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APPLICATION OF TRANEXAMIC ACID FOR THE PERIOPERATIVE PERIOD OF PATIENTS UNDERGOING SCOLIOSIS CORRECTION SURGERY

This study aimed to investigate the efficacy of tranexamic acid (TXA) for the perioperative period of patients undergoing scoliosis correction surgery. 355 patients with scoliosis who were admitted to The Second Affiliated Hospital of Jiamusi University, China, from January 30, 2017, to January 30, 2019, were randomly divided into five groups: experimental group 1 (S1), experimental group 2 (S2), experimental group 3 (S3), experimental group 4 (S4) and control group (D0). Patients in experimental groups were treated with different doses of TXA (15, 30, 45 and 60 mg/kg bw) intravenously, 30 minutes before surgery and sustained infusion of 15 mg/kg bw/h TXA from the beginning until the end of the operation. Patients in D0 group received 30 mg/kg bw normal saline as control. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), haemoglobin, platelet (PT), intraoperative blood loss and postoperative drainage volume in all groups were detected before and after the operation. Plasma levels of tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6 and IL-8 were measured in S2 group and D0 group before, during and after the operation, and then, postoperative complications were recorded. The results showed that the PT, APTT and TT postoperative levels in D0 group were significantly increased compared with the levels in S2, S3 and S4 groups, and the FIB postoperative level significantly decrease compared with the level in S2, S3 and S4 groups. Postoperative levels of haemoglobin and PT in the D0 group were significantly lower compared with the levels in the S1, S2, S3 and S4 groups. The intraoperative blood loss and postoperative drainage volume in the S1 group were significantly increased compared with the levels from S2, S3 and S4 groups. The dose of 60 mg/kg bw TXA determines an increase of cases with complicated embolism compared with lower doses. The optimal dose of TXA was set at 30 mg/kg bw. The plasma levels of TNF-α, IL-1, IL-6 and IL-8 in S2 group were significantly decreased compared with the control group, indicating that the use of low doses of TXA can effectively reduce perioperative bleeding without increasing the risk of complications. In conclusion, 30 mg/kg bw is the optimal dose of TXA showing anti-inflammatory effects at different stages of the systemic inflammatory response induced by surgery.


Introduction
Thoracic scoliosis is a spinal deformity in which one or more vertebral segments of the spine are bent laterally with vertebral body rotation. This deformity determines appearance changes as unequal shoulder height, bilateral thoracic asymmetry, shoulder blade uplift on one side and depression on the other side [1][2][3]. Its mild symptoms include fatigue, shoulder and back pain and difficulty in concentration; in severe cases, in addition to the above-mentioned symptoms, severe back pain and restricted activities of the thoracic vertebra may occur [4][5][6]. Currently, the risk of massive haemorrhage that leads to postoperative anaemia that appears during orthopaedic surgery is very high [7][8][9][10]. In cases of intraoperative blood loss above 500 mL, severe lifethreatening symptoms can develop leading to decreased blood pressure and reduced packed cell volume, thus, it is essential to avoid bleeding in the perioperative period [11,12]. Tranexamic acid (TXA), a synthetic derivative of the amino acid lysine, is an anti-fibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin with fibrin, thereby preventing dissolution of the fibrin clot. TXA has proven to be a cost-effective method in decreasing transfusion rates and avoiding complications associated with low blood volume. Several relevant studies have shown that the use of TXA in surgery can effectively reduce the extracorporeal circulation and intraoperative blood loss during spinal surgery. It reduces bleeding by inhibiting the enzymatic degradation of fibrin blood clots by the serine protease plasmin. During fibrinolysis, plasminogen binds to fibrin via lysing binding sites, where it is converted to the active fibrinolytic enzyme plasmin by tissue plasminogen activator [13]. Lin et al. administered TXA as a bolus of 50 mg/kg bw after induction and before incision, followed by a continuous infusion of 5 mg/kg bw/h during the whole procedure until the wound was closed [14]. They found that there were three thromboembolic complications, including one pulmonary embolism and two deep vein thromboses (DVTs), which were all treated successfully with anticoagulation. There were no cases of myocardial infarction, seizure, stroke, or acute renal failure. Slattery et al. review the literature for the use of TXA in spine surgery to better understand its safety profile and optimal dosage [15]. They reported that the most common dose in the literature is a 10 mg/kg bw loading dose, followed by 1 mg/kg bw/h. Besides, initial loading doses vary between 2 and 100 mg/kg bw, and continuous infusion typically varies between 3 and 10 mg/kg bw/h. Despite this dosing variation, the mode of administration was always intravenous [16]. Therefore, it is of great significance to obtain an optimal dose of TXA to reduce extracorporeal circulation and intraoperative blood loss at the perioperative period without causing complications in patients undergoing scoliosis correction surgery. This study aimed to assess the efficacy of preoperative application of TXA for patients undergoing scoliosis correction surgery.

Patients
In the present study, 355 patients with scoliosis, who underwent scoliosis correction surgery in The Second Affiliated Hospital of Jiamusi University from January 30, 2017, to January 30, 2019, were recruited. They were divided into five groups using the random number table method, 71 patients per group: experimental group 1 (S1; 36 males and 35 females; a range of age, 21 -68 years old), experimental group 2 (S2; 43 males and 28 females; a range of age, 24 -65 years old), experimental group 3 (S3; 29 males and 42 females; a range of age, 22 -68 years old), experimental group 4 (S4; 25 males and 46 females; a range of age, 24 -64 years old) and control group (D0; 34 males and 27 females; a range of age, 25 -70 years old). The study was approved by the Ethics Committee of The Second Affiliated Hospital of Jiamusi University, China. The patients signed the written informed consent form before commencing the study. Inclusion criteria: patients aged ≥ 20 years old; patients with normal liver and kidney functions; patients with normal coagulation function before surgery; patients with no history of taking anticoagulant drugs. Exclusion criteria: patients with poor compliance with therapy and those who were unable to complete the examination; patients with renal insufficiency; patients with contraindications to the use of TXA; patients with chronic diseases; or patients with genetic blood disorders. Surgical procedures All patients were prohibited to drink water 10 h before surgery. Peripheral vein access was opened during surgery and left radial artery catheterization was performed. All patients received an intravenous injection of 0.05 mg/kg bw midazolam (Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China), 0.5 µg/kg bw sufentanil (Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China), 1.5 mg/kg bw propofol (Jiangsu Hengrui Pharmaceutical Co., Ltd., Nanjing, China) and 0.2 mg/kg bw cisatracurium (Jiangsu Hengrui Pharmaceutical Co., Ltd., Nanjing, China) for anaesthesia. Then, a clinical single-chamber dual-capsule endotracheal tube was constructed and connected to the ventilator. The tidal volume was set to 7 ~ 10 mL/kg bw, the respiratory rate was 12 ~ 14 times/min and the patient was placed in a prone position. During the surgery, 5 mg/kg bw/h propofol, 0.2 µg//kg bw/min sufentanil and 0.8 µg/kg bw/min cisatracurium were used. Furthermore, 1 -3 mg/kg bw cisatracurium was administered for 30 min until 0.5 h before the end of surgery. It is noteworthy to maintain arterial pressure in the range of 80 -90 mmHg during surgery. TXA treatment Patients in S1, S2, S3 and S4 groups received an intravenous injection of 15, 30, 45 and 60 mg/kg bw TXA (Changchun Tiancheng Pharmaceutical Co., Ltd., Changchun, China) for 20 min starting 0.5 h before the operation, respectively, and sustained infusion of 15 mg/kg bw/h was maintained from the beginning until the end of the operation. Patients in the D0 group received the same volume of normal saline as control.

Blood sample collection and serum factor detection
During the operation, 6 mL arterial blood was collected on heparin anti-coagulant before cardiopulmonary bypass (CPB), during CPB and 5 h after CPB. The arterial blood was centrifuged at 3000 rpm for 30 min and the supernatant was extracted and stored at -20°C. The levels of tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood samples were detected by double-antibody sandwich enzymelinked immunosorbent assay according to manufacturer instructions (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China). Briefly, the coated plate was incubated at 37°C for 0.5 h and then, the sealing film was removed and dried. Each hole was washed with the concentrated washing solution (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) 5 times in a row. Then 55 μL of enzyme-labelled reagent (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) was added to each hole and the steps before were repeated. Then 55 μL of chromogenic agent A (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) and 55 μL of chromogenic agent B (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) were added to each hole, mixed by shocking and colour development was performed at 37°C for 20 min. 55 μL of termination fluid was added to each hole (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) to stop the colour reaction. The absorbance of each hole was measured at a wavelength of 550 nm within 20 min after the colour reaction was stopped. Immunohistochemistry (IHC) Peripheral blood mononuclear cells (PBMCs) of all patients were stained by IHC. The phosphoric acid buffer solution (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) was used to dilute 3 mL blood at a ratio of 1:1 and it was centrifuged at 3000 rpm for 30 min to collect a layer of milky white liquid suspended in the middle of the test tube. The PBMC sample was soaked at 25°C for 30 min with 35% hydrogen peroxide (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China), and then, it was washed three times with distilled water. Bovine serum albumin (BSA) (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) was added and incubated at 25°C for 25 min, and then, diluted primary anti-goat anti-rabbit IgG antibody (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) was added. It was incubated at room temperature for about 3 h and washed three times with phosphate-buffered saline (PBS). Secondary biotinylated goat anti-rabbit IgG antibody (Beijing Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) was added and incubated at 25°C for 30 min. Finally, the samples were incubated with 3,3'-diaminobenzidine (DAB) (Zhongshan Jinqiao Biological Co., Ltd., Beijing, China) at room temperature for 20 min, and then, rinsed with tap water for colour development. Interpretation criteria were adopted as previously described [17]. The semi-quantitative method was adopted for analysis. For the number of positive cells: 0 and 1 point indicated the positive cells were less than 10% and 10% -25%, respectively; 2 and 3 points suggested the positive cells were 25% -75% and higher 75%, respectively. For the staining intensity: 0 mean the cells were not stained and 1, 2 and 3 indicate that the cells were stained into light yellow, brownish yellow and brownish-purple, respectively. Then, points of the two indicators were added together: 0 referred to negative (-), 1 -4 point(s) referred to weakly positive (+), 5 -8 points indicated positive (++) and 9 -12 points suggested strongly positive (+++).

Observation indicators
The basic data of the patients from the five groups (age, height, weight, body temperature, number of spinal segments, operative time and infusion volume) were collected. The blood coagulation function indicators were detected and recorded before and after the surgery with the PUN-2048B (Prelong New Technology Co., Ltd., Beijing of China), including prothrombin time (PT), activated partial thromboplastin time (APTT), Fibrinogen (FIB) and thrombin time (TT). After the set of the optimal dose of TXA was set, plasma levels of TNF-a, IL-1, IL-6 and IL-8 were detected in S2 group and D0 group before, during and after the operation. The preoperative and postoperative haemoglobin was detected by latex-enhanced turbidimetric immunoturbidimetric assay (LETIA) and PT level was detected by low cytometry (FCM). Besides, the intraoperative blood loss and postoperative drainage volume in 24 hours were recorded. Follow-up was conducted and patients were admitted to the ward 24 h postoperation to identify the symptoms related to wrong anaesthesia and whether there were concurrent vascular embolism, anaemia and other adverse events and the number of patients was recorded as well.

Statistical analysis
The data were statistically analysed by SPSS 19.0 software (IBM, Armonk, NY, USA) and the measured data were expressed as mean ± standard deviation (ẋ ± s). The Student's t-test was used for making a comparison between each pair of groups. p < 0.05 was considered statistically significant.

Results and Discussion
Basic data of patients There were no statistically significant differences in age, height, weight, body temperature, number of spinal segments, operative time and infusion volume between each pair of groups (p > 0.05) (Figure 1).

Figure 1.
Comparison of basic data of patients among S1, S2, S3, S4 and D0 groups A: the patients' age, height, weight and body temperature; B: the number of spinal segments, operative time and infusion volume; C: a patient's CT image

Levels of coagulation function before and after the surgery
There was no statistically significant difference in levels of PT, APTT, FIB and TT before surgery in each group (p > 0.05). In the S1, S2, S3 and D0 groups, the levels of PT, APTT and TT after surgery were noticeably higher than those before surgery and the postoperative level of FIB was markedly lower than the preoperative level (p < 0.05). Postoperative levels of APTT, FIB and TT in the S4 group were significantly higher than those preoperatively and PT level was markedly lower than the preoperative level (p < 0.05). Postoperative levels of PT, APTT and TT in S1 group were significantly higher than those in S2, S3 and S4 groups, and the level of FIB was remarkably lower than that in S2, S3 and S4 groups (p < 0.05). Postoperative levels of PT and APTT in the S2 group were significantly higher than those in S3 and S4 groups, and FIB level was notably lower than that in S3 and S4 groups (p < 0.05). Postoperative PT level in S3 group was dramatically higher than that in the S4 group, and FIB level was significantly lower than that in the S4 group (p < 0.05). The increased levels of PT, APTT and TT in the D0 group were markedly higher than those in S2, S3 and S4 groups (p < 0.05) (Figure 2).
There was no statistically significant difference in levels of PT, APTT, FIB and TT before surgery in each group (p > 0.05). In the S1, S2, S3 and D0 groups, the levels of PT, APTT and TT after surgery were noticeably higher than those before surgery and the postoperative level of FIB was markedly lower than the preoperative level (p < 0.05). Postoperative levels of APTT, FIB and TT in the S4 group were significantly higher than those preoperatively and PT level was markedly lower than the preoperative level (p < 0.05). Postoperative levels of PT, APTT and TT in S1 group were significantly higher than those in S2, S3 and S4 groups, and the level of FIB was remarkably lower than that in S2, S3 and S4 groups (p < 0.05). Postoperative levels of PT and APTT in the S2 group were significantly higher than those in S3 and S4 groups, and FIB level was notably lower than that in S3 and S4 groups (p < 0.05). Postoperative PT level in S3 group was dramatically higher than that in the S4 group, and FIB level was significantly lower than that in the S4 group (p < 0.05). The increased levels of PT, APTT and TT in the D0 group were markedly higher than those in S2, S3 and S4 groups (p < 0.05) (Figure 2).  T  T  T  T  T   T  T  T  T  T  T  T  T  T  T   T  T  T  T   Basic   feature   S1  S2  S3  S4  Levels of coagulation function before and after operation among S1, S2, S3, S4 and D0 groups A: the PT level before and after the operation; B: the APTT level before and after the operation; C: the FIB level before and after the operation; D: the TT level before and after the operation; * p < 0.05 compared with D0; # p < 0.05 compared with S1; & p < 0.05 compared with S2

Figure 3.
Changes in haemoglobin and PT levels before and after the operation in S1, S2, S3, S4 and D0 groups A: the haemoglobin level before and after the operation; B: the PT level before and after the operation * p < 0.05 compared with D0; # p < 0.05 compared with S1 Changes in haemoglobin and PT levels before and after the operation There was no statistically significant difference between the groups in the levels of haemoglobin and PT before the operation (p > 0.05). The postoperative levels of haemoglobin and PT in each group were significantly lower than those before the operation (p > 0.05). The postoperative levels of haemoglobin and PT in the D0 group were noticeably lower than those in the S1, S2, S3 and S4 groups. Postoperative levels of haemoglobin and PT in the S1 group were dramatically lower than those in S2, S3 and S4 groups, and significantly higher than those in the D0 group (p < 0.05). There was no significant difference in postoperative levels of haemoglobin and PT between each pair of S1, S2 and S3 groups (p > 0.05). Postoperative levels of haemoglobin and PT in S1, S2 and S3 groups were significantly higher than those in the D0 group (p < 0.05) (Figure 3).

Intraoperative blood loss and postoperative drainage volume
Intraoperative blood loss and postoperative drainage volume in the D0 group were significantly increased compared with the other groups (p < 0.05). The intraoperative blood loss and postoperative drainage volume were significantly increased in the S1 group compared with S2, S3 and S4 groups (p < 0.05). There was no statistically significant difference in intraoperative blood loss and postoperative drainage volume between S2 and S3 group (p > 0.05). The intraoperative blood loss and postoperative drainage volume in the S4 group were significantly decreased compared with S2 and S3 groups (p < 0.05) (Figure 4).  Postoperative complications As shown in Figure 5, in the S1 group, 2 patients were complicated with postoperative vascular embolism and 5 patients were complicated with anaemia. There was no case with postoperative vascular embolism and 2 cases with postoperative anaemia in S2 group. One patient in the S3 group was complicated with vascular embolism and 2 with anaemia postoperatively. In the S4 group, there were 7 cases of postoperative vascular embolism and 1 case of postoperative anaemia. In the D0 group, 11 patients were complicated with vascular embolism and 13 with anaemia. The number of cases with postoperative vascular embolism and anaemia in the D0 group was significantly higher than that in other experimental groups. The number of patients in the S4 group with concurrent vascular embolism was significantly increased compared with those in the S1, S2 and S3 groups. The number of patients with concurrent anaemia in the S1 group was significantly increased compared with those in S2, S3 and S4 groups.

Comparing plasma levels of TNF-α, IL-1, IL-6 and IL-8 between S2 group and control group
Since the TXA dose of 30 mg/kg bw was found as the optimum dose, the plasma levels of TNF-α, IL-1, IL-6 and IL-8 were compared between S2 group and the control group at different periods. There was no significant difference in TNF-, IL-1, IL-6 and IL-8 in the S2 group and D0 group before surgery (p > 0.05). The intraoperative and postoperative period TNF-, IL-1, IL-6 and IL-8 in the S2 group were significantly lower than those in the control group (p < 0.05) ( Figure 6).  Scoliosis correction surgery is complicated and timeconsuming and a patient's body often bleeds heavily during the whole process. Previous researches reported that the perioperative use of TXA can effectively reduce the amount of blood loss, while there is no unified standard for the optimum dosage of TXA [17][18][19]. Therefore, in the present study, the TXA dose was set to 15, 30, 45 and 60 mg/kg bw. The results showed that the increased levels of PT, APTT and TT in the control group were significantly increased compared with the levels from S2, S3 and S4 groups (p < 0.05), and the decrease of postoperative FIB levels was significantly increase compared with those in S2, S3 and S4 groups (p < 0.05), which was consistent with Yuan et al.'s findings [20]. This is associated with the ability of TXA that is a lysine analogue, to bind to the enzyme activator, and effectively inhibit the activation of the enzyme, thereby reducing the activity of plasminogen. Besides, postoperative levels of PT, APTT and TT in S1 group were significantly higher compared with those in S2, S3 and S4 groups, and the level of FIB was significantly lower compared with those in S2, S3 and S4 groups (p < 0.05), which suggested that a dose of 15 mg/kg bw TXA was not enough to achieve the optimal clinical effect during the perioperative period [21]. Several scholars pointed out that TXA can inhibit the activation of PT and thus play a role in PT protection. In the current study, it was found that the postoperative levels of haemoglobin and PT in the control group were remarkably lower than those in the S1, S2, S3 and S4 groups (p < 0.05), which was in agreement with previous studies. It was further demonstrated that TXA can bind to a spot on the PT membrane and also bind more strongly than fibrinogen or fibrin [22]. Intraoperative blood loss and postoperative drainage volume are of great significance to assess the blood protection effect during the operation. In the current research, it was unveiled that the intraoperative blood loss and postoperative drainage volume in the control group were markedly higher than those in all experimental groups (p < 0.05), which was consistent with Fauzi et al. results [23]. It indicated that TXA could effectively reduce the bleeding and blood transfusion in patients during scoliosis correction surgery. The intraoperative blood loss and postoperative drainage volume in the S1 group were notably higher than those in S2, S3 and S4 groups (p < 0.05). Also, there was no statistically significant difference in intraoperative blood loss and postoperative drainage volume between the S2 group and S3 group (p > 0.05). Additionally, to analyse the safe application of TXA, follow-up was conducted and the postoperative complications in all the groups were recorded. The results of the current research uncovered that there were noticeably more cases of postoperative vascular embolism and anaemia in the control group than those in other experimental groups, which indicated that TXA was safe and feasible for surgical application, and also did not increase the risk of concurrent vascular embolism events [25]. However, the number of patients in the S4 group with complicated vascular embolism was markedly higher than that in the S1, S2 and S3 groups, which reflected that the high dose of TXA administered at 60 mg/kg bw may lead to the risk of postoperative complicated vascular embolism [25][26][27][28]. Also, plasma levels of TNF-α, IL-1, IL-6 and IL-8 were compared before and after the operation in the S2 group and the control group, and it was disclosed that the levels of TNF-a, IL-1, IL-6 and IL-8 in the S2 group were significantly decreased compared with those in the control group (p < 0.05), which indicated that TXA had an antiinflammatory effect on different stages of the systemic inflammatory response induced by surgery, possibly because TXA can indirectly play an anti-inflammatory role by protecting inflammation-related PTs [27].

Conclusions
In the current research, the clinical significance of the preoperative application of TXA in patients undergoing scoliosis correction surgery was analysed by setting different doses of TXA. However, the sample size was relatively small and the follow-up period was short. In summary, TXA can effectively reduce perioperative bleeding in patients undergoing scoliosis correction surgery without increasing the risk of postoperative complications, and it can play an anti-inflammatory role at different stages of systemic inflammatory response. TXA at a dose of 30 mg/kg bw is the optimum dose for blood protection. We will conduct a large * sample size with long-term follow-up on patients with scoliosis and improve the efficacy and safety analysis of TXA.