3- P. Van Der Linden - Hydroxyethyl Starches vs Gelatins

7/28/2019 3- P. Van Der Linden - Hydroxyethyl Starches vs Gelatins

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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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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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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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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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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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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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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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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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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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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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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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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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(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

3- P. Van Der Linden - Hydroxyethyl Starches vs Gelatins

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