The Effect of Tranexamic Acid on Blood Loss During Orthognathic Surgery: A Randomized Controlled Trial

J Oral Maxillofac Surg 67:125-133, 2009

The Effect of Tranexamic Acid on Blood Loss During Orthognathic Surgery: A Randomized Controlled Trial Wing Shan Choi, MDS, MOSRCS,* Michael G. Irwin, MD, FRCA,† and Nabil Samman, FRCS, FDSRCS‡ Purpose: Tranexamic acid has been used to reduce blood loss and the subsequent need for transfusion

in orthopedic, spinal, and cardiac surgery. Orthognathic surgery can be associated with significant bleeding yet its efficacy in this setting is not clear. The purpose of this study was to investigate the effect of tranexamic acid on blood loss during bimaxillary osteotomy. Patients and Methods: Seventy-three consecutive patients, scheduled for elective bimaxillary osteotomy, were included in this double blind, randomized, controlled trial. They received either a bolus of tranexamic acid (20 mg/kg) or placebo (normal saline) intravenously just before surgery. All patients received induced mild hypotension and had surgery according to a standard protocol. Intraoperative blood loss, operation time, transfusion of blood products, perioperative hemoglobin, and hematocrit were recorded. Results: The total blood loss and blood loss during maxillary surgery was reduced significantly in the tranexamic acid group compared with the control group (878.6 ⫾ 577.7 mL vs 1,257.2 ⫾ 817.8 mL and 428.0 ⫾ 233.3 mL vs 643.8 ⫾ 430.0 mL, respectively; P ⬍ .05). Considering the duration of operation and the treatment groups only, the mean total blood loss in the control group was 422 mL more than that in the tranexamic acid group (P ⬍ .001). There was no significant difference in blood transfusion or the length of hospital stay between the 2 groups. Conclusion: Preoperative intravenous bolus administration of tranexamic acid at 20 mg/kg reduces blood loss compared with placebo during bimaxillary osteotomy. © 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:125-133, 2009 has been reported to reduce total blood loss by as much as 40% and improve the surgical field by 27% in orthognathic surgery.4 However, there is a risk of ischemic complications5 with prolonged moderate hypotension especially in patients with altered baseline autoregulatory mechanisms (hypertension) or those likely to be particularly vulnerable (eg, diabetes, coronary artery disease, stroke, chronic renal failure). The Medical Protection Society has recently urged caution in this regard and it would seem prudent to investigate other methods to reduce bleeding. Tranexamic acid, a synthetic amino acid that inhibits fibrinolysis, has been shown to reduce blood loss and the need for blood transfusion in total knee arthroplasty,6,7 spine surgery,8 and cardiac surgery.9 Topical tranexamic acid has been used for treatment of postoperative bleeding in anticoagulated patients after oral surgery.10-16 Senghore and Harris17 showed that a single intravenous preoperative dose of tranexamic acid was effective in preventing excessive postoperative bleeding in healthy adult patients undergoing third molar extraction. The use of tranexamic acid in orthognathic surgery was evaluated by Zellin et al18 in

Orthognathic surgery is a well-established method to correct various forms of dentofacial deformity. With the current standards of surgery and anesthesia, this elective procedure is considered relatively safe with good results. However, as the orofacial region is very vascular, significant blood loss can occur and a subsequent need for blood transfusion is often encountered.1 Adverse effects of blood transfusion include transmission of infectious disease, immunosuppression, and incompatibility reactions.2 Hypotension can be induced deliberately to minimize blood loss3 and

Received from the University of Hong Kong, Hong Kong, P.R. China. *Resident, Oral and Maxillofacial Surgery, Faculty of Dentistry. †Head, Department of Anesthesiology, Faculty of Medicine. ‡Professor and Program Director, Oral and Maxillofacial Surgery, Faculty of Dentistry. Address correspondence and reprint requests to Dr Samman: Oral and Maxillofacial Surgery, Prince Philip Dental Hospital, 34 Hospital Road, Hong Kong; P.R. China; e-mail: [email protected] © 2009 American Association of Oral and Maxillofacial Surgeons

0278-2391/09/6701-0019$34.00/0 doi:10.1016/j.joms.2008.08.015

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126 a retrospective study. They reported that blood loss during orthognathic surgery under hypotensive anesthesia could be reduced significantly when a combination of tranexamic acid and desmopressin was added.18 Adverse events with tranexamic acid therapy including nausea or diarrhea, and occasionally orthostatic reaction, are uncommon.19 Isolated cases of thromboembolism after the use of tranexamic acid have been reported20; however, these observations have not been confirmed by results of controlled clinical studies.7 Insufficient evidence is available regarding the use of tranexamic acid as the only pharmacologic means to reduce blood loss during orthognathic surgery. The aim of this study was to assess the effect of a single intravenous preoperative dose of tranexamic acid on blood loss during bimaxillary osteotomy under mild controlled hypotension.

Patients and Methods PATIENT SELECTION

This study was approved by the ethics committee of the Faculty of Dentistry, University of Hong Kong. All American Society of Anesthesiologists (ASA) Class I patients between 16 and 40 years of age scheduled for bimaxillary osteotomy at Queen Mary Hospital between November 2005 to January 2008 were consecutively recruited to the study after written informed consent. Patients who had bone disease (eg, fibrous dysplasia), cleft lip and palate, craniofacial syndromes (eg, hemifacial microsomia, Treacher Collins Syndrome), or scheduled to receive simultaneous rhinoplasty, temporomandibular joint surgery, or bone graft harvest were excluded from consideration. PREOPERATIVE PREPARATION

All patients were admitted to the hospital for preoperative assessment and anesthetic consultation 1 to 3 days before operation. After routine history taking and clinical examination, a blood sample was taken for complete blood picture (CBP), prothrombin time (PT), activated partial thromboplastin time (APTT), liver function tests (LFT), renal function tests (RFT), random glucose (RG), and cross matching. Three measurements of blood pressure were taken at 1 hour, 5 hours, and 9 hours after admission. RANDOMIZATION

Patients were randomized by computer generated numbers to receive 20 mL study drug (20 mg/kg tranexamic acid or 0.9% normal saline) immediately before surgery. Sealed envelopes containing the information of the randomization allocation were prepared and kept by clerical staff not involved in the study. The specific envelope was transferred to a

TRANEXAMIC ACID EFFECTS ON BLOOD LOSS

specific member of the surgical team not involved in the surgery just before the induction of anesthesia. The study drug was prepared by this surgeon accordingly and was transferred to the anesthetist for administration over 15 minutes after induction of anesthesia. The envelope was sealed again and kept in the patient’s folder until the end of the study period. All members of the surgical team, nursing staff, and the anesthetist were unaware of the allocation. Subject enrollment and allocation is summarized in a CONSORT flow diagram (Fig 1). ANESTHETIC PROTOCOL

Patients did not receive premedication. Anesthesia was induced with propofol (2-3 mg/kg), remifentanil (0.5 ␮g/kg/min) infusion with rocuronium (0.5 mg/ kg) for muscle relaxation. After nasoendotracheal intubation, a urinary catheter was inserted. Anesthesia was maintained with isoflurane in an air/oxygen mix delivered by intermittent positive pressure ventilation to normocapnia, and a remifentanil infusion (0.15-0.5 ␮g/kg/min). No positive end– expiratory pressure was applied. Blood pressure was monitored continuously by radial artery catheter or blood pressure cuff at 5-minute intervals and maintained at 25% to 30% below the mean preoperative level by incremental doses of labetalol and/or metoprolol. A temperature probe, continuous oxygen saturation, and electrocardiogram were used. The patient was positioned supine with a 15° head up tilt, and care was taken to avoid obstruction of venous return from the head. INTRAOPERATIVE PROCEDURE

Penicillin G, dexamethasone, and the study drug were given intravenously just before commencement of the surgery. If the patient was allergic to penicillin, clindamycin was used instead. The operation was carried out by qualified surgical staff with the assistance of surgical trainees, or by senior surgical trainees under supervision at this training centre. The surgical procedures comprised of a combination of maxillary and mandibular osteotomies, including: 1. Maxillary surgery: -Le Fort I with or without segmentalization; -Anterior maxillary (Wunderer) osteotomy; -Posterior maxillary (Schuchardt) osteotomy; or -Le Fort I maxillary distraction. 2. Mandibular surgery: -Anterior subapical (Hofer) osteotomy; -Body (Step) osteotomy; -Sagittal split ramus osteotomy; -Vertical subsigmoid osteotomy; -Genioplasty; or -Mandibular body osteotomy and distraction.

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FIGURE 1. CONSORT flow diagram. Choi, Irwin, and Samman. Tranexamic Acid Effects on Blood Loss. J Oral Maxillofac Surg 2009.

The estimated blood loss (EBL) was measured hourly and after completion of each surgical procedure (such as the subapical or Wunderer part of the operation) by calculating the difference in weight between the fluid in suction bottles, blood-soaked gauze, and the irrigation fluid used. Perioperatively, all patients received standard fluid replacement therapy with crystalloids (0.9% saline or lactated Ringer’s solution) at 4 mL/kg/hour or 3 times the EBL to maintain urine output greater than 0.5 mL/kg/hour. When 15% of the estimated blood volume (EBV) was lost, hydroxyethyl starch (Voluven; Fresenius Kabi Pharmaceutical, Bad Homburg, Germany) was given on a matching basis (mL for mL) or according to the vital signs (pulse and blood pressure) and urine output (⬎0.5 mL/kg/hour). Packed red cells were transfused when the EBL was greater than 25% of the EBV (70 mL/kg for males, 65 mL/kg for females), and the hemoglobin level was less than 8 g/dL as measured by the HemoCue B-hemoglobin photometer (HemoCue AB, Angleholm, Sweden). Blood samples were taken at 4, 24, and 48 hours postoperatively for CBP, PT, and APTT. Blood loss was estimated by calculating the difference in pre- and postoperative hemoglobin and he-

matocrit values according to the following formulae (assuming the blood volume was normalized at 48 hours postoperatively and the hemoglobin level could be raised by 1 g/dL for every pack of red blood cells transfused): 1. Hbloss ⫽ Hbpre ⫺ Hbpost ⫹ t CBL ⫽ BV ⫻ (Hbloss/Hbpre) (modified from Johansson et al21); and 2. RBCL ⫽ BV ⫻ (Hctpre ⫺ Hctpost) ⫹ 320 t CBL ⫽ RBCL/[(Hctpre ⫹ Hctpost)/2] (adapted from Hurle et al22) Abbreviations: BV, blood volume (mL) [70 mL/kg for males, 65 mL/kg for females]; CBL, calculated blood loss (mL); Hbpost, hemoglobin level at postoperative 48 hours (g/dL); Hbpre, preoperative hemoglobin level (g/ dL); Hctpost, hematocrit level at postoperative 48 hours (%); Hctpre, preoperative hematocrit level (%); RBCL, red blood cell loss (mL); t, unit of packed red cells transfused. POWER ESTIMATION AND STATISTICAL ANALYSIS

According to an internal clinical audit of this training center in 2005 to 2006, the blood loss of bimax-

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Table 1. DEMOGRAPHIC CHARACTERISTICS AND PREOPERATIVE COMPARISON OF THE TREATMENT GROUPS

Characteristics

Tranexamic Acid Group (n ⫽ 32)

Control Group (n ⫽ 29)

Gender (F/M) Age (y) Weight (kg) Smoking habit Drinking habit Blood volume (mL) Diagnosis of maxilla Maxillary hypoplasia in AP Maxillary hypoplasia in transverse Maxillary dentoalveolar hyperplasia in AP Vertical maxillary excess Maxillary hypoplasia in vertical Diagnosis of mandible Mandibular hypoplasia in AP Mandibular hyperplasia in AP Mandibular dentoalveolar hyperplasia Asymmetric mandibular hyperplasia Hemimandibular hyperplasia Unilateral condylar hyperplasia Geniohypoplasia Geniohyperplasia

22/10 23.9 ⫾ 6.1 56.3 ⫾ 9.3 2 0 3,761.3 ⫾ 731.4

18/11 22.8 ⫾ 4.5 57.7 ⫾ 11.7 4 0 3,866.5 ⫾ 877.8

11 0 14 16 3

16 1 16 7 1

9 8 18 0 1 6 6 1

5 1 18 4 0 4 8 0

Abbreviation: AP, anteroposterior. Continuous data are expressed in mean ⫾ SD. Study groups were compared by 2-sample t test or ␹2 test, as appropriate. Choi, Irwin, and Samman. Tranexamic Acid Effects on Blood Loss. J Oral Maxillofac Surg 2009.

illary osteotomy was within a range of 600 mL to 2,000 mL, with a mean of 1,000 mL and standard deviation (SD) of 350 mL (unpublished data). Previous studies showed the use of tranexamic acid to be associated with a reduction of intraoperative blood loss by 30% to 50%.20,23-25 A power analysis using these assumptions showed that 22 patients per group offered a 80% chance to detect a 30% difference between the 2 groups at the 0.05 level of significance using a two-sample t test. Statistical analysis was carried out using SPSS for Windows (version 13.0; SPSS, Chicago, IL) to compare the study and control groups in terms of baseline information, intraoperative, and postoperative findings. When comparing the 2 groups, continuous data were summarized by means and SD and analyzed using the 2-sample t test and confidence intervals. Tables were used to summarize and compare categoric variables between treatment groups, and the data were analyzed using ␹2 tests. Logistic regression was used when analyzing binary outcome and ANCOVA was applied to identify which variables were independently predictive for total blood loss. Results of the statistical tests were considered to be significant if the P value was less than .05.

Results Seventy-three consecutive patients were included in the study initially. However, 12 patients had to be

excluded due primarily to incomplete data collection (9 patients), or postoperative re-intubation/re-operation (3 patients). Therefore, only 61 sets of data could be analyzed. There was no significant difference in demographic data and baseline hemodynamic data between the treatment groups (Table 1). The blood loss during anterior mandibular surgery, maxillary surgery, ramus surgery, and the total blood loss was reduced in the tranexamic acid group. A statistical difference was observed during maxillary surgery (428.0 ⫾ 233.3 mL vs 643.8 ⫾ 430.0 mL; P ⬍ .05) and total blood loss (878.6 ⫾ 577.7 mL vs 1,257.2 ⫾ 817.8 mL; P ⬍.05) (Table 2). Further statistical analysis using ANCOVA showed that both the operation time and treatment group (P ⬍ .001) affected the total blood loss. Considering both variables in the analysis, the total blood loss in the control group was 422 mL greater than that in the tranexamic acid group. The total blood loss increased as the operation time increased (Fig 2). However, there was no significant difference in total operation, percentage of transfusion, and length of hospital stay between treatment groups. Logistic regression showed that total blood loss was the only factor that affected the chance of transfusion (P ⬍ .05). The length of hospital stay was associated with perioperative transfusion and duration of surgery (P ⬍ .05). For both groups, significant reduction in hemoglobin (Hb) and hematocrit (Hct) levels was observed at 4, 24, and 48 hours postoperatively. The

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Table 2. INTRAOPERATIVE AND POSTOPERATIVE COMPARISON BETWEEN TREATMENT GROUPS

Anterior mandibular surgery Hofer osteotomy only Step osteotomy Hofer osteotomy ⫹ genioplasty MAP control Below target Within target Above target Duration (min) Blood loss (mL) Maxillary surgery Le Fort I osteotomy Le Fort I ⫻ 2 pieces Le Fort I ⫻ 4 pieces Maxillary distraction Wunderer ⫹ posterior Le Fort I osteotomy Schuchardt osteotomy MAP control Below target Within target Above target Duration (min) Blood loss (mL)* Ramus surgery Bilateral SSO Bilateral VSSO VSSO on one side ⫹ SSO on the other side Mandibular body distraction MAP control Below target Within target Above target Duration (min)* Blood loss (mL) Total operation time (min) Total blood loss (mL)* Calculated blood loss by difference in Hb value (mL)* Calculated blood loss by difference in Hct value (mL)* Patients requiring transfusion (%) Length of hospital stay (d)

Tranexamic Acid Group

Control Group

14 0 7

17 1 5

2/21 6/21 13/21 131 ⫾ 33 277.0 ⫾ 211.7 4 5 16 0 6 1

1/23 7/23 15/23 140 ⫾ 42 415.9 ⫾ 314.2 4 4 15 1 5 0

2/32 12/32 18/32 166 ⫾ 43 428.0 ⫾ 233.3

2/29 11/29 16/29 170 ⫾ 44 643.8 ⫾ 430.0

10 9 2 3

8 8 0 1

8/24 5/24 11/24 108 ⫾ 43 287.0 ⫾ 216.3 376 ⫾ 108 878.6 ⫾ 577.7 746.8 ⫾ 448.2 774.7 ⫾ 529.3 4/32 (12.5) 7.2 ⫾ 2.1

7/17 2/17 8/17 77 ⫾ 32 329.3 ⫾ 233.4 366 ⫾ 110 1,257.2 ⫾ 817.8 1,173.6 ⫾ 700.1 1,207.6 ⫾ 701.4 7/29 (24.1) 7.5 ⫾ 2.3

Abbreviations: Hb, hemoglobin; Hct, hematocrit; MAP, mean blood pressure; SSO, sagittal split osteotomy; VSSO, vertical subsigmoid osteotomy. Continuous data expressed in mean ⫾ SD. Study groups are compared by 2-sample t test or ␹2 test as appropriate. *Statistically significant difference between treatment groups (P ⬍ .05). Choi, Irwin, and Samman. Tranexamic Acid Effects on Blood Loss. J Oral Maxillofac Surg 2009.

platelet count also was decreased significantly and the PT was prolonged until 24 hours postoperatively. The APTT was reduced significantly during 4 to 48 hours postoperatively. No significant difference in the postoperative hematologic results between 2 groups was observed (Table 3). There were 3 incidences of perioperative hemorrhage during maxillary osteotomy. One was due to laceration of the descending palatine artery that was cauterized. Oozing from the pterygoid plexus was encountered in the other 2 cases. All 3 were controlled by packing absorbable hemostat (Surgicel; Johnson &

Johnson, Ethicon Inc, Somerville, MA) and gauze in the wound. No blood transfusion was required in these cases. No adverse reactions or thromboembolic events were observed. There were no transfusion reactions in any patient receiving blood in this study.

Discussion Randomized controlled trials (RCT) are considered the best method to investigate the value of an intervention26 because they are designed to minimize possible bias and maximize attribution. Although RCT is

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TRANEXAMIC ACID EFFECTS ON BLOOD LOSS

Randomization group Control (C) Tranexamic Acid (T)

Total Blood Loss (mL)

3000

Fit line for C Fit line for T

2000

1000

R Sq Linear = 0.502 R Sq Linear = 0.563 0 2

3

4

5

6

7

8

9

10

Total Operation Time (Hour) FIGURE 2. Relationship between total blood loss and operation time. Choi, Irwin, and Samman. Tranexamic Acid Effects on Blood Loss. J Oral Maxillofac Surg 2009.

difficult to use in surgical care,27 we tried to reduce the possible effects of confounding factors in this study by randomization and strict anesthetic and surgical protocols in an attempt to generate the strongest evidence for the effect of tranexamic acid in orthognathic surgery. The biologic half life was reported to be 1.9 hours28 and according to Pilbrant et al,29 after intravenous administration of 1 gram tranexamic acid, the drug is

eliminated in 3 exponential phases with over 95% excretion in urine. As cited by Dunn and Goa,30 other studies showed that around 30% of the intravenous dose of 10 mg/kg of tranexamic acid was detected in the urine during the first hour after administration. The total excretion rose to 45% after 3 hours and approximately 90% after 24 hours. There is no consensus on the best time for administration of this drug. Most studies advocate the use of tranexamic

Table 3. POSTOPERATIVE HEMATOLOGIC COMPARISON BETWEEN TREATMENT GROUPS

Hb level (g/dL) T C Hct level (%) T C Platelet level (⫻109/L) T C PT (s) T C APTT (s) T C

Preoperative

Postoperative (4 h)

Postoperative (24 h)

Postoperative (48 h)

13.5 ⫾ 1.8 13.8 ⫾ 1.2

11.0 ⫾ 1.9* 10.4 ⫾ 1.6*

11.1 ⫾ 2.1* 10.6 ⫾ 1.6*

11.0 ⫾ 2.1* 10.2 ⫾ 1.6*

39.6 ⫾ 4.8 40.3 ⫾ 3.1

33.4 ⫾ 8.0* 30.4 ⫾ 4.9*

32.5 ⫾ 6.1* 30.8 ⫾ 4.7*

32.2 ⫾ 6.0* 29.7 ⫾ 4.8*

246.0 ⫾ 54.5 260.9 ⫾ 50.7

217.8 ⫾ 43.3* 226.0 ⫾ 55.6*

232.8 ⫾ 53.5* 234.5 ⫾ 64.0*

246.2 ⫾ 55.3 245.7 ⫾ 56.3

11.7 ⫾ 1.0 11.5 ⫾ 0.8

12.8 ⫾ 1.1* 13.4 ⫾ 1.3*

12.7 ⫾ 1.1* 12.8 ⫾ 0.9*

11.7 ⫾ 0.7 12.0 ⫾ 1.1

30.0 ⫾ 2.8 29.9 ⫾ 2.0

26.6 ⫾ 3.7* 26.5 ⫾ 2.2*

28.2 ⫾ 3.1* 28.4 ⫾ 1.9*

27.3 ⫾ 1.9* 27.6 ⫾ 2.3*

Abbreviations: APTT, activated partial thromboplastin time; C, control group; Hb, hemoglobin; Hct, hematocrit; PT, prothrombin time; T, tranexamic acid group. Continuous data expressed in mean ⫾ SD. *Statistically significant difference compared to preoperative value (P ⬍ .05). Choi, Irwin, and Samman. Tranexamic Acid Effects on Blood Loss. J Oral Maxillofac Surg 2009.

CHOI, IRWIN, AND SAMMAN

acid preoperatively with or without continuous infusion intraoperatively. Different dosages have been reported in the literature, ranging from a bolus administration of 1 gram regardless of body weight18 to 100 mg/kg over 15 minutes, continued with an infusion of 10 mg/kg/hour until wound closure.31 Horrow et al32 showed that prophylactic tranexamic acid at 10 mg/kg followed by 1 mg/kg/hour for 12 hours decreases bleeding after extracorporeal circulation. Larger doses do not provide additional hemostatic benefit. In view of the duration of surgery and the pharmacodynamics of tranexamic acid, we chose to give a bolus injection of 20 mg/kg on induction of anesthesia. This should provide therapeutic plasma concentrations (5 to 10 mg/L)30 for 10 hours after administration, which should cover the longest possible duration of orthognathic cases in the study. The mean total blood loss in the tranexamic acid group and the control group was 878.6 mL and 1,257.2 mL, respectively, which was higher in comparison to previous studies.1,33 This may be due to several reasons. First, many of our cases involved segmental osteotomies in both the maxilla and mandible leading to multiple bone cuts and additional cancellous bone and intrabony capillaries exposure. The increased complexity of the surgical procedures in the context of a training center often resulted in prolonged operation time and increased blood loss. Furthermore, the level of controlled hypotension was variable in this study. For safety reasons, we intended to lower the mean blood pressure by no more than 25% to 30% compared with the preoperative level and consequently we did not feel it was ethical to pursue this aggressively. The lower limit of the target mean blood pressure for all patients was above 50 mm Hg. Although a standard anesthetic protocol was implemented, less than 50% of cases had a mean blood pressure reduction within the range of 25% to 30% of preoperative values (Table 2). Often, the mean blood pressure was only slightly reduced. Blood loss was estimated intraoperatively as described in Patients and Methods. Blood on surgical drapes, gowns, and instruments was difficult to quantify accurately. Although a throat pack was placed in every case, a small amount of blood might still have been swallowed. The suction bottle contained not only irrigation fluid and blood, but also saliva and bone powder produced during the osteotomy. All these uncertainties contributed to the inaccuracy of blood loss estimation although these would apply to all cases. There was a discrepancy between estimated blood loss measured intraoperatively and calculated blood loss by comparison of pre- and postoperative hemoglobin and hematocrit levels. The calculation was done based on 2 assumptions: the blood volume would have normalized by 48 hours postoperatively and 1 pack (320 mL) of red blood

131 cells transfused could raise the hemoglobin by approximately 1 g/dL. There might still be hemodilution due to postoperative intravenous fluid administration and the rise in Hb level varied in different individuals depending on the body size. Furthermore, postoperative bleeding was not measured. No suction drains were used in intraoral wounds and a significant amount of blood could have been swallowed during the early postoperative period (concealed blood loss). Therefore, the postoperative Hb and Hct values only supplement the estimation of blood loss, and may not represent the true blood loss. In this study, we were only able to show a significant decrease in blood loss in the tranexamic acid group during maxillary surgery and the whole operation, but not for the mandibular surgery. The maxilla is more vascular than the mandible. Blood loss during maxillary surgery, therefore, accounts for a large percentage of the total blood loss. The extent of reduction of blood loss during the mandibular surgery did not reach statistical significance probably because of the small sample size. The data was affected by many variables, including the complexity and combination of different surgical procedures, different surgeons, and different levels of blood pressure. The total blood loss in the treatment group was 422 mL less than the control group, which was not only significant statistically, but is also a clinically significant amount. The total operation time was not significantly different but the mean surgical time for ramus surgery was 31 minutes longer in the treatment group than in the control group. This might be due to increased surgical time for adaptation and placement of distractors during mandibular body distraction (range ⫽ 1 hour to 3 hours 20 minutes). Three cases of mandibular body distraction were randomized to receive tranexamic acid whereas only 1 case was in the control group. Although the operation time for ramus surgery was increased significantly in the treatment group, the blood loss during this procedure was less than that in the control group (287.0 ⫾ 216.3 mL vs 329.3 ⫾ 233.4 mL, respectively). We were not able to show a statistically significant reduction of transfusion in the treatment group, nevertheless, the percentage of patients requiring transfusion in the control group was larger than the treatment group (24.1% vs 12.5%). The high transfusion rate may be related to the increased blood loss that was mentioned above. A total of 11 patients received transfusion (4 in the treatment group, 7 in the control group). Both the mean blood loss and the operation time for these patients were higher in the control group than the treatment group (2,291 ⫾ 831.7 mL, 505 minutes ⫾ 94 minutes vs 1,732 ⫾ 856.8 mL, 469 minutes ⫾ 118 minutes). Twenty-eight patients had long operations (⬎6 hours). Nine of them received blood transfusion (6 in

132 the control group, 3 in the treatment group). These findings suggest that tranexamic acid may be useful in reducing blood loss, especially when the total operation time is long (Fig 2). There was no clinical or statistical difference in the length of hospital stay between the 2 groups of patients. The PT was prolonged postoperatively, presumably due to hemodilution, but this phenomenon was not observed in other studies.32,34 Deep vein thrombosis (DVT) and pulmonary embolism (PE) are considered to be rare in Asia. Cheuk et al35 reported that the overall annual incidences of DVT and PE in Hong Kong were 17.1 and 3.9 per 100,000 population, respectively, representing significantly lower figures than those reported in Western countries. The majority of DVTs and PEs were not associated with surgery, with an overall incidence of postoperative DVT and PE of only 0.13% and 0.04%, respectively. Therefore, routine thromboprophylaxis was not given in this study in keeping with the accepted standard of care in this population. No adverse reactions or complications associated with the use of tranexamic acid was observed in this study; however, no special investigations were carried out as a routine to look for silent thromboembolism. The potential for this antifibrinolytic agent to be associated with an increased risk of thromboembolic events has been a concern, especially after major surgery. There was no evidence of an increased incidence in thromboembolism in patients using tranexamic acid during total knee arthroplasty7,20,36 or liver transplantion.37 A retrospective case-controlled study also showed no increased risk of venous thrombosis in women taking tranexamic acid for menorrhagia.38 Theoretically, tranexamic acid does not alter blood clotting. It is a clot stabilizer that slows down the dissolution of the blood clot and does not initiate blood clot formation spontaneously. Benoni et al23 suggested the reason tranexamic acid was not associated with thromboembolic events is that its effects are more pronounced in operative wounds than in peripheral venous vessels. Nevertheless, vascular thrombosis has been reported, although at a low incidence rate, in prospective controlled studies.39,40 Casati41 raised a concern that the use of high doses of tranexamic acid in patients with preexisting vascular disease might facilitate the formation of thrombus and result in stroke. Thiagarajamny et al42 reviewed 12 articles and found that 5 prospective randomized trials reported myocardial ischemia, pulmonary embolism, and neurologic dysfunction. To date, there is no strong evidence available showing a definite risk of thromboembolism associated with the use of tranexamic acid. However, it should be used with caution and should be avoided in patients with a high risk for thrombosis (eg, history of a thromboembolic event or a family history of thromboembolic disease). Because

TRANEXAMIC ACID EFFECTS ON BLOOD LOSS

tranexamic acid is excreted in the urine, dose reduction may also be required in patients with renal insufficiency. Other drugs have been shown to be effective in reducing blood loss during surgery. These include aprotinin,43,44 epsilon–aminocaproic acid,45 desmopressin,46 and recombinant factor VII.47 However, tranexamic acid was considered to be more cost effective and easiest to handle compared with other drugs.48,49 Besides pharmacologic methods, other blood-saving strategies are also available. Mild hypotension,50-52 normovolemic hemodilution,53-56 preoperative autologous blood donation,33 cell salvage techniques,57,58 positioning the operating table 20° head-up, avoiding venous obstruction, and maintaining hypocapnia have been used individually or in combination to minimize blood loss and transfusion. This involves special knowledge and skill as well as intensive monitoring. Moreover, the cost of autologous blood donation and cell salvage is much higher than the use of tranexamic acid while achieving a similar clinical outcome in conjunction with the above techniques. A single preoperative dose (20 mg/kg) of tranexamic acid given intravenously immediately before surgery reduced blood loss during maxillary osteotomy and bimaxillary osteotomy but had no significant effect on the incidence of blood transfusion or length of hospital stay. No adverse reaction or complication associated with the use of tranexamic acid was noted in this study.

References 1. Samman N, Cheung LK, Tong AC, et al: Blood loss and transfusion requirements in orthognathic surgery. J Oral Maxillofac Surg 54:21, 1996 2. Goodnough LT, Brecher ME, Kanter MH, et al: Transfusion medicine. First of two parts—Blood transfusion. N Engl J Med 340:438, 1999 3. Rodrigo C: Induced hypotension during anesthesia with special reference to orthognathic surgery. Anesth Prog 42:41, 1995 4. Chan W, Smith DE, Ware WH: Effects of hypotensive anesthesia in anterior maxillary osteotomy. J Oral Surg 38:504, 1980 5. Murphy MA: Bilateral posterior ischemic optic neuropathy after lumbar spine surgery. Ophthalmology 110: 2003 6. Hynes M, Calder P, Scott G: The use of tranexamic acid to reduce blood loss during total knee arthroplasty. Knee 10:375, 2003 7. Ho KM, Ismail H: Use of intravenous tranexamic acid to reduce allogeneic blood transfusion in total hip and knee arthroplasty: A meta-analysis. Anaesth Intensive Care 31:529, 2003 8. Neilipovitz DT: Tranexamic acid for major spinal surgery. Eur Spine J 13(Suppl):S62, 2004 9. Laupacis A, Fergusson D: Drugs to minimize perioperative blood loss in cardiac surgery: Meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg 85:1258, 1997 10. Patatanian E, Fugate SE: Hemostatic mouthwashes in anticoagulated patients undergoing dental extraction. Ann Pharmacother 40:2205, 2006 11. Carter G, Goss A, Lloyd J, et al: Tranexamic acid mouthwash versus autologous fibrin glue in patients taking warfarin undergoing dental extractions: A randomized prospective clinical study. J Oral Maxillofac Surg 61:1432, 2003 12. Carter G, Goss A: Tranexamic acid mouthwash—A prospective randomized study of a 2-day regimen vs 5-day regimen to prevent

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13.

14.

15.

16.

17.

18.

19. 20.

21.

22.

23.

24.

25.

26.

27.

28.

29. 30. 31.

32. 33.

34.

35.

postoperative bleeding in anticoagulated patients requiring dental extractions. Int J Oral Maxillofac Surg 32:504, 2003 Souto JC, Oliver A, Zuazu-Jausoro I, et al: Oral surgery in anticoagulated patients without reducing the dose of oral anticoagulant: A prospective randomized study. J Oral Maxillofac Surg 54:27, 1996 Ramstrom G, Sindet-Pedersen S, Hall G, et al: Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. J Oral Maxillofac Surg 51:1211, 1993 Borea G, Montebugnoli L, Capuzzi P, et al: Tranexamic acid as a mouthwash in anticoagulant-treated patients undergoing oral surgery. An alternative method to discontinuing anticoagulant therapy. Oral Surg Oral Med Oral Pathol 75:29, 1993 Sindet-Pedersen S, Ramstrom G, Bernvil S, et al: Hemostatic effect of tranexamic acid mouthwash in anticoagulant-treated patients undergoing oral surgery. N Engl J Med 320:840, 1989 Senghore N, Harris M: The effect of tranexamic acid (Cyklokapron) on blood loss after third molar extraction under a day case general anesthetic. Br Dent J 186:634, 1999 Zellin G, Rasmusson L, Palsson J, et al: Evaluation of hemorrhage depressors on blood loss during orthognathic surgery: A retrospective study. J Oral Maxillofac Surg 62:662, 2004 Verstraete M: Clinical application of inhibitors of fibrinolysis. Drugs 29:236, 1985 Hiippala ST, Strid LJ, Wennerstrand MI, et al: Tranexamic acid radically decreases blood loss and transfusions associated with total knee arthroplasty. Anesth Analg 84:839, 1997 Johansson T, Engquist M, Pettersson LG, et al: Blood loss after total hip replacement: A prospective randomized study between wound compression and drainage. J Arthroplasty 20: 967, 2005 Hurle R, Poma R, Maffezzini M, et al: A simple mathematical approach to calculate blood loss in radical prostatectomy. Urol Int 72:135, 2004 Benoni G, Lethagen S, Fredin H: The effect of tranexamic acid on local and plasma fibrinolysis during total knee arthroplasty. Thromb Res 85:195, 1997 Husted H, Blond L, Sonne-Holm S, et al: Tranexamic acid reduces blood loss and blood transfusions in primary total hip arthroplasty: A prospective randomized double-blind study in 40 patients. Acta Orthop Scand 74:665, 2003 Tanaka N, Sakahashi H, Sato E, et al: Timing of the administration of tranexamic acid for maximum reduction in blood loss in arthroplasty of the knee. J Bone Joint Surg Br 83:702, 2001 Altman DG, Schulz KF, Moher D, et al: The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med 134:663, 2001 Fung EK, Lore JM Jr: Randomized controlled trials for evaluating surgical questions. Arch Otolaryngol Head Neck Surg 128: 631, 2002 Eriksson O, Kjellman H, Pilbrant A, et al: Pharmacokinetics of tranexamic acid after intravenous administration to normal volunteers. Eur J Clin Pharmacol 7:375, 1974 Pilbrant A, Schannong M, Vessman J: Pharmacokinetics and bioavailability of tranexamic acid. Eur J Clin Pharmacol 20:65, 1981 Dunn CJ, Goa KL: Tranexamic acid: A review of its use in surgery and other indications. Drugs 57:1005, 1999 Sethna NF, Zurakowski D, Brustowicz RM, et al: Tranexamic acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery. Anesthesiology 102:727, 2005 Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 82:383, 1995 Moenning JE, Bussard DA, Lapp TH, et al: Average blood loss and the risk of requiring perioperative blood transfusion in 506 orthognathic surgical procedures. J Oral Maxillofac Surg 53: 880, 1995 Shore-Lesserson L, Reich DL, Vela-Cantos F, et al: Tranexamic acid reduces transfusions and mediastinal drainage in repeat cardiac surgery. Anesth Analg 83:18, 1996 Cheuk BL, Cheung GC, Cheng SW: Epidemiology of venous thromboembolism in a Chinese population. Br J Surg 91:424, 2004

133 36. Benoni G, Fredin H: Fibrinolytic inhibition with tranexamic acid reduces blood loss and blood transfusion after knee arthroplasty: A prospective, randomized, double-blind study of 86 patients. J Bone Joint Surg Br 78:434, 1996 37. Molenaar IQ, Warnaar N, Groen H, et al: Efficacy and safety of antifibrinolytic drugs in liver transplantation: A systematic review and meta-analysis. Am J Transplant 7:185, 2007 38. Berntorp E, Follrud C, Lethagen S: No increased risk of venous thrombosis in women taking tranexamic acid. Thromb Haemost 86:714, 2001 39. Reid RW, Zimmerman AA, Laussen PC, et al: The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 84:990, 1997 40. Zonis Z, Seear M, Reichert C, et al: The effect of preoperative tranexamic acid on blood loss after cardiac operations in children. J Thorac Cardiovasc Surg 111:982, 1996 41. Casati V: About dosage schemes and safety of tranexamic acid in cardiac surgery. Anesthesiology 99:236, 2003 42. Thiagarajamurthy S, Levine A, Dunning J: Does prophylactic tranexamic acid safely reduce bleeding without increasing thrombotic complications in patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 3:489, 2004 43. Ickx BE, van der Linden PJ, Melot C, et al: Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation. Transfusion 46:595, 2006 44. Bulutcu FS, Ozbek U, Polat B, et al: Which may be effective to reduce blood loss after cardiac operations in cyanotic children: Tranexamic acid, aprotinin or a combination? Paediatr Anaesth 15:41, 2005 45. Camarasa MA, Olle G, Serra-Prat M, et al: Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: A randomized clinical trial. Br J Anaesth 96:576, 2006 46. Guyuron B, Vaughan C, Schlecter B: The role of DDAVP (desmopressin) in orthognathic surgery. Ann Plast Surg 37:516, 1996 47. Tanos M, Dunning J: Is recombinant activated factor VII useful for intractable bleeding after cardiac surgery? Interact Cardiovasc Thorac Surg 5:493, 2006 48. Casati V, Guzzon D, Oppizzi M, et al: Hemostatic effects of aprotinin, tranexamic acid and epsilon-aminocaproic acid in primary cardiac surgery. Ann Thorac Surg 68:2252, 1999 49. Bernet F, Carrel T, Marbet G, et al: Reduction of blood loss and transfusion requirements after coronary artery bypass grafting: Similar efficacy of tranexamic acid and aprotinin in aspirintreated patients. J Card Surg 14:92, 1999 50. Cincikas D, Ivaskevicius J: Application of controlled arterial hypotension in endoscopic rhino surgery. Medicina (Kaunas) 39:852, 2003 51. Yu CN, Chow TK, Kwan AS, et al: Intra-operative blood loss and operating time in orthognathic surgery using induced hypotensive general anesthesia: Prospective study. Hong Kong Med J 6:307, 2000 52. Mackie D: Hypotensive anesthesia and orthognathic surgery. Anesth Analg 76:667, 1993 53. Suttner SW, Piper SN, Lang K, et al: Cerebral effects and blood sparing efficiency of sodium nitroprusside-induced hypotension alone and in combination with acute normovolemic hemodilution. Br J Anaesth 87:699, 2001 54. Segal JB, Blasco-Colmenares E, Norris EJ, et al: Preoperative acute normovolemic hemodilution: A meta-analysis. Transfusion 44:632, 2004 55. Jovic MD, Calija BM, Radomir BJ, et al: The use of acute normovolemic hemodilution in patients undergoing cardiac surgery. Cardiovasc Surg 11:201, 2003 56. Murray D: Acute normovolemic hemodilution. Eur Spine J 13(Suppl):S72, 2004 57. Fong J, Gurewitsch ED, Kang HJ, et al: An analysis of transfusion practice and the role of intraoperative red blood cell salvage during cesarean delivery. Anesth Analg 104:666, 2007 58. Bridgens JP, Evans CR, Dobson PM, et al: Intraoperative red blood-cell salvage in revision hip surgery. A case-matched study. J Bone Joint Surg Am 89:270, 2007