HEta-actualización.pdf

Clinical Practice Review Journal of Veterinary Emergency and Critical Care 24(6) 2014, pp 642–661
doi: 10.1111/vec.12208
Hydroxyethyl starch: A review of
pharmacokinetics, pharmacodynamics,
current products, and potential clinical
risks, benefits, and use
Polly A. Glover, DVM; Elke Rudloff, DVM, DACVECC and Rebecca Kirby, DVM, DACVIM,
DACVECC
Abstract
Objective – To review and summarize the pharmacokinetics and pharmacodynamics of hydroxyethyl starch
(HES), as well as reported risks and benefits of HES infusion, and to provide administration and monitoring
recommendations for HES use in dogs and cats.
Data Sources – Veterinary and human peer-reviewed medical literature, including scientific reviews, clinical
and laboratory research articles, and authors’ clinical experience.
Summary – HES solutions are the most frequently used synthetic colloid plasma volume expanders in human
and veterinary medicine. The majority of research in human medicine has focused on the adverse effects of
HES infusion, with emphasis on acute kidney injury and coagulation derangements. The studies often differ
in or fail to report factors, such as the type, amount, interval, and concentration of HES administered; the
patient population studied; or concurrent fluids administered. Currently, there is no definitive clinical evidence
that the reported adverse effects of HES use in human medicine occur in veterinary species. There is little
information available on HES administration techniques or simultaneous administration of additional fluids
in human and veterinary medicine. The rationale for HES use in small animals has been largely extrapolated
from human medical studies and guidelines. A controlled approach to intravenous fluid resuscitation using
crystalloid and HES volumes titrated to reach desired resuscitation end point parameters is outlined for small
animal practitioners.
Conclusion – The extrapolation of data from human studies directly to small animals should be done with the
knowledge that there may be species variations and different pharmacokinetics with different HES solutions.
Veterinary reports indicate that bolus and continuous rate infusions of 6% hetastarch solutions at moderate
doses are well tolerated in feline and canine subjects. Further research in domesticated species is necessary to
better define and expand the knowledge regarding use of HES solutions in small animal medicine.
(J Vet Emerg Crit Care 2014; 24(6): 642–661) doi: 10.1111/vec.12208
Keywords: canine and feline, hetastarch, plasma substitutes
Abbreviations
AKI acute kidney injury
COP colloid osmotic pressure
CRI constant rate infusion
CVP central venous pressure
From the Emergency & Critical Care Department, Lakeshore Veterinary
Specialists, 2100 W. Silver Spring Drive, Glendale, WI 53209.
The authors declare no conflict of interests.
Address correspondence and reprint requests to
Dr. Polly A. Glover, Coral Springs Animal Hospital, 2160 N. University
Drive, Coral Springs, FL 33073, USA. Email: pglovervet@hotmail.com
Submitted November 02, 2012; Accepted May 26, 2014.
FDA United States Food and Drug Administration
FVIII:C factor VIII coagulant
HE hydroxyethyl
HES hydroxyethyl starch
HP hydrostatic pressure
HSA human serum albumin
MAP mean arterial pressure
MS molar substitution
MW molecular weight
PCT platelet closure time
PMN polymorphonuclear cells; neutrophils
PRAC Pharmacovigilance Risk Assessment Commit-
tee
RCT randomized control trial(s)
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Veterinary Emergency and Critical Care Society 2014

Hydroxyethyl starch review
RES reticuloendothelial system
RL Ringer’s lactate solution
RRT renal replacement therapy
SABP systolic arterial blood pressure
SIRS systemic inflammatory response syndrome
TEG thromboelastography
USG urine specific gravity
vWF von Willebrand factor
Introduction
Hydroxyethyl starch (HES) is the parent name of a group
of synthetic polymers that are the most frequently used
plasma expanders in human and veterinary medicine.1
The primary use of HES solutions has been to increase
intravascular volume during hypovolemic shock and
to bolster intravascular colloid osmotic pressure (COP)
during hypoalbuminemic states. Metcalf et al2
pub-
lished one of the first clinical studies investigating the
intravascular volume expansion properties of HES in
normovolemic human patients. Since that time, indi-
cations for their use in human medicine has expanded
and HES solutions are now also used for isovolemic
hemodilution during cardiopulmonary bypass surgery
(CPB),3
erythrocyte sedimentation agents during
plasmapheresis and leukapheresis,4
and prevention of
cellular desiccation during cryopreservation.5
HES is synthesized from amylopectin, a natural starch
derived from either corn or potatoes, which is hydrox-
ylated to prevent rapid degradation by circulating ␣-
amylase. The first HES product to become commercially
available in the United States was 6% HES 450/0.75
(Hespan)a
in 1972. Since that time, subsequent gener-
ations of HES products have been developed that differ
in average molecular weight (MW), molar substitution
(MS), and pattern of substitution (C2/C6 ratio).6
It is
the degree and pattern of hydroxyethyl (HE) molecule
substitution on starch glucose subunits that determines
the pharmacokinetic and pharmacodynamic profiles of
the different HES products. Currently, HES solutions are
commercially available in the form of a hetastarch, hex-
astarch, pentastarch, or tetrastarch preparations.
The first reports of HES administration in dogs were
published in 1966, when Ballinger et al7
infused 6% HES
in saline solution and Dillon et al8
infused 7% HES in
Ringer’s lactate (RL) solution into research dogs during
controlled, hemorrhagic shock. In 1992, the veterinary
literature described the use of 6% HES 450/0.75 and 10%
HES 200/0.5 in combination with hypertonic saline in re-
search dogs undergoing controlled hemorrhagic shock.9
The veterinary literature has since expanded to include
clinical reports of the use and dosage of HES in small
animals.10–13
Figure 1: Modified Starling-Landis equation defining the driv-
ing forces for fluid movement across the normal continuous capil-
lary membrane. NDF, net driving force; HP, hydrostatic pressure;
COP, colloid osmotic pressure; c, capillary; t, interstitial tissue; g,
subendothelial glycocalyx.
Despite the benefits reported from the administration
of HES solutions, controversy exists regarding the risk of
clinically relevant adverse effects on kidney and coagu-
lation function. Research has suggested that the weight-
averaged MW, degree of MS, and concentration may
have an impact on the risk of toxicity.
Little data exist on the clinical use of HES in vet-
erinary medicine. Differing or unreported information,
such as concentration, weight-average MW, MS, admin-
istration dose or technique, and concurrent fluid admin-
istration in human studies, make it difficult to draw
specific conclusions. This clinical practice review will
explore the physiology behind the use of colloids, and
the pharmacokinetics and pharmacodynamics of the dif-
ferent HES solutions. Guidelines for interpretation of
HES%/MW/MS and C2/C6 ratio label information will
be provided. Beneficial and adverse effects reported in
human and animal patients will be discussed. The review
will conclude with author recommendations regarding
the dosing of HES solutions and monitoring their clinical
use in small animals, with suggested monitoring proce-
dures.
COP
The forces responsible for the movement of fluid into
and out of the capillary have been characterized by the
modified Starling-Landis equation (Figure 1).14
The in-
travascular hydrostatic pressure (HP) is the pressure ex-
erted on the walls of the capillary by the intravascu-
lar fluid and cells, and is the result of cardiac output
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P. A. Glover et al.
Figure 2: HES nomenclature. HES, hydroxyethyl starch.
and systemic vascular resistance. When the intravascu-
lar HP is greater than the tissue HP, fluids and parti-
cles of a size and charge capable of passing through the
capillary membrane will move into the tissue compart-
ment. Counteracting this force for outward movement
is the intravascular COP, provided by plasma colloid
particles.
A colloid is a large hydrophilic molecule in solution
that does not pass freely through a semipermeable mem-
brane. When the intravascular COP is greater than the
subendothelial glycocalix COP, the driving force for fluid
movement will be into the capillary. The natural particles
in blood that create COP are proteins—globulins, fibrino-
gen, and albumin. Albumin is the most numerous and
the smallest intravascular colloid, approximately 64–67
kDa in dogs.15
HES is a synthetic colloid that will increase
the capillary COP when administered intravenously.
Pharmacokinetics and Pharmacodynamics
Three numbers now identify all HES products on their
packaging: concentration, weight-average MW in kilo-
dalton, and MS (Figure 2). An additional characteristic,
the C2/C6 ratio, is typically provided in the package in-
sert. This information is meant to properly identify the
type of HES solution and aid the clinician in the selection
and administration of the most appropriate product for
the patient.
Concentration
Commercial HES solutions are available in 3%, 6%, and
10% concentrations. The concentration mainly influences
the initial volume effect. The concentration of the HES
solution, and patient intravascular volume status and
COP will play a role in how much vascular volume
expansion occurs after intravascular infusion. Studies
report that 6% HES 450/0.75 has less volume expand-
ing effects in normal people compared to people with
hypovolemia.16–27
The 10% solutions are hyperoncotic,
with a reported volume effect that exceeds the infused
volume by approximately 145%.28
Molecular weight
HES solutions are polydisperse mixture of molecules
that can range in MW from under 10 kDa to well
over 1,000 kDa.29
These solutions can be represented by
the number-average MW or the weight-average MW.
The weight-average MW determines what fraction of
the total mass of the solution each molecular size con-
tributes and is typically the number that is represented
on the HES packaging. This is calculated by multiply-
ing the weight fraction of a specific sized molecule by
the MW of that molecule, and then adding the cal-
culated portions together. The weight-average MW of
available HES products ranges from 70 to 670 kDa
(Table 1).
Previous methods for determining the weight-average
MW of an individual molecule used size exclusion
chromatography. This method underestimated the true
weight-average MW of HES solutions.30
A newer
method that uses low-angle laser light scattering has de-
termined that 6% hetastarch formerly labeled as 450/0.75
is actually 600/0.75. Similarly, HES 70/0.5 was referred
to in older papers as HES 40/0.5.31
For consistency, this
review will report the MW as it was reported in the orig-
inal article cited.
Osmotic effectiveness of HES depends on the number
of particles in solution per unit volume. HES molecules
with a MW below the renal threshold (45–60 kDa) are
rapidly excreted in the urine, reducing the circulating
number of HES particles and decreasing the osmotic ef-
fect of the circulating HES. The higher MW molecules
(greater than the renal threshold) are progressively hy-
drolyzed in the plasma by ␣-amylase into two or more
smaller molecules. This process provides an on-going
supply of osmotically effective plasma molecules un-
til the molecules are hydrolyzed to a size below renal
threshold.29,32–36
Molar substitution
The MS designates the average number of HE residues
per glucose subunit on the HES molecule. Hydroxyl
groups are replaced by larger HE groups at different
sites on the carbon atoms of the glucose subunits
(Figure 3). The number of sites of substitution will de-
termine the shape and size of the specific HES molecule,
and ultimately, what access ␣-amylase has to the
intermolecular bonds for degradation. HES with higher
MS will typically persist longer in the intravascular
space.31
The MS is represented within the name of the
specific HES product. For example, the MS number 0.7
in the description of a hetastarch preparation indicates
that there are on average 7 HE residues per 10 glucose
subunits. The other products include: hexastarch (MS =
0.6), pentastarch (MS = 0.5), and tetrastarch (MS = 0.4).
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Veterinary Emergency and Critical Care Society 2014, doi: 10.1111/vec.12208

Table 1: Commonly used HES solutions
HES Concentration MW MS C2/C6 ratio COP (mm Hg) Carrier solution Manufacturer
Hetastarch
Hespan 6% 600 0.75 4–5:1 26 0.9% NaCl B. BraunTM∗
Hextend 6% 670 0.75 4:1 31 Balanced electrolyte HospiraTM∗∗
Hexastarch
EloHES 6% 200 0.62 9:1 25 0.9% NaCl Fresenius KabiTM∗∗∗
Pentastarch
Pentaspan 10% 200 0.4–0.5 4–5:1 66 0.9% NaCl Dupont PharmaTM†
Hemohes 6% 200 0.4–0.5 4–5:1 30–35 0.9% NaCl B. BraunTM∗
Rhoehes 6% 70 0.5 3:1 30 0.9% NaCl B. BraunTM∗
Tetrastarch
Voluven 10% 130 0.38–0.45 9:1 70–80 0.9%NaCl Fresenius KabiTM
VetStarch, Voluven 6% 130 0.38–0.45 9:1 36 0.9% NaCl AbbottTM‡
, HospiraTM∗∗
Volulyte 6% 130 0.38–0.45 9:1 36 Balanced electrolyte Fresenius KabiTM∗∗∗
HES, hydroxyethyl starch; MW, weight-average molecular weight; MS, molar substitution; COP, colloid osmotic pressure.
∗
B. Braun Medical, Inc, Irvine, CA.
∗∗
Hospira, Inc, Lake Forest, IL.
∗∗∗
Fresenius Kabi, Bad Homburg, Germany.
†
Dupont Pharma, Inc, Mississauga, ON, Canada.
‡
Abbott Animal Health, Abbott Park, IL.
Figure 3: Structure of HES molecule. A segment of hetastarch is
shown as amylopectin with hydroxyethyl groups substituted for
hydroxyl groups at C2 and C6. Alpha-amylase, an endo-amylase,
hydrolyzes bonds within the molecular structure. The more sub-
stitutions there are at the C2 position, the more difficult it is for
amylase to reach the bonds.
Pattern of substitution (C2/C6 ratio)
The pattern of substitution describes the locations of HE
residues on the glucose subunits. The C2 and C6 carbon
atoms are the main target for substitution with a lesser
amount attached onto the C3 atom (Figure 3). HE groups
positioned on the C2 atom will inhibit the access of ␣-
amylase to the linking bonds more effectively than when
substitution is at the C6 position. A high C2/C6 ratio
will favor slower breakdown of the HES molecule. Treib
et al37
compared the longevity of 2 pentastarch solutions
with differing C2/C6 ratios (10% HES 200/0.5/13.4:1 and
10% HES 200/0.5/5.7:1) after daily IV infusions over a
10-day period in healthy human subjects. The subjects re-
ceiving the HES with the lower C2/C6 ratio (5.7:1) had a
lower in vivo MW and a significantly lower plasma con-
centration of 10% HES 200/0.5 after 3 days. This study
concluded that the higher C2/C6 ratio slowed hydroly-
sis by ␣-amylase and lead to greater plasma accumula-
tion of 10% HES 200/0.5/13.4:1. Of all the characteristics
HES possesses, the pattern of substitution and MS are
the most important factors that determine the pharma-
cokinetics of an HES solution.
Distribution and clearance
The elimination half-life of hetastarch (6% HES 450/0.75)
in healthy dogs is 7.45 days compared to people where
the elimination half-life is 12.8 days.38
This difference
has been attributed to dogs having a higher plasma ␣-
amylase concentration than humans.38
Renal excretion
accounts for approximately 70% of the total HES elimina-
tion. Clearance of 10% tetrastarch (HES 130/0.4) has been
shown in human studies to be approximately 23 times
higher than 6% hetastarch (HES 450/0.75), and almost 5
times higher than 10% pentastarch (HES 200/0.5).6
Secondary routes of HES elimination include ex-
travasation and uptake with transient storage in the
reticuloendothelial (RES) cells of the liver, spleen, and
lymph nodes. HES deposition in dogs has been demon-
strated by histopathology in intravascular and intersti-
tial spaces; hepatocytes; proximal renal tubular cells; and
in the RES of the liver, spleen, and lymph nodes at 3 and
6 days but not 30 days postinfusion.39
The changes that
did occur were reported to be transient and to not inter-
fere with organ function. With time, HES molecules are
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P. A. Glover et al.
catabolized by proteolytic enzymes in the RES cells
or gradually redistributed into the circulation and
excreted.29,40
A third, minor route of elimination is
through excretion in bile.
With increasing MS there is increased tissue storage of
HES molecules. There is 75% less tissue storage of 10%
HES 130/0.4 than 10% HES 200/0.5, and both have sig-
nificantly less tissue storage than 6% HES 450/0.75.29,40
Repetitive administration of HES with MS 0.4 re-
sults in HES accumulation in plasma and tissues.34,36,41
Tetrastarches with lower MS were developed to reduce
HES retention in circulation and tissues, and possibly
negative side effects of HES.6
Reported Side Effects
Despite the amount of data published, it remains diffi-
cult to draw specific conclusions regarding side effects
associated with HES infusion. The studies often differ in
the type, amount, concentration, and time course of HES
administered, as well as the patient population studied
and concurrent fluids administered. The extrapolation
of data from human studies directly to domestic animals
should be done with the knowledge that there may be
species variations and differing protocols for HES ad-
ministration in small animals. In addition, the results of
HES studies performed in healthy subjects may not be
representative of typical emergency or ICU patient pop-
ulations. The adverse effects of HES solutions have been
found to be related to the cumulative dose and not the
dose infused within a 24-hour period.4,42,43
Reported side effects with HES administration include
volume overload, coagulopathies, acute kidney injury
(AKI), proinflammatory effects, and allergic reactions.
Allergic reactions attributable to HES are rare in all
species due to the similarity of the HES molecule to
glycogen.44–46
However, foamy macrophage syndrome
and delayed-onset refractory pruritus are complications
reported in humans and are unique to the HES family
of colloids. Neither of these adverse effects has been re-
ported in veterinary medicine.
Foamy macrophage syndrome (hydrops lysosomalis
generalisatus) is an acquired lysosomal storage disease
that has been reported to occur in people, particularly
those requiring chronic plasmapheresis that utilizes HES
as a diluent.4,45
Delayed onset-refractory pruritus has
been reported to occur in 3–54% of people47–52
receiv-
ing manufacturer recommended doses of HES solutions
of all MW, MS, and C2/C6 ratios.52
Pruritus is the re-
sult of HES deposition in cutaneous Langerhans cells.
These patients present in a pruritic crisis, a severe, pro-
tracted course of pruritus that is refractory to treatment.
Typically, several weeks elapse from the time of HES
administration and the onset of pruritus, with clinical
signs persisting for up to 12–24 months.52
Myburgh et
al53
reported a significantly higher development of pru-
ritus in human general ICU patients treated with 6%
HES 130/0.4 versus 0.9% NaCl (4.0% versus 2.2%). HES-
related coagulopathies and AKI have been extensively
studied in human medicine. In 2004, head-to-head ran-
domized comparisons of different HES solutions found
that the effects on coagulation and renal function were
similar between generations.54
A systematic review of
clinical studies reported in 2011, which included the
majority of HES formulations (6% HES 450/0.75, 6%
HES 200/0.62, 6% HES 200/0.5, 10% HES 200/0.5, 6%
HES 120/0.7, 6% HES 130/0.42, and 6% HES 130/0.4),
concluded that past and present data does not sup-
port a consistent difference between HES generations,
with regard to mortality, morbidity, hemorrhage, and
AKI.55
Reported Renal Side Effects
A major controversy in critically ill patients revolves
around the selection of the type of IV fluid that will
maintain optimal renal perfusion without causing or
exacerbating injury to the kidneys. Several mechanisms
have been proposed for the cause of AKI that is reported
to be associated with HES administration. The first is
that HES macromolecules are reabsorbed into proximal
renal tubular cells causing an osmotic nephrosis (vac-
uolization and swelling of the cells). These nonspecific
histopathological findings have also been observed with
administration of dextrans, mannitol, sucrose, contrast
media, and even RL solution.56,57
Tubular osmotic
lesions have been noted in porcine isolated renal per-
fusion models as early as 6 hours after exposure to 20.0
± 1.2 mL/kg 10% HES 200/0.5, and 33.0 ± 7.6 mL/kg
6% HES 130/0.4256
; and have been documented on
postmortem examinations in humans for up to 10
years after HES exposure.57,58
HES molecules have not
been detected within the vacuoles.59,60
The significance
and effect of osmotic lesions on renal function is
unknown since the lesions have been found without
accompanying AKI.59,60
A second theory is that HES and other colloid flu-
ids cause hyperoncotic AKI.61
An increase in intravas-
cular COP due to unfiltered, osmotically active colloid
molecules coupled with low renal perfusion pressure
in the glomerular arterioles is proposed to cause alter-
ation of intraglomerular colloid osmotic forces, leading
to the reduction or cessation of glomerular filtration.62,63
Renal excretory function is proposed to be further com-
promised by back-leak of filtrate across damaged tubular
epithelium.62
Baron59,60
has postulated this to occur with
both 6% and 10% HES solutions, with an increased risk
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with the 10% HES solutions or repeated administration
of HES with high in vivo MW.
Wiedermann et al64
proposed that the specific prop-
erties of a colloid molecule and not its COP or osmo-
lality were responsible for reported renal injury. The
meta-analysis of 11 randomized controlled trials (RCT)
concluded that dilutional hypoalbuminemia caused by
HES administration may be an additional mechanism of
HES-associated nephrotoxicity due to decreased levels
of renoprotective albumin.65–69
Dehne et al70
administered varying 6% HES solutions
(200/0.5, 200/0.62, and 450/0.75) at 15 mL/kg to 60 hu-
man surgical patients that had no prior renal impairment
and compared renal function to similar patients treated
with RL. No significant differences were found between
the groups regarding postinfusion glomerular filtration
rate, renal plasma flow, or tubular and glomerular in-
tegrity. Neff et al71
found that repetitive large-dose infu-
sion (up to 70 mL/kg/d) of 6% HES 130/0.4 in patients
with severe head injury had no negative impact on renal
function. A 2005 study by Fenger-Eriksen et al72
admin-
istered HES to achieve a 30% decline in hematocrit from
baseline. They concluded that 6% HES 130/0.4 was su-
perior to 0.9% NaCl at preserving effective renal plasma
flow during hypotensive anesthesia in their human pa-
tients.
Other studies in human medicine have implicated
that certain MS and concentrations of administered HES
have a correlation with an increase in AKI and need
for renal replacement therapy (RRT) when compared to
crystalloid administration. In a porcine kidney model,
administration of 10% HES 200/0.5 (20.0 ± 1.2 mL/kg)
was associated with more renal macrophage infiltration
and interstitial inflammation than with 6% HES 130/0.42
(33.0 ± 7.6 mL/kg).56
In an ovine model of ful-
minant endotoxemia, 10% HES 200/0.5 admin-
istered in 5 mL/kg boluses (up to 20 mL/kg)
was compared to 6% HES 130/0.4 in 5 mL/kg
boluses (up to 20 mL/kg), and a balanced crystalloid
solution was given in 10 mL/kg boluses.73
The 10%
HES 200/0.5 was shown to have earlier renal effects
(increased plasma urea and creatinine concentration)
compared to the other solutions, and more pronounced
renal tubular injury within 12 hours of administration.
The Efficacy of Volume Substitution and Insulin Ther-
apy in Severe Sepsis42
study from 2008 demonstrated
that renal toxicity appeared to increase with accumulat-
ing doses of HES in human patients with severe sep-
sis or septic shock. Patients were given either 10% HES
200/0.5 for up to 21 days, with a median cumulative dose
of 70.4 mL/kg body weight, or a modified RL solution.
The 10% HES 200/0.5 group had a significantly higher
rate of AKI than the RL group (34.9% versus 22.8%) and
needed more days of RRT (18.3% versus 9.2%). The rate
of death at 28 days did not differ significantly between
the groups. The HES solution utilized was 10% (hyper-
oncotic) pentastarch, which is not currently available for
clinical use for plasma volume expansion in either the
United States or the European Union. Hyperoncotic so-
lutions, dextrans (concentrations were not reported), and
20% or 25% human serum albumin (HSA), both hyperon-
cotic solutions, have been associated with AKI in people
(38% incidence for HSA).61
A Cochrane meta-analysis74
from 2010 examined the
effect of all HES types compared to other fluid therapies
(crystalloids, dextrans, gelatin, HSA, blood, fresh frozen
plasma) on kidney function. The doses and duration of
HES therapy cited in the papers ranged from 1.7 L over
1 day to 70 mL/kg with a median duration of 14 days.
Only 34 of 671 studies reviewed were RCT in which HES
was compared to an alternate fluid therapy for preven-
tion or treatment of intravascular volume depletion in
human subjects. The primary outcomes measured were
the need for RRT, author-defined renal failure, and AKI
as defined by the Risk Injury Failure Loss End-Stage
criteria.75
The Cochrane review found no difference be-
tween treatment groups with respect to AKI risk or the
need for RRT in surgical and trauma patients. Sepsis
patients treated with HES had a 55% increased risk of
developing AKI and a 59% increased risk of requiring
RRT. The reviewers concluded that the ‘potential for in-
creased risk of AKI should be considered when weighing
the risks and benefits of HES for volume resuscitation,
particularly in septic patients.’74
The Cochrane meta-analysis also identified 5 studies
that compared different HES types and risk for AKI as
defined by Risk Injury Failure Loss End-Stage criteria or
the need for RRT. In comparing 6% HES 130/0.4 to either
6% HES 200/0.571,76-78
or 6% HES 200/0.62,79
there was
insufficient evidence to determine if 6% HES 130/0.4 is
associated with reduced risk of AKI compared to other
HES preparations.
Myburgh et al53
conducted the largest RCT ever
undertaken, investigating the effects of HES (CHEST
study). Seven thousand human general ICU patients
were randomized to receive either 6% HES 130/0.4 or
0.9% NaCl. In the HES group, significantly more pa-
tients received RRT (7.0% versus 5.8%). The study also
found that the 28- and 90-day mortality incidence was
not significantly different (18% versus 17%) in the whole
population or in the sepsis subgroup (n = 1,937).
Perner et al80
conducted an RCT (6S Study) of 804
human patients with severe sepsis. Patients received ei-
ther 6% HES 130/0.4 or Ringer’s acetate in total trial
fluid doses of 44 and 47 mL/kg, respectively. The HES
group was found to have a significantly higher risk of
receiving RRT (22% versus 16%), and a significantly
higher 90-day mortality incidence (51% versus 43%).
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P. A. Glover et al.
Randomized control trials and meta-analyses including
critically ill human patients, the majority with severe
sepsis, have documented similar results to Perner et al
with the use of 6% HES 130/0.4–0.42.81–86
There are no published studies that have specifically
evaluated the effects of differing HES solutions on
canine or feline renal histology or function. A recent
study did report that in normal, euvolemic dogs, 20
mL/kg of 6% HES 670/0.75 increased urine specific
gravity (USG) without changing urine osmolality.12
The
urinary excretion of the HES molecules increases the
density of the urine and the refractive index, elevating
the USG value. This increase in USG is not an accurate
reflection of urine osmolality.
Reported Coagulation Side Effects
The clinical significance of any HES-induced coagulation
derangement is the subject of an on-going debate.87
Sim-
ilar to large volume crystalloid infusion, colloid infusion
can cause a dilutional coagulopathy.88,89
In people, HES
administration has also been associated with platelet
dysfunction, as well as decreased concentrations of von
Willebrand factor (vWF), factor VIII coagulant (FVIII:C),
factor VIII related antigen, and factor VIII ristocetin co-
factor (Table 2).88,90
Enhanced fibrinolysis has also been
reported after administration of HES.91–95
Multiple hu-
man studies have documented a significant increase in
the need for blood product transfusion and bleeding ten-
dencies with the use of HES solutions.80,82,84,96
Overall, studies on HES-induced coagulopathies
in veterinary medicine are lacking. In both dogs and
people, the administration of a single dose of 25
mL/kg of hetastarch is generally accepted to have
minimal to no effect on bleeding or coagulation
parameters.10
In dogs receiving large doses of hetastarch
(30mL/kg), an increase in incisional bleeding, as well
as increased bleeding into the body cavities has been
documented.97,98
Abnormalities of platelet number and
function, coagulation factor levels, and fibrin clot for-
mation have been associated with significant bleeding
in animals receiving a volume of hetastarch exceeding
25% of their blood volume.90
It should be noted that
people receiving daily or weekly hetastarch infusions
over long periods of time have not shown significant
coagulation derangements.17,99,100
Platelets
HES solutions have been shown to compromise human
platelet function in vitro101–103
and in vivo106–110
as mea-
sured by flow cytometry,101,102,104,106
thromboelastogra-
phy (TEG),103,105,106,108,109
platelet aggregometry,110
and
platelet function analysis.99,106–108
Studies in human pa-
tients have demonstrated that HES solutions with MW
200 kDa or MS 0.5 have a more pronounced effect on
platelet function,104,105,107
and that hetastarch solutions
invoke the most dysfunction.105
Investigations looking at platelet function changes re-
lated to HES in small animals are limited to dogs. In
14 normal dogs undergoing elective orthopedic surgery,
a 10 mL/kg bolus infusion of either 6% HES 600/0.75
or RL significantly increased buccal mucosal bleeding
time and decreased platelet count 1 hour after infu-
sion of the HES but not the RL, but platelet aggregation
was not affected.13
Parameters returned to normal at the
5-hour testing point and no clinical bleeding was ob-
served. When compared to 0.9% NaCl, 6% HES 670/0.75
at a 20 mL/kg bolus infusion in normal dogs signifi-
cantly increased platelet closure time (PCT) up to 5 hours
postinfusion.111
There are significant differences in the
redistribution characteristics of crystalloids compared to
colloids given at equivalent doses, making it difficult to
identify any effect of hemodilution in this study.
There are several mechanisms by which platelet ad-
hesion may decrease following HES infusion (Table 2).
Specific binding of HES molecules to the platelet sur-
face was confirmed by using fluorescein isothiocyanate
coupled 6% HES 200/0.5,101
and binding was shown not
to occur at the fibrinogen receptor binding site. Deusch
et al101
postulated that the bound HES macromolecules
impair access of ligands to binding sites on the platelet
surface, and may inhibit conformational activation of
surface receptors when the platelet is stimulated.
Several studies have reported the effects of HES on
canine platelets. Calcium added to the HES carrier
fluid may increase platelet reactivity by increasing in-
tracellular calcium concentrations.102,104,112–115
However,
when canine-citrated whole blood mixed with 6% HES
670/0.75 containing 5 mEq/L calcium in a balanced elec-
trolyte solution was compared in vitro to 6% HES 600/0.7
in 0.9% NaCl and to colloid-free 0.9% NaCl, all solutions
prolonged PCT.116
Both colloid solutions did so more
than the 0.9% NaCl.
Classen et al117
investigated the in vitro effect of
HES 130/0.42 or 0.9% NaCl dilution of canine blood
on platelet function. A platelet function analyzer was
used to measure platelet function at dilutions of 1:3 and
1:9 with either solution. Both solutions significantly pro-
longed PCTs at the 1:3 dilution with the HES PCT greater
than the saline. The 1:9 dilutions did not significantly
prolong PCT for either test solution.
McBride et alb,c
analyzed canine PCTs in vivo and in
vitro after HES infusion. The concentration of the HES
solution was not reported in either study. However, the
authors indicate that a 6% HES 130/0.4 was used in the
in vivo study, and both a 6% HES 130/0.4 and 10% HES
200/0.5 were used in the in vitro study.d
The in vivo
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Table 2: HES effects on coagulation
Coagulation parameter Proposed HES mechanisms
Decreased platelet adhesion 1. Diminished circulating levels of vWF interfering with platelet binding to subendothelial collagen115
2. Interference with platelet integrin ␣IIb-␤3 expression and activation101
3. HES macromolecular binding to platelet surface101
4. HES macromolecular nonspecific coating of platelet surface102
Decreased circulating levels 1. Unidentified mechanism of action201
of vWF 2. vWF-FVIII complex binding with HES molecules leading to accelerated elimination in urine113
Decreased FVIII:C 1. Reduced half-life secondary to decreased circulating vWF
2. vWF-FVIII complex binding with HES molecules leading to accelerated elimination in urine113
Increased fibrinolysis Diminished thrombin-fibrinogen and FXIIIa-fiber polymer interactions via:
1. HES-induced efflux of coagulation factors from IV to interstitium reduces physical contact of factors for clot
formation92,106,202
2. Steric interactions of HES and fibrin polymers lessens transit of proteases, protease inhibitors, and/or FXIIIa in
forming clot matrix130
3. HES molecule entrapment in microcompartments of developing clot prevents adequate intermolecular spacing
of fibrin polymers for cross-linking130
4. Inhibits binding of TAFI130
5. Poor ␣2-antiplasmin-mediated protection of fibrin molecules from plasmin130
HES, hydroxyethyl starch; MW, weight-average molecular weight; MS, molar substitution; COP, colloid osmotic pressure polymers; vWF, von Willebrand
factor; FVIII, coagulation factor VIII; FVIII:C, coagulation factor VIII coagulant activity; FXIIIa, activated coagulation factor XIII; TAFI, thrombin-activated
fibrinolysis inhibitor.
studyb
was a hemorrhagic shock model comparing 20
mL/kg HES 130/0.4 to 80 mL/kg 0.9% NaCl admin-
istered over 20 minutes. Neither the HES 130/0.4 nor
the 0.9% NaCl increased the PCT above baseline. The
in vitro studyc
evaluated canine whole blood samples
diluted to 1:9 (10 mL/kg) and 1:3 (30 mL/kg) with 6%
HES 130/0.4, HES 200/0.5, and 0.9% NaCl. The 1:3 dilu-
tion with HES 200/0.5 significantly prolonged the PCT
over 0.9% NaCl. The 1:3 HES 130/0.4 dilution did not
significantly increase the PCT over 0.9% NaCl.
FVIII and vWF
The decline in FVIII:C activity and vWF concentration
and activity cannot be attributed solely to a dilutional
effect by HES solutions.31,113,118
HES solutions have been
demonstrated to lower concentrations of both vWF and
FVIII in vivo in addition to FVIII:C and vWF activity
(see Table 2).37,76,81,105,115,118–124
However, the quantita-
tive changes of vWF and FVIII:C associated with HES
infusion has not been reproduced in vitro. Several au-
thors have proposed that large HES molecules bind to
the vWF-FVIII:C complex.113
The accelerated elimina-
tion of these complexes in urine may delay generation of
sufficient thrombin to convert fibrinogen to fibrin, ampli-
fying coagulation abnormalities.125
The rapid clearance
of 6% HES 130/0.4 from circulation is thought to mini-
mize contact of FVIII and vWF with the HES molecules,
thereby dampening its effect on coagulation.31
Chohan et al13
compared coagulation parameters in
14 normal dogs undergoing elective orthopedic surgery
that received a 10 mL/kg bolus infusion of either 6% HES
600/0.75 or RL. Parameters were measured at baseline,
1 hour postinfusion, and 24 hours postinfusion. There
was no significant change in vWF antigen or FVIII:C at
any time interval, although the vWF concentration had
decreased by 27% in the RL group compared to 56%
in the HES group at the 1-hour mark. All parameters
were within normal range at 24 hours. Blood loss during
surgery and postoperative incisional bleeding was sub-
jectively evaluated as equivalent and normal in both of
the study groups.
The effect of 40 mL/kg of 6% HES 130/0.4 or
0.9% NaCl administration on coagulation in dogs with
lipopolysaccharide-induced systemic inflammation was
examined.e
In both study groups, the partial thrombo-
plastin time was significantly increased, with a more sub-
stantial increase in the HES group. TEG documented
hypocoagulability with HES administration, but not
with 0.9% NaCl infusion. The results of the study may
have been affected by hemodilution, as the same dose
was administered despite the difference in distribution
patterns of the solutions.
The results of HES studies performed in healthy
subjects with normal baseline FVIII and vWF con-
centrations are not necessarily representative of a
typical emergency or ICU population. As acute phase
proteins, FVIII and vWF concentrations may increase
during critical illness, trauma, and inflammation and
affect coagulation parameters independently of fluids
administered.87,126
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P. A. Glover et al.
Fibrinolysis
In 2009, Fenger-Eriksen89
reported that the most impor-
tant mechanism of coagulopathy from HES infusion may
be acquired fibrinogen deficiency. HES has been found to
significantly accelerate fibrinolysis in human subjects by
reducing thrombin-fibrinogen and activated factor XIII
fibrin polymer interactions.91–95
Fibrinogen is the first
factor to become critically low with HES infusion.127,128
The effect of HES on fibrinolysis can be attenuated with
the administration of fibrinogen concentrate.94,129,130
An in vitro study comparing TEG results follow-
ing the dilution of human plasma samples with ei-
ther 6% HES 450/0.75 or 6% HES 130/0.4 found that
the tetrastarch was responsible for the formation of
“far weaker and faster dissolving clots” than dilu-
tions with the hetastarch.130
The tetrastarch interfered
with thrombin-fibrinogen interactions to a significantly
greater extent than the hetastarch. The tetrastarch was
found to disrupt the thrombin-thrombin activatable fib-
rinolysis inhibitor interrelationship, hastening the onset
of fibrinolysis.
In a recent in vitro study by Falco et al,131
canine whole
blood samples were diluted to 1:10 (10 mL/kg) and 1:4
(30 mL/kg) with 6% HES 130/0.4 or NaCl 0.9%. The ef-
fect on thromboelastometry profiles was evaluated, and
only the HES dilutions resulted in a hypocoagulable pat-
tern. The authors surmised that the hypocoagulability
from the 6% HES 130/0.4 was dose-dependent (ie, the
1:4 dilution had the greatest effect), and was related to
alterations in fibrinogen concentration and inhibition of
platelet function.
HES-Suspended Authorization and New Warnings
Europe
Three recent studies42,53,80
investigating the safety and
efficacy of HES products (6% HES 130/0.40–0.42 and
10% 200/0.50) demonstrated that patients with severe
sepsis treated with HES were at a significantly greater
risk of AKI requiring RRT than those patients that re-
ceived crystalloids for volume replacement. Two of the
studies42,80
also documented a significantly higher risk
of mortality with HES versus crystalloid therapy. On
November 29, 2012, these results prompted the Ger-
man Medicines Agency, Federal Institute for Drugs
and Medical Devices (BfArM), to call for a review of
all HES infusion solutions by the European Medicines
Agency’s Pharmacovigilance Risk Assessment Com-
mittee (PRAC). PRAC evaluated data submitted from
companies, scientific literature, and sought expert
opinion.
On June 13, 2013, PRAC concluded that in patients
treated with HES, when compared to crystalloids, the
risk of AKI requiring RRT and the risk of mortality
was greater. PRAC determined that available data only
showed a limited benefit of HES solutions when infused
for hypovolemia. The suspension (ie, the “HES ban”)
of the marketing authorization for HES solutions was
instituted, and will remain in place unless a marketing-
authorization holder can provide data supporting that
HES benefits outweigh risks in a patient population. Op-
ponents of the PRAC suspension argue that the results
were extrapolated to all patients irrespective of underly-
ing conditions; use of HES in nonseptic patients was not
addressed in the studies reviewed42,53,80
; and extrapola-
tion to nonseptic patients remains controversial due to
unpublished data.132,133
The Coordination Group for Mutual Recognition
and Decentralised Procedures (Human CMDh) is a
medicines regulatory body that represents the entire
body of EU Member States. Human CMDh has received
the PRAC recommendations, and a review and consen-
sus vote on HES utilization and suspension is underway.
The Human CMDh will forward its position to the Eu-
ropean Commission for adoption as an EU-wide legally
binding decision.
United States of America
The United States Federal Drug Administration (FDA)
has approved four HES products for use in human pa-
tients (Hespan,a
Hextend,f
6% 450/0.7 in 0.9% NaCl,
Voluven). On September 6–7, the FDA convened a Pub-
lic Workshop to evaluate the risks and benefits of HES
solutions. RCTs, meta-analyses, and observational stud-
ies highlighting the association of HES infusion in criti-
cally ill adults (including those with sepsis) with an in-
creased incidence of AKI requiring RRT43,53,74,80,85,136–138
and mortality80,85,86,134,135
were presented. In addition, a
meta-analysis of 18 RCTs supported an increased risk of
bleeding in patients infused with HES while undergo-
ing CPB was reviewed.95
The increased risk of hemor-
rhage was found with all generations of HES solutions,
regardless of the degree of molar substitution or molec-
ular weight.
Based on the preponderance of evidence that HES in-
fusion carries an increased risk of AKI requiring RRT,
mortality, and hemorrhage during CPB, the FDA ap-
proved changes to HES product prescription information
on November 25, 2013.137
A new Boxed Warning about
the risk of mortality and RRT in critically ill adults, in-
cluding septic patients, was added. A new warning on
the package insert regarding the increased risk of hem-
orrhage during CPB was added to the Warnings and
Precautions section. FDA recommendations for patients
receiving HES (Table 3), and for health professionals us-
ing HES therapy (Table 4) were provided.
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Table 3: FDA recommendations for human patients137
1. Be aware that severe kidney damage has been associated with the
use of HES solutions
2. Be sure to follow-up with your healthcare provider as requested and
follow all instructions
3. Report any unusual symptoms immediately
4. Symptoms of kidney damage can include
•Change in frequency, amount, or color of urine
• Blood in the urine
• Difficultly urinating
• Swelling of the legs, ankles, feet, face, or hands
• Unusual weakness or fatigue
• Nausea and vomiting
FDA, United States Federal Drug Administration.
Table 4: FDA recommendations for human medical health
professionals137
1. Do not use HES solutions in critically ill adult patients, including
those with sepsis
2. Avoid use in patients with preexisting renal dysfunction
3. Discontinue use of HES at the first sign of renal injury
4. Need for RRT has been reported up to 90 days after HES
administration. Continue to monitor renal function for at least 90 days
in all hospitalized patients
5. Monitor the coagulation status of patients undergoing open heart
surgery in association with cardiopulmonary bypass as excess
bleeding has been reported with HES solutions (6% HES 450/0.7 in
0.9% NaCl) in this population. Discontinue HES at the first sign of
coagulopathy
6. Do not use HES products in patients with severe liver disease
7. Monitor liver function in patients receiving HES products
FDA, United States Federal Drug Administration.
Veterinary Medicine and HES
At present there is no veterinary literature or data to
support the restriction or cessation of HES product
use in small animal veterinary patients. In critically ill
and septic veterinary patients, the association of HES
infusion with AKI, the need for RRT, and mortality
cannot be extrapolated from human data. These patient
populations are those that tend to benefit the most from
the addition of intravascular COP support; and, the
aforementioned adverse effects have not been reported
in veterinary medicine. The small number of veterinary
patients undergoing CPB makes the new warning
relatively insignificant for the majority of veterinary
practitioners. The authors encourage veterinarians to
become familiar with the reported benefits and compli-
cations of HES, particularly in veterinary patients, and
consider the lack of reports on any association between
HES and AKI or mortality in veterinary patients.
Clinical Applications
Intravascular volume resuscitation
An essential task of emergency and critical care man-
agement is to restore and maintain effective circulating
intravascular volume. Hulse et al138
summarized 9 hu-
man studies examining volume expansion after infusion
of 6% HES 600/0.75. All plasma volume measurements
were determined by direct methods using radioisotopes
and dye. This review found that a volume expansion
occurred, which was between 100% and 172% of the in-
fused volume occurred.
Experimental research in dogs and clinical research
in people has shown that hetastarch is an efficacious
plasma volume expander at least equivalent to 5% HSA
and dextran 70, and superior to plasma and whole
blood.29,39,65,139–143
A 500 mL infusion of 6% HES 480/0.7
solution expanded the plasma volume by 300 mL in nor-
movolemic and 720 mL in hypovolemic humans.16–27
When the infused dose of HES was doubled from 500
to 1,000 mL in hypovolemic people, an even greater (av-
erage 900 mL) plasma expansion occurred; but, it did
not equate to a 1,440 mL plasma expansion, double the
720 mL expansion, that might be expected.2
In normo-
volemic, healthy dogs, the initial expansion of blood vol-
ume following the administration of 450 mL 6% HES
450/7.5 was 450 mL.142
Thirty minutes after infusion,
blood volume was increased by 650 mL. This was at-
tributed to redistribution of extravascular fluid into the
vascular space.
In veterinary and human medicine, there is an on-
going debate (ie, the crystalloid-colloid, or CRYCO de-
bate) over the most effective fluid strategy to achieve
resuscitation goals. Silverstein et al142
compared the
changes in blood volume over 240 minutes following the
administration of 80 mL/kg 0.9% NaCl to 20 mL/kg 6%
HES 450/0.75. The largest immediate increase in blood
volume occurred in the group infused with 0.9% NaCl,
but fell below that of HES by 30 minutes postinfusion.
At the end of the study period, the HES group had sus-
tained a greater expansion compared to the 0.9% NaCl
group (26 ± 8.6% versus 18 ± 9.7%).
Perel and Roberts143
reviewed 65 RCTs of different col-
loids, including HES (2.5%, 4.5%, 5%, 10%, 25%), plasma
protein fraction, modified gelatin, and dextran (40, 60,
70) compared to crystalloids used during intravascular
volume replacement in human patients. The outcome
assessed was mortality. The authors concluded that the
risk of death did not decrease in patients resuscitated
with colloids with trauma, burns, or following surgery.
A different review144
compared 70 RCT reporting the
effects of different colloids (HES, HSA, plasma protein
fraction, modified gelatins, and dextran 70) adminis-
tered for fluid resuscitation in humans. The outcomes
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P. A. Glover et al.
considered were mortality, the amount of whole blood
transfused, and the incidence of adverse reactions. Not
all outcomes were reported in all studies. These authors
concluded that the studies provided no evidence that
one colloid solution was more effective or safer than any
other. However, the confidence intervals were wide and
did not exclude clinically significant differences between
colloids.
Myburgh et al53
found that when compared to 0.9%
NaCl, human ICU patients resuscitated with 6% HES
130/0.4 received less fluid volume (526 ± 425 versus
616 ± 488 mL/d), had higher central venous pressures
(CVPs), and significantly fewer patients developed new
circulatory failure (36.5% versus 39.9%). The CRYSTMAS
study84
utilized the same resuscitation fluids, and found
that significantly less HES was used to reach hemo-
dynamic stabilization in human severe sepsis patients
(1,379 ± 886 mL in HES group versus 1,709 ± 1,164 mL
in 0.9% NaCl group). Feldheiser et al145
examined the
use of 6% HES 130/0.4 versus Ringer’s acetate in hu-
man patients undergoing cancer surgery. The study doc-
umented that 63% treated with HES versus 92% treated
with Ringer’s acetate reached the maximum dose limit
of 50 mL/kg, indicating a significantly more efficacious
volume effect of HES.
Clinical studies in the dog and cat have reported that
6% hetastarch solutions are tolerated well by cats and
dogs in the emergency and critical care setting. 10,146
In
27 hypotensive cats, the combination of 6% HES 450/7.50
(2.5–18.5 mL/kg) with a buffered isotonic crystalloid
(10–33 mL/kg) was efficacious at restoring normal or
near normal systolic arterial blood pressure (SABP) with
few adverse effects.g
In 16 hypotensive dogs, the com-
bination of 6% HES 450/0.75 (6.88–31.25 mL/kg) with
a buffered isotonic crystalloid (10–30 mL/kg) rapid in-
fusion significantly improved SABP with no reported
adverse effects.h
In canine hemorrhagic shock models,
6% hetastarch has been reported to significantly improve
oxygen delivery, serum lactate clearance, and hemody-
namic parameters.147–149
In a canine hypotensive hemor-
rhagic shock model, Muir et al148
reported that 19 mL/kg
6% HES 670/0.75 normalized and maintained systolic ar-
terial pressure at significantly smaller doses than those
needed with 75 mL/kg RL over 2 hours.
COP Support
The normal COP for healthy dogs is 17.5–22.7 mm
Hg,150,151
and has been reported to range between 5.8
and 12.7 mm Hg in hypoalbuminemic dogs.10
The mod-
ified Starling equation identifies intravascular COP as
an integral force for maintenance of intravascular fluid
volume.14
Since albumin is the main natural plasma col-
loid, a reduction in plasma albumin through decreased
production or loss through capillary leakage can lead to
loss of plasma COP.
Hypoalbuminemia and COP
Hypoalbuminemia is a common finding in surgical and
ICU patients, and is often caused by an increased pro-
duction of acute phase proteins or loss through capillary
leakage.152–155
The subsequent decrease in intravascular
COP is in part responsible for the development of loss of
intravascular volume, tissue edema, and ascites that can
cause or exacerbate tissue hypoxia. HES solutions have
been shown to be effective in increasing the intravascular
COP in hypoproteinemic dogs and people.11,29,139,153,156
In a study by Moore et al,11
30 hypoalbuminemic dogs
were administered a single dose (average 18.1 mL/kg)
of 6% HES 450/0.7 over 6 hours. There was a signifi-
cant increase in intravascular COP from baseline (11.83
± 3.64 mm Hg) after HES administration in all dogs
(14.92 ± 4.59 mm Hg) except those with acute gastroin-
testinal disease. The significant difference in COP was
no longer present at 12 hours postinfusion. The authors
recommended that in dogs with hypoalbuminemia, con-
tinued COP support be provided by multiple doses of
HES. Their recommendations are reflected in the current
common practice of utilizing HES constant rate infusions
(CRIs) in patients with the need for maintenance of COP
over extended time periods.
Rackow et al152
researched the effects of 0.9% NaCl
(659 ± 20 mL/kg) and 6% HES 450/0.75 (200 ± 33
mL/kg) infusions given over 5 hours in hypoprotein-
emic dogs. Dogs who received 0.9% NaCl developed
massive peripheral edema, ascites, and diarrhea. The de-
velopment of pulmonary edema in the crystalloid group
was evidenced by significantly higher extravascular lung
water measurements and decreased oxygenation of arte-
rial blood. Similar effects were not observed in the HES
group. The plasma COP was significantly higher in the
HES group (20.1 ± 1.6 mm Hg) compared to the 0.9%
NaCl group (3.3 ± 1.3 mm Hg) at the end of the study pe-
riod. Overall, the HES was administered in smaller vol-
umes, and the relative increase in plasma COP achieved
comparable increases in plasma volume and microvas-
cular pressure without increasing the risk of edema, as-
cites, and diarrhea.
In a later study by Smiley et al,10
26 hypoalbumine-
mic dogs (albumin 20 g/L [2.0 g/dL]) were adminis-
tered single or multiple doses of hetastarch (unknown
type; mean total dose 30.69 ± 14.21 mL/kg) over 6–8
hours. The mean plasma COP after the first dose of het-
astarch was significantly higher than pre-HES values.
Subsequent hetastarch doses did not have a significant
additive impact on intravascular COP values. There was
no correlation between the change in intravascular COP,
652 C

hetastarch dose, interval between first and second het-
astarch doses, or time between hetastarch administration
and COP measurement. Eighteen of the 26 hypoalbu-
minemic dogs had either peripheral edema or body cav-
ity effusion, and 83% of these dogs (15/18) experienced
either clinical improvement or resolution of edema or
effusion, which was attributed to hetastarch administra-
tion.
Increased Capillary Permeability
Critically ill patients, regardless of their primary disease
process, are at risk for increased capillary permeabil-
ity as a result of circulating inflammatory compounds,
ischemia-reperfusion injury, and regional or global tissue
hypoxia. The capillaries in different body tissues have
varying reflection coefficients, or relative protein perme-
ability, which make their host organ inherently more or
less susceptible to edema and its sequelae.157
Examina-
tion of the microvasculature has suggested that increased
capillary permeability is primarily due to endothelial
cell contraction with separation of endothelial cell junc-
tions almost exclusively in postcapillary venules.158–160
In 1988, electron microscopy revealed that separation of
interendothelial clefts (ie, pores) is not necessary for in-
creases in microvascular permeability.161
Most recently,
the integrity of the endothelial glycocalyx has become
the focus of vascular permeability research.162,163
Several theories exist regarding the benefits of HES in-
fusion during states of increased capillary permeability.
The theory of HES molecules physically plugging leaks
in capillaries was first introduced in multiple studies
by Zikria et al.158,164,165
The efficacy of various HES MW
fractions at preventing albumin extravasation was exam-
ined in rat jejunal scald burn models.158
The test subjects
that had received a medium range (100–300 kDa) had
the least amount of albumin leakage.
In a more recent in vivo study by Tian et al,166
the au-
thors postulated that modulation in capillary permeabil-
ity was affected by immune modulation. They studied
the effects of different doses of 6% HES 200/0.5 on lung
capillary permeability in endotoxic rats. The parame-
ters measured included lung capillary permeability, neu-
trophil (PMN) influx into and accumulation in lungs, ex-
pression of C11b on blood PMN surfaces, lung cytokine-
induced PMN chemoattractant-1 concentration, as well
as the activation in blood and lung PMN of nuclear factor
␬B (NF-␬B). Maximal inhibition of all measured param-
eters occurred at a dose of 7.5 mL/kg infused over a 2- to
4-hour period and loss of inhibition at the higher doses
(15 or 30 mL/kg) given over the same period of time. The
effects of HES on immune modulation have also been in-
vestigated in systemic inflammatory response syndrome
(SIRS) conditions.
SIRS and Sepsis Support
Sepsis, pancreatitis, heat stroke, severe polytrauma,
burns, neoplasia, and immune disease are common con-
ditions in veterinary medicine associated with SIRS.167
The release of vasoactive mediators and altered vascu-
lar endothelial function leads to the maldistribution of
fluid within the microvasculature, venous pooling, and
increased microvascular permeability.168
During sep-
sis, hypoalbuminemia commonly develops as a conse-
quence of albumin efflux from the plasma to the in-
terstitium at a rate 3-fold higher than normal.168
If
left unchecked, the extravasation of fluid and macro-
molecules results in hypovolemia, inadequate venous
return, decreased cardiac output, and compromised
oxygen and nutrient flow to tissues. Patients with
SIRS/sepsis are at an increased risk of mortality asso-
ciated with hypovolemia, and often require large vol-
umes of IV fluids for resuscitation and maintenance of
intravascular volume. The optimal fluid to reach these
goals remains undetermined.
Holbeck and Grände169
investigated 6% HES 200/0.5
infusion in a model of feline intestinal perfusion and
metabolism during Escherichia coli endotoxemia. The 6%
HES 200/0.5 was administered at 5 mL/kg over the first
30 minutes, and then at a rate of 2.5 mL/kg/h for the
remaining 4 hours of the study. The control group did
not receive any IV fluids during the 4 hours postendo-
toxin administration. At completion of the study, im-
provements were observed in mesenteric arterial blood
flow, intestinal vascular resistance, oxygen extraction ra-
tio, blood and intestinal tissue lactate and pyruvate con-
centrations, and arterial pH in all subjects that received
HES. The measured parameters progressively deterio-
rated in the control group. Although this study provided
excellent data that colloid infusion may serve to improve
therapy and survival in septic feline patients, a control
group receiving crystalloid solution would better define
the benefit of HES over crystalloids.
In the Efficacy of Volume Substitution and Insulin
Therapy in Severe Sepsis study,42
10% HES 200/0.5 was
administered to human patients as repeated bolus in-
fusions over multiple days. This study demonstrated
that side effects attributed to the HES increased with ac-
cumulating doses. Renal impairment occurred at doses
ࣘ22 mL/kg/d in a significant number of patients, and a
significantly higher 90-day mortality rate was seen in pa-
tients given doses 22 mL/kg/d (57.6% versus 30.9%).
Overall, research investigating the effects of HES
on inflammation has showed mixed results. HES with
different MW/MS have been associated with a decrease
leukocyte recruitment and adhesion,166,170–179
an increase
in inflammation,56,180,181
as well as no effect at all,182
in
vivo or in vitro. It remains to be seen whether fluids with
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P. A. Glover et al.
differing MW/MS and doses may show beneficial effects
on inflammation in specific clinical conditions in specific
species.
Several clinical studies of dogs and cats with SIRS-
related conditions that received 6% HES 450/0.75 have
been reported. The dog studies used HES in dogs with
naturally occurring gastric dilatation and volvulus and
no adverse consequences from HES were reported.146,183
Haak et al146
administered HES as a bolus infusion with
an isotonic crystalloid during resuscitation (mean of 18.4
mL/kg; range 10.5–37.3 mL/kg). Green et al183
adminis-
tered HES as a bolus infusion with an isotonic crystalloid
during resuscitation at a dose of 5–10 mL/kg increments
until resuscitation end points were achieved. HES CRI
(dose not reported) was continued following resuscita-
tion. In a feline study, HES was administered during fluid
resuscitation in cats and as a CRI.184
HES was given with
isotonic crystalloids as a bolus infusion (mean of 9.12
± 5.2 mL/kg; range 1.96–25.55 mL/kg) during initial
resuscitation, dosing to reach desired end points of re-
suscitation followed by a subsequent CRI of HES (mean
of 1.3 ± 0.94 mL/kg/h, range 0.37–1.81 mL/kg/h) and
crystalloids for maintenance of fluid support. The ad-
ministration techniques of HES in these clinical studies,
wherein HES was used during initial volume resuscita-
tion to resuscitation end point parameters, and contin-
ued as a CRI during maintenance fluid support, differ
from those used in human medicine. CRI dosing exceed-
ing several hours duration is not described in people.
Hypercoagulable states
HES infusion may have positive therapeutic effects in hy-
percoagulable patients. Physicians use HES solutions as
a prophylactic measure to prevent venous thromboem-
bolic complications in various patient populations.185
HES has also been used to hemodilute patients suf-
fering from myocardial infarction or acute ischemic
conditions.186
The use of HES infusions in veterinary
medicine for disease states involving vascular endothe-
lial damage, hypercoagulability, and abnormal blood
flow (ie, Virchow’s triad) warrants further investigation.
Isovolemic Hemodilution
Isovolemic hemodilution with 6% HES 450/0.75 has
been shown in an experimental setting to reverse AKI
induced by renal ischemia. Rajagopalan et al187
sub-
jected unilaterally nephrectomized dogs to occlusion of
the remaining kidney’s renal artery and vein, and ureter
to create experimental ischemic AKI. The experimental
group of dogs had simultaneous phlebotomy and
isovolemic hemodilution with 6% hetastarch (range
350–700 mL/dog) until their hematocrit decreased to ࣘ
25%. The control group received no other fluids during
the study period. All of the dogs in the control group
died from AKI by day 7. The AKI in the 6% hetastarch
hemodilution group began to resolve after day 4, and
there was significant improvement in serum creatinine
and clinical status in all dogs by day 7. Further studies
comparing hemodilution with crystalloids to hemo-
dilution with hetastarch are needed to better define the
specific benefits of hetastarch hemodilution.
Recommendations for administration
Recommendations on the quantity, infusion rate, mode
of administration (rapid bolus versus slow infusion ver-
sus CRI), and whether or not there should be concurrent
crystalloid administration have not been defined in clin-
ical studies from the human literature. In addition, dif-
ferent conclusions are made with differing MS and con-
centration of the HES solution studied. The authors have
used 6% HES 450(600)/0.75 in small animal patients for
30 years, and have published clinical studies reporting
successful resuscitation of dogs and cats with the com-
bination of 6% HES and isotonic balanced crystalloids
as their primary means of fluid support.146,183,184,g,h
The
authors have also applied these techniques when using
6% HES 130/0.4. Neither AKI nor clinically significant
bleeding has been observed by the authors in the dog and
cat as complications of 6% HES 450(600)/0.75 or 6% HES
130/0.4 administration using the following administra-
tion techniques. These complications also have not been
documented to occur with their clinical use in small ani-
mal veterinary medicine. Recommendations put forth in
this paper are made based upon these experiences and
currently available information.
Compared to the traditional approach to shock
resuscitation with crystalloids (dogs: 80–90 mL/kg;
cats: 40–60 mL/kg),188
most of the animals in the
HES studies were administered HES products alone.
The authors recommend the simultaneous infusion of
both 6% HES and isotonic balanced crystalloids. This
combination of fluid types can meet the immediate
fluid and electrolyte needs of the different fluid spaces,
using the crystalloids to replace interstitial deficits and
the colloid for the majority of the intravascular volume
deficit. The selection of specific crystalloid and colloid
is based upon availability and the needs of the patient.
Rather than infusing predetermined fluid quantities,
the amount of each fluid type administered is directed
toward meeting specific cardiovascular goals targeted
to the individual patient. This approach has been called
end point resuscitation in veterinary literature,189
and
early goal directed therapy in human literature.190
In an
evidence-based review of early goal directed therapy in
severely septic human patients, it was concluded that
654 C

during the first 6 hours of resuscitation, the goals should
include all of the following: CVP of 8–12 mm Hg (10–
16 cm H2O), mean arterial pressure (MAP) ࣙ 65 mm
Hg, urine output ࣙ 0.5 mL/kg/h, and central venous or
mixed venous oxygen saturation ࣙ 70%.190
Another approach for the use of fluid therapy dur-
ing resuscitation from shock in human trauma patients
is termed hypotensive resuscitation.191
The goal is to
avoid exacerbating blood loss that can occur if arterial
blood pressure is corrected into normal range. Bickwell
et al192
showed that rapid high-dose crystalloid infusion
(80 mL/kg) in a hemorrhagic model in swine increases
the circulating volume and SABP, but increased volume
of hemorrhage and mortality. Additional animal models
of uncontrolled hemorrhagic shock have demonstrated
improved outcomes when a lower than normal blood
pressure (MAP 60–70 mm Hg) is taken as the blood pres-
sure target for fluid administration until hemostasis is
accomplished.193
In a review of animal studies of pen-
etrating trauma, Jackson and Nolan194
have suggested
that moderate underresuscitation aiming for a MAP of
60 mm Hg might be a compromise between increasing
hemorrhage and maintaining tissue perfusion. Guide-
lines for treatment of traumatic brain injury put forth by
the Brain Trauma Foundation, the American Association
of Neurologic Surgeons, and the Joint Section on Neuro-
trauma and Critical Care suggest titrating small volumes
of crystalloids to an SABP target ࣙ 90 mm Hg based on
human clinical studies, and they state that the use of low
volume HES solutions are not associated with increased
mortality.195
When the condition of the patient can potentially ben-
efit from aggressive IV fluid resuscitation while tolerat-
ing a rapid increase in intravascular HP, high end points
are selected. However, should it be estimated that this
increase in intravascular HP could be harmful, low end
points are selected. Problems associated with trauma,
hemorrhage, lung edema, brain edema, oliguric renal
failure, and heart failure can be exacerbated by rapid
and substantial increases in IV HP. The authors therefore
recommend an initial selection of low end resuscitation
end points with titrated fluid infusion when the potential
for any of these problems is present.
The doses recommended for resuscitation from hypo-
volemic shock in this section are for 6% HES 600/0.75
and 6% HES 130/0.4, currently the most commonly
used HES solutions in clinical veterinary medicine. The
authors have categorized the administration technique
for the balanced isotonic crystalloid and HES combina-
tion as either large volume or small volume. In dogs, the
small volume technique of crystalloid and HES infusion
is 10–15 and 5 mL/kg, respectively. Large volume infu-
sion for the dog constitutes 20–50 mL/kg of crystalloid,
and 5–15 mL/kg of HES. In cats, the authors use only
the small volume infusion technique comprising 5–10
mL/kg of crystalloid, and 2–5 mL/kg of HES. In all cases,
an initial dose of fluids is administered, and the patient
is reassessed prior to administering subsequent doses.
The canine patient assessed to benefit from rapid and
aggressive IV fluid resuscitation (ie, tolerate sudden in-
crease in intravascular HP) will receive IV fluids rapidly
and in large volumes. This technique should only be
used to target high end resuscitation end points in the
dog. When the dog needs less dramatic changes in in-
travascular HP, smaller volumes of fluids are titrated
to reach the low end points selected. The patient is re-
assessed throughout the resuscitation period with ad-
justments made in end point selection and fluid infu-
sion technique according to the needs of the individual
patient.
Cats appear to benefit from small volume titration
techniques for crystalloid and HES infusion, regardless
of high or low end point selection. Hypothermia, hy-
potension, and bradycardia are typical clinical findings
in the cat suffering from shock and may contribute to the
fluid intolerance often exhibited after aggressive resusci-
tation. Research has demonstrated an altered adrenergic
reactivity in hypothermic cats.196
Rapid patient rewarm-
ing without intravascular volume replacement can result
in peripheral vasodilation and exacerbation of perfusion
deficits.197
The authors therefore recommend a balanced
approach, including external warming techniques in the
feline patient.
Initial small volume infusion techniques using re-
placement isotonic crystalloids and 6% HES are utilized
to support intravascular volume, targeting an indirect
SABP ࣙ 40–60 mm Hg. The IV fluids are then contin-
ued at a maintenance rate while aggressive external
warming brings the rectal temperature 98°F (37°C)
within 30 minutes if the hypothermia is secondary
to hypovolemic shock (a slower rewarming time is
utilized with primary hypothermia).198
Heat support is
continued as needed to maintain body temperature and
the patient’s perfusion and hydration are reassessed
with additional crystalloids and colloids titrated to
reach selected end point parameters.
When resuscitation end point parameters cannot be
reached in the dog or cat despite adequate fluid replace-
ment, causes of nonresponsive shock are identified and
treated. The use of vasopressors, blood products, or other
pharmacologic means of blood pressure support are con-
sidered.
Maintenance COP Support
Once the correction of perfusion deficits has been
achieved by reaching desired end point parameters, 6%
HES infusion is continued at a CRI dose 20–30 mL/kg/d
C

P. A. Glover et al.
in an effort to maintain the plasma COP until perfu-
sion parameters have stabilized, capillary integrity is
restored, and recovery is eminent. In hypoalbumine-
mic dogs and cats with adequate perfusion at presen-
tation and tissue edema unrelated to myocardial failure
or SIRS-related diseases, 6% HES can be infused at a
lower dose over time to bolster and maintain COP with-
out causing intravascular volume overload. As part of
the fluid therapy plan, an initial 6% HES infusion can be
titrated at doses between 5 and 20 mL/kg over 4–6 hours.
The quantity infused will be dependent upon the ability
of the patient to tolerate intravascular HP changes. In-
travascular COP support is then maintained with a CRI
dose of 20–30 mL/kg/d of 6% HES. Isotonic replacement
crystalloids are administered concurrently with main-
tenance HES infusion to restore and maintain hydra-
tion at a dose determined to meet the patient’s ongoing
needs.
Monitoring HES Therapy
Careful patient monitoring provides a means for assess-
ing resuscitation end points using 6% HES, identifying
complications related to 6% HES therapy, and determin-
ing when 6% HES therapy is no longer necessary. Fre-
quent assessment of the physical perfusion parameters
(ie, heart rate, capillary refill time, pulse intensity, mu-
cus membrane color, SABP) and CVP is warranted to
ensure cardiovascular homeostasis. A urine output ࣙ1
mL/kg/h can be an indirect reflection of adequate re-
nal perfusion. If urine output acutely declines, an ad-
justment in fluid infusion rate and volume is made and
causes of reduced renal perfusion and urine output are
investigated.
Close monitoring for signs of intravascular fluid over-
load is imperative, particularly in patients with car-
diopulmonary disease and oliguric renal failure. Signs
of fluid overload include the development of a serous
nasal discharge, an increase in respiratory rate and ef-
fort, moist lung sounds, peripheral edema, and pleural
or abdominal fluid accumulation. Monitoring the CVPs
for increasing values may provide an early indication
of increasing intravascular HP that could lead to fluid
overload.
Like any fluid, HES administration will have a dilu-
tional effect that will be reflected by a decrease in packed
cell volume, albumin concentration, and serum potas-
sium concentration.45
HES administration can increase
USG, but not urine osmolality; therefore, USG may not
accurately reflect renal concentrating ability post-HES
administration.12
Clotting times can increase after HES administration.
Activated clotting time, prothrombin time, activated par-
tial prothrombin time, and TEG or ROTEMi
parameters
can be monitored and changes expected. When large
volumes of HES (30 mL/kg) are required to reach re-
suscitation end point parameters, the degree of change
in clotting times and physical evidence of bleeding will
direct the need for plasma administration to improve
coagulation.
In addition to assessing the intravascular volume sta-
tus, measuring plasma COP can assist in determining
whether a colloid will be beneficial in patients with low
plasma protein. Refractometer readings of total solids do
not accurately reflect plasma COP, and underestimate
COP changes with 6% HES administration.199
Colloid
osmometers are the gold standard for measuring serum,
plasma, or whole blood colloid particles larger than 30
kDa.200
Colloid osmometers are not commonly used in
small animal private practice, but can provide specific
information regarding intravascular COP. However, the
patient’s clinical picture can be evaluated for resolution
of clinical signs of hypovolemia, tissue edema, ascites,
and the primary cause of the SIRS process to determine
when 6% HES therapy can be discontinued. Tolerance of
enteral feeding can also be a sign that integral albumin
synthesis will resume. The HES infusion can be tapered
or abruptly suspended.
Conclusions
HES solutions are the most frequently used synthetic
colloid plasma volume expanders in veterinary and hu-
man medicine. Differences between human and animal
species in amylase concentration as well as dose and
administration techniques should be considered when
assessing the relevance of reported side effects to a par-
ticular species. While the safety profile of the different
HES solutions has not been specifically determined for
domesticated species, HES solutions have been reported
to be effective with minimal side effects in dogs and cats
using the above recommended doses and administration
techniques.
In the authors’ experience, benefits in veterinary pa-
tients of combination HES and crystalloid therapy com-
pared to crystalloid administration alone have included
volume resuscitation with smaller volumes of IV fluids,
shorter fluid infusion times, longer intravascular dura-
tion of infused fluids, and maintenance of intravascu-
lar volume despite low serum albumin concentrations.
These benefits could be significant in patients with a
smaller body mass, in particular cats who seem uniquely
susceptible to volume overload. Further laboratory and
clinical research in domesticated species is necessary to
better define and expand the knowledge regarding the
pharmacokinetics and pharmacodynamics of HES solu-
tions in veterinary patients.
656 C

Footnotes
a
Hespan, B. Braun Medical, Inc, Irvine, CA. Through new techniques
for measuring MW, 6% HES 450/0.75 is now considered to be 6% HES
600/0.75.
b
McBride D, Hosgood G, Raisis A, et al. Platelet closure time in dogs
with hemorrhagic shock treated with hydroxyethyl starch 130/0.4 or 0.9%
NaCl. J Vet Emerg Crit Care 2012; 22(S2):S7.
c
McBride D, Hosgood G, Smart L, et al. The effect of hydroxyethyl starch
130/0.4 and 200/0.5 on canine platelet function in vitro. J Vet Emerg Crit
Care 2012; 22(S2):S7–S8.
d
Personal communication, Lisa Smart, BVSc, DACVECC, Murdoch Uni-
versity, Murdoch, WA, Australia, 2013.
e
Gauthier V, Bersenas A, Holowaychuk M, et al. Effect of synthetic colloid
administration on coagulation in dogs with systemic inflammation. J Vet
Emerg Crit Care 2012; 22(S2):S5.
f
Hextend, Hospira, Inc, Lake Forest, IL.
g
Garcia AM, Rudloff E, Kirby R. Efficacy and adverse effects of het-
astarch/crystalloid combination in 21 hypotensive cats. J Vet Emerg Crit
Care 2002; 12(3):196.
h
Garcia AM, Rudloff E, Kirby R. Efficacy and adverse effects of het-
astarch/crystalloid combination in 16 hypotensive dogs. J Vet Emerg Crit
Care 2002; 12(3):200.
i
ROTEM, TEM innovation GmbH, Munich, Germany.
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