fell by day 3 post-operatively such that 34 of 59 patients received 68 units of packed red blood cells, an average of two units per patient. There were no thrombo-embolic events recorded.
Total knee arthroplasty (TKA) is associated with significant peri-operative blood loss, leading to calls for implementation of blood conservation strategies, including correction of pre-operative anaemia, the use of pharmacological agents to promote haemostasis, and alternatives to donor blood 11.
In meta-analysis tranexamic acid (TA) has been shown to be effective in TKA when given intravenously 3,12, and a number of recent studies have suggested that local application of TA is also an effective route of administration without systemic side effects 5-9, not only in single primary TKA but also in simultaneous bilateral TKA 13, when compared to a control population.
In this study however, in an attempt to remove possible confounders, we have evaluated the effect of TA versus placebo in the same patient undergoing concurrent bilateral TKA in double blind prospective manner. Early post-operative blood loss from intra-articular drains, clamps released one hour after tourniquet deflation, was similar for both knees. There was also no difference in swelling between knees treated with TA or placebo, a marker for covert blood loss into the tissues. As both groups had had TA and NS, haematological markers could not be used to differentiate blood loss.
There were significant falls in haemoglobin values over the first three post-operative days, however these were not overtly different to the control group in our previous study on intravenous TA10, nor was the requirement for allogenic transfusion in more than half the patients. Collectively these results suggest that in this group of patients intra-articular TA as administered does not have a significant effect on post-operative bleeding, results which are in conflict with previously published work.
The reasons for this discrepancy are unclear. By randomising the order in which the TA was administered, any effect of systemic absorption following release of the first tourniquet should be eliminated, though previous work has shown such absorption to be minimal anyway 5. The right knee was operated on first in all cases, the tourniquet inflated before skin preparation and draping, which explains the difference in tourniquet times between right and left knees.
A recent meta-analysis of the use of haemostatic agents after major surgery concluded that topical application of TA (and aminocaproic acid) is a promising strategy, though while reducing post-operative blood loss, few studies reported a significant reduction in transfusions, intensive care unit stay, or length of hospitalisation 14.
Intra-articular application of tranexamic acid in one knee did not lead to a significant reduction in measured blood loss versus placebo in the other knee, in patients undergoing concurrent bilateral total knee arthroplasty.
Robin G MacGillivray FCA(SA) The American Hospital Dubai, Dubai, UAE
Samih B Tarabichi MD Chairman, Tarabichi Joint Replacement Institute, Dubai, UAE firstname.lastname@example.org
Nayzak T Raoof FRCA The American Hospital Dubai, Dubai, UAE
Marwan F Hawari MD The American Hospital Dubai, Dubai, UAE
Usame Hassan Saleh MD Orthopaedic Surgeon, Tarabichi Joint Replacement Institute, Dubai, UAE email@example.com
Acknowledgements: We thank Mr Dieter Kaufmann, MSc, Outcomes and PMS coordinator Int Clinical Affairs, Zimmer GmbH, Winterthur CH, for statistical support; our colleagues of theDepartments of Anesthesia and Orthopedics, and the nursing staff of the Joint Replacement Unit of the American Hospital Dubai, UAE, for assistance with data collection.
Financial disclosure: None declared.
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