Some colloids are more equal than others:

Does our choice matter?

Sibylle A. Kozek-Langenecker

Evangelic Hospital Vienna

www.perioperativebleeding.org

sibylle.kozek@aon.at

Cochrane Analysis 2011:

… no evidence that one colloid solutionis more effective or safe than any other …

Cochrane Analysis 2011:

…hard to see how their continued use can be justified …

Why can‘t we see the difference?

• unjustified end point of mortality• only RCTs: methodological limitations• understimation of the risks of hypervolemia• overestimation of direct costs for colloids• inappropriate fluid monitoring & target values• inadequate risks-benefits balance

Colloidal fluid therapy UNI-MED Verlag AG Bremen – London – Boston 1. Auflage 2009. ISBN 978-3-8374-1184-3

2. editionin Englishin press

Volume efficacy: HES 130 > GelatinVan der Linden. Review. Can J Anaesth 2006;53:S30-9

Kroll et al,. 1983

Effect of 500 ml volume bolus

650 660700

640

40

320

580570

280

120

400400

0

100

200

300

400

500

600

700

800

End of Infusion 30 min 60 min 120 min

HES 200/0.5, 6% Gelatin 3.5% Ringers's Lactate

Hot topic: Colloids in critical illness

…effects of gelatin on kidney function unclear…… anaphylactic potential, limited volume effect compared with HES…

Cardiac & stroke volume

… tetrastarch superior to gelatin

Cardiac & stroke volume

… tetrastarch superior to albumin

Anzahl der Patienten mit Vasopressorbedarf

Time

*

0

2

4

6

8

10

12

1 3 6 9 11 15 20 25 30 35 40 45 50 55

Ringers

Gelatin

Voluven

*P<0.05

Palacio F. 2002Volume Preload (VP) before spinal anaesthesia for caesarean section

Tetrastarch was superior:

less vasopressor use

better HD stability

But we WANT to use arterial blood pressure!

Volume efficacyHES : Gelatin

1 : 0Choi. Crit Care Med 1999;27:200-10

Microcirculation & inflammation

… tetrastarch sustains pulmonary gas exchange…

Allison K. J Trauma 1999

Pulmonary functionHES superior to gelatin

MicrocirculationPulmonary function

6% Tetrastarch : Gelatin

1 : 0

HES ≠ HES

Schortgen. Lancet 2001; 357: 911-916

……… 6% hexastarch = independent risk factor

Brunkhorst. NEJM 2008; 358: 125-139

VISEP studyEfficacy of Volume Substitution and Insulin Therapy in Severe Sepsis

……… 10% pentastarch: accumulation + toxicity

Tetrastarch vs. Gelatin in der ICUSchabinski. Intensive Care Med 2009; 35: 1539-47

Kidney function ….

6% Tetrastarch : Gelatin ….

0 : 0Winkelmayer . Kidney Int 2003;64:1046-9 Davidson. Eur J Anaesthesiol 2006;23:721-38Wiedermann. Intensive Care Med 2004;30:519-20 Wiedermann. Wien Klin Wochenschr 2004;116:583-94 Suttner. Anasthesiol Intensivmed Notfallmed Schmerzther 2004;39:71-7

%

0

0.2

0.4

Gelatine Dextran Albumin HES

Laxenaire. Ann Fr Anaesth Réanim 1994

*

0.345%0.273%

0.099% 0.058%

* Heta- and Pentastarch

Anaphylactic reactions after colloids

Safety: anaphylaxisHES : Gelatin

1 : 0Barron. Arch Surg 2004;139:552-63

Coagulopathy & bleeding

Anesthesiology 2005;103:654. Transfus Altern Transfus Med 2007;9:173. Best Pract Res Clin Anaesth 2009; 23: 225

Differences in platelet-coating capacity

Deusch. Anesth Analg 2003;97:680

0

10

20

30

40

50

60

70

80

90

0% 1% 3% 5% 10% 20% 40%

hemodilution

FIT

C-p

os

itiv

e p

late

lets

(%

ga

ted

)

*

*

*

Franz. Anesth Analg 2001;92:1402

*p<0.05

-40

-30

-20

-10

0

10

20

30

40

Me

an

flu

ore

sc

en

ce

in

ten

sit

y o

fP

AC

-1 (

% c

ha

ng

e)

saline HES 70 HES 130 HES 200

* ** *HES 450

**

ADP TRAP

Differences between 2nd and 3rd HES generationPooled analysis: tetrastarch versus pentastarch

Kozek. Anesth Analg 2008; 107: 382

HES 130/0.4 versus

HES 200/0.5

p value

Estimated blood loss (mL) -404 [-689; -119] 0.006

Drainage loss (mL) -271 [-474; -70] 0.009

Calculated RBC loss (mL) -149 [-247; -50] 0.003

RBC transfusion volume (mL) -137 [-231; -43] 0.004

0

10

20

30

40

50

60

70

80

90

undil

uted

cont

rol

oxyp

olyge

latin

HES 130

norm

al sa

line

mod

ified

gelat

in

HES 200

HES 450

urea

-linke

d ge

latin

HES 550

PA

C-1

bin

din

g t

o p

late

lets

(%

gat

ed)

#

**

#

*

Thaler. Anaesthesia 2005;60:554-9

Differences in platelet-inhibiting capacity

132 adult patients undergoing cardiac surgery

Total Total ICU

study drug red blood cell loss length of stay(mg/kg) (ml) (h)

Gelatin 48.9 ± 14.6 504 ± 327 43Tetrastarch 48.9 ± 17.2 544 ± 305 24P N.S. N.S. N.S.

Head-to-head comparison: Gelatin versus Tetrastarch

Van der Linden. Anesth Analg 2005; 101: 629

Haas. Anesth Analg 2008;106:1078

30 pigs after 60% blood volume withdrawal

intervention:4 ml/kg hypertonic saline (7.2%) / HES (6% 200/0.62)50 ml/kg 4% gelatin41 ml/kg 6% tetrastarch

MCF blood lossHS-HES 11 mm (10,11) 725 ml (375, 900) tetrastarch 3.5 mm (2.3,4) 1600 ml (1500,1800) gelatin 4.5 mm (3,5.8) 1625 ml (1275,1950)

p = 0.0034 p =0.004

Small volume resuscitation

Meta-analysis: Gelatins versus HES

Cheng. TATM 2007; 9 (Suppl): 3

Review : ColloidsComparison: 87 Blood Loss, HES v GEL Outcome: 01 Blood Loss during Study Period, HES v GEL, mL

Study HES GEL WMD (f ixed) Weight WMD (f ixed)or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

01 0.4 and belowBoldt 01 HES 0.4 GEL 25 590.00(210.00) 25 790.00(210.00) 18.92 -200.00 [-316.42, -83.58] Boldt 03 HES0.4 GEL 20 980.00(230.00) 20 1050.00(250.00) 11.57 -70.00 [-218.88, 78.88] Haisch 01 HES0.4 GEL 21 740.00(250.00) 21 690.00(220.00) 12.64 50.00 [-92.43, 192.43] Haish Abd HES0.4 GEL 21 480.00(250.00) 21 580.00(290.00) 9.56 -100.00 [-263.76, 63.76]

Subtotal (95% CI) 87 87 52.69 -93.34 [-163.10, -23.58]Test for heterogeneity: Chi² = 7.22, df = 3 (P = 0.07), I² = 58.4%Test for overall effect: Z = 2.62 (P = 0.009)

02 Above 0.4Boldt 00 HES 0.5 GEL 100 1275.00(640.00) 50 1230.00(440.00) 8.38 45.00 [-129.95, 219.95] Boldt 01 HES0.5 GEL 25 680.00(230.00) 25 790.00(210.00) 17.20 -110.00 [-232.09, 12.09] Boldt 92 HES0.5 GEL 12 550.00(210.00) 12 560.00(220.00) 8.66 -10.00 [-182.08, 162.08] Innerh 02 HES0.5 GEL 20 656.00(269.00) 20 611.00(270.00) 9.19 45.00 [-122.04, 212.04] Karout 99 HES0.6 GEL 15 821.00(374.00) 15 1064.00(385.00) 3.48 -243.00 [-514.63, 28.63] MortelmansHES0.5 GEL 21 3437.00(1578.00) 21 2778.00(956.00) 0.41 659.00 [-130.10, 1448.10]

Subtotal (95% CI) 193 143 47.31 -37.23 [-110.84, 36.39]Test for heterogeneity: Chi² = 8.44, df = 5 (P = 0.13), I² = 40.7%Test for overall effect: Z = 0.99 (P = 0.32)

Total (95% CI) 280 230 100.00 -66.79 [-117.43, -16.15]Test for heterogeneity: Chi² = 16.83, df = 9 (P = 0.05), I² = 46.5%Test for overall effect: Z = 2.59 (P = 0.010)

-1000 -500 0 500 1000

Favours HES Favours GEL

Cunpublished data, 2011

Meta-Analysis: Tetrastarch and gelatine

Head-to-head comparison

… blood loss similar after tetrastarch and gelatin …

Bleeding risk ….

tetrastarch : gelatin ….

0 : 0

Conclusion

dilutional-hyperchloremic acidosis = transient & benign

Crit Care 2010;14:325

Hinkelmann J / Westphal M 2009 (unpublished data).

Effects of potato vs. waxy maize HES on the gut mucosal microcirculation in septic rats

n = 2 rats per group

Red

blo

od c

ell v

eloc

ity (µ

m/s

)

0

200

400

600

800

1000

1200

Sham Stero ISO

CLP Stero ISO

CLPTetraspan

CLP Volulyte

Waxy maize-derived HES and potato-derived HES are not bioequivalent,

since there is clear difference in AUC and plasma clearance.

Lehmann G, et al. Drugs RD 2007, 8: 229

Hot topic: Colloids in pediatric patients

… tetrastarch approved in children & best cost-effectiveness and safety profile….

Legal aspects

HES : GEL

1 : 1

Gelatin no longer approved in USADaily dose limit for HES in Europe

YES …..our choice (on drug, timing and dosing) matters

… 6% tetrastarch is more equal than gelatin:efficacy & safety

4:1

Some colloids are more equal than others:

Does our choice matter?

Honoraria for lectures and travel reimbursement:

B. BraunFresenius Kabi

Conflicts of interest

1st International ICU-Thromboprophylaxis

Day 2.12.2011 in Vienna

Risk factors & thromboprophylaxis - guidelines & current

practice

Anticoagulation despite bleeding risks

Anticoagulation during extracorporeal circulation

Monitoring issues

Future perspective

www.clotwork.at

www.perioperativebleeding.orgsibylle.kozek@aon.at

Thank you for your attention !

Exposure to colloids and clinical outcome:

Which comparison is correct?

1. Macrocirculation: volume efficacy of gelatin 4% > tetrastarch 6%

2. Allergic reactions: frequency after albumin > gelatins

3. Renal failure: old HES ≥ 6% is safer than newer tetrastarch 6%

4. Blood loss after tetrastarch is less than after pentastarch ☺