Intravenous versus topical tranexamic acid in lumbar interbody fusion: A protocol of randomized controlled trial

Abstract

Background:
Questions still remain about the safest and most effective route of administration for tranexamic acid (TXA) in lumbar interbody fusion. As such, the goal of this randomized clinical trial was to assess the efficacy and safety of topical TXA compared with intravenous TXA in lumbar interbody fusion.

Methods:
This was a prospectively randomized trial that investigated the effectiveness and safety of the intravenous and topical administrations of TXA with regard to lumbar interbody fusion. Approval from Clinical Studies Ethical Committee in our hospital was obtained. The patients were randomized to 1 of 2 treatment options:Patients, surgeons, anesthesiologists, nurses, and research assistants collecting data were blinded to group allocation. The primary outcome measures were perioperative calculated blood loss, total drain output at 24 hours, and perioperative blood transfusion rate. Secondary outcomes included an analysis of complications, namely symptomatic venous thromboembolism, cerebrovascular accident, and arterio-occlusive events. Data were analyzed using the statistical software package SPSS version 25.0 (Chicago, IL).

Results:
There are several limitations to this study. We did not include a group of patients who did not receive TXA. Another potential limitation is that the study population contains heterogeneity such as varying patient diagnosis and surgical technique/approach. Despite these limitations, the validity of our results should be maintained, as the same methodology was applied to both treatment arms.

Trial registration:
This study protocol was registered in Research Registry (researchregistry5564).

Full text

Intravenous versus topical tranexamic acid in
lumbar interbody fusion
A protocol of randomized controlled trial
Fei Song, MD, Zhouhai Zheng, MD
∗
Abstract
Background: Questions still remain about the safest and most effective route of administration for tranexamic acid (TXA) in lumbar
interbody fusion. As such, the goal of this randomized clinical trial was to assess the efficacy and safety of topical TXA compared with
intravenous TXA in lumbar interbody fusion.
Methods: This was a prospectively randomized trial that investigated the effectiveness and safety of the intravenous and topical
administrations of TXA with regard to lumbar interbody fusion. Approval from Clinical Studies Ethical Committee in our hospital was
obtained. The patients were randomized to 1 of 2 treatment options:
(1) topical group and
(2) intravenous group.
Patients, surgeons, anesthesiologists, nurses, and research assistants collecting data were blinded to group allocation. The
primary outcome measures were perioperative calculated blood loss, total drain output at 24hours, and perioperative blood
transfusion rate. Secondary outcomes included an analysis of complications, namely symptomatic venous thromboembolism,
cerebrovascular accident, and arterio-occlusive events. Data were analyzed using the statistical software package SPSS version
25.0 (Chicago, IL).
Results: There are several limitations to this study. We did not include a group of patients who did not receive TXA. Another potential
limitation is that the study population contains heterogeneity such as varying patient diagnosis and surgical technique/approach.
Despite these limitations, the validity of our results should be maintained, as the same methodology was applied to both treatment
arms.
Trial registration: This study protocol was registered in Research Registry (researchregistry5564).
Abbreviation: TXA =tranexamic acid.
Keywords: lumbar interbody fusion, prospective, protocol, tranexamic acid
1. Introduction
Lumbar interbody fusion has been associated with substantial
blood loss and risk of transfusion. Postoperative anemia will
impede physical functioning, delay rehabilitation, and increase
mortality.
[1]
As a result, approximately one-thirds of the patients
may require allogeneic blood transfusion. However, allogeneic
transfusion is associated with risks for disease transmission,
immunosuppression, and transfusion reactions.
[2]
Recently, the use of tranexamic acid (TXA), a lysine analog
and antifibrinolytic agent, has become more common. Surgical
trauma causes hyperfibrinolysis, which induces fibrin clot
dissolution to sustain bleeding.
[3]
TXA act as a lysine analog
which inhibits hyperfibrinolysis by blocking the interaction of
plasminogen with fibrin to prevent the dissolution of the fibrin
clot and thereby reduce bleeding.
[3–7]
Many studies have
confirmed that TXA has an effective hemostatic function in
joint-replacement surgery.
[8–12]
TXA application is relatively late
for lumbar interbody fusion, which requires additional study in
many aspects.
Many published studies have reported that the intravenous or
topical administration of TXA plays a role in reducing the blood
loss and blood transfusion rates during the perioperative period
of posterior lumbar interbody fusion.
[1,13]
However, questions
still remain about the safest and most effective route of
administration. If the drug is administered systemically, throm-
bosis may be a concern in certain populations. Therefore, some
This study was supported by the National Natural Science Foundation of China
(No. 81777408). The funders had no role in study design, decision for
publication and preparation of the manuscript.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or
analyzed during the current study.
Department of Orthopedics, People’s Hospital of Nanchuan District, Chongqing,
China.
∗
Correspondence: Zhouhai Zheng, People’s Hospital of Nanchuan District,
Chongqing, Chongqing China (e-mail: xiaozhi8740@163.com).
Copyright ©2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
How to cite this article: Song F, Zheng Z. Intravenous versus topical tranexamic
acid in lumbar interbody fusion: a protocol of randomized controlled trial.
Medicine 2020;99:24(e20619).
Received: 6 May 2020 / Accepted: 8 May 2020
http://dx.doi.org/10.1097/MD.0000000000020619
Study Protocol Clinical Trial Medicine®
OPEN
1

practitioners advocate topical application of TXA in the surgical
wound. However, the efficacy and safety of topical TXA have not
been well reported. As such, the goal of this randomized clinical
trial was to assess the efficacy and safety of topical TXA
compared with intravenous TXA in lumbar interbody fusion.
2. Materials and methods
2.1. Study design
This was a prospectively randomized trial that investigated the
effectiveness and safety of the intravenous and topical admin-
istrations of TXA with regard to lumbar interbody fusion.
Approval from Clinical Studies Ethical Committee in our hospital
was obtained. This study has been published at the Research
Registry (researchregistry5564). We followed the Consolidated
Standards of Reporting Trials guidelines for reporting random-
ized trials and provided a consolidated standards of reporting
trials flow diagram (Fig. 1).
2.2. Patients
Patients diagnosed with lumbar degenerative disease at our
hospital and who had no history of posterior lumbar
decompression or interbody fusion with pedicle screw fixation
were selected for this study. Before surgery, informed consents
were obtained from all patients after a full explanation of the
therapeutic procedure.
The exclusion criteria were as follows:
(1) history of thromboembolism or evidence of existing throm-
bus on preoperative vascular B-mode ultrasound;
(2) use of antiplatelet aggregation drugs within 6 months or
symptom of coagulation dysfunction before surgery;
(3) internal diseases such as cardiovascular disease, hepatorenal
insufficiency, and hematologic system disease;
(4) confirmed allergy history or high risk of allergy to TXA;
(5) history of smoking (more than 10 cigarettes per day for more
than 6 months) or drinking (at least 50 g of liquor with an
alcohol volume ratio over 40% per day for more than 3
months) with unsuccessful cessation within 6 months before
surgery; 6) a body mass index less than 18.5 or over 30.0; and
7) an inability to understand the study protocol after
explanation or an unwillingness to participate.
2.3. Randomization and blinding
The patients were randomized to 1 of 2 treatment options: A)
topical group and B) intravenous group. Randomization was
Assessed for eligibility
n= ?
Excluded (n = ?)
Eligible for enrolment
n= ?
Refused to participate
(n = ?)
Consented and randomized
n= ?
Randomized to group A Randomized to control group B
n = ? n = ?
Figure 1. Flow diagram of the study.
Song and Zheng Medicine (2020) 99:24 Medicine
2

performed without any stratification. Randomization listings
were prepared with a probability of 0.4 to 0.6 and after that,
randomization letters were printed according to the results of the
randomization. After the patient had given consent, a member of
the in-hospital clinical study center chose 1 of the 2 letters and the
patient was assigned to 1 group. Patients, surgeons, anesthesi-
ologists, nurses, and research assistants collecting data were
blinded to group allocation.
2.4. Surgical techniques and rehabilitation exercise
All operations were performed using the same surgical technique.
After performing posterior decompression, 2 polyetheretherke-
tone cages for interbody fusion and posterior stabilization with
pedicle screws and rods were utilized in all patients. To improve
bone fusion, a mixture of a locally-harvested autograft obtained
during posterior decompression and a demineralized bone matrix
was packed inside and outside the polyetheretherketone cages.
All patients were managed with the same postoperative
medications and rehabiliation program protocols. Patients wore
a lumbo-sacral orthosis for 3 months after the surgery and were
allowed to ambulate on the first day post-surgery. Patients were
not permitted to sit for long periods of time for the first month
after surgery, and at 3 months post-surgery, patients were
allowed to resume normal activities.rehabilitation exercise.
2.5. Interventions
For patients in the intravenous group, the TXA (15 mg/kg
dissolved in 100 mL of normal saline) was started 30 minutes
before surgery and completed 15 minutes before surgery. During
surgery, the intravenous administration of TXA was maintained
at a dose of 1 mg/kg, and 4 pieces of gelatin sponges soaked in 50
mL of saline for 5 minutes were placed in the surgical area before
incision closure. For the topical group, 100 mL of normal saline
was administered intravenously 30 minutes before surgery, and 4
pieces of gelatin sponge saturated with TXA (1 g TXA dissolved
in 50 mL of normal saline and gelatin sponge soaked therein for 5
minutes) were placed flat in the surgical area before incision
closure. A standard closed suction drain was placed before the
wound was closed. All drains were removed 24 hours after
placement.
2.6. Outcome measures
The primary outcome measures were perioperative calculated
blood loss, total drain output at 24 hours, and perioperative
blood transfusion rate. The calculated blood loss was deter-
mined from the difference between the preoperative hemoglobin
level and the lowest postoperative hemoglobin level during the
hospital stay (or prior to transfusion, if applicable) according to
the formula by Nadler et al. Of note, drain output is not
accounted for in this calculation. Other, secondary outcomes
included an analysis of complications, namely symptomatic
venous thromboembolism, cerebrovascular accident, and arte-
rio-occlusive events (such as myocardial infarction). The criteria
for the transfusion of blood products were a hemoglobin level of
<8 g/dL or a hemo globin lev el of <10 g/dL in a patient with
symptomatic anemia or deemed at high risk because of notable
underlying cardiac comorbidities. Blood was administered 1
unit at a time, and the presence of symptoms or signs was
reassessed.
2.7. Statistical analysis
Data were analyzed using the statistical software package SPSS
version 25.0 (Chicago, IL). Continuous variables were described
as the mean ±standard deviation, and differences between groups
were analyzed using a series of one-way analysis of variance
(ANOVA) with Bonferroni’s post-hoc test, while differences
between groups over time were analyzed using multi-way
ANOVA with Bonferroni post-hoc test. Categorical variables
were described as the number (%), and were analyzed by Fisher
exact test. A Pvalue of <.05 was considered statistically
significant.
3. Discussion
TXA has gained popularity because of itsefficacy and ease of
administration. Numerous studies have shown that intravenous
TXA reduces perioperative blood loss and postoperative
transfusion rates through its action as a potent antifibrino-
lytic.
[14,15]
Despite several recent studies reporting the safety of
intravenous TXA in spine surgery, there is still concern about its
safety profile.
[16,17]
Topical TXA has been utilized as an
alternative; however, the efficacy and safety of topical TXA
have not been well reported, as the majority of studies have been
underpowered randomized clinical trials or retrospective in
nature.
[18]
Therefore, the goal of the present study was to
perform an adequately powered, high-quality randomized
clinical trial analyzing the efficacy and safety of both
intravenous and topical TXA in lumbar interbody fusion,
with an emphasis on perioperative calculated blood loss, total
drain output at 24 hours, and perioperative blood transfusion
rate.
There are several limitations to this study. We did not include a
group of patients who did not receive TXA. From an ethical
standpoint, it is reasonable to assert that the literature at this
point would not support TXA versus no-TXA groups. Another
potential limitation is that the study population contains
heterogeneity such as varying patient diagnosis and surgical
technique/approach. Despite these limitations, the validity of our
results should be maintained, as the same methodology was
applied to both treatment arms.
Author contributions
Conceptualization: Fei Song.
Data curation: Fei Song.
Formal analysis: Fei Song.
Funding acquisition: Zhouhai Zheng.
Investigation: Fei Song, Zhouhai Zheng.
Methodology: Zhouhai Zheng.
Resources: Zhouhai Zheng.
Software: Zhouhai Zheng.
Supervision: Zhouhai Zheng.
Validation: Fei Song.
Visualization: Fei Song.
Writing –original draft: Fei Song, Zhouhai Zheng.
Writing –review & editing: Fei Song, Zhouhai Zheng.
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