Intensive Care Med (2012) 38:368–383
DOI 10.1007/s00134-012-2472-9
Konrad Reinhart
Anders Perner
Charles L. Sprung
Roman Jaeschke
Frederique Schortgen
A. B. Johan Groeneveld
Richard Beale
Christiane S. Hartog
Received: 3 January 2012
Accepted: 5 January 2012
Published online: 10 February 2012
Ó Copyright jointly held by Springer and
ESICM 2012
Electronic supplementary material
The online version of this article
(doi:10.1007/s00134-012-2472-9) contains
supplementary material, which is available
to authorized users.
K. Reinhart ())
C. S. Hartog
Department for Anesthesiology and
Intensive Care Medicine, Jena University
Hospital, Friedrich-Schiller University,
Erlanger Allee 101, 07747 Jena, Germany
e-mail: konrad.reinhart@med.uni-jena.de
Tel.: ?49-3641-9323101
Fax: ?49-3641-9323102
A. Perner
Department of Intensive Care,
Rigshospitalet, Copenhagen University
Hospital, Copenhagen, Denmark
C. L. Sprung
Department of Anesthesiology and Critical Methods: Meta-analyses, system-
Care Medicine, Hadassah Hebrew
University Medical Center,
Jerusalem, Israel
R. Jaeschke
Department of Medicine and Department
of Clinical Epidemiology and Biostatistics, organ donor patients. Clinical end-
McMaster University, Hamilton,
ON, Canada
SPECIAL ARTICLE
Consensus statement of the ESICM task
force on colloid volume therapy in critically
ill patients
F. Schortgen
Réanimation Médicale, AP-HP,
Groupe Hospitalier Albert Chenevier,
Henri Mondor, Créteil, France
A. B. Johan Groeneveld
Erasmus Medical Centre, Rotterdam,
The Netherlands
R. Beale
Department of Adult Critical Care,
Guy’s and St Thomas’ NHS Foundation
Trust, London, UK
Abstract Purpose: Colloids are
administered to more patients than
crystalloids, although recent evidence
suggests that colloids may possibly be
harmful in some patients. The Euro-
pean Society of Intensive Care
Medicine therefore assembled a task
force to compile consensus recom-
mendations based on the current best
evidence for the safety and efficacy of
the currently most frequently used
colloids—hydroxyethyl starches
(HES), gelatins and human albumin.
atic reviews and clinical studies of
colloid use were evaluated for the
treatment of volume depletion in
mixed intensive care unit (ICU), car-
diac surgery, head injury, sepsis and
points included mortality, kidney
function and bleeding. The relevance
of concentration and dosage was also
assessed. Publications from 1960
until May 2011 were included. The
quality of available evidence and
strength of recommendations were
based on the Grading of Recommen-
dations Assessment, Development,
and Evaluation (GRADE) approach.
Recommendations and conclu-
sions: We recommend not to use
HES with molecular weight
C200 kDa and/or degree of substitu-
tion [0.4 in patients with severe
sepsis or risk of acute kidney injury
and suggest not to use 6% HES
130/0.4 or gelatin in these popula-
tions. We recommend not to use
colloids in patients with head injury
and not to administer gelatins and
HES in organ donors. We suggest not
to use hyperoncotic solutions for fluid
resuscitation. We conclude and rec-
ommend that any new colloid should
be introduced into clinical practice
only after its patient-important safety
parameters are established.
Keywords Recommendations

Systematic review
Colloids

Hydroxyethyl starch
Gelatin

Albumin
Adverse effects

Rationale
Fluid resuscitation with colloids is a difficult issue for
practising clinicians. The European Society of Intensive
Care Medicine (ESICM) is striving to improve patient
care and has the mission to assist clinical decision-making
based on the available evidence base. Recent clinical data
indicate that colloids in general do not improve patient
outcomes and may be harmful or beneficial depending on
the setting and type of colloid. Therefore, the society
deemed an independent evaluation of the efficacy and
safety of colloids in critically ill patients to be timely, and
assembled a task force to address this issue and compile
consensus recommendations based on the current best
evidence.
Consensus recommendations may be more urgent now
after the publication of several meta-analyses and one
recent study on fluid therapy with albumin versus
hydroxyethyl starch (HES) which was found to be fraud-
ulent [1, 2]. Fortunately, it seems clear that withdrawal of
these studies does not change the cumulated evidence
[3–7]. Synthetic colloids received market approval in the
1960s or earlier without evaluation of their efficacy and
safety in large phase III clinical trials (more detail in ESM
A. ‘‘Historical Background’’). Presently, they are more
frequently administered to resuscitate critically ill patients
than crystalloids [8] and HES is the most widely used
colloid, followed by gelatins and human albumin [8, 9].
The primary question addressed in this review is an
independent evaluation of the efficacy and safety of col-
loids. This work extends and updates previous guidelines
endorsed by medical societies [10–12], systematically
addressing and grading evidence on the safety of newer
starches and gelatin. It differs specifically from guidelines
which have been criticised for their poor methodology
[13, 14].
Methods
Search strategy
Meta-analyses and systematic reviews
We systematically searched for meta-analyses and sys-
tematic reviews on the safety and/or efficacy of colloids
or colloid fluid classes based on Cochrane Collaboration
search strategies with comprehensive screening of elec-
tronic databases (MEDLINE via PubMed, OVID and ISI
Web of Knowledge and EMBASE, CENTRAL) by an
electronic search strategy (see ESM). The updated search
period extends from 1960 until May 2011.
In addition, we had searched own literature archives as
well as most recent systematic analyses on fluid therapy
[15–19]. To assess safety issues of colloid use, we also
used other sources such as the study roster for the market
369
approval of HES 130/0.4 in the USA (further details see
ESM B. ‘‘Supplementary Methods’’).
Validation and grading of evidence
Results identified by this search were considered to rep-
resent the best-quality evidence. These results were
tabulated according to patient population, intervention,
control and outcome (PICO) because we believe that the
efficacy and safety of any intervention may be context
dependent (i.e. dependent on different patient popula-
tions, type of intervention and comparator fluids,
and different measured outcomes; C. ‘‘Supplementary
Methods’’). Judgment was based on the GRADE
approach (C. ‘‘Supplementary Methods’’). The GRADE
approach does not grade quality of individual studies but
sequentially assesses the quality of evidence for individ-
ual outcomes of interest coming from the body of best
available studies (Fig. 1) followed by assessment of the
balance between benefits versus risks, burden and cost.
Results
Twenty-five meta-analyses, four systematic reviews and
two health technology assessment reports were identified;
a complete overview is given in Tables 1 and 2. Meta-
analyses assessed survival as well as safety outcomes. In
addition, 31 randomized, non-randomized and observa-
tional studies and reports, which assessed clinically
relevant outcomes, were identified since 2002 (Table 3).
Most outcome data was found for albumin and HES.
There was less clinical data for gelatin, probably because
it was withdrawn from the market in the USA in 1978 due
to concerns about bleeding complications [20]. Dextran is
rarely used nowadays in adults, and therefore was not
included.
Colloids in mixed ICU patient populations
Albumin
Survival: In 1998, the Cochrane injuries group reported
that human albumin and plasma protein fraction (PPF)
compared with no human albumin or PPF or with crys-
talloids in patients with hypovolaemia, burns or
hypoalbuminaemia resulted in a significantly higher risk
of death [21, 22], whereas another meta-analysis in mixed
patient populations indicated no effect of albumin on
mortality [23]. Therefore, a blinded RCT in 7,000 criti-
cally ill ICU patients was designed and conducted which
demonstrated that survival after 4% albumin or 0.9%
saline was similar [relative risk (RR) of death, 0.99; 95%
confidence interval (CI) 0.91–1.09] [24]. A subsequent
370
Evidence (QoE)
Study design
Randomized baseline for well done
trials RCTs or upgraded
observational data
downgraded RCTs
or upgraded Moderate (B)
observational data
Observational baseline for well
studies done observational
studies or
downgraded RCT
downgraded observa-
tional or RCT data
Fig. 1 Quality of evidence. The QoE reflects the panel’s opinion
that the available data reflects the true effect of an intervention and
is sufficient to support particular recommendation. The following
judgment on strength of recommendation (strong versus weak)
reflects the judgment that the desirable effects of following the
recommendation (health benefits, less effort and inconvenience and
lower cost) will clearly outweigh the undesirable effects (harms,
meta-analysis including critically ill patients [25] sup-
ported the findings of the SAFE study with similar
outcomes. One meta-analysis that compared albumin with
no albumin or lower-dose albumin suggested an overall
reduction in morbidity by albumin, defined as incidence
of complications including death [26].
Safety: Albumin is a human blood product and therefore
carries the potential risk of viral disease transmission
(e.g. hepatitis A, parvovirus) and prion disease transmission
(e.g. Creutzfeldt–Jacob disease). In a pharmacovigilance
study including data from 10 major suppliers between 1998
and 2000, no incidence of viral disease transmission was
reported [27]. One meta-analysis assessed the effect of
albumin administration on morbidity, defined as the inci-
dence of complications including death, in acutely ill
hospitalized patients [26]. It found that albumin signifi-
cantly reduced overall morbidity, with RR of 0.92 (CI
0.86–0.98) [26]. On the basis of large-scale pharmacovig-
ilance study results, albumin infusion resulted in a low rate
of both total adverse events (3.1–8.6 per 105 infusions) and
serious adverse events (1.3 per 106 infusions) [28]. In the
SAFE study, days of renal replacement therapy were similar
in the 4% albumin and 0.9% saline group (0.48 ± 2.28
versus 0.39 ± 2.0 days) [24]. The most recent systematic
review on colloid safety confirmed the findings that albu-
min was the safest colloid [29].
Synthetic colloids
Survival: A meta-analysis updated in 2007 and 2009
found no statistically significant differences in mortality
in patients treated with HES versus crystalloid, modified
Quality of
Factors influencing baseline QoE
Increase Large effect
High (A) (applies mostly (may increase by 1 or 2
to well done levels)
observational
studies) Dose response
Lower Risk of bias
(each factor
Heterogeneity
Low (C) may lower by 1
(Inconsistency)
or 2 levels)
Indirectness to
question asked
Very low (D)
Imprecision
burdens and costs): A strong recommendation (labelled as 1)
reflects panel’s certainty that actions consistent with given recom-
mendations will result in more good than harm, while a weak
recommendation (suggestion, labelled as 2) reflects the panel’s
opinion that the balance of benefits and harms is likely in favour of
a given recommendation, but panel members are not confident in
this judgment
gelatin versus crystalloid, dextran versus crystalloid, in a
mixed patient population including trauma, burns, sepsis
or undergoing surgery [3].
Safety: One meta-analysis examined the effects of HES on
kidney function compared with other fluid resuscitation
therapies in perioperative and ICU patients with intra-
vascular volume depletion. The review included 34
studies (2,607 patients). Overall, the RR of author-defined
kidney failure was 1.50 (95% CI 1.20–1.87; n = 1,199)
and 1.38 for requiring renal replacement therapy (RRT)
(95% CI 0.89–2.16; n = 1,236) in HES-treated patients
compared with other fluid therapies [18]. Another meta-
analysis assessed the effect of HES solutions on renal
outcomes and mortality among critically ill patients.
Twenty-two trials (n = 1,865 patients) were included.
RRT was more likely after HES in comparison with an
alternative resuscitation fluid [odds ratio (OR) 1.90, 95%
CI 1.22–2.96; n = 749] [30]. Three systematic reviews
suggested that all synthetic colloids HES, gelatin and
dextran exhibited renal side-effects [28, 29, 31]. On the
other hand, a large European multicentric observational
study in 3,147 ICU patients found that HES administra-
tion was not associated with increased risk for subsequent
RRT (OR 0.417; CI 0.05–3.27). Total HES dose per
patient was low (approx. 15 mL/kg) [32].
With albumin as the reference colloid, the incidence
rate ratio for anaphylactoid reactions was 4.51 (95% CI
2.06–9.89) after HES, 2.32 (95% CI 1.21–4.45) after
dextran and 12.4 (95% CI 6.40–24.0) after gelatin. Pru-
ritus occurrence was significantly increased by HES
exposure (OR 1.78; 95% CI 1.23–2.58) [28]. There are no
RCTs with study periods over 24 h for gelatin in mixed
ICU patients (data not shown), and no RCTs for HES

Table 1 Colloids versus crystalloids or alternatives
Author Type Main characteristics
Any crystalloid versus colloid
Velanovich [81] MA P: Trauma and non-trauma
patients
I: Any crystalloid
C: Any colloid
O: Mortality
Bisonni [82] MA P: Injured patients with
hypovolaemia, patients with
surgical stress, patients with
pulmonary failure
I: Any crystalloid
C: Any colloid
O: Mortality
Schierhout and Roberts [83] MA P: Injured patients with
hypovolaemia, patients with
surgical stress, patients with
pulmonary failure
I: Any crystalloid
C: Any colloid
O: Mortality
Himpe et al. [84] MA P: Colloidal pump priming
solutions for cardiopulmonary
bypass
I: Any crystalloid
C: Any colloid except dextran
O: Mortality and various
outcomes
Heier [16] HTA P: Patients with acute bleeding in
trauma and surgery within
24 h after the start of bleeding
I: Transfusion
C: Alternative treatment
modalities
O: Length of hospital stay,
survival, complications and
use of blood products
Cochrane Injuries Group: Alderson [85]; MA P: Patients with trauma, burns or
Roberts [86]; Perel [3, 19] sepsis, or undergoing surgery
I: Any crystalloid
C: Any colloid
O: Mortality
Akech et al. [87] SR P: Children with severe infection
an shock
I: Crystalloids
C: Colloids
O: Efficacy in the treatment of
shock, mortality and reported
adverse effects
371
Direction of effect
Non-significant trend towards crystalloids
associated with lower mortality in trauma
patients
No statistically significant differences in
mortality between groups in injured
patients with hypovolaemia
Non-significant trend towards crystalloids
being more effective than colloids for
trauma patients
Mortality or postoperative bleeding between
colloids and crystalloids did not differ.
Colloids produced significantly higher
oncotic pressures and less positive fluid
balances. Platelet counts were
significantly favoured by crystalloids;
compared with albumin, platelet counts
were significantly disfavoured only by
starches
Three sections: (1) volume replacement,
(2) oxygen transportation and (3)
haemostasis.
On volume replacement: No documentation
exists of albumin superiority over
artificial colloids or crystalloids. No
evidence was found that artificial colloids
are to be preferred over crystalloids in
bleeding patients. One of the difficulties
with treatment strategies in acutely
bleeding patients is the scarcity of
published evidence for or against basic
intervention strategies
No evidence from RCTs that resuscitation
with colloids reduces risk of death
compared with resuscitation with
crystalloids, in patients with trauma, burns
or following surgery. For meta-analyses of
HES versus crystalloid, modified gelatin
versus crystalloid, dextran versus
crystalloid, there were no statistically
significant differences in mortality. When
the trials by Boldt et al. were removed
from the three preceding analyses, the
results were unchanged
No trial reported mortality; three studies
which reported at least one death showed
better survival in children resuscitated
with colloids. Studies were
heterogeneous, so combined estimates
were not calculated
372

Table 1 continued
Author Type Main characteristics Direction of effect

Isotonic crystalloid versus colloid

Choi et al. [88] MA P: Adults requiring fluid
resuscitation
I: Any crystalloid
C: Any colloid
O: Mortality
Any i.v. fluid versus another treatment or fluid
Dretzke et al. [15] HTA P: Trauma patients who have
haemorrhage-induced
hypotension due to trauma
excluding patients with head
injury
I: Prehospital IV fluid
replacement
C: No IV fluid replacement or
delayed fluid replacement
O: Benefit and costs
Cyna et al. [89] MA P: Pregnant women receiving
spinal anaesthesia for
Caesarean section
I: Prophylactic interventions
C: Placebo or alternative
treatment
O: Prevention of hypotension
following neural block
Cochrane Peripheral Vascular Diseases Group: MA P: Patients requiring IV fluids for No single fluid affected any outcome
Toomtong et al. [17] abdominal aortic surgery
I: Non-blood replacement fluids
C: Other non-blood replacement
fluids
O: Mortality
Tables based on Dretzke et al. [15] and brought up to date
MA meta-analysis, HTA health technology assessment report, SR systematic review
No difference between crystalloid and
colloid resuscitation with respect to
mortality and pulmonary oedema;
subgroup analysis suggested a statistically
significant difference in mortality in
trauma in favour of crystalloid
resuscitation
No reliable evidence was found from
systematic reviews to suggest that a
particular type of fluid is more beneficial
over another type of fluid in trauma
patients, although there was a trend
favouring crystalloids over colloids. There
is no evidence to suggest that prehospital
IV fluid resuscitation is beneficial, but
some evidence that it may be harmful and
that patients do comparatively well when
fluids are withheld
Crystalloids were more effective than no
fluids, and colloids were more effective
than crystalloids to prevent hypotension
following neural block. No single method
completely prevented hypotension; no
difference existed between doses, no
differences were detected for different
doses, rates or methods of administering
colloids or crystalloids
measure significantly more than another
fluid across a range of outcomes. For
primary outcome death, results were
limited

130/0.4 in this population [6]. We consider the evidence
for renal effects as having moderate quality for HES with
molecular weight C200 kDa and/or degree of substitution
[0.4, and low quality for HES 130/0.4. Taking into
account the lack of direct evidence of safety for other
synthetic colloids it is our judgment that such evidence
could be applied indirectly to this category of drugs, i.e.
low quality for gelatin.
Colloids in specific patient populations
Albumin
Sepsis and severe infection. Survival: A recent meta-
analysis on albumin for resuscitation of patients with
sepsis included 17 studies that randomized 1,977 patients
[5]. Use of albumin in comparison with non-albumin
fluids was associated with a reduction in mortality with
OR of 0.82 (95% CI 0.67–1.0) [5]. Recent meta-analyses
also suggested a decreased risk of dying with albumin
administration in children with malaria when compared
with gelatin (RR 0.19; 95% CI 0.06–0.59; p = 0.004)
[33], however it cannot be ruled out that the mortality
difference may be due to harmful effects from gelatin. A
pre-defined subgroup analysis of 1,218 patients with
severe sepsis from the SAFE trial showed a trend towards
reduced 28-day mortality after albumin [24]. A sub-
sequent analysis found an adjusted OR for death for
albumin versus saline of 0.71 (95% CI 0.52–0.97) using
multivariate logistic regression analysis adjusted for
baseline factors in patients with complete baseline data
(919/1,218; 76%) [34]. On the other hand, in a recent
multicentre RCT, fluid boluses significantly increased
48-h mortality in critically ill children with severe
infection [10.6% deaths (n = 111/1,050) in children who
received 5% albumin, 10.5% deaths (n = 110/1,047) in
children receiving saline and 7.3% deaths (n = 76/1,044)
in children who received no fluid bolus] [35]. Of note,
 373

Table 2 Colloid classes versus other fluids

Author Type Main characteristics Direction of effect

Colloid versus different classes of colloids

Bunn et al. [90], MA P: Patients requiring volume replacement or No statistically significant difference between
Bunn [4] maintenance of colloid osmotic pressure albumin/plasma protein fraction (PPF) versus
I: Any colloid gelatin (7 studies), modified gelatin versus HES
C: Any different class of colloid (18 studies) or albumin/PPF versus HES (25
O: Mortality studies), or albumin/PPF versus dextran (4
studies). Relative risk (RR) was not estimable in
the gelatin versus dextran and HES versus
dextran groups
For albumin or PPF versus hydroxyethyl starch
(HES), 25 trials (n = 1,234) reported mortality.
The pooled relative risk (RR) was 1.14 [95%
confidence interval (CI) 0.91–1.43]. When the
trials by Boldt are removed from the analysis
the pooled RR was 0.97 (95% CI 0.70–1.35)
Barron et al. [28] SR and MA P: Patients requiring volume replacement or Evidence sought from controlled trials, cohort
maintenance of colloid osmotic pressure studies, pharmacovigilance studies and prior
I: Any colloid meta-analyses showed that—with albumin as
C: Any other fluid the reference colloid—artificial colloids had an
O: Clinical outcomes increased risk for anaphylactoid reactions and
pruritus and were consistently associated with
coagulopathy and clinical bleeding, most
frequently in cardiac surgery patients receiving
hydroxyethyl starch
Davidson [31] SR P: Both clinical and model system studies were Artificial colloids HES, gelatin and dextran all
eligible for consideration exhibited troublesome renal side-effects
I: Any colloid
C: Any other fluid
O: Renal outcomes
Groeneveld et al. SR P: Acutely ill patients receiving colloids for New safety data, since 2002, predominantly
[29] hypovolaemia, cardiopulmonary bypass, concerned albumin or HES. Albumin did not
augmentation of serum albumin or colloid adversely affect survival in critically ill
oncotic pressure; reported no earlier than 2002 patients. Acute kidney injury and a dose-
I: Any colloid dependent increase in mortality were observed
C: Any other colloid in patients with severe sepsis or septic shock
O: Clinical outcomes (mortality, morbidity, receiving HES. Impaired coagulation and
bleeding and impaired coagulation, and acute clinical bleeding were frequently reported after
kidney injury) HES infusion, especially in cardiac surgery. In
head-to-head randomized comparisons of
different HES solutions, observed effects on
coagulation and renal function were similar.
Gelatin showed less impairment of coagulation
than HES. Very few safety data related to
dextran were identified
Albumin or albumin/PPF versus no albumin, other colloids or crystalloids
Cochrane Injuries MA P: Critically ill patients with hypovolaemia, burns For each patient category the risk of death in the
Group [21]; or hypoalbuminaemia albumin-treated group was significantly higher
Alderson et al. I: Albumin/PPF than in the comparison group
[22] C: No albumin/PPF or crystalloid
O: Mortality
Wilkes et al. [23] MA P: Patients with surgery or trauma, burns, Albumin administration did not significantly
hypoalbuminaemia, ascites, high-risk neonates affect mortality in any category of indications
and other indications
I: Albumin
C: Crystalloid therapy, no albumin or lower doses
of albumin
O: Mortality
Alderson et al. MA updated P: Critically ill patients with hypovolaemia, burns No evidence that albumin reduces mortality in any
[25] after or hypoalbuminaemia of the specified patient groups
SAFE I: Albumin/PPF
trial [24] C: No albumin/PPF or crystalloid
O: Mortality
374

Table 2 continued
Author Type Main characteristics Direction of effect

Vincent et al. [26] MA P: Hospitalized patients Albumin significantly reduced overall morbidity
I: Albumin in hospitalized patients
C: Crystalloids, no albumin or lower-dose
albumin
O: Morbidity (defined as incidence of
complications, including death)
Russell et al. [37] MA P: Adult and paediatric patients undergoing Albumin prime significantly reduced the on-
cardiac surgery with cardiopulmonary bypass bypass drop in platelet counts. Albumin prime
(CPB) reduced on-bypass positive fluid balance and
I: Albumin postoperative weight gain compared with
C: Crystalloid crystalloid
O: Platelets, fluid balance
Akech et al. [33] MA P: Children with severe malaria In the three included studies, albumin consistently
I: Albumin and significantly reduced risk of death
C: Gelatin or saline compared with saline or Gelofusine fluid
O: Mortality boluses
Liberati et al. [91] MA P: Critically ill patients with hypovolaemia, No difference overall. In the subgroup of patients
burns or hypoalbuminaemia with burns, relative risk of death was increased
I: Albumin/PPF after albumin administration
C: No albumin/PPF or crystalloid
O: Mortality
Jacob et al. [59] MA P: Patients with surgery or trauma, burns, No effect of 20–25% albumin on survival; limited
hypoalbuminaemia, ascites, high-risk evidence of clinical benefit, such as reduction in
neonates and other indications morbidity in high-risk neonates and brain
I: Hyperoncotic albumin (20–25%) injury, avoidance of major organ oedema in
C: HES, crystalloid, no albumin or lower-dose surgery and high-risk neonates, and
albumin preservation of renal function in surgery and
O: Mortality and various clinical outcomes liver disease
Delaney et al. [5] MA P: Population or subgroup of participants with Use of albumin for resuscitation of patients with
sepsis sepsis was associated with a reduction in
I: Albumin-containing solutions mortality. Excluding retracted studies by Boldt
C: Other fluid resuscitation regimen et al., the estimate of the odds ratio for
O: Mortality mortality for patients with severe sepsis who are
resuscitated with regimens that include albumin
solutions is 0.76 (95% confidence limits
0.62–0.95, p = 0.015)
HES versus albumin, other HES, or other fluids
Wilkes et al. [44] MA P: Cardiopulmonary bypass (CPB) patients Postoperative bleeding was significantly lower in
I: Albumin the albumin group. Bleeding differences
C: HES between albumin and either high (HES 450) or
O: Postoperative bleeding medium molecular weight HES (HES 200) were
similar
Kozek- MA of P: Patients receiving surgery Analysis of seven clinical trials in the
Langenecker pooled I: 6% HES 130/0.4 perioperative setting showed that estimated
et al. [75] data C: 6% HES 200/0.5 blood loss was reduced after HES 130
O: Postoperative blood loss
Wiedermann [41] MA P: Patients with severe sepsis HES increased the risk of acute renal failure
I: HES among patients with sepsis and might also
C: Other fluids reduce the probability of survival
O: Clinical outcomes
Zarychanski et al. MA P: Critically ill patients requiring acute volume HES increased the risk for renal replacement
[30] resuscitation therapy. There was no difference in overall
I: HES mortality but a trend toward increased risk of
C: Other fluids death after HES in trials that included patients
O: Renal outcomes and mortality with severe sepsis and septic shock, in high-
quality and multicentre trials, and in trials with
adequate allocation concealment

Table 2 continued
Author Type Main characteristics
Dart et al. [18] MA P: Patients in need of fluid resuscitation
I: HES
C: Other fluids
O: Renal outcomes
Wiedermann MA P: Patients receiving hyperoncotic colloids
et al. [60] I: Hyperoncotic HES
C: Hyperoncotic albumin
O: Renal outcomes and mortality
Hartog et al. [6] SR P: Patients in need of fluid resuscitation
I: 6% HES 130/0.4
C: Other fluids
O: Clinical outcomes
Tables based on Dretzke et al. [15] and brought up to date
MA meta-analysis, HTA health technology assessment report, SR systematic review
these were mostly children without hypotension and
treated outside the ICU.
Safety: In a pre-defined subgroup analysis of an RCT
with 1,218 patients with severe sepsis, 113/603 (18.7%)
of patients assigned albumin were treated with RRT
compared with 112/615 (18.2%) assigned saline
(p = 0.98); duration of RRT was also comparable
between patients with sepsis receiving 4% albumin
(1.2 ± 3.6 days) or 0.9% saline (1.0 ± 3.1 days) [34].
An as yet unpublished French trial (EARSS clinicaltri-
als.gov NCT00327704) randomized 800 septic patients to
placebo or 20% albumin to reverse hypoalbuminaemia.
The results were reported at the ISICEM 2011 meeting,
and there was no difference in incidence of renal failure
or mortality between the groups. Currently, 20% albumin
is being assessed in an Italian trial (ALBIOS study, ESM).
Cardiac surgery. Survival: Albumin use was associated
with reduced risk for death in a retrospective analysis of
nearly 20,000 patients undergoing cardiac surgery with
coronary artery bypass compared with HES or dextran use
(OR 0.80; 95% CI 0.67–0.96) [36].
Safety: One meta-analysis assessed the effects of albumin
versus crystalloid for pump priming in 21 trials with
1,346 adult and paediatric patients and found similar
blood loss [mL, pooled group mean (CI) 817 (587–1,048)
versus 881 (693–1,069)] [37].
Head injury. Survival: The subgroup of trauma patients
with head injury from the SAFE trial who received 4%
human albumin instead of 0.9% saline had a significantly
higher risk of death [24]. These patients showed a higher
375
Direction of effect
Overall, HES increased the risk of author-defined
kidney failure. Subgroup analyses suggested
increased risk in septic patients compared with
non-septic (surgical/trauma) patients, but
studies in non-septic patients had low statistical
power. Only limited data were obtained for
analysis of kidney outcomes by the RIFLE
criteria. Clinical data are inadequate to address
the claim that safety differences exist between
different HES products
Clinical indications were ascites, surgery, sepsis
and spontaneous bacterial peritonitis.
Hyperoncotic albumin decreased the odds of
acute kidney injury (AKI) and improved
survival compared with hyperoncotic HES
Published studies on HES 130 are inadequately
designed and do not allow relevant conclusions
about safety. The extent of fluid load reduction
that can be achieved by HES 130/0.4 is
overestimated
long-term mortality rate and more neurological sequelae
after 2 years [38].
Synthetic colloids
Sepsis. Survival: One RCT which compared 10% HES
200/0.5 with Ringer’s lactate found a trend towards a
higher mortality rate in the starch group [39]. The rate of
death at 90 days was significantly increased (58% versus
31%; p \ 0.001) for patients who received higher doses
of HES (136 mL/kg over 21 days) as compared with
those who received lower doses (48 mL/kg over 21 days)
[39]. This association between cumulative dose and
mortality was not seen in the crystalloid group [39].
Another RCT which compared HES against gelatin found
no effect on mortality but was not powered to show sur-
vival differences [40]. One subsequent meta-analysis
suggested a trend towards increased mortality after HES
in comparison with alternative resuscitation fluids in trials
that included patients with severe sepsis and septic shock,
in high-quality and multicentre trials [30].
Safety: Patients with severe sepsis who received HES
received significantly more red blood cell transfusion
units than patients receiving Ringer’s lactate (median 6,
interquartile range 4–12 versus 4, 2–8) [39].
One RCT that compared 6% HES 200/0.6 preparation
with 3% gelatin in severe sepsis patients found increased
incidence of acute kidney injury (AKI) defined as a
twofold increase in creatinine with HES [27/65 (42%)
versus 15/64 (23%), p = 0.03] [40]. Another multicentre
comparison of 10% HES 200/0.5 preparation with
376

Table 3 Other studies and reports

Author Type of study Population Primary outcomes or study design

Arellano [65] Multicentre blinded RCT Major reconstructive head/neck Effect of 10% HES 264/0.45 versus 5% albumin
surgery on 24-h blood loss
Auwerda [68] Cohort study Plasmapheresis Plasma chitotriosidase activity (marker for
lysosomal storage)
Avorn [46] Case–control study Coronary artery bypass surgery Effect of 6% HES 450/0.7 on postoperative
bleeding
Bayer [92] Before-and-after cohort study Severe sepsis Effect of predominantly HES 130/0.4, 4% gelatin
and only crystalloids on renal function
Boussekey [71] Cohort study ICU patients Effect of 6% HES 130/0.4 on kidney function
Brunkhorst [39] Multicentre RCT Severe sepsis Effect of 10% HES 200/0.5 on 28-day mortality
Cittanova [53] RCT Brain-dead organ donors Kidney graft function after 6% HES 200/0.6 or
3% gelatin
Deman [57] Multicentre cohort study Brain-dead organ donors Kidney graft function after 6% HES 200/0.5, 6%
HES 450/0.6 and no HES
Finfer [24] Multicentre blinded RCT ICU patients Effect of 4% albumin versus 0.9% saline on
28-day mortality
Finfer [34] Predefined subgroup analysis Severe sepsis Effect of 4% albumin versus 0.9% saline on
28-day mortality
Ginz [69] Case report ICU patient Autopsy
Giral [55] Cohort study Brain-dead organ donors Kidney graft function after HES
Gondos [93] Multicentre RCT ICU patients Fluid loading with Ringer’s acetate, 4% gelatin,
6% HES 130/0.4 or 5% albumin over 30 min
Hecht-Dolnik RCT Off-pump coronary bypass Effect of 1L 6% HES 450/0.7 or 5% albumin on
[94] surgery postoperative bleeding
Hokema [56] Cohort study Recipients of kidney grafts Kidney graft function after intra-operative 6%
HES 130/0.4 and no HES
Kasper [72] RCT Coronary artery bypass surgery Effect of 6% HES 130/0.4 or 6% HES 200/0.5 on
postoperative bleeding
Lissauer [50] Retrospective cohort study Trauma patients Outcome after 6% HES 450/0.7 and no HES
Magder [49] Blinded RCT Hypovolaemia after cardiac Need for vasopressors at 24 h after 0.9% saline or
surgery 10% HES 200/0.5
Maitland [35] Multicentre RCT African children with severe Effect of fluid bolus with 5% albumin or 0.9%
infection saline or no bolus on 48-h mortality
Moskowitz [45] Cohort study Cardiac surgery Effect of doses \20 mL/kg 6% HES 450/0.7 on
postoperative bleeding
Myburgh [38] Post hoc follow-up study Traumatic head injury Vital status and functional neurologic outcomes
24 months
Neff [52] RCT Traumatic head injury Effect of 6% HES 130/0.4 or 6% HES 200/0.5
Rioux [48] Cohort study Cardiac surgery Risk of acute kidney injury after 10% HES
200/0.45
Robert [54] Multicentre prospective cohort Brain-dead organ donors Kidney graft function after HES
study
Sakr [32] Multicentre prospective cohort ICU patients Influence of fluid administration
study
Schabinski [42] Before-and-after cohort study Surgical ICU patients Effect of predominantly HES 130/0.4 and 4%
gelatin on renal function
Schmidt-Hieber Case report ICU patient Biopsies
[70]
Schortgen [40] Multicentre RCT Severe sepsis Effect of 6% HES 200/0.6 versus 3% gelatin on
renal function
Schortgen [61] Multicentre prospective cohort ICU patients Influence of different types of colloids and
study crystalloids on the occurrence of renal events
Sedrakyan [36] Multicentre retrospective Coronary artery bypass surgery Influence of protein and non-protein colloids on
cohort study mortality
Tseng [51] Cohort study Aneurysmal subarachnoid 6-Month outcome after synthetic colloids (HES
haemorrhage or gelatin) and only crystalloids
Van der Heijden RCT Septic and non-septic ICU Fluid loading with 0.9% saline, 4% gelatin, 6%
[95] patients HES or 5% albumin 5% for 90 min
Wu [58] RCT Living kidney donors Kidney graft function after 6% HES 130/0.4 or
4% gelatin
 377

Ringer’s lactate in severe sepsis patients found a dose- brain injury in a retrospective review of 2,225 adult
dependent higher incidence of renal failure [39]. These trauma patients (OR 2.5; 95% CI 1.77–3.54) [50].
finding were confirmed by the three meta-analyses
Safety: A retrospective analysis of prospectively collected
that compared HES with other fluids [18, 30, 41]. Ret-
data of 160 patients with aneurysmal subarachnoid
rospective data with multivariate analysis using AKI as
haemorrhage found that a higher daily dose of synthetic
dependent binary variable showed that cumulative doses
colloids (HES or gelatin) for initial resuscitation was
[33 mL/kg of either HES (OR 1.85; 95% CI 1.01–3.41)
associated with more need for blood transfusions
or gelatin (OR 1.99; 95% CI 1.05–3.79) were associated
(p = 0.003). One cohort study in patients with aneurys-
with higher risk of AKI than doses below 33 mL/kg. AKI
mal intracerebral haemorrhage suggested that gelatin or
was defined as new need for RRT or at least a twofold
HES was dose-dependently associated with more
increase in baseline creatinine in sepsis patients
requirements for blood transfusions (p = 0.003) and
(n = 205) [42].
unfavourable neurological outcome at 6 months (OR
In severe sepsis patients, 3% gelatin solution may have
4.45; 95% CI 1.11–17.77) [51]. In a RCT of 31 head
resulted in significantly lower incidence of renal failure
injury patients, the rate of bleeding complications was
than 6% HES 200/0.6 because of an overall lower colloid
similar after HES 200/0.5 or HES 130/0.4 [52].
load in the gelatin group [40]. Retrospective data showed
that the incidence of AKI was similarly high in patients
Resuscitation of organ donors. Graft function: In 1996,
with severe sepsis receiving primarily HES 130/0.4 or 4%
one RCT found that more kidney transplant recipients
gelatin [42].
required RRT in the first 8 days if they had received
A prospective sequential comparison suggested that
organs from donors after resuscitation with 6% HES
4% gelatin and 6% HES 130/0.4 were risk factors for AKI
200/0.6 than if donors had been resuscitated with only 3%
compared with crystalloids in patients with severe sepsis
gelatin [27 (33%) versus 20 (5%), p = 0.029] [53].
(OR 3.65; 95% CI 1.81–7.35 and OR 4.52; 95% CI
Subsequent non-randomized cohort studies confirmed that
2.27–8.99, respectively) [43].
HES was a risk factor for delayed graft function in these
patients [54, 55] or found no difference in comparison
Cardiac surgery. Survival: A retrospective analysis of
with fluid therapy with only crystalloids or other colloids
nearly 20,000 patients undergoing cardiac surgery with
[56, 57]. A recent RCT which compared 4% gelatin or
coronary artery bypass found that albumin use was
HES 130/0.4 for resuscitation of 77 living donors found
associated with reduced risk for death compared with
no difference in urine output within 4 days after surgery
HES or dextran use (OR 0.80; 95% CI 0.67–0.96) [36].
[58].
Safety: Medium and high molecular weight HES prepa-
rations in cumulative doses below 20 mL/kg were
Effects of synthetic colloids: dependency of oncocity
associated with increased postoperative bleeding in car-
and dose
diac surgical patients compared with albumin [pooled
standardized mean difference, 0.24 (95% CI -0.40, Hyperoncotic versus non-hyperoncotic colloids
-0.08)] [44]. Two cohort studies found increased bleeding
or chest tube drainage after use of HES in cardiac surgery One meta-analysis on small-volume resuscitation com-
[45, 46]. Subsequently, the Food and Drug Administration paring hyperoncotic albumin with a control regimen for
(FDA) changed the warning label for HES 450/0.7 [47]. A volume expansion found that survival was unaffected by
retrospective evaluation of 563 cardiac surgical patients hyperoncotic albumin (RR 0.95; 95% CI 0.78–1.17) [59].
found that pentastarch (10% HES 200/0.45) was inde- On the other hand, a recent meta-analysis comparing
pendently associated with AKI defined as a 50% rise in hyperoncotic albumin and HES solutions found that
serum creatinine within 4 days with an adjusted odds ratio hyperoncotic human albumin decreased the odds for AKI
per mL/kg of 1.08 (95% CI 1.04–1.12) [48]. On the other and improved survival while hyperoncotic HES increased
hand, a recent RCT of 237 patients who received goal- the risk of AKI [60]. However, five of seven trials
directed fluid therapy for hypovolaemia after cardiac included patients with cirrhosis in whom albumin was
surgery with either normal saline or 10% pentastarch given for ascites with or without infection.
found no difference in renal function; however, mean HES In an international, prospective cohort study, use of
dose was only 887 ± 546 mL, and prior to the fluid hyperoncotic colloids (i.e. 6% or 10% dextrans and HES
intervention, patients in both groups had received 750 mL and 20–25% albumin) but not crystalloids or hypooncotic
HES in the cardiac pump priming solution [49]. colloids (i.e. gelatin and 4% albumin) was associated
with adverse renal effects in patients resuscitated for
Head injury or intracranial bleeding. Survival: Use of shock (OR 2.5; 95% CI 1.2–5.0 and OR 6.0; 95% CI
hetastarch, in comparison with not receiving this solution, 2.8–13.1, respectively); moreover, volumes [2 L of
was associated with greater risk of death in patients with synthetic hyperoncotic colloids were risk factors for renal
378
adverse events [61]. An international Consensus Con-
ference on the Issues of Prevention and Management of
Acute Renal Failure in the ICU Patient stated that
hyperoncotic solutions (starches, dextrans, 20–25%
albumin) are not recommended because of their risk of
renal failure [11].
In an as yet unpublished French trial (EARSS, clini-
caltrials.gov NCT00327704), using 20% albumin after
fluid resuscitation to reverse hypoalbuminaemia in septic
patients did not increase the incidence of renal failure or
mortality. Until the results of the ongoing studies (ESM)
become available and in the absence of other RCTs
comparing the use of hyperoncotic albumin with other
fluid for shock resuscitation, the safety of hyperoncotic
albumin remains unclear for the correction of hypoalbu-
minaemia and for resuscitation in shock.
Dose-dependency of adverse effects of synthetic colloids
Cumulative dose limits for synthetic colloids do not exist
in most countries. In France, following pharmacovigi-
lance reports of severe adverse bleeding events in patients
with intracranial haemorrhage, a cumulative dose limit of
80 mL/kg was introduced for 6% HES 200/0.6 [62]. No
daily or cumulative dose limits exist for gelatin. Dose-
dependency of side-effects related to synthetic colloids
only came into focus in recent years, although the dose-
dependency of coagulopathy associated with dextran or
HES was apparent when synthetic colloids were initially
introduced into clinical practice [63]. Because the legis-
lation at the time of market introduction did not require
large-scale clinical trials to assess the potential risk of
new interventions/medications, such trials were never
performed, and accurate data on dose–response curves or
safe cumulative doses are still lacking.
As noted above, a number of systematic reviews and
clinical studies suggest that the adverse effects of synthetic
colloids, i.e. coagulopathy, renal impairment and HES-
associated pruritus, may be related to dosage [28, 39, 48,
51, 61, 64, 65]. High doses were reported in case reports
and small observational studies which demonstrated that
repetitive HES administration in the context of plasma-
pheresis or longer ICU stays may result in severe organ
damage. Permanent renal failure occurred after 140 mL/kg
body weight (BW) 10% pentastarch over 2 months [66]
and 80 mL/kg 6% HES 130/0.4 over 4 days [67].
Post mortem examinations and marrow biopsies of
patients who received repetitive plasmapheresis with HES
in cumulative doses between 143 and 364 mL/kg BW
instead of plasma protein solutions or gelatins demon-
strated tissue infiltration and presence of foamy
macrophages in bone marrow [68]. Extensive tissue infil-
trates with foam cells, organomegaly, ascites and
myelofibrosis were also seen after administration of
100 mL/kg BW HES and 90 mL/kg BW dextran [69].
Thrombocytopaenia, and liver failure were demonstrated
after 170 mL/kg BW of HES 130/0.4 and HES 200/0.5
[70]. In RCTs with septic patients using lower cumulative
HES doses, risk of AKI was twofold higher after 31 mL/kg
BW of 6% HES 200/0.6 than after 3% gelatin [40] and
acute renal failure (ARF) increased after 70.4 mL/kg BW
of 10% HES 200/0.5 in comparison with Ringer’s lactate
[39]. An observational survey found a significantly
increased risk of AKI (OR 2) in comparison with crystal-
loids and hypooncotic colloids when more than 28 mL/kg
HES was used within 8 days of resuscitation [9]. Follow-
ing cardiac surgery in patients who received 10% HES
250/0.45 intra-operatively and until the end of the first
postoperative day the optimal cut-off volume predicting
AKI was 14 mL/kg [48]. On the other hand, clinical studies
with low doses of HES did not find increased occurrence of
renal failure, such as a retrospective study with 168 ICU
patients who received 763 ± 593 mL HES 130/0.4 during
the first 48 h (corresponding to approx. 10 mL/kg) [71] or
an observational study where the median amount of HES
per ICU patient was 1,000 (IQR 500–2,250) mL in 2 (1–3)
days (approx. 15 mL/kg HES) [32].
For HES, recommended maximum daily doses range
from 20 to 50 mL/kg BW depending on molecular weight
and degree of substitution. The extended daily dose limit
of 50 mL/kg for 6% HES 130/0.4 is difficult to support
with the evidence we have found. It is based on retro-
spective review of studies not designed as dose-finding
safety investigations; moreover, other starches were used
as comparators [52, 72] or gelatin was also used in both
groups [72]. One high-dose study that compared 6% HES
130/0.4 with a control consisting of HES 200/0.5 and
gelatin in patients with severe head injury was stopped
prematurely due to concerns of the institutional ethical
review board about the abnormally high incidence of
intracranial bleeding complications in the control group
[52]. The incidence of bleeding complications, however,
was comparable and [30% in both groups [52]. In two
unpublished RCTs, which are part of the FDA study roster
on HES 130/0.4 [73], HES 130/0.4 was used in high
doses: one of these was a multicentre trial on the treat-
ment of sudden hearing loss; 10% HES 130/0.4 was
compared with 6% HES 200/0.5, and the trial was stopped
prematurely after enrolment of 187 patients. After a
cumulative HES dose of 71 mL/kg, the incidence of
pruritus was significantly higher among HES 130/0.4
recipients (19%) than in the HES 200/0.5 group (8%; OR
2.8; CI 1.1–8.3, unpublished study HS-13-16-DE [73]).
Another RCT compared 45 mL/kg HES 130/0.4 with
33 mL/kg HES 200/0.5 in 61 cardiac surgery patients.
Bleeding complications occurred in five (16%) versus two
patients (7%, unpublished study HS-13-24-DE [73]),
suggesting that HES 130/0.4 did not cause less adverse
effects than HES 200/0.5, which has been associated with
increased bleeding [44]. According to the FDA, this
unpublished study was the basis for increasing dose limits

for HES 130/0.4 to 50 mL/kg in Europe [73]. In another
analysis in comparison with crystalloids, increased inci-
dence of renal failure was observed with 6% HES 130/0.4
and gelatins at median cumulative doses of 46 and
43 mL/kg BW, respectively [43]. Therefore, we suggest
that fluid manufacturers and European regulatory agen-
cies fully disclose the published and unpublished data on
which the present dose recommendation or the lack of
recommendations are based. Physicians who use synthetic
colloids should be aware of the fact that, based on the
existing clinical data, it is difficult to define safe dose
limits and that clinically relevant adverse effects may
occur at cumulative dose levels well below the currently
recommended maximum daily doses.
Safety of newer starch solutions
One meta-analysis supports the claim that ‘‘newer’’ gen-
eration starch (HES 130/0.4) is devoid of adverse effects
on coagulation [74]. It pooled data on blood loss in
patients undergoing surgery and found that estimated
blood loss was reduced after HES 130/0.4 compared with
older HES 200/0.5 [75]. Two other meta-analyses, and a
recent systematic review, however, found inadequate and
controversial clinical data to address the hypothesis that
safety differences exist between ‘‘older’’ and ‘‘newer’’
HES solutions with different MW and substitution ratio
regarding renal function or blood loss [18, 29, 30].
An international survey found similar incidences of
renal adverse events with ‘‘newer’’ and ‘‘older’’ starches
(20/119, 17% and 53/270, 20%, respectively; p = 0.51)
[61]. A retrospective matched-paired study found that the
rate of delayed graft function was similar with a fluid
regimen of HES 200/0.6 or HES 130/0.4 [76]. The data of
21 studies that were filed by one manufacturer for market
approval for HES 130/0.4 in the USA [73] and the results
of two recent systematic reviews that comprised all RCTs
on HES 130/0.4 versus other fluids [6, 77] found no signal
for superiority of HES 130/0.4 over the control fluids and
demonstrate that these studies were not designed to allow
firm conclusions about the safety of HES 130/0.4 [6, 73].
Two smaller RCTs were recently published results. The
first included patients with severe sepsis (results published
online on www.clinicaltrials.gov NCT00464204). The
hypothesis that 6% HES 130/0.4 would allow earlier ent-
eral nutrition and require significantly less resuscitation
fluid than 0.9% NaCl was refuted. The second was in
trauma patients [78, 79]. Both studies reported a trend
towards higher mortality in the HES groups. There was
also a trend towards higher incidence of renal failure in
sepsis patients, whereas the subgroup of patients with
penetrating trauma seemed to have a significant benefit
from resuscitation with starches in respect to renal function
and lactate clearance. Due to small sample size we consider
those results exploratory and not conclusive.
379
Recommendations
The choice of fluid for the treatment of volume depletion
is based on the available evidence weighing potential
benefits against risks. Lack of evidence of safety com-
bined with the presence of alternatives with known safety
profiles gives us at least moderate confidence in
expressing our opinion on the use of colloids. For most
indications there is no evidence for the superiority of one
type of fluid over another in terms of mortality, hence we
give greater weight to potential side-effects and adverse
events.
Values and Preference statement: We have issued a
number of strong recommendations despite the lack
of high-quality evidence—in each case recommen-
dations reflect the high value we place on the
suggestion of harm in the setting of available
alternatives.
As with other guidelines [80], this consensus docu-
ment focusses mostly on completed studies that have
undergone peer review and achieved publication. The
quality of evidence may change once the results of
ongoing high-quality clinical trials (more details in ESM)
become available.
The opinions represent a collective assessment of what
can be recommended and what might remain to be
learned concerning fluid replacement therapy in critically
ill patients (voting results in Supplementary Table 2).
I. We recommend not to use HES with molecular
weight C200 kDa and/or degree of substitution [0.4 in
patients with severe sepsis (grade 1B) and recommend
not to use these HES solutions in other intensive care
patients with increased risk for AKI1 (grade 1C).
(Rationale: See ‘‘Safety of newer starch solution’’).
II. We suggest that HES 130/0.4 be used in severe
sepsis and other ICU patients with increased risk for AKI1
or bleeding only in the context of clinical trials rather than
in routine clinical practice (grade 2C). (Rationale: See
‘‘Safety of newer starch solution’’).
III. We suggest that albumin may be included in the
resuscitation of severe sepsis patients (grade 2B). (Ratio-
nale: See ‘‘Colloids in specific patient populations’’).
IV. We recommend that solutions other than albumin
be used in patients with head injury (grade 1C). We
recommend not to use synthetic colloid in patients with
head injury or intracranial bleeding (grade 1C). (Ratio-
nale: See ‘‘Colloids in specific patient populations’’).
V. We suggest not to use gelatin in ICU patients who
are at increased risk for renal failure1 or bleeding outside
the context of clinical trials (grade 2C). (Rationale: See
‘‘Colloids in specific patient populations’’).
1
Increased risk of AKI was defined by a recent consensus confer-
ence as advanced age, sepsis, cardiovascular surgery, contrast
nephropathy [64].
380

VI. We recommend not to use HES or gelatin in organ
donors outside the context of clinical trials (grade 1C).
(Rationale: See ‘‘Colloids in specific patient populations’’).
VII. We recommend that any new colloid should be
introduced into clinical practice only after its patient-
important safety parameters are established, rather than
introduced on the basis of small ‘bridging’ studies based
mostly on haemodynamic parameters (grade 1C).
(Rationale: See ESM E).
VIII. We suggest not to use hyperoncotic solutions for
fluid resuscitation outside the context of clinical trials
(grade 2C). (Rationale: See ‘‘Colloids in specific patient
populations’’).
IX. We recommend reassessment of existing dose
limits for HES and an assessment of whether dose limi-
tations should apply for gelatins (grade 1B). (Rationale:
See ‘‘Effects of synthetic colloids: dependency of on-
cocity and dose’’).
X. Acknowledging the likelihood that, despite our
recommendation or suggestion to the contrary, clinicians
will continue to use HES, we discussed the possibility of
issuing a statement describing cumulative threshold doses.
Given the differences of opinions among members of the
task force, we conducted a formal vote on preferences and
the results are as follows: Six of eight panel members
preferred not to issue such a statement (using as a rationale
that we do not know if such a ‘safe’ dose exists); two of
those presented nevertheless their ‘best guess thresholds’
(10 mL/kg for HES with molecular weight C200 kDa and/
or degree of substitution [0.4 and 10 mL/kg and 15 mL/
kg for HES 130/0.4). Two out of eight were in favour of
issuing such a statement, putting respective thresholds at
cumulative doses of 0 and 30 mL/kg for HES with
molecular weight C200 kDa and/or degree of substitution
[0.4, and 14 and 50 mL/kg for HES 130/0.4. Based on
these results, we decided not to issue a formal recom-
mendation but rather describe the range of opinions.
(Rationale: see ‘‘Effects of synthetic colloids: dependency
of oncocity and dose’’).
Summary and Conclusions
We recommend not to use HES with molecular weight
C200 kDa and/or degree of substitution [0.4 in patients
with severe sepsis or risk of acute kidney injury and
suggest not to use 6% HES 130/0.4 or gelatin in these
populations outside the context of clinical trials. We
recommend not to use colloids in patients with head
injury and not to administer gelatins and HES in organ
donors. We suggest not to use hyperoncotic solutions for
fluid resuscitation. We conclude and recommend that any
new colloid should be introduced into clinical practice
only after its patient-important safety parameters are
established.
Acknowledgments Support was provided solely from institutional
and/or departmental sources.
Conflicts of interest C.L.S., R.J., F.S., A.B.J.G., R.B., and C.S.H.
declare no conflict of interest. A.P. has received support for
research from B. Braun Medical and Fresenius Kabi and honoraria
from Ferring Pharmaceuticals. A.B.J.G. has received unrestricted
research grants from B. Braun in the past. K.R. has received
unrestricted research grant for the conduct of the VISEP trial and
consultancy fees from B. Braun Melsungen.

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