Introduction
Posterior lumbar interbody fusion (PLIF) is widely performed for lumbar degenerative spondylolisthesis, spondylolytic spondylolisthesis, and foraminal stenosis and has contributed to favorable clinical and radiographic results [1]. However, conventional PLIF results in substantial intraoperative and postoperative bleeding, often >1,000 mL, primarily from the epidural venous plexus and spongy vertebrae [2]. Substantial intraoperative blood loss may result in anemia, necessitating allogenic transfusion, which may result in severe complications, particularly in older patients [3]. Prolonged postoperative bleeding can cause symptomatic epidural hematoma, and severe cases can lead to neurological disorders [4].
Tranexamic acid (TXA), a synthetic antifibrinolytic drug, competitively blocks the lysine-binding sites of plasminogen, plasmin, and tissue plasminogen activator and thus helps minimize bleeding [5]. Intravenous TXA has been administered to effectively reduce perioperative blood loss in various orthopedic surgeries, including spinal surgery [2,6,7].
Compared with low-dose intravenous TXA, relatively high-dose to high-dose intravenous TXA (≥2 g or 30 mg/kg as a single bolus) has been demonstrated to minimize perioperative bleeding and transfusion requirements [2,8,9]. However, high-dose intravenous TXA may cause complications, such as seizures, deep vein thrombosis (DVT), and pulmonary embolism (PE) [9–11]. Therefore, topical TXA has been applied to avoid the risk of such complications and has shown efficacy in reducing total blood loss in spine surgery [12]. A systematic review revealed that topical TXA demonstrates a similar hemostatic efficacy to intravenous TXA [7]. Nevertheless, whether intravenous or topical TXA is more effective in reducing postoperative bleeding in spinal surgery remains unclear given the limitations of previous studies, such as differences in the methods, dosages, and timing of administration between intravenous and topical TXA.
Therefore, in this retrospective study, the use of topical TXA and relatively high-dose intravenous TXA in single-level PLIF was evaluated, and their efficacy and safety in reducing postoperative blood loss were compared. Both formulations were administered at the same timing.
Materials and Methods
Patients and grouping
This nonrandomized, retrospective, cohort study was conducted in compliance with the principles of the Declaration of Helsinki. It was approved by the Institutional Review Board (IRB) of the authors’ affiliated institutions (IRB no., 1333). All participants provided written informed consent.
Clinical data of consecutive patients who underwent single-level PLIF for single-level degenerative lumbar disease at our hospital between 2016 and 2024 were analyzed. The TXA (iv) group included patients who were administered TXA intravenously between 2019 and 2021, and the TXA (t) group included patients who received topical TXA between 2021 and 2024. For comparison, patients who did not receive TXA between 2016 and 2019 were also included in the control group. Patients who received anticoagulation therapy and those with renal dysfunction (creatinine >2.0 mg/dL), liver cirrhosis, thromboembolic diseases, ischemic heart diseases, intraoperative surgical complications (massive bleeding, i.e., >1,000 mL, or dural tears), or postoperative complications (e.g., dural tear, surgical site infection, and pneumonia) were excluded. Patients with missing data were also excluded.
In the control group, the drain was released 20 minutes after wound closure began. In the TXA (iv) group, 2 g of TXA (Transamin; Daiichi-Sankyo Co. Ltd., Tokyo, Japan) was administered intravenously immediately before wound closure, and the drain was released 20 minutes after intravenous TXA administration. In the TXA (t) group, 1 g of TXA diluted in 100 mL of normal saline was poured into the surgical wound to fill it while the skin was pulled up with a Gelpi Retractor (Codman, Raynham, MA, USA) and soaked for 5 minutes to ensure adequate penetration into the subcutaneous tissue, fascia, cut bone surface, and epidural vein (Fig. 1). A portion of the saline-containing TXA solution was suctioned to insert the drain and suture the surgical wound, whereas the remaining saline-containing TXA solution was left in the surgical field to soak the dura and osteotomy sites of the surgical wound. Finally, the drain was opened 20 minutes after topical TXA administration.
Surgical technique and perioperative management
In all patients, single-level conventional PLIF was performed with the same technique by one of three spine surgeons, who had >10 years of spinal surgery experience. Intraoperatively, two cages and autologous bone blocks harvested from the resected bone were inserted into the clean intervertebral space after bilateral total facetectomy, as described elsewhere [1]. The pedicle screw and rod system were used to fix the two cages and autologous block bones tightly into the intervertebral space. Hemostatic agents, such as the gelatin–thrombin matrix sealant, were not used. Preoperative blood storage was not utilized; however, an intraoperative blood cell salvage system was employed, and all autologous blood was administered intraoperatively. At the end of the surgical operation, a negative-pressure suction drain (SB Vac system with a tube diameter of 4 mm; Sumitomo Bakelite Co., Tokyo, Japan) was placed under the deep fascia, and negative pressure (27 kPa) was maintained before removal 48 hours after the operation. All patients had a foot pump on both legs intraoperatively and bed rest postoperatively.
Evaluation
The primary outcome was postoperative blood loss obtained by measuring the output from the suction drain. Changes in postoperative drain output volume over time were recorded from immediately after to 2 hours after the operation and from 2 to 6 hours, 6 to 12 hours, 12 to 24 hours, and 24 to 48 hours afterward. Then, the total postoperative blood loss was calculated.
Secondary outcomes included estimated total perioperative blood loss, hemoglobin (Hb) level, Hb variations (Hbv), and incidence of allogeneic blood transfusion. Blood tests were routinely performed to measure the Hb level preoperatively, immediately after the operation, and on postoperative days (POD) 1, 4, and 7. Hbv (g/dL) was calculated from before surgery to POD4 and POD7, and the lower of the two values was included in the analyses. The total perioperative blood loss was calculated using the following formulas [13,14]:
where Hbloss (g) indicates the amount of Hb lost, Hbt (g) indicates the total amount of allogeneic and autologous Hb transfused, and Hbi (g/dL) indicates the preoperative Hb concentration.
Statistical analysis
We hypothesized that the administration of topical TXA would lead to a reduction in postoperative blood loss compared with the absence of TXA and use of intravenous TXA. With a power of 80% and a two-sided alpha level of 0.025, at least 39 patients were required to reach significance based on previous assumptions. All values are expressed as means±standard deviations. Statistical analysis of comparisons among the three groups was performed with Fisher’s exact test and one-way analysis of variance, followed by the Tukey-Kramer test.
Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R software (R Foundation for Statistical Computing, Vienna, Austria) [17]. The significance threshold was set at a p-value of <0.05.
Results
Patient characteristics
Among the 174 patients who underwent single-level PLIF between 2016 and 2024, 140 met the inclusion criteria (Fig. 2). The control, TXA (iv), and TXA (t) groups included 58, 39, and 43 patients, respectively.
Patient characteristics are shown in Table 1. No significant differences in age, body mass index, sex, or preoperative hematological parameters were found among the three groups. The operative time and intraoperative blood loss were also not significantly different.
Postoperative blood loss
The total postoperative blood loss was significantly lower in the TXA (t) group than in the control and TXA (iv) groups (Fig. 3); specifically, blood loss was 44.4% lower than that in the control group and 22.4% lower than that in the TXA (iv) group.
Compared with the control group, the TXA (t) group had significantly less postoperative blood loss (Fig. 4). Furthermore, changes in postoperative blood loss in the TXA (t) group were significantly lower than those in the TXA (iv) group from immediately after to 2 hours after the operation and from 24 to 48 hours afterward. In contrast, changes in postoperative blood loss in the TXA (iv) group were significantly lower than those in the control group from 2 to 6 hours and from 6 to 12 hours postoperatively.
Hb levels and total perioperative blood loss
No significant differences in Hb levels were found between the three groups from immediately after surgery to POD1 (Table 2). However, the Hb levels in the TXA (t) group were significantly higher than those in the control group from POD4 to POD7. The Hbv value and total perioperative blood loss were significantly lower in the TXA (t) group than in the control and TXA (iv) groups. The total perioperative blood loss tended to be lower in the TXA (iv) group than in the control group, although not significant difference. However, the Hbv value was significantly lower in the TXA (iv) group than in the control group. Two patients in the control group required allogeneic blood transfusion; however, none of the patients in either the TXA (iv) or TXA (t) groups did, and the differences in allogeneic blood transfusion rates were not significant.
DVT and complications
The D-dimer values and values >10 μg/mL were not significantly different among the three groups (Table 3). None of the patients had symptomatic DVT or PE during the perioperative period; however, one patient in the control group had peripheral asymptomatic DVT. In the control group, two patients required reoperation because of massive postoperative bleeding and neurological deficits from an epidural hematoma. No serious in-hospital systemic complications were observed in any of the groups.
Discussion
In this study, the efficacy of topical TXA and relatively high-dose intravenous TXA in reducing blood loss during single-level PLIF was compared. TXA (t) showed a longer-lasting hemostatic effect than TXA (iv).
A meta-analysis of the efficacy of TXA in spinal surgery showed no significant differences between topical and intravenous TXA in reducing drainage volume, blood loss, and blood requirement rates [18]. However, intravenous and topical TXA dose regimens for spinal surgeries vary widely. Furthermore, the timing of the administration of both topical and intravenous TXA varies between studies in that intravenous TXA was administered continuously or at different times, such as before, during, and after the operation [2,8,19,20], and topical TXA was administered before wound closure [19,20]. In the present study, topical and intravenous TXA were administered immediately before wound closure, allowing us to compare their hemostatic effects on postoperative blood loss.
Compared with intravenous TXA, topical TXA significantly reduced the total postoperative blood loss, total perioperative blood loss, and Hb variations. The topical TXA group did not require allogeneic blood transfusion. These results indicate that topical TXA reduces postoperative blood loss more effectively than intravenous TXA and that less postoperative blood loss reduces total perioperative blood loss and Hb variations, thus decreasing the need for allogeneic blood transfusion.
In addition, the hemostatic efficacy of topical TXA was continuously observed within 48 hours until the removal of the suction drain. Compared with intravenous TXA, topical TXA significantly reduced the changes in postoperative blood loss from immediately after to 2 hours after the operation and 24 to 48 hours afterward. In contrast, the hemostatic efficacy of intravenous TXA was observed from 2 to 6 hours and from 6 to 12 hours postoperatively. Thus, the hemostatic efficacy of topical TXA started more rapidly and continued for longer than that of intravenous TXA. This difference in hemostatic efficacy may be attributed to the ability of topical TXA administered at high concentrations to directly inhibit plasmin activity. Moreover, given its deposition in tissue, it exhibits a longer elimination half-life and mean residence time than intravenous TXA [21]. In this study, although most TXA would have been excreted, the remaining absorbed TXA may have contributed to bleeding cessation. A study has also indicated that topical TXA exhibits long-lasting hemostatic effects that persist for up to 3 days [19]. In contrast, in the present study, the hemostatic efficacy of intravenous TXA was strongly observed from 2 to 6 hours postoperatively. During this period, no significant differences in the changes in postoperative blood loss were noted between topical and intravenous TXA, showing that the strength of the hemostatic effect of topical TXA was equivalent to that of intravenous TXA. Therefore, topical TXA reduces postoperative blood loss more effectively than intravenous TXA because of its rapid and prolonged hemostatic efficacy, not the strength of the hemostatic effect.
The optimal concentration and ideal contact time for topical TXA application in spinal surgery have not yet been established [7]. In this study, the administration of 1% topical TXA for 20 minutes significantly reduced the total postoperative blood loss by 44.4% compared with the control group. This result is consistent with previous studies, where applying 1% topical TXA for 5 minutes reduced the total postoperative blood loss by 41%–77% compared with the control group [19,22]. In other studies, the administration of 10% topical TXA for 1 and 6 hours reduced the total postoperative blood loss by 47% and 26%, respectively [20,23]. Although those studies have evaluated topical TXA at higher concentrations and longer contact time than the present study, the results were similar to ours. Therefore, topical TXA appears to exert hemostatic effects effectively if the concentration is >1% and the contact time is >5 minutes. However, the administration of 1% topical TXA for 3 minutes 3 times (after exposure, after decompression, and before wound closure) was reported to reduce perioperative bleeding [24]. Topical TXA may exert hemostatic effects even with shorter contact times; therefore, more studies are needed to investigate the optimal concentration and contact time for topical TXA.
The incidence of DVT after spinal surgery varies between 0.3% and 15.5% [15,25,26]. D-dimer is a reliable blood marker for predicting DVT and PE, with cutoff values of 10 and 10.8 μg/mL, respectively, postoperatively [15,16]. In this study, patients with D-dimer levels >10 μg/mL on POD7 were evaluated by ultrasonographic examinations and contrast-enhanced CT. One patient with peripheral asymptomatic DVT was detected in the control group, but none was found in the intravenous or topical TXA groups. Symptomatic DVT or PE did not occur in any of the groups. These results are consistent with the findings of previous studies, which revealed that neither intravenous nor topical TXA increased the incidence of PE and DVT after spinal surgery [2,19,20,23]. This finding can be attributed to the mechanism by which TXA works mainly by inhibiting fibrinogen activation that results in the dissolution of fibrin clots rather than activating the coagulation cascade [5]. Additionally, the serum levels of topical TXA are remarkably low [21]; therefore, topical TXA may be even less likely than intravenous TXA to cause systemic complications.
This study has several limitations. First, the surgical techniques and number of fused segments were matched to ensure homogeneity among the three groups, and no significant differences in operative duration and intraoperative blood loss were observed among the three groups. However, this study employed a retrospective design, which may be subject to various confounders, including surgeon technique and surgical timing. Second, this study included one patient with DVT in the control group. A greater number of participants might include more cases of DVT and PE. Not all DVT and PE cases might have been detected because only patients with D-dimer levels >10 μg/mL were evaluated by ultrasonographic examinations and contrast-enhanced CT. Third, intravenous TXA was administered only once before wound closure to prevent massive postoperative bleeding and symptomatic epidural hematoma caused by prolonged postoperative bleeding. However, that is an unusual timing of the intravenous TXA administration, which is generally administered not only after surgery but also before and during surgery to minimize intraoperative blood loss [2,19,20]. Fourth, for a more accurate comparison, the surgical wound needs to be soaked in 100 mL of normal saline in the TXA (iv) and control groups; however, this procedure was not implemented given the retrospective cohort design of the study.
Conclusions
This study compared the efficacy and safety of topical TXA and relatively high-dose intravenous TXA in minimizing blood loss during single-level PLIF. Topical TXA demonstrated rapid and long-lasting effects on the reduction of postoperative blood loss compared with twice the amount of intravenous TXA, without causing venous thromboembolic complications.
Key Points
Topical tranexamic acid (TXA) administration reduced postoperative blood loss more effectively than intravenous TXA.
Topical TXA exhibited more rapid and longer-lasting hemostatic effects than intravenous TXA.
Neither intravenous nor topical TXA caused complications associated with thromboembolic events.
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