Safety and Efficacy of Local Tranexamic Acid for the Prevention of Surgical Bleeding in Soft-Tissue Surgery

A Review of the Literature and Recommendations for Plastic Surgery

Kjersti Ausen, M.D., Ph.D.; Reidar Fossmark, M.D., Ph.D.; Olav Spigset, M.D., Ph.D.; Hilde Pleym, M.D., Ph.D.

Plast Reconstr Surg. 2022;149(3):774-787.

Abstract and Introduction

Abstract

Background: Although high-bleed surgery routinely utilizes the antifibrinolytic drug tranexamic acid, most plastic surgical procedures are conducted in soft tissue with low-volume bleeding. Unease regarding possible systemic adverse effects prevents widespread systemic use, but local use of tranexamic acid is gaining popularity among plastic surgeons. Randomized controlled trials on topical use of tranexamic acid are mainly from high-bleed surgeries, and few studies address the effect in soft tissue. This article reviews the scientific evidence regarding local use of tranexamic acid in soft-tissue surgery, discusses pharmacological effects and possible adverse reactions, and presents recommendations for use in plastic surgery.

Methods: A systematic search of databases for studies on local use of tranexamic acid in soft-tissue surgery was performed. Randomized controlled trials were included for a systematic review on effect; a narrative review regarding other clinically relevant aspects is based on extensive literature searches combined with the authors' own research.

Results: Fourteen randomized controlled trials, including 1923 patients, were included in the systematic review on local use of tranexamic acid in soft-tissue surgery.

Conclusions: Local use of tranexamic acid may reduce blood loss comparably to intravenous prophylactic use with negligible risk of systemic adverse effects, but high-quality randomized controlled trials are few. Prolonged exposure to high local concentrations is discouraged, and direct contact with the central nervous system may cause seizures. No single superior means of administration or dosage is supported in the literature, and lowest effective dose is unknown. There may not be one single ideal dosing regimen, but rather many possibilities adaptable for different surgical situations.

Introduction

Although most plastic surgical procedures are not associated with major blood loss, bleeding causes swelling, bruising and pain, need for drains and bandage changes, and reoperations, and may increase the risk of infection and wound ruptures. Keeping surgical bleeding to a minimum is, thus, beneficial for both patient and provider. Fear of bleeding may also prevent plastic surgeons from using adequate thromboprophylactic measures as addressed by the American Society of Plastic Surgeons Venous Thromboembolism Prevention Task Force.^[1]

In surgery, a balance between coagulation and fibrinolysis is needed to prevent bleeding yet maintain circulation. If fibrinolysis exceeds coagulation, bleeding may occur despite adequately performed hemostasis. While meticulous surgical technique, use of cautery, and local infiltration of wound edges with adrenaline can largely control bleeding in soft-tissue surgery, bony tissue cannot be infiltrated or manipulated to the same extent. Measures such as hypotensive anesthesia and pharmacological aids are, therefore, used to control bleeding in bony tissue.

Antifibrinolytic drugs have been the only available pharmacological means of a general reduction of bleeding with an acceptable safety profile in patients without coagulation deficiencies.^[2] Tranexamic acid is a synthetic low-cost antifibrinolytic drug manufactured and approved for intravenous and oral use, and systemic prophylactic use reduces both bleeding volume and transfusion needs by 30 to 40 percent.^[3,4] Although large studies have found little evidence of a prothrombotic effect from tranexamic acid,^[5–8] contradictory studies do exist.^[9–11] Moreover, a dose-dependent increase in seizures has been documented from intravenous use of tranexamic acid in cardiac surgery.^[12] Fear of possible adverse effects has, therefore, limited routine systemic use to surgery with expected high-volume bleeding and frequent need of blood transfusions; this includes mostly surgery affecting skeletal structures, such as joint arthroplasties, craniomaxillofacial surgery, and cardiac surgery, with its associated thoracotomy, use of cardiopulmonary bypass, and high-dose anticoagulation. Use in burns^[13,14] is not established, probably because of uncertainties regarding adverse effects of tranexamic acid during ongoing hyperfibrinolysis.^[15]

An alternative to systemic use of tranexamic acid is local administration, which may provide sufficient drug concentrations at the wound surface with negligible risk of systemic adverse effects. Three meta-analyses on the use of topical tranexamic acid in surgery^[16–18] all demonstrate a significant reduction of blood loss and transfusion needs without any increase in adverse events. However, in the two first meta-analyses by Ker et al. in 2013^[16] and Montroy et al. in 2018,^[17] only two of 29 and three of 66 studies, respectively, addressed surgery conducted in soft tissues. In the latest meta-analysis, by Teoh et al. in 2020,^[18] seven of 71 studies addressed soft-tissue surgery.

The term "plastic surgery" encompasses exceedingly diverse procedures. Both systemic and topical use of tranexamic acid have already been explored in plastic surgical fields that involve skeletal structures such as rhinoplasty, craniomaxillofacial, and orthognathic surgery.^[19–22] Yet, the larger bulk of plastic surgery takes place in soft tissue, and the effect of tranexamic acid according to type of tissue may be as clinically relevant as the effect in specific procedures.

Local use of tranexamic acid has been adopted by influential plastic surgeons and is receiving increasing attention.^[23–27] Four published reviews on the use of tranexamic acid in plastic surgery since 2016^{[19,21,26,28]} have, however, only identified a total of three randomized controlled trials on topical use, with two in orthognathic surgery^[29,30] and only one in soft tissue (i.e., reduction mammaplasty).^[31]

The aim of this article is to provide insight on the pharmacological effects and adverse effects of tranexamic acid, review the current scientific evidence regarding local use in soft-tissue surgery, and present recommendations for use of tranexamic acid in plastic surgery.

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Table 1. Randomized Controlled Trials on Local Use of Tranexamic Acid in Soft-Tissue Surgery: Superficial Tissue, Topical Application
Reference, Year, Publication Type	TXA Group (total sample size)	Procedure	Concentration of TXA, Volume, Mode of Administration	Comparator	Bleeding*	Postoperative Hemorrhagic Incidence/Intervention/Transfusion†
Ausen 2015, article³¹	28 (56)	Reduction mammaplasty	25 mg/ml, 20 ml, topical moistening	20 ml saline as placebo	Drain production at 24 h (ml) median (range)TXA 12.5 (0–44) vs placebo 20.5 (0–100), p = 0.038	Hematoma warranting reoperation before drain removal (n): TXA = 0 vs placebo = 2
Ausen 2019, article⁵⁸	101 (202)	Mastectomy	25 mg/ml, 20 ml, topical moistening	20 ml saline as placebo	Drain production at 24 h (ml) mean (95% CI); TXA 110 (97–123) vs placebo 144 (122–167), p = 0.01	Hematoma warranting reoperation before drain removal (n): TXA = 1 vs placebo = 7
Albirmawy 2013. article⁵⁷	200 (400)	Adenoidectomy in children	100 mg/ml, 10 ml, topical bolus left for 5 minutes before suction removal.	10 ml saline as placebo	Intraoperative blood loss (ml) TXA 19 ± 2.5 vs placebo 26 ± 4.3, p = 0.003	Postoperative hemorrhage (n); TXA = 5 vs placebo = 12; Nasal packing needed: TXA = 1 vs placebo = 4. Transfusion TXA = 0 vs placebo = 2
Parisi 2013, conference abstract⁵⁹	50 (100)	Subcutaneous pocket for cardiac pacemaker	100 mg/ml, 10 ml, topical irrigation	No irrigation as control	Not measured	Presence of hematoma within 15 days (n): TXA = 2 vs control = 12. Surgical revision needed: TXA = 1 vs control = 8

TXA, tranexamic acid; CI, confidence interval.
*Values are mean ± SD unless otherwise stated.
†Values (n) are number of patients unless otherwise stated.

Table 2. Randomized Controlled Trials on Local Use of Tranexamic Acid in Soft-Tissue Surgery: Superficial Tissue, Local Infiltration
Reference, Year, Publication Type	TXA Group (total sample size)	Procedure	Concentration of TXA, Volume, Mode of Administration	Comparator	Bleeding*	Postoperative Hemorrhagic Incidence/Intervention/Transfusion
Zilinsky 2019, article⁶¹	60 (127)	Mohs microsurgery in head/neck	Lidocaine20 mg/ml diluted 1:1 with 100 mg/ml TXA	Lidocaine 20 mg/ml diluted with saline as placebo	Ratio of dressing blood stain to surgical wound size TXA = 1.8 vs placebo = 2.5, p < 0.001	Not assessed
Sagiv 2018, article⁶⁰	17 (34)	Upper blepharoplasty	Lidocaine 20 mg/ml diluted 1:1 with 100 mg/ml TXA	Lidocaine 20 mg/ml diluted with saline as placebo	No difference in blood weight in pads or cautery time	No significant difference in ecchymoses

TXA, tranexamic acid.
*Values are mean ± SD unless otherwise stated.

Table 3. Randomized Controlled Trials on Local Use of Tranexamic Acid in Soft-Tissue Surgery: Inner Organs, Open Surgery
Reference, Year, Publication Type	TXA Group (total sample size)	Procedure	Concentration of TXA, Volume, Mode of Administration	Comparator	Bleeding*	Postoperative Hemorrhagic Incidence/Intervention/Transfusion†
Sabry 2018, article⁶⁴	35 (70)	Lung decortication	30 mg/ml, 100 ml, poured into pleural cavity, drains clamped for 30–45 minutes	100 ml saline as placebo	Postoperative blood loss drain production at 48 h (ml); TXA = 383 ± 120 vs placebo = 633 ± 164	Transfusion need (units of transfused blood) mean ± SD: TXA = 0.7 ± 0.9 vs placebo = 1.5 ± 1.1
Sallam 2019, article⁶⁵	43 (86)	Open hysterectomy	20 mg/ml, 50 ml irrigation, 50 ml intraabdominally	50 + 50 ml saline as placebo	Total blood loss (ml)TXA 395 ± 118 vs placebo 609 ± 119, p < 0.001	Transfusion need (n): TXA = 2 vs placebo = 4
Shady 2018, article⁶⁶	35 (70)	Open myomectomy	20 mg/ml, 100 ml, soaked gauze for 5 minutes	100 ml saline as placebo	Total blood loss (ml) TXA = 684 ± 215 vs placebo = 1080 ± 126, p < 0.001	Transfusion need (n): TXA = 7 vs placebo = 19
Pourfakhr 2016, article⁶³	186 total	Prostatectomy	100 mg/ml, 5ml, topical irrigation after resection	5 ml saline as placebo	Total blood loss (ml) TXA = 340 ± 152 vs placebo 515 ± SD not given, p = 0.01	Transfusion need (n): TXA = 0 vs placebo = 5

TXA, tranexamic acid; SD, standard deviation.
*Values are mean unless otherwise stated.
†Values (n) are number of patients unless otherwise stated.

Table 4. Randomized Controlled Trials on Local Use of Tranexamic Acid in Soft-Tissue Surgery: Inner Organs, Minimally Invasive Procedures
Reference, Year, Publication Type	TXA Group (total sample size)	Procedure	Concentration of TXA, Volume, Mode of Administration	Comparator	Bleeding*	Postoperative Hemorrhagic Incidence/Intervention/Transfusion†
Abdullah 2012, conference abstract⁶⁷	52 total	TURP	0.5 mg/ml in irrigation fluid	Standard irrigation fluid	Drop in Hb (g/dl) on first and second POD; TXA 0.87 and 0.31 vs placebo 0.98 and 0.95	Not assessed
Rani 2018, article⁶⁹	30 (60)	TURP	0.2 mg/ml in irrigation fluid	Standard irrigation fluid	Intraoperative blood loss (ml) TXA = 145 ± 13 vs placebo 198 ± 18, p < 0.01 Drop in Hb (g/dl) TXA = 0.81 ± 0.40 vs. placebo = 1.46 ± 0.37, p < 0.01	No transfusions in either group
Bansal 2017, article⁶⁸	200 (400)	Percutaneous nephrolithotomy	1 mg/ml in irrigation fluid	Distilled water as placebo in irrigation fluid	Total blood loss (ml) TXA = 155 ± 47 vs placebo 213 ± 68, p < 0.001	Transfusion need (n): TXA = 10 vs placebo = 25. Need of angioembolization (n): TXA = 1 vs placebo = 8
Rasheedy 2019, article⁷⁰	40 (80)	Hysteroscopic myomectomy	1 mg/ml in distention fluid	Glycine as placebo in distention fluid	Drop in Hb after 24 h (g/dl) TXA = 1.11 ± 0.58 vs placebo = 1.46 ± 0.61, p = 0.001	Excessive perioperative bleeding reported by surgeon (n): TXA = 1 vs placebo = 9. Good surgical view (n): TXA = 23 vs placebo = 8

TXA, tranexamic acid; TURP, transurethral prostatectomy; Hb, hemoglobin; POD, postoperative day.
*Values are mean ± SD unless otherwise stated.
†Values (n) are number of patients unless otherwise stated.

Table 5. Randomized Controlled Trials on Local use of Tranexamic Acid in Orthognathic and Endoscopic Sinus Surgery
Reference, Year, and Publication Type	TXA Group (total sample size), n	Procedure	TXA Concentration, Volume, Mode of Administration	Comparator	Bleeding*	Postoperative Hemorrhagic Incidence/Intervention/Transfusion*
Jabalameli 2006, brief report⁷⁴	26 (56)	Endoscopic sinus surgery	50 mg/ml, 20 ml of bolus instillation	20 ml saline as placebo	Intraoperative bleeding (ml) TXA = 174 ± 11 vs placebo 229 ± 24, p < 0.05	Surgical visual field score according to Boezaart (0–5): TXA = 2.31 ± 0.20 vs placebo 2.53 ± 0.15, p < 0.05
Athanasiadis 2007, article⁷¹	20 (40)	Bilateral endoscopic sinus surgery	Paired case/control. Investigation of two different concentrations. 100 mg/ml, 10 ml (n = 10) and 10 mg/ml, 10 ml (n = 10) topical irrigation after resection	10 ml saline as placebo	Operating site assessed as bleeding the least by surgeon (n): TXA = 16 vs placebo = 4, p = 0.007	None in either group
Kaewpradub 2011, article⁷⁶	20 (40)	Orthognathic surgery	0.5 mg/ml in irrigation fluid	Standard irrigation solution	Intraoperative bleeding (ml) TXA = 833 ± 316 vs comparator 918 ± 424, p = 0.47	Transfusion need (units of transfused blood): TXA = 0.15 ± 0.36 vs comparator = 0.25 ± 0.55, p = 0.50
Jahanshahi 2014, article⁷⁵	30 (60)	Endoscopic sinus surgery	50 mg/ml in combination with adrenaline 5 mg/ml, soaked pledgets applied for 10 minutes before surgery	5 mg/ml adrenaline solution as comparator	Blood loss from initiation until 45 minutes (ml) TXA = 100 ± 53 vs placebo 170 ± 46, p = 0.001	Surgical visual field score according to Boezaart (0–5): grading significantly lower in TXA group up to 30 minutes (p = 0.003) but not at 45 minutes (p = 0.163)
Shehata 2014, article⁷⁷	25 (50)	Endoscopic sinus surgery	50 mg/ml, 20 ml, for packing and irrigation during surgery	20 ml saline as placebo	Intraoperative blood loss (ml) TXA = 214 ± 77 vs placebo = 273 ± 178, p < 0.01	Surgical visual field score according to Boezaart (0–5): TXA = 1.92 ± 0.64 vs placebo 2.64 ± 0.7, p < 0.01
Eftekharian 2015, article⁷³	28 (56)	Orthognatic surgery	1 mg/ml in irrigation fluid	Standard irrigation fluid	Intraoperative blood loss (ml) TXA = 575 ± 287 vs comparator 818 ± 262, p < 0.05	No transfusion needs in either group. Postoperative bleeding not measured
Barandaran-far 2017, article⁷²	30 (60)	Endoscopic sinus surgery	5 mg/ml in first 400 ml of irrigation fluid	Standard irrigation fluid	Intraoperative blood loss (ml) TXA = 236 vs comparator = 234 (SD not given), p = 0.31	Surgical visual field according to Boezaart (0–5): TXA = 2.73 vs comparator 3.0 (SD not given) p = 0.305