JBI Database of Systematic Reviews & Implementation Reports JBLOLL ; 11(5)

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1 Effectiveness of intravenous Tranexamic Acid (TXA) administration in managing perioperative blood loss in patients undergoing spine surgery: a systematic review protocol Jennifer Badeaux CRNA, MN 1 Diane Hawley PhD, RN, ACNS-BC, CCNS, CNE 1 1. Texas Christian University (TCU) Center for Evidence Based Practice and Research: A Collaborating Center of the Joanna Briggs Institute Corresponding Author: Jennifer Badeaux jbadea@lsuhsc.edu Review question/objective Is the intravenous administration of tranexamic acid (TXA) effective in the management of blood loss during the perioperative phase of spine surgery? The objective of this review is to identify the effectiveness of intravenous TXA administration in managing perioperative blood loss in patients undergoing spine surgery. Background The fundamental role of the spinal column as the human body s supporting axis has been a subject of medical study for centuries. References to spinal column treatment date back to ancient times. Hippocrates ( B.C.) is regarded as the father of spine surgery because of the two apparatuses he discovered to reduce displaced vertebrae. They are considered to be the precursors to the sophisticated techniques used in spine surgery today. 1 In 1814, Clyne was documented to have made the first incision into the spine which subsequently resulted in complications associated with blood loss. 2 Today, patients of all ages undergo an array of spinal procedures with prodigious results, yet practitioners continue to fight the battle of surgical blood loss which can lead to negative patient outcomes. 3 The spine is composed of vertebrae, intervertebral discs, the spinal cord, and vascular structures which are all supported by ligaments. There are a total of 33 spinal vertebrae which include seven cervical, 12 thoracic, five lumbar, five sacral and four coccygeal vertebrae. Numerous surgical procedures are performed on all areas of the spine which include but are not limited to anterior and posterior spinal Page 123

2 fusions, microdiscectomy, laminectomy, and kyphoplasty. The most common indications for spinal surgical procedures are: spinal instability, fracture, stenosis, degenerative disease, tumor resection or removal, disc herniation, vertebral osteomylitis, tuberculosis, scoliosis and failed previous spinal fusions. 4 Improvements in surgical techniques and technologies which have evolved over centuries have afforded surgeons the opportunity to perform extremely complex spinal surgeries on patients of any age. Although spinal surgery is performed routinely, it is associated with a considerable amount of blood loss and subsequent allogeneic blood transfusions. This is particularly true for surgical procedures performed for spinal malformation, procedures involving bone grafting from the pelvic bone, metal implantation, and combined anterior and posterior spinal procedures. 5 Several patient and procedural factors are known to affect intraoperative and postoperative blood loss, which will be collectively referred to as perioperative blood loss in this review. Contributing patient factors are patient height, perioperative mean arterial blood pressure and coagulation status. 6 Contributing procedural factors include length and technique of surgical procedure, number of vertebral levels involved, anesthetic technique, and use of anti-fibrinolytic medications. 3 Blood loss in spinal surgery is variable and can lead to devastating outcomes if it is not controlled. Large-vein bleeding is the major source of blood loss and its persistence can lead to enhanced fibrinolysis which is a potential contributing factor to blood loss during spinal surgery. 6 Although the cause of blood loss is multifactorial, the initiation of blood clotting and fibrinolysis does not discriminate between different age groups. Blood loss associated with spinal surgery is a common cause of patient morbidities such as pulmonary and cerebral edema due to fluid shifts. 5 Blood transfusions are often required to maintain tissue perfusion and prevent end-organ damage when a significant quantity of intra-operative and postoperative blood is lost. Therefore, patients may be subjected to the known risks of blood transfusion including transmission of diseases, transfusion-related reactions, immune suppression, and a decrease in coagulation factors. 8,9 Different techniques including hypotensive anesthesia, preoperative autologous blood donation, acute normovolemic hemodilution, perioperative blood salvage, and the prophylactic administration of synthetic antifibrinolytic drugs such as Aprotinin, epsilon aminocaproic acid (EACA) and TXA have been suggested to minimize intraoperative and postoperative blood loss and the need for blood transfusion requirements during spinal surgery. 7 Aprotinin was shown to be effective in slowing down fibrinolysis, but after it was associated with increased mortality compared with TXA in a large randomized controlled trial in high-risk cardiac surgery (RR = 1.55; 95% CI, it was removed from the market and is no longer commercially available in the United States. 10,11 EACA has been shown to be effective but is associated with hypotension, cardiac arrhythmias, myopathy, and rhabdomyolysis. TXA is also considered to have 10 times the potency of EACA. 12 The perioperative administration of TXA is of particular interest in spinal surgery because it is the most promising alternative to either Aprotinin or EACA due to its fewer side effects and favorable benefit-risk ratio. 13,14 The increased risk of thrombolytic events with TXA has not been shown in clinical trials. 15 TXA is a synthetic derivative of the amino acid lysine and can be used to treat or prevent excessive blood loss during surgery. 16 It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin. 12,15,17 Fibrin is a protein that forms the framework of blood clots. 15 Since the Page 124

3 introduction of TXA in the 1960s, several randomized controlled trials and systematic reviews have been published to support the effectiveness of administering antifibrinolytic drugs to reduce perioperative blood loss in cardiac and orthopedic procedures. 11,16,18 More recent studies have shown the effectiveness of TXA administration in the reduction of blood loss in patients undergoing spine surgeries. Shapiro et al noted that TXA significantly reduced (p<0.001) both perioperative blood loss and allogeneic blood transfusion requirements in spine fusions for treatment of scoliosis in patients with Duchenne muscular dystrophy. 19 Elwatidy et al found that the prophylactic use of high-dose TXA was an effective, safe and inexpensive method for reducing blood loss during and after spine operations. 20 Wong et al reported significantly reduced (p = 0.017) perioperative blood loss during elective posterior thoracic or lumbar spine fusion with instrumentation in adults. 21 A systematic review published in 2008 considered randomized controlled trials to evaluate the effect of antifibrinolytics on perioperative blood loss in children who were 18 years of age or younger undergoing scoliosis surgery. 22 A 2008 meta-analysis conducted by Gill et al evaluated antifibrinolytic agents and the reduction of blood loss and blood transfusions in patients undergoing spine surgery. 23 The meta-analysis focused on all antifibrinolytic agents, whereas this review will focus only on TXA and include not only randomized controlled trials but also observational studies. Keywords Tranexamic acid; Tranexamic; Cyclohexanecarboxylic; Spine surgery; Diskectomy; Laminectomy; Spinal Fusion; Blood loss; perioperative blood loss; intraoperative blood loss; postoperative blood loss; surgical blood loss Inclusion criteria Types of participants This review will consider studies that include patients undergoing any type of spine surgery who received intravenous TXA and all patients with comorbidities. There was no restriction on the age of the patients because the initiation and process of blood clotting and fibrinolysis does not discriminate between different age groups. There is no restriction on the age of these patients. Patients with coagulopathies or those receiving preoperative anticoagulant therapy will be excluded. Types of intervention(s)/phenomena of interest This review will consider studies that evaluate the effectiveness of intravenous TXA administration on perioperative blood loss on all patients undergoing spine surgery. The administration of TXA will be compared to either patients receiving no TXA or a placebo of saline as reported. Studies comparing TXA to other antifibrinolytics will be excluded. Types of outcomes This review will consider studies that include the following outcome measures: intraoperative and postoperative blood loss collectively referred to as perioperative blood loss. The intraoperative blood loss will be measured by weighing surgical sponges, measuring the volume of blood collected in suction Page 125

4 canisters and subtracting the irrigation fluid, and cell salvage devices and reported as estimated blood loss (EBL). Postoperative blood loss is measured from the volume of blood collected in the drainage bag or collecting reservoir. A secondary outcome to be measured will be the intravenous loading and maintenance dose of TXA administered to patients undergoing spine surgery. Types of studies This review will consider any experimental study design including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies and case control studies for inclusion. Prior to inclusion in the review the independent reviewers will use standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Search strategy The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published from 1960 to March 2013 will be considered for inclusion in this review. The year 1960 was the year in which TXA was introduced and first documented in the literature. The search will be limited to English language publications. The databases to be searched include: Academic Search Complete CINAHL Cochrane Library Embase EBSCO Medline ProQuest PubMed Science Direct The search for unpublished studies will include: Google Scholar MEDNAR ProQuest Nursing and Allied Health Source ProQuest Dissertations and Theses OpenSIGLE Virginia Henderson Library Page 126

5 Initial keywords to be used will be: Tranexamic acid or Tranexamic or Cyclohexanecarboxylic Spine surgery OR Diskectomy OR Laminectomy OR Spinal Fusion Blood loss, perioperative blood loss, intraoperative blood loss, postoperative blood loss, surgical blood loss Assessment of methodological quality Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion. Data collection Data will be extracted from papers included in the review will be conducted by two independent reviewers using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. The attempt to contact authors will be made in the event of missing data. Data synthesis Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as weighted mean differences for continuous data of perioperative blood loss and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. If variance appears to exist in subgroups such as types of spine surgery, clinical heterogeneity will be explored. Conflicts of interest No conflicts of interest Acknowledgements Harris College of Nursing and Health Sciences Center for Evidence Based Practice and Research: A Collaborating Center of the Joanna Briggs Institute Page 127

6 References 1. Marketos S, Skiadas P. Hippocrates. The father of spine surgery. Spine. 1999: Knoeller SM, Seifried C. Historical Perspective History of Spine Surgery. Spine. 2000: Mervyn R. Perioperative bleeding in spinal surgery: identification and management. Pharmacological management of perioperative bleeding. CME Network.1996: Wilkey B. In L. Chu L, Fuller A. Spine Surgery. Manual of Clinical Anesthesiology.2012: Urban, MK. The Efficacy of Antifibrinolytics in the Reduction of Blood Loss During Complex Adult Reconstructive Spine Surgery. Spine.2001; 26(10): Florentino-Pineda I, Thompson GH, Poe-Kochert C, Huang RP, Haber LL, Blakemore LC. The Effect of Amicar on Perioperative Blood Loss in Idiopathic Scoliosis: The Results of a Prospective, Randomized Double-Blind Study. Spine.2004; 29(3): Farrokhi MR, Kazemi AP, Eftekharian H, Akbari K. Efficacy of Prophylactic Low Dose of Tranexamic Acid in Spinal Fixation Surgery: A Randomized Clinical Trial. J Neurosurg Anesthesiol. 2011; 23(4): Stefan E, 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 Surgery. 2011;11(29). 9. Yagi M, Hasegawa J, Nagoshi N, Lizuka S. Does the Intraoperative Tranexamic Acid Decrease Operative Blood loss during posterior spinal fusion for treatment of adolescent idiopathic scoliosis. Spine.2012; 37(21): Baldus C, Bridwell K, Lenke LG, Okunadejo GO. Can we Safely Reduce Blood Loss During Lumbar Pedicle Subtraction Osteotomy Procedures Using Tranexamic Acid or Aprotinin? Spine.2010; 35(2): Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. New England Journal of Medicine. 2008; 358(22): Hardy JF, Desroches J. Natural and Synthetic antifirinolytics in cardiac surgery. Canadian Journal Anesthesiology. 1992; 39(4): Cap AP, Baer DG, Orman JA, Aden J, Ryan K, Blackbourne LH. Tranexamic acid for trauma patients: a critical review of the literature. Journal of Trauma. 2011; 71: Ong YL, Hull DR, Mayne EE. Menorrhagia in von Willebrand disease successfully treated with single daily dose tranexamic acid. Haemophilia.1998;4(1): Dunn CJ, Karen GL. Tranexamic acid: a review of its use in surgery and other indications. Drugs.1999; 57(6): Ho KM, Ismail H. Use of intravenous tranexamic acid to reduce allogeneic blood transfusion in total hip and knee arthroplasty: a meta-analysis. Anaesth Intensive Care. 2003;31: Page 128

7 17. Neilipovitz DT, Murto K, Hall L. A randomized trial of tranexamic acid to reduce blood transfusion for scoliosis surgery. Anesthesia Analog.2001;93(1): Zufferey P, Merquiol F, Laporte S, Decousus H, Mismetti P, Auboyer C, et al. Do antifibrinolutics reduce allogenic blood transfusion in orthopedic surgery? Anesthesiology.2006;105: Shapiro F, Zurakowski, D, Sethna, N. Tranexamic acid diminishes intraoperative blood loss and transfusion in spinal fusions for Duchenne muscular dystrophy scoliosis. SPINE.2007;32(20): Elwatidy S, Jamjoom Z, Turkistani A, El-Dawlatly A. Efficacy and safety of prophylactic large dose of tranexamic acid in spine surgery: a prospective, randomized, double-blind, placebo-controlled study. Spine.2008: Wong J, El Beheiry H, Rampersaund Y, Lewis S, Ahn H. Tranexamic acid reduces perioperative blood loss in adult patients having spinal fusion surgery. Anesth Analg.2008; 107: Tzortzopoulou A, Cepeda MS, Schumann R, Carr DB. Anitfibrinolytic agents for reducing blood loss in scoliosis surgery in children. Cochrane Database of Systematic Reviews. 2008;(3). 23. Gill JB, Chin Y, Levin A, Feng D. The Use of Antifibrinolytic Agents in Spine Surgery A Meta- Analysis. The Journal of Bone and Joint Surgery.2008; 90: Insert page break Page 129

8 Appendix I: Appraisal instruments MAStARI Appraisal instrument this is a test message Insert page break Page 130

9 Appendix II: Data extraction instruments MAStARI data extraction instrument Page 131