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Relevance of non-albumin colloids in intensive caremedicine

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 therapygelatin

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 crystalloidsalone 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 hae-

mostasis. 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.: 49 251 83 47255; Fax: 49 251 83 48667.

E-mail address: [email protected] (C. Ertmer).

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Anaesthesiologyj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b e a n

1521-6896/$ see front matter 2008 Elsevier Ltd. All rights reserved.

doi:10.1016/j.bpa.2008.11.001

Best Practice & Research Clinical Anaesthesiology 23 (2009) 193212
mailto:[email protected]://www.sciencedirect.com/science/journal/15216896http://www.elsevier.com/locate/beanhttp://www.elsevier.com/locate/beanhttp://www.sciencedirect.com/science/journal/15216896mailto:[email protected]


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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 pharmacoki-

netics. 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, random-

ized studies is required. Such studies are currently ongoing and

their results should be awaited before drawing final conclusions on

the HES preparations.

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 fluidbalance, 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 hyper-

volaemic.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 conse-quences 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.46 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 resusci-

tation 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 toa 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 intra-

cellular 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 thisideal standard.

This chapter gives a detailed overview of the variety of synthetic colloid solutions currently avail-

able, 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.1216

C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193212194


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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 syntheticcompound 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 wasa 4% solution with a mean molecular weight of 50 000 Da. However, since the synthetic polymer was

not enzymatically degradable, molecules


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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-embolicprophylaxis24, which has been reported to be similarly effective as unfractionated heparin. 2527 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

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.



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Table 1

Pharmacological properties of different dextran, gelatin and hydroxyethyl starch preparations.

Preparation Concentration Trade name MMW

(Da)

Specification

range (kDa)

Top

fraction

(kDa)

Bottom

fraction

(kDa)

MS C2/C6

ratio

Dextrans

Dextran 40 3.5% Rheomacrodex 40 000 25 n/a n/a n/a n/a Dextran 40 10% Rheomacrodex,

Longasteril 40

40 000 25 80 10 n/a n/a

Dextran 60 6% Macrodex 60 000 30 110 25 n/a n/a

Dextran 70 6% Longasteril 70 70 000 7 125 25 n/a n/a

Gelatins

Gelatin polysuccinate 4% Gelafusin 30 000 3 n/a n/a n/a n/a

Urea-cross-linked

polymerized peptides

3.5% Haemaccel 30 000 5 n/a n/a n/a n/a

HESs

Hetastarch

HES 450/0.7 6% Plasmasteril, Hespan 450 000 150 2170 19 0.7 45

HES 670/0.7 6% Hextend 670 000 175 2500 20 0.75 4

Hexastarch

HES 200/0,62 6% Elohes 200 000 25 900 15 0.62 9

Pentastarch

HES 70/0.5 6% Rheohes, Expafusin 70 000 10 180 7 0.5 3

HES 200/0.5 10% HAES-steril, Hemohes 200 000 50 780 13 0.5 45



Tetrastarch (waxy-maize-derived)

HES 130/0.4 10% Voluven 130 000 20 380 15 0.4 9

HES 130/0.4 6% Voluven, Volulyte 130 000 20 380 15 0.4 9

Tetrastarch (potato-derived)HES 130/0.42 10% Tetraspan 130 000 15 n/a n/a 0.42 6

HES 130/0.42 6% Venofundin, Tetraspan,

VitaHES

130 000 15 n/a n/a 0.42 6

Bottom fraction,


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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 mole-

cules. 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-molecular-

weight dextran therapy. In neonates and children, 0.3 mL/kg is usually considered appropriate. Duringthe 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


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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 againstdextrans.

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 (50 C. The abovementioned chemical

modifications result in sufficient water solubility at room temperature. However, during long-termstorage 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.

C. Ertmer et al. / Best Practice & Research Clinical Anaesthesiology 23 (2009) 193212 199


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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 00035 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 (7080%) and

OHHO

O

N N

Hydroxylysine residues

Urea link

Fig. 5. Molecular characteristics of urea-linked gelatin.

OH

HO

O

NN

O

Hydroxylysine residues

Succinyl link

Fig. 6. Molecular characteristics of succinylated gelatin.



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the duration of volume expansion (23 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 hypo-

smolality, 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 23 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 haemo-

dilution, 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 cross-

matching. The rate of anaphylactic reactions is the highest among the synthetic colloids, and severe

reactions occur in 0.050.1% 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 (19591975).

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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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 HESpreparations ranges between 70 000 and 670 000 Da. Within each HES species, the particular mole-

cules 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

Starch(amylopectin)

Acid hydrolysis

Determination of

molecular weight

Hydroxyethylation

Determination of molar

substitution and C2/C

6ratio

Ultrafiltration(elimination of small molecules)

Determination of molecular

weight range

R-O-H R-O-CH2-CH2OHR-O- + H+ CH2-CH2

Obase base

Starch Ethylen oxide 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.

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.



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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, third-

generation 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


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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 ofHES therefore improves microcirculatory blood flow.39 However, it is important to discriminate

between the particular raw materials and the pharmacological properties when assessing advan-

tages 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 prosta-glandins43). 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 haemo-

stasis 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-endothelialsystem 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 prepara-

tions 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 (OR3.83), 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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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 dis-

cussed topics in the colloid literature of the 21st Century.5761 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 thekidney, 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. 6567 Most cases

were associated with large amounts of dextran infusion in the presence of dehydration. Pre-

existing renal damage, such as diabetic nephropathy, also appears to increase the risk of dextran-

induced renal failure. In subjects with an intact glomerular barrier, only dextran molecules


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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 theuse 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 crit-

ically 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 Ringers

lactate solution in 537 patients with severe sepsis. The authors reported a dose-dependent asso-ciation 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

21.996.2) 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 79180). According to these limitations, the

results of the latter two studies should be interpreted with caution. In a large, prospective obser-vational 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 prepa-

rations, 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 hyperoncoticalbumin represents an independent risk factor for renal dysfunction.32 Unfortunately, some iso-

oncotic 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 under-

going cardiac surgery even suggest less marked changes in kidney function and a reduced endo-

thelial 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 manufacturers 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



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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 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 40), Tollofsrud et al compared haemodynamic and pulmonary effects of Ringersacetate, 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 gelatinin 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 0.801.25; 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 gelatin83,8692, and 184 patients

allocated to tetrastarch vs succinylated gelatin.60,75,9395

The multitude of preparations used in thedifferent 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 gelatin8789,92, capillary perme-

ability 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 admin-

istered in doses up to 50 mL/kg) does not increase blood loss compared with gelatine. 9395 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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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 investi-

gated 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 onperi-operative blood loss in patients undergoing major surgery98 or cardiopulmonary bypass graft-

ing.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 200/0.5.99101 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 (hetas-tarch, hexastarch and pentastarch) have repeatedly been shown to impair renal function 59,61 and

haemostasis83,98, especially when hyperoncotic solutions are infused and/or maximum recom-

mended doses are exceeded, no such events have been reported with the use of modern tetra-

starch 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 tobe 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 tetra-

starches. 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

http://clinicaltrials.gov/http://clinicaltrials.gov/


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References

1. Schadt JC & Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. The

American Journal of Physiology 1991; 260: H305H318.2. Vincent JL & Weil MH. Fluid challenge revisited. Critical Care Medicine 2006; 34: 13331337.3. Hinder F, Stubbe HD, Van Aken H et al. Early multiple organ failure after recurrent endotoxemia in the presence

of vasoconstrictor-masked hypovolemia. Critical Care Medicine 2003; 31: 903909.4. Moller AM, Pedersen T, Svendsen PE & Engquist A. Perioperative risk factors in elective pneumonectomy: the impact

of excess fluid balance. European Journal of Anaesthesiology 2002; 19: 5762.5. Schuller D, Mitchell JP, Calandrino FS & Schuster DP. Fluid balance during pulmonary edema. Is fluid gain a marker or

a cause of poor outcome? Chest 1991; 100: 10681075.6. Simmons RS, Berdine GG, Seidenfeld JJ et al. Fluid balance and the adult respiratory distress syndrome. The American

Review of Respiratory Disease 1987; 135: 924929.7. Rehm M, Haller M, Orth V et al. Changes in blood volume and hematocrit during acute preoperative volume loading

with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. Anesthesiology 2001; 95: 849856.*8. Rehm M, Zahler S, Lotsch M et al. Endothelial glycocalyx as an additional barrier determining extravasation of 6%

hydroxyethyl starch or 5% albumin solutions in the coronary vascular bed. Anesthesiology 2004; 100: 12111223.9. Lang K, Boldt J, Suttner S & Haisch G. Colloids versus crystalloids and tissue oxygen tension in patients undergoing

major abdominal surgery. Anesthesia and Analgesia 2001; 93: 405409.10. Boldt J, Ducke M, Kumle B et al. Influence of different volume replacement strategies on inflammation and endothelial

activation in the elderly undergoing major abdominal surgery. Intensive Care Medicine 2004; 30: 416422.11. Boldt J. Pro: use of colloids in cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia 2007; 21: 453456.12. Chalidis B, Kanakaris N & Giannoudis PV. Safety and efficacy of albumin administration in trauma. Expert Opinion on

Drug Safety 2007; 6: 407415.13. Wong F. Drug insight: the role of albumin in the management of chronic liver disease. Nature Clinical Practice.

Gastroenterology & Hepatology 2007; 4: 4351.14. Liberati A, Moja L, Moschetti I et al. Human albumin solution for resuscitation and volume expansion in critically ill

patients. Internal and Emergency Medicine 2006; 1: 243245.15. MendezCM, McClain CJ & Marsano LS.Albumintherapy in clinicalpractice. Nutrition in Clinical Practice 2005; 20: 314320.16. Alderson P, Bunn F, Lefebvre C et al. Human albumin solution for resuscitation and volume expansion in critically ill

patients. Cochrane Database of Systematic Reviews (Online) 2004; 4. CD001208.17. Bayliss WM. Intravenous injection in wound shock. British Medical Journal 1918; 1: 553.

18. Le Gal YM. A review of the history of blood replacement from the 17th to the 20th centuries. Review of Surgery 1975; 32:229239.

19. Hogan JJ. The intravenous use of colloidal (gelatin) solutions in shock. The Journal of the American Medical Association1915; 64: 721.

20. Hecht G & Weese H. Periston, ein neuer Blutflussigkeitsersatz. MMW, Munchener Medizinische Wochenschrift 1943;90: 11.

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

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 influenceplatelet 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



18/20

21. Wesse H & Scholtan W. Pharmacology of periston N. Deutsche Medizinische Wochenschrift (1946) 1951; 76: 14921493.22. Gronwall A & Ingelman B. Untersuchungen uber Dextran und sein Verhalten bei parenteraler Zufuhr. I. Chemische und

physikalisch-chemische Untersuchungen uber Dextran. Acta Physiologica Scandinavica 1944; 7: 97107.23. Aktories K. General and specific pharmacology and toxicology. 9th edn. Munich: Elsevier, Urban & Fischer, 2006.24. Koekenberg LJ. Experimental use of macrodex as a prophylaxis against post-operative thrombo-embolism. Bulletin de la

Societe Internationale de Chirurgie 1962; 21: 501512.

25. Gruber UF. Prevention of fatal postoperative pulmonary embolism by heparin dihydroergotamine or dextran 70. TheBritish Journal of Surgery 1982; 69(Suppl.): S54S58.26. Gruber UF, Saldeen T, Brokop T et al. Incidences of fatal postoperative pulmonary embolism after prophylaxis with

dextran 70 and low-dose heparin: an international multicentre study. British Medical Journal 1980; 280: 6972.27. Hohl MK, Luscher KP, Tichy J et al. Prevention of postoperative thromboembolism by dextran 70 or low-dose heparin.

Obstetrics and Gynecology 1980; 55: 497500.28. Kamler M, Pizanis N, Hagl S et al. Extracorporal-circulation-induced leukocyte/endothelial cell interaction is inhibited

by dextran. Clinical Hemorheology and Microcirculation 2004; 31: 139148.29. Ljungstrom KG. The antithrombotic efficacy of dextran. Acta Chirurgica Scandinavica. Supplementum 1988; 543: 2630.30. Bronwell AW, Artz CP & Sako Y. Evaluation of blood loss from a standardized wound after dextran. Surgical Forum 1955;

5: 809814.31. Kruger K, Seifart W & Freudenberg R. Infusion incidents with dextran. Acta Anaesthesiologica 1988; 13: 259271.

*32. Schortgen F, Girou E, Deye N & Brochard L. The risk associated with hyperoncotic colloids in patients with shock.Intensive Care Medicine 2008; 34: 21572168.

33. Godwin G. Dextrans and compatibility testing. Transfusion 1987; 27: 366367.

34. Schortgen F, Deye N & Brochard L. Preferred plasma volume expanders for critically ill patients: results of an inter-national survey. Intensive Care Medicine 2004; 30: 22222229.

35. Hussain SF & Drew PJ. Acute renal failure after infusion of gelatins. British Medical Journal 1989; 299: 11371138.36. Wiedersheim M. An investigation of oxyethylstarch as a new plasma volume expander in animals. Archives Inter-

nationales de Pharmacodynamie et de Therapie 1957; 111: 353361.37. Mishler JM. Pharmacology of hydroxyethyl starch use in therapy and blood banking. New York, Toronto: Oxford

University Press, 1982.38. Food and Drug Administration. FDA approves voluven to treat serious blood volume loss following surgery. Available

from: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01765.html .39. Hoffmann JN, Vollmar B, Laschke MW et al. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves

microcirculation during normotensive endotoxemia. Anesthesiology 2002; 97: 460470.40. Singh N, Singh S, Kaur L et al. Morphological, thermal and rheological properties of starches from different botanical

sources. Food Chemistry 2003; 81: 219231.41. Sommermeyer R, Cech F & Schossow R. Differences in chemical structures between waxy maize- and potato-starch-

based hydroxyethyl starch volume therapeutics. Transfusion Alternatives in Transfusion Medicine 2007; 9: 127133.42. Godet MC, Tran V, Colonna P & Buleon A. Inclusion/exclusion of fatty acids in amylose complexes as a function of the

fatty acid chain length. International Journal of Biological Macromolecules 1995; 17: 405408.43. Szejtli J & Banky-Elod I. Determination of dissociation-constants of amylose clathrates. Starke 1978; 30: 8591.

*44. Jungheinrich C, Scharpf R, Wargenau M et al. The pharmacokinetics and tolerability of an intravenous infusion of thenew hydroxyethyl starch 130/0.4 (6%, 500 mL) in mild-to-severe renal impairment. Anesthesia and Analgesia 2002; 95:544551.

45. Yacobi A, Stoll RG, Sum CY et al. Pharmacokinetics of hydroxyethyl starch in normal subjects. Journal of ClinicalPharmacology 1982; 22: 206212.

46. Treib J, Haass A, Pindur G et al. HES 200/0.5 is not HES 200/0.5. Influence of the C2/C6 hydroxyethylation ratio ofhydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics. Thrombosis and Haemostasis 1995;74: 14521456.

47. Treib J, Haass A, Pindur G et al. Influence of intravascular molecular weight of hydroxyethyl starch on platelets.European Journal of Haematology 1996; 56: 168172.

48. Neff TA, Doelberg M, Jungheinrich C et al. Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in

patients with severe head injury. Anesthesia and Analgesia 2003; 96: 14531459.49. Stander S, Szepfalusi Z, Bohle B et al. Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study. Cell and Tissue Research 2001; 304: 261269.

50. Waitzinger J, Bepperling F, Pabst G & Opitz J. Hydroxyethyl starch (HES) [130/0.4], a new HES specification: pharma-cokinetics and safety after multiple infusions of 10% solution in healthy volunteers. Drugs in R&D 2003; 4: 149157.

51. Sirtl C, Laubenthal H, Zumtobel V et al. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related.British Journal of Anaesthesia 1999; 82: 510515.

52. Murphy M, Carmichael AJ, Lawler PG et al. The incidence of hydroxyethyl starch-associated pruritus. The British Journalof Dermatology 2001; 144: 973976.

53. Klemm E, Bepperling F, Burschka MA & Mosges R. Hemodilution therapy with hydroxyethyl starch solution (130/0.4) inunilateral idiopathic sudden sensorineural hearing loss: a dose-finding, double-blind, placebo-controlled, internationalmulticenter trial with 210 patients. Otology & Neurotology 2007; 28: 157170.

54. Rudolf J. Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: a randomized,placebo-controlled phase II safety study. Cerebrovascular Diseases (Basel, Switzerland) 2002; 14: 3341.

55. Ring J & Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977; 1:

466469.56. Laxenaire MC, Charpentier C & Feldman L. Anaphylactoid reactions to colloid plasma substitutes: incidence, risk factors,

mechanisms. A French multicenter prospective study.Annales Franaises DanesthesieetdeReanimation 1994; 13: 301310.57. Davidson IJ. Renal impact of fluid management with colloids: a comparative review. European Journal of Anaesthesiology

2006; 23: 721738.

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01765.htmlhttp://www.fda.gov/bbs/topics/NEWS/2007/NEW01765.html


19/20

*58. Boldt J & Priebe HJ. Intravascular volume replacement therapy with synthetic colloids: is there an influence on renalfunction? Anesthesia and Analgesia 2003; 96: 376382.

*59. Schortgen F, Lacherade JC, Bruneel F et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis:a multicentre randomised study. Lancet 2001; 357: 911916.

60. Boldt J, Brenner T, Lehmann A et al. Influence of two different volume replacement regimens on renal function inelderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. Intensive Care

Medicine 2003; 29: 763769.*61. Brunkhorst FM, Engel C, Bloos F et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. The NewEngland Journal of Medicine 2008; 358: 125139.

62. Moran M & Kapsner C. Acute renal failure associated with elevated plasma oncotic pressure. The New England Journal ofMedicine 1987; 317: 150153.

63. Boldt J. Hydroxyethylstarch as a risk factor for acute renal failure in severe sepsis. Lancet2001; 358: 581583.64. Thomas G, Balk EM & Jaber BL. Effect of intensive insulin therapy and pentastarch resuscitation on acute kidney injury

in severe sepsis. American Journal of Kidney Diseases 2008; 52: 1317.65. Matheson NA & Diomi P. Renal failure after the administration of dextran 40. Surgery, Gynecology & Obstetrics 1970;

131: 661668.66. Mailloux L, Swartz CD, Capizzi R et al. Acute renal failure after administration of low-molecular weight dextran. The

New England Journal of Medicine 1967; 277: 11131118.67. Morgan T & Little JM. Renal failure and low-molecular-weight dextran. British Medical Journal 1967; 1: 635.68. Vogt N, Brinkmann A & Georgieff M. The effect of HES, dextran and gelatin on kidney function. Anasthesiologie,

Intensivmedizin, Notfallmedizin, Schmerztherapie 1998; 33: 268270.

69. Dickenmann M, Oettl T & Mihatsch MJ. Osmotic nephrosis: acute kidney injury with accumulation of proximal tubularlysosomes due to administration of exogenous solutes. American Journal of Kidney Diseases 2008; 51: 491503.

70. Legendre C, Thervet E, Page B et al. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation.Lancet 1993; 342: 248249.

71. Eisenbach C, Schonfeld AH, Vogt N et al. Pharmacodynamics and organ storage of hydroxyethyl starch in acutehemodilution in pigs: influence of molecular weight and degree of substitution. Intensive Care Medicine 2007; 33:16371644.

72. Vogt NH, Bothner U, Lerch G et al. Large-dose administration of 6% hydroxyethyl starch 200/0.5 total hip arthroplasty:plasma homeostasis, hemostasis, and renal function compared to use of 5% human albumin. Anesthesia and Analgesia1996; 83: 262268.

*73. Sakr Y, Payen D, Reinhart K et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients.British Journal of Anaesthesia 2007; 98: 216224.

74. Ertmer C, Pinto BB, Rehberg S et al. Incidence of renal replacement therapy in intensive care patients treated withdifferent hydroxyethyl starch solutions. Intensive Care Medicine 2008; 34(Suppl. 1): S196.

*75. Boldt J, Brosch C, Rohm K et al. Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renalfunction and inflammatory response in elderly cardiac surgery patients. British Journal of Anaesthesia 2008; 100:457464.

*76. Perel P & Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database ofSystematic Reviews (Online) 2007; 4. CD000567.

*77. Bunn F, Trivedi D & Ashraf S. Colloid solutions for fluid resuscitation. Cochrane Database of Systematic Reviews (Online)2008; 1. CD001319.

78. Karanko MS. Effects of three colloid solutions on plasma volume and hemodynamics after coronary bypass surgery.Critical Care Medicine 1987; 15: 10151022.

79. Tollofsrud S, Svennevig JL, Breivik H et al. Fluid balance and pulmonary functions during and after coronary arterybypass surgery: Ringers acetate compared with dextran, polygeline, or albumin. Acta Anaesthesiologica Scandinavica1995; 39: 671677.

80. Hiippala S, Linko K, Myllyla G et al. Replacement of major surgical blood loss by hypo-oncotic or conventional plasmasubstitutes. Acta Anaesthesiologica Scandinavica 1995; 39: 228235.

81. Charlet P, Zerr C, Robert D et al. Comparative trials of fluid gelatins on hemostasis in heart surgery in adults. Cahiers

Danesthesiologie 1991; 39: 233238.82. Beards SC, Watt T, Edwards JD et al. Comparison of the hemodynamic and oxygen transport responses to modified fluidgelatin and hetastarch in critically ill patients: a prospective, randomized trial. Critical Care Medicine 1994; 22:600605.

83. Boldt J, Knothe C, Zickmann B et al. Influence of different intravascular volume therapies on platelet function in patientsundergoing cardiopulmonary bypass. Anesthesia and Analgesia 1993; 76: 11851190.

84. Asfar P, Kerkeni N, Labadie F et al. Assessment of hemodynamic and gastric mucosal acidosis with modified fluid versus6% hydroxyethyl starch: a prospective, randomized study. Intensive Care Medicine 2000; 26: 12821287.

85. Molnar Z, Mikor A, Leiner T & Szakmany T. Fluid resuscitation with colloids of different molecular weight in septicshock. Intensive Care Medicine 2004; 30: 13561360.

86. Allison KP, Gosling P, Jones S et al. Randomized trial of hydroxyethyl starch versus gelatine for trauma resuscitation. TheJournal of Trauma 1999; 47: 11141121.

87. Beyer R, Harmening U, Rittmeyer O et al. Use of modified fluid gelatin and hydroxyethyl starch for colloidal volumereplacement in major orthopaedic surgery. British Journal of Anaesthesia 1997; 78: 4450.

88. Huttner I, Boldt J, Haisch G et al. Influence of different colloids on molecular markers of haemostasis and platelet

function in patients undergoing major abdominal surgery. British Journal of Anaesthesia 2000; 85: 417423.89. Kumle B, Boldt J, Piper S et al. The influence of different intravascular volume replacement regimens on renal function

in the elderly. Anesthesia and Analgesia 1999; 89: 11241130.90. Niemi TT, Suojaranta-Ylinen RT, Kukkonen SI & Kuitunen AH. Gelatin and hydroxyethyl starch, but not albumin, impair

hemostasis after cardiac surgery. Anesthesia and Analgesia 2006; 102: 9981006.



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91. Van der Linden PJ, De Hert SG, Daper A et al. 3.5% urea-linked gelatin is as effective as 6% HES 200/0.5 for volumemanagement in cardiac surgery patients. Canadian Journal of Anaesthesia 2004; 51: 236241.

92. Verheij J, van Lingen A, Raijmakers PG et al. Effect of fluid loading with saline or colloids on pulmonary permeability,oedema and lung injury score after cardiac and major vascular surgery. British Journal of Anaesthesia 2006; 96: 2130.

93. Haisch G, Boldt J, Krebs C et al. Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation incardiac surgical patients. Journal of Cardiothoracic and Vascular Anesthesia 2001; 15: 316321.

94. HaischG, Boldt J, Krebs C et al.The influence of intravascularvolume therapy with a newhydroxyethyl starchpreparation(6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery. Anesthesia and Analgesia 2001; 92:565571.

95. Van der Linden PJ, De Hert SG, Deraedt D et al. Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for volumeexpansion in cardiac surgery patients: the effects on perioperative bleeding and transfusion needs. Anesthesia and

Analgesia 2005; 101: 629634.96. Boldt J, Zickmann B, Rapin J et al. Influence of volume replacement with different HES-solutions on microcirculatory

blood flow in cardiac surgery. Acta Anaesthesiologica Scandinavica 1994; 38: 432438.97. Gan TJ, Bennett-Guerrero E, Phillips-Bute B et al. Hextend, a physiologically balanced plasma expander for large volume

use in major surgery: a randomized phase III clinical trial. Hextend study group. Anesthesia and Analgesia 1999; 88:992998.

98. Boldt J, Haisch G, Suttner S et al. Effects of a new modified, balanced hydroxyethyl starch preparation (Hextend) onmeasures of coagulation. British Journal of Anaesthesia 2002; 89: 722728.

99. Langeron O, Doelberg M, Ang ET et al. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causesfewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesthesia and Analgesia 2001; 92:

855862.100. Gallandat Huet RC, Siemons AW, Baus D et al. A novel hydroxyethyl starch (Voluven) for effective perioperative plasma

volume substitution in cardiac surgery. Canadian Journal of Anaesthesia 2000; 47: 12071215.101. Boldt J, Lehmann A, Rompert R et al. Volume therapy with a new hydroxyethyl starch solution in cardiac surgical

patients before cardiopulmonary bypass. Journal of Cardiothoracic and Vascular Anesthesia 2000; 14: 264268.102. Boldt J, Schollhorn T, Munchbach J & Pabsdorf M. A total balanced volume replacement strategy using a new balanced

hydoxyethyl starch preparation (6% HES 130/0.42) in patients undergoing major abdominal surgery. European Journal ofAnaesthesiology 2007; 24: 267275.

103. Kozek-Langenecker SA, Jungheinrich C, Sauermann W & Van der Linden P. The effects of hydroxyethyl starch 130/0.4(6%) on blood loss and use of blood products in major surgery: a pooled analysis of randomized clinical trials. Anesthesiaand Analgesia 2008; 107: 382390.

104. Boldt J, Brosch C, Ducke M et al. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidneyfunction in cardiac surgery patients with compromised renal function: a comparison with human albumin. Critical CareMedicine 2007; 35: 27402746.

105. Wilkes NJ, Woolf RL, Powanda MC et al. Hydroxyethyl starch in balanced electrolyte solution (Hextend) pharma-cokinetic and pharmacodynamic profiles in healthy volunteers. Anesthesia and Analgesia 2002; 94: 538544.

106. Jungheinrich C & Neff TA. Pharmacokinetics of hydroxyethyl starch. Clinical Pharmacokinetics 2005; 44: 681699.107. Boldt J. Volume therapy in cardiac surgery: does the kind of fluid matter? Journal of Cardiothoracic and Vascular

Anesthesia 1999; 13: 752763.108. Boldt J. Volume replacement therapy. Stuttgart: Georg Thieme, 2001.109. Tonnessen T, Tollofsrud S, Kongsgaard UE & Noddeland H. Colloid osmotic pressure of plasma replacement fluids. Acta

Anaesthesiologica Scandinavica 1993; 37: 424426.


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