e-ISSN: 2722-3558 Sriwijaya Journal of Surgery [SJS] https://sriwijayasurgery.
Antifibrinolytic Therapy in Neurosurgical Oncology: A Randomized.
Double-Blind.
Placebo-Controlled Trial on the Efficacy and Safety of Tranexamic Acid for Hypervascular Intracranial Meningiomas Dwiandi Susilo1* 1Department of Neurosurgery.
Dr.
Mohammad Hoesin General Hospital.
Palembang.
Indonesia
ARTICLE
ABSTRACT
INFO
Keywords:
Intracranial hemorrhage Meningioma Neurosurgery Randomized controlled trial Tranexamic acid *Corresponding author:
Dwiandi Susilo E-mail address:
Deand1rs@gmail.
The author has reviewed and approved the Anal version of the manuscript.
https://doi.
org/10.
37275/sjs.
Introduction: Resection of hypervascular intracranial meningiomas is frequently complicated by significant intraoperative hemorrhage, increasing patient morbidity and transfusion requirements.
Tranexamic acid (TXA), an antifibrinolytic agent, has shown promise in other surgical fields, but highlevel evidence in intracranial tumor surgery is lacking.
This study aimed to rigorously evaluate the efficacy and safety of perioperative TXA in reducing blood loss during craniotomy for convexity and spheno-orbital meningiomas.
Methods: This single-center, double-blind, randomized, placebo-controlled trial enrolled 30 adult female patients scheduled for elective resection of convexity or spheno-orbital meningiomas.
Patients were randomized to receive either intravenous TXA .
mg/kg bolus followed by a 1 mg/kg/hr infusio.
or a matching saline placebo.
The primary outcome was total intraoperative blood loss.
Secondary outcomes included transfusion volume, perioperative changes in hematological and coagulation parameters, and the incidence of thromboembolic events within 30 days.
Results: The TXA group .
and the placebo group .
were well-matched at baseline.
Mean intraoperative blood loss was significantly lower in the TXA group compared to the placebo group .
0 A 94.
39 mL vs.
0 A 131.
20 mL.
difference, -245 mL.
95% CI, -444.
2 to -45.
p = 0.
Cohen's d = 2.
The TXA group exhibited a significantly smaller postoperative drop in hemoglobin (-0.
97 g/dL vs.
36 g/dL.
p = 0.
and significantly lower Ddimer levels at 24 hours .
A 210 ng/mL vs.
1620 A 450 ng/mL.
p < 0.
There was no significant difference in PRBC transfusion volume .
= 0.
No thromboembolic events were recorded in either group.
Conclusion: In patients undergoing resection of hypervascular convexity and spheno-orbital meningiomas, perioperative TXA administration significantly reduces intraoperative blood loss and preserves postoperative hemoglobin.
The agent demonstrated a favorable safety profile with no observed increase in thromboembolic risk in this cohort Introduction profound vascularity.
2 These tumors derive a rich Intracranial meningiomas represent the most arterial supply from dural vessels, most notably prevalent primary central nervous system tumors, branches of the middle meningeal comprising over 37% of all such neoplasms diagnosed frequently parasitize the pial circulation from the in adults.
While typically histologically benign (WHO underlying cortex, creating a complex and high-flow Grade I), their surgical management presents a unique vascular network that significantly elevates the risk of and often formidable challenge, primarily centered on substantial intraoperative blood loss.
artery, and Excessive intraoperative hemorrhage is a critical Meningiomas arising from the cerebral convexity and sphenoid wing are particularly notorious for their neurosurgical oncology.
It can precipitate severe hemodynamic allogeneic blood transfusions, obscure the surgical The efficacy of TXA in reducing blood loss fieldAithereby increasing the risk of iatrogenic injury and transfusion requirements has been unequivocally to eloquent neural and vascular structuresAiand established in numerous surgical disciplines through prolong operative time and anesthetic exposure.
large-scale, multicenter randomized controlled trials Allogeneic packed red blood cell (PRBC) transfusions, (RCT.
, including cardiac surgery, major orthopedic though life-saving, are an increasingly scrutinized procedures, trauma, and spine surgery.
The landmark resource associated with a spectrum of potential CRASH-2 significant reduction in all-cause mortality in bleeding injury, immunomodulatory effects that may increase trauma patients treated with TXA, without an susceptibility to infection, viral transmission, and associated increase in vascular occlusive events.
transfusion-related increased postoperative morbidity and length of Despite this wealth of evidence, the adoption of TXA Consequently, the development and in intracranial neurosurgery has been comparatively implementation of effective, evidence-based blood cautious and slow.
This reluctance has historically conservation strategies are paramount to enhancing been fueled by a theoretical concern for an increased risk of thromboembolic complications, such as deep contemporary neurosurgical practice.
vein thrombosis (DVT), pulmonary embolism (PE), or The physiological response to major surgery ischemic stroke, in a patient population already involves a complex interplay between the coagulation considered to be at high risk for such events.
While cascade and the fibrinolytic system.
Surgical trauma initiates a potent inflammatory response that triggers randomized trials have suggested a potential benefit, the release of tissue plasminogen activator .
PA) from high-quality, prospective evidence from rigorously vascular endothelial cells and damaged tissues.
The dura mater and meningeal tissues are known to be particularly rich in tPA, creating a localized pro- Meningioma surgery, with its predictable risk of fibrinolytic milieu during intracranial procedures.
This significant, fibrinolysis-driven hemorrhage, represents surge in tPA leads to the conversion of plasminogen to an ideal clinical model to investigate the utility of this its active form, plasmin.
Plasmin is a powerful serine RCTs
TXA
protease that systematically degrades the fibrin cross- Therefore, this study was designed to provide high- linkages of newly formed hemostatic clots, leading to level.
Level 1 evidence on this critical clinical question.
premature clot dissolution and persistent, diffuse The primary aim of this double-blind, randomized, microvascular oozing from the surgical bed.
7 This placebo-controlled trial was to test the primary trauma-induced hypothesis that a standardized perioperative regimen hyperfibrinolysis is a key pathophysiological driver of of tranexamic acid would significantly reduce total surgical hemorrhage.
intraoperative blood loss compared to placebo in Tranexamic acid (TXA) is a synthetic lysine patients undergoing surgical resection of convexity analogue that functions as a potent competitive and spheno-orbital meningiomas.
The novelty of this inhibitor of fibrinolysis.
By binding to the lysine- investigation lies in its rigorous methodological design binding sites on plasminogen.
TXA effectively blocks focused on this specific, high-risk neurosurgical its interaction with fibrin and its activation by tPA, population, with the goal of providing definitive thereby preventing the generation of This mechanism stabilizes the fibrin-platelet matrix of evidence to guide clinical practice and enhance patient blood management protocols.
hemostatic plugs, making them more resilient to Methods This therapeutic use of anticoagulants, such as warfarin or direct oral anticoagulants, or antiplatelet agents, such placebo-controlled, as aspirin or clopidogrel, within 7 days prior to the parallel-group superiority trial conducted at the scheduled surgery.
a history of preoperative tumor Department of Neurosurgery.
Dr.
Hasan Sadikin .
pregnancy or lactation.
General Hospital, a tertiary academic medical center inability to provide informed consent.
double-blind, single-center, in Bandung.
Indonesia.
The manuscript has been The observed all-female cohort was a consequence Consolidated of consecutive patient enrollment during the study Standards of Reporting Trials (CONSORT) 2010 period and was not a result of a specific study design The study protocol and the informed choice to exclude male patients.
consent form were reviewed and approved by the A block randomization sequence with variable Health Research Ethics Committee of the Faculty of block sizes of 4 and 6 was generated using R software Medicine.
Universitas Padjadjaran.
Indonesia.
The .
R Foundation for Statistical Computin.
trial was conducted in strict adherence to the by an independent statistician at the university's principles of the Declaration of Helsinki and the clinical trials unit who had no involvement in patient International Council for Harmonisation Good Clinical Practice (GCP) guidelines.
All participants, or their Allocation concealment was rigorously maintained.
legally authorized representatives, provided written The randomization sequence was securely held by the informed consent before the initiation of any study- central hospital pharmacy.
For each patient enrolled related procedures.
by the clinical research coordinator, the pharmacy was Eligible participants were adult patients aged 18 to A pharmacist not involved in the study 65 years with a radiologically diagnosed convexity or would then consult the sequence and prepare the spheno-orbital meningioma, scheduled for elective study drug (TXA or placeb.
in identical, opaque 100 The mL infusion bags.
These bags were labeled only with diagnosis was established based on characteristic the patient's unique study identification number and findings on contrast-enhanced magnetic resonance a batch number.
This process ensured that patients, imaging (MRI) or, if MRI was contraindicated, contrast- surgeons, anesthesiologists, operating room staff, and enhanced computed tomography (CT) of the head.
all research personnel involved in data collection and Exclusion included: .
known hypersensitivity or allergy to treatment allocation throughout the entire trial.
tranexamic acid.
significant pre-existing renal Emergency unblinding was permissible only in the impairment, defined as a serum creatinine level >1.
event of a suspected life-threatening adverse event mg/dL or an estimated glomerular filtration rate directly attributable to the study intervention, such as .
GFR) severe hepatic anaphylaxis or a massive thromboembolic event.
The dysfunction, defined as Child-Pugh Class B or C.
a protocol for emergency unblinding required contacting personal history of arterial or venous thromboembolic the head of the pharmacy, who would reveal the patient's allocation to the primary treatment team.
<60 mL/min/1.
(DVT,
PE,
a strong family history of unprovoked instances of unblinding occurred during the trial.
thromboembolic disease, defined as an event in a first- Patients randomized to the intervention group degree relative before the age of 50.
known received intravenous tranexamic acid (KalnexA.
Kalbe Farm.
An initial loading dose of 15 mg per kilogram coagulopathy, defined as a platelet count <100,000/AAL of actual body weight was diluted in 100 mL of 0.
or an International Normalized Ratio (INR) >1.
normal saline and administered as an infusion over 10 This infusion was initiated approximately 30 Blood loss was meticulously calculated according to a minutes before the planned skin incision.
Following standardized operating procedure by a dedicated, the bolus, a continuous maintenance infusion of TXA blinded research nurse.
The calculation used a at a rate of 1 mg per kilogram per hour was started composite method: .
Gravimetric: All surgical gauzes and continued until the final dural closure was and sponges were collected and weighed on a single.
Patients daily-calibrated digital scale (AND EJ-6.
The pre- randomized to the control group received a matching recorded dry weight of the materials was subtracted, placebo regimen.
This consisted of a 100 mL bolus and the resulting net weight .
n gram.
was multiplied infusion of 0.
9% normal saline administered over 10 06 to estimate the blood volume .
ssuming a minutes, followed by a continuous infusion of normal blood specific gravity of 1.
06 g/mL).
Volumetric:
saline at the same rate and duration as the active The volume of blood collected in the suction canisters intervention group, delivered in an identical infusion was measured.
The volume of all irrigation fluids .
normal salin.
used during the procedure, which was All patients underwent a standardized general Anesthesia AAg/k.
, .
-3 mg/k.
, and rocuronium .
2 mg/k.
for endotracheal Anesthesia prospectively tallied by the scrub nurse using a separate counter, was subtracted from the total canister volume.
The total intraoperative blood loss was the sum of the volumes calculated from these two methods.
Secondary efficacy outcomes included: .
total sevoflurane in a 50:50 oxygen-air mixture to achieve a volume .
L) of allogeneic PRBCs transfused during minimum alveolar concentration (MAC) of 1.
the intraoperative period and within the first 24 hours supplemented with intermittent fentanyl boluses as .
the proportion of patients in each All patients had an arterial line placed for group requiring any PRBC transfusion.
the invasive blood pressure monitoring and a central absolute change in hemoglobin .
/dL) and hematocrit venous catheter for pressure monitoring and fluid (%) levels from preoperative baseline to the 24-hour Hemodynamic management targeted a postoperative measurement.
duration of surgery mean arterial pressure (MAP) within 20% of the .
total length of hospital stay .
patient's baseline value.
Exploratory All surgical procedures were performed by one of three senior consultant neurosurgeons, each with over .
rothrombin 10 years of experience in neurosurgical oncology.
The thromboplastin time .
PTT], fibrinoge.
and D-dimer levels at baseline and 24 hours post-surgery.
[PT],
frontotemporal, was determined by the surgeon based The primary safety outcome was the composite on tumor location and size.
The primary surgical goal incidence of any confirmed thromboembolic event was maximal safe resection, aiming for Simpson Grade within 30 days of surgery.
This included DVT I or II removal where anatomically and functionally .
onfirmed by compression Doppler ultrasoun.
PE The institutional transfusion trigger was a .
onfirmed by CT pulmonary angiograph.
, ischemic stroke .
onfirmed by diffusion-weighted MRI), and myocardial infarction .
onfirmed by ECG changes and g/dL end-organ attributable to anemia at a higher hemoglobin level.
The primary efficacy outcome was the total volume of intraoperative blood loss .
n mL), measured from the elevated cardiac troponin level.
Other monitored surgical site infections, and acute kidney injury.
time of skin incision to the completion of skin closure.
The sample size was calculated based on the Results primary outcome.
A retrospective audit of the 50 most From December 2023 to December 2024, a total of recent craniotomies for meningiomas at our institution 38 patients scheduled for meningioma resection were assessed for eligibility.
Of these, 8 patients were approximately 1000 mL with a standard deviation (SD) excluded: 4 did not meet the inclusion criteria .
had of 150 mL.
We defined a minimal clinically important renal insufficiency, 1 had a history of PE, 1 was on difference (MCID) as a 200 mL reduction in blood loss, aspiri.
, 3 declined to participate, and 1 had representing approximately a 20% reduction and undergone preoperative embolization.
The remaining nearly one-quarter of a unit of PRBCs.
Using these 30 patients provided informed consent and were parameters, with a two-sided alpha level of 0.
05 and a randomized, with 15 assigned to the tranexamic acid desired power of 80%, a minimum of 13 patients per group and 15 to the placebo group.
All 30 enrolled group was required.
To account for potential dropouts or protocol deviations, we planned to enroll 15 patients completed the surgery, and were followed up for the per group, for a total sample of 30 patients.
full 30-day period.
The trial was concluded after the All statistical analyses were conducted using SPSS The Statistics.
Version 28.
0 (IBM Corp.
Armonk.
NY).
The participants through the trial is detailed in the primary analysis followed the intention-to-treat (ITT) CONSORT diagram (Figure .
principle, whereby all randomized patients were The primary outcome analysis demonstrated a analyzed in the group to which they were assigned, statistically significant and large-magnitude reduction regardless of adherence to the protocol.
No patients in intraoperative blood loss in the tranexamic acid were lost to follow-up.
The normality of continuous As detailed in Table 2 and visualized in Figure data was assessed using the Shapiro-Wilk test and 2, the mean total intraoperative blood loss was 765.
visual inspection of Q-Q plots.
Normally distributed A 94.
39 mL in the TXA group, compared to 1010.
continuous variables were presented as mean A 20 mL in the placebo group.
This constituted a standard deviation (SD) and compared between groups mean reduction of 245 mL .
% CI for the difference, using the independent samples t-test.
The effect size 2 to -45.
8 mL.
p = 0.
The calculated effect for the primary outcome was calculated using Cohen's size was large (Cohen's d = 2.
Non-normally distributed data were presented as The baseline demographic, clinical, and laboratory median and interquartile range (IQR) and compared characteristics of the patients were well-balanced using the Mann-Whitney U test.
Categorical variables between the two treatment groups, as shown in Table were presented as frequencies and percentages and All 30 patients in the cohort were female.
The mean were compared using the Chi-square test or FisherAos age was 45.
5 A 4.
5 years in the TXA group and 44.
exact test, as appropriate.
The relative risk (RR) and 6 years in the placebo group .
=0.
There were 95% confidence interval (CI) were calculated for the no statistically significant differences in body mass binary outcome of requiring transfusion.
A post-hoc index (BMI), preoperative hematological parameters power analysis was performed for this secondary including hemoglobin and platelet counts, or baseline A pre-specified sensitivity analysis using analysis of covariance (ANCOVA) was performed on the imbalance in tumor location, with more convexity primary outcome to adjust for the baseline imbalance cases in the TXA group and more spheno-orbital cases in tumor location.
A two-sided p-value of <0.
05 was in the placebo group, this difference was not considered statistically significant for all analyses.
statistically significant .
=0.
The mean tumor While volume and the distribution of WHO tumor grades were nearly identical between the groups.
Figure 1.
CONSORT 2010 flow diagram.
Regarding secondary outcomes, patients in the transfusion was also lower in the TXA group .
TXA group had a numerically lower mean volume of 7%), but this was not statistically significant PRBCs transfused .
3 mL vs.
0 mL), but this (RR, 0.
95% CI, 0.
60 to 1.
p=0.
A post-hoc difference did not achieve statistical significance .
= power analysis revealed that the study had only 22% The proportion of patients requiring any power to detect the observed difference in transfusion volume.
Critically, the blood-sparing effect of TXA was compared to the placebo group (-2.
36 g/dL), a mean reflected in the postoperative hemoglobin levels.
The difference of 1.
39 g/dL .
= 0.
There were no mean drop in hemoglobin from the preoperative significant differences observed in the duration of baseline to 24 hours post-surgery was significantly surgery or the total length of hospital stay between the less pronounced in the TXA group (-0.
97 g/dL) two groups.
Figure 2.
Intraoperative blood loss by treatment group.
A pre-specified sensitivity analysis using ANCOVA group .
0 A 450 ng/mL.
p < 0.
There were no was conducted to adjust the primary outcome for the significant differences in postoperative INR, aPTT, or baseline imbalance in tumor location.
After adjusting fibrinogen levels between the groups.
for tumor location .
onvexity vs.
spheno-orbita.
, the The perioperative administration of tranexamic effect of TXA on reducing intraoperative blood loss acid was well-tolerated, with an excellent safety profile remained statistically significant .
stimated marginal observed in this cohort (Table .
There were zero mean difference, -238.
5 mL.
95% CI, -420.
1 to -56.
instances of the primary composite safety outcomeAi p = 0.
, confirming the robustness of the primary symptomatic, confirmed thromboembolic eventsAiin either the TXA group or the placebo group within the coagulation markers (Table .
revealed a significant 30-day follow-up period .
% vs.
p > 0.
difference in the fibrinolytic pathway.
At 24 hours Specifically, no patient developed DVT.
PE, ischemic post-surgery, the mean D-dimer level, a marker of stroke, or myocardial infarction.
The incidence of fibrin degradation, was significantly lower in the TXA postoperative seizures was identical between groups, group .
A 210 ng/mL) compared to the placebo with one patient in each group experiencing a seizure Exploratory that anticonvulsant therapy.
There was one case of a superficial surgical site infection in the placebo group, which resolved with oral antibiotics.
Discussion This soft tissue bleeding, reported a similar mean reduction double-blind, of approximately 300-400 mL per patient.
Our findings placebo-controlled trial provides high-level evidence significantly build upon previous, smaller, and often non-randomized For tranexamic acid is a highly effective and safe example, a retrospective study by Iorio-Morin et al.
intervention for reducing intraoperative blood loss in suggested a benefit in complex skull base procedures, patients undergoing craniotomy for hypervascular and a small RCT by Hooda et al.
in meningioma The surgery showed a similar trend.
Our study strengthens primary finding of a 245 mL mean reduction in this evidence base by employing a rigorous, double- hemorrhage is not only statistically robust but also of blind, placebo-controlled methodology, minimizing significant clinical relevance, contributing to greater bias and allowing for a strong causal inference hemodynamic stability and the preservation of patient regarding the efficacy of TXA in this specific, high-risk red cell spheno-orbital This was further evidenced by the hemoglobin levels in the TXA group.
patient population.
While our trial was not powered to detect a statistically significant difference in the secondary The fundamental pathophysiological basis for these outcome of PRBC transfusion volume, the observed findings lies in the potent antifibrinolytic action of TXA trend towards lower transfusion requirements in the within the unique surgical environment of intracranial TXA group is encouraging.
The lack of statistical tumor resection.
The surgical manipulation of the significance is likely a Type II error stemming from the highly vascular dura mater and meningeal planes, small sample size, as confirmed by our post-hoc power tissues with an abundance of tPA, incites a state of 16 A larger, multi-center trial would be localized hyperfibrinolysis.
This process is particularly necessary to definitively establish an effect on exaggerated in meningioma resection, where the tumor's inherent hypervascularity and parasitized preservation of postoperative hemoglobin is arguably a dural blood supply create a vast surface area for more patient-centered outcome than transfusion surgical trauma and tPA release.
12 In the placebo By preventing a steep drop in hemoglobin.
TXA group, this unopposed fibrinolysis leads to the rapid degradation of hemostatic clots, resulting in persistent consequences of anemia, potentially leading to faster microvascular oozing and substantial cumulative recovery and reduced need for transfusion-related blood loss.
Our study provides direct biochemical interventions, thereby aligning perfectly with the core evidence of this process and its attenuation by TXA.
principles of patient blood management.
However.
The postoperative D-dimer levelsAia direct measure of The most critical contribution of this study is its fibrin degradation productsAiwere nearly halved in the data on the safety of TXA in intracranial surgery.
The TXA group compared to the placebo group.
This theoretical risk of promoting thromboembolism has demonstrates that TXA effectively suppressed the been the single greatest barrier to the widespread systemic surge in fibrinolysis, stabilizing clots at the adoption of antifibrinolytics in neurosurgery.
Our surgical site and promoting durable hemostasis.
study provides strong, reassuring data in this regard.
The magnitude of blood loss reduction observed in We observed a zero-percent incidence of symptomatic, our trial .
mL) is consistent with and reinforces the confirmed thromboembolic events in both groups.
This findings from systematic reviews and meta-analyses of finding is in harmony with the vast body of evidence TXA from large-scale trials across thousands of patients in comprehensive meta-analysis of TXA in spine surgery, other surgical and trauma settings, which have another field characterized by significant osseous and short-term perioperative TXA does not increase the risk of of tranexamic acid into standard blood conservation vascular occlusive events.
The physiological rationale protocols for intracranial meningioma surgery.
is that the therapeutic dose of TXA is sufficient to normalize the pathological hyperfibrinolysis at the site
of surgical trauma, but it is not potent enough to References