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The effect of tranexamic acid on blood loss in orthognathic surgery: a meta-analysis of randomized controlled trials
Vol. 115 No. 5 May 2013
The effect of tranexamic acid on blood loss in orthognathic surgery: a meta-analysis of randomized controlled trials Guodong Song, DDS,a Ping Yang, MD,b Jing Hu, DDS,a Songsong Zhu, DDS,a Yunfeng Li, DDS,a and Qiushi Wang, DDSa Sichuan University, Chengdu, China
Objective. The objective of this article was to evaluate the efficacy of tranexamic acid on blood loss in orthognathic surgery. A meta-analysis was performed. Study Design. The PubMed and EMBASE electronic databases were searched until June 30, 2012. Eligible studies were restricted to randomized controlled trials (RCTs). Results. Four RCTs with 183 patients were included. The results showed that intraoperative blood loss in the tranexamic acid group was statistically reduced (weighted mean difference [WMD] ⫽ ⫺93.56, 95% CI ⫽ ⫺132.59-54.52, P ⬍ .00001). However, the postoperative levels of hemoglobin (Hb) and hematocrit (Hct) have no significant difference compared with placebo groups (WMD ⫽ 0.50, 95% CIs ⫽ ⫺0.43-1.43, P ⫽ .29 and WMD ⫽ 0.18, 95% CIs ⫽ ⫺1.64-1.99, P ⫽ .85, respectively). Conclusions. This meta-analysis confirms that tranexamic acid can effectively reduce intraoperative blood loss in orthognathic surgery, especially by intravenous administration. But, tranexamic acid cannot affect postoperative levels of Hb and Hct. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:595-600)
Orthognathic surgery is a well-established method to correct various forms of dentofacial deformity.1 Although this procedure is considered relatively safe with desired results, significant blood loss can occur and blood transfusion is often required.2,3 The leading reason is that the blood supply in the orofacial region is very rich. The incidence of blood transfusion, including autologous blood use during orthognathic surgery, was about 20% to 60%.4-6 Simultaneously, blood transfusion has the risks of infectious disease, incompatibility reactions, and immunosuppression.7 Currently, hypotension has been applied to minimize blood loss during orthognathic surgery and receives a favorable effect.8 However, the risk of ischemia owing to prolonged moderate hypotension may accompany the therapeutic process, especially in patients with hypertension or chronic renal failure.9,10 Therefore, exploring other procedures with minor adverse effects for decreasing blood loss during surgery is increasingly important. Tranexamic acid, an antifibrinolytic agent, is a synthetic amino acid lysine analog that forms a reversible complex with both plasminogen and plasmin by binding at lysine-binding sites. By competitively blocking a
Department of Oral and Maxillofacial Surgery, West China School of Stomatology, Sichuan University, Chengdu, China. b Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China. Received for publication July 10, 2012; returned for revision Sept 3, 2012; accepted for publication Sept 19, 2012. © 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.09.085
the conversion of plasminogen to plasmin, this binding inhibits the proteolytic action of plasmin on fibrin clot and platelet receptors so as to inhibit fibrinolysis at the surgical wound.11,12 Numerous studies have demonstrated tranexamic acid can effectively reduce bleeding in total knee arthroplasty, spinal surgery, and cardiac surgery.13-15 The same results for topical tranexamic acid have also been obtained in anticoagulated patients undergoing oral surgery.16,17 Senghore and Harris18 showed that intravenous administration of tranexamic acid was effective in preventing excessive postoperative bleeding in healthy adult patients undergoing third molar extraction. Since a retrospective study by Zellin et al.,19 there have been some studies on tranexamic acid decreasing blood loss in orthognathic surgery; however, evidence-based medicine does not support tranexamic acid as an effective pharmacologic means to reduce blood loss during orthognathic surgery. In addition, the potential risks on the use of antifibrinolytic agents, such as stroke, myoclonus, allergic reactions, and so on,20-22 cannot be ignored, especially in patients with hereditary blood disease. Cost-effectiveness analysis also showed there was a large benefit for the
Statement Tranexamic acid, an antifibrinolytic agent, has been shown to have the capability of reducing bleeding in orthognathic surgery. For further evaluating the efficacy of tranexamic acid in orthognathic surgery, a meta-analysis on published articles was performed.
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ORAL AND MAXILLOFACIAL SURGERY 596 Song et al.
intraoperative use of tranexamic acid by reducing transfusion rate and volume, and shortening hospital stays and length of time in the intensive care unit.23,24 Here, we first performed a meta-analysis of published randomized controlled trials (RCTs) on tranexamic acid and placebo, the aim of which was to determine whether tranexamic acid significantly reduces blood loss in orthognathic surgery.
MATERIAL AND METHODS Search strategy A search was conducted of 2 electronic databases: PubMed and EMBASE (the last date was updated on June 30, 2012). The following search terms were used: tranexamic acid, hemodynamics, osteotomy, oral surgery, orthognathic surgery, orthognathic surgical procedures, antifibrinolytic agents. The search was done on studies conducted on human subjects, restricted to the English language. The reference lists of reviews and retrieved articles were handsearched at the same time. We did not consider abstracts or unpublished reports. Inclusion and exclusion criteria We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (1) the studies were to evaluate the effect of tranexamic acid on blood loss in patients undergoing orthognathic surgery; (2) the studies were RCTs, whereas the intervention in the control group was placebo; and (3) the studies had to contain sufficient raw data for WMD (weighted mean difference) with 95% confidence intervals (CIs). We excluded articles according to the following criteria: (1) without raw data available; (2) duplicate publication; (3) no usable data reported. Data extraction Data were extracted from each study by 2 reviewers (G.D.S., P.Y.) independently according to the prespecified selection criteria. Any discrepancy during screening and quality assessment was resolved by discussion. Statistical analysis The statistical analysis was performed by using RevMan5.0 software, which was provided by the Cochrane Collaboration (Copenhagen, Denmark). P less than .05 was considered statistically significant. Heterogeneity was checked by 2 test. If the results of the trials had heterogeneity, a random effects model was used for meta-analysis. Otherwise, a fixed effects model was used. The result was expressed with WMD for the categorical variable and 95% CIs.
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Assessment of study quality Included studies were reviewed and appraised for methodological quality using the Jadad composite scale.25 High-quality trials scored more than 2 of a maximum possible score of 5.26
RESULTS Study characteristics There were 2194 articles relevant to the searching words (Fig. 1). Through the step of filtering the title, 834 of these articles were excluded (294 reviews, 540 nonabstracts). RCTs from 262 articles were reviewed and an additional 1428 articles were excluded (1048 non-RCTs, 380 nonhuman studies). Of these, 258 were excluded (125 were nonplacebo controls, 6 duplicates, and 127 nonorthognathic surgeries); thus, 4 articles,27-30 which included 183 cases, were found to conform to our inclusion criteria. Four RCT studies, from the Islamic Republic of Iran, India, Thailand, and China, were included in this meta-analysis. The characteristics of these studies are presented in Table I. Quality of included studies The 4 studies were randomized, double-blind controlled trials and all had a detailed description of methods for randomization, 3 with a computer-generated list allocation, and 1 with drawing lots random. The mean Jadad score of the included studies was more than 3 (Table I). The main studying limitations included smaller sample size and allocation concealment. Intraoperative blood loss Four RCT studies all showed intraoperative blood loss data. The heterogeneity was not observed among 4 studies (2 ⫽ 2.46, P ⫽ .29, I2 ⫽ 19%) (Fig. 2), so the fixed effects model was used. The results showed that the difference was statistically significant (WMD ⫽ ⫺93.56, 95% CI ⫽ ⫺132.59 to ⫺54.52, P ⬍ .00001) (Fig. 2), suggesting that tranexamic acid had the capability of reducing intraoperative blood loss compared with the placebo groups. According to analysis of the administered route, the result obtained from intravenous administration was statistically significant (WMD ⫽ ⫺93.82, 95% CI ⫽ ⫺133.44 to ⫺54.20, P ⬍ .00001) (Fig. 3). Because the heterogeneity was not observed among 3 studies (2 ⫽ 2.45, P ⫽ .12, I2 ⫽ 59%) (Fig. 3), the fixed effects model was used. On the contrary, there is no statistical difference in topical application (WMD ⫽ ⫺85.01, 95% CI ⫽ ⫺313.14-143.12, P ⫽ 0.47). This suggested intravenous administration was an effective route in preventing intraoperative blood loss during orthognathic surgery.
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Fig. 1. Studies identification, inclusion, and exclusion.
Hemoglobin Two studies reported significant reduction in postoperative hemoglobin (Hb) levels relative to preoperative examination; however, the comparison showed that there was no significant difference in the postoperative Hb level between tranexamic acid and placebo groups.27,30 Choi and colleagues27 observed Hb level in the tranexamic acid group is 11.1 ⫾ 2.1 at 24 hours postoperatively, whereas the placebo group is 10.6 ⫾ 1.6. Similarly, in the study conducted by Karimi et al.,30 Hb concentration was 11.8 g/dL (the tranexamic acid group) and 10.84 g/dL (the placebo group) at 6 hours after operation. Our meta-analysis on 2 studies also demonstrated the same result (WMD ⫽ 0.50, 95% CI ⫽ ⫺0.43-1.43, P ⫽ .29) (Fig. 4). Hematocrit Three RCT studies examined hematocrit (Hct) concentration at 24 hours after operation. The heterogeneity was not observed among 3 studies (2 ⫽ 2.18, P ⫽ .14, I2 ⫽ 54%) (Fig. 5), so the fixed effects model was used. The results showed that the difference was not statistically significant (WMD ⫽ 0.18, 95% CI ⫽ ⫺1.64-1.99, P ⫽ .85) (Fig. 5), suggesting that tranexamic acid had no obvious influence on postoperative Hct level compared with the placebo group.
Sensitivity analyses and publication bias Removing individual study from the list did not change the level of significance for the most important clinical outcomes (intraoperative blood loss, Hb, Hct). Because of the limited number of articles included in this metaanalysis, we did not evaluate publication bias with Begg’s funnel plot.
DISCUSSION Orthognathic surgeries, especially those involved in maxillary interventions, such as Le Fort I osteotomies, are known to occasionally result in significant loss of blood. Yu and colleagues31 reported that 72.4% of orthognathic patients require bimaxillary surgery, and the volume of blood loss in Le Fort I osteotomies is about 50% of multiple segmentalized osteotomies. In addition, about 30% of patients undergoing bimaxillary osteotomies have need of a blood transfusion.2,32 Various approaches have been applied to reduce blood loss and the need for blood transfusions, because blood products are not only a finite resource but also present the risk of transmission of infectious disease.7 Currently, tranexamic acid as an antifibrinolytic drug has been demonstrated to be effective in reducing perioperative and postoperative blood loss in various surgical fields.
Intravenous 20 mg/kg 16/16 Islamic Republic of Iran Karimi (2012)30
2010.8-2011.1
Tissue irrigation Intravenous 0.05%TXA/NS 10 mg/kg 20/20 25/25 DNR DNR Thailand India Kaewpradub (2011)28 Sankar (2012)29
DNR, data not reported; HB, perioperative hemoglobin level; Hct, perioperative hematocrit level; HST, hospital stay time; IBL, intraoperative blood loss; MIF, amount of irrigant fluid; NS, normal saline; OT, operation time; TBP, transfusion of blood products; TXA, tranexamic acid group.
5 IBL, OT, TBP, HB, Hct, HST
3 5 IBL, OT, TBP, Hct, MIF IBL, OT, TBP
5 IBL, OT, TBP, HB, Hct
Computer-generated numbers Drawing lots Computer-generated numbers Computer-generated codes Intravenous 20 mg/kg 32/29 2005.11-2008.1 China Choi (2009)27
Administration route Dose TXA/Control Study period Country Authors (year)
Table I. Basic characteristic of included randomized controlled trials in the meta-analysis
Randomization method
Observed indicators
Jadad scores
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In this meta-analysis, the data demonstrated tranexamic acid could reduce intraoperative blood loss during orthognathic surgery compared with the placebo groups. However, in the levels of Hb and Hct, there was no statistical significance between the 2 groups. These results are consistent with previous studies. The leading discrepancy from different examined indicators may be related to the drug half-life, the volume of intraoperative blood transfusion and intravenous fluid, and postoperative bleeding.27,33 Choi et al.27 observed the blood loss of bimaxillary osteotomy was within a range of 600 to 2000 mL, with a mean of 1000 mL and an SD of 350 mL, and the use of tranexamic acid was associated with a reduction of intraoperative blood loss by 30%. Moreover, a significant decrease in blood loss only occurred in maxillary and bimaxillary operations, but not in mandibular surgery.27 This suggests surgical type is an important factor affecting operative bleeding. Tranexamic acid as a synthetic derivative of the amino acid lysine exerts its antifibrinolytic effect through the reversible blockade of lysine-binding sites on plasminogen molecules. It competitively inhibits activation of plasminogen, thereby reducing conversion of plasminogen to plasmin, an enzyme that degrades fibrin clot, fibrinogen, and other plasma proteins, including procoagulant factors V and VIII. It is 5 to 10 times more potent than epsilon amino caproic acid.11,12 Tranexamic acid can be administrated via the intravenous or topical route. In our study, intravenous administration included 3 articles,27,29,30 and 1 was topical application.28 Stratified analysis showed that different administration resulted in distinct therapy effect on blood loss during orthognathic surgery. Kaewpradub et al.28 used 0.05% tranexamic acid in normal saline for tissue irrigation and cooling of the instrument. This concentration was approximately equal to fivefold of that in which tranexamic acid 15 to 25 mg/kg was administered intravenously; however, results showed 0.05% tranexamic acid used as an irrigant fluid did not reduce intraoperative bleeding significantly compared with placebo. The factors affecting topical treatment may be related to serum concentrations and contact time of irrigating fluid with traumatic tissue.34-37 As in most meta-analyses, these results should be interpreted with caution. There are several limitations, although the research includes 4 high-quality studies. First, some studies lacked of definite allocation concealment. Therefore, there may be selection bias, implementation bias, and measurement bias. Second, the 4 studies included only small numbers of patients. The largest number of patients was only 61.27 Third, the difference in surgical type, calculation of blood loss, and detected time will result in confounding bias. Last,
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Fig. 2. Intraoperative blood loss forest plot (TXA vs. Control).
Fig. 3. Intraoperative blood loss forest plot by intravenous administration (TXA vs. Control).
Fig. 4. Postoperative Hb level forest plot (TXA vs. Control).
Fig. 5. Postoperative Hct level forest plot (TXA vs. Control).
3 studies28-30 did not stratify analysis for different surgical strategies before randomization, which perhaps affects the accuracy of the results of this meta-analysis. In conclusion, this meta-analysis confirms that tranexamic acid can effectively reduce intraoperative blood loss in orthognathic surgery, especially by intravenous administration. But, tranexamic acid cannot affect postoperative levels of Hb and Hct. Consequently, large-scale studies need to be conducted with different surgical approaches, which will help us to further understand the therapeutic effect of tranexamic acid on blood loss in orthognathic surgery. We thank En Luo, PhD, DDS, for his thoughtful review.
REFERENCES 1. Baliga M, Upadhyaya C. Versatility of orthognathic surgery in the management of maxillofacial deformities. Kathmandu Univ Med J (KUMJ) 2006;4:109-14. 2. Samman N, Cheung LK, Tong AC, Tideman H. Blood loss and transfusion requirements in orthognathic surgery. J Oral Maxillofac Surg 1996;54:21-4. 3. Dodson TB. Blood loss following orthognathic surgery varies widely and sometimes transfusions are needed. J Evid Based Dent Pract 2011;11:185-6. 4. Piñeiro-Aguilar A, Somoza-Martín M, Gandara-Rey JM, GarcíaGarcía A. Blood loss in orthognathic surgery: a systematic review. J Oral Maxillofac Surg 2011;69:885-92. 5. Ervens J, Marks C, Hechler M, Plath T, Hansen D, Hoffmeister B. Effect of induced hypotensive anaesthesia vs isovolaemic haemodilution on blood loss and transfusion requirements in orthognathic surgery:
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a prospective, single-blinded, randomized, controlled clinical study. Int J Oral Maxillofac Surg 2010;39:1168-74. Böttger S, Streckbein P, Hartmann B, Schaaf H, Howaldt HP, Junger A. Retrospective analysis of autologous blood use in bimaxillary repositioning osteotomy surgery: a quality improvement study. Transfusion 2009;49:1747-53. Squires JE. Risks of transfusion. South Med J 2011;104:762-9. Anderson JA. Deliberate hypotensive anesthesia for orthognathic surgery: controlled pharmacologic manipulation of cardiovascular physiology. Int J Adult Orthodon Orthognath Surg 1986;1:133-59. Rodrigo C. Anesthetic considerations for orthognathic surgery with evaluation of difficult intubation and technique for hypotensive anesthesia. Anesth Prog 2000;47:151-6. Murphy MA. Bilateral posterior ischemic optic neuropathy after lumbar spine surgery. Ophthalmology 2003;110:1454-7. McCormack PL. Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis. Drugs 2012;72:585-617. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs 1999;57:1005-32. Aguilera X, Videla S, Almenara M, Fernandez JA, Gich I, Celaya F. Effectiveness of tranexamic acid in revision total knee arthroplasty. Acta Orthop Belg 2012;78:68-74. Endres S, Heinz M, Wilke A. Efficacy of tranexamic acid in reducing blood loss in posterior lumbar spine surgery for degenerative spinal stenosis with instability: a retrospective case control study. BMC Surg 2011;11:29. Chakravarthy M, Muniraj G, Patil S, Suryaprakash S, Mitra S, Shivalingappa B. A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery. Ann Card Anaesth 2012;15:105-10. Ramström G, Sindet-Pedersen S, Hall G, Blombäck M, Alander U. Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. J Oral Maxillofac Surg 1993;51:1211-16. Sindet-Pedersen S, Ramström G, Bernvil S, Blombäck M. Hemostatic effect of tranexamic acid mouthwash in anticoagulanttreated patients undergoing oral surgery. N Engl J Med 1989; 320:840-3. Senghore N, Harris M. The effect of tranexamic acid (cyclokapron) on blood loss after third molar extraction under a day case general anaesthetic. Br Dent J 1999;186:634-6. Zellin G, Rasmusson L, Pålsson J, Kahnberg KE. Evaluation of hemorrhage depressors on blood loss during orthognathic surgery: a retrospective study. J Oral Maxillofac Surg 2004;62:662-6. Cabrera-Naranjo F, González-Hernández A, Fabre-Pi O, Carolina A, Veloso L, Díaz-Nicolás S, Cubero-González A. Extensive stroke associated with tranexamic acid therapy. Can J Neurol Sci 2010;37:692-3. Hui AC, Wong TY, Chow KM, Szeto CC. Multifocal myoclonus secondary to tranexamic acid. J Neurol Neurosurg Psychiatry 2003;74:547. Imbesi S, Nettis E, Minciullo PL, Di Leo E, Saija A, Vacca A, Gangemi S. Hypersensitivity to tranexamic acid: a wide spectrum of adverse reactions. Pharm World Sci 2010;32:416-9. Guerriero C, Cairns J, Perel P, Roberts H, Shakur I, CRASH 2 Trial Collaborators. Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLoS ONE 2011;6:e18987.
OOOO May 2013 24. Sepah YJ, Umer M, Ahmad T, Nasim F, Chaudhry MU, Umar M. Use of tranexamic acid is a cost effective method in preventing blood loss during and after total knee replacement. J Orthop Surg Res 2011;6:22. 25. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 26. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998; 352:609-13. 27. Choi WS, Irwin MG, Samman N. The effect of tranexamic acid on blood loss during orthognathic surgery: a randomized controlled trial. J Oral Maxillofac Surg 2009;67:125-33. 28. Kaewpradub P, Apipan B, Rummasak D. Does tranexamic acid in an irrigating fluid reduce intraoperative blood loss in orthognathic surgery? A double-blind, randomized clinical trial. J Oral Maxillofac Surg 2011;69:e186-9. 29. Sankar D, Krishnan R, Veerabahu M, Vikraman B. Evaluation of the efficacy of tranexamic acid on blood loss in orthognathic surgery. A prospective, randomized clinical study. Int J Oral Maxillofac Surg 2012;41:713-7. 30. Karimi A, Mohammadi SS, Hasheminasab M. Efficacy of tranexamic acid on blood loss during bimaxillary osteotomy: a randomized double blind clinical trial. Saudi J Anesth 2012;6: 41-5. 31. Yu CN, Chow TK, Kwan AS, Wong SL, Fung SC. Intraoperative blood loss and operating time in orthognathic surgery using induced hypotensive general anaesthesia: prospective study. HK Med J 2000;6:307-11. 32. Flood TR, Ilankovan V, Moos KF, el-Attar A. Cross-match requirements in orthognathic surgery: an audit. Br J Oral Maxillofac Surg 1990;28:292-4. 33. Neilipovitz DT, Murto K, Hall L, Barrowman NJ, Splinter WM. A randomized trial of tranexamic acid to reduce blood transfusion for scoliosis surgery. Anesth Analg 2001;93:82-7. 34. Damji KF, Noël LP, Peterson RG, Ma PE, Clarke WN, Gilberg S, et al. Topical versus intravenous administration of tranexamic acid: a comparison of intraocular and serum concentrations in the rabbit. Can J Ophthalmol 1998;33:308-13. 35. Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, Pan L. Treatment of melasma with oral administration of tranexamic acid. Aesthetic Plast Surg 2012;36:964-70. 36. Gluud LL, Klingenberg SL, Langholz E. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2012;1:CD006640. 37. Alimian M, Mohseni M. The effect of intravenous tranexamic acid on blood loss and surgical field quality during endoscopic sinus surgery: a placebo-controlled clinical trial. J Clin Anesth 2011;23:611-5. Reprint requests: Jing Hu, DDS Department of Oral and Maxillofacial Surgery West China School of Stomatology Sichuan University Chengdu, 610041, China [email protected]
The effect of tranexamic acid on blood loss in orthognathic surgery: a meta-analysis of randomized controlled trials Guodong Song, DDS,a Ping Yang, MD,b Jing Hu, DDS,a Songsong Zhu, DDS,a Yunfeng Li, DDS,a and Qiushi Wang, DDSa Sichuan University, Chengdu, China
Objective. The objective of this article was to evaluate the efficacy of tranexamic acid on blood loss in orthognathic surgery. A meta-analysis was performed. Study Design. The PubMed and EMBASE electronic databases were searched until June 30, 2012. Eligible studies were restricted to randomized controlled trials (RCTs). Results. Four RCTs with 183 patients were included. The results showed that intraoperative blood loss in the tranexamic acid group was statistically reduced (weighted mean difference [WMD] ⫽ ⫺93.56, 95% CI ⫽ ⫺132.59-54.52, P ⬍ .00001). However, the postoperative levels of hemoglobin (Hb) and hematocrit (Hct) have no significant difference compared with placebo groups (WMD ⫽ 0.50, 95% CIs ⫽ ⫺0.43-1.43, P ⫽ .29 and WMD ⫽ 0.18, 95% CIs ⫽ ⫺1.64-1.99, P ⫽ .85, respectively). Conclusions. This meta-analysis confirms that tranexamic acid can effectively reduce intraoperative blood loss in orthognathic surgery, especially by intravenous administration. But, tranexamic acid cannot affect postoperative levels of Hb and Hct. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:595-600)
Orthognathic surgery is a well-established method to correct various forms of dentofacial deformity.1 Although this procedure is considered relatively safe with desired results, significant blood loss can occur and blood transfusion is often required.2,3 The leading reason is that the blood supply in the orofacial region is very rich. The incidence of blood transfusion, including autologous blood use during orthognathic surgery, was about 20% to 60%.4-6 Simultaneously, blood transfusion has the risks of infectious disease, incompatibility reactions, and immunosuppression.7 Currently, hypotension has been applied to minimize blood loss during orthognathic surgery and receives a favorable effect.8 However, the risk of ischemia owing to prolonged moderate hypotension may accompany the therapeutic process, especially in patients with hypertension or chronic renal failure.9,10 Therefore, exploring other procedures with minor adverse effects for decreasing blood loss during surgery is increasingly important. Tranexamic acid, an antifibrinolytic agent, is a synthetic amino acid lysine analog that forms a reversible complex with both plasminogen and plasmin by binding at lysine-binding sites. By competitively blocking a
Department of Oral and Maxillofacial Surgery, West China School of Stomatology, Sichuan University, Chengdu, China. b Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China. Received for publication July 10, 2012; returned for revision Sept 3, 2012; accepted for publication Sept 19, 2012. © 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.09.085
the conversion of plasminogen to plasmin, this binding inhibits the proteolytic action of plasmin on fibrin clot and platelet receptors so as to inhibit fibrinolysis at the surgical wound.11,12 Numerous studies have demonstrated tranexamic acid can effectively reduce bleeding in total knee arthroplasty, spinal surgery, and cardiac surgery.13-15 The same results for topical tranexamic acid have also been obtained in anticoagulated patients undergoing oral surgery.16,17 Senghore and Harris18 showed that intravenous administration of tranexamic acid was effective in preventing excessive postoperative bleeding in healthy adult patients undergoing third molar extraction. Since a retrospective study by Zellin et al.,19 there have been some studies on tranexamic acid decreasing blood loss in orthognathic surgery; however, evidence-based medicine does not support tranexamic acid as an effective pharmacologic means to reduce blood loss during orthognathic surgery. In addition, the potential risks on the use of antifibrinolytic agents, such as stroke, myoclonus, allergic reactions, and so on,20-22 cannot be ignored, especially in patients with hereditary blood disease. Cost-effectiveness analysis also showed there was a large benefit for the
Statement Tranexamic acid, an antifibrinolytic agent, has been shown to have the capability of reducing bleeding in orthognathic surgery. For further evaluating the efficacy of tranexamic acid in orthognathic surgery, a meta-analysis on published articles was performed.
595
ORAL AND MAXILLOFACIAL SURGERY 596 Song et al.
intraoperative use of tranexamic acid by reducing transfusion rate and volume, and shortening hospital stays and length of time in the intensive care unit.23,24 Here, we first performed a meta-analysis of published randomized controlled trials (RCTs) on tranexamic acid and placebo, the aim of which was to determine whether tranexamic acid significantly reduces blood loss in orthognathic surgery.
MATERIAL AND METHODS Search strategy A search was conducted of 2 electronic databases: PubMed and EMBASE (the last date was updated on June 30, 2012). The following search terms were used: tranexamic acid, hemodynamics, osteotomy, oral surgery, orthognathic surgery, orthognathic surgical procedures, antifibrinolytic agents. The search was done on studies conducted on human subjects, restricted to the English language. The reference lists of reviews and retrieved articles were handsearched at the same time. We did not consider abstracts or unpublished reports. Inclusion and exclusion criteria We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (1) the studies were to evaluate the effect of tranexamic acid on blood loss in patients undergoing orthognathic surgery; (2) the studies were RCTs, whereas the intervention in the control group was placebo; and (3) the studies had to contain sufficient raw data for WMD (weighted mean difference) with 95% confidence intervals (CIs). We excluded articles according to the following criteria: (1) without raw data available; (2) duplicate publication; (3) no usable data reported. Data extraction Data were extracted from each study by 2 reviewers (G.D.S., P.Y.) independently according to the prespecified selection criteria. Any discrepancy during screening and quality assessment was resolved by discussion. Statistical analysis The statistical analysis was performed by using RevMan5.0 software, which was provided by the Cochrane Collaboration (Copenhagen, Denmark). P less than .05 was considered statistically significant. Heterogeneity was checked by 2 test. If the results of the trials had heterogeneity, a random effects model was used for meta-analysis. Otherwise, a fixed effects model was used. The result was expressed with WMD for the categorical variable and 95% CIs.
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Assessment of study quality Included studies were reviewed and appraised for methodological quality using the Jadad composite scale.25 High-quality trials scored more than 2 of a maximum possible score of 5.26
RESULTS Study characteristics There were 2194 articles relevant to the searching words (Fig. 1). Through the step of filtering the title, 834 of these articles were excluded (294 reviews, 540 nonabstracts). RCTs from 262 articles were reviewed and an additional 1428 articles were excluded (1048 non-RCTs, 380 nonhuman studies). Of these, 258 were excluded (125 were nonplacebo controls, 6 duplicates, and 127 nonorthognathic surgeries); thus, 4 articles,27-30 which included 183 cases, were found to conform to our inclusion criteria. Four RCT studies, from the Islamic Republic of Iran, India, Thailand, and China, were included in this meta-analysis. The characteristics of these studies are presented in Table I. Quality of included studies The 4 studies were randomized, double-blind controlled trials and all had a detailed description of methods for randomization, 3 with a computer-generated list allocation, and 1 with drawing lots random. The mean Jadad score of the included studies was more than 3 (Table I). The main studying limitations included smaller sample size and allocation concealment. Intraoperative blood loss Four RCT studies all showed intraoperative blood loss data. The heterogeneity was not observed among 4 studies (2 ⫽ 2.46, P ⫽ .29, I2 ⫽ 19%) (Fig. 2), so the fixed effects model was used. The results showed that the difference was statistically significant (WMD ⫽ ⫺93.56, 95% CI ⫽ ⫺132.59 to ⫺54.52, P ⬍ .00001) (Fig. 2), suggesting that tranexamic acid had the capability of reducing intraoperative blood loss compared with the placebo groups. According to analysis of the administered route, the result obtained from intravenous administration was statistically significant (WMD ⫽ ⫺93.82, 95% CI ⫽ ⫺133.44 to ⫺54.20, P ⬍ .00001) (Fig. 3). Because the heterogeneity was not observed among 3 studies (2 ⫽ 2.45, P ⫽ .12, I2 ⫽ 59%) (Fig. 3), the fixed effects model was used. On the contrary, there is no statistical difference in topical application (WMD ⫽ ⫺85.01, 95% CI ⫽ ⫺313.14-143.12, P ⫽ 0.47). This suggested intravenous administration was an effective route in preventing intraoperative blood loss during orthognathic surgery.
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Fig. 1. Studies identification, inclusion, and exclusion.
Hemoglobin Two studies reported significant reduction in postoperative hemoglobin (Hb) levels relative to preoperative examination; however, the comparison showed that there was no significant difference in the postoperative Hb level between tranexamic acid and placebo groups.27,30 Choi and colleagues27 observed Hb level in the tranexamic acid group is 11.1 ⫾ 2.1 at 24 hours postoperatively, whereas the placebo group is 10.6 ⫾ 1.6. Similarly, in the study conducted by Karimi et al.,30 Hb concentration was 11.8 g/dL (the tranexamic acid group) and 10.84 g/dL (the placebo group) at 6 hours after operation. Our meta-analysis on 2 studies also demonstrated the same result (WMD ⫽ 0.50, 95% CI ⫽ ⫺0.43-1.43, P ⫽ .29) (Fig. 4). Hematocrit Three RCT studies examined hematocrit (Hct) concentration at 24 hours after operation. The heterogeneity was not observed among 3 studies (2 ⫽ 2.18, P ⫽ .14, I2 ⫽ 54%) (Fig. 5), so the fixed effects model was used. The results showed that the difference was not statistically significant (WMD ⫽ 0.18, 95% CI ⫽ ⫺1.64-1.99, P ⫽ .85) (Fig. 5), suggesting that tranexamic acid had no obvious influence on postoperative Hct level compared with the placebo group.
Sensitivity analyses and publication bias Removing individual study from the list did not change the level of significance for the most important clinical outcomes (intraoperative blood loss, Hb, Hct). Because of the limited number of articles included in this metaanalysis, we did not evaluate publication bias with Begg’s funnel plot.
DISCUSSION Orthognathic surgeries, especially those involved in maxillary interventions, such as Le Fort I osteotomies, are known to occasionally result in significant loss of blood. Yu and colleagues31 reported that 72.4% of orthognathic patients require bimaxillary surgery, and the volume of blood loss in Le Fort I osteotomies is about 50% of multiple segmentalized osteotomies. In addition, about 30% of patients undergoing bimaxillary osteotomies have need of a blood transfusion.2,32 Various approaches have been applied to reduce blood loss and the need for blood transfusions, because blood products are not only a finite resource but also present the risk of transmission of infectious disease.7 Currently, tranexamic acid as an antifibrinolytic drug has been demonstrated to be effective in reducing perioperative and postoperative blood loss in various surgical fields.
Intravenous 20 mg/kg 16/16 Islamic Republic of Iran Karimi (2012)30
2010.8-2011.1
Tissue irrigation Intravenous 0.05%TXA/NS 10 mg/kg 20/20 25/25 DNR DNR Thailand India Kaewpradub (2011)28 Sankar (2012)29
DNR, data not reported; HB, perioperative hemoglobin level; Hct, perioperative hematocrit level; HST, hospital stay time; IBL, intraoperative blood loss; MIF, amount of irrigant fluid; NS, normal saline; OT, operation time; TBP, transfusion of blood products; TXA, tranexamic acid group.
5 IBL, OT, TBP, HB, Hct, HST
3 5 IBL, OT, TBP, Hct, MIF IBL, OT, TBP
5 IBL, OT, TBP, HB, Hct
Computer-generated numbers Drawing lots Computer-generated numbers Computer-generated codes Intravenous 20 mg/kg 32/29 2005.11-2008.1 China Choi (2009)27
Administration route Dose TXA/Control Study period Country Authors (year)
Table I. Basic characteristic of included randomized controlled trials in the meta-analysis
Randomization method
Observed indicators
Jadad scores
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In this meta-analysis, the data demonstrated tranexamic acid could reduce intraoperative blood loss during orthognathic surgery compared with the placebo groups. However, in the levels of Hb and Hct, there was no statistical significance between the 2 groups. These results are consistent with previous studies. The leading discrepancy from different examined indicators may be related to the drug half-life, the volume of intraoperative blood transfusion and intravenous fluid, and postoperative bleeding.27,33 Choi et al.27 observed the blood loss of bimaxillary osteotomy was within a range of 600 to 2000 mL, with a mean of 1000 mL and an SD of 350 mL, and the use of tranexamic acid was associated with a reduction of intraoperative blood loss by 30%. Moreover, a significant decrease in blood loss only occurred in maxillary and bimaxillary operations, but not in mandibular surgery.27 This suggests surgical type is an important factor affecting operative bleeding. Tranexamic acid as a synthetic derivative of the amino acid lysine exerts its antifibrinolytic effect through the reversible blockade of lysine-binding sites on plasminogen molecules. It competitively inhibits activation of plasminogen, thereby reducing conversion of plasminogen to plasmin, an enzyme that degrades fibrin clot, fibrinogen, and other plasma proteins, including procoagulant factors V and VIII. It is 5 to 10 times more potent than epsilon amino caproic acid.11,12 Tranexamic acid can be administrated via the intravenous or topical route. In our study, intravenous administration included 3 articles,27,29,30 and 1 was topical application.28 Stratified analysis showed that different administration resulted in distinct therapy effect on blood loss during orthognathic surgery. Kaewpradub et al.28 used 0.05% tranexamic acid in normal saline for tissue irrigation and cooling of the instrument. This concentration was approximately equal to fivefold of that in which tranexamic acid 15 to 25 mg/kg was administered intravenously; however, results showed 0.05% tranexamic acid used as an irrigant fluid did not reduce intraoperative bleeding significantly compared with placebo. The factors affecting topical treatment may be related to serum concentrations and contact time of irrigating fluid with traumatic tissue.34-37 As in most meta-analyses, these results should be interpreted with caution. There are several limitations, although the research includes 4 high-quality studies. First, some studies lacked of definite allocation concealment. Therefore, there may be selection bias, implementation bias, and measurement bias. Second, the 4 studies included only small numbers of patients. The largest number of patients was only 61.27 Third, the difference in surgical type, calculation of blood loss, and detected time will result in confounding bias. Last,
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Fig. 2. Intraoperative blood loss forest plot (TXA vs. Control).
Fig. 3. Intraoperative blood loss forest plot by intravenous administration (TXA vs. Control).
Fig. 4. Postoperative Hb level forest plot (TXA vs. Control).
Fig. 5. Postoperative Hct level forest plot (TXA vs. Control).
3 studies28-30 did not stratify analysis for different surgical strategies before randomization, which perhaps affects the accuracy of the results of this meta-analysis. In conclusion, this meta-analysis confirms that tranexamic acid can effectively reduce intraoperative blood loss in orthognathic surgery, especially by intravenous administration. But, tranexamic acid cannot affect postoperative levels of Hb and Hct. Consequently, large-scale studies need to be conducted with different surgical approaches, which will help us to further understand the therapeutic effect of tranexamic acid on blood loss in orthognathic surgery. We thank En Luo, PhD, DDS, for his thoughtful review.
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