Does Administering Tranexamic Acid Decrease Blood Loss During Craniotomy?

Blood loss is one of the major complications in surgery, especially neurosurgery, due to interference with the surgical view. Substantial bleeding often requires blood and isotonic fluid replacement as blood loss compromises the cerebral perfusion pressure. Low cerebral perfusion pressure decreases oxygen availability to the cranium and consequently, renders secondary insult.

Major blood transfusion amends hemodynamic changes. However, this intervention can have adverse consequences, including allergic reaction, acidosis, citrate toxicity, hypocalcemia, and anemia.1 As a result, further ancillary supply is required to remedy the initial problem, blood loss.

Further replacement using a large volume of isotonic fluid dilutes red blood cells and coagulation factors; inevitably, this confers the risk of coagulopathic disorder which can enhance blood loss.1 There exists an apparent ‘vicious cycle’ of complications that exacerbate the primary problem. This technique is both resourcefully and economically wasteful, increasing supply use, cost, and time without amending the overriding problem. Additionally, major transfusion is associated with volume circulatory overload, which can potentially cause pulmonary edema and lung injury.

Despite the negative consequences associated with blood transfusion, it is necessary to replenish cells that do not proliferate quickly, for example, red blood cells. Conventional approaches which reduce blood loss and transfusion requirements have been implemented, such as cell savers or autologous blood donation.2 However, autologous blood donation may be insufficient and requires planning. Also, these few alternative approaches are costly.

One pharmacological approach is the administration of tranexamic acid, a technique that is economical and can be feasibly integrated into the anesthetic management to reduce blood loss and transfusion requirements.

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Tranexamic acid is a fibrinolytic composed of 4 trans aminomethyl cyclohexane carboxylic acid. Its structure mirrors lysine but has a greater affinity with plasminogen.1 It competitively competes with lysine to prevent the activation of plasminogen to plasmin, an enzyme that disintegrates clots and increases the risk of bleeding.1 Tranexamic acid decreases this risk and maintains clots that are already formed. This literature review aims to evaluate the current evidence regarding the benefits of tranexamic acid in facilitating blood loss reduction during craniotomy.

Relevant literature regarding tranexamic acid and its effect on blood loss during craniotomy was retrieved from various databases (PubMed, Proquest, Ebscohost, and Cochrane). The search focuses on studies examining the efficacy of tranexamic acid in reducing blood loss during craniotomy. The initial search was overgeneralized, yielding numerous and ambiguous results. An advanced search was used to narrow down the number of articles. The followintransfusiong keywords were used in the advanced search section: “tranexamic acid” “neurosurgery,” “craniotomy,” “beneficial,” “blood loss,” and “transfusion.” The search was limited to works from the year 2014 to the present, and full-text published articles and peer-reviewed journals. The search yielded about 30 articles, most with randomized controlled trials.

A randomized controlled trial was conducted to evaluate the effect of tranexamic acid on blood loss reduction in 100 participants (ages 18-60 years) undergoing elective craniotomy for tumor resection.1 Participant had ASA 1 and 2 with supratentorial tumors.1 Participant with coagulopathy, renal, hepatic disorders and prescribed anticoagulants were excluded from the study.1 Each patient was induced with fentanyl 2 mcg/kg, thiopental 5mg/kg and vecuronium 0.1mg/kg.1 EtCO2 was kept at 30-33mmHg, core temperature was maintained between 36 C to 37 C and standard monitoring procedures were conducted (e.g. arterial line).

The 100 participants were allocated randomly into two groups. Fifty participants comprised the tranexamic acid group (TXA), while the remaining 50 participants were given saline in the saline or placebo group.1 An initial bolus of 10 mg/kg over 10 minutes was given, followed by 1mg/kg/h, which was administered 20 minutes before incision.1 The same volume of saline was administered to the placebo group. To limit surgical technique bias, an attending neurosurgeon with at least 10 years of experience performed the tumor excision.

Blood loss was monitored and calculated every two hours. Estimated blood loss was calculated using 1000 x Hb loss/ Hb pre and was calculated using the following equation: (Hb pre-Hbe) x BV + Hbt.1 PT-INR, Hgb. Moreover, electrolytes, fibrinogen, and platelets were monitored every three hours.1 The number of crystalloids or colloids administered was recorded every two hours. Heart rate was recorded every 2 hours for up to 10 hours. 1 Blood transfusions were supplemented to maintain normal hemodynamics.1 The initiation of transfusion was based on practice guidelines.1 However, there were no parameters or delineation of the practice guidelines given within the paper. Tranexamic acid decreases potential complications from fibrinolysis, such as deep vein thrombosis; hence, a variety of postoperative complications were also monitored.

Vet et al reported a statistically significant reduction in blood loss in the tranexamic acid (TXA) group compared to the saline group (p=0.01)1. The TXA group cumulatively lost in the mean standard error were 817.00±423.3 ml of blood whereas the saline group lost 1084.00±604.8 ml.1 Furthermore, the TXA group was more hemodynamically stable, with HR lower from 2h to 6h (2h p< 0.001; 6hp 0.05).

After much analysis, the authors reported that the TXA group had significantly higher postoperative Hb and Hct compared to saline controls, (hbg, p=0.02; hct, p=0.03)1. Fibrinogen levels remained markedly higher in the TXA group compared to controls (another prospective randomized, double-blind controlled study was performed to analyze the effect of tranexamic acid on the reduction of intraoperative blood loss craniotomy by Hooda et al.2 This study sampled 60 participants (16-60 years, ASA I to II) scheduled for elective meningioma excision.2 The neurosurgeon who operated had at least three years of experience.2 Participants with the following factors were excluded: allergy to tranexamic acid, history of bleeding diathesis, family history of thromboembolism, medication with coagulation, epilepsy, plasma creatinine >1.5mg/dl, pregnant or lactating, and tumor > 4 cm.2

Standard monitoring was used such as arterial line, and baseline coagulation was taken to rule out antecedent coagulopathy.2 To decrease the confounding variable, a standard induction regimen was used to facilitate intubation: propofol 2mg/kg, fentanyl 2mcg/kg, and rocuronium 1 mg/kg.2 A mixture of nitrous oxide and oxygen with sevoflurane of 1.5 MAC to maintain anesthesia was given.2 Similar to the previous study, during the surgery the following parameters were maintained: EtCo2 at 30 to 35 mmHg, MAP at 20% above baseline, and temperature at 36 C to 37 C via the use of air warmers.

Sixty participants were randomized into two groups with 30 receiving tranexamic acid (Group T) and 30 receiving normal saline (Group P)2. Two thousand mg of tranexamic acid was diluted into 50 ml of saline making a concentration of 40mg/ml.2 The saline group received 50 ml of 0.9 % isotonic fluid.2 The syringe was labeled a test drug to prevent differentiation of the two drugs by the attending anesthesiologist.2 The drugs were infused over 20 minutes at 0.5ml/kg before skin incision and followed by a maintenance infusion of 0.025 ml/kg/hr.2 Blood loss was measured by visual assessment of soaked sponges, count of cotton pledges, and difference taken between irrigation fluid used and amount aspirated into the canister.2 Visual assessment varies depending on the anesthesia provider and thus, this type of assessment is subjective. Supplementary isotonic fluids and blood transfusion were used at the discretion of the anesthesiologist to amend hemodynamic changes2. Packed RBC was given if hemoglobin dropped to 1.5, and platelets were transfused when they were The study reported that blood loss was significantly less in the tranexamic acid group (830 ml) in comparison to the placebo group (1124 ml) (p=0.03).2 Further, less blood transfusion was required in group T (13 participants) in comparison to the placebo group (17 participants). However, these findings were statistically insignificant (p=0.460)2. Moreover, FFP and platelets were also required less in the tranexamic acid group in comparison to the placebo group, although these findings also did not reach significance.2 Four participants in both groups required transfusion of FFP. However, the tranexamic acid group required 300ml less FFP than controls (p=0.21).2 More participants required platelet transfusion in the tranexamic acid than in the placebo group. However, a greater volume of platelet transfusion was needed in the placebo group but remained statistically insignificant (p=0.97).2 Overall, tranexamic acid reduced blood loss by 27% for elective craniotomy and facilitated better surgical hemostasis intraoperatively, decreasing surgical time. Moreover, TXA promoted superior recovery while decreasing postoperative complications, although the findings remained statistically insignificant with a p-value of 0.49.

Another prospective randomized double-blind controlled trial was done to examine the effect of tranexamic acid on blood loss reduction in pediatrics undergoing craniofacial surgery. There were 30 pediatrics (mean age=1.5 years) with ASA of I and I randomly allocated into two groups. There were 15 participants in the TXA group and 15 in the placebo group.4 The TXA group received an initial bolus of 10mg/kg followed by an infusion of 3 ml/kg of maintenance dose whereas the saline group received 0.9 % of isotonic saline with an initial bolus of 0.1 mg/kg followed by 2.5 ml/h infusions.4 Hemoglobin < 5.0 required fluid transfusions of isotonic saline starting at 4ml/kg for the first 10mg/kg plus 2 ml/kg for every kg > 10 kg and addition of 1 ml/kg for > 20kg. To calculate estimated blood loss EBV = ERCVlost(ml)/ [weight (kg) x hctpreoperative/100].4 There was no mention of methods to actually calculate blood loss during the intraoperative phase.

The results were similar to the two aforementioned studies in that tranexamic acid significantly reduced intraoperative blood loss as shown in the TXA group, 8.2 ml/kg, while it was higher in the placebo group, 14.1ml/kg (p= 0.006).4 Postoperative blood loss was also less in the TXA group, although it was not statistically significant, p=0.41.4 There was also less intraoperative fluid required in the TXA group, although not significantly (p=0.34).4 A notably similar finding to that of Vet et al was reported regarding increased fibrinogen level, which was statistically significant (p=0.01) in comparison to the placebo group.4,1 There were no hypercoagulation complications throughout the trial.4 Overall, tranexamic acid reduced blood loss. Patients required less fluid and supplementary blood and platelet transfusion, and had no hypercoagulopathy postoperative complications, regardless of increased fibrinogen level.4 Data reported by Cranford et al highlighted the same trends.

There is a consensus amongst the literature that the implementation of tranexamic acid facilitates the reduction of blood loss during both the intraoperative and postoperative phases. The control group, tranexamic acid, necessitated fewer supplementary transfusions to remedy blood loss, and subsequently, were more cost-effective. Although the trials did not track the amount of tranexamic acid used, the number of blood products given to the placebo group required more supplementary blood supply. Perhaps future studies should include the total amount of tranexamic acid used as it can affect the cos and also have a direct relationship with an increase in fibrinogen level. When considering cost, an ampule of tranexamic acid is about 1.86 dollars.6 Approximately 3000mg is required for a moderate risk of bleeding, which translates to 11.20 dollars, and high-risk bleeding requires 6000 mg or 22.40 dollars.6 The average cost of blood products areis the following: packed RBC $US210.74 ± 37.9, platelets $US533.90 ± 69, fresh frozen plasma $US60.70 ± 20.9 Clearly, tranexamic acid is more economically feasible to administer than blood products. There were additional costs associated with blood product transfusion as well, such as screening, $50.00 ± 120, storage and retrieval cost, $68.00 ± 81 per unit.9 If each blood product was used, an approximate total expenditure of $923.34 was incurred, in comparison to $25.00 for 6000mg of tranexamic acid.6,9 The cause of cost inflation of blood products is due to shortage.9 Implementing the use of tranexamic acid prior before before incision reduces blood loss and subsequent transfusion, which conserves blood products, enabling them to be allocated for emergency use.

This review aimed to evaluate whether The small us small use of tranexamic acid reduces blood loss during craniotomy. Three randomized controlled trials were reviewed. All three trials reported that tranexamic acid significantly reduces blood loss during craniotomy. Although there was disparate data in terms of a significant reduction in blood product transfusion, the data amongst all three studies indicated a reduction in blood product consumption. The implementation of isotonic fluids was also reduced in all three studies. Moreover, the laboratory findings amongst the trials showed an increase in fibrinogen levels with no hypercoagulopathy complications.

Each study used a small sample size, in which Vet et al had the largest (100 participants) while Fenger-Eriksen et al had only 30 participants. Small sample size was noted as a significant limitation by the authors of all three studies; this small sample size may result in insufficient statistical power and, therefore, less reliable analysis and results. Despite this, all data reporting indicated that the tranexamic acid group required less supplementary blood transfusion. If given a larger sample size similar to the CRASH 2 trial consisting of 20,221 participants, similar results as in this trial may yield the same outcome.7 The CRASH 2 trial concluded tranexamic acid reduces the requirement for blood product transfusion and mitigates blood loss significantly during craniotomy.

Considering all the factors and limitations, there remains strong evidence that administering tranexamic acid before fewer craniotomy reduces blood loss significantly. Tranexamic acid reduces blood loss as well as the use of blood products and isotonic fluid without causing known postoperative complications. Additionally, it is a more economical intervention than blood products transfusion and thus is more cost-effective both for the hospital and the patient. Hence, I recommend the use of tranexamic acid for craniotomy as it reduces blood loss and requires less supplementary pro cuts ar while yielding more stable hemodynamics without known postoperative hypercoagulopathy complications.