Nephrol Dial Transplant (2015) 30: 178–187
doi: 10.1093/ndt/gfu005
Advance Access publication 23 January 2014
A critical appraisal of intravenous fluids: from the
physiological basis to clinical evidence
David Severs1, Ewout J. Hoorn1 and Maarten B. Rookmaaker2
Department of Internal Medicine – Nephrology & Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands and 2Department of
1
Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
Correspondence and offprint requests to: David Severs; E-mail: d.severs@erasmusmc.nl
A B S T R AC T
Fluid management has been a vital part of routine clinical care
for more than 180 years. The increasing number of available
fluids has generated controversy about the optimal choice of re-
suscitation fluid. In this review, we provide a critical overview of
the different fluids available, their composition, the relevant
FULL REVIEW
physiology as well as the published evidence on clinical out-
comes to guide their use. Commonly used infusion fluids
include semisynthetic colloids and crystalloids; the latter com-
prises both normal saline (NaCl 0.9%) and the more chloride-re-
stricted ‘balanced’ crystalloids. Despite their significantly greater
intravascular persistence, semisynthetic colloids have an import-
antly adverse safety profile and are associated with greater inci-
dence of renal failure and increased mortality; their use should
be restricted. To date, evidence for clinical benefits associated
with albumin solutions is generally lacking; its merits in specific
clinical situations are the subject of further investigation. Infu-
sion of normal saline, with its supraphysiological chloride
content, is associated with higher serum chloride concentrations
and metabolic acidosis, as well as renal vasoconstriction in
animal and human models. Infusion of ‘balanced’ crystalloids is
not linked to such changes. Although data on clinical outcomes
associated with crystalloid infusion are heterogeneous, advan-
tages of balanced salt solutions might include a lower need of
blood products, and lower incidence of renal replacement
therapy, hyperkalaemia and postoperative infections. Taken to-
gether, a critical appraisal of the data suggests that balanced salt
solutions deserve consideration as infusates of first choice.
Keywords: chloride, colloids, crystalloids, saline
INTRODUCTION
In 1832, Dr Thomas Latta first reported on an attempt to
intravenously replace fluids and salts lost in cholera sufferers.
He made up a solution containing ‘two to three drachms of
© The Author 2014. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
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muriate of soda and two scruples of the subcarbonate of soda
in six pints of water’. Faced with failure of earlier attempts at
oral rehydration, and with ‘no precedent to direct him’, he
proceeded to ‘throw the fluid immediately into the circulation
[1]’. This highly successful intervention led to a number of im-
portant experiments—in 1834, Dr John Mackintosh first used
intravenous albumin [2], Ringer’s solution was introduced in
1876 by Dr Sydney Ringer and a modification was made by Dr
Alexis Hartmann in 1932 to include lactate [3]. Given impetus
by a better understanding of the principles of membrane per-
meability, fluid tonicity and osmosis at the time, it appears
that the in vitro studies of the Dutch physiologist Hartog
Jakob Hamburger in the 1890s led to the acceptance of NaCl
0.9% as isotonic to human blood. Noting that erythrocytes
were least likely to lyse in this solution, he called it ‘indifferent’
saline [4, 5]. While the use of intravenous gelatin in animals was
reported as early as 1894 [6], and a first study in humans was
performed in 1915 [7], interest in gelatins as well as other larger
molecules to expand the intravascular volume was renewed only
in the Second World War [8]. Asanguineous infusion fluids are
most commonly classified as crystalloids (small electrolytes in
water) or colloids (larger molecules that are meant to remain in
circulation for a longer time). Crystalloids include 0.9% NaCl
(‘normal’ saline) as well as buffered and more ‘balanced’ solu-
tions such as lactated Ringer’s solution.
Today, fluid management is a vital part of routine care for a
wide range of settings. In volume replacement, the goal is to
replete intravascular fluid volume in trauma or sepsis, while in
‘dehydration’ (contraction of the extracellular fluid volume),
the total extracellular space is the target of fluid repletion.
A third potential goal of infusion is to restore the composition
of the extracellular fluid by altering its electrolyte contents or
acidity, which will not be discussed in this review. Finally,
another aim of fluid infusion may be the maintenance of flow
in the distal renal tubules and urinary tract to prevent toxicity
or precipitation of drugs or radiocontrast. Indeed, the question
of the optimal choice of infusion fluid for this indication has
led to a number of trials, mostly making a comparison
178
between colloid and crystalloid infusions or more specifically
between infusion of normal saline and sodium bicarbonate so-
lutions. A more in-depth discussion of this indication is
beyond the scope of this article (for review, see [9–11]). Of
note, infusion therapy often serves more than one purpose, e.
g. fluid repletion and electrolyte correction.
The choice of a particular infusion fluid has generated con-
siderable controversy. Arguments are predominantly based on
theoretical and physiological considerations as well as pre-
clinical studies (Table 1). The number of clinical studies is
limited and restricted to the field of general surgery, kidney
transplantation and intensive care medicine. The aim of this
review is to provide a nephrological readership with an over-
view of the different fluids available for volume resuscitation
and fluid repletion. This review will not consider blood pro-
ducts other than albumin. First, we give an introduction on in-
fusion fluid characteristics and physiology. We then
summarize the relevant chemical properties of commonly
used infusates and discuss studies that evaluate their physio-
logical effects and potential side effects. We proceed by high-
lighting the available evidence on outcomes in clinical studies
in general surgery, kidney transplantation and intensive care
units (ICUs). We conclude that the available evidence merits
consideration as infusates of first choice for balanced salt solu-
tions, although definitive large-scale studies are still needed.
REVIEW CRITERIA
We performed a search for original full-text English language
papers in Medline, EMBASE and the Cochrane library, using
the search terms ‘crystalloid’, ‘saline’, ‘Ringer’, ‘Hartmann’,
‘Plasma-Lyte’, ‘Sterofundin’, ‘colloid’ and their synonyms,
alone and in combination (last accessed 21 November 2013).
We also selected further relevant papers by following reference
lists of identified articles.
I N F U S I O N F L U I D C H A R AC T E R I S T I C S
A N D P H Y S I O LO G Y
The ionic composition of infusion fluids is important because
it directly affects biological processes like signal transduction
and coagulation. The choice of infusate can be guided by the
Table 1. Summary of haemodynamic effects, advantages
disadvantages of commonly used infusion fluids
Colloids Normal saline Balanced
crystalloids
Intravascular Long Short Short
persistence
Advantages Larger Extensive Most closely
haemodynamic experience resemble ionic
effects composition of
blood
Disadvantages Nephrotoxicity, Hyperchloraemic Slightly
greater mortality acidosis hypotonic
Costs High Low Low
Intravenous fluids: a critical appraisal
intention to maintain or deliberately change the composition
of body fluids. It is of note that clinical laboratories generally
report the electrolyte concentrations in serum. Concentrations
in the aqueous fraction of plasma are 7% higher due to the
presence of proteins and lipids. It follows that if the electrolyte
contents of an infused fluid are to be proportionate to the cor-
responding aqueous fraction of blood plasma and effects on
acidity are to be minimal, it should contain 153 mmol/L Na+,
111 mmol/L Cl−, 4.8 mmol/L K+, 2.7 mmol/L Ca2+ and 1.35
mmol/L Mg2+, and be able to maintain a plasma pH of 7.35–
7.45 [12]. Surprisingly, however, no such fluid is available
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(Table 2). A change in plasma Ca2+ concentration, for
example, will change cellular (de)polarization, whereas
changes in acidity directly influence processes like coagulation
[13–17]. This is in line with the profound impairment in
factor VIIa (FVIIa), FVIIa/tissue factor and FXa/FVa activity
with decreases in pH [16]. In vitro and animal models also
suggest increased extracellular acidity may alter the immune
response in multiple ways, ranging from a change in produc-
tion of proinflammatory mediators to impaired leucocyte
chemotaxis and lymphocyte cytotoxicity [18, 19].
The distribution of infused fluids between the intracellular
and extracellular compartments is dictated by the osmotic
pressure in the different compartments. The osmotic pressure
is determined by the amount of solutes and their osmotic coef-
ficients, which describe the deviation of the osmotic behaviour
of solutes from their theoretical osmotic behaviour. When
FULL REVIEW
considering the tonicity of an infused fluid, it is important to
appreciate the differences between theoretical ‘osmolarity’ (ob-
tained by addition of all osmotically active molecules to 1 L of
solution) and ‘actual’ ‘osmolality’ (mOsmol/kg solvent), espe-
cially in vivo. As sodium and chloride, when dissolved, only
partially dissociate, and as such are only partially osmotically
active (osmotic coefficient 0.926), the actual osmolality of a
fluid in which they are dissolved is lower than their added mo-
larities. The osmolality of a fluid is derived from the ‘ideal’
osmolarity, the osmotic coefficient and the solvent content
(93% water for plasma) and may be directly measured via
freezing point depression. Surprisingly, the measured osmolal-
ity of plasma (288 mOsmol/kg H2O) is practically identical to
the calculated osmolarity (291 mOsmol/L) [12, 20]. This is in
stark contrast to the difference between the theoretical osmo-
larity of NaCl 0.9% (308 mOsmol/L) and its actual osmolality
of 286 mOsmol/kg H2O. It is of note that changes in the
osmolality and volume of the blood plasma lead to more
and
limited, yet potentially important changes in erythrocyte
volume, and may have significant rheological effects [21].
In contrast to small solutes, plasma proteins move across
the capillary wall only to a limited degree, subsequently acting
as effective osmoles, impeding filtration of water into the inter-
stitium. The osmotic pressure generated by plasma proteins is
commonly referred to as the colloid osmotic or oncotic pres-
sure [22]. The oncotic pressure depends on both the difference
in plasma protein concentrations and the barrier between the
intravascular compartment and the interstitium. This barrier
is predominantly formed by the endothelial glycocalyx layer
(EGL) but also by the endothelial basement membrane and
extracellular matrix in the interstitial space [23, 24]. The EGL
179
 Table 2. Characteristics of commonly available infusion fluids

Plasma Crystalloids Colloids

0.9% NaCl Lactated Ringer’s Plasma-Lyte Sterofundin Voluven (HES 6%) Gelofusinea Dextran 40
+
Na (mmol/L) 142 154 130 140 140 154 154 154
Cl− (mmol/L) 103 154 109 98 127 154 120 154
K+ (mmol/L) 4.5 0 4 5 4 0 0 0
Ca2+ (mmol/L) 2.5 0 2.7 0 2.5 0 0 0
Mg2+ (mmol/L) 1.25 0 0 1.5 1 0 0 0
Bufferb (mmol/L) 24 0 28 50 29 0 0 0
Colloid (g/L) 35–45 0 0 0 0 60 40 100

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Oncotic pressure (mmHg) 25 0 0 0 0 36 26–29 168–191
Osmolarity (mOsmol/L) 291 308 273 295 304 308 274 308
Osmolality (mOsmol/kg) 288 286 254 N/K 290 N/A N/A N/A
HES, hydroxyethyl starch; N/A, not applicable; N/K, not known.
a
Contains 4% gelatin.
b
The buffer in plasma is bicarbonate, in lactated Ringer’s lactate, in Plasma-Lyte acetate (27 mmol/L) and gluconate (23 mmol/L), in Sterofundin acetate (24 mmol/L) and maleate
(5 mmol/L).

consists of a dense network of proteoglycans associated with
various glycosaminoglycans and coats the luminal side of
healthy vascular endothelium [25]. The polyanionic nature of
the glycosaminoglycans makes the EGL semipermeable to
anionic macromolecules, such as albumin, depending on their
size and structure [26]. Under physiological conditions, while
continuously subject to degradation and reconstitution, its
thickness is estimated to be as little as 0.2 μm in the microcir-
culation and up to 8 μm in the large vessels [27]. Several
FULL REVIEW
Various colloids are currently available. Human albumin is
available in iso-oncotic 4–5% solutions and hyperoncotic 20–
25% solutions. The high cost of human albumin has limited
its use. Gelatins are proteins formed by hydrolysis of animal-
derived connective tissue. Because high-MW gelatin solutions
tend to gel, the average MW of present solutions is limited to
30–35 kDa, which reduces their oncotic pressure and intravas-
cular persistence. Dextran ‘40’ (MW 40 kDa) and ‘70’ (MW
70 kDa) are the products of acid hydrolysis and ethanol frac-

factors that contribute to EGL degradation, leading to shed-
ding of its components and compromise of its function, have
now been identified. Among them are inflammatory mediators
[28–32], but also hypervolaemia, such as when induced by
rapid crystalloid infusion in healthy volunteers [28, 33]. It is of
note that the oncotic pressure gradient between the intravascu-
lar and interstitial spaces is insufficient to counter the hydraul-
ic pressure found in the intravascular space [24, 34]. Since the
subglycocalyx space is nearly protein free, it is likely the
oncotic pressure gradient across the EGL, and not, as previous-
ly assumed, across the endothelium, which restricts water loss
across the vascular wall [24]. Hence, in summary, the effect of
a fluid infused in the intravascular compartment on its extra-
vascular counterpart depends on hydrostatic and (colloid)
osmotic pressure gradients as well as EGL function and factors
in the endothelial basement membrane and the extracellular
matrix.
C O L LO I D S
Colloid is the collective noun for all infusion fluids that
contain large molecules which are meant to keep the infusate
in the intravascular space for a longer time by exerting an
oncotic pressure [35]. Colloid infusates comprise blood pro-
ducts such as human albumin solution and the more com-
monly used semisynthetic products: gelatins, dextrans and
hydroxyethyl starch (HES) solutions. Their effect on plasma
volume expansion depends on their oncotic pressure, influ-
enced directly and indirectly by molecular weight (MW) and
plasma half-life [36].
tionation of highly branched polysaccharide molecules synthe-
sized by the B512 strain of Leuconostoc mesenteroides [37].
Finally, HESs are derivatives of maize or potato starch, amylo-
pectin, in which intravascular amylase-driven degradation of
the molecules is slowed by substitution of the hydroxyl radicals
in positions C2, C3 and C6 with hydroxyethyl radicals [38].
This molecular modification renders HES more prone to accu-
mulation in reticular connective tissues, such as the spleen,
skin, liver and kidneys [39–42], and it may explain the finding
of lesions with a histological appearance of osmotic nephrosis
in animals subjected to HES infusion [43]. Semisynthetic col-
loids are considerably cheaper than human albumin, but still
usually at least an order of magnitude more expensive than
crystalloids.
The use of albumin solutions in volume replacement in re-
suscitation of critically ill patients has a number of theoretical
advantages over crystalloids, but its actual clinical benefits and
safety profile are uncertain. The addition of human albumin to
normal saline, bringing the solution to iso-oncoticity, in
theory expands this fluid’s capacity to provide intravascular
volume expansion. Indeed, in one large randomized controlled
trial comparing resuscitation with albumin or normal saline,
40% greater average volumes of saline were infused [44]. Simi-
larly, greater increases in plasma volume and cardiac index
were obtained with infusion of 5% albumin compared with
normal saline in cardiac surgery and sepsis [45, 46]. Moreover,
pre-clinical studies suggest albumin may reduce vascular
endothelial leucocyte adhesion [47–49].
A first meta-analysis by the Cochrane collaboration was
published in 1998, comparing the use of albumin or plasma
protein fraction with crystalloids in patients with hypovolaemia,

180 D. Severs et al.

burns or hypoalbuminaemia [50]. Its most important result, a
pooled relative risk (RR) of death of 1.68 [95% confidence
interval (CI), 1.26–2.23; P < 0.01] associated with albumin,
caused a large uproar and a significant drop in the clinical use
of albumin, but the investigators also attracted staunch criti-
cism pertaining to limitations of included studies, review meth-
odology and interpretation. The last decade saw publications of
the Saline versus Albumin Fluid Evaluation (SAFE) study, in
which 6997 critically ill, ICU-admitted adults were randomized
between resuscitation with 4% albumin or normal saline [44],
and the Fluid Expansion as Supportive Therapy (FEAST)
study, in which 3141 febrile, critically ill children were random-
ly assigned to receive boluses of 5% albumin, normal saline or
no bolus of resuscitation fluid [51]. While neither the FEAST
nor the SAFE study detected differences in clinical outcomes
between groups receiving normal saline or albumin, a post hoc
subgroup analyses from the SAFE study showed higher mortal-
ity associated with albumin in 460 patients with traumatic
brain injury (RR, 1.63; 95% CI, 1.17–2.26; P = 0.003) [52]. In
contrast, another post hoc subgroup analysis of the SAFE study
indicated a potential decrease in the adjusted risk of death with
albumin in severely septic patients [odds ratio (OR), 0.71; 95%
CI, 0.52–0.97; P = 0.03] [53]. A 2011 update of the above Co-
chrane review, which relied heavily on the SAFE study, no
longer detected mortality differences between albumin and
crystalloid solutions (RR, 1.02; 95% CI, 0.92–1.13, P = 0.35)
[54]. Three trials addressing the use of albumin solutions spe-
cifically in early septic shock are under way (NCT00707122,
NCT00327704 and NCT00819416).
Several clinical studies have confirmed that, in analogy to
albumin solutions, semisynthetic colloids provide more intra-
vascular fluid repletion than crystalloids. In a randomized
clinical trial in 67 patients who had undergone cardiac or
major vascular surgery, patients receiving colloid solutions (an
average of 1600 mL of gelatin 4%, HES 6% or albumin 5%)
had significantly greater increases, during the 90 min of infu-
sion, in plasma volume (19 versus 3%) and cardiac index (22
versus 13%) compared with patients receiving normal saline
[55]. Similarly, in a randomized trial with 25 septic patients
and 24 non-septic hypovolaemic patients, fluid loading with
semisynthetic colloids resulted in greater increases in cardiac
filling, output and stroke work than loading with normal
saline did [56]. The increased intravascular volume repletion
was also demonstrated in a study with 10 healthy volunteers
who received infusion with 1 L of gelatin (4% succinylated
gelatin in 0.7% saline), HES (6% HES 130/0.4 in 0.9% saline)
or 0.9% saline alone. HES and gelatin suppressed plasma renin
activity (PRA) more than saline, but this difference did not
reach statistical significance [57]. Finally, a study reported on a
nurse-delivered algorithm, in which, after cardiac surgery, 237
patients were randomly allocated to receive 250-mL boluses of
either normal saline or a HES solution based on haemo-
dynamic parameters. Although the study did not report total
volumes of infused fluids, significantly more catecholamines
were used in the group assigned to receive normal saline [58].
However, serious concerns have risen over deleterious
effects of semisynthetic colloids on specific systems, such as
haemostasis [59] and renal function [60–62]. Significant
Intravenous fluids: a critical appraisal
reductions in FVIII and von Willebrand factor are observed
after infusion of dextrans, gelatins and HES, with high-mo-
lecular HES and dextran having the greatest effect on haemo-
stasis [59]. Moreover, concerns about nephrotoxicity have
assumed prominence since the introduction of semisynthetic
colloids, owing to a host of evidence published in the last few
decades to suggest greater incidence of renal dysfunction and
renal replacement therapy associated with semisynthetic
colloid infusion. Importantly, evidence of a survival benefit of
semisynthetic colloids over crystalloids has been lacking.
Much of the attention has focused on HES. Four well-de-
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signed, large randomized controlled trials, published in 2008,
2012 and 2013, compared the use of HES with Ringer’s acetate
or lactate [63, 64] with normal saline [65, 66], and demon-
strated increased risk of death [63] and the use of renal re-
placement therapy [63–66] in the groups assigned to receive
HES. A recent Cochrane review, which also included two of
these studies, found no evidence from randomized controlled
trials that colloids (dextran ‘70’, gelatins, HES, albumin and
plasma protein fraction) are superior to isotonic or hypertonic
crystalloids as a treatment for intravascular volume resuscita-
tion in critically ill patients [67]. Notably, the pooled RR of
mortality with HES versus crystalloids was 1.10 (95% CI, 1.02–
1.19), implying a potential mortality hazard associated with
HES [67]. A 2011 Cochrane review found no evidence of su-
periority of one particular colloid solution in critically ill and
surgical patients requiring volume replacement, noting,
FULL REVIEW
however, a relative lack of direct comparisons and wide CIs
[68]. Furthermore, two recent meta-analyses, including one
Cochrane review, exclusively compared HES with other resus-
citation fluids and found a significantly increased risk of mor-
tality and acute kidney injury associated with the use of HES
[69, 70]. Of particular interest is the finding that these detri-
mental effects only became visible after exclusion of seven pre-
1999 trials initiated by Dr Joachim Boldt, whose subsequent
publications have been retracted because of scientific miscon-
duct [71, 72]. In addition, observational data suggest that gela-
tins may be nephrotoxic similarly to HES [73]. A very recently
published, large, multi-centre, randomized controlled trial in
patients admitted to the ICU and presenting specifically with
hypovolaemic shock (CRISTAL) allocated 2857 patients to
receive either exclusively colloids (various semisynthetic col-
loids and albumin solutions) or crystalloids in an unblinded
fashion. Patients were randomized at the onset of resuscitation.
Contrasting with previous studies, investigators found no dif-
ference in 28-day mortality (RR, 0.96, 95% CI, 0.88–1.04; P =
0.26), whereas the secondary outcome, 90-day mortality, was
lower in the group receiving colloids (RR, 0.92, 95% CI, 0.86–
0.99; P = 0.03) [74]. The latter finding should be interpreted
with caution, since the CI approaches 1. No difference in the
risk of receiving renal replacement therapy was found. Unfor-
tunately, the pragmatic design of this study leaves questions on
the contribution of individual fluid types to these outcomes,
and especially the distinction between albumin and semi-
synthetic colloids.
Taken together, growing concerns about safety, especially
concerning semisynthetic colloids, and the lack of consistent
clinical superiority of colloids, suggest that their application
181
 should be minimized and the less expensive crystalloids
should be the infusates of choice, while we await clarification
from ongoing trials on the potential benefit of albumin infu-
sion specifically in septic shock.
C R Y S TA L LO I D S
The term crystalloid is typically used to refer to solutions in
water of small inorganic ions and small organic molecules.
Purely NaCl-based solutions are most commonly used. Alter-
natives include various concentrations of potassium, calcium,
magnesium and organic anions such as lactate to more closely
resemble the ionic pattern of blood plasma.
Normal saline
‘Normal saline’ (NS, 0.9% or 154 mM NaCl) is the most
frequently prescribed crystalloid in clinical practice [75], yet
remarkably few studies address the time scale and extent of its
effects in normal subjects on haemodynamic parameters,
blood dilution and excretion. After infusion, normal saline is
rapidly distributed between the compartments of the extracel-
lular space but remains in the body for a long time.
In normovolaemic subjects, expansion of the intravascular
volume persists for as long as 6 h after infusion of normal
saline, even though most of the infused volume is found in the
interstitial compartment. A study in 28 healthy volunteers
FULL REVIEW
found that 30 min after completion of a 20-min infusion of
10–30 mL/kg, 64% of the infused volume had diffused into the
interstitial compartment [76]. Studies in pre-surgical patients
and healthy volunteers receiving a 2-L normal saline infusion
over the course of 1 or 2 h reported intravascular retention of
the infused fluid of 18–24% (calculations based on haemato-
crit values) [77–79]. After 6 h, 60% of the fluid volume still re-
mained in the body, an estimated 13% in the intravascular
space [78, 79]. Finally, it is of note that during anaesthesia and
surgery, distribution and elimination of infused crystalloids
are delayed when compared with healthy volunteers [80].
Owing to the non-physiological ion content and the lack of
buffering capacity, normal saline infusion can be complicated
by metabolic acidosis. The determination of saline-induced
acidosis is subject to vivid debate [81]. The most commonly
used method for interpreting acid-base disturbances is the
Henderson–Hasselbalch equation, in which the dependent
variable pH is calculated from the variables PaCO2 and plasma
bicarbonate. The acidosis resulting from normal saline infu-
sion is often interpreted as dilutional, i.e. the result of de-
creased bicarbonate concentrations relative to stable PaCO2
[81]. The model assumes changes in the volume of distribu-
tion of bicarbonate with changes in pH [82, 83]. Advocates of
the alternative Stewart approach, introduced in 1983 [84],
argue that the essential change is not dilution of bicarbonate
(HCO− −
3 ) but infusion of the ‘strong ion’ Cl . This explanation
is based on the concept that independent variables—PaCO2,
the strong ion difference and the total concentration of non-
volatile weak acids—influence the dependent variables pH and
bicarbonate concentration [85]. Indirect effects of chloride
loading might also be responsible for the acidosis.
182
Intraluminal chloride is needed for pendrin-mediated bicar-
bonate excretion [86–88]. We therefore speculate that exces-
sive chloride loading might be involved in disproportionate
urinary bicarbonate loss. However, it should be noted that in
animal models, pendrin protein expression is rapidly downre-
gulated in response to induction of acidosis [89]. In addition,
the presence of chloride ions in an infusion fluid is instrumen-
tal in this fluid’s capacity to suppress renin release, and subse-
quently its capacity to suppress aldosterone availability and
bicarbonate retention [90]. The latter was demonstrated in ex-
periments in healthy, sodium-restricted volunteers, in whom
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no suppression of PRA was found after infusion of 750 mL
1.4% NaHCO3, whereas infusion of 500 mL 0.9% NaCl led to
a 50% decrease in PRA [91]. Regardless of the explanatory
model, reductions in blood pH on infusion of saline, not in
the more balanced Ringer’s solution, were demonstrated in
healthy human volunteers who received 50 mL/kg over 1 h
(average pH reduction 0.04 ± 0.04) [92], and, as described later
in this review, in patients undergoing gynaecological surgery
(average pH reduction 0.13) [93] and pancreatico-hepatobiliary
surgery [94].
As normal saline contains a supraphysiological concentra-
tion of chloride [12], its infusion increases plasma chloride
concentrations [93], which is associated with renal vasocon-
striction and decreased glomerular filtration rate (GFR). In an
animal model, intrarenal infusion of chloride-rich solutions to
denervated kidneys resulted in decreases in renal blood flow
(RBF) and GFR compared with low-chloride solutions of
equal tonicity [95, 96]. Two studies with healthy human vo-
lunteers consistently showed a longer time to first micturition
after infusion of normal saline compared with a low-chloride
solution [79, 92]. Changes in plasma osmolality must be taken
into account in these studies, where the low-chloride solution
had a lower osmolality than normal saline, with a potential
effect on the release of antidiuretic hormone. Strengthening
the hypothesis of renal vasoconstriction by chloride infusion,
however, a study in healthy volunteers showed significant re-
ductions in renal artery flow velocity and renal cortical tissue
perfusion during and after infusion of normal saline, but not
with a low-chloride solution (Plasma-Lyte 148) [97]. Such in-
creases in renal cortical tissue perfusion were also seen when
healthy volunteers received 1-L infusions of 6% HES sus-
pended in a low-chloride solution compared with 6% HES
suspended in normal saline [98]. The effect may be due to
luminal chloride concentrations in the cortical thick ascending
limb of the loop of Henle being a rate-limiting step in tubulo-
glomerular feedback [95, 99–101], a mechanism that induces
alterations in the GFR by influencing afferent arteriolar vaso-
constriction. Finally, chloride has been shown to be actively in-
volved in the suppression of renin release, as described above.
‘Balanced’ crystalloids
Some of the above effects can be prevented by using a
solution that more closely mimics the ionic make-up of
the aqueous fraction of plasma. Acidosis can be avoided by in-
clusion of bicarbonate or metabolizable anions, such as
acetate, lactate, malate and citrate. Examples of more balanced
crystalloid solutions are lactated Ringer’s solution, Hartmann’s
D. Severs et al.
solution, featuring slightly different ionic concentrations,
Plasma-Lyte and Sterofundin. Their characteristics are sum-
marized in Table 2. As described above, the use of infusates
with metabolizable anions instead of chloride has been shown
not to increase plasma acidity [92, 93]. In addition, balanced
salt solutions did not reduce renal artery flow and renal cortical
perfusion seen after infusion of normal saline (see above) [97].
Unfortunately, some of the most commonly used ‘balanced’
solutions (like lactated Ringer’s solution) are neither isotonic
nor precisely balanced. With an osmolarity of 273 mOsmol/L
and a measured osmolality of 254 mOsmol/kg, infused lac-
tated Ringer’s solution leads to a small decrease in plasma
osmolality [79, 92]. Theoretical concerns with slightly hypo-
tonic infusion fluids include a potential increase in brain water
[102] and effects on diuresis. Interestingly, Hartmann’s solu-
tion (a slightly modified form of Ringer’s solution) when com-
pared with normal saline, doubled urine output in the 6 h
after infusion, and subsequently had a shorter persistence in
the body [79]. Such effects may be relevant considering the
goals of infusion therapy. Commercial initiatives, such as
Plasma-Lyte 148 and Sterofundin, have attempted to address
concerns over differences in tonicity and ionic composition
between plasma and the infused fluid. Unfortunately, there are
no published studies that address potential differences in ki-
netics and the effect on plasma osmolality between the more
balanced solutions.
CLINICAL STUDIES
In light of concerns raised around colloids, their use should be
restricted. For (intravascular) volume repletion, crystalloids
deserve consideration as infusates of first choice. Below, we
compare the use of normal saline with balanced salt solutions
in clinical outcome studies.
Surgery
The risk of hyperchloraemic acidosis in patients receiving
normal saline was demonstrated in surgical patients. Subjects
undergoing intra-abdominal gynaecological surgery were ran-
domly assigned to receive normal saline or lactated Ringer’s,
with an average volume of 6 L over 2 h. Predictably, hyper-
chloraemia and metabolic acidosis were more prevalent in the
normal saline group (average pH 7.28 versus 7.41, chloride
115 versus 107 mmol/L) [93]. Such metabolic derangements
associated with the use of normal saline in comparison with
Plasma-Lyte were also seen in a study including 30 patients
undergoing major hepatobiliary or pancreatic surgery [94]. In
a randomized controlled trial in 46 trauma patients, resuscita-
tion with Plasma-Lyte resulted in a quicker resolution of acid-
base disturbances compared with normal saline [103].
Although the data on clinical outcomes in patients under-
going surgery are heterogeneous, advantages of balanced salt
solutions might include lower need of blood products, lower
incidence of renal replacement therapy and postoperative in-
fections. A 2012 Cochrane review, using pooled data, found no
influence of the choice of buffered or non-buffered infusion
fluids in the perioperative period on mortality, renal function
Intravenous fluids: a critical appraisal
and blood loss [104]. In the non-buffered group, however, the
average volume of platelet concentrates transfused was 242%
greater (95% CI, 24.61–848.77; P = 0.02) [104]. Unfortunately,
the trials included in this review were highly heterogeneous
with regard to study groups, outcomes reported and adminis-
tered infusion fluids, which included hypertonic and colloid
solutions. In a recent large observational study, outcomes of
30 994 adult patients undergoing major abdominal surgery
who received normal saline were compared with 926 patients
who received only a non-calcium-containing balanced crystal-
loid solution (Plasma-Lyte) [105]. Unadjusted in-hospital
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mortality was far greater in the saline group than in the ba-
lanced crystalloid group (5.6 versus 2.9%). After propensity
matching, mortality in the saline group remained higher, but
the difference lost its statistical significance. However, treat-
ment with balanced crystalloids was associated with fewer
complications (OR, 0.79, 95% CI, 0.66–0.97; P < 0.05). Recipi-
ents of normal saline infusions were 4.8 times more likely to
require haemodialysis (P < 0.001), and had greater blood
transfusion requirements and more frequent postoperative in-
fections [105]. Another double-blind randomized trial in 66
patients undergoing abdominal aortic reconstructive surgery
found no statistically significant difference in blood loss, but
an increased need for fresh frozen plasma and platelet transfu-
sions in the group that received normal saline compared with
the lactated Ringer’s group [106].
FULL REVIEW
Kidney transplantation
Balanced salt solutions appear to reduce the incidence of
metabolic acidosis and hyperkalaemia after kidney transplant-
ation, but no differences in transplant outcome have been re-
ported. In one Turkish double-blind trial, 90 recipients of
kidney transplants of living related donors were randomized
to receive either normal saline, lactated Ringer’s or Plasma-
Lyte. Patients receiving normal saline had a significant de-
crease in pH and increase in serum Cl−, which was not seen in
patients receiving lactated Ringer’s or Plasma-Lyte. No signifi-
cant differences in renal function were seen, although the 24-h
urine output in the first three postoperative days was signifi-
cantly larger in the group receiving normal saline, which is in
contrast with the expected effect of the increased chloride load
in the normal saline group [107]. In an Iranian double-blind
randomized trial, 52 adults undergoing kidney transplantation
were either prescribed normal saline or lactated Ringer’s.
Mean serum potassium values were lower in the group receiv-
ing lactated Ringer’s, despite the presence of potassium in this
infusion fluid. No statistically significant differences in urine
output or renal function were seen [108]. In a Korean study in
60 kidney transplant recipients, the use of Plasma-Lyte was as-
sociated with lower plasma Cl− concentrations and lower inci-
dence of metabolic acidosis, and no differences in
postoperative creatinine values or urine output [109]. Finally,
another double-blinded randomized trial in 51 renal trans-
plant recipients was suspended prematurely after a planned
interim analysis showed a greater incidence of hyperkalaemia
and metabolic acidosis in patients administered normal saline
compared with the group receiving lactated Ringer’s. No dif-
ference in the primary outcome, the serum creatinine
183
 concentration on the third postoperative day, was seen [110].
Eight patients (31%) in the group receiving normal saline were
prescribed NaHCO3 in an attempt to correct acidosis. Interest-
ingly, those patients treated for acidosis had significantly
higher 4- and 48-h postoperative urine output, and significant-
ly lower 24-h and 1-week postoperative creatinine values com-
pared with the patients who received normal saline but no
correction for acidosis [110].
Published evidence on the optimal fluid choice in precondi-
tioning kidney donors revolves around a very limited number
of trials, in which comparisons usually involve a colloid. These
studies have been reviewed elsewhere [111, 112]. There is no
clinical evidence to guide the choice of a particular crystalloid
in healthy donors in the preoperative and perioperative
period.
Critical care medicine
Recently, a large prospective, non-randomized, before-and-
after study in a tertiary ICU was published [113]. Investigators
allowed intravenous fluid administration as usual in patients
admitted to the ICU during a 6-month control period. During
the 6-month intervention period, which was timed to start at
the same season a year later, the use of chloride-rich fluids was
restricted to specific conditions. Instead, patients received
Hartmann’s, Plasma-Lyte or, less frequently, human albumin.
Biochemical effects of the policy change included fewer epi-
sodes of severe acidosis, more episodes of metabolic alkalosis,
FULL REVIEW
slightly higher lactate levels and no differences in sodium or
potassium concentrations [113]. Importantly, in a separate
publication the investigators reported a significantly better
kidney function during ICU stay in the chloride-restricted
group as well as significantly less renal injury and failure ac-
cording to the RIFLE criteria (OR, 0.52, 95% CI, 0.37–0.75;
P < 0.001), and subsequently, fewer episodes of renal replace-
ment therapy (OR, 0.52, 95% CI, 0.33–0.81; P = 0.004) [114].
Interestingly, no significant difference in mortality was seen
between the chloride-liberal and chloride-restricted groups
[114]. The latter finding is difficult to reconcile with the 50%
reduction in renal replacement therapy in the chloride-
restricted group.
Miscellaneous
A small number of studies compared the use of balanced
crystalloids with saline in resuscitation in diabetic ketoacidosis
and choleriform diarrhoea, and found faster resolution of
acidosis with the use of balanced crystalloids. One study in
diabetics presenting with ketoacidosis randomly allocated 45
patients to groups resuscitated either with Plasma-Lyte or
normal saline, and found that postresuscitation serum chlor-
ide was significantly higher (111 [110–112] versus 105 [103–
108]) and bicarbonate significantly lower (17 [15–18] versus
20 [18–21]) in the normal saline group compared with the
Plasma-Lyte group, respectively [115]. A retrospective analysis
of 23 patients treated for diabetic ketoacidosis with either
normal saline or Plasma-Lyte by another group yielded com-
parable results [116]. Finally, in a Peruvian study, 40 severely
dehydrated patients presenting with choleriform diarrhea re-
ceived infusions of either lactated Ringer’s or normal saline,
184
and faster resolution of acidosis was attained in the group re-
ceiving lactated Ringer’s [117].
CONCLUSIONS
We have reviewed the available experimental and clinical data
on colloid and crystalloid infusates. In view of an overall
lack of survival benefit with albumin, recent evidence on
adverse safety outcomes associated with semisynthetic col-
loids, as well as the effects of the retraction of a large body of
Downloaded from https://academic.oup.com/ndt/article-abstract/30/2/178/2337064 by Shearman and Sterling user on 29 July 2020
work by Dr Joachim Boldt due to integrity concerns, the use
of colloid infusates is to be limited. Therefore, we have focused
on balanced salt solutions and normal saline.
Infusion of normal saline is clearly associated with hyper-
chloraemia and metabolic acidosis [93, 94], and such derange-
ments can be prevented by using balanced crystalloids [93,
94]. Studies in surgical and ICU patients reported a signifi-
cantly lower incidence of renal replacement therapy in groups
receiving balanced crystalloids compared with those receiving
normal saline [105, 114]. Interestingly, one study involving
kidney transplant recipients found that correction of acidosis
was associated with significantly lower creatinine levels and in-
creased diuresis [110]. One explanation for this phenomenon
is that by inducing renal vasoconstriction, hyperchloraemia
appears to reduce RBF and GFR [95–97]. Acidosis leads to a
dysfunction of various cellular and extracellular mechanisms,
most notably coagulation [13–17]. This may explain the in-
creased need for blood products in surgical patients receiving
normal saline [104, 105].
A shortcoming in the literature is the absence of a direct
comparison between the various balanced crystalloids and the
relatively small study participant numbers. Furthermore, in
the largest meta-analysis on this subject to date, relatively het-
erogeneous data on various salt solutions were pooled to
compare balanced with unbalanced crystalloids. Even though
the documented negative safety outcomes pertaining to the
use of normal saline seem relatively persistent across studies,
the heterogeneity of studies leaves questions on the size of the
mentioned effects in clinical scenarios, especially mortality,
unanswered.
In conclusion, there is a growing body of evidence that ba-
lanced crystalloids are preferred over normal saline in clinical
practice and that the positive effects of these solutions are not
restricted to one specific application only. In our opinion, ba-
lanced crystalloids therefore deserve consideration as first
choice infusates. Obviously, individual situations might
require different infusion fluids. Knowledge of the physiologic-
al characteristics of the different infusion fluids is important in
guiding this choice. However, the quality of the evidence avail-
able leaves room for a large, well-designed randomized con-
trolled trial.
C O N F L I C T O F I N T E R E S T S TAT E M E N T
All authors confirm they have no conflicts of interest with
regard to this submission.
D. Severs et al.

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doi: 10.1093/ndt/gfu104
Advance Access publication 12 May 2014
Iron dosing in kidney disease: inconsistency of evidence
and clinical practice
Adam E. Gaweda1†, Yelena Z. Ginzburg2,†, Yossi Chait3, Michael J. Germain4, George R. Aronoff1 and
Eliezer Rachmilewitz5
1
University of Louisville, Louisville KY, USA, 2New York Blood Center, New York, NY, USA, 3University of Massachusetts, Amherst, MA, USA,
4
Baystate Medical Center, Tufts University School of Medicine, Boston, MA, USA and 5The Edith Wolfson Medical Center, Holon, Israel
Correspondence and offprint requests to: Adam E. Gaweda; E-mail: adam.gaweda@louisville.edu
†
Dr Ginzburg and Dr Gaweda should be considered as joint lead authors.
A B S T R AC T
The management of anemia in patients with chronic kidney
disease (CKD) is difficult. The availability of erythropoiesis-
stimulating agents (ESAs) has increased treatment options for
© The Author 2014. Published by Oxford University Press
on behalf of ERAEDTA. All rights reserved.
transplantation using the Stewart and base excess methods. Transplant
Proc 2013; 45: 2191–2196
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Received for publication: 14.10.2013; Accepted in revised form: 3.1.2014
FULL REVIEW
previously transfusion-requiring patients, but the recent evi-
dence of ESA side effects has prompted the search for comple-
mentary or alternative approaches. Next to ESA, parenteral
iron supplementation is the second main form of anemia treat-
ment. However, as of now, no systematic approach has been
187