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Blutprodukte in der Sepsis:Faktorenkonzentrate und POC
Dietmar Fries
Klinik für
Allgemeine und Chirurgische Intensivmedizin,
Medizinische Universität Innsbruck
www.clotwork.at
Partners:
Tel HashomerMedical University of TelAviv, Israel
US Army, Fort Sam Houton, Texas, USA
Dept. of Bioengineering, Univ. of San Diego, USA
Dept. for Anesthesia, Aarhus, Denmark
Dept. for Hematology, Kings College London, UK
Dept. for Trauma Surgery, Cologne Merheim Medical Center, Germany
Financial disclosure:
Industrial grants/support/lecture fee
Astra Zeneca, AOP Orphan, Baxter, Bayer, Braun, Biotest, CSL Behring,
Delta Select, Dade Behring, Edwards, Fresenius, Glaxo, Haemoscope,
Hemogem, Lilly, LFB-France, Mitsubishi Pharma, NovoNordisk, Octapharm,
Pfizer, TEM-Innovation.
Public grants/support
Austrian National Bank Trust, Deutsche Bundeswehr, Ministerium für
Landesverteidigung und Sport, US Army, US Department of Defense.
Gerinnungsmonitoring beim kritisch Kranken
Sepsis – Gerinnung
Gerinnungstherapie - DIC
Gerinnungsmonitoring beim kritisch Kranken
Sepsis – Gerinnung
Gerinnungstherapie - DIC
PT aPTT TZ
PT aPTT TZ
50% 50sec 50G/L
Partielle Thromboplastinzeit (PTT)
Citratblut + Phospholipidantikörper + oberflächenaktiven
Substanz (z. B. Kaolin) + Calciumionen
Der Normalwert: 20 bis 38 Sekunden.
Die PTT ist verlängert:
Mangel: Faktor I, II, V, VIII, X, XI, XII
Vitamin-K-Mangel bzw. unter Macrumar-Therapie
Heparin-Therapie
Von Willebrand Syndrom
Citratblut + Phospholipidantikörper + oberflächenaktiven
Substanz (z. B. Kaolin) + Calciumionen
Der Normalwert: 20 bis 38 Sekunden.
Die PTT ist verlängert:
Mangel: Faktor I, II, V, VIII, X, XI, XII
Vitamin-K-Mangel bzw. unter Macrumar-Therapie
Heparin-Therapie
Von Willebrand Syndrom
Lupus Antikoagulans
Antiphosphilipidantikörper
Faktor XII Mangel
Partielle Thromboplastinzeit (PTT)
58-y.o patient following CABG: ECMO, IABP, CVVH, ...
Massive bleeding > 10 RBC per day
PT: 39%
pTT: 114 sec
Fibrinogen: 150 mg/dL
FXIII: 32%
platelets: 49.000
?
Partielle Thromboplastinzeit (PTT)
detection of heparin
Add Protamin to
the sample
Inhibition of Heparin
with Heparinase
HepTEM® = Heparinase TEM
He
pa
rin
eli
min
ati
on
wit
h H
ep
ari
nas
e
InT
EM
®
Hep
TE
M®
?
FVIII: 79%FIX: 50%FXII: 13%
Partielle Thromboplastinzeit (PTT)
58-y.o patient following CABG: ECMO, IABP, CVVH, ...
Massive bleeding > 10 RBC per day
PT: 39%
pTT: 114 sec
Fibrinogen: 150 mg/dL
FXIII: 32%
platelets: 49.000
Vv Ecmo bei Patienten mit Bleomycin
induziertem toxischem Lungenversagen …
Antikoagulation: UF Heparin
Monitoring: ACT, aPTT
0
50
100
150
200
800IUHeparin
1200IUHeparin
1800IUHeparin
800IUHeparin
ACT
aPTT
Partielle Thromboplastinzeit (PTT)
Vv Ecmo bei Patienten mit Bleomycin
induziertem toxischem Lungenversagen …
Antikoagulation: UF Heparin
Monitoring: ACT, aPTT
0
50
100
150
200
800IUHeparin
1200IUHeparin
1800IUHeparin
800IUHeparin
ACT
aPTT
Partielle Thromboplastinzeit (PTT)
Vv Ecmo bei Patienten mit Bleomycin
induziertem toxischem Lungenversagen …
Antikoagulation: UF Heparin
Monitoring: ACT, aPTT
Partielle Thromboplastinzeit (PTT)
Vv Ecmo bei Patienten mit Bleomycin
induziertem toxischem Lungenversagen …
Antikoagulation: UF Heparin
Monitoring: ACT, aPTT
Partielle Thromboplastinzeit (PTT)
UFH anti Xa: 0,6
HepTEM CT 180 sec; CT InTEM 235 sec
Partielle Thromboplastinzeit (PTT)
Vv Ecmo bei Patienten mit Bleomycin
induziertem toxischem Lungenversagen …
Antikoagulation: UF Heparin
Monitoring: ACT, aPTT
Citratplasma + Calcium + Gewebsthromboplastin = optische
Messung der Gerinnunszeit und Vergleich mit Normalplasma.
Der Quick-Wert ist vermindert bei:
Mangel an Faktor II, V, VII und X.
Fibrinogenmangel
Leberdysfunktion
Vitamin K Mangel
Quick Wert, Prothrombinzeit (PT)
Citratplasma + Calcium + Gewebsthromboplastin = optische
Messung der Gerinnungszeit und Vergleich mit Normalplasma.
Der Quick-Wert ist vermindert bei:
Mangel an Faktor II, V, VII und X.
Fibrinogenmangel
Leberdysfunktion
Vitamin K Mangel
Quick Wert, Prothrombinzeit (PT)
Cave: Quick bildet nicht das Gleichgewicht zwischen Pro-
und Antikoagulatoren (AT, Protein C, Protein S, etc.)
ICU Patient, 63 Jahre, Z.n. A-Dissektion, Bentall OP und Sepsis …
Quick Wert, Prothrombinzeit (PT)
Patient with severe Sepsis/MODS, planned central venous lineapplication ...
Standard Coagulation Tests:
platelets 80.000/µL
pT 25%
pTT 61%
Blutung oder Thrombose?
Quick Wert, Prothrombinzeit (PT)
Standard Coagulation Tests:
platelets 80.000/µL
pT 25%
pTT 61%
Patient with severe Sepsis/MODS, planned central
venous line application ...
Thrombelastography as a better indicator of hypercoagulable
state after injury than PT or aPTT.
Park MS, Martini WZ et al. J Trauma 2009
PT and aPTT were prolonged.
Clot formation: hypercoagulable
state.
Patients: lower protein C,
antithrombin III and higher
fibrinogen.
Conclusion: TEG detected
hypercoagulable state which was
not proved by plasma PT or aPTT.
Patients: nonburn trauma (n = 33), burned (n =
25), and healthy (control) subjects (n = 20).
22 ICU patients with prolonged aPTT, PT
FFP 12.2ml/kg vs 33.5ml/kg
Coagulation factor analysis before/after FFP
Critical concentration: <30%, Fib (<100mg/dL)
in 50% no need for transfusion
12mL/kg: no increase
30mL/kg FFP: mild increase
Efficacy of standard dose and 30ml/kg FFP
in critically ill patientsChowdhury P. British J Haematol 2004;125:69
standard tests futile
standard dosages: not effective
We suggest that fresh frozen plasma not be used tocorrect laboratory clotting abnormalities in the absenceof bleeding or planned invasive procedures (grade 2D).In addition, transfusion of fresh frozen plasmausually fails to correct the prothrombin time in non-bleedingpatients with mild abnormalities. No studies suggest that correction of more severe coagulationabnormalities benefits patients who are not bleeding.
Dellinger RP, et al. Intensive Care Med 2013;39:165–228
Prospective multicentre observational study including1.923 ICU admissions
Reasons for plasma transfusion:48% bleeding, 15% pre-procedural prophylaxis,36% prophylaxis without any procedure.
Indication for FFP transfusion: PT prolongation
FFP, fresh frozen plasma; ICU, intensive care unit; PT, prothrombin time Stanworth SJ, et al. Crit Care 2011;15:R108
Each unit of FFP was independently
associated with a 2.1% higher risk of
MOF and a 2.5% higher risk of ARDS.
Transfusion of FFP Gabe was associated with:
VAP with (RR 5.42) and without shock (RR 1.97)
Septic shock with positive blood culture (RR 3.35)
Non-specified septic shock (RR 3.22)
RR for transfusion of FFP and all infections: 2.99
3-fold increase!
FFP, fresh frozen plasma; RR, relative risk; VAP, ventilator-associated pneumonia Sarani B, et al. Crit Care Med 2008;36:1114–8
Outcome FFP(n=44)
No FFP(n=71)
p-value
New bleeding episodes, n (%) 3 (6.8) 2 (2.8) 0.369
New onset of acute lung injury, n (%) 8 (18.2) 3 (4.2) 0.021
Hospital mortality, n (%) 11 (25.6) 20 (28.2) 0.763
Median (IQR) ICU length of stay, days 2.4 (1.7–6.8) 2 (0.9–3) 0.184
No difference in new bleeding episodes
New onset acute lung injury was more frequent in the
transfused group (18% vs 4%, p=0.021)
Risk-benefit ratio of FFP transfusion in critically ill medical
patients with coagulopathy may not be favourable
FFP, fresh frozen plasma; ICU, intensive care unit; IQR, interquartile range Dara SI, et al. Crit Care Med 2005;33:2667–71
ROTEM reduced FFP transfusion by 98% (4 versus 220 U)
Platelets and platelet transfusion
surgical procedure:
high risk of bleeding > 50.000/µL
low risk of bleeding 20.000-50.000µL
neurosurgical procedure 70.000-100.000µL
ophthalmic procedure 70.000-100.000µL
acute bleeding:
transfusion of ≥ 1RBC/d) >100.000µL
no transfusion necessary no transfusion
acute liver failure >20.000µL
chronic liver failure >10.000µL
Recommendations of platelet transfusion by the joint
thrombocyte working party of the German Societies of
Transfusion Medicine and Immunohaematology (DGTI),
Thrombosis and Haemostasis Research (GTH), and
Haematology and Oncology (DGHO)
Low platelets
High fibrinogen,
high von Willebrand Factor,
decreased ADAMTS 13, FVIII, …
Platelets in Sepsis, liver failure, …
Fibrinogen concentrate improves clot firmness similar to platelet transfusionSchenk B et al. BJA; accepted for publication
ABS 0; A10EX 36 mm; PC 14 x 109/L
ABS 3; A10EX 27 mm; PC 15 x 109/L
ABS 8; A10EX 23 mm; PC 13 x 109/L
Gerinnungsmonitoring beim kritisch Kranken
Sepsis – Gerinnung – DIC
Gerinnungstherapie - DIC
Pathophysiologie der DIC:
1. Aktivierung der Gerinnung
2. Mangel an Inhibitoren der Gerinnung
3. Hemmung der Fibrinolyse
Plasmatische Gerinnung
1. Aktivierung der Gerinnung
Ursache:
1. Freisetzung von Thromboplastin (= Tissue Factor)
führt zu einer Kontaktaktivierung des extrinsischen
Systems ab FVIIa
2. IL-6
3. ...
woher kommen erhöhte TF Spiegel bei DIC/Sepsis?
TFTFTF
TF+ FVIIa FXa Fibrin DIC
Monozyt
2. Mangel an Inhibitoren der Gerinnung
Antithrombin:
Synthese
Verbrauch
Abbau durch Leukozytenelastase
Protein C
Verminderung von Thrombomodulinrezeptors bei
Sepsis/DIC z.B durch erhöhte TNF Spiegel.
Protein S
Bindung an Regulatorprotein (C4bB8) des
Complementsystems mit folgender Inaktivierung.
3. Hemmung der Fibrinolyse
Gerinnungsaktivierung stimuliert normalerweise auch
fibrinolytische System um Hämostase = Gleichgewicht
aufrecht zu erhalten
DIC: Wiederauflösung gebildeter Thrombi unterbleibt!
Ursachen:
1. PAI (Plasminogen-Aktivator-Inhibitor) durch Endotoxin erhöht
2. FXI Aktivierung
3. Inaktivierung von Plasminogen-Aktivator durch Thrombin
Entzündungsinduzierte
„disseminierte“ Thrombingeneration mit
intravaskulärer Fibrinablagerung
Beeinträchtigung antikoagulatorischer
Reaktionswege
Beeinträchtigung der Fibrinolyse
Schädigung des mikrovaskulären Endothels
intravaskuläre
Fibrinablagerung
Plasmatische Gerinnung und Sepsis/DIC
Coagulation disorders in sepsis – does it matter?
Survival time (days)
40
20Pati
en
ts a
live %
0
60
80
100
10 20 30 40 50 60 700 80 90
Placebo (N = 115, censored = 57)
Placebo (N = 162, censored = 111)
„Kybersept-Study“ High-dose antithrombin III in severe sepsis
Warren BL et al. JAMA 2001
DIC and mortality:
DIC
no DIC
28-day mortality of „overt“ DIC
K. Bakhtiari et al., Crit Care Med 2004
20
10
mortality in %
0
30
40
50
60
70
DIC Score
1 2 3 4 5 6 7
overt DIC
Diagnosis and Definition of DIC
ISTH-non-overt-DIC-Score
Score ≥ 5 = non-overt DIC
Underlying disease
compatible with DIC
Platelets < 100.000/µL
aPTT and/or PT
increased
DIC unplausible DIC probable
no
yes
yes
yes
Platelets and Sepsis
Thrombocytopenia:
< 150x109/L 35 bis 44 %
< 100x109/L 20 bis 25 %
< 50x109/L 12 bis 15 %
Usually within the first 4 days after ICU
admission
Severity of sepsis correlates with
extent of thrombocytopenia
Levi M. Platelets. Crit Care Med 2005; 33:523-25
Fibrinogen (mean): Survivor(L)
Fibrinogen (mean): Non-survivor(L)
CRP (mean): Survivor(R)
CRP (mean): Non-survivor(R)
day -3
day -2
day -1
day 0
day 1
day 2
day 3420
440
460
480
500
520
540
560
580
600
620
640
660
680
700F
ibri
no
ge
n [
mg
/dl]
10
12
14
16
18
20
22
24
26
28
30
32
CR
P [
mg
/dl]
Plasma fibrinogen in patients with severe sepsis/septic shock:
In survivors, fibrinogen levels were significantly higher!
CRP, C-reactive protein
Mean; Whisker: 95% conf idence interv alF
ibrinogen [
mg/d
l]
Surv iv al: non-surv iv or
Surv iv al: surv iv orday -3 day -2 day -1 day 0 day 1 day 2 day 3
350
400
450
500
550
600
650
700
750
Retrospective analysis of 250 medical and trauma ICU patients
Fibrinogen levels were significant higher (*p<0.05) in “Survivor”than in “Non-survivor”group
ICU, intensive care unit
fibrin fibrils
GAS bacteria
efflux of cytosoliccontent
Påhlman LI, et al. Thromb Haemost 2013;109:930–9
Illustration of Fibrin 1
α-thrombin catalyses conversion of fibrinogen to fibrin release of fibrinopeptides A + B from the N-
termini of the Aα and Bß chains
***
***
• Release of fibrinopeptide B exposes 28 amino acid long peptide sequence at the N-terminal end of the ß-chain
• Antimicrobial activity of a cleavage product of fibrinogen against GAS, GBS and S. aureus, whereas it seems to have no effect on E. coli, E. faecalis and S. epidermidis:
Surv
ival
(%
)
140
120
100
80
60
40
20
0GAS GBS S. aureus E. faecalis E. coli
6 µM60 µM
***
Påhlman LI, et al. Thromb Haemost 2013;109:930–9
S. aureus (5 x 105 CFU/mL) was incubated with plasma samples from healthy blood donors treated with different amounts of fibrinogen (0, 300, 600 and 900 mg/dL, respectively). Students t-test revealed a significant p-value for differences between baseline (0 mg/dL fibrinogen) and fibrinogen-treated plasma samples. *** p<0.001
CFU, colony-forming unit
Growth reduction (CFUs) of S. aureus in plasma of 3 different blood donors treated with fibrinogen.
CFU
*10
5/d
L
S. aureus
S. aureusin plasma
Plasma +300 mg/dLfibrinogen
Plasma +600 mg/dLfibrinogen
Plasma +900 mg/dLfibrinogen
*** ***
***
Treatment of DIC
DIC:
therapeutic options
rhAPC Antithrombin
Heparin
FFP
GRH 28, … fibrinolysis inhibitors
Thrombo
modulin
OPTIMIST: TFPI (Tifacogin): no influence on mortality, increased
numbers of bleeding†
Antithrombin
Intensive Care Med (2008) 34:17–61DOI 10.1007/s00134-007-0934-2 SPECIAL ARTICLE
R. Phillip DellingerMitchell M. LevyJeanM. CarletJulian BionMargaret M. ParkerRoman JaeschkeKonrad ReinhartDerek C. AngusChristian Brun-BuissonRichard BealeThierry CalandraJean-FrancoisDhainautHerwig GerlachMaurene HarveyJohnJ. MariniJohn MarshallMarco RanieriGraham RamsayJonathan SevranskyB. Taylor ThompsonSean TownsendJeffreyS. VenderJaniceL. ZimmermanJean-LouisVincent
Surviving Sepsis Campaign:International guidelines for managementof severe sepsis and septic shock: 2008
Received: 3 August 2007Accepted: 25 October 2007Published online: 4 December 2007© Society of Critical Care Medicine 2007
The article will also be published in CriticalCare Medicine.
The original article was published inIntensive Care Med (2008) 34:17–60(doi: 10.1007/s00134-007-0934-2).
* Sponsor of 2004 guidelines; ** Sponsorof 2008 guidelines but did not participateformally in revision process; *** Membersof the 2007 SSC Guidelines Committee arelisted in Appendix I.; **** Please see Ap-pendix J for author disclosure information.
for the International Surviving SepsisCampaign Guidelines Committee***, ****
Sponsoring Organizations: American Asso-ciation of Critical-Care Nurses*, AmericanCollege of Chest Physicians*, AmericanCollege of Emergency Physicians*, Cana-dian Critical Care Society, European Soci-ety of Clinical Microbiology and InfectiousDiseases*, European Society of IntensiveCare Medicine*, European RespiratorySociety*, Indian Society of Critical CareMedicine**, International Sepsis Forum*,Japanese Association for Acute Medicine,Japanese Society of Intensive Care Medi-
cine, Society of Critical Care Medicine*,Society of Hospital Medicine**, SurgicalInfection Society*, World Federation ofCritical Care Nurses**, World Federation ofSocieties of Intensive and Critical CareMedicine**. Participation and endorsementby the German Sepsis Society and the LatinAmerican Sepsis Institute.
R. P. Dellinger ( )Cooper University Hospital,One Cooper Plaza, 393 Dorrance,Camden 08103, NJ, USAe-mail: [email protected]
M. M. Levy ·S. TownsendRhode Island Hospital,Providence RI, USA
J. M. CarletHospital Saint-Joseph,Paris, France
J. BionBirmingham University,Birmingham, UK
M. M. ParkerSUNY at Stony Brook,Stony Brook NY, USA
R. JaeschkeMcMaster University,Hamilton, Ontario, Canada
K. ReinhartFriedrich-Schiller-University of Jena,Jena, Germany
D. C. AngusUniversity of Pittsburgh,Pittsburgh PA, USA
C. Brun-BuissonHopital Henri Mondor,Créteil, France
R. BealeGuy’s and St Thomas’ Hospital Trust,London, UK
T. CalandraCentre Hospitalier Universitaire Vaudois,Lausanne, Switzerland
J.-F. DhainautFrench Agency for Evaluation of Researchand Higher Education,Paris, France
H. GerlachVivantes-Klinikum Neukoelln,Berlin, Germany
M. HarveyConsultants in Critical Care, Inc.,Glenbrook NV, USA
J. J. MariniUniversity of Minnesota,St. Paul MN, USA
25
Table5 Other Supportive Therapy of Severe Sepsis
Blood product administrationStrength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after eachguide-line. For added clarity: • Indicates a strong recommendation or “we recommend”; ◦ indicates a weak recommendation or “we suggest”• Give red blood cells when hemoglobin decreases to < 7.0 g/dl (< 70 g/L) to target a hemoglobin of 7.0–9.0 g/dl in adults. (1B)– A higher hemoglobin level may be required in special circumstances (e. g.: myocardial ischaemia, severe hypoxemia, acute
haemorrhage, cyanotic heart disease or lactic acidosis)• Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons. (1B)◦ Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures. (2D)• Do not use antithrombin therapy. (1B)◦ Administer platelets when: (2D)
– counts are < 5000/mm3 (5× 109/L) regardless of bleeding.
– counts are 5000 to 30,000/mm3 (5–30 × 109/L) and there is significant bleeding risk.
– Higher platelet counts (≥ 50,000/mm3 (50× 109/L)) are required for surgery or invasive procedures.Mechanical ventilation of sepsis-induced acute lung injury (ALI )/ARDS• Target a tidal volume of 6 ml/kg (predicted) body weight in patients with ALI/ARDS. (1B)• Target an initial upper limit plateau pressure ≤ 30 cm H2O. Consider chest wall compliance when assessing plateau pressure. (1C)• Allow PaCO2 to increase above normal, if needed to minimize plateau pressures and tidal volumes. (1C)• Positive end expiratory pressure (PEEP) should be set to avoid extensive lung collapse at end expiration. (1C)◦ Consider using the prone position for ARDS patients requiring potentially injurious levels of FiO2 or plateau pressure,
provided they are not put at risk from positional changes. (2C)• Maintain mechanically ventilated patients in a semi-recumbent position (head of the bed raised to 45 ◦ ) unless contraindicated (1B) ,
between 30◦ –45◦ (2C) .◦ Non invasive ventilation may be considered in the minority of ALI/ARDS patients with mild-moderate hypoxemic respiratory failure.
The patients need to be hemodynamically stable, comfortable, easily arousable, able to protect/clear their airway and expectedto recover rapidly. (2B)
• Use a weaning protocol and a spontaneous breathing trial (SBT) regularly to evaluate the potential for discontinuingmechanical ventilation. (1A)– SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T-piece.– Before the SBT, patients should:– be arousable– be haemodynamically stable without vasopressors– have no new potentially serious conditions– have low ventilatory and end-expiratory pressure requirement– require FiO2 levels that can be safely delivered with a face mask or nasal cannula
• Do not use a pulmonary artery catheter for the routine monitoring of patients with ALI/ARDS. (1A)• Use a conservative fluid strategy for patients with established ALI who do not have evidence of tissue hypoperfusion. (1C)Sedation, analgesia, and neuromuscular blockade in sepsis• Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients. (1B)• Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily
interruption/lightening to produce awakening. Re-titrate if necessary. (1B)• Avoid neuromuscular blockers (NMBs) where possible. Monitor depth of block with train of four when using continuous infusions. (1B)Glucose control• Use IV insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU. (1B)◦ Aim to keep blood glucose < 150 mg/dl (8.3 mmol/L) using a validated protocol for insulin dose adjustment. (2C)• Provide a glucose calorie source and monitor blood glucose values every 1–2 hrs (4 hrs when stable) in patients receiving
intravenous insulin. (1C)• Interpret with caution low glucose levels obtained with point of care testing, as these techniques may overestimate arterial blood
or plasma glucose values. (1B)Renal replacement◦ Intermittent hemodialysis and continuous veno-venous haemofiltration (CVVH) are considered equivalent. (2B)◦ CVVH offers easier management in hemodynamically unstable patients. (2D)Bicarbonate therapy• Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating
hypoperfusion-induced lactic acidemia with pH ≥ 7.15. (1B)Deep vein thrombosis(DVT) prophylaxis• Use either low-dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH), unless contraindicated. (1A)• Use a mechanical prophylactic device, such as compression stockings or an intermittent compression device, when
heparin is contraindicated. (1A)◦ Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for DVT. (2C)◦ In patients at very high risk LMWH should be used rather than UFH. (2C)Stressulcer prophylaxis• Provide stress ulcer prophylaxis using H2 blocker (1A) or proton pump inhibitor (1B) . Benefits of prevention of upper GI bleed must
be weighed against the potential for development of ventilator-associated pneumonia.Consideration for limitation of support• Discuss advance care planning with patients and families. Describe likely outcomes and set realistic expectations. (1D)
40
20
Pati
en
ts a
live %
0
60
80
100
Survival time (days)10 20 30 40 50 60 700 80 90
40
20P
ati
en
ts a
live
%
0
60
80
100
AT III (N = 114, censored = 77)
AT III (N = 172, censored = 122)
Placebo (N = 115, censored = 57)
Placebo (N = 162, censored = 111)
DIC (non-overt and/or
overt) - ITT analysis
No DIC - ITT analysis
Antithrombin in DIC
P = 0.007
P 0.2
28 days: RR 0.64 (0.43 – 0.94) p = 0.024
90 days: RR 0.68 (0,49 – 0.93) p = 0.015
„Kybersept-Study“ High-dose antithrombin III in severe sepsis
Warren BL et al. JAMA 2001
Antithrombin and heparin
90 d mortality in patients with no concomitant heparin:
42,8% versus 55,1% (p=0.04)
40
20
0
60
80
100
10 20 30 40 50 60 700 80 90
Pa
tie
nts
ali
ve
%Survival followed-up for 90 days in patients without concomitant heparin
SAPS II, stratum II - ITT analysis
Placebo (N = 162, censored =
75)
ATIII (N = 140, censored = 81)
Survival time (days)
Wilcoxon test: P = 0.04
Activated
recombinant Protein C
aktiviertes Rekombinantes Protein C (Xigris®)
PROWESS: 6% verminderte Mortalität (28d) durch aPC bei Patienten mit schwerer Sepsis und hohem Mortalitätsrisiko.
ENHANCE: bei Patienten mit niedrigem Risiko: kein Vorteil; Inzidenz schwerer Blutungen erhöht; Abbruch der Studie nach Interimsanalyse
ADRESS: Einfluss von Heparin auf die Wirksamkeit von aPC;
Prowess-Shock: Kein Einfluss von aPC auf Mortalität.
Thrombomodulin
Thrombomodulin activates Protein C
DIC patients (n=234) were randomized to receive
ART-123 (= rh_thrombomodulin) or heparin.
28 day Mortality rate:
rhTM 25%
Control 47% (p=0.027)
SOFA score: decreased sig.
(p=0.028) in the rhTM group
compared to the control group.
65 patients with DIC: n=26 rhTM, n=54 control
Vincent JL et al. Crit Care Med 2013 Sep;41(9):2069-79
A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and
suspected disseminated intravascular coagulation.
Vincent JL et al. Crit Care Med 2013 Sep;41(9):2069-79
A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and
suspected disseminated intravascular coagulation.
Vincent JL et al. Crit Care Med 2013 Sep;41(9):2069-79
Heparin
Schiffer ER, et al. Crit Care Med 2002;30:2689–99:Anti-inflammatory effects of heparin and decreased tissue oedema …
Elsayed E and Becker LC. J Thromb Thrombolysis 2003;15:11–8: Inhibition of leucocytes and decreased production of inflammatory mediators …
Sjouke H et al. Crit Care Med 2005: LMWH is effective in thromboembolic prophylaxis and therapy but unable to decrease inflammatory mediators …
Heparin and inflammation
Ojective: RCT to test heparin (UFH) as complementary treatment for sepsis.
PATIENTS: 319 with sepsis.
MEASUREMENTS AND MAIN RESULTS:The median length of stay in the
placebo group was 12.5 days and 12 days in the heparin group (p = 0.976).
The MOD score improved for the placebo and heparin groups (p = 0.240),
respectively. The overall 28-day mortality was 16% in the placebo group and
14% in the heparin group (p = 0.652).
CONCLUSIONS: UFH was not able to demonstrate a beneficial effect.
Jaimes F et al. Unfractioned heparin for treatment of sepsis:
A randomized clinical trial (The HETRASE Study).
Crit Care Med. 2009 Apr;37(4):1185-96.
DIC:
therapeutic options
rhAPC Antithrombin
Heparin
FFP
GRH 28, … fibrinolysis inhibitors
Thrombomodulin
†OPTIMIST – TFPI (Tifacogin): no influence on mortality, increased incidence of bleeding1
1.Abraham E, et al. JAMA 2003;290:238–47
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