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Philippe Van der Li nden MD, PhD
CHU Brugmann-HUDERF, Free University of BrusselsBrussels, Belgium
HES 130/0.4 Vs. Gelatins:Effects on Hemostasis
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In the past 5 years, I have received honoraria or travel support for consulting or lecturing from the following companies:
Fresenius-Kabi GmbHCSL Behring GmbHJanssen-Cilag SA
Conflict o f Interest
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Effects of Fluids on Hemostasis
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Gelatins
Degradation products of collagenIntroduced in the sixtiesno recent development
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Hydroxyethyl Starches
Modified natural polysaccharides
Hydroxyethylation of glucose molecules
Substitution ratio
C2/C6 ratio
Mw - Mn
Kozek-Langenecker SA. Anesthesiology 2005; 103:654-60
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Hydroxyethyl Starches: The in vivo Molecular Weight
HES 130 / 0.4 - 9.1 6%
molecular substitution C2/C6 concentrationweight ratio ratio
"In vivo" molecular weight determines:intravascular persistencetissue storage
Volemic expansionSide effects
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Hydroxyethyl Starches: characteristics
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Effects of Colloids on Hemostasis
Non specific effects Dilution of plasmatic and cellular coagulation factors
Hemodilution < volume expansionBlood loss
AnemiaMechanical effectBiological effects
Specific effects Platelet function Coagulation factors Quality of clot formation Fibrinolysis
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Effects of Colloids on Hemostasis
In vitro : blood from healthy volunteers mixed with the studiedfluid submitted to biological tests
Ex vivo : blood from patients having received the studied fluidsubmitted to biological tests coagulation
In vivo assessment of the clinical consequences of theadministration of the studied fluid
Clinical Interpretation
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Effects of Colloids on Hemostasis
Interpretation of coagulation tests
Classical laboratory tests
Viscoelastic tests: TEG , ROTEM , Sonoclot
Clinical conditions
Healthy volunteers Vs. Patients
Hemodilution Vs. volume loading
Medical Vs. surgical context
Surgical bleeding risk
Trauma Vs. surgical bleeding
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Effects of Gelatins on Hemostasis
Inhibition of primary hemostasis
ristocetin-induced platelet aggregationDe Jonge et al. Thromb Haemost 1998; 79:286-90.
ADP- PAF- epinephrine-induced platelet aggregation
with urea-linked gelatins (high calcium concentration)Evans PA et al. Br J Anaesth 1998; 81:198-202.
Reduced quality clot formationMardel SN et al. Br J Anaesth 1998; 80: 204-7.
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Effects of Gelatins on Hemostasis
Dose-dependent reduction in clot strength for increasingdilution of fresh whole blood with either modified fluid gelatinor urea-linked gelatin
66% dilution with NaCl 0.9%Mardel SN et al. Br J Anaesth 1998; 80:204-7.
66% dilution with urea-linked gelatins
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Effects of Hydroxyethyl Starches on Hemostasis
Kozek-Langenecker SA. Anesthesiology 2005; 103:654-60
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Effects of Hydroxyethyl Starches on Hemostasis
Inhibition of primary hemostasis Von Willebrands disease type 1
Treib J et al. Thromb Haemost 1997;78:974-83.
Decreased platelet aggregation
Franz A et al. Anesth Analg 2001;92:1402-7.
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Effects of Hydroxyethyl Starches on Hemostasis
Decreased platelet aggregationDecreased GPIIb-IIIa expression
coating effect ? Conformational change ?
Unaltered GPIb expression Platelet adhesion not affected
Unaltered P-selectin expression Intracellular mechanisms not affected
Decreased platelet volume (oncotic effect ? EDTA artifact ?)
From Franz A et al. Anesth Analg 2001;92:1402-1407.
Influence of invivo Mw
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Effects of Hydroxyethyl Starches on Hemostasis
From Franz A et al. Anesth Analg 2001;92:1402-1407.
-40
-20
0
20
40Expression of activated GP IIb IIIa (% change)
Saline HES 70/.5 HES 130/.4 HES 200/.6
TRAP ADP
**
* *
* p< 0.05 vs pre-infusion values
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Effects of Hydroxyethyl Starches on Hemostasis
Inhibition of primary hemostasis Von Willebrands disease type 1
Treib J et al. Thromb Haemost 1997;78:974-83.
Decreased platelet aggregation
Franz A et al. Anesth Analg 2001;92:1402-7.
Alteration in fibrin formation and polymerization
Hemodilution with HES may accelerate the onset of clotting Impaired polymerization of fibrin monomers in presence of HES
De Lorenzo C et al. Anesth Analg 2006;102:1194-200.
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Effects of Hydroxyethyl Starches on Hemostasis
From De Lorenzo C et al. Anesth Analg 2006;102:1194-200.
Whole blood clot
Electron microscopy after ROTEM measurement (1:1400)
60% dilution + fibrinogen
NaCl 0.9%
HES 130/0.4
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Effects of Hydroxyethyl Starches on Hemostasis
Inhibition of primary hemostasis Von Willebrands disease type 1
Treib J et al. Thromb Haemost 1997;78:974-83.
Decreased platelet aggregation
Franz A et al. Anesth Analg 2001;92:1402-7.
Impairment of fibrin polymerizationDe Lorenzo C et al. Anesth Analg 2006;102:1194-200.
Increased fibrinolysis: controversial results (in vivo and in vitro studies)Strauss RG et al. Transfusion 2002;42:27-36.Mittermayer M et al. Br J Anaesth 1998;100: 307-14.
Effects related to"in vivo"Mw
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In vi tro Effects of HES and Gelatins on Coagulation
Whole blood from 10 healthy male volunteers diluted by 33 and 66% witheither Ringers lactate, gelatin, balanced & unbalanced HES 130/0.4
Coagulation analyzed with SONOCLOT and ROTEM
From Casutt M et al. Br J Anaesth 2010;105:273-81.
33% Testsaltered
Fisher-Freeman-
Halton test
RL 3/16 0.01
GEL 11/16 NS
HES unbal 10/16 NS
HES bal 11/16 NS
66% Testsaltered
Fisher-Freeman-
Halton test
RL 12/16 NS
GEL 13/16 NS
HES unbal 14/16 NS
HES bal 15/16 NS
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Effects of Hydroxyethyl Starches on Hemostasis
HES130/0.4
Gelatin
Van der Linden 2005 Cardiac surgery 64 68
Yap 2007 Cardiac surgery 20 20
Volta 2007 Cancer surgery 12 12
Mittermayer 2008 Orthopedic surgery 19 21
Godet 2008 Abdominal vascularsurgery
32 33
Ooi 2009 Cardiac surgery 45 45
Jin 2010 Cancer surgery 12 12
Schramko 2010 Cardiac surgery 15 15
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HES 130/0.4 Vs. Gelatins: Effects on Blood Loss
Blood loss (mL)
V a n d
e r L i n
d e n 2
0 0 5
Y a p 2
0 0 7
G o d e
t 2 0 0
8
O o i 2
0 0 9
J i n 2 0
1 00
500
1000
1500
2000
2500HES 130/0.4
GELATIN
Blood loss (mL)
V a n d
e r L i n
d e n 2
0 0 5
Y a p 2
0 0 7
G o d e
t 2 0 0
8
O o i 2
0 0 9
J i n 2 0
1 00
500
1000
1500
2000
2500HES 130/0.4
GELATIN
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HES 130/0.4 Vs. Gelatins: Effects on RBC Transfusion
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HES Solutions & Bleeding in Cardiovascular Surgery
Quantitative and qualitative analysis of all pertinent randomizedcontrolled trials (up to December 2010)
52 randomized trials; 3234 patients (23 trials with HES130/0.4)
From Shi XY et al. Eur J Clin Pharmacol 2011;67:767-82.
Blood loss N Std mean diff (95% CI)
HES 130/0.4 vsalbumin
7 -0.54 (-0.99, -0.09)
HES 130/0.4 vsgelatin
10 -0.02 (-0.16, 0.12)
HES 130/0.4 vscrystalloids
3 -0.19 (-0.45, 0.08)
Transfusion N RR(95% CI)
p
HES 130/0.4 vsalbumin
4 0.77 (0.62, 0.94) 0.01
HES 130/0.4 vsgelatin
4 1.03 (0.86, 1.24) 0.74
HES 130/0.4 vscrystalloids
1 0.67 (0.13, 3.44) 0.63
Boldt studies not retrieved !
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6% HES 130/ 0.4 Vs. 4 % Gelatin in Cardiac Surgery
Prospective randomized single-blind studyElective surgery crystalloid-based pump prime; no TXA
Fluid administration immediately after ICU admission: 6% HES 130/ 0.4 (N=15) 4% Modified fluid gelatin (N=15) Ringers acetate (N=15)
Monitoring of coagulation:Modified thromboelastometry (ROTEM)
Hemodynamics & blood transfusion guided by strict protocols
From Schramko A et al. Br J Anaesth 2010;104:691-7.
3 bolus of 7 mL/kg + 7mL/kg over 12h
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6% HES 130/ 0.4 Vs. 4 % Gelatin in Cardiac Surgery
From Schramko A et al. Br J Anaesth 2010;104:691-7.
Monitoring of coagulation: modified TEM (ROTEM) Clot formation time and clot strength after infusion of 7, 14 and 21 mL/kg of either colloid compared with Ringers acetate clot strength after 14 and 21 mL/kg of Ringers acetate Clot strength lower in the gelatin than in the Ringers acetate group on POD1
Allogeneic bloodtransfusion: NS
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Effects of Hydroxyethyl Starches on Hemostasis
1st objective: effects on total blood loss with two synthetic colloids:
3% modified fluid gelatin (N=64) or 6% HES 130/0.4 (N=68)
in patients undergoing coronary artery surgery (up to 20 h postop)
Max daily dose: 50 ml/kg
Prospective randomized single-blind study
Assuming the 2 fluid regimens are similar with regard to the calculated blood loss, a difference< 195 mL (Hct 100%) was considered as clinically equivalent. Based on an estimated net RBCloss of 529 277 mL on POD5, a total of at least 60 patients per group appeared appropriateto have a power of 0.9 and =0.05
From Van der Linden P et al. Anesth Analg 2005;101: 629-34.
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Effects of Hydroxyethyl Starches on Hemostasis
From Van der Linden P et al. Anesth Analg 2005;101: 629-34.
Studied colloid (mL/kg)
P e r - o
p
P o s t -
o p ( 2 0 h
) T o
t a l0
20
40
60
80Gelatin
HES 130/0.4
Studied colloid (mL/kg)
P e r - o
p
P o s t -
o p ( 2 0 h
) T o
t a l0
20
40
60
80Gelatin
HES 130/0.4
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Effects of Hydroxyethyl Starches on Hemostasis
From Van der Linden P et al. Anesth Analg 2005;101: 629-34.
(POD5)
Gel group: 21/64 were transfused (0 [0-6] units)HES 130/0.4: 24/68 were transfused (0 [0-6] units)
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HES 130/0.4, Gelatins and Hemostasis: Conclusions
The effects of HES 130/0.4 on hemostasis have been moreintensively studied than those of Gelatins
The in vitro and ex vivo effects of both colloids oncoagulation appear quite similar
HES 130/0.4 does not appear to be associated with a higher bleeding risk than Gelatins
True effects of fluids on hemostasis will depend on clinicalcircumstances. Recommended doses need to be respected