- Department of Neurosurgery, Faculty of Medicine Universitas Airlangga – Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia.
Correspondence Address:
Joni Wahyuhadi, Department of Neurosurgery, Faculty of Medicine Universitas Airlangga – Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia.
DOI:10.25259/SNI_19_2021
Copyright: © 2021 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.How to cite this article: Resi Prastikarunia, Joni Wahyuhadi, Rahadian Indarto Susilo, Irwan Barlian Immadoel Haq. Tranexamic acid to reduce operative blood loss in brain tumor surgery: A meta-analysis. 12-Jul-2021;12:345
How to cite this URL: Resi Prastikarunia, Joni Wahyuhadi, Rahadian Indarto Susilo, Irwan Barlian Immadoel Haq. Tranexamic acid to reduce operative blood loss in brain tumor surgery: A meta-analysis. 12-Jul-2021;12:345. Available from: https://surgicalneurologyint.com/?post_type=surgicalint_articles&p=10963
Abstract
Background: Major blood loss during neurosurgery may result in a variety of complications, such as potentially fatal hemodynamic instability. Brain tumor and skull base surgery is among the high bleeding risk procedures. Tranexamic acid (TXA) has been found to reduce bleeding events in various fields of medicine.
Methods: We searched for all randomized controlled trials published in English or Bahasa which compared the use of TXA with placebo in brain tumor surgery. The studies should include adult patients with intracranial tumor who received TXA before skin incision. The primary and secondary outcomes are intraoperative blood loss and the need of transfusion.
Results:
Conclusion: TXA reduced the volume of blood loss but did not reduce the need of blood transfusion.
Keywords: Brain tumor, Intraoperative bleeding, Tranexamic acid, Transfusion
INTRODUCTION
Major blood loss during neurosurgical procedures will complicate the treatment and reduce tissue perfusion to vital brain tissue.[
Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine that acts as antifibrinolytic. TXA has been used in various setting to reduce blood loss.[
MATERIALS AND METHODS
Types of studies
We searched for all randomized controlled trials (RCTs), prospective, and retrospective studies published in English or Bahasa which compared the use of TXA with other agents or placebo.
Types of participants
Adult (≥18 years old) patients of either gender diagnosed with intracranial tumor who underwent craniotomy and tumor resection procedure.
Types of interventions
Studies with intravenous administration of tranexamic acid at any dose, by bolus and/or by intravenous drip, will be included. The comparison could be placebo or other antifibrinolytic agents.
Types of outcome measure
Primary outcome
Mean blood loss
Secondary outcome
The need of PRC and/or whole blood transfusion The need of colloid administration as volume expander
Search methods for identification of studies
The sampling technique in this study was using online literature search results filtering based on the flow of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) according to the PICO that has been determined. We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and ProQuest. Search was limited to papers published between 2010 and 2020. Our search strategy is shown in [
We also searched Google Scholar using any of the possible combination mentioned above.
Data collection and analysis
Selection of studies
The search results were first excluded based on the relevancy of the titles and then on the relevancy of the abstracts. Non-English/non-Bahasa publications were automatically excluded. Full-text articles were then assessed by all authors (JW, RP, IBIH, and RIS) for potentially eligible RCTs. The reasons of exclusion were noted and reported.
Data extraction and management
Demographic data about age, sex, diagnosis, TXA dose and administration, blood loss, and transfusion requirement were collected and presented in [
Assessment of risk of bias in included studies
Risk of bias was assessed by all four authors (JW, RP, IBIH, and RIS). Should conclusion be unmet, a third party from neurosurgery department would be asked to give his/ her opinion. Assessed biases are those mentioned in the Cochrane Collaboration Tool for Assessing Risk of Bias in Randomized Trials published in 2011.[
Measures of treatment effect
We undertook statistical analysis using the statistical software, Review Manager 5.4, of the Cochrane Collaboration. We used risk ratios to measure treatment effect for proportions (dichotomous outcomes) among primary and secondary outcomes. Random effect model will be used should evidence of significant heterogeneity is present. A statistically significant difference between intervention and control groups was assumed if the 95% CI did not include the value of no differential effect.
Assessment of heterogeneity
Heterogeneity is addressed by the I2 value on forest plot construction using RevMan 5.4. The statistical model used is switched to random effect should I2 yield the value of ≥50% as the studies are deemed heterogeneous.[
RESULTS
Description of studies
Description of studies can be seen on [
Results of the search
The exclusion processes based on the flow of PRISMA are shown in [
Included studies
After careful consideration from each authors, we decided to include three studies.[
Excluded studies
There are four studies which most likely met our criteria and did report the required data for our primary outcome, but were unfortunately ruled out. Two of them were due to unavailability of full text[
Ongoing studies
By the time of our search, we found one study which has not been concluded yet.[
Risk of bias in included studies
Risk of bias of included studies was assessed using the Cochrane Collaboration Tool for Assessing Risk of Bias in Randomized Trials published in 2011.[ Random sequence generation Allocation concealment Blinding of participant and personnel Blinding of outcome and assessment Incomplete outcome data Selective reporting Other bias
The result of the assessment is shown in [
Randomization and allocation concealment
Hooda et al. randomized the study’s subjects using computer-generated randomization chart. The TXA infusion was prepared by an anesthesiologist who was not involved in patient management.[
Blinding
All three studies did blind the neurosurgeons and the anesthesiologists involved in the surgical procedure.[
Incomplete outcome data
All studies’ subjects were included in the result section. No subjects dropped-out of the studies.[
Selective reporting
We found that all outcomes mentioned in the methods section were reported in the studies.[
Other potential sources of bias
Hooda et al. did not report the standard error of the mean blood loss. An attempt to contact the author has not been fruitful. To complete the missing data, we utilized RevMan Calculator tool by Cochrane which is accessible in their website.[
Summary of findings
Summary of findings from each studies and quality of evidence for each outcome can be found in [
All three included studies reported their results on blood loss and the need of blood transfusion. Sutanto et al. included 40 subjects who were distributed evenly into the study arms. The study compared 20 mg/kg of TXA in 100 cc of NaCl 0.9% with 100 cc of NaCl 0.9%. Either of the infusions was administered for 5–10 min. Baseline PT and aPTT were not different between the two groups. The authors reported that there were patients in the control group who eventually needed fresh frozen plasma (FFP) transfusion (mean 73.50 ± 121.926 cc).[
Hooda et al. had 60 study subjects who were equally distributed into TXA group and placebo group. This study administered TXA continuously until the surgery concluded. The dose was 20 mg/kg bolus continued with continuous drip at a dose of 1 mg/kg/h. The comparison was 0.5 ml/kg bolus of NaCl 0.9% continued with 0.025 ml/kg/h NaCl 0.9% continuous drip. Four patients received FFP transfusion in each group, with administered volume of 600 cc and 900 cc in the TXA and placebo group, respectively. Three patients in the TXA group also received platelet transfusion (total transfused volume 250 cc), while two patients in the placebo group received 306 cc of platelet.[
The differences between studies are (1) timing and ending of TXA administration, (2) type of tumor, (3) tumor size, (4) embolization history, and (5) pregnancy status, as shown in [
Effects of interventions
The effect of intervention is shown in [
DISCUSSION
This meta-analysis sought to find out if TXA can reduce intraoperative blood loss and blood transfusion in brain tumor surgery. We identified five studies but unfortunately needed to exclude two of them. The included studies yield a total of 200 patients. Massive blood loss from surgical procedure has been associated with mortality and morbidity.[
The CRASH-3 trial, the most recent and largest clinical trial about TXA, found that TXA administration in the first 3 h of acute traumatic brain injury (TBI) reduced mortality. However, this trial did not specifically sought intraoperative blood loss or the need of transfusion.[
To this day, the use of TXA in neurosurgery has been limited to TBI or subarachnoid hemorrhage (SAH) cases, primarily due to the fear of thrombotic adverse effects.[
The evidence for use of TXA to treat massive blood loss during intracranial surgery is weak and is even more scarce in terms of brain tumor surgery.[
The administration of TXA has demonstrated positive results in spine procedures. In most studies, the preferred TXA dose ranged from 10 mg/kg to 30 mg/kg immediately on performing an incision, a maintenance dose of 0.5–2 mg/kg/h, followed by a preferable 1-mg/kg/h dose until the end of the surgical procedure. High TXA doses did not necessarily increase rates of thromboembolism or convulsions in the case of ASA I and ASA II patients, with no risk factors for thromboembolism or significant renal changes.[
The trials were pooled in a Cochrane study, which concluded that TXA may reduce mortality in TBI patients, but the standard of evidence is poor and there is significant uncertainty.[
The above trials were pooled in a Cochrane study, which concluded that TXA may reduce mortality in TBI patients, but the standard of evidence is poor and there is significant uncertainty.
Headache, fatigue, vomiting, diarrhea, dyspepsia, dysmenorrhea, dizziness, back pain, numbness, phosphenes, and anemia are some of the side effects of TXA when used for an extended period of time.[
Our meta-analysis revealed that TXA reduced intraoperative blood loss at a mean of 292.80 cc (95% CI, −431.63, −153.96). Despite consisting only of 100 subjects and a relatively few included studies, these studies were considered homogenous. The need of transfusion, however, did not seem to be affected by TXA. The pooled mean difference of blood transfusion was −85.36 (95% CI, −213.23 – [42.51]). The range of CI indicated that the TXA group did not always have less blood transfusion. It is also important to recognize the considerable heterogeneity among studies in regard to transfusion volume.
Overall completeness and applicability of evidence
The overall methodological quality of these studies is considered good. There was, however, a considerable heterogeneity in respect to the secondary outcome. One study did not provide the standard error of both mean blood loss and mean blood transfusion. The inclusion criteria between studies were quite similar as well.
Quality of the evidence
We deem that the conclusion for both our primary and secondary outcomes belongs to moderate and low-quality evidence, respectively, mainly due to the presence of at least one type of bias in all of the studies and the inconsistency with regard to transfusion volume. The studies were also heterogeneous in terms of transfusion volume.
Agreements and disagreements with previous meta-analysis or review
We are unaware of any such meta-analysis or review which compare different dose of mannitol for brain tumor surgery.
AUTHORS’ CONCLUSIONS
Implications for practice
TXA is beneficial in reducing the volume of blood loss. However, this does not always translate to less blood transfusion.
Implications for research
Further research to assess (1) the most effective dose and (2) the timing of TXA administration is needed, as they are among the points not covered by this meta-analysis.
Declaration of patient consent
Patient’s consent not required as there are no patients in this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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