Asian Pacific Journal of Tropical Medicine (2014)918-921 918

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Document heading doi: 10.1016/S1995-7645(14)60162-0 Effect of ulinastatin combined rivaroxaban on deep vein thrombosis in major orthopedic surgery Xi Yu1,2, Yi Tian2, Ka Wang2,Ying-Lin Wang2, Guo-Yi Lv1, Guo-Gang Tian2*

1Department of Anesthesiology, 2nd hospital of Tianjin Medical University, Tianjin 300211, China 2Department of Anesthesiology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou 570208, China

ARTICLE INFO ABSTRACT

Article history: Objective: ( ) To explore the effect of ulinastatin UTI continuous infusion combined RivaroxabanMethods: Received 24 August 2014 on the deep vein thrombosis in patients undergoing major orthopedic surgery. Received in revised form 10 September 2014 Forty-five patients undergoing major orthopedic surgery were randomly divided into three Accepted 15 October 2014 (U ) (U ) Available online 20 November 2014 groups:ulinastatin continuous infusion c group, ulinastatin single injection s group and control (C) group. All patients received patient-controlled intravenous analgesia (PCIA) after R 10 12 U (5 000 U ) Keywords: operation, and took ivaroxaban mg orally hours after operation. linastatin /kg was given intravenously to both Uc and Us groups preoperatively. Group C was given isometric Ulinastatin normal saline, group Uc was pumped UTI continuous intravenously at the end of surgery (10 000 Rivaroxaban U/kg) to 48 hours through PCIA pump. The values of hematocrit (HCT), thrombomodulin (TM), DVT Interleukin (IL-6), -antithrombin complex (TAT), D-Dimer (D-D) were normally tested Orthopedic surgery ( ) ( ) ( ) ( ) ( ) before surgeryResults: T1 , at the end of the surgery T2 , 12 hours T3 , 24 hours T4 and 48 hours T5 C T1 TM IL 6 TAT after surgery. ompared with P , there was an upward tendency in , - , , and D D C ( 0 05) T - after operation in group group < . . Phe values of them were significantly increased 24 U ( 0 05) I U from nearly -hour after surgery in s Pgroup Conclusions:< . . n group c, there were no significant changes in these indices after operation ( >0.05). During the perioperative period, ulinastatin continuous infusion combined Rivaroxaban can correct blood hypercoagulability through different approaches in patients undergoing major orthopedic surgery.

anticoagulation and unpredictable blood drug concentration 1. Introduction is limiting its application. Ulinastatin, an acid which contained in the fresh urine of healthy humans, is Deep vein thrombosis (DVT) is the most common and well known to inhibit the activity of . The serious complication after the major orthopedic surgery, recent researches show that UTI could inhibit which includes total hip replacement (THR), total knee and fibrolysis by inhibiting the leukocyte activity. Therefore, replacement (TKR) and hip fractures surgery (HFS). Despite the combination therapy of revaroxban and UTI perhaps active anticoagulant therapy is given after the surgery, the advance the development of anticoagulant regiment. fatality rate of the DVT can reached 3.8%, and the fatality rate of the pulmonary thromboembolism (PTE) can reached 2. Materials and methods 38.9%[1]. Although compared to traditional anticoagulants, the new 2.1. Participants and inclusion criteria oral anticoagulant- rivaroxaban has advantages of safe dose rang and noninvasive administration, but the single mode of After local ethics committee approval and written informed consent, 45 ASA 栺 or 栿 patients, aged 40-90 yr, scheduled *Corresponding author: Guo-Gang Tian, Department of Anesthesiology, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou 570208, for elective total hip replacement or hip fracture surgery, China. were enrolled in this study. Patients with such coexisting Tel: +86-18222471718 E-mail: [email protected] diseases or conditions as preoperative bleeding, clotting Foundation project: It is supported in part by Scientific Research Fund of Hainan disorders, an abnormal coagulation test, thrombocytopenia, Provincial Health Department (No.2010-83). Xi Yu et al./Asian Pacific Journal of Tropical Medicine (2014)918-921 919 and severe renal, hepatic or heart disease were excluded. 3. Results Aspirin and other antiplatelet agents were discontinued 7 days before the scheduled procedure. 3.1. General observation Patients were randomly divided into three groups: ulinastatin continuous infusion (Uc) group, ulinastatin single injection (Us) group and control (C) group. The general data compared with treatment group and (T 1) 2.2. Treatments control group as followsP able , and there was no significantly differences ( >0.05) in sex, age, type of surgery, etc. No significant change of the HCT was found between After enter the operating room and before the anesthesia three groups in each time point, which excluded the effect of induction, Uc and Us group were premedicated with UTI blood dilution on the experimental results (Table 2). [2] 5 000 U/kg , which was dissolved in normal saline 100 mL, Table 1 Group C was given isometric normal saline. Spinal anesthesia Comparison of background variables. was performed at the L2-L3 interspace as the patient in lateral position. All patients received a patient-controlled Issues Uc Us C intravenous analgesia (PCIA) for 48 h postoperatively. The Sex (M/F) 8/7 9/6 8/7 PCIA setting was as follows: background infusion fentanyl Age 68.27依13.26 69.80依11.97 66.73依13.89 BMI 22.31依1.55 21.92依1.47 21.51依1.60 20 毺g/kg and ondansetron 8 mg, which was dissolved in NS to 100 mL, at a rate of 2 mL/h, bolus dose 0.5 mL, lockout Type (THR/HFS) 11/4 12/3 11/4 inerval 15 min. The patients in Uc group were received UTI OR time(min) 79.00依23.69 80.33依28.31 80.33依26.35 continuous infusion of 10 000 U/kg to 48 hours with the help Blood loss(mL) 124.00依61.04 150.67依78.96 142.33依72.97 of infusion pump. If visual analog scale (VAS) >3 in spite of Infusion(mL) 973.33依187.91 923.33依273.77 1 093.33依405.26 treatment, a second dose of analgesic (fentanyl 0.05 mg) was Table 2 n given. Changes of hematocrit in three groups ( =15, %, mean依sd). All the operations were conducted by the same surgery Indexes Uc Us C and anesthesia team. All the patients took rivaroxaban HCT T1 38.31依3.93 36.34依4.75 38.36依3.65 10 mg orally 12 hours after the operation. Tests would be T2 33.75依4.38 31.63依4.32 33.37依3.30 discontinued if the tendency of bleeding occurred. T3 34.3依5.66 33.5依5.77 33.30依3.17 2.3. Clinical evaluation and laboratory examination T4 32.42依5.93 31.57依3.36 32.25依3.27 T5 30.91依5.50 29.76依3.24 30.85依2.52

The operation time, blood loss and the infusion were 3.2. TM scores recorded. Blood sample were obtained for analysis of Hematocrit A T 3 TM (HCT), thrombomodulin (TM), Interleukin-6 (IL-6), thrombin- s shown in able , score was graduallyP increased C 48 ( 0 05) H antithrombin complex (TAT), D-Dimer (D-D) levels at 5 in group till hours after theP surgery < . . owever, U ( 0 05) T TM intervals: before surgery (T1) , at the end of the surgery (T2) it was declined in c group < . . he scoreP was , 12 hours (T3) , 24 hours (T4), 48 hours (T5) after the surgery. significantly increase 24 hours after single injection ( <0.05). HCT were detected with hematology analyzer (SysmexXE- 3.3. IL-6 scores 2100). Serum IL-6, TAT, D-D, TM concentrations were assayed by ELISA (R&D company, America). As shown in Table 4, after the surgery, both ulinastatin 2.4. Statistical analysis single injection group and ulinastatin continuous Pinfusion group showed no conspicuous change in IL-6 ( >0.05). 2 H IL 6 Statistical analysis was performed with the 氈 test of owever, theP level of - in control group was significantly the sex and type of surgery. One-way factorial analysis of increased ( <0.05). But 24 hours after single injection, the (ANOVA) IL-6 score in Uc group were significant increase as in C varianceP was used in analysis of other demographic P ( 0 05) N U data. value <0.05 was considered as statistically significant group < . . o outstanding changeP was observed in c difference. group till 48 hours after the surgery ( >0.05).

Table 3 n Changes of TM in three groups ( =15,毺g/L, mean依sd). Groups T1 T2 ●▲ T3 ●▲ T4 ●▲ T5 ●▲

Uc 47.36依15.07 40.42依9.37 ● 40.60依8.80● 34.82依6.19 ▲ 43.98依13.14▲

Us 41.93依11.42 42.35依8.45▲ 44.18依8.98▲ 50.50依14.33▲ 57.00依9.52▲

C 44.33依8.00▲ 51.62依7.66 53.86依7.47 54.72依8.47 57.10依8.31 ● P P Compared with group C, <0.05; Compared with T1, <0.05. Xi Yu et al./Asian Pacific Journal of Tropical Medicine (2014)918-921 920 3.4. TAT scores diagnosed from imageology, it is hard to be cured. So the early prophylaxis and discovery of thrombophilia is the key From Table 5, it showed that TAT exhibited roughly to prevent DVT. 48 C P increasingP tendency after the surgery for hours in revious studies showed that low molecular heparin ( 0 05) H U U group < . , owever,P c group and s group showed no injected subcutaneously could be used to prevent and cure significant changes ( >0.05). DVT effectively. Meanwhile, the potent anticoagulant effect 3.5. D-D scores could cause bleeding tendency, and it is one typical side effect. Moreover, the way of invasive administration reduces the clinical compliance of patients. Recently, it has been As shown in Table 6, 12 hours after the surgery, no reported that one kind of new oral anticoagulant rivaroxaban remarkable changes was found in D-D serous concentration is replacing its anticoagulation status gradually as a result U R of both linastatin single injectionP group and ulinastatin of simple and noninvasive application. ivaroxaban plays continuous infusion group ( >0.05). Nevertheless, the a role in restraining the process of blood coagulation as a D D F controlP group showed very significant increase in - kind of highly selective xa inhibitor, and it has been widely ( 0 05) A 12 D D U B level < . . lso after hours, - concentrationP in c used in clinic currently. ut there are some scruples with its group was significantly lower than that of C group ( <0.05). using process, for example, the drug lacks of individualized A D D U [5] [6] lthough the P- level in s group was higher compared treatment plan , and it still induces bleeding tendency . C ( 0 05) U with groupP < . , and no significant difference was linastatin, an acid glycoprotein which was contained observed ( >0.05). in the fresh urine of healthy humans, is well known to 3.6. Comparison of clinical adverse reaction inhibit the activity of inflammation. The recent researches showed that UTI could inhibit coagulation and fibrolysis by inhibiting the leukocyte activity[7]. This function is Both three groups showed no hemorrhagic tendency. very important in regulating coagulation system. So it is hypothesized that Ulinastatin may take effect on preventing 4. Discussion DVT. Because of this, during the treatment,’ we especially emphasize on changing’ patients hypercoagulabale state, Patients with trauma and orthopedic surgery can cause not just aim to theirs single anticoagulation’ function. The local tissue swelling, inflammation infiltration, endothelial treatment target is to improve patients medication safety by cells damage at the same time, which promote the blood assisting in regulating the coagulation system. platelet aggregation and adhesion. In perioperative The results in this study suggest that the combination of UTI period the restrict mobility, the using of bone cement and and rivaroxaban can significantly decrease the incidence of tourniquet in the surgery, and general anesthesia, obesity, postoperative DVT as detection by laboratory examination. etc, are all risk factors for DVT occurred[3,4]. Once DVT was Even in those patients with the highest tendency to develop

Table 4 n Changes of IL-6 in three groups ( =15, ng/L, mean依sd)

Groups T1 T2 T3 ● T4 ● T5 ●

Uc 478.82依124.01 468.86依112.99 455.24依84.37 493.31依66.12 ▲ 499.26依107.78▲

Us 538.09依162.15 537.71依122.96▲ 585.67依87.92 ▲ 641.45依111.81▲ 635.61依101.65▲

●C 471.83依69.12 ▲ 528.50依114.09 546.35依102.79 574.47依93.21 601.32依150.73 P P Compared with group C, <0.05; Compared with T1, <0.05. Table 5 n Changes of TAT in three groups ( =15, ng/L, mean依sd).

Groups T1 T2 T3 ● T4 ● T5 ● Uc 640.95依120.73 620.34依73.38 577.86依94.73 632.43依97.47 644.06依120.21 Us 636.99依87.23 639.55依61.93▲ 617.04依49.63▲ 675.41依109.81▲ 710.31依113.13▲

●C 605.91依67.11▲ 693.63依121.11 664.35依86.78 752.56依100.95 736.97依71.15 P P Compared with group C, <0.05; Compared with T1, <0.05. Table 6 n Changes of D-D in three groups ( =15,毺g/L, mean依sd). Groups T1 T2 T3 ● T4 ● T5 ●

Uc 763.91依121.34 763.30依176.93 729.28依151.75▲ 656.90依176.05▲ 705.69依193.90▲

Us 760.32依112.21 799.80依121.28▲ 877.62依152.11▲ 1 008.53依250.67▲ 1 141.09依218.54▲

●C 764.37依129.71▲ 881.75依132.10 870.60依97.17 938.17依110.67 1 065.70依145.44 P P Compared with group C, <0.05; Compared with T1, <0.05. Xi Yu et al./Asian Pacific Journal of Tropical Medicine (2014)918-921 921 thrombosis, such as elderly patients having major orthopedic the low molecular fragment originated from active operations. There was no complication occurrence after pharmacological reaction still have effect, this suggests administrating the drugs. that in theory, if single dose of UTI was administered at the Previously, Virchow stated that venous thrombosis was beginning of the surgery, the effect would maintain for a long caused by changes in one or more of three important time[12]. In this experiment, the results show that the effect factors- blood flow,“ venous ’endothelium,” and the clotting of UTI just lasted for 12-24 hours if single injection, while mechanism[8]. And Virchow s triad is of prime importance all the investigated indices were kept stable in condition in the prevention of thrombosis. of continuous injection of UTI. It means that UTI combined In our experiment, though rivaroxaban was routinely given with rivaroxaban is a satisfactory method of preventing the for anticoagulation therapy postoperatively in C group, a DVT. rising curve of L-6, TAT, D-D and TM occurred and lasted In this study, we explored the effect of combined UTI from the completion of the surgery to 48 hours after the with rivaroxaban on preventing DVT. The conclusion was surgery. UTI can inhibit the rise of these parameters. This drawn that the combination of UTI and Rivaroxaban was finding was consistent with those of several precious reports. more effective than using rivaroxaban only, and it is also Sympathetic excitation and further vasoconstriction resulted important for UTI to be intravenously injected continuously. from Trauma and surgery, the use of alkaline anesthetics, However, this study is lack of large-scale and multicenter the -reperfusion injury caused by tourniquet are all clinical verification. Moreover, we just observed the changes considered to play a part in the endothelial cells disorder. of indices in 48 hours after the surgery. Thus, further TM, a type of membrane receptor locating on the surface of studies are still needed to search for a reasonable drug vascular endothelial cells, would be released into the blood administration time and the suitable dosage. when the cell was damaged. This experiment suggests that Conflict of interest statement UTI has a role on protecting endothelial cell and contrarily less role effect on rivaroxaban; in single injection group, endothelial cells are observed to start damaging 24 hours We declare that we have no conflict of interest. after the surgery. The primary mechanisms of the UTI on the References protection of endothelial cells may not only depending on inhibiting the activity of secreted by neutrophils, but also directly inhibit the secretion of the enzyme itself[9]. [1] Bosson JL, Labarere J, Sevestre MA, Belmin J, Beyssier L, Elias TAT is induced by thrombin and has a rapid turnover. A, et al. 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