Transcript
Lira and Pinsky Annals of Intensive Care 2014, 4:38
http://www.annalsofintensivecare.com/content/4/1/38
REVIEW
Open Access
Choices in fluid type and volume during
resuscitation: impact on patient outcomes
Alena Lira and Michael R Pinsky*
Abstract
We summarize the emerging new literature regarding the pathophysiological principles underlying the beneficial
and deleterious effects of fluid administration during resuscitation, as well as current recommendations and recent
clinical evidence regarding specific colloids and crystalloids. This systematic review allows us to conclude that there
is no clear benefit associated with the use of colloids compared to crystalloids and no evidence to support the unique
benefit of albumin as a resuscitation fluid. Hydroxyethyl starch use has been associated with increased acute kidney
injury (AKI) and use of renal replacement therapy. Other synthetic colloids (dextran and gelatins) though not well
studied do not appear superior to crystalloids. Normal saline (NS) use is associated with hyperchloremic metabolic
acidosis and increased risk of AKI. This risk is decreased when balanced salt solutions are used. Balanced crystalloid
solutions have shown no harmful effects, and there is evidence for benefit over NS. Finally, fluid resuscitation should be
applied in a goal-directed manner and targeted to physiologic needs of individual patients. The evidence supports use
of fluids in volume-responsive patients whose end-organ perfusion parameters have not been met.
Keywords: Colloids; Crystalloids; Osmolality; Glycocalyx; Intravascular volume replacement; Systematic review
Review
Introduction
Fluid administration is perhaps the most ubiquitous therapeutic intervention in critically ill patients. There is a
growing pool of evidence available to guide resuscitation
and fluid administration practices. Some recommendations can be made unequivocally, while others continue to
be subject of an ongoing discourse [1-3]. An interesting
question arises from our review of the literature, as described below: Does practice follow the evidence? Specifically, in 2010, Finfer et al. [4] published results of a
cross-sectional study conducted in 391 intensive care
units across 25 countries around the world to evaluate
fluid resuscitation practices. Their study revealed markedly desperate results. Despite available evidence, resuscitation practices varied significantly, with overall
preference for the use of colloids. Importantly, choice
of resuscitation fluid differed by country and took far
less into consideration patients’ individual characteristics
and available evidence than local practices. The practice is
likely further shaped by economic considerations and local
* Correspondence:
[email protected]
Department of Critical Care Medicine, University of Pittsburgh, 606 Scaife
Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA
product availability [5]. Clearly, impressing evidencebased behaviors requires overcoming considerable traction of regional custom practices. Since the Finfer et al.
study was conducted, multiple large high-quality prospective clinical trials have been published [Table 1]
[6-10], and multiple meta-analyses [Table 2] [11-17]
attempted to synthesize the evidence to help in developing
clear consensus guidelines taking into consideration
pathophysiological principles associated with resuscitation context as well as individual patient characteristics.
This review will address these issues. As to the disparity
between the evidence and practice, one only speculates
why it exists. We reviewed the existing medical literature
using both PubMed and Google Scholar search engines
for the primary search terms such as clinical trial, fluids,
resuscitation, crystalloids, and colloids and then expanded
our search as linked citations indicated. We limited this
search to studies published in English since the last
Cochran Review on this subject [1].
Fluid administration is a vital component of resuscitation therapy in the hemodynamically unstable patient.
Despite its ubiquity, however, for years this intervention
remains a subject of an ongoing controversy. The discussion as to what fluid, how much, and when to give it was
© 2014 Lira and Pinsky; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly credited.
Lira and Pinsky Annals of Intensive Care 2014, 4:38
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Table 1 Characteristics of included randomized controlled trials
Trial
N
Population
Type of fluid
Outcomes
Intervention
N
Myburgh 2012 6,651 ICU patients
(CHEST)
6% HES (130/0.4)
3,315 Saline
Perner 2012
798
ICU patients with
severe sepsis
6% HES (130.0.42) 398
Yates 2013
202
Medium to high
risk elective
colorectal surgery
patients
6% HES (130/0.4)
Annane 2013
(CRISTAL)
2,857 ICU patients with
Colloids (gelatins, 1,414 Crystalloids
hypovolemic shock dextrans, HES, 4%
(isotonic or
or 20% albumin)
hypertonic saline,
Ringer’s lactate)
Caironi 2014
(ALBIOS)
1,810 ICU patients with
severe sepsis or
septic shock
104
20% albumin and 903
crystalloid
Control
Conclusion
N
3,336 90-day mortality,
AKI, RRT
No mortality difference;
increased AKI and RRT
use with HES
Ringer’s acetate
400
90-day mortality,
RRT
Increased 90-day mortality
with HES; increased use of
RRT with HES
Hartmann’s
solution
98
Day 5 post-op GI
morbidity; post-op
complications, LOS,
coagulation and
inflammation
No difference in any of
the measured outcomes
1,443 28- and 90-day
No difference in 28-day
mortality; days alive
mortality; 90-day mortality
without the need for
lower in colloid group
RRT, MV, or vasopressors
Crystalloid solution 907
28- and 90-day
mortality; organ
dysfunction, LOS
No difference in
mortality or other
outcomes
N, number of patients; ICU, intensive care unit; HES, hydroxyethyl; AKI, acute kidney injury; RRT, renal replacement therapy; MV, mechanical ventilation; LOS,
length of stay (ICU or hospital).
initially centered around the choice between colloid or
crystalloid solutions, debating which was a better resuscitation fluid in terms of its ability to initially support intravascular volume and promote tissue perfusion, without
causing interstitial edema [18-20]. Since all resuscitation
fluids will expand the intravascular space to a greater or
lesser degree [21], the debate now focuses more on the
safety and efficacy of each particular fluid in resuscitation
and improving longer-term patient outcomes. As newer
colloid and crystalloid solutions entered the market, it became increasingly clear that differences in electrolyte
composition and colloid particle size and composition had
independent effects on these outcome measures [21]. The
available colloids now include albumin, hydroxyethyl
starch (HES), gelatin, and dextran. Available crystalloids
include 0.9% normal saline (NS), lactated Ringer’s (LR)
and its nearly identical brother Hartmann’s solution, and
several similar balanced salt solutions (e.g., Plasma-Lyte,
Normo-Sol). Not surprisingly, with more available clinical
trial data, the debate behind fluid administration has expanded to include controversies surrounding particular
solutions within each group, such as between HES versus
albumin, and NS versus more balanced crystalloid solutions [22-24].
Importantly, for the following discussion, fluid administration needs to be placed in perspective. The practice of
fluid administration in critically ill patients includes a variety of indications from simple replacement of insensible
intravascular volume loss in patients unable to take fluids
orally, replacement of volume deficits associated with
hypovolemia or hemorrhage, to augmentation of volume
in patients with pathology presenting with relative intravascular depletion, such as sepsis [25].
Historically, the administration of fluids directly into the
circulation evolved to reverse severe dehydration resulting
from volume loss due to diarrhea or vomiting in cholera
patients [26]. The introduction of colloid came much later,
during World War II, with infusion of albumin to maintain intravascular volume in trauma and severe burn patients [27]. The way in which fluids exert their therapeutic
effects is by expansion of one of the three body volume
compartments: intravascular, interstitial, and intracellular.
The main goal for fluid resuscitation remains intravascular
volume repletion from a functional hypovolemic state
causing hemodynamic instability as manifested by endorgan hypoperfusion and extravascular volume depletion
as manifested by dehydration and hyperosmolarity.
Initially, choices of a particular crystalloid solution
were determined by availability and cost. For example,
NS originally was less than half the cost of the other
crystalloids and came in varying degrees of dilution (0.9,
0.45, and 0.225 N NaCl). It was also available alone or
with 5% dextrose. Importantly, NS solutions are compatible with co-infusion of blood products. LR and other
balanced salt solutions containing Ca+2 not only were
more expensive, but also carried the risk of clotting infusion lines when blood transfusions were given. For all
these reasons, the default crystalloid solution for resuscitation was NS except when hemostasis was needed, as
often occurring in trauma or intraoperative resuscitation,
wherein LR was usually prescribed [28]. These early concerns have now been minimized since all crystalloid
Study
Number Number of Population
of trials patients
Intervention
Control
Outcomes
Conclusion
Serpa Neto
2014
10
4,624
Septic patients
HES
Crystalloids
28- and 90- day mortality, AKI, RRT,
transfusion, LOS, fluid intake
HES shows increase in AKI, RRT,
need for RBC transfusion, and 90-day
mortality
Zarychanski
2013
38
10,880
Critically ill, including sepsis,
HES
trauma, burn, hypovolemic shock
Crystalloids, gelatin,
albumin
Mortality, AKI, LOS, MV
After exclusion of Boldt studies, HES
increased mortality, AKI, and RRT
Gattas 2013 35
10,391
Critically ill or surgical patients
6% HES 130/0.4-0.42
Other fluids
Mortality, RRT, AKI, transfusion,
bleeding
Increased risk of RRT with HES
Hasse 2013
9
3,456
ICU patients with sepsis
6% HES 130/0.38-0.45
Crystalloids or albumin
All cause mortality, RRT, AKI, bleeding HES increased RRT, increased blood
and transfusion, adverse effects as
transfusion, increased incidence of
defined in the individual studies
adverse effects
Gillies 2013
19
1,567
Surgical patients
6% HES
Other colloids or
crystalloids
Postoperative in hospital mortality,
AKI, RRT
No difference in measured outcomes,
no demonstrable benefit of HES
Perel 2013
70
22,392
Cochrane review 2013,
critically ill
Colloids
Crystalloids
Mortality
Colloids do not decrease mortality,
HES may increase mortality
Mutter 2013 42
11,399
Cochrane review
HES
Other fluids
Renal function
Increased need for RRT with all HES
products in all patient populations
Bunn 2012
86
5,484
Critically ill and surgical patients
in need of volume resuscitation,
Cochrane review
Any one colloid
Any other colloid
Mortality, need for blood transfusion,
(included albumin, HES, (included albumin, HES, adverse events
dextran, gelatin)
dextran, gelatin)
No benefit of one type of colloid
over another
Thomas40
Ruedel 2012
3,275
Adult and pediatric, primarily
elective surgery, as well as ICU
and ED
Gelatin
Albumin or crystalloid
Mortality, blood products
administration, AKI, RRT
Unable to determine safety due to
small studies and large heterogeneity
Rochwerg
2014
18,916
Adult patients with sepsis and
septic shock
Any fluid (colloid or
crystalloid)
Any fluid (colloid or
crystalloid)
Mortality, blood products
administration, AKI, RRT
Reduced mortality with balanced
crystalloids and albumin compared
to other fluids
14
Lira and Pinsky Annals of Intensive Care 2014, 4:38
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Table 2 Meta-analyses and systematic reviews
ICU, intensive care unit; HES, hydroxyethyl starch; AKI, acute kidney injury; RRT, renal replacement therapy; MV, mechanical ventilation; LOS, length of stay (ICU or hospital); ED, emergency department.
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solutions cost the same and multi-lumen infusion catheters simplify infusion compatibility concerns. Similarly,
the choice of colloid solution remains influenced by cost
and shelf life. The cost of albumin continues to vary
considerably across countries and continents, and it has
a limited shelf life, whereas starches and gelatins are
cheaper and have a longer shelf life. Thus, economic
considerations play an important role in determining
which colloids are available regionally, but less so in the
choice of crystalloids.
Without economic considerations, a decision on which
is the optimal resuscitation fluid is often driven by the
indications for fluid use and by what physiologic endpoint needs to be targeted. Further consideration is often
given to the underlying pathophysiology and how different fluid compositions will affect the milieu interior. Assuming that all other treatments are done similarly and
correctly, one can then analyze the effectiveness and
safety of specific fluid types in determining outcome.
This presumption is difficult to accept, however, if the
studies comparing one solution to another are retrospective chart reviews, or if prospective designs are unblinded or only partially blinded. Importantly, many new
large multicenter clinical trials have provided insight as
to the potential deleterious effects of specific types of solutions [29-33], making the choice of fluid less an academic exercise and more a therapeutic one.
Basic pathophysiology and volume kinetics
A fundamental rationale for intravascular fluid resuscitation is to sustain an effective circulating intravascular
volume or restore it to normal once initially depleted by
hemorrhage or other causes of volume loss such as capillary leak, vomiting, diuresis, or diarrhea. These principles need to be taken into account when defining the
clinical state as normovolemia, absolute or relative
hypovolemia, and volume overload manifested as edema/
anasarca.
Plasma water and solutes freely associate and move
from the intravascular into the interstitial space at least
once in a day owing to the greater hydrostatic pressure
in the vascular space as compared in the interstitial
space and the level of permeability of the vascular endothelium. This movement of fluid is increased to several
times a day under pathophysiological conditions associated with systemic inflammation (trauma, sepsis) owing
to increased capillary permeability [34,35]. Fluid return
to the vascular space is only minimal due to resorption
back into the vascular system and mainly occurs by
drainage back through the lymphatic system [36]. The
balance of forces defining the rate of fluid transmission
across the capillary endothelial barrier is described by
the Starling equation:
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J v ¼ K f Pc − P i − σ½πi − π c
where Jv is the net fluid movement between compartments, [Pc − Pi] − σ [πi − πc] the net driving force, Pc the
capillary hydrostatic pressure, Pi the interstitial hydrostatic pressure, πc the capillary oncotic pressure, πi the
interstitial oncotic pressure, Kf the filtration coefficient
for pressure-dependent fluid shifts, and σ the reflection
coefficient for osmotically active vascular to interstitial
gradient equilibration. Importantly, as will be discussed
below, in many acute illnesses, both Kf and σ can decrease rapidly as the vascular endothelium’s glycocalyx is
denuded [37,38], making arguments as to which colloid
or crystalloid solution will remain within the intravascular state mute.
Hydrostatic intravascular pressure is determined by
both the upstream arteriolar resistance and downstream
venous pressure, whereas hydrostatic interstitial pressure
is determined primarily by tissue pressure. Gravitational
pressure increases both venous pressure and tissue pressure equally, thus favoring hydrostatic translocation of
fluid into the interstitium in dependent regions of the
body. Oncotic pressure is determined by the solute concentration in the fluid. Since there is usually a higher
concentration of solute in the plasma space owing to retention of albumin and other proteins such as globulins,
normal oncotic pressure gradients promote reabsorption
of interstitial fluid into the vascular space from the interstitial space [36]. The wild card in this balance is the
relative resistance to fluid and solute flux across the
semipermeable membranes of the vascular endothelium
[39]. Under normal conditions, the endothelial membranes lining the capillaries are relatively impermeable
with intercellular tight junctions holding neighbor endothelial cells together and the intravascular glycocalyx
forming a protein barrier to solute flow [40]. These variables normally limit fluid flux in either direction [41].
However, adenosine triphosphate (ATP)-dependent transport mechanisms within the vascular lining endothelial
cells promote significant solute transport across this barrier, such that in a steady state, there is a net loss of fluid
into the interstitial space from the intravascular space
which equals the entire circulating blood volume over a
day [34].
Important in this process is the property that not all
vascular beds have the same hydrostatic pressure or capillary permeability [42]. The splanchnic circulation has
a greater degree of permeability than the muscle, brain,
and kidney, owing to the hepatic sinusoidal structure.
Thus, changes in blood flow distribution from splanchnic to muscle or vice versa will alter edema formation
and the need for fluids to sustain normal homeostasis.
Since anesthesia profoundly alters blood flow distribution,
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it also alters the steady-state balance of fluid resorption
and lymphatic drainage [43,44].
Disease states associated with inflammation like trauma,
burns, sepsis, and acute pancreatitis are characterized by a
marked reduction in the vascular endothelial glycocalyx
[45-47]. The glycocalyx is the primary structure limiting
free fluid flux across the vascular space [35]. Furthermore,
if tissue injury also occurs, as often is the case in acute
lung injury, vascular endothelial tight junction disruption
will also occur in areas typically relatively resistant to fluid
translocation, markedly opening up the interstitium to
fluid translocation resulting in further imbalance between
the intravascular and extravascular fluid and local interstitial edema [48]. Since different vascular regions of the
body allow proteins to pass through the capillary membrane at different rates, as exemplified by the loose barrier
in the liver and tight barrier in the brain, interstitial edema
formation is not usually uniform throughout the body.
Many of the plasma proteins in patients experiencing
acute systemic inflammation will be cytokines and
protein-bound hormones. Thus, the metabolic effect of
differentially altered permeability and plasma leak may
play a role in the regional expression of a generalized
inflammatory response. Since most, if not all, fluid return from the extravascular space to the vasculature
happens via lymphatic drainage [49], if transcapillary
leakage is increased, the lymphatic system may become
overwhelmed, further contributing to the development
of edema and a relative intravascular volume deficit
despite no actual loss of fluid outside the body. This
fluid flux imbalance is accentuated further by slower
lymphatic flow resulting from immobility in bedridden
patients. Accumulation of intravascular fluid in the interstitial space is therefore dependent on multiple factors described in the Starling force equation above, permeability
of the vascular membrane, as well as the capacity of the
lymphatic system [50].
Based on the original Starling force concept, it made
sense to use colloids with their higher oncotic pressure as
a fluid resuscitation option, because in theory it would result in less capillary leak and edema formation while better
supporting the intravascular volume needs. Regrettably,
this theoretical model does not explain the observation
that volume requirements during resuscitation in septic
shock with either albumin or crystalloids are similar when
both fluids are given in a blinded fashion [1,51]. Indeed,
even if the goal were to sustain a normal intravascular
oncotic pressure, it has been repeatedly observed that the
most balanced approach does not occur with infusion of
colloids to crystalloids at a ratio of 1:3 as initially postulated [1,52], but rather 1:1.3 [53]. This simplification is further complexed by the use of other synthetic colloids
which when compared to albumin have different rates of
degradation and half-life of elimination [34]. Furthermore,
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due to the increased capillary permeability in critical illness which results in accumulation of both fluid and
macromolecules in the extracellular space, colloids may
theoretically worsen edema by increasing interstitial
oncotic pressure, resulting in further impediment of tissue perfusion and lymphatic return. This counterbalancing process as seen in otherwise healthy hypovolemia
and inflammatory states is stylized in Figure 1.
Woodcock et al. [36] recently evaluated the basic
physiological and molecular principles behind transvascular fluid exchange and called into question completeness
of the initial Starling force principle. They propose a revised Starling model, which takes into account not only
the composition of the intravascular fluid and the interstitial fluid, but also the physical characteristics of the transvascular barrier, which comprises of the endothelial
glycocalyx layer and endothelial basement membrane,
with tight junctions between cells and the extracellular
matrix [40]. According to this revised model, when the
vascular barrier is intact, transcapillary movement of
fluid is unidirectional, as there is no absorption of fluid
from the interstitium back to the intravascular space,
and drainage of the interstitium is accomplished primarily
by lymphatic clearance. Transcapillary movement is then
dependent on capillary pressure. At supranormal capillary
pressures, infusion of colloid solution preserves oncotic
pressure and increases capillary pressure, thus increasing
movement of fluid into the interstitial space. Under the
same conditions, infusion of crystalloid solutions also
increases capillary pressure, but by dilution decreases
oncotic pressure, thus resulting in more transcapillary
movement than colloids. At subnormal capillary pressures, transcapillary movement nears zero; thus, infusion of both crystalloids and colloids results in increase
in capillary pressure, but no change in transcapillary
movement.
The tissues that can accumulate large amounts of interstitial fluid during physiologic stress in their healthy state
contain non-fenestrated capillaries. These include the liver
and gut mucosa. These capillaries’ vascular endothelial
barriers can undergo phenotypic changes from nonfenestrated to fenestrated, resulting in both endothelial
dysfunction and increased permeability in response to
physical and chemical stress. This change in the physical
characteristics of the transcapillary barrier is largely responsible for increase in permeability leading to changes
in volume kinetics, interstitial fluid accumulation manifested as edema, and its accompanying intravascular
depletion.
This newly proposed mechanism explains why volume
expansion with albumin in critically ill patients does not
match that predicted by the Starling force model. Furthermore, it may explain why albumin has not been
shown to provide benefit in volume expansion compared
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Figure 1 Schematic diagram of the primary forces defining transcapillary fluid movement. The opposing forces defining the steady-state
net flow of fluid from the capillary into the interstitial space are defined by the hydrostatic pressure differences between the capillary lumen (Pc)
and interstitial pressure (Pi) as opposed by the filtration coefficient (Kf) which itself is a function of the vascular endothelial cell integrity and the
intraluminal glycocalyx. This net efflux of fluid out of the capillary into the interstitium is blunted by an opposing oncotic pressure gradient moving
fluid in the opposite direction because capillary oncotic pressure (πc) is greater than interstitial oncotic pressure (πi). And like hydrostatic
pressure-dependent flow, oncotic dependent flow is blunted by the reflection coefficient (σ) which like Kf is a function of the glycocalyx and
vascular endothelial integrity. Under normal conditions (left side), both Kf and σ are high minimizing fluid flux resulting in a slight loss of plasma into
the interstitium which is removed by lymphatic flow. However, if the vascular endothelium and glycocalyx are damaged (right side), oncotic pressure
gradients play a minimal role because a large amount of protein-rich plasma translocated into the interstitial space minimizing the oncotic pressure
gradient, whereas the constant Pc promotes massive fluid loss and interstitial edema.
to crystalloids under conditions wherein endothelial glycocalyx disruption commonly occurs. The varying vascular
permeability model underscores the integrity of the glycocalyx as one of the key factors involved in fluid dynamics
and suggests that its restoration needs to be one of the
therapeutic goals in conditions of physiologic stress
[49,50]. Regrettably, at this time, no specific therapies
have been shown to augment glycocalyx restoration.
Crystalloids
We use the term ‘crystalloids’ to describe aqueous fluids
that contain crystal-forming elements (electrolytes), which
easily pass through vascular endothelial membrane barriers followed by water, leading to their equilibration between the intravascular and extracellular space. As noted
above, in theory, this redistribution results in smaller
retained intravascular volume of the initial infusion solution and development of edema when compared to colloid
solutions [51-54].
Crystalloid solutions can contain a variety of inorganic
cations, such as K+, Ca++, and Mg++, and organic anions,
such as lactate, acetate, gluconate, or bicarbonate as well
as Cl−, allowing the Na+, Cl−, and K+ values to vary
independent of each other [Table 3]. The term ‘normal’ saline is a misnomer which was coined because its concentration is 0.9% w/v ‘normal’ or about 3,000 mOsm/L or
9 g/L, not because its composition is normal or ‘physiologic’ as an electrolyte solution. It is slightly hypertonic
and has equal amounts of Na+ and Cl−, making it both
hypernatremic and very hyperchloremic relative to the
plasma. Thus, massive NS infusion will lead to hypernatremia and hyperchloremic metabolic acidosis and its associated sequelae such as renal vasoconstriction [55]. This
reality by itself suggests that the best candidates for use of
NS may be patients with the propensity for developing
hyponatremia, hypochloremia, and metabolic alkalosis, as
seen in severe persistent vomiting. Similarly, in patients in
whom development of hyperchloremic metabolic acidosis
could carry a significant morbidity (e.g., patients with
compromised renal function or already existing acidosis),
NS maybe contraindicated as a resuscitation fluid [56,57].
Furthermore, blood ionic concentration changes can
markedly alter pharmacodynamics. For example, studies
in healthy volunteers demonstrated that when compared
to solutions with lower chloride content, NS has slower
excretion [55,58].
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Table 3 Characteristics of resuscitation fluids
Solute
Plasma
Colloids
4% albumin
Crystalloids
6% HES
130/0.4
Dextran
Gelatin
Normal saline
Ringer’s
lactate
Hartmann’s
solution
Plasma-Lyte
Na+
135 to 145
148
154
154
154
154
130
131
140
K+
4.0 to 5.0
0
0
0
0
0
4.5
5
5
Ca2+
2.2 to 2.6
0
0
0
0
0
2.7
4
0
Mg2+
1.0 to 2.0
0
0
0
0
0
0
0
1.5
Cl
95 to 110
128
154
154
120
154
109
111
98
Acetate
0
0
0
0
0
0
0
0
27
Lactate
0.8 to 1.8
0
0
0
0
0
28
29
0
Gluconate
0
0
0
0
0
0
0
0
23
Bicarbonate
23 to 26
0
0
0
0
0
0
0
0
Osmolarity
291
250
286 to 308
308
274
308
280
279
294
Colloid
35 to 45
20
60
100
40
0
0
0
0
−
Osmolarity (mOsm/L); colloid (g/L); all other solutes (mmol/L).
Crystalloid alternatives to NS represent fluids more
closely, resembling the electrolyte composition of plasma.
The most frequently used ones are lactated Ringer’s solution or its nearly identical twin, Hartmann’s solution, and
Plasma-Lyte (Table 3). Newer more balanced solutions are
continuing to enter the market. LR has historically been
used most frequently, but neither its ionic composition
nor its tonicity is equivalent to that of plasma. Theoretically, discrepancies in tonicity can affect fluid distribution
and pharmacodynamics-associated diuresis, both of which
can have clinical implications [59]. Therefore, both the
pharmacodynamics alterations due to tonicity and the
metabolic effects of the ionic solute composition are of
consideration when choosing between crystalloids.
Colloids
The term ‘colloids’ refers to aqueous solutions that contain
both large organic macromolecules and electrolytes.
Presumably, the large molecular size of the dissolved
molecules limited their ability to cross the endothelial
membrane. These molecules are retained within the
intravascular space to a greater degree than pure crystalloids, owing to their higher oncotic pressure.
The first colloid solution used clinically was albumin.
Albumin is harvested from human plasma. It is available
in several concentrations (4%, 5%, 20%, and 25%). The
greatest barrier to its use has been its cost, which varies
widely across the world. Synthetic colloids, in particular
starches (HES), gelatins, and dextran, present more economical alternatives. Gelatins are derived from bovine
gelatin, and their colloid base is protein. HES are derived
from the starch of potatoes or maize, and their colloid
base is a large carbohydrate molecule. Solutions of various
molecular weight are available, namely, 130, 200, and
450 kD. Dextran is also a carbohydrate-based colloid, a
polysaccharide molecule made by bacteria during ethanol fermentation process. Oncotic pressure of these solutions varies depending on the molecular weight and
concentration, and both hypo-oncotic (gelatins, 4% and
5% albumin) and hyper-oncotic solutions (20% or 25%
albumin, dextran, and HES 6% and 10%) are available.
The physiological actions, volume expansion properties,
as well as potential morbidities of these solutions are
determined by multiple factors which include oncotic
pressure, molecular weight, half-life of degradation, chemical alteration of the macromolecules, and their tissue accumulations [60,61]. The hydroxylation of starches, for
instance, results in their accumulation in particular tissues
including the skin, kidney, or liver, resulting in organspecific clinical manifestations and potential morbidities
such as acute kidney injury (AKI) or liver injury [62-64].
Clinical evidence
Colloid versus crystalloid
Albumin controversy The rationale behind using albumin and other colloids was driven by a theoretical assumption that colloids lead to better intravascular volume
expansion compared to crystalloids. Though colloids result in transient greater increase in intravascular volume,
it has not been shown that greater intravascular volume
expansion translates to improvement in mortality outcomes. At the moment, no clear evidence exists to support widespread use of albumin resuscitation.
The early controversy on the use of albumin solutions
in resuscitation was fueled by a Cochrane meta-analysis
published in 1998, which showed that albumin use was associated with an increased mortality [65]. This metaanalysis used diverse data collated over decades and was
of questionable validity. Importantly, the large multicenter
SAFE trial, published in 2004 [66], showed no difference
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in mortality with the use of albumin versus NS, with the
exception of the subgroup of traumatic brain injury (TBI)
patients whose outcomes were worse with albumin [67].
FEAST study in 2011 [68] also showed no benefit of albumin over crystalloids. In that study, both colloids and crystalloids when used as a bolus in pediatric patients lead to
increased mortality due to cardiovascular collapse. Not
only did these studies show albumin did not increase mortality, but importantly, the SAFE study revealed in its subgroup analysis the use of albumin to be associated with
decreased 28-day mortality in severe sepsis, suggesting a
potential benefit of albumin use in this population in particular [69]. Recent meta-analysis by Rochwerg et al.
resulting in composite global mortality risk comparisons
of individual resuscitation fluids to one another in a multimodal analysis suggests that albumin is superior to other
colloids, and its benefits over saline but not balanced crystalloids are supported by some studies with a moderate
level of confidence [15].
The most recent clinical trial to address this issue was
the ALBIOS trial [9] comparing 20% albumin to crystalloid in septic patient resuscitation. One thousand eight
hundred patients with severe sepsis and septic shock were
treated with either albumin and crystalloids, or crystalloids
alone for 7 days (1:1 distribution). This trial showed that
albumin-treated patients had significantly higher serum albumin level and had higher mean arterial pressure. However, these markers did not result in differences in
mortality at 28 or 90 days. These data suggest that achieving higher perfusion pressures and oncotic goals does not
equate improving survival. A post hoc subgroup analysis
which looked at septic shock patients (>1,100 of the
1,800) showed that albumin-treated patients with septic
shock did demonstrate decrease in mortality at 90 days,
whereas the albumin-treated group in patients without
septic shock had an increased mortality. Since this was a
post hoc analysis, it is subject to bias and this data will require follow-up studies. Therefore, although the use of albumin does not portend harm, the evidence for its benefit
does not exist, and at this time, the use of albumin in resuscitation of septic patients is not supported by clinical
evidence.
Three additional clinical trials are currently underway attempting to answer the question of potential albumin benefit in sepsis, one of which is specifically
looking at patients with septic shock. These trials are
RASP (NCT01337934) evaluating use of LR compared
to 4% albumin in patients with early sepsis, PRECISE
(NCT00819416) looking at 5% albumin versus NS in
early septic shock, and EARRS (NCT00327704) comparing NS to 20% albumin. Until these trials are completed,
there is no evidence to show albumin to have any benefit over crystalloid solutions. Current guidelines and
recommendations cannot endorse the use of albumin
Page 8 of 13
in light of its expense and current lack of proven
benefit.
Hydroxyethyl starch controversy Synthetic colloids are
often used in resuscitation, especially in the operating
room and outside of North America. Multiple studies and
recent meta-analyses evaluated the outcomes associated
with the use of synthetic colloids, showing no benefit of
individual synthetic colloids over other colloids or over
crystalloids [7,8,10,14,15]. Larger debate has emerged
surrounding HES in particular, with controversy compounded, by the discovery that many of the original
data published by Joachim Boldt showing outcome benefits of HES were falsified, resulting in subsequent retraction of these studies [70,71]. The lack of mortality
benefit of HES has been shown in several large recent
randomized control trials (RCTs). Perner et al. in 2012
[7] showed increase in 90-day mortality with HES when
compared to LR in 800 patients with severe sepsis. The
CHEST trial [8] showed no difference in mortality between HES and NS in a 7,000 patient general intensive
care unit (ICU) population, and Bagshaw et al. [10]
showed no mortality difference in a 7,000 patient multicenter RCT comparing HES to NS. Similarly, a study
evaluating goal-directed fluid therapy in colorectal surgery showed no mortality benefit of HES over balanced
crystalloid solution [69]. Three recent meta-analyses by
Zarychanski et al. [12], Serpa Neto et al. [13], and
Rochwerg et al. [15] support the conclusion that use of
HES in resuscitation does not reduce mortality when
compared to other resuscitation fluids. To the contrary,
some studies suggest increase in mortality with HES
[7], and after exclusion of studies by Boldt, the metaanalysis by Zarychanski et al. also showed a similar nonsignificant trend toward HES causing harm.
Contrasting this is the recent CRISTAL trial, which
enrolled 2,857 patients with hypovolemic shock, sepsis,
and trauma in multiple centers from five different countries [6]. This trial compared administration of colloids
(hypo- as well as hyper-oncotic) to crystalloids (including isotonic and hypertonic saline as well as balanced solutions) and detected a difference in 90-day mortality,
favoring the use of colloids. HES was the most commonly
used colloid (used in 70% of patients in the colloid group),
and NS was the most commonly used crystalloid (used in
80% of patients in the crystalloid group). The study observed no difference in 28-day mortality between treatment groups. They also found no difference in the need
for renal replacement therapy between groups. It is unclear why the results of this large study differ from other
large recent studies but may be attributed to several peculiarities in the actual treatment each group received. The
data was analyzed based on intention to treat analysis.
However, many deviations from the assigned treatment
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were noted in both the colloid and crystalloid groups. Further confounding may have resulted from the period prior
to randomization, when many patients received resuscitation fluids different from those to which they were then
assigned upon randomization. Furthermore, given that the
data regarding HES varies with variables such as molecular weight in ways that is not consistent with any particular hypothesis, this suggests that other confounding
factors may exist that are not being accounted for. One
of such confounding factors may in fact be the electrolyte composition of the solution used for preparation of
the starches.
Although the HES controversy still surrounds mortality,
there is significant evidence that HES increases morbidity.
Its use has been shown to result in increase in serum
creatinine and increased use of renal replacement therapy (RRT) both in clinical trials [7,8] and meta-analyses
[10-17]. Although the results of these meta-analyses
were driven primarily by the large trials, they also included numerous smaller studies, confirming this finding of HES association with increase in AKI and need
for RRT. One meta-analysis [22] did not show such association, but it is difficult to interpret its findings because it compared HES to any other resuscitation fluid
in surgical patients, including 19 small studies of which
only three compared HES to crystalloids and reported
on AKI. Interestingly, none of the meta-analyses included the CRISTAL trial, and again, the CRISTAL trial
data did not support the findings of increased need for
RRT with HES, in contrast to the other large trials such
as CHEST [8] and 6S [7]. There are a few differences
that distinguish these trials. These include using as the
comparison group LR or NS, the clinical acuity of the
enrolled patients, the pre-randomization fluid type and
volume, as well as use of maintenance fluids. We now
know that in a particularly susceptible population, NS
may have some deleterious effects on the kidney, which
until recently were underappreciated. It is possible that
the HES versus LR comparison and HES versus NS
comparison do not yield the same results. The level of
clinical acuity may deem a patient susceptible to developing clinically relevant AKI in the setting of an offending agent, and furthermore, once AKI develops, it may
be more poorly tolerated, posing a greater contributor
to mortality. There may be additional patient susceptibility factors that also provide a biologically plausible
explanation for the differences between the studies’
outcomes which are not presently obvious.
Debate raised by these studies addresses questions of
superiority of crystalloids versus colloids, and benefits
and drawbacks of the use of HES in comparison to other
fluids. The discussion largely explores the question of
equivalence of colloid solutions, but it does not address
the question of equivalence of the different crystalloid
Page 9 of 13
solutions. Crystalloids were assumed to be equal and by
bias equally bad at restoring intravascular volume, when
the study designs were initially created. Those large trials
which did not support differences in mortality or renal injury between synthetic colloids and crystalloids, namely,
those by Bagshaw et al. and Annane et al. [6,10], compared HES to NS. This raises the question whether the
choice of crystalloid solution may play a role in the mortality and morbidity outcomes. If NS carried its own mortality and morbidity effect, then the studies using NS in
the crystalloid arm might not reflect actual colloid versus
crystalloid difference in mortality and morbidity. In light
of the complexity that continues to emerge, the original
question of choosing between colloids versus crystalloids
may need to be rephrased. Owing to the fact that albumin
appears superior to other colloids and balanced solutions
are different from NS, comparing colloids to crystalloids
as groups becomes less informative than initially thought.
Chloride-liberal versus chloride-restricted crystalloids
The above question brings into focus the need for headto-head comparison of the different crystalloid solutions.
There has been a recent surge in the literature comparing
different crystalloid solutions in resuscitation, in particular
chloride-liberal (i.e., NS) versus chloride-restricted solutions [32,72]. These results come primarily from perioperative literature including mainly trauma patients and
inpatients undergoing major abdominal surgery and suggest that the use of balanced salt solutions in some patient
populations decreases mortality and the incidence of AKI
when compared to NS. This provoked a more rigorous
evaluation of the effects of NS in comparison to balanced
crystalloids in critically ill patients [33,73]. A clinical trial
by Yunos et al. involving 2,012 patients demonstrated a
decreased AKI incidence and use of RRT in ICU patients
with implementation of chloride-restricted strategy [33].
The use of NS has long been known to be associated with
an increased risk of hyperchloremic metabolic acidosis
[74], but it has only recently been shown that these metabolic changes can result in decreased renal blood flow and
renal cortical hypoperfusion, as demonstrated in healthy
volunteers [55]. Several studies now have shown perioperative mortality and morbidity benefits of balanced solutions over NS, and growing evidence exists suggesting
greater benefit in critically ill patients [32,33,75,76].
Goal-directed therapy
Although not the focus of our review, aside from the type
of fluid, consideration should be given to the amount of
fluid during resuscitation and its timing relative to the
exogenous stress. Much of the approach to the decisions regarding volume of fluid resuscitation comes
from perioperative literature [77-81]. Recent studies on
perioperative fluid administration challenge prior usual
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practices and suggest that significant benefit can be
achieved by individualizing therapy based on patient response. Perioperative fluid management has long been
dictated by the generalized formulaic approach, rather
than physiologic and homeostatic needs [82]. However,
both perioperative fluid under-resuscitation as well as
over-resuscitation can have deleterious effects and lead
to increased morbidity and mortality [78,81,83].
Goal-directed fluid resuscitation therapy targets physiologic goals of hemodynamic stabilization, and benefit of
such approach has been shown in multiple studies and recent meta-analyses [84-86]. The main goal of such therapy
is maintenance of end-organ perfusion, achieved by adequate circulating volume as well as adequate function
of the cardiovascular system. All of these components
can be altered perioperatively by anesthetic agents,
body temperature, or other factors. Thus, fluid resuscitation should be used to achieve these specific goals
when monitoring suggests the patient to be fluid responsive [87,88]. The counterargument is raised by
studies evaluating fluid resuscitation in the septic patient, where the field has been driven by the Surviving
Sepsis Campaign [89], and further addressed by the recent ProCESS and ARISE trials [86,90]. Interestingly,
the recently completed ProCESS trial showed no difference in outcome of sepsis patients treated in an emergency department with early goal-directed therapy versus
two types of usual care. Importantly, all three arms of that
study received roughly the same amount of fluid therapy
both in the initial few hours and over the first day [90].
Recent analysis by Wachter et al. has looked at the interplay between volume resuscitation and use of vasopressors
[91] and maintains that volume resuscitation is critical in
septic patients in the early phase of the illness. Also, the
patients who exhibited lowest in hospital mortality were
the ones who received moderate to high fluid volume in
the first 6 h of resuscitation, but delayed vasopressor use
until adequate volume resuscitation has been obtained.
The other recent trial in the septic population is the
ARISE trial [86]. Here investigators compared the implementation of early goal-directed therapy with ‘standard’
practice and found that patients in the early goal-directed
therapy (EGDT) arm received higher resuscitation fluid
volume and higher amount of vasopressors, and were
noted to have higher blood pressures, but this finding did
not translate into change in 90-day mortality, suggesting
that goal-directed therapy in early sepsis does not yield
survival benefit.
Although seemingly in contrast to one another and to
the perioperative literature, we believe that the overall
message is the same once interpretation is taken in context. First, it must be questioned whether a decade of
EGDT has changed our practice to the point that our
‘standard’ practice has moved away from formulaic
Page 10 of 13
approaches, and favors more aggressive volume and vasopressor resuscitation based on physiological principles.
Second, we note that in the perioperative literature, the
goal-directed approach to resuscitation typically results in
more conservative volume resuscitation, whereas in septic
patients, the goal-directed approach results in greater volume administration, suggesting that the goal-directed
approach potentially unmasks greater volume needs in
patients in early sepsis as their physiology progresses
into a more distributive and vasodilatory state. In contrast, intraoperative resuscitation may be reflective of a
state that is more vasoconstrictive owing to a combination
of different anesthetic agents, pharmacologic vasogenic
agents, and intraoperative hypothermia.
Hence, it is probably not just the amount of volume, but
mostly the ability to stabilize the critically ill patient with
that volume that defines outcome [92,93]. Volume responsiveness is only one of the components of the perioperative or septic physiologic state, the others being need and
responsiveness to vasoactive agents and inotropic support.
Therefore, fluid resuscitation therapy should not be used
in isolation since the goals of therapy are to make the patient cardiovascularly sufficient. Clearly, expert knowledge
of understanding the pathophysiologic principles and how
they contribute to each individual’s acute pathophysiologic
state, the type of surgical procedure or stress, and unique
underlying comorbidities needs to be incorporated into
the treatment plan [79]. Fluid therapy therefore should be
used only in volume-responsive patients and only when
end-organ perfusion goals are not met. Of note is that it is
not sufficient to target volume administration to arterial
blood pressure, as recent study by Asfar et al. showed that
improved arterial blood pressure was not necessarily
associated with better outcomes [94]. Hence, determining fluid need is dependent on dynamic parameters of
hemodynamic monitoring and should be individualized
to each patient [95]. Studies comparing goal-directed
fluid administration strategies with fluid-liberal strategies show improved outcomes with goal-directed therapies [96-98].
Conclusions
Keeping with the current evidence, organizations and collaborations such as the European Society of Intensive Care
Medicine (ESICM) and Cochrane umbrella the spectrum
of findings under consensus statement and create a set of
recommendations [1,3]. In summarizing these most recent
recommendations and with addition of the literature that
emerged over the past couple of years, the following conclusions can be drawn.
1. Colloids at large: There has not been a clear benefit
associated with the use of expensive colloids
compared to inexpensive crystalloids. Colloids as a
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2.
3.
4.
5.
6.
7.
whole have, however, shown to have increased
mortality in patients with TBI. No indications
currently exist for the routine use of colloids over
crystalloids.
Albumin: There is no evidence to support the
unique benefit of use of albumin as a resuscitation
fluid. With the inclusion of the latest ALBIOS trial,
mortality benefit in sepsis has not thus far been
proven. In light of the cost and limited shelf life,
the use of albumin as a resuscitation fluid is not
supported.
HES: The benefit of using HES has been refuted. To
the contrary, HES is associated with increased harm.
Though it is not clearly associated with increase in
mortality, evidence clearly shows increased AKI and
use of RRT associated with the use of HES. It is
further associated with coagulopathy and increased
use of blood transfusion. The effects seem to be
dose dependent, but no consensus has been reached
as to a safe dose of HES. As such, the use of HES in
resuscitation should be avoided.
Dextran and gelatins: Other synthetic colloids
(dextran and gelatins) are not well studied in the
literature. Although there is no evidence showing
harm beyond what is seen with other colloids, there
is also no evidence showing benefit. In light of the
lack of evidence, and the theoretical potential for
adverse effect, the suggestion is not to use gelatins
or dextran.
0.9% saline: The use of NS has been shown to be
associated with development of hyperchloremic
metabolic acidosis and increased risk of AKI in
susceptible patients, especially those with diabetic
ketoacidosis. This risk is decreased when balanced
salt solutions are used. The use of balanced
crystalloid solutions rather then NS when possible
should be considered in these populations.
Balanced crystalloid solutions: These solutions have
shown no harmful effects in any particular patient
population. There is evidence for benefit over NS
as a means of preventing development of
hyperchloremic metabolic acidosis and its associated
effects. There is no head-to-head study comparing
different balanced crystalloids to each other, and
therefore, no consensus exists on a single preferred
solution. Current literature supports use of balanced
crystalloids when possible and in particular in
patients in which NS may cause adverse effects,
as mentioned above.
Volume: Fluid resuscitation should be applied in a
goal-directed manner and targeted to physiologic
needs of individual patients. The evidence supports
use of fluids in volume-responsive patients whose
end-organ perfusion parameters have not been met.
Page 11 of 13
Studies show improved outcomes with the use of
goal-directed therapy over fluid-liberal approach.
Abbreviations
AKI: acute kidney injury; ATP: adenosine triphosphate; ESICM: European
Society of Intensive Care Medicine; HES: hydroxyethyl starch; ICU: intensive
care unit; Jv: net fluid movement between compartments; Kf: filtration constant;
LR: lactated Ringer’s; NS: normal saline; Pc: capillary hydrostatic pressure;
Pi: interstitial hydrostatic pressure; RRT: renal replacement therapy;
TBI: traumatic brain injury; πc: capillary oncotic pressure; πi: interstitial
oncotic pressure; σ: reflection coefficient.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
AL performed the systematic review searches and reviewed the primary
manuscripts cited in this review, wrote the initial draft of the manuscript,
and contributed to revisions of the final version. MP reviewed the initial
search results and all the primary manuscripts cited in this review, and revised
and wrote the final version of the manuscript. Both authors read and approved
the final manuscript.
Received: 1 August 2014 Accepted: 14 November 2014
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doi:10.1186/s13613-014-0038-4
Cite this article as: Lira and Pinsky: Choices in fluid type and volume
during resuscitation: impact on patient outcomes. Annals of Intensive
Care 2014 4:38.