J Korean Assoc Oral Maxillofac Surg 2024; 50(2): 86~93
Effect of tranexamic acid on blood loss reduction in patients undergoing orthognathic surgery under hypotensive anesthesia: a single-center, retrospective, observational study
Keisuke Harada1, Noritaka Imamachi2, Yuhei Matsuda1, Masato Hirabayashi3, Yoji Saito3,4, Takahiro Kanno1
1Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Izumo, 2Department of Anesthesiology, Saitama Medical University, Saitama, 3Department of Anesthesiology, Shimane University Faculty of Medicine, Izumo, 4Department of Palliative Care, Shimane University Faculty of Medicine, Izumo, Japan
Takahiro Kanno
Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan
TEL: +81-853-20-2301
E-mail: tkanno@med.shimane-u.ac.jp
ORCID: https://orcid.org/0000-0003-0635-9084
Received January 19, 2024; Revised April 22, 2024; Accepted April 24, 2024.; Published online April 30, 2024.
© Korean Association of Oral and Maxillofacial Surgeons. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Objectives: Orthognathic surgery is a surgical procedure performed by intraoral approach with established and safe techniques; however, excessive blood loss has been reported in rare cases. In response, investigative efforts to identify methods to reduce the amount of blood loss have been made. Among such methods, the administration of tranexamic acid was reported to reduce the amount of intraoperative blood loss. However, few studies to date have reported the effect of tranexamic acid in orthognathic surgery under hypotensive anesthesia. The present study aimed to investigate the effect of the administration of tranexamic acid on intraoperative blood loss in patients undergoing bimaxillary (maxillary and mandibular) orthognathic surgery under hypotensive anesthesia.
Patients andMethods: A total of 156 patients (mean age, 27.0±10.8 years) who underwent bimaxillary orthognathic surgery under hypotensive anesthesia performed by the same surgeon between June 2013 and February 2022 were included in this study. The following data were collected from the medical records of each patient: background factors (age, sex, and body mass index), use of tranexamic acid, surgical procedures, previous medical history, duration of surgery, American Society of Anesthesiology physical status findings before surgery, intraoperative blood loss as a primary outcome, in–out balance, and blood test results. Descriptive statistics were calculated for statistical analysis, and a t -test and the chi-squared test were used for between-group comparisons. Group comparisons were performed after 1:1 propensity score matching to adjust for confounding factors. Statistical significance was set at P<0.05.
Results: Comparison between the groups based on the use of tranexamic acid revealed a significant difference in operation time. Propensity score matching analysis revealed that intraoperative blood loss was significantly lower in the tranexamic acid group.
Conclusion: The administration of tranexamic acid was effective in reducing intraoperative blood loss in patients undergoing bimaxillary orthognathic surgery under hypotensive anesthesia.
Keywords: Orthognathic surgery, Tranexamic acid, Anesthesia, Blood loss, Propensity score
I. Introduction

Dentofacial deformities are diagnosed based on the patient’s chief complaint, findings of cephalometric analysis, masticatory function, mandibular movement, dental model analysis, computed tomography and magnetic resonance imaging, and the results of psychological assessment1. Long-term follow-up is important, as the treatment strategy for dentofacial deformity surgery includes both preoperative and postoperative orthodontic treatment in addition to surgery1. Orthognathic surgery is a surgical procedure performed by intraoral approach increasingly to correct dentofacial deformities in recent years. The most commonly used surgical techniques for orthognathic surgery include Le Fort I osteotomy (LF-I) for the maxilla and sagittal split ramus osteotomy (SSRO) and intraoral vertical ramus osteotomy (IVRO) for the mandible2. Although these techniques are well-established, complications may occur during the surgeries. Major complications include trigeminal sensory nerve damage, such as damage to the infraorbital, lingual, and inferior alveolar nerve bundles; postoperative infection; massive bleeding owing to damage to the descending palatine artery, sphenopalatine artery, or inferior alveolar artery; abnormal fractures; sleep apnea; dental root damage; and temporomandibular joint dysfunction3-6. Among those major complications, a large amount of intraoperative blood loss and associated blood transfusions are the complications that should be avoided perioperatively. In a previous study by Ulker et al.7, intraoperative vascular complications were observed in 10 patients (5%) among 200 patients undergoing LF-I osteotomy. The most common source of bleeding was the descending palatine artery and pterygomaxillary plexus in eight patients (4%) and two patients (1%), respectively, and the causes of bleeding were maxillary down-fracture and separation of the pterygomaxillary junction in eight and two patients7. Separately, the mean intraoperative blood loss amounts during maxillary and mandibular osteotomy are approximately 345 mL and 436 mL as reported in previous studies8,9.

One of the measures to prevent intraoperative bleeding includes the use of hypotensive anesthesia and the administration of tranexamic acid. Hypotensive anesthesia is an anesthesia technique where blood pressure is intentionally lowered so as to reduce intraoperative blood loss and improve the quality of surgery10. This approach has also been reported to improve the visibility of the surgical field and shorten the operative time11,12. Hypotensive anesthesia is mainly used in the fields of orthopedic spine surgery and total hip replacement; however, it is also known to reduce intraoperative blood loss in patients undergoing orthognathic surgery and was also adopted for this study13-15.

Tranexamic acid, a synthetic amino acid with antiplasminic properties widely recognized to be a hemostatic agent, is used to control bleeding owing to increased fibrinolysis16. A multicenter, randomized controlled trial conducted in 2010 at 284 centers across 44 countries revealed that the administration of tranexamic acid to trauma patients was effective in reducing all-cause mortality and deaths by bleeding. Moreover, it was found to improve the prognosis for patient survival. Based on these findings, tranexamic acid has been used in the management of intraoperative hemorrhage17. Although tranexamic acid has been used in orthopedic joint-replacement surgery and open heart surgery18,19, it may induce complications like hypotension, nausea and vomiting, diarrhea, allergic dermatitis, visual disturbances, and color blindness. Notably, the risk of thromboembolism is high when its intravenous administration is completed rapidly20-22.

Although hypotensive anesthesia and tranexamic acid can both be used for controlling intraoperative bleeding, it is unclear whether these measures must be implemented simultaneously in orthognathic surgery. Therefore, the present study aimed to investigate the effect of the administration of tranexamic acid on reducing blood loss in patients undergoing bimaxillary orthognathic surgery under hypotensive anesthesia.

II. Patients and Methods

1. Data collection

Data were collected from the medical records of eligible patients according to the inclusion criteria in a single-center, retrospective, observational study. Patients with non-craniomaxillofacial syndromic dentofacial deformity who visited the Department of Oral and Maxillofacial Surgery of Shimane University Hospital between June 2013 and February 2022 and underwent bimaxillary orthognathic surgery, including maxillary and mandibular osteotomies, under hypotensive anesthesia performed by the same experienced oral-maxillofacial surgeon on a single surgical team were included in this study. We excluded patients (1) with hemorrhagic diathesis, (2) who were receiving anticoagulants or antiplatelet drugs, or (3) who were receiving maxillary or mandibular orthognathic surgery only. This study was approved by the Medical Research Ethics Committee, Shimane University Faculty of Medicine (No. 20220120-1) and the written informed consent was obtained from all patients.

2. Background data

Data for the following variables were collected: age (years), sex (male/female), body mass index (kg/m2), surgical technique (LF-I for the maxilla and bilateral sagittal split ramus osteotomy [BSSRO] alone or in combination with IVRO for the mandible; additional simultaneous surgeries included genioplasty, multiple-segment osteotomy, mandibular midline osteotomy, and tooth extraction), existence of systemic disease (hypertension, liver disease, diabetes mellitus, and abnormal blood clotting), duration of surgery, American Society of Anesthesiology physical status (ASA-PS), in–out balance (mL), and results of blood tests (hemoglobin change [g/dL], hematocrit change [%], preoperative platelet count [104/µL], and preoperative international normalized ratio of prothrombin time [PT-INR]). The requirement for blood transfusions and the incidence rates of postoperative pulmonary emboli and seizures were also investigated.

3. Usage protocol of tranexamic acid

The patients were divided into two groups; among them, the treatment group received continuous intravenous administration of 1 g of tranexamic acid intraoperatively, while the non-treatment group did not receive tranexamic acid during the surgery. However, both groups received continuous intravenous administration of 1 g of tranexamic acid postoperatively over a 12-hour period.

4. Hypotensive anesthesia

Hypotensive anesthesia was based on the definition provided by the Japanese National Health Insurance and usually involved systemic management of patients with a target of 40% reduction in systolic blood pressure or 60 to 70 mmHg reduction in mean arterial pressure.

5. Outcome measures

The primary outcome was the amount of intraoperative blood loss. Secondary outcomes included changes in hemoglobin and hematocrit levels, the duration of surgery, postoperative blood loss, and the incidence of postoperative pulmonary emboli. Data regarding intraoperative and postoperative blood loss (mL) were gathered from the medical records.

6. Statistical analysis

Descriptive data (as percentage or mean±standard deviation values) were selected for the statistical analyses, and their normality was confirmed using the Shapiro–Wilk test. The chi-squared test and t-tests were used to perform between-group comparisons. Propensity scores were calculated via logistic regression analysis, and 1:1 propensity score matching was performed to adjust for confounding factors (sex, age, body mass index, operative time, and ASA-PS). Analysis 1 focused on intraoperative blood loss, while Analysis 2 focused on postoperative bleeding.(Fig. 1) Group comparisons were performed using IBM SPSS Statistics software (ver. 26; IBM Corp.). Two-tailed P-values were calculated for all analyses, and the alpha level of significance was set at P<0.05.

III. Results

1. Patient characteristics

Table 1 summarizes the patient characteristics. A total of 156 patients with a mean age of 27.0±10.8 years were enrolled in this study. Among these 156 patients, 47 (30.1%) were males. Tranexamic acid was administered to 139 patients (89.1%). The mean duration of surgery was 197.6±38.3 minutes, and the mean volume of intraoperative blood loss was 124.0±38.3 mL. Blood transfusions were not required in any of the included cases, and no instance of postoperative pulmonary embolism or seizure occurred.

2. Group comparison

Table 2 presents the results of the comparisons between the treatment and the non-treatment groups. The operation time was significantly increased in the non-treatment group (248.2±37.4 minutes) compared to the treatment group (191.4±33.7 minutes; P<0.05).

3. Group comparison using propensity score matching

Tables 3 and 4 present the results of between-group comparisons performed following propensity score matching. Twenty-six patients were matched after adjusting for sex, age, body mass index, duration of surgery, and ASA-PS. Notably, the amount of intraoperative bleeding was significantly reduced in the treatment group (53.1±52.5 mL) compared to the non-treatment group (145.8±79.4 mL; P<0.05).

IV. Discussion

The major findings of this study were that tranexamic acid reduced both the amount of intraoperative blood loss and the operation time in patients undergoing bimaxillary orthognathic surgery under hypotensive anesthesia. Additionally, no pulmonary embolisms or other complications attributable to transamine usage occurred, confirming that transamine can be used safely in patients undergoing bimaxillary orthognathic surgery.

Surgical stress or surgical trauma activates the fibrinolytic system by stimulating the release of tissue plasminogen activator, the primary enzyme responsible for the conversion of plasminogen to plasmin23,24. Tranexamic acid is a synthetic fibrinolysis inhibitor that blocks the lysine-binding sites on plasminogen25. The plasminogen–tranexamic acid complex then detaches from the fibrin surface and inhibits plasmin from binding with fibrinogen and fibrin monomers, delaying fibrinolysis25.

Compression hemostasis is especially difficult to perform in patients undergoing maxillary osteotomies, as the wound is open. The primary source of bleeding may be vessels located in the soft tissue, such as the gingiva and nasal mucosa, or the bone marrow. Tranexamic acid is also used as a hemostatic agent in nasal surgery, and it has been shown to improve the visibility of the surgical field in nasal surgery26. The antifibrinolytic properties of tranexamic acid act on the bone marrow to reduce bleeding27. The results of this study also suggest that the administration of tranexamic acid during a state of increased fibrinolysis may reduce bleeding by delaying fibrinolysis.

No optimal dosage nor duration of tranexamic acid administration to achieve hemostatic effects during surgery has been established; however, the therapeutic plasma concentration of tranexamic acid is 10 ng/mL, and an 80% reduction in plasmin activity is considered necessary28,29. The same mechanism of action may have been effective in suppressing plasmin activity by >80% during the anesthetic management of patients undergoing bimaxillary orthognathic surgery in the present study. The observed reduction in the duration of surgery may be attributed to an improvement in the visibility of the surgical field owing to the reduction of intraoperative blood loss via the mechanism of action described above11.

The administration of tranexamic acid before surgery had no effect on the amount of postoperative blood loss or the blood test results. The minimum concentration of tranexamic acid required to inhibit fibrinolysis is 5 to 10 mg/L for significant inhibition, with concentrations of 10 to 15 mg/L ensuring maximum inhibition of fibrinolysis30. Benoni et al.31 reported that postoperative plasminogen levels were significantly lower in their study’s tranexamic acid group compared to those in the placebo group. Tranexamic acid interferes with the measurement of plasminogen and has been reported to reduce measured plasminogen levels by 16%31. Thus, a total dose of 1 g of tranexamic acid is considered sufficient for patients undergoing bimaxillary orthognathic surgery under hypotensive anesthesia, as there is no evidence supporting the administration of higher doses32. However, an intravenous administration of 10 mg/kg of tranexamic acid maintains the plasma concentration for only 3 hours20. Therefore, the continuous administration of 1 g of tranexamic acid postoperatively is considered necessary to suppress postoperative bleeding, as the preoperative administration of 1 g of tranexamic acid alone cannot be expected to suppress postoperative bleeding.

Activation of fibrinolysis is a cascade process and most likely to be inhibited in its early stages33. In other words, it may be sufficient to administer tranexamic acid preoperatively, as the findings are consistent with reports that tranexamic acid has little effect when administered after massive bleeding33. Therefore, an effect of preoperative administration of a 1-g dose of tranexamic acid on postoperative bleeding in long orthognathic surgery was not expected.

A randomized controlled trial conducted by Jozefowicz et al.16 reported a mean reduction in blood loss of approximately 193 mL with the administration of tranexamic acid. A meta-analysis by Siotou et al.34 reported that the use of tranexamic acid reduces intraoperative blood loss by approximately 217.18 mL. However, few studies to date have examined the effects of both hypotensive anesthesia and tranexamic acid, as hypotensive anesthesia was not used in such a combination in the abovementioned studies. Salma et al.8, who conducted their study using both hypotensive anesthesia and tranexamic acid, concluded that a 10% reduction in intraoperative blood loss can be expected with the use of tranexamic acid under hypotensive anesthesia. It is worth noting here that these studies reported bleeding volumes ranging from 391 to 875 mL. Systematic reviews have also reported that 300 to 400 mL of blood loss is common16. A difference that should be noted here is that the average intraoperative blood loss in the present study was only 124 mL, which is far less than the range of 391 to 875 mL reported in the previous study16. Thus, the use of hypotensive anesthesia and tranexamic acid may be effective regardless of the skill of the surgeon, suggesting that tranexamic acid may be used even in bimaxillary orthognathic operations that may be completed in a short time with limited blood loss.

The effectiveness of tranexamic acid observed in the present study may be attributed in part to the operative time at our department being 197.6±38.3 minutes, which is faster than that of other centers, and the use of a single dose of 1 g to sufficiently control intraoperative hemorrhage.

The results of this study are also consistent with reports that the administration of tranexamic acid does not directly correlate with fibrinolytic variables (D-dimer and fibrinogen-/fibrin-degradation products)35. Therefore, the administration of tranexamic acid for bimaxillary orthognathic surgery under hypotensive anesthesia should be initiated preoperatively to achieve a limited hemostatic effect intraoperatively.

One of the disadvantages of the administration of tranexamic acid is the risk of venous thromboembolism. Thus, the dosage for patients with a history of myocardial infarction or cerebral thrombosis should be considered carefully. However, previous clinical studies have reported low incidence rates of venous thrombosis in both the placebo and tranexamic acid groups and also that the incidence of venous thromboembolic events did not differ between tranexamic acid and control groups36,37. As a highly safe drug, tranexamic acid could be considered as one of the methods to effectively control bleeding in orthognathic surgery.

This study has three main limitations due to the following reasons. First, the duration of hypotensive anesthesia intraoperatively was not standardized. Second, the optimal plasma concentration of tranexamic acid and activation of the fibrinolytic system were not assessed. Third, the detailed surgical techniques for the directions of placement of the osteotomy segments with or without additional surgical involvement and the device used for osteosynthesis were not standardized, which may have affected the results. However, the study data were obtained for analysis from those patients who underwent surgeries performed by the same experienced oral and maxillofacial surgeon on a single surgical team over the study period. Future research should include a randomized controlled trial with a constant dose of tranexamic acid and standardized duration of hypotensive anesthesia.

V. Conclusion

A reduction in intraoperative blood loss was observed following the administration of tranexamic acid in patients undergoing orthognathic surgery under hypotensive anesthesia. In addition, it was suggested that a decrease in intraoperative blood loss may be associated with a reduction in operative time.

Acknowledgement

We would like to express our appreciation to the staff members of the Department of Oral and Maxillofacial Surgery and the Department of Anesthesiology of the Shimane University Faculty of Medicine.

Authors’ Contributions

K.H., N.I., and M.H. participated in data collection and writing the manuscript. N.I., Y.M., Y.S., and T.K. participated in the study design and performed the statistical analysis. N.I., Y.S., and T.K. participated in the study design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

This study was approved by the Medical Research Ethics Committee, Shimane University Faculty of Medicine (No. 20220120-1), and the written informed consent was obtained from all patients.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Figures
Fig. 1. Flowchart from patient enrollment to analysis.
Tables

Descriptive statistics of included patients who underwent bimaxillary orthognathic surgery for dentofacial deformity (n=156)

Variable Category Value
Sex Male 47 (30.1)
Female 109 (69.9)
Age (yr) 27.0±10.8
Body mass index (kg/m2) 21.3±3.1
Tranexamic acid No use 17 (10.9)
Use 139 (89.1)
Type of surgery LF1+BSSRO (yes) 156±100
Multiple answers allowed IVRO (yes) 6 (3.8)
Genioplasty (yes) 5 (3.2)
Multi-segment osteotomy (yes) 2 (1.3)
Mandibular midline osteotomy (yes) 1 (0.6)
Tooth extraction (yes) 2 (1.3)
Systemic disease Hypertension 4±0
Liver disease 14±0
Diabetes mellitus 1±0
Abnormal blood clotting 3±0
Operation time (min) 197.6±38.3
ASA-PS Class 1 70 (44.9)
Class 2 86 (55.1)
Intraoperative blood loss (mL) 124.0±38.3
In–out balance (mL) 876.8±506.6
Blood test Hemoglobin change (g/dL) −1.9±1.0
Hematocrit change (%) −5.8±4.2
Preoperative platelet in count (104/µL) 253.6±50.3
Preoperative PT-INR in preoperation 0.984±0.07

(LF-1: Le Fort I osteotomy, BSSRO: bilateral sagittal split ramus osteotomy, IVRO: intraoral vertical ramus osteotomy, ASA-PS: American Society of Anesthesiology physical status, PT-INR: international normalized ratio of prothrombin time)

Values are presented as number (%) or mean±standard deviation.


Comparison of clinical data between the tranexamic acid treatment group and the non-treatment group (n=156)

Variable Category Tranexamic acid treatment (n=139) Tranexamic acid non-treatment (n=17) P-value
Sex Male 40 (28.8) 7 (41.2) 0.40
Female 99 (71.2) 10 (58.8)
Age (yr) 27.3±11.1 24.8±8.1 0.38
Body mass index (kg/m2) 21.3±3.2 21.9±2.2 0.45
Operation time (min) 191.4±33.7 248.2±37.4 <0.001*
ASA-PS 1.58±0.5 1.4±0.5 0.08
Intraoperative blood loss (mL) 120.0±152.4 156.8±100.9 0.33
In–out balance (mL) 902.6±504.8 665.6±485.6 0.07
Blood test Hemoglobin change (g/dL) −1.9±1.1 −1.7±0.8 0.40
Hematocrit change (%) −5.9±4.4 −5.1±2.0 0.45

(ASA-PS: American Society of Anesthesiology physical status)

*P<0.05.

Values are presented as number (%) or mean±standard deviation.


Comparison of the propensity matched data between the tranexamic acid treatment group and the non-treatment group (n=26)

Variable Category Tranexamic acid treatment (n=13) Tranexamic acid non-treatment (n=13) P-value
Sex Male 3 (23.1) 5 (38.5) 0.67
Female 10 (76.9) 8 (61.5)
Age (yr) 21.9±5.9 24.2±7.6 0.38
Body mass index (kg/m2) 22.6±4.1 21.9±1.8 0.57
Operation time (min) 233.9±34.1 238.5±34.0 0.74
ASA-PS 1.5±0.5 1.4±0.5 0.71
Intraoperative blood loss (mL) 53.1±52.5 145.8±79.4 0.002*
In–out balance (mL) 983.1±419.4 665.0±533.1 0.10
Blood test Hemoglobin change (g/dL) −1.9±0.7 −1.7±0.9 0.58
Hematocrit change (%) −6.0±0.7 −5.2±2.1 0.42

(ASA-PS: American Society of Anesthesiology physical status)

*P<0.05.

Values are presented as number (%) or mean±standard deviation.

The propensity score method was used to adjust for sex, age, body mass index, operative time, and ASA-PS.


Comparison of propensity matched data between the tranexamic acid treatment group and the non-treatment group (n=26)

Variable Category Tranexamic acid treatment (n=13) Tranexamic acid non-treatment (n=13) P-value
Sex Male 4 (30.8) 5 (38.5) >0.99
Female 9 (69.2) 8 (61.5)
Age (yr) 24.9±13.7 24.2±7.6 0.88
Body mass index (kg/m2) 23.2±4.3 21.9±1.8 0.33
Operation time (min) 237.2±27.8 238.5±34.0 0.92
ASA-PS 1.5±0.5 1.4±0.5 0.45
Post-bleeding (mL) 87.2±30.5 86.5±26.6 0.95
In–out balance (mL) 933.8±439.9 665.0±533.1 0.17
Blood test Hemoglobin change (g/dL) −1.8±0.8 −1.7±0.9 0.71
Hematocrit change (%) −3.5±8.5 −5.2±2.1 0.53

(ASA-PS: American Society of Anesthesiology physical status)

Values are presented as number (%) or mean±standard deviation.

The propensity score method was used to adjust for sex, age, body mass index, operative time, and ASA-PS.


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