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The impact of RoTEM generation coagulation data on transfusion practices in trauma Al-Masrouri, Safiya Mohammed Hamed 2015

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!THE!IMPACT!OF!ROTEM!GENERATION!COAGULATION!DATA!ON!TRANSFUSION!PRACTICES!IN!TRAUMA!!!by!!Safiya!Al*Masrouri!!M.D.,!Sultan!Qaboos!University,!2012!!!!A!THESIS!SUBMITTED!IN!PARTIAL!FULFILLMENT!OF!THE!REQUIREMENTS!FOR!THE!DEGREE!OF!!MASTER!OF!SCIENCE!!in!!The!Faculty!of!Graduate!and!Postdoctoral!Studies!!(Surgery)!!!!THE!UNIVERSITY!OF!BRITISH!COLUMBIA!(Vancouver)!!June!2015!!!©Safiya!Al*Masrouri,!2015!! ii!Abstract!!BACKGROUND:!Coagulopathy! in! trauma! is! believed! to! result! from! complex! hemostatic! disturbances!known! as! Acute! Traumatic! Coagulopathy.! The! current! diagnostic! modalities! fail! to!characterize! these! disturbances! in! clinically! relevant! time! frames.! Recently,! there! has!been! an! increasing! interest! in! utilizing! of! Viscoelastic! Hemostatic! Assays! (RoTEM,!Rotational!Thromboelastometry;!TEG,!Thromboelastometry)!in!the!diagnosis!of!ATC!and!guiding!initial!phases!of!resuscitation.!We!aim!in!this!study!to!assess!the!role!of!RoTEM!assay!in!the!diagnosis!and!management!of!ATC.!!!METHODS!AND!RESULTS:!!We! conducted! a! systematic! review! to! investigate! the! role! of! RoTEM! assays! in! the!diagnosis! and! the!management! of! ATC.! A! total! of! 20! studies!were! included! and! they!have!shown!that!not!only!RoTEM!parameters!had!a!good!detection!rate!of!ATC,!but!also!they!provided!more!data!on!clot! firmness,!stability!and! lysis! in!a!shorter!span!of!time.!Moreover,! they! were! independent! predictors! of! mortality,! morbidity! and! massive!transfusion.!Utilizing! these!parameters! to!guide!blood!transfusion!has! the!potential! to!decrease!the!exposure!of!allogeneic!blood!products.!!In!addition,!we!designed!a!before*and*after!study!to!assess!the!role!of!RoTEM!assays!in!early! diagnosis! of! ATC! and! on! utilization! of! blood! products! among! all! trauma! team!activations! in!a! level*1! trauma!center! setting.! Interim!analysis! (October!2014!–!March!2015)!have!revealed!that!out!of!63!trauma!patients,!only!one!(1.6%)!had!INR!<!1.2!and!two! (3.2%)! had! fibrinogen! <! 1.4! g/L.! RoTEM! parameters! had! a! significant! correlation!with! CCT! parameters! and! appeared! to! be! more! sensitive! than! CCT! in! detecting!coagulation! disturbances! in! stable! but! severely! injured! patients.! The! impact! on!transfusion!practices!was!not!assessed!as!the!study!recruited!small!number!of!patients.!!!!! iii!CONCLUSION:!!RoTEM!assays!are!potentially!useful!diagnostic!tools!in!the!field!of!trauma!resuscitation.!They! provide! a! rapid! a! reliable! means! to! assess! coagulation! disturbances.! Obtaining!these! assays! in! clinically! relevant! time! frames! allows! for! targeted! hemostatic! therapy!and!that!can!potentially!reduce!the!exposure!to!allogeneic!blood!products.!The!impact!of! these!assays!on! transfusion!practices!and!patients’!outcomes! is! yet! to!be!validated!through!multicenter!randomized!clinical!trials.!!! iv!Preface!! • Chapter! two! *! Systematic! Review!was! conducted! under! the! supervision! of! Dr.!Richard!Simons,!Dr.! Tyler! Smith!and!Dr.!Naisan!Garraway.! I!was! responsible!of!conducting!the!literature!search!in!the!databases!and!the!initial!screening!of!the!citations.!Potentially!relevant!articles!were!reviewed!by!Dr.!Simons!and!myself!to!select!the!studies!to!be!finally!included!in!the!review.!I!was!then!responsible!of!conducting! methodological! quality! assessment,! data! extraction,! analysis! and!writing!the!final!manuscript!under!the!supervision!of!the!above!committee.!!* Contents! of! this! chapter!were!presented! as! an!oral! presentation! in! the!Trauma!Association!Canada!Annual!Scientific!Meeting!April!10!*11,!2015.!The!abstract! is!published! in! the!Canadian! Journal!of! Surgery,!Vol.! 58! (2!Suppl.!1)!April!2015.!DOI:!10.1503/cjs.003415.!! • Chapter! Three! *! Prospective! Study! was! conducted! in! collaboration! between!Trauma!services!division!*!Department!of!Surgery!and!Hematopathology!division!–!Department!of!Pathology.!The!supervising!committee!consisted!of!Dr.!Richard!Smith!(as!the!Principle! Investigator)!and!Drs.!Tyler!Smith,!Naisan!Garraway!and!Penny!Brasher!as!Co*investigators.!!* Under! the! supervision! of! the! research! group,! I! was! responsible! of!formulating! the! research! objectives,! the! study! design,! obtaining! the!ethical!approval,!data!collection!(chart!review),!data!analysis!and!writing!the!manuscript.!!* Ms.! Margret! Walsh! (Hematopathology! division! –! Department! of!Pathology)! performed! data! collection! of! the! laboratory! and! transfusion!data!of!the!study!sample.!!!* Dr.! Penny! Brasher! (Center! for! Clinical! Epidemiology! and! Evaluation)!provided!assistance!in!the!project!design!and!data!analysis.!!! v!* Ms.!Nasira!Lakha!and!Ms.!Heather!Wong!(Trauma!services!*!Department!of! Surgery)! were! heavily! involved! in! the! process! of! implementing! the!RoTEM!guided!resuscitation!protocol!and!they!facilitated!communication!between! trauma! services! division,! hematopatholgy! and! Emergency!Department.!!!* Ms.! Erin! Shangguan! (British! Columbia! Trauma! Registry)! provided!assistance! in! calculating! the! injury! severity! scores! and! the! abbreviated!injury!scales!of!the!study!population.!!* Ethical! approval!was!obtained! from! the!University!of!British!Columbia’s!Clinical!Ethics!Board!(No.!H14*02872*A001).!! vi!Table!of!Contents!!Abstract!.......................................................................................................................!ii!Preface!.......................................................................................................................!iv!Table!of!Contents!........................................................................................................!vi!List!of!Tables!.............................................................................................................!viii!List!of!Figures!..............................................................................................................!ix!List!of!Abbreviations!....................................................................................................!x!Acknowledgment!.......................................................................................................!xii!Dedication!................................................................................................................!xiii!Chapter!1! Introduction!............................................................................................!1!1.1! Background!................................................................................................................!2!1.2! Acute!traumatic!coagulopathy!....................................................................................!3!1.2.1! Definition!...................................................................................................................!3!1.2.2! Pathophysiology!of!ATC!.............................................................................................!4!1.3! Diagnosis!of!ATC!.........................................................................................................!5!1.3.1! Viscoelastic!Hemostatic!Assays!..................................................................................!6!1.4! Resuscitation!in!trauma!..............................................................................................!9!1.5! Overall!research!hypothesis!.....................................................................................!10!1.6! Overall!research!objective!........................................................................................!10!1.7! Thesis!format,!structure!and!objectives!of!research!studies!......................................!10!Chapter!2! The!Role!Of!RoTEM!Assays!In!The!Diagnosis!And!The!Management!Of!Acute!Traumatic!Coagulopathy:!A!Systematic!Review!................................................!12!2.1! Chapter!Summary!....................................................................................................!13!2.2! Methods!...................................................................................................................!14!2.2.1! Search!protocol!and!eligibility!Criteria!.....................................................................!14!2.2.2! Data!extraction!and!analysis!....................................................................................!15!2.3! Results!.....................................................................................................................!15!2.3.1! Characteristics!of!the!studies!...................................................................................!16!2.3.2! Quality!of!the!methodology!of!the!selected!studies!................................................!17!2.3.3! RoTEM!in!the!diagnosis!of!ATC!................................................................................!19!2.3.4! Prognostic!value!of!RoTEM!parameters!...................................................................!26!2.3.5! Utilization!of!RoTEM!parameters!in!goal*directed!therapy!.....................................!34!2.4! Discussion!................................................................................................................!36!2.4.1! Main!Findings!...........................................................................................................!36!2.4.2! Limitations!................................................................................................................!37!2.5! Conclusion!................................................................................................................!38!! vii!Chapter!3! The!Impact!Of!RoTEM!Generated!Coagulation!Data!On!The!Early!Diagnosis!Of!Acute!Traumatic!Coagulopathy!And!Implications!On!Management:!A!Prospective!Study!......................................................................................................!40!3.1! Chapter!Summary!....................................................................................................!41!3.2! Methods!...................................................................................................................!42!3.2.1! Study!Design!.............................................................................................................!42!3.2.2! Patient!Selection!(inclusion!and!exclusion!criteria)!.................................................!43!3.2.3! Blood!sampling!and!RoTEM!analysis!........................................................................!44!3.2.4! Transfusion!Protocol!at!Vancouver!General!Hospital!..............................................!45!3.2.5! Data!collection!and!definitions!................................................................................!46!3.2.6! Data!Analysis!............................................................................................................!47!3.3! Results!.....................................................................................................................!47!3.3.1! Baseline!Characteristics!of!the!study!population!.....................................................!47!3.3.2! Diagnosis!of!Coagulopathy!(ATC)!by!RoTEM!vs.!CCT!................................................!50!3.3.3! Correlation!between!RoTEM!and!CCT!......................................................................!53!3.3.4! Turnaround!Time!for!RoTEM!vs.!CCT!.......................................................................!54!3.4! Discussion!................................................................................................................!56!3.4.1! Main!Findings!...........................................................................................................!56!3.4.2! Limitations!................................................................................................................!58!3.5! Conclusion!................................................................................................................!59!Bibliography!..............................................................................................................!60!Appendices!................................................................................................................!66!Appendix!A:!Vancouver!General!Hospital!(VGH)!Trauma!Exsanguination!Protocol!(TEP)!....!66!Appendix!B:!RoTEM!Guided!Resuscitation!Algorithm!.........................................................!67!! viii!List!of!Tables!!!TABLE!2*1!QUALITY!OF!THE!INCLUDED!STUDIES!USING!NEWCASTLE*OTTAWA!SCALE!FOR!COHORT!STUDIES!........!18!TABLE!2*2!CHARACTERISTICS!AND!MAIN!FINDINGS!OF!STUDIES!REPORTING!ON!THE!ROLE!OF!ROTEM!ASSAYS!IN!THE!DIAGNOSIS!OF!ATC!.............................................................................................................!22!TABLE!2*3!CHARACTERISTICS!AND!MAIN!FINDINGS!OF!STUDIES!REPORTING!ON!THE!ROLE!OF!ROTEM!ASSAYS!IN!THE!DIAGNOSIS!OF!HYPERFIBRINOLYSIS!........................................................................................!25!TABLE!2*4!CHARACTERISTICS!AND!MAIN!FINDINGS!OF!STUDIES!REPORTING!ON!THE!ROLE!OF!ROTEM!ASSAYS!IN!PREDICTION!OF!MORTALITY!AND!MORBIDITY!.................................................................................!27!TABLE!2*5!CHARACTERISTICS!AND!MAIN!FINDINGS!OF!STUDIES!REPORTING!ON!THE!ROLE!OF!ROTEM!ASSAYS!IN!PREDICTING!MASSIVE!TRANSFUSION!OR!ANY!PRBC!TRANSFUSION!....................................................!31!TABLE!2*6!CHARACTERISTICS!AND!MAIN!FINDINGS!OF!STUDIES!REPORTING!ON!THE!ROLE!OF!ROTEM!ASSAYS!IN!GOAL*DIRECTED!THERAPY!..........................................................................................................!35!TABLE!3*1!CHARACTERISTICS!OF!THE!STUDY!POPULATION!(N=63)!..............................................................!49!TABLE!3*2!PREVALENCE!OF!COAGULOPATHY!AS!DEFINED!BY!ROTEM!AND!CONVENTIONAL!COAGULATION!TESTS!(CCT)!ON!ADMISSION!(N=63)!.....................................................................................................!50!TABLE!3*3!DETECTION!OF!INR!ABNORMALITIES!BY!EXTEM!CT!(N=63)!......................................................!51!TABLE!3*4!DETECTION!OF!HYPOFIBRINOGENEMIA!BY!FIBTEM!A10!VS.!FIBRINOGEN!LEVELS!(N=63)!...............!52!TABLE!3*5!DETECTION!OF!PLATELET!DYSFUNCTION!BY!EXTEM!A10!VS.!PLATELET!LEVELS!(N=63)!..................!53!TABLE!3*6!SPEARMAN'S!RANK!CORRELATION!(R)!BETWEEN!ROTEM!AND!CCT!(N=63)!.................................!54!TABLE!3*7!TURNAROUND!TIMES!(TAT)!FOR!ROTEM!VS.!CONVENTIONAL!COAGULATION!TESTS!IN!MINUTES!(N=63)!...................................................................................................................................!55!! ix!List!of!Figures!!FIGURE!1*1!ROTEM!TRACING!(26)!........................................................................................................!8!FIGURE!2*1!STUDY!FLOW!DIAGRAM!OF!THE!SYSTEMATIC!REVIEW!................................................................!16!FIGURE!3*1!FLOW!DIAGRAM!OF!PATIENTS!THROUGH!THE!STUDY!................................................................!48!FIGURE!3*2!RELATIONSHIP!BETWEEN!INR!AND!EXTEM!CT!SEPARATED!BY!(A)!INJURY!SEVERITY,!(B)!MORTALITY!OUTCOME!AND!(C)!MECHANISM!OF!INJURY.!(INR,!INTERNATIONAL!NORMALIZED!RATIO;!ISS,!INJURY!SEVERITY!SCORE;!NON*SURVIVORS,!IN*HOSPITAL!MORTALITY)!..........................................................!51!FIGURE!3*3!RELATIONSHIP!BETWEEN!FIBRINOGEN!LEVELS!AND!FIBTEM!A10!SEPARATED!BY!(A)!INJURY!SEVERITY,!(B)!MORTALITY!OUTCOME!AND!(C)!MECHANISM!OF!INJURY.!(INR;!INTERNATIONAL!NORMALIZED!RATIO;!ISS,!INJURY!SEVERITY!SCORE;!NON*SURVIVORS,!IN*HOSPITAL!MORTALITY)!..........................................!52!FIGURE!3*4!RELATIONSHIP!BETWEEN!PLATELET!COUNT!AND!EXTEM!A10!SEPARATED!BY!FIBTEM!A10!LEVELS!(NORMAL!FIBTEM!A10!>!10!MM,!LOW!FIBTEM!A10!=<!10!MM)!.................................................!53!FIGURE!3*5!TURNAROUND!TIMES!(SAMPLE!COLLECTION!TO!REPORTING!RESULTS,!MIN)!OF!(A)!ROTEM!VERSUS!(B)!CONVENTIONAL!COAGULATION!TESTS!(CCT)!(N=63)!.................................................................!55!FIGURE!3*6!MEDIAN!TURNAROUND!TIMES!(TAT)!FOR!ROTEM!ASSAYS!VS.!CCTS!OVER!THE!PERIOD!OF!THE!STUDY!(MIN,!N=63)!............................................................................................................................!56!!!! x!List!of!Abbreviations!!TIC! Trauma!induced!coagulopathy!ATC! Acute!traumatic!coagulopathy!ED! Emergency!department!INR! International!normalized!ratio!PT! Prothrombin!time!aPTT! Activated!partial!thromboplastin!time!ISS! Injury!severity!score!BE! Base!excess!CCT! Conventional!coagulation!tests!TEG! Thrombelastography!RoTEM! Rotational!thromboelastometry!rTEG! Rapid!thrombelastography!CT! Clotting!time!CFT! Clot!formation!time!A5!! Amplitude!at!5!minutes!A10!! Amplitude!at!10!minutes!!A15! Amplitude!at!15!minutes!MCF! Maximum!clot!firmness!LI! Lysis!Index!!ML%! Percentage!of!maximum!clot!lysis!!HF! Hyperfibrinolysis!!TF! Tissue!factor!aPC! Activated!protein!C!PAP! Plasmin*antiplasmin!complex!PRBC! Packed!red!blood!cells!FFP! Fresh!frozen!plasma!! xi!PCC! Prothrombin!complex!concentrate!TXA! Tranexamic!acid!ICU! Intensive!care!unit!RCT! Randomized!controlled!trial!GCS! Glasgow!coma!scale!SBP! Systolic!blood!pressure!ISS!! Injury!Severity!Score!TRISS! Trauma!and!injury!severity!score!!RISC! Revised!injury!severity!classification!RTS! Revised!trauma!score!!MT! Massive!transfusion!!TEP!! Trauma!exsanguination!protocol!!BCTR! British!Columbia!trauma!registry!!PCIS!! Patient!care!information!system!!! !! xii!Acknowledgment!!I!would! like! to!express!my!deepest!gratitude!to!my!supervisor,!Dr.!Richard!Simons! for!sharing! his! pearls! of! wisdom! with! me! during! the! course! of! this! project.! This! thesis!wouldn’t!be!possible!without!his!endless!support!and!constant!guidance.!!!My! special! thanks! goes! to! my! committee! members,! Dr.! Tyler! Smith,! Dr.! Naisan!Garraway! and! Dr.! Penny! Brasher,! who! provided! insight! and! expertise! that! greatly!nourished!my!thesis.!!To!Ms.!Margret!Walsh!for!her!kind!contribution!in!the!process!of!data!collection.!!!I!am!also!thankful!to!Ms.!Heather!Wong,!Ms.!Nasira!Lakha!and!the!staff!at!the!trauma!services! division! *! Vancouver! General! Hospital! for! their! efforts! in! facilitating! the!implementation!of!this!project.!!!I! would! also! like! to! thank! Dr.! Alice! Mui! (MSc! program! coordinator)! and! Dr.! Morad!Hameed!for!accepting!to!be!part!of!the!defense!committee.!!!Finally,!I!would!like!to!thank!my!home!institute,!Sultan!Qaboos!University!and!on!top!of!that! the! head! of! Department! of! Surgery,! Dr.! Hani! Al*Qadhi! for! giving! me! this!opportunity!to!pursue!this!degree.!!! xiii!Dedication!!!I!would!like!to!dedicate!this!thesis!to:!!!!My!loving!parents,!my!sun!and!moon,!Mohammed!and!Sheikha.!My!deepest!feelings!of!gratitude! goes! to! them! both! for! everything! they! had! to! offer;! all! along! my! path!providing!all!means!of!continuous!love!and!assistance.!Your!support!is!my!nourishment.!!My! supportive! brothers! and! sisters! who! believed! in!me! like! no! other.! Thank! you! for!making!my!stressful!days!very!easy!to!conquer.!!My!amazing!friends!A’reem,!Rihab!and!Fatma,!who!have!accompanied!me!throughout!this!course,!whether!they!were!around!or!thousands!of!miles!away.!Thank!you!for!being!part!of!this!journey!!!!!!! 1!Chapter!1 Introduction!!! 2!1.1 Background!! Injury!is!one!of!the!major!causes!of!death!worldwide.!It!was!estimated!that!5.8! million! people! worldwide! die! every! year! secondary! to! trauma,! a! figure! that!represent!10%!of!total!deaths!(1).!In!Canada,!trauma!and!unintentional!injuries!are!the! fifth! leading! cause! of! death,! accounts! for! almost! 4.3%! of! total! deaths! (2).!According! to! the! National! Trauma! Registry! report! (2010*2011),!more! than! 15,000!cases!were!hospitalized!due!to!major!trauma!(3).!!Despite! all! the! advances! in! trauma! resuscitation! and! the! availability! of! blood!products,!bleeding!continues!to!be!the!second!leading!cause!of!in*hospital!mortality!following!major!trauma!accounting!for!almost!40%!of!all!trauma!mortalities!(4,5).!A!major!contributing! factor! to!this!bleeding! is!a!hemostatic!defect!known!as!Trauma!Induced!Coagulopathy!(TIC).!This!condition!was!historically!thought!to!be!iatrogenic!in! origin,! secondary! to! excessive! infusion! of! hypocoagulable! resuscitation! fluids!during! the! initial! phases! of! resuscitation.! These! resuscitation! measures! were!thought! to! result! in! dilutional! coagulopathy,! hypothermia! and! acidosis! or! what! is!known!as!the!“triad!of!death”.!This!was!the!most!widely!accepted!understanding!of!TIC!until!Brohi!et!al.!proposed!a!new!concept!of!an!endogenous!component!for!TIC.!This! study! demonstrated! that! approximately! 25%! of! severely! injured! trauma!patients! had! evidence! of! coagulopathy! before! the! institution! of! resuscitation!measures! and! before! the! onset! of! any! significant! hypothermia! or! acidosis.! This!observation! pointed! towards! an! endogenous! component! of! TIC! termed! Acute!Traumatic!Coagulopathy!(5,6).!!!! 3!1.2 Acute!traumatic!coagulopathy!!1.2.1 Definition!!! Acute! Traumatic! Coagulopathy! (ATC)! is! an! evolving! field! in! trauma.! The!current! understanding! is! that! it! is! an! endogenous! derangement! in! hemostasis!believed! to! be! triggered! by! the! presence! of! severe! tissue! injury! and! systemic!hypoperfusion!(5).!This!condition!develops!within!minutes!from!the!onset!of!injury.!Floccard! et! al! have! shown! that! 56%! of! trauma! patients! (n=45)! had! abnormal!coagulation!profile!on*scene!before!administration!of!intravenous!fluids!(7).!!Consensus! is! still! lacking! on! the! best! test! or! threshold! to! define! ATC.! The! most!widely!used!test!is!the!Prothrombin!time!ratio!(PTr)!or!international!normalized!ratio!(INR)! with! varying! cut*off! limits! ranging! between! 1.2! –! 1.5.! A! multicenter!retrospective! cohort! study! of! 3646! trauma! patients! had! shown! that! patients!with!INR!>!1.2!had!significantly!higher!mortality!rates!and!transfusion!requirements!(p!<!0.001),!hence! the! researchers!proposed! this!cut*off! limit! to!be!used! to!define!ATC!clinically! (5).! Similarly,! other! studies! have! shown! a! significant! increase! in! overall!mortality!and!in!the!need!for!massive!transfusion!among!trauma!patients!with!INR!≥!1.5!(8,9).!!The! diagnosis! of! ATC! has! been! associated! with! poor! outcome! among! trauma!patients.!It!was!shown!to!be!an!independent!predictor!of!mortality!after!accounting!for! other! potential! risk! factors! (10,11)! and! it! has! been! associated!with! a! four*fold!increase! in! mortality! in! trauma! patients! (12).! Frith! et! al! had! identified! a! dose*dependent! increase! in! mortality! and! transfusion! requirements! among! trauma!patients! diagnosed! with! ATC! (INR! >! 1.2)! (5).! Moreover,! ATC! has! been! shown! be!associated! with! complicated! in*hospital! course! in! terms! of! longer! duration! of!ventilation,! hospital! and! ICU! admission! and! progression! to! multiorgan! failure!(5,13,14).!!! 4!1.2.2 Pathophysiology!of!ATC!!!! ATC! is! a! complex! phenomenon! that! encompasses! several!disturbances/defects! in! the!coagulation!process.!Knowledge!about! these!defects! is!rapidly!evolving!with!the!evolution!of!diagnostic!techniques!and!growing!interest!in!this! field.! These! defects! include! low! fibrinogen! levels,! hyperfibrinolysis,! systemic!anticoagulation! through! activation! of! protein! C,! platelets! dysfunction,! endothelial!injury,!and!factor!V!depletion!(6,13,15*17).!!Fibrinogen! depletion! following! major! trauma! had! been! documented! in! animal!studies!(18)!but!the!exact!threshold!levels!to!diagnose!hypofibrinogenemia!have!not!been! defined! for! trauma! patients.! Recently,! a! prospective! cohort! study! of! 517!patients!showed!that!14%!of!trauma!patient!had!fibrinogen!levels!below!1.5!g/L!and!these! levels!were! independently! associated!with! higher! injury! severity! scores! and!shock!(P!<!0.001)!(11).!!!Interest! in! documenting! the! role! of! hyperfibrinolysis! in! ATC! has! been! increasingly!growing! especially! with! the! advances! in! the! diagnostic! modalities;! namely! the!viscoelastic! assays.! Hyperfibrinolysis! is! a! significant! independent! predictor! of!mortality! (19,20)! and! it! has! been! associated!with! the! development! of!multiorgan!failure! (21).!Moreover,! the!survival!advantage!by! the!administration!of! tranexamic!acid!to!trauma!patients!as!was!revealed!by!the!CRASH*2!trials!confirms!the!central!role!of!hyperfibrinolysis!in!ATC!(17).!!!!Platelet! counts! do! not! decline! frequently! to! clinically! significant! levels! that!would!explain! the! magnitude! of! coagulopathy! after! injury.! This! suggests! that! platelets’!contribution! to! ATC! is!mainly! qualitative! rather! than! quantitative.! A! retrospective!study! of! platelets! function! using! multiple! electrode! aggregometry! in! 163! trauma!! 5!patients! showed! a!minor! but! significant! decrease! in! platelet! function! among!non*survivors!(15).!!1.3 Diagnosis!of!ATC!! Expeditious! diagnosis! and! treatment! of! ATC! is! challenging! but! essential! if!exsanguinating!trauma!patients!are!to!be!salvaged.!Empiric!treatment!strategies!for!bleeding!trauma!patients!have!been!developed!in!anticipation!of!ATC!being!present,!though!these!do!not!target!the!patient!specific!deficiencies!in!coagulation!that!may!or! may! not! be! present.! Early! identification! of! these! specific! defects! is! critical! to!targeted! therapy.! The!majority!of! trauma! centers!worldwide!use! the! conventional!coagulation!profile!tests!(PT;!Prothrombin!Time,!INR;!International!Normalized!Ratio!and!aPTT;!Activated!Partial!Thromboplastin!Time)!along!with!the!platelet!count!and!fibrinogen!level!as!a!standard!to!diagnose!ATC.!However,!these!tests!fail!to!provide!a!comprehensive!description!of!platelets! function,! clot! firmness! and! lysis,!which!are!important!contributors!to!the!pathophysiology!of!ATC.!The!poor!sensitivity!of!these!tests!to!detect!these!defects!in!ATC!is!partially!due!to!the!fact!that!they!were!initially!designed! to! diagnose! coagulation! factor! deficiencies! and! dysfunction! (often!secondary! to! anticoagulation! therapy).! Moreover,! these! tests! are! performed! in!plasma! rather! than! whole! blood! excluding! the! cellular! components! of! the!coagulation!process!and!hence! they!cannot!be!used! to! reflect! in! the!entire! in*vivo!coagulation!disturbances!(22).!!!The!turnaround!time!for!conventional!coagulation!profile!has!been!estimated!to!be!around!40*60!minutes! (23)! and! can! reach!up! to! 88!minutes! in! some! centers! (24).!These!delays!compromise!their!utility!in!trauma!resuscitation!settings.!!!!! 6!1.3.1 Viscoelastic!Hemostatic!Assays!!! Viscoelastic! Hemostatic! Assays! (VHAs)! (RoTEM:! Rotational!Thromboelastometry! and! TEG! Thromboelastography)! are! real! time,! point! of! care!tests! that! measure! the! viscoelastic! properties! of! the! clot.! They! give! a! dynamic!picture! of! the! coagulation! process! starting!with! initiation! of! the! clot! formation! to!clot! propagation! and! firmness! and! then! ending! with! clot! lysis.! These! assays! are!performed!on!whole!blood,!a! fact! that!allows! them!to! identify!different!defects! in!the! coagulation! process! beyond! clotting! factor! deficiencies! including! the!contribution! of! platelets! and! fibrinogen! to! clot! stability! and! the! presence! of!abnormal!fibrinolysis.!!!RoTEM!analysis!is!performed!on!a!citrated!whole!blood!sample!that!is!aliquoted!into!a!test!cuvette.!The!reaction!is!initiated!by!adding!a!specific!reagent!to!the!cuvettes!to! activate! coagulation.! A! cylindrical! pin! that! rotates! right*and*left! at! an! angle! of!4.75°!and!is!vertically!immersed!into!the!cuvette.!As!the!coagulation!progresses,!the!forming! clot! exerts! increasing! resistance! on! the! rotating! pin! which! is! detected!optically!and!displayed!graphically!versus!time.!TEG!machines!operate!on!the!same!basic!principle!with!the!exception!that!in!TEG!the!cuvette!is!rotating!rather!than!the!pin.!Since!the!pin!is!suspended!freely!from!a!thin!wire,!TEG!is!susceptible!to!vibration!and!mechanical!shocks!(25).!!!Limitations!of!VHAs:!• Insensitive! to! the! effect! of! anti*platelet! agents! (aspirin,! clopidogrel! and!abciximab)!and!von!Willebrand!factor.!!• Normal!result!does!not!exclude!the!presence!of!anticoagulants.!!!!! 7!1.3.1.1 RoTEM!Assays!and!Terminology!! The!RoTEM!machine!is!a!four*channel!system!that!is!able!to!run!four!assays!simultaneously!for!the!same!patient!using!different!activating!or!inhibiting!reagents.!In!the!EXTEM!assay,!the!reaction!is!activated!by!tissue!factor!(as!in!PT).!It!is!therefore!sensitive!to!deficiencies!in!the!extrinsic!pathway!of!the!coagulation!process!(factors!VII,! X,! V,! II,! and! Fibrinolysis).! In! contrast,! the! INTEM! assay! is! activated! by! contact!phase!(as! in!aPTT)!to!detect!deficiencies! in!the!intrinsic!pathway!(factors!XII,!XI,! IX,!VIII,!X,!V,! II! and! fibrinogen).!Both!EXTEM!and! INTEM!are!also! capable!of!detecting!platelet!dysfunction!and! fibrinolysis!as!well.! In! the!FIBTEM!assay,!cytochalasin!D! is!added!to!the!reaction!to!block!the!effect!of!platelet!function!and!hence!isolate!the!effect!of!fibrinogen!on!clot!firmness.!Adding!aprotinin!to!the!reaction!(APTEM!assay)!inhibits!fibrinolysis! in!vitro!and!comparing!this!assay!to!EXTEM!allows!for!early!and!accurate!detection!of!fibrinolysis!that!is!amenable!to!antifibrinolytic!therapy.!Finally,!adding!heparinase!to!the! INTEM!assays!blocks!the!effect!of!any!heparin!present! in!the! sample.! Comparing! this! assay! (HEPTEM! assay)! to! INTEM! assay! allows! for!detection!of!heparin*related!coagulation!disturbances!(16,19,26).!!The!results!of!these!assays!are!generally!displayed!by!the!RoTEM!system!in!a!graph![graph]! with! numeric! values! pertaining! to! the! different! measured! timings,! clot!strength!and!clot!lysis.!The!main!reported!parameters!are:!!* Clotting!Time!(CT):!the!time!from!the!start!of!the!reaction!to!the!initiation!of!clotting.! This! value! reflects!mainly! the! concentration!of! coagulation! factors!and!fibrinogen.!!* Clot! Formation! Time! (CFT):! the! time! from! initiation! of! clotting! until! the!machine! detects! 20! mm! of! clot! firmness.! This! value! depends! on! fibrin!polymerization,!thrombin!formation!and!stabilization!of!the!clot!by!FXIII.!!* A5!or!A10:!the!clot!firmness!amplitude!at!5!or!10!minutes!respectively.!!! 8!* Maximum! Clot! Firmness! (MCF):! the! maximum! clot! firmness! amplitude!detected! during! the! entire! analysis.! It! reflects! increasing! polymerization! of!the!clot!by!fibrin,!platelets!and!FXIII.!!* Maximum! Lysis! (ML%):! is! the! percentage! of! the! reduction! in! clot! firmness!after!reaching!maximum!firmness!at!different!points!of!time!(i.e.!at!10!or!30!minutes)!(16,19,26).!!!Figure!1W1!RoTEM!Tracing!(26)!! !1.3.1.2 Interpretation!of!TEG!and!RoTEM!parameters!!! Prolongation! of! the! CT! indicates! hypocoagulability! and! decrease! in! the!concentration!of! the!coagulation! factors,!which!can!be!due!to!several! reasons! (i.e.!consumption,!dilution!or! loss).!Decreases! in! the!early!amplitudes! (i.e.!A5!and!A10)!and! the! MCF! indicate! hypofibrinogenemia! and/or! decreased! platelets! number/!function.!Fibrinogen!contribution!to!the!clot!firmness!is!determined!by!FIBTEM*MCF!and! the!platelet! contribution!by! the! formula!EXEM*MCF!–!FIBTEM*MCF.! Increased!ML%!(i.e.!>!15%!at!60!minutes)!indicates!hyperfibrinolysis,!which!can!be!confirmed!by!a!normal!APTEM*ML%!(19).!!!!! 9!1.4 Resuscitation!in!trauma!! The! main! focus! of! resuscitation! in! exsanguinating! trauma! patients! is! to!maintain! critical! organ! perfusion! and! tissue! oxygenation! until! definitive! control! of!bleeding!is!achieved!at!which!point!full!restoration!of!hemostasis!becomes!possible.!These! measures! are! crucial! in! the! initial! phases! of! resuscitation! to! avoid! the!progression!of!acidosis!and!hypothermia!from!uncontrolled!hemorrhage!that!further!exacerbate!coagulopathy! (27).!The!concepts!of!damage!control! resuscitation! (DCR)!and! massive! transfusion! focus! on! rapid! identification! of! patients! at! risk,! early!administration!of!blood!products!along!with!limited!the!use!of!crystalloids! in!order!to! restore! perfusion! and! reverse! coagulation! abnormalities.! These! measure! are!taken! to! avoid! the! development! of! the! “lethal! triad”:! coagulopathy,! acidosis! and!hypothermia! which! have! been! associated! with! the! poor! outcomes! in! trauma!patients! (28).! In! the! absence! of! rapid! and! reliable! diagnostic! modalities! to! guide!blood! transfusion,! blood! products! are! administered! empirically! or! at! fixed! ratios!according! to! the! institutions!policies/protocols.! The!optimum! ratio! at!which!blood!products! (PRBC,! FFP!and!platelets)! should!be!administered! remains!unknown.!The!PROPPR! trial! have! shown! that! those! patients! who! received! transfusion! with! FFP:!Platelets:!PRBC!at!a!ratio!of!1:1:1!achieved!more!hemostasis!and!had!lower!rates!of!death! from! exsanguination! compared! to! those! who! received! a! ratio! of! 1:1:2.!However,!there!was!no!significant!difference!between!the!two!groups!in!terms!of!24!h!or!30!days!mortality!(29).!!!With! the! increasing! interest! in! utilizing! VHAs! (RoTEM! and! TEG)! in! trauma! setting,!clinicians!can!potentially!diagnose!the!specific!coagulation!disturbances!in!a!clinically!relevant!time!frame!and!hemostatic!management!can!be!targeted!or!“goal*directed”!according!to!the!identified!defects!and!patient’s!needs.!Moreover,!these!assays!can!be!potentially!useful!in!monitoring!the!patient’s!response!to!any!intervention.!These!advantages!might! help! in! a!more! efficient! correction! of! coagulation! abnormalities!! 10!with! improved! hemostasis! as! well! as! reducing! exposure! to! allogeneic! blood!products,!avoiding!the!complications!associated!with!empiric!use!of!blood!products!and!over!transfusion!(TRALI,!volume!overload,!sepsis,!etc.)!(30,31).!!!1.5 Overall!research!hypothesis!! We! hypothesize! that! incorporating! RoTEM! assays! in! trauma! resuscitation!protocols!will! lead!to!rapid!and!accurate!identification!of!coagulation!disturbances!and!hence! will! aid! in! targeted! resuscitation! and!more! rapid! correction! of! patient! specific!coagulopathy.!!!1.6 Overall!research!objective!! The!overall!objective!of!this!thesis!is!to!evaluate!the!role!of!RoTEM!assays!in!the!diagnosis!and!management!of!ATC!in!the!published!studies!and!in!the!clinical!setting!of!a!level!1!trauma!center.!!!!1.7 Thesis!format,!structure!and!objectives!of!research!studies!! This! thesis! consists! of! two! connected! projects! (a! systematic! review! and! a!prospective!study),!reporting!the!methods!and!results!of!each!of!them!separately.!These!two! projects! share! a! common!objective! of! assessing! the! role! of! RoTEM!assays! in! the!setting!of!trauma!resuscitation.!!* Chapter!one!presents!background! information!on!the!topic!of!Acute!Traumatic!Coagulopathy! and! the! current! challenges! related! to! the! diagnosis! and!management!of!this!condition.!!! 11!* Chapter! two! is! a! systematic! review! that! aims! to! review! the! current! literature!regarding! the! role! of! RoTEM! in! diagnosing! ATC! and! further! guide! the!management!of!this!condition.!!* Chapter! three! is!a!prospective!study!that!was!conducted! in!Vancouver!General!Hospital.! The!aim!of! the! study!was! to! evaluate! the! impact!of! implementing!of!RoTEM!guided!resuscitation!protocol!for!trauma!patients!admitted!to!Vancouver!General!Hospital!on!early!identification!of!ATC!and!utilization!of!blood!products.! 12!Chapter!2 The!Role!Of!RoTEM!Assays! In!The!Diagnosis!And!The!Management! Of! Acute! Traumatic! Coagulopathy:! A!Systematic!Review!!!! 13!2.1 Chapter!Summary!!BACKGROUND!Hemorrhage! is! one! of! the! leading! causes! of! mortality! in! major! trauma,! and! is! often!exacerbated! by! a! complex! coagulation! derangement! called! Acute! Traumatic!Coagulopathy!(ATC).!Early!and!accurate!assessment!of!hemostasis!in!trauma!patients!is!required!before! targeted! therapy! for!ATC!can!be! instigated!and!hemorrhage!arrested.!Current!Conventional!Coagulation!Tests!(CCTs)!are!time!consuming!and!do!not!provide!a!comprehensive! description! of! all! potential! coagulation! disturbances! in! ATC.! To!overcome!these!limitations,!two!point*of*care!viscoelastic!assays!(Thromboelastography!(TEG)! and! Rotational! Thromboelastometry! (RoTEM)! have! been! increasingly! used! to!diagnose!ATC.!The!aim!of!this!paper!is!to!review!the!current!literature!regarding!the!role!of!RoTEM!in!diagnosing!and!managing!ATC.!!!!METHODS!A! systematic! review! of! the! published! literature! from! 2003! till! March! 2015! was!conducted!in!Medline!(OvidSP),!EMBASE!(OvidSP)!and!Cochrane!Library!(CENTRAL).!!!RESULTS!A!total!of!20!clinical!studies!were!reviewed.!Key!findings!were!that!RoTEM!parameters:!![1]!Had!good!detection!rates!for!ATC,!showed!moderate!to!strong!correlation!with!the!standard! coagulation! tests,! and!provided!extra! information! regarding! the!dynamics!of!clot!formation,!stability!and!lysis!in!a!shorter!span!of!time!(<!15!minutes).!![2]!Were!independent!predictors!of!mortality,!injury!severity!and!the!need!for!massive!transfusion.!![3]!Can!guide!resuscitation!of!bleeding!trauma!patients!with!allogeneic!blood!products,!Fibrinogen!and!recombinant!factors.!!!!! 14!CONCLUSION!RoTEM! Assay! provides! rapid! and! reliable! means! to! assess! the! complex! coagulation!disturbances! in! trauma! patients.! This! advantage! allows! for! potentially! early*targeted!utilization! of! blood! products! and! hence! minimizing! complications! associated! with!empiric!transfusion!of!allogeneic!blood!products.!!!2.2 Methods!!2.2.1 Search!protocol!and!eligibility!Criteria!!! A! systematic! review! of! the! published! literature! on! the! role! of! RoTEM! in! the!diagnosis! and! management! of! ATC! in! the! following! databases:! Medline! (OvidSP),!EMBASE! (OvidSP)! and! Cochrane! Library! (CENTRAL).! A! combination! of! MeSH! and!keywords! search! was! used! to! identify! all! the! possible! articles.! Keywords! used! were:!“thromboelastometry”,! “thromoelastometry”,! “ROTEM”,! “thromboelastgraophy”,!“trauma! induced! coagulopathy”,! “coagulopathy! of! trauma! shock”,! “acute! traumatic!coagulopathy”,! “multiple! trauma”,! “penetrating! trauma”.! The! resulting! citations! from!the! preliminary! search!were! screened! by! title! and! potentially! relevant! citations!were!selected!to!be!fully!reviewed.!Database!search!was!further!augmented!by!bibliography!search!to!further!identify!any!potentially!relevant!studies.!!!The!following! limits!were!applied!during!the!search!process:!Human,!English! language,!age! (18! *!65!years!old),! time!period!2003! till!March!2014.!Review!articles,! conference!abstracts,!case*series/reports!and!studies!reporting!on!the!use!of!TEG!exclusively!were!excluded.! In!addition,! studies! reporting!on! the!used!of!RoTEM! in!non*trauma! settings!(including! those! on! burns! exclusively),! animal! and! ex*vivo! studies! and!were! excluded!from!the!analysis!as!well.!!!! 15!!2.2.2 Data!extraction!and!analysis!!! All! the! relevant! articles!meeting! the! inclusion! criteria! were! reviewed! in! detail!and! the! following! data! were! abstracted! from! them:! study! design,! main! objective,!characteristics! of! the! study! population,! RoTEM! assays! used,! transfusion! protocol! and!outcomes!(mortality!and!blood!product!utilization).!!The!methodology!of!these!studies!was!evaluated!using!Newcastle*Ottawa!Scale!for!non*randomized!studies!(32).!For!cohort!studies,!a!study!can!be!awarded!one!star!for!each!component!in!the!selection!and!outcome!categories,!while!two!stars!can!be!awarded!in!the! comparability! category.! The!maximum!possible!number!of! starts! awarded! for! any!given! study! is! 9.! Exposure! in! this! setting! was! defined! as! diagnosis! and!management!using! RoTEM! Assays.! Non*exposed! cohort! was! defined! as! a! comparable! cohort! of!patients! managed! using! assays! other! than! RoTEM.! Outcome! was! defined! as! the!diagnosis!of!ATC!defects!by!RoTEM!or!the!prediction!of!the!need!of!blood!transfusion,!poor!outcome!and!mortality.!!Data!pooling!and!metaanalysis!was!not!carried!out!due!to!qualitative!heterogeneity! in!the!selected!studies!as!different!researchers!used!different!cut*off!values!to!define!ACT!and!utilized!different!RoTEM!assays!and!parameters.!Extracted!data!was!summarized!in!tabular!format!and!they!were!grouped!into!different!themes!according!to!the!outcomes!they!reported!on.!!!2.3 Results!!!! The! search! protocol! yielded! 866! citations! [figure! 2! –! 1],! after! excluding! the!duplicates!and!screening!the!citations!by!title!and!abstract!we!identified!29!potentially!! 16!relevant! articles.! These! articles!were! fully! evaluated! and! 9! of! them!were! excluded! as!they! violated! the! inclusion! criteria.! A! total! of! 20! studies! were! finally! selected! to! be!included!in!this!review.!!!!!Figure!2W1!Study!flow!diagram!of!the!systematic!review!! !!!2.3.1 Characteristics!of!the!studies!!! All!of!the!included!studies!were!observational!(14!prospective!cohort!studies!and!7!retrospective!Cohort!studies)!with!no!Randomized!Controlled!Trials!(RCTs).!!A! total! of! ten! studies! were! reporting! on! the! role! of! RoTEM! in! the! diagnosis! of!coagulation!defects! in!ATC,! seven! studies! on! its! role! to! predict! blood! transfusion! and!identify!the!optimum!FFP:!PRBC!ratios!in!trauma!resuscitation,!five!studies!on!its!role!in!predicting!mortality!and!poor!outcomes!and!only!two!studies!on!the!role!of!RoTEM!to!guide!resuscitation.!!!! 17!The!grand!total!number!of!patients!included!in!these!studies!was!3804!patients!(range:!!20!–!601).!Two!studies!did!not!report!on!the!percentage!of!males!included!(21,33),!but!the!majority!of! these!patients!were!males! (75.5%,! range!59.0%! *!100%).!The!mean!of!median!(or!mean)!age!was!39.6!years!(range:!21!–!58.9!years)!and!the!mean!of!median!(or!mean)!ISS!was!26.5!(range:!10!–!55).!!!!2.3.2 Quality!of!the!methodology!of!the!selected!studies!!! All! of! the! included! studies! were! non*controlled! except! one! (30)! in! which! the!outcomes!of!patients!managed!by!RoTEM!based!resuscitation!protocol!were!compared!to! a! historical! group!managed! by! CCT.! Two! studies! compared! RoTEM! parameters! to!healthy! volunteers! to! study! the! effect! of! RoTEM!parameters! defect!with! the! patients!outcomes!(25,34).!!!The!average!Newcastle*Ottawa!Scale![Table!2!*1]!was!6.0!stars!(out!of!9,!SD:!0.56),!with!majority!of!studies! losing!2!stars!due!to! lacking!an!appropriate!non*exposed!cohort! in!addition!to!in*adequacy!of!follow*up!in!two!studies!(35,36).!!! 18!Table!2W1!Quality!of!the!included!studies!using!NewcastleWOttawa!Scale!for!cohort!studies!(32)!Author,!year!(Reference)! Selection! Comparability!of!Cohorts! Outcome! Total!!Representativeness!of!the!exposed!cohort!!Selection!of!nonWexposed!cohort!!Ascertainment!of!exposure!! Outcome!not!present!at!baseline!!Assessment!of!Outcome!! FollowWup!duration! Adequacy!of!followWup! !Meyer!et!al,!2014!(37)! *! *! *! *! *! *! *! *! 6/9!Woolley!et!al,!2013!(34)! *! *! *! *! *! *! *! *! 6/9!Reed!et!al,!2013!(33)! *! *! *! *! *! *! *! *! 6/9!Davenport!et!al,!2011!(38)! *! *! *! *! *! *! *! *! 6/9!Tauber!et!al,!2011!(16)! *! *! *! *! *! *! *! *! 6/9!Doran!et!al,!2010!(36)! *! *! *! *! *! *! *! *!! 5/9!Rugeri!et!al,!2007!(25)! *! *! *! *! *! *! *! *! 6/9!Raza!et!al,!2013!(39)! *! *! *! *! *! *! *! *! 6/9!Kutcher! et! al,!2012!(21)! *! *! *! *! *! *! *! *! 6/9!Rourke!et!al,!2012!(11)! *! *! *! *! *! *! *! *! 6/9!Levrat!et!al,!2008!(40)! *! *! *! *! *! *! *! *! 6/9!Schöchl!et!al,!2011!(41)! *! *! *! *! *! *! *! *! 6/9!Leemann!et!al,!2010!(42)! *! *! *! *! *! *! *! *! 6/9!Theusinger!et!al,!2011!(20)! *! *!! *! *! *! *! *! *! 6/9!Schochl!et!al,!2011!!(43)! *! *! *! *! *! *! *! *! 6/9!Schochl!et!al,!2009!(44)! *! *! *! *! *! *! *! *! 6/9!Schochl!et!al,!2010!!(45)! *! *! *! *! *! *! *! *! 6/9!Schochl!et!al,!2011!(46)! *! *! *! *! *! *! *! *! 8/9!Khan!et!al,!2014!!(47)! *! *! *! *! *! *! *! *! 6/9!Davenport!et!al,!2011!(35)! *! *! *! *! *! *! *! *! 5/9!A!study!can!be!awarded!one!star!in!the!selection!and!outcome!category,!while!two!stars!can!be!awarded!in!the!comparability!category.!Exposure!in!this!setting!was!considered!management!using!RoTEM!Assays!and!non*exposed!group!is!considered!representative!if!a!comparable!group!was!managed!using!assays!other!than!RoTEM.!Maximum!possible!score!is!9.!!!! 19!2.3.3 RoTEM!in!the!diagnosis!of!ATC!!2.3.3.1 Diagnosis!of!coagulopathy!!Eight!studies!reported!on!the!role!of!RoTEM!in!the!diagnosis!of!ATC,!six!of!them!reported!on!the!degrees!of!correlation!between!different!RoTEM!and!CCT!parameters.!The!definition!of!ATC!by!CCT!or!RoTEM!was! variable! across!different! research! groups![Table!2*2].!!A! prospective! study! of! 88! trauma! patients! showed! that! patients!with! ATC! (INR! >! 1.6!and/or!aPTT!>!60!s!and/or!a!platelet!count!<!100x109!L*1!and/or!a!fibrinogen!<!1!g!L*1)!had!significant!increase!in!CT!and!CFT!with!a!decrease!in!amplitudes!at!10!min,!15!min!and!MCF.!There!was!a!significant!correlation!between!RoTEM!and!CCT!parameters!(PT!and! EXTEM! A15! (r=0.66),! aPTT! and! INTEM! CFT! (r=0.91),! fibrinogen! and! FIBTEM! A10!(r=0.85),! platelet! count! and! INTEM*A15! (r=0.57),! all! p! <! 0.001)! (25).! In! another!prospective! cohort! study! of! trauma! patients! (n=334),! ROTEM!parameters! (EXTEM!CT,!EXTEM!MCF!and!FIBTEM!MCF)!were!significantly!correlated!with!CCTs!(all!Spearman!r>!0.5,!p!<0.001)!(16).!!!Early! RoTEM!amplitudes! (A5)! had! been! shown! to! be! as! sensitive! as!MCF! to! diagnose!fibrinogen! depletion! and! platelet! dysfunction.!Davenport! et! al! (n=! 300)! reported! that!EXTEM!amplitudes!at!5!minutes! (EXTEM!A5!≤!35!mm)!were!able! to!detect!ATC! (INR!>!1.2)!correctly!in!77%!of!the!times!in!severely!injured!patients!(38).!Furthermore,!Rourke!et! al! (n=517)! reported! that! EXTEM! and! FIBTEM! amplitudes! at! A5! and! maximal! clot!formation!(MCF)!were!significantly!correlated!with!fibrinogen!levels!(r2!=!0.35!and!r2!=!0.44!respectively,!P!<!0.001).!The!sensitivity!and!specificity!of!FIBTEM!A5!<!9.5!mm!for!discriminating! patients! with! admission! fibrinogen! levels! below! 1.5! g! L! were! 78%! and!70%,!respectively!(11).!!!!! 20!RoTEM! assays! have! been! utilized! to! diagnose! ATC! in! military! trauma! settings.! In! a!prospective!study!of!patients!meeting!massive! transfusion!criteria,!RoTEM!parameters!significantly! detected! more! coagulation! disturbances! compared! to! CCT! (64%! vs.! 10%!respectively,! p!<!0.001)! (36).!Moreover,!Woolley!et! al! compared! the!ability!of!RoTEM!EXTEM!early!amplitudes!(A10)!to!detect!ATC!defined!as!EXTEM!MCF!<!40!mm.!EXTEM!A10!had!100%!sensitivity!and!70%!specificity! (n=!108! samples,!40!patients).!However,!The!level!of!agreement!between!EXTEM!CT!(ATC!<!40!mm)!and!INR!(>!1.5)!on!detecting!ATC!was!poor!(58%!of!the!samples,!Cohen!kappa!of!0.0377,!p!=!0.41),!but!the!number!of!samples!was! too! small! (n=40!samples)! for! the!authors! to!draw!a!definitive!conclusion!based!on!that!(34).!!!A!recent!prospective!study!of!182!severely!injured!adult!patients!showed!that!patients!diagnosed! with! trauma*induced! coagulopathy! (TIC;! defined! by! INR! >! 1.2)! had!significantly!lower!RoTEM!amplitudes!(EXTEM,!INTEM!and!FIBTEM!at!A5,!A10!and!MCF)!compared!to!non*TIC!patients.!Furthermore,!they!showed!that!fibrinogen!concentration!and!platelet!count!had!moderate!correlation!with!RoTEM!parameters!(0.3!≤!ρ!≤!0.7,!p!<!0.001),!the!greatest!degree!being!with!the!amplitude!at!10!minutes!(A10)!compared!to!A5!(p!<!0.001)!(37).!!!2.3.3.2 Diagnosis!of!hyperfibrinolysis!! The! accuracy! of! RoTEM! parameters! (clot! lysis! reversible! by! the! addition! of!aprotinin)!has!been!validated!against!euglobulin!lysis!time!(ELT!<!90!min),!the!traditional!gold! standard! test! for! the! diagnosis! of! hyperfibrinolysis! (HF)! [Table! 2*3].! Levrat! et! al!(n=23)!in!a!study!comparing!the!above!two!tests!concluded!that!RoTEM!parameters!can!rapidly!(≤!15!min!for!RoTEM!vs.!180!min!for!ELT)!and!accurately!detect!HF!(EXTEM*MCF,!100%!sensitivity!and!specificity)!(40).!!!! 21!Another! prospective! study! (n=288)! compared! the! performance! of! RoTEM!parameters!against! plasmin! anti*plasmin! complexes! levels! (HF:! PAP! >! 1500! μg/L)! to! diagnose! HF!showed!that!RoTEM!parameters!were!able!to!detect!HF!only!when!PAP!complex!levels!were!increased!to!30!times!normal!(P!<!0.001)!(39).!! 22!Table&2(2&Characteristics&And&Main&Findings&Of&Studies&Reporting&On&The&Role&Of&RoTEM&Assays&In&The&Diagnosis&Of&ATC&No.!! Author&& Sample&& Characteristics&& Type&of&study&(recruitment&period)&& Definitions&& Intervention&& Main&Findings&&1! Meyer!et!al.!(2014)!(37)! Adult!trauma!patients!meeting!local!TTA!criteria!(n=182)!!!Age:!43!(30A58)!ISS:!17!(9A26)!!Male:!75%! Prospective!cohort!study!!(Mar!2010!ADec!2011)!!ATC:!INR!>!1.2! None!!! TIC! patients! had! significantly! lower!amplitudes! in! TEG/RoTEM! compared!with!nonATIC!patients.!Fibrinogen! concentration! and! platelet!count!had!the!greatest!correlation!with!A10!compared!to!A5!(0.3!<!ρ!<!0.7!and!p!<!0.01). !! 2! Woolley!et!al.!(2013)!(34)! Severely!injured!patients!(n=48)!(108!samples)!!!!Age:!24!(21A26)!ISS:!34!(17A43)!!Male:!100%!!Prospective!cohort!study!!(21!May!2009!–!3!Jul!2009)!!ATC:!!INR!>!1.5!EXTEM!MCF!<!40!mm!Or!2/3!rule!“abnormality!in!the!two!of!three!coagulation!domains:!initiation,!dynamic!and!strength”.!!!None!! EXTEM! A5! and! A10! predicted!coagulopathy!(as!defined!by!MCF!<!40!mm)! with! sensitivities/specificities! of!0.96/0.58!(A5)!and!1.00/!0.70!(A10).!!There!was!a!poor!agreement!between!RoTEM!parameters!and!CCTs!(58%!but!the!sample!was! small,!n=40!samples),!kappa!of!0.0377!(p!=!0.41).!!3! Reed!et!al.!(2013)!(33)! Adult!patients!with!hemorrhagic!shock!(n=40)!No.!Trauma:!20!ISS:!10!(1A19.75)!! Prospective!cohort!study!!(28!Sep!2010!A!31!Aug!2011)!ATC:!INR!≥!1.5!! None!! FIBTEM! A10! vs.! fibrinogen! correlated!with!a!k!coefficient!of!0.33,!EXTEM!A10!vs.! platelet! count! correlated! with! a! k!coefficient! of! 0.24.! ! EXTEM! A10! A!FIBTEM! A10! vs.! platelets! correlated!! 23!No.!! Author&& Sample&& Characteristics&& Type&of&study&(recruitment&period)&& Definitions&& Intervention&& Main&Findings&&!! ! with!a!k!coefficient!of!0.06.!EXTEM!A10!was!an!excellent!marker!for!coagulopathy.!!A10!and!MCF!correlated!well!(k!=!0.98).!!RoTEM! obtained! 7! min! earlier! than!CCTs.!!!4! Rourke!et!al.!(2012)!(11)! Adult!trauma!patients!(≥16!years)!(n=517)!!!!Age:!36!(23A51)!ISS:!14!(8A27)!Male:!78%!!Prospective!cohort!study!!(Jan!2008!–!Dec!2010)!ATC:!!INR!>!1.2!and/or!EXTEM!A5!≤!35!mm.!!!None!!! EXTEM! and! FIBTEM!A5! and!MCF!were!significantly! correlated! with! Clauss!fibrinogen! levels! (p! <! 0.001).! A5!showed!stronger!correlations!than!MCF!for! both! FIBTEM! (r2! =! 0.44,!p! <! 0.001)!and!EXTEM!(r2!=!0.35,!P!<!0.001).!!ExAvivo! fibrinogen! administration!reversed! abnormalities! in! ROTEM!parameters.!5! Davenport!et!al.!(2011)!(38)!Adult!trauma!patients!(>!15!yrs)!meeting!the!criteria!for!TTA!(n=300)!Age:!33!ISS:!12!Male:!82%! Prospective!cohort!study!&(Jan!2007!–!Jun!2009)!ATC:!INR!>!1.2!! None!(physicians!blinded!to!the!results).!! EXTEM! A5! ≤! 35! mm! had! a! detection!rate!of!77%!for!ATC.!!61%!of!patients!with! severe! injury!and!shock! had! A5! ≤! 35! mm! compared! to!33%!with!INR!>1.2.!!!6! Tauber!et!al.!!(16)! Blunt!trauma!patients!(Injury!Severity!Score!≥15!or!Glasgow!Coma!Score!≤14)!(n=!334).!!!!Age:!43!ISS:!34!(24,!45)!Male:!77.8%!!Prospective!cohort!study!!(Jul!2005!–!Jul!2008)!ATC:!INR!>!1.5!! None!! ROTEM! parameters! were! significantly!correlated!with!plasmatic!tests!(EXTEM!CT! vs.! PT! r=! A! 0.535,! EXTEM! MCF! vs.!platelet!count!r=!0.660,!EXTEM!MCF!vs.!fibrinogen# r=! 0.793,! FIBTEM! MCF! vs.!fibrinogen!r=!0.811,!p!<0.001).!!! 24!No.!! Author&& Sample&& Characteristics&& Type&of&study&(recruitment&period)&& Definitions&& Intervention&& Main&Findings&&7! Doran!et!al.!!(2010)!(36)! Trauma!patients!meeting!MT!activation!criteria!(n=25)!Age:!21!(18A35)!MT!ISS:!35!(25A50)!NonAMT!ISS:!20!(19A20)!!Male:!100%!Prospective!cohort!study!!(Jan!2009!–!Mar!2009)!ATC:!PT>!18!s!and/or!aPTT!>!60s!!!None! ROTEM!detected!more!ATC! cases! than!CCT!(64%!vs.!10%,!p=!0.0005).!!EXTEM! A10! min! was! associated! with!abnormal!MCF.!8! Rugeri!et!al.!(2007)!(25)! Adult!trauma!patients!(n=88)!!!Age:!34!±!16!ISS:!22!(12A34)!!Male:!77.2%!!Prospective!cohort!study!!(July!–!October!2004)!!!ATC:!INR!>!1.6!and/or!an!APTT!>!60!s!and/or!a!platelet!count!<!100.109!LA1!and/or!a!fibrinogen!less!than!1!g!LA1.!!!None!! Significant! correlations! were! observed!between! PT! and! EXTEM! A15! (r=0.66),!aPTT! and! INTEM! CFT! (r=0.91),!Fibrinogen! and! FIBTEM! A10! (r=0.85)!and! Platelet! count! and! INTEM! A15!(r=0.57)!(p<0.001).!!!Cutoff! values! for! EXTEM! A15! and!FIBTEM! A10! had! a! good! sensitivity,!specificity,! positive! and! negative!predictive!value!in!predicting!a!PT!>!1.5!of! control! value! and! a! fibrinogen! less!than!1!g!LA1.!TTA,!Trauma! team!activation;!MT,!Massive! transfusion;!TIC,!Trauma! induced!coagulopathy;! ISS,! Injury! severity! score;! INR,! International!normalized! ratio;!PT,!Prothrombin!time;!aPTT,!activated!partial!thromboplastin!time!!&! 25!Table&2(3&Characteristics&And&Main&Findings&Of&Studies&Reporting&On&The&Role&Of&RoTEM&Assays&In&The&Diagnosis&Of&Hyperfibrinolysis&No.!! Author&! Sample&! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!1! Raza!et!al.!(2013)!(39)! Patients!meeting!TTA!criteria!(age!>!15!yrs)!(n=288)! Age:!37!(36A39)!!ISS:!10!(4A25)!!Male:!81.9%!&Prospective!cohort!study!!(Jan!2007A!Jun!2009)!HF:!RoTEM:!ML!>!15%!!Plasmin!antiAplasmin!complexes!(>!1500).!None!! Only! 5%! of! patients! had! severe!fibrinolysis!on!TEM,!but!57%!of!patients!had! evidence! of! ‘moderate’! fibrinolysis,!with! PAP! complex! levels! elevated! to!over! twice! normal! (>! 1500! μg! LA1)!without!lysis!on!TEM.!!RoTEM! detected! clot! lysis! only! when!PAP!complex!levels!were!increased!to!30!times!normal!(P!<!0.001).!2! Levrat!et!al.!(2008)!(40)& Adult!trauma!patients!(n=87)!!!Age:!29!(21A43)!!ISS:!20!(11A29)!Male:!78%!!Prospective!cohort!study!!(4!July!2004!–!31!Oct!2004)!!!!HF:!!ELT!<!90!min!RoTEM:!Reduction!in!amplitudes!that!was!reversible!by!Aprotinin.!!None!! EXTEM!MCF! (18!mm),! CL! 30! (71%)! and!APTEM!MCF! (increase! by! 7%)! detected!HF!with!a!sensitivity!of!100%,!75%,!80%!respectively!and!specificity!of!100%.!!MCF! showed! the! best! correlation! with!the! ELT! score! (r2:! 0.68;! slope:! 20.06;!P<0.001).!!RoTEM! was! obtained! in! shorted!turnaround! time! (RoTEM:! <! 15! min! vs.!ELT:!180!min).!!HF,!Hyperfibrinolysis;!TTA,!Trauma!team!activation;!ISS,!Injury!severity!score;!ELT,!Euglobulin!lysis!time.!! 26!2.3.4 Prognostic.value.of.RoTEM.parameters...2.3.4.1 Prediction.of.mortality.and.poor.outcomes... The!diagnosis!of!hyperfibrinolysis!and!reduced!clot!firmness!by!RoTEM!has!been!associated!with!higher!rates!of!mortality!and!poor!outcomes![Table!2=4].!HF!was!shown!to! be! an! independent! predictor! of! mortality! (16,19,20).! A! retrospective! study! of! 33!trauma!patients!with!HF!showed!that!different!patterns!of!HF!(fulminant!HF:!100%!lysis!within! 30!min,! intermediate! HF:! 100%! lysis!within! 30=60!min! and! late! HF:! 100%! lysis!after! 60! minutes)! resulted! in! different! rates! of! mortality! (100%,! 91%,! or! 73%!respectively)!(19).!Moreover,!HF!was!shown!to!be!associated!with!multiorgan!failure!in!a!prospective!study!of!11!trauma!patients!(HF:!63.2%!vs.!Non=HF:!24.6%,!p!=!0.004)!(21).!!!Similarly,!decreased!MCF!was!shown!to!be!an!independent!predictor!of!24!h!mortality!(n=334,!mortality=!47)!(OR!0.94,!95%!confidence!interval:!0.9–0.99,!adjusted!for!Hb!and!BE)!(16).!!!!In!patients!with!isolated!severe!head!injury!(AIS!head!≥!3!and!AIS!extracranial!<!3,!n=88),!non=survivors! had! significantly! longer! CT! and! CFT! (for! both! INTEM! and! EXTEM)! and!reduced!MCF!(EXTEM,!INTEM!and!FIBTEM)!(p<!0.001).!EXTEM!MCF!was!shown!to!be!the!best! predictor! of!mortality! in! this! cohort! of! patients!with! AUC! =! 0.77! (95%! CI! 0.665=0.850,!p<0.001)!(43).!! 27!Table&2(4&Characteristics&and&Main&Findings&of&Studies&Reporting&on&the&Role&of&RoTEM&Assays&in&Prediction&of&Mortality&and&Morbidity&No.!! Author&! Sample&description&(n)! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!1! Kutcher!et!al.!(2012)!(21)! Adult! trauma!patients! with!critical! trauma!!(≥18! years)!(n=115)!!Age:!40.8!(19.2)!ISS:!22.0!(14.5)!!&Prospective!cohort!study!!(Nov!2010!–!Mar!2012)!HF:! ML! ≥! 10%!reversible! by!aprotinin!treatment.!!None!! HF! by! RoTEM! was! associated! with!multiorgan!failure!(63.2%!vs.!24.6%,!p!=!0.004),!24Wh!mortality! (34.8%!vs.!3.5%,!p! <! 0.001)! and! inWhospital! mortality!(52.2%!vs.!12.9%,!p!<!0.001).!!Temperature!≤!36.0!C,!pH!≤7.2,!relative!coagulopathy! (INR!≥!1.3!or!aPTT!≥!30),!or! relative! thrombocytopenia! (platelet!count! ≥! 200)! identified! HF! with! 100%!sensitivity! and! 55.4%! specificity! (AUC!0.777).!!2! Theusinger!et!al.!(2011).!(20)& All!emergency!patients!with!HF!(trauma!and!nonWtrauma,!n=35).!!!Control:!24!polytrauma!patients!with!no!HF.!!!Trauma!HF:!!W Age:!42.2!(15.4)!W ISS:!55!(19)!W Male:!69.2%!!Trauma!NonWHF:!W Age:!36.3!(15.9)!W ISS:!43!(14)!!W Male:!70.8%!Retrospective!cohort!study!!!(Apr!2008!–!Apr!2010)!!!HF:!EXTEM!and!INTEM!ML! ︎ ≥!15%/h!reversible!by!aprotinin!(APTEM)!treatment.!!!!9!out!of!13!patients!received!1W2!g!IV!TXA.!!HF! was! an! independent! predictor! of!mortality! (at! 30Wdays)! in! trauma!patients! (p=0.017)! compared! to! nonWtrauma!patients!and!the!matched!nonWHF!patients.!!3! Tauber!et!al.! Blunt!trauma! Age:!43!! Prospective! ATC:!INR!>!1.5! None!! Decreased! MCF! and! HF! were!! 28!No.!! Author&! Sample&description&(n)! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!(2011)!(16)& patients!(Injury!Severity!Score!≥15!or!GCS!≤14)!(n=!334)!!!ISS:!34!(24,!45)!!Male:!77.8%!!!cohort!study!!(Jul!2005!–!Jul!2008)!! independently! associated! with! early!mortality!(24!h)!(MCF!OR!=!0.94,!95%!CI!(0.9–0.99);! LI! 60! OR! =! 0.96,! 95%! CI!(0.938,! 0.983)! after! adjusting! for! Hb!and!BE).!!4! Schochl!et!al.!(2011).!(43)& Trauma!patients!with!isolated!severe!head!injury!(AIS!head!≥!3!and!AIS!extracranial!<!3)!(n=88)!!Age:!47!(26W66)!ISS!survivors:!20!(16W26.25)!ISS!nonWsurvivors:!29!(25W30.75)!Male:!76%!!!Retrospective!cohort!study!!(Jan!2005W!Oct!2010)!ATC:!INR!>!1.3!and/or!aPTT!>!35!s!and/or!Plt!>!100!and/or!Fibrinogen!<!1.5!g/L.!!RoTEM:!EXTEM!(CT!>!80!s,!CFT!>!159!s,!MCF!<!50!m),!INTEM!(CT!240!s,!CFT!110!s,!MCF!<!50!mm)!and!FIBTEM!(MCF!<!7mm).!None!! NonWsurvivors! had! significantly!prolonged!CT!and!CFT!(for!both!EXTEM!and!INTEM)!and!lower!MCF!(for!EXTEM,!INTEM! and! FIBTEM)! compared! to!survivors! (p<! 0.001).! No! significant!difference!in!ML!and!LI!60.!!EXTEM! MCF! and! aPTT! were! the! best!predictors!of!mortality!(MCF!AUC!0.77,!95%!CI!(0.665W0.850,!p<0.001)).!!!5! Schochl!et!al.!(2009)!(19)& Adult!trauma!patients!with!HF!(n=33)!!!!Age:!45!(20W88)!!ISS:!47!(14)!Male:!67%!!!Retrospective!cohort!study!!(Jan!2003W!Dec!2007)!Fulminant!HF:!100%!lysis!within!30!min,!Intermediate!HF:!100%!lysis!within!30W60!min!and!late!HF:!100%!lysis!after!60!min.!!None!! HF! was! an! independent! predictor! of!overall!mortality.!NonWsurvivors! had! prolonged! CFT! (p! =!0.042),! and! lower!platelet! contribution!to! maximum! clot! firmness! (MCFEX! W!MCFFIB)!(p!=!0.026).!Overall! mortality! rates! were! different!among! different! patterns! of! HF!(Fulminant! HF:! 100%;! intermediate! HF!! 29!No.!! Author&! Sample&description&(n)! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!91%!and!late!HF:!73%).!!TTA,!Trauma! team!activation;!MT,!Massive! transfusion;! ISS,! Injury! severity! score;!AIS,!Abbreviated! injury! scale;! INR,! International!normalized! ratio;!PT,!Prothrombin! time;!aPTT,!activated!partial!thromboplastin!time;!HF,!Hyperfibrinolysis;!Hb,!Hemoglobin;!BE,!Base!excess;!AUC,!Area!under!the!curve;!GCS,!Glasgow!coma!scale!! 30!2.3.4.2 Prediction.of.the.need.of.blood.transfusion..! Several! RoTEM! parameters! have! been! shown! to! predict! the! need! for!massive!transfusion!(MT;!defined!as!≥!10!units!PRBC!in!24!hours)!in!trauma!settings![Table!2H5].!A!retrospective!analysis!of!EXTEM!and!INTEM!parameters! in!53!trauma!patients!(18!of!which! were! MTs)! showed! that! INTEM! MCF! and! hemoglobin! ≤! 10! mg/dl! were!independent!predictors!of!MT.!Using!abnormal!INTEM!MCF!as!a!single!predictor!of!MT!revealed!an!area!under!the!ROC!curve!of!0.824!(95%!confidence!interval:!0.708–0.941;!p!<!0.001)!(42).!A!similar!study!was!conducted!by!Schochl!et!al!(n=323,!MT=78)!with!the!inclusion! of! FIBTEM! assay! (in! addition! to! INTEM! and! EXTEM),! which! revealed! that!FIBTEM!MCF!and!A10!amplitudes!were! the!best!RoTEM!parameters! for!predicting!MT!(AUC! =! 0.84,! 95%! CI! (0.79! to! 0.88),! AUC=! 0.83,! 95%! CI! (0.78! to! 0.87)! respectively).!Although! hemoglobin! and! PT!were! better! predictors! in! this! study,! RoTEM! assays! can!provide!these!information!in!a!shorter!period!of!time!(41).!!!Davenport!et!al!(n=300)!showed!that!EXTEM!A5!≤!35!mm!had!a!better!detection!rate!for!the!need!of!MT!(≥!10!PRBC/!12!h)!compared!to!INR!>!1.2!(71%!vs.!43%!respectively,!p!<!0.001)!with!a!negative!predictive!value!of!99%!for!MT.!Finally!a!recent!study!by!Meyer!et!al!showed!that!A10!was!significantly!lower!in!MT!patients!compared!to!nonHtransfused!patients!in!all!RoTEM!assays!except!for!FIBTEM!(37).!!RoTEM!parameters!were!also!associated!with!the!need!for!any!PRBC!or!FFP!transfusion.!EXTEM! A5! ≤! 35! mm! was! found! to! be! associated! with! higher! likelihood! of! PRBC!transfusion!(46%!vs.!17%,!p!<!.001)!and!of!FFP!transfusion!(37%!vs.!11%,!p!<!.001)!(38).!In!another!study!(n=334),!FIBTEM!MCF!<!7!mm!was!found!to!be!significantly!associated!with!need!for!any!PRBC!transfusion!(OR!0.92,!95%!CI!0.87–0.98)!(16).!!! 31!Table&2(5&Characteristics&and&Main&Findings&of&Studies&Reporting&on&the&Role&of&RoTEM&Assays&in&Predicting&Massive&Transfusion&or&Any&PRBC&Transfusion&No.!! Author&! Sample&! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!1! Meyer!et!al.!(2014)!(37)! Adult!trauma!patients!meeting!TTA!criteria!(n=182)!!Age:!43!(30@58)!ISS:!17!(9@26)!!Male:!75%! Prospective!cohort!study!!!(Mar!2010!@!Dec!2011)!!ATC:!INR!>!1.2! None!!(Patients! are!managed! using!1:1:1,! bleeding!patients! not! in!shock! were!managed!according!to!TEG!using! FFP,!Fibrinogen,!Cryo,!TXA!and!plt.)!A10! (for! both! EXTEM! and! INTEM! but!not! FIBTEM)! was! the! only! parameter!that! was! different! between! non@transfused! and! patients! receiving! ≥! 10!RBC!units.!!!2! Schöchl!et!al.!(2011)!(41)! Adult!trauma!patients!with!ISS!≥!16.!!(n=!323)!MT:!78!Non@MT:!245!Age:!44!(26@59)!ISS.!MT:!27!(20@30)!ISS!non@MT:!42!(34@50)!Male:!78.9%!!!!Retrospective!cohort!study!!!(Jan!2005!–!Dec!2010)!!MT:!≥!10!PRB/24!h!!! None!!Patients!were!managed!according!to!RoTEM!results,!primarily!by!PRBC,!PCC!and!fibrinogen!!MT! group! had! significantly! lower!MCF!(for!INTEM,!EXTEM!and!FIBTEM).!!FibTEM!MCF! and! A10! values!were! the!best! in! predicting! massive! transfusion!(AUC!0.84!and!0.83!respectively).!A10! ≤4! mm! and!MCF! ≤7! mm! had! the!best! sensitivity! (63.6%! and! 78.2!respectively)! and! specificity! to! detect!MT!(82.9%!and!86.8%!respectively).!!Hemoglobin! ≤! 10.1! g/dL! had! slightly! a!betted! predictive! value! of! MT! (AUC!0.87,!95%!CI!0.83!to!0.91).!!3! Davenport!et!al.!(2011)!(38)! Adult!trauma!patients!(>!15!yrs.)!meeting!the! Age:!median!33!ISS:!median!12!Male:!82%! Prospective!cohort!study!! ATC:!INR!>!1.2!MT:!≥!10!PRBC/!12!hr.!! None!(blinded!to!the!results).!! A5! ≤! 35! mm! detected! MT! in! 71%,!compared! to! 43%! for! INR! >! 1.2! (p! <!0.001).! A5! ≤! 35! mm! had! a! negative!! 32!No.!! Author&! Sample&! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!criteria!for!TTA!(n=300)!! !! (Jan!2007!–!Jun!2009)! ! predictive!value!of!83%!for!any!red!cell!transfusion,!and!99%!for!MT.!!Patients! with! A5! ≤! 35! had! higher!likelihood! to! receive! PRBC! transfusion!(46%! vs.! 17%,! p! <! .001)! and! FFP! (37%!vs.!11%,!p!<!.001)!4! Tauber!et!al.!!(16)! Blunt!trauma!patients!(Injury!Severity!Score!≥15!or!Glasgow!Coma!Score!≤14)!(n=!334).!!Age:!43!y!Male:!77.8%!ISS:!34!(24,!45)!! Prospective!cohort!study!!(Jul!2005!–!Jul!2008)!ATC:!INR!>!1.5!! None!! FIBTEM! MCF! was! significantly!associated!with!need!for!red!blood!cell!transfusion! (OR! 0.92,! 95%! CI! 0.87–0.98).! FIBTEM! MCF! <! 7! mm! provided!the! maximum! sum! of! sensitivity! and!specificity!for!PRBC!transfusion. !5! Leemann!et!al.!(2010)!(42)! Patients!with!ISS!≥!16!and!available!RoTEM!results!(n=53)!!MT:!18!Non@MT:!35!!Age:!36.9!(2.5)!ISS:!31.1!(1.7)!Male:!75.5%!!!Retrospective!cohort!study!!(Jan!2006!–!Dec!2006)!MT:!≥!10!U!PRBC/!24!h.!!ATC:!!None!! MT! patients! had! significantly! longer!CFT!and!lower!amplitudes!on!admission!compared! with! non@MT! patients! (p! <!0.05).!!Abnormal! INTEM!MCF!and!hemoglobin!≤! 10.0! g/dl! were! independent!predictors!of!MT!(separately).!INTEM! MCF! as! a! single! variable! to!predict! MT! AUC! of! 0.824! (95%! CI!0.708–0.941;!p!<!0.001).!6! Davenport!et!al.!(2011)!(35)!&Trauma!patients!who!receive!>!4!U!PRBC!(Age!≥16)!(n!=50)!!Age:!42!(26!–!57)!ISS:!29!(24!–!38)!!Male:!82%!!!Prospective!cohort!study!!(Jan!2007!–!Aug!2009)!ATC:!INR!>!1.2!! None!! RoTEM! and! CCT! coagulation!parameters! deteriorated! with! FFP:!PRBC!ratios!<1:2.!!Patients!who!received!FFP:!PRBC!ratios!of! 1:2! to! 3:4! showed! the! maximal!! 33!No.!! Author&! Sample&! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!hemostatic!effects;!12%!decrease!in!PT!(p! <! 0.006),! 56%! decrease! in! CT! (p! <!0.047),! and! 38%! increase! in! MCF! (p! <!0.024).!Transfusion! with! >! 1:1! ratio! was! not!associated! with! any! additional!improvement! with! beneficial! effects!being! confined! to! coagulopathic!patients.!!7! Khan!et!al.!(2014)!(47)& Trauma!patients!who!receive!>!4!U!PRBC!(Age!≥16)!(n!=106)!!Age:!44!(30!–!60)!!ISS:!34!(25!–!41)!!Male:!76%!!!Prospective!cohort!study!!(Jan!2008!–!Jan!2013)!ATC:!!INR!>!1.2!!RoTEM:!A5!≤!35!mm,!CT!>!94!s,!CFT!>!171!s,!MCF!<!54!mm,!alpha!<!65!degrees.!None!(patients!managed!by!major!hemorrhage!protocol).!!43%!of!patients!were!coagulopathic!(A5!≤!35).!This!percentage!increased!as!the!hemorrhage! was! ongoing.! There! was!no! improvement! in! any! RoTEM!parameter!during!ongoing!bleeding.!TTA,!Trauma! team!activation;!MT,!Massive! transfusion;! ISS,! Injury! severity! score;!AIS,!Abbreviated! injury! scale;! INR,! International!normalized! ratio;!PT,!Prothrombin! time;!aPTT,!activated!partial!thromboplastin!time;!HF,!Hyperfibrinolysis;!Hb,!Hemoglobin;!BE,!Base!excess;!AUC,!Area!under!the!curve;!GCS,!Glasgow!coma!scale;!FFP,!Fresh!frozen!plasma;!Cryo,!Cryoprecipitate;!TXA,!Tranexamic!acid;!PRBC,!Packed!red!blood!cells!!! 34!2.3.5 Utilization-of-RoTEM-parameters-in-goal9directed-therapy---- There!were!only!two!studies!reporting!on!the!outcomes!associated!with!utilizing!RoTEM!assays!in!goal;directed!therapy![Table!2;6].!Schochl!et!al!showed!that!mortality!rate! of! trauma! patients! managed! by! RoTEM! guided! resuscitation! protocol! (using!fibrinogen!and!prothrombin!complex!concentrate,!or!PCC,!for!factor!replacement)!was!significantly!lower!than!the!predicted!mortality!rate!by!the!TRISS!score!but!not!the!RISC!score! (p! ! =!0.032!and!p!>!0.05! respectively).!After!excluding!17!patients!with! isolated!head! injury,! the!difference! in!mortality!rate!was!more!pronounced!compared!to!TRISS!and!RISC!(p=0.0018!and!p=0.014!respectively)!(45).!!!The! same! authors! conducted! a! retrospective! study! to! compare! PRBC! and! platelet!transfusion!rates!among!trauma!patients!managed!by!RoTEM!guided!fibrinogen!and!PCC!therapy!with!no!FFP!(n=80)!to!a!previous!cohort!of!patients!managed!primarily!by!FFP!guided! by! CCT! (n=601).! They! reported! that! PRBC! transfusion! was! avoided! in! 29%! of!patients!managed!by!fibrinogen!and!PCC!compared!to!only!3%!in!patients!managed!by!FFP!transfusion!(P!<!0.001).!Transfusion!of!platelet!concentrate!was!avoided!in!91%!of!patients!in!the!fibrinogen;PCC!group,!compared!with!56%!in!the!FFP!group!(P!<!0.001).!There! was! no! significant! difference! in! mortality! rates! between! the! two! cohorts! of!patients!(30).!! 35!Table&2(6&Characteristics&and&Main&Findings&of&Studies&Reporting&on&the&Role&of&RoTEM&Assays&in&Goal(Directed&Therapy&No.!! Author&! Sample&! Characteristics&& Type&of&study&(recruitment&period)&& Definitions&! Intervention&! Main&Findings&!1! Schöchl!et!al.!(2010)!(45)! Adult!trauma!patients!who!received!≥!5!units!PRBC!!(n=!131)!!Age:!46!(18)!ISS:!38!(15)!Male:!73%!&Retrospective!cohort!study!!(Jan!2005!–!April!2009)!!!ATC:!>!1.5!times!EXTEM!CT,!and/or!FibTEM!MCF!<!10!mm.!!!RoTEM!guided!resuscitation:!2Z4!g!Fibrinogen!for!decreased!firmness!1,000! –! 1,500! U!PCC! for!prolonged!clotting!time.!!Mortality!rate!(24.4%)!was!significantly!lower!than!the!rates!predicted!by!TRISS!score!(33.7%,!p!=!0.032)!but!not!by!RISC!scores!(28.7%,!p!>!0.05).!!After!excluding!patients!with!traumatic!brain! injury! (n=17),! the! observed! in!mortality! rate! (14%)! was! significantly!lower!than!the!rates!predicted!by!TRISS!(27.8%,!p!!=!0.0018)!and!RISC!(24.3%,!p!!=!0.014).!2! Schöchl!et!al.!(2011)!(30)& Adult!trauma!patients!with!!ISS!≥16!and!base!deficit!≥!2!mmol/L.!!!FibrinogenZPCC!group!(n!=!80)!FFP!group!(n!!=!601)!FibrinogenZPCC!group:!!Age:!37.3!(14.5)!ISS:!35.5!(10.5)!Male:!79%!!FFP!group:!!Age:!39.1!(14.5)!Male:!74%!ISS:!35.2!(12.5)!Retrospective!cohort!study!!FibrinogenZPCC!group!(2006!–!2009)!FFP!group!(2005!–!2008)!!ATC:!>!1.5!times!EXTEM!CT,!and/or!FibTEM!MCF!<!10!mm.!!RoTEM!guided!resuscitation:!2Z4!g!Fibrinogen!for!decreased!firmness!1,000!–!1,500!U!PCC!for!prolonged!clotting!time.!!PRBC! transfusion! was! avoided! in! 29%!of!patients!in!the!fibrinogenZPCC!group!compared! with! only! 3%! in! the! FFP!group!(P!<!0.001).!Platelet! concentrate! transfusion! was!avoided! in! 91%! of! patients! in! the!fibrinogenZPCC! group,! compared! with!56%!in!the!FFP!group!(P!<!0.001).!Mortality! was! comparable! between!groups.!ISS,! Injury! severity! score;! FFP,! Fresh! frozen! plasma;! PCC,! Prothrombin! concentrate;! PRBC,! Packed! red! blood! cells;! RISC,! Revised! injury! severity! classification! score;! TRISS,!Trauma!and!injury!severity!score!!&&! 36!2.4 Discussion+!2.4.1 Main+Findings++ In!this!systematic!review!we!identified!20!studies!reporting!on!the!role!of!RoTEM!assays!in!the!diagnosis!of!ATC,!predicting!massive!transfusion,!mortality!and!morbidity.!!The! majority! of! studies! reported! an! overall! good! correlation! between! RoTEM!parameters! and! CCT! with! the! strongest! being! between! fibrinogen! levels! and! clot!firmness! parameters! (MCF! for! both! EXTEM! and! FIBTEM)! (11,16,25,37).! Early! clot!amplitudes! (A5,! A10! and! A15)! were! found! to! be! strongly! correlated! with! MCF! and!fibrinogen! levels,! providing! the! treating! physician! reliable! data! on! clot! firmness! in!approximately!less!than!15!minutes!(33,34,36,37).!!!Moreover! RoTEM! assays! were! able! to! delineate! additional! hemostatic! disturbances!(decreased!clot! firmness,!platelet!dysfunction!and!hyperfibrinolysis)! in! the!coagulation!process! compared! to! CCT.! These! disturbances! have! been! demonstrated! to! have! an!important!role!in!predicting!mortality,!morbidity,!massive!transfusion!and!the!need!for!any! PRBC! transfusion! accurately.! Although! the! predictive! value! of! RoTEM!parameters!was! somewhat! similar! of! that! of! hemoglobin! (41,42),! these! assays! can! identify! the!specific!hemostatic!defects!in!realPtime!allowing!for!targeted!management.!!!Utilizing!RoTEM!assay!as!a!pointPofPcare!test!to!guide!resuscitation!in!trauma!has!been!shown!to!be!potentially!useful! in! reducing!exposure! to!allogeneic!blood!products! (30)!but! its! impact! on!mortality! is! yet! to! be! defined.! A! single! center! RCT! among! patients!undergoing! cardiac! surgery! had! shown! a! significant! decrease! in! transfused! PRBC,! FFP!and! platelet! concentrates! among! patients! managed! by! RoTEM! guided! transfusion!protocol! compared! to! CCT.! Moreover,! these! patients! had! lower! cost! of! hemostatic!therapy,! duration! of! mechanical! ventilation,! ICU! stay! and! 6Pmonths! mortality! (48).!! 37!However,! a! Cochrane! review! (49)! on! the! utility! of! RoTEM! assays! to! guide! massive!transfusion!in!cardiac!and!liver!surgery!settings!demonstrated!its!effect!in!reducing!the!mount!of!transfused!blood!product!but!the!was!no!improvement!in!patients!outcomes!in!terms!of!mortality!and!morbidity.!!!Recently,!a!Cochrane!review!was!conducted!to!evaluate!the!accuracy!of!RoTEM!and!TEG!assays! in! the! diagnosis! of! ATC! (50).! Three! observational! studies!were! included! in! the!review! (25,34,38)! in! which! early! RoTEM! amplitudes! (A5,! A10! and! A15)! were! used! to!diagnose!ATC.!Due!to!the!small!number!of!the!included!studies,!the!authors!concluded!that!there! is!very! limited!evidence!with!regards!to!the!accuracy!of!RoTEM!parameters!and!they!recommended! limiting!the!use!of!RoTEM!assays!to!research!settings!until! its!role!is!proven!in!larger!scale!prospective!controlled!studies.!Another!systematic!review!was! recently! published! (51)! on! the! role! of! TEG! and! RoTEM! in! the! diagnosis! of! ATC,!guiding!blood!transfusion!and!reducing!mortality! in!trauma!patients,!which!found!that!although!the!performance!of!TEG/RoTEM!might!be!superior!to!CCT,!but!strong!evidence!is!lacking!on!whether!their!use!reduces!allogeneic!blood!transfusion!or!mortality!rates.!!!!2.4.2 Limitations++ There!are!several!limitations!to!this!systematic!review.!The!most!important!is!the!quality!of!the!methodology!of!the!included!studies.!The!majority!of!these!studies!were!unPcontrolled,!singlePcenter!and!observational! in!nature,! limiting!the!generalizability!of!the!their!findings.!In!addition,!many!of!the!studies!had!small!sample!sizes.!The!primary!objective! of! the!majority! of! the! studies!was! to! assess! the! feasibility! of! implementing!RoTEM! assays! or! to! describe! the! prevalence! of! coagulopathy! as! defined! by! RoTEM!parameters! but! not! to! assess! the! accuracy! of! RoTEM! parameters! in! specifically!diagnosing!ATC.!!!! 38!A!second!limitation!is!the!inconsistency!in!the!definition!of!ATC!or!HF!between!different!research! groups! (as! per! RoTEM! or! CCTs)! in! terms! of! the! parameters! used! and! the!abnormal!threshold!levels!of!these!parameters.!Different!research!groups!used!different!hemostatic! resuscitation! protocols,! with! the! European! systems! relying! primarily! on!fibrinogen! and! PCCs! while! North! American! groups! tend! to! administer! FFP! and!cryoprecipitate.!These!discrepancies!limited!the!comparability!of!their!findings!and!data!pooling!for!metaPanalysis.!!!A!third!limitation!is!the!fact!that!there!is!very!limited!amount!of!literature!reporting!on!the!role!of!RoTEM!assays!in!trauma,!with!only!two!studies!reporting!on!potential!roles!of!RoTEM!guided!resuscitation!on!patient!outcomes.!+Finally,!a!fourth!limitation!is!related!to!our!search!protocol.!!Some!relevant!articles!could!have! been! excluded! by! limiting! the! search! to! three! databases! on! and! restricting! the!inclusion! criteria! to! articles! published! in! English,! though! such! studies! could! have! an!increased!likelihood!of!methodologic!concerns!and!publication!bias.!!!2.5 Conclusion++RoTEM!assays! are!promising! tools! that! can!potentially!provide! the! treating!physicians!with! reliable!data!on!coagulation!disturbances! in!clinically! relevant! time.!These!assays!provide!a!dynamic!description!of! the!entire! coagulation!process! in! realPtime,! allowing!them! to! be! used! in! goal! directed! therapy.! There! is! limited! evidence! on! the! role! of!RoTEM! in! reducing!blood! transfusion! requirements! and! improving!patients’! outcomes!with! one! retrospective! study! demonstrating! the! potential! role! of! these! assays! in!reducing!exposure!to!allogeneic!blood.!There!is!an!urgent!need!for!a!large!scale,!multiPcenter! controlled! trial! to! properly! evaluate! the! accuracy! of! RoTEM! assays,! the!parameters! and! thresholds! that! best! diagnose!ATC!and! the! impact! of! utilizing!RoTEM!! 39!assays! to! guide! blood! transfusion! on! exposure! to! blood! products,! morbidity! and!mortality.!!! 40!Chapter+3 The+ Impact+ Of+ RoTEM+ Generated+ Coagulation+ Data+On+The+Early+Diagnosis+Of+Acute+Traumatic+Coagulopathy+And+Implications+On+Management:+A+Prospective+Study+!! 41!3.1 Chapter+Summary++BACKGROUND+ATC! is! a! complex! phenomenon! that! results! from! interplay! of! different! hemostatic!defects.!The!detection!of!which!remains!limited!with!the!conventional!coagulation!tests!(CCTs).!Viscoelastic!assays!(Thromboelastography!and!Rotational!Thromboelastometry)!have!been!increasingly!used!to!detect!these!hemostatic!defects!in!trauma!patients.!Our!aim!was!to!assess!whether!RoTEM!assays!(a)!provide!the!treating!clinicians!with!more!useful!data!than!conventional!coagulation!tests! (CCTs)!and!(b)!Can!be!obtained!within!clinically!significant!timings!or!shorter!time!spans!than!CCTs.!!+METHODS+A!prospective!observational!study!was!conducted!at!our!center.!All!patients!meeting!the!trauma! team! activation! criteria! who! had! RoTEM! assay! on! admission! were! included.!Clinical!data,!laboratory!results!and!blood!transfusion!requirements!in!the!first!24!hours!were!recorded.!ATC!was!defined!by!presence!of!at!least!one!of!the!following:!INR!>!1.2,!aPTT!>!38!seconds,! fibrinogen!<!1.5!g/L,!or!platelet!count!<!100!x!109/L.!RoTEM!assay!results!were!correlated!with!CCTs,!injury!characteristics!and!transfusion!requirements!+RESULTS+A!total!of!63!patients!met!inclusion!criteria!from!Oct!2014!to!March!2015.!One!patient!of!these!had!an!INR!>!1.2!and!two!patients!had!fibrinogen!levels!<!1.5!g/L.!EXTEMC!CT!and!FIBTEM!A10!detected!100%!of!patients!with!ATC!defined!by!CCT!with!a!specificity!of!90.3%! and! 85.2%! respectively.! In! addition,! FIBTEM! A10! potentially! detected!coagulopathy! in! severely! injured! patients! that!would! have! been! otherwise!missed! by!CCT!parameters.!There!was!an!overall!significant!correlation!between!analogous!RoTEM!and!CCT!parameters!(all!Spearman!r!≥!0.35,!p!<!0.05).!!Although!the!median!turnaround!time!(TAT)!for!RoTEM!results!(35.0!min;!IQR:!29.0–!49.0!min)!was!slightly!longer!than!for!! 42!CCTs!(31!min;!IQR:!25.0!–!42.5!min)!there!was!a!progressive!improvement!in!TAT!during!the!study!period!as!the!process!efficiency!improved!over!time.!+CONCLUSION+RoTEM!assay!results!correlate!well!with!CCTs.!The!study!recruited!too!few!patients!with!major!hemorrhage!to!comment!on!the!utility!of!RoTEM!in!guiding!transfusion!practices.!In!stable!but!severely!injured!patients,!RoTEM!appears!to!be!more!sensitive!than!CCTs!in!detecting!subtle!coagulation!abnormalities.!The!clinical!significance!of!this!finding!is!yet!to!be!determined!though!it!is!intuitive!that!patients!with!the!potential!for!hemorrhagePrelated!injury!complications!may!benefit!from!correction!of!coagulation!defects!before!further! complications! evolve.!A! laboratoryPbased!RoTEM!program!does! not! appear! to!have! any! timeliness! advantage! over! CCTs! but! having! a! centrally! located! RoTEM! does!offer!certain!practical!advantages!over!pointPofPcare!usage.!!!3.2 Methods++!3.2.1 Study+Design++! This! interim! analysis! is! part! of! prospectively! collected! data! for! an! ongoing!beforePandPafter! study! to! evaluate! the! effect! of! implementing! RoTEM! guided!resuscitation! protocol! on! utilization! of! blood! products.! The! study! will! compare!transfusion! practices! in! patients! requiring! massive! transfusion! before! and! after!implementation!of!RoTEM.!Data!are!collected!prospectively!for!all!adult!trauma!patients!meeting!the!criteria!of!trauma!team!activation!(TTA)!and!had!RoTEM!assay!on!admission!to! the! ED! since! October! 8,! 2014! to! September! 30,! 2015.! A! subset! of! these! patients!(those!requiring!massive!transfusion)!will!form!the!study!cohort!and!will!be!compared!to!a!previous!cohort!of!similar!trauma!patients!admitted!during!the!period!October!2011!to!September!2014.!!! 43!!This!component!of!the!thesis!is!a!descriptive!study!reflecting!an!interim!analysis!of!data!collected! on! the! cohort! of! patients! admitted! from!Oct! 8! 2014! to!March! 31! 2015! on!whom! data! was! collected! and! includes! all! patients! irrespective! of! transfusion!requirements.!!!!3.2.2 Patient+Selection+(inclusion+and+exclusion+criteria)++ • Inclusion+Criteria:+All!adult!patients!(≥18!years!old)!admitted!to!Vancouver!General!Hospital!Emergency!Department!(VGH!ED)!meeting!the!criteria!for!trauma!team!activation!(TTA)!and!had!RoTEM!assay!performed!on!admission!to!the!ED!were!included.!TTA!criteria!are!met!in!the!presence!of!any!of!the!following:!P Physiological!Criteria:!• Respiratory!Rate!<!10!breaths/min!or!>!29!breaths/min!• Systolic!blood!pressure!<!90!mmHg!• Glasgow!Coma!Scale!≤!13!P Anatomical!Criteria:!• Penetrating!injury!(head!to!pelvis)!• Flail!chest!• Trauma!+!burn!>!20%!of!body!surface!area!• Unstable!pelvis!• Amputation!(proximal!to!hand/wrist)!• Traumatic!limb!paralysis!!• Two!or!more!long!bone!fractures!P Mechanism!of!injury:!• Trauma!in!pregnancy!with!major!mechanism!at!any!stage!!!! 44!• Exclusion+Criteria:+The!following!patients!were!excluded!from!the!study:!!P Any!patient!<!18!years!old!!P Patients!on!antiplatelet!agent!or!anticoagulant!therapy!P Patients!with!severe!liver!disease!!P Pregnant!patients.!P Patients!transferred!from!other!hospitals!with!an!extended!transfer!time!P Patients!who!received!any!blood!products!or!hemostatic!therapy!before!ED!presentation!!!3.2.3 Blood+sampling+and+RoTEM+analysis+!Blood!samples!for!the!routine!trauma!panel!and!RoTEM!analysis!were!drawn!immediately! after! insertion! of! intravenous! catheters! upon! admission! to! the! ED.!!!RoTEM!samples!were!collected!in!citrated!blood!tubes!(BD!Vacutainer®,!containing!3.2%!buffered!sodium!citrate!solution).!These!samples!were!immediately!sent!to!the!lab!via!pneumatic! tube! in!a! special! specimen!bag!with!a!RoTEM! flasher.! Since! the!RoTEM!assay!was!not!available!as!an!electronic!order!during!the!study!period,! the!lab!technicians!needed!to!be!notified!by!trauma!team!leader!to!run!test,!which!also!helped!expedite!RoTEM!machine!and!reagent!preparedness!!!RoTEM! analysis! was! performed! according! to! the! manufacturer! recommendations!(TEM! international,!Munich,! Germany).! Both! EXTEM! and! FIBTEM! assays!were! run!simultaneously!and!the!following!parameters!were!reported:!EXTEM!CT,!EXTEM!A10,!FIBTEM!A10,!EXTEM!ML%! (10!minutes)!and!EXTEM!ML%! (30!minutes).!The! results!were!faxed!from!the! lab!to!the!trauma!bay!or!the!operating!room!after!10!and!30!minutes!of!analysis.!Abnormal! reference!values! for! these!assays!were:!ECTEM!CT>!95! s,! EXTEM! A10! <! 50!mm,! FIBTEM! A10! <! 10!mm! and! EXTEM!ML%! >! 10%! at! 10!! 45!minutes.! These! thresholds! were! obtained! from! a! group! of! 25! healthy! volunteers!prior!to!implementing!the!RoTEM!guided!resuscitation!protocol!for!trauma!patients.!!INR,!aPTT,!platelet!count!and!fibrinogen!levels!were!measured!in!parallel!according!to!the!standard!laboratory!methods!at!VGH.!!++3.2.4 Transfusion+Protocol+at+Vancouver+General+Hospital+!Exsanguinating! trauma! patients! are! managed! according! to! The! Trauma!Exsanguination! Protocol! (TEP)! that! was! implemented! in! VGH! in! August! 2011! and!modified!in!October!2014.!The!activation!criteria!included!the!following:!P Any! patient! admitted! with! active! traumatic! hemorrhage! with! Systolic!Blood!Pressure!(sBP)!<!90!mmHg!(or!impalpable!radial!pulse)!and!failed!to!respond!to!0.5!–!1!L!Plasmalyte!bolus!OR!P Any!patient!admitted!with!active!traumatic!hemorrhage!with!Transfused!>!4!units!in!<!4!hours.!!!!Patients! typically! receive! a! bolus! of! 1! g! of! Tranexamic! acid! (TXA)! followed! by! an!infusion! of! 1! g! over! 8! hours.! PRBC! and! FFP! are! administered! in! a! 1:1! ratio! with!platelets!being!added!at!the!same!ratio!after!transfusing!the!fourth!paired!units!of!PRBC! and! FFP.! Blood! product! transfusion!was! guided! by! the! physiologic! response!along!with!the!results!of!the!routine!laboratory!tests.!!!Once! RoTEM! (and! CCT)! results! are! obtained,! resuscitation! of! these! patients! is!intended! to! be! goalPdirected,! targeting! specific! defects! in! the! coagulation! process![Appendices! A! and! B].! EXTEM! A10! value! of! <! 50! mm! is! used! to! define! Trauma!Induced!Coagulopathy.!EXTEM!CT!>!95!s!is!an!indication!to!administer!4!units!of!FFP!while!FIBTEM!A10!<!10!mm!is!an!indication!to!administer!10!U!of!cryoprecipitate!or!4g!of!fibrinogen.!Platelets!are!administered!if!EXTEM!A10!<!50!mm!and!FIBTEM!A10!! 46!>!10!mm.!Hyperfibrinolysis!is!diagnosed!if!EXTEM!Maximal!Lysis!(ML)!>!10%!and!it!is!an! indication! to! administer! an! additional! bolus! of! 2! g! tranexamic! acid.! These!parameters!are!interpreted!in!view!of!the!patient’s!clinical!picture.!!!!3.2.5 Data+collection+and+definitions+! Information! on! patients’! demographics,! medical! background,! injury! details!(onset,!mechanism!abbreviated! injury!scale!of!six!body!regions! (Head,!Face,!Chest,!Abdomen,! Extremities! (including! Pelvis),! External! and! Injury! Severity! Score)! were!collected.! In! addition,! admission! vital! signs,! Glasgow! coma! Scale! (GCS),! any!emergency! intervention! within! the! first! 4! hours! of! ED! admission! (laparotomy,!thoracotomy,! Interventional! Radiology! and! others)! and! length! of! hospital! and! ICU!stay!were!recorded.!!!Initial! laboratory! results! recorded! include! hemoglobin,! hematocrit,! platelet! count,!international! normalized! ratio! (INR),! activated! partial! thromboplastin! time! (aPTT),!fibrinogen,! lactate,!base!excess,! ionized!calcium! in!addition! to!RoTEM!parameters:!EXTEM! CT,! EXTEM! A10,! FIBTEM! A10,! EXTEM! ML%! along! with! their! respective!turnaround!times!were!documented.!In!addition,!the!type!and!number!of!transfused!blood!products!units!and!amount!of!administered!tranexamic!acid!were!recorded!at!6!and!24!hours!after!ED!admission.!!!ATC!was!defined!by!CCT!results!as!the!presence!of!any!of!the!following:!!INR!>!1.2,!aPTT!>!38!sec,!fibrinogen!<!1.5!g/L,!or!platelet!count!<!100!x!109/L.!Severe!injury!was!defined!as!ISS!≥!15![citation].!!!Data! was! abstracted! from! the! patients’! medical! charts,! British! Columbia! trauma!registry!(BCTR),!Patient!Care!Information!System!(PCIS)!and!lab!data!system.!Since!all!! 47!of!the!patients!were!managed!according!to!the!standard!of!care!at!VGH,!the!study!was! judged! to! be! of! minimal! risk! and! The! University! of! British! Columbia! Clinical!Research!Ethics!Board!approved!the!study!protocol!to!be!conducted!with!a!waived!consent!(UBC!CREB!No.!H14P02872).!!!3.2.6 Data+Analysis+! Descriptive! statistics!were!used! to!describe! the! characteristics!of! the! study!population! (as! mean! ±! standard! deviation! for! normally! distributed! continuous!variables,!median!and!interPquartile!range!(IQR)!for!other!no!parametric!continuous!variables! and! as! percentages! for! categorical! variables).! Student! tPtest!was!used! to!detect!statistical!differences!in!the!means!between!population!subgroups!while!ChiPsquare! or! Fisher’s! exact! test! were! used! to! detect! statistical! differences! in!proportions! where! appropriate.! Spearman’s! Rank! correlation! test! was! used! to!examine!correlations!between!RoTEM!and!CCT!parameters.!Test! turnaround! times!were! compared! graphically! using! stacked! histograms! and! point! and! interval!estimates!were!determined!for!the!betweenPgroup!difference.!!The! level! of! significance!was! set! at! p! <! 0.05.! ! Data!was! collected! using!Microsoft!Excel!(2007)!and!data!analysis!was!carried!out!using!R!program!(version!3.1.2).!!3.3 Results++3.3.1 Baseline+Characteristics+of+the+study+population++! A!total!of!141!patients!met!the!TTA!activation!criteria!during!the!period!October!8,! 2014! to! March! 31,! 2015.! Out! of! these,! eightyPtwo! patients! had! RoTEM! assay! on!! 48!admission! to! ED.! Nineteen! patients! were! excluded! from! the! study! as! they! were! not!fitting!the!inclusion!criteria![Figure!3!–!1].!!!!!Figure+3T1+Flow+diagram+of+patients+through+the+study+!!!A! total! of! 63! patients!were! finally! included.! The!demographic! data,! injury! details! and!clinical! characteristics! are! detailed! in! [Table! 3! –! 1].! The! median! age! of! the! study!population!was!45!years!(IQR:!29!–!57)!and!79.4%!of!them!were!males.!The!median!time!from!injury!to!ED!presentation!was!44.5!min!(IQR:!30.3!–!85.3)!and!the!median!ISS!was!17!(IQR:!7!–!26).!Fifteen!patients!(23.8%)!required!a!major!intervention!within!the!first!4!hours! of! ED! admission! (thoracotomy,! laparotomy,! interventional! radiology! and!craniotomy).!!!! 49!Table+3T1+Characteristics+of+the+study+population+(n=63)+Characteristics++ Median+(IQR)+or+Number+(%)+Age!(years)! 45!(29!–!57)!!Males!–!number!(%)! 50!(79.4%)!Time!from!Injury!until!ED!arrival,!min! 44.5!(30.3!–!85.3)!Systolic!blood!Pressure,!mmHg! 130!(120!–!155)!Injury!Severity!Score!(ISS)!! 17!(7!–!26)!P ISS!<!15! 29!(46.0%)!P ISS!≥!15! 34!(54.0%)!Glasgow!Coma!Scale!(GCS)!! 15!(14!–!15)!Surgery!within!4!hours!–!number!(%)! 15!(23.8%)!Mechanism+of+Injury++ Number+(%)!Blunt!injuries!! 46!(73.0)!Penetrating!injuries!! 16!(25.4%)!Burn! 1!(1.6%)!Laboratory+Data++ Median+(IQR)!Hemoglobin,!g/L! 132!(119!–!145)!!Platelets,!109/L! 220!(190!–!285)!INR! 1.0!(0.9!–!1.0)!!Fibrinogen,!g/L! 2.30!(2.00!–!2.75)!Lactate*!! 2.6!(1.4!–!4.9)!!Base!Excess*,!mEq/L! P!2.0!(P7.0!–!P1.0)!Blood+Transfusion+(6+hours)+ Number+(%)+Any!PRBC! 12!(19.0%)!Any!FFP! 6!(9.5%)!Any!Platelets! 5!(7.9%)!Any!Cryoprecipitate!! 4!(6.3%)!Any!TXA!! 8!(12.7%)!Clinical+Outcomes+ Median+(IQR)+or+Number+(%)!Duration!of!Hospital!stay!(Days)! 7!(3!–!14.)!Duration!of!ICU!stay!(Days)! 0!(0!–!3)!!InPHospital!mortality!P!number!(%)! 6!(9.5%)!!*! Data! missing! for! 21! patients.! Data! are! shown! as! number! (%)! or! median! (interPquartile!range).!INR,!International!Normalized!Ratio;!PRBC,!Packed!Red!Blood!Cells;!FFP,!Fresh!Frozen!Plasma;!TXA,!Tranexamic!Acid;!ICU,!Intensive!Care!Unit.!Number+(%)+or+Median+(IQR)!!!! 50!3.3.2 Diagnosis+of+Coagulopathy+(ATC)+by+RoTEM+vs.+CCT+++ The!prevalence!of!ATC!as!defined!by!CCT!and!RoTEM!are!presented!in![Table!3!–!2].!Using!CCTs,! INR!>!1.2!was!observed! in!one!patient!only! (1.6%)!and! low! fibrinogen!levels! (<! 1.5! g/L)! were! detected! in! two! patients! only! (3.2%).! In! contrast,! a! higher!percentage! of! patients! showed! abnormalities! in! RoTEM! assays.! Seven! patients! had!prolonged!clotting!time!in!EXTEM!(11.1%),!16!patients!had!low!EXTEM!A10!(25.4%)!and!11!patients!had!low!FIBTEM!A10!(17.5%).!Hyperfibrinolysis!(at!30!minutes)!was!detected!in!one!patient!(1.6%).!!!+Table+3T2+Prevalence+of+Coagulopathy+as+defined+by+RoTEM+and+Conventional+Coagulation+Tests+(CCT)+on+Admission+(n=63)+! Number+(%)+CCT+ !INR!>!1.2! 1!(1.6%)!Fibrinogen!<!1.5!g/L! 2!(3.2%)!Platelets!<!100!x!109/L! 0!(0.0%)!aPTT!>!38!s!! 2!(3.2%)!RoTEM++ !EXCTEM!CT!>!95!s! 7!(11.1%)!EXTEM!A10!<!50!mm! 16!(25.4%)!FIBTEM!A10!<!10!mm! 11!(17.5%)!ML!>!15%!(10!min)! 0!(0.0%)!ML!>!15%!(30!min)! 1!(1.6%)!!INR,!International!Normalized!Ratio;!aPTT,!Activated!Partial!Thromboplastin!Time;!EXTEM!CT,!Clotting!time;!EXTEM!A10,!EXTEM!Amplitude!at!10!minutes;!FIBTEM!A10,!FIBTEM!Amplitude!at!10!minutes;!ML,!Maximum!Lysis.!!!!!3.3.2.1 Detection+of+coagulation+factor+deficiencies+by+EXTEM+CT+vs.+INR+! EXTEM!CT!(>!95!s)!detected!100%!of!patients!with!INR!>!1.2!with!a!specificity!of!90.3%.!There!were!six!additional!patients!with!prolonged!CT!that!had!normal!INR!(INR!≤!1.2)![Table!3!–!3].!Scatterplots!of!INR!vs.!EXTEM!CT![figure!3!–!2]!showed!that!all!of!these!! 51!six!patients!had!a!blunt!injury,!two!of!them!had!severe!injury!(ISS!≥!15)!and!one!was!a!nonPsurvivor.!!!!Table+3T3+Detection+of+INR+abnormalities+by+EXTEM+CT+(n=63)+!+++++++++!Figure+3T2+Relationship+between+ INR+and+EXTEM+CT+separated+by+(A)+ Injury+severity,+(B)+Mortality+ outcome+ and+ (C)+Mechanism+ of+ Injury.+ (INR,+ International+ Normalized+Ratio;+ISS,+Injury+Severity+Score;+NonTSurvivors,+inThospital+mortality)!++! INR+>+1.2+ INR+≤+1.2+ Total++EXTEM+CT+>+95+s+ 1! 6! 7!EXTEM+CT+≤+95+s+ 0! 56! 56!! 1! 62! 63!! 52!3.3.2.2 Detection+of+hypofibrinogenemia+by+FIBTEM+A10+vs.+Clauss+fibrinogen+! FIBTEM!A10!had!a!detection!rate!of!100%!for!patients!with!low!fibrinogen!levels!(<! 1.5! g/L)! with! specificity! of! 85.2%[Table! 3! –! 4].! The! majority! of! patients! with! low!FibTEM!but!normal!fibrinogen!levels!had!severe!injuries!(ISS!≥!15)!compared!to!patients!with!normal!test!results!for!both!FIBTEM!A10!and!fibrinogen!levels!(88.8%!vs.!46.2%,!p!=!0.0139).!They!also!had!significantly!higher!rates!of!inPhospital!mortality!(22.2%!vs.!5.8%,!p! =! 0.0371)! and! cryoprecipitate! transfusion! (33.3%! vs.! 1.9%,! p=! 0.0172).! PRBC!transfusion! was! higher! among! this! group! as! well! but! it! did! not! reach! the! level! of!significance.!!!Table+3T4+Detection+of+Hypofibrinogenemia+by+FIBTEM+A10+vs.+Fibrinogen+levels+(n=63)++ Fibrinogen+<+1.5+g/L+ Fibrinogen+≥+1.+5+g/L+ Total++FIBTEM+A10+<+10+mm+ 2! 9! 11!FIBTEM+A10+≥+10+mm+ 0! 52! 52!+ 2! 61! 63!++!Figure+3T3+Relationship+between+Fibrinogen+levels+and+FIBTEM+A10+separated+by+(A)+Injury+Severity,+(B)+Mortality+outcome+and+(C)+Mechanism+of+Injury.+(INR;+International+Normalized+Ratio;+ISS,+Injury+Severity+Score;+NonTsurvivors,+inThospital+mortality)!! 53!3.3.2.3 Detection+of+Platelet+Dysfunction+by+RoTEM+parameters+++! There! were! no! patients! with! a! platelet! count! of! <! 100! x! 109/L! in! our! sample![Table!3!–!5].!However,! there!were!8!patients!with! low!EXTEM!A10! that! could!not!be!explained! by! low! FIBTEM! A10,! suggesting! a! possibility! of! platelet! dysfunction! in! this!category!of!patients![Figure!3!–!3].!!!++Table+3T5+Detection+of+Platelet+Dysfunction+by+EXTEM+A10+vs.+Platelet+levels+(n=63)++ Platelets+<+100+x+109/L+ Platelets+≥+100+x+109/L+ Total++EXTEM+A10+<+50+mm+ 0+ 16+ 16+EXTEM+A10+≥+50+mm+ 0+ 47+ 47++ 0+ 63+ 63!+++!Figure+3T4+Relationship+between+Platelet+Count+and+EXTEM+A10+separated+by+FIBTEM+A10+levels+(Normal+FIBTEM+A10+>+10+mm,+Low+FIBTEM+A10+=<+10+mm)+!!3.3.3 Correlation+between+RoTEM+and+CCT++! There!was!an!overall!significant!correlation!between!RoTEM!parameters!and!the!corresponding! CCT! parameters! [Table! 3! –! 6]! (all! Spearman! r! >! 0.3,! p! <! 0.05).! The!strongest! correlation!was!between!FIBTEM!A10!and! fibrinogen! levels! (r=!0.75,! 95%!CI!0.62!–!0.84,!p!<!0.001).!!!! 54!!Table+3T6+Spearman's+Rank+Correlation+(r)+between+RoTEM+and+CCT+(n=63)+++++3.3.4 Turnaround+Time+for+RoTEM+vs.+CCT++! Turnaround! Times! (TAT)! for! RoTEM! assays! compared! to! CCTs! are! detailed! in![Table!3!–!7].!The!median!TAT!(sample!collection!to!results)!for!RoTEM!was!35!minutes!(IQR:! 29.0! –! 49.0)! compared! to! a!median! of! 31.0!minutes! for! CCT! (IQR:! 25.0! –! 42.5).!Graphical!distributions!of!TATs!of!both!tests!revealed!the!presence!of!outliers!(i.e.:!rightPskewed)!for!RoTEM!assay!TAT!compared!to!CCT![Figure!3!–!4].!!The!median!time!for!sample!delivery!to!the!lab!was!8!minutes!(5!–!10!min)!and!from!lab!receipt!until!commencing!RoTEM!analysis!was!13!minutes!(9!–!19!min).!The!median!time!from!starting!RoTEM!analysis!until!release!of!A10!results!was!14!minutes!(11!–!18!min).!!!!!+! r" 95%+CI+ pTvalue+EXTEM+CT+ ! ! !P INR!! 0.35! 0.11!–!0.55! 0.005!EXTEM+A10+ ! ! !P Fibrinogen!! 0.58! 0.39!–!0.72! <!0.001!P Platelet!count!! 0.52! 0.31!–!0.68! <!0.001!FIBTEM+A10++ ! ! !P Fibrinogen!! 0.75! 0.62!–!0.84! <!0.001!EXTEM+A10+–+FIBTEM+A10+ ! ! !P Platelet!count!! 0.42! 0.12!–!0.60! 0.001!INR,!International!Normalized!Ratio;!EXTEM!CT,!Clotting!time;!EXTEM!A10,!EXTEM!Amplitude!at!10!minutes;!FIBTEM!A10,!FIBTEM!Amplitude!at!10!minutes;!ML,!Maximum!Lysis.!! 55!Table+3T7+Turnaround+Times+(TAT)+for+RoTEM+vs.+Conventional+Coagulation+Tests+in+minutes+(n=63)+Turnaround+Times+(TAT)+ RoTEM+ CCT+Collection!to!time!received!in!lab! 8.0!(5.0!–!10.0)! 8.0!(5.0!–!10.0)!Time!received!in!lab!to!results! 27.0!(21.0!–!37.0)! 22.0!(18!–!29)!P Time!received!in!lab!to!running!test! 13.0!(9.0!–!19.0)! P!P Running!test!to!results! 14.0!(11.0!–!18.0)! P!Collection!to!Result! 35.0!(29.0!–!49.0)! 31.0!(25.0!–!42.5)!Data!are!shown!as!median!(IQR)!!!!!!!Figure+3T5+Turnaround+Times+(Sample+collection+to+reporting+results,+min)+of+(A)+RoTEM+versus+(B)+Conventional+Coagulation+Tests+(CCT)+(n=63)+!!! 56!!Figure+3T6+Median+Turnaround+Times+(TAT)+for+RoTEM+Assays+vs.+CCTs+over+the+period+of+the+study+(min,+n=63)+!Median! turnaround! times! for! RoTEM! assays! showed! a! decreasing! trend! over! the!duration!of!the!study,!reaching!to!29!minutes!for!RoTEM!versus!39!minutes!for!CCTs!in!March![Figure!3P5].!!!3.4 Discussion++ +3.4.1 Main+Findings+! Our! study! had! shown! that! the! prevalence! of! ATC! as! defined! by! RoTEM!parameters!is!far!higher!than!its!prevalence!as!defined!by!CCT!(11.1%!by!EXTEM!CT!vs.!1.6%! by! INR! and! 17.5%! by! FIBTEM! A10! vs.! 3.2%! by! Clauss! fibrinogen).! RoTEM!parameters!had!a!detection!rate!of!100%!for!both!low!INR!(<!1.2)!and!fibrinogen!levels!(<1.5!g/L)!with!specificities!of!90.3%!and!85.2%,!respectively.!Furthermore,!there!was!a!significant! correlation! between! RoTEM! and! CCT! parameters! with! the! strongest! being!between! EXTEM! and! FIBTEM! clot! amplitudes! and! Clauss! fibrinogen! levels,! confirming!the!findings!in!previous!studies!(10,15,24,37).!!! 57!!ATC! has! been! historically! defined! by! INR! (or! PT)! and/or! Clauss! fibrinogen,! but! using!these! parameters! potentially! underestimates! the! prevalence! and! magnitude! of!coagulopathy! in! trauma! patients.! With! the! evolution! in! the! understanding! of! this!complex! phenomenon,! it! is!well! known! that! the! disturbances! in!ATC! go! far! beyond! a!simple! deficiency! in! coagulation! factors! and! that! low! fibrinogen! levels! and!hyperfibrinolysis! are! important! components! in! the!pathophysiology!of!ATC! (24,36,49).!RoTEM!assays!have!the!apparent!advantage!of!being!able!to!detect!more!coagulopathic!disturbances! compared! to! CCT,! potentially! allowing! earlier! hemostatic! correction! via!plasma! and/or! cryoprecipitate! transfusion! therapy! (24,36,37).! In! our! study,! the!additional!patients!who!were!identified!as!coagulopathic!by!RoTEM!FIBTEM!A10!but!not!by!CCTs!were!severely!injured!(ISS!≥!15)!and!had!higher!rates!of!mortality!(p!<!0.05).!!!RoTEM!assays! can!also!potentially!diagnose!platelet!dysfunction!by! comparing!EXTEM!and!FIBTEM!assays!(14).!!In!our!sample,!there!were!8!patients!with!low!clot!amplitudes!at! 10! minutes! in! EXTEM! assay! that! could! not! be! explained! by! low! platelet! count,!fibrinogen! levels! or! FIBTEM! A10.! This! observation! suggests! the! possibility! of! platelet!dysfunction! in! this! population! but! the! sample! size! is! very! small! and! lack! of! bleeding!outcome!data!preclude!drawing!definitive!conclusions.!!+Although! another! potential! benefit! of! RoTEM! is! faster! results,! our! results! showed! a!longer!median!turnaround!time!for!RoTEM!assays!compared!to!CCT.!At!face!value!this!finding!is!opposite!to!expectations!and!to!what!is!reported!in!literature!(32,50),!but!this!can!be!accounted!for!by!improved!CCT!turn!around!times!at!our!institution!compared!to!that!reported!in!the!literature!as!well!as!learning!curve!challenges!with!implementation!of!a!new!process!and!test!such!as!RoTEM.!Reed!et!al!reported!a!mean!TAT!of!50!minutes!(SD! =! 45)! for! RoTEM! A10! amplitudes! compared! 57! minutes! (SD! =! 28)! for! CCT! (32).!However,!RoTEM!assays!were!run!by!trained!personnel!for!research!purposes!only!and!the!samples!were!not!processed!at!an!urgent!basis!for!results!to!be!available!to!guide!! 58!resuscitation.!!In!another!study,!the!median!time!from!the!start!of!the!assay!until!EXTEM!A10!result!was!11!minutes!with!minimal!variation!(37).!In!contrast,!our!analysis!time!had!a!longer!median!time!of!14!minutes!with!increased!variation!(IQR!11!–!18!minutes).!!!Another!important!explanation!for!these!findings!is!the!fact!that!RoTEM!was!used!as!a!labPbased!rather!than!a!pointPofPcare!test!in!our!study.!Moreover,!this!study!represents!the!initial!phases!of!implementing!RoTEM!base!resuscitation!protocol!in!trauma!at!VGH.!!During! this!period,! the! test!was!not!available!as!an!electronic!order! (compared!to! the!regular!trauma!panel!blood!work)!and!it!had!to!be!ordered!by!phone!call!by!the!trauma!staff.! The! time! delay! for! sample! transport! and! RoTEM! reagent! preparation! was! on!average!20!minutes.!!Fortunately,!there!was!a!progressive!improvement!in!TAT!during!the!study!period!as!the!process! efficiency! improved! over! time.! By! the! end! of! the! study,! RoTEM! assays! were!available!to!treating!clinicians!10!minutes!earlier!on!average!than!CCTs.!!+3.4.2 Limitations+! There!are!several!limitations!to!this!study.!!First,!the!sample!size!is!small,!which!limits!the!analysis!power!and!inferential!analysis.!The!challenges!associated!with!placing!the!telephone!order!for!RoTEM!in!combination!with!the!busy!nature!of!trauma!practice!led! to!RoTEM!not!being!ordered! in!a!number!of!exsanguinating!and!massively! injured!patients.! !Second,!RoTEM!assays!were!ordered!only!on!admission!to!the!ED!and!it!was!not!repeated!during!the!initial!phases!of!hemostatic!resuscitation.!Serial!RoTEM!assays!might! have! improved! the! diagnostic! accuracy! of! ATC! and! aided! in! assessing! the!response!to!targeted!resuscitation.!!!Third,!the!lack!of!a!gold!standard!test!to!diagnose!ATC!and!platelet!dysfunction!makes!it!difficult!to!assess!the!superiority!of!RoTEM!over!any!other!available!diagnostic!tests.!!! 59!!Finally,! we! did! not! assess! the! impact! of! implementing! RoTEM! assay! on! transfusion!practice!due!to!the!small!number!of!massively!transfused!trauma!patients!encountered!during!the!study!period.!!!3.5 Conclusion++! RoTEM!parameters!may!be!potentially!useful!diagnostic!tools! in!trauma!settings.!They!have!an!excellent!correlation!and!detection!rates!for!coagulations!defects!in!ATC.!In!addition,!they!offer!a!more!dynamic!description!of!the!coagulation!process!and!may!be! able! to! detect! more! coagulation! disturbances! than! CCTs! in! nonPbleeding! severely!injured!patients.!However,!the!clinical!significance!of!these!findings!on!blood!transfusion!practices!and!on!patients’!outcome!was!not!assessed!in!this!study.!!!If!these!assays!could!be!obtained!in!even!shorter!time!spans!than!in!our!study,!such!as!with! pointPofPcare! usage,! it! would! offer! further! benefit! to! guide! transfusion! therapy!during!resuscitation.!Bedside!RoTEM!could!potentially!avoid!approximately!20!minutes’!delay!(sample!delivery!to!the!lab!and!reagent!preparation)!though!would!come!with!its!own! challenges,! such! as! changing! patient! location! during! resuscitation! and! meeting!quality!standards!for!device!operation.!Having!RoTEM!as!an!electronic!order!as!part!of!the!trauma!blood!work!panel!could!aid!in!reducing!the!number!of!missed!cases!and!may!also!partially!improve!turnaround!times,!though!not!as!much!as!pointPofPcare!usage.!!!In!summary,!although!this!study!suggests!potential!advantages!of!RoTEM!over!CCTs! in!the! trauma! setting,! the! impact! of! 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