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Can Topical Application of Tranexamic Acid Reduce Blood Loss in Thoracic Surgery? A Prospective Randomised Double Blind Investigation
ORIGINAL ARTICLE
Original Article
Can Topical Application of Tranexamic Acid Reduce Blood Loss in Thoracic Surgery? A Prospective Randomised Double Blind Investigation Andrea Dell’Amore, MD ∗ , Guido Caroli, MD, Asadi Nizar, MD, Nicola Cassanelli, MD, Giulia Luciano, MD, Domenico Greco, MD, Giampiero Dolci, MD, Alessandro Bini, PhD and Franco Stella, PhD Thoracic Surgery Operative Unit, S.Orsola Malpighi University Hospital, Bologna, Italy
Objective: The systemic or topical use of antifibrinolytic agents is effective in reducing postoperative bleeding and blood product transfusion in cardiac surgery. We sought to study the effect of the topical application of tranexamic acid into the pleural space to reduce postoperative bleeding after lung surgery. Methods: This was a prospective randomised double blind placebo controlled investigation. From May-2010 to February-2012, 89-patients, scheduled for pulmonary resection, were randomly allocated to one of the two study groups. Group-A received 5 g of tranexamic-acid in 100 ml of saline solution. Group-B received 100 ml of saline solution as placebo. Results: The blood loss in the first 12-h was significantly less in group-A. The same trend was observed in the first 24-h but without reaching a true statistical significance. The mean volume of blood transfusion was statistically lower in group-A. The analysis between post-operative haemoglobin concentration, haematocrit, platelet-count, internationalnormalised-ratio, fibrinogen and partial-thromboplastin-time of both groups was not statistically significant. Conclusion: In our experience, the topical use of tranexamic-acid after lung surgery reduces postoperative bleeding and blood transfusion volume. The topical administration of tranexamic-acid is safe without increasing the risk of post-operative complications related to pharmacological side-effects. (Heart, Lung and Circulation 2012;21:706–710) © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Postoperative bleeding; Thoracic surgery; Antifibrinolityc agents; Tranexamic acid; Blood saving
Introduction
A
ctivation of fibrinolysis during and after surgery is a well known phenomenon [1,2]. Several mechanisms are related to coagulation defect: surgical trauma, operative blood loss with consumption of clotting factors and platelets, administration of crystalloids and/or colloids during and after surgery, hypothermia, acidosis, foreign materials, etc. [2–5]. At the same time different studies have shown that re-exploration for bleeding has a negative impact on patient outcome, increasing the morbidity rate and in-hospital mortality [6,7]. The systemic infusion of antifibrinolytic agents has been used effectively to reduce post-operative blood loss and transfusion requirements in different kinds of surgical procedures Received 10 May 2012; received in revised form 20 June 2012; accepted 29 June 2012; available online 28 July 2012 ∗
Corresponding author at: S.Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, Bologna Italy. Tel.: +39 0516364206; fax: +39 0516364199. E-mail address: [email protected] (A. Dell’Amore).
[2,8,9]. Therefore, the systemic infusion of fibrinolytic inhibitors increases the thrombotic tendency with a significant risk of thromboembolic complications. To avoid or reduce these theoretical risks the effect of topical application of tranexamic-acid (TA) has been studied in cardiac and non-cardiac surgery with encouraging results [8–13]. The aim of our study was to understand whether the topical application of TA is effective reducing post-operative blood loss and blood transfusion requirements in thoracic surgery. To our knowledge, this is the first study on the effectiveness of topical antifibrinolytics therapy in thoracic surgery.
Materials and Methods From May 2010 to February 2012 all patients scheduled for pulmonary resection (lobectomy, atypical resection) in our department were scrutinised for eligibility enrolment. The exclusions criteria of the study were: preoperative anti-platelets or chronic anticoagulant therapy, liver cirrhosis, renal failure (creatinine >2 mg/dl), primary
© 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.06.016
bleeding diathesis (haemophilia, etc.), known allergy to TA, preoperative documented ischaemic heart disease, presence of coronary or other arterial stents, redo surgery, pleuro/pneumonectomy or pleurectomy/decortication for mesothelioma, pleurectomy/decortication for empyema, thoracoscopic surgery, pneumonectomy, neoadjuvant chemotherapy. Following these criteria, 89 patients were randomly allocated to one of the two study groups. The patients enrolled in group-A (45 patients) received 5 g (10 fl) of TA (Ugurol, Rottapharm S.P.A., Milano, Italy) diluted in 100 ml of sterile saline solution. Group-B (44 patients) received 100 ml of normal sterile saline solution as placebo. The study was performed as a prospective randomised double blind placebo controlled investigation. The first step was the enrolment of the patients in the study following the inclusion and exclusion criteria. The second step was the randomisation. The day before surgery, the patients were randomised using the random number-tables by a research medical doctor (GC). After randomisation, the same doctor (GC) prepared the solutions (TA or placebo) in a sterile 100 ml bottles. The day of surgery the bottles were delivered to the operating room. The operation room staff, the ward staff and the intensive care unit staff were blinded regarding the study solution. In all patients only two thoracic surgeons (AD, GD) were responsible for the surgical haemostasis and closure of the chest at the end of the operation. The solution at room temperature was poured into the chest at the end of the lung resection and radical lymphadenectomy, after careful and complete haemostasis and aerostasis, before the placement of the paravertebral catheter and the chest tubes. After chest closure, the thoracic drains were connected to a collection system on continuous suction at −20 cmH2 O. The mean time between the solution irrigation and the drains suction was 26.8 ± 14.8 min. There was no systemic appliance of TA or other antifibrinolytic drugs in any patient. Red blood cell (RBC) transfusion was given when the haemoglobin level decreased to less than 8 g/dl and/or hematocrit to less than 25% during surgery or in the post-operative period. Fresh frozen plasma was transfused if the post-operative blood loss increased to 150 ml/h for three consecutive hours or when the International Normalized Ratio (INR) was >1.8. In the case of continuous blood loss and a platelet count less than 60 × 109 l−1 , platelet concentrate was transfused. Re-operation for bleeding was performed in the case of chest drainage >300 ml/h for two consecutive hours or in the case of haemodynamic instability associated with bleeding >200 ml/h or massive pleural effusion documented on post-operative chest X-ray or computed tomography. Haemoglobin level (Hb, g/dl), haematocrit value (Hct, %), platelet count (109 l−1 ), INR, partial thromboplastin time (PTT, s) and fibrinogen level (mg/dl) were measured before the operation and after the patient’s arrival in the intensive care unit or the ward. Postoperative blood loss from the chest tube was recorded at 12 and 24 h from chest closure.
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707
Table 1. Patient Demographics. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Age (year) Gender Active smokers History of smoke Diabetes Hypertension COPD Low FEV1
65.8 ± 7.9 29 male (66%) 21 (48%) 34 (77.3%) 9 (20.9%) 29 (66%) 24 (54.5) 9 (20.9%)
67.7 ± 6.4 31 male (72%) 19 (44.2%) 31 (72%) 7 (16.3%) 28 (65%) 26 (61%) 7 (16.3%)
ns ns ns ns ns ns ns ns
COPD: Chronic Obstructive Pulmonary Disease; FEV1 : Forced Expiratory Volume in 1 s.
Statistical analysis was performed using SPSS (Statistical Package for Social Science) version 19.0 for windows (SPSS, Inc, Chicago, IL). Continuous variables were given as mean ± SD, categorical variables were given as percentages. The independent-sample t-test was used to compare continuous variables and the χ2 -test for categorical variables. A p-value less than 0.05 was considered to be statistically significant.
Results The demographic characteristics of both groups are reported in Table 1. There was no statistically significant difference between the group’s risk factors or demographic data. Two patients, one from each group, suffered major post-operative bleeding requiring surgical revision. In both cases an active surgical source of bleeding was discovered and the patients were thus withdrawn from the study. A total of 87 patients were therefore enrolled in the study, 44 patients in group-A and 43 patients in groupB. Globally we performed 68 lobectomies, 16 wedge or atypical resections and 3 bi-lobectomies. In all patients we performed radical lymphadenectomy, even after limited resections. Both groups were comparable with respect to operative data without statistical differences as shown in Table 2. The statistical analysis between the pre-operative and post-operative haemoglobin concentration, haematocrit value, platelet count, INR, fibrinogen levels and PTT of both groups showed no significant difference, as reported in Tables 3 and 4. Table 2. Operative Results. Variables Type of resection Lobectomies Wedge resections Bi-lobectomies Histology Adenocarcinomas Squamous cell carcinomas Carcinoids Pathological stage I II III
Group-A (n = 44)
Group-B (n = 43)
p-Value
35 (79.5%) 7 (15.9%) 2 (4.5%)
33 (76.7%) 9 (20.9%) 2 (4.6%)
ns ns ns
28 (63.6%) 15 (34.1) 1 (2.2%)
30 (69.8%) 12 (27.9%) 1 (2.3%)
ns ns ns
15 (34.1%) 17 (38.6%) 7 (15.9%)
13 (30%) 25 (58%) 5 (11.6%)
ns ns ns
ORIGINAL ARTICLE
Heart, Lung and Circulation 2012;21:706–710
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Dell’Amore et al. Can Topical Application of Tranexamic Acid Reduce Blood Loss
Heart, Lung and Circulation 2012;21:706–710
Table 3. Pre-operative Haematological Profile. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Haemoglobin (g/dl) Haematocrit (%) Platelet INR PTT (s) Fibrinogen (mg/l)
13.3 ± 1.8 39 ± 2.6 197 × 109 ± 40.7 1.2 ± 0.1 41.8 ± 3.4 327.1 ± 48.3
13.2 ± 1.9 38.5 ± 3.1 181 × 109 ± 50.4 1.3 ± 0.1 42.7 ± 2.1 331.9 ± 51.7
ns ns ns ns ns ns
Table 4. Post-operative Haematological and Clinical Profile. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Haemoglobin (g/dl) Haematocrit (%) Platelets INR PTT (s) Fibrinogen (mg/l)
11.5 ± 1.5 33 ± 3.0 118.9 × 109 ± 50 1.4 ± 0.1 43.4 ± 2.9 343.8 ± 54
11.6 ± 1.5 32 ± 3.7 131.6 × 109 ± 17.2 1.4 ± 0.1 44.5 ± 2.4 342.6 ± 58
ns ns ns ns ns ns
Table 5. Post-operative Clinical Parameters. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Blood loss 12 h (ml) Blood loss 24 h (ml) Transfused RBC (ml) (Mean Unit for Patient) Drains removal (days) Hospital stay (days)
298.2 ± 73 589.5 ± 109.6 450.8 ± 155 (1.5 U × Pt)
458.1 ± 89 633.72 ± 184.4 580.4 ± 256 (1.9 U × Pt)
0.02 0.06 0.04
3.6 ± 1.1 8.5 ± 2.6
3.9 ± 1.1 8.7 ± 2.7
ns ns
RBC: red blood cells.
Nevertheless, the blood loss through the chest drains in the first 12 h was significantly lower in group-A (298.2 ± 73 vs 458.1 ± 89, p < 0.02). The same trend was observed in the in the first 24 h chest tube drainage but without reaching true statistical significance (589.5 ± 109.6 vs 633.72 ± 184.4, p = 0.06) (Table 5). There was no statistical difference between the two groups in terms of time of chest tube removal and hospital stay, as summarised in Table 5. In group-A the need for blood transfusion was statistically lower than in group-B (1.5 U of RBC vs 1.9 U of RBC, p < 0.04). The use of other banked donor blood products was not significantly different between the two groups. Fresh frozen plasma was infused in one patient (2.2%) in the group-A and in one patient (2.3%) in group-B (p = ns). Platelet replacement was never used in either study group (p = ns). We had no operative death and no side effects, toxicity or thromboembolic events related with the topical use of TA. The major post-operative complications were three cases of bacterial pneumonia (2 group-A, 1 group-B), 1 respiratory failure with prolonged ventilation (groupA), seven prolonged air-leaks (4 group-A, 3 group-B), 15 supraventricular arrhythmias (7 group-A, 8 group-B), one acute myocardial infarction (group-B) without statistical difference between the groups.
Conclusions Re-thoracotomy for post-operative haemorrhage is a well known complication in cardio-thoracic surgery [6,7]. In thoracic surgery the reported incidence of re-exploration for bleeding ranges from 1 to 3.7% and the need for
blood transfusion ranges from 20 to 52% in haemorrhagic patients [13,14]. Re-operation for bleeding is associated with an increased incidence of post-operative complications such as infection, sepsis, renal failure, respiratory complications, acute lung injuries and wound dehiscence. Haemorrhagic patients have a longer hospital stay, need intensive care unit admission more frequently with higher hospitalisation costs. It has also been demonstrated that re-exploration is associated with increased mortality [6,7]. Different peri-operative pharmacological protocols have therefore been applied to reduce coagulation defects and bleeding complications, in particular after cardiac surgery [1,2,8]. The systemic infusion of antifibrinolytics drugs has proved to be effective in reducing post-operative bleeding and transfusion requirements after different surgical procedures [8,9,12,13]. In 2001, Ali Bedirhan et al. [13] published the results of a randomised double-blind study on the systemic administration of aprotinin to reduce post-operative bleeding and blood transfusion in thoracic surgery. They showed a significant reduction in perioperative use of blood products and a marked reduction of total chest tube drainage and post-operative blood loss during major thoracic operations. However, a large number of studies have raised growing concerns about serious adverse effects observed following the systemic infusion of antifibrinolytics agents, in particular aprotinin. Increased mortality, thromboembolic events, seizure, acute renal failure, anaphylactic reactions, graft vessels occlusion and acute myocardial infarction have been documented [8,9,15]. In order to avoid or reduce these serious complications, various authors have studied the efficacy of
Dell’Amore et al. Can Topical Application of Tranexamic Acid Reduce Blood Loss
the topical application of antifibrinolytic agents such as aprotinin and tranexamic acid [9–12]. In particular some interesting studies come from cardiac surgery. De Bonis et al. [10] reported a significant reduction of post-operative bleeding in patients undergoing coronary by-pass operation who received 1 g of intrapericardial tranexamic acid before chest closure. In particular, they demonstrated that the haemostatic effect of 1% solution of TA topically applied in the pericardial cavity lasted for 3–4 h. This observation agrees with the results obtained in different studies in which the reduction of bleeding is statistically significant in the first post-operative 12 h. In 2007, Baric et al. [11] reported a statistical reduction of post-operative bleeding in the first 12 and 24 h after cardiac surgery using topical application of aprotinin or tranexamic acid versus placebo. Both antifibrinolytics agents efficiently reduced blood loss with no difference between aprotinin or tranexamic acid effectiveness. Our results further confirm these observations. Indeed we found a statistical difference (p < 0.02) between group-A and group-B in terms of blood loss in the first 12-h. If we consider the blood loss in the first 24-h there is a trend towards a lower bleeding tendency in group-A but without reaching true statistical difference (p = 0.06). In 2009, a systematic review and meta-analysis of the literature concluded that the topical application of TA or aprotinin in cardiac surgery patients can reduce post-operative blood loss and the volume of allogenic red blood cell transfusion to a degree that is both statistically and clinically significant [9]. In our study the patients in group-B received a statistically significant higher volume of transfused RBC compared to group-A (p < 0.04). Conversely, the incidence of RBC transfusion was not statistically different between the two groups. After surgical insult, the serous membranes (pleura, pericardium, peritoneum, meninges) release a high amount of plasminogen activators which can lead to increased local fibrinolytic activity and thus excessive bleeding [16,17]. In the literature it has been hypothesized that the topical delivery of antifibrinolytic agents can directly target the source of bleeding, reducing the local activation of the fibrinolytic process. Conversely, the serous membranes act as a natural barrier that minimise the systemic absorption of the antifibrinolytic agents, avoiding their side effects [9,16,17]. Until now no studies have reported any side effects after the topical application of TA or aprotinin. Some authors have tested the absorption of the drugs using blood samples. They reported no detectable systemic absorption [9,10]. These results confirm the safety of the topical application of these agents. What is the correct and sufficient topical concentration of TA to be delivered is, in our opinion, still not clear. In the pericardial cavity some authors used 1 g of TA in 100 ml of normal saline solution, others used 2.5 g of TA in 250 ml of saline solution or 2 g of TA in 100 ml of saline solution with concordant results [9–12]. In our study we used a dose of 5 g of TA in 100 ml of saline solution. The use of this higher dosage of TA is arbitrary, based on the wider contact surface of the pleura space compared with the pericardial cavity. In our experience too, we had no side effects related to TA application. To our knowledge, this is
the first study in thoracic surgery on the topical application of TA and thus we have no terms of comparison. The present study has several limitations. The study population is relatively small, and we excluded patients at high risk for bleeding and patients with planned extensive surgical procedures. In these patients the topical effect of TA would be more evident. In this study we preferred to select patients with a low risk of major bleeding to obtain a homogeneous population, limiting confounding factors such as complex intra-operative haemostasis, pharmacological coagulopathies, etc. The intra-operative dosage of TA is somewhat arbitrary. In thoracic surgery it is difficult to discern between the haemorrhagic and non-haemorrhagic serous component of thoracic drainage. In conclusion the topical use of TA to the pleural space after lung surgery significantly reduces blood loss and the volume of RBC post-operative transfusion. The topical administration of TA is safe without increasing the risk of post-operative complications related to pharmacological side-effects. In our opinion further studies are needed to clarify some important aspects such as the real systemic absorption and dose-response analysis of different topic concentrations of TA. In thoracic surgery it could be of interest to analyse the effectiveness of intrapleural TA in patients in whom a generalised oozing of the operating field cannot be related to a demonstrable surgical source of bleeding, for example after decortication, pleurectomy, chest wall surgery or in patients treated chronically with antiplatelet or anticoagulant agents in whom discontinuation of the therapy is not safe.
References [1] Litle VR, Swanson SJ. Postoperative bleeding: coagulopathy, bleeding, hemothorax. Thorac Surg Clin 2006;16:203–7. [2] Pavie A, Szefner J, Leger P, Gandjbakhch L. Preventing, minimizing and managing postoperative bleeding. Ann Thorac Surg 1999;68:705–10. [3] Tanaka KA, Key NS, Levy JH. Blood coagualtion: hemastasis and thrombin regulation. Anesth Analg 2009;108:143–46. [4] Hardy JF, Desroches J. Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anaesth 1992;39:353–65. [5] Fries D, Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. Br J Anaesth 2010;105:116–21. [6] Kristensen KL, Rauer LJ, Mortensen PE, Kjeldsen BJ. Reoperation for bleeding in cardiac surgery. Interact Cardiovasc Surg 2012;24:1–5. [7] Ranucci, Bozzetti G, Ditta A, Cotza M, Carboni G, Ballotta A. Surgical reexploration after cardiac operations: why a worse outcome? Ann Thorac Surg 2008;86:1557–62. [8] Dunn CJ, Goa KL. Tranexanic acid: a review of its use in surgery and other indication. Drugs 1999;57:1005–32. [9] Abrishami A, Chung F, Wong J. Topical application of antifibrinolytic drugs for on-pump cardiac surgery: a systematic review and meta-analysis. Can J Anesth 2009;56:202–12. [10] De Bonis M, Cavaliere F, Alessandrini F, Lapenna E, Santarelli F, Moscato U, et al. Topical use of tranexamic acid in coronary artery bypass operations: a double-blind, prospective, randomized, placebeo-controlled study. J Thorac Cardiovasc Surg 2000;119:575–80.
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[11] Baric D, Biocina B, Unic D, Sutlic Z, Rudez I, Vraca VB, et al. Topical use of antifibrinolytic agents reduces postoperative bleeding: a double-blind, prospective, randomized study. Eur J Cardiothorac Surg 2007;31:366–71. [12] Spegar J, Vanek T, Snircova J, Fajt R, Straka Z, Pazderkova P, et al. Local and sustemic application of tranexamic acid in heart valve surgery: a prospective, randomized, double blind LOST study. J Thromb Thrombolysis 2011;32:303–10. [13] Berdirhan MA, Turna A, Yagan N, Tasci O. Aprotinin reduces postoperative bleeding and the need for blood products in thoracic surgery: results of a randomized double-blind study. Eur J Cardiothorac Surg 2001;20:1122–7.
[14] Sirbu H, Bush T, Aleksic I, Lofti S, Ruschewski W, Dalichau H. Chest re-exploration for complications after lung surgery. Thorac Cardiovasc Surg 1999;47:73–6. [15] Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801–13. [16] Wang NS. Anatomy and physiology of the pleural space. Clin Chest Med 1985;6:3–16. [17] Khali PN, Ismail M, Kalmar P, von Knobelsdorff G, Marx G. Activation of fibrinolysis in the pericardial cavity after cardiopulmonary bypass. Thromb Haemost 2004;92:568–74.
Original Article
Can Topical Application of Tranexamic Acid Reduce Blood Loss in Thoracic Surgery? A Prospective Randomised Double Blind Investigation Andrea Dell’Amore, MD ∗ , Guido Caroli, MD, Asadi Nizar, MD, Nicola Cassanelli, MD, Giulia Luciano, MD, Domenico Greco, MD, Giampiero Dolci, MD, Alessandro Bini, PhD and Franco Stella, PhD Thoracic Surgery Operative Unit, S.Orsola Malpighi University Hospital, Bologna, Italy
Objective: The systemic or topical use of antifibrinolytic agents is effective in reducing postoperative bleeding and blood product transfusion in cardiac surgery. We sought to study the effect of the topical application of tranexamic acid into the pleural space to reduce postoperative bleeding after lung surgery. Methods: This was a prospective randomised double blind placebo controlled investigation. From May-2010 to February-2012, 89-patients, scheduled for pulmonary resection, were randomly allocated to one of the two study groups. Group-A received 5 g of tranexamic-acid in 100 ml of saline solution. Group-B received 100 ml of saline solution as placebo. Results: The blood loss in the first 12-h was significantly less in group-A. The same trend was observed in the first 24-h but without reaching a true statistical significance. The mean volume of blood transfusion was statistically lower in group-A. The analysis between post-operative haemoglobin concentration, haematocrit, platelet-count, internationalnormalised-ratio, fibrinogen and partial-thromboplastin-time of both groups was not statistically significant. Conclusion: In our experience, the topical use of tranexamic-acid after lung surgery reduces postoperative bleeding and blood transfusion volume. The topical administration of tranexamic-acid is safe without increasing the risk of post-operative complications related to pharmacological side-effects. (Heart, Lung and Circulation 2012;21:706–710) © 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Postoperative bleeding; Thoracic surgery; Antifibrinolityc agents; Tranexamic acid; Blood saving
Introduction
A
ctivation of fibrinolysis during and after surgery is a well known phenomenon [1,2]. Several mechanisms are related to coagulation defect: surgical trauma, operative blood loss with consumption of clotting factors and platelets, administration of crystalloids and/or colloids during and after surgery, hypothermia, acidosis, foreign materials, etc. [2–5]. At the same time different studies have shown that re-exploration for bleeding has a negative impact on patient outcome, increasing the morbidity rate and in-hospital mortality [6,7]. The systemic infusion of antifibrinolytic agents has been used effectively to reduce post-operative blood loss and transfusion requirements in different kinds of surgical procedures Received 10 May 2012; received in revised form 20 June 2012; accepted 29 June 2012; available online 28 July 2012 ∗
Corresponding author at: S.Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, Bologna Italy. Tel.: +39 0516364206; fax: +39 0516364199. E-mail address: [email protected] (A. Dell’Amore).
[2,8,9]. Therefore, the systemic infusion of fibrinolytic inhibitors increases the thrombotic tendency with a significant risk of thromboembolic complications. To avoid or reduce these theoretical risks the effect of topical application of tranexamic-acid (TA) has been studied in cardiac and non-cardiac surgery with encouraging results [8–13]. The aim of our study was to understand whether the topical application of TA is effective reducing post-operative blood loss and blood transfusion requirements in thoracic surgery. To our knowledge, this is the first study on the effectiveness of topical antifibrinolytics therapy in thoracic surgery.
Materials and Methods From May 2010 to February 2012 all patients scheduled for pulmonary resection (lobectomy, atypical resection) in our department were scrutinised for eligibility enrolment. The exclusions criteria of the study were: preoperative anti-platelets or chronic anticoagulant therapy, liver cirrhosis, renal failure (creatinine >2 mg/dl), primary
© 2012 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2012.06.016
bleeding diathesis (haemophilia, etc.), known allergy to TA, preoperative documented ischaemic heart disease, presence of coronary or other arterial stents, redo surgery, pleuro/pneumonectomy or pleurectomy/decortication for mesothelioma, pleurectomy/decortication for empyema, thoracoscopic surgery, pneumonectomy, neoadjuvant chemotherapy. Following these criteria, 89 patients were randomly allocated to one of the two study groups. The patients enrolled in group-A (45 patients) received 5 g (10 fl) of TA (Ugurol, Rottapharm S.P.A., Milano, Italy) diluted in 100 ml of sterile saline solution. Group-B (44 patients) received 100 ml of normal sterile saline solution as placebo. The study was performed as a prospective randomised double blind placebo controlled investigation. The first step was the enrolment of the patients in the study following the inclusion and exclusion criteria. The second step was the randomisation. The day before surgery, the patients were randomised using the random number-tables by a research medical doctor (GC). After randomisation, the same doctor (GC) prepared the solutions (TA or placebo) in a sterile 100 ml bottles. The day of surgery the bottles were delivered to the operating room. The operation room staff, the ward staff and the intensive care unit staff were blinded regarding the study solution. In all patients only two thoracic surgeons (AD, GD) were responsible for the surgical haemostasis and closure of the chest at the end of the operation. The solution at room temperature was poured into the chest at the end of the lung resection and radical lymphadenectomy, after careful and complete haemostasis and aerostasis, before the placement of the paravertebral catheter and the chest tubes. After chest closure, the thoracic drains were connected to a collection system on continuous suction at −20 cmH2 O. The mean time between the solution irrigation and the drains suction was 26.8 ± 14.8 min. There was no systemic appliance of TA or other antifibrinolytic drugs in any patient. Red blood cell (RBC) transfusion was given when the haemoglobin level decreased to less than 8 g/dl and/or hematocrit to less than 25% during surgery or in the post-operative period. Fresh frozen plasma was transfused if the post-operative blood loss increased to 150 ml/h for three consecutive hours or when the International Normalized Ratio (INR) was >1.8. In the case of continuous blood loss and a platelet count less than 60 × 109 l−1 , platelet concentrate was transfused. Re-operation for bleeding was performed in the case of chest drainage >300 ml/h for two consecutive hours or in the case of haemodynamic instability associated with bleeding >200 ml/h or massive pleural effusion documented on post-operative chest X-ray or computed tomography. Haemoglobin level (Hb, g/dl), haematocrit value (Hct, %), platelet count (109 l−1 ), INR, partial thromboplastin time (PTT, s) and fibrinogen level (mg/dl) were measured before the operation and after the patient’s arrival in the intensive care unit or the ward. Postoperative blood loss from the chest tube was recorded at 12 and 24 h from chest closure.
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Table 1. Patient Demographics. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Age (year) Gender Active smokers History of smoke Diabetes Hypertension COPD Low FEV1
65.8 ± 7.9 29 male (66%) 21 (48%) 34 (77.3%) 9 (20.9%) 29 (66%) 24 (54.5) 9 (20.9%)
67.7 ± 6.4 31 male (72%) 19 (44.2%) 31 (72%) 7 (16.3%) 28 (65%) 26 (61%) 7 (16.3%)
ns ns ns ns ns ns ns ns
COPD: Chronic Obstructive Pulmonary Disease; FEV1 : Forced Expiratory Volume in 1 s.
Statistical analysis was performed using SPSS (Statistical Package for Social Science) version 19.0 for windows (SPSS, Inc, Chicago, IL). Continuous variables were given as mean ± SD, categorical variables were given as percentages. The independent-sample t-test was used to compare continuous variables and the χ2 -test for categorical variables. A p-value less than 0.05 was considered to be statistically significant.
Results The demographic characteristics of both groups are reported in Table 1. There was no statistically significant difference between the group’s risk factors or demographic data. Two patients, one from each group, suffered major post-operative bleeding requiring surgical revision. In both cases an active surgical source of bleeding was discovered and the patients were thus withdrawn from the study. A total of 87 patients were therefore enrolled in the study, 44 patients in group-A and 43 patients in groupB. Globally we performed 68 lobectomies, 16 wedge or atypical resections and 3 bi-lobectomies. In all patients we performed radical lymphadenectomy, even after limited resections. Both groups were comparable with respect to operative data without statistical differences as shown in Table 2. The statistical analysis between the pre-operative and post-operative haemoglobin concentration, haematocrit value, platelet count, INR, fibrinogen levels and PTT of both groups showed no significant difference, as reported in Tables 3 and 4. Table 2. Operative Results. Variables Type of resection Lobectomies Wedge resections Bi-lobectomies Histology Adenocarcinomas Squamous cell carcinomas Carcinoids Pathological stage I II III
Group-A (n = 44)
Group-B (n = 43)
p-Value
35 (79.5%) 7 (15.9%) 2 (4.5%)
33 (76.7%) 9 (20.9%) 2 (4.6%)
ns ns ns
28 (63.6%) 15 (34.1) 1 (2.2%)
30 (69.8%) 12 (27.9%) 1 (2.3%)
ns ns ns
15 (34.1%) 17 (38.6%) 7 (15.9%)
13 (30%) 25 (58%) 5 (11.6%)
ns ns ns
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Table 3. Pre-operative Haematological Profile. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Haemoglobin (g/dl) Haematocrit (%) Platelet INR PTT (s) Fibrinogen (mg/l)
13.3 ± 1.8 39 ± 2.6 197 × 109 ± 40.7 1.2 ± 0.1 41.8 ± 3.4 327.1 ± 48.3
13.2 ± 1.9 38.5 ± 3.1 181 × 109 ± 50.4 1.3 ± 0.1 42.7 ± 2.1 331.9 ± 51.7
ns ns ns ns ns ns
Table 4. Post-operative Haematological and Clinical Profile. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Haemoglobin (g/dl) Haematocrit (%) Platelets INR PTT (s) Fibrinogen (mg/l)
11.5 ± 1.5 33 ± 3.0 118.9 × 109 ± 50 1.4 ± 0.1 43.4 ± 2.9 343.8 ± 54
11.6 ± 1.5 32 ± 3.7 131.6 × 109 ± 17.2 1.4 ± 0.1 44.5 ± 2.4 342.6 ± 58
ns ns ns ns ns ns
Table 5. Post-operative Clinical Parameters. Variables
Group-A (n = 44)
Group-B (n = 43)
p-Value
Blood loss 12 h (ml) Blood loss 24 h (ml) Transfused RBC (ml) (Mean Unit for Patient) Drains removal (days) Hospital stay (days)
298.2 ± 73 589.5 ± 109.6 450.8 ± 155 (1.5 U × Pt)
458.1 ± 89 633.72 ± 184.4 580.4 ± 256 (1.9 U × Pt)
0.02 0.06 0.04
3.6 ± 1.1 8.5 ± 2.6
3.9 ± 1.1 8.7 ± 2.7
ns ns
RBC: red blood cells.
Nevertheless, the blood loss through the chest drains in the first 12 h was significantly lower in group-A (298.2 ± 73 vs 458.1 ± 89, p < 0.02). The same trend was observed in the in the first 24 h chest tube drainage but without reaching true statistical significance (589.5 ± 109.6 vs 633.72 ± 184.4, p = 0.06) (Table 5). There was no statistical difference between the two groups in terms of time of chest tube removal and hospital stay, as summarised in Table 5. In group-A the need for blood transfusion was statistically lower than in group-B (1.5 U of RBC vs 1.9 U of RBC, p < 0.04). The use of other banked donor blood products was not significantly different between the two groups. Fresh frozen plasma was infused in one patient (2.2%) in the group-A and in one patient (2.3%) in group-B (p = ns). Platelet replacement was never used in either study group (p = ns). We had no operative death and no side effects, toxicity or thromboembolic events related with the topical use of TA. The major post-operative complications were three cases of bacterial pneumonia (2 group-A, 1 group-B), 1 respiratory failure with prolonged ventilation (groupA), seven prolonged air-leaks (4 group-A, 3 group-B), 15 supraventricular arrhythmias (7 group-A, 8 group-B), one acute myocardial infarction (group-B) without statistical difference between the groups.
Conclusions Re-thoracotomy for post-operative haemorrhage is a well known complication in cardio-thoracic surgery [6,7]. In thoracic surgery the reported incidence of re-exploration for bleeding ranges from 1 to 3.7% and the need for
blood transfusion ranges from 20 to 52% in haemorrhagic patients [13,14]. Re-operation for bleeding is associated with an increased incidence of post-operative complications such as infection, sepsis, renal failure, respiratory complications, acute lung injuries and wound dehiscence. Haemorrhagic patients have a longer hospital stay, need intensive care unit admission more frequently with higher hospitalisation costs. It has also been demonstrated that re-exploration is associated with increased mortality [6,7]. Different peri-operative pharmacological protocols have therefore been applied to reduce coagulation defects and bleeding complications, in particular after cardiac surgery [1,2,8]. The systemic infusion of antifibrinolytics drugs has proved to be effective in reducing post-operative bleeding and transfusion requirements after different surgical procedures [8,9,12,13]. In 2001, Ali Bedirhan et al. [13] published the results of a randomised double-blind study on the systemic administration of aprotinin to reduce post-operative bleeding and blood transfusion in thoracic surgery. They showed a significant reduction in perioperative use of blood products and a marked reduction of total chest tube drainage and post-operative blood loss during major thoracic operations. However, a large number of studies have raised growing concerns about serious adverse effects observed following the systemic infusion of antifibrinolytics agents, in particular aprotinin. Increased mortality, thromboembolic events, seizure, acute renal failure, anaphylactic reactions, graft vessels occlusion and acute myocardial infarction have been documented [8,9,15]. In order to avoid or reduce these serious complications, various authors have studied the efficacy of
Dell’Amore et al. Can Topical Application of Tranexamic Acid Reduce Blood Loss
the topical application of antifibrinolytic agents such as aprotinin and tranexamic acid [9–12]. In particular some interesting studies come from cardiac surgery. De Bonis et al. [10] reported a significant reduction of post-operative bleeding in patients undergoing coronary by-pass operation who received 1 g of intrapericardial tranexamic acid before chest closure. In particular, they demonstrated that the haemostatic effect of 1% solution of TA topically applied in the pericardial cavity lasted for 3–4 h. This observation agrees with the results obtained in different studies in which the reduction of bleeding is statistically significant in the first post-operative 12 h. In 2007, Baric et al. [11] reported a statistical reduction of post-operative bleeding in the first 12 and 24 h after cardiac surgery using topical application of aprotinin or tranexamic acid versus placebo. Both antifibrinolytics agents efficiently reduced blood loss with no difference between aprotinin or tranexamic acid effectiveness. Our results further confirm these observations. Indeed we found a statistical difference (p < 0.02) between group-A and group-B in terms of blood loss in the first 12-h. If we consider the blood loss in the first 24-h there is a trend towards a lower bleeding tendency in group-A but without reaching true statistical difference (p = 0.06). In 2009, a systematic review and meta-analysis of the literature concluded that the topical application of TA or aprotinin in cardiac surgery patients can reduce post-operative blood loss and the volume of allogenic red blood cell transfusion to a degree that is both statistically and clinically significant [9]. In our study the patients in group-B received a statistically significant higher volume of transfused RBC compared to group-A (p < 0.04). Conversely, the incidence of RBC transfusion was not statistically different between the two groups. After surgical insult, the serous membranes (pleura, pericardium, peritoneum, meninges) release a high amount of plasminogen activators which can lead to increased local fibrinolytic activity and thus excessive bleeding [16,17]. In the literature it has been hypothesized that the topical delivery of antifibrinolytic agents can directly target the source of bleeding, reducing the local activation of the fibrinolytic process. Conversely, the serous membranes act as a natural barrier that minimise the systemic absorption of the antifibrinolytic agents, avoiding their side effects [9,16,17]. Until now no studies have reported any side effects after the topical application of TA or aprotinin. Some authors have tested the absorption of the drugs using blood samples. They reported no detectable systemic absorption [9,10]. These results confirm the safety of the topical application of these agents. What is the correct and sufficient topical concentration of TA to be delivered is, in our opinion, still not clear. In the pericardial cavity some authors used 1 g of TA in 100 ml of normal saline solution, others used 2.5 g of TA in 250 ml of saline solution or 2 g of TA in 100 ml of saline solution with concordant results [9–12]. In our study we used a dose of 5 g of TA in 100 ml of saline solution. The use of this higher dosage of TA is arbitrary, based on the wider contact surface of the pleura space compared with the pericardial cavity. In our experience too, we had no side effects related to TA application. To our knowledge, this is
the first study in thoracic surgery on the topical application of TA and thus we have no terms of comparison. The present study has several limitations. The study population is relatively small, and we excluded patients at high risk for bleeding and patients with planned extensive surgical procedures. In these patients the topical effect of TA would be more evident. In this study we preferred to select patients with a low risk of major bleeding to obtain a homogeneous population, limiting confounding factors such as complex intra-operative haemostasis, pharmacological coagulopathies, etc. The intra-operative dosage of TA is somewhat arbitrary. In thoracic surgery it is difficult to discern between the haemorrhagic and non-haemorrhagic serous component of thoracic drainage. In conclusion the topical use of TA to the pleural space after lung surgery significantly reduces blood loss and the volume of RBC post-operative transfusion. The topical administration of TA is safe without increasing the risk of post-operative complications related to pharmacological side-effects. In our opinion further studies are needed to clarify some important aspects such as the real systemic absorption and dose-response analysis of different topic concentrations of TA. In thoracic surgery it could be of interest to analyse the effectiveness of intrapleural TA in patients in whom a generalised oozing of the operating field cannot be related to a demonstrable surgical source of bleeding, for example after decortication, pleurectomy, chest wall surgery or in patients treated chronically with antiplatelet or anticoagulant agents in whom discontinuation of the therapy is not safe.
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