Application progress of tranexamic acid in neurosurgery

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Application progress of tranexamic acid in neurosurgery

Application progress of tranexamic acid in neurosurgery.  Neurosurgery is often due to the rich blood supply of the scalp, skull, nervous system, and spine, and the operation time is long, and there is a risk of hemorrhage.

Although clinical changes in surgical methods, expansion hemodilution, and autologous blood reinfusion have been used to reduce perioperative bleeding and allogeneic blood transfusion, there are still some cases of blood loss that cannot avoid allogeneic blood transfusion.

Massive blood loss often leads to complications such as hypotension, end organ damage, and coagulation dysfunction, and allogeneic blood transfusion also has the risk of causing transfusion immunosuppressive reactions and postoperative infections.

In recent years, many studies have shown that the antifibrinolytic drug tranexamic acid (TXA) can reduce perioperative bleeding and reduce the mortality rate due to bleeding. This article reviews the application progress of TXA in neurosurgery.

1.  Pharmacology of TXA

TXA is a synthetic lysine analogue that can competitively bind to the lysine site of plasminogen to prevent it from binding to plasmin, inhibit plasmin activation and binding to fibrin, and prevent thrombus dissolution. So as to play an anti-fibrinolytic effect. TXA can also reduce the release of plasmin-mediated vasoactive peptides (such as bradykinin and histamine). Studies have shown that TXA can reduce the early increase of D-dimer caused by fibrinolysis when high fibrinolysis is the pathological basis, such as trauma and postpartum hemorrhage.

Common ways of administration of TXA include intravenous injection, oral and topical use. The protein binding rate is 3%, and it is quickly distributed in the synovium and other tissues after intravenous injection, including umbilical cord blood, cerebrospinal fluid (10% plasma concentration) and breast milk (1% plasma concentration). TXA is eliminated by glomerular filtration as a prototype, and is excreted in urine 2 to 3 hours after administration. Its antifibrinolytic effect can last for 7-8 hours. 24 hours after a single intravenous injection, the elimination rate reached 90%. The plasma concentration of TXA reaches its peak about 3 hours after oral administration, the half-life is 1 to 2 hours, and the bioavailability is about 40%.

2.   Clinical application of TXA

TXA has been widely used in heart, orthopedics, and obstetrics and gynecology operations to reduce perioperative bleeding. The relevant key research is as follows (Table 1). The earliest CRASH‑2 (corticosteroid randomisation after significant head injury‑2) trial has attracted attention from all walks of life. The trial included 20 211 patients within 8 hours after trauma and found that the application of TXA can significantly reduce all-cause deaths in patients It is recommended that TXA be used in all trauma patients. Subsequently, the author analyzed the results of CRASH‑2 again, suggesting that the use of TXA within 3 hours after trauma can reduce the risk of hemorrhagic death, but after 3 hours it seems to increase the risk.

In 2018, the Meta analysis of Gayet-Ageron et al. also indicated that the immediate administration of TXA after acute bleeding increased the survival rate by more than 70%. After that, the survival benefit would be reduced by 10% for every 15 min delay until 3 h after the trauma, and there would be nothing after that. benefit. WOMAN (World Maternal Antifibrinolytic) trial studies the application of TXA in postpartum hemorrhage. TXA 1 g (100 g/L) is used for intravenous infusion at a rate of 1 ml/min. If the bleeding is not relieved within 30 minutes or if the bleeding is recurring within 24 hours of administration A second dose of TXA can be given at the same dose as before. Studies have shown that the number of deaths due to bleeding among women in the TXA group is significantly reduced, especially in patients receiving treatment within 3 hours.

However, the dose of TXA used in the perioperative period is still controversial. For most adults, a total dose of 1 g seems to be sufficient, and there is no clear evidence to support the use of larger doses. However, large doses are used for cardiac surgery, and the total dose in some studies may exceed 5 g. Due to lack of experience, many studies still refer to the use of CRASH‑2. With the widespread use of TXA, some spinal surgery studies have explored the differences in the application effects of different doses of TXA.

The results show that higher doses can reduce blood loss and lower blood transfusion rates, and the difference in safety is not statistically significant. Meta-analysis showed that as the TXA dose increased from 10 mg/kg to 20 mg/kg, the trend of blood loss and blood transfusion rate decreased was not obvious. In various surgical fields, a single intravenous injection of TXA (the most commonly used dose of 15 mg/kg) before surgery can reduce the blood transfusion rate by 72% without increasing the risk of thromboembolism. Therefore, a single dose of TXA can be considered before surgery. , Especially elective day surgery.

In order to reduce the adverse effects of intravenous infusion of TXA, there are trials and studies on topical application of TXA, and it is found that it can also effectively reduce blood loss. However, Fatima et al.’s Meta analysis showed that topical TXA in spinal deformity surgery did not reduce intraoperative blood loss, but was significant Reduce postoperative blood loss and blood transfusion rate; and subgroup analysis shows that low-dose TXA (250~500 mg) is more effective than high-dose (1~3 g) regimen in reducing postoperative blood loss. Moreover, more and more clinical studies have focused on oral TXA, confirming that it has the same clinical effect as intravenous infusion, and this method is economical and easy to implement, and it is expected to be applied in clinical practice.

3 The application of TXA in neurosurgery

3.1 　 Application in adult neurosurgery

3.1.1 　 Application in patients with brain tumors

Some craniocerebral tumors are deep and rich in blood supply, and surgical resection is difficult and takes a long time; and severe hemorrhage associated with craniocerebral tumor resection may affect the complete resection of the tumor. Meningiomas and skull base tumors respectively cause more bleeding due to the parasitism of the pia mater and invasion of the nearby sinuses and blood vessels, and some studies suggest that the pia mater may be rich in tissue-type plasminogen activator, which may aggravate the local high fibrinolysis of the meningioma Intraoperative bleeding. In 2015, Vel et al. analyzed the effect of low-dose TXA (loading dose 10 mg/kg, maintenance dose 1 mg·kg−1·h−1) on intraoperative blood loss in patients undergoing craniotomy for tumor resection. The study showed that intraoperative blood loss in TXA group The amount is less than that of the control group [(817±423) ml to (1 084±605) ml, P=0.012]. Although the rate of allogeneic blood transfusion is reduced, the difference is not statistically significant (21% vs. 30%, P=0.109) . Hooda et al. observed the effect of TXA on blood loss during craniotomy for meningioma. The study doubled the loading dose of TXA while maintaining the same dose and reached the same conclusion. Goobie et al. used higher doses of TXA (loading dose 50 mg/kg, maintenance dose 5 mg·kg−1·h−1) in pediatric premature craniosynostosis surgery and also found that intraoperative blood transfusion was significantly reduced. In 2016, a retrospective study of complex skull base surgery by Mebel et al. included 529 patients with complex skull base surgery. After adjusting for preoperative Hb, tumor diameter, and surgical type, TXA was an independent protective factor for perioperative blood transfusion (OR 0.32, 95%CI 0.15~0.65), and did not significantly increase the risk of epilepsy or thrombotic complications. However, the time span of the study is large, the dose of TXA is not clear and the application is not random, and the results may be biased.

3.1.2 Application for patients with tumors in the spinal canal

Tumors in the spinal canal often involve multiple segments, and the cancellous bone of the spine has more bleeding, which may cause massive bleeding. Recently published a retrospective study on the application of TXA in 60 cases of intraspinal (T1~S1) tumor resection. The TXA group was given a loading dose of 10 mg/kg and a maintenance dose of 1 mg·kg 30 minutes before surgery. −1·h−1 to the end of the operation. The results of this study suggest that perioperative use of TXA can reduce intraoperative bleeding [(253±54) ml to (362±62) ml, P<0.05] and postoperative drainage [(84±30) ml to (140±34) ) Ml, P<0.05], and did not increase the incidence of deep vein thrombosis and other complications.

3.1.3 　 Application in patients with craniocerebral injury

In addition to reducing perioperative bleeding, TXA is also used for the prevention and treatment of nervous system bleeding; the use plan is the same as the CRASH-2 trial. Patients with cerebral hemorrhage progress rapidly and require early intervention. And with the loss of a large amount of blood, the reduction of clotting factors can lead to more severe bleeding.

In the CRASH‑3 trial, after excluding cases with a very poor prognosis (GCS score = 3 points or bilateral pupil unresponsiveness), the head injury-related fatality rate of the treatment group was significantly reduced (P=0.05); subgroup analysis indicated that treatment The group reduced the head injury-related deaths of patients with mild to moderate (GCS score 9-15 and pupil response) craniocerebral injury, but did not reduce the mortality of patients with severe (GCS score 3-8) injury; and Early treatment (within 3 hours) for patients with mild to moderate injury is more effective, and the treatment effect for severely injured patients has little to do with time.

However, after excluding deaths related to craniocerebral injury, although the difference was not statistically significant, other mortality rates in the TXA group were still relatively high, so the safety of TXA still needs more clinical trials to confirm (such as the PATCH trial, etc.). Recently, the Meta-analysis of July and Pranata and Chen and Chen also showed that TXA is related to the reduction of the mortality rate of traumatic brain injury and the increase of hemorrhage. It is worth noting that July and Pranata in a subgroup analysis of randomized controlled trials with a low risk of bias found that the incidence of vascular occlusion events in the TXA group was slightly lower. This may be due to the role of TXA in patients with traumatic brain injury.

Fibrinolysis is not related, but due to its inherent anti-inflammatory effects, protection of endothelial damage and improvement of platelet function. However, Chen and Chen’s analysis showed that the two groups have similar risks of thromboembolism, so a large double-blind randomized controlled trial is still needed to evaluate the potential benefit of TXA on the outcome of vascular occlusion events.

In summary, the current evidence shows that TXA can reduce the risk of perioperative bleeding during neurosurgery in adults without increasing the risk of thrombosis, but it cannot reduce the rate of allogeneic blood transfusion. The common use regimen for adults is intravenous TXA with a loading dose of 10-20 mg/kg and a maintenance dose of 1 mg·kg−1·h−1. The inability of TXA to reduce the blood transfusion rate may be related to the lower dose. The best application plan should be further explored to balance the need to reduce the blood transfusion rate and the possible increased risk of thrombosis.

3.2 The application of TXA in pediatric neurosurgery

In recent years, more and more studies have begun to pay attention to the application of TXA in pediatric neurosurgery. A case study in 2011 reported that a 2-year-old child suffered from massive hemorrhage during lateral ventricle choroid plexus cancer resection, which could not be controlled after routine rescue measures. Finally, TXA 10 mg/kg was injected. About 8 minutes later, the surgeon assessed that the hemostatic effect was good. Lateral ventricle choroid plexus cancer is a malignant tumor of choroid plexus epithelial cells that originates in the ventricle. About 80% of them occur in children. They are hypervascular tumors. Hemorrhage is a key factor for the success of the operation. In 2014, some scholars reported that two cases of lateral ventricle choroid plexus cancer resection in children with TXA (loading dose 50 mg/kg, maintenance dose 5 mg·kg−1·h−1) made blood loss less than 20% of circulating blood volume. %, and the blood loss in a case of not using TXA reached 122% of the circulating blood volume. A retrospective study suggested that TXA (dose not specified) can effectively reduce the amount of blood loss and blood transfusion in children undergoing epilepsy focal resection, and that it is more significant in children under 3 years of age.

Children with premature cranial suture are at greater risk of bleeding during the perioperative period due to the abundant capillary network of the skull. Studies have shown that relatively low doses (loading dose 10 mg/kg, maintenance dose 3 mg·kg−1·h−1 infusion for 8 hours) TXA treatment can reduce postoperative and overall blood loss in children with premature craniosynostosis. The amount of blood transfusion. A study by Ongun et al. observed that there is a linear correlation between intraoperative blood transfusion and postoperative blood transfusion in children with premature craniosynostosis (the greater the intraoperative blood transfusion, the higher the necessity of postoperative blood transfusion, P=0.015). The metabolic needs of young children are higher than those of other age groups. Not only are postoperative blood loss, but the loss of tissue fluid at the incision site will also change hemodynamics and metabolic requirements. Therefore, the postoperative period is also very important. Therefore, TXA surgery should be studied. Post-application to balance the pros and cons of the drug to minimize potential risks.

4.   Adverse reactions of TXA

Studies have shown that the use of TXA has central nervous system adverse reactions such as blurred vision, headache, dizziness, vomiting, and fatigue, which are related to the infusion rate. The faster the infusion rate, the higher the incidence. Probably due to rapid infusion, the blood concentration increases rapidly, the coagulation mechanism is dominant, the blood viscosity increases, the blood flow resistance increases, and the blood flow is not smooth, resulting in insufficient blood supply to the brain, resulting in symptoms such as dizziness and headache.

TXA achieves hemostasis by slowing down the degradation rate of blood clots, rather than changing the coagulation function. There is no significant change in coagulation indexes in patients with TXA before and after surgery. At the same time, studies have reported that TXA does not increase the incidence of thromboembolic events. The CRASH‑2 trial found that TXA can reduce the incidence of acute myocardial infarction. However, some case reports suggest that in patients with a relatively low risk of thrombosis, TXA administration may be associated with an increased risk of acute myocardial infarction.

Therefore, TXA should be used with caution in patients with hypercoagulable states caused by various reasons, such as HIV-infected persons and contraceptive users. Seizures after TXA is a relatively rare complication, which is common in the early postoperative period after cardiac surgery. The related possible mechanism is: TXA is a competitive antagonist of type A gamma-aminobutyric acid receptor and a structural analogue of glycine. Type A gamma-aminobutyric acid receptor and glycine receptor are the main inhibitors of the central nervous system.

Sex mediators, the anion channels gated by these mediators are the targets of TXA, which makes the central nervous system “disinhibited” and increase excitability. There is a dose-dependent relationship between the use of TXA and the risk of seizures. TXA>100 mg/kg is an independent risk factor for postoperative epilepsy. There is no relevant literature report in neurosurgery, and we look forward to further research.

5. Outlook

Neurosurgery often results in inevitable blood transfusion due to excessive blood loss, and blood transfusion may increase related risks (immune rejection, postoperative infection, etc.), so reducing perioperative bleeding is a common challenge for us.

TXA has been widely used in heart, orthopedics and obstetric surgery to reduce perioperative bleeding and blood transfusion needs. The existing small sample size clinical research evidence also shows that the use of TXA in neurosurgery can reduce perioperative bleeding.

In the future, a large-scale, high-quality randomized controlled study is still needed to further explore the effectiveness and safety of TXA in neurosurgery, especially in neurosurgery patients with high risk of epilepsy and thrombosis.

(source:internet, reference only)

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