Objective To provide a comprehensive review of the current literature in human and veterinary medicine
evaluating the impact of resuscitation fluid choice on patient outcome and adverse effects.
Data Sources Prospective and retrospective studies, experimental models, and review articles in both human
and veterinary medicine retrieved via PubMed.
Human Data Synthesis A series of recent, large, randomized controlled trials in critically ill human patients
comparing crystalloid versus colloid driven fluid resuscitation algorithms have demonstrated no outcome benefit with the use of natural or synthetic colloids. Synthetic colloidal solutions are associated with an increased
incidence of adverse effects including acute kidney injury, need for renal replacement therapy, and coagulopathies. Further, colloidal solutions demonstrate a larger volume of distribution in the setting of critical illness
than hypothesized. These findings have created controversy regarding colloid fluid resuscitation in critically ill
patients and challenge current resuscitation strategies. A thorough review of the most influential human data
is provided.
Veterinary Data Synthesis No veterinary clinical outcome data pertaining to fluid resuscitation choice currently exist. Veterinary data from experimental and small clinical trials evaluating the coagulopathic effects of
hydroxyethyl starch solutions are described. Data pertaining to the use of natural colloids and albumin products in clinical veterinary patients are reviewed. In addition, data pertaining to the comparative intravascular
volume expansion effectiveness of different fluid types in canine patients are reviewed.
Conclusions Clinical data from critically ill human patients have failed to demonstrate an outcome advantage
associated with colloidal fluid resuscitation and indicate that hydroxyethyl starch solutions may be associated
with significant adverse effects, including acute kidney injury, need for renal replacement therapy, coagulopathies, and pathologic tissue uptake. The ability to apply these findings to veterinary patients is unknown;
however, similar pathophysiology may apply, and critical re-evaluation of resuscitation strategies is justified.
(J Vet Emerg Crit Care 2015; 25(1): 619) doi: 10.1111/vec.12281
Keywords: AKI, coagulopathy, colloid, fluid resuscitation, hydroxyethyl starch
Abbreviations
AKI
COP
CT
EG
ESL
HES
HDS
HSA
ICU
LPS
MS
MW
RRT
RCT
RIFLE
vWF
hemodynamic stabilization
human serum albumin
intensive care unit
lipopolysaccharide
molar substitution
molecular weight
renal replacement therapy
randomized controlled trial
risk, injury, failure, loss, end-stage kidney disease
von Willebrand factor
Dr. Prittie is an Assistant Editor for the Journal, but only participated in the
peer review process as an author. The authors declare no other conflict of
interest.
Introduction
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Crystalloids-colloid controversy
Crystalloid Fluids
Isotonic crystalloid fluid solutions remain the mainstay
of fluid resuscitation in both human and veterinary
medicine. Crystalloids are salt solutions that convey
negligible oncotic pressure across the endothelial
barrier. Infusion results in rapid dissemination into
the entire extracellular fluid space, with 6080% of the
administered volume redistributed out of the vascular
space and into the interstitium within 3060 minutes.
Substantial fluid volumes are required to adequately
expand the intravascular space, correct hypovolemia,
and restore end-organ perfusion in circulatory failure.3,5
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Colloidal Solutions
The selection of a resuscitation fluid with a volume of
distribution limited to the intravascular space should
minimize tissue edema formation. This purported
advantage over isotonic crystalloids has led to the increasingly common use of colloidal resuscitation fluids
in both human and veterinary medicine. Both natural
and synthetic colloids carry the attractive theoretical
benefit of a volume-sparing effect with a decreased risk
of inducing a positive fluid balance.27 These solutions
contain large molecules that cannot cross an intact
vascular barrier. The effective oncotic pressure imparted
by colloids across the endothelium is variable between
specific solutions. According to Starlings classic model
of transcapillary fluid exchange, solutions hyperoncotic
to plasma may generate a larger oncotic gradient
across the endothelial barrier. This gradient functions to
impede fluid movement to the interstitium and further
augment the intravascular volume.10,27 In this regard,
the theoretical volume-expanding ability of certain
colloids may exceed the volume of fluid administered.
Natural Colloids
The existence of a readily available, isooncotic, speciesspecific albumin accounts for the more common
implementation of natural colloidal solutions in human
over veterinary fluid resuscitation algorithms. Albumincontaining fluids are theorized to confer benefits that
surpass the colloidal and volume-sparing effects, including roles in serum drug and hormone binding, protection
from oxidative damage, anticoagulant effects, and maintenance of vascular integrity.28 The most frequently utilized natural colloid in human critical care is 4% human
8
Crystalloids-colloid controversy
Generation
MW/MS
Concentration
Classification
C2/C6
Carrier Solution
Trade Name
1st
670/0.75
600/.07
480/0.7
200/0.62
200/0.5
70/0.5
130/0.42
130/0.42
6%
6%
6%
6%
6% or 10%
6%
6% or 10%
6% or 10%
Hetastarch
Hetastarch
Hetastarch
Hexastarch
Pentastarch
Pentastarch
Tetrastarch
Tetrastarch
4.5:1
5:1
5:1
9:1
5:1
3:1
6:1
6:1
Balanced
Saline
Saline
Saline
Saline
Balanced
Saline
Balanced
Hextend
Hespan
Plasmasteril
Elohes
Pentaspan
Hemohes
Tetraspan Vetstarch Voluven
Volulyte
2nd
3rd
adverse events including febrile nonhemolytic transfusion reactions (FNHTR), transfusion-related acute
lung injury (TRALI), immunomodulation, and potential
pathogen transmission.4,37 Large volumes of plasma
are required to increase serum albumin concentrations
and affect plasma COP, especially in the face of ongoing
protein loss (eg, 40 mL/kg of plasma is required to
increase serum albumin concentration by 1 g/dL).29
In veterinary patients, limited availability and expense
must also be taken into consideration.
Synthetic Colloids
Artificial colloids were developed as an alternate resuscitation fluid to albumin.39 Hydroxyethyl starch (HES)
solutions were first introduced in the 1970s and are the
most common synthetic colloid currently utilized in human and veterinary patients in the United States.40 The
remaining 2 classes of synthetic colloids, gelatins and
dextrans, are used less frequently.39 Accordingly, the majority of recently published clinical data comparing the
use of colloidal to crystalloid fluids for resuscitation focus on HES solutions.4144 Hydroxyethyl starch solutions
are readily available and inexpensive, provide rapid
volume expansion, and have a volume of distribution
theoretically limited to the intravascular space, making
them an appealing replacement for isotonic crystalloids
and natural colloids.40,45 Despite these promising characteristics, clinical evidence of morbidity reduction and
survival advantage in ill patients is lacking.
Hydroxyethyl starches
Hydroxyethyl starches are polydisperse modified natural polysaccharides, structurally similar to glycogen,
dissolved in saline or a more balanced salt carrier.
These polysaccharides are derived from amylopectin,
a complex plant starch polymer obtained from waxy
maize or potatoes.40,45 Natural starches cannot be used
as a plasma substitute due to their relative instability
and rapid degradation by plasma amylases.45 However,
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Figure 1: Structural formula of hydroxyethyl starch, with carbons 16 of the base glucose subunit labeled. The polymerized glucose
units are principally connected via 14 linkages, as depicted above, but also have several 16 starch branch points. R=H or hydroxyethy
(CH2CH2OH) substitution point; R1H, hydroxyethyl group or glucose branching point. Cleavage by serum -amylase occurs between
the C14 polymer linkages (labeled A).
Adverse Effects
The most significant adverse effects reported with the
use of synthetic colloids are coagulation disorders, AKI,
and increased mortality. Other documented adverse
effects include pruritus, reticuloendothelial dysfunction,
hepatopathies, and anaphylactoid reactions.8 Specific
patient populations, particularly septic patients, appear
to be at higher risk of adverse effects, and administration
of artificial colloids to these patients may be associated
with increased mortality. Significant debate surrounds
the safety of HES solutions with the most recent clinical
data prompting the ban of their use in Europe and
guidelines recommending against their use in certain
patient cohorts.54,55 It has yet to be determined whether
these safety data extend into all patient populations and
across species.
Coagulopathy
Increased postoperative bleeding and transfusion
requirements following synthetic colloid administration
were first described decades ago and continue to be
reported today.5661 The mechanism of coagulopathy is
incompletely elucidated, but is thought to be mediated
by direct effects of colloid molecules on the coagulation
system and not exclusively via hemodilution.50,62 These
effects are known to be dose-dependent with HES
solutions and have been reported with administration
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Crystalloids-colloid controversy
Safety
As more clinical data accrue, a questionable safety
profile of synthetic colloidal solutions in critical care
has been uncovered. As described in detail previously,
HES solutions are associated with clinically significant
adverse effects, the most detrimental of which are
coagulopathies and AKI. In the VISEP study, patients in
the HES arm of the trial had a higher rate of AKI (34.9%
versus 22.8%, P = 0.002), increased need for RRT (18.3%
versus 9.2%, P = 0.001), lower median platelet count,
and received more units of packed red cells.41 In posthoc univariate analysis, there was a direct correlation
between the cumulative dose of HES, the need for RRT,
and rate of death at 90 days. Group differences in AKI
occurrence and mortality were not evident until greater
than 20 days into the study period.41 The findings of this
study have been heavily criticized for numerous reasons
including the use of a hyperoncotic HES solution,
which is considered more likely to cause nephrotic renal
tubular lesions and hyperviscosity-mediated AKI.
Concerns with the safety profile of tetrastarches have
prompted further studies. In the CRYSTMAS study,
patients were only administered Voluven for 4 days,
a significantly shorter duration than in other studies.
Patients received this fluid at standard doses (50
mL/kg/d on day 1 and 25 mL/kg/d on days 24),
with a lower total dose than reported in the VISEP
study.96 Patients in both the tetrastarch and saline
groups had comparable kidney function as assessed
by risk, injury, failure, loss, end-stage kidney disease
(RIFLE) and acute kidney injury network (AKIN)
scoring systems. Likewise, there was no evidence of
AKI utilizing urinary biomarker analysis. Coagulation
parameters were similar between groups and there were
no difference in transfusion requirements.96 The number
of patients enrolled in this trial was much smaller (196
total) and the short duration of tetrastarch administration may have played a role in the lack of documented
adverse effects. Similarly, the CRISTAL trial, a large,
randomized trial evaluating the use of isotonic crystalloids versus any colloid (70% treated with HES) for
fluid resuscitation of patients with hypovolemic shock,
found no evidence of increased need for RRT between
patients in the crystalloid and colloid treatment arm.97
Conversely, the two largest and most influential
studies disclosed significant safety concerns with the
use of HES in critical illness.42,43 The S6 trial found an
increased need for RRT in the HES group (22% versus
16%, P = 0.04) and a positive correlation between RRT
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Outcome
There has been minimal clinical evidence to date
that the incorporation of colloidal solutions into fluid
resuscitation algorithms affords a survival advantage.
The SAFE trial found no outcome difference between
patients randomized to crystalloid versus 4% HSA,
concluding that the 2 solutions were equivalent.101
No significant adverse effects associated with colloid
administration were identified, refuting the conclusions
of a previously published Cochrane review that suggested the use of albumin was associated with increased
mortality among critically ill patients.110 The Cochrane
group incorporated all RCTs on albumin resuscitation,
including trials that employed hyperoncotic albumin
formulations, which may account for the discrepancy
in results. Though the SAFE study was not powered
or designed to detect benefits or risks in specific subgroup populations, it suggested a mortality advantage
associated with albumin administration in the sepsis
cohort.101 The ALBIOS trial later investigated the use of
albumin in septic human patients and found albumin
administration did not provide a survival advantage or
improvement in any measured secondary outcomes.102
Trials comparing resuscitation with crystalloids to
synthetic colloids have had somewhat disparate results.
In the S6 trial, an increased risk of death at day 90 in the
HES group as compared with the Ringers acetate group
was demonstrated (51% versus 43%, P = 0.03).72 Divergence of Kaplan-Meier survival curves did not begin to
evolve between groups until close to 20 days poststudy
enrollment. The CHEST trial failed to demonstrate a
difference in 90-day mortality between crystalloid and
HES-resuscitated individuals, the primary endpoint of
the trial.43 The crystalloid versus colloid Cochrane review found no evidence that resuscitation with colloids
reduces the risk of death when compared with crystalloid resuscitation and suggested that the use of HES in
particular may increase the risk of death.105 However,
15
Veterinary Implications
Despite the recent surge in clinical data in the field of
human critical care, minimal safety and efficacy data
exist in veterinary medicine regarding the use of HES as
a resuscitation fluid. The large-scale veterinary clinical
trials required to establish an influence of HES resuscitation on patient outcome and adverse effects are likely
not logistically feasible in the near future. Veterinary
studies are often not powered to detect mortality differences in a diverse patient population with a myriad of
underlying comorbidities. Caution must be used when
extrapolating human data and associated conclusions
to veterinary patient populations given several patient
and population-dependent factors, which confer an
inherent risk of error. Human and veterinary ICU
patients are two distinctly different patient populations.
16
Crystalloids-colloid controversy
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
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