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(Minerva Anestesiol 2011;77:xxx-xxx)

E X PE RT O P I N I O N

Type of fluid in severe sepsis and septic shock

J.-L. VINCENT 1, L. GOTTIN

1Department of Intensive Care, Erasme Hospital, Universit Libre de Bruxelles, Bruxelles, Belgium; 2Department of
Anesthesiology and Intensive Care, University of Verona, Verona, Italy

ABSTRACT
Fluid resuscitation is an essential aspect of the management of patients with severe sepsis and septic shock, especially in the early stages of disease. Which fluid should be used for this purpose has been a topic of ongoing and
sometimes heated debate for many years, yet this is still little evidence to support one fluid over another. Each fluid
type has specific adverse effects, and all fluids when given in excess can be detrimental. In this article, we will review
the advantages and limitations of the key fluid types currently used for the resuscitation of critically ill patients
with sepsis, including the crystalloids (saline solutions and Ringers lactate), and the colloids (albumin, gelatins,
dextrans, and hydroxyethyl starches). We will then briefly summarize the limited evidence to support use of one
fluid type over another, and provide general suggestions for fluid use in these patients.
(Minerva Anestesiol 2011;77:xxx-xxx)
Key words: Crystalloid solutions - Colloids - Albumins.

any acutely ill patients experience external

fluid losses related to dehydration (because of, for example, diarrhea and/or vomiting, cutaneous losses, lack of fluid intake), acute
trauma or surgery. Such fluid losses are obvious
and, therefore, relatively easy to assess. However,
many other processes in acutely ill patients can
influence vascular capacity and volemia in a less
obvious fashion. For example, many critically
ill patients experience an inflammatory reaction associated with marked vasodilation resulting in increased plasma volume capacity that
can further increase fluid requirements. In the
same conditions, the release of inflammatory
mediators increases capillary permeability and
further alters vascular tone. In all acutely ill patients, insufficient volume therapy can result in
inadequate tissue perfusion, with a risk of organ
(especially renal) failure, but fluid overload may
result in edema (especially in the lungs). Care-

Vol. 76 - No. 4

ful assessment of ongoing fluid needs is therefore

crucial in the management of such patients.
The choice of fluid that should be administered in such patients is determined by several
factors, including the type of fluid which has
been lost, the degree of edema present and its
likely consequences, the adverse effects of each
intravenous fluid, local fluid availability and
costs. Fluid management in various groups of
critically ill patients has been a topic of ongoing
and sometimes heated debate for many years, yet
this is still little evidence to support one fluid
over another. Each fluid type has specific adverse
effects, and all fluids when given in excess can be
detrimental.
The purpose of this review was to provide an
update on the latest evidence and current thinking in this field. In this context, we will discuss
the different intravenous fluid types: crystalloids
(essentially small electrolytes in water) and col-

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Fluid in severe sepsis and septic shock

loids (larger molecules). Blood products, other

than albumin, will not be considered here.
Different fluids
Crystalloids
Saline solutions
Although widely used, saline solutions are not
without adverse effects. Indeed, the infusion of
large amounts of saline solution may result in
hypernatremia and, especially, in hyperchloremic
acidosis associated with a reduction in the strong
ion difference (SID), notably reported in the perioperative period.1, 2 Although the clinical consequences of hyperchloremic acidosis are not well
defined, there is evidence to suggest it may have
negative effects on coagulation and on renal, cerebral, gastrointestinal, and respiratory function.3
Until further clarification of these effects is available, infusion of large amounts of normal saline
should probably be avoided when possible.
Hypertonic saline solutions can induce fluid
shifts from the intracellular to the extracellular
compartment. They have been proposed for use
as an early resuscitation fluid in patients with
sepsis and may have valuable effects on restoration of intravascular volume, improvement of
cardiac output, and improvement of regional
microcirculation.4 Experimental studies have
also suggested additional anti-inflammatory effects.5 However, further clinical studies are needed to confirm whether or not these fluids have a
place in the resuscitation of patients with sepsis.
Lactated Ringers (Hartmann) solution
The so-called balanced solutions were developed to provide fluids that were closer in content
to normal body fluids 6 and thus carry less risk
of causing iatrogenic electrolyte imbalance. Such
fluids usually contain around 130 mEq Na, 4
mEq K, 3 mEq Ca, 109 mEq Cl and 28 mEq
of lactate per liter (the exact composition may
vary slightly according to the manufacturer), at a
pH of 6.5. With an osmolarity of less than 280
mOsm/L, these solutions are slightly hypotonic, so that they should be avoided in hypotonic
states or in cases of brain edema (including brain

trauma).7 Even the small amount of potassium

may not be desirable in the presence of severe
hyperkalemia, and the calcium can bind to the
citrated anticoagulants in blood products or hemofiltration circuits, thus promoting the formation of clots, so that, whenever possible, Ringers
lactate should not be infused with red blood
cells.8 Administration of large amounts of these
solutions may theoretically be associated with
hyperlactatemia but there are no data supporting such an effect in critically ill patients.
Other balanced solutions contain acetate,
gluconate, malate, or citrate, which are eventually metabolized to carbon dioxide and water,
requiring the consumption of hydrogen cations.
Some of these solutions aim to reproduce the
electrolyte composition of the blood as closely as
possible, with a pH close to 7.40.
These newer solutions tend not to contain calcium. The effects of administering large amounts
of these solutions in the acute resuscitation of the
hypovolemic patient have not been well studied.
Colloids
Albumin
Human albumin is a natural colloid, which,
with a molecular weight (MW) of around 69
kDa, accounts for close to 80% of the plasma
oncotic pressure. Albumin has an important natural role, not only in maintaining plasma oncotic pressure, but also as a natural antioxidant and
transporter of various natural molecules, including oligo-elements, fatty acids, bilirubin, and
hormones. Albumin also plays an important role
in drug transport. The important physiological
role of albumin is supported by the finding that
hypoalbuminemia, often present in critically ill
patients, is associated with a worse prognosis.9, 10
Albumin solutions have several advantages,
including that they are natural, well tolerated,
and safe. Experimental and clinical studies have
demonstrated the anti-oxidant and anti-inflammatory effects of albumin.11, 12 Albumin solutions are available as 4% or 5% solutions (used
primarily for fluid resuscitation) or in 20% to
25% solutions (used primarily to increase albumin levels in edematous patients). Although

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Fluid in severe sepsis and septic shock

J.-L. VINCENT

doubts were raised about the safety of albumin

solutions in critically ill patients in a Cochrane
meta-analysis,13 these concerns were not supported by the results of a large prospective, randomized, controlled study in Australasia, which
included almost 7000 patients who required a
fluid challenge, and randomized them to receive
either 4% albumin or 0.9% NaCl solutions.14
Mortality was almost identical at 30% in both
groups. An interesting finding was that, in the
subgroup of patients with sepsis, 28-day mortality was slightly, but not significantly, reduced
in the patients who received albumin compared
to those who received saline (30.7% vs. 35.3%,
relative risk, 0.87; 95% confidence interval,
0.74 to 1.02; P=0.09).14 There was also perhaps
a slight decrease in mortality in patients with
hypoalbuminemia on admission, although again
this was not significant (23.7% vs. 26.2%, OR
0.87, 95% CI 0.73-1.05, P=0.14).15 As a consequence, mortality rates were lower in patients
with sepsis and hypoalbuminemia who received
albumin. Controlled studies in the acutely ill
have shown that albumin administration may
decrease the incidence of complications in acutely ill patients.9, 10 The major obstacle to the use
of albumin solutions is their high cost.
Synthetic colloids
There are three main types of synthetic colloid currently available: Gelatins, dextrans, and
hydroxyethylstarch (HES) solutions.
Gelatin solutions.These are hydrolysates
of connective tissues of animal origin, made
of either succinylated (or modified) or ureabound polypeptides (also called polygelins). As
gelatin solutions of high MW increase viscosity
and have a tendency to gel, the average MW of
present solutions is limited to 30 to 35 kDa, i.e.,
much lower than albumin. Gelatin solutions,
therefore, have limited oncotic effects and their
intravascular persistence is quite short (two to
three hours). These solutions may induce anaphylactic reactions, even though they are usually
transient and of limited severity. Adverse renal
effects have also been reported.16 These solutions
are not available in the USA, but are appreciated
in other countries for their relatively low cost.

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Dextran solutions.Dextrans are made of

mixtures of glucose polymers synthesized by the
bacterium, Leuconostoc mesenteroides. Dextran
40 (MW 40 kDa) has been essentially used for
its rheological and anti-thrombotic properties
and dextran 70 (MW 70 kDa) for fluid therapy.
These molecules are degraded into small molecules eliminated by the kidney or metabolized
into carbon dioxide and water.
Dextran solutions present a substantial risk
of anaphylactic reaction, so that a neutralizing
substance for the hapten, dextran 1, is generally given simultaneously and has been shown
to reduce the occurrence of severe reactions by
at least 30-fold.17 Dextrans also have anti-hemostatic effects, typically similar to those of von
Willebrand disease, decreasing platelet adhesion
to the vascular wall. In addition, dextrans can
cause formation of rouleaux, which may complicate the type and crossmatch in case of blood
transfusions. Dextran solutions may precipitate
renal failure by precipitation of the molecule or
hyperviscosity. For all these reasons, the use of
dextran solutions is declining.
Hydroxyethylstarch solutions.These molecules are synthesized by the partial hydrolysis
of maize or potato starch, amylopectin, with
replacement of the hydroxyl (OH) radicals
(present in position C2, C3 and C6) by hydroxyethyl radicals to decrease the degradation of the
molecule by amylase. They are characterized by
four elements, defining the size as well as the degree of persistence of the molecules in the body:
molecular weight. HES solutions contain
molecules of very different MWs, ranging from
70 to 670 kDa.18 During the first hours following their administration, the smaller molecules
are eliminated by the kidneys, whereas the larger
molecules are degraded, so that the MW rapidly
decreases in the circulation;
the degree of substitution, i.e., the proportion of glucose molecules that have a hydroxyethyl radical in place of the hydroxyl radical; it
is usually 0.4 (tetrastarch) to 0.7 (hetastarch). A
high degree of substitution slows down the degradation process;
the C2/C6 ratio, characterizing the type
of substitution (substitution is only possible at

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Fluid in severe sepsis and septic shock

level 2, 3 or 6). As hydroxyethylation at C2 gives

the most resistance to amylase, the elimination is
slowed down when this ratio is high;
the concentration (generally 6% or 10%
[for HES 200/0.5]).
The pharmacokinetics of HES solutions are
complex, and determined by the degree of substitution, the C2/C6 ratio, the concentration
(6% or 10%) and their MW.
Use of HES solutions has been associated with
several problems. First, they alter hemostasis in a
dose-dependent fashion. These alterations are primarily due to a von Willebrand type of disease, as
for dextrans. Second, HES solutions can persist in
the organism sometimes for very prolonged periods of time, especially in the reticulo-endothelial
system (RES). The immunological consequences
of this effect are purely speculative, but persistence in the subcutaneous tissues may result in
pruritus.19 Third, these solutions may alter renal
function, possibly as the result of the development of osmotic-nephrosis-like damage. A multicenter French study of 129 patients with severe
sepsis showed that an HES solution (6%, 200
kDa with a 0.6-0.66 of substitution) increased
the risk of renal failure by a factor of 2.57 (95 %
CI: 1.13-5.83) compared to a gelatin solution.20
However, analysis of data from the large observational SOAP study reported that HES administration was not independently associated with an
increased risk of renal failure or need for RRT.21 In
a before-after retrospective study of surgical ICU
patients, Schabinski et al.22 reported that the incidence of acute renal failure was similar in patients
who received predominantly HES (6% 130/0.04)
fluid therapy and in those who received predominantly gelatin 4%; moderate cumulative doses of
either solution was associated with a higher risk of
acute renal failure. In the randomized Efficacy of
Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study, reported that administration of HES (10%, 200 kDa, 0.45-0.55 grade
of substitution) in patients with severe sepsis was
associated with a larger incidence of renal failure
and need for extracorporeal support compared to
Ringers lactate.23 There was also an overall trend
toward increased mortality among HES recipients, and mortality at 90 days was correlated with
cumulative HES dose (P=0.001).

Three recent meta-analyses also reported that

HES administration was associated with an increased risk of renal failure in patients with sepsis.24-26 The first 24 assessed 12 randomized trials
that compared HES with other fluids in patients
with sepsis, involving a total of 1062 patients.
HES administration increased the incidence of
acute renal failure compared with gelatin (odds
ratio, 2.57; 95% CI, 1.13-5.83) and crystalloid
(odds ratio, 1.81; 95% CI, 1.22-2.71). The second meta-analysis included 22 RCTs that compared HES with another fluid in the acute volume resuscitation of critically ill patients.26 HES
use was associated with a greater risk of RRT in all
patients and in those with severe sepsis. Finally,
in a meta-analysis from the Cochrane database,25
which included 2607 patients from 34 studies in
which HES was compared to an alternate fluid
therapy for the prevention or treatment of effective intravascular volume depletion, the relative
risk of kidney failure was 1.50 (95% CI 1.20 to
1.87;) and for requiring RRT was 1.38 (95% CI
0.89 to 2.16) in HES treated individuals compared with other fluid therapies, with higher risk
ratios in patients with sepsis.
It has been suggested that the adverse effects
of HES solutions may be largely dependent on
the MW of the molecules, and that more recent
(rapidly degradable) HES solutions with lower
MWs (130 kDa), a degree of substitution of
0.42, and a C2/C6 ratio of 10% may be associated with fewer complications.27 There may
also be differences among solutions derived from
potato and maize starches.27 However, there are
currently insufficient data related to the newer
HES solutions, particularly in patients with
sepsis,28, 29 and the results of further studies are
awaited. Until such results are available, concerns remain regarding the use of HES solutions
and the quantity of HES solutions administered
to septic patients should be limited.
Crystalloid or colloid: which is best?
Crystalloid solutions are composed of small
particles dissolved in water, which pass easily
through the endothelial barrier, and have a short
intravascular persistence. But, they are readily
available, cheap and well tolerated. With their

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J.-L. VINCENT

Table I.Potential unwanted consequences of intravenous fluid choices.

Fluid

Adverse effects

COLLOIDS (general)
Albumin
Gelatins
Dextrans
HES*
CRYSTALLOIDS (general)
NaCl 0.9 (%)
Ringers lactate
Plasmalyte

Costs/risks of fluid overload/hyperconcocity-induced renal failure/altered hemostasis

High costs
Limited efficacy/allergic reactions
Allergic reactions/altered blood crossmatching, altered hemostasis, renal failure
Altered hemostasis/long persistence in the body/pruritus/renal failure
Short-lived hemodynamic effects/electrolyte changes
Hyperchloremic acidosis
Hypotonicity/lactate load/Ca content
Acetate and gluconate load

*most studies have been conducted with higher MW HES solutions.

relatively high MW, colloids do not easily cross

semi-permeable membranes, so that they maintain plasma oncotic pressure better and remain
longer in the intravascular space than crystalloid
solutions. It is generally estimated that one must
give two to three times more crystalloid than
colloid to achieve the same resuscitation endpoints.30 During sepsis, however, membrane
permeability is altered, resulting in a greater
movement of colloids into the interstitium. The
differences between colloids and crystalloids in
terms of oncotic properties and intravascular
persistence may, therefore, be reduced. Nevertheless, Trof et al. reported that administration
of colloid solutions was associated with a greater
cardiac response than administration of saline in
septic and non-septic critically ill patients with
hypovolemia.31 Increased extravasation of large
colloid molecules as a result of the altered membrane permeability could potentially cause an increase in perimicrovascular oncotic forces, thus
worsening edema.32 However, van der Heijden et
al. demonstrated that there were no differences
between colloids and crystalloids in pulmonary
edema formation in hypovolemic septic and
non-septic patients.33 Nevertheless, edematous
patients treated with colloid solutions are also
often given diuretics. Treatment with albumin
and furosemide in hypoproteinemic patients
with acute lung injury/acute respiratory distress
syndrome (ALI/ARDS) significantly improved
oxygenation, with a greater net negative fluid
balance and better maintenance of hemodynam-

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ic stability, compared to treatment with furosemide alone.34

No fluid type is perfect and each has specific
limitations ranging from effects on coagulation
or renal function to high costs and limited availability (Table I). International guidelines for the
management of the patient with sepsis concluded
in 2008 that there is no evidence-based support
for one type of fluid over another.35 In a large
animal model of severe sepsis and septic shock,
albumin and HES solutions resulted in higher
cardiac output and oxygen delivery, and lower
blood lactate levels than gelatin and Ringers lactate, but there were no differences in outcomes
among the four groups.36 Indeed, the most vital
aspect of fluid resuscitation seems to be to recognize the importance of early fluid administration. Rivers et al. showed that early goal-directed
therapy was associated with improved outcomes
in patients with severe sepsis and septic shock.37
Patients in the early goal-directed therapy group
received more fluid (5 versus 3.5 L, P<0.001) in
the first 6 hours of diagnosis than the standard
treatment group, emphasizing the importance
of early fluid administration. In a recent study
evaluating the effects of Ringers lactate or 4%
albumin on the microcirculation, fluid administration improved microvascular perfusion in
the early but not the late phase of sepsis.38 The
microcirculatory effects were independent of the
type of solution used. The type of fluid used is
likely less important than the timing,39 although
physicians should be aware of the specific ad-

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Fluid in severe sepsis and septic shock

vantages and limitations of each fluid type when

making their choices.
Conclusions
Any solution administered in excessive
amounts can have undesirable effects. There is
no evidence that any one fluid is better than the
others for fluid resuscitation in patients with
sepsis, although until further data are available
infusion of HES solutions should probably be
limited. Fluids should be considered as a medication and the risks and benefits of each fluid
type weighed for the individual patient and circumstance. It seems reasonable to use several intravenous fluids rather than excessive amounts of
any one, until further data are available on the
benefits of individual fluids. Given the greater
costs of colloid solutions and lack of clear advantages over other fluids in most patients, crystalloids should form the basis for fluid resuscitation and maintenance. Gelatins and/or HES
solutions can be helpful for fluid challenges, and
albumin should be used in severely ill patients
with hypoalbuminemia.
End-points for fluid administration remain
unclear but should include careful clinical examination including evidence of pulmonary or
systemic edema, urinary output, peripheral perfusion, and mean arterial pressure, blood lactate
levels and mixed venous oxygenation. Patients
need to be carefully and regularly assessed to
determine ongoing fluid requirements, using repeated fluid challenges.40 As new data become
available, in addition to effects on intravascular volumes, potential anti-inflammatory, antioxidant, and microcirculatory effects of fluids
need to be taken into account when considering
which fluid(s) to prescribe.
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Received on September 13, 2010 Accepted for publication on May 31, 2011.
Corresponding author: J.-L. Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, 1070 Brussels,
Belgium. E-mail: jlvincen@ulb.ac.be

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