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      Serum Concentrations and Pharmacokinetics of Tranexamic Acid after Two Means of Topical Administration in Massive Weight Loss Skin-Reducing Surgery

      research-article
      , M.D. 1 , , , M.D., Ph.D. 1 , , Ph.D. 1 , , Ph.D. 1 , , M.D., Ph.D. 1 , , M.D. 1 , , M.D., Ph.D. 1
      Plastic and Reconstructive Surgery
      Lippincott Williams & Wilkins

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Background:

          Topical administration of tranexamic acid to reduce bleeding is receiving increasing attention, as it is inexpensive, simple, and possibly beneficial in most surgery. Concerns regarding potential systemic adverse effects such as thromboembolic events and seizures may prevent general use of tranexamic acid. Although serum concentrations after topical application are assumed to be low, proper pharmacokinetic studies of tranexamic acid after topical application are lacking.

          Methods:

          The authors have investigated systemic absorption of tranexamic acid after two means of topical administration in patients undergoing abdominoplasty after massive weight loss: a bolus of 200 ml of 5 mg/ml into the wound cavity versus moistening the wound surface with 20 ml of 25 mg/ml. Twelve patients were recruited in each group. Serum concentrations achieved were compared with those after administration of 1 g as an intravenous bolus to arthroplasty patients. Serial blood samples for tranexamic acid analysis were obtained for up to 24 hours.

          Results:

          After intravenous administration, the peak serum concentration was 66.1 ± 13.0 µg/ml after 6 ± 2 minutes. Peak serum concentration after topical moistening was 5.2 ± 2.6 µg/ml after 80 ± 33 minutes, and in the topical bolus group, it was 4.9 ± 1.8 µg/ml after 359 ± 70 minutes. Topical moistening resulted in homogenous and predictable absorption across the individuals included, whereas topical bolus administration caused variable and unpredictable serum concentrations.

          Conclusion:

          Topical administration of tranexamic acid in patients undergoing abdominoplasty results in low serum concentrations, which are highly unlikely to cause systemic effects.

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          Most cited references66

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          Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.

          Tranexamic acid can reduce bleeding in patients undergoing elective surgery. We assessed the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients. This randomised controlled trial was undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other. All analyses were by intention to treat. This study is registered as ISRCTN86750102, Clinicaltrials.govNCT00375258, and South African Clinical Trial RegisterDOH-27-0607-1919. 10 096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10 060 and 10 067, respectively, were analysed. All-cause mortality was significantly reduced with tranexamic acid (1463 [14.5%] tranexamic acid group vs 1613 [16.0%] placebo group; relative risk 0.91, 95% CI 0.85-0.97; p=0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI 0.76-0.96; p=0.0077). Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients. UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis

            Objective To assess the effect of tranexamic acid on blood transfusion, thromboembolic events, and mortality in surgical patients. Design Systematic review and meta-analysis. Data sources Cochrane central register of controlled trials, Medline, and Embase, from inception to September 2011, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of relevant articles. Study selection Randomised controlled trials comparing tranexamic acid with no tranexamic acid or placebo in surgical patients. Outcome measures of interest were the number of patients receiving a blood transfusion; the number of patients with a thromboembolic event (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism); and the number of deaths. Trials were included irrespective of language or publication status. Results 129 trials, totalling 10 488 patients, carried out between 1972 and 2011 were included. Tranexamic acid reduced the probability of receiving a blood transfusion by a third (risk ratio 0.62, 95% confidence interval 0.58 to 0.65; P<0.001). This effect remained when the analysis was restricted to trials using adequate allocation concealment (0.68, 0.62 to 0.74; P<0.001). The effect of tranexamic acid on myocardial infarction (0.68, 0.43 to 1.09; P=0.11), stroke (1.14, 0.65 to 2.00; P=0.65), deep vein thrombosis (0.86, 0.53 to 1.39; P=0.54), and pulmonary embolism (0.61, 0.25 to 1.47; P=0.27) was uncertain. Fewer deaths occurred in the tranexamic acid group (0.61, 0.38 to 0.98; P=0.04), although when the analysis was restricted to trials using adequate concealment there was considerable uncertainty (0.67, 0.33 to 1.34; P=0.25). Cumulative meta-analysis showed that reliable evidence that tranexamic acid reduces the need for transfusion has been available for over 10 years. Conclusions Strong evidence that tranexamic acid reduces blood transfusion in surgery has been available for many years. Further trials on the effect of tranexamic acid on blood transfusion are unlikely to add useful new information. However, the effect of tranexamic acid on thromboembolic events and mortality remains uncertain. Surgical patients should be made aware of this evidence so that they can make an informed choice.
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              Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial.

              Topical application of tranexamic acid to bleeding wound surfaces reduces blood loss in patients undergoing some major surgeries, without systemic complications. The objective of the present trial was to assess the efficacy and safety of the topical application of tranexamic acid on postoperative blood loss in patients undergoing primary unilateral total knee arthroplasty with cement. In a prospective, double-blind, placebo-controlled trial, 124 patients were randomized to receive 1.5 or 3.0 g of tranexamic acid in 100 mL of normal saline solution or an equivalent volume of placebo (normal saline solution) applied into the joint for five minutes at the end of surgery. The primary outcome was blood loss calculated from the difference between the preoperative hemoglobin level and the corresponding lowest postoperative value or hemoglobin level prior to transfusion. The safety outcomes included Doppler ultrasound in all patients and measurement of plasma levels of tranexamic acid one hour after release of the tourniquet. Twenty-five patients were withdrawn for various reasons; therefore, ninety-nine patients were included in the intention-to-treat analysis. The postoperative blood loss was reduced in the 1.5 and 3-g tranexamic acid groups (1295 mL [95% confidence interval, 1167 to 1422 mL] and 1208 mL [95% confidence interval, 1078 to 1339 mL], respectively) in comparison with the placebo group (1610 mL [95% confidence interval, 1480 to 1738 mL]) (p < 0.017). The postoperative hemoglobin levels were higher in the 1.5 and 3.0-g tranexamic acid groups (10.0 g/dL [95% confidence interval, 9.5 to 10.4 g/dL] and 10.1 g/dL [95% confidence interval, 9.8 to 10.5 g/dL], respectively) in comparison with the placebo group (8.6 g/dL [95% confidence interval, 8.2 to 9 g/dL]) (p < 0.017). With the numbers studied, there was no difference in the rates of deep-vein thrombosis or pulmonary embolism between the three groups. Minimal systemic absorption of tranexamic acid was observed. At the conclusion of a total knee arthroplasty with cement, topical application of tranexamic acid directly into the surgical wound reduced postoperative bleeding by 20% to 25%, or 300 to 400 mL, resulting in 16% to 17% higher postoperative hemoglobin levels compared with placebo, with no clinically important increase in complications being identified in the treatment groups.
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                Author and article information

                Journal
                Plast Reconstr Surg
                Plast. Reconstr. Surg
                PRS
                Plastic and Reconstructive Surgery
                Lippincott Williams & Wilkins
                0032-1052
                1529-4242
                June 2019
                29 May 2019
                : 143
                : 6
                : 1169-1178
                Affiliations
                Trondheim, Norway
                [1 ]From the Section for Plastic and Reconstructive Surgery, Clinic of Surgery, the Clinic of Anesthesia and Intensive Care, and the Department of Clinical Pharmacology, St. Olav’s University Hospital; the Departments of Circulation and Medical Imaging and Clinical and Molecular Medicine, Norwegian University of Science and Technology; and the Section for Plastic Surgery, Aleris Medical Center.
                Author notes
                Kjersti Ausen, M.D., Section for Plastic and Reconstructive Surgery, Clinic of Surgery, St. Olav’s University Hospital, P.O. Box 3250 Torgarden, N-7006 Trondheim, Norway, kjerstiausen@ 123456gmail.com
                Article
                00016
                10.1097/PRS.0000000000005620
                6553511
                31136475
                eea6106d-d789-459f-ba3c-d3a4df1e4a06
                Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 3 June 2018
                : 17 October 2018
                Categories
                Cosmetic: Original Articles
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