Pediatric Anesthesia ISSN 1155-5645

ORIGINAL PAPER

Isovolaemic hemodilution with gelatin and

hydroxyethylstarch 130/0.42: effects on hemostasis
in piglets
Lars Witt1, Wilhelm Alexander Osthaus1, Wiebke Jahn1, Niels Rahe-Meyer2, Alexander Hanke1,
Florian Schmidt3, Martin Boehne3 & Robert Sumpelmann1
1 Clinic of Anaesthesiology, Hannover Medical School, Hannover, Germany
2 Department of Anaesthesiology, St. Franziskus Hospital Bielefeld, Bielefeld, Germany
3 Department for Paediatric Cardiology and Intensive Care, Hannover Medical School, Hannover, Germany

Keywords
gelatin; hydroxyethyl starch; i.v. infusions;
multiple electrode impedance
aggregometry; thrombelastometry
Correspondence
Lars Witt, Clinic of Anaesthesiology,
Hannover Medical School,
Carl-Neuberg-Str.1, 30625 Hanover,
Germany
Email: witt.lars-henrik@mh-hannover.de
Section Editor: Andrew Davidson
L. W. and W. A. O. contributed equally to
the study.
Accepted 20 December 2011
doi:10.1111/j.1460-9592.2012.03798.x

Summary
Objectives: Articial colloids, frequently used to prevent hemorrhagic shock
in children, impair blood coagulation. To determine the impact of acute
isovolaemic hemodilution with articial colloids on clot formation, we conducted an experimental study in a pediatric animal model.
Methods: Fifteen piglets underwent hemorrhage by withdrawing 40 mlkg)1
of blood volume in steps of 10 mlkg)1 each within 1 hour. After each
withdrawal, the blood loss was randomly compensated by administering
4% gelatin (GEL) or hydroxylethyl starch 130/0.42 (HES) in a ratio of
1 : 1, or isotonic crystalloid solution (ICS) in a ratio of 1 : 4 for isovolaemic hemodilution. Quality of clot formation and platelet function was measured using Thrombelastometry (ROTEM) and Multiple electrode
impedance aggregometry (Multiplate) after 10, 20, and 40 mlkg)1 blood
replacement.
Results: Moderate hemodilution (1020 mlkg)1 blood replacement) caused
no signicant differences among groups (e.g. INTEM-MCF after
20 mlkg)1 blood replacement (ICS vs GEL vs HES, P > 0.05). Profound
hemodilution with 40 mlkg)1 blood replacement showed a signicant difference between ICS and both colloids (P < 0.05), but no signicant differences between GEL and HES.
Conclusions: Impairment of clot formation by moderate isovolaemic hemodilution did not signicantly differ between ICS, GEL, and HES. Profound hemodilution of more than 50% of the estimated blood volume with
GEL and HES caused signicant impairment of clot formation in comparison to ICS and has to be considered when using high amounts of these
synthetic colloids.

Introduction
Prevention of acute or delayed hemorrhagic shock with
articial colloids to maintain blood volume and tissue
perfusion is a standard procedure during major pediatric surgery. However, all articial colloids provoke
dilutional coagulopathy and interact specically with
the coagulation system (1,2). Hydroxyethylstarch
2012 Blackwell Publishing Ltd
Pediatric Anesthesia 22 (2012) 379385

(HES) solutions and gelatin preparations, frequently

used in pediatric anesthesia (3), have negative impact
on blood coagulation in vivo and in vitro, although
third-generation 6% HES 130/0.4 with a lower molecular weight and a lower molar substitution seems to
have a signicantly reduced effect on hemostasis (48).
Until now, only a few studies have investigated
the effect of moderate doses (1020 mlkg)1) of
379

Hemodilution effects of colloids on hemostasis

third-generation 6% HES 130/0.4 and gelatin on hemostasis in children (9,10). The effect of high doses
(e.g. 40 mlkg)1) of articial colloids on hemostasis in
children (including platelet aggregation) have never
been studied. Therefore we conducted a prospective,
randomized experimental animal study with a focus on
thrombelastometry (ROTEM) and multiple electrode
impedance aggregometry (Multiplate) in piglets to
determine the inuence of acute isovolaemic hemodilution with moderate and high doses (40 mlkg)1) of articial colloids on hemostasis in an established pediatric
animal-model (11). We hypothesized that both, 6%
HES 130/0.42 and 4% gelatin inuence ROTEM and
Multiplate parameters in the same manner and to the
same extent.
Methods
After approval of the study by the local animal experimentation committee (Protocol No. 42502-04-09/1794),
fteen 4-week-old female German landrace piglets were
included in the study. The used pediatric animal model
is well established in our study group and the anesthetic
and perioperative management has been described previously (12). Heart rate, body temperature, and endtidal carbon dioxide were continuously measured using a
patient monitoring system (Cardiocap 5; Datex-Ohmeda, Freiburg, Germany). Using standard cut down
techniques, 5 F percutaneous sheath introducer sets
(Arrow, Reading, PA, USA) were inserted in the right
jugular vein and the right common carotid artery.
Through the venous introducer set, a 4 F two-lumen
central venous catheter (Arrow) was placed in the superior vena cava for central venous pressure (CVP)
recording. Through the arterial introducer set a 4F
thermodilution catheter (Pulsiocath, 4 F PV 2024L;
Pulsion, Munich, Germany) was inserted to determine
continuously mean arterial pressure (MAP) and cardiac
output (CO) with a standard hemodynamic monitor
system (PiCCO plus; Pulsion). Cardiac index (CI)
adapted to the piglets body surface was calculated by
using the formula of Mack (K equals the piglets body
surface area constant):
CI

K

CO
l  min1 m2 
p
3
bodyweight2

(13). After insertion of the cervical catheters and suturing the neck the rst blood samples for blood gas analysis using a standard blood gas oximetry system (ABL
735; Radiometer, Copenhagen, Denmark) were collected into heparinised syringes. In each sample,
pH, paO2, paCO2, base excess, bicarbonate, sodium,
380

L. Witt et al.

chloride, potassium, lactate, hemoglobin, and hematocrit were measured. A further blood sample was drawn
in a citrated tube (S-Monovette; Sarstedt, Numbrecht,
Germany) for thrombelastometry coagulation analysis
(ROTEM; Pentapharm, Munich, Germany). In addition, blood was drawn into tubes containing recombinant hirudin for multiple electrode impedance
aggregometry analysis (Multiplate; Dynabyte Medical, Munich, Germany). All blood samples were drawn
from the right carotid artery without stasis, whereby
the rst 5 ml of blood were discarded. The animals
subsequently underwent hemorrhage by withdrawing
40 mlkg)1 of the estimated total blood volume
(70 mlkg)1) within 1 hour (in steps of 10 mlkg)1
each). After each blood withdrawal, the blood loss was
compensated by administering either 4% gelatin (GEL,
Gelafundin 4%; Braun, Melsungen, Germany) in a
ratio of 1 : 1 or hydroxylethyl starch 130/0.42 (HES,
Tetraspan 6%; Braun) in a ratio of 1 : 1 or as a control group isotonic crystalloid solution (ICS, Sterofundin ISO; Braun) in a ratio of 1 : 4. A computergenerated randomization list was used for the allocation to the treatment groups. Further blood samples
for blood gas-, ROTEM- and Multiplate -analysis
were collected after 10 mlkg)1, 20 mlkg)1, 40 mlkg)1
blood replacement, respectively. When the infusion
was stopped, the last blood sample was collected and
the piglets were euthanized by intravenous injection of
pentobarbital.
Measurements
Thrombelastometry
ROTEM was used for assessing changes in coagulation. It was carried out according to the manufacturers guidelines in samples of citrated blood at
37C. The following tests were performed: INTEM
(Pentapharm) to measure clot formation triggered by
phospholipids and EXTEM (Pentapharm) to measure
clot formation triggered by the activation of the extrinsic, tissue factor dependent pathway, and FIBTEM
(Pentapharm), which is based on EXTEM, but
contains cytochalasin D to inhibit the contribution
of platelets to measure the contribution of brin/
brinogen to the clot rmness.
By digital data processing, the following typical variables are obtained: clotting time (CT), which is the
time from start of measurement until the onset of clotting; clot formation time (CFT), which is the time
between onset of clotting and the moment when clot
rmness reaches an amplitude of 20 mm; and maximum clot rmness (MCF), which corresponds to the
maximum amplitude of the curve.
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Pediatric Anesthesia 22 (2012) 379385

Data is expressed as medians (range), P1 value at baseline, GEL vs HES vs ICS, P2 value at 10 mlkg)1 blood replacement GEL vs HES vs ICS, P3 value at 20 mlkg-1 blood replacement
GEL vs HES vs ICS, P4 value at 40 mlkg)1 blood replacement GEL vs HES vs ICS. *P < 0.05, baseline vs 40 mlkg)1 blood replacement.

ns 3.8 (0.8)* 3.5 (0.6)* 4.1 (2.2)* ns

ns 12.2 (2.3)* 11.5 (1.9)* 13.2 (6.6)* ns
ns 304 (214) 106 (135) 278 (166)
ns
ns 60 (10)*
60 (40)*
70 (80)*
ns
ns 66 (27)
68 (14)
58 (13)* 0.03
ns 4.4 (0.8)* 4.9 (1.5)* 4.4 (1.1)* ns
ns 214 (84)
196 (79)
162 (86)
ns
ns
9 (2)
9 (6)
8 (2)*
ns
ns 5.3 (1.4) 5.0 (1.0) 5.4 (1.4)
ns 16.8 (4.2) 16.0 (2.8) 17.0 (4.3)
ns 305 (337) 225 (169) 270 (85)
ns 70 (10)
80 (50)
80 (40)
ns 70 (14)
67 (36)
63 (13)
ns 3.9 (1.2) 3.9 (2.2) 4.2 (1.1)
ns 208 (94) 194 (95) 175 (120)
ns
8 (2)
8 (6)
7 (3)
7.8
24.3
377
120
75
3.9
175
6
7.8
24.4
298
130
75
3.8
198
6
8.9
27.7
498
101
69
3.0
144
8
Hemoglobin (gdl)1)
Hematocrit (%)
Platelets (109 l)1)
Fibrinogen (mgdl)1)
Mean arterial pressure (mmHg)
Cardiac index (mlmin)1 m)2)
Global end-diastolic volume (ml)
Central venous pressure (mmHg)

(2.1)
(6.4)
(610)
(10)
(21)
(1.7)
(66)
(5)

HES

(2.3)
(6.9)
(216)
(90)
(20)
(1.6)
(77)
(3)

ICS

(1.3)
(4.1)
(92)
(20)
(14)
(1.2)
(87)
(2)

ns 6.7 (1.2) 6.2 (1.6) 6.4 (1.5)

ns 20.9 (3.6) 19.3 (4.9) 20.2 (4.4)
ns 385 (536) 225 (241) 302 (62)
ns 90 (10)
95 (60)
90 (20)
ns 67 (20) 81.0 (16)
67 (18)
ns 3.4 (1.7) 3.9 (1.5) 4.2 (0.9)
ns 181 (84) 185 (118) 170 (100)
ns
9 (5)
9 (6)
7 (4)

P4
ICS
HES
P3 GEL
P1 GEL

HES

ICS

P2 GEL

HES

ICS

40 mlkg)1
20 mlkg)1

GEL

All fteen piglets used in the study received their

intended treatment and were analysed as reported. The
three groups were comparable for weight [GEL- group
12.8 (range 5.4) kg, HES-group 13.2 (5.4) kg, ICSgroup 12.8 (5.6) kg] and length [GEL-group 74 (range
12) cm, HES-group 74 (9] cm, ICS-group 77 (11) cm.
At baseline, no signicant differences with regard to
hemodynamics, acid-base-balance and hemostasis were
observed among groups (Tables 1 and 2, Figures 13).
The intrinsic thrombelastometry (INTEM; Pentapharm) showed a signicant increase in CFT in the
HES-group, whereas gelatin caused a signicant extension of CFT not until 40 mlkg)1 blood replacement
(Figure 1). The ICS-group revealed a small, but signicant increase of CFT after 20 and 40 mlkg)1 blood
replacement (Figure 1). The INTEM clotting time

Variable

Results

10 mlkg)1

The power calculation was carried out using the nQuery Advisor software 6.0 (Statistical solutions, Cork, Ireland) with a power of 90% and a signicance level (a)
of 0.05. This showed that a sample size of ve piglets
per group would allow detection of a difference of 10%
in the ROTEM- and Multiplate values. For demographic data and measured values before, during and
after hemodilution, nonparametric statistical tests were
performed. The KruskalWallis test (H test) was used
to determine differences between the groups at baseline
and 10 mlkg)1, 20 mlkg)1 respectively 40 mlkg)1
blood replacement. Wilcoxons test and the Mann
Whitney U test were used as appropriate to compare
within-group and between-group differences. The level
of statistical signicance was set at P < 0.05. Values
are expressed as medians and ranges. Recorded data
were analysed using the SPSS 16.0 software for Windows
(SPSS Software, Munich, Germany).

Baseline

Statistical analyses

Blood replacement

Multiple electrode impedance aggregometry

Multiplate technology is based on impedance aggregometry, assessing platelet aggregation in whole blood
after activation with adenosine diphosphate (ADP),
collagen (COL) or thrombin receptor-activating protein (TRAP) in the presence of the direct thrombin
inhibitor hirudin (14,15). Three hundred micolitres of
saline and 300 ll of blood were pipetted into single use
test cells. After incubation the impedance change
caused by the adhesion of the platelets onto the sensor
surfaces was plotted against time. The area under the
aggregation curve was used to measure the aggregation
response, quantied in arbitrary aggregation units (U).

Hemodilution effects of colloids on hemostasis

Table 1 Comparison of hemoglobin, hematocrit and hemodynamic parameters at baseline and different proportions of blood replacement, gelatin (GEL) ratio of 1 : 1, hydroxylethyl starch
6% (HES) ratio of 1 : 1, isotonic electrolyte solution (ICS) ratio of 1 : 4

L. Witt et al.

381

382

137
3.5
1.4
101
4.7
7.5
6.3
29.4
1.4
Sodium (mM)
Potassium (mM)
Calcium (mM)
Chloride (mM)
Glucose (mM)
pH
Base excess (mM)
Bicarbonate (mM)
Lactate (mM)

Data is expressed as medians (range), P1 value at baseline, GEL vs HES vs ICS, P2 value at 10 mlkg)1 blood replacement GEL vs HES vs ICS, P3 value at 20 mlkg)1 blood replacement
GEL vs HES vs ICS, P4 value at 40 mlkg)1 blood replacement GEL vs HES vs ICS. *P < 0.05, baseline vs 40 mlkg-1 blood replacement.

0.04
ns
ns
0.01
ns
ns
ns
0.04
ns
138
3.6
1.4
103
4.1
7.5
5.3
28.7
1.6
136
4.2
1.4
98
5.0
7.5
6.9
30.7
1.6
137
3.7
1.4
100
4.4
7.5
5.8
29.7
1.3
ns
ns
ns
ns
ns
ns
ns
ns
ns
137
3.5
1.3
102
4.4
7.5
5.0
28.4
2.5
137
4.1
1.4
98
3.9
7.5
7.2
30.9
1.3
137
3.7
1.4
101
3.8
7.5
6.2
30.0
1.1
0.03
ns
ns
ns
ns
ns
ns
ns
ns
138
3.5
1.3
99
5.0
7.4
4.9
29.0
3.0
136
3.6
1.5
98
3.7
7.5
5.9
30.2
1.3

GEL
Variable

(4)
(0.8)
(0.2)
(8)
(2.3)
(0.2)
(6.9)
(6.0)
(1.8)

HES

(2)
(0.6)
(0.2)
(4)
(1.5)
(0.2)
(4.3)
(4.0)
(1.5)

ICS

(3)
(1.0)
(0.2)
(3)
(4.1)
(0.1)
(7.0)
(7.6)
(1.9)

P1

GEL

(2)
(0.5)
(0.3)
(3)
(2.9)
(0.1)
(4.7)
(4.2)
(1.6)

(4)
(0.7)
(0.3)
(4)
(1.4)
(0.1)
(4.7)
(5.9)
(1.4)

ICS
HES

(2)
(0.4)
(0.2)
(3)
(2.9)
(0.1)
(3.8)
(3.8)
(1.5)

P2

GEL

(3)
(0.5)
(0.2)
(3)
(3.3)
(0.1)
(4.1)
(4.2)
(1.5)

HES

(4)
(0.9)
(0.2)
(6)
(1.9)
(0.0)
(5.6)
(5.6)
(1.4)

ICS

(2)
(0.7)
(0.3)
(2)
(3.4)
(0.1)
(3.9)
(3.5)
(1.5)

0.04
ns
ns
0.03
ns
ns
ns
ns
ns

138
3.8
1.4
101
5.0
7.5
5.0
28.9
1.7

(1)
(0.5)
(0.2)
(3)
(3.4)
(0.1)
(4.3)
(4.3)
(1.6)

135 (3)
3.9 (1.0)
1.4 (0.2)
99 (5)
5.5 (1.4)*
7.5 (0.1)
6.1 (5.4)
29.8 (4.7)
2.0 (1.0)*

138
3.7
1.4
105
4.7
7.5
3.9
27.9
2.6

(2)
(0.6)
(0.2)
(3)*
(3.5)
(0.1)
(4.6)
(3.5)
(1.4)

P4
ICS
HES
GEL
P3

40 mlkg)1
20 mlkg)1
10 mlkg)1
Baseline
Blood replacement

Table 2 Comparison of electrolyte, acid-base parameters and glucose at baseline and different proportions of blood replacement, gelatin (GEL) ratio of 1 : 1, hydroxylethyl starch 6%
(HES) ratio of 1 : 1, isotonic electrolyte solution (ICS) ratio of 1 : 4

Hemodilution effects of colloids on hemostasis

L. Witt et al.

showed no signicant alterations, whereas MCF

decreased signicantly in all groups (Figure 1).
EXTEM revealed a prolonged clotting time in the
HES-group at study end and as well a continuous
decrease of MCF in all groups (Figure 2). The HES
application caused additionally a prolonged CFT from
10 mlkg)1 blood replacement upward, whereas ICS
showed a signicant increase at 40 mlkg)1 blood
replacement (Figure 2). The effect of isovolaemic hemodilution on FIBTEM was a signicant prolonged
clotting time in the GEL- and the HES-group at study
end, respectively, after 20 and 40 mlkg)1 blood
replacement (HES-group), whereas CFT showed no
major alterations. The MCF decreased again both,
after HES and GEL application and at 40 mlkg)1
blood replacement even in the control group. Induction of platelet aggregation by TRAP and ADP
showed no signicant changes during blood replacement, whereas the COL-induced aggregometry revealed
a signicant reduction by all solutions at 40 mlkg)1
blood replacement (Figure 3).
At the end of the study hemoglobin, hematocrit,
and brinogen decreased signicantly in all groups,
whereas platelets and acid-base parameters did not
change signicantly. Even hemodynamics remained
stable or even increased (cardiac index) during the
course of the study, with the exception of a small, but
signicant decrease of the MAP in the ICS-group after
40 mlkg)1 blood replacement.
Discussion
Appropriate uid replacement is essential for patients
safety during pediatric anesthesia. Although synthetic
colloids are commonly used during major pediatric
surgery, the effects of high doses of these solutions on
blood coagulation and platelet aggregation in infants
and children have never been studied.
The objective of this experimental animal study was
therefore to determine the impact of isovolaemic
hemodilution on hemostasis by articial colloids, commonly used in pediatric anesthesia. In accordance to
our hypothesis, key ndings were a comparable, dose
dependent impairment of clot formation with 4% gelatin and 6% HES 130/0.42 in comparison to the control
group. The experimental study design was chosen to
illustrate profound blood replacement under standardized conditions in an approved pediatric animal model
(11), which is also applicable for hemostatic analyses
(5,11) and provides comparable blood volumes with
infants (16). Furthermore, similarities in the human
and porcine coagulation system favor the use of
porcine models when researching blood coagulation.
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Hemodilution effects of colloids on hemostasis

Velik-Salchner et al. (17) demonstrated the applicability of ROTEM analysis for porcine blood, even
though they found a potentially methodical bias for
the FIBTEM MCF value, which should therefore be
interpreted with caution (17). Despite the fact that
Multiplate has not been validated for porcine blood,
the suitability of the domestic swine as a model for
impedance aggregometry was demonstrated previously
(18).
Although circulating blood volume was not directly
measured, changes in preload parameters like global
end-diastolic volume and CVP as well as hemodynamic
changes were comparable between groups (with the

exception of MAP, Table 1) and made a comparable

hemodilution in this study setting likely. The signicant lower MAP in the ICS-group after 40 mlkg)1
blood replacement may point to an insufcient hemodynamic effect of isovolaemic ICS infusion in comparison to colloids.
Hypovolaemia is the most common cause of circulatory failure in children and can lead to critical tissue
perfusion. Unlike crystalloids, colloids may be used to
rapidly treat or prevent hypovolaemia with the advantage of markedly reducing the total volume of the
administered infusion and simultaneously the need of
blood transfusion (2). For several years, the impact of

Figure 1 Intrinsic thrombelastometry (INTEM) analysis: coagulation time (CT); clot formation time (CFT); maximal clot firmness
(MCF) at baseline and different proportions of blood replacement,
gelatin (GEL) ratio of 1 : 1, hydroxylethyl starch 6% (HES) ratio of
1:1, isotonic electrolyte solution (ICS) ratio of 1 : 4. Data are

expressed as medians, 25% and 75% percentile, whiskers are highest and lowest values that are not outliers, circles are extreme values (more than three times the interquartile range), *P < 0.05,
baseline vs 10 mlkg)1, 20 mlkg)1, 40 mlkg)1 blood replacement,
respectively, #P < 0.05 GEL vs HES vs ICS.

Figure 2 Extrinsic thrombelastometry (EXTEM) analysis: CT, CFT

maximal clot firmness (MCF) at baseline and different proportions
of blood replacement, gelatin (GEL) ratio of 1 : 1, hydroxylethyl
starch 6% (HES) ratio of 1 : 1, ICS ratio of 1 : 4. Data are expressed
as medians, 25% and 75% percentile, whiskers are highest and

lowest values that are not outliers, circles are extreme values (more
than three times the interquartile range), *P < 0.05, baseline vs
10 mlkg)1, 20 mlkg)1, 40 mlkg)1 blood replacement, respectively,
#P < 0.05 GEL vs HES vs ICS.

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Pediatric Anesthesia 22 (2012) 379385

383

Hemodilution effects of colloids on hemostasis

L. Witt et al.

Figure 3 Multiple electrode impedance aggregometry (Multiplate)

analysis: Platelet aggregation after activation with adenosine diphosphate (ADP), collagen (COL) or thrombin receptor-activating protein
(TRAP) coagulation at baseline and different proportions of blood
replacement, gelatin (GEL) ratio of 1 : 1, hydroxylethyl starch 6%
(HES) ratio of 1 : 1, ICS ratio of 1 : 4. Data are expressed as medi-

ans, 25% and 75% percentile, whiskers are highest and lowest values that are not outliers, circles are extreme values (more than
three times the interquartile range), *P < 0.05, baseline vs
10 mlkg)1, 20 mlkg)1, 40 mlkg)1 blood replacement, respectively,
#P < 0.05 GEL vs HES vs ICS.

gelatin infusion on coagulation system appeared limited due to dilution of coagulation factors and platelets
until the reduction in clot quality with gelatin-based
colloids was demonstrated in vitro (19). Despite this,
the clinical relevance of the impairment of hemostasis
after gelatin infusion remains uncertain. Perioperative
infusion of moderate doses of gelatin in children does
not alter coagulation to an extent above the effect of
hemodilution (10) and thrombelastographic parameters
remain within the reference range (9). In our study,
isovolaemic hemodilution with gelatin did not signicantly differ from the control group at 10 and
20 mlkg)1 blood replacement. It was only the high
doses of 40 mlkg)1 blood replacement seems to impair
clot formation including platelet function beyond the
effect of hemodilution.
First generation hydroxyethyl starch (HES) preparations were manufactured with high average molecular
weight (MW 450650 kDa, hetastarch), but were soon
found to have signicant adverse effects regarding
coagulation. This was due not only to hemodilution
but also to inhibition of blood platelet function,
decrease of coagulation factors, such as von Willebrand factor, factor VIII, and brinogen (8). The second generation of HES with a molar substitution of
around 0.5 (MW 200 kDa, pentastarch) led to fewer
adverse effects. Finally the third generation HES preparations with molar substitution of around 0.4 (MW
130 kDa, tetrastarch) present even more favorable
physicochemical properties and are approved for use
in children with a maximal daily dose of 50 mlkg)1
(2). Pooled analysis of prospective and randomized

studies comparing second generation HES 200/0.5 with

the new third generation HES 130/0.4 reporting
decreased effects on coagulation by the latest HES
generation (20). A recent in vitro study on coagulation
effects of balanced, nonbalanced HES 130/0.42, and
gelatin revealed pronounced inhibitory effects of these
colloids compared with crystalloids on blood coagulation following 33% and 66% hemodilution, but no
signicant differences between the colloids (4). A study
of infants and toddlers compared the impact of
15 mlkg)1 HES 130/0.4, albumin or gelatin on hemostasis (9). For all tested colloids, thrombelastographic
parameters and routine coagulation tests were signicantly altered from baseline values. These changes
were very similar for albumin and gelatin, but signicantly more pronounced following HES (9). In contrast, a more recent clinical trial investigating
alterations in thrombelastographic parameters in
children receiving moderate doses of HES 130/0.42 or
gelatin, reported thrombelastographic parameters
within the reference range (10). In our study, moderate
isovolaemic hemodilution with the third generation
HES 130/0.42 impaired thrombelastographic parameters and platelet function, but only the blood replacement of 40 mlkg)1 caused signicant differences to the
control group. However, a recent clinical study in children undergoing cardiac surgery revealed a comparable
blood loss following 50 mlkg)1 of HES 130/0.4 or
albumin, which has minimal effects on hemostasis (21).
The study even reported a reduced requirement for
allogenic blood transfusion after HES 130/0.4 infusion
indicating, that marked changes in clot formation

384

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Pediatric Anesthesia 22 (2012) 379385

L. Witt et al.

Hemodilution effects of colloids on hemostasis

because of high amounts of HES 130/0.4 do not automatically imply a clinical impact on blood coagulation
and blood loss. In addition, a recent multicenter safety
study revealed no clinical serious adverse effects (e.g.
clotting disorders or anaphylactoid reactions) after
moderate doses of HES 130/0.42 in 316 children
during pediatric anesthesia (22).
In conclusion, the impairment of clot formation by
isovolaemic hemodilution up to 20 mlkg)1 blood
replacement did not signicantly differ between isotonic crystalloid solution and 4% gelatin, respectively,
HES 130/0.42 in this pediatric animal model. Therefore, a severe impact on clot formation with this infusion volume in a clinical setting seems to be negligible.
In addition, profound hemodilution of more than 50%
of the estimated blood volume with 4% gelatin and
HES 130/0.42 caused signicant impairment of clot

formation in comparison to isotonic electrolyte solution (ICS). This has to be considered when using high
amounts of these synthetic colloids, even though an
increased blood loss or transfusion need is not necessarily implied.
Acknowledgments
The authors thank B. Buchalik for providing excellent
laboratory assistance. This research was carried out
without funding.
Conflict of interest
No conicts of interest declared.

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