The efficacy and safety of high-dose tranexamic acid in adolescent idiopathic ... · 2021. 1....

RESEARCH ARTICLE Open Access

The efficacy and safety of high-dosetranexamic acid in adolescent idiopathicscoliosis a meta-analysisIndra K Shrestha Tian-Yi Ruan Lan Lin Miao Tan Xue-Qing Na Qi-Cai Qu Jian-Chun Chen Yong-Yu Si andJian-Ping Tao

Abstract

Background This study aimed to evaluate the efficacy and safety of using high-dose intravenous tranexamic acid(TXA) to reduce blood loss in idiopathic scoliosis surgery

Methods This study was a meta-analysis which consisted of retrospective cohort studies (RCSs) and randomizedcontrol trials (RCTs) found by searching electronic databases namely PubMed Web of Science The CochraneCentral Register of Controlled Trials (CENTRAL) and the Google Scholar Database dating from 1960 to 2019 Thepoints of interest included total blood loss a need for transfusion and transfusion criteria surgery time and theevidence of intraoperative and postoperative complications such as seizures or thromboembolic events Theweighted mean differences (WMD) and 95 confidence interval (CI) of blood loss in the TXA intervention groupcompared to the control or placebo group were extracted and combined using the random effects model

Results In this meta-analysis there was a total of three RCSs and two RCTs which involved 334 patients Theresults showed that blood loss is significantly reduced with a weighted mean difference in the TXA group (WMD =minus 52514 P = 00000 CI ranged from minus 83983 minus 21044 I2 = 82) Heterogeneity was assessed using the randomeffects model

Conclusions A high dose of intravenous TXA reduced blood loss during adolescent idiopathic scoliosis surgeryand did not lead to any significant thromboembolic event Therefore a high dose appears to be effective and safefor adolescent idiopathic scoliosis surgery However more high-quality research based on larger randomizedcontrolled trials is still needed

Keywords Scoliosis surgery Posterior spinal fusion Tranexamic acid Blood loss Thromboembolic event

BackgroundPosterior spinal fusion (PSF) an operation in whichthe spine is stabilized by grafting bone to fuse it is amajor procedure for the treatment of idiopathic scoli-osis A PSF involves a significant soft tissue dissectionand bone cut which can result in excessive bleeding

and increases the time of the operation and the needfor a blood transfusion Often for the above reasonsthe surgeon and anesthetist are concerned aboutsignificant blood loss during the intraoperative andpostoperative period A blood transfusion may beallogeneic and autologous but both have the side ef-fects and reactions related to transfusion The poten-tial complications of allogeneic blood transfusions areas follows infection (ie hepatitis B virus (HBV)hepatitis C virus (HCV) human immunodeficiency

copy The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 40 International Licensewhich permits use sharing adaptation distribution and reproduction in any medium or format as long as you giveappropriate credit to the original author(s) and the source provide a link to the Creative Commons licence and indicate ifchanges were made The images or other third party material in this article are included in the articles Creative Commonslicence unless indicated otherwise in a credit line to the material If material is not included in the articles Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use you will need to obtainpermission directly from the copyright holder To view a copy of this licence visit httpcreativecommonsorglicensesby40The Creative Commons Public Domain Dedication waiver (httpcreativecommonsorgpublicdomainzero10) applies to thedata made available in this article unless otherwise stated in a credit line to the data

Correspondence siyy698521163com taojp952014aliyuncomDepartment of Anesthesiology The Second Affiliated Hospital of KunmingMedical University No374 of Dianmian Avenue Wuhua District Kunming650101 Yunnan China

Shrestha et al Journal of Orthopaedic Surgery and Research (2021) 1653 httpsdoiorg101186s13018-020-02158-8

virus (HIV)) alloimmunization transfusion-relatedacute lung injury renal impairment or failuretransfusion-related circulatory overload andtransfusion-induced coagulopathy [1] Thus tranex-amic acid (TXA) has been used to prevent the com-plications mentioned above and also to minimize therate of morbidity and mortality associated with bloodlossTXA is a synthetic antifibrinolytic that inhibits the ac-

tivation of plasminogen to plasmin thereby inhibitingbinding to fibrin which prevents fibrinolysis It can re-duce bleeding during scoliosis surgery and help to pre-vent inflammation and platelet degradation [2]according to individual studies as well as meta-analyseswhich compared the efficacy and safety of low doseTXA with a placebo TXA was first prescribed to womenwith heavy menstrual blood loss and patients withhereditary bleeding disorders [3] It is used in pediatricadult and geriatric patients and studies show it hasbeen used in cardiac surgery spine surgerygynecological and obstetrics surgery orthopedic surgery(knee and hip replacement) liver surgery ENT surgeryand urological surgery [4ndash9] Despite the several meta-analyses that have been done concerning the use of lowdose TXA for posterior spinal fusion there is a lack ofstudies of high dose TXA in adolescent idiopathic scoli-osis surgeryRecently several researchers have used high doses of

TXA to reduce intraoperative and postoperative bleedingduring major operative procedures Therefore we con-ducted this meta-analysis to evaluate the effectivenessand safety of high-dose TXA in reducing the amount ofblood loss and minimizing the transfusion of allogeneicblood in patients with adolescent idiopathic scoliosissurgery

Materials and methodsLiterature search strategyIn this meta-analysis we searched PubMed Web ofScience and The Cochrane Central Register of Con-trol Trials to identify the relevant studies includingprospective and retrospective cohort studies (RCTs)review articles meta-analyses and randomized controltrials (RCTs) carried out between 1960 and December2019 The key words were as follows scoliosissurgery posterior spinal fusion tranexamic acid andhigh dose tranexamic acid Different databases adoptdifferent search strategies Taking PubMed as anexample the search entry was (ldquoScoliosis Surgery[Mesh]rdquo OR ldquoPosterior spinal fusionrdquo) AND (ldquotranex-amic acid [Mesh]rdquo OR ldquoHigh dose tranexamic acidrdquo)We used EndNote X4 (Duke University) to check forduplication and removed all duplication by using End-Note Medline (PC) and EndNote RIS

Criteria for inclusion in the studyThe study design consisted of RCTs and RCSs After athorough evaluation two RCTs and three RCSs werefound that met the inclusion criteria The basic charac-teristics of criteria for inclusion were as follows (1) Allpatients should have undergone idiopathic scoliosis sur-gery (2) the study should involve preoperative intraven-ous administration of a high dose ge 50 mgkg bolus oftranexamic acid and an intraoperative maintenance doseof TXA which was compared with a control group (ieone with no TXA or a placebo of normal saline) (3) allthe studies should include reported outcomes of the fol-lowing total blood loss (perioperative) need for bloodtransfusion either allogeneic or cell salvage and compli-cations during the intraoperative and postoperativeperiodOther studies were excluded due to case reports re-

views (systematic and narrative) meta-analysis no rele-vant intervention or procedures comments case-controldesign and editorials A flow chart of the study selectionprocedure is shown in Fig 1 and the characteristics ofthe included studies are detailed in Table 1

Data extractionThe included data were extracted independently by twoauthors and the features of each study were recordedwith their outcomes The general features of the in-cluded studies were as follows author names patientdemographics types of study design publication datetype of surgical procedure and anesthesia method inter-vention (ie intravenous TXA and control with no TXAor placebo with normal saline) need for transfusion (ieallogeneic blood packed blood cell cell salvage) duringintraoperative and postoperative periods after measuringHb levels and the measurements of outcomes with orwithout complications

The quality assessmentThe quality assessment of the included RCTs followedthe recommendations of the Cochrane Handbook forSystematic Reviews consisting of random sequence gen-eration allocation concealment blinding incompleteoutcome data selective reporting and other bias [15]The quality assessment of the included RCSs comprisedmeasuring exposure or non-exposed measuring out-comes follow-up analysis of the cohort confoundingbias strengths (multiple multiple exposures) and weak-nesses (cost and time prone to bias) The Newcastle-Ottawa Scale (NOS) was used to assess the quality of thenonrandomized studies from three broad perspectivesnamely the selection of the study groups the compar-ability of the groups and ascertaining either exposure oroutcome of interest The included studies have an NOSscore higher than 5 which signifies a good quality study

Shrestha et al Journal of Orthopaedic Surgery and Research (2021) 1653 Page 2 of 9

Fig 1 Method of selection for inclusion in the study

Table 1 Blood loss and Surgery time of included studies

Study High dose tranexamic acid Controlplacebo

No ofpatient

Blood loss(mL)

SD Surgery time(h)

SD No ofpatient

Blood loss(mL)

SD Surgery time(h)

SD

Ng et al [10] 55 182611 108145 728 204 35 38896 24408 836 14

da Rocha et al[11]

21 10973 3239 4 12 19 14065 3721 43 14

Sethna et al [12] 23 1072 425 66 18 21 1420 644 61 18

Lykissas et al [13] 25 537 320 NR NR 24 1245 896 NR NR

Goobie et al [14] 56 836 373 45 12 55 1031 484 42 096

NR not reported h hour SD standard deviation


Subgroup analysisOnly five studies were included in this meta-analysisand due to the limited sample size the subgroup analysiswas difficult to complete This was because when wetried to conduct the subgroup analysis according to theintervention level only one study used 50 mgkg TXAand the other four studies used 100 mgkg TXA

The main points of interestIn this study the main points of interest were totalblood loss surgery time and the evidence of intraopera-tive and postoperative complications

The total blood lossThe total blood loss was defined as the total blood lossduring the surgery which was evaluated during the sur-gery It was measured by counting all sponges and tapesand weighing them accurately by standard measurementmeasuring the amount of blood collected in cell salvageand intraoperative suction drainage and subtracting thefluids irrigated during surgery including the irrigation inthe surgical field The clinical significance was the factthat this index can be used to evaluate the extent of sur-gical trauma

The surgery timeThe surgery time was defined as the duration of thewhole surgery which was evaluated from the beginningof the operation being the given time of incision toclosure of skin at the end of the operation This indexcan be used to evaluate the degree of difficulty of theoperation

ComplicationsIn this study the intraoperative and postoperative com-plications were defined as the adverse reactions that oc-curred during and after surgery such as seizurethromboembolic events infection kidney failure arterialocclusion or gastrointestinal dysfunction This indexcan be used to evaluate the complications of theoperation

Statistical methodsWe conducted the statistical analysis by using STATA150 and Review Manager RevMan version 53 Themeans and standard deviations were pooled from all in-cluded studies to measure the weighted mean difference(WMD) of blood loss and operative time comparing thetranexamic acid group with the control or placebogroup Dichotomous outcomes were analyzed using rela-tive risk (RR) and 95 confidence intervals (CIs) A ran-dom effects model or fixed effects model was used topool the data and the statistical heterogeneity betweensummary data was assessed by the chi-squared test and

its extent was quantified by the I2 statistic The fixed ef-fects model was employed when there was no evidenceof heterogeneity I2 le 50 A P lt 005 was considered toindicate statistical significance in this meta-analysis

ResultsLiterature search resultsBased on a literature search of electronic databases ini-tially a total of 147 articles were identified as matchingthe inclusion criteria PubMed (n = 66) Web of Science(n = 80) and the Cochrane Library (n = 1) After review-ing the articles we excluded all irrelevant and duplicatearticles and finally focused on five studies [10ndash14] ofRCSs and RCTs most of which were published recentlyand one of which was published in 2005 [12]

General characteristicsA total of 334 patients participated in the studies formeta-analysis There were 180 patients in the TXAgroup and 154 patients in the control group In fourstudies [10ndash13] a dose of 100 mgkg was used bolusranging from 15ndash30min IV and in one study [14] adose of 50 mgkg bolus was used The participants werepatients undergoing adolescent scoliosis surgery Theintervention in the TXA group was a high dose of TXAwhile the intervention in the control group was 09normal saline or no TXA The maintenance dose ofTXA from the beginning of surgery to skin closure was10 mgkgh in four of the studies [10ndash14] and 30 mgkgh in the other study [11] (Tables 1 and 2) The biasrisk assessment for each RCT study is shown in Fig 2

The effects of TXA in reducing blood loss in scoliosissurgeryThe WMD of blood loss and blood transfusion in theTXA group and placebo group were extracted Signifi-cant heterogeneity was found between the studies with P= 0000 and I2 = 82 and a random effects model wasused for continuous outcomes The results showed thata high dose of TXA was effective in reducing blood lossduring adolescent idiopathic scoliosis surgery and thedifference was statistically significant [random modelWMD = minus 52514 ml of blood loss 95 CI ranged fromminus 83983 to minus 21044 P = 0000] (Fig 3) The dosagehelped to minimize the risk of bleeding-relatedhemodynamic instability To assess the stability of theresult of the five studies a sensitivity analysis was per-formed by omitting each individual study in turn Sincethere was no alteration in the results they appear to bereliable The sensitivity analysis is shown in Fig 4

Calculation of surgery timeFour out of the five studies had reported surgery timeThe times reported in the TXA group ranged from 40 plusmn


12 to 728 plusmn 204 h and in the control group from 43 plusmn14 to 836 plusmn 143 h The TXA seems to have minimizedthe surgery time regardless of the level of spinal fusionBlood loss and surgery time are directly proportional tothe level of spinal fusion but depend upon the surgeonthe techniques used and the patientrsquos position Signifi-cant heterogeneity existed between the five studies withP = 0006 and I2 = 756 and they all used a random ef-fects model for continuous outcomes All the statisticallyanalyzed results indicated that the TXA group had re-duced surgery times as compared with the placebo or

control group [WMD = minus 016 95 CI minus 087 056 P =0006] (Fig 5) To assess the stability of the results of thestudies a sensitivity analysis was performed by succes-sively omitting each individual study There was no al-teration in the results which shows they were reliablewith respect to surgery time The sensitivity analysis isdetailed in Fig 6

The effects of TXA on reducing the need for bloodtransfusion or cell salvageAll five studies reported that TXA reduced the bloodloss which directly minimized the transfusion rate ascompared to the control or placebo group da Rochaet al demonstrated that the use of TXA reduced bloodtransfusion by 188 compared to the control group[11] Lykissas et al reported there being a significantdifference between the TXA and the control groups (426plusmn 247 mL vs 740 plusmn 604 mL P = 0022) [13] SimilarlyNg et al reported that patients received a significantlylower volume of cell saver blood transfused back (06 Lvs 17 L P lt 001) [10] Finally Goobie et al demon-strated that TXA diminishes blood transfusion by twothirds ie median 1 unit vs 3 units P lt 0001 [14]

The side effects of TXA during intraoperative andpostoperative periodsDespite the high dose of TXA used to reduce blood lossin adolescent idiopathic scoliosis surgery none of thefive studies mentioned any complications such as athromboembolic event during the intraoperative andpostoperative period However an incidence of 13 to38 of clinical convulsive seizures was reported afterthe administration of a high dose of TXA in cardiopul-monary bypass and open heart-chamber cardiac surgeryespecially in older patients [16 17]

DiscussionMassive hemorrhage in spinal surgery can lead to un-stable vital signs of patients increase the risk of

Table 2 Characteristics of the included studiesStudy Age No of

patientsStudydesign

Participants Intervention Comparison Levelof fused

Transfusioncriteria

Surgery Bodyweight (kg)

TXA C TXA C TXA C TXA C TXA C

Ng et al [10] 1516 153 55 35 RCS Patients receivedASS

100 mgkg + 10 mgkgh

No TXA 135 121 Hb lt 8 gdL PSF 4525 4288

da Rocha et al[11]

18 216 21 19 RCS Patients receivedASS

100 mgkg + 30 mgkgh

No TXA 94 92 Not reported PSF 555 518

Sethna et al [12] 136 14 23 21 RCT Patients receivedASS

100 mgkg + 10 mgkgh

NS 09 14 13 Hb lt 9 gdL PSF 594 524

Lykissas et al [13] 147 135 25 24 RCS Patients receivedASS

100 mgkg + 10 mgkgh

No TXA 107 126 Hb lt 7 gdL PSF Notreported

Goobie et al [14] 149 147 56 55 RCT Patients receivedASS

50 mgkg + 10 mgkgh NS 09 10 9 Hb le73 gdL

PSF 551 516

TXA tranexamic acid C control PSF posterior spinal fusion NS normal saline RCS retrospective cohort studies RCT randomized control trials ASS adolescentscoliosis surgery

Fig 2 Bias risk assessments for each RCT study (ldquo+rdquo indicates presentor yes and ldquoblankrdquo indicates unclear)


hypoperfusion of important organs and increase theprobability of hematoma formation nerve compressionsecondary operation allogeneic blood transfusion andother events which can seriously affect the surgical ef-fect and prognosis of patients Therefore the control ofperioperative bleeding in spinal surgery has always beenan important concern of spinal surgery teams and anes-thesiologists There are various natural antagonists ofplasminogen in the blood circulation such as antiplas-min Under normal circumstances the activity of anti-fibrinolytic substances in the blood circulation is manytimes higher than that of fibrinolytic substances so

fibrinolytic bleeding will not occur However these an-tagonists cannot block the plasmin that is activated byactivators absorbed by the fibrin network Plasmin cancleave the arginine and lysine peptide chains of fibrino-gen in a neutral environment leading to the degradationof fibrin and the dissolution and bleeding of blood clotsTXA is a synthetic derivative and homolog of lysinewhich can pass through the blood cerebrospinal fluidbarrier It has a high affinity with the lysine binding siteof fibrinogen which can block the interaction betweenfibrinogen containing lysine residues and heavy chains ofplasmin preventing fibrinolytic enzymes from degrading

Fig 3 Forest plot of the effect of TXA on estimated blood loss

Fig 4 Sensitivity analysis of blood loss


fibrin and thereby playing a hemostatic effect in theperioperative period of spinal surgery [2] At presentspinal surgeons have also begun to use tranexamic acidto reduce perioperative blood loss and have achievedgood results Although some meta-analyses have beendone on low-dose TXA for posterior spinal fusion thereis no study of the efficacy and safety of high-dose TXAin adolescent idiopathic scoliosis surgeryIn this meta-analysis a total of three RCSs and two

RCTs were included involving 334 patients The out-comes of this study showed that a high dose of TXA re-duced blood loss during adolescent idiopathic scoliosissurgery (WMD = minus 52514 95 CI minus 83983 minus 21044 P= 0000) the TXA group had reduced surgery timeswhen compared with the placebo or control group(WMD = minus 016 95 CI minus 087 056 P = 0006) andthe difference was statistically significantThe most significant finding of this study of high-dose

intravenous TXA is that it can lead to a reduction inblood loss and the transfusion rate During scoliosis sur-gery there is a risk of significant perioperative bleedingcausing the formation of spinal hematoma which mayresult in spinal cord or cauda equina compression [1819] However none of the studies in this meta-analysisnor other studies that are not included mention anycomplications such as thromboembolic events or sei-zures during the operation or the postoperative period[10ndash14] Nevertheless despite the positive outcomes forefficacy and safety Myles et al mention that TXA hasan associated risk of postoperative seizures [6] The re-duction in blood loss depends on the maintenance ofmean arterial pressure within a band and depends onthe surgeonrsquos technical skills for pedicular instrumenta-tion and hemostasis [11] Most of the studies to datewere focused on hip replacement surgery knee surgery

and cardiac surgeries and some studies have focused onthe field of gynecology and obstetrics All of the studies[10ndash14] mentioned that the intraoperative blood losswas reduced by 41ndash51 for those that used TXA ascompared to a placebo or non-TXA group Popovskyet al [20] mentioned that autologous donors were twelvetimes more likely than general donors to experience anadverse event that required hospitalization In the litera-ture it was reported that an autologous blood transfu-sion also has complications that depend on the quantityof blood used [13 20] Even preoperatively donated au-tologous blood has an inherent level of risk [13] Lykis-sas et al [13] stated that aprotinin was associated withcardiac or renal failure myocardial infarction stroke ordeath Xie et al [21] mentioned that with a high dosethe previously studied low dose showed no signs of renaltoxicity seizures DVT or MI Based on our five studiesand the above results we can conclude that a high doseof TXA is safe and effective but an optimum doseshould be recommended to avoid over-generalizationThere are a number of other studies concerning TXA

some of which support our findings while others do notJohnson et al [2] stated that a high or very high dosetransfusion is an especially high risk for hospital-acquired infections thrombotic events occurred 4ndash5times more commonly than a renal respiratory or is-chemic event and mortality increased linearly over theentire dose range and exceeded 50 after 50 erythrocyteunits Chiem et al [22] reported that tranexamic acidcaused an anaphylactic reaction in a 15-year-old patientscheduled for posterior spinal fusion and another caseof an anaphylactic reaction involved a 72-year-old malewho underwent coronary artery bypass graft surgeryafter a bolus of tranexamic acid On the other hand Huiet al [23] reported that a high dose of TXA can reduce

Fig 5 Forest plot of operative time


intraoperative allogeneic blood transfusion operativetime and cell salvage transfusion compared to a lowdose Perel et al [24] mentioned that TXA can reducemortality in emergency and urgent surgery which is as-sociated with a high risk of bleeding and death In a ran-domized double-blinded placebo-control trial Goobieet al [14] demonstrated that a 50 mgkg bolus and a 10mgkgh maintenance dose were effective in reducingblood loss in PSF surgery and none of the TXA grouppatients required allogeneic blood transfusion or suf-fered any side effects However Bosch et al [25] in acomparison of coagulation profiles reported that TXAuse in PSF in AIS patients decreased the transfusion ratebut showed no significant change in blood loss Zhonget al [26] demonstrated that TXA was effective inreducing surgical time intraoperative blood loss andallogeneic blood transfusion without any increase incomplications in AIS Research on the whole seems topoint to the benefits of using TXA since the reductionof blood loss during the intraoperative and postoperativeperiods has a direct effect on minimizing hospital staysand any financial burden as well as increasing the likeli-hood of a good prognosis Thus it would appear that inscoliosis surgery the use of TXA is safer and cheaperthan other antifibrinolytics

LimitationsThis meta-analysis has a number of limitations First al-though it was the first meta-analysis to date to studyhigh-dose TXA administration there were only three

RCSs and two RCTs Second the subgroup analysiscould not be done due to the limited sample size andthis indirectly influenced the final result Thus furtherresearch is necessary Third the follow-up of this meta-analysis was short-term and another longer-term studyon the safety of tranexamic acid is still required Lastlythere needs to be more research into different doses ofTXA and different time duration of bolus doses

ConclusionsA high dose of intravenous tranexamic acid reducedblood loss during adolescent idiopathic scoliosis surgeryand was connected with no significant thromboembolicevents Therefore a high dose of TXA seems to beeffective and safe for adolescent idiopathic scoliosis sur-gery However further studies with a larger sample sizeare required to confirm the safety of a high dose of TXAfor such surgery

AbbreviationsCI Confidence interval PSF Posterior spinal fusion TXA Tranexamic acidRCT Randomized control trial RCSs Retrospective cohort studiesNOS Newcastle-Ottawa Scale RR Relative risk CIs Confidence intervals

AcknowledgementsWe are particularly grateful to all the people who have given us help on ourarticle

Authorsrsquo contributionsIndra K Shrestha conceived the idea Tian-Yi Ruan conceptualized the studyLan Lin collected the data Miao Tan and Xue-Qing Na analyzed the data Qi-Cai Qu and Jian-Chun Chen drafted the manuscript Yong-Yu Si and Jian-Ping Tao reviewed the manuscript All authors read and approved the finaldraft

Fig 6 Sensitivity analysis of operative time


FundingThis study was funded by1 National Natural Science Foundation of China (81060033)2 The Yunnan Natural Science Foundation (2009CD176)3 The Yunnan Clinical Research Fund (D-201213)The funding body had no role in the design of the study and collectionanalysis and interpretation of data and in writing the manuscript

Availability of data and materialsWe declared that materials described in the manuscript including allrelevant raw data will be freely available to any scientist wishing to usethem for non-commercial purposes without breaching participantconfidentiality

Ethics approval and consent to participateI confirm that I have read the Editorial Policy pages This study wasconducted with approval from the Ethics Committee of the Second AffiliatedHospital of Kunming Medical University This study was conducted inaccordance with the declaration of Helsinki Written informed consent wasobtained from all participants

Consent for publicationAll participants signed a document of informed consent

Competing interestsThe authors declare that they have no competing interests

Received 21 October 2020 Accepted 14 December 2020

References1 Lee YH An overview of meta-analysis for clinicians Korean J Intern Med

201833277ndash832 Johnson DJ Johnson CC Goobie SM et al High-dose vs low-dose

tranexamic acid to reduce transfusion requirements in pediatric scoliosissurgery J Pediatr Orthop 201737e552ndash7

3 Tengborn L Blombaumlck M Berntorp E Tranexamic acid- an old drug stillgoing strong and making a revival Thromb Res 2015135231ndash42

4 Farrokhi MR Kazemi AP Eftekharian HR Akbari K Efficacy of prophylacticlow dose of tranexamic acid in spinal fixation surgery a randomized clinicaltrial J Neurosurg Anesthesiol 201123290ndash6

5 Elwatidy S Jamjoom Z Elgamal E Zakaria A Turkistani A El-Dawlatly AEfficacy and safety of prophylactic large dose of tranexamic acid in spinesurgery a prospective randomized double-blind placebo-controlled studySpine 2008332577ndash80

6 Myles PS Smith JA Painter T Tranexamic acid in patients undergoingcoronary-artery surgery reply N Engl J Med 20173761893

7 Reid RW Zimmerman AA Laussen PC Mayer JE Gorlin JB Burrows FA Theefficacy of tranexamic acid versus placebo in decreasing blood loss inpediatric patients undergoing repeat cardiac surgery Anesth Analg 199784990ndash6

8 Breau RH Lavalleacutee LT Cnossen S et al Tranexamic acid versus placebo toprevent blood transfusion during radical cystectomy for bladder cancer(TACT) study protocol for a randomized controlled trial Trials 201819261

9 Dalmau A Sabateacute A Koo M et al The prophylactic use of tranexamic acidand aprotinin in orthotopic liver transplantation a comparative study LiverTranspl 200410279ndash84

10 Ng BK Chau WW Hung AL Hui AC Lam TP Cheng JC Use of tranexamicacid (TXA) on reducing blood loss during scoliosis surgery in Chineseadolescents Scoliosis 20151028

11 da Rocha VM de Barros AG Naves CD et al Use of tranexamic acid forcontrolling bleeding in thoracolumbar scoliosis surgery with posteriorinstrumentation Rev Bras Ortop 201550226ndash31

12 Sethna NF Zurakowski D Brustowicz RM Bacsik J Sullivan LJ Shapiro FTranexamic acid reduces intraoperative blood loss in pediatric patientsundergoing scoliosis surgery Anesthesiology 2005102727ndash32

13 Lykissas MG Crawford AH Chan G Aronson LA Al-Sayyad MJ The effect oftranexamic acid in blood loss and transfusion volume in adolescentidiopathic scoliosis surgery a single-surgeon experience J Child Orthop20137245ndash9

14 Goobie SM Zurakowski D Glotzbecker MP et al Tranexamic acid isefficacious at decreasing the rate of blood loss in adolescent scoliosissurgery J Bone Joint Surg 20181002024ndash32

15 Systematic reviews of interventions (version 510) httpwwwcochranehandbook org Accessed 5 Jan 2012

16 Murkin JM Falter F Granton J et al High-dose tranexamic acid is associatedwith nonischemic clinical seizures in cardiac surgical patients Anesth Analg2010110(2)350ndash3

17 Shrestha IK Si Y Y and Tao J P Role of tranexamic acid to reduce bloodloss and transfusion of allogeneic blood in the field of surgery Asian J MedSci 202011(2)89ndash95

18 Kebaish KM Awad JN Spinal epidural hematoma causing acute caudaequina syndrome Neurosurg Focus 200416e1

19 Sokolowski MJ Garvey TA Perl J et al A prospective study of postoperativelumbar epidural hematoma incidence and risk factors Spine 200833108ndash13

20 Popovsky MA Safety of RBC apheresis and whole blood donation inallogeneic and autologous blood donors Transfus Apher Sci 200634205ndash11

21 Xie J Lenke LG Li T et al Preliminary investigation of high-dose tranexamicacid for controlling intraoperative blood loss in patients undergoing spinecorrection surgery Spine J 201515647ndash54

22 Chiem J Ivanova I Parker A Krengel W Jimenez N Anaphylactic reaction totranexamic acid in an adolescent undergoing posterior spinal fusionPaediatr Anaesth 201727774ndash5

23 Hui S Xu D Ren Z et al Can tranexamic acid conserve blood and saveoperative time in spinal surgeries A Meta-analysis Spine J 2018181325ndash37

24 Perel P Ker K Morales Uribe CH Roberts I Tranexamic acid for reducingmortality in emergency and urgent surgery Cochrane Database Syst Rev20131CD010245

25 Bosch P Kenkre TS Soliman D Londino JA Novak NE Comparison of thecoagulation profile of adolescent idiopathic scoliosis patients undergoingposterior spinal fusion with and without tranexamic acid Spine Deform20197910ndash6 httpsdoiorg101016jjspd201904005

26 Zhong J Cao K Wang B Zhou X Lin N Lu H The perioperative efficacy andsafety of tranexamic acid in adolescent idiopathic scoliosis WorldNeurosurg 2019129e726ndash32

Publisherrsquos NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations


Abstract

Background

Methods

Results

Conclusions

Background

Materials and methods

Literature search strategy

Criteria for inclusion in the study

Data extraction

The quality assessment

Subgroup analysis

The main points of interest

The total blood loss

The surgery time

Complications

Statistical methods

Results

Literature search results

General characteristics

The effects of TXA in reducing blood loss in scoliosis surgery

Calculation of surgery time

The effects of TXA on reducing the need for blood transfusion or cell salvage

The side effects of TXA during intraoperative and postoperative periods

Discussion

Limitations

Conclusions

Abbreviations

Acknowledgements

Authorsrsquo contributions

Funding

Availability of data and materials

Ethics approval and consent to participate

Consent for publication

Competing interests

References

Publisherrsquos Note

virus (HIV)) alloimmunization transfusion-relatedacute lung injury renal impairment or failuretransfusion-related circulatory overload andtransfusion-induced coagulopathy [1] Thus tranex-amic acid (TXA) has been used to prevent the com-plications mentioned above and also to minimize therate of morbidity and mortality associated with bloodlossTXA is a synthetic antifibrinolytic that inhibits the ac-

tivation of plasminogen to plasmin thereby inhibitingbinding to fibrin which prevents fibrinolysis It can re-duce bleeding during scoliosis surgery and help to pre-vent inflammation and platelet degradation [2]according to individual studies as well as meta-analyseswhich compared the efficacy and safety of low doseTXA with a placebo TXA was first prescribed to womenwith heavy menstrual blood loss and patients withhereditary bleeding disorders [3] It is used in pediatricadult and geriatric patients and studies show it hasbeen used in cardiac surgery spine surgerygynecological and obstetrics surgery orthopedic surgery(knee and hip replacement) liver surgery ENT surgeryand urological surgery [4ndash9] Despite the several meta-analyses that have been done concerning the use of lowdose TXA for posterior spinal fusion there is a lack ofstudies of high dose TXA in adolescent idiopathic scoli-osis surgeryRecently several researchers have used high doses of

TXA to reduce intraoperative and postoperative bleedingduring major operative procedures Therefore we con-ducted this meta-analysis to evaluate the effectivenessand safety of high-dose TXA in reducing the amount ofblood loss and minimizing the transfusion of allogeneicblood in patients with adolescent idiopathic scoliosissurgery

Materials and methodsLiterature search strategyIn this meta-analysis we searched PubMed Web ofScience and The Cochrane Central Register of Con-trol Trials to identify the relevant studies includingprospective and retrospective cohort studies (RCTs)review articles meta-analyses and randomized controltrials (RCTs) carried out between 1960 and December2019 The key words were as follows scoliosissurgery posterior spinal fusion tranexamic acid andhigh dose tranexamic acid Different databases adoptdifferent search strategies Taking PubMed as anexample the search entry was (ldquoScoliosis Surgery[Mesh]rdquo OR ldquoPosterior spinal fusionrdquo) AND (ldquotranex-amic acid [Mesh]rdquo OR ldquoHigh dose tranexamic acidrdquo)We used EndNote X4 (Duke University) to check forduplication and removed all duplication by using End-Note Medline (PC) and EndNote RIS

Criteria for inclusion in the studyThe study design consisted of RCTs and RCSs After athorough evaluation two RCTs and three RCSs werefound that met the inclusion criteria The basic charac-teristics of criteria for inclusion were as follows (1) Allpatients should have undergone idiopathic scoliosis sur-gery (2) the study should involve preoperative intraven-ous administration of a high dose ge 50 mgkg bolus oftranexamic acid and an intraoperative maintenance doseof TXA which was compared with a control group (ieone with no TXA or a placebo of normal saline) (3) allthe studies should include reported outcomes of the fol-lowing total blood loss (perioperative) need for bloodtransfusion either allogeneic or cell salvage and compli-cations during the intraoperative and postoperativeperiodOther studies were excluded due to case reports re-

views (systematic and narrative) meta-analysis no rele-vant intervention or procedures comments case-controldesign and editorials A flow chart of the study selectionprocedure is shown in Fig 1 and the characteristics ofthe included studies are detailed in Table 1

Data extractionThe included data were extracted independently by twoauthors and the features of each study were recordedwith their outcomes The general features of the in-cluded studies were as follows author names patientdemographics types of study design publication datetype of surgical procedure and anesthesia method inter-vention (ie intravenous TXA and control with no TXAor placebo with normal saline) need for transfusion (ieallogeneic blood packed blood cell cell salvage) duringintraoperative and postoperative periods after measuringHb levels and the measurements of outcomes with orwithout complications

The quality assessmentThe quality assessment of the included RCTs followedthe recommendations of the Cochrane Handbook forSystematic Reviews consisting of random sequence gen-eration allocation concealment blinding incompleteoutcome data selective reporting and other bias [15]The quality assessment of the included RCSs comprisedmeasuring exposure or non-exposed measuring out-comes follow-up analysis of the cohort confoundingbias strengths (multiple multiple exposures) and weak-nesses (cost and time prone to bias) The Newcastle-Ottawa Scale (NOS) was used to assess the quality of thenonrandomized studies from three broad perspectivesnamely the selection of the study groups the compar-ability of the groups and ascertaining either exposure oroutcome of interest The included studies have an NOSscore higher than 5 which signifies a good quality study

Shrestha et al Journal of Orthopaedic Surgery and Research (2021) 1653 of 9




No ofpatient

Blood loss(mL)

SD Surgery time(h)

SD No ofpatient

Blood loss(mL)

SD Surgery time(h)

SD

Ng et al [10] 55 182611 108145 728 204 35 38896 24408 836 14

da Rocha et al[11]

21 10973 3239 4 12 19 14065 3721 43 14

Sethna et al [12] 23 1072 425 66 18 21 1420 644 61 18


Goobie et al [14] 56 836 373 45 12 55 1031 484 42 096





















patientsStudydesign


Transfusioncriteria




100 mgkg + 10 mgkgh


da Rocha et al[11]


100 mgkg + 30 mgkgh



100 mgkg + 10 mgkgh

NS 09 14 13 Hb lt 9 gdL PSF 594 524


100 mgkg + 10 mgkgh




PSF 551 516




























































Abstract

Background

Methods

Results

Conclusions

Background




Data extraction


Subgroup analysis



The surgery time

Complications

Statistical methods

Results







Discussion

Limitations

Conclusions

Abbreviations

Acknowledgements


Funding




Competing interests

References





No ofpatient

Blood loss(mL)

SD Surgery time(h)

SD No ofpatient

Blood loss(mL)

SD Surgery time(h)

SD

Ng et al [10] 55 182611 108145 728 204 35 38896 24408 836 14

da Rocha et al[11]

21 10973 3239 4 12 19 14065 3721 43 14

Sethna et al [12] 23 1072 425 66 18 21 1420 644 61 18


Goobie et al [14] 56 836 373 45 12 55 1031 484 42 096





















patientsStudydesign


Transfusioncriteria




100 mgkg + 10 mgkgh


da Rocha et al[11]


100 mgkg + 30 mgkgh



100 mgkg + 10 mgkgh

NS 09 14 13 Hb lt 9 gdL PSF 594 524


100 mgkg + 10 mgkgh




PSF 551 516




























































Abstract

Background

Methods

Results

Conclusions

Background




Data extraction


Subgroup analysis



The surgery time

Complications

Statistical methods

Results







Discussion

Limitations

Conclusions

Abbreviations

Acknowledgements


Funding




Competing interests

References




















patientsStudydesign


Transfusioncriteria




100 mgkg + 10 mgkgh


da Rocha et al[11]


100 mgkg + 30 mgkgh



100 mgkg + 10 mgkgh

NS 09 14 13 Hb lt 9 gdL PSF 594 524


100 mgkg + 10 mgkgh




PSF 551 516




























































Abstract

Background

Methods

Results

Conclusions

Background




Data extraction


Subgroup analysis



The surgery time

Complications

Statistical methods

Results







Discussion

Limitations

Conclusions

Abbreviations

Acknowledgements


Funding




Competing interests

References


























































Abstract

Background

Methods

Results

Conclusions

Background




Data extraction


Subgroup analysis



The surgery time

Complications

Statistical methods

Results







Discussion

Limitations

Conclusions

Abbreviations

Acknowledgements


Funding




Competing interests

References


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