Our experience in spinal surgery: a systematic review comparing the single and combined use of Tranexamic acid

Introduction

In spinal surgery, the operation time is too long, and the incision is too large, which easily causes massive blood loss and has a great adverse impact on the prognosis of patients.¹ The data showed that the average bleeding volume of instrument lumbar fusion in spinal surgery reached 1517 ml.² This massive blood loss can cause cardiopulmonary risks, venous thromboembolism, surgical site infection, and other problems.^3–5 There is no doubt that finding effective and safe haemostatic agents is still a challenge to be overcome.⁶

Antifibrinolytic drugs are safe and can significantly reduce bleeding. Patients without coagulation defects are the target population for this drug.⁷ As a widely used antifibrinolytic drug, (TXA) is effective in controlling blood loss during spinal surgery.⁸ The administration methods include intravenous injection,⁹ topical medication, and oral administration.¹⁰ Previous studies used intravenous administration of TXA,¹¹ the experimental data suggested that intravenous administration significantly reduced bleeding in patients. A recent study showed that pouring TXA into the incision has a better haemostatic effect than intravenous injection of TXA.¹² However, it is unclear whether the combined use of TXA has a more significant haemostatic effect than the single use of TXA. Therefore, this meta-analysis sought a better mode of administration in spinal surgery by analysing the efficacy and safety of TXA in the single injection group compared with TXA in the combined injection group in patients undergoing spinal surgery.

Methods

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines,¹³ and the AMSTAR (assessing the methodological quality of systematic reviews) guidelines.¹⁴ The author registered this study in Prospero.

Results

Study selection

The databases (PubMed, Embase, Web of Science) were searched using search terms, including mesh terms, emtree, and free words, and preliminarily determined 75 studies. After deduplication and article summary reading, the contents of all 37 studies were read. After exclusion according to the established criteria, five studies^20–24 were finally selected and included in the summary analysis ( Figure 1).

Figure 1. Flow diagram.

Flow diagram based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Blood loss

The forest plot shows the results of the single group on blood loss compared with the combined group. There were three subgroups of blood loss. Eight studies (n=682) provided IBL data, three studies (n=211) provided PBL data and seven studies (n=602) provided TBL data. Pooled results showed that the combined use of TXA significantly reduced IBL and TBL compared to single TXA administration. (IBL: MD=48.63, 95%CI=[12.61, 84.65], P=0.008, I²=88%; PBL: MD=38.83, 95%CI=[-56.21, 133.88], P=0.42, I²=0%; TBL: MD=140.95, 95%CI= [25.97, 255.93], P=0.02, I²=75%) ( Figure 2).

Figure 2. Summary of bias risk.

+: low risk of bias; -: high risk of bias; ?: bias unclear.

Hb and D-dimer

The forest plot (4a) compares Hb levels. The Hb level was divided into two subgroups. Three studies (n=290) provided preoperative and postoperative Hb results. The summary analysis results showed no significant difference in Hb levels between the two groups before and after surgery (Preoperative Hb: MD=2.00, 95%CI = [-1.80,5.79], P=0.30, I²=19%; postoperative Hb: MD=-0.19, 95%CI= [-3.04,2.66], P=0.90, I²=0%).

The forest plot (4b) compares D-dimer levels. D-dimer levels were divided into preoperative and postoperative D-dimer levels. We extracted D-dimer level data from three studies (n=261). No significant difference was detected in D-dimer levels between the two groups postoperatively. However, there was a significant difference in D-dimer levels between the two groups before surgery (preoperative D-dimer: MD=-0.15, 95%CI=[-0.19, -0.11], P<0.00001, I²=0%).

Postoperative D-dimmer: MD=0.16, 95%CI=[−0.49, 0.81], P=0.63, I²=72%) ( Figure 3).

Figure 3. Forest plot of blood loss (IBL: intraoperative blood loss; PBL: postoperative blood loss; TBL: Total blood loss).

Operative time

Six studies assessed the operative time (n=472). The results in Figure 4 show that the indicator did not vary between single and combined treatments. (MD=-0.24, 95%CI=[-10.23, 9.75], P=0.96, I²=42%) ( Figure 4).

Figure 4. (a) Forest plot of Hb level. (b) Forest of D-dimmer level. (Hb: hemoglobin).

Complication

Three studies evaluated complications (n=290). As shown in Figure 5, the results did not vary between single and combined treatments. (RR=1.23, 95%CI=[0.58, 2.59], P=0.59, I²=0%) ( Figure 5).

Figure 5. Forest plot of operative time.

Bias risk

The Cochrane tool was used to assess the quality of the four RCTs.²⁵ NOS was adopted to assess the quality of the RCS.¹⁶ In the four RCTs, the risk of selection bias was very low and the randomization and allocation processes were clearly reported. However, none of the four RCTs reported detection or other biases ( Figure 6). The score of RCS is six, 0-4 points are considered high bias, 4-6 points are considered as medium bias, and 6-9 points are considered as low bias ( Table 4).

Figure 6. (a) Forest plot of drainage volume. (b) Forest plot of LOH. (c) Forest plot of blood transfusion rate.

Table 4. NOS Scoring Table.

First author	Quality evaluation	Case definition	Representativeness	Selection of Controls	Definition of Controls	Comparability	Ascertainment of exposure	Same method?	Non Response rate
Weissmann	6	1	1	1	0	1	1	1	0

Publication bias

To analyse publication bias, we plotted a funnel plot of bleeding ( Figure 7). The P-values of the Begg and Egger tests were both less than 0.05, which proved that there was no significant publication bias in the study.

Figure 7. Funnel plot of bleeding: no significant publication biais in the study.

Discussion

The antifibrinolytic drug tranexamic acid inhibits fibrinolysis.²⁶ Tranexamic acid is often used to reduce intraoperative bleeding in orthopaedics, general surgery, and obstetric surgery.²⁷ Currently, the administration routes of tranexamic acid include the most common intravenous injection,⁹ topical administration,¹⁰ and oral administration.²⁸ The administration regimen of TXA is usually intravenous injection before incision, followed by continuous infusion during the operation.²⁹ In several studies, intravenous TXA was compared with placebo (0.9% sodium chloride solution) in randomized controlled trials. A significant reduction in intraoperative bleeding was observed in the intravenous group.^30,31 In addition, a meta-analysis of 581 patients from nine studies demonstrated that the intravenous group experienced less bleeding during spinal surgery than the placebo group.³² The Xiong et al. This study compared the efficacy of intravenous injections of TXA with placebo. According to the results, both high- and low-dose groups could effectively reduce the different kinds of bleeding and blood transfusion rates in adolescents with spinal deformities, and the postoperative Hb levels of the two groups were similar.³³ However, intravenous administration of TXA may pose risks to patients, including thrombosis and myocardial infarction.^8,27 Therefore, randomized controlled trials using TXA usually exclude patients with haemorrhagic disease or a hypercoagulable state.^21–24 However, according to Yang et al., the incidence of adverse events did not differ between intravenous and placebo groups.³²

The possibility of thrombosis caused by intravenous TXA necessitates the search for a safer application strategy, resulting in the emergence of topical use.¹⁰ For topical administration, gelatine sponges were immersed in a mixture of TXA and saline before the incision was closed and placed horizontally in the surgical area 5 minutes later. The results of a 2017 study showed that compared with placebo (0.9% sodium chloride solution), the total perioperative blood loss decreased, and complications were not more common among the topical group.³⁴ A meta-analysis of total knee replacement in 2017 compared topical and intravenous treatment.³⁵ Blood loss and Hb levels did not differ between the intravenous and placebo groups, and there was no indication that complications increased. Xiong et al. compared the outcome indicators of intravenous and topical groups in spinal non-malformation surgery; blood loss and transfusion rates did not vary by treatment.³⁵ However, this meta-analysis was restricted to non-malformed spinal surgery. Recently, many studies have compared the combined use of TXA with the single use of TXA to observe its efficacy, but their results seem contradictory.^14,20–23 To understand the use of TXA in two ways in unrestricted spinal surgeries, we conducted a meta-analysis that included all spine surgeries. Follow-up studies should include more studies to supplement the existing research results.

Outcome indicators included IBL, PBL, TBL, Hb and D-dimer levels, operative time, and complications. Forest plots of a previous study²⁰ showed no statistical difference in BL between the single and combined treatments. However, our meta-analysis found statistically significant differences in the two types of blood loss (IBL and TBL) between the two groups. This suggests that TXA, when administered in combination, reduces bleeding more than when administered alone.³⁶ The Hb level for patients with total knee replacement³⁷ decreased better than that for those receiving topical treatment. In terms of operative time and complications, the forest plot results of this study were the same as those of a previous meta-analysis.²⁴

D-dimer is a specific degradation product of fibrin monomers hydrolysed by plasmin in vivo and is used as an important indicator of coagulation function.²⁵ A significant difference in postoperative D-dimer between the single and combined treatments could not be detected. However, the difference in D-dimer levels before surgery was significant and could not reflect the change in blood coagulation function.

As a common and effective method, TXA can control bleeding during spinal surgery. Both the single use of TXA and combined use of TXA seem to effectively control intraoperative bleeding. However, the mechanism through which TXA can be used remains unclear. These results suggest that combined treatment seems to be a better solution if we consider reducing bleeding. This provides a reference for the best clinical-use scheme.

According to RCTs conducted by Dong et al., four cases of complications in patients in the intravenous group and five cases of complications with combined treatment were found. According to Li et al., seven cases of wound leakage were found in the intravenous group, two cases of deep vein embolism (DVT), five cases of wound leakage were found in the topical group, one case of DVT, and four cases of wound leakage were found in the combined group. There is a need for more valuable studies to assess adverse events, as the number of included studies was small.

However, this meta-analysis has several limitations. First, few studies were originally included, including only four RCTs and one RCS, three of which contained two experimental comparisons.^20–22 Second, the quality of the included research was not high enough, and more suitable RCTs or observational studies need to be included in subsequent analyses. Third, the drug administration schemes included in this study were different, and the optimal dose could not be determined. Finally, the surgical teams in this study were obtained from different countries, and the surgical methods were also different.

Conclusion

The results of this meta-analysis showed that there was no significant difference in PBL, preoperative Hb level, postoperative Hb level, postoperative D-dimer level, operative time, or complications between the single and combined groups. However, significant differences in IBL, TBL, and preoperative D-dimer levels were observed between the two groups. In the future, we will consider including more appropriate RCTs to further improve the analytical results and enhance the credibility of the conclusions.