Workshop Massaal Bloedverlies

WORKSHOP MASSAAL BLOEDVERLIES

VICTOR VIERSEN, ANESTHESIOLOOG 15 OKTOBER AIOSDAG URGENTIEGENEESKUNDE

WORKSHOP MASSAAL BLOEDVERLIES

▸ Opgebouwd uit aantal “prikkelende vragen”

▸ Ik ga uit van een bepaalde mate van basiskennis maar vraag vooral als het iets niet weet

▸ Interactieve discussie dus praat vooral lekker door elkaar heen!

▸ Ander antwoord dan de gegeven opties is ook mogelijk

▸ http://www.slideshare.net/VictorViersen

http://www.slideshare.net/VictorViersen

VOOR HET INSCHATTEN VAN DE MATE VAN SHOCK GEBRUIK IK:

A. de ATLS shock classificatie

B. klinisch beeld

C. Hb en stolling

D. Arterieel Bloedgas

E. kan je niet inschatten!

ATLS SHOCKCLASSIFICATIE

Belangrijkste conclusie: HF, AF, BP nemen toe/af naarmate shock erger wordt maar niet in de mate zoals in de ATLS shock

Bloeddruk: ATLS klasse 1,2 (SBP >100) klasse 3,4 (SBP<100)geen verschil in HR (83 vs 88), AF (20,20) en GCS (12,14)

Hartslag: HR <100 100-120 120-140 >140mSBP 136 138 133 130

Resuscitation 84 (2013) 309–313

Contents lists available at ScienceDirect

Resuscitation

journa l homepage: www.e lsev ier .com/ locate / resusc i ta t ion

Clinical paper

A critical reappraisal of the ATLS classification of hypovolaemic shock: Does itreally reflect clinical reality?!

M. Mutschlera,∗, U. Nienaberb, T. Brockampa, A. Wafaisadea, H. Wyenc, S. Peinigera, T. Paffratha,B. Bouillona, M. Maegelea, the TraumaRegister DGUd

a Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), Cologne, Germanyb Academy for Trauma Surgery, Berlin, Germanyc Department of Trauma, Hand and Reconstructive Surgery, Frankfurt, Germany

a r t i c l e i n f o

Article history:Received 24 February 2012Received in revised form 29 May 2012Accepted 9 July 2012

Keywords:ATLSShockVital signsTrauma

a b s t r a c t

Aim: The aim of this study was to validate the classification of hypovolaemic shock given by the AdvancedTrauma Life Support (ATLS).Methods: Patients derived from the TraumaRegister DGU® database between 2002 and 2010 wereanalyzed. First, patients were allocated into the four classes of hypovolaemic shock by matching thecombination of heart rate (HR), systolic blood pressure (SBP) and Glasgow Coma Scale (GCS) according toATLS. Second, patients were classified by only one parameter (HR, SBP or GCS) according to the ATLS clas-sification and the corresponding changes of the remaining two parameters were assessed within thesefour groups. Analyses of demographic, injury and therapy characteristics were performed as well.Results: 36,504 patients were identified for further analysis. Only 3411 patients (9.3%) could be adequatelyclassified according to ATLS, whereas 33,093 did not match the combination of all three criteria givenby ATLS. When patients were grouped by HR, there was only a slight reduction of SBP associated withtachycardia. The median GCS declined from 12 to 3. When grouped by SBP, GCS dropped from 13 to3 while there was no relevant tachycardia observed in any group. Patients with a GCS = 15 presentednormotensive and with a HR of 88/min, whereas patients with a GCS < 12 showed a slight reduced SBP of117 mmHg and HR was unaltered.Conclusion: This study indicates that the ATLS classification of hypovolaemic shock does not seem toreflect clinical reality accurately.

© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Advanced Trauma Life Support (ATLS) is a training programmefor the initial assessment and management of multiply injuredpatients in the emergency department.1 One key aspect of ATLSis the early recognition and management of hypovolaemic shock.For this purpose, ATLS suggests four classes of hypovolaemic shock(classes I–IV) based upon an estimated blood loss in percent andcorresponding vital signs (Table 1). For each class, ATLS allocatestherapeutic recommendations, for example the replacement of flu-ids and the administration of blood products.1,2

! A Spanish translated version of the summary of this article appears as Appendixin the final online version at http://dx.doi.org/10.1016/j.resuscitation.2012.07.012.

∗ Corresponding author at: Department of Trauma and Orthopedic Surgery,Cologne-Merheim Medical Center (CMMC), University of Witten/Herdecke, Ostmer-heimerstr. 200, D-51109 Cologne, Germany.

E-mail address: [email protected] (M. Mutschler).d Working Group on Polytrauma of the German Society for Trauma Surgery (DGU).

Although ATLS has become widely accepted over the last decadeand is currently educated in more than 50 countries worldwide,validation of the ATLS classification of hypovolaemic shock in theliterature is still limited.2,3 Recently, Guly et al. have questioned itsvalidity when applying it onto emergency department data frominjured patients derived from the Trauma Audit and Research Net-work (TARN) database. These authors demonstrated an associationbetween increased heart and respiratory rate and decreased sys-tolic blood pressure, but by far less pronounced as claimed bythe ATLS classification. Furthermore, they discussed the recipro-cal association between hypotension and tachycardia, commonlyconsidered as a compensatory mechanism for maintaining cardiacoutput, as a too simple view of the altered physiology in states ofshock.3,4

In the present study, we undertook another attempt to vali-date the ATLS classification of hypovolaemic shock by applyingit onto datasets of severely injured patients derived from theTraumaRegister DGU® database (Trauma registry of the GermanSociety for Trauma Surgery). In contrast to the TARN registry, the

0300-9572/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.http://dx.doi.org/10.1016/j.resuscitation.2012.07.012

36504 patienten TraumaRegister DGU 2002-2010 Alleen HF, BP, GCS (rest niet geregistreerd) 9,3% kwam overeen met ATLS categorien

RESEARCH Open Access

Renaissance of base deficit for the initialassessment of trauma patients: a base deficit-based classification for hypovolemic shockdeveloped on data from 16,305 patients derivedfrom the TraumaRegister DGU®

Manuel Mutschler1,2*, Ulrike Nienaber3, Thomas Brockamp1, Arasch Wafaisade1, Tobias Fabian1, Thomas Paffrath1,Bertil Bouillon1, Marc Maegele1 and the TraumaRegister DGU4

See related commentary by Privette et al., http://ccforum.com/content/17/2/124

Abstract

Introduction: The recognition and management of hypovolemic shock still remain an important task during initialtrauma assessment. Recently, we have questioned the validity of the Advanced Trauma Life Support (ATLS)classification of hypovolemic shock by demonstrating that the suggested combination of heart rate, systolic bloodpressure and Glasgow Coma Scale displays substantial deficits in reflecting clinical reality. The aim of this study wasto introduce and validate a new classification of hypovolemic shock based upon base deficit (BD) at emergencydepartment (ED) arrival.

Methods: Between 2002 and 2010, 16,305 patients were retrieved from the TraumaRegister DGU® database,classified into four strata of worsening BD [class I (BD ≤ 2 mmol/l), class II (BD > 2.0 to 6.0 mmol/l), class III (BD >6.0 to 10 mmol/l) and class IV (BD > 10 mmol/l)] and assessed for demographics, injury characteristics, transfusionrequirements and fluid resuscitation. This new BD-based classification was validated to the current ATLSclassification of hypovolemic shock.

Results: With worsening of BD, injury severity score (ISS) increased in a step-wise pattern from 19.1 (± 11.9) in classI to 36.7 (± 17.6) in class IV, while mortality increased in parallel from 7.4% to 51.5%. Decreasing hemoglobin andprothrombin ratios as well as the amount of transfusions and fluid resuscitation paralleled the increasing frequencyof hypovolemic shock within the four classes. The number of blood units transfused increased from 1.5 (± 5.9) inclass I patients to 20.3 (± 27.3) in class IV patients. Massive transfusion rates increased from 5% in class I to 52% inclass IV. The new introduced BD-based classification of hypovolemic shock discriminated transfusion requirements,massive transfusion and mortality rates significantly better compared to the conventional ATLS classification ofhypovolemic shock (p < 0.001).

Conclusions: BD may be superior to the current ATLS classification of hypovolemic shock in identifying thepresence of hypovolemic shock and in risk stratifying patients in need of early blood product transfusion.

* Correspondence: [email protected] of Trauma and Orthopedic Surgery, Cologne-Merheim MedicalCenter (CMMC), University of Witten/Herdecke, Ostmerheimerstr. 200, D-51109 Cologne, GermanyFull list of author information is available at the end of the article

Mutschler et al. Critical Care 2013, 17:R42http://ccforum.com/content/17/2/R42

© 2013 Mutschler et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

Bloedverlies -> Shock -> Metabole Acidose





Abstract








instability. Given these results, BD indicates the pre-sence of hypovolemic shock related to hemostatic resus-citation need, transfusion requirements, laboratoryfindings, and mortality.To the best of our knowledge, there is no gold stan-

dard to assess the presence of hypovolemic shock andto trigger therapeutic interventions. Thus, there is nooption yet to test our novel approach against a goldstandard. Therefore, the authors have decided to testagainst the current ATLS classification of hypovolemicshock given that this approach has been widely imple-mented in daily clinical routine as a standard protocolof care and for the initial assessment and treatment intrauma centers. Both the percentage of patients whohad received at least one blood product and MTs wereincreased throughout the groups I to IV in both classifi-cations. However, transfusion requirements were signifi-cantly higher when patients were classified by BD.Similar results were observed for mortality. Obviously,stratification by BD was associated with superior discri-mination of trauma patients with respect to outcome

and need for early blood products. In this context,ATLS seems to dramatically underestimate the need forblood product transfusion, particularly in group III andIV patients.In summary, we suggest assessing patients in the ED

on the basis of BD. Davis and colleagues [6] havealready proposed that, in patients with a BD of less than6 mmol/L, blood typing should be sufficient but thatpatients with a BD of at least 6 mmol/L should undergoblood typing and cross-match. Given MT rates and theidentification of patients who are in need of emergenttransfusion, a BD of 6 mmol/L could also be suggestedas a threshold. Table 4 displays our suggestion for amodified version of the current ATLS classification ofhypovolemic shock based upon BD as a principal triggerfor action. Following the ATLS paradigm of ‘keep algo-rithms simple’, specific recommendations are presentedwith regard to preparation and use of blood products.For class I and II patients, a careful observation shouldbe sufficient unless clinical circumstances dictate other-wise. In class III patients, preparation for transfusion

Figure 2 Transfusion requirements and mortality in patients classified according to either admission base deficit (BD) or the ATLSclassification of hypovolemic shock. (a) Percentage of patients with at least one blood product. (b) Percentage of patients with massivetransfusion, defined as at least 10 blood units until intensive care unit (ICU) admission. (c) Mortality (percentage). ***P < 0.001; n = 16,305. ATLS,Advanced Trauma Life Support; n.s., not significant.


Page 7 of 9





Abstract








blood units and in the percentage of patients whorequired any blood transfusion (≥ 1 blood unit).Furthermore, worsening BD paralleled increasing risk ofongoing hemorrhage as reflected by increasing TASHscores. The mean amount of blood products adminis-tered increased from 1.5 ± 5.9 to 20.3 ± 27.2 units withworsening BD category. These findings are consistentwith those of a previous analysis demonstrating thatworsening of BD was associated with an increased need

for blood product transfusions [6,7,32]. Through thegroups I to IV, the increasing amounts of intravenousfluids and vasopressors administered indicate the pre-sence of hemodynamic instability and validated theresults previously reported by Rixen and colleagues [7].Laboratory findings such as decreases in hemoglobinlevels and platelet counts and an impaired coagulationas reflected by a Quick’s value of less than 70% werefurther interpreted as evidence for hypovolemic

Figure 1 Hemostatic and fluid resuscitation in patients classified by base deficit (BD) into classes I to IV. (a) Total amounts of packedred blood cells (pRBCs), fresh frozen plasma (FFP), and thrombocyte concentrate (TC) transfused. (b) Transfusion requirements and fluidresuscitation (n = 16,305; P < 0.001). ED, emergency department; IV fluids, intravenous fluids; SD, standard deviation; TASH, Trauma-AssociatedSevere Hemorrhage.


Page 6 of 9





Abstract








WAT IS NOU PRECIES DE OORZAAK VOOR STOLLINGSPROBLEMEN?A. met name verdunning

B. Verbruik en verlies van stollingsfactoren

C. Acidose en hypothermie

D. Endogeen antistollingsproces

E. als je netjes narcose geeft krijg je geen stollingsproblemen

DE LETHAL TRIADCoagulopathy

HypothermiaAcidosis

40

M. Maegele

©

2009 The Author(s)Journal compilation

©

2009 International Society of Blood Transfusion,

Vox Sanguinis

(2009)

97

, 39–49

acute post-traumatic coagulopathy. As each abnormalityitself may substantially exacerbate the other a downwardspiral is initiated rapidly accelerating to death [6]. However,the adverse outcomes from uncontrolled non-surgicalhaemorrhage and disturbed haemostasis are not restricted tomortality only but also include organ dysfunction and lossdue to prolonged haemorrhagic shock as well as the earlytermination of surgical procedures in order to preserve life[6]. Thus, early recognition accompanied by adequate andaggressive management of acute early coagulopathy wouldsubstantially reduce mortality and improve outcome inseverely injured patients [7]. A comprehensive review ofthe mechanisms involved in traumatic coagulopathy hasrecently been published [4].

The scope of the present paper is threefold. First, theclinical impact of the problem is emphasized by providingactual incidence rates of early acute post-traumatic coagulo-pathy present already upon emergency room (ER) admission.Second, as early identification of patients at risk for severebleeding requiring massive transfusion (MT) is ratherdifficult in the acute clinical setting but may substantiallyinfluence therapeutic strategies towards a more aggressivestabilization of the disturbed haemostatic system, a simplescoring system allowing an early and reliable estimation forthe probability of MT as a surrogate for life-threateninghaemorrhage after severe multiple injuries is presented.Third, key issues to be considered during acute care of thebleeding trauma patient including novel approaches towardsa more balanced transfusion therapy are presented.

Materials and methods

The data presented here are a synopsis of previously publisheddata based on different analyses of datasets from severely

multiple-injured patients derived from the TR-DGU database(Trauma Registry of the Deutsche Gesellschaft für Unfallchir-urgie (DGU)/German Society of Trauma Surgery) (Arbeitsge-meinschaft Scooring DGU [8]).

The Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie (TR-DGU)

The Trauma Registry of the Deutsche Gesellschaft fürUnfallchirurgie (TR-DGU) (Arbeitsgemeinschaft Scoring DGU[8]) was founded in 1993 by the German Society of TraumaSurgery (Deutsche Gesellschaft für Unfallchirurgie (DGU))and is run by a small steering group from different traumacentres in Germany (Working Group on Polytrauma/AGPolytrauma). It is a prospective, multicentre, standardizedand anonymous documentation of multiple-injured traumapatients at four consecutive post-trauma stages from injuryto hospital discharge: (i) the pre-hospital phase; (ii) emergencyroom and initial surgery (until admission to the intensive careunit (ICU)); (iii) ICU; and (iv) outcome status at discharge anddescription of injuries and procedures. The registry containsdetailed information on demographics, injury pattern,comorbidities, pre- and in-hospital management, timecourse, relevant laboratory findings including data ontransfusion, and outcome of each individual. Through 2006data from a total of 29·353 trauma victims have been enteredinto the registry, with approximately 3·000 new cases addedeach year. Since the introduction of the online version of theregistry in 2002, the use of fresh frozen plasma (FFP) unitsis routinely documented. Between 2002 and 2006, 17·935patients have been entered into the registry. Currently, thereare 140 hospitals affiliated with the registry, mostly fromGermany (

n

= 90), of which 100 are actually contributingdata into the database. Contributing hospitals are mostly

Fig. 1 Potential mechanisms involved in acute post-traumatic coagulopathy. Besides dilutional coagulopathy, haemorrhage may also induce shock which is followed by acidemia and hypothermia further triggering coagulopathy forming the so-called ‘lethal triad’. Trauma with shock thus causing hypoperfusion and hypoxia can also cause acute coagulopathy of trauma-shock (ACoTS) associated with further consumption and hyperfibrinolysis. The clinical importance of inflammation for the development of acute post-traumatic coagulopathy is not yet fully understood (Adopted/Modified from [4]).

EARLY COAGULOPATHY OF TRAUMA AND SHOCK

Proteïne-C gemedieerde antistolling en hyperfibrinolyse door weefselschade en hypoperfusie

Rodent responses to shock and trauma

Animals in all four groups received a mean of 11–13%estimated circulating volume of normal saline. This resulted ina similar drop in hemoglobin (Hb) and hematocrit (Hct) forboth H and TH groups (Hb: H 8.0 vs. TH 9.5g dL)1, P = ns;Hct: H 25 vs. TH 29%,P = ns). Arterial lactate concentrationwas increased in hemorrhagic shock compared with shamcontrols (H 6.7 vs. S 2.3mmol L)1; P < 0.001), but notsignificantly increased by trauma (TH 8.6 vs. H 6.7mmol L)1;P = ns) (Fig. 3A). An increase in lactate was associated with

mildmetabolic acidosis (pH:H 7.30 vs. S 7.40,P < 0.001), butnot significantly increased by trauma (TH 7.25 vs. H 7.30,P = ns).

Rats subjected to trauma alone did not have a differentcoagulation function compared with sham controls, whilehemorrhage caused a small, but statistically insignificant,prolongation of both PT and APTT (Fig. 3B). Significantcoagulopathy was seen only in rats subjected to a combinationof trauma and hemorrhagic shock (PTr = 1.3, APT-Tr = 1.36). Comparing all rats with a significant lactate rise(> 6 mmol L)1) regardless of group, only injured rats devel-oped a statistically significant coagulopathy (PTr: 1.28 vs. 1.21,P < 0.01; APTTr: 1.55 vs. 1.31, P < 0.05). The rat model ofcombined trauma hemorrhage produced an endogenouscoagulopathy consistent with ATC observed in the clinicalpopulation.

Discussion

Wehave shown that ATC is associated with worse outcomes ata PT ratio > 1.2. This may be a more appropriate definition

2A

B

1.91.81.71.61.5

Pro

thro

mbi

n ra

tioM

orta

lity

(%)

1.41.3

< 16

> 35

> 12

16–24

6.1–120.1–6

Base deficit(mmol L–1)


≤ 0

> 126.1–12

0.1–6≤ 0

25–35ISS

∗

∗

∗∗

∗

∗

∗∗∗

∗

∗ ∗∗

∗

∗

∗∗

∗

∗∗∗

∗1.21.1

1

60

70

50

40

30

20

10

0

< 16

> 3516–24 25–35

ISS

Fig. 2. The relationship between injury severity and shock. (A) Medianprothrombin ratios of patients grouped according to injury severity score(ISS) and base deficit (BD). *P < 0.001 compared with ISS < 16,BD £ 0. (B) Mortality of patients grouped according to ISS and BD.*P < 0.001 compared with ISS < 16, BD £ 0.

35A

B

C

30

25

∗

∗∗

∗

20

Mor

talit

y (%

)U

nits

Pre

vale

nce

(%)

15

12

30

25

20

15

10

5

0

10RBC FFP

∗

∗∗

∗

+

++

+

8

6

4

2

0

10

5

10

0.8–0.9 1.1–1.2 1.3–1.4 1.5–1.6 1.7–1.8 1.9–2.0

10.8–0.9

0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2

1.1–1.2 1.3–1.4 1.5–1.6 1.7–1.8 1.9–2.0

Prothrombin ratio

Prothrombin ratio

Prothrombin ratio

Fig. 1. Relationships between acute traumatic coagulopathy (ATC) andclinical outcomes. (A) Increasing mortality with increasing prolongationsof the prothrombin time (PT). *P < 0.001 compared with prothrombintime ratio (PTr) = 1. (B) Increasing 24-h administration of transfusionproducts with increasing prolongations of the PT. *P < 0.001 comparedwith PTr = 1.+P < 0.001 compared with PTr = 1. (C) The prevalenceof prothrombin ratios in the emergency department.

1922 D. Frith et al

! 2010 International Society on Thrombosis and Haemostasis

ISS = Injury severity Score als maat voor weefselschade door traumaProthrombin ratio = INR

ORIGINAL ARTICLE

Definition and drivers of acute traumatic coagulopathy: clinicaland experimental investigationsD. FR ITH ,* J . C . G OSL INGS ,! C . GA ARD E R ," M. MAEGELE ,§ M . J . COHEN,– S . ALLARD,**P . I . JOHANSSON,!! S . STANWORTH,"" C. TH IEMERMANN§ § and K . B ROHI **Trauma Clinical Academic Unit, The Royal London Hospital, Bart#s & The London School of Medicine & Dentistry, Queen Mary University

London, UK; !Trauma Unit Department of Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef, Amsterdam, the

Netherlands; "Trauma Unit, Oslo University Hospital, Ulleval, Oslo, Norway; §Department of Trauma and Orthopedic Surgery, Trauma Registry of

the Deutsche Gesellschaft fur Unfallchirurgie/German Trauma Society (TR-DGU), University of Witten/Herdecke, Cologne-Merheim Medical

Center (CMMC), Cologne, Germany; –Department of Surgery, University of California, San Francisco, CA, USA; **Department of Haematology,

Royal London Hospital, Bart#s & The London School of Medicine & Dentistry, Queen Mary University London, UK; !!Capital Region Blood Bank,

Section for Transfusion Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; ""National Health Service Blood &

Transplant and Oxford Radcliffe Hospitals, John Radcliffe Hospital, Headington, Oxford, UK; and §§William Harvey Research Institute, Bart#s &

The London School of Medicine & Dentistry, Queen Mary University, London, UK

To cite this article: Frith D, Goslings JC, Gaarder C, Maegele M, Cohen MJ, Allard S, Johansson PI, Stanworth S, Thiemermann C, Brohi K.

Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost 2010; 8: 1919–25.

Summary. Background:Acute traumatic coagulopathy (ATC)is an impairment of hemostasis that occurs early after injury andis associated with a 4-fold higher mortality, increased transfu-sion requirements and organ failure.Objectives:The purpose ofthe present study was to develop a clinically relevant definitionof ATC and understand the etiology of this endogenouscoagulopathy. Patients/methods:We conducted a retrospectivecohort study of trauma patients admitted to five internationaltrauma centers and corroborated our findings in a novel ratmodel of ATC. Coagulation status on emergency departmentarrivalwas correlatedwith traumaand shock severity,mortalityand transfusion requirements. 3646 complete records wereavailable for analysis. Results: Patients arriving with a pro-thrombin time ratio (PTr) > 1.2 had significantly highermortality and transfusion requirements than patients with anormalPTr (mortality: 22.7%vs. 7.0%;P < 0.001. Packed redblood cells: 3.5 vs. 1.2 units; P < 0.001. Fresh frozen plasma:2.1 vs. 0.8 units; P < 0.001). The severity of ATC correlatedstrongly with the combined degree of injury and shock. The ratmodel controlled for exogenously induced coagulopathy andmirrored the clinical findings. Significant coagulopathy devel-opedonly inanimals subjected toboth traumaandhemorrhagicshock (PTr: 1.30. APTTr: 1.36; bothP < 0.001 comparedwithsham controls). Conclusions: ATC develops endogenously inresponse to a combination of tissue damage and shock. It is

associated with increased mortality and transfusion require-ments in a dose-dependent manner. When defined by standardclotting times, a PTr > 1.2 should be adopted as a clinicallyrelevant definition of ATC.

Keywords: coagulopathy, hemorrhage, rat, shock, transfusion,trauma.

Introduction

Hemorrhage is responsible for 40% of all trauma deaths and iscommonly associated with coagulopathy [1–3]. Acute trau-matic coagulopathy (ATC) is an endogenous impairment ofhemostasis that occurs early after injury [4]. The presence ofATC is associated with a 4-fold higher mortality, increasedtransfusion requirements and worse organ failure [5–8]. Whilethere is now a significant body of evidence confirming theexistence of ATC, there is no clinically relevant definition andits etiology remains obscure.

To date, identification of ATC has been based on traditionaltransfusion triggers recommended by generic massive transfu-sion guidelines [9–11]. Most commonly these are a 50%prolongation of the prothrombin time (PT) or partial throm-boplastin time (PTT). However, this threshold is arbitrary andits clinical significance in terms of actual clinical outcomes isunknown. Patients with less severe ATC may also have worseoutcomes and potentially benefit from therapeutic intervention.The reported prevalence of ATC varies widely and will dependin part on a robust definition.

Coagulopathy in the trauma patient is often multifactorialand partly induced by therapeutic intervention. However,ATC appears to have an endogenous component as a result ofcombined shock and tissue damage, and can develop in the

Correspondence: Karim Brohi, Trauma Clinical Academic Unit, The

Royal London Hospital, Whitechapel Road, London E1 1BB, UK.

Tel.: +44 20 7377 7695; fax: +44 20 7377 7044.

E-mail: [email protected]

Received 20 January 2010, accepted 28 May 2010

Journal of Thrombosis and Haemostasis, 8: 1919–1925 DOI: 10.1111/j.1538-7836.2010.03945.x


EARLY COAGULOPATHY OF TRAUMA AND SHOCK

▸ 34% van alle traumapatienten

▸ Vroege mortaliteit 13% versus 1,5%

▸ Totale mortaliteit 28,4% versus 8,4%

▸ 30% ontwikkelt multiorgaanfalen

©

2009 The Author(s) Journal compilation

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Vox Sanguinis

(2009)

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, 39–49

Clinical aspects of acute post-traumatic coagulopathy

41

level I trauma centres. The data are not dominated by singletrauma centres but this does not exclude potential centreeffects due to different levels and strategies of trauma care.The TR-DGU is not an obligatory registry. The participationis free of charge, and data are contributed on a voluntarybasis. It is estimated that from the total number of severetrauma cases in Germany, approximately 30% are covered bythe registry. The trauma registry is approved by the reviewboard of the German Society of Trauma Surgery (DGU) andis in compliance with the institutional requirements.

Results

1. The incidence of acute post-traumatic coagulopathy in multiple injuries upon emergency room (ER) admission

A retrospective analysis using the TR-DGU database wasconducted to determine (i) to what extent clinically relevantcoagulopathy has already been established upon ER admission,and whether its presence was associated (ii) with the amountof intravenous fluids (i.v.) administered during the pre-hospital phase of care, (iii) with the magnitude of injury, and(iv) with impaired outcome and mortality [9]. A total of 8·724patients with complete datasets were screened. Coagulopathywas defined by the presence of abnormal coagulationparameters upon ER arrival of the patient, i.e. prothrombintime (PT) test (Quick’s value) < 70% and/or platelets <100·000/

µ

l [10]. In Germany, the PT is preferentially reportedand documented as Quick’s value in percentage (70–130%= normal [10]). A Quick’s value of < 70% is equivalent to aPT ratio of approximately 1·4 [11,12].

Acute post-traumatic coagulopathy upon ER admissionwas present in 2·989 (34·2%) of all patients. Males were moreaffected than females (72·5% vs. 27·5%) and in 96% the traumamechanism was blunt. There was an increasing incidencefor coagulopathy with increasing amounts of intravenousfluids administered during the pre-hospital phase of care(Fig. 2). The incidence of pre-hospital coagulopathy wasalso associated with trauma load as reflected by injuryseverity scores (ISS). Four out of five patients with coagulo-pathy had an ISS >/= 16 upon hospital admission, and thefrequency of coagulopathy increased with higher ISS scores(Fig. 2). There was a trend towards a lower incidence for acutepost-traumatic coagulopathy over the observation periodbut without statistical significance. The presence of acutepost-traumatic coagulopathy was associated with impairedoutcome and increased mortality. Twenty-nine per cent of allpatients with coagulopathy developed multiorgan failurewithin their later hospital course. Early in-hospital mortality(< 24 h) was 13% in patients with coagulopathy vs. 1·5% inpatients without coagulopathy; overall in-hospital mortalitytotalled 28% vs. 8·4% (

P

< 0·001). Mortality increased with

injury severity but was generally higher in patients withcoagulopathy across all severity grades studied. Figure 3depicts mortality rates of patients with and without coagu-lopathy with respect to their magnitude of injury as reflectedby ISS.

2. The TASH score: A simple scoring system to reliably predict the probability for massive transfusion after severe multiple injuries

The lack of reliable early indicators for the individual’s risk formassive transfusion (MT) and thus persisting haemorrhage

Fig. 2 Incidence of coagulopathy in subgroups according to injury severity scores (ISS, four subgroups) and intravenous fluids administered during the pre-hospital phase of care (five subgroups). Each line represents a group of patients with a similar ISS score, while each vertical group represents patients who had received comparable amounts of i.v. fluids during the pre-hospital phase of care. Sample sizes for the groups ranged between n = 68 and n = 1439.

Fig. 3 Mortality in patients with and without acute post-traumatic coagulopathy upon emergency room arrival according to the magnitude of injury as reflected by ISS (injury severity score).

Frequency, risk stratification and therapeutic management of acute post-traumatic coagulopathy. Maegele M et al. Vox Sanguinis 2009; 97:39–49 German Trauma registry Data 2002-2006

EARLY COAGULOPATHY OF TRAUMA AND SHOCKORIGINAL ARTICLE

Definition and drivers of acute traumatic coagulopathy: clinicaland experimental investigationsD. FR ITH ,* J . C . G OSL INGS ,! C . GA ARD E R ," M. MAEGELE ,§ M . J . COHEN,– S . ALLARD,**P . I . JOHANSSON,!! S . STANWORTH,"" C. TH IEMERMANN§ § and K . B ROHI **Trauma Clinical Academic Unit, The Royal London Hospital, Bart#s & The London School of Medicine & Dentistry, Queen Mary University

London, UK; !Trauma Unit Department of Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef, Amsterdam, the

Netherlands; "Trauma Unit, Oslo University Hospital, Ulleval, Oslo, Norway; §Department of Trauma and Orthopedic Surgery, Trauma Registry of

the Deutsche Gesellschaft fur Unfallchirurgie/German Trauma Society (TR-DGU), University of Witten/Herdecke, Cologne-Merheim Medical

Center (CMMC), Cologne, Germany; –Department of Surgery, University of California, San Francisco, CA, USA; **Department of Haematology,

Royal London Hospital, Bart#s & The London School of Medicine & Dentistry, Queen Mary University London, UK; !!Capital Region Blood Bank,

Section for Transfusion Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; ""National Health Service Blood &

Transplant and Oxford Radcliffe Hospitals, John Radcliffe Hospital, Headington, Oxford, UK; and §§William Harvey Research Institute, Bart#s &

The London School of Medicine & Dentistry, Queen Mary University, London, UK

To cite this article: Frith D, Goslings JC, Gaarder C, Maegele M, Cohen MJ, Allard S, Johansson PI, Stanworth S, Thiemermann C, Brohi K.

Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost 2010; 8: 1919–25.

Summary. Background:Acute traumatic coagulopathy (ATC)is an impairment of hemostasis that occurs early after injury andis associated with a 4-fold higher mortality, increased transfu-sion requirements and organ failure.Objectives:The purpose ofthe present study was to develop a clinically relevant definitionof ATC and understand the etiology of this endogenouscoagulopathy. Patients/methods:We conducted a retrospectivecohort study of trauma patients admitted to five internationaltrauma centers and corroborated our findings in a novel ratmodel of ATC. Coagulation status on emergency departmentarrivalwas correlatedwith traumaand shock severity,mortalityand transfusion requirements. 3646 complete records wereavailable for analysis. Results: Patients arriving with a pro-thrombin time ratio (PTr) > 1.2 had significantly highermortality and transfusion requirements than patients with anormalPTr (mortality: 22.7%vs. 7.0%;P < 0.001. Packed redblood cells: 3.5 vs. 1.2 units; P < 0.001. Fresh frozen plasma:2.1 vs. 0.8 units; P < 0.001). The severity of ATC correlatedstrongly with the combined degree of injury and shock. The ratmodel controlled for exogenously induced coagulopathy andmirrored the clinical findings. Significant coagulopathy devel-opedonly inanimals subjected toboth traumaandhemorrhagicshock (PTr: 1.30. APTTr: 1.36; bothP < 0.001 comparedwithsham controls). Conclusions: ATC develops endogenously inresponse to a combination of tissue damage and shock. It is

associated with increased mortality and transfusion require-ments in a dose-dependent manner. When defined by standardclotting times, a PTr > 1.2 should be adopted as a clinicallyrelevant definition of ATC.

Keywords: coagulopathy, hemorrhage, rat, shock, transfusion,trauma.

Introduction

Hemorrhage is responsible for 40% of all trauma deaths and iscommonly associated with coagulopathy [1–3]. Acute trau-matic coagulopathy (ATC) is an endogenous impairment ofhemostasis that occurs early after injury [4]. The presence ofATC is associated with a 4-fold higher mortality, increasedtransfusion requirements and worse organ failure [5–8]. Whilethere is now a significant body of evidence confirming theexistence of ATC, there is no clinically relevant definition andits etiology remains obscure.

To date, identification of ATC has been based on traditionaltransfusion triggers recommended by generic massive transfu-sion guidelines [9–11]. Most commonly these are a 50%prolongation of the prothrombin time (PT) or partial throm-boplastin time (PTT). However, this threshold is arbitrary andits clinical significance in terms of actual clinical outcomes isunknown. Patients with less severe ATC may also have worseoutcomes and potentially benefit from therapeutic intervention.The reported prevalence of ATC varies widely and will dependin part on a robust definition.

Coagulopathy in the trauma patient is often multifactorialand partly induced by therapeutic intervention. However,ATC appears to have an endogenous component as a result ofcombined shock and tissue damage, and can develop in the

Correspondence: Karim Brohi, Trauma Clinical Academic Unit, The

Royal London Hospital, Whitechapel Road, London E1 1BB, UK.

Tel.: +44 20 7377 7695; fax: +44 20 7377 7044.

E-mail: [email protected]

Received 20 January 2010, accepted 28 May 2010

Journal of Thrombosis and Haemostasis, 8: 1919–1925 DOI: 10.1111/j.1538-7836.2010.03945.x


Rodent responses to shock and trauma

Animals in all four groups received a mean of 11–13%estimated circulating volume of normal saline. This resulted ina similar drop in hemoglobin (Hb) and hematocrit (Hct) forboth H and TH groups (Hb: H 8.0 vs. TH 9.5g dL)1, P = ns;Hct: H 25 vs. TH 29%,P = ns). Arterial lactate concentrationwas increased in hemorrhagic shock compared with shamcontrols (H 6.7 vs. S 2.3mmol L)1; P < 0.001), but notsignificantly increased by trauma (TH 8.6 vs. H 6.7mmol L)1;P = ns) (Fig. 3A). An increase in lactate was associated with

mildmetabolic acidosis (pH:H 7.30 vs. S 7.40,P < 0.001), butnot significantly increased by trauma (TH 7.25 vs. H 7.30,P = ns).

Rats subjected to trauma alone did not have a differentcoagulation function compared with sham controls, whilehemorrhage caused a small, but statistically insignificant,prolongation of both PT and APTT (Fig. 3B). Significantcoagulopathy was seen only in rats subjected to a combinationof trauma and hemorrhagic shock (PTr = 1.3, APT-Tr = 1.36). Comparing all rats with a significant lactate rise(> 6 mmol L)1) regardless of group, only injured rats devel-oped a statistically significant coagulopathy (PTr: 1.28 vs. 1.21,P < 0.01; APTTr: 1.55 vs. 1.31, P < 0.05). The rat model ofcombined trauma hemorrhage produced an endogenouscoagulopathy consistent with ATC observed in the clinicalpopulation.

Discussion

Wehave shown that ATC is associated with worse outcomes ata PT ratio > 1.2. This may be a more appropriate definition

2A

B

1.91.81.71.61.5

Pro

thro

mbi

n ra

tioM

orta

lity

(%)

1.41.3

< 16

> 35

> 12

16–24

6.1–120.1–6



≤ 0

> 126.1–12

0.1–6≤ 0

25–35ISS

∗

∗

∗∗

∗

∗

∗∗∗

∗

∗ ∗∗

∗

∗

∗∗

∗

∗∗∗

∗1.21.1

1

60

70

50

40

30

20

10

0

< 16

> 3516–24 25–35

ISS

Fig. 2. The relationship between injury severity and shock. (A) Medianprothrombin ratios of patients grouped according to injury severity score(ISS) and base deficit (BD). *P < 0.001 compared with ISS < 16,BD £ 0. (B) Mortality of patients grouped according to ISS and BD.*P < 0.001 compared with ISS < 16, BD £ 0.

35A

B

C

30

25

∗

∗∗

∗

20

Mor

talit

y (%

)U

nits

Pre

vale

nce

(%)

15

12

30

25

20

15

10

5

0

10RBC FFP

∗

∗∗

∗

+

++

+

8

6

4

2

0

10

5

10

0.8–0.9 1.1–1.2 1.3–1.4 1.5–1.6 1.7–1.8 1.9–2.0

10.8–0.9

0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2

1.1–1.2 1.3–1.4 1.5–1.6 1.7–1.8 1.9–2.0

Prothrombin ratio

Prothrombin ratio

Prothrombin ratio

Fig. 1. Relationships between acute traumatic coagulopathy (ATC) andclinical outcomes. (A) Increasing mortality with increasing prolongationsof the prothrombin time (PT). *P < 0.001 compared with prothrombintime ratio (PTr) = 1. (B) Increasing 24-h administration of transfusionproducts with increasing prolongations of the PT. *P < 0.001 comparedwith PTr = 1.+P < 0.001 compared with PTr = 1. (C) The prevalenceof prothrombin ratios in the emergency department.

1922 D. Frith et al


HEMODILUTIE

©

2009 The Author(s) Journal compilation

©


Vox Sanguinis

(2009)

97

, 39–49

Clinical aspects of acute post-traumatic coagulopathy

41

level I trauma centres. The data are not dominated by singletrauma centres but this does not exclude potential centreeffects due to different levels and strategies of trauma care.The TR-DGU is not an obligatory registry. The participationis free of charge, and data are contributed on a voluntarybasis. It is estimated that from the total number of severetrauma cases in Germany, approximately 30% are covered bythe registry. The trauma registry is approved by the reviewboard of the German Society of Trauma Surgery (DGU) andis in compliance with the institutional requirements.

Results

1. The incidence of acute post-traumatic coagulopathy in multiple injuries upon emergency room (ER) admission

A retrospective analysis using the TR-DGU database wasconducted to determine (i) to what extent clinically relevantcoagulopathy has already been established upon ER admission,and whether its presence was associated (ii) with the amountof intravenous fluids (i.v.) administered during the pre-hospital phase of care, (iii) with the magnitude of injury, and(iv) with impaired outcome and mortality [9]. A total of 8·724patients with complete datasets were screened. Coagulopathywas defined by the presence of abnormal coagulationparameters upon ER arrival of the patient, i.e. prothrombintime (PT) test (Quick’s value) < 70% and/or platelets <100·000/

µ

l [10]. In Germany, the PT is preferentially reportedand documented as Quick’s value in percentage (70–130%= normal [10]). A Quick’s value of < 70% is equivalent to aPT ratio of approximately 1·4 [11,12].

Acute post-traumatic coagulopathy upon ER admissionwas present in 2·989 (34·2%) of all patients. Males were moreaffected than females (72·5% vs. 27·5%) and in 96% the traumamechanism was blunt. There was an increasing incidencefor coagulopathy with increasing amounts of intravenousfluids administered during the pre-hospital phase of care(Fig. 2). The incidence of pre-hospital coagulopathy wasalso associated with trauma load as reflected by injuryseverity scores (ISS). Four out of five patients with coagulo-pathy had an ISS >/= 16 upon hospital admission, and thefrequency of coagulopathy increased with higher ISS scores(Fig. 2). There was a trend towards a lower incidence for acutepost-traumatic coagulopathy over the observation periodbut without statistical significance. The presence of acutepost-traumatic coagulopathy was associated with impairedoutcome and increased mortality. Twenty-nine per cent of allpatients with coagulopathy developed multiorgan failurewithin their later hospital course. Early in-hospital mortality(< 24 h) was 13% in patients with coagulopathy vs. 1·5% inpatients without coagulopathy; overall in-hospital mortalitytotalled 28% vs. 8·4% (

P

< 0·001). Mortality increased with

injury severity but was generally higher in patients withcoagulopathy across all severity grades studied. Figure 3depicts mortality rates of patients with and without coagu-lopathy with respect to their magnitude of injury as reflectedby ISS.

2. The TASH score: A simple scoring system to reliably predict the probability for massive transfusion after severe multiple injuries

The lack of reliable early indicators for the individual’s risk formassive transfusion (MT) and thus persisting haemorrhage

Fig. 2 Incidence of coagulopathy in subgroups according to injury severity scores (ISS, four subgroups) and intravenous fluids administered during the pre-hospital phase of care (five subgroups). Each line represents a group of patients with a similar ISS score, while each vertical group represents patients who had received comparable amounts of i.v. fluids during the pre-hospital phase of care. Sample sizes for the groups ranged between n = 68 and n = 1439.

Fig. 3 Mortality in patients with and without acute post-traumatic coagulopathy upon emergency room arrival according to the magnitude of injury as reflected by ISS (injury severity score).

Early coagulopathy in multiple injury: An analysisfrom the German Trauma Registry on8724 patients

Marc Maegele a,*, Rolf Lefering b, Nedim Yucel a, Thorsten Tjardes a,Dieter Rixen a, Thomas Paffrath a, Christian Simanski a,Edmund Neugebauer b, Bertil Bouillon a

The AG Polytrauma of the German Trauma Society (DGU)aDepartment of Trauma and Orthopedic Surgery, University of Witten/Herdecke,Cologne-Merheim Medical Center (CMMC), Ostmerheimerstr. 200, D-51109 Cologne, Germanyb Institute for Research in Operative Medicine (IFOM), University of Witten/Herdecke,Cologne-Merheim Medical Center (CMMC), Ostmerheimerstr. 200, D-51109 Cologne, Germany

Accepted 10 October 2006

Injury, Int. J. Care Injured (2007) 38, 298—304

www.elsevier.com/locate/injury

KEYWORDSCoagulopathy;Resuscitation;Injury severity score;Outcome;Mortality

Summary

Background: There is increasing evidence for acute traumatic coagulopathy occur-ring prior to emergency room (ER) admission but detailed information is lacking.Patients and methods: A retrospective analysis using the German Trauma Registrydatabase including 17,200 multiple injured patients was conducted to determine (a)to what extent clinically relevant coagulopathy has already been established upon ERadmission, and whether its presence was associated (b) with the amount of intrave-nous fluids (i.v.) administered pre-clinically, (c) with the magnitude of injury, and (d)with impaired outcome and mortality. Eight thousand seven hundred and twenty-fourpatients with complete data sets were screened.Results: Coagulopathy upon ER admission as defined by prothrombin time test(Quick’s value) <70% and/or platelets <100,000 ml!1, was present in 34.2% of allpatients. There was an increasing incidence for coagulopathy with increasing amountsof i.v. fluids administered pre-clinically. Coagulopathy was observed in >40% ofpatients with >2000 ml, in >50% with >3000 ml, and in >70% with >4000 mladministered. Ten percentage of patients presented with clotting disorders althoughpre-clinical resuscitation was limited to 500 ml of i.v. fluids maximum. The mean ISSscore in the coagulopathy group was 30 (S.D. 15) versus 21 (S.D. 12) ( p < 0.001).Twenty-nine percentage of patients with coagulopathy developed multi organ failure

* Corresponding author. Tel.: +49 221 989 57 0; fax: +49 221 989 57 21.E-mail address: [email protected] (M. Maegele).

0020–1383/$ — see front matter # 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.injury.2006.10.003

HEMODILUTIE

Association recommend that fibrinogen and PCC be admin-istered only in the case of proven deficiencies. For example,PCC should be administered for perioperative bleeding onlywhen the residual activity of factors II, VII, IX and X is<40%.22 Factor analysis is extremely time-consuming andthus useless to a clinician. In such a situation a Thrombe-lastograph! analyses might be very helpful. On the onehand, it facilitates fast diagnosis of the actual coagulation

status within a few minutes and, on the other hand, it canhelp check the efficacy of current therapy. Moreover,Thrombelastograph! data can be helpful in detecting iso-lated factor deficiencies and in some cases in treating themwith coagulation factors, so that FFP may not be needed.23 24

The influence of only fibrinogen concentrate on dilutionalcoagulopathy was previously examined in vitro and in ananimal model. Specimens were obtained from healthy con-trols and diluted by 55% with crystalloids, with differentHES solutions including the newly developed 6% HES 130/0.4 and with dextrans in vitro and monitored by aThrombelastograph! analyser. The diminished clot strengthwas thrombelastographically compensated by administeringfibrinogen concentrate, but not factor VIII concentrate orplatelets.25 In an animal model previously performed by us,!65% of the estimated total blood volume was withdrawnfrom pigs and compensated with gelatin. Fibrinogen con-centrate or a placebo was subsequently administered. Heretoo, compensation exclusively with fibrinogen concentratenormalized the impaired clot strength. Moreover, uncon-trolled bleeding was induced in the animals by means ofa stab incision to the liver. The animals who received fib-rinogen concentrate showed statistically significantly lessblood loss after the liver injury.8

PCC usually contains factors II, VII, IX and X and proteinC and trace amounts of heparin and have been used for yearsin the treatment of hereditary coagulation deficiencies and asan antagonist to warfarin-like anticoagulants.26 A furtherindication for the administration of PCC is the acquired factordeficiency, but there are only limited in vivo data on the use ofmodern PCC preparations in patients exhibiting acquiredcoagulation factor deficiencies caused by massive bloodloss, massive transfusion or both. It is known that 1 Ukg"1 PCC body weight increases PT by !1%. Staudingerand colleagues27 investigated the effect of PCC on plasmacoagulation in critically ill patients and found that a dose of2000 factor IX units of PCC (mean 30 U kg"1 body weight)normalized PT by raising the plasma concentration of coagu-lation factors II, VII, IX and X in patients with moderatelyreduced coagulation activity. PCC preparations containdefined amounts of clotting factors and is able to quicklycompensate imbalances in the coagulation system causedby clotting factor deficiencies. In contrast, FFP, which areprepared from healthy blood donors, contain large amounts ofalbumin and water, while the procoagulatory factors and theirinhibitors too are present in their normal physiologically lowconcentrations, which, however, can vary considerably withthe individual donor.

The effect of coagulation therapy achieved byadministering clotting factor concentrates to counteractuncontrolled haemorrhage was previously examined inseveral animal studies using recombinant activated factorVII (rFVIIa, NovoSeven!, Novo Nordisk, Copenhagen,Denmark). In contrast to our findings, these studies mainlyfound no effect of rFVIIa on blood loss after liver injury28–31

although mortality was reduced. However, formation of

A

B

C

Fig 3 Electron microscopy scan of a ·3000 magnified blood clot in (A)

non-diluted state: dense, branched and meshed reticular fibrin network,(B) blood clot after !65% haemodilution with 6% HES 130/0.4: clearly

rarefied fibrin network, (C) blood clot after administration of PCC and

fibrinogen concentrate to compensate for dilutional coagulopathy: in

comparison to (B) the fibrin network is again markedly compact.

Coagulation factor concentrates for reversal of coagulopathy

465







A

B

C







465

FIBRINOGEEN (FACTOR I)‣ Belangrijkste

stollingsfactor voor patient met een bloeding(bouwsteen voor stolsel)

‣ Bepaald dus bij bloedende patient ook altijd fibrinogeen en nooit alleen INR







A

B

C







465

STOLLINGSPROBLEMEN BIJ BLOEDVERLIES

‣ “Earlytrauma+ccoagulopathy” (ETC,TIC,ECOTS)

‣ Verhoogdefibrinolyse‣ VerdunningvanStollingsfactoren

(Hemodilu+e)‣ Verbruikvanstollingsfactoren(met

namefibrinogeen)‣ Beschadigingstollingsfactorendoor

hypothermie&acidose‣ Hyperfibrinolyse

MIJN ZIEKENHUIS HEEFT EEN ROTEM DUS IK WACHT MET TRANEXAMINEZUUR TOT ER SPRAKE IS VAN HYPERFIBRINOLYSE OP DE ROTEM:

▸ eens

▸ oneens

CRASH 2 TRIAL

‣ CRASH 2 trial (Lancet 2010;376:20-22)

‣ Multicenter RCT: tranexaminezuur versus placebo

‣ 10.069 trauma patiënten ‣ “All cause mortality”

van 16% naar 14,5% ‣ Minder thromboembolische

complicaties

HYPERFIBRINOLYSIS

HYPERFIBRINOLYSIS ORIGINAL ARTICLE

Hyperfibrinolysis After Major Trauma: Differential Diagnosis ofLysis Patterns and Prognostic Value of Thrombelastometry

Herbert Schochl, MD, Thomas Frietsch, MD, Michaela Pavelka, MD, and Csilla Jambor, MD

Background: The aim of this study was to diagnose hyperfibrinolysis(HF) and its pattern using thrombelastometry and to correlate the diag-nosis with mortality. Furthermore, routine laboratory based and therotational thrombelastometry analyzer (ROTEM)-derived variables werealso correlated with survival.Methods: Severe trauma patients showing HF in ROTEM were consecu-tively enrolled in the study. Three different HF patterns were compared:fulminant breakdown within 30 minutes, intermediate HF of 30 to 60minutes, and late HF after 60 minutes. Injury severity score (ISS), hemody-namics, hemoglobin, hematocrit, platelet count (PC), fibrinogen, andROTEM variables at admission were analyzed. The observed mortality wascompared with the predicted trauma and injurity severity score mortality.Results: Thirty-three patients were diagnosed with HF. The mean ISS was47 ! 14. Fulminant, intermediate, or late HF (n " 11 each group) resultedin 100%, 91%, or 73% mortality, respectively, with the best prognosis forlate HF (p " 0.0031). The actual overall mortality of HF (88%) exceeded thepredicted trauma and injurity severity score mortality (70%) (p " 0.039).Lower PC (123 ! 53 vs. 193 ! 91; p " 0.034), ROTEM prolonged clotformation time [CFT, 359 (140/632) vs. 82 (14/190); p " 0.042], and lowerplatelet contribution to maximum clot firmness [MCFEXTEM # MCFFIBTEM,34 (20/40) vs. 46 (40/53); p " 0.026] were associated with increasedmortality.Conclusion: ROTEM-based diagnosis of HF predicted outcome. Further inde-pendent predictors of death were combination of HF with hemorrhagic shock,low PC, and prolonged CFT in ROTEM. ROTEM-based point of care testing inthe emergency room is thus able to identify prognostic factors such as prolongedCFT and low platelet contribution to clot firmness (MCFEX # MCFFIB) earlierthan standard laboratory-based monitoring.Key Words: Multiple trauma, Hyperfibrinolysis, Thrombelastometry,Thromboelastometry, Thrombelastography, ROTEM, Coagulopathy.

(J Trauma. 2009;67: 125–131)

Severe trauma is the leading cause of death in the first fourdecades of life.1 Analysis of a European database on

severe trauma (the German Trauma Registry) has indicatedthat hemorrhage, massive blood transfusion, and coagulopa-

thy are the most important factors affecting outcome.2 Inef-fective coagulation in combination with a high injury severityscore (ISS) results in a mortality rate of up to 100%.3

There are several reasons for coagulation disorders inmajor trauma. Major blood loss always includes the loss ofclotting factors to a variable degree. Dilution-induced coagu-lopathy during fluid resuscitation results in critical plasmaconcentrations of coagulation factors.4 Massive release oftissue factor from the site of injury extensively activates thecoagulation cascade and consumes clotting factors, especiallyfibrinogen.5 Furthermore, hypothermia, acidosis, hypovole-mia, and hypoperfusion are frequent problems in severetrauma patients and lead to further deterioration of the coag-ulation process.6–8

The breakdown of fresh clots, a phenomenon termedhyperfibrinolysis (HF), contributes to coagulopathy to anunknown degree. The incidence of HF is still unknown buthas been estimated in the range of 15% to 20%.9 HF may beunderdiagnosed because routine coagulation tests are unableto detect it reliably. The gold standard for detection of HF isthrombelastography or thrombelastometry.10,11

The aim of our study was to analyze the pattern of HFand correlate it to mortality of HF, induced by severe trauma.Furthermore, routine laboratory-based and the rotational throm-belastometry analyzer (ROTEM) parameters in survivors andnonsurvivors of HF were compared. We hypothesized that (i)HF is associated with increased ISS and mortality, (ii) thesurvival time of the patients is independent of the pattern ofHF, and (iii) thrombelastography is superior to routine labanalysis for detection of HF.

PATIENTS AND METHODSROTEM analysis is routinely performed as a part of

coagulation monitoring for all trauma alarms that request thefull trauma team in the emergency room (ER). BetweenJanuary 2003 and December 2007, all trauma patients withthe ROTEM diagnosis of “HF” were consecutively enrolledin this study. HF was diagnosed, when the thrombelastogra-phy variable “maximum lysis (ML)” equaled 100% (Fig. 1).This reflects the complete breakdown of the clot in thethrombelastography trace (compared with a normal trace bynormal coagulation status).

The ROTEM device, a modification of the classicalthrombelastography first described by Hartert in 1948,12 mea-sures the viscoelastic properties of the clot during its forma-tion and subsequent lysis. After recalcification of the bloodsample and addition of an activator such as rabbit brain tissue

Submitted for publication February 26, 2008.Accepted for publication August 20, 2008.Copyright © 2009 by Lippincott Williams & WilkinsFrom the Departments of Anesthesiology and Intensive Care (H.S.) and Surgery

(M.P.), AUVA Trauma Hospital, Salzburg, Austria; Clinic for Anesthesiologyand Critical Care Medicine (T.F.), University Hospital Giessen, Marburg,Germany; and Clinic for Anaesthesiology (C.J.), University of Munich,Munich, Germany.

Address for reprints: Csilla Jambor, MD, Clinic for Anesthesiology, Univer-sity of Munich, Max-Lebsche-Platz 32, D-81377 Munich, Germany; email:[email protected].

DOI: 10.1097/TA.0b013e31818b2483

The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 67, Number 1, July 2009 125

A [50 (45/77) mg/dL] and B [49 (44/87) mg/dL] when com-pared with group C [104 (85/131) mg/dL] (p ! 0.048 for both).

DISCUSSIONThe main finding of this prospective cohort study was

an association between the pattern of HF diagnosed byROTEM and the outcome of severe trauma in patients ad-mitted to our hospital during a 5-year period. Additionalindependent predictors of death included the combination ofHF with hemorrhagic shock, low PC, and prolonged CFT inROTEM. ROTEM-based point of care testing in the ER wasable to identify prognostic factors such as prolonged CFT andlow platelet contribution to clot firmness (MCFEX " MCFFIB),earlier than standard laboratory based monitoring.

Our results have considerable implications for the currentpractice of severe trauma care. Although HF occurs with anunknown incidence, we have associated the outcome of severetrauma to various forms of HF and the coexistence of hemor-rhagic shock. Although the prognostic value of low perfusion inshock and coagulopathy, as determined by low PC is not surprisingfor severe trauma, the presence and pattern of HF has not beenwidely recognized in that context. Thrombelastography-baseddiagnosis and treatment of HF has been thoroughly discussed inliver transplantation, cardiac surgery, and other types of sur-gery,18–22 but not in trauma thus far.

The relevance of HF to trauma remains unknown,although coagulopathy occurs in a fourth of trauma patients.3The consecutive documentation of HF cases in this studycannot give a reliable estimate of prevalence, because datafrom trauma patients without HF were not collected. Theconsecutive enrolment of HF cases favors a more homoge-nous group of patients with mostly severe trauma and higherISS. Because the exact ISS is taken in the ER during thesecondary survey, the exact incidence of HF in severe traumapatients at our center (approximately 80 full trauma alarms peryear) cannot directly extracted from the admissions database. Ina great number of cases, trauma cases are down-graded afterthe ER survey. Thus, we assume that the incidence of HF insevere trauma is approximately 8.25% (33 patients during 5years, 80 severe trauma cases per year). A prospective studyis now underway. Levrat et al.23 recently observed five HFcases in a population of 89 consecutive trauma patients in aprospective trauma cohort at a university hospital. The inci-dence of HF was found to be 6%. However, all of thesepatients showed very severe HF with a mortality of 100%, anISS of 75 (maximum) and no measurable fibrinogen concen-tration. We suggest that HF in these patients might have beena marker of a nonsurvivable injury and that 6% was actuallythe incidence of late stage coagulopathy or nearly dead ERadmission.

This study suggests that HF solely occurs in severetrauma (ISS #25), as the mean ISS in our collective was 47(Table 2), and ISS values of less than 20 were not observed(Fig. 4). The absolute number of patients with HF increasedconcomitantly with the ISS (Fig. 4). However, in generaltrauma cohorts, higher ISS scores are not seen as frequentlyas moderate or low level injuries.24

The association of higher ISS and HF is in accord withthe results of Kaufmann et al.,25 who used thrombelastogra-phy for coagulation monitoring of trauma patients in the ERand did not observe HF. The mean ISS of the patients in thatstudy was low (mean ISS 12.3).25 These findings suggest adisproportionately higher incidence of HF for injuries withincreased severity.

An important result of our study, however, is that theseverity of injury influences the pattern of HF. In our small studypopulation, there was a trend toward fulminant and intermediateHF in patients with more severe injuries in groups A and B(mean ISS 48 $ 14 and 52 $ 10, respectively). Late HF and thebest prognosis were associated with group C, which presentedthe lowest mean ISS (mean ISS 42 $ 16).

Facing an unknown but sufficient (considering our esti-mation of around 8%) incidence of HF in severe trauma, theimportance of early diagnosis becomes evident for daily prac-tice, as effective treatment might have impact on outcome.

In this context, the question arises as to whether routinelaboratory panels can be considered standard of care, sinceidentification of HF now seems to be the domain of thrombelas-tographic methods.10,11 Gando et al.26 failed to demonstrate D-dimers (fibrin formation and degradation), plasmin-antiplasmincomplexes (plasmin generation), fibrinopeptide B!15-42(plasmin activation), or plasminogen activator inhibitor 1(plasmin inhibition) as indicators for increased fibrinolysis

TABLE 2. Basic Characteristics, ISS Score, Observedand Predicted (TRISS) Mortality Overall and in theHyperfibrinolysis Groups Fulminant (Group A), Intermediate(Group B), and Late (Group C)

Overall Fulminant Intermediate Late

Number of patients 33 11 11 11Age (median/range) 45/20–88 45/20–74 44/24–80 48/22–88Male (%) 67 73 64 64ISS (Mean $ SD) 47 $ 14 48 $ 14 52 $ 10 42 $ 16Mean observed mortality

(%)88* 100† 91‡ 73§

Mean predicted mortality(TRISS, %)

70 70 78 63

*p ! 0.039; †p ! 0.065; ‡p ! 0.499; §p ! 0.708 compared with predictedmortality.

0

2

4

6

8

10

12

14

16

18

ISS

Num

ber o

f pat

ient

s

0-25 26-49 50-75

Figure 4. Number of HF cases according to ISS in the studypopulation (n ! 33).

The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 67, Number 1, July 2009 Hyperfibrinolysis After Major Trauma

© 2009 Lippincott Williams & Wilkins 129

A [50 (45/77) mg/dL] and B [49 (44/87) mg/dL] when com-pared with group C [104 (85/131) mg/dL] (p ! 0.048 for both).

DISCUSSIONThe main finding of this prospective cohort study was

an association between the pattern of HF diagnosed byROTEM and the outcome of severe trauma in patients ad-mitted to our hospital during a 5-year period. Additionalindependent predictors of death included the combination ofHF with hemorrhagic shock, low PC, and prolonged CFT inROTEM. ROTEM-based point of care testing in the ER wasable to identify prognostic factors such as prolonged CFT andlow platelet contribution to clot firmness (MCFEX " MCFFIB),earlier than standard laboratory based monitoring.

Our results have considerable implications for the currentpractice of severe trauma care. Although HF occurs with anunknown incidence, we have associated the outcome of severetrauma to various forms of HF and the coexistence of hemor-rhagic shock. Although the prognostic value of low perfusion inshock and coagulopathy, as determined by low PC is not surprisingfor severe trauma, the presence and pattern of HF has not beenwidely recognized in that context. Thrombelastography-baseddiagnosis and treatment of HF has been thoroughly discussed inliver transplantation, cardiac surgery, and other types of sur-gery,18–22 but not in trauma thus far.

The relevance of HF to trauma remains unknown,although coagulopathy occurs in a fourth of trauma patients.3The consecutive documentation of HF cases in this studycannot give a reliable estimate of prevalence, because datafrom trauma patients without HF were not collected. Theconsecutive enrolment of HF cases favors a more homoge-nous group of patients with mostly severe trauma and higherISS. Because the exact ISS is taken in the ER during thesecondary survey, the exact incidence of HF in severe traumapatients at our center (approximately 80 full trauma alarms peryear) cannot directly extracted from the admissions database. Ina great number of cases, trauma cases are down-graded afterthe ER survey. Thus, we assume that the incidence of HF insevere trauma is approximately 8.25% (33 patients during 5years, 80 severe trauma cases per year). A prospective studyis now underway. Levrat et al.23 recently observed five HFcases in a population of 89 consecutive trauma patients in aprospective trauma cohort at a university hospital. The inci-dence of HF was found to be 6%. However, all of thesepatients showed very severe HF with a mortality of 100%, anISS of 75 (maximum) and no measurable fibrinogen concen-tration. We suggest that HF in these patients might have beena marker of a nonsurvivable injury and that 6% was actuallythe incidence of late stage coagulopathy or nearly dead ERadmission.

This study suggests that HF solely occurs in severetrauma (ISS #25), as the mean ISS in our collective was 47(Table 2), and ISS values of less than 20 were not observed(Fig. 4). The absolute number of patients with HF increasedconcomitantly with the ISS (Fig. 4). However, in generaltrauma cohorts, higher ISS scores are not seen as frequentlyas moderate or low level injuries.24

The association of higher ISS and HF is in accord withthe results of Kaufmann et al.,25 who used thrombelastogra-phy for coagulation monitoring of trauma patients in the ERand did not observe HF. The mean ISS of the patients in thatstudy was low (mean ISS 12.3).25 These findings suggest adisproportionately higher incidence of HF for injuries withincreased severity.

An important result of our study, however, is that theseverity of injury influences the pattern of HF. In our small studypopulation, there was a trend toward fulminant and intermediateHF in patients with more severe injuries in groups A and B(mean ISS 48 $ 14 and 52 $ 10, respectively). Late HF and thebest prognosis were associated with group C, which presentedthe lowest mean ISS (mean ISS 42 $ 16).

Facing an unknown but sufficient (considering our esti-mation of around 8%) incidence of HF in severe trauma, theimportance of early diagnosis becomes evident for daily prac-tice, as effective treatment might have impact on outcome.

In this context, the question arises as to whether routinelaboratory panels can be considered standard of care, sinceidentification of HF now seems to be the domain of thrombelas-tographic methods.10,11 Gando et al.26 failed to demonstrate D-dimers (fibrin formation and degradation), plasmin-antiplasmincomplexes (plasmin generation), fibrinopeptide B!15-42(plasmin activation), or plasminogen activator inhibitor 1(plasmin inhibition) as indicators for increased fibrinolysis

TABLE 2. Basic Characteristics, ISS Score, Observedand Predicted (TRISS) Mortality Overall and in theHyperfibrinolysis Groups Fulminant (Group A), Intermediate(Group B), and Late (Group C)

Overall Fulminant Intermediate Late

Number of patients 33 11 11 11Age (median/range) 45/20–88 45/20–74 44/24–80 48/22–88Male (%) 67 73 64 64ISS (Mean $ SD) 47 $ 14 48 $ 14 52 $ 10 42 $ 16Mean observed mortality

(%)88* 100† 91‡ 73§

Mean predicted mortality(TRISS, %)

70 70 78 63

*p ! 0.039; †p ! 0.065; ‡p ! 0.499; §p ! 0.708 compared with predictedmortality.

0

2

4

6

8

10

12

14

16

18

ISSN

umbe

r of p

atie

nts

0-25 26-49 50-75

Figure 4. Number of HF cases according to ISS in the studypopulation (n ! 33).

The Journal of TRAUMA® Injury, Infection, and Critical Care • Volume 67, Number 1, July 2009 Hyperfibrinolysis After Major Trauma

© 2009 Lippincott Williams & Wilkins 129

Resuscitation 83 (2012) 1451– 1455

Contents lists available at SciVerse ScienceDirect

Resuscitation

jo u rn al hom epage : www.elsev ier .com/ locate / resusc i ta t ion

Clinical Paper

Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers ofhypoperfusion!

V.A. Viersena, S. Greutersa, A.R. Korfagea, C. Van der Rijsta, V. Van Bochovea, P.W. Nanayakkarab,E. Vandewalleb, C. Boera,∗

a Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlandsb Department of Emergency Medicine, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands


Article history:Received 16 December 2011Received in revised form 15 April 2012Accepted 11 May 2012

Keywords:Cardiopulmonary arrestHaemostasisShockFibrinolysis

a b s t r a c t

Aim of the study: This study investigated the incidence of hyperfibrinolysis upon emergency department(ED) admission in patients with out of hospital cardiac arrest (OHCA), and the association of the degreeof hyperfibrinolysis with markers of hypoperfusion.Methods: From 30 OHCA patients, cardiopulmonary resuscitation (CPR) time, pH, base excess (BE), andserum lactate were measured upon ED admission. A 20% decrease of rotational thromboelastometrymaximum clot firmness (MCF) was defined as hyperfibrinolysis. Lysis parameters included maximumlysis (ML), lysis onset time (LOT) and lysis index at 30 and 45 min (LI30/LI45). The study was approvedby the Human Subjects Committee.Results: Hyperfibrinolysis was present in 53% of patients. Patients with hyperfibrinolysis had longermedian CPR times (36 (15–55) vs. 10 (7–18) min; P = 0.001), a prolonged activated partial thromboplastintime (54 ± 16 vs. 38 ± 10 s; P = 0.006) and elevated D-dimers (6.1 ± 2.1 vs. 2.3 ± 2.0 !g/ml; P = 0.02) whencompared to patients without hyperfibrinolysis. Hypoperfusion markers, including pH (6.96 ± 0.11 vs.7.17 ± 0.15; P < 0.001), base excess (−20.01 ± 3.53 vs. −11.91 ± 6.44; P < 0.001) and lactate (13.1 ± 3.7 vs.8.0 ± 3.7 mmol/l) were more disturbed in patients with hyperfibrinolysis than in non-hyperfibrinolyticsubjects, respectively. The LOT showed a good association with CPR time (r = −0.76; P = 0.003) and lac-tate (r = −0.68; P = 0.01), and was longer in survivors (3222 ± 34 s) than in non-survivors (1356 ± 833;P = 0.044).Conclusion: A substantial part of OHCA patients develop hyperfibrinolysis in association with markersfor hypoperfusion. Our data further suggest that the time to the onset of clot lysis may be an importantmarker for the severity of hyperfibrinolysis and patient outcome.


1. Introduction

Out-of-hospital cardiac arrest (OHCA) remains a significantcause of morbidity and mortality among the general population.Despite advances in cardiopulmonary resuscitation, the prognosisafter OHCA remains very poor, with survival rates around 10% inEurope.1

Cardiac arrest and resuscitation are characterised by reducedcardiac output and blood flow, resulting in shock and tissuehypoperfusion.2–4 Animal and human studies showed markedactivation of inflammation and coagulation after cardiac arrest

! A Spanish translated version of the abstract of this article appears as Appendixin the final online version at http://dx.doi.org/10.1016/j.resuscitation.2012.05.008.

∗ Corresponding author at: Department of Anesthesiology, VU University MedicalCenter, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.Tel.: +31 0 20 4443830; fax: +31 20 4444385.

E-mail address: [email protected] (C. Boer).

and resuscitation, resulting in intravascular coagulation, systemicformation of microthrombi and impairment of microcirculatoryperfusion.5–7 These changes may contribute to the developmentof ischemic injury and the post-resuscitation syndrome, which isfurther characterised by a systemic inflammation response, reper-fusion injury, adrenal dysfunction, myocardial dysfunction andeventually organ failure.8,9 In particular, an increased duration ofcardiopulmonary resuscitation is associated with a rise in coagula-tion abnormalities and mortality.8,10

Recent studies have shown that markers of shock andhypoperfusion in trauma patients are frequently paralleled byhyperfibrinolysis, which in turn is associated with higher mortalityrates.11–13 One of the proposed mechanisms is that hypoperfusion-associated thrombin formation leads to systemic hyperfibrinolysisthrough the protein C pathway, but the underlying mechanisms arenot well understood.11,12,14 Secondly, hypoxia may lead to exces-sive release of tissue plasminogen activator (t-PA) and therebycontribute to the presence of hyperfibrinolysis.15


1454 V.A. Viersen et al. / Resuscitation 83 (2012) 1451– 1455

Fig. 2. Pearson correlations (r) between lysis onset time and cardiopulmonaryresuscitation time (panel A), base excess (panel B) and lactate levels (panel C).P-values are shown in the figures.

fibrinolysis and in some cases inhibition of fibrinolysis.10 In particu-lar, hyperfibrinolysis was associated with increased early mortality,but the authors did not look further into the association betweenthe degree of shock and the level of hyperfibrinolysis.10 In agree-ment with their study, we found that about 50% of the patientswith cardiopulmonary arrest developed hyperfibrinolysis.10 More-over, we found a good correlation between chest compressiontime and lactate with the onset time of hyperfibrinolysis, sug-gesting an association between hypoperfusion and excessivefibrinolysis in OHCA patients. However, even though mean pH,BE and lactate levels were higher in the group of patients withhyperfibrinolysis, patients in the non-hyperfibrinolysis group alsosuffered from severe metabolic acidosis. Further studies are nec-essary to unravel the involvement of endothelial activation, t-PArelease and the inhibition of PAI and TAFI in order to gain moreinsight in the cause of hyperfibrinolysis in patients with cardiacarrest.

This is the first study that uses rotational thromboelastometryto diagnose hyperfibrinolysis in the patients with cardiopulmonaryarrest. Hyperfibrinolysis is not detectable by classical haemostatictesting such as the aPTT or PT. Schöchl et al. were the first to showthat trauma patients with hyperfibrinolysis as measured by throm-boelastometry were at higher risk for unfavourable outcome.11

Interestingly, they also detected hyperfibrinolysis in a small groupof patients with isolated traumatic brain injury in the absence ofextracranial haemorrhage, suggesting that excessive bleeding isno prerequisite for hyperfibrinolysis.20 As the number of hospi-tals with point-of-care coagulation testing increases, more insightmight be obtained of the association between out of hospital cardiacarrest and hyperfibrinolysis.

There is currently no consensus with respect to the validity ofthe fibrinolytic parameters provided by rotational thromboelas-tometry. Moreover, it is unclear whether the level or the onset timeof fibrinolysis is more important to determine the severity level ofhyperfibrinolysis. Most studies use the maximum lysis index (ML),which shows the extent of lysis as percentage of the maximum clot-ting amplitude (MCF) after 60 min of runtime. In particular, Schöchlet al. used a categorical classification for late, intermediate and ful-minant hyperfibrinolysis.11 The solely use of the ML may lead to anunderestimation of the degree of hyperfibrinolysis in cases wherea maximum lysis is reached before 60 min of runtime. We there-fore used the lysis onset time (LOT) as the point where the declinein clot firmness starts. Theoretically, this parameter seems mostappropriate for determining the degree of hyperfibrinolysis as itprovides a measure for hyperfibrinolysis for every patient with clotlysis within 60 min of ROTEM runtime. Moreover, in contrast to themaximum lysis, the LOT has no maximum. The choice for the LOT inour study matches with previous ex vivo research by Nielsen et al.,who showed a relation between increasing tPA concentrations andthe time to clot disintegration.21 Further studies are necessary tovalidate the use of the lysis onset time to quantify the degree ofhyperfibrinolysis.

Our investigation did not include body temperature regis-trations of included patients. As hypothermia may deterioratecoagulation, our findings might be confounded in case of low bodytemperature. Part of our study population received prehospital flu-ids up to 500 ml, but these data were also not included in our studydatabase. It is however not expected that the fluid administrationdid affect the time to hyperfibrinolysis in our study population.This study was not powered to determine differences in outcomebetween patients with or without hyperfibrinolysis, and no con-clusions may be drawn from these data regarding final outcome.However from the seven patients with unfavourable outcome inthe emergency room, six patients showed hyperfibrinolysis. On onehand, this may suggest that excessive fibrinolysis is associated withearly death, although larger studies are warranted to support thisconcept. On the other hand, a state of hyperfibrinolysis may the-oretically be beneficial in patients in severe shock by maintainingvascular patency and end-organ perfusion. The question remainswhether hyperfibrinolysis in patients with cardiopulmonary arrestis an evolutionary end-of-life indicator or a physiological phe-nomenon to prevent further ischemic and thromboembolic injuryand ensure end-organ perfusion under stressful conditions.

Disclosures

None of the authors have disclosures.

Financial support

This study was financially supported by the Department ofAnaesthesiology, VU University Medical Center.

V.A. Viersen et al. / Resuscitation 83 (2012) 1451– 1455 1453

Table 1Characteristics of patients without or with hyperfibrinolysis.

No hyperfibrinolysis Hyperfibrinolysis P

N 14 16Age (years) 65 ± 18 68 ± 13 ns

Resuscitation parametersMedian transportation time (min) 44 (34–49) 38 (32–53) nsMedian CPR time (min) 10 (7–18) 36 (15–55) 0.001Median time to 1st output (min) 16 (13–28) 44 (33–58) 0.007

Coagulation parametersHaemoglobin (mmol/l) 8.3 ± 1.0 8.5 ± 1.2 nsHaematocrit 0.41 ± 0.05 0.43 ± 0.06 nsaPTT (s) 38 ± 10 54 ± 16 0.006INR 1.55 ± 1.03 2.04 ± 1.42 nsPlatelet count (10−9)* 217 ± 92 186 ± 90 nsFibrinogen (g/l) 3.4 ± 1.0 1.9 ± 1.4 nsD-dimers (!g/ml) 2.3 ± 2.0 6.1 ± 2.1 0.02

Markers for hypoperfusionpH 7.17 ± 0.15 6.96 ± 0.11 <0.001BE −11.91 ± 6.44 −20.01 ± 3.53 <0.001Lactate (mmol/l) 8.0 ± 3.7 13.1 ± 3.7 0.001Median pO2 (kPa) 237 (127–405) 92 (54–124) 0.001Median pCO2 (kPa) 44 (35–52) 59 (46–78) 0.03

Values are presented as mean ± SD or median with interquartile range. CPR, cardiopulmonary resuscitation; aPTT, activated partial thromboplastin time; INR, internationalnormalised ratio in the prothrombin time; BE, base excess; pO2, arterial oxygen pressure; pCO2, arterial carbon dioxide pressure; ns, not significant.

* P < 0.05 was considered as statistically different.

3.2. Relation hyperfibrinolysis parameters and markers ofhypoperfusion

In patients with hyperfibrinolysis, the lysis index of the EXTEMat 30 and 45 min estimated 72 ± 43% and 56 ± 42%, respectively. Thelysis onset time was 1798 ± 970 s, with a lysis time of 1487 ± 1159 s.Overall, the lysis onset time ranged from 514 to 2947 s. The max-imum lysis was 64 ± 39%. Fig. 2 show the association of the lysisonset time with cardiopulmonary resuscitation (CPR) time (panelA), base excess (panel B) and lactate levels (panel C). The lysis onsettime showed a good correlation with the CPR time and lactate lev-els. Lactate, and not base excess, was overall associated with themaximum lysis (r = 0.52; P = 0.04), LI30 (r = −0.61; P = 0.01) and LI45(r = −0.87; P < 0.001).

3.3. Patient outcome

In the total group, 19 patients (63%) died after hospital admis-sion. The study was not powered to compare mortality in patientswith or without hyperfibrinolysis. Overall, mortality in patientswith or without hyperfibrinolysis estimated 69% and 57%, respec-tively. Patients with hyperfibrinolysis who died showed a shorterlysis onset time (1356 ± 833 s) when compared to survivors withhyperfibrinolysis (3222 ± 34 s; P = 0.044).

Fig. 1. ROTEM lysis parameters: MCF, maximum clot formation, LOT, lysis onsettime, LT, lysis time, LI30, lysis index at 30 min, LI45, lysis index at 45 min, ML,maximum lysis.

4. Discussion

This is the first clinical study showing hyperfibrinolysis usingrotational thromboelastometry in a majority of the patients admit-ted after witnessed out of hospital cardiac arrest. Hyperfibrinolysiswas associated with profound disseminated intravascular coagu-lopathy compared to patients without hyperfibrinolysis. The mostinteresting marker for hyperfibrinolysis was the lysis onset time,which was related to the cardiopulmonary resuscitation time andlactate levels. A delayed start of hyperfibrinolysis was less fre-quently associated with markers for hypoperfusion and mortality.Our study shows that a significant part of out of hospital cardiacarrest patients develop hyperfibrinolysis, in particular in case ofsigns of hypoperfusion. This supports the hypothesis that hyper-fibrinolysis may be induced by shock and hypoperfusion solely,without the presence of trauma or massive blood loss.

Primary fibrinolysis is a local tissue phenomenon that supportsblood clot breakdown. Under physiological conditions, fibrinol-ysis is activated by urokinase or tissue plasminogen activator(tPA) that is released by the damaged endothelium. Urokinaseand tPA are inhibited by plasminogen activator inhibitor (PAI) 1or 2. After conversion of plasminogen to plasmin, plasmin is pri-mary inhibited by alpha-2-antiplasmin, while thrombin activatablefibrinolysis inhibitor (TAFI) further inhibits fibrinolysis itself.15–17

Secondary fibrinolysis refers to an abnormal clot breakdown underpathophysiological circumstances, like trauma or disturbances intissue perfusion, which may confer to hyperfibrinolysis. One ofthe proposed mechanisms underlying excessive fibrinolysis is theactivation of protein C, which subsequently inhibits PAI-1 andTAFI.10,12,14 Moreover, hypoxia induces a systemic release of t-PA,leading to excessive fibrinolysis.15,18,19 Our findings warrant closerevaluation of levels of t-PA, activated protein C, plasminogen, PAIand TAFI in OHCA patients in order to understand the pathophysi-ology of hyperfibrinolysis during cardiopulmonary arrest.

Cardiac arrest and resuscitation have previously been shownto be associated with activation of coagulation and inflammationthat closely resembled the changes observed in sepsis. Adrie et al.showed that patients who were successfully resuscitated after car-diopulmonary arrest had a systemic inflammatory response withactivation of coagulation, reduction of anticoagulation, activation of

Resuscitation 83 (2012) 1451– 1455


Resuscitation

jo u rn al hom epage : www.elsev ier .com/ locate / resusc i ta t ion

Clinical Paper

Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers ofhypoperfusion!

V.A. Viersena, S. Greutersa, A.R. Korfagea, C. Van der Rijsta, V. Van Bochovea, P.W. Nanayakkarab,E. Vandewalleb, C. Boera,∗

a Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlandsb Department of Emergency Medicine, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands


Article history:Received 16 December 2011Received in revised form 15 April 2012Accepted 11 May 2012

Keywords:Cardiopulmonary arrestHaemostasisShockFibrinolysis

a b s t r a c t

Aim of the study: This study investigated the incidence of hyperfibrinolysis upon emergency department(ED) admission in patients with out of hospital cardiac arrest (OHCA), and the association of the degreeof hyperfibrinolysis with markers of hypoperfusion.Methods: From 30 OHCA patients, cardiopulmonary resuscitation (CPR) time, pH, base excess (BE), andserum lactate were measured upon ED admission. A 20% decrease of rotational thromboelastometrymaximum clot firmness (MCF) was defined as hyperfibrinolysis. Lysis parameters included maximumlysis (ML), lysis onset time (LOT) and lysis index at 30 and 45 min (LI30/LI45). The study was approvedby the Human Subjects Committee.Results: Hyperfibrinolysis was present in 53% of patients. Patients with hyperfibrinolysis had longermedian CPR times (36 (15–55) vs. 10 (7–18) min; P = 0.001), a prolonged activated partial thromboplastintime (54 ± 16 vs. 38 ± 10 s; P = 0.006) and elevated D-dimers (6.1 ± 2.1 vs. 2.3 ± 2.0 !g/ml; P = 0.02) whencompared to patients without hyperfibrinolysis. Hypoperfusion markers, including pH (6.96 ± 0.11 vs.7.17 ± 0.15; P < 0.001), base excess (−20.01 ± 3.53 vs. −11.91 ± 6.44; P < 0.001) and lactate (13.1 ± 3.7 vs.8.0 ± 3.7 mmol/l) were more disturbed in patients with hyperfibrinolysis than in non-hyperfibrinolyticsubjects, respectively. The LOT showed a good association with CPR time (r = −0.76; P = 0.003) and lac-tate (r = −0.68; P = 0.01), and was longer in survivors (3222 ± 34 s) than in non-survivors (1356 ± 833;P = 0.044).Conclusion: A substantial part of OHCA patients develop hyperfibrinolysis in association with markersfor hypoperfusion. Our data further suggest that the time to the onset of clot lysis may be an importantmarker for the severity of hyperfibrinolysis and patient outcome.


1. Introduction

Out-of-hospital cardiac arrest (OHCA) remains a significantcause of morbidity and mortality among the general population.Despite advances in cardiopulmonary resuscitation, the prognosisafter OHCA remains very poor, with survival rates around 10% inEurope.1

Cardiac arrest and resuscitation are characterised by reducedcardiac output and blood flow, resulting in shock and tissuehypoperfusion.2–4 Animal and human studies showed markedactivation of inflammation and coagulation after cardiac arrest

! A Spanish translated version of the abstract of this article appears as Appendixin the final online version at http://dx.doi.org/10.1016/j.resuscitation.2012.05.008.

∗ Corresponding author at: Department of Anesthesiology, VU University MedicalCenter, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.Tel.: +31 0 20 4443830; fax: +31 20 4444385.

E-mail address: [email protected] (C. Boer).

and resuscitation, resulting in intravascular coagulation, systemicformation of microthrombi and impairment of microcirculatoryperfusion.5–7 These changes may contribute to the developmentof ischemic injury and the post-resuscitation syndrome, which isfurther characterised by a systemic inflammation response, reper-fusion injury, adrenal dysfunction, myocardial dysfunction andeventually organ failure.8,9 In particular, an increased duration ofcardiopulmonary resuscitation is associated with a rise in coagula-tion abnormalities and mortality.8,10

Recent studies have shown that markers of shock andhypoperfusion in trauma patients are frequently paralleled byhyperfibrinolysis, which in turn is associated with higher mortalityrates.11–13 One of the proposed mechanisms is that hypoperfusion-associated thrombin formation leads to systemic hyperfibrinolysisthrough the protein C pathway, but the underlying mechanisms arenot well understood.11,12,14 Secondly, hypoxia may lead to exces-sive release of tissue plasminogen activator (t-PA) and therebycontribute to the presence of hyperfibrinolysis.15


HYPERFIBRINOLYSIS AFTER MAJOR TRAUMA

▸ epifenomeen van diepe shock ongeacht onderliggende oorzaak (hypovolemie of cardiogeen)

▸ Klinisch niet relevant

▸ Behandeling is het behandeling van bloedverlies met bloedproducten.

▸ Tranexaminezuur hoort er dan al lang in te zitten!

BIJ MASSAAL BLOEDVERLIES MEET IK FIBRINOGEEN:A. Postoperatief

B. Iedere paar uur

C. Ieder uur

D. ieder half uur

E. eigenlijk nooit

FIBRINOGEEN

▸ Hoe snel fibrinogeen daalt is geen enkel artikel over te vinden!

▸ Richtlijnen spreken alleen van “vroege en herhaalde metingen”

▸ Invloed van verschillende soorten letsels (leverlaceratie, neurotrauma) op de snelheid van dalen is niks over te vinden. (leverlaceraties, neurotrauma’s, fluxus)

▸ Als je niet vaak meet kom je soms voor verassingen te staan!

FIBRINOGEEN

ALS IK FIBRINOGEEN WIL CORRIGEREN GEEF IK :A. FFP of SDP (plasma)

B. Fibrinogeen concentraat

C. Tranexaminezuur

D. Novo seven


Clinical effectiveness of fresh frozen plasmacompared with fibrinogen concentrate:a systematic reviewSibylle Kozek-Langenecker1*, Benny Sørensen2,3, John R Hess4 and Donat R Spahn5

Abstract

Introduction: Haemostatic therapy in surgical and/or massive trauma patients typically involves transfusion of freshfrozen plasma (FFP). Purified human fibrinogen concentrate may offer an alternative to FFP in some instances. Inthis systematic review, we investigated the current evidence for the use of FFP and fibrinogen concentrate in theperioperative or massive trauma setting.

Methods: Studies reporting the outcome (blood loss, transfusion requirement, length of stay, survival and plasmafibrinogen level) of FFP or fibrinogen concentrate administration to patients in a perioperative or massive traumasetting were identified in electronic databases (1995 to 2010). Studies were included regardless of type, patientage, sample size or duration of patient follow-up. Studies of patients with congenital clotting factor deficiencies orother haematological disorders were excluded. Studies were assessed for eligibility, and data were extracted andtabulated.

Results: Ninety-one eligible studies (70 FFP and 21 fibrinogen concentrate) reported outcomes of interest. Fewwere high-quality prospective studies. Evidence for the efficacy of FFP was inconsistent across all assessedoutcomes. Overall, FFP showed a positive effect for 28% of outcomes and a negative effect for 22% of outcomes.There was limited evidence that FFP reduced mortality: 50% of outcomes associated FFP with reduced mortality(typically trauma and/or massive bleeding), and 20% were associated with increased mortality (typically surgicaland/or nonmassive bleeding). Five studies reported the outcome of fibrinogen concentrate versus a comparator.The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of alloutcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found tobe superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length ofintensive care unit and hospital stay and increasing plasma fibrinogen levels. We found no fibrinogen concentratecomparator studies in patients with haemorrhage due to massive trauma, although efficacy across all assessedoutcomes was reported in a number of noncomparator trauma studies.

Conclusions: The weight of evidence does not appear to support the clinical effectiveness of FFP for surgical and/or massive trauma patients and suggests it can be detrimental. Perioperatively, fibrinogen concentrate wasgenerally associated with improved outcome measures, although more high-quality, prospective studies arerequired before any definitive conclusions can be drawn.

* Correspondence: [email protected] of Anaesthesia and Intensive Care, Evangelical Hospital Vienna,Hans-Sachs-Gasse 10-12, 1180-Vienna, AustriaFull list of author information is available at the end of the article

Kozek-Langenecker et al. Critical Care 2011, 15:R239http://ccforum.com/content/15/5/R239

© 2011 Kozek-Langenecker et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

comparator trials, 70% of outcomes showed a benefit offibrinogen concentrate over the control. Importantly,the control was FFP in three of the studies, thus provid-ing some evidence that fibrinogen concentrate is moreefficacious than FFP across a range of clinical outcomesin the perioperative setting.The strongest support for a benefit for FFP derives

from studies reporting survival, where 50% suggestedthat FFP (typically at higher FFP:RBC ratios) reducesmortality; however, FFP was associated with increasedmortality in 20% of studies. In general, studies reportingan association of higher doses of FFP with improvedsurvival assessed the effect of FFP:RBC ratios duringmassive transfusion. This finding is in agreement withthe meta-analysis performed by Murad and colleagues[5]. Many studies targeting higher FFP:RBC ratios did soby increasing the amount of FFP administered in theearly phase of massive haemorrhage. This temporalaspect of FFP administration was highlighted in a recentpublication which found that patients who received anearly high FFP:RBC ratio were in less severe shock andless likely to die early from uncontrollable haemorrhagethan were those patients in the low FFP:RBC ratiogroup, who never achieved a high ratio [117]. The survi-val advantage associated with the higher FFP:RBC ratioscurrently being lauded in the literature may be duepartly to selection, whereby patients in such studies diewith a low FFP:RBC ratio, not because of a low ratio.Fibrinogen deficiency manifests early in bleedingpatients. It is possible that an improvement in survival

rates at higher FFP:RBC ratios was due in part to earliersupplementation of plasma fibrinogen in the resuscita-tion effort and not to a benefit of FFP per se. The fibri-nogen concentrate studies identified were typicallysmall, with a mean of only 10 patients per arm. Conse-quently, there were almost no deaths reported in eithergroup, making a robust assessment of any survival bene-fit following the administration of fibrinogen concen-trate (early or late) virtually impossible.In this review, we examined relevant outcomes of

interest by analysing the literature regarding one of twointerventions: FFP and fibrinogen concentrate. However,haemostatic support during surgery or massive traumais rarely achieved by the administration of one productalone; therefore, the majority of the studies included inthis review involved the administration of other pro-ducts, particularly RBC, but also PC, cryoprecipitate,prothrombin complex concentrate, tranexamic acid,aprotinin and others. The influence of coadministeredproducts on the outcomes of interest was not studied inthis review, though the potential for an impact shouldbe considered when drawing any conclusions regardingthe impact of each intervention on these outcomes, par-ticularly in studies where cryoprecipitate was adminis-tered, as this would provide a more concentrated doseof fibrinogen than FFP alone.

Risk versus benefitThe benefits of any intervention should outweigh therisks. In this review, we found inconsistent and

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11

4

59

1

3

8

12

2

26

0% 20% 40% 60% 80% 100%

Blood loss

Allogeneic transfusions

Survival

LOS

Plasma fibrinogen

Overall

Studies assessing FFP vs any comparator

Benefit

No difference

Decrement

2a

3

5

4

4

16

1

3

1

2

7

0% 20% 40% 60% 80% 100%

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Survival

LOS

Plasma fibrinogen

Overall

Studies assessing fibrinogen concentrate vs any comparator

Benefit

No difference

Decrement

2b2b2b2b

1

2

3

12

7

3

5

1

28

2

5

3

11

0% 20% 40% 60% 80% 100%

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LOS

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Overall

Studies assessing FFP vs crystalloids/colloids/no FFP

Benefit

No difference

Decrement

2c

1

3

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4

4

16

3

1

2

7

0% 20% 40% 60% 80% 100%

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LOS

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Overall

Studies assessing fibrinogen concentrate vs crystalloids/FFP/no fibrinogen concentrate

Benefit

No difference

Decrement

2d

1

Figure 2 Summary of efficacy outcomes from comparator trials. Numbers represent number of outcomes. FFP = fresh frozen plasma; LOS =length of stay.


Page 17 of 25RESEARCH Open Access


Abstract








FIBRINOGEEN CORRECTIE MET FFP‣ Ondergrens is 1,5 - 2,0 g/L ‣ Fibrinogeen concentratie van omniplasma (sanquin) is 2,6 g/L ‣ 1 unit omniplasma 200ml is dus totaal 0,5 gram fibrinogeen

‣ Bij het geven van een massaal transfusieprotocol met een PC-FFP ratio van 1:1 geef je dus 2,6 / 2 = 1,3 g/L

‣ Het is dus onmogelijk om met omniplasma je fibrinogeen concentratie te corrigeren!!!

‣ Laat staan dat je ongoing verlies en verbruik kan bijbenen!

‣ Fibrinogeen concentraat is 10g/L

WELKE FIBRINOGEEN CONCENTRATIE STREEF JE NA:

A. 1,0 g/L

B. 1,5 g/L

C. 2,0 g/L

D. 2,5 g/L

FIBRINOGEEN 1,0 1,5 OF 2,O OF NOG MEER?OBSTETRICS

Association between fibrinogen level and severityof postpartum haemorrhage: secondary analysisof a prospective trialM. Cortet1,2,3,4*, C. Deneux-Tharaux5, C. Dupont6,7, C. Colin8, R.-C. Rudigoz9, M.-H. Bouvier-Colle5

and C. Huissoud2,9,10

1 Hospices civils de Lyon, Service de Biostatistique, F-69003, Lyon, France2 Universite de Lyon, F-69000, Lyon, France3 Universite Lyon 1, F-69100, Villeurbanne, France4 CNRS, UMR 5558, Laboratoire de Biometrie et Biologie Evolutive, Equipe Biostatistique-Sante, F-69100, Villeurbanne, France5 INSERM U953 Epidemiological Research Unit on Perinatal Health and Women’s and Children’s Health, UPMC Paris 6, Paris, France6 Aurore Perinatal Network, Hopital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France7 Universite de Lyon, EA Sante-Individu-Societe 4129, F-69002 Lyon Cedex 03, France8 Hospices civils de Lyon, Pole Information Medicale Evaluation Recherche, F-69003 Lyon, France9 Hospices civils de Lyon, Service de Gynecologie-Obstetrique de l’Hopital de La Croix-Rousse, F-69000 Lyon, France10 INSERM U846, Stem Cell and Brain Research Institutes, F-69500 Bron, France

* Corresponding author. E-mail: [email protected]

Editor’s key points

† The aim of the study wasto observe whether thefibrinogen level atdiagnosis of postpartumhaemorrhage (PPH) isassociated with theseverity of bleeding.

† This study suggests that alow fibrinogen level atPPH diagnosis isassociated with a higherrisk of severe PPH,independently of theother laboratoryindicators.

Background. The aim of the study was to determine whether the fibrinogen level atdiagnosis of postpartum haemorrhage (PPH) is associated with the severity of bleeding.

Methods. This is a secondary analysis of a population-based study in 106 French maternity unitsidentifying cases of PPH prospectively. PPH was defined by a blood loss exceeding 500 ml duringthe 24 h after delivery or a peripartum haemoglobin decrease of more than 20 g litre21. Thisanalysis includes 738 women with PPH after vaginal delivery. Fibrinogen levels were comparedin patients whose PPH worsened and became severe and those whose PPH remained non-severe. Severe PPH was defined as haemorrhage by occurrence of one of the following events:peripartum haemoglobin decrease ≥40 g litre21, transfusion of concentrated red cells, arterialembolization or emergency surgery, admission to intensive care, or death.

Results. The mean fibrinogen concentration at diagnosis was 4.2 g litre21 [standard deviation(SD)¼1.2 g litre21] among the patients without worsening and 3.4 g litre21 (SD¼0.9 g litre21)(P,0.001) in the group whose PPH became severe. The fibrinogen level was associated withPPH severity independently of other factors [adjusted odds ratio¼1.90 (1.16–3.09) forfibrinogen between 2 and 3 g litre21 and 11.99 (2.56–56.06) for fibrinogen ,2 g litre21].

Conclusions. The fibrinogen level at PPH diagnosis is a marker of the risk of aggravation andshould serve as an alert to clinicians.

Keywords: blood coagulation; fibrinogen; postpartum haemorrhage

Accepted for publication: 26 January 2012

Postpartum haemorrhage (PPH) remains a major cause ofmaternal mortality throughout the world,1 including inFrance.2 Specific guidelines describe preventive and curativetreatments for PPH.3 – 5 Its risk factors have been well identi-fied and studied repeatedly.6 – 9 The risk factors for its aggra-vation, however, have been studied much less.10

Coagulation plays an important role in postpartumhaemostasis. Primary and especially secondary coagulationdisorders are risk factors for PPH that have not been suffi-ciently evaluated. Pregnancy-induced hypercoagulability

tends to reduce the risk of haemorrhage naturally.Pregnancy-related coagulation changes are expressed by aprogressive and significant increase in the fibrinogen level,while the standard indicators, such as prothrombin time(PT) and activated coagulation time (ACT), vary little.11

Coagulation disturbances are frequent and occur rapidlyduring PPH. There is, however, no consensus about thethresholds that should trigger specific management, butmaintaining the plasma fibrinogen concentration is import-ant for limiting excessive blood loss.12 13 Because fibrinogen

British Journal of Anaesthesia 108 (6): 984–9 (2012)Advance Access publication 6 April 2012 . doi:10.1093/bja/aes096

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.For Permissions, please email: [email protected]

at Universiteit van A

msterdam

on May 23, 2012

http://bja.oxfordjournals.org/D

ownloaded from

▸ Gemiddelde fibrinogeen spiegel 4,2 g/L

▸ Gemiddelde fibrinogeen spiegel bij ernstige fluxus 3,4g/L

▸ Fibrinogeen 2-3 g/L odds ratio 1,9 voor ernstige fluxus

▸ Fibrinogeen <2 g/L odds ratio 11,99 voor ernstige fluxus



Abstract









Prevalence, predictors and outcome ofhypofibrinogenaemia in trauma: a multicentreobservational studyJostein S Hagemo1,2*, Simon Stanworth3, Nicole P Juffermans4,5, Karim Brohi6, Mitchell Jay Cohen7,Pär I Johansson8,9, Jo Røislien1,10, Torsten Eken11, Paal A Næss12 and Christine Gaarder12

Abstract

Introduction: Exsanguination due to trauma-induced coagulopathy is a continuing challenge in emergency traumacare. Fibrinogen is a crucial factor for haemostatic competence, and may be the factor that reaches critically lowlevels first. Early fibrinogen substitution is advocated by a number of authors. Little evidence exists regarding theindications for fibrinogen supplementation in the acute phase. This study aims to estimate the prevalence ofhypofibrinogenaemia in a multi-center trauma population, and to explore how initial fibrinogen concentrationrelates to outcome. Also, factors contributing to low fibrinogen levels are identified.

Methods: Patients arriving in hospital less than 180 minutes post-injury requiring full trauma team activation in fourdifferent centers were included in the study. Time from injury, patient demographics, injury severity scores (ISS) and 28days outcome status were recorded. Initial blood samples for coagulation and blood gas were analyzed. Generalizedadditive regression, piecewise linear regression, and multiple linear regression models were used for data analyses.

Results: Out of 1,133 patients we identified a fibrinogen concentration ≤1.5g/L in 8.2%, and <2 g/L in 19.2%. A non-linearrelationship between fibrinogen concentration and mortality was detected in the generalized additive and piecewise linearregression models. In the piecewise linear regression model we identified a breakpoint for optimal fibrinogen concentrationat 2.29 g/L (95% confidence interval (CI): 1.93 to 2.64). Below this value the odds of death by 28 days was reduced by afactor of 0.08 (95% CI: 0.03 to 0.20) for every unit increase in fibrinogen concentration. Low age, male gender, lengthenedtime from injury, low base excess and high ISS were unique contributors to low fibrinogen concentrations on arrival.

Conclusions: Hypofibrinogenaemia is common in trauma and strongly associated with poor outcome. Below anestimated critical fibrinogen concentration value of 2.29 g/L a dramatic increase in mortality was detected. This findingindicates that the negative impact of low fibrinogen concentrations may have been previously underestimated. A numberof clinically identifiable factors are associated with hypofibrinogenaemia. They should be considered in the managementof massively bleeding patients. Interventional trials with fibrinogen substitution in high-risk patients need to be undertaken.

IntroductionDespite the implementation of damage control resuscita-tion principles, exsanguination remains a frequent cause ofdeath in hospital [1,2]. Early coagulopathy is identified in10 to 34% of patients arriving in hospital and is associatedwith increased mortality [3]. Fibrinogen plays a pivotal

role in coagulation as it is converted into fibrin, whichin conjunction with platelets forms a stable blood clot asthe end haemostatic product [4]. Low fibrinogen levels orinefficient fibrinogen utilisation may adversely impact onpatient outcomes.Besides low fibrinogen levels due to blood loss and

increased consumption, a number of factors affect fibrino-gen metabolism in a massively bleeding trauma patient.Hypothermia reduces fibrinogen synthesis [5] whereasacidaemia following hypoperfusion leads to increased

* Correspondence: [email protected] of Research, Norwegian Air Ambulance, Stiftelsen NorskLuftambulanse Postboks 39 1441, Drøbak, Norway2Department of Anaesthesiology, Oslo University Hospital, Avdeling forAnestesiologi/Ullevål Postboks 4950 Nydalen 0424, Oslo, NorwayFull list of author information is available at the end of the article

© 2014 Hagemo et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

Hagemo et al. Critical Care 2014, 18:R52http://ccforum.com/content/18/2/R52



Abstract











Figure 1 Multivariable generalised additive model and piecewise linear model for relationship between fibrinogen concentration and28-day survival. Results from the multivariable generalised additive model (GAM) and the piecewise linear model for the relationship betweenfibrinogen concentration and 28-day survival, adjusted for Injury Severity Score, age, time from injury, mechanism of injury, base excess, InternationalNormalized Ratio, platelet count and gender. The functional relationship is clearly nonlinear (a), resulting in a corresponding nonconstant odds ratio acrossthe observed range of fibrinogen values (b). For the piecewise linear model, the breakpoint (95% confidence interval (CI)) is estimated at 2.29 (1.93, 2.64).

Table 2 Linear and piecewise linear multiple logistic regression models with 28-day mortality as the dependent variableLinear model Piecewise linear model

Odds ratio v P value Segment Odds ratio (95% CI) P value

Fibrinogen (g/l)a 0.46 < 0.001 Lower 0.08 < 0.001

(0.03, 0.20)(0.31, 0.67)

Upper 1.77 0.076

(0.94, 3.32)

Injury severity scoreb 1.03 0.008 Lower 1.18 < 0.001

(1.10, 1.27)(1.01, 1.05)

Upper 0.93 0.001

(0.89, 0.97)

Age (years) 1.05 < 0.001 1.04 < 0.001

(1.03, 1.06) (1.02, 1.06)

Time from injury (minutes) 0.99 0.166 0.99 0.018

(0.99, 1.00) (0.98, 1.00)

Mechanism of injury (penetrating) 0.73 0.546 0.33 0.06

(0.25, 1.90) (0.10, 1.05)

Base excess (mEq/l) 0.90 < 0.001 0.92 0.002

(0.85, 0.95) (0.87, 0.97)

International normalized ratio 3.21 0.012 1.65 0.29

(1.33, 8.53) (0.65, 4.18)

Platelet count (109/l) 1.00 0.61 1.00 0.92

(1.00, 1.00) (1.00, 1.00)

Gender (male) 0.45 0.006 0.33 0.001

(0.26, 0.81) (0.18, 0.62)aBreakpoint for fibrinogen is 2.29 g/l (95% confidence interval (CI): 1.93, 2.64). bBreakpoint for Injury Severity Score is 25.7 (95% CI: 21.8, 29.7).

Hagemo et al. Critical Care 2014, 18:R52 Page 4 of 8http://ccforum.com/content/18/2/R52



Abstract











HOE DOSEER JIJ FIBRINOGEEN CONCENTRAAT?

A. altijd 2 gram!

B. 20 mg/kg

C. Afhankelijk van de concentratie

D. Ik reken het uit

E. Hoe harder het bloed hoe meer ik geef

FIBRINOGEEN CONCENTRAAT DOSEREN

▸ Farmacotherapeutisch Kompas:“In het algemeen begindosis 1–2 g, gevolgd door aanvullende infusies afhankelijk van de fibrinogeenconcentratie in plasma en de klinische toestand van de patiënt. In ernstige gevallen, bijvoorbeeld bij loslating van de placenta, kan een hogere dosis (4–8 g) nodig zijn.”

▸ Streef concentratie 2,0 g/L, uitgaande van 5L bloed is er totaal 10 gram fibrinogeen in het lichaam. je kan dus enigszins berekenen wat je nodig hebt om een bepaalde concentratie te bereiken.

▸ Hou ook rekening met de tijd om toe te dienen en het verlies wat ondertussen doorgaat

JE KAN STOLLINGSPROBLEMEN DOOR BLOEDVERLIES PRIMA CORRIGEREN MET 4 FACTOREN CONCENTRAAT EN FIBRINOGEEN!

A. Eens

B. Oneens

COMBINATIE 4 FACTOREN CONCENTRAAT EN FIBRINOGEEN‣20 varkens met 65% bloedverlies,

65% substitutie met HES, therapie (1,2) gestandaardiseerde incisie in de lever

‣1. Fibrinogeen 200mg/kg, PCC 35IE/kg 2. Placebo

‣groep 1: bloedverlies 240ml -> 100% survival groep 2: bloedverlies 1800ml -> 20% survival

‣“chirurgisch bloedverlies” is 7,5 keer zo groot bij een gestoorde stolling. Goed te behandelen met factoren

British Journal of Anaesthesia 97 (4): 460–7 (2006)

doi:10.1093/bja/ael191 Advance Access publication August 1, 2006

Efficacy of fibrinogen and prothrombin complex concentrateused to reverse dilutional coagulopathy—a porcine model

D. Fries1*, T. Haas3, A. Klingler3, W. Streif4, G. Klima5, J. Martini1,H. Wagner-Berger2 and P. Innerhofer2

1Division of General and Surgical Intensive Care Medicine, 2Division of Anaesthesiology,3Department of Theoretical Surgery, 4Department of Paediatrics and

5Department of Histology and Embryology, Innsbruck Medical University,Anichstrasse 35, 6020 Innsbruck, Austria

*Corresponding author. E-mail: [email protected]

Background. This study was conducted to assess whether the combined administration offibrinogen and prothrombin complex concentrate (PCC) enables the reversal of dilutional co-agulopathy resulting from intended blood loss and fluid replacement, and whether this treatmentreduces further blood loss and mortality.

Methods. In 20 anaesthetized pigs, !65% of the estimated blood volume was withdrawn andreplaced with the same amount of hydroxyethyl starch (6% HES 130/0.4) to mimic blood loss andto develop a dilutional coagulopathy. Pigs (randomized) received either fibrinogen (200 mg kg"1)and PCC (35 IU kg"1) (n=10), or placebo (n=10). Thereafter, a standard liver laceration wasperformed to induce uncontrolled haemorrhage. The subsequent blood loss and survival timewere determined as primary outcome variables. Throughout the experiment serial blood sampleswere obtained to assess the competence of the haemostatic system using standard coagulationtests, modified Thrombelastograph! measurements (ROTEM!) and electron microscopy clotimaging.

Results. As compared with baseline, after haemodilution both groups showed statistically sig-nificant impairment of haemostasis as measured with standard coagulation tests and thrombe-lastography. These parameters significantly improved after administration of the study drugs whileaPPT measurements remained unchanged. Blood loss after liver injury was significantly less in thetreatment group as compared with placebo: 240 ml (50–830) vs 1800 ml (1500–2500) (P<0.0001).All treated animals survived, whereas 80% of the placebo group died (P<0.0001).

Conclusion. During haemodilution, substitution of fibrinogen and PCC causes an enhancementof coagulation and final clot strength. This reversal of dilutional coagulopathy may reduce bloodloss and mortality when large amounts of colloids are needed to maintain normovolaemia duringhuge blood losses.

Br J Anaesth 2006; 97: 460–7

Keywords: blood, prothrombin complex concentrate; complications, coagulopathy;complications, haemorrhage; fluid, therapy; measurement techniques, Thrombelastograph!;pig; protein, fibrinogen concentrate

Accepted for publication: May 10, 2006

The concept of adequately administering crystalloid andcolloid fluids to maintain normovolaemia in patientsexhibiting blood loss and the restrictive use of plasma-free red cell concentrates are the reasons why anaesthesi-ologists are now more frequently confronted with patientsdeveloping severe coagulopathy. The i.v. fluids not onlydilute clotting factor concentrations but also exert specificeffects on the coagulation system which have been

extensively investigated in vitro and in vivo.1–5 Generally,artificial and natural colloids impair coagulation to a largerextent than crystalloids.6 7 We have previously shown thatcolloids decrease clot strength primarily by impairing fibrinpolymerization, the final pathway of the coagulation pro-cess.6 In our previous experiments we were able to show thatadministration of fibrinogen concentrate results in quickand effective reversal of decreased clot strength, while,

" The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: [email protected]







A

B

C







465

Prothrombin complex concentrate vs fresh frozen plasma forreversal of dilutional coagulopathy in a porcine trauma model

G. Dickneite†* and I. Pragst†

Department of Pharmacology and Toxicology, CSL Behring GmbH, Marburg, Germany*Corresponding author. E-mail: [email protected]

Background. Fluid resuscitation following traumatic injury causes haemodilution and cancontribute to coagulopathy. Coagulation factor replacement may be necessary to preventbleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP),prothrombin complex concentrate (PCC) may potentially offer a more rapid and effectivemeans of normalizing coagulation factor levels.

Methods. In anaesthetized mildly hypothermic pigs, 65–70% of total blood volume was substi-tuted in phases with hydroxyethyl starch and red cells. Animals were then treated with 15 mlkg21 isotonic saline placebo, 25 IU kg21 PCC, or 15 ml kg21 FFP. Immediately thereafter,either a standardized femur or spleen injury was inflicted, and coagulation function, includingthrombin generation, and bleeding were assessed. An additional group received high-dose FFP(40 ml kg21) before femur injury.

Results. Haemodilution markedly prolonged prothrombin time and reduced peak thrombingeneration. PCC, but not FFP, fully reversed those effects. Compared with 15 ml kg21 FFP,PCC shortened the time to haemostasis after either bone (P¼0.001) or spleen (P¼0.028)trauma and reduced the volume of blood lost (P,0.001 and P¼0.015, respectively).Subsequent to bone injury, PCC also accelerated haemostasis (P¼0.003) and diminished bloodloss (P¼0.006) vs 40 ml kg21 FFP.

Conclusions. PCC was effective in correcting dilutional coagulopathy and controlling bleedingin an in vivo large-animal trauma model. In light of its suitability for more rapid administrationthan FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in traumaand surgery.

Br J Anaesth 2009; 102: 345–54

Keywords: blood, haemodilution; complications, haemorrhagic disorder; complications,trauma; fresh frozen plasma; prothrombin complex concentrate

Accepted for publication: December 16, 2008

Uncontrolled bleeding associated with major trauma andsurgery is often life-threatening. Acquired coagulopathy oftrauma is responsible for the majority of postoperativetraumatic haemorrhagic fatalities, and the onset of acutecoagulopathy is associated with increased overall mor-tality.1 The coagulopathy of trauma is a manifestation ofthe combined effects of blood loss and dilution, coagu-lation factor and platelet consumption, hypothermic plate-let dysfunction, acidosis-induced decreases in coagulationfactor activity, and fibrinolysis.2

A recognized complication of massive transfusion isdilutional coagulopathy, which occurs when lost blood isreplaced with fluids that do not contain coagulation

factors. Dilutional coagulopathy is distinct from the morerecently recognized phenomenon of acute traumatic coagu-lopathy, which is independent of i.v. fluid administrationand appears to be mediated through activation of theprotein C pathway.3 The shift from whole blood transfu-sion in the past to the current practice of specific bloodcomponent therapy has resulted in earlier occurrence ofthrombocytopenia and clotting factor deficiency in traumapatients.4 5 Trauma resuscitation usually starts with crystal-loid or colloid solutions followed by red blood cell

†Declaration of interest. Gerhard Dickneite and Ingo Pragst areemployees of CSL Behring.

# 2009 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/

licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


doi:10.1093/bja/aen391 Advance Access publication January 24, 2009

Haemostasis

After either experimental bone or spleen trauma, PCC sig-nificantly shortened time to haemostasis compared withFFP (Fig. 3). Haemostasis was achieved by all 13PCC-treated animals. Over the course of the 120 minobservation period, bleeding failed to cease in four of 14saline recipients (29%), five of 13 animals in the 15 mlkg21 FFP group (38%), and three of four evaluable pigs(75%) treated with 40 ml kg21 FFP. Compared with FFP,PCC also significantly lowered the volume of blood lostfollowing either bone or spleen trauma (Fig. 4).

From a baseline median of 117 s, SBT was more thandoubled by haemodilution (Table 2). Saline placebo andFFP showed little effect in shortening the prolonged SBT.However, PCC normalized SBT.

DiscussionAcquired coagulopathy following trauma is an importantdeterminant of outcome. Coagulopathic patients, includingthose with head injury, experience worse outcomes thanpatients with the same injury severity but no clotting

15

5

20

10

0

25

100

0

20

40

60

80

Thr

ombi

n pe

ak (

nM)

Pro

thro

mbi

n tim

e (s

)

A

B

Baseline median

Baseline Haemodilution Saline PCC15 ml kg–1 40 ml kg–1

C

1400

0

200

400

600

800

1000

1200

ET

P (

nM m

in)

Group Median change from baseline (CI)

Saline 7.1 (6.5 to 8.2)

15 ml kg–1 FFP 3.4 (2.8 to 3.9)

40 ml kg–1 FFP 1.6 (1.0 to 2.2)

PCC 0.9 (0.6 to 2.2)


Saline –38.7 (–42.6 to –36.2)

15 ml kg–1 FFP –32.7 (–35.6 to –30.5)

40 ml kg–1 FFP –23.4 (–28.9 to –17.9)

PCC 1.8 (–2.8 to 7.7)


Saline –38.5 (–69.5 to 0.2)

15 ml kg–1 FFP –15.2 (–33.2 to 1.5)

40 ml kg–1 FFP –40.0 (–87.5 to –6.0)

PCC 565.8 (529.3 to 605.3)

Fig 2 (A) Prothrombin time, (B) peak thrombin generation, and (C) ETP after haemodilution and subsequent administration of saline, FFP, or PCC.

Graphic conventions as in Figure 1. CI, 95% confidence interval; FFP, fresh frozen plasma; ETP, endogenous thrombin potential; PCC, prothrombincomplex concentrate.

PCC for correcting dilutional coagulopathy

349

Prothrombin complex concentrate vs fresh frozen plasma forreversal of dilutional coagulopathy in a porcine trauma model

G. Dickneite†* and I. Pragst†

Department of Pharmacology and Toxicology, CSL Behring GmbH, Marburg, Germany*Corresponding author. E-mail: [email protected]

Background. Fluid resuscitation following traumatic injury causes haemodilution and cancontribute to coagulopathy. Coagulation factor replacement may be necessary to preventbleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP),prothrombin complex concentrate (PCC) may potentially offer a more rapid and effectivemeans of normalizing coagulation factor levels.

Methods. In anaesthetized mildly hypothermic pigs, 65–70% of total blood volume was substi-tuted in phases with hydroxyethyl starch and red cells. Animals were then treated with 15 mlkg21 isotonic saline placebo, 25 IU kg21 PCC, or 15 ml kg21 FFP. Immediately thereafter,either a standardized femur or spleen injury was inflicted, and coagulation function, includingthrombin generation, and bleeding were assessed. An additional group received high-dose FFP(40 ml kg21) before femur injury.

Results. Haemodilution markedly prolonged prothrombin time and reduced peak thrombingeneration. PCC, but not FFP, fully reversed those effects. Compared with 15 ml kg21 FFP,PCC shortened the time to haemostasis after either bone (P¼0.001) or spleen (P¼0.028)trauma and reduced the volume of blood lost (P,0.001 and P¼0.015, respectively).Subsequent to bone injury, PCC also accelerated haemostasis (P¼0.003) and diminished bloodloss (P¼0.006) vs 40 ml kg21 FFP.

Conclusions. PCC was effective in correcting dilutional coagulopathy and controlling bleedingin an in vivo large-animal trauma model. In light of its suitability for more rapid administrationthan FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in traumaand surgery.

Br J Anaesth 2009; 102: 345–54

Keywords: blood, haemodilution; complications, haemorrhagic disorder; complications,trauma; fresh frozen plasma; prothrombin complex concentrate

Accepted for publication: December 16, 2008

Uncontrolled bleeding associated with major trauma andsurgery is often life-threatening. Acquired coagulopathy oftrauma is responsible for the majority of postoperativetraumatic haemorrhagic fatalities, and the onset of acutecoagulopathy is associated with increased overall mor-tality.1 The coagulopathy of trauma is a manifestation ofthe combined effects of blood loss and dilution, coagu-lation factor and platelet consumption, hypothermic plate-let dysfunction, acidosis-induced decreases in coagulationfactor activity, and fibrinolysis.2

A recognized complication of massive transfusion isdilutional coagulopathy, which occurs when lost blood isreplaced with fluids that do not contain coagulation

factors. Dilutional coagulopathy is distinct from the morerecently recognized phenomenon of acute traumatic coagu-lopathy, which is independent of i.v. fluid administrationand appears to be mediated through activation of theprotein C pathway.3 The shift from whole blood transfu-sion in the past to the current practice of specific bloodcomponent therapy has resulted in earlier occurrence ofthrombocytopenia and clotting factor deficiency in traumapatients.4 5 Trauma resuscitation usually starts with crystal-loid or colloid solutions followed by red blood cell

†Declaration of interest. Gerhard Dickneite and Ingo Pragst areemployees of CSL Behring.

# 2009 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/

licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


doi:10.1093/bja/aen391 Advance Access publication January 24, 2009

FFP VERSUS CONCENTRATEN

The impact of fresh frozen plasma vs coagulation factor concentrates on morbidityand mortality in trauma-associated haemorrhage and massive transfusion

Ulrike Nienaber a, Petra Innerhofer b,*, Isabella Westermann b, Herbert Schochl c, Rene Attal d,Robert Breitkopf b, Marc Maegele a,e

a Institute for Research in Operative Medicine (IFOM), University of Witten/Herdecke, Cologne, Germanyb Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Innsbruck, Austriac Department of Anaesthesiology and Critical Care Medicine, Unfallkrankenhaus Salzburg, Salzburg, Austriad Department of Trauma Surgery and Sportsmedicine, Innsbruck Medical University, Innsbruck, Austriae Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), University of Witten/Herdecke, Cologne, Germany

Introduction

Uncontrolled haemorrhage is still responsible for more than50% of all trauma-related deaths within the first 48 h after hospitaladmission.34 Clinical observations together with recent researchhighlighted the central role of coagulopathy in acute traumacare4,5,17,22,23 and early recognition and adequate aggressivemanagement have been shown to substantially reduce mortalityand improve outcome in severely injured bleeding patients.3,24 To

date, the use of fresh frozen plasma (FFP) is an integral part ofmassive transfusion protocols in most trauma centers30,31 and itsearly use has been advocated.14 Several retrospective studies havedemonstrated a survival benefit for bleeding trauma patients whentransfused with an early high red blood cell (RBC):FFP 1:1 ratioboth in civilian and military settings.3,15,24,39 However, theseresults may have been influenced by the fact that quite a fewpatients died before having had the chance to receive any FFPtransfusion, suggesting a considerable bias of results.27 Interest-ingly, prospectively collected data could not confirm a beneficialeffect of aggressively transfused FFP in trauma patients.35

Moreover, there are several well-established risks together withFFP administration in trauma and other critical states of illness, for

Injury, Int. J. Care Injured 42 (2011) 697–701

A R T I C L E I N F O

Article history:Accepted 16 December 2010

Keywords:Coagulation factor concentratesFresh frozen plasmaHaemorrhageOutcomeTraumaTransfusion

A B S T R A C T

Introduction: Clinical observations together with recent research highlighted the role of coagulopathy inacute trauma care and early aggressive treatment has been shown to reduce mortality.Methods: Datasets from severely injured and bleeding patients with established coagulopathy uponemergency room (ER) arrival from two retrospective trauma databases, (i) TR-DGU (Germany) and (ii)Innsbruck Trauma Databank/ITB (Austria), that had received two different strategies of coagulopathymanagement during initial resuscitation, (i) fresh frozen plasma (FFP) without coagulation factorconcentrates, and (ii) coagulation factor concentrates (fibrinogen and/or prothrombin complexconcentrates) without FFP, were compared for morbidity, mortality and transfusion requirementsusing a matched-pair analysis approach.Results: There were no major differences in basic characteristics and physiological variables upon ERadmission between the two cohorts that were matched. ITB patients had received substantially lesspacked red blood cell (pRBC) concentrates within the first 6 h after admission (median 1.0 (IQR25–75 0–3)vs 7.5 (IQR25–75 4–12) units; p < 0.005) and the first 24 h as compared to TR-DGU patients (median 3(IQR25–75 0–5) vs 12.5 (8–20) units; p < 0.005). Overall mortality was comparable between both groupswhilst the frequency for multi organ failure was significantly lower within the group that had receivedcoagulation factor concentrates exclusively and no FFP during initial resuscitation (n = 3 vs n = 15;p = 0.015). This translated into trends towards reduced days on ventilator whilst on ICU and shorteroverall in-hospital length of stays (LOS).Conclusion: Although there was no difference in overall mortality between both groups, significantdifferences with regard to morbidity and need for allogenic transfusion provide a signal supporting themanagement of acute post-traumatic coagulopathy with coagulation factor concentrates rather thanwith traditional FFP transfusions. Prospective and randomised clinical trials with sufficient patientnumbers based upon this strategy are advocated.

! 2011 Published by Elsevier Ltd.

* Corresponding author. Tel.: +43 (0)512 504 80407;fax: +43 (0)512 504 28430.

Contents lists available at ScienceDirect

Injury

jo ur n al ho m epag e: ww w.els evier . c om / lo cat e/ in ju r y

0020–1383/$ – see front matter ! 2011 Published by Elsevier Ltd.doi:10.1016/j.injury.2010.12.015

MOET IK DAN STOPPEN MET PLASMA GEVEN?

A. Nee want je hebt nog meer nodig dan alleen fibrinogeen

B. Plasma is ook goed voor je endotheel/glycocalyx

REVIEW Open Access

The endothelial glycocalyx and itsdisruption, protection and regeneration: anarrative reviewUlf Schött1,2*, Cristina Solomon3,4, Dietmar Fries5 and Peter Bentzer1,2

Abstract

The glycocalyx is a carbohydrate-rich layer that lines the luminal side of the vascular endothelium. Its solublecomponents exist in a dynamic equilibrium with the bloodstream and play an important role in maintainingendothelial layer integrity. However, the glycocalyx can be easily damaged and is extremely vulnerable to insultsfrom a variety of sources, including inflammation, trauma, haemorrhagic shock, hypovolemia and ischaemia-reperfusion. Damage to the glycocalyx commonly precedes further damage to the vascular endothelium. Preclinicalresearch has identified a number of different factors capable of protecting or regenerating the glycocalyx. Initialinvestigations suggest that plasma may convey protective and regenerative effects. However, it remains unclearwhich exact components or properties of plasma are responsible for this protective effect. Studies have reportedprotective effects for several plasma proteins individually, including antithrombin, orosomucoid and albumin; thelatter of which may be of particular interest, due to the high levels of albumin present in plasma. A furtherpossibility is that plasma is simply a better intravascular volume expander than other resuscitation fluids. It has alsobeen proposed that the protective effects are mediated indirectly via plasma resuscitation-induced changes in geneexpression. Further work is needed to determine the importance of specific plasma proteins or other factors forglycocalyx protection, particularly in a clinical setting.

Keywords: Bleeding management, Fresh frozen plasma, Glycocalyx, Protection, Regeneration

BackgroundThe endothelial glycocalyx is a carbohydrate-rich layerthat lines the vascular endothelium. The presence of aprotein layer on the endothelium was first proposed byDanielli in 1940 [1] and was visualised using electronmicroscopy in 1966 [2]. Initial investigations of the gly-cocalyx were hampered as previous staining and fixingtechniques destroyed this fragile structure [3]. However,contemporary methods preserve the glycocalyx and haveenabled more detailed examination of the structure andphysiology of this layer [4].The glycocalyx is connected to the endothelium via

several cell-bound core molecules, mainly proteoglycansand glycoproteins (Fig. 1). On the luminal surface, the

glycocalyx is formed by soluble plasma components, ei-ther linked to each other directly or via soluble proteo-glycans, glycosaminoglycans and sialoproteins [5, 6]. Adynamic equilibrium exists between the layer of solublecomponents and the bloodstream, where the blood flowconstantly affects both the composition and the thick-ness of the glycocalyx [5]. For example, Ueda and col-leagues reported that the glycocalyx in bovine aorticendothelial cells increase in thickness as sheer stress in-creases up to 3.0 Pa [7]. Additionally, the glycocalyxcontains a large volume of non-circulating plasma; es-timated at 1–1.7 L [8, 9], and has a net negativecharge that affects its interaction with plasma constit-uents, platelets and red blood cells, thereby counter-acting microvascular thrombosis and maintainingrheology [4, 10, 11].Situated between the endothelium and the blood-

stream, the glycocalyx serves several functions includinglimiting access of particular molecules to the

* Correspondence: [email protected] of Clinical Sciences Lund, Medical Faculty, University of Lund,Lund, Sweden2Department of Intensive and Perioperative Care, Skane University Hospital,Lund, SwedenFull list of author information is available at the end of the article

© 2016 Schött et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Schött et al. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine (2016) 24:48 DOI 10.1186/s13049-016-0239-y

ConclusionsThe glycocalyx plays a fundamental role in the microcir-culation and in the initiation and regulation of coagula-tion and inflammation. Therapeutic strategies aimed atprotecting this delicate layer are poorly understood atthis time. While the various beneficial effects of FFPhave been demonstrated, there is still no information asto what the mode of action is and if this is due to a par-ticular constituent of the plasma. Further research is ne-cessary to understand how FFP and other therapeuticstrategies can benefit protect the glycocalyx and ultim-ately the patient.

AbbreviationsCOP: colloid osmotic pressure; FFP: fresh frozen plasma; GPCR: G protein-coupled receptor; SDP: spray-dried plasma; sTM: soluble thrombomodulin;vWF: von Willebrand factor.

Competing interestsUS has received grants from CSL Behring. CS was an employee of CSLBehring at the time of writing and previously received speaker honoraria andresearch support from Tem International and CSL Behring and travel supportfrom Haemoscope Ltd (former manufacturer of TEG®). DF has receivedhonoraria for consulting, lecture fees and sponsoring for academic studiesfrom the following companies: Astra Zeneca, AOP Orphan, Baxter, Bayer, B.Braun, Biotest, CSL Behring, Delta Select, Dade Behring, Edwards, Fresenius,Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk,Octapharm, Pfizer, Tem-Innovation. PB has no conflicts of interest to declare.

Authors’ contributionsAll authors have made substantial contributions to drafting the article,revising it critically for important intellectual content and have given finalapproval of the version to be submitted.

AcknowledgementsEditorial assistance with linguistic revision was provided by MeridianHealthComms, funded by CSL Behring.

Author details1Department of Clinical Sciences Lund, Medical Faculty, University of Lund,Lund, Sweden. 2Department of Intensive and Perioperative Care, SkaneUniversity Hospital, Lund, Sweden. 3Department of Anesthesiology,Perioperative Medicine and General Intensive Care, Paracelsus MedicalUniversity, Salzburg, Austria. 4CSL Behring, Marburg, Germany. 5Departmentof Surgical and General Critical Care Medicine, Medical University Innsbruck,Innsbruck, Austria.

Received: 29 October 2015 Accepted: 6 April 2016

References1. Danielli JF. Capillary permeability and oedema in the perfused frog.

J Physiol. 1940;98(1):109–29.2. Luft JH. Fine structures of capillary and endocapillary layer as revealed by

ruthenium red. Fed Proc. 1966;25(6):1773–83.3. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers

Arch. 2000;440(5):653–66.4. Chelazzi C, Villa G, Mancinelli P, De Gaudio AR, Adembri C. Glycocalyx and

sepsis-induced alterations in vascular permeability. Crit Care. 2015;19:26.5. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The

endothelial glycocalyx: composition, functions, and visualization. PflugersArch. 2007;454(3):345–59.

6. Li L, Ly M, Linhardt RJ. Proteoglycan sequence. Mol Biosyst. 2012;8(6):1613–25.7. Ueda A, Shimomura M, Ikeda M, Yamaguchi R, Tanishita K. Effect of

glycocalyx on shear-dependent albumin uptake in endothelial cells.Am J Physiol Heart Circ Physiol. 2004;287(5):H2287–94.

8. Rehm M, Zahler S, Lotsch M, Welsch U, Conzen P, Jacob M, et al.Endothelial glycocalyx as an additional barrier determining extravasation of

6 % hydroxyethyl starch or 5 % albumin solutions in the coronary vascularbed. Anesthesiology. 2004;100(5):1211–23.

9. Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van LieshoutMH, Levi M, et al. Loss of endothelial glycocalyx during acutehyperglycemia coincides with endothelial dysfunction and coagulationactivation in vivo. Diabetes. 2006;55(2):480–6.

10. Alphonsus CS, Rodseth RN. The endothelial glycocalyx: a review of thevascular barrier. Anaesthesia. 2014;69(7):777–84.

11. Bansch P, Nelson A, Ohlsson T, Bentzer P. Effect of charge on microvascularpermeability in early experimental sepsis in the rat. Microvasc Res. 2011;82(3):339–45.

12. Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, et al. Sheddingof the endothelial glycocalyx in patients undergoing major vascular surgerywith global and regional ischemia. Circulation. 2007;116(17):1896–906.

13. Henry CB, Duling BR. Permeation of the luminal capillary glycocalyx isdetermined by hyaluronan. Am J Physiol. 1999;277(2 Pt 2):H508–14.

14. Lipowsky HH, Gao L, Lescanic A. Shedding of the endothelial glycocalyx inarterioles, capillaries, and venules and its effect on capillary hemodynamicsduring inflammation. Am J Physiol Heart Circ Physiol. 2011;301(6):H2235–45.

15. Constantinescu AA, Vink H, Spaan JA. Endothelial cell glycocalyx modulatesimmobilization of leukocytes at the endothelial surface. Arterioscler ThrombVasc Biol. 2003;23(9):1541–7.

16. Vink H, Duling BR. Capillary endothelial surface layer selectively reducesplasma solute distribution volume. Am J Physiol Heart Circ Physiol. 2000;278(1):H285–9.

17. Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM. Heparansulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res.2003;93(10):e136–42.

18. Kolarova H, Ambruzova B, Svihalkova Sindlerova L, Klinke A, Kubala L.Modulation of endothelial glycocalyx structure under inflammatoryconditions. Mediators Inflamm. 2014;2014:694312.

19. Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D. Degradation of theendothelial glycocalyx in clinical settings: searching for the sheddases.Br J Clin Pharmacol. 2015;80(3):389–402.

20. Yen W, Cai B, Yang J, Zhang L, Zeng M, Tarbell JM, et al. Endothelial surfaceglycocalyx can regulate flow-induced nitric oxide production inmicrovessels in vivo. PLoS One. 2015;10(1):e0117133.

21. Biddle C. Like a slippery fish, a little slime is a good thing: the glycocalyxrevealed. AANA J. 2013;81(6):473–80.

22. Henry CB, Duling BR. TNF-alpha increases entry of macromolecules intoluminal endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol. 2000;279(6):H2815–23.

23. Bruegger D, Jacob M, Rehm M, Loetsch M, Welsch U, Conzen P, et al. Atrialnatriuretic peptide induces shedding of endothelial glycocalyx in coronaryvascular bed of guinea pig hearts. Am J Physiol Heart Circ Physiol. 2005;289(5):H1993–9.

24. Gouverneur M, Spaan JA, Pannekoek H, Fontijn RD, Vink H. Fluid shear stressstimulates incorporation of hyaluronan into endothelial cell glycocalyx. AmJ Physiol Heart Circ Physiol. 2006;290(1):H458–2.

25. Subramanian SV, Fitzgerald ML, Bernfield M. Regulated shedding ofsyndecan-1 and −4 ectodomains by thrombin and growth factor receptoractivation. J Biol Chem. 1997;272(23):14713–20.

26. Zuurbier CJ, Demirci C, Koeman A, Vink H, Ince C. Short-term hyperglycemiaincreases endothelial glycocalyx permeability and acutely decreases linealdensity of capillaries with flowing red blood cells. J Appl Physiol (1985). 2005;99(4):1471–6.

27. Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, et al. Plasmarestoration of endothelial glycocalyx in a rodent model of hemorrhagicshock. Anesth Analg. 2011;112(6):1289–95.

28. Torres LN, Sondeen JL, Ji L, Dubick MA, Torres FI. Evaluation of resuscitationfluids on endothelial glycocalyx, venular blood flow, and coagulation functionafter hemorrhagic shock in rats. J Trauma Acute Care Surg. 2013;75(5):759–66.

29. Mulivor AW, Lipowsky HH. Inflammation- and ischemia-induced shedding ofvenular glycocalyx. Am J Physiol Heart Circ Physiol. 2004;286(5):H1672–80.

30. Sillesen M, Rasmussen LS, Jin G, Jepsen CH, Imam A, Hwabejire JO, et al.Assessment of coagulopathy, endothelial injury, and inflammation aftertraumatic brain injury and hemorrhage in a porcine model. J Trauma AcuteCare Surg. 2014;76(1):12–9.

31. Chappell D, Bruegger D, Potzel J, Jacob M, Brettner F, Vogeser M, et al.Hypervolemia increases release of atrial natriuretic peptide and shedding ofthe endothelial glycocalyx. Crit Care. 2014;18(5):538.

Schött et al. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine (2016) 24:48 Page 7 of 8

REVIEW Open Access

The endothelial glycocalyx and itsdisruption, protection and regeneration: anarrative reviewUlf Schött1,2*, Cristina Solomon3,4, Dietmar Fries5 and Peter Bentzer1,2

Abstract

The glycocalyx is a carbohydrate-rich layer that lines the luminal side of the vascular endothelium. Its solublecomponents exist in a dynamic equilibrium with the bloodstream and play an important role in maintainingendothelial layer integrity. However, the glycocalyx can be easily damaged and is extremely vulnerable to insultsfrom a variety of sources, including inflammation, trauma, haemorrhagic shock, hypovolemia and ischaemia-reperfusion. Damage to the glycocalyx commonly precedes further damage to the vascular endothelium. Preclinicalresearch has identified a number of different factors capable of protecting or regenerating the glycocalyx. Initialinvestigations suggest that plasma may convey protective and regenerative effects. However, it remains unclearwhich exact components or properties of plasma are responsible for this protective effect. Studies have reportedprotective effects for several plasma proteins individually, including antithrombin, orosomucoid and albumin; thelatter of which may be of particular interest, due to the high levels of albumin present in plasma. A furtherpossibility is that plasma is simply a better intravascular volume expander than other resuscitation fluids. It has alsobeen proposed that the protective effects are mediated indirectly via plasma resuscitation-induced changes in geneexpression. Further work is needed to determine the importance of specific plasma proteins or other factors forglycocalyx protection, particularly in a clinical setting.

Keywords: Bleeding management, Fresh frozen plasma, Glycocalyx, Protection, Regeneration

BackgroundThe endothelial glycocalyx is a carbohydrate-rich layerthat lines the vascular endothelium. The presence of aprotein layer on the endothelium was first proposed byDanielli in 1940 [1] and was visualised using electronmicroscopy in 1966 [2]. Initial investigations of the gly-cocalyx were hampered as previous staining and fixingtechniques destroyed this fragile structure [3]. However,contemporary methods preserve the glycocalyx and haveenabled more detailed examination of the structure andphysiology of this layer [4].The glycocalyx is connected to the endothelium via

several cell-bound core molecules, mainly proteoglycansand glycoproteins (Fig. 1). On the luminal surface, the

glycocalyx is formed by soluble plasma components, ei-ther linked to each other directly or via soluble proteo-glycans, glycosaminoglycans and sialoproteins [5, 6]. Adynamic equilibrium exists between the layer of solublecomponents and the bloodstream, where the blood flowconstantly affects both the composition and the thick-ness of the glycocalyx [5]. For example, Ueda and col-leagues reported that the glycocalyx in bovine aorticendothelial cells increase in thickness as sheer stress in-creases up to 3.0 Pa [7]. Additionally, the glycocalyxcontains a large volume of non-circulating plasma; es-timated at 1–1.7 L [8, 9], and has a net negativecharge that affects its interaction with plasma constit-uents, platelets and red blood cells, thereby counter-acting microvascular thrombosis and maintainingrheology [4, 10, 11].Situated between the endothelium and the blood-

stream, the glycocalyx serves several functions includinglimiting access of particular molecules to the

* Correspondence: [email protected] of Clinical Sciences Lund, Medical Faculty, University of Lund,Lund, Sweden2Department of Intensive and Perioperative Care, Skane University Hospital,Lund, SwedenFull list of author information is available at the end of the article

© 2016 Schött et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Schött et al. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine (2016) 24:48 DOI 10.1186/s13049-016-0239-y

“ENDOTHELIOPATHY OF TRAUMA”Modulating the endotheliopathy of trauma: Factor concentrate

versus fresh frozen plasma

Shibani Pati, MD, PhD, Daniel R. Potter, PhD, Gyulnar Baimukanova, MD, PhD, David H. Farrel, MD,John B. Holcomb, MD, and Martin A. Schreiber, MD, San Francisco, California

BACKGROUND: Transfusion of balanced ratios of plasma to platelets and red blood cells has been shown to reduce early death from exsanguination intrauma patients. Aside from hemostasis, recent work has shown that plasma reduces vascular endothelial permeability, inflammation,and organ edema after hemorrhagic shock (HS), all components of the endotheliopathy of trauma.We hypothesized that Kcentra could haveprotective effects on the endotheliopathy of trauma comparable with fresh frozen plasma (FFP).

METHODS: In vitro, endothelial cell (EC) barrier function was assessed by measuring changes in transendothelial electrical resistance for Kcentra, FFP,and albumin. In vivo, a modified Miles assay was used on mice to study the effects of Kcentra, FFP, and albumin on vascular permeabilityinduced by VEGF-A. The same groups were studied in a second in vivo model of pulmonary vascular leak induced by HS and laparotomy.The identification of proteins in Kcentra was assessed by liquid chromatography/mass spectrometry.

RESULTS: We found that FFP and Kcentra inhibit EC permeability. We also found that Kcentra and FFP have equivalent capacity to restore ECadherens junction breakdown induced by VEGF-A. In vivo, we found that Kcentra and FFP, but not albumin, significantly inhibited vas-cular permeability induced by VEGF-A and HS-induced vascular permeability in mice. Investigation of the protein content of Kcentra bymass spectroscopy revealed that there are a number of proteins in Kcentra, derived from plasma that may have contributory roles in thenoted effects of Kcentra on vascular leak.

CONCLUSION: Taken together, we have demonstrated that FFP and Kcentra inhibit vascular permeability in vivo and in vitro. These beneficial effects ofKcentra may be due in part to the modulation of vascular function by soluble factors present in Kcentra aside from the known clotting fac-tors II, VII, IX, and X. The clinical implications of these findings are unknown and warrant further investigation. (J Trauma Acute CareSurg. 2016;80: 576–585. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.)

KEYWORDS: Kcentra; vascular permeability; hemorrhagic shock; FFP; coagulant function.

R etrospective and prospective observational trials have shownan association between high-ratio transfusion of plasma and

red blood cells (RBCs) with improved survival and decreased re-suscitation requirements.1–3 The damage-control resuscitationclinical practice guideline created by the US military and mostcivilian massive transfusion protocols now dictate the use ofplasma, platelets, and RBCs in a 1:1:1 ratio in an effort to repro-duce the effects of whole blood.4 In some settings, plasma is be-ing used as a primary resuscitation fluid in lieu of crystalloidsand colloids.5 The PROPPR trial revealed that trauma patientsresuscitated with plasma, platelets, and RBCs in a 1:1:1 ratiowere less likely to die of exsanguination at 24 hours.6

The beneficial effects of plasma have traditionally been at-tributed to its ability to correct coagulopathy and stop bleeding.

More recent work by our group and others has demonstrated thatplasma has potent effects on vascular permeability and inflam-mation in preclinical models of traumatic injury.7–12 Our studiesare based around the central hypothesis that fresh frozen plasma(FFP) has the capacity to repair injured endothelium and theendotheliopathy of trauma, a process defined by prolonged vas-cular permeability, nonspecific initiation of coagulation, endo-thelial cell (EC) contraction and death, interstitial edema,leukocyte infiltration, inflammation, and tissue hypoxia.10,13,14

FFP resuscitation in a rat model of hemorrhagic shock (HS)has also been shown to partially restore a damaged endothelialglycocalyx, modulate inflammation, and increase syndecan 1expression.9,15,16 Restoration of the glycocalyx physically rein-forces the endothelial barrier by providing a protective coatingthat attenuates leukocyte/EC adhesion and EC contractil-ity.9,15,16 Work by Alam et al. has demonstrated that FFP admin-istration can decrease blood-brain barrier compromise, cerebraledema, and mortality in an established swine model of traumaticbrain injury.7,12,17 The mechanisms of action of FFP are still un-known but may be attributable to soluble factors present inplasma. There are more than 1,000 proteins in plasma, manyof which are biologically active and have unknown functions.18

Some of these proteins are likely present in prothrombin com-plex concentrate, a plasma-derived product used to restore he-mostasis in bleeding patients on coumadin.

Kcentra is a four-factor prothrombin complex concentratethat contains vitamin K–dependent coagulation factors and anti-coagulant factors; however, the exact composition of all proteinspresent in the product has not been reported to date.19,20 The

Submitted: September 10, 2015, Revised: November 24, 2015, Accepted: November25, 2015, Published online: January 21, 2016.

From the Blood Systems Research Institute (S.P., D.R.P., G.B.); and Department ofLaboratory Medicine (S.P., D.R.B., G.B.), University of California San Francisco,San Francisco, California; Department of Surgery (J.B.H.), University of Texas-Houston Medical School, Houston, Texas; and Department of Surgery (D.H.F.,M.A.S.), Oregon Health & Science University, Portland, Oregon.

This study was presented at the 74th annual meeting of the American Association forthe Surgery of Trauma, September 9–12, 2015, in Las Vegas, Nevada.

Supplemental digital content is available for this article. Direct URL citations appear inthe printed text, and links to the digital files are provided in the HTML text of thisarticle on the journal's website (www.jtrauma.com).

Address for reprints: Martin A. Schreiber, MD, Department of Surgery, Oregon Health& Science University, 3181 SWSam Jackson Park Rd, Mail Code L611, Portland,OR 97239; email: [email protected].

DOI: 10.1097/TA.0000000000000961

AAST 2015 PLENARY PAPER

576J Trauma Acute Care Surg

Volume 80, Number 4

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

have demonstrated, in an established mouse fixed-pressuremodel of HS and laparotomy (Fig. 4A), that HS induces pul-monary vascular permeability that is attenuated by transfu-sion with FFP at volumes equivalent to shed blood lost.8,9

To evaluate the effects of FFP and Kcentra transfusion onHS and lung injury, we studied hemodynamic measures andlung vascular permeability in HS mice (Fig. 4B and C). Mice(n = 7 per group) were subjected to 90 minutes of hypoten-sion. The mean arterial pressures (MAPs) for all groups aredepicted in graph form in Figure 4B. Mean arterial blood pres-sure traces from FFP-, Kcentra-, and albumin-treated micewere similar, where slight elevation of MAPs is noted afterthe resuscitation period but not back to sham levels, likely be-cause of the resuscitation volumes that were less than the vol-ume of the shed blood.

To evaluate the ability of Kcentra to reduce the vascu-lar leak associated with HS, we studied permeability in thelungs of mice subjected to HS using an infrared tagged dyeof 10-kD size (Fig. 4C). Mice were subjected to 90 minutesof shock, a timeframe when lung permeability is maximal.8,9

Mice were resuscitated with FFP (200 μL), Kcentra (50 U/kgin 200-μL saline [PBS]), or albumin (6 mg/kg in 200-μL sa-line). The lungs were harvested, and the leak of the dye intothe lung tissue was quantified (Fig. 4D). The data, expressedas average pixel intensity, are normalized to the presence ofdye in the lungs of the sham animals, which have beenthrough the entire procedure (cannulation, anesthesia) with-out the hemorrhage or injury. Animals resuscitated with FFPand Kcentra exhibited significantly lower dye permeabilitycompared with shock animals. FFP and Kcentra groups were

Figure 1. Kcentra andFFPdecrease ECmonolayer permeability, butnot albumin.A, TEER ECIS traces andareaunder the curvequantitationat1hourofcontrol (1.0±0.012),1-U/mLKcentra(1.054±0.022),FFP10%(1.112±0.0084),andFFP30%(1.169±0.028,n=8).*Allgroupsweresignificantlydifferent fromoneanother(p<0.05).B,TEERtraceandareaunderthecurvequantitationat1hourofcontrol (1.0±0.0078),12-μg/mL albumin (1.027 ± 0.0068), 1,200-μg/mL albumin (1.013 ± 0.010), and FFP 10% (1.11 ± 0.010) (*p < 0.05 from control).C, Representative images of ECs after VEGF-A (50 ng/mL) treatment stainedwith antibodies reactive to VE-cadherin (green). Qualitatively,cells pretreatedwith FFP and Kcentra display reconstituted intact AJs after VEGF-A treatment.

J Trauma Acute Care SurgVolume 80, Number 4 Pati et al.

© 2016 Wolters Kluwer Health, Inc. All rights reserved. 579


▸ Zowel FFP als 4 factoren concentraat voorkomen het ontstaan van vasculaire permeabiliteit

▸ Totaal 15 verschillende eiwitten in 4 Factorenconcentraat

Modulating the endotheliopathy of trauma: Factor concentrateversus fresh frozen plasma

Shibani Pati, MD, PhD, Daniel R. Potter, PhD, Gyulnar Baimukanova, MD, PhD, David H. Farrel, MD,John B. Holcomb, MD, and Martin A. Schreiber, MD, San Francisco, California

BACKGROUND: Transfusion of balanced ratios of plasma to platelets and red blood cells has been shown to reduce early death from exsanguination intrauma patients. Aside from hemostasis, recent work has shown that plasma reduces vascular endothelial permeability, inflammation,and organ edema after hemorrhagic shock (HS), all components of the endotheliopathy of trauma.We hypothesized that Kcentra could haveprotective effects on the endotheliopathy of trauma comparable with fresh frozen plasma (FFP).

METHODS: In vitro, endothelial cell (EC) barrier function was assessed by measuring changes in transendothelial electrical resistance for Kcentra, FFP,and albumin. In vivo, a modified Miles assay was used on mice to study the effects of Kcentra, FFP, and albumin on vascular permeabilityinduced by VEGF-A. The same groups were studied in a second in vivo model of pulmonary vascular leak induced by HS and laparotomy.The identification of proteins in Kcentra was assessed by liquid chromatography/mass spectrometry.

RESULTS: We found that FFP and Kcentra inhibit EC permeability. We also found that Kcentra and FFP have equivalent capacity to restore ECadherens junction breakdown induced by VEGF-A. In vivo, we found that Kcentra and FFP, but not albumin, significantly inhibited vas-cular permeability induced by VEGF-A and HS-induced vascular permeability in mice. Investigation of the protein content of Kcentra bymass spectroscopy revealed that there are a number of proteins in Kcentra, derived from plasma that may have contributory roles in thenoted effects of Kcentra on vascular leak.

CONCLUSION: Taken together, we have demonstrated that FFP and Kcentra inhibit vascular permeability in vivo and in vitro. These beneficial effects ofKcentra may be due in part to the modulation of vascular function by soluble factors present in Kcentra aside from the known clotting fac-tors II, VII, IX, and X. The clinical implications of these findings are unknown and warrant further investigation. (J Trauma Acute CareSurg. 2016;80: 576–585. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.)

KEYWORDS: Kcentra; vascular permeability; hemorrhagic shock; FFP; coagulant function.

R etrospective and prospective observational trials have shownan association between high-ratio transfusion of plasma and

red blood cells (RBCs) with improved survival and decreased re-suscitation requirements.1–3 The damage-control resuscitationclinical practice guideline created by the US military and mostcivilian massive transfusion protocols now dictate the use ofplasma, platelets, and RBCs in a 1:1:1 ratio in an effort to repro-duce the effects of whole blood.4 In some settings, plasma is be-ing used as a primary resuscitation fluid in lieu of crystalloidsand colloids.5 The PROPPR trial revealed that trauma patientsresuscitated with plasma, platelets, and RBCs in a 1:1:1 ratiowere less likely to die of exsanguination at 24 hours.6

The beneficial effects of plasma have traditionally been at-tributed to its ability to correct coagulopathy and stop bleeding.

More recent work by our group and others has demonstrated thatplasma has potent effects on vascular permeability and inflam-mation in preclinical models of traumatic injury.7–12 Our studiesare based around the central hypothesis that fresh frozen plasma(FFP) has the capacity to repair injured endothelium and theendotheliopathy of trauma, a process defined by prolonged vas-cular permeability, nonspecific initiation of coagulation, endo-thelial cell (EC) contraction and death, interstitial edema,leukocyte infiltration, inflammation, and tissue hypoxia.10,13,14

FFP resuscitation in a rat model of hemorrhagic shock (HS)has also been shown to partially restore a damaged endothelialglycocalyx, modulate inflammation, and increase syndecan 1expression.9,15,16 Restoration of the glycocalyx physically rein-forces the endothelial barrier by providing a protective coatingthat attenuates leukocyte/EC adhesion and EC contractil-ity.9,15,16 Work by Alam et al. has demonstrated that FFP admin-istration can decrease blood-brain barrier compromise, cerebraledema, and mortality in an established swine model of traumaticbrain injury.7,12,17 The mechanisms of action of FFP are still un-known but may be attributable to soluble factors present inplasma. There are more than 1,000 proteins in plasma, manyof which are biologically active and have unknown functions.18

Some of these proteins are likely present in prothrombin com-plex concentrate, a plasma-derived product used to restore he-mostasis in bleeding patients on coumadin.

Kcentra is a four-factor prothrombin complex concentratethat contains vitamin K–dependent coagulation factors and anti-coagulant factors; however, the exact composition of all proteinspresent in the product has not been reported to date.19,20 The

Submitted: September 10, 2015, Revised: November 24, 2015, Accepted: November25, 2015, Published online: January 21, 2016.

From the Blood Systems Research Institute (S.P., D.R.P., G.B.); and Department ofLaboratory Medicine (S.P., D.R.B., G.B.), University of California San Francisco,San Francisco, California; Department of Surgery (J.B.H.), University of Texas-Houston Medical School, Houston, Texas; and Department of Surgery (D.H.F.,M.A.S.), Oregon Health & Science University, Portland, Oregon.

This study was presented at the 74th annual meeting of the American Association forthe Surgery of Trauma, September 9–12, 2015, in Las Vegas, Nevada.

Supplemental digital content is available for this article. Direct URL citations appear inthe printed text, and links to the digital files are provided in the HTML text of thisarticle on the journal's website (www.jtrauma.com).

Address for reprints: Martin A. Schreiber, MD, Department of Surgery, Oregon Health& Science University, 3181 SWSam Jackson Park Rd, Mail Code L611, Portland,OR 97239; email: [email protected].

DOI: 10.1097/TA.0000000000000961

AAST 2015 PLENARY PAPER

576J Trauma Acute Care Surg

Volume 80, Number 4


TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK:EVALUATION OF DIFFERENT RESUSCITATION STRATEGIES

IN A LARGE ANIMAL MODEL OF COMBINED INSULTS

Guang Jin,* Marc A. deMoya,* Michael Duggan,* Thomas Knightly,*Ali Y. Mejaddam,* John Hwabejire,* Jennifer Lu,* William Michael Smith,*

Georgios Kasotakis,* George C. Velmahos,* Simona Socrate,† and Hasan B. Alam**Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts

General Hospital/Harvard Medical School, Boston; and †Institute for Soldier Nanotechnologies,Massachusetts Institute of Technology, Cambridge, Massachusetts.

Received 22 Jan 2012; first review completed 8 Feb 2012; accepted in final form 26 Mar 2012

ABSTRACT—Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related mortalityand morbidity. Combination of TBI and HS (TBI + HS) is highly lethal, and the optimal resuscitation strategy for this com-bined insult remains unclear. A critical limitation is the lack of suitable large animal models to test different treatment strategies.We have developed a clinically relevant large animal model of TBI + HS, which was used to evaluate the impact of differenttreatments on brain lesion size and associated edema. Yorkshire swine (42Y50 kg) were instrumented to measure hemo-dynamic parameters and intracranial pressure. A computer-controlled cortical impact device was used to create a TBI througha 20-mm craniotomy: 15-mm cylindrical tip impactor at 4 m/s velocity, 100-ms dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 h of shock, animals were randomizedto one of three resuscitation groups (n = 5/group): (a) normal saline (NS); (b) 6% hetastarch, Hextend (Hex); and (c) fresh frozenplasma (FFP). Volumes of Hex and FFP matched the shed blood, whereas NS was three times the volume. After 6 h ofpostresuscitation monitoring, brains were sectioned into 5-mm slices and stained with TTC (2,3,5-triphenyltetrazolium chloride)to quantify the lesion size and brain swelling. Combination of 40% blood loss with cortical impact and a period of shock (2 h)resulted in a highly reproducible brain injury. Total fluid requirements were lower in the Hex and FFP groups. Lesion sizeand brain swelling in the FFP group (2,160 T 202.6 mm3 and 22% T 1.0%, respectively) were significantly smaller than thosein the NS group (3,285 T 130.8 mm3 and 37% T 1.6%, respectively) (P G 0.05). Hex treatment decreased the swelling (29% T1.6%) without reducing the lesion size. Early administration of FFP reduces the size of brain lesion and associated swelling ina large animal model of TBI + HS. In contrast, artificial colloid (Hex) decreases swelling without reducing the actual size ofthe brain lesion.

KEYWORDS—Traumatic brain injury, hemorrhage, edema, swine, shock

INTRODUCTION

In patients with traumatic brain injury (TBI), fluid resuscita-tion plays a critical role in restoring and maintaining systemicand cerebral circulations (1). It is widely recognized that sec-ondary insults can markedly worsen outcomes after TBI. A re-view of the Traumatic Coma Databank has identified hypotensionand hypoxemia to be independently associated with significantincreases in morbidity and mortality from severe head injury(2). This association has also been confirmed in well-controlledanimal models. For example, Jenkins et al. (3) reported an in-crease in CA1 neuronal death when hypotension was combinedwith TBI, and Matsushita et al. (4) reported an increase incontusion area when hemorrhagic shock (HS) followed fluidpercussion injury in rodent models. These studies strongly sug-gest that HS significantly increases TBI-related morbidity andmortality.

The optimal resuscitation strategy following a combinedTBI + HS remains unclear. Characteristics of an ideal resus-citation fluid include an ability to minimize cerebral edema,attenuation of primary neuronal damage, and prevention of sec-ondary brain injury. Isotonic crystalloids are commonly used forresuscitation, but they do not have any specific protective prop-erties besides restoring intravascular volume and maintaining ap-propriate osmotic environment. As these fluids rapidly move outof the vascular compartment, it often requires large volumes tomaintain the desired blood pressure. Artificial colloids (6%hetastarch solution) have been the preferred fluids for resusci-tation in combat casualty settings because of logistical advan-tages (less volume and weight). In several animal models,resuscitation with 6% hetastarch, Hextend (Hex), required lessvolume and improved cerebrovascular functions compared withcrystalloids (5, 6). However, administration of colloid solutionsin TBI patients is controversial, as a post hoc analysis of theSAFE (Saline vs. Albumin Fluid Evaluation) study reported asignificantly higher mortality rate in TBI patients assigned toalbumin resuscitation compared with saline (1). Mechanisms bywhich these fluids affect the progression of cell death followingTBI (and alter outcomes) remain largely unknown. One of themajor barriers is lack of a clinically meaningful large animalmodel of TBI that can be used by researchers to answer keytranslational questions. An ideal model would have a reprodu-cible, reliable, and severe (but potentially reversible) brain injury;

49

SHOCK, Vol. 38, No. 1, pp. 49Y56, 2012

Address reprint requests to Hasan B. Alam, MD, Division of Trauma, EmergencySurgery and Surgical Critical Care, Harvard Medical School/Massachusetts GeneralHospital, 165 Cambridge St, Suite 810, Boston, MA 02114. E-mail: [email protected].

This study was funded by a grant from the US Army Medical Research MaterialCommand GRANTT00521959 (to H.B.A.) and by the U.S. Army Research Officeunder contract number W911NF-07-D-0004 (to SS).

This study was presented at the New England Surgical Society 92nd AnnualMeeting, at the Omni Mount Washington Hotel, Bretton Woods, NH. September 2011.DOI: 10.1097/SHK.0b013e3182574778Copyright ! 2012 by the Shock Society

Copyright © 2012 by the Shock Society. Unauthorized reproduction of this article is prohibited.

TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK:EVALUATION OF DIFFERENT RESUSCITATION STRATEGIES

IN A LARGE ANIMAL MODEL OF COMBINED INSULTS

Guang Jin,* Marc A. deMoya,* Michael Duggan,* Thomas Knightly,*Ali Y. Mejaddam,* John Hwabejire,* Jennifer Lu,* William Michael Smith,*

Georgios Kasotakis,* George C. Velmahos,* Simona Socrate,† and Hasan B. Alam**Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts

General Hospital/Harvard Medical School, Boston; and †Institute for Soldier Nanotechnologies,Massachusetts Institute of Technology, Cambridge, Massachusetts.

Received 22 Jan 2012; first review completed 8 Feb 2012; accepted in final form 26 Mar 2012

ABSTRACT—Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related mortalityand morbidity. Combination of TBI and HS (TBI + HS) is highly lethal, and the optimal resuscitation strategy for this com-bined insult remains unclear. A critical limitation is the lack of suitable large animal models to test different treatment strategies.We have developed a clinically relevant large animal model of TBI + HS, which was used to evaluate the impact of differenttreatments on brain lesion size and associated edema. Yorkshire swine (42Y50 kg) were instrumented to measure hemo-dynamic parameters and intracranial pressure. A computer-controlled cortical impact device was used to create a TBI througha 20-mm craniotomy: 15-mm cylindrical tip impactor at 4 m/s velocity, 100-ms dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 h of shock, animals were randomizedto one of three resuscitation groups (n = 5/group): (a) normal saline (NS); (b) 6% hetastarch, Hextend (Hex); and (c) fresh frozenplasma (FFP). Volumes of Hex and FFP matched the shed blood, whereas NS was three times the volume. After 6 h ofpostresuscitation monitoring, brains were sectioned into 5-mm slices and stained with TTC (2,3,5-triphenyltetrazolium chloride)to quantify the lesion size and brain swelling. Combination of 40% blood loss with cortical impact and a period of shock (2 h)resulted in a highly reproducible brain injury. Total fluid requirements were lower in the Hex and FFP groups. Lesion sizeand brain swelling in the FFP group (2,160 T 202.6 mm3 and 22% T 1.0%, respectively) were significantly smaller than thosein the NS group (3,285 T 130.8 mm3 and 37% T 1.6%, respectively) (P G 0.05). Hex treatment decreased the swelling (29% T1.6%) without reducing the lesion size. Early administration of FFP reduces the size of brain lesion and associated swelling ina large animal model of TBI + HS. In contrast, artificial colloid (Hex) decreases swelling without reducing the actual size ofthe brain lesion.

KEYWORDS—Traumatic brain injury, hemorrhage, edema, swine, shock

INTRODUCTION

In patients with traumatic brain injury (TBI), fluid resuscita-tion plays a critical role in restoring and maintaining systemicand cerebral circulations (1). It is widely recognized that sec-ondary insults can markedly worsen outcomes after TBI. A re-view of the Traumatic Coma Databank has identified hypotensionand hypoxemia to be independently associated with significantincreases in morbidity and mortality from severe head injury(2). This association has also been confirmed in well-controlledanimal models. For example, Jenkins et al. (3) reported an in-crease in CA1 neuronal death when hypotension was combinedwith TBI, and Matsushita et al. (4) reported an increase incontusion area when hemorrhagic shock (HS) followed fluidpercussion injury in rodent models. These studies strongly sug-gest that HS significantly increases TBI-related morbidity andmortality.

The optimal resuscitation strategy following a combinedTBI + HS remains unclear. Characteristics of an ideal resus-citation fluid include an ability to minimize cerebral edema,attenuation of primary neuronal damage, and prevention of sec-ondary brain injury. Isotonic crystalloids are commonly used forresuscitation, but they do not have any specific protective prop-erties besides restoring intravascular volume and maintaining ap-propriate osmotic environment. As these fluids rapidly move outof the vascular compartment, it often requires large volumes tomaintain the desired blood pressure. Artificial colloids (6%hetastarch solution) have been the preferred fluids for resusci-tation in combat casualty settings because of logistical advan-tages (less volume and weight). In several animal models,resuscitation with 6% hetastarch, Hextend (Hex), required lessvolume and improved cerebrovascular functions compared withcrystalloids (5, 6). However, administration of colloid solutionsin TBI patients is controversial, as a post hoc analysis of theSAFE (Saline vs. Albumin Fluid Evaluation) study reported asignificantly higher mortality rate in TBI patients assigned toalbumin resuscitation compared with saline (1). Mechanisms bywhich these fluids affect the progression of cell death followingTBI (and alter outcomes) remain largely unknown. One of themajor barriers is lack of a clinically meaningful large animalmodel of TBI that can be used by researchers to answer keytranslational questions. An ideal model would have a reprodu-cible, reliable, and severe (but potentially reversible) brain injury;

49

SHOCK, Vol. 38, No. 1, pp. 49Y56, 2012

Address reprint requests to Hasan B. Alam, MD, Division of Trauma, EmergencySurgery and Surgical Critical Care, Harvard Medical School/Massachusetts GeneralHospital, 165 Cambridge St, Suite 810, Boston, MA 02114. E-mail: [email protected].

This study was funded by a grant from the US Army Medical Research MaterialCommand GRANTT00521959 (to H.B.A.) and by the U.S. Army Research Officeunder contract number W911NF-07-D-0004 (to SS).

This study was presented at the New England Surgical Society 92nd AnnualMeeting, at the Omni Mount Washington Hotel, Bretton Woods, NH. September 2011.DOI: 10.1097/SHK.0b013e3182574778Copyright ! 2012 by the Shock Society


it should also allow the researchers precise control of the injurydegree (more or less severe) and be suitable for monitoring clin-ically relevant physiological parameters and long-term functional/cognitive outcomes. To overcome this deficiency, our team car-ried out a series of experiments to characterize the response ofbrain to kinetic energy transfer and then used these data to developa computer-controlled device that could create a very precisebrain injury in swine (7).

To exaggerate neuronal damage, a period of HS was addedto this model, with the goal of producing severe but potentiallyreversible brain lesions in swine. Our hypothesis was that, inthis combined (TBI + HS) injury model, primary lesion sizeand brain swelling would be altered by the choice of resusci-tation fluids.

MATERIALS AND METHODSAll the research was conducted in compliance with the Animal Welfare Act

and other Federal statutes and regulations relating to animals and experimentsinvolving animals. The study adhered to the principles stated in the Guide forthe Care and Use of Laboratory Animals, Institute for Laboratory AnimalResearch (1996), and was approved by the appropriate institutional animal careand use committees. All the procedures were performed under the supervisionof a veterinarian. Specific details about the protocol are given below.

Animal selection and preparationFemale Yorkshire swine (40Y50 kg; Tufts Veterinary School, Grafton,

Mass) were used for this experiment. They were allowed to acclimate for 3days and examined by a veterinarian to ensure good health. Food was withheldthe night before surgery, but access to drinking water was maintained. Animalswere sedated with an intramuscular injection of 8 mg/kg of Telazol (50 mg/mLof tiletamine hydrochloride and 50 mg/mL of zolazepam hydrochloride; FortDodge Animal Health, Fort Dodge, Iowa) mixed with 1.5 mg of atropine sul-fate. They were placed in supine position, and anesthesia was induced with 4%inhaled isoflurane in 100% oxygen. Animals were then intubated with a cuffedsilastic endotracheal tube 7.0 mm (internal diameter) 55 cm long, andmechanical ventilation was started (Narkomed-M; North American Drager,

Telford, Pa). Initial respiratory settings included a tidal volume of 10 mL/kgbody weight, peak pressure of 20 cm H2O, and a respiratory rate of 10 breaths/min to maintain an end-tidal PCO2 of 40 T 2 mmHg. Isoflurane was adjustedbetween 1% and 3% to maintain inhaled anesthesia.

Instrumentation and monitoringThe right femoral artery (blood pressure monitoring), left femoral vein

(treatment/fluid administration), left femoral artery (blood withdrawal, hem-orrhage, intraoperative laboratory draws), and right external jugular vein(Swan-Ganz) were all cannulated using a cut-down technique. Once all ofthese vessels were instrumented, blood samples were drawn for the baseline(BL) time point. Finally, a midline laparotomy was preformed to place acystostomy tube for measurement of urine output. Cardiac output (CO), SvO2,and core body temperature were continuously monitored (Vigilance II Mon-itor; Edwards Lifesciences, Irvine, Calif). Invasive hemodynamic monitoringwas continuously performed (Eagle 4000 Patient Monitor; GE Marquette,Piscataway, NJ), and blood pressure readings were recorded every 5 min. End-tidal CO2 was also measured throughout the experiment (V9004; SurgiVet,Waukesha, Wis) along with pulse oximetry. Head was fixed in a custom-madestereotactic frame with a mouthpiece and two skull pegs affixed to the zygomato prevent movement (Fig. 1A). A 20-mm bur hole was made on the right sideof the skull, next to the coronal and sagittal sutures over the frontal lobe toexpose the dura (Fig. 1D). Bone was carefully removed so as not to disturb thedura and the underlying brain tissue. A catheter for intracranial pressure (ICP)monitoring (Integra Lifesciences, Plainsboro, NJ) was inserted through a boltplaced in a 2-mm bur hole on the left side of the skull, 10 mm lateral and 10mm anterior to the bregma (Fig. 2, B and D).

Controlled cortical impactA computer-controlled cortical impact (CCI) device developed by the

Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology,was used for these experiments (7). The impactor device assembly (Fig. 1, Cand D) consisted of a voice coil linear actuator with a built-in LVDT dis-placement transducer (H2W Technologies Inc, Santa Clarita, Calif) connectedto a closed-loop motion control board (Galil Motion Control, Rocklin, Calif).A 15-mm cylindrical impactor tip was mounted on the shaft of the actuator,and the dynamics were precisely controlled to deliver an impact with 4 m/svelocity, 100-ms dwell time, and 12-mm penetration depth. The CCI devicewas attached to the stereotactic frame and secured in place for firing (Fig. 1, Cand D). After impact, the bur hole was sealed with bone wax to prevent leakageof cerebrospinal fluid and to eliminate any artifact in ICP monitoring.

FIG. 1. A, Swine head fixed in custom-made stereotactic frame to prevent movement during impact. After creating a CCI, craniotomy site is sealed byreplacing the bone fragment and applying bone wax. B, Schematic of swine skull showing the location of the bur hole for the injury to the right frontal lobe.Location of the ICP monitor anterior to the bregma 1 cm and lateral 1 cm on the left side is also shown. C, The TBI device mounted on surgical table. D, The ICPmonitoring probe is in place, and TBI device is adjusted above 20-mm circular craniotomy.

50 SHOCK VOL. 38, NO. 1 JIN ET AL.


Hemorrhage and resuscitation protocolTotal blood volume was estimated, and 40% of it was withdrawn through

the femoral arterial catheter using a Masterflex pump, model L/S Compu-terized Drive with an MF easy load II Pump-head, model 77201-60 (Cole-Palmer, Vernon Hills, Ill). Bleeding was started concurrent with TBI at a rateof 3.15% total blood volume per minute and was captured in a Terumo bloodcollection bag (CPDA and AS-5). Isoflurane was decreased with the onset ofhypotension. If mean arterial pressure (MAP) dropped less than 30 mmHg,hemorrhage was briefly held, and a small volume of saline was infused throughthe femoral venous line. Once the MAP reached 35 mmHg, saline infusion wasstopped, and hemorrhage was restarted. Using this protocol, MAP was main-tained between 30 and 35 mmHg until 40% of the estimated blood volume waswithdrawn in a controlled fashion. Following hemorrhage, animals were left inshock for 120 min, and MAP was maintained between 30 and 35 mmHg bysimply titrating the dose of inhaled isoflurane. After 2 h of shock, animals wererandomly assigned to one of three resuscitation groups (n = 5/group): (a)normal saline (NS) at 165 mL/min, (b) Hex at 50 mL/min, and (c) fresh frozenplasma (FFP) at 50 mL/min. Volumes of Hex and FFP matched the shed blood,whereas NS was three times the volume. Fluids were infused into the femoralvein using a Masterflex pump. Timeline of the TBI and HS model are shown inFigure 2A.

Observation and harvest samplesAnesthesia was maintained, and the animals were monitored for 6 h after

resuscitation in an intensive care environment. Physiologic parameters werecontinuously measured and recorded every 5 min. All the animals were keptwarm (Bair Hugger Model 505; Arizant Healthcare, Inc, Eden Prairie, Minn),and electrolytes were replaced as needed. At the end of the experiment, ani-mals were killed by an intravenous injection of Euthasol (sodium pentobarbital[100 mg/kg]). A detailed autopsy was performed to evaluate all the thoracicand abdominal organs, and brain and other organs were collected.

Calculation of brain infarction and swellingBrains were sliced into 5-mm coronal sections beginning 10 mm anterior

and ending 30 mm posterior to the lesion. Slices were incubated in 2% TTC(2,3,5-triphenyltetrazolium chloride) (Sigma Chemical Co, St Louis, Mo) to

demonstrate the presence of nonviable tissue (8). Size of lesion was measuredwith computer-assisted image analysis software ImageJ (National Institutes ofHealth). Brain swelling was calculated by comparing it to the uninjuredhemisphere: [(ipsilateral hemisphere’s volume / contralateral hemisphere’svolume) j 1] ! 100 (9). True infarction volumes were corrected by theswelling factor (10, 11).

Statistical analysisAll data are presented as means T SEM, unless mentioned otherwise.

Analyses of variance with Dunnett post hoc test were performed usingGraphPad Prism version 5.00 (GraphPad Software, San Diego Calif ). Stat-istical significance was defined as P G 0.05.

RESULTS

Lethality

During the 2-h shock period (following TBI and hemorrhage),10% of the animals died. All of the animals that reached theresuscitation time point went on to survive the entire experiment.

Hemodynamic data

The MAP data are presented in Figure 2B. Volume-controlled hemorrhage caused an equal degree of hypotensionin all the groups, which persisted throughout the 2-h shockperiod. Infusion of NS or Hextend increased the MAP to nearBL levels (NS: 64 T 2.5 mmHg and Hex: 68 T 4.5 mmHg), andthe MAP in Hex group was maintained greater than 60 mmHgover 6-h observation time. However, the MAP in the NS groupgradually declined to 51 T 3.4 mmHg during first 2 h of

FIG. 2. A, Timeline of the TBI and HS model. The x axis shows time in minutes. PS indicates postshock; PR, post resuscitation; OB, observation. Meanarterial pressure (B), heart rate (C), and CO (D) at selected times during the experiment; x axis is time in minutes from initiation of TBI. Data presented as groupmeans T SEM, n = 5/group. *P G 0.05 NS vs. Hextend, #P G 0.05 FFP vs. Hextend.

SHOCK JULY 2012 RESUSCITATION IN BRAIN INJURY 51


variability, recoil, and inability to control/titrate the kineticenergy transfer, and so on. These issues can be resolved byfixing the cranium in a stereotactic device, delivering kineticenergy directly to the brain, and by using an electromechanicalactuator where the impact speed, dwell time, penetration depthand direction of impact can be precisely controlled. This typeof well-controlled model could serve as a suitable platform forgenerating reliable translational data. To our knowledge, noother laboratory is using such a model of TBI, especially incombination with HS.

Crystalloid fluids are commonly used in trauma-resuscita-tion protocols (1, 19), although the evidence supporting thesestrategies is limited, especially in the setting of TBI. Currentfluid resuscitation protocols for TBI patients advocate infusionof isotonic crystalloids to normalize the blood pressure (20).Brain Trauma Foundation guidelines also recommend thathypotensive patients with severe TBI should be resuscitatedwith isotonic fluids, but this is based on low-quality evidence(from class III studies or class II studies with contradictoryfindings) (21). However, as NS is commonly used, we selectedit as the control group. We also included a hetastarch groupbecause there is some evidence that hetastarch solutions maybe protective after TBI (6). Furthermore, military has startedusing hetastarch solutions in the battlefield for logistical rea-sons (lower volume and weight). Finally, plasma group wasadded because of emerging data suggesting that early plasmainfusion may offer a survival benefit in patient with poly-trauma, including TBI (22). Although these retrospective dataare provocative, it remains unclear whether plasma resuscita-tion really influences the progression of brain injury and, if so,through what mechanisms.

In our study, MAP and CO rapidly recovered in response toaggressive NS infusion (three times the volume of shed blood).However, these benefits were transient as the MAP declined,to the lowest levels among the three groups during the obser-vation period. In contrast, resuscitation with the colloids Hexor FFP required much less volume and resulted in much bettermaintenance of MAP (Fig. 2B). This was not surprising as

physiological studies have suggested that colloid-based strat-egies can maintain/augment plasma oncotic pressure andminimize extravasation of intravascular fluid into the braininterstitium (23). In our experiment, brain swelling was sig-nificantly reduced in the Hex and FFP groups compared withthe NS group, which supports this concept. Limited brainedema in these groups was most likely due to a combination ofsuperior oncotic effect, as well as overall lower volumes offluid administration (24, 25). Changes in CVP following salineand colloid resuscitation were very similar. This further sug-gests that a large portion of infused saline rapidly moved fromthe vascular compartment into the tissues, which can worsenthe edema.

In our experiment, administration of FFP prevented pro-gression of brain injury and effectively reduced brain swel-ling (Fig. 4). Although Hex produced similar hemodynamicchanges, it failed to reduce the lesion size (Figs. 2 and 4). Useof colloids after TBI is controversial. A large prospectiverandomized study (SAFE trial) has reported higher mortalityin TBI patients who were resuscitated with an albumin-basedfluid (1). Although no mechanism was identified to accountfor this finding, others have proposed that development ofa dilution coagulopathy in the context of severe TBI couldhave worsened the outcome (26, 27). On the other hand, thereare studies that suggest that Hex and FFP may actually bebeneficial after TBI (6, 22). It should be emphasized that FFPis not simply an albumin-based solution, but a complex phys-iological fluid that contains hundreds of proteins, buffers, freeradical scavengers, and clotting factors. Indeed, our previousstudies have demonstrated that infusion of FFP, even withoutany red blood cells, can effectively correct posttrauma coagul-opathy and result in excellent early survival, whereas Hextendtreatment creates coagulopathy and worsens survival (28Y30).Furthermore, FFP can be converted into a shelf-stable, driedproduct that is suitable for use in prehospital environment(29, 30); we did not evaluate markers of coagulopathy in thisstudy, but it would be an interesting study for the future.Theoretically, colloids can worsen brain edema, if these

FIG. 4. Brain injury after resuscitation with different fluids. Top panel shows representative brain slices stained with TTC, whereas the bar graphs at thebottom show lesion size and brain swelling in different groups. Brain swelling is shown as percent increase compared with the contralateral hemisphere. Datapresented as group means T SEM, n = 5/group. *P G 0.05 compared with saline group.

54 SHOCK VOL. 38, NO. 1 JIN ET AL.


WAT IS HET NUT VAN EEN MASSAAL TRANSFUSIE PROTOCOL?:

A. Vaste Ratio van producten

B. Snellere beschikbaarheid

C. Verbetering logistiek

D. Minder gez#*k van de bloedbank

▸ Vergelijking tussen 2 periodes met en zonder MTP

▸ Minder massale transfusies (meer dan 10 packed cells)

▸ Packed cell - FFP ratio van 1:3 naar 1:2

▸ Minder verspilling van bloedproducten

▸ Daling van aantal opnamedagen

A major haemorrhage protocol improves the delivery of blood component therapyand reduces waste in trauma massive transfusion

Sirat Khan a,*, Shubha Allard b,c, Anne Weaver b, Colin Barber b,c, Ross Davenport a, Karim Brohi a

a Trauma Sciences, Blizard Institute Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UKb Barts and the London NHS Trust, UKc NHS Blood and Transplant, UK

Introduction

Background

Death due to traumatic injury is the leading cause of life yearslost throughout the world.1 Haemorrhage accounts for almost 50%

of deaths and the majority of these occur in the first 24 h.2 Up to15% of patients in major trauma centres receive a massivetransfusion and over 25% of these will die, most within 6 h ofinjury.3 Patients who survive a massive transfusion have anincreased incidence of sepsis, multi-organ failure, longer hospitalstays and higher healthcare costs.4,5

The concept of massive transfusion was originally introduced tohighlight the complications that result from large volume PRBCinfusion – principally late dilutional coagulopathy.6 Massivetransfusion protocols (MTPs) therefore delivered PRBCs initiallyand provided relatively small volumes of blood componenttherapy (plasma, platelets and cryoprecipitate) only after sufficientunits of PRBC had been transfused to cause dilutional coagulationdysfunction.3,7 MTPs may therefore be considered reactionary tolarge volume blood product replacement in comparison to majorhaemorrhage protocols (MHP). The discovery of acute traumatic

Injury, Int. J. Care Injured 44 (2013) 587–592

A R T I C L E I N F O

Article history:Accepted 28 September 2012

Keywords:TraumaTransfusionProtocolsHaemorrhage

A B S T R A C T

Background: Major haemorrhage protocols (MHP) are required as part of damage control resuscitationregimens in modern trauma care. The primary objectives of this study were to ascertain whether a MHPimproved blood product administration and reduced waste compared to traditional massive transfusionprotocols (MTP).Methods: Datasets on adult trauma admissions 1 year prior and 1 year post implementation of a MHP ata Level 1 trauma centre were obtained from the trauma registry. Demographic and clinical data werecollected prospectively including mechanism of injury, physiological observations, ICU admission andlength of stay. The volume of blood components (packed red blood cells, platelets, cryoprecipitate andfresh frozen plasma) issued, transfused, returned to stock and wasted within the first 24 h was gatheredretrospectively.Results: Over the 2-year study period 2986 patient records were available for analysis. 40 patientsrequired a 10+ Units of packed red blood ells transfusion in the MTP group vs. 56 patients post MHPimplementation. The administration of blood component therapy improved significantly post MHPimplementation. FFP:PRBC transfusion improved from 1:3 to 1:2 (p < 0.01) and CRYO:PRBC improvedfrom 1:10 to 1:7 (p < 0.05). We reported a significant reduction in the waste of platelets from 14% to 2%(p < 0.01). Outcomes had improved: Median hospital length of stay was reduced from 54 days to 26 days(p < 0.05).Conclusion: Implementation of a MHP results in improved delivery of blood components and a reductionin the waste of blood products compared to the older model of MTP. In combination with educationalprogrammes MHP can significantly improve blood product administration and patient outcomes intrauma haemorrhage.Level of evidence: Level III diagnostic test study.

Crown Copyright ! 2012 Published by Elsevier Ltd. All rights reserved.

* Corresponding author at: Trauma Clinical Academic Unit, Floor 12, Ward D, TheRoyal London Hospital, London E1 1BB, United Kingdom. Tel.: +44 0203 594 0722;fax: +44 0203 594 3261.

E-mail addresses: [email protected],[email protected] (S. Khan), [email protected](S. Allard), [email protected] (A. Weaver),[email protected] (C. Barber),[email protected] (R. Davenport),[email protected] (K. Brohi).


Injury

jo ur n al ho m epag e: ww w.els evier . c om / lo cat e/ in ju r y

0020–1383/$ – see front matter . Crown Copyright ! 2012 Published by Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.injury.2012.09.029

RATIO DRIVEN VS GOAL DIRECTED THERAPY:▸ ik ga voor ratio driven, simpel en bewezen effectief

▸ ik ga voor goal directed therapy met ROTEM

PROPPR TRIALONLINE FIRST

ORIGINAL ARTICLE

The Prospective, Observational, Multicenter,Major Trauma Transfusion (PROMMTT) StudyComparative Effectiveness of a Time-Varying Treatment With Competing Risks

John B. Holcomb, MD; Deborah J. del Junco, PhD; Erin E. Fox, PhD; Charles E. Wade, PhD; Mitchell J. Cohen, MD;Martin A. Schreiber, MD; Louis H. Alarcon, MD; Yu Bai, MD, PhD; Karen J. Brasel, MD, MPH; Eileen M. Bulger, MD;Bryan A. Cotton, MD, MPH; Nena Matijevic, PhD; Peter Muskat, MD; John G. Myers, MD; Herb A. Phelan, MD, MSCS;Christopher E. White, MD; Jiajie Zhang, PhD; Mohammad H. Rahbar, PhD; for the PROMMTT Study Group

Objective: To relate in-hospital mortality to early trans-fusion of plasma and/or platelets and to time-varying plas-ma:red blood cell (RBC) and platelet:RBC ratios.

Design: Prospective cohort study documenting the tim-ing of transfusions during active resuscitation and pa-tient outcomes. Data were analyzed using time-dependent proportional hazards models.

Setting: Ten US level I trauma centers.

Patients: Adult trauma patients surviving for 30 min-utes after admission who received a transfusion of at least1 unit of RBCs within 6 hours of admission (n=1245,the original study group) and at least 3 total units (ofRBCs, plasma, or platelets) within 24 hours (n=905, theanalysis group).

Main Outcome Measure: In-hospital mortality.

Results: Plasma:RBC and platelet:RBC ratios were notconstant during the first 24 hours (P! .001 for both).

In a multivariable time-dependent Cox model, in-creased ratios of plasma:RBCs (adjusted hazard ra-tio=0.31; 95% CI, 0.16-0.58) and platelets:RBCs (ad-justed hazard ratio=0.55; 95% CI, 0.31-0.98) wereindependently associated with decreased 6-hour mortal-ity, when hemorrhagic death predominated. In the first6 hours, patients with ratios less than 1:2 were 3 to 4 timesmore likely to die than patients with ratios of 1:1 or higher.After 24 hours, plasma and platelet ratios were unasso-ciated with mortality, when competing risks from non-hemorrhagic causes prevailed.

Conclusions: Higher plasma and platelet ratios early inresuscitation were associated with decreased mortalityin patients who received transfusions of at least 3 unitsof blood products during the first 24 hours after admis-sion. Among survivors at 24 hours, the subsequent riskof death by day 30 was not associated with plasma or plate-let ratios.

JAMA Surg. 2013;148(2):127-136. Published onlineOctober 15, 2012. doi:10.1001/2013.jamasurg.387

I NJURY IS INCREASING IN INCI-dence, the second leading causeof death worldwide, and the lead-ing cause of years of life lost inthe United States.1,2 Uncon-

trolled hemorrhage after injury is the lead-ing cause of potentially preventabledeath.3-9 As opposed to other major causesof traumatic death (eg, traumatic braininjury and multiple organ failure), hem-orrhagic deaths occur quickly and are

frequently associated with massivetransfusion (MT) (traditionally defined as"10 units of red blood cells [RBCs] in 24hours).10,11 Current transfusion practices

consist of infusing crystalloid, RBCs,plasma, and platelets and date back to the1970s when separation of donated wholeblood into its component parts becamecommonplace.12-16

A new resuscitation strategy, termeddamage control resuscitation, is challeng-ing the status quo.17 The term originatedin the US military and refers to theguidelines developed for combat casual-ties with substantial bleeding in Iraq andAfghanistan. Among other interventions,this approach recommends earlier andmore balanced transfusion of plasma andplatelets along with the first units ofRBCs (ie, maintaining plasma:platelet:RBC ratios closer to the 1:1:1 ratio ofwhole blood) while simultaneously mini-mizing crystalloid use18-27 in patients toavert or reverse the triad of coagulopa-

CME available online atwww.jamanetworkcme.comand questions on page 108

Author AffTranslationDivision ofDepartmenHolcomb, dCotton, andDepartmenLaboratoryMedical SchBiostatisticsDesign Corand Transladel Junco, FSchool of BInformaticsDivision ofHuman GenEnvironmeof Public HUniversityScience CenDivision ofDepartmenof MedicineCalifornia,Cohen); DiCritical CarSurgery, SchOregon HeaUniversity,Schreiber);and GeneraDepartmenof MedicinePittsburgh,PennsylvanDivision ofCare, DepaMedical CoMilwaukeeof Trauma aDepartmenof MedicineWashingtonBulger); DiTrauma/CriDepartmenof MedicineCincinnati,(Dr MuskatTrauma, DeSchool of Mof Texas Heat San AntoDepartmenArmy MediHouston (DAntonio; anBurn/TraumDepartmenSchool, UnSouthwesteDallas (Dr PGroup InfoPROMMTTmembers arthis article.

Author Affiliations are listed atthe end of this article.Group Information: ThePROMMTT Study Groupmembers are listed at the end ofthis article.

JAMA SURG/ VOL 148 (NO. 2), FEB 2013 WWW.JAMASURG.COM127

©2013 American Medical Association. All rights reserved.

Downloaded From: http://archsurg.jamanetwork.com/ by a Vrije Universiteit User on 03/23/2014

▸ Eerste massa transfusie RCT

▸ gerandomiseerd tussen 1:1:1 en 1:1:2

▸ 12 level 1 centra met 680 patienten

▸ primaire uitkomstmaten 24 uurs en 30 dagen mortaliteit

ONLINE FIRST

ORIGINAL ARTICLE









In a multivariable time-dependent Cox model, in-creased ratios of plasma:RBCs (adjusted hazard ra-tio=0.31; 95% CI, 0.16-0.58) and platelets:RBCs (ad-justed hazard ratio= 0.55; 95% CI, 0.31-0.98) wereindependently associated with decreased 6-hour mortal-ity, when hemorrhagic death predominated. In the first6 hours, patients with ratios less than 1:2 were 3 to 4 timesmore likely to die than patients with ratios of 1:1 or higher.After 24 hours, plasma and platelet ratios were unasso-ciated with mortality, when competing risks from non-hemorrhagic causes prevailed.














MAARRRR‣ beide groepen waren niet

gelijk! ‣ 1:1:2 groep had geen

thrombocyten in de eerste box Uiteindelijk dus 1:1.7:1.3 versus 1:1.2:1.8

‣ De overleving was lager dan in de sample size berekening 17 versus 12,7% (21 vs 11 berekend)

‣ Dus om deze studie significant te krijgen hadden ze 4x zoveel patienten moeten includeren!

ONLINE FIRST

ORIGINAL ARTICLE









In a multivariable time-dependent Cox model, in-creased ratios of plasma:RBCs (adjusted hazard ra-tio=0.31; 95% CI, 0.16-0.58) and platelets:RBCs (ad-justed hazard ratio= 0.55; 95% CI, 0.31-0.98) wereindependently associated with decreased 6-hour mortal-ity, when hemorrhagic death predominated. In the first6 hours, patients with ratios less than 1:2 were 3 to 4 timesmore likely to die than patients with ratios of 1:1 or higher.After 24 hours, plasma and platelet ratios were unasso-ciated with mortality, when competing risks from non-hemorrhagic causes prevailed.














Figure 2 ROTEM-guided treatment algorithm: managing trauma-induced coagulopathy and diffuse microvascular bleeding (AUVATrauma Hospital, Salzburg, Austria). The algorithm represents standard operating procedure for ROTEM-guided haemostatic therapy uponadmission of trauma patients to the emergency room. In parentheses: haemostatic agents suggested for use in clinics where coagulation factorconcentrates are not available. * For patients who are unconscious or known to be taking platelet inhibitor medication, Multiplate tests(adenosine diphosphate [ADP] test, arachidonic acid [ASPI] test, and thrombin receptor activating peptide-6 [TRAP] test) are also performed. § Ifdecreased ATIII is suspected or known, consider co-administration of ATIII. † Any major improvement in APTEM parameters compared tocorresponding EXTEM parameters may be interpreted as a sign of hyperfibrinolysis. ‡ Only for patients not receiving TXA at an earlier stage ofthe algorithm. Traumatic brain injury: platelet count 80,000-100,000/μl. Normal values: EXTEM/APTEM coagulation time (CT): 38-79 seconds;EXTEM/APTEM clot amplitude at 10 minutes (CA10): 43-65 mm; EXTEM/APTEM maximum lysis (ML) < 15%; FIBTEM CA10: 7-23 mm; INTEM CT:100-240 seconds. CA10, clot amplitude at 10 minutes; BGA, blood gas analysis; BW, body weight; Ca, calcium; CT, clotting time; FFP, fresh frozenplasma; ISS, injury severity score; MCF, maximum clot firmness; ML, maximum lysis; PCC, prothrombin complex concentrate; TXA, tranexamic acid.

Schöchl et al. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2012, 20:15http://www.sjtrem.com/content/20/1/15

Page 5 of 11

GOAL DIRECTED THERAPY VERSUS RATION DRIVEN

Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.910 www.anesthesia-analgesia.org October 2016 Volume 123 Number 4

Copyright © 2016 International Anesthesia Research SocietyDOI: 10.1213/ANE.0000000000001516

Trauma is the leading cause of death worldwide in indi-viduals aged 18 to 39 years, and, despite advances in trauma management, a significant proportion of these

deaths are because of hemorrhage.1–3 Associated with severe trauma is a unique, complex, and multifactorial coagulopa-thy, the mechanisms of which are not fully determined.4–6

In addition to a lack of clarity regarding the pathophysiol-ogy of trauma-associated coagulopathy, no consensus exists regarding the nomenclature used to describe the process.7 Various terms have been suggested—acute traumatic coagu-lopathy, acute coagulopathy of trauma, acute coagulopathy of trauma shock, trauma-induced coagulopathy (TIC), and early

TIC.4,8,9 These terms are often used interchangeably, adding to the confusion. In this article, we will use the term TIC.

Several mechanisms have been proposed to explain the development of TIC. TIC is characterized by reduced clot strength related to hypofibrinogenemia/dysfibrinogen-emia, platelet dysfunction, hyperfibrinolysis, and endo-thelial dysfunction.10 TIC is subsequently compounded by acidosis, hypothermia, hemodilution, and factor consump-tion associated with severe hemorrhage and large volume fluid resuscitation (Figure 1).11

Central to the proposed mechanisms is the effect of direct tissue injury, shock, and hypoperfusion on the endo-thelium, which causes systemic anticoagulation and hyper-fibrinolysis.12 The role of tissue injury is supported by the observation that the degree of coagulopathy is proportional to injury severity and is present before large volume fluid or blood product transfusion.13,14 In the presence of tissue hypoperfusion and hypoxia, thrombomodulin (TM) expres-sion is increased. TM binds thrombin (also generated in response to tissue trauma), and the resulting TM–thrombin complex activates the protein C (PC) pathway. Activated PC (aPC) inactivates factor Va and VIIIa, producing a hypo-coagulable state. In addition, aPC inactivates plasmino-gen activator inhibitor-1 (PAI-1), causing fibrinolysis.12,15 Hyperfibrinolysis is further enhanced by the release of tis-sue plasminogen activator. A 2016 study suggests that the increased levels of tissue plasminogen activator that com-plex with PAI-1 play a larger role in hyperfibrinolysis than aPC-driven PAI-1 inactivation.16

The neurohormonal axis and the endothelial glycoca-lyx may also contribute to TIC. In response to tissue injury and shock, a catecholamine surge results, which triggers an up-regulation of the endothelial cells and a shedding of

Hemorrhage in the setting of severe trauma is a leading cause of death worldwide. The pathophysiology of hemorrhage and coagulopathy in severe trauma is complex and remains poorly understood. Most clinicians currently treating trauma patients acknowledge the presence of a coagulopathy unique to trauma patients—trauma-induced coagulopathy (TIC)—independently associated with increased mortality. The complexity and incomplete understanding of TIC has resulted in significant controversy regarding optimum manage-ment. Although the majority of trauma centers utilize fixed-ratio massive transfusion proto-cols in severe traumatic hemorrhage, a widely accepted “ideal” transfusion ratio of blood to blood products remains elusive. The recent use of viscoelastic hemostatic assays (VHAs) to guide blood product replacement has further provoked debate as to the optimum transfusion strategy. The use of VHA to quantify the functional contributions of individual components of the coagulation system may permit targeted treatment of TIC but remains controversial and is unlikely to demonstrate a mortality benefit in light of the heterogeneity of the trauma population. Thus, VHA-guided algorithms as an alternative to fixed product ratios in trauma are not universally accepted, and a hybrid strategy starting with fixed-ratio transfusion and incorporating VHA data as they become available is favored by some institutions. We review the current evidence for the management of coagulopathy in trauma, the rationale behind the use of targeted and fixed-ratio approaches and explore future directions. (Anesth Analg 2016;123:910–24)

Targeted Coagulation Management in Severe Trauma: The Controversies and the EvidenceJames Winearls, BSc, MBBS, MRCP, FCICM,*† Michael Reade, MBBS, MPH, DPhil, FANZCA, FCICM,‡ Helen Miles, MBBS,* Andrew Bulmer, BAppSc, PhD,†§ Don Campbell, MBBS, FACEM,∥ Klaus Görlinger, MD,¶# and John F. Fraser, MD, MBChB, PhD, MRCP, FRCA, FCICM**

From the *Intensive Care Unit, Gold Coast University Hospital, Southport, Queensland, Australia; †Gold Coast University Hospital Critical Care Research Group, Queensland, Australia; ‡Joint Health Command, Australian Defence Force and Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia; §Heart Foundation Research Centre, School of Medicine, Griffith University, Gold Coast, Queensland, Australia; ∥Trauma Department, Gold Coast University Hospital, Queensland, Australia; ¶Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany; #Tem International GmbH, Munich, Germany; and **Critical Care Research Group, The Prince Charles Hospital and University of Queensland, Brisbane, Queensland, Australia.Accepted for publication June 9, 2016.Funding: The program of trauma research is supported by grants from the Queensland Emergency Medicine Research Foundation and Gold Coast University Hospital Foundation.Conflict of Interest: See Disclosures at the end of the article.Reprints will not be available from the authors.Address correspondence to Klaus Görlinger, MD, Department of Anesthe-siology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany; and Tem Inter-national GmbH, Munich, Germany. Address e-mail to [email protected] and [email protected].

NARRATIVE REVIEW ARTICLEE

CME

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E NARRATIVE REVIEW ARTICLE

922 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

61. Johansson PI, Stensballe J. Effect of haemostatic control resusci-tation on mortality in massively bleeding patients: a before and after study. Vox Sang. 2009;96:111–118.

62. Inaba K, Rizoli S, Veigas PV, et al; Viscoelastic Testing in Trauma Consensus Panel. 2014 Consensus conference on viscoelastic test-based transfusion guidelines for early trauma resuscitation: report of the panel. J Trauma Acute Care Surg. 2015;78:1220–1229.

63. Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med. 2009;17:45.

64. Tauber H, Innerhofer P, Breitkopf R, et al. Prevalence and impact of abnormal ROTEM® assays in severe blunt trauma: results of the ‘Diagnosis and Treatment of Trauma-Induced Coagulopathy (DIA-TRE-TIC) study’. Br J Anaesth. 2011;107:378–387.

65. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecu-tive trauma patients. Ann Surg. 2012;256:476–486.

66. Goodman MD, Makley AT, Hanseman DJ, Pritts TA, Robinson BR. All the bang without the bucks: defining essential point-of-care testing for traumatic coagulopathy. J Trauma Acute Care Surg. 2015;79:117–124.

67. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.

68. Schöchl H, Maegele M, Solomon C, Görlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med. 2012;20:15.

69. Schöchl H, Nienaber U, Hofer G, et al. Goal-directed coagulation management of major trauma patients using thromboelastom-etry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14:R55.

70. Schöchl H, Schlimp CJ. Trauma bleeding management: the concept of goal-directed primary care. Anesth Analg. 2014;119:1064–1073.

71. Tobin JM, Tanaka KA, Smith CE. Factor concentrates in trauma. Curr Opin Anaesthesiol. 2015;28:217–226.

72. Gonzalez E, Moore EE, Moore HB, et al. Goal-directed hemo-static resuscitation of trauma-induced coagulopathy: a prag-matic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg. 2016;263:1051–1059.

73. Johansson PI, Sørensen AM, Larsen CF, et al. Low hemorrhage-related mortality in trauma patients in a level I trauma center employing transfusion packages and early thromboelastogra-phy-directed hemostatic resuscitation with plasma and plate-lets. Transfusion. 2013;53:3088–3099.

74. Johansson PI, Stensballe J, Oliveri R, Wade CE, Ostrowski SR, Holcomb JB. How I treat patients with massive hemorrhage. Blood. 2014;124:3052–3058.

75. Stensballe J, Ostrowski SR, Johansson PI. Viscoelastic guidance of resuscitation. Curr Opin Anaesthesiol. 2014;27:212–218.

76. Stephens CT, Gumbert S, Holcomb JB. Trauma-associated bleeding: management of massive transfusion. Curr Opin Anaesthesiol. 2016;29:250–255.

77. Hartert H. [Thrombelastography, a method for physical analy-sis of blood coagulation]. Z Gesamte Exp Med. 1951;117:189–203.

78. Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol. 2014;89:228–232.

79. Ganter MT, Hofer CK. Coagulation monitoring: current tech-niques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:1366–1375.

80. Keene DD, Nordmann GR, Woolley T. Rotational thrombo-elastometry-guided trauma resuscitation. Curr Opin Crit Care. 2013;19:605–612.

81. Espinosa A, Seghatchian J. What is happening? The evolv-ing role of the blood bank in the management of the bleeding patient: the impact of TEG as an early diagnostic predictor for bleeding. Transfus Apher Sci. 2014;51:105–110.

82. Anderson L, Quasim I, Steven M, et al. Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelastography and rotational thrombo-elastometry. J Cardiothorac Vasc Anesth 2014;28:1550–1557.

83. Gronchi F, Perret A, Ferrari E, et al. Validation of rotational thromboelastometry during cardiopulmonary bypass: a prospective, observational in-vivo study. Eur J Anaesthesiol. 2014;31:68–75.

84. Ortmann E, Rubino A, Altemimi B, Collier T, Besser MW, Klein AA. Validation of viscoelastic coagulation tests during cardio-pulmonary bypass. J Thromb Haemost. 2015;13:1207–1206.

85. Dunham CM, Rabel C, Hileman BM, et al. TEG® and RapidTEG® are unreliable for detecting warfarin-coagulopa-thy: a prospective cohort study. Thromb J 2014;12:4.

86. Schmidt DE, Holmström M, Majeed A, Näslin D, Wallén H, Ågren A. Detection of elevated INR by thromboelastometry and thromboelastography in warfarin treated patients and healthy controls. Thromb Res. 2015;135:1007–1011

87. Meyer AS, Meyer MA, Sørensen AM, et al. Thrombelastography and rotational thromboelastometry early amplitudes in 182 trauma patients with clinical suspicion of severe injury. J Trauma Acute Care Surg. 2014;76:682–690.

88. Görlinger K, Dirkmann D, Solomon C, Hanke AA. Fast inter-pretation of thromboelastometry in non-cardiac surgery: reli-ability in patients with hypo-, normo-, and hypercoagulability. Br J Anaesth. 2013;110:222–230.

89. Dirkmann D, Görlinger K, Peters J. Assessment of early throm-boelastometric variables from extrinsically activated assays with and without aprotinin for rapid detection of fibrinolysis. Anesth Analg. 2014;119:533–542.

90. Schöchl H, Frietsch T, Pavelka M, Jámbor C. Hyperfibrinolysis after major trauma: differential diagnosis of lysis pat-terns and prognostic value of thrombelastometry. J Trauma. 2009;67:125–131.

91. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associ-ated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012;73:365–370.

92. Da Luz LT, Nascimento B, Shankarakutty AK, Rizoli S, Adhikari NK. Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review. Crit Care. 2014;18:518.

93. Larsen OH, Fenger-Eriksen C, Christiansen K, Ingerslev J, Sørensen B. Diagnostic performance and therapeutic conse-quence of thromboelastometry activated by kaolin versus a panel of specific reagents. Anesthesiology. 2011;115:294–302.

94. Solomon C, Sørensen B, Hochleitner G, Kashuk J, Ranucci M, Schöchl H. Comparison of whole blood fibrin-based clot tests in thrombelastography and thromboelastometry. Anesth Analg. 2012;114:721–730.

95. Paniccia R, Priora R, Liotta AA, Abbate R. Platelet func-tion tests: a comparative review. Vasc Health Risk Manag. 2015;11:133–148.

96. Petricevic M, Konosic S, Biocina B, et al. Bleeding risk assess-ment in patients undergoing elective cardiac surgery using ROTEM(®) platelet and Multiplate(®) impedance aggregome-try. Anaesthesia. 2016;71:636–647.

97. Karon BS, Tolan NV, Koch CD, et al. Precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet agent therapy. Clin Chem. 2014;60:1524–1531.

98. Hans GA, Besser MW. The place of viscoelastic testing in clini-cal practice. Br J Haematol. 2016;173:37–48.

99. Görlinger K, Dirkmann D, Hanke AA. Rotational Thromboelastometry (ROTEM®). In: Gonzalez E, Moore HB, Moore EE, eds. Trauma Induced Coagulopathy. 1st ed. New York: Springer, 2016.

100. Sankarankutty A, Nascimento B, Teodoro da Luz L, Rizoli S. TEG® and ROTEM® in trauma: similar test but different results? World J Emerg Surg. 2012;7(suppl 1):S3.

101. Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci. 2008;38:15–23.

102. Tanaka KA, Bolliger D, Vadlamudi R, Nimmo A. Rotational thromboelastometry (ROTEM)-based coagulation manage-ment in cardiac surgery and major trauma. J Cardiothorac Vasc Anesth. 2012;26:1083–1093.

103. Weber CF, Görlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy

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18. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endo-thelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112:1289–1295.

19. Ostrowski SR, Johansson PI. Endothelial glycocalyx degrada-tion induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73:60–66.

20. Pati S, Potter DR, Baimukanova G, Farrel DH, Holcomb JB, Schreiber MA. Modulating the endotheliopathy of trauma: fac-tor concentrate versus fresh frozen plasma. J Trauma Acute Care Surg. 2016;80:576–585.

21. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–965.

22. Holcomb JB, del Junco DJ, Fox EE, et al; PROMMTT Study Group. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effective-ness of a time-varying treatment with competing risks. JAMA Surg. 2013;148:127–136.

23. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313:471–482.

24. Solomon C, Traintinger S, Ziegler B, et al. Platelet function following trauma. A multiple electrode aggregometry study. Thromb Haemost. 2011;106:322–330.

25. Kutcher ME, Redick BJ, McCreery RC, et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73:13–19.

26. Chapman MP, Moore EE, Moore HB, et al. Early TRAP path-way platelet inhibition predicts coagulopathic hemorrhage in trauma. Shock. 2015;43(6 suppl 1):33.

27. Moore HB, Moore EE, Chapman MP, et al. Viscoelastic mea-surements of platelet function, not fibrinogen function, pre-dicts sensitivity to tissue-type plasminogen activator in trauma patients. J Thromb Haemost. 2015;13:1878–1887.

28. Rourke C, Curry N, Khan S, et al. Fibrinogen levels dur-ing trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342–1351.

29. Hagemo JS, Stanworth S, Juffermans NP, et al. Prevalence, pre-dictors and outcome of hypofibrinogenaemia in trauma: a mul-ticentre observational study. Crit Care. 2014;18:R52.

30. Hagemo JS, Christiaans SC, Stanworth SJ, et al. Detection of acute traumatic coagulopathy and massive transfusion require-ments by means of rotational thromboelastometry: an interna-tional prospective validation study. Crit Care. 2015;19:97.

31. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopa-thy. J Trauma. 2003;54:1127–1130.

32. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma. 2003;55:39–44.

33. Holcomb JB. Optimal use of blood products in severely injured trauma patients. Hematology Am Soc Hematol Educ Program. 2010;2010:465–469.

34. Gonzalez EA, Moore FA, Holcomb JB, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfu-sion. J Trauma. 2007;62:112–119.

35. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63:805–813.

36. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248:447–458.

37. Snyder CW, Weinberg JA, McGwin G Jr, et al. The relationship of blood product ratio to mortality: survival benefit or survival bias? J Trauma. 2009;66:358–364.

38. Schuster KM, Davis KA, Lui FY, Maerz LL, Kaplan LJ. The sta-tus of massive transfusion protocols in United States trauma centers: massive transfusion or massive confusion? Transfusion. 2010;50:1545–155.1

39. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscita-tion: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62:307–310.

40. Dirks J, Jørgensen H, Jensen CH, Ostrowski SR, Johansson PI. Blood product ratio in acute traumatic coagulopathy—effect on mortality in a Scandinavian level 1 trauma centre. Scand J Trauma Resusc Emerg Med. 2010;18:65.

41. Simmons JW, White CE, Eastridge BJ, Mace JE, Wade CE, Blackbourne LH. Impact of policy change on US Army combat transfusion practices. J Trauma. 2010;69(suppl 1):S75–S80.

42. Davenport R, Curry N, Manson J, et al. Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma. 2011;70:90–96.

43. Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg. 2010;210:957–965.

44. Ho AM, Dion PW, Yeung JH, et al. Prevalence of survivor bias in observational studies on fresh frozen plasma:erythrocyte ratios in trauma requiring massive transfusion. Anesthesiology. 2012;116:716–728.

45. Novak DJ, Bai Y, Cooke RK, et al; PROPPR Study Group. Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. Transfusion. 2015;55:1331–1339.

46. Shanwell A, Andersson TM, Rostgaard K, et al. Post-transfusion mortality among recipients of ABO-compatible but non-identi-cal plasma. Vox Sang. 2009;96:316–323.

47. Inaba K, Branco BC, Rhee P, et al. Impact of ABO-identical vs ABO-compatible nonidentical plasma transfusion in trauma patients. Arch Surg. 2010;145:899–906.

48. Balvers K, Saleh S, Zeerleder SS, et al. Are there any alternatives for transfusion of AB plasma as universal donor in an emer-gency release setting? Transfusion. 2016;56:1469–1474.

49. Nascimento B, Callum J, Tien H, et al. Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients with severe trauma: a randomized feasi-bility trial. CMAJ. 2013;185:E583–E589.

50. Tapia NM, Chang A, Norman M, et al. TEG-guided resuscita-tion is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74:378–386.

51. Stanworth SJ, Davenport R, Curry N, et al. Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice. Br J Surg. 2016;103:357–365.

52. Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI, Gracias VH. Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Crit Care Med. 2008;36:1114–1118.

53. Watson GA, Sperry JL, Rosengart MR, et al; Inflammation and Host Response to Injury Investigators. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma. 2009;67:221–230.

54. Bolton-Maggs PH, Cohen H. Serious hazards of transfusion (SHOT) haemovigilance and progress is improving transfusion safety. Br J Haematol. 2013;163:303–314.

55. Clifford L, Jia Q, Subramanian A, et al. Characterizing the epidemiology of postoperative transfusion-related acute lung injury. Anesthesiology. 2015;122:12–20.

56. Clifford L, Jia Q, Yadav H, et al. Characterizing the epidemi-ology of perioperative transfusion-associated circulatory over-load. Anesthesiology. 2015;122:21–28.

57. Simmons JW, Pittet JF. Revealing the real risks of periop-erative transfusion: rise of the machines! Anesthesiology. 2015;122:1–2.

58. Haas T, Fries D, Tanaka KA, Asmis L, Curry NS, Schöchl H. Usefulness of standard plasma coagulation tests in the man-agement of perioperative coagulopathic bleeding: is there any evidence? Br J Anaesth. 2015;114:217–224.

59. Toulon P, Ozier Y, Ankri A, Fléron MH, Leroux G, Samama CM. Point-of-care versus central laboratory coagulation test-ing during haemorrhagic surgery. A multicenter study. Thromb Haemost. 2009;101:394–401.

60. Davenport R, Manson J, De’Ath H, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med. 2011;39:2652–2658.

Copyright © 2016 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.910 www.anesthesia-analgesia.org October 2016 Volume 123 Number 4

Copyright © 2016 International Anesthesia Research SocietyDOI: 10.1213/ANE.0000000000001516

Trauma is the leading cause of death worldwide in indi-viduals aged 18 to 39 years, and, despite advances in trauma management, a significant proportion of these

deaths are because of hemorrhage.1–3 Associated with severe trauma is a unique, complex, and multifactorial coagulopa-thy, the mechanisms of which are not fully determined.4–6

In addition to a lack of clarity regarding the pathophysiol-ogy of trauma-associated coagulopathy, no consensus exists regarding the nomenclature used to describe the process.7 Various terms have been suggested—acute traumatic coagu-lopathy, acute coagulopathy of trauma, acute coagulopathy of trauma shock, trauma-induced coagulopathy (TIC), and early

TIC.4,8,9 These terms are often used interchangeably, adding to the confusion. In this article, we will use the term TIC.

Several mechanisms have been proposed to explain the development of TIC. TIC is characterized by reduced clot strength related to hypofibrinogenemia/dysfibrinogen-emia, platelet dysfunction, hyperfibrinolysis, and endo-thelial dysfunction.10 TIC is subsequently compounded by acidosis, hypothermia, hemodilution, and factor consump-tion associated with severe hemorrhage and large volume fluid resuscitation (Figure 1).11

Central to the proposed mechanisms is the effect of direct tissue injury, shock, and hypoperfusion on the endo-thelium, which causes systemic anticoagulation and hyper-fibrinolysis.12 The role of tissue injury is supported by the observation that the degree of coagulopathy is proportional to injury severity and is present before large volume fluid or blood product transfusion.13,14 In the presence of tissue hypoperfusion and hypoxia, thrombomodulin (TM) expres-sion is increased. TM binds thrombin (also generated in response to tissue trauma), and the resulting TM–thrombin complex activates the protein C (PC) pathway. Activated PC (aPC) inactivates factor Va and VIIIa, producing a hypo-coagulable state. In addition, aPC inactivates plasmino-gen activator inhibitor-1 (PAI-1), causing fibrinolysis.12,15 Hyperfibrinolysis is further enhanced by the release of tis-sue plasminogen activator. A 2016 study suggests that the increased levels of tissue plasminogen activator that com-plex with PAI-1 play a larger role in hyperfibrinolysis than aPC-driven PAI-1 inactivation.16

The neurohormonal axis and the endothelial glycoca-lyx may also contribute to TIC. In response to tissue injury and shock, a catecholamine surge results, which triggers an up-regulation of the endothelial cells and a shedding of

Hemorrhage in the setting of severe trauma is a leading cause of death worldwide. The pathophysiology of hemorrhage and coagulopathy in severe trauma is complex and remains poorly understood. Most clinicians currently treating trauma patients acknowledge the presence of a coagulopathy unique to trauma patients—trauma-induced coagulopathy (TIC)—independently associated with increased mortality. The complexity and incomplete understanding of TIC has resulted in significant controversy regarding optimum manage-ment. Although the majority of trauma centers utilize fixed-ratio massive transfusion proto-cols in severe traumatic hemorrhage, a widely accepted “ideal” transfusion ratio of blood to blood products remains elusive. The recent use of viscoelastic hemostatic assays (VHAs) to guide blood product replacement has further provoked debate as to the optimum transfusion strategy. The use of VHA to quantify the functional contributions of individual components of the coagulation system may permit targeted treatment of TIC but remains controversial and is unlikely to demonstrate a mortality benefit in light of the heterogeneity of the trauma population. Thus, VHA-guided algorithms as an alternative to fixed product ratios in trauma are not universally accepted, and a hybrid strategy starting with fixed-ratio transfusion and incorporating VHA data as they become available is favored by some institutions. We review the current evidence for the management of coagulopathy in trauma, the rationale behind the use of targeted and fixed-ratio approaches and explore future directions. (Anesth Analg 2016;123:910–24)

Targeted Coagulation Management in Severe Trauma: The Controversies and the EvidenceJames Winearls, BSc, MBBS, MRCP, FCICM,*† Michael Reade, MBBS, MPH, DPhil, FANZCA, FCICM,‡ Helen Miles, MBBS,* Andrew Bulmer, BAppSc, PhD,†§ Don Campbell, MBBS, FACEM,∥ Klaus Görlinger, MD,¶# and John F. Fraser, MD, MBChB, PhD, MRCP, FRCA, FCICM**

From the *Intensive Care Unit, Gold Coast University Hospital, Southport, Queensland, Australia; †Gold Coast University Hospital Critical Care Research Group, Queensland, Australia; ‡Joint Health Command, Australian Defence Force and Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia; §Heart Foundation Research Centre, School of Medicine, Griffith University, Gold Coast, Queensland, Australia; ∥Trauma Department, Gold Coast University Hospital, Queensland, Australia; ¶Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany; #Tem International GmbH, Munich, Germany; and **Critical Care Research Group, The Prince Charles Hospital and University of Queensland, Brisbane, Queensland, Australia.Accepted for publication June 9, 2016.Funding: The program of trauma research is supported by grants from the Queensland Emergency Medicine Research Foundation and Gold Coast University Hospital Foundation.Conflict of Interest: See Disclosures at the end of the article.Reprints will not be available from the authors.Address correspondence to Klaus Görlinger, MD, Department of Anesthe-siology and Intensive Care Medicine, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany; and Tem Inter-national GmbH, Munich, Germany. Address e-mail to [email protected] and [email protected].

NARRATIVE REVIEW ARTICLEE

CME

!

Massaal transfusie protocol VUmc

VRAGEN?

WAAROM IN GODSNAAM 250 SUFENTA!!???

“DUTTON APPROACH”

ANESTHESIA FOR TRAUMA (J-F PITTET, SECTION EDITOR)

Choice of General Anesthetics for Trauma Patients

Robert A. Sikorski • A. Ken Koerner •

L. Yvette Fouche-Weber • Samuel M. Galvagno Jr.

Published online: 10 June 2014! Springer Science + Business Media New York 2014

Abstract The trauma anesthesiologist has multiplecompeting concerns when supporting the patient with

major trauma, but the priority must be focused on adequate

resuscitation to facilitate surgical hemostasis. A broad,evidence-informed knowledge of airway management,

resuscitation, physiology, pharmacology, and critical care

is required to address the unique pathophysiological pro-cesses encountered in trauma. Judicious selection of

anesthetic agents is crucial to ensure optimal outcomes. In

this review, we describe approaches for the induction andmaintenance of general anesthesia for the patient with

major trauma. Considerations for ongoing resuscitation and

hemodynamic instability will be explored and discussedwith respect to the administration of anesthetic induction

and maintenance agents. Practices at our institution are

reviewed, including the administration of high-dose

opioids as an integral part of both resuscitation and anes-thesia for the patient with major trauma.

Keywords Trauma anesthesia ! General anesthesia fortrauma ! Trauma anesthesiology ! Traumatic injury !General anesthesia ! Anesthetic considerations

Introduction

The anesthesiologist’s role while managing patients with

major trauma is multi-faceted. Seriously injured patientsoften require damage control surgery (DCS), as well as

damage control resuscitation (DCR), and many present with

unknown or suboptimally managed pre-existing conditions[1]. A broad, evidence-informed knowledge of airway man-

agement, resuscitation, physiology, pharmacology, and crit-

ical care is required to address the unique pathophysiologicalprocesses observed in trauma [1]. In this review, we will

describe approaches for the induction and maintenance of

general anesthesia for patients with major trauma. Consider-ations for ongoing resuscitation and hemodynamic instability

will be explored and discussed with respect to the adminis-tration of anesthetic induction and maintenance agents.

Induction Agents

Rapid sequence induction and intubation (RSII) is employedfor newly admitted trauma patients using induction agents

and neuromuscular blockers. A comprehensive review of

RSII is beyond the scope of this review, but a brief overviewis presented because these agents have important pharma-

cological and physiological effects in the severely injured

trauma patient. For a thorough appraisal of RSII, the reader

R. A. Sikorski ! A. K. Koerner ! L. Y. Fouche-Weber !S. M. Galvagno Jr. (&)Division of Trauma Anesthesiology, Department ofAnesthesiology, Program in Trauma, R Adams Cowley ShockTrauma Center, University of Maryland School of Medicine,22 South Greene Street, Baltimore, MD 21201, USAe-mail: [email protected]

R. A. Sikorskie-mail: [email protected]

A. K. Koernere-mail: [email protected]

L. Y. Fouche-Webere-mail: [email protected]

S. M. Galvagno Jr.Division of Critical Care Medicine, Department ofAnesthesiology, R Adams Cowley Shock Trauma Center,University of Maryland School of Medicine, 22 South GreeneStreet, Baltimore, MD 21201, USA

123

Curr Anesthesiol Rep (2014) 4:225–232

DOI 10.1007/s40140-014-0066-5

TEKST

“DUTTON APPROACH”

▸ bloedverlies geeft vasoconstrictie, slechte perifere perfusie, SIRS, endotheel schade

▸ Opioiden geven sympathicolyse. Reactie daarop zegt dus iets over mate van vasoconstrictie

▸ “Dutton”: ik geef net zo lang opioiden tot ik geen reactie meer zie op een bolus van 250mcg Fentanyl

▸ Geen enkele evidence voor! Beschreven door full time trauma anestesiologen van R Adams Cowely Shock Trauma center, Baltimore, USA

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