trauma 4

C

REVIEW

CURRENTOPINION Logistics of transfusion support for patients with

massive hemorrhage

opyright © Lippincott Will

www.co-anesthesiology.com

a,b c c
Lawrence T. Goodnough , David A. Spain , and Paul Maggio
Purpose of review

Traditionally, trauma resuscitation protocols have advocated sequential administration of therapeuticcomponents, beginning with crystalloid solutions infused to replace lost intravascular volume. However,rapid restoration of the components of blood is essential for ensuring adequate tissue perfusion and forpreventing acidosis, coagulopathy, and hypothermia, referred to as the ‘lethal triad’ in trauma settings. Thereview summarizes practical approaches for transfusion support of patients with massive hemorrhage.

Recent findings

Massive transfusion protocols for blood transfusion support are reviewed, including practical considerationsfrom our own. We maintain an inventory of thawed, previously frozen plasma (four units each of bloodgroup O and A), which can be issued immediately for patients in whom the blood type is known. Asfrozen plasma requires 45 min to thaw, liquid AB plasma (26 day outdate) functions as an excellentalternative, particularly for patients with unknown or blood group B or AB types.

Summary

Close monitoring of bleeding and coagulation in trauma patients allows goal-directed transfusions tooptimize patients’ coagulation, reduce exposure to blood products, and to improve patient outcomes.Future studies are needed to understand and demonstrate improved patient outcomes.

Keywords

coagulopathy, hemorrhage, trauma

aDepartment of Pathology, bDepartment of Medicine and cDepartment ofSurgery, Stanford University, Stanford, California, USA

Correspondence to Lawrence Tim Goodnough, MD, Professor of Path-ology & Medicine, Stanford University, Director of Transfusion Services,Stanford University Medical Center, 300 Pasteur Dr, Room H-1402,5626, Stanford, CA 94305-5626, USA. Tel: +1 650 723 6037; fax: +1650 723 9178; e-mail: [email protected]

Curr Opin Anesthesiol 2013, 26:208–214

DOI:10.1097/ACO.0b013e32835d6f8f

INTRODUCTION

In the modern era of fractionated blood componenttherapy, optimal management of massive hemor-rhage is an evolving concept [1

&

,2,3&

]. Resuscitationgoals for a patient with massive hemorrhage aftertraumatic injury are to establish rapid control ofbleeding and restore systemic oxygen delivery.The trauma literature defines two phases of resusci-tation: an immediate phase directly after injury withongoing hemorrhage, and a maintenance phaseafter stabilization [4]. Traditionally, trauma resusci-tation protocols had advocated sequential adminis-tration of therapeutic components, beginning withcrystalloid solutions infused to replace lost intra-vascular volume. Red blood cells (RBCs) were trans-fused to restore oxygen-carrying capacity, andclotting factors and platelets (PLTs) were deliveredto restore physiologic hemostasis. It is now recog-nized, however, that rapid restoration of the com-ponents of blood is essential for ensuring adequatetissue perfusion and for preventing acidosis, coagul-opathy, and hypothermia, referred to as the ‘lethaltriad’ in trauma settings.

iams & Wilkins. Unautho

Current concepts in trauma resuscitation are tobe proactive and immediately target ‘hemostaticresuscitation’. Adequate replacement of plasmacomponents is particularly important for avoidingdilutional coagulopathy and treating consumptivecoagulopathy in patients with massive hemorrhage.Finally, close monitoring of bleeding and coagu-lation in trauma patients allows goal-directed, trans-fusions to optimize patients’ coagulation, reduceexposure to blood products, and to improve patientoutcomes [5

&

].

rized reproduction of this article is prohibited.

Volume 26 � Number 2 � April 2013

mailto:[email protected]

KEY POINTS

� Massive transfusion protocols improve outcomes intrauma patients.

� Pre-emptive transfusions of coagulation factors andplatelets improve trauma-associated coagulopathy.

� Point-of-care coagulation monitoring and transfusionalgorithms may be an alternative to protocols with fixedRBC : plasma ratios.

� Further research is needed to identify improvement inclinical patient outcomes.

Transfusion support for trauma patients Goodnough et al.

MASSIVE TRANSFUSION PROTOCOLS

Massive transfusion protocols (MTPs) have beenadopted by many hospitals with accredited traumacenters [6,7]. The trauma center verification processadministered by the American College of SurgeonsCommittee on Trauma (ACS-COT) stipulates thatinstitutions address the role of the transfusionservice in support of the massively hemorrhagingpatient, defined as more than 10 units RBC trans-fused within a 24-h time frame [8]. Motivation tostandardize resuscitation has led to the develop-ment of MTPs in which the surgical or medical teamspecifies the transfusion of RBC, plasma, and PLTs inpredetermined or standardized ratios. Protocols andratios of blood components differ among medicalfacilities but are intended to treat coagulopathyuntil hemorrhage is controlled [6,9,10].

An estimated time line for issuing blood at ourinstitution is detailed in Table 1. The clinical team isresponsible for activating the MTP when a traumapatient presents with life-threatening hemorrhage.Our MTP for the trauma service [11,12

&

] provides anemergency release ‘package’’ consisting of six unitsof uncrossmatched, blood group O or type-specificRBCs, four units of plasma (liquid or thawed), andone apheresis PLT unit (Fig. 1). The 6:4:1 ratio ofRBCs, plasma, and PLTs was designed to replaceapproximately 70% of the total RBC volume and

Copyright © Lippincott Williams & Wilkins. Unau

Table 1. Estimated time lines for issuing emergencyrelease blood

Blood group O, uncrossmatched blood

2 units 2 min

6 units 5–10 min

Type-specific blood 15 min

Electronic crossmatched blood(antibody screen negative)

60 min

Coomb’s crossmatched blood(antibody screen positive)

90 min or more

0952-7907 � 2013 Wolters Kluwer Health | Lippincott Williams & Wilk

60% of the total circulating plasma volume of a70 kg individual. Whole blood is the ideal replace-ment therapy for massive hemorrhage, and this6:4:1 combination of RBCs, plasma, and apheresisPLTs is a 6:5 volume-to-volume ratio of RBC toplasma. Women of childbearing age (less than 50years of age) are prioritized to receive O negativeunits, whereas men and women more than 50 yearsof age may receive O positive units, depending on Onegative blood inventory. Type-specific units areissued after patients’ blood type can be confirmed.The complement of blood products can be com-piled, electronically issued, and provided to a cou-rier from the operating room, delivery room, oremergency department within 5–10 min.

Safety considerations for emergency release ofuncrossmatched blood have been well documented.A retrospective review of 161 trauma patients at asingle center who received 581 uncrossmatched,blood group O RBCs found no acute hemolytictransfusion reactions in this setting [13]. Of 10 Rhnegative men who received group O positive blood(average 16.9 units/patient), only one subsequentlydeveloped anti-D antibodies. A subsequent studyconfirmed that transfusion of emergency releaseblood before completion of antibody screen testingcarries a low risk of non-ABO alloantibody-mediatedhemolytic transfusion reactions (one in 265, or0.4%) [14].

There is evidence that such algorithms havebeen associated with survival in both military andcivilian populations [15–17]. However, there arealso studies in which a high fresh frozen plasma(FFP): RBC regimen has shown no benefit withregard to survival [18,19]. Experience at our owninstitution found that the introduction of ‘massivetransfusion packages’ resulted in a significantreduction in mortality without a change in theFFP:RBC ratio given in the first 24 h [20]. FFP (169versus 254 min) and PLTs (241 versus 418 min) wereadministered much earlier after the introduction ofour MTP. There are several important aspects toconsider when interpreting results of studies show-ing a benefit of a high FFP:RBC ratio in traumapatients [21]. The data are retrospective and prim-arily refer to young, previously healthy malepatients with penetrating injuries. In addition, theFFP: RBC ratio usually is calculated for the first 24 hof treatment. There may be a survivor bias in thatthose with the worst injury and bleeding died tooearly to receive a large amount of FFP [22]. Inaddition, FFP transfusion is associated with adverseeffects such as increased incidence of nosocomialinfections [23], multiple organ failure [24], lunginjury [22,24], and possibly mortality [22,25]. Therecently published AABB guidelines [16] and the

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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

PT at risk for unconrollablebleeding, medical team activation

STAT blood raw

Indication forimmediate

transfusion?

Anticipate total requirements> 10 packed RBC units?

Activate MTP with initial MTP package 6 units packed RBCs 4 units FFP 1 apheresis platelet

Redraw initials labs:PT/PTT, Fibrinogen/D-dimer, CBC

Lab resultsnormal?

Anticipate ongoingbleeding?

Deactivate MTPCriteria: Normalize lab values and/or noevidence of ongoing bleeding

Transfusion service to check on team ifMTP has not been deactivated and noproducts have been sent for > 60 minutes

Repeat initial MTP pack Repeat labs

Yes

Yes

If INR > 1.5* give 4 units FFP * repeat until INR controlled

If PLT count < 25 Give 1 apheresis package to increase PLTs by 25 to 30 000

If fibrinogen < 100 mg/dL give a 10 pack of cryoprecipitate to increase fibrinogen

Conventional resuscitationOngoing evaluation

Labs

No

No

No

No

Yes

Yes

DIC panel PT PTT Fibrinogen Thrombin time D-dimer CBC, ABG Type and screen

FIGURE 1. Massive transfusion protocol algorithm. The clinical team sends blood samples for initial laboratory tests to theclinical laboratory upon initiation of the massive transfusion protocol (MTP). The tests requested include prothrombin time (PT),partial thromboplastin time (PTT), D-dimer, and a complete blood count (CBC). If a patient continues to hemorrhage or futurehemorrhage is anticipated, additional 6 : 4 : 1 packages can be requested from the transfusion service, provided thatadditional coagulation laboratory kits are sent with each request. Importantly, the massive transfusion guideline does notpreclude customized ordering of other blood products and pharmaceuticals. Later in resuscitation, abnormal laboratory valuessuch as prolonged PT and/or platelet (PLT), low PLT count, and low fibrinogen values can be addressed individually asdepicted. Reproduced with permission from [11].

Trauma and transfusion

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Contact(XIIa)

tissuer factor(TF: VIIa)

Activation


updated European guideline on the management ofbleeding after major trauma [15] do not recommendtransfusion of plasma at a FFP:RBC ratio of 1 : 3 ormore.

Thrombin

PlasminPlasminogen

Release of tPAProtein C activationRelease of TFP inhibitor

Fibrin (m)

Va, Ca++

Xa

IXa platelet-associatedprothombinase complex

VIIa, Ca++X

Fibrin (p)D-dimers

FSP

PAI1

tPA

Fibrinogen

PT fragment 1.2

Prothrombin

FVIIIa, FVa, FXIIIaplatelet activation/consumption

FVIII, FXIIIFV, platelets

FPA

XIIIa

FIGURE 2. Mechanisms and effects of excessive hemostaticactivation with cardiac surgery. The coagulation system issubdivided into three pathways intrinsic or contact, extrinsicor tissue factor, and common (i.e., below conversion of X toXa); the conversion of factor X to Xa is within all threepathways. Dashed line designates release of proteincleavage by-products. Abbreviations (activated factors aredesignated using a small ‘a’, whereas inactivated factors aredesignated using a small ‘i’): factor XII, XII; factor VII, VII;factor X, X; factor VIII, VIII; factor IX, IX; factor V, V; factorXIII, XIII; prothrombin fragment 1.2, PT 1.2; calcium ions,Caþþ; fibrinopeptide A, FPA; PL, phospholipid; PAP,plasmin-antiplasmin complexes; EC, endothelial cells;tPA:PAI1, tPA PAI1 complexes; fibrin monomer, fibrin (m);fibrin polymer, fibrin (p); fibrin cross-linked polymer, fibrin(L); plasminogen activator inhibitor, PAI1; tissue plasminogenactivator, tPA; fibrinogen/fibrin split products (FSPs) aredegradation products ¼ FDP; polymerized fibrin degradationproducts ¼ D-dimers; � designates endothelial cell related.Reproduced with permission from [34].

COAGULOPATHY IN MASSIVEHEMORRHAGE AND TRANSFUSION

The presence of coagulopathy is associated withpoor outcomes in patients with severe hemorrhagein both civilian and military settings [26,27]. Up to25% of trauma patients exhibit abnormal coagu-lation parameters at the time of presentation, whichis associated with a three-fold increase in mortality[28,29]. Military patients with hemorrhage who hadan international normalized ratio (INR) of morethan 1.5 had a mortality of 30%, compared withonly 5% in those with a normal INR at presentation[26,30]. There are multiple factors that contributeto disturbances in coagulation. Immediately afterinjury, hypoperfusion influences coagulopathythrough tissue injury/reperfusion, consumption,and increased fibrinolysis (Fig. 2) [31–34]. Hemodi-lution also occurs when crystalloid and RBC therapyare administered without concomitant plasmacomponent therapy [31,35]. Plasma therapy earlyin resuscitation is intended to lessen the develop-ment of coagulopathy and ameliorate the severity ofblood loss.

Routine underutilization of plasma during mas-sive hemorrhage is described in the trauma literature[36]. Moreover, a recently published mathematicalmodel of whole-blood loss during hemorrhagicshock advocates unit-for-unit coadministration ofplasma and RBCs during resuscitation to reversedilutional coagulopathy [37]. Plasma and PLTs aredelivered with RBCs in the MTP package to facilitateplasma repletion.

Identification and treatment of coagulopathy inthe early stages of patient presentation may improveoutcomes in patients undergoing massive hemor-rhage and transfusion [38

&

]. However, clinical out-comes are variable in studies of patients receivingplasma therapy, including the trauma setting. Arecent update of a systematic review of randomized,controlled trials found no consistent evidence ofsignificant benefit for prophylactic or therapeuticuse of plasma across a wide range of indications, inlarge part due to poor methodologic quality forthese clinical trials [39

&&

]. A second systematic liter-ature review also found very low quality evidencebut suggested that plasma infusion in traumapatients with massive hemorrhage may be associ-ated with a reduction in risk of multiorgan failureand death [22]. However, a retrospective, multicen-ter review comparing 284 trauma patients receiving

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plasma matched to 284 patients who did not, foundno differences in survival (17.3 versus 14.1%,respectively) irrespective of the plasma to RBC ratiotransfused [40]. Moreover, the overall complicationrate was significantly higher for patients receivingplasma (26.8 versus 18.3%), including a 12-foldincrease in acute respiratory distress syndromeand a six-fold increase in multiorgan dysfunctionsyndrome (MODS). On the contrary, use of a pro-tocol for patients with massive hemorrhage in ourown institution [20] as well as another study [41]was associated with a reduction in mortality and inrisk of organ failure and postinjury complications,respectively.

SPECIAL CONSIDERATIONS

Because we are a busy tertiary care hospital, we areable to maintain an inventory of thawed, previously



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frozen plasma (four units each of blood group O andA, which can be issued immediately as part of theMTP for patients in whom the blood type is known;these units are compatible with 80% of patients’blood types). As FFP requires up to 45 min to thawand issue from the transfusion service, liquid ABplasma functions is an excellent alternative, particu-larly for patients with unknown or blood group B orAB types. Liquid plasma has some advantages overFFP: liquid plasma is refrigerated and never frozen,and therefore, can be issued immediately for emer-gency release. For whole blood collected in adeninesaline preservative solution, liquid plasma preservedin citrate-phosphate-dextrose has a 26-day outdatecompared to a 5-day shelf life for thawed, frozenplasma [42]. Never-frozen liquid plasma containsnormal activity for all coagulation factors over26 days, with the exception of diminished levelsof FV and FVIII. Plasma FVIII activity decreases byapproximately 50% in the first 24 h of storage at 48Cand then remains stable [43]. Because the process offreezing has little effect on the activity of plasmacoagulation proteins, thawed FFP and liquid plasmacontain comparable levels of the labile clotting FVand FVIII. Thawed FFP retains approximately 50%FV and 50% FVIII activity [44,45]. Potential disad-vantages are as follows: intact lymphocytes arepresent in never-frozen liquid plasma; and RBCs’liquid plasma is, therefore, not ‘cytomegalovirussafe’ and also carries a risk of transfusion-associatedgraft versus host disease (TA-GVHD). For this reason,liquid plasma units are irradiated in order to preventTA-GVHD. Because intact RBCs are also present,women of child-bearing age transfused with liquidplasma from an Rh positive donor should be ident-ified and administered Rh immune globulin pro-phylaxis. Although no randomized clinical trialsupports the equivalence of liquid plasma and FFPin resuscitation of hemorrhagic shock, the benefitsof immediate plasma availability in a trauma resus-citation protocol outweigh these potential, unlikelyrisks.

One clinical practice guideline has recom-mended that plasma transfusions be withheld untilthe prothrombin time (PT) or activated partialthromboplastin time (PTT) time is 1.5 times normal[32]. However, there can be a significant intervalbetween the time that tests are ordered and resultsare available [46]. Additional time (approximately30–45 min) may be required to thaw and issuemultiple units of blood type-specific plasma. Thus,laboratory-guided component therapy is limited as adecision-guiding tool during cases of rapid, massiveexsanguination [46]. Reports have noted thatblood components may be associated with anincreased risk of infection and multiorgan failure

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[23,33,47,48,49&

,50]. Nevertheless, when productsare transfused early as part of a protocol for traumapatients, the overall number of blood productstransfused over the first 24 h actually decreases[10,51].

Blood draws for essential coagulationparameters are integrated into the MTP. These arenot intended to dictate blood product therapy inreal time, but results can be used retrospectively forprogrammatic assessments. Figure 1 illustrates ourMTP workflow, in which the clinical team orderslaboratory tests at initiation of the MTP. The labora-tories include PT, PTT, fibrinogen, D-dimer, and acomplete blood count. If a patient continues tohemorrhage or future hemorrhage is anticipated,additional 6 : 4 : 1 packages can be requested fromthe transfusion service and additional coagulationtests are sent with each request (Fig. 1). Importantly,the MTP does not preclude customized ordering ofother blood products and pharmaceuticals. Later inresuscitation, abnormal laboratory values such asprolonged PT and/or PTT, low PLT count, and/orlow fibrinogen values can also be addressed.

Laboratory data are usually unavailable duringthe immediate phase of resuscitation because ofthe time required for the hospital laboratory toperform these tests. The results of laboratorycoagulation testing (PT, PTT, fibrinogen, andPLT count) are best used to guide replacementtherapy during the maintenance phase of resusci-tation. Threshold coagulation parameters, such asprolongation of the PT and PTT to above 1.5 timesthe normal range, PLT counts below 50�109/l,and fibrinogen concentrations below 100 mg/dl,are useful indicators for optimal fractionatedblood product therapy [52,53]. Coagulation (PT,APTT, fibrinogen, D-dimer) and hematology (com-plete blood count) results are accomplished onlyafter a blood sample is sent to the laboratory via apneumatic tube system and the specimen is acces-sioned, aliquoted, transported to instruments, andanalyzed. The standard for turnaround of a statlaboratory test is 60 min, with ‘super-stat’ coagu-lation results typically available in 15–30 min [54].An MTP allows the anesthesiologist and surgeon totreat presumptive coagulopathies during thedynamic and unstable acute phase of resuscita-tion, when laboratory tests are not available inreal time. Lessons learned from MTPs for traumapatients are as follows:

(1)

riz

Importance of liquid plasma (AB blood group)(a) A unique, licensed product code(b) A 26-day shelf life(c) Can be used for patients with blood groups

ed r

B, AB, or unknown blood type

eproduction of this article is prohibited.


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0952

Importance of good communication lanes
(2) (3) Need an initial specimen for type and cross-
match (T&C)
(4) Need an ABO/Rh blood group verification speci-
men
(5) Monitor status (6) When to terminate MTP
FUTURE AREAS OF INVESTIGATION

The use of point-of-care (POC) testing to providemore real-time assessment of coagulationparameters using thromboelastography (TEG) orROTEM (rotational TEG) shows promise for provid-ing a more targeted approach for treatment of coa-gulopathies in the trauma setting [55]. Rapid TEG orROTEM results are available within 5–15 min, cor-relate with laboratory-based test results, and arepredictive of a need for early plasma and PLTtherapy [56

&

]. Use of POC testing coupled withtransfusion algorithms has been well establishedin coagulopathic cardiac surgery and in traumapatients, demonstrating a reduction in postopera-tive chest tube losses and number of blood com-ponents transfused [57,58

&&

] as well as mortality[59

&

]. However, the most recent Cochrane databasesystemic review comparing TEG/ROTEM monitor-ing versus usual care in patients with massive trans-fusion, found only weak-to-moderate evidence tosupport use of TEG/ROTEM in cardiac surgery orliver transplant patients; and beneficial outcomeswere secondary (bleeding or number of componentstransfused), rather than for the primary outcome ofmortality [60

&&

]. Others have advocated calculationsof plasma deficit rather than plasma: RBC ratios aspredictors of mortality and need for therapy in thetrauma setting [61

&

]. Future treatment of trauma-induced coagulopathy may be based on use ofsystemic antifibrinolytics coupled with targetedtherapeutics such as fibrinogen concentrates,prothrombin complex concentrates, recombinantfactor VIIa, and recombinant factor VIII [62

&

].

CONCLUSION

Published guidelines have provided an evidence-based, multidisciplinary approach to the manage-ment of critically injured trauma patients [15].Evaluation of MTP protocols to address massivehemorrhage should include several parameters:clinical outcomes (survival, length of hospital stay,multisystem organ failure, infection rate, etc.) inconjunction with postresuscitation laboratoryparameters (hemoglobin, PT/PTT, fibrinogen, andPLT count) as well as 24-h/total blood componentand crystalloid use. Future trials are also needed tounderstand the basis of enhanced survival. In

pyright © Lippincott Williams & Wilkins. Unau

-7907 � 2013 Wolters Kluwer Health | Lippincott Williams & Wilk

theory, MTPs prevent coagulopathy, and they alsoappear to decrease overall blood component useand, importantly, crystalloid use, which has beenindependently linked with poor outcome [10].Elucidating the potential mechanism behindimproved survival with use of MTP protocols deliv-ering higher ratios of plasma to RBC will ultimatelyimprove our overall understanding of pathophysi-ology of massive hemorrhage.

Acknowledgements

None.

Conflicts of interest

There are no conflicts of interest.

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38.&

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The authors update their previous systemic review of level 1 clinical trials of plasmatherapy and conclude that there is little improvement in overall methodologicalquality; and there is no consistent evidence of significant benefit for prophylactic ortherapeutic use across a wide range of indications.

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56.&

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In this study, consecutive major trauma activations were prospectively entered intoa database. Rapid TEG results were available within minutes of patient arrival andcorrelated with conventional measures of coagulation. Because of its rapid results,TEG may allow for more ‘goal-directed’ therapy during massive transfusion.57. Despotis GJ, Grishaber JE, Goodnough LT. The effect of an intraoperative

treatment algorithm on physicians’ transfusion practice in cardiac surgery.Transfusion 1994; 34:290–296.

58.&&

Schochl H, Nienaber U, Maegele M, et al. Transfusion in trauma: thromboe-lastometry-guided coagulation factor concentrate-based therapy versus stan-dard fresh frozen plasma-based therapy. Crit Care 2011; 15:R83.

Use of POC testing coupled with transfusion algorithms reduces number of bloodcomponents transfused in trauma patients, 80 patients treated with fibrinogenconcentrate and prothrombin complex concentrate, compared to 601 patientstreated with plasma.59.&

Weber CF, Gorlinger K, Meininger D, et al. Point-of-care testing: a prospec-tive, randomized clinical trial of efficacy in coagulopathic cardiac surgerypatients. Anesthesiology 2012; 117:531–547.

POC testing compared to conventional treatment reduces postop chest tubelosses, number of blood components transfused, and improves survival.60.&&

Afshari A, Wikkelso A, Brok J, et al. Thrombelastography (TEG) or thromboe-lastometry (ROTEM) to monitor haemotherapy versus usual care in patientswith massive transfusion. Cochrane Database Syst Rev 2011:CD007871.

The most recent Cochrane analysis comparing TEG/ROTEM monitoring versususual care in patients with massive transfusion, found beneficial outcomes inbleeding and number of blood components transfused, but not for mortality.61.&

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The authors advocate measurements for plasma deficit, rather than empiricplasma: RBC ratios as a predictor for mortality in trauma.62.&

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This concise review of trauma-induced coagulopathy provides a summary of newand emerging POC-driven strategies for hemorescusative therapies.

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