The Spine Journal 15 (2015) 647–654

Clinical Study

Preliminary investigation of high-dose tranexamic acid for controlling intraoperative blood loss in patients undergoing spine correction surgery Jingming Xie, MDa,*, Lawrence G. Lenke, MDb, Tao Li, MDa, Yongyu Si, MDc, Zhi Zhao, MDa, Yingsong Wang, MDa, Ying Zhang, MDa, Jie Xiao, MDa a

Department of Orthopaedic Surgery, 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road 374, Kunming, Yunnan Province, P.R. China, 650101 b Department of Orthopaedic Surgery, Washington University Medical Center, Suite 11300, Campus Box 8233, St. Louis, MO 63110, USA c Department of Anesthesiology, 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road 374, Kunming, Yunnan Province, P.R. China, 650101 Received 20 August 2012; revised 8 November 2014; accepted 24 November 2014

Abstract

BACKGROUND CONTEXT: With a significant increase in the number and complexity of spinal deformity corrective surgeries, blood loss, often requiring massive intraoperative transfusions, becomes a major limiting factor during surgery. This scenario is particularly during posterior vertebral column resection (PVCR), where extensive intraoperative blood loss may pose a major risk to the patient, preventing smooth execution of the procedure. Tranexamic Acid (TXA) has been used in cardiac and orthopedic surgeries, including major spinal surgeries, to reduce blood loss and transfusion requirements for decades. PURPOSE: To assess the efficacy and safety of high doses of TXA in posterior spinal deformity corrective surgery, including PVCR procedures. STUDY DESIGN: A retrospective study from a single institution. PATIENT SAMPLE: Fifty-nine patients (age range 7 to 46 years old) with spinal deformities undergoing spinal corrective surgeries were included. The patients were divided into two groups: the TXA group (total of 26 patients, including 8 PVCR patients) and the control group (total of 33 patients, including 9 PVCR patients). OUTCOME MEASURES: The analyzed outcome measures included estimated intraoperative blood loss, real blood loss (RBL; blood loss/blood volume
100%), blood transfusion requirements, coagulation parameters, complete blood count, liver function, and renal function. Lower limb vein thrombus, symptomatic pulmonary embolism, symptomatic myocardial infarction, seizures, and acute renal failure were also recorded. METHODS: Before skin incision, the patients in the TXA group received an intravenous loading dose of 100 mg/Kg over a 20-minute period, followed by a maintenance infusion of 10 mg/Kg/h until skin closure was completed. The patients in the control group received saline infusion of a similar volume. Statistics included estimated intraoperative blood loss, RBL, blood transfusion requirements, coagulation parameters, complete blood count, liver function, and renal function. All

FDA device/drug status: Not applicable. Author disclosures: JXie: Nothing to disclose. LGL: Royalties: Medtronic (I) Quality Medical Publishing (A); Consulting: DePuy Synthesis Spine (C, Monies donated to a charitable foundation), K2M (D, Monies donated to a charitable foundation), Medtronic (F, Monies donated to a charitable foundation); Speaking and or Teaching Arrangements: Depuy (C), Synthesis Spine (C), K2M (D), Medtronic (F); Trips/Travel: AOSpine (E), BroadWater (E), DePuy Synthes Spine (E), K2M (E), Medtronic (E), Seattle Science Foundation (E), Scoliosis Research Society (E). Stryker Spine (E); Endowments: The Jerome J. Gilden Endowed Professor of Orthopaedic Surgery (H, paid directly to institution); Research support (Investigator Salary, Staff/Materials): Setting Scoliosis Straight Foundation (D, Paid directly to institution), EOS Imaging (A, Paid directly to institution), Axial Biotech (B, Paid http://dx.doi.org/10.1016/j.spinee.2014.11.023 1529-9430/Ó 2015 Elsevier Inc. All rights reserved.

directly to institution), Fox Family Foundation (H, Paid directly to institution); Grants: Fox Family Foundation (H, Paid directly to institution) Fellowship Support: AOSpine North America (D, Paid directly to institution). TL: Nothing to disclose. YS: Nothing to disclose. ZZ: Nothing to disclose. YW: Nothing to disclose. YZ: Nothing to disclose. JXia: Nothing to disclose. The disclosure key can be found on the Table of Contents and at www.TheSpineJournalOnline.com. No funds were received in support of this research. There are no specific conflicts of interest and associated biases in this study. * Corresponding author. Department of Orthopaedic Surgery, 2nd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China. Tel.: þ86-871-65351281; fax: þ86-871-65352087. E-mail address: [email protected] (J. Xie)

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patients in this study were also carefully monitored for consciousness level, breathing status, chest tightness or pain, and urine output after surgery. These were done to detect the presence or absence of pulmonary embolism, myocardial infarction, seizures, and acute renal failure. Patients treated with TXA were examined via vascular ultrasound before and after surgery. RESULTS: There were no significant differences in the demographic or surgical traits between the two groups. The blood loss of the patients in the TXA group was 2,44161,666 mL, whereas that of the control group patients was 4,78964,719 mL. The difference was statistically significant (p!.05). The average RBL of the patients in the TXA group was 80.6%649.6% versus 160.8% 6163.1% in the control group (p!.05). The blood transfusion requirements for the patients in the TXA group were significantly less than that in the control group (p!.05). Blood loss, RBL, and blood transfusion requirements were all significantly lower in the TXA group, compared with the control group among both PVCR patients and non-PVCR patients. In the TXA group, there was an average of 57.4% reduced blood loss in patients who received PVCR and 39.8% in patients not receiving PVCR. There were no differences in liver and renal functions between the TXA and control groups. There was no lower limb vein thrombus, symptomatic myocardial infarction, symptomatic pulmonary embolism, seizures, or acute renal failure reported in the TXA group. CONCLUSIONS: In our study, high doses of TXA have been shown to effectively control blood loss and reduce the transfusion requirement. This effect was more apparent in patients receiving PVCR. No adverse drug reaction was recorded in the study. In the future, prospective randomized controlled trials to validate our results will be necessary. Future studies conducted on older patient cohort may also be necessary to confirm the safety of extending the use of TXA to the older patients. Ó 2015 Elsevier Inc. All rights reserved. Keywords:

Spinal deformities; Posterior spinal deformity corrective surgery; Posterior vertebral column resection; Tranexamic acid; Blood loss; Blood transfusion

Introduction Posterior spinal deformity corrective surgery is being widely performed nowadays. Posterior vertebral column resection (PVCR) was initially introduced in 2002 [1], and it is now an accepted procedure in the treatment of severe rigid spinal deformity. Posterior spinal deformity corrective surgery has been associated with significant blood loss. Posterior vertebral column resection, in particular, can be associated with significant blood loss because of the long fusion levels, prolonged operative time, and resection of the vertebral body where large epidural veins reside. Blood loss of 10 L (twice the amount of adult human blood volume) can be expected during a PVCR procedure [2]. Extensive blood loss can lead to massive blood transfusions, pulmonary or cerebral edema, and shock [3]. Blood transfusions pose inherent risks, for example, blood-borne disease transmission, increased incidence of wound infections, and hemolytic and non-hemolytic transfusion reactions [4]. Morbidity and mortality because of intraoperative blood loss and associated blood transfusion complications are significant and have become major limiting factors in the widespread use of PVCR procedure. To minimize bleeding during spinal deformity corrective surgery, many attempts have been made using different antifibrinolytics since 1990. Aprotinin, epsilon-aminocaproic acid, and tranexamic acid (TXA) have all been used. They have shown effectiveness in reducing blood loss and the number of transfusions necessary in patients undergoing spinal surgery [5].

Aprotinin was once considered to be one of the best drugs available for significantly reducing blood loss during surgery. It was first used in open heart surgery in 1960, where it successfully reduced the perioperative blood loss. It then became the drug of choice for many surgical procedures. From 2006 onwards, Aprotinin fell out of favor after clinical evidence showed a potential link to renal failure, myocardial infarction, cerebral vascular accident, and even death [6,7]. Epsilon-aminocaproic acid and TXA were both found to be effective with no severe adverse effects. However, TXA had shown to be more effective than Epsilon-aminocaproic for major orthopedic surgery in reducing intraoperative blood loss [8]. Tranexamic acid was first released in the 1970s [9] and was then used in cardiac and orthopedic surgeries, including major spinal surgeries. Tranexamic acid is a synthetic antifibrinolytic amino acid derivative that forms a reversible complex with both plasminogen and plasmin by binding at lysine binding sites. This binding completely blocks the interaction of plasminogen and plasmin with lysine residues on the surface of fibrin, thereby preventing proteolytic action of plasmin on fibrin and inhibiting fibrinolysis at the surgical wound [10]. Many regimens of TXA have been used in the control of bleeding in surgical procedures. There has been no established guideline for the dosage for these procedures. Also, there have been no studies focusing on TXA in patients undergoing PVCR. The purpose of our study was to assess the efficacy and safety of high doses of TXA in spinal deformity corrective surgery, especially in PVCR.

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Materials and methods Sixty-six patients underwent posterior spinal correction surgery from February 2009 to October 2010 at our institution. Pediatric patients with single hemivertebra and patients diagnosed with bleeding disorder or taking medications (such as nonsteroidal anti-inflammatory drugs) that can affect coagulation situation were excluded from the present study. Seven patients were excluded from the study. Four patients were excluded from February 2009 to February 2010 and three were excluded from February 2010 to October 2010. Finally, 59 patients with spinal deformity were enrolled in the present study. The patients in the study all underwent posterior spinal deformity corrective surgery, and all procedures were done by the same senior surgeon. In our institution, we began using TXA to reduce blood loss and transfusion requirements since February 2010. In the study, the patients were divided into two groups: the TXA group (from February 2010 to October 2010, 26 patients) and the control group (from February 2009 to February 2010, 33 patients). Eight patients in the TXA group and nine patients in the control group had the PVCR procedure. This study was approved by the institutional review board of our hospital. For patients receiving TXA, all patients older than 18 years signed the informed consent forms, and we also obtained the informed consent forms from the parent or guardian for patients younger than 18 years. The patients in the TXA group received an intravenous loading dose at 100 mg/Kg, given over a 20-minute period before skin incision, followed by a continuous infusion of 10 mg/Kg/h until skin closure. An equal amount of normal saline in terms of volume was given to the patients in the control group. General anesthesia was used in all patients. The anesthesiologist was the same for all surgeries. After a routine monitor was put in place, an endotracheal tube was inserted after anesthesia induction. Anesthesia was induced with intravenous midazolam, fentanyl, propofol, and a muscle relaxant and maintained by controlled ventilation with sevoflorane/isoflorane, an intravenous muscle relaxant, intravenous propofol, and remifentanil. Esophageal temperature was maintained above 36 C. Intraarterial line via the radial artery was inserted after anesthesia induction to constantly monitor the blood pressure during the procedure. Mean arterial blood pressure was maintained between 60 and 70 mmHg by ventilating the patient with isoforane, sometimes in combination with an intravenous infusion of nitroglycerin. Controlled hypotension was continued until the completion of screw placement. For the PVCR procedure, arterial blood pressure was then returned to within 20% of the baseline pressure. Adequate replacement and maintenance of intravascular volume by intravenous crystalloid and colloid solutions were guided by arterial blood pressure, urinary output, and arterial blood gas. Packed red blood cells were transfused when the hematocrit decreased to 25% or less. Other blood products, such as

Context Tranexamic acid (TXA) has gained popularity recently as a means of controlling intraoperative blood loss in major spinal surgery. The authors review their experience using TXA in individuals undergoing spine surgery for the correction of deformity. Contribution The authors were able to include 59 patients in this retrospective analysis. Twenty-six patients were treated with TXA, including eight who underwent posterior vertebral column resections. TXA was found to effectively reduce intraoperative blood loss and the need for transfusion, particularly for patients undergoing posterior vertebral column resections. Implications This study reinforces earlier findings regarding the efficacy of TXA in reducing blood loss and the need for transfusion in patients undergoing major spinal surgery. As a retrospective review, however, this study is potentially confounded by the substantial clinical heterogeneity present within the study groups. Furthermore, the low number of patients undergoing posterior vertebral column resections (less than 10 in both cohorts) precludes the real capacity for generalization of this study’s findings to that subset of patients. —The Editors

fresh frozen plasma, platelets, and cryoprecipitate, were administered in accordance with the recommendations of the American Society of Anesthesiologists Task Force on Blood Component Therapy [11]. Blood loss was determined from the suction, cell saver, and by weighing the sponges on an hourly basis. The total amount of blood transfused was calculated from the volume of the cell saver and the units of allogeneic packed erythrocytes. Blood loss, blood transfusions, and real blood loss (RBL; blood loss/blood volume
100%) were calculated. Coagulation parameters, complete blood count, and liver and renal functions were tested before and after surgery. All patients in this study were monitored for any clinical symptoms, such as level of consciousness, breathing status, chest tightness, and chest pain typical of symptomatic myocardial infarction, symptomatic pulmonary embolism, or seizures. If there is any suspicion, troponin, computed tomography pulmonary angiography, and electroencephalogram would be performed. Urine output and serum creatinine levels were calculated to monitor renal function. The patients in the TXA group also received a vascular ultrasound examination to detect possible deep vein thrombosis at their lower extremities before and after surgery.

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Table 1 Demographic and surgical traits of the two patient groups Characteristic Age (y) Sex (M/F) Weight (Kg) Blood volume (mL) Operation time (min) Fusion levels Mean arterial blood pressure (mmHg)

TXA group (n526)

Control group (n533)

p

18.969.0 11/15 44.3612.3 3,0106829 5486166 1363 65.563.3

18.667.7 15/18 45.2612.6 3,0536867 4766157 1264 64.863.2

.926 .858* .792 .860 .123 .555 .785

TXA, tranexamic acid; M, male; F, female. Note: Study groups were compared by Student t test and chi-square test (marked with *), as appropriate.

The data were statistically analyzed by SPSS software package, version 17.0 (SPSS, Inc, Chicago, IL, USA). Within-group means6standard deviation and betweengroup differences in means with 95% confidence intervals were computed for each outcome. Independent Student t test and chi-square test were calculated. In our study, p!.05 was considered statistically significant.

Results There were 59 patients, 26 males and 33 females, aged 7 to 46 years, enrolled in either the TXA (n526) or control group (n533). There were 12 pediatric patients (younger than 18 years) in the TXA group and 15 pediatric patients (older than 18 years) in the control group. There were eight patients who received PVCR in the TXA group and nine patients who received PVCR in the control group. There were no significant differences in patient demographic profiles and surgical traits in the TXA or the control group. Patients in both groups had similar age, gender, body weight, blood volume, procedure duration, and spinal fusion levels, as shown in Table 1. These parameters were also similar among the PVCR patients and non-PVCR patients in both groups (Table 2). Table 3 showed that the blood loss in patients in the TXA group was 2,44161,666 mL, whereas that in the control group was 4,78964,719 mL. The difference was statistically

significant (p!.05). The average RBL in patients in the TXA group was 80.6%649.6% versus 160.8%6163.1% in the control group (p!.05). The blood transfusion requirement in patients in the TXA group was significantly less than that in the control group (p!.05). The blood loss, RBL, and blood transfusion requirement were significantly lower in the TXA group, compared with the control group among both PVCR patients and non-PVCR patients. In the TXA group, there was a 57.4% reduction in blood loss in patients who had undergone PVCR and 39.8% reduction in blood loss in patients without PVCR. Tranexamic acid showed effectiveness both in pediatric patient and adult patient groups (Table 4). The reduction in blood loss (47.1% vs. 49.4%) and blood transfusion (45.7% vs. 44.2%) were similar in pediatric and adult patients. Tables 5 and 6 showed that less fresh frozen plasma was transfused to the patients in the TXA group than that in the control group (p!.05) among patients with PVCR and without PVCR. Patients in both groups had similar needs for crystalloids, colloids, cryoprecipitates, and platelets (Tables 5 and 6). Pre- and postoperative parameters, such as hemoglobin, hematocrit, prothrombin time, activated partial thromboplastin time, liver enzymes, urine output, and serum creatinine levels were also compared between the two groups in PVCR patients and non-PVCR patients, and the results showed no significant difference (pO.05) (Tables 5 and 6). There was no evidence indicating liver or renal toxicity or failure on direct clinical evaluation. Lower extremity vascular ultrasound studies showed no deep venous thrombus in patients who received TXA. There were no clinical signs or symptoms suggesting symptomatic myocardial infarction, symptomatic pulmonary embolism, or seizures in TXA treated group.

Discussion Antifibrinolytic agents have been shown to decrease blood loss associated with major surgical procedures [12,13]. The present study aims to evaluate whether intravenous high doses of TXA can reduce intraoperative blood loss and blood transfusion requirements in patients undergoing posterior spinal deformity correction surgery and whether

Table 2 Demographic and surgical traits of PVCR and non-PVCR patients PVCR

non-PVCR

Characteristic

TXA (n58)

Control (n59)

p

TXA (n518)

Control (n524)

p

Age (y) Sex (M/F) Weight (Kg) Blood volume (mL) Operation time (min) Fusion levels Mean arterial blood pressure (mmHg)

24.4612.0 4/4 46.9617.1 3,22761,173 721695 1264 66.363.6

20.366.0 5/4 48.2616.7 3,28161,203 6356123 1365 65.163.5

.385 .832* .872 .926 .129 .891 .766

15.764.7 7/11 42.868.9 2,8866570 4496103 1363 64.463.1

17.868.5 10/14 43.868.3 2,9456668 4006107 1264 64.163.6

.404 .737* .772 .792 .202 .360 .845

PVCR, posterior vertebral column resection; TXA, tranexamic acid; M, male; F, female. Note: Study groups were compared by Student t test and chi-square test (marked with *), as appropriate.

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Table 3 Blood loss, real blood loss, and blood transfusion between the two groups Characteristic All patients Blood loss (mL) Real blood loss (%) Blood transfusion (mL) PVCR patients Blood loss (mL) Real blood loss (%) Blood transfusion (mL) Non-PVCR patients Blood loss (mL) Real blood loss (%) Blood transfusion (mL)

Control group

TXA group

Mean difference (95% CI)

p

4,78964,719 160.86163.1 3,23662,938

2,44161,666 80.6649.6 1,75061,334

2,348 (444, 4,252) 80.2 (15.0, 145.4) 1,486 (247, 2,725)

.020 .019 .022

9,90665,251 332.96191.8 6,25563,401

4,21961,386 134.2636.4 2,98661,458

5,687 (1,556, 9,818) 198.7 (53.7, 343.7) 3,239 (479, 5,999)

.012 .015 .023

2,36661,364 79.3641.7 1,80661,043

1,4256627 49.9621.8 1,0426502

941 (212, 1,670) 29.4 (6.4, 52.4) 764 (202, 1,326)

.013 .014 .010

PVCR, posterior vertebral column resection; TXA, tranexamic acid; CI, confidence interval. Note: Study groups were compared by Student t test.

mg/Kg followed by 1 mg/Kg/h reduced perioperative blood loss by 25% to 35% in adult patients undergoing spinal fusion surgery. In dose-response trials of adults undergoing cardiac surgery, Karski et al. [19] demonstrated that the TXA dose regimen of 70 mg/Kg was more effective at reducing blood loss than 10 mg/Kg, and a dose of 100 mg/Kg was more effective than 50 mg/Kg, and equally effective to 150 mg/ Kg in a second trial. Reid et al. [12] indicated that the loading dose of 100 mg/Kg followed by a 10 mg/Kg/h maintenance dose could reduce blood loss and transfusion requirements by 24% and 38%, respectively, in pediatric cardiac patients. There were no dose-response studies available in spinal surgery, and a relationship between TXA doses in controlling blood loss was not well established. However, previous studies have suggested that high doses of TXA were more effective than smaller doses. The study by Shapiro et al. [15] reported a significant reduction in transfusion requirements in Duchene muscular dystrophy patients treated with high-dose TXA. Consistent with the findings by Shapiro et al. [15], our present study showed that high-dose TXA effectively reduced transfusion requirements. Sethna et al. [14] also reported a significant decrease in blood transfusions in secondary scoliosis patients treated with high-dose TXA, but no significant differences were seen between the idiopathic scoliosis and

it may increase the risk of thromboembolism, seizure, and liver and renal toxicity. More importantly, we wanted to assess the efficacy and safety of high doses of TXA during PVCR procedure. We found that high-dose TXA is effective in controlling intraoperative blood loss and reducing the number of blood transfusions in our study, especially in PVCR patients. We found no adverse drug reactions in the TXA group, including patients who had PVCR. In the present study, the use of high-dose TXA was associated with significant reduction of blood loss of 39.8% in non-PVCR patients. Our results are similar to previous reported studies. Sethna et al. [14] found that high-dose TXA reduced intraoperative blood loss by 41% in pediatric patients undergoing scoliosis surgery, and Shapiro [15] et al. found that high-dose TXA reduced intraoperative blood loss by 42% in Duchene muscular dystrophy scoliosis surgery. Smaller TXA doses using loading dose of 10 mg/Kg followed by 1 mg/Kg/h had been tried by Neilipovitz et al. [16] and were found ineffective in reducing blood loss for scoliosis surgery. Similar results were shown by Baldus et al. [17] in their study, with a loading dose of 10 mg/ Kg followed by a maintenance dose of 0.5 mg/Kg/h. Baldus et al. [17] pointed out that the results would have been different if a higher dose TXA regimen had been used. Wong et al. [18] found that a smaller loading dose of TXA of 10 Table 4 Blood loss, real blood loss, and blood transfusion between different age groups Characteristic $18-y-old patients Blood loss (mL) Real blood loss (%) Blood transfusion (mL) !18-y-old patients Blood loss (mL) Real blood loss (%) Blood transfusion (mL)

Control group

TXA group

Mean difference (95% CI)

p

6,65765,376 198.26184.9 4,26463,432

3,37161,706 98.8654.3 2,31561,500

3,286 (284, 6,288) 99.4 (9.4, 189.4) 1,949 (92, 3,806)

.030 .035 .041

2,50462,208 110.16110.8 1,91961,271

1,3256616 56.8634.1 1,0716682

1,179 (113, 2,245) 53.3 (8.7, 97.9) 848 (179, 1,517)

.042 .038 .043

TXA, tranexamic acid; CI, confidence interval. Note: Study groups were compared by Student t test.

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Table 5 Comparison of non-PVCR patients Characteristic and lab test

TXA group (n518)

Control group (n524)

Mean difference (95% CI)

p

FFP (mL) Crystalloids (mL) Colloids (mL) Cryoprecipitate (u) Platelets (u) Hemoglobin (g/L) Preoperative First day after surgery Hematocrit (%) Preoperative First day after surgery PT (s) Preoperative First day after surgery APTT (s) Preoperative First day after surgery ALT (U/L) Preoperative First day after surgery AST (U/L) Preoperative First day after surgery Scr (umol/mL) Preoperative First day after surgery Intraoperative urine output (mL)

214.36254.5 1,942.96494.5 2,013.26463.3 2.863.6 2.261.8

581.66429.9 1,723.7.06983.2 2,186.86403.9 3.764.9 2.661.6

367.3 219.2 173.6 0.9 0.4

.005 .451 .616 .133 .546

(630.7, 103.9) (366.2, 804.6) (567.1, 219.9) (5.0, 3.2) (3.6, 2.8)

136.969.6 97.8612.6

133.0610.9 96.5616.7

3.9 (3.7, 11.5) 1.3 (10.2, 12.8)

.305 .812

44.4612.7 28.663.7

40.362.9 27.068.0

4.1 (2.2, 10.4) 1.6 (3.3, 6.5)

.194 .501

14.461.4 18.562.4

14.160.8 17.861.8

0.3 (0.6, 1.2) 0.7 (0.9, 2.3)

.465 .362

31.169.2 31.865.8

32.865.1 32.866.1

1.7 (6.9, 3.5) 1.0 (5.4, 3.4)

.509 .648

16610 26615

1668 22613

0.3 (6.5, 5.9) 3.9 (9.2, 17.0)

.902 .542

2564 79629

2266 60617

2.6 (1.1, 6.3) 18.7 (5.3, 42.7)

.173 .115

6.4 (15.2, 2.4) 9.7 (58.7, 39.3) 52 (460, 356)

.141 .647 .795

5368 64635 1,2796567

59614 74623 1,3316556

PVCR, posterior vertebral column resection; TXA, tranexamic acid; CI, confidence interval; FFP, fresh frozen plasma; PT, prothrombin time; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Scr, serum creatinine. Note: Study groups were compared by Student t test.

control groups in transfusion requirements. Neilipovitz et al. [16] and Wong et al. [18] used a small TXA dosing regimen: 10 mg/Kg loading dose followed by 1 mg/Kg/h. They found no significant differences in transfusion requirements between the TXA and control groups. The unique point of our study is that we evaluated the blood loss, RBL, and transfusion requirements in patients who underwent PVCR. It showed that blood loss in the TXA group patients with PVCR decreased by approximately 57.4%. In a previous study, the blood loss of patients undergoing PVCR decreased significantly when the patients were treated with aprotinin [20]. Posterior vertebral column resection was initially reported by Suk et al. [1] in 2002, and it was primarily used to correct severe rigid spinal deformity. We have successfully used this procedure on many of our patients with severe spinal deformities [21]. The combination of long fusion levels, prolonged operative time, and a complex resection procedure in the vertebral body where large epidural veins reside usually lead to major blood loss. The need for substantial transfusion in the perioperative period is not uncommon. The average blood loss in PVCR procedures reported by Suk et al. [2] ranged from 2,450 to 11,000 mL. Their upper range was almost twice that of adult human blood volume. These data explained why major blood transfusions in PVCR were perceived as routine necessities. The

vital signs were difficult to maintain with the development of the PVCR procedure. Particularly in the vertebral column resection procedure, massive blood loss may seriously obscure the surgical field and hamper the surgeon’s ability to complete an elaborate and potentially dangerous procedure, thereby increasing the risk of spinal cord injury. The leading cause of mortality and morbidity of PVCR may primarily be because of the extensive blood loss and transfusion associated complications. Blood loss was significantly decreased with the use of TXA, the anesthesiologist was more able to maintain the patient’s vital signs, and the surgeon could operate with clear vision and in an easy-going situation. In the TXA group, blood loss of patients who had PVCR decreased much more than it did in the non-PVCR patients (57.4% vs. 39.8%). It was true that extensive blood loss and transfusion occurred during the early stages of the PVCR procedure and usually implied bad outcomes. Extensive blood loss might lead to massive transfusions and the associated complications. The complications resulting from significant transfusions, such as coagulopathy, hypothermia, thrombocytopathy, and dilutional thrombocytopenia may lead to more bleeding. Then a vicious cycle, not uncommon in PVCR procedure, is triggered. Therefore, control of blood loss in PVCR is crucial. The use of TXA could delay or even break this vicious cycle. That may be the reason why TXA provided more protection to the patients who

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Table 6 Comparison of PVCR patients Characteristic and lab test

TXA group (n58)

Control group (n59)

Mean difference (95% CI)

p

FFP (mL) Crystalloids (mL) Colloids (mL) Cryoprecipitate (u) Platelets (u) Hemoglobin (g/L) Preoperative First day after surgery Hematocrit (%) Preoperative First day after surgery PT (s) Preoperative First day after surgery APTT (s) Preoperative First day after surgery ALT (U/L) Preoperative First day after surgery AST (U/L) Preoperative First day after surgery Scr (umol/mL) Preoperative First day after surgery Intraoperative urine output (mL)

1,050.06507.1 1,887.56700.4 3,053.26893.5 12.564.6 8.863.5

2,325.061,518.5 2,345.06863.0 3,387.36903.4 16.0610.8 12.067.9

1,275.0 457.5 334.1 3.5 3.2

.016 .427 .684 .133 .258

145.9613.7 95.5612.5

140.9616.4 95.0614.8

5.0 (10.7, 20.7) 0.5 (14.2, 15.2)

.509 .943

43.064.1 28.363.5

42.564.2 24.969.5

0.5 (3.7, 4.7) 3.4 (4.3, 11.1)

.801 .358

15.262.1 18.962.2

14.161.2 17.261.5

1.1 (0.7, 2.9) 1.7 (0.3, 3.7)

.183 .083

36.268.7 39.566.9

34.563.9 33.865.0

1.7 (5.1, 8.5) 5.7 (0.5, 11.9)

.613 .069

20612 1766

19610 1966

0.6 (10.6, 11.8) 2 (8, 4)

.926 .491

2365 68621

2266 59613

0.6 (5.2, 6.4) 8.6 (10.4, 27.6)

.884 .362

0.6 (25.3, 26.5) 9.6 (8.2, 27.4) 719 (1,872, 434)

.960 .264 .196

63625 68613 1,6816569

62625 58612 2,40061,444

(2,298.3, 151.7) (1,257.9, 342.9) (1,174.1, 505.9) (11.7, 4.7) (9.2, 2.8)

PVCR, posterior vertebral column resection; TXA, tranexamic acid; CI, confidence interval; FFP, fresh frozen plasma; PT, prothrombin time; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Scr, serum creatinine. Note: Study groups were compared by Student t test.

underwent the PVCR procedure than patients who did not have PVCR. Sethna et al. [14] showed similar results in their study. In the placebo group, the mean blood loss in secondary scoliosis was almost twice as much as it was in idiopathic scoliosis. The blood loss in secondary scoliosis patients was significantly lower in the TXA groups than in the placebo group, but the blood loss in the idiopathic patients was not significantly lower in the TXA group. Our study suggests that the use of TXA will be more meaningful to PVCR and other major spinal surgeries that were potentially associated with extensive blood losses. The potential adverse effects related to high doses of intravenous TXA were also evaluated in our present study. There were no adverse drug reactions, such as seizure, myocardial infarction, renal, liver failure, and deep vein thrombosis, in the present study. Because of the lengthy duration of the PVCR procedure, the amount of the TXA used in the PVCR procedure was higher than in the non-PVCR surgery. There was also no adverse reaction reported in patients undergoing PVCR. In spinal surgery, the adverse effect of TXA was not common. The only complications reported with TXA use were in the study by Wong et al. [18], in which they used small dose of TXA. One patient in the TXA group developed an asymptomatic non-Q myocardial infarction 6 days after surgery and recovered fully.

The complications with TXA use were reported more often in cardiac surgery. Murkin et al. [22] showed seizure activity in elderly patients undergoing cardiac surgery treated with high-dose TXA in their recent study. Martin et al. [23] reported that approximately 2.2% patients experienced acute myocardial infarction and 5.9% patients experienced renal failure in a study that enrolled 592 elderly patients. The low incidence of complications in spinal surgery might be because the patients included in our study were few and the patients were younger than those who underwent cardiac surgery. In addition to TXA, controlled hypotension was also used to control bleeding in our study. The main concern with controlled hypotension is postoperative loss of vision, which is estimated to occur in 0.09% of patients undergoing spine surgery in the prone position [24]. Controlled hypotension was maintained between 60 and 70 mmHg and was continued until the completion of screw placement in our study. It is a relatively short time and the target mean blood pressure in our study was higher than it was in the study by Sethna et al. [14], who found no complications related to the combination of hypotensive techniques and TXA. The same results could be found in other studies focused on TXA [15,16]. We also found no complications in the present study and we did not observe that the hypotension affected neurophysiologic monitoring.

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The potential weakness of our study is that it is retrospective and nonrandomized. When the TXA was considered efficacious, it was difficult not to use TXA to reduce blood loss, which in itself might have increased the risk of patients or even led to death, especially in PVCR procedure. We have made a conscientious effort to minimize the potential bias and confounding variables in the present study. Patients in the control and the TXA groups were enrolled in the present study for two consecutive years; it can bring the influence of the advances in surgical techniques and other biases to the minimum. Moreover, there were no significant differences in patient demographic profiles and surgical traits between the two groups. In conclusion, high doses of TXA can provide beneficial effects in controlling blood loss and decreasing transfusion requirements in posterior spinal deformity corrective surgery, especially in PVCR. No adverse drug events were detected in this study. Future prospective randomized controlled trials to further validate the results of this study will be helpful. Studies conducted on older adult population should also be performed to confirm the safety of TXA.

Acknowledgments The authors thank Wanda Reese (of Jade Medical Communications Group, Los Angeles, CA, USA) who provided professional English-language editing of this article before its final acceptance for publication. The authors also thank Hee Hwan Tak (Medical Director and Senior Consultant, Pinnacle Spine & Scoliosis Centre; Associate Editorial Board Member of the Spine Journal) who provided professional English-language editing of this article before its final acceptance for publication.

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