| Background:Total knee arthroplasty(TKA) is the most effictive procedure for patients who suffer from the osteoarthritis pain, which may have contributed to the higher risk of perioperative bleeding with new generation anticoagulant. Tranexamic acid(TXA), a synthetic derivative of the lysine, has been used to reduce the blood loss by inhibiting fibrinolysis. It has shown TXA has not been associated with increased thromboembolic events due to TKA with traditional anticoagulants as thromboprophylaxis. However, there are a few reports of serious adverse events such as cerebral infarction and renal failure. Moreover, in most of the studies the patients were only clinically screened. The potential risk of venous thromboembolism(VTE) events due to the anti-fibrinolytic effect of TXA remains a cause of hesitance to its administration of route, timing and dosing in TKA patients. Further, there was little literature about TXA in simultaneous bilateral TKAs where blood loss, transfusion rate and thromboembolic risk are likely to be higher. Hence, there is a pressing need to develop an antifibrinolytic regimen that would maximize hemostatic effect and avoid VTE risk. Purpose:We conducted this prospective randomized controlled study in order to compare the effect and safety of intravenous(IV), topical and combined administrations of TXA on lowering blood loss and transfusion rate in patients undergoing unilateral TKA. Moreover, we performed this prospective study to evaluate the effect and safety of fixed dose TXA in patients undergoing simultaneous bilateral TKAs. Further, We investigate the effect of preoperative IV and intraoperative topical administrations of TXA on lowering blood loss and transfusion rate in patients undergoing simultaneous bilateral TKAs, and to compare its effect with that of a single IV does. Methods:1. The study protocol of Section A was approved by the Institution Ethics Committee and registered in ClinicalTrials of National Institutes of Health. Between April 2014 and December 2015, 150 consecutive patients that were candidates for simultaneous bilateral TKAs in our institution were offered enrollment in this prospective randomized double-blinded parallel-controlled study. All subjects were allocated to receive either(1) 1 g of TXA using IV injection 15 minutes before tourniquet inflation(IV group),(2) 1 g of TXA in 10 mL normal saline using intraarticular application intraoperatively after joint capsule closure(topical group), or(3) 1 g of TXA using IV injection 15 minutes before tourniquet inflation and 1 g of TXA using intraarticular application intraoperatively after joint capsule closure(combined group). Preventive anticoagulant therapy using rivaroxaban was initiated postoperatively. Doppler ultrasound scan was routinely used to diagnose VTE. Adverse events were assessed and documented until postoperative week 6. The primary outcome measures were total blood loss. The secondary outcome measures were blood transfusion rate, transfusion units, drainage volumes, intraoperative blood loss, hidden blood loss, postoperative suprapatellar girth increment and VTE events.2. The study protocol of Section B was approved by the Institution Ethics Committee and registered in Chinese Clinical Trial Registry and ClinicalTrials of National Institutes of Health. Between January 2013 and June 2014, 120 consecutive patients that were candidates for unilateral TKAs in our institution were enrolled in this prospective randomized double-blinded placebo-controlled study. All subjects were allocated to receive either(1) 1 g of TXA using IV injection 15 minutes before tourniquet inflation(treatment group), or(2) isovolumetric normal saline(control group). Preventive anticoagulant therapy using rivaroxaban was initiated postoperatively. Doppler ultrasound scan was routinely used to diagnose VTE. Adverse events were assessed and documented until postoperative week 6. The primary outcome measures were total blood loss. The secondary outcome measures were blood transfusion rate, transfusion units, drainage volumes, intraoperative blood loss, hidden blood loss, postoperative suprapatellar girth increment, knee society score(KSS) and VTE events.3. After obtaining institutional review board approval of Section C, inpatient medical records and preoperative and postoperative outpatient clinical charts of 80 consecutive patients(40 in each group) undergoing simultaneous bilateral TKAs in our institution between July 2015 and January 2016 were analyzed in this retrospective study. For patients in IV group, 1 g of TXA in 100 mL of saline was administered intravenously before tourniquet inflation. In combined group, 1 g of TXA was injected intravenously 15 minutes before tourniquet inflation followed by 1 g of TXA using intraarticular application intraoperatively after each joint capsule closure. Preventive anticoagulant therapy using rivaroxaban was initiated postoperatively. Doppler ultrasound scan was routinely used to diagnose VTE. The primary outcome measures were total blood loss. The secondary outcome measures were blood transfusion rate, transfusion units, drainage volumes, intraoperative blood loss, hidden blood loss, suprapatellar girth increment and VTE events. Results:1. We compared the effect of IV, topical and combined administrations of TXA on lowering blood loss and transfusion rate in patients undergoing unilateral TKA. The total blood loss in the IV, topical and combined group was 1055.7 ± 337.2, 1064.8 ± 327.1 and 780.4 ± 273.2 mL, respectively, with a significant intergroup difference(P < 0.001). The total blood loss was also significantly less in the combined group compared to the IV and topical groups(P < 0.001). No significant difference was found between IV and topical group(P = 0.079). There was 1 patient in the IV group and 2 patients in the topical group requiring blood transfusion on postoperative day 3, but no one required transfusion in the combined group. No significant difference was found among groups(P = 0.773). The suprapatellar girth increments did not differ among groups on postoperative day 5(P = 0.718). 1 patient with thrombosis of popliteal vein was found in the topical group. There were 5(10%) patients in the IV group, 2(4%) patients in the topical group and 4(8%) patients in the combined group that developed unilateral calf muscle vein thrombosis(CMVT). There were no differences in the incidence of CMVT among groups(P = 0.718). Neither symptomatic pulmonary embolism(PE), myocardial infarction(MI), stoke nor all-cause mortality occurred during follow-up.2. We evaluated the effect and safety of fixed dose TXA on blood loss after simultaneous bilateral TKAs. The total blood loss was 1739.48 ± 609.12 ml in the treatment group, whereas the total blood loss was 2392.89 ± 538.77 ml in the control group. There was a significant difference between two groups(P < 0.001). The total blood loss on the day of the surgery was significantly lower in the treatment group than in the control group(P < 0.001). No significant difference was found between groups on days after the surgery. The intraoperative blood loss and drainage volume of bilateral knees in the treatment group was significantly lower than that in the control group. However, the hidden blood loss did not differ between the groups, which was supported by the finding of almost the same suprapatellar girth increments in the treatment group compared to the control group on postoperative day 5 and week 6(P = 0.251 and 0.299). Transfusion requirements were decreased from 96.7% to 60.0%(P < 0.001). Additionally, the knee score and function score were not different between the treatment and control groups on postoperative week 6. No symptomatic VTE complications, including deep vein thrombosis, PE were found in any patient. There were 10(16.7%) patients in the treatment group and 9(15.0%) patients in the control group that developed CMVT. There were no differences in the incidence of CMVT between the treatment and control group(P = 0.570). All cases with CMVT were confirmed by an ultrasound scan on postoperative week 6. Also, 9(15.0%) patients of bruises and 7(11.7%) patients of nausea occurred in the treatment group. 10(16.7%) patients of bruises and 5 patients of nausea occurred in the control group. Incidence of adverse events in the two groups was not significantly different. Neither deep infection nor all-cause mortality occurred during follow-up.3. We investigate the effect of preoperative IV and intraoperative topical administrations of TXA on lowering blood loss and transfusion rate in patients undergoing simultaneous bilateral TKAs. The total blood loss was 1410.48 ± 480.3 ml in the combined group, whereas the total blood loss was 1760.2 ± 648.1 ml in the IV group. There was a significant difference between two groups(P = 0.008). The drainage volume and hidden blood loss were significantly lower in the combined group than that in the IV group(P = 0.004 and 0.025, respectively). However, the intraoperative blood loss did not differ between the groups(P = 0.202). Although the transfusion rate and transfusion units in the combined group were less than that in the IV group, the difference failed to reach significance(P = 0.370 and 0.632, respectively). No significant difference in suprapatellar girth increments was found in the combined group compared to the control group on postoperative day 5 and week 6(P = 0.177 and 0.072, respectively). There were 12.5% patients in the combined group and 17.5% patients in the IV group that developed CMVT. There were no differences in the incidence of CMVT between groups. Incidence of adverse events in the two groups was not significantly different. Neither deep infection nor all-cause mortality occurred during follow-up. Conclusion:1. The combined administration of intravenous and topical TXA can effectively lower blood loss in patients undergoing unilateral TKA without increasing the risk of thromboembolic complications. The blood loss was significantly less in the combined group compared to the IV and topical groups. However, no significant difference was found between IV and topical group.2. Fixed dose of TXA for patients undergoing simultaneous bilateral TKAs was effective in reducing total blood loss and allogeneic blood transfusion needs without any additional thromboembolic risk, including asymptomatic and symptomatic VTE events. However, TXA did not significantly reduce the hidden blood loss.3. The combined administration of TXA can more effectively lower blood loss in patients undergoing simultaneous bilateral TKAs. The transfusion reqirement in the combined group were not less significantly than that in the IV group. The combined administration of TXA did not decrease joint swelling without increasing risk of VTE. It may serve as an ideal option for simultaneous bilateral TKAs where thromboembolic risk are likely to be higher.In summary, the combined administration of TXA, which has the advantage of route, timing and multiple-dosing, can most effectively lower blood loss in patients undergoing unilateral and simultaneous bilateral TKAs with new generation anticoagulant. Moreover, it may avoid high risk of VTE with the increase in dose. The antifibrinolytic regimen has considerably lowered transfusion reqirement of TKAs and conserved blood resources in our institution, which has obtained good economic and social benefits. It has built a very solid foundation of improving the existing comprehensive blood management strategy. |
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