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Tranexamic acid to reduce operative blood loss in brain tumor surgery: A meta-
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DOI: 10.25259/SNI_19_2021

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Surgical Neurology International

Editor-in-Chief: Nancy E. Epstein, MD, Clinical Professor of Neurological Surgery, School of
Medicine, State U. of NY at Stony Brook.
SNI: Neuro-oncology Editor
 Mitsutoshi Nakada, MD
 Kanazawa University, Ishikawa, Japan
Open Access

Original Article

Tranexamic acid to reduce operative blood loss in brain

tumor surgery: A meta-analysis
Resi Prastikarunia, Joni Wahyuhadi, Rahadian Indarto Susilo, Irwan Barlian Immadoel Haq
Department of Neurosurgery, Faculty of Medicine Universitas Airlangga – Dr. Soetomo General Academic Hospital, Surabaya, East Java, Indonesia.

E-mail: Resi Prastikarunia - resi.prast@gmail.com; *Joni Wahyuhadi - joniwahyuhadi@fk.unair.ac.id; Rahadian Indarto Susilo - rahadian-i-s@fk.unair.ac.id;

Irwan Barlian Immadoel Haq - immadoelhaq@gmail.com

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
 *Corresponding author: use of TXA with placebo in brain tumor surgery. The studies should include adult patients with intracranial
Joni Wahyuhadi, tumor who received TXA before skin incision. The primary and secondary outcomes are intraoperative blood loss
Department of Neurosurgery, and the need of transfusion.
Faculty of Medicine Universitas
Results: This meta-analysis included a total of 200  patients from three studies. TXA resulted in less blood
Airlangga – Dr. Soetomo
loss with pooled mean difference of −292.80 (95% CI, −431.63, −153.96, P<0.05). The need of transfusion was
General Academic Hospital, not significant between TXA and control group (pooled mean difference −85.36, 95% CI, −213.23 – (42.51),
Surabaya, East Java, Indonesia. P=0.19).
joniwahyuhadi@fk.unair.ac.id
Conclusion: TXA reduced the volume of blood loss but did not reduce the need of blood transfusion.

Received : 08 January 2021 Keywords: Brain tumor, Intraoperative bleeding, Tranexamic acid, Transfusion
Accepted : 28 May 2021
Published : 12 July 2021
INTRODUCTION
DOI
10.25259/SNI_19_2021 Major blood loss during neurosurgical procedures will complicate the treatment and reduce tissue
Quick Response Code: perfusion to vital brain tissue.[1] Excessive blood loss is indeed not desired by neurosurgeons as
anemia and related hypoperfusion is deleterious for the brain.[15,24] Anemia was significantly
higher in patients who had a blood volume deficit of more than 20% in the postoperative cycle.[29]
Brain tumor and skull base surgery is among the procedures most likely to cause high-volume
bleeding.[21,25,29]
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.[10] This
meta-analysis aims to analyze the effect of TXA on the volume of blood loss in brain tumor
surgery.

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 Prastikarunia, et al.: Tranexamic acid for brain tumor surgery

MATERIALS AND METHODS Table 1: Search strategy.

Types of studies Search terms

We searched for all randomized controlled trials (RCTs), 1 Tranexamic acid [MeSH Terms]
2 Meningioma [MeSH Terms]
prospective, and retrospective studies published in English or
3 Antifibrinolytics [MeSH Terms]
Bahasa which compared the use of TXA with other agents or 4 Agents, antifibrinolytic [MeSH Terms]
placebo. 5 Antifibrinolytic*
6 Meningioma
Types of participants 7 Tranexamic acid
8 Brain neoplasm [MeSH Terms]
Adult (≥18  years old) patients of either gender diagnosed 9 Brain tumor
with intracranial tumor who underwent craniotomy and 10 Glioma [MeSH Terms]
tumor resection procedure. 11 Glioma
Combination
Types of interventions 12 #1 and #2
13 (#3 OR #4) AND #2
Studies with intravenous administration of tranexamic 14 #6 AND #7
acid at any dose, by bolus and/or by intravenous drip, will 15 #5 AND #6
be included. The comparison could be placebo or other 16 (#1 OR #3 OR #4 OR #5 OR #7) AND (#8 OR #9)
antifibrinolytic agents. 17 (#1 OR #3 OR #4 OR #5 OR #7) AND (#10 OR #11)

Types of outcome measure Data extraction and management

Primary outcome Demographic data about age, sex, diagnosis, TXA dose and
administration, blood loss, and transfusion requirement
• Mean blood loss were collected and presented in [Table  1]. Base hemostasis
data were also noted when available.
Secondary outcome

• The need of PRC and/or whole blood transfusion Assessment of risk of bias in included studies
• The need of colloid administration as volume expander
Risk of bias was assessed by all four authors (JW, RP, IBIH,
and RIS). Should conclusion be unmet, a third party from
Search methods for identification of studies neurosurgery department would be asked to give his/
The sampling technique in this study was using online her opinion. Assessed biases are those mentioned in the
literature search results filtering based on the flow of Cochrane Collaboration Tool for Assessing Risk of Bias in
Preferred Reporting Items for Systematic Reviews and Randomized Trials published in 2011.[17]
Meta-Analysis (PRISMA) according to the PICO that has
been determined. We searched PubMed, Cochrane Central Measures of treatment effect
Register of Controlled Trials (CENTRAL), and ProQuest. We undertook statistical analysis using the statistical software,
Search was limited to papers published between 2010 and Review Manager 5.4, of the Cochrane Collaboration. We
2020. Our search strategy is shown in [Table 1]. used risk ratios to measure treatment effect for proportions
We also searched Google Scholar using any of the possible (dichotomous outcomes) among primary and secondary
combination mentioned above. outcomes. Random effect model will be used should
evidence of significant heterogeneity is present. A statistically
Data collection and analysis significant difference between intervention and control
groups was assumed if the 95% CI did not include the value
Selection of studies of no differential effect.
The search results were first excluded based on the relevancy
Assessment of heterogeneity
of the titles and then on the relevancy of the abstracts.
Non-English/non-Bahasa publications were automatically Heterogeneity is addressed by the I2 value on forest plot
excluded. Full-text articles were then assessed by all authors construction using RevMan 5.4. The statistical model used is
(JW, RP, IBIH, and RIS) for potentially eligible RCTs. The switched to random effect should I2 yield the value of ≥50%
reasons of exclusion were noted and reported. as the studies are deemed heterogeneous.[16]

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 Prastikarunia, et al.: Tranexamic acid for brain tumor surgery

RESULTS
Description of studies

Description of studies can be seen on [Appendix 1].

Results of the search

The exclusion processes based on the flow of PRISMA are

shown in [Figure 1].

Included studies

After careful consideration from each authors, we decided to

include three studies.[19,37,39] All of them were RCTs.

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[23,35] while the other two were due to
being published in Arabic[36] and Russian.[27]

Ongoing studies

By the time of our search, we found one study which has not
been concluded yet.[11]

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.[17] The domain of the
biases is as follows:
1. Random sequence generation
2. Allocation concealment
3. Blinding of participant and personnel
4. Blinding of outcome and assessment
5. Incomplete outcome data
6. Selective reporting
7. Other bias
The result of the assessment is shown in [Figure 2].

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.[19] Sutanto et al. randomized the Figure 1: Study flow diagram according to PRISMA guidelines.
patient using an enclosed envelope based on the principle
of consecutive sampling. It was not clearly stated who
prepared the TXA.[37] Vel et al. used a computer-generated stating that the anesthesiologists were blinded, it was not
randomization chart to allocate the patient. Despite clearly clear who prepared the drugs.[39]

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 Prastikarunia, et al.: Tranexamic acid for brain tumor surgery

been fruitful. To complete the missing data, we utilized

RevMan Calculator tool by Cochrane which is accessible
in their website.[30] Hooda et al. did not mention the mean
and standard deviation for the need of transfusion either.
Therefore, we used the estimation method described by Shi
et al.[34] to find the mean transfusion volume based on the
provided median, minimum, and maximum value.

Summary of findings

Summary of findings from each studies and quality of

evidence for each outcome can be found in [Tables 2 and 3],
respectively.
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).[37]
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
Figure 2: Risk of bias of included studies. 0.025  ml/kg/h NaCl 0.9% continuous drip. Four patients
received FFP transfusion in each group, with administered
Blinding
volume of 600 cc and 900 cc in the TXA and placebo
All three studies did blind the neurosurgeons and the group, respectively. Three patients in the TXA group also
anesthesiologists involved in the surgical procedure.[19,37,39] received platelet transfusion (total transfused volume
The person in charge of assessing intraoperative blood 250 cc), while two patients in the placebo group received
loss were blinded in Hooda et al.[19] Despite blinding the 306 cc of platelet.[19] Vel et al. had the biggest number of
neurosurgeons and the anesthesiologist, Sutanto et al. and patients (100). The intervention dose was 10 mg/kg bolus
Vel et al. did not make clear who counted the blood loss, thus for 10  min continued with 1  mg/kg/h drip. The placebo
we consider this a potential source of bias.[37,39] dose was equivalent volume of NaCl 0.9% administered as
bolus and drip. No FFP transfusion was reported in this
Incomplete outcome data study.
The differences between studies are (1) timing and ending of
All studies’ subjects were included in the result section. No
TXA administration, (2) type of tumor, (3) tumor size, (4)
subjects dropped-out of the studies.[19,37,39]
embolization history, and (5) pregnancy status, as shown
in [Table  2]. Sutanto administered the TXA 30  min before
Selective reporting skin incision while Hooda et al. and Vel et al. started the
We found that all outcomes mentioned in the methods intervention 20  min before skin incision.[19,37,39] Besides the
section were reported in the studies.[19,37,39] dose, the manner in which TXA was administered was also
different. Vel et al. and Hooda et al.[19,39] continued the initial
Other potential sources of bias TXA dose with continuous drip while Sutanto et al. did not
do so.[37] Sutanto et al. and Hooda et al.[19,37] only included
Hooda et al. did not report the standard error of the mean meningioma cases while Vel et al. included all supratentorial
blood loss. An attempt to contact the author has not tumor.[39]

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 Prastikarunia, et al.: Tranexamic acid for brain tumor surgery

Effects of interventions Based on the need of transfusion, the studies were considerably
heterogeneous (I2 = 74%). This can be seen on the forest plot as
The effect of intervention is shown in [Figure  3]. All studies two studies’ CI crossed the zero line, indicating inconsistency
did assess intraoperative blood loss and the need of PRC and/ in the respective studies. The pooled mean difference for the
or WB transfusion. This meta-analysis amassed a total of need of transfusion was −85.36  (95% CI, −213.23 – (42.51),
100 patients from three studies. All three studies showed that P = 0.19. The funnel plot is also shown in [Figure 4].
TXA reduced the volume of blood loss with pooled mean
difference of −292.80  (95% CI, −431.63, −153.96, P<0.05). DISCUSSION
The studies were considered homogenous in terms of blood
loss (I2 = 0%). That said, it is important to note that data from This meta-analysis sought to find out if TXA can reduce
Hooda et al. for this meta-analysis were calculated using intraoperative blood loss and blood transfusion in brain tumor
Cochrane’s tool instead of actual number from the paper. surgery. We identified five studies but unfortunately needed

Table 2: Summary of findings from each studies.

Authors Participants+ TXA dose Mean Blood Loss MD (95% Mean PRC/WB MD (95% CI)
(cc) CI) Transfusion (cc)
Sutanto 40 patients 20 mg/kg in 100 cc of NaCl 0.9% for 1008.51 ± 327,192 -338.49 89.3 ± 152.97 -217.55
2019 5 – 10 minutes (-614.87, (-336.66, -98.4)
-62.105)
100 cc of NaCl 0.9% for 5 – 10 1347.85 ± 539.12 306.85 ± 224.63
minutes

Hooda 60 patients 20 mg/kg bolus  1 mg/kg/h until 830 ± 511.8* -294.0 375.08 ± 189.92 -29.55
2017 the end of surgery (-553, -34.9) (-160.47, 101.37)

0.5 ml/kg bolus of NaCl 0.9%  1124 ± 511.8* 404.63 ± 312.7

0.025 ml/kg/h NaCl 0.9% until the
end of surgery
Vel 2015 100 patients 10 mg/kg bolus for 10 minutes  1 817 ± 423.3 -267.0 445.2 ± 229.6 -14.48
mg/kg/h (-471.62, (-108.04, 79.08)
NaCl 0.9% of equal volume as TXA 1084±604.8 -62.38) 459.68 ± 247.4
not provided in the paper. Estimated using calculator provided by Cochrane[30]
*

All studies distributed the subjects equally to both arms

+

Table 3: Quality of evidence for each outcome.

Tranexamic acid for intraoperative blood loss in brain tumor surgery
Patient or population: Adult with brain tumor
Settings: India and Indonesia
Intervention: Tranexamic acid
Comparison: Placebo
Outcomes Relative effect Number of participants Quality of the evidence Comments
(95% CI) (Studies) (GRADE)
Blood loss −292.80 (−431.63, −153.96) 100 ⊕⊕⊕⊝ Presence of bias
Moderate
PRC/WB −76.98 (−141.12, −12.84) 100 ⊕⊕⊝⊝ Presence of bias, imprecision
transfusion Low (indicated by the CI range)
GRADE working group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate
quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality:
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality:
We are very uncertain about the estimate

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 Prastikarunia, et al.: Tranexamic acid for brain tumor surgery

to exclude two of them. The included studies yield a total of in Significant Hemorrhage-2 trial of TXA in bleeding trauma
200  patients. Massive blood loss from surgical procedure patients showed a statistically significant reduction in mortality
has been associated with mortality and morbidity.[22] A with no increase in thromboembolic effects.[28]
retrospective study found that blood loss exceeding 20% of The evidence for use of TXA to treat massive blood loss
estimated blood volume in brain tumor surgery strongly during intracranial surgery is weak and is even more
correlated with postoperative complications.[21] Another scarce in terms of brain tumor surgery.[2] In addition to the
study found that the need of blood transfusion predicted administration of massive volumes of crystalloids, significant
perioperative complications.[31] Therefore, any means to reduce intraoperative bleeding must also be supplemented by several
intraoperative blood loss are desirable. units of blood and blood components.[38] However, the use
The CRASH-3 trial, the most recent and largest clinical trial of these substances can result in hypokalemia, anaphylactic
about TXA, found that TXA administration in the first 3  h reactions, pulmonary trauma, infection, hemolytic reactions,
of acute traumatic brain injury (TBI) reduced mortality. cardiovascular overload, and sepsis.[6,26,32]
However, this trial did not specifically sought intraoperative The administration of TXA has demonstrated positive results
blood loss or the need of transfusion.[23] In a meta-analysis, in spine procedures. In most studies, the preferred TXA dose
TXA reduced intracranial hemorrhage progression in TBI.[41] ranged from 10 mg/kg to 30 mg/kg immediately on performing
TXA has also been studied in other fields such as obstetrics an incision, a maintenance dose of 0.5–2  mg/kg/h, followed
and gynecology. Prophylactic use of TXA was found to reduce by a preferable 1-mg/kg/h dose until the end of the surgical
blood loss and transfusion volume in a meta-analysis.[40] procedure. High TXA doses did not necessarily increase rates
To this day, the use of TXA in neurosurgery has been limited of thromboembolism or convulsions in the case of ASA I and
to TBI or subarachnoid hemorrhage (SAH) cases, primarily ASA II patients, with no risk factors for thromboembolism or
due to the fear of thrombotic adverse effects.[12,13] The risk of significant renal changes.[4,5,33,42] According to Yutthakasemsunt
thrombotic events in TXA theoretically could occur. However, et al. (2013),[40] the mean overall hemorrhage growth in TBI was
evidence from the Clinical Randomization of an Antifibrinolytic smaller in the TXA community relative to the placebo group.

Figure 3: Pooled proportion of (a) blood loss and (b) the need of transfusion.

a b
Figure 4: Funnel plot of (a) blood loss and (b) the need of transfusion.

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 Prastikarunia, et al.: Tranexamic acid for brain tumor surgery

The trials were pooled in a Cochrane study, which concluded Agreements and disagreements with previous meta-
that TXA may reduce mortality in TBI patients, but the standard analysis or review
of evidence is poor and there is significant uncertainty.[20] TXA
therapy resulted in decreasing the rebleeding incidence, varying We are unaware of any such meta-analysis or review which
from 10.8% to 2.4%, and a reduction in mortality due to compare different dose of mannitol for brain tumor surgery.
rebleeding by 80% in patients diagnosed with SAH within 48 h
of first hospitalization, with no rise in drug-related ischemic and AUTHORS’ CONCLUSIONS
vasospasm cases.[18] Grant et al. (2009)[14] recently reported that
Implications for practice
using TXA during pediatric scoliosis surgery reduced the number
of intraoperative PRBC transfusions by 50%. Just two researches[9] TXA is beneficial in reducing the volume of blood loss.
found that an antifibrinolytic treatment reduced intraoperative However, this does not always translate to less blood
blood loss in children undergoing craniofacial surgery.[8] transfusion.
The above trials were pooled in a Cochrane study, which
concluded that TXA may reduce mortality in TBI patients, Implications for research
but the standard of evidence is poor and there is significant
uncertainty. Further research to assess (1) the most effective dose and
(2) the timing of TXA administration is needed, as they are
Headache, fatigue, vomiting, diarrhea, dyspepsia, among the points not covered by this meta-analysis.
dysmenorrhea, dizziness, back pain, numbness, phosphenes,
and anemia are some of the side effects of TXA when used Declaration of patient consent
for an extended period of time.[20] However, if the patients
have any history of an active thromboembolic case or illness, Patient’s consent not required as there are no patients in this
DIC, renal dysfunction, or a new coronary or vascular stent, study.
TXA is not recommended.[3] Thrombotic threats have been
the most common and concerning adverse events.[20] Financial support and sponsorship
Our meta-analysis revealed that TXA reduced intraoperative Nil.
blood loss at a mean of 292.80 cc (95% CI, −431.63,
−153.96). Despite consisting only of 100 subjects and a
Conflicts of interest
relatively few included studies, these studies were considered
homogenous. The need of transfusion, however, did not There are no conflicts of interest.
seem to be affected by TXA. The pooled mean difference of
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APPENDIX

Appendix 1: Description of Studies.

Study ID Inclusion Criteria Exclusion Criteria TXA administration
Sutanto 2019 Adult 18 – 65 y.o History of thromboembolic events 20 mg/kg in 100 cc of NaCl 0.9% for
ASA I - II History of coagulopathy/is on anticoagulant 5 – 10 minutes
Elective meningioma Impaired renal function
surgery Impaired liver function TXA administered 30 minutes prior
History of allergic reaction to TXA to incision
Recurrent tumor
Proven metastatic tumor
Preoperative embolization
Pregnant or is within first 6 weeks of post-partum
Hooda 2017 Adult 18 – 60 y.o History of allergic reaction to TXA 20 mg/kg bolus  1 mg/kg/h
ASA I-II History suggestive of bleeding diathesis until the end of surgery
Elective meningioma History of hromboembolic episode prior to surgery or
surgery family history of thromboembolism TXA administered 20 minutes prior
On medication that could interfere with coagulation to incision
Epilepsy Plasma creatinine values more than 1.5 mg/dl Transfused blood was
Pregnant or lactating
Patients who were planned for preoperative
embolization, with tumor size less than 4 cm or operating
neurosurgeon’s estimate of likely intra-operative blood
loss less than 20% of patient’s EBV
Vel 2015 Adult 18-60 y.o Preexisting renal and hepatic disorders 10 mg/kg bolus for 10 minutes  1
ASA I-II Bleeding diathesis/abnormal coagulation parameters mg/kg/h
Elective supratentorial On anticoagulant a week before surgery
tumor Patients undergoing intracranial vascular surgery TXA administered 20 minutes prior
to incision
ASA: American Society of Anesthesiologist Physical Status, EBV: Estimated Blood Volume, TXA: Tranexamic Acid, VTE: Venous thromboembolism

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