Effect of early continuously intravenous tranexamic acid on perioperative blood loss in thoracolumbar burst fractures with neurological symptoms

Abstract

There is still a conflict between early surgical decompression and increased bleeding resulting from early surgery for thoracolumbar burst fractures (TBF) with neurological symptoms. The aim of this study is to investigate the effect of early continuously intravenous tranexamic acid (TXA) on perioperative blood loss in TBF with neurological symptoms who underwent early surgery. A retrospective comparative analysis was performed. The patients in study group were treated with intravenous TXA 15 mg/kg every 24 hours after admission besides intravenous TXA 15 mg/kg before skin incision and patients in control group were treated with intravenous TXA 15 mg/kg before skin incision only. Perioperative blood loss was compared between the 2 groups. The hemoglobin at admission, before surgery, 1 day and 3 days after surgery, the operation time, drainage time, blood transfusion and volume, incidence of complications and length of hospital stay were also compared. The operation time, preoperative, intraoperative, total, hidden amounts of blood loss in TXA group were significantly lower than those in control group (P < .001). The hemoglobin level in the TXA group was significantly higher than that in the control group before and 1 day after surgery (P < .05). The remove drainage time, hospitalization time, blood transfusion rate and volume in the TXA group were significantly lower than those in the control group (P < .001). There was no significant difference in the incidence of lower limb thrombosis between the 2 groups (P > .05). Early continuously intravenous TXA reduces the perioperative blood loss of patients with TBF who underwent early posterior fracture reduction, nerve decompression and pedicle screw fixation.

1. Introduction

Spinal fracture is common in the thoracolumbar segment due to its location on the junction of spinal biomechanical stress. It is mainly caused by high-energy trauma and 20–40% of patients present neurological symptom.^[1] For patients with neurological compression, posterior fracture reduction, nerve decompression and pedicle screw fixation were deemed as a better choice to decompress neurologic tissues for recovery. However, the surgery timing is controversial.^[2] It is generally considered that early surgical intervention within 72 hours of injury can reduce hospital stay, length of ICU stays, ventilator days and hospitalization costs.^[3] On the other hand, some scholars hold that early surgical intervention may cause a “second hit”, resulting in increased intraoperative bleeding, which not only affects the operation, but also is not conducive to the enhanced recovery after surgery (ERAS) of patients.^[4] Therefore, a strategy for balancing early surgical decompression with bleeding seems to be the key of improving treatment outcomes.

Tranexamic acid (TXA) is an antifibrinolytic agent and it has been confirmed safe and effective in reducing perioperative and traumatic bleeding.^[5–8] TXA has been also applied in reducing surgical blood loss in posterior lumbar interbody fusion.^[9] Recent reports showed that intravenous TXA before surgical incision, topical use of TXA after wound incision or intravenous TXA before skin incision combined with postoperative continuously use decrease perioperative blood loss effectively and safely.^[4,10,11] But for patients with TBF, some time periods are ignored in these studies. The bleeding started at the time of the injury so that TXA applied before, during or after operation could not reduce bleeding caused by trauma. Bleeding caused by trauma not only affect the safety of surgery, but also affect the ERAS of patients. The purpose of this study was to investigate the efficacy and safety of early continuously use of TXA in reducing perioperative bleeding in TBF patients with interval time <72 hours.

2. Materials and Methods

This study was approved by the Ethics Committee of Chongqing Dong Nan Hospital and performed in line with the Declaration of Helsinki international ethical guidelines. Written informed consent was obtained from all patients after admission to hospital. From May 2016 to April 2021, TFB patients with neurological symptoms undergoing early posterior fracture reduction, nerve decompression and pedicle screw fixation were retrospectively enrolled in this study. Before July 2019, patients were treated with intravenous TXA only before skin incision. After that, all the patients were treated with intravenous TXA continuously from admission to preoperation besides before skin incision.

2.1. Inclusion criteria

The inclusion criteria of this study were: (1) age of 18–50 years old; (2) Bone mineral density (BMD) of lumbar spine and hip > -1.0; (3) time from injury to admission <12 hours; (4) time from admission to surgery <72 hours; (5) single fracture segment A3 or A4 style according to OA classification and located in T11–L2; (6) ASIA impairment scale grade C or D.^[12]

2.2. Exclusion criteria

The exclusion criteria of this study were: (1) multiple fracture segments or multiple injuries; (2) pathological fractures caused by tumors, infections, osteoporosis, etc; (3) severe dysfunction of the heart, lung, liver, or kidney or coagulation dysfunction; (4) allergy to TXA; (5) anticoagulant therapy such as antiplatelet drugs or warfarin before injury; (6) coagulation dysfunction or preoperative examination found thrombosis, or a history of thrombosis within 6 months; (7) anemia on admission, hemoglobin (Hb) < 120 g/L for men and hemoglobin (Hb) < 110 g/L for women; (8) leakage of cerebrospinal fluid was found during surgery.

2.3. Treatment

Blood routine including Hb and hematocrit (HCT), and ultrasound of lower limbs examination were completed immediately after admission for all patients. Then, patients in the study group were given TXA 15 mg/kg intravenously, and it was repeated every 24 hours until the day of surgery. Besides, patients were given TXA 15 mg/kg intravenously 30 minutes before skin incision, In the control group, patients were given TXA 15 mg/kg intravenously only 30 minutes before skin incision. Hb and hematocrit (HCT) were repeated before surgery (on the day of surgery).

All the patients underwent a standard surgical procedure of posterior incision, laminectomy, decompression, fracture reduction and short segment internal fixation by a single senior surgeon who specialized in spine surgery and had 10 years of experience within 72 hours of the injury. Briefly, under general anesthesia, patients were positioned pronely and a midline skin incision was made. The fascia adjacent to the spinous process was cut and the sacrospinous muscle was dissected subspinous and extended laterally to the transverse process. After that, the pedicle screws were implanted into the fractured vertebral body and adjacent upper and lower vertebral bodies with the aid of C-arm fluoroscopy. A unilateral laminectomy was performed to check the protruded bony fragment encroach the canal. Then, an impactor was used to repair the protruded bony fragment and relieve nerve compression. Connecting bars were installed, and spreader forceps were used to restore body height to 80% of the original vertebral body. The wound was thoroughly rinsed, and hemostasis was attempted by gelatin sponge and electrocoagulation. Two drainage tubes were placed on both sides of the wound, and then the wound was sutured layer by layer.

Patients were instructed to perform isometric contraction and exercise of bilateral lower limb muscles after the operation. The drainage tube was removed when the drainage volume was <50 mL. The Hb and HCT were detected at the first and third day postoperatively (POD1 and POD3). During hospitalization, lower limb ultrasound was performed when patients presented with leg pain, swelling and other suspicious venous thrombosis manifestations. When patients’ Hb < 70 g/L or between 70 and 100 g/L with anemic symptoms, allogenic transfusion was applied. The lower limb ultrasound was reviewed at the outpatient follow-up 1 month after discharge.

2.4. Data collection

Data was collected from hospital electronic medical record system. The main bleeding related indicators include preoperative blood loss (preBL), intraoperative blood loss (IBL), postoperative blood loss (PBL), hidden blood loss (HBL), total blood loss (TBL). Venous thrombosis was confirmed by ultrasound of the lower extremities. Besides, the general information including gender, age, body mass index (BMI), preoperative preparation time (time from admission to surgery), duration of surgery and length of hospital stay was also collected.

On the basis of classical calculation formula of bleeding^[13,14]: preoperative blood volume (PBV) = k1 × height (m)3 + k2 × weight (kg) + k3, of which k1 = 0.3669, k2 = 0.03219, k3 = 0.6041 for men; TBL = PBV × (HCTpre-HCTpost)/HCTave, of which HCTpre is the preoperative hematocrit, HCTpost is the lowest postoperative hematocrit during hospitalization or prior to transfusion, and HCTave is the mean of the HCTpre and HCTpost. In this study, all the patients actually experienced 2 bleeding events, 1 caused by trauma and the other caused by surgery. Therefore, the patient’s total blood loss was composed of preoperative blood loss (preBL) and operation-related blood loss which is labeled as TBL in this study. preBL = PBV × (HCT_admission – HCT_pre)/HCT_{(admission + pre)/2}, TBL = PBV × (HCT_pre – HCT_POD3)/HCT_{(pre + POD3)/2}, HBL = TBL-IBL-PBL, IBL was estimated by weighing surgical sponges, measuring blood collected by suction canisters, and subtracting all irrigations fluids added to the surgical feld, PBL = wound drainage volume × HCT_{(pre + POD3)/2}.

2.5. Statistical treatment

There are 75 patients were treated with TXA 15 mg/kg intravenously every 24 hours after admission besides TXA 15 mg/kg intravenously before skin incision and 141 patients were treated with TXA 15 mg/kg intravenously before skin incision only. To minimize selection bias, propensity score matching was performed prior to analysis. As shown in Figure 1, all patients treated with TXA 15 mg/kg intravenously every 24 hours after admission besides TXA 15 mg/kg intravenously before skin incision (study group, n = 75) were included in the final analysis and matched with patients who were treated with TXA 15 mg/kg intravenously before skin incision only (control group, n = 75). Patients in 2 groups did not differ significantly in terms of age, sex, BMI, time from injury to admission, preoperative preparation time, AO type of fracture, ASIA grade, Hb and HCT level on admission (Tables 1 and 2). For further statistical analyzes, numerical data are presented as the mean ± standard deviation (mean ± SD) and qualitative data are presented as frequencies and percentages. Student t test for continuously data and the χ² test for categorical data were used for comparisons of variables between the 2 groups. SPSS 23.0 statistical software (Chicago, IL) was used to analyze the data in this study and P < .05 was considered statistically significant.

Figure 1.

Flowchart demonstrating patient selection.

Table 1.

Comparison of baseline characteristics.

	Study group (n = 75)	Control group (n = 75)	P
Gender (male/female)	44/32	48/27	0.161
Age (yr)	39.48 ± 5.12	38.86 ± 4.81	0.631
BMI (kg/cm2)	24.38 ± 2.89	24.21 ± 2.47	0.284
ASIA grades (C/D)	52/23	49/25	0.245
T1 (h)	8.47 ± 2.16	8.15 ± 3.03	0.412
T2 (h)	43.19 ± 14.88	45.76 ± 13.64	0.812
Operative duration (min)	105.45 ± 12.68	122.38 ± 15.36	<0.001

ASIA = American Spinal Injury Association, BMI = body mass index, T1 = time from injury to admission, T2 = time from admission to surgery.

Table 2.

Comparison of Hb and blood loss.

	Study Group (n = 75)	Control Group (n = 75)	P
Hb (g/L)
Admission	142.35 ± 16.32	139.88 ± 13.89	0.644
preoperation	138.54 ± 10.66	127.18 + 8.96	0.026
POD1	122.38 ± 13.68	110.39 ± 12.85	<0.001
POD3	116.58 ± 15.28	110.87 ± 11.54	0.068
Blood (mL)
preBL	136.22 ± 21.56	218.66 ± 41.22	<0.001
TBL	498.68 ± 44.59	684.68 ± 48.98	<0.001
IBL	142.63 ± 18.39	207.12 ± 22.47	<0.001
PBL	105.27 ± 11.55	148.46 ± 35.88	<0.001
HBL	250.78 ± 28.86	329.10 ± 36.99	<0.001

Hb = hemoglobin, HBL = hidden blood loss, IBL = intraoperative blood loss, PBL = postoperative blood loss, POD1/3 = postoperative days 1/3, preBL = preoperative blood loss, TBL = total blood loss.

3. Results

The study group had less operation time than control group (P < .001) (Table 1). Hb levels were significantly higher in the study group before surgery (P = .026) and at POD1 (P < .001), but without significant difference at POD3 (P > .05). Moreover, the preBL, TBL, IBL, PBL, and HBL were significantly less in the study group than those in the control group (P < .001) (Table 2).

In the study group, 2 patient required administration of red cell suspension (RCS) postoperatively (200 mL per person) and in the control group, 7 patients required postoperative RCS transfusion (400 mL for 1 patient and 200 mL for each of the other 6 patients). The blood transfusion rate and volume were significantly lower in the study group (P < .001). The study group had shorter removal time of drainage tube and length of hospital stay (P < .001). There was no lower limb thrombosis in the 2 groups before surgery. Within 1 month after surgery, there were 5 cases of lower limb intermuscular vein thrombosis in the study group and 4 cases in the control group (P > .05). All 9 patients recovered by oral rivaroxaban and immobilization of affected limbs. The data above were shown in Table 3.

Table 3.

Comparison of postoperative condition.

	Study group (n = 75)	Control group (n = 75)	P
Transfusion rate (%)	2.67 (2/75)	9.33 (7/75)	<0.001
Transfusion volume (mL)	400	1600	–
Removal time of drainage tube (d)	2.23 ± 0.58	3.38 ± 0.61	<0.001
Length of hospital stay (d)	7.54 ± 1.78	10.35 ± 2.19	<0.001
Rate of venous thrombosis (%)	6.67 (5/75)	5.33 (4/75)	0.372

4. Discussion

Tranexamic acid (TXA) has been widely used in surgical hemostasis with good results. Recent studies by Cahueque M^[15] and Colomina MJ^[16] have shown that TXA can effectively reduce perioperative blood loss in adults undergoing major spinal surgery. However, perioperative blood loss during spinal surgery is affected by various factors such as disease type and surgical method. For example, the blood loss of spinal tumor resection is much greater than that of discectomy for disc herniation. For discectomy, the blood loss of percutaneous endoscopic nucleus pulposus excision was much lower than that of open surgery. Therefore, the present study strictly limited the disease type (thoracolumbar single-segment fracture of the spine) and the surgical method (posterior incision, unilateral laminectomy decompression, fracture reduction, short segment internal fixation) to minimize the bias effect of different diseases and surgical methods.

Although many studies have confirmed the effect of TXA in reducing blood loss in spinal surgery, most researchers focus on spinal degenerative diseases and tumors. Therefore, TXA was generally used intravenously or locally before or during surgery to reduce bleeding associated with surgery.^[17–19] Spinal fracture, especially thoracolumbar burst fracture with nerve symptoms requiring decompression and internal fixation, has its particularity in terms of blood loss. First, TBF is usually caused by high-energy trauma, which can lead to a series of complex clotting disorders such as diffuse microvascular bleeding.^[20] Early open surgery again activated the plasminogen system, leading to a further increase in the risk of vertebral cancellous bone hemorrhage.^[21] Therefore, the conflicts between early surgical nerve decompression and increased risk of bleeding have become the focus of the debate on whether early surgery should be performed for this type of injury. In addition, the bleeding caused by fracture trauma itself (severe soft tissue injury and blood clot are often seen during surgery) is also an important factor affecting patients’ blood safety which is neglected often. Therefore, how to effectively reduce blood loss caused by fracture trauma not only provides a safer blood environment for early surgery, but also lays a foundation for early postoperative rehabilitation of patients. TXA is an antiplasminogen lysine analogue that competently inhibits plasma plasminogen, plasminogen and tissue plasminogen activators at lysine binding sites.^[22] This characteristic makes it an excellent choice for perioperative blood loss control. Our results showed that Hb in the control group decreased by about 12 g/L and blood loss was (218.66 ± 41.22) mL from admission to surgery. In the study group, Hb decreased <3 g/L and blood loss was reduced obviously (136.22 ± 21.56 mL). Both sets of data suggested that blood loss from fracture trauma is significant, and that TXA early use can effectively reduce blood loss during this period. In addition, we found that the range and volume of soft tissue hematoma in the study group was significantly smaller than that in the control group intraoperatively, which also confirmed the view that the early use of TXA can effectively reduce blood loss caused by fracture trauma.

Many studies reported that intravenous TXA before surgery or local application of TXA before decompression can effectively reduce IBL, TBL, PBL, and HBL in posterior spinal surgery.^{[9,10,16,23,24]} In this study, similar results were obtained when intravenous TXA was used at the early stage after injury combined with intravenous TXA half an hour before skin incision. The Hb value of POD1 in the study group was significantly higher than that of the control group, but there was no statistic difference for Hb of POD3 between 2 groups. The decrease of Hb difference on POD3 may be related to a variety of factors such as the patient’s diet and blood dilution caused by postoperative fluid replenishment. The results of this study also showed that our project of TXA treatment can significantly shorten the time of drainage, reduce the transfusion rate and transfusion volume, thus helping to reduce the increased risk of infection caused by prolonged drainage time, as well as the potential safety problems caused by the use of blood products. Earlier removal of drainage tube and less perioperative blood loss lay a foundation for ERAS of patients, and also effectively shorten the length of hospital stay of patients. In this study, the length of hospital stay in the study group was significantly shorter than that in the control group, which also confirmed such results.

At present, TXA is mainly used by intravenous or local. Previous studies have shown that intravenous TXA has a potential risk of thrombosis.^[16] However, Min Gong et al^[9] recently conducted a meta-analysis and found that intravenous TXA did not increase the risk of lower limb thrombosis while effectively reducing surgical blood loss after posterior lumbar fusion. In this study, patients in the study group were applied continuously intravenous TXA after admission, and no lower limb thrombosis was found before surgery. A very small number of patients in both groups developed lower limb intermuscular vein thrombosis after surgery, but there was no significant difference between the 2 groups. These results suggested that surgical trauma and postoperative bed rest may be more important factors for lower extremity venous thrombosis than intravenous TXA use.

To the best of our knowledge, this is the first study on continuously intravenous TXA combined with intravenous TXA before surgical skin incision in the early stage after TBF injury. However, some limitations remain in this study. First, we can’t administer TXA immediately at the time of injury so that the action time of TXA is delayed. Then, this was a retrospective study with a small number of patients. Therefore, TXA applied at the prehospital emergency and prospective randomized controlled trials with larger sample sizes should be applied in the future to confirm our findings.

5. Conclusion

Continuously intravenous TXA combined with intravenous TXA before surgical skin incision in the early stage after TBF injury can safely and effectively reduce perioperative blood loss, as well as preoperative blood loss caused by fracture itself. It is more conducive to the early surgical relief of nerve compression in such patients, and is conducive to the faster recovery of patients after surgery.

Author contributions

Conceptualization: Yun Tan.

Data curation: Enhui Lu.

Formal analysis: Tianji Huang.

Investigation: Yun Tan.

Methodology: Enhui Lu, Yun Tan.

Project administration: Enhui Lu.

Software: Tianji Huang.

Supervision: Yun Tan.

Writing—original draft: Enhui Lu.

Writing—review & editing: Enhui Lu.