Injectable hemostatic adjuncts...
Transcript of Injectable hemostatic adjuncts...
Injectable hemostatic adjuncts
FIinTIC-Study
Marc Maegele
Department for Trauma and Orthopedic Surgery(Director: Prof. Dr. Bertil Bouillon)
Cologne-Merheim Medical Center (CMMC)
Institute for Research in Operative Medicine(IFOM)
(Director: Prof. Dr. Edmund Neugebauer)
University of Witten/Herdecke
Campus Cologne-Merheim
Uncontrolled Bleeding is a Major Causeof Death in Trauma
(Patients dying in-hospital within the first 48 hours after trauma)
Sauaia et al., J Trauma 1995; 38: 185-193Evans et al., World J Surg 2010; 34: 1720-21
Exsanguination
10
20
30
40
Mor
talit
y <
48 h
ours
afte
r Tra
uma
in (%
)50
60
CNS CNS +Exsang.
Organfailure
Other
The Incidence of Acute Post-TraumaticCoagulopathy upon ER Admission
(25% of trauma patients are coagulopathic upon ER admission)
10
20
Trau
ma
Pat
ient
s in
(%) 3
0
40
BrohiJ Trauma
2003n=1,088
MacLeodJ Trauma
2003n=10,790
MaegeleInjury2007
n=8,724
RugeriJ Th Hem
2007n=88
25% !
The Clinical Significance of Acute Post-Traumatic Coagulopathy : Mortality
20
Mor
talit
y in
(%)
40
60
BrohiJ Trauma
2003n=1,088
MacLeodJ Trauma
2003n=10,790
MaegeleInjury2007
n=8,724
BrohiAnn Surg
2007n=208
x 4,6
normal coagulationcoagulopathy
Key Recommendations for the Management ofAcute Traumatic Hemorrhage: S3-Guideline
„Polytrauma“
Trauma-induced coagulopathy=
„own clinical entity“
Recommendation 23We recommend that
monitoring and measuresto support coagulation be
initiated as early aspossible (Grade 1C).
The current concept
Maegele et al. , Shock 2013
The role of fibrinogen
Primary haemostasis: Ligand between activated platelets GP receptor IIb/IIIa has a high affinity
to fibrinogen
Secondary haemostasis Precursor for fibrin formation Fibrinogen is the substrate of the
coagulation process
Mosesson et al. J Thromb Haemost 2005
Reasons for low fibrinogen
Bleeding Consumption Dilution (Hyper)fibrinolysis Hypothermia Acidosis
Schlimp CJ, Schöchl H. Haemostasiologie 2014
Normovolaemic hemodilution
McLoughlin et al. Anasth Anal 1996
10 20 30 40 50 60 70 80% Original blood volume exchanged
250
200
150
100
50
Platelets
FibrinogenFibrinogenFi
brin
ogen
[mg/
dL]
Plat
elet
s [1
09/L
]
Floccard et al. Injury 2012
Early coagulopathy in trauma:An on-scene and hospital admission study
On-scene coagulation factor concentrates as a function of injuryseverity
Fibrinogen: First factor to reach criticallevels during severe bleeding replaced
with plasma and fluids (Hippala et al., 1995)
Fibrinogen levels at Ermergency Roomadmission and mortality
N = 517
24-hours mortality 28-days mortality
Alive Dead
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Fibr
inog
en le
vel (
g/L)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Fibr
inog
en le
vel (
g/L)
***
Alive Dead
***
Rourke et al. J Thromb Haemost 2012
Impact of fibrinogen levels on outcomeafter acute injury in patients with
massive transfusion
The role of Fibrinogen
Substate for clotting (coverted into fibrin by thrombin)!
Thrombin
The role ofFibrinogen
Maegele, Textbook of Surgery 2014 (in press)
Clotting interaction of platelets, fibrin, aFXIIIaFXIII, activated factor XIII; CFT, clot formation time; CT, clotting time; MA, maximum amplitude; MCF, maximum clot firmness
Fibrinogen: 835mg/dl
Absolute strength of the clot is reflected byamplitude in mm
Impact of fibrinogen on maximum clotfirmness / stability
Plotkin AJ, et al. J Trauma 2008;64:S64, Leemann H, et al. J Trauma 2010;69:1403Davenport R, et al. Crit Care Med 2011;39:2652, Tauber H, et al. Brit J Anaesth 2011;107:378
Schöchl H, et al. J Neurotrauma 2011;28:2033, Cotton BA, et al. J Trauma 2011;71:407Schöchl H, et al. Crit Care 2011;15:R265, Holcomb J, et al. Ann Surg 2012;256:476
Low MCF/MA is associated withincreased blood loss, blood transfusion
requirement and higher mortality
FIBTEM baseline 33% Dilution with Saline
Saline Dilution + FXIIISaline Dilution + Fibrinogen Saline Dilution + Fib + FXIII
FIBTEM examples of normal, salinediluted and substituted clots
Fibrinogen in the treatment of post-traumatic coagulopathy
Fries et al., Br J Anaesth 2005
Electronmicroscopic findings
Normal clotting Dilution
Diluted clot after administrationof fibrinogen
Schöchl et al. , Crit Care 2011
Coagulation parameters and their valuesto predict massive transfusion
.... what does the literature say ?
Spahn et al., Crit Care 2013
Substitution: Fib-Concentrate vs FFP vs Cryo
Prospective, randomised, controlled and double-blind Study, N = 60 patients Early administration of 50 mg/kg BW fibrinogen concentrate
versus placeboin bleeding trauma patients.
Assessment time points:Inclusion (at site of the accident) (T1)Immediately after trauma bay arrival (T2)after 3 hours (T3)after 9 hours (T4)after 24 hours (T5)after 48 hours (T6)after 1 week (T7)
Study design
1. Change in plasma coagulation2. Transfusion requirements/blood loss3. Thromboembolic complications4. Clinical endpoint/morbidity/LOS
Pilot /proof of concept study to investigatethe effect of early treatment with fibrinogenconcentrate on:
Study aim
Inclusion criteria:1.Trauma patient (Age 18-85 years)
2.Patients admitted to a FIinTIC study center
3.Patients with visible or suspected bleeding and state of shock
(RRsyst <110 mmHG)
4.Confirmed of bleeding after completed diagnostic procedures (CT)
Exclusion criteria1. Patients with history of or known thombembolic events
2. Patients with survivable trauma/deth at scene
3. Pregnancy
Number of patients:
60 patients (30 plazebo, 30 verum)
expected/calculated „drop out rate“: 50%
Patients per emergency vehicle/rescue helicopter:
9 patients in 2 years per center
Patienten per hospital
12 patients in 2 years per center
Further parameters:• Blood loss: documentation of (calculated) blood loss transfusion
requirements• Clinical endpoints• Volume requirement• Use of further coagulation products (coagulation factor
concentrates, antifibrinolytic agents, DDAVP, buffer therapy, …).
Primary endpoint: Fibrinogen polymerisation measure with the FIBTEM® MCF
Secondary endpoints: • Other ROTEM® and biological parameters• Number of thromboses at 7 days assessed by duplex ultrasound
Endpoints
FGTW: Fibrinogen concentrate, LFB France (1,5 g in
100 mL)
Dosage: 1x 50 mg/kg KG (1 package per 30 kg KG)
storage: room temperature
Temp range of -20 up to + 40 C0: 6 month
at room temperature: 3 years
Test substance
Austria
Active CenterInitiated but inactive CenterClosed CenterNew Initiated Center
H01Christophorus 1 Innsbruck PI: Dr. Marc Kaufmann
H03Christophorus 6 SalzburgPI: Dr. Bernhard Ziegler
H06Christophorus 14NiederöblarnPI: Dr. Christine Wimmer
H07Martin 2 Karres PI: Dr. Christian Niederwanger
H08NEF InnsbruckPI: Univ. Doz. Dr. MichaelBaubin
H11NAW VöcklabruckPI: Prim. Mag. Dr. Günther
H12Christophorus 5 ZamsPI: Dr. Manuel Mauerer
H13NEF TelfsPI: Dr. Markus Thaler
Austria
Germany
G01Cologne-Merheim Medical CenterDepartment for Trauma Surgery undOrthopedicsPI & National Coordinator:Prof. Dr. Marc Maegele
G03Federal Armed Forces MedicalCenter UlmDepartment of General, Visceral andThoracic SurgeryPI: Dr. Thorsten Hauer
Frankfurt / Kempten /Duisburg ???
Czech Republic
C01University Hospital Hradec KraloveDepartment for Anaesthesiology and Intensive CarePI & National Coordinator: Dr. Anatolij Truhlar
K01Christoph 06 Hradec Kralove PI: Dr. Anatolij Truhlar
DenmarkD01Aarhus UniversityHospitalDepartment ofAnaesthesiologyPI & NationalCoordinator:Dr. Christian Fenger-Eriksen
N01 / H1AkutlægehelikopterKarup LufthavnPI: Dr. Christian Fenger-Eriksen
Network
Project management (KKS Innsbruck): 74.000 €Statistics (Department of Biostatistics Innsbruck): 13.200 €Labelling (Pharmacy Salzburg): 4.000 €IMP Shipment (Salzburg): 2.000 €CRF-Print: 4.000 €Travel Costs: 10.000 €Monitoring and Pharmacovigilance: 108.000 €Employment of 2 labors: 172.000 €Total: 497.200 €
Actual Funding:LFB – unrestricted grant: 100.000€Coalition Warfare Grant/US Army 207.000€University Innsbruck: 200.000 €Total: 507.000 €
Kosten
TheCologneprotocol
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