Combined Application of Tranexamic Acid and Thrombelastography in Pediatric

This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. From Department of Anesthesiology, Department of Neurology, Xuanwu Hospital, Beijing, China; Department of Anesthesiology, Beijing Children's Hospital, Capital Medical University, Beijing, China.


September, 2017
Volume 4 Number 5 E pilepsy is a chronic neurological disorder (1). Surgery is the most effective way to control seizures in drug-resistant focal epilepsy, and surgery may results in improvements in cognition, behavior and quality of life, especially in children (2). Because the head of children accounts for 19% of the body, compared to 19% in the adults, a large percentage of cardiac output is directed to the brain and results in greater cerebral blood volume, compared to adults; meanwhile children have less autoregulatory reserves and less blood volume. These factors place the infants at risk for significant hemodynamic instability during neurosurgical procedures, as compared to adults (3). Besides, long term antiepileptic drugs (AEDs) taken often cause coagulopathies, such as hypofibrinogenemia (4). Therefore pediatric patients undergoing epilepsy surgery are under high risks of bleeding, hemodynamic instability and coagulopathies. Coagulation management is thus very essential in pediatric epilepsy surgery to maintain hemodynamic stability, reduce allogenetic transfusion and decrease corresponding complications.
Lacking of timely and accurate monitorings of coagulation status in this kind of surgery, component blood transfusion had to rely on anesthetists' experience. Relying on prothrombin time (PT) and active partial thromboplastin time (APTT) tested prior to operation may result in misunderstanding of coagulation status, because they could not reflect the whole coagulation process and timely coagulation status during operation. Thrombelastography (TEG) plays an important role in perioperative transfusion guidelines, and has been proven useful for rapid assessment of homeostasis in patients with coagulopathy (5)(6)(7)(8). TEG permits characterization of clotting process in whole blood by visualizing the viscoelastic changes that occur during coagulation in vitro, then provideing a graphical representation of the fibrin polymerization process.
Tranexamic acid (TXA) is a potent antifibrinolytic drug that prevents plasminogen activated by plasminogen activator (9). It is useful in the treatment of bleeding, without increasing the risk of thromboembolism in adult cardiac surgery, knee replacement surgery, and hip fracture surgery (10)(11)(12), as well as in pediatric cardiac surgery, spine surgery and craniosynostosis sur-gery (13)(14)(15).
The main goal of this study is to investigate whether combined application of TXA and TEG in pediatric epilepsy surgery can decrease blood loss, transfusion requirements and post-operation complications.

Patients and Ethical Approval
The study was conducted at the Department of Anesthesiology, Xuanwu Hospital, Beijing, China, from 1 June 2014 to 31 March 2016, after obtaining approval from the Ethic Committee of Xuanwu Hospital and informed consents signed by patients' guardians.
Thirty-two pediatric patients aged 1-10 years, graded as American Society of Anesthesiologists physical status (ASA) I-II, scheduled for elective epilepsy surgery under general anesthesia were randomized by random number table to Group T (Group T=Group Treatment, n=16) and Group C (Group C=Group Control, n=16, Figure 1). Patients with hepatic dysfunction, renal dysfunction, blood disease, family history of hemorrhagic disease, allergies history of TXA or operation duration was less than 3 hours or over 8 hours were excluded. Cases undergoing a second surgery because of severe post-operative complications were removed from the study.

Anesthesia Process
All patients received general anesthesia. Electrocardiogram (ECG), heart rate (HR), pulse oxygen saturation (SpO 2), end-tidal partial pressure of carbon dioxide (PETCO2) and nasopharyngeal temperature (NT), invasive blood pressure (IBP) and pulse pressure variation (PPV), central venous pressure (CVP) were continuously monitored via a multifunctional monitor (AS/5, Datex-Ohmeda, Finland). Sedation depth was monitored by bispectral index (BIS, Covidien, MA, USA) and maintained between 40 and 60 during surgery. NT was controlled between 36℃ and 37℃ by an automatic heating blanket and heated air device. Ketamine of 5-7 mg/kg was injected intramuscularly prior to induction if patients can't cooperate with anesthetists. Otherwise, uncooperative patients were induced by inhalation of 8% sevoflurane in 8 l/min fresh gas for 5 minutes. After ve-nous access in the upper limb was obtained, anesthesia induction was performed with propofol of 1-2 mg/kg, fentanil of 3 µg/kg, and rocuronium of 0.6 mg/kg, and then endotracheal intubation was performed. Patients were ventilated with 50% oxygen in air. Tidal volume was set as 8-10 ml/kg, and I:E ratio was 1:2. PETCO2 was maintained between 30 mm Hg and 35 mm Hg. Anesthesia was maintained with a continuous infusion of propofol (6-8 mg/kg/h) and remifentanyl (0.2-0.4 µg/kg/ min). Goal directed fluid therapy (GDFT) strategy was employed during operation to maintain the PPV value between 13% . Postoperative analgesia was carried out by intravenous parecoxib sodium (1 mg/kg) and 0.25% ropivacaine was used as local infiltration anesthesia at the incision site.

Coagulation Management
TEG analyses (CFMS TM, Sinopharm Cmic, Beijing, China) was used to guide clotting factors supplement. TEG curve reflects different phases of the clotting process. The parameters used in this study are defined as follows: R (reaction/clotting) time is the period from the initiation of test till the beginning of the clot formation, reflecting coagulation factor activities. The α-angle is the angle between the baseline and the tangent to the TEG curve through the starting point of coagulation (the split after the end point of the Rtime), indicating shortage of fibrinogen (Fib). Maximal amplitude (MA) is a direct measure of the highest point on the TEG curve and represents clot strength. Low MA means reduced platelet function. Ly30 is calculated on basis of the reduction in the area under the curve, which reflects fibrinolysis (6).
At the beginning of surgery, Group T was given TXA at a loading dose of 10 mg/kg in 15 minutes and then maintained at the speed of 5 mg/ kg/h; while Group C was given the same dosage of normal saline. TEG and blood gas analysis were taken at the following time points: the beginning of surgery (T1), opening the dura mater (T2), closing the dura mater (T3) and the end of surgery (T4) in both groups. As T1-T4 were the key procedures of the surgery and between T1-T4 were the main procedures causing bleeding.
Transfusion strategy of fresh frozen plasma (FFP), platelet (PLT), and Fib was made by experience according to evaluated volume of blood loss and blood gas results, without knowing the TEG results in Group C. While in Group T, it was made according to TEG results : 1) if R>8 minutes, FFP of 8 ml/kg was transfused; 2) when α-an-gle<53°, Fib of 15 mg/kg was given; 3) if MA<50 mm, platelet concentrates of 1 unit was infused.    Red blood cells (RBC) were transfused when hemoglobin (Hb) in blood gas analysis was less than 70 g/l or circulatory instability in both groups.
The primary endpoints of this study were blood loss and transfusion requirements. The secondary endpoints were postoperative hospital stay and relative complications. The volume of blood loss, blood transfusion, post-operative drainage and complications were recorded. The results of TEG test and blood gas analysis at T1-T4 were recorded, so were blood routine examinations and coagulation tests piror to and following operation.

Statistical Analysis Sample Size Calculation
According to the preliminary experiments in 2012-2014 in our Hospital, a sample size of 13 patients per group would give a power of 90% at a level of 0.05 to detect 30% or more reduction in allogenetic transfusion, which was 41% in pediatric elective epilepsy surgery. 32 patients were recruited to compensate any exclusion. Data are presented as means± standard deviation or medians with ranges, 25% and 75% percentiles.

Data Analysis
Statistical analysis was performed with SPSS19.0. All quantitative data were evaluated for Gaussian distribution and homogeneity before statistical analysis. Mann-Whitney U-test was used intra and between groups with non-normally distributed quantitative data. Normally distributed quantitative data was analyzed by unpaired t-test with between groups, and One-way ANOVA intragroup. Χ 2 test was used for categorical data. P< 0.05 was considered as a statistical significance.

RESULTS
32 pediatric patients undergoing elective epilepsy surgery (frontal lobe resection or temporal lobe resection) were recruited and randomized into two groups. There is no significant difference in general condition (Table 1), pre-operative Hb, pre-operative hematocrit (Hct) or baseline coagulation function ( Table 2). The incidence of fibrinogen inefficiency was 31.25% and 37.50% in Group T and Group C individually (P=0.710).
Intra-operative blood gas analysis showed a significant difference in Hb ( (Figure 2, Figure 3). TEG showed similar results at the end of surgery (T4) compared to the beginning of surgery (T1) in both groups, except MA values at T4 were significantly decreased com -

DISCUSSION
Epilepsy is a chronic neurological disease and may impair cognition progressively. For refractory epilepsy, surgery is indicated (1). Patients undergoing epilepsy surgery suffering long period of operation and extensive insult, are under high risks of blood loss, coagulopathy and transfusion related complications, especially in children who have less blood volume and inadequate automatic circulatory regulation. AEDs taken before surgery also result in coagulation dysfunction, such as thrombocytopenia, abnormal platelet function and hypofibrinogenemia Coagulation Management in Pediatric Epilepsy Surgery Qing-Fang Duan et al.   The beginning of surgery (T1), opening the dura mater (T2), closing the dura mater (T3) ,the end of surgery (T4); a P<0.05 (compared to T1); b P<0.05 (compared to Group C).

Table 4. Volume of Intra-Operative Blood Loss and Intra-Operative
Transfusions.   (16)(17)(18)(19). Besides, extensive tissue injury of the surgery induced large amount of tissue activators of fibrinolytic system, which leads to hyperfibrinolysis. Thus, reducing transfusions and related complications by coagulation management is essential in pediatric epilepsy surgery. Current strategy of transfusion is almost relying on anesthetists' experience and laboratory examination. RBC was transfused when Hb was less than 70 g/L, and FFP administered only when PT and APTT are >1.5 times the normal value. PLT transfusions may be indicated to maintain concentrations greater than 50 × 10 9 /l (20). However, tests taken after massive bleeding, leading to delayed transfusion, and PT, APTT or PLT tested pre-operatively could not reflect whole procedure of coagulation. It's difficult to reduce transfusion and complications caused by massive blood loss, such as low body temperature, circulatory failure, coagulopathy, allergy, pyrexia, or infectious disease, etc (21).
TEG gives us a new choice in pediatric coagulation management. It could reflect whole procedure of coagulation and fibrinolysis, and thereby provides a global assessment of haemostatic function. The technology is based on measurements of the viscoelastic changes associated with fibrin polymerization that are happening during coagulation of a whole blood sample in vitro. The viscoelastic changes are recorded and finally converted to a curve. It may help doctors evaluate coagulation fuction to decrease the risk for bleeding and reduce the allogeneic blood transfusion in cardiac surgery with cardiopulmonary bypass and in liver surgery (6,(22)(23)(24). TXA reversibly blocks the lysine binding sites of plasminogen, prevents activation of plasmin and stops lysis of polymerized fibrin. When massive blood loss is expected, prophylactic use of TXA can be a part of blood conservation strategy (9,25). TXA prevents massive bleeding caused by AED related hypofibrinogenemia and surgery related hyperfibrinolysis, without increasing the risk of thromboembolism. However, few researches revealed pharmacokinetics and dosage regimen of TXA in pediatric patients. We used a TXA loading dose of 10 ml/kg and followed by continuous infusion of 5ml/kg/h, which was recommended by pharmacokinetic modeling (15,26). Our results suggested combined application of TXA and TEG in pediatric epilepsy surgery may decrease perioperative hemorrhage and allogeneic blood transfusion ratio, which was consistent with the previous studies performed in other kinds of surgeries. In a case report with 3 pediatric patients undergoing elective hemispherectomy, using the same dosage of TXA together with hourly TEG results, observed a decrease in transfusions than reported (27). There was no significant difference in RBC and FFP transfusion volume per kilogram, and further study with enlarged sample size was indicated. Evenmore, in our study, as revealed by the TEG results, no hyper coagulative status was induced by this strategy. Post-operative seizures were less than pre-operation apparently.
No death occurred in 32 pediatric patients during hospital stay; postoperative hospital stay was shortened significantly in Group T. It suggested combined application of TXA and TEG may contribute to better postoperative recovery. Further studies were indicated.
Although our study suggested combined application of TXA and TEG in Group T may have many advantages over Group C, there are still some limitations. Firstly, this study was performed only in one center and the sample size was small. It may cover some side effects of our strategy. Secondly, this study recruited patients undergoing resection of frontal and temporal lobes. Although patients were randomized into two groups, the difference of excision location and size may still influence volume of blood loss. Thus, further study should enlarge the sample size to eliminate the difference and explore long-term effects.

CONCLUSIONS
Infusion of TXA and TEG guided coagulation management in pediatric epilepsy surgery may decrease blood loss, reduce transfusion requirements and shorten postoperative hospitalization. This strategy may not increase the risks of thromboembolism.