Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Anaesthesiology
journal homepage: www.elsevier.com/locate/bean
5
Relevance of non-albumin colloids in intensive care
medicine
Christian Ertmer, MD, Senior Research Fellow *, Sebastian Rehberg, MD,
Senior Research Fellow, Hugo Van Aken, MD, FRCA, FANZCA,
Head of the Department of Anaethesiology and Intensive Care,
Martin Westphal, MD, PhD, Consultant
Department of Anaesthesiology and Intensive Care, University of Muenster, Albert-Schweitzer-Street 33, 48149 Muenster, Germany
Keywords:
colloids
dextrans
fluid therapy
gelatin
hydroxyethyl starch
intensive care medicine
sepsis
Current guidelines on initial haemodynamic stabilization in shock
states suggest infusion of either natural or artificial colloids or
crystalloids. However, as the volume of distribution is much larger
for crystalloids than for colloids, resuscitation with crystalloids
alone requires more fluid and results in more oedema, and may
thus be inferior to combination therapy with colloids. This chapter
describes the currently available synthetic colloid solutions [i.e.
dextran, gelatin and hydroxyethyl starch (HES)] in detail, and
critically discusses their specific effects including potential adverse
effects. Literature was selected from medical databases (including
Medline and the Cochrane library), as well as references extracted
from the available publications. Dextrans appear to have the most
unfavourable risk/benefit ratio among the currently available
synthetic colloids due to their relevant anaphylactoid potential,
risk of renal failure and, particularly, their major impact on haemostasis. The effects of gelatin on kidney function are currently
unclear, but potential disadvantages of gelatin include a high
anaphylactoid potential and a limited volume effect compared
with dextrans and HESs. Modern HES preparations have the lowest
risk of anaphylactic reactions among the synthetic colloids. Older
HES preparations (hetastarch, hexastarch and pentastarch) have
repeatedly been reported to impair renal function and hemostasis,
especially when the dose limit provided by the manufacturer is
exceeded, but no such effects have been reported to date for
modern tetrastarches compared with gelatin and albumin.
* Corresponding author. Tel.: þ49 251 83 47255; Fax: þ49 251 83 48667.
E-mail address: [email protected] (C. Ertmer).
1521-6896/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpa.2008.11.001
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C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
However, no large-scale clinical studies have investigated the
impact of tetrastarches on the incidence of renal failure in critically
ill patients. When considering the efficacy and risk/benefit profile
of synthetic colloids, modern tetrastarches appear to be most
suitable for intensive care medicine, given their high volume
effect, low anaphylactic potential and predictable pharmacokinetics. However, the impact of tetrastarch solutions on mortality
and renal function in septic patients has not been fully determined,
and further comparison with crystalloids in prospective, randomized studies is required. Such studies are currently ongoing and
their results should be awaited before drawing final conclusions on
the HES preparations.
Ó 2008 Elsevier Ltd. All rights reserved.
The treatment of hypovolaemia is one of the most frequent challenges in intensive care medicine.
Whereas absolute hypovolaemia may be caused by bleeding, capillary leakage or negative fluid
balance, relative hypovolaemia typically derives from regional or systemic vasodilation.1 From
a physiological point of view, it therefore appears rational to treat absolute hypovolaemia by infusion of
iso-oncotic solutions that remain within the intravascular space, whereas relative hypovolaemia may
best be counteracted by goal-directed infusion of vasopressor agents. In real-life intensive care
medicine, however, the situation is more complex. At first, it is almost impossible to distinguish
explicitly between absolute and relative hypovolaemia at the bedside. In addition, one often cannot
even guarantee whether the patient is normovolaemic, still slightly hypovolaemic or already hypervolaemic.2 In fear of a vasoconstrictor-masked hypovolaemia, which may trigger multiple organ
failure3, liberal amounts of fluid are often infused to ensure that the patient is not hypovolaemic when
being treated with catecholamines to increase systemic blood pressure.
While artificial overhydration was not regarded as a major problem for a long time, the consequences of excessive fluid therapy have become evident during recent years. In this regard, a positive
fluid balance has been reported as an independent risk factor for poor outcome in a variety of clinical
settings.4–6 In addition, hypervolaemia per se may neither be an effective nor a harmless measure to
stabilize cardiovascular function.7 Notably, iatrogenic hypervolaemia may damage the endothelial
glycocalix, thereby increasing the albumin escape rate from the intravascular to the extravascular
space.7,8 Thus, the volume effect of a specific solution depends on the volume status of the patient. The
latter phenomenon is also referred to as ‘context-sensitive volume effect’.7
In most European countries, crystalloids are used in conjunction with colloids for fluid resuscitation in critically ill patients. Crystalloids are often administered with the intention of preventing
unwanted side-effects of artificial colloids. However, since only 20% of isotonic crystalloids remain
within the intravascular space, 80% expand the extracellular space and thus largely contribute to
a positive fluid balance and weight gain. In this regard, crystalloids themselves may not be free of
adverse effects if given in high doses, and may result in microcirculatory dysfunction9 and an
aggravation of systemic inflammation.10 Thus, rational use of colloids may prevent microcirculatory
failure and excessive weight gain associated with fluid resuscitation, and may, at least theoretically,
improve outcome.11
The ideal synthetic plasma substitute is considered: (1) to be iso-oncotic and isotonic, (2) to
have an intermediate volume effect and predictable intravascular half-life, (3) not to increase
plasma viscosity, (4) to be either excretable by the kidneys or rapidly degradable without intracellular storage, (5) not to have adverse pharmacological activity besides volume effect, (6) to pose
no risk of specific adverse events or infection, and (7) to be inexpensive and storable at room
temperature on a long-term basis. Modern balanced tetrastarch solutions most likely approach this
ideal standard.
This chapter gives a detailed overview of the variety of synthetic colloid solutions currently available, and their relevance in intensive care medicine. Reviews on the impact of the natural colloid
albumin have been published recently and can be read elsewhere.12–16
C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
195
Fig. 1. Monomer structure of polyvinylpyrrolidon.
Pharmacology of different synthetic colloids
The development of synthetic colloids was markedly driven during times of war to facilitate
transport of wounded soldiers to medical centres, where blood transfusions were available. Gum
arabic, a natural colloid from the Acacia senegalis tree based on polysaccharides, was the first synthetic
compound to be tested successfully as a plasma substitute in bled dogs in 1906. It was used clinically
during World War I, as reported by the physiologist William M. Bayliss17, but use ceased in 1937 when
the multiple adverse effects (including liver toxicity and antigenity) became apparent.18 In parallel,
(native) gelatin was first infused to wounded soldiers during World War I.19 The first commercially
available synthetic colloid was polyvinylpyrrolidon (Fig. 1), which was developed by Prof. Walter Reppe
in 1939 and introduced clinically by Hellmuth Weese during World War II. It was used successfully by
the German army medical corps and was labelled ‘Periston’.20 The initial preparation of Periston was
a 4% solution with a mean molecular weight of 50 000 Da. However, since the synthetic polymer was
not enzymatically degradable, molecules <25 000 Da were excreted rapidly by the kidneys, whereas
molecules with a higher mass were stored within the reticulo-endothelial system, liver and kidney
(‘collidon kidney’) on a long-term basis.21 Thus, from 1952, only preparations with a mean molecular
weight of 25 000 Da were available, until Periston was withdrawn from the market completely in the
early 1960s.
At the present time, dextrans, hydroxyethyl starches (HESs) and gelatin solutions are available as
synthetic colloids, with some regional differences in availability. These colloids are classically diluted
in isotonic, 0.9% saline, but are also available in hypotonic, hypertonic (e.g. 7.2–7.5% saline) or
balanced, isotonic electrolyte solutions. From a physiological point of view, the latter certainly
represent the most rational solution. However, no clinical study to date has shown a difference in
outcome between patients treated with balanced infusions and patients treated with saline-based
solutions.
Dextrans
Structure and pharmacokinetics
Dextrans are neutral, high-molecular-weight glucopolysaccharides based on glucose monomers
(Fig. 2). The polysaccharides are derived from extracellular, enzymatic synthesis from sucrose by the
bacteria Leuconostoc mesenteroides or dextranicum, which catalyse the a-1,6-glycosidic linkage of
glucose monomers. The first dextran (dextran 75) was introduced to the market for blood volume
replacement by Grönwall and Ingelman from Sweden in 194422, and approval by the US Food and Drug
Administration (FDA) ensued in September 1952.
Rapidly after infusion, most dextran molecules with a molecular weight <50 000 Da are excreted
via the kidneys. A small amount, however, is stored within the reticulo-endothelial system and slowly
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Fig. 2. Polymer structure of dextran moleculs. Glucose monomers are mainly connected via a-1,6-glycosidic linkage and branched
via a-1,3-glycosidation.
degraded to CO2 and water (w70 mg/kg/day). The slow cleavage of the dextran molecule can be
explained by the a-1,6-glycosidic linkage of the glucose monomers, which is different from the natural
a-1,4-linkage in endogenous glycogen polymers.
Pharmacodynamics
Dextrans are available as solutions with an average mean molecular weight of 40 000 Da (dextran
40; 3.5% iso-oncotic or 10% hyperoncotic), 60 000 Da (dextran 60; 4% iso-oncotic or 6% hyperoncotic) or
70 000 Da (dextran 70; 6% hyperoncotic) in 0.9% saline. The colloid osmotic pressure and the volume
effect mainly depend on the dextran concentration. The pharmacological characteristics of the specific
dextran preparations are summarized in Table 1.
Interestingly, the haemodynamic effect lasts longer than would be expected by the molecular mass
of the dextran molecule. This can best be explained by the fact that dextrans (in contrast to HESs) are
not degradable by plasma amylase due to their a-1,6-glycosidic structure.
Advantages
Advantages of dextran solutions include their relatively low production costs and their ability to be
stored on a long-term basis at room temperature. In glass bottles, dextran may be stored for up to
10 years, whereas the dextran concentration may change with time in plastic bags due to significant
evaporation of water.23
In addition to volume replacement, infusion of dextrans induces effective thrombo-embolic
prophylaxis24, which has been reported to be similarly effective as unfractionated heparin.25–27 In this
context, it is noteworthy that dextrans impact on platelet aggregation by reducing the activity of factor
VIII, von Willebrandt factor and the glycoprotein IIb/IIIa receptor. In addition, reduced leukocyte–
endothelial interaction has been noticed in response to dextran infusion.28 Erythrocyte aggregation is
Table 1
Pharmacological properties of different dextran, gelatin and hydroxyethyl starch preparations.
Bottom
fraction
(kDa)
MS
C2/C6
ratio
In-vitro
COP
(mmHg)
Initial
volume
effect (%)
T½a
(h)
T½b
(h)
Clearance
(ml/min)
25
25
n/a
80
n/a
10
n/a
n/a
n/a
n/a
60
170
100
175–200
n/a
n/a
n/a
n/a
n/a
n/a
60 000
70 000
30
7
110
125
25
25
n/a
n/a
n/a
n/a
26
59
110–130
120
n/a
n/a
n/a
n/a
n/a
n/a
30 000
30 000
3
5
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
33
25–29
70–90
70–80
n/a
n/a
n/a
n/a
n/a
n/a
Plasmasteril, Hespan
Hextend
450 000
670 000
150
175
2170
2500
19
20
0.7
0.75
4–5
4
26
n/a
100
100
n/a
6.3
300
46.4
n/a
0.98
6%
Elohes
200 000
25
900
15
0.62
9
25
110
5.08
69.7
1.23
6%
10%
6%
3%
Rheohes, Expafusin
HAES-steril, Hemohes
HAES-steril, Hemohes
HAES-steril, Hemohes
70 000
200 000
200 000
200 000
10
50
50
50
180
780
780
780
7
13
13
13
0.5
0.5
0.5
0.5
3
4–5
4–5
4–5
30
50–60
30–35
15–18
90
145
100
60
n/a
3.35
n/a
n/a
n/a
30.6
n/a
n/a
n/a
9.24
4.88
n/a
Voluven
Voluven, Volulyte
130 000
130 000
20
20
380
380
15
15
0.4
0.4
9
9
70–80
36
200
100
1.54
1.39
12.8
12.1
26.0
31.4
Tetraspan
Venofundin, Tetraspan,
VitaHES
130 000
130 000
15
15
n/a
n/a
n/a
n/a
0.42
0.42
6
6
60
36
150
100
n/a
n/a
n/a
12.0
n/a
19
Concentration
Trade name
MMW
(Da)
Dextrans
Dextran 40
Dextran 40
3.5%
10%
40 000
40 000
Dextran 60
Dextran 70
6%
6%
Rheomacrodex
Rheomacrodex,
Longasteril 40
Macrodex
Longasteril 70
Gelatins
Gelatin polysuccinate
Urea-cross-linked
polymerized peptides
4%
3.5%
Gelafusin
Haemaccel
Hetastarch
HES 450/0.7
HES 670/0.7
6%
6%
Hexastarch
HES 200/0,62
Pentastarch
HES 70/0.5
HES 200/0.5
HES 200/0.5
HES 200/0.5
Specification
range (kDa)
HESs
Tetrastarch (waxy-maize-derived)
HES 130/0.4
10%
HES 130/0.4
6%
Tetrastarch (potato-derived)
HES 130/0.42
10%
HES 130/0.42
6%
C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
Top
fraction
(kDa)
Preparation
Bottom fraction, <10% of molecules are less than the molecular weight defined by the bottom fraction; top fraction, <10% of molecules exceed the molecular weight defined by the top fraction; COP,
colloid osmotic pressure; HES, hydroxyethyl starch; MMW, mean molecular weight; MS, molar substitution; n/a, not applicable/available; T½a, distribution half-life; T½b, elimination half-life.
Data are extracted from manufacturers’ product information as well as references.105–109
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increased by dextrans with a molecular weight >56 000 Da and reduced by low-molecular-weight
dextrans. An altered thrombus structure as well as dilution of coagulation factors may further
contribute to the antithrombotic effects.29 Direct inhibition of coagulation factors becomes evident
with doses exceeding 1.5 g/kg/day, which represents the maximum recommended dose for all
dextrans. With higher doses, especially in the peri-operative setting, dextrans may be associated with
increased bleeding complications.30
Disadvantages
Major adverse events associated with dextran infusion include anaphylactoid reactions resulting
from preformed endogenous anti-polysaccharide antibodies which cross-react with dextran molecules. Most likely, these antibodies are generated after glucopolysaccharide ingestion with normal
food. Prophylactic infusion of monovalent dextran haptens (1000 Da; dextran 1) has been available
since 1982, and is obligatory to bind preformed antibodies without subsequent complement activation,
and may therefore largely reduce the incidence of anaphylactoid reactions after dextran infusion
(Fig. 3). Typically, 20 mL (3 g) of dextran 1 is infused in adults 20 min or less before high-molecularweight dextran therapy. In neonates and children, 0.3 mL/kg is usually considered appropriate. During
the 48 h following high-molecular-weight dextran therapy, repetitive dextran infusion is considered to
be safe without prior infusion of dextran 1. If 48 h is exceeded between two dextran infusions, hapten
prophylaxis must be repeated. Hapten prophylaxis has been reported to decrease the probability of
severe anaphylactoid reactions (grade III or higher; i.e. severe hypotension with systolic blood pressure
<60 mmHg and bronchospasm) from 1:500–2000 (without prophylaxis)31 to 1:70 000–200 000.
Anaphylactoid reactions after dextran infusion in shock states are rarely observed, possibly due to high
endogenous catecholamine concentrations and immunosuppression associated with shock states.
Newborns are almost never affected, most probably because they do not express dextran-reactive
antibodies. The incidence of anaphylactoid reactions appears to be higher in females, but the severity is
more pronounced in male subjects.31 The reasons for these age- and gender-dependent differences
remain unclear and need further investigation.
Osmotic kidney failure has been reported with the usage of hyperoncotic dextran preparations.
Such solutions should therefore be avoided in critically ill patients, who have an increased risk of renal
failure per se.32
Dextran infusion without
hapten prophylaxis
Dextran infusion with prior
hapten prophylaxis
Fig. 3. Schematic illustration of the mechanisms of dextran hapten prophylaxis. Large ellipses characterize high-molecular-weight
dextrans, whereas small circles reflect dextran hapten molecules. ‘Y’s represent dextran-reactive antibodies.
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199
It has been reported that dextran infusion may also alter the results of erythrocyte cross-matching
prior to packed red blood cell transfusion due to in-vivo and in-vitro erythrocyte aggregation.33 Thus,
whenever blood transfusions may be required in a patient, material for erythrocyte cross-matching
should be taken prior to dextran infusion.
Contra-indications for dextran infusion as detailed in the product information leaflets include
severe congestive heart failure, renal failure, hypervolaemia and known hypersensitivity against
dextrans.
In view of the multiple adverse events and the high anaphylactoid potential, dextrans have been
withdrawn from the market in a number of countries (e.g. Germany). Therefore, dextrans account for
the smallest market share of all synthetic colloids (<10%), and are mainly used in Russia, China, Eastern
Europe and Scandinavia (especially Sweden).34 However, dextran usage is also declining in these
countries.
Gelatin
Structure and pharmacokinetics
Gelatin products are derived from bovine collagen and prepared as polydispersive solutions by
multiple chemical modifications. Denaturation (Fig. 4) and hydrolysation of the natural collagen
produce polypeptide fractions that are cross-linked by distinct additives (e.g. glyoxal, succinate
anhydride, diisocyanate). Commercially available gelatin preparations contain either oxypolygelatin, polygelin (urea cross-linked polymerized polypeptides, Fig. 5) or gelatin polysuccinate.
Succinylation induces spreading of the molecular structure (Fig. 6) that, in turn, increases the
volume effect compared with equal molecular masses of non-succinylated gelatins. The succinylation degree (i.e. the number of succinyl amid residue per amino acid) of modern gelatin preparations is 0.026.
Untreated gelatin is only water soluble at temperatures >50 C. The abovementioned chemical
modifications result in sufficient water solubility at room temperature. However, during long-term
storage or in a cold environment, part of the gelatin may precipitate, and thus require warming before
infusion.
Approximately 50% of gelatin molecules are excreted into the urine during or shortly after infusion.
The larger molecules remain within the intravascular space until they are degraded by endogenous
peptidase and filtrated by the kidneys. Therefore, repeated infusions of gelatin are necessary to
maintain adequate blood volume.
Fig. 4. Process of raw gelatin generation from collagen.
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Hydroxylysine residues
O
N
N
OH
HO
Urea link
Fig. 5. Molecular characteristics of urea-linked gelatin.
Gelatins for volume therapy have been withdrawn from the US market due to the high rate of
anaphylactic reactions.
Pharmacodynamics
Conventional gelatin preparations have a mean molecular weight of 30 000–35 000 Da and a low
molecular mass range (Table 1). According to the relatively low mean molecular weight, most of the
gelatin is excreted into the urine within minutes after infusion. Thus, the volume effect (70–80%) and
Hydroxylysine residues
HO
O
N
N
O
HO
Succinyl link
Fig. 6. Molecular characteristics of succinylated gelatin.
C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
201
the duration of volume expansion (2–3 h) are limited and not comparable with dextrans or HES. Since
the cross-linked gelatin molecules contain negative charges, chloride concentrations of the solvent
solution are reduced in contrast to other types of colloid. Since the latter fact results in slight hyposmolality, infusion of large amounts of gelatin solutions may reduce plasma osmolality and ultimately
foster the genesis of intracellular oedema.
Advantages
Gelatin products are quite inexpensive and may be stored for 2–3 years at room temperature. The
impact on the coagulation system appears to be limited due to the dilution of coagulation factors,
platelets and red blood cells.
Gelatins are conventionally regarded to have minimal effects on coagulation in excess of haemodilution, and are considered to be safe in terms of renal function, despite individual negative reports.35
According to information from recent scientific meetings, the rate of renal failure and need for renal
replacement therapy in intensive care patients is not reduced by switching from HES to gelatin.
Disadvantages
The rapid urinary excretion of gelatin is associated with increased diuresis and has to be substituted
by adequate crystalloid infusion to prevent dehydration. Gelatin infusion may furthermore increase
blood viscosity and facilitate red blood cell aggregation without influencing the results of crossmatching. The rate of anaphylactic reactions is the highest among the synthetic colloids, and severe
reactions occur in 0.05–0.1% of patients.
Hydroxyethyl starch
Structure and pharmacokinetics
HES has been synthesized for industrial purposes since 1934. However, it was as late as 1957 that
Wiedersheim (who labelled it as ‘oxyethylstarch’) used it as an experimental plasma substitute.36
Thereafter, HES was used extensively to treat wounded soldiers during the Vietnam War (1959–1975).
The raw material for the production of HES is amylopectin, a highly branched polymer of glucose,
derived from either waxy-maize or potato starch (Fig. 7). This multibranched structure makes it the
first synthetic colloid with a globular configuration similar to the natural colloid albumin. Thus, HES
has a much lower viscosity than dextran or gelatin, but does not reach the low viscosity of albumin.
HES is generated by nucleophilic substitution of amylopectin to ethylene oxide in the presence of an
alkaline catalyst (Fig. 8).37 Residual solvents are removed by repeated ultrafiltration.
Fig. 7. Molecular structure of amylopectin, the raw substance for hydroxyethyl starch production.
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Starch
Acid hydrolysis
(amylopectin)
Hydroxyethylation
Determination of molar
substitution and C2/C6 ratio
Determination of
molecular weight
R-O-H
Starch
base
O
R-O + H CH2-CH2
-
+
Ethylen oxide
base
Ultrafiltration
(elimination of small molecules)
Determination of molecular
weight range
R-O-CH2-CH2OH
Hydroxyethyl starch
Fig. 8. Schematic illustration of the synthesis of hydroxyethyl starch from raw starch. (Upper part) Physicochemical reactions
required to produce hydroxyethyl starch from amylopectin. (Lower part) Nucleophilic substitution of amylopectin to ethylene oxide
results in hydroxyethylation of glucose monomers.
Glucose residues of HES are predominantly linked by a-1,4-glycosidation, whereas a-1,6-glycosidic
linkage only exists in small side chains (Fig. 9). The mean molecular weight of the different HES
preparations ranges between 70 000 and 670 000 Da. Within each HES species, the particular molecules are distributed around the mean molecular weight of the specific preparation (Fig. 10). The
hydroxyethyl residues are mainly attached to the C2 and C6 positions of the glucose rings. The average
Fig. 9. Molecular structure of branched hydroxyethyl starch. Numbers label the position of carbon atoms within the glucose
monmers. Single and double asterisks characterize a-1,4- and a-1,6-glycosidic linkage, respectively. Open and closed arrows
demonstrate hydroxyethylation in C2 and C6 positions, respectively.
C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
203
Fig. 10. Molecular weight distribution in hydroxyethyl starch solutions. The abscissa determines the molecular weight in logarithmic scale in relation to the number of molecules displayed on the ordinate axis. Perpendicular lines reflect the mean molecular
weights of either preparation. HES, hydroxyethyl starch.
number of hydroxyethyl groups per glucose molecule is specified by the molar substitution, ranging
between 0.4 (tetrastarch) and 0.7 (hetastarch). Accordingly, HESs with a molar substitution of 0.5 or 0.6
are referred to as ‘pentastarch’ or ‘hexastarch’, respectively. In this regard, first-generation HESs declare
heta- and hexastarches, whereas pentastarch is assigned to the second generation. The latest, thirdgeneration HESs consist of modern tetrastarches (HES 130/0.4 and HES 130/0.42).
In the nomenclature of HESs, the concentration is followed by the mean molecular weight in kDa
and the molar substitution. Thus, 6% HES 130/0.4 specifies a 6% HES solution with a mean in-vitro
molecular weight of 130 000 Da, which contains an average of four hydroxyethyl residues per 10
glucose molecules.
Following infusion of HES, small molecules <60 000 Da are filtrated into the urine, whereas larger
molecules are degraded by plasma amylase. The kinetics of this degradation are mainly determined by
the molar substitution and the C2/C6 ratio (i.e. the quotient of the numbers of glucose residues
hydroxyethylated at positions 2 and 6, respectively). A high molar substitution and a high C2/C6 ratio
make the HES molecule less susceptible to plasma amylase, and thus increases the intravascular halflife of HES molecules. Part of the HES is stored within the reticulo-endothelial system and slowly
degraded to CO2 and water. However, massive infusion of old, high-molecular-weight preparations
with a high degree of substitution (particularly heta- and hexastarch) may be associated with excessive
tissue storage. With modern preparations (i.e. 6% HES 130/0.4), no plasma accumulation and greatly
reduced tissue storage have been reported in the literature. VoluvenÔ 6% (waxy-maize-derived 6% HES
130/0.4 in 0.9% saline) was approved by the US FDA in 2007.38
Pharmacodynamics
The volume effect of HES mainly depends on its concentration, in-vivo molecular weight and colloid
osmotic pressure (COP). Whereas 6% HES 130/0.4 with an in-vitro COP of 36 mmHg exerts a volume
effect of approximately 100%, the hyperosmotic 10% HES 200/0.5 (COP 59–82 mmHg) binds water from
the interstitium and has an initial volume effect of up to 150%. Ideally, steady degradation of large
molecules and excretion of smaller molecules results in a stable in-vivo molecular weight for several
hours. For example, HES 130/0.4 maintains an in-vivo molecular weight of approximately 60 000–
70 000 Da by continuous liberation of degraded molecules from a high-molecular-weight pool.
Whereas for older solutions with high molar substitution, a daily maximum dose of 1.5–2 g/kg (derived
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from the dose limitation for dextrans) is recommended, up to 3 g/kg/day of modern preparations
(i.e. HES 130/0.4) may be infused.
Advantages and disadvantages
HES is an effective plasma substitute that is capable of decreasing blood viscosity. Infusion of
HES therefore improves microcirculatory blood flow.39 However, it is important to discriminate
between the particular raw materials and the pharmacological properties when assessing advantages and disadvantages of a specific HES preparation. Potato- and waxy-maize-derived starches
are not bioequivalent. Waxy-maize starch consists of about 98% amylopectin, whereas potato
starch is a composite of 75% amylopectin and 25% amylose. Therefore, the degree of branching is
lower40 and the viscosity is higher in potato-derived HES. The reduction in viscosity of HES
solutions results from the globular structure associated with the high degree of branching.41 In
addition, the C2/C6 pattern in HES 130/0.4 derived from potato starch (6:1) differs from waxy-maize
starch (9:1), which decelerates breakdown by amylase more effectively in the latter product.
Differences in amylose content and negative charges within potato starch enable the formation of
inclusion complexes with several endogenous lipophilic molecules (e.g. fatty acids42 and prostaglandins43). The clinical relevance of this finding, however, is currently unclear and requires further
investigation.
In general, modern waxy-maize-derived tetrastarches appear to have a safe pharmacokinetic
profile, even in subjects with impaired kidney function.44 In contrast, older preparations with high
molar substitution cumulate after repetitive infusion, even in healthy subjects with normal kidney
function.45 In addition, modern tetrastarch preparations are less likely to impair platelet function and
coagulation compared with older penta-, hexa- or hetastarches.46,47 If used in pharmacologically
recommended doses, third-generation tetrastarch solutions do not exert relevant effects on haemostasis besides haemodilution itself.48 The anaphylactoid potential of HES is the lowest among the
synthetic colloids.
Early-generation HESs have been repeatedly reported to accumulate in the reticulo-endothelial
system and, in a dose-dependent manner, even in epithelial and perineural cells.49 In contrast,
repeated infusion of third-generation tetrastarches does not accumulate in plasma, even after repeated
infusion in healthy volunteers.50 Skin tissue storage is attributed as the main reason for refractory
pruritus days to months after HES infusion.51 Incidence and severity of pruritus are mainly influenced
by molar substitution and cumulative dosage.52 In a randomized controlled trial of patients with
sudden auditory loss, pruritus incidence following tetrastarch infusion was comparable with the
control group treated with 5% glucose during the 90-day follow-up period.53 In patients with acute
ischaemic stroke, hypervolaemic haemodilution with 10% HES 130/0.4 was found to be well tolerated
and to show the same safety profile regarding the incidence of adverse events including pruritus when
compared with 0.9% saline.54
Anaphylactoid reactions following synthetic colloids
Although frequently discussed in the literature, severe, life-threatening anaphylactic/anaphylactoid
reactions in response to either of the three synthetic colloids are very rare with the use of modern
preparations.55,56 Within all three types of synthetic colloid, optimization of the particular preparations has been associated with a marked reduction in anaphylactic reactions during the last decades. A
French prospective multicentre study published in 1994 observed an overall frequency of 0.219%
among 19 593 patients treated with either albumin (frequency 0.099%), gelatin (frequency 0.345%),
dextrans (frequency 0.273%) or HES (frequency 0.058%).56 Among these anaphylactoid reactions, about
20% were reported as severe (grade III or IV). Multivariate analysis revealed four independent risk
factors for anaphylactoid reactions, i.e. gelatin infusion [odds ratio (OR) 4.81], dextran infusion (OR
3.83), history of drug allergy (OR 3.16) and male gender (OR 1.98). Whereas the relative risk of
anaphylactoid reactions was similar between albumin and HES, it was six times higher with gelatin and
4.7 times higher with dextran compared with HES. Table 2 gives an overview of the event rates
determined in the French study.
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205
Table 2
Anaphylactoid rates of clinically available colloid solutions.
Colloid
Natural colloids
Dextran
Gelatin
HES
Subtype
Albumin
Total
Dextran 60/75
Dextran 40
Total
Urea-linked
Succinylated
Total
HES 200/0.6
HES 200/0.5
Total
Total
Anaphylactoid reactions (%)
Patients (n)
Total
Severe (III –IV )
0.099
0.099
0.286
0.270
0.273
0.852
0.325
0.345
0.115
0.047
0.058
0.032
0.032
None
0.067
0.054
0.284
0.056
0.065
None
0.023
0.019
3020
3020
350
1484
1834
352
8907
9259
4271
873
5144
0.219
0.047
19 257
HES, hydroxyethyl starch.
Modified from Laxenaire et al.56
If a patient experiences an anaphylactoid reaction, immuno-allergological testing should be
assessed to identify potential specific antibodies. If such antibodies are detected, the patient should
never receive the particular type of colloid again.56
Effects of synthetic colloids on renal function
The impact of synthetic colloids on renal function is one of the most frequently studied and discussed topics in the colloid literature of the 21st Century.57–61 The increase in intravascular volume and
the decrease in plasma viscosity associated with modern synthetic colloids usually improve renal
perfusion in hypovolaemic patients. However, since all synthetic colloids are mainly eliminated via the
kidney, impaired renal function may contribute to colloid accumulation. As critically ill patients per se
have a considerable risk to develop renal dysfunction, the impact of synthetic colloids on renal integrity
is of major interest for the safety of these compounds.
Some studies found an association between colloid infusion and renal failure.59,61,62 However, most
of these studies were criticized due to severe methodological shortcomings.63,64
Given the high incidence of renal impairment following dextran infusion, dextran-associated
kidney injury will be described to exemplify the pathophysiology of colloid-induced renal failure.
The first reports on dextran-induced renal failure were published in the late 1960s.65–67 Most cases
were associated with large amounts of dextran infusion in the presence of dehydration. Preexisting renal damage, such as diabetic nephropathy, also appears to increase the risk of dextraninduced renal failure. In subjects with an intact glomerular barrier, only dextran molecules
<50 000 Da are filtrated, and larger molecules can be found in the primary urine when glomerular
permeability is increased. Therefore, intratubular viscosity may markedly increase and decrease
urine flow.68 In addition, some of the dextran molecules are transferred into the lysosomes of
proximal tubular epithelial cells via pinocytosis. In light microscopy, proximal tubulus cells show
osmotic nephrosis-like lesions69, which may be associated with cellular swelling and, thus, an
additional decrease in urine flow. Infusion of hyperoncotic solution may further impair renal
function by reducing glomerular water filtration.32 It therefore appears reasonable that 10%
dextran 40 with a COP of approximately 170 mmHg and a large fraction of filtrated molecules is
associated with the highest risk of renal dysfunction.68 In contrast, HES preparations are less likely
to produce renal dysfunction compared with dextran. This may be explained by the high water
solubility preventing excessive increases in urine viscosity. Thus, up to 1991, no cases of HESassociated renal failure had been described in the literature. On the other hand, 10% HES 200/0.5
may increase urine viscosity by a factor of 2.5 (compared with 5.1 for 10% dextran 40).68 Tubular
osmotic nephrosis-like lesions have repeatedly been reported with the use of HES with high molar
substitution in brain dead kidney donors.70 Due to the large spectrum of pharmacologically
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different HES preparations, the impact on renal function should be judged for each specific
preparation.
Using a pig model of haemodilution, Eisenbach et al noticed that tissue storage of hexastarch is
more pronounced compared with pentastarch.71 However, considerable amounts of all three colloids
(6% solutions of HES 200/0.62, HES 200/0.5, and HES 100/0.5) were detected in kidney tissue. In
patients undergoing orthopaedic surgery, no negative effect on renal function was observed with the
use of 6% HES 200/0.5 compared with 5% albumin (colloid dose w35 mL/kg in both groups).72
However, two multicentre studies demonstrated a significant impairment of renal function in critically ill patients treated with hexastarch and pentastarch solutions. In this context, Schortgen et al
reported on 129 patients with severe sepsis or septic shock who were randomized to receive either
6% HES 200/0.62 or 3% succinylated gelatin.59 The frequency of acute renal failure was markedly
increased with the use of 6% HES 200/0.62. However, the study was criticized for shortcomings in
the study design and conclusions. These critical issues included differences in baseline creatinine
values (in favour of the gelatin group), a questionable primary endpoint (two-fold increase in
creatinine concentrations from baseline) and unclear crystalloid support.63 In the German VISEP
study61, volume therapy with 10% HES 200/0.5 was compared with infusion of a modified Ringer’s
lactate solution in 537 patients with severe sepsis. The authors reported a dose-dependent association of 10% HES 200/0.5 infusion with requirements for renal replacement therapy. However, the
VISEP study was also criticized for: (1) using a hyperoncotic colloid solution with potentially
harmful effects on renal integrity as shown in experimental research71, (2) markedly exceeding the
pharmaceutically recommended daily dose limit for 10% HES 200/0.5, i.e. 20 mL/kg/day, by more
than 10% in >38% of patients, and (3) pre-existing renal dysfunction in w10% of study patients,
which represents a contra-indication for infusion of 10% HES 200/0.5.64 A post-hoc analysis revealed
that patients treated with 22 mL/kg/day (median cumulative dose 48.3 mL/kg; interquartile range
21.9–96.2) of 10% HES 200/0.5 (i.e. almost appropriate dosage) tended to have a better outcome
compared with patients markedly exceeding maximum recommended doses (>22 mL/kg/day;
median cumulative dose 136 mL/kg; interquartile range 79–180). According to these limitations, the
results of the latter two studies should be interpreted with caution. In a large, prospective observational study (Sepsis Occurrence in Acutely Ill Patients study), HES infusion of any type (w500 mL/
day) did not represent an independent risk factor for renal impairment.73 Recently, the authors’
study group found that in a large cohort of critically ill patients (w8000 subjects), infusion of 10%
HES 200/0.5 instead of HES 130/0.4 represents an independent risk factor for renal replacement
therapy.74
Gelatins are generally regarded as safe in terms of renal function. However, an association
between gelatin use and renal dysfunction has been reported at recent scientific meetings. Due to
the low colloid concentration, low in-vivo molecular weight and short half-life of gelatin preparations, gelatin-associated kidney injury is less likely compared with high-molecular-weight
hyperoncotic colloids (e.g. 10% dextran 40). This is underlined by a recent prospective observational
study which suggested that resuscitation with either hyperoncotic artificial colloids or hyperoncotic
albumin represents an independent risk factor for renal dysfunction.32 Unfortunately, some isooncotic preparations (such as 6% HES 130/0.4) were erroneously allocated to the hyperoncotic
group by the authors. Therefore, the latter results should be judged with caution and may not be
assignable to each of the particular solutions. In this context, recent clinical studies demonstrated
that 6% HES 130/0.4 (with its medium in-vivo molecular weight and lack of plasma accumulation)
has comparable renal effects with succinylated gelatin.60 Recent clinical trials in patients undergoing cardiac surgery even suggest less marked changes in kidney function and a reduced endothelial inflammatory response with 6% HES 130/0.4 than with gelatin 4%.75 However, large-scale
clinical studies are needed to clarify whether modern tetrastarches are free of adverse renal effects
if used within the manufacturer’s dose limit.44
Comparative randomized clinical studies of different synthetic colloids
To date, no randomized controlled trial has demonstrated a survival benefit associated with the
infusion of colloids compared with crystalloids alone.76 In addition, a meta-analysis revealed no
C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
207
significant differences in outcome between either albumin and synthetic colloids or different types of
synthetic colloid.16,77
However, previous meta-analyses have not distinguished between the particular subtypes among
dextrans, gelatin and HES.76,77 Therefore, the following paragraphs will summarize current knowledge
from randomized clinical trials comparing specific colloid preparations.
Dextrans vs gelatin
In a small clinical study (n ¼ 48) comparing plasma protein solutions, 6% dextran 70 and 5.5%
oxypolygelatin in patients undergoing coronary artery bypass grafting, Karanko reported that the
duration and quantity of volume effect exerted by 6% dextran 70 are higher compared with 5.5%
oxypolygelatin.78 However, survival was not affected by treatment allocation. Investigating a similar
study population (n ¼ 40), Tollofsrud et al compared haemodynamic and pulmonary effects of Ringer’s
acetate, 6% dextran 70, 3.5% polygelin and 4% albumin.79 The authors reported no relevant differences
in haemodynamics or pulmonary function between groups.
Dextrans vs HES
Hiippala et al investigated the effects of 4% HES 120/0.7, 3% dextran 70 (both hypo-oncotic), 5%
albumin (iso-oncotic) and 6% HES 120/0.7 (hyperoncotic) on peri-operative COP, albumin and protein
concentrations, and fluid balance in 60 patients with major surgical blood loss.80 The authors found
transient differences in plasma COP (as expected), but renal function and outcome were similar
between groups.
Comparison of different gelatin preparations
The only clinical study to compare different gelatin preparations revealed a lower platelet count
and fibrinogen concentration with the use of urea-linked gelatin compared with succinylated gelatin
in 54 patients undergoing cardiopulmonary bypass.81 No further differences were noticed by the
authors.
Gelatin vs HES
The overall relative risk of death between gelatin and HES reported in the most recent meta-analysis
was 1.00 (95% confidence interval 0.80–1.25; total events among 1337 patients: 93 per group).
Differential analysis of randomized controlled trials revealed a total of 73 patients allocated to
hetastarch vs succinylated gelatin82,83, 193 patients allocated to hexastarch vs succinylated
gelatin59,84,85, 394 patients allocated to pentastarch vs succinylated gelatin83,86–92, and 184 patients
allocated to tetrastarch vs succinylated gelatin.60,75,93–95 The multitude of preparations used in the
different studies, however, does not allow conclusions on outcome.
Hetastarch is associated with increased blood loss compared with 3.5% gelatin.83 Hexastarch exerts
similar effects on cardiopulmonary function, but impairs renal function and gastric mucosal perfusion
in comparison with succinylated gelatin.59,84 Whereas cardiopulmonary and renal function are
comparable in clinical trials comparing pentastarch and succinylated gelatin87–89,92, capillary permeability is reduced by pentastarch.86,92 Coagulation and blood loss during cardiopulmonary bypass,
however, appear to be negatively affected by pentastarch.90,91 In contrast, tetrastarch (when administered in doses up to 50 mL/kg) does not increase blood loss compared with gelatine.93–95 In addition,
renal function is either equally60 or better75 maintained with tetrastarch compared with gelatin in
patients undergoing cardiopulmonary bypass.
Comparison of different HES preparations
In total, 611 patients were included in 12 randomized clinical studies comparing different starch
preparations. Boldt et al investigated the effects of hetastarch (HES 450/0.7), hexastarch (HES 200/0.62)
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C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
and two different pentastarch solutions (HES 200/0.5 and HES 70/0.5) on microcirculation during
cardiac surgery, and reported that microvascular blood flow was only maintained with HES 200/0.5,
whereas it decreased in the other groups.96 In patients undergoing major surgery, Gan et al investigated the efficacy and safety of normal hetastarch (HES 450/0.7) and an HES 670/0.75 preparation in
balanced electrolyte solution, and found that blood loss was reduced with the balanced solution.97 Two
additional studies by Boldt et al compared the impact of hetastarches, pentastarch and tetrastarch on
peri-operative blood loss in patients undergoing major surgery98 or cardiopulmonary bypass grafting.83 Notably, blood loss was reduced with HES 130/0.4 compared with balanced HES 670/0.75 98, and
with HES 200/0.5 compared with HES 450/0.7.83 It therefore appears that a high molar substitution and
a high in-vivo molecular weight impair haemostasis in surgical patients. This notion is confirmed by
three randomized clinical trials including a total of 171 patients comparing volume substitution with
HES 130/0.4 and HES 200/0.5.99–101 These studies clearly demonstrated that peri-operative blood loss is
reduced with the use of tetrastarch compared with pentastarch. Another study by Boldt et al compared
electrolyte-balanced and saline-based solutions of HES 130/0.4, and found no negative impact on
kidney function and coagulation (as determined by thrombelastography), but a less pronounced
metabolic acidosis with the balanced solution.102 Finally, a pooled analysis of seven clinical trials (449
patients) comparing haemostatic effects of tetrastarch and pentastarch clearly demonstrated that 6%
HES 130/0.4 is associated with less peri-operative blood loss and transfusion requirements compared
with 6% HES 200/0.5.103
Conclusions
Among the currently available synthetic colloids, dextrans appear to have the worst risk/
benefit ratio due to their relevant anaphylactoid potential, risk of renal failure and, particularly,
the major influence on haemostasis. The effects of gelatin on kidney function are currently
unclear, but the disadvantages of gelatin include its high anaphylactoid potential and the limited
volume effect compared with dextrans and HESs. Modern HES preparations have the lowest risk
of anaphylactic reactions among the synthetic colloids. Whereas older HES preparations (hetastarch, hexastarch and pentastarch) have repeatedly been shown to impair renal function59,61 and
haemostasis83,98, especially when hyperoncotic solutions are infused and/or maximum recommended doses are exceeded, no such events have been reported with the use of modern tetrastarch compared with albumin and gelatin.60,93,104 However, to date, no large-scale clinical
studies have prospectively investigated the impact of HES 130/0.4 on the incidence of renal
failure in critically ill septic patients. In this regard, several large multicentre studies are ongoing
to evaluate the efficacy and safety of 6% HES 130/0.4 for initial haemodynamic stabilization in
patients with severe sepsis (e.g. the CRYSTMAS study,ClinicalTrials.gov Identifier NCT00464204).
The primary endpoint of the latter study includes the amount of study drug needed for initial
haemodynamic stabilization.
When considering the efficacy and safety of synthetic colloids, modern tetrastarches appear to
be the most suitable synthetic colloids in intensive care medicine. This notion is underlined by the
high volume effect, low anaphylactic rate and predictable pharmacokinetics of modern tetrastarches. Pharmacological differences between HES types, such as accelerated metabolism and
excretion, indicate that the latest HES generation is superior to older starches. Since the impact of
tetrastarch solutions on mortality and renal function has not yet been determined in prospective,
randomized studies, such results should be awaited before drawing final conclusions on these HES
preparations.
Practice points
fluid resuscitation with synthetic colloids may be favourable to crystalloid infusion alone in
terms of pulmonary function, microcirculation and systemic inflammation
C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193–212
209
dextrans should not be used for fluid resuscitation due to negative effects on kidney function
and coagulation
gelatin preparations have the highest risk of anaphylactoid reactions among all types of
colloids
older HES preparations (hetastarch, hexastarch, pentastarch) may negatively influence
platelet function and increase the risk of renal failure, especially in critically ill patients
previous data on modern tetrastarch solutions, although limited in extent, suggest that these
substances do not impair coagulation and renal function, and have a low risk of anaphylactoid
reactions
Research agenda
effects of tetrastarch solutions on renal function in septic patients
comparison of the effects of tetrastarch solutions and sole crystalloids on renal function and
mortality in patients with severe sepsis
large-scale clinical studies comparing potato-based and waxy-maize-based HES preparations
clinical studies evaluating the potential benefits of balanced vs saline-based colloids in
critically ill patients
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