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ORIGINAL ARTICLE
Medizinische Hochschule Hannover, Klinik fur Anasthesiologie und Intensivmedizin, Hannover, Germany
Olga-Hospital, Klinik fur Anasthesie und operative Intensivmedizin, Stuttgart, Germany
Department of Anesthesiology and General Intensive Care, Danube Hospital Vienna, Vienna, Austria
Department of Anesthesia, Sophias Children Hospital, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands
Faculty Hospital Motol, Clinic of Anaesthesiology and Resuscitation, Prague, Czech Republic
Universitatsklinikum Carl Gustav Carus, Klinik und Poliklinik fur Anasthesiologie und Intensivtherapie, Dresden, Germany
Abteilung Anasthesie, Kinderintensiv-und Notfallmedizin, Kinderkrankenhaus auf der Bult, Hannover, Germany
Department of Anesthesiology, Academic Medisch Centrum (AMC), Amsterdam, the Netherlands
Keywords
hydroxyethyl starch; safety; adverse drug
reactions; neonates; infants; children
Correspondence
Robert Sumpelmann, MD, Professor,
Medizinische Hochschule Hannover,
Klinik fur Anasthesiologie-OE 8050,
Carl-Neuberg-Str. 1, D-30625 Hannover,
Germany
Email: suempelmann.robert@
mh-hannover.de
Section Editor: Andrew Davidson
Accepted 23 November 2011
doi:10.1111/j.1460-9592.2011.03776.x
Summary
Introduction: Third-generation hydroxyethyl starch (HES) is now approved also for
the use in children, but safety studies including large numbers of pediatric patients are
still missing. Therefore, we performed an European multicentric prospective observational postauthorization safety study (PASS) to evaluate the use of HES 130/0.42/6:1
in normal saline (ns-HES) or a balanced electrolyte solution (bal-HES) in children
undergoing surgery.
Methods: Children aged up to 12 years with ASA risk scores of IIII receiving nsHES (Venofundin 6%; Braun) or bal-HES (Tetraspan 6%; Braun) were followed
perioperatively. Demographic data, surgical procedures performed, anesthesia, hemodynamic and laboratory data, adverse events (AE), and adverse drug reactions
(ADR) were documented using a standardized case report form.
Results: Of 1130 children studied at 11 European pediatric centers from 2006 to 2009
(ns-HES, 629 children; bal-HES, 475 children; mean age, 3.6 3.8 [range, day of
birth12 years]; and body weight, 15.4 13 [0.990 kg]), 1104 were included for analysis. The mean infused HES volume was 10.6 5.8 (0.8350) mlkg)1. In the 399
(36.1%) cases with blood gas analysis before and after HES infusion, hemoglobin and
strong ion difference decreased signicantly in both groups, whereas bicarbonate and
base excess (BE before infusion: ns-HES )1.8 3.1, bal-HES )1.2 3.3 mM; after
infusion: ns-HES )2.5 2.8; bal-HES )1.1 3.2 mM, P < 0.05) decreased only
with ns-HES but remained stable with bal-HES. Chloride concentrations increased in
both groups and were signicantly higher with ns-HES (Cl before infusion: ns-HES
105.5 3.6, bal-HES 104.9 2.9 mM; Cl after infusion: ns-HES 107.6 3.4, balHES 106.3 2.9 mM, P < 0.05). For the AE/ADR rates, doseresponse but no age
relationships could be demonstrated. No serious and no severe ADR directly related
to HES (i.e. anaphylactoid reaction, clotting disorders, renal failure) were observed.
Conclusion: Moderate doses of HES 130/0.42/6:1 for perioperative plasma volume
replacement seem to be safe even in neonates and small infants. The probability of
serious ADR is lower than 0.3%. Changes in acidbase balance may be decreased
when HES is used in an acetate-containing balanced electrolyte solution instead of
normal saline. Caution should be exercised in patients with renal function disturbances and those with an increased bleeding risk.
371
Introduction
Hypovolemia is the most common cause of decreased
tissue perfusion during the perioperative period in children. Appropriate uid management is therefore essential for maintaining or restoring circulatory function in
children intra- and postoperatively. Solutions available
for intravenous uid management during major pediatric surgery may be either crystalloid or colloid.
Although the relative merits of the two methods of
uid management remain controversial, the use of colloid solutions seems to be more effective with regard
to stabilizing the intravascular blood volume and
avoiding interstitial uid overload (13). In the past,
human albumin (HA) was frequently used in pediatric
anesthesia (4), but recently, a number of hydroxyethyl
starch solutions (HES) have been shown to be as effective and safe and less costly as HA in several clinical
studies in children (review in Ref. (5)). Generally, HES
preparations are dened by mean molecular weight
(Mw), molar substitution (MS), and the C2/C6 ratio of
substitution. The rst generation of HES with Mw
>450 kDa was associated with negative side effects
with regard to coagulation, organ function, and accumulation. The second and the new third generation of
HES (Mw 200 and 130 kDa, respectively) have been
developed to improve safety while maintaining efcacy
(review in Ref. (6)). Third-generation HES 130/0.42/
6:1 (Mw/MS/C2:C6) is now approved also for children,
but the summary of product characteristics (SPC) recommends the use only after careful benet/risk assessment, and safety studies with large numbers of
pediatric patients are still missing (7). We, therefore,
performed an European multicentric prospective observational postauthorization safety study (PASS) to evaluate the perioperative use of HES 130/0.42/6:1 in
children, particularly focusing on possible serious
adverse drug reactions (ADR). This study started in
2006 using HES 130/0.42/6:1 dissolved in normal saline (ns-HES), and the preliminary results have been
published recently (8). The data showed that this HES
solution was safe and effective in a cohort of 316
patients including neonates and small infants. After
the marketing authorization of HES 130/0.42/6:1 in a
balanced electrolyte solution (bal-HES) with a more
physiological electrolyte pattern and acetate as bicarbonate precursor, this bal-HES was investigated in a
second study phase, and preliminary results comparing
a cohort with ns-HES or bal-HES, respectively (composition of both preparations see Table 1), were published thereafter (9). The data showed that infusionrelated iatrogenic acidbase and electrolyte alterations
could be minimized by using HES in a balanced
372
R. Sumpelmann et al.
Table 1 Composition of hydroxyethyl starch in normal saline (nsHES) or balanced solution (bal-HES)
Sodium (mM)
Potassium (mM)
Calcium (mM)
Magnesium (mM)
Acetate (mM)
Malate (mM)
Chloride (mM)
Osmolarity (mOsmoll)1)
ns-HES
bal-HES
154
154
308
140
4
2.5
1
24
5
118
296
R. Sumpelmann et al.
SD
[range])
58.4%/41.6%
3.6 3.8 (012)
15.4 13 (0.990)
89 33 (30179)
2.42 1.44 (0.3312.5)
R. Sumpelmann et al.
Table 3 Changes in acidbase, electrolyte, and hemoglobin concentrations during infusion of hydroxyethyl starch in normal saline (ns-HES)
or in a balanced electrolyte solution (bal-HES)
Before infusion
All
pH
Bicarbonate (mM)
Base excess (mM)
Sodium (mM)
Potassium (mM)
Chloride (mM)
Lactate (mM)
Anion gap (mM)
SID (mM)
Hemoglobin (gdl)1)
Hematocrit (%)
7.38
23.3
)1.6
137.5
4.1
105.3
1.6
12.5
34.3
11.3
33.7
After infusion
ns-HES
0.07
3
3.2
3.2
0.6
3.4
0.8
3.4
3.6
2.2
6.5
7.37
23
)1.8
137.5
4
105.5
1.5
12.7
34.4
11.3
33.6
bal-HES
0.07
2.8
3.1
3.3
0.6
3.6
0.8
3.7
3.7
2.1
6.4
7.38
23.7
)1.2
137.5
4.2
104.9
1.6
12
34
11.3
33.7
0.07
3.3
3.3
3.1
0.6
2.9
0.9
2.8
3.3
2.3
6.7
P-valuea
All
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
7.37
23.2
)1.9
137.2
4.1
107.2
1.6
10.1
31.5
10
29.5
ns-HES
0.07*
3*
3.1*
3.5*
0.6
3.3*
0.9*
3.3*
3.3*
2*
5.6*
7.36
22.5
)2.5
137.4
4
107.6
1.7
10.5
31.5
10
29.6
P-valueb
bal-HES
0.07
2.8*
2.8*
3.6
0.5
3.4*
0.8*
3.5*
3.4*
1.8*
5.3*
7.38
23.9
)1.1
137
4.2
106.3
1.6
9.4
31.6
9.92
29.5
0.07
3
3.2
3.4*
0.5
2.9*
0.9
2.9*
3.2*
2.2*
6*
n.s.
<0.001
<0.0001
n.s.
n.s.
<0.05
n.s.
<0.05
n.s.
n.s.
n.s.
R. Sumpelmann et al.
Figure 3 Hemoglobin and acidbase values before and after infusion of hydroxyethyl starch in normal saline (ns-HES) and balanced
electrolyte solution (bal-HES) (mean SD).
retain within the intravascular space, whereas crystalloids are distributed within the extracellular space
(which is the sum of the intravascular and interstitial
space), and as a consequence, higher volumes of crystalloid solution are needed for replacing plasma decits
as compared to colloids (3). Chappell et al. (2) stated
that when using crystalloids as a substitute of signicant acute blood losses, interstitial uid edema is the
obligatory consequence. As interstitial uid overload
may be related to postoperative complications, the
authors recommended to use crystalloids only to
replace losses because of urine production and insensible perspiration and to use colloids for the substitution
of acute blood loss or when the patients circulation is
in need of additional volume. Iatrogenic acute hypervolemia may damage the endothelial surface layer of
the capillaries; thus, carefully maintaining intravascular
volume without hypervolemic peaks was hypothesized
to be the most promising concept. Accordingly, we
found in a previous animal experimental study (3) with
almost total plasma replacement in piglets that body
2011 Blackwell Publishing Ltd
Pediatric Anesthesia 22 (2012) 371378
R. Sumpelmann et al.
ry effects and the tubular damage were more pronounced after HES 200/0.5 than after HES 130/0.42.
Liet et al. (27) found in 13 healthy neonates that
10 mlkg)1 HES 200/0.5 did not increase serum creatinine concentrations. In the study of Hanart et al.
(25), diuresis and both urea and creatinine concentrations after 50 mlkg)1 of HES 130/0.4 were comparable to the ndings after use of albumin in children
undergoing cardiac surgery. Jungheinrich et al. (28)
concluded in a study including 19 adult volunteers
with renal function disorders that 500 ml of HES 130/
0.4 can be safely administered even to adult patients
with severe renal impairment as long as urine ow is
preserved. Studies investigating HES infusion in children with impaired renal function are still missing.
Therefore, the results of this study suggest in accordance with previous studies (21,22,25) that HES 130
can be used safely even in small children with normal
renal function but is probably not the rst-choice colloid for children with signicantly impaired renal
function.
Several studies and case reports in adults showed a
correlation between administration of slow-degradable
HES products and pruritus (review in Ref. (29)). The
pathophysiological basis of the pruritus observed are
HES tissue deposits within perineural cells and endoneural connective tissue cells that were observed in
light and electron microscopy, and this effect was
judged as dose dependent and time related (30). In an
animal experimental study, the tissue storage was signicantly lower with rapidly degradable HES 130/0.4
than with slower-degradable HES 200/0.5 (31). In our
study, the follow-up was too short to detect HESrelated pruritus, but a Medline search produced no
published articles reporting on cases of HES-related
pruritus in children. Although there is currently no evidence available, the risk of skin itching and other consequences of tissue accumulation should be low when
using moderate doses of rapid-degradable HES products in children (10).
In the study presented here, moderate HES doses
(<20 mlkg)1) were used more frequently than high
HES doses (>20 mlkg)1). The possible HES-related
ADRs (i.e., coagulation disorders, renal function
impairment, and tissue storage) are dose dependent,
and the lack of serious ADR observed may, therefore,
be due to the low number of patients receiving high
HES volumes. Hanart et al. (25) used high HES doses
of up to 50 mlkg)1 in 60 children and did not observe
severe ADRs. Generally, moderate HES doses are sufcient in most pediatric patients undergoing major surgery procedures. High HES doses close to the
maximum daily dose of 50 mlkg)1 should be used with
2011 Blackwell Publishing Ltd
Pediatric Anesthesia 22 (2012) 371378
R. Sumpelmann et al.
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Pediatric Anesthesia 22 (2012) 371378
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