This document reviews the debate around the use of crystalloid versus colloid fluids for resuscitation in critical care. Recent large human studies have failed to show an outcome benefit of colloids over crystalloids, and colloids such as hydroxyethyl starch have been associated with increased risks of adverse effects like acute kidney injury. While no veterinary outcome data exists, similar pathophysiology may apply. The document provides an overview of various fluid types used in human and veterinary medicine, including crystalloids, natural colloids like albumin, and synthetic colloids like hydroxyethyl starch, discussing their properties, uses, and risks.

1. State of the Art Review Journal of Veterinary Emergency and Critical Care 25(1) 2015, pp 6–19
doi: 10.1111/vec.12281
The crystalloid-colloid debate: Consequences
of resuscitation fluid selection in veterinary
critical care
Dava Cazzolli, DVM and Jennifer Prittie, DVM, DACVIM, DACVECC
Abstract
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 ben-
efit 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 coagu-
lopathies. 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 cur-
rently 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 prod-
ucts 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, coagu-
lopathies, 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): 6–19) doi: 10.1111/vec.12281
Keywords: AKI, coagulopathy, colloid, fluid resuscitation, hydroxyethyl starch
Abbreviations
AKI acute kidney injury
COP colloid osmotic pressure
CT closure time
EG endothelial glycocalyx
ESL endothelial surface layer
HES hydroxyethyl starch
From the Animal Medical Center, Department of Emergency and Critical
Care, New York, NY.
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.
Address correspondence and reprint requests to
Dr. Dava Cazzolli, Animal Medical Center, 510 East 62nd Street, New York,
NY 10065. Email: dava.cazzolli@amcny.org
Submitted March 28, 2014; Accepted October 30, 2014.
HDS hemodynamic stabilization
HSA human serum albumin
ICU intensive care unit
LPS lipopolysaccharide
MS molar substitution
MW molecular weight
RRT renal replacement therapy
RCT randomized controlled trial
RIFLE risk, injury, failure, loss, end-stage kidney dis-
ease
vWF von Willebrand factor
Introduction
Intravenous fluid resuscitation plays a pivotal role in
the treatment of circulatory failure in the emergency
and intensive care unit (ICU) settings. Early goal
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2. Crystalloids-colloid controversy
directed therapy has demonstrated an outcome benefit
in human septic shock patients and likely imparts a
survival advantage in other patient populations as
well.1,2
This treatment strategy directs resuscitation
toward restoration of an effective circulating blood
volume and adequate end-organ perfusion. Expansion
of the intravascular space with exogenous fluids is a
first line therapeutic intervention to restore perfusion
and a fundamental component of early goal directed
therapy. In the past decade, evidence-based clinical data
have evolved in the human medical field, evaluating
the impact of resuscitation fluid choice on patient mor-
bidity and mortality.3
Until similar data are available
evaluating fluid choice in veterinary shock patients, vet-
erinarians are, in part, reliant on extrapolation of results
from human clinical trials to guide resuscitation efforts.
Across species, the optimal choice of resuscitation fluid
remains controversial and is a matter of ongoing debate.
Administration of any fluid intravenously will induce
immediate plasma volume expansion. However, fluid
types have variable systemic effects beyond expansion of
the intravascular space and these effects may impact pa-
tient outcome.3–5
As with other drugs utilized in the crit-
ical care setting, the pharmacologic properties of certain
fluids can impact organ function, modulate the immune
system, and alter coagulation. In addition, fluids can in-
fluence microcirculatory flow and perfusion by both di-
rect and indirect effects on blood viscosity, red blood cell
rheology, and endothelial function.5–7
The use of IV flu-
ids in the medical field predates the initiation of modern
stringent drug approval regulations by the Federal Drug
Administration and until recently there has been little to
no testing on the safety or efficacy of many of the com-
monly used fluid types.8,9
No individual fluid is ideal,
each type carrying its own inherent safety and toxicity
profile. The most utilized resuscitation fluids in human
and veterinary medicine are reviewed, with a specific
focus on the expanding body of evidence surrounding
the controversy between crystalloid and colloid driven
resuscitation strategies in the critical care setting.
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 60–80% of the
administered volume redistributed out of the vascular
space and into the interstitium within 30–60 minutes.
Substantial fluid volumes are required to adequately
expand the intravascular space, correct hypovolemia,
and restore end-organ perfusion in circulatory failure.3,5
Normal saline (0.9%) is the most frequently used
replacement fluid in the human medical field. Although
isotonic, normal saline is not a physiologic solution, con-
taining a significantly higher chloride concentration and
lower strong ion difference when compared to plasma.10
Resuscitation of critically ill patients with large vol-
umes of normal saline may result in hypernatremia,
hyperchloremia, and contribute to the development of
a hyperchloremic metabolic acidosis. In addition, there
is documented risk of hyperchloremia-induced acute
kidney injury (AKI). This kidney injury is postulated
to result from high chloride levels inducing renal
vasoconstriction, decreased glomerular filtration, and
subsequent ischemic renal tubular damage.11
Given the potential complications associated with
0.9% saline, isotonic crystalloid solutions such as
lactated Ringer’s and Normosol-R have become increas-
ingly popular for resuscitative purposes. These solutions
are more physiologic than saline, containing a myriad
of electrolytes as well as a buffer, typically lactate or
acetate. The buffer additive requires metabolism prior
to excretion, so theoretical contraindications to use of
these solutions exist in particular disease states such
as hepatic dysfunction.3
Human clinical trials have
demonstrated that administration of a balanced salt
solution over normal saline in surgical patients and
critically ill patients was associated with a significant
decrease in the rate of major complications, including
postoperative infection, renal replacement therapy
(RRT), and need for blood transfusion.12,13
A recent
large, retrospective study in critically ill adults with
sepsis found that resuscitation with balanced solutions,
as opposed to normal saline, was associated with a lower
risk of in-hospital mortality.14
A large scale, randomized
controlled trial (RCT) comparing the effects of saline
and balanced salt solutions is yet to be completed.
The net positive fluid balance that occurs secondary
to aggressive resuscitation with crystalloids is associ-
ated with worsened patient outcome.15
Expansion of
the total extracellular space causes direct damage to
the architecture of the endothelial surface layer (ESL),
culminating in impaired capillary exchange. Progressive
capillary leak, tissue edema, and hypoxia ensue, with
subsequent detrimental effects on cardiovascular, pul-
monary, gastrointestinal, and renal function.5
Isotonic
crystalloid administration induces a proinflammatory
state, with augmented inflammatory cytokine produc-
tion and endothelial cell activation.4,5
This exaggerated
inflammatory response exacerbates the deleterious
effects of fluid overload, generating worsened edema
formation. Other forms of resuscitation injury include
development of dilutional coagulopathy, compartment
syndromes, and impaired tissue healing.5
At the cellular
level, aggressive volume resuscitation incites cellular
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3. D. Cazzolli J. Prittie
swelling, leading to cytosolic acidification, altered
intracellular protein function and signaling pathways,
and ultimately impaired cell activity.5
Several publications in the human medical field
have demonstrated that fluid overload in the ICU
setting is a common problem and is independently
associated with increased morbidity and mortality.16–25
Hospitalized critically ill veterinary patients are likely
prone to a similar increased risk for fluid overload and
the related negative sequelae. A recent retrospective
study comparing critically ill dogs to a stable popu-
lation of neuroorthopedic dogs found that, over the
course of hospitalization, critically ill dogs acquired a
higher percent fluid overload (11.8 ± 1.7% versus 0.9 ±
2.6%, P = 0.001), which was directly correlated with
mortality.26
Initial concerns that fluid overload may be a
biomarker of illness severity have been replaced by the
common belief that fluid overload in itself is a morbidity.
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 in-
creasingly 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 Starling’s 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, species-
specific albumin accounts for the more common
implementation of natural colloidal solutions in human
over veterinary fluid resuscitation algorithms. Albumin-
containing fluids are theorized to confer benefits that
surpass the colloidal and volume-sparing effects, includ-
ing roles in serum drug and hormone binding, protection
from oxidative damage, anticoagulant effects, and main-
tenance of vascular integrity.28
The most frequently uti-
lized natural colloid in human critical care is 4% human
serum albumin (HSA), an isooncotic solution of purified
albumin. Purified HSA solutions are also commercially
available in concentrations ranging from 4% to 25%.
Human serum albumin has been utilized in clinical
veterinary patients, despite concerns regarding incom-
plete protein homology among species.28–31
Several
veterinary reports have demonstrated severe, even fatal,
type III hypersensitivity reactions in dogs treated with
HSA.32,33
There is also a significant risk with repeat
administration, as high levels of anti-HSA antibody are
produced in dogs within weeks of administration.34
Se-
vere hypersensitivity reactions were purportedly limited
to HSA administration to healthy dogs, due to an ab-
sence of documentation with administration to critically
ill dogs. This disparity has been postulated to be related
to the immune compromise that occurs in the setting
of critical illness,35
as critically ill patients are often less
able to mount a significant immune response. In accord
with this theory, decreased HSA-antibody production
has been documented in critically ill as compared with
healthy dogs.34
However, Powell et al recently published
confirmed type III hypersensitivity reactions in 2 ill dogs
treated with HSA, demonstrating that critical illness
does not preclude the risk of antigenic reactions to this
solution.35
The administration of HSA solutions to vet-
erinary patients is controversial and likely not indicated
for resuscitation purposes. This solution may have a
role in treatment of specific populations of severely
hypoalbuminemic veterinary patients provided there is
clinician recognition of the associated risks.
There is currently no equivalent, commercially
available, species-specific, isooncotic natural colloid for
use in veterinary patients. Lyophilized canine-specific
albumin is sporadically available and may play a central
role in canine fluid resuscitation in the future. In a
small veterinary clinical trial, canine-specific albumin
administration in 7 dogs with septic peritonitis resulted
in increased albumin concentrations, colloid osmotic
pressure (COP), and diastolic blood pressure 2 hours
post-transfusion, as compared with a matched, clinician-
directed therapy control group.36
The product appeared
to have an acceptable safety profile. At this time, other
clinical safety and efficacy data for this product are
lacking and larger clinical trials are warranted.
Plasma products such as frozen plasma (FP) and
fresh frozen plasma (FFP) are isooncotic natural
colloids that can be incorporated into resuscitation
algorithms in sick human and veterinary patients.
Across species, plasma (and other blood) products are
used primarily for patients with acute hemorrhage or
coagulopathy.4,37,38
These solutions provide albumin,
coagulation factors, and immunoglobulins, among
other plasma components. The administration of
plasma products carries the risk of transfusion-related
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Table 1: Nomenclature and classification of various available HES solutions42
Generation MW/MS Concentration Classification C2/C6 Carrier Solution Trade Name
1st 670/0.75 6% Hetastarch 4.5:1 Balanced Hextend
600/.07 6% Hetastarch 5:1 Saline Hespan
480/0.7 6% Hetastarch 5:1 Saline Plasmasteril
2nd 200/0.62 6% Hexastarch 9:1 Saline Elohes
200/0.5 6% or 10% Pentastarch 5:1 Saline Pentaspan
70/0.5 6% Pentastarch 3:1 Balanced Hemohes
3rd 130/0.42 6% or 10% Tetrastarch 6:1 Saline Tetraspan Vetstarch Voluven
130/0.42 6% or 10% Tetrastarch 6:1 Balanced Volulyte
MW, molecular weight; MS, molar substitution.
adverse events including febrile nonhemolytic trans-
fusion 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 resus-
citation fluid to albumin.39
Hydroxyethyl starch (HES)
solutions were first introduced in the 1970s and are the
most common synthetic colloid currently utilized in hu-
man 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 ma-
jority of recently published clinical data comparing the
use of colloidal to crystalloid fluids for resuscitation fo-
cus on HES solutions.41–44
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 char-
acteristics, clinical evidence of morbidity reduction and
survival advantage in ill patients is lacking.
Hydroxyethyl starches
Hydroxyethyl starches are polydisperse modified nat-
ural 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,
modification of the base polysaccharide by substitution
of hydroxyethyl groups in place of hydroxyl groups
results in increased solubility and decelerates the
hydrolysis of the molecule by serum amylase.46,47
The
molecular modification of the polysaccharide creates
significant variation in the pharmacokinetic and phar-
macodynamic profile of the resultant HES solution.40
Hydroxyethyl starch solutions are available in an isoon-
cotic formulation (6%) and hyperoncotic formulation
(10%), the latter of which has gone out of favor due to
safety concerns.48
These fluids are named based on their
concentration, average molecular weight (MW), and
molar substitution (MS). The nomenclature used for
HES solutions is outlined in Table 1 and described briefly
below.
Degradation of HES molecules, and ultimately HES
half-life, is determined by serum amylase activity as
well as the molecular structure of HES.40
Differences
in serum amylase activity exist between species. Dogs
have 3 times more serum amylase activity than people,
and accordingly, have documented accelerated plasma
HES clearance.49
The rate of HES degradation by serum
amylase is dependent on the product MW, MS, and
C2/C6 substitution ratio. Of these, MS and C2/C6 ratio
are the most influential features.47
Continuous degrada-
tion of larger HES molecules into smaller ones functions
as a reservoir for colloidal replenishment. This affords
larger MW solutions a longer overall plasma half-life
and greater capacity for ongoing oncotic support.40
Molar substitution refers to the number of hydroxy-
ethyl groups substituted per 100 available anhydrous
glucose residue binding sites; hence, an MS of 0.5 indi-
cates that 50% of available binding sites are occupied.
The MS dictates starch classification, eg, 0.4 MS is a
tetrastarch, 0.5 a pentastarch. Increasing MS is positively
correlated with HES plasma half-life and retarded
degradation, with plasma clearance of tetrastarches
at least 20 times higher than that of hetastarch or
pentastarch.50
Tetrastarch solutions, such as Voluven,
Vetstarch, and Tetraspan, were introduced to the clinical
market most recently and are considered late generation.
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5. D. Cazzolli J. Prittie
Figure 1: Structural formula of hydroxyethyl starch, with carbons 1–6 of the base glucose subunit labeled. The polymerized glucose
units are principally connected via 1–4 linkages, as depicted above, but also have several 1–6 starch branch points. R=H or hydroxyethy
(CH2CH2OH) substitution point; R1–H, hydroxyethyl group or glucose branching point. Cleavage by serum ␣-amylase occurs between
the C1–4 polymer linkages (labeled A).
These products were expected to carry improved safety
profiles compared to early generation, high MW/MS
solutions, due to conjectured diminished plasma and
tissue retention.40
Hydroxyethyl groups are substituted on the C2, C3,
and C6 carbons of the base glucose monomer (Figure 1).
The pattern of substitution among these 3 sites affects
amylase affinity and ultimately degradation efficacy.
Substitution on the C2 position in particular leads to
allosteric inhibition of the cleavage of the HES molecule
by plasma amylases, resulting in an increased plasma
half-life of the HES solution. Comparable products,
ie, with the same MW/MS, that differ solely in the
C2/C6 substitution ratio have been shown to have very
different pharmacokinetics and plasma half-lives; an
increase in the C2/C6 substitution ratio is inversely cor-
related with rate of degradation.37,46,47
These molecular
modifications prolong plasma half-life and can lead to
significant plasma accumulation of colloid, even in the
presence of high amylase activity. Highly substituted
HES products have a terminal half-life that increases
with repetitive dosing as well as with longer infusion
durations.46
After initial intravascular hydrolysis by serum amy-
lase, smaller HES molecules (55 kDa) are excreted
unchanged in the urine or are taken up into tissues,
namely, cells of the reticuloendothelial system.40
Cellular
uptake of larger HES molecules (55 kDa) also occurs
but with decreased frequency, and subsequent slow
intracellular degradation ensues.40
Cellular lysosomes
lack the amylase enzymes required for efficient HES
hydrolysis, making the half-life of HES in tissues far
longer than in plasma.
In the presence of an intact, healthy ESL, the volume
of distribution of HES solutions is theoretically limited
to the intravascular space.51–53
The large osmotically
active particles in these solutions retain water within
the plasma compartment and impede tissue edema.
Moreover, the large MW of HES molecules allows for
absorption into the glycocalyx layer of the ESL and
further augments resistance to ultrafiltration of fluid
across the capillary barrier.51
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.56–61
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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within the manufacturer recommended daily dosing
range. Administration of HES has been shown to lead
to platelet dysfunction, reduced von Willebrand factor
(vWF) and factor VIII activity, and an acquired fibrino-
gen deficiency or dysfunction.50
Likewise, both gelatin
and dextran solutions have demonstrated interference
with both primary and secondary hemostasis.62
The pathophysiology of HES-induced platelet
dysfunction is multifactorial. Hydroxyethyl starch
molecules induce cellular abnormalities that result in de-
creased agonist-induced expression of the glycoprotein
(GP) ␣IIb/␤3 receptor on platelet surfaces, culminating
in inhibited platelet adhesion and aggregation and pro-
longed measured platelet closure time (CT).50
There is
additional evidence that HES molecules may bind to and
coat the platelet surface, leading to further inhibition of
activation, aggregation, and adhesion to fibrinogen. Ef-
fects on platelet dysfunction are more pronounced with
administration of early generation HES solutions, and
this has been corroborated by both human and veteri-
nary data.50,62–71
Smart et al performed an in vivo study
evaluating the effect of a 20 mL/kg dose of HES 670/0.75,
a high MW HES solution, on platelet function in healthy
dogs and found a significantly prolonged platelet CT
that persisted for 24 hours.65
The effect on platelet func-
tion of this HES solution has also been evaluated after
a 24-hour constant rate infusion (CRI) in healthy dogs.
Administration of a CRI caused a significant increase in
platelet CT from baseline until the end of the infusion.
A CRI of 2 mL/kg/hr resulted in a platelet CT above
the normal reference interval in a majority of the treated
dogs.72
No clinical evidence of bleeding was detected in
any dog in this study. Additional veterinary in vitro data,
including data on newer generation HES solutions, have
shown a dose-dependent prolongation of platelet CT
with HES as compared with saline-hemodilution.66–70
Along with alterations in primary hemostasis, syn-
thetic colloids can also produce changes in secondary
hemostasis. Acquired von Willebrand syndrome with
decreased factor VIII activity is a recognized conse-
quence of administration of all classes of synthetic
colloids.50,62
Data from both patients and healthy
human volunteers have shown up to 80% reduction
in circulating factor VIII and vWF activity after HES
administration within the manufacturer dosing range.
Although the precise pathophysiology remains in-
completely understood, binding of colloids to factor
VIII/vWF complexes is postulated to accelerate complex
clearance from the plasma.50,62
Clinical data have also revealed reduced fibrino-
gen concentrations, impaired fibrin crosslinking, and
compromised clot stability associated with the admin-
istration of both dextran and HES solutions.71
Current
data demonstrate that hemodilution with HES results
in a weaker clot, less stable fibrin network, and less firm
platelet aggregation, as compared to crystalloid or al-
bumin hemodilution.64
Viscoelastic coagulation studies
in human and veterinary patients have demonstrated
patterns consistent with hypocoaguability following
both in vivo and in vitro HES hemodilution.64,73–75
A recent systematic review on viscoelastic analysis
of HES 130/0.4 in human patients that incorporated
data from 7 in vitro and 7 in vivo studies found
a significant hypocoagulatory effect of HES on the
kinetics of clot formation.64
This effect was found to be
dose-dependent; however, significant effects were still
noted at low doses (40 mL/kg). Falco et al reported a
hypocoaguable thromboestometric pattern with in vitro
HES 130/0.4-hemodilution (eg, Vetstarch) of canine
blood (1:4 and 1:10 dilutions), purportedly mediated
by changes in fibrinogen concentration and platelet
function.75
A small randomized, prospective veterinary
trial was published evaluating the hemostatic effects
and clinical bleeding associated with 6% HES (600/.75),
as compared with lactated Ringer’s solution (LRS), in
healthy dogs anesthetized for orthopedic surgery.76
Dogs in this study were given either a 10 mL/kg bolus
of HES or LRS, followed by a maintenance infusion of
10 mL/kg/hr of LRS during anesthesia. Although there
was a significant prolongation of prothrombin time and
buccal mucosal bleeding time at 1 hr postinfusion in
both groups, there was no significant difference between
groups in vWF antigen concentration, fVIII coagu-
lant activity, platelet aggregation or clinical bleeding.76
Hypotheses that tetrastarches would be devoid of hemo-
static impairment in people remain unsubstantiated,
and recent data evaluating these solutions have shown
reduced, but not absent, HES-associated coagulation
abnormalities and clinical bleeding tendencies.57–60
The
risk for clinical bleeding in veterinary patients treated
with HES solutions has not been clarified.
Acute Kidney Injury
All classes of synthetic colloids have been associated
with renal impairment; however, HES solutions have
been cited most frequently.39,77–79
Shortgen et al pub-
lished the first large, RCT documenting an increased
incidence of AKI with HES (6%, 200/0.6) administration
as compared to a 3% gelatin solution in human patients
with sepsis or septic shock.80
Since then, several RCTs
have demonstrated increased incidence of AKI and need
for RRT in heterogeneous human patient populations
treated with HES solutions.41–44,81–84
The pathophysi-
ology of HES-associated AKI is not fully understood,
and several mechanisms have been proposed to explain
the tubular injury incurred. Hyperviscosity-mediated
ischemic injury, HES uptake by the renal interstitial
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7. D. Cazzolli J. Prittie
reticuloendothelial system, and osmotic nephrosis have
been proposed pathophysiologies.85–87
Hyperviscosity-
mediated injury has largely been discounted but is
theoretically possible if a hyperoncotic colloid (eg, 10%
HES solutions) is used in a dehydrated patient.87,88
Filtration of HES molecules into the tubular fluid gener-
ates a hyperviscous urine, resulting in stasis of flow and
obstruction of the tubular lumen. This mechanism of in-
jury relies on the creation of hyperoncotic tubular fluid,
which has debatable clinical relevance in the setting of
critical illness. Experimental models have demonstrated
HES-induced renal interstitial cell proliferation and
macrophage infiltration and these changes are believed
to contribute to the development of AKI.86,87
Lastly,
HES solutions can induce osmotic nephrosis, a process
of vacuolization and swelling of proximal renal tubular
cells after exogenous solute administration, within a few
hours of exposure.89
These tubular lesions are reversible
structural changes that can be associated with AKI
and have been documented with both early and late
generation HES administration. Preferential uptake of
HES molecules occurs in proximal tubular luminal ep-
ithelial cells via pinocytosis, and intracellular lysosomal
storage can lead to accumulation of intracellular water,
cytoplasmic swelling, and altered cellular integrity and
function, culminating in tubular damage and the clinical
syndrome of AKI.87,89
Late generation HES solutions
were postulated to be less nephrotoxic; however, human
clinical trials have continued to document AKI in
patients treated with these solutions.42–44
Tissue Accumulation and Pruritus
HES molecules have been shown to accumulate in
numerous tissues after infusion in human patients
and animal models, including reticuloendothelial cells,
dermal cells, nerve cells, and hepatocytes, an effect
that appears to be unique to HES over other synthetic
colloids.90
While tissue uptake of HES is both dose- and
time-dependent, HES can accumulate in cytoplasmic
vacuoles that can persist for long periods of time even
after relatively low-dose infusions of a HES solution for
volume replacement.90–92
Intracellular HES accumula-
tion is implicated in the pathogenesis of major complica-
tions and organ dysfunction. For example, tissue uptake
in small peripheral nerves and skin is implicated in HES-
associated pruritus and has a reported incidence ranging
from 30% to 60% in HES-treated human patients.93
HES-
induced pruritus has a delayed onset (typically 1–6
weeks postexposure), is refractory to available thera-
pies, and can last up to 24 months.94,95
Current data
have failed to support previous hypotheses that newer
generation lower MW HES solutions will have reduced
tissue uptake and expedited renal excretion. In fact, a
recently meta-analysis demonstrated a 42.3% overall
tissue uptake of low MW HES ( 200 kDa), as compared
with a 24.6% tissue uptake of a high MW HES.91
In-
creased renal tubular cell uptake has been postulated to
explain the persistent renal toxicity associated with late
generation HES solutions.89
Given that many adverse
effects, including AKI and potentially mortality, may be
correlated with HES cellular uptake, the overall safety
profile of late generation HES solutions is challenged.
Crystalloid versus Colloid Fluid Resuscitation: The
Evidence
The absence of a confirmed survival advantage in
conjunction with increased documentation of adverse
effects is the core of the controversy of continued use
of colloidal solutions in the resuscitation of critically
ill human patients. Significant disparity exists between
the theorized advantages of colloidal therapy and sup-
portive clinical data, particularly in patient cohorts with
higher illness severity scores. In the past decade several
well-designed RCTs have been published in human
critical care comparing fluid resuscitation with colloid
versus crystalloid.41–44,96,97
Results of these trials have
led to safety concerns regarding synthetic colloids and
recommendations against their use in several patient
populations.
Efficacy
The efficacy of a resuscitation fluid can be defined as
its ability to restore effective circulating blood volume,
organ perfusion, and tissue oxygenation while mini-
mizing unnecessary fluid loading that could contribute
to a positive fluid balance. In several recent studies in
critically ill human patients, the volume-sparing effect of
colloidal solutions as compared to crystalloids has been
marginal, with intravascular volume expansion efficacy
close to a ratio of 1.2–1.4:1 for crystalloid:colloid.41–44,96
This is in contrast to the anticipated superior volume
expansion predicted from the physiologic properties of
colloidal solutions. If only marginal differences in fluid
volumes needed to restore effective circulating volume
exist between crystalloid and colloid resuscitation in the
critically ill state, the inherent advantage of a colloid
becomes greatly diminished.
Past data from healthy human volunteers and ex-
perimental animals demonstrated 3–4 times as much
crystalloid than colloid infusion are needed to achieve an
equivalent increase in intravascular volume.51,98
Silver-
stein et al reported on the comparative change in blood
volume in healthy dogs, as assessed by an in-line hemat-
ocrit monitor, after an IV bolus of different fluid types. An
80 mL/kg of saline, 4 mL/kg of hypertonic saline (7.5%),
20 mL/kg of dextran-70, and 20 mL/kg of 6% HES were
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8. Crystalloids-colloid controversy
compared.99
Infusion of saline resulted in the largest
immediate increase in blood volume, as the percent in-
crease was directly correlated with the volume infused.
However, this increase was transient and followed by a
rapid decline, attributed to prompt fluid redistribution
into the interstitium. The synthetic colloidal solutions
generated the largest cumulative effects between 30 and
240 minutes, with blood volumes that continued to
increase beyond the administration interval. However,
through the total study period (0–240 min), there was no
statistically significant difference in the volume expand-
ing efficiency of either synthetic colloid compared with
normal saline.99
A more recent comparative veterinary
research study evaluated the effect of tetrastarch ad-
ministration on hemodynamic and laboratory variables
in healthy dogs and dogs with lipopolysaccharide
(LPS)-induced systemic inflammation, as compared
with an equal volume of saline.100
Comparable volume-
expanding efficacy was found after administration of
saline or HES in both healthy and LPS-treated dogs. This
was evidenced by similar changes in PCV and plasma
protein concentration. Tetrastarch administration led to
an expected increase in plasma COP, whereas saline led
to a dilutional-associated decrease in COP. Despite the
provision of oncotic support, no significant beneficial
effect on hemodynamic stabilization (HDS) in the
LPS-treated dogs was demonstrated with tetrastarch
over normal saline.100
Several human clinical RCTs have investigated the
efficacy of colloids as compared to crystalloids in their
ability to achieve HDS, as well as the fluid volume
required to reach these goals. The SAFE trial, published
a decade ago, is the largest published RCT to date
comparing the use of 4% HSA to normal saline for
fluid resuscitation in human ICU patients. Enrolling
approximately 7,000 patients, this study found albumin
administration to be safe, but failed to demonstrate
a significant volume-sparing effect.101
Similar total
fluid volumes were administered between groups. The
overall ratio of albumin:crystalloid administration over
the first 4 days of the study was 1:1.4.101
More recently,
the ALBIOS trial evaluated the use of albumin in human
patients with severe sepsis or septic shock.102
Patients
were randomized to receive either 20% albumin and
crystalloid solution or crystalloid solution alone. Al-
bumin replacement, as compared to crystalloids alone,
did afford some hemodynamic benefits. However, no
significant difference in total administered fluid volume
was found between groups.102
The landmark VISEP trial, published in 2008, ran-
domized 537 patients with severe sepsis or septic shock
to resuscitation with Ringer’s lactate solution (LRS) or a
pentastarch solution (10% HES 200/0.5).41
Although pa-
tients in the LRS group received more total resuscitation
fluid than patients in the HES group, the ratio of total
fluid administered in the LRS group compared to that in
the HES group was 1.32:1 for the entire study period.41
Similarly, the CRYSTMAS trial, a prospective, random-
ized, double-blinded study in 196 patients with severe
sepsis, compared resuscitation with 6% HES 130/0.4
(Voluven) versus normal saline. Significantly less study
fluid was required to achieve HDS in HES-treated com-
pared with saline-treated patients (1379 ± 886 mL versus
1709 ± 1164 mL, P = 0.0185).90
However, cumulative
volume of study fluid used over 4 days was similar
between groups. Although time to HDS was expedited
and initially more efficient with the use of HES, this did
not translate into a sustainable volume-sparing effect.
Two large, well-designed RCTs, the Scandinavian
Starch Trial (S6) and the CHEST trial, were published
in 2012 comparing fluid resuscitation with crystalloids
alone versus algorithms incorporating colloidal solu-
tions in critically ill human patients.42,43
The S6 trial was
a multicenter, parallel-group, blinded trial, enrolling
800 patients with severe sepsis. Patients were randomly
assigned to fluid resuscitation in the ICU with either
6% HES 130/0.4 (Tetraspan) or Ringer’s acetate at
doses up to 33 mL /kg/d.42
No significant difference
in trial fluid volumes was found between groups,
failing to support a substantial volume-sparing effect of
colloid administration in this ill patient population. The
CHEST trial has been the largest and most influential
study to date critically evaluating the use of HES as
a resuscitation fluid in a heterogeneous human ICU
patient population. This double-blinded RCT, enrolling
7,000 intensive care patients, compared 6% HES 130/0.4
(Voluven) with normal saline resuscitation in the ICU
setting.43
During the first 4 days, the HES group received
significantly less study fluid than the saline group (526
± 425 mL versus 616 ± 488 mL, P 0.001), with most
of the volume administered in the first 24 hours of ICU
admission. The HES group also received significantly
less nonstudy fluid than the saline group (851 ± 675 mL
versus 1115 ± 993 mL, P 0.001), resulting in a lower
positive net fluid balance (921 ± 1069 mL versus 982 ±
1161 mL, P = 0.03).43
However, as with previous studies,
the documented volume-sparing effect of colloidal
therapy was far less than predicted. The HES group
experienced more rapid HDS, reduced vasopressor
doses, and significantly higher central venous pressures
than the saline group. Other parameters, such as time
to normalization of serum lactate, heart rate, and blood
pressure were similar between groups. Evaluating
the first 4 days of treatment, there was no difference
between groups on overall achievement of HDS.43
These data show colloidal solutions have a larger than
predicted volume of distribution in critically ill patients.
Augmented fluid dissemination out of the intravascular
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9. D. Cazzolli J. Prittie
space is likely multifactorial. Systemic inflammation
and the upregulated cytokine production that often
accompany critical illness lead to endothelial injury,
degradation of the EG, and consequent capillary
leak.5
In addition, aggressive fluid resuscitation can
exacerbate the already compromised integrity of the
vascular barrier by causing direct damage to the
EG.52
Patient intravascular volume status may also
play a significant role in the distribution of solutions
through fluid compartments. Colloidal resuscitation
has been demonstrated to be most efficacious in the
treatment of intravascular hypovolemia, with 80–100%
of the infused volume remaining in the intravas-
cular space. Conversely, administration of a bolus
of isooncotic fluids into the circulation of a normo-
volemic patient has a reduced plasma volume-
expanding effect, with upwards of 60% of the infused
volume being shifted into the interstitium.27,103
This
increased volume of distribution is proposed to be
mediated by hypervolemia-associated damage to the
endothelial barrier. Iatrogenic hypervolemia stimulates
the release of atrial natriuretic peptide (ANP), a hormone
that plays a direct role in endothelial glycocalyx (EG)
degradation.27
Accurate determination of intravascular
volume status in clinical practice is inherently difficult
and not well correlated to macrohemodynamics.104
Approximately 50% of hemodynamically unstable
critically ill human patients treated with pragmatic
volume loading are nonresponders, meaning there is
no increase in cardiac stroke volume after an IV fluid
challenge.104
These volume nonresponders are treated
with IV fluids without the associated benefit of an
improved cardiac output. The seemingly unavoidable
“failed” fluid challenge in certain ill patient cohorts, a
portion of whom are euvolemic, carries a risk of further
compromise to the ESL and accelerated evolution of
tissue edema and a positive fluid balance.
The revised Starling model and glycocalyx paradigm
of transvascular exchange highlights the importance of
an intact ESL in the maintenance of transcapillary fluid
exchange and provides new insights into the physiology
of microvascular fluid flux.52,53
In this revised model,
the oncotic pressure differential across the EG layer
limits but does not eliminate or reverse fluid movement
from the intravascular space to the interstitium. Fluid
reabsorption from the interstitium does not occur in the
venous capillary bed, but rather the majority of filtered
fluid is returned to the vasculature via the lymphatics. A
healthy EG is essential to avoid capillary leak and tissue
edema formation.52
These features of transcapillary
fluid exchange highlight the intrinsic limitations asso-
ciated with attempts to impede or correct edema with
colloid administration in patients with low capillary
hydrostatic pressures or ESL damage.52
With these
alterations in place, differences in distributive volume
between crystalloids and colloids become less apparent.
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 post-
hoc 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 2–4),
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 administra-
tion 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 crys-
talloids 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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10. Crystalloids-colloid controversy
and 90-day mortality was found.42
Increased incidence
of severe bleeding was also documented in the HES
group (10% versus 6%, P = 0.09). In the CHEST trial,
there was a statistically significant increased need for
RRT in the HES group (7.0% versus 5.8%, P = 0.04), with
paradoxically more AKI, based on RIFLE scores, in the
saline arm.43
The discrepancy between AKI diagnosis
and need for RRT is reconciled by close evaluation of
the study findings. Treatment with HES was associated
with increased urine output in patients with less severe
AKI as compared with similar patients receiving saline.
This was postulated to be mediated by increased in-
travascular volume or a direct diuretic effect. Despite an
increased urine production, patients in the HES group
showed consistently higher serum creatinine concen-
trations as compared with the saline group. Since urine
output is incorporated into the RIFLE scoring system,
higher RIFLE injury scores were documented in the
saline group despite the greater need for RRT in the HES
group.43
Several influential meta-analyses were published in
2013 evaluating the current clinical data on the safety of
colloidal fluid resuscitation.81,105–109
A Cochrane review
assessed all RCT comparing colloids versus crystalloids
for fluid resuscitation in critically ill patients.105
An
overall increased risk of AKI, RRT, and kidney failure
was found in HES-treated individuals. As described
above, this increased risk of AKI with HES persisted
despite a paradoxical superior maintenance of urine
output. An average of 16 days passed before 50% of pa-
tients receiving HES developed AKI, although subgroup
analysis demonstrated group differences evolving after
only 3 days in certain cohorts. No significant differences
were found between septic and nonseptic patients. In
addition, specific HES solution formulation (MW, MS,
C2/C6) and total HES dose did not impact development
of AKI across included studies.105
A second Cochrane
review specifically evaluated the effect of HES on kidney
function, as compared with any other fluid therapy.106
This is the most complete systematic review of RCTs
published on the effects of HES on kidney function. A
significant increase in the need for RRT was found in the
HES-treated individuals (RR = 1.31). Although the risk
of meeting RIFLE-R (risk) criteria for AKI was higher in
patients receiving any fluid other than HES, HES-treated
individuals were more susceptible to development of
more severe RIFLE outcomes.106
No differences in
need for RRT and RIFLE-F-based outcomes were seen
between sepsis versus nonsepsis patients in subgroup
analysis, between high versus low MW and MS HES so-
lutions, or based on total volume of HES administered.
This study concluded that all HES products increase
the risk of AKI and RRT across patient populations and
that a safe volume of any HES solution has yet to be
determined. An additional influential meta-analysis was
published in late 2013 and included RCTs of critically ill
adult patients treated in an emergency or ICU setting.81
Pooled results from 10,290 patients involved in 28 trials
found, in accordance with other reports, incidence of
AKI and need for RRT (reported in a total of 5 trials
involving 8,725 patients) were significantly higher (RR =
1.27 and 1.32, respectively) in patients receiving HES.81
These authors concluded that in most clinical situations
it is likely that these risks outweigh any benefits, and
that alternate volume replacement therapies should be
used in place of HES products. Currently, there are no
published data confirming an association between HES
administration and AKI in the veterinary population.
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 sug-
gested 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 sub-
group 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 Ringer’s acetate group
was demonstrated (51% versus 43%, P = 0.03).72
Diver-
gence 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 re-
view found no evidence that resuscitation with colloids
reduces the risk of death when compared with crystal-
loid resuscitation and suggested that the use of HES in
particular may increase the risk of death.105
However,
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11. D. Cazzolli J. Prittie
the aforementioned meta-analysis demonstrated HES
was significantly associated with increased risk of death
(R = 1.09).81
In contrast, in the CRISTAL trial, while no difference
in primary outcome of 28-day mortality was found
between patients resuscitated with crystalloid versus
colloid, there were fewer deaths at 90 days in the colloid
arm (30.7% versus 34.2%, P = 0.03).97
Approximately
70% of the 1,414 patients in the colloid cohort were
treated with HES. The results of this trial are in contrast
to the previously discussed major trials and possible
explanations include tight control over daily colloid
dose limits; colloid-associated reduction in cardiovas-
cular and respiratory failures that may have inferred
renal protection (by way of less need for vasopressor
therapies); and use of chloride-rich solutions (saline) in a
majority of patients in the crystalloid arm. Compared to
the previously discussed RCTs, the CRISTAL trial had a
less rigorous design with some overlap in colloidal types
administered to each patient, making conclusions refer-
able to a particular colloid type inherently challenging.
Resuscitation with colloidal solutions in lieu of a
purely crystalloid-driven regimen in the setting of severe
illness has not demonstrated a survival advantage. The
reported adverse effects associated with HES have been
compelling enough to prompt the current Surviving
Sepsis Campaign Guidelines to recommend against
the use of HES for fluid resuscitation of severe sepsis
and septic shock (grade 1B).55
They instead suggest the
incorporation of HSA in the fluid resuscitation plan
of patients with severe sepsis and septic shock when
substantial amounts of crystalloids are required (grade
2C).55
In addition, the use of HES solutions has been
banned from use in the European market.54
In spite of
these studies, HES solutions are still used with frequency
in human and veterinary medicine in the United States.
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 resusci-
tation on patient outcome and adverse effects are likely
not logistically feasible in the near future. Veterinary
studies are often not powered to detect mortality differ-
ences 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.
It is unknown whether the data from critically ill human
patients are representative of a risk that spans across
species and are applicable to all patient populations.
Overall illness severity in veterinary ICU patients is far
less than in their human counterparts, attributable to the
impact of veterinary client financial constraints and the
ability to elect for humane euthanasia in severe disease
states. A majority of the aforementioned human clinical
trials evaluating the use of HES as a resuscitation fluid
enrolled patients who were diagnosed with severe sepsis
or septic shock, on aggressive vasopressor therapy and
often reliant on mechanical ventilation.41–44
In veterinary
medicine, sepsis is not treated with nearly the same fre-
quency, nor is illness severity within this patient popula-
tion comparable to that of human patients. Although this
severely ill cohort represents a percentage of veterinary
ICU patients, it does not represent the population as a
whole. Moreover, a large disparity exists in the duration
of hospitalization between patient populations. Criti-
cally ill human patients commonly have hospitalizations
that are on the order of weeks to months, whereas aver-
age veterinary ICU hospitalizations are days in duration.
Accordingly, the total administered volume of most re-
suscitation fluids is far less in veterinary patients, owing
to the significantly shorter mean duration of hospital-
ization in conjunction with lower illness severity and
perceived global volume deficits. The HES-associated
adverse effects of AKI and mortality have been noted to
be dose- and time-dependent in some trials. Hydroxy-
ethyl starch-associated AKI typically becomes evident
5–20 days after ICU admission.106
The abbreviated hospi-
talization in veterinary patients may mitigate the risk of
HES toxicity. Patients in the CRYSTMAS trial who were
treated with HES for only 4 days did not develop a HES-
associated AKI that other large trials, with longer dura-
tions of treatment and total administered volumes, have
reported.96
Conversely, some subgroup analyses have
shown renal impairment within 3 days in high-risk pa-
tient populations, which may represent a differentiated
risk for the more severely ill cohorts discussed above.106
Of importance is the absence of validated alternate
means of provision of intravascular oncotic support
to veterinary patients. As outlined earlier, a species-
specific, readily available, cost effective natural colloid
solution does not currently exist. With the known
morbidity associated with large volume crystalloid
administration and positive net fluid balance, there is
a drive to provide resuscitation that may limit these
effects. Adjunct colloidal support is often required to
adequately resuscitate a patient with substantial circula-
tory failure and achieve normalization of hemodynamic
parameters without causing a net positive fluid balance.
The results of the CRISTAL and CRYSTMAS trials are
intriguing and may be more pragmatic and applicable
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12. Crystalloids-colloid controversy
to veterinary ICU patients, as these trials focused
on hypovolemic patients with severe volume deficits
requiring rapid correction and short duration HES
use.96,97
Careful analysis of the current data also sug-
gests that veterinary patients may not be as susceptible
to or at risk for the adverse effects documented in
human patients. A judicious, thoughtful use of HES in
veterinary patients is merited, with astute consideration
of the potential side effects, as is prudent with the use
of any drug in the intensive care setting. Adherence to
manufacturer recommended daily dosing is advocated,
with consideration of earlier use of vasopressors and
inotrope therapy in the treatment of circulatory failure
once initial fluid resuscitation has failed. There is
compelling evidence supporting avoidance of use of
HES solutions in certain human patient populations,
including patients with known renal dysfunction and
patients with sepsis, systemic inflammation or suspected
severe capillary leak and third spacing. The application
of these restrictions to veterinary patients may not be
justified at the present time; however, as mentioned
previously, safety evaluations have not been performed.
In addition, although the potential toxicities associated
with synthetic colloids are widely acknowledged in
human critical care, the potential benefit in hypovolemic
resuscitation remains an unsettled dispute. Veterinary
clinical data evaluating the effect of synthetic colloid
fluid resuscitation on incidence of adverse effects and
patient outcome are lacking and warranted.
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