British Journal of Anaesthesia, 120 (2): 397e402 (2018)

doi: 10.1016/j.bja.2017.11.090
Advance Access Publication Date: 8 January 2018
Review Article

Intravenous fluids: effects on renal outcomes

D. J. McLean1 and A. D. Shaw2,*
1
Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center,
Rochester, NY, USA and 2Department of Anesthesiology, Vanderbilt University, Nashville, TN, USA

*Corresponding author. E-mail: Andrew.shaw@Vanderbilt.edu.

Abstract
Intravenous fluid therapy is the most commonly prescribed inpatient medication in hospitals around the world. Intra-
venous fluids are drugs and have an indication, a dose, and expected and unintended effects. The type and amount of
fluid given to patients are both important, and can either hasten or slow recovery depending on how they are admin-
istered. This narrative review provides a brief summary of the effect of intravenous fluid administration on kidney
function and on renal outcome measures of relevance to both patients and clinicians. Several large clinical trials of fluid
therapy are currently underway, the results of which are likely to change clinical practice.

Keywords: colloids; critical care; crystalloids; goal-directed fluid therapy; peri-operative; renal insufficiency; resuscitation

Since the initial description by Lewins,1 intravenous (i.v.)
fluid resuscitation has become one of the most ubiquitous
interventions in healthcare. Advances in resuscitation fluid
composition have included the use of balanced crystal-
loids, albumin, and synthetic starch-based colloids. Fluid
choice remains a controversial topic, due largely to
inconsistent and opposing results from clinical trials. The
main focus of the clinical trials reviewed in this article is
the association between fluid administration and adverse
renal outcomes.
Renal outcomes can be defined from several perspectives:
that of the physician, patient, and clinical trialist. Physicians
may describe renal outcomes based upon laboratory values
such as serum creatinine and urea. For patients, the more
significant outcomes are those that relate to morbidity and
quality of life, such as persistent renal dysfunction and
requirement for renal replacement therapy. For the clinical
trialist, outcomes need to encompass both the measure of
function and dysfunction at the cellular and organ level, and
patient-level outcomes.
Resuscitation fluid should be treated with the same level of
consideration as any other prescription medication. Choosing
the appropriate dose and type of fluid has significant impli-
cations for patient outcomes.2e6 This narrative review focuses
primarily on renal outcomes, although it is worth noting that
the physiological implications of fluid administration extend
beyond the kidney.7 The authors discuss their current un-
derstanding of how fluid therapies impact renal function
through dose and type of fluids administered, summarize
recent trial data, and offer advice to physicians in order to
guide practice.
Physiology
The kidney is a dynamic organ that plays a fundamental role
in regulating plasma osmolality and water excretion in
response to wide changes in fluid intake. During water re-
striction, the kidney produces more concentrated urine in an
effort to conserve water. The kidney creates and maintains an
osmotic gradient that becomes increasingly concentrated
from the cortex to the medulla. By arranging the loops of Henle

Editorial decision: November 17, 2017; Accepted: November 17, 2017

© 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

397
 398 - D.J. McLean, A.D. Shaw
and collecting ducts in a counter-current fashion with the
renal osmotic gradient, the gradient is maintained and allows
for reabsorption of the majority of water that passes through
the kidney.8,9
Urea is the primary waste product excreted by the kidney,
but also plays a role in urine concentration, particularly in the
inner medulla.8 The inner medullary nephrons are differen-
tially permeable to urea and water in the descending and
ascending limbs of the loop of Henle. This helps create an
osmotic gradient that aids in water reabsorption from the
collecting ducts and into the vasa recta.8,10,11
I.V. fluid administration is necessary to replace fluid deficits,
maintain ongoing fluid requirements, and to administer medi-
cations. In the setting of critical illness, the classical model of the
vascular compartment is less applicable because of increased
permeability and disruption of the endothelial glycocalyx.3 The
physiologic stress of surgery can transiently mimic the physi-
ology of critical illness, albeit in a less severe form.
Factors associated with i.v. fluid
administration and adverse renal outcomes
Dose
Traditional methods of i.v. fluid dosing relied upon pre-set
formulae accounting for fluid deficits and ongoing re-
quirements that have been shown to perform poorly.12,13
Specific goal-directed therapeutic targets, such as central
venous pressure thresholds and urine output, have not been
shown to correlate well with intravascular volume, and have
been suggested to worsen outcome.14 Alternative measures,
such as pulse pressure variation, stroke volume variation, or
other dynamic measures of fluid responsiveness, offer
improved prediction of fluid requirements.15e17
Kidney function, as with most organ systems, relies upon
appropriate intravascular volume in order to maintain
adequate organ perfusion. Prior understanding suggested that
intravascular volume expansion was universally protective of
renal function, however in a large, multicentre outcomes study,
Shin and colleagues2 showed that both volume excess and
insufficiency are deleterious. Liberal i.v. fluid administration
can negatively impact renal function by creating alveolar-
capillary edema, impairing gas exchange, and contributing to
acid-base disturbances. Moderately restrictive fluid adminis-
tration strategies have been shown to be associated with
improved renal outcomes,2 although the definitions of restric-
tive, moderate, and liberal approaches vary widely.
‘Restrictive’ intraoperative fluid strategies can vary from
<900 ml up to 2740 m, and ‘liberal’ strategies vary from 2700 to
5388 ml.2,18 The variability in definitions of liberal and
restrictive fluid doses is likely a result of the variability in
clinical context. A liberal strategy for a thoracic surgical pa-
tient is likely to be different from that of a patient undergoing
extensive colonic resection. Therefore, it is necessary for the
clinician to determine an individual patient’s fluid require-
ment taking into account comorbidity, current fluid status,
ongoing losses, surgical duration, and the effects of fluid on
the surgical site.
Type of i.v. fluid
I.V. fluids include both colloids and crystalloids, although
further nuances exist within these categories.7 Colloids
include synthetic hydroxyethyl starches (HES), gelatin-based
colloids, and albumin. For crystalloids, the most important
distinction is between balanced and unbalanced chloride-rich
fluids.
Colloids are defined by their molecular weight, level of
molecular substitution, and by the crystalloid solution in
which they are formulated. Colloids were initially met
favourably based on the notion that they would remain in the
vascular compartment longer than crystalloids, and therefore
contribute less to overall fluid burden. This concept is now
outdated and colloids have partially fallen out of favour as a
resuscitation fluid because of a growing body of data that
suggest that their use is associated with an increased inci-
dence of acute kidney injury and decreased survival.4e6
However, the majority of these data are from critically-ill pa-
tients, and there are insufficient studies to show that this can
be extrapolated to the surgical population.
Balanced vs unbalanced crystalloids
Crystalloids are ionic solutions composed of a variety of spe-
cific ions designed to mimic physiological extracellular fluid.
‘Normal’ saline (0.9% NaCl) contains 154 mEq of both sodium
and chloride, which results in a strong ion difference of zero
and a concentration of chloride that is 50% higher than in
plasma. When given in sufficient quantities, this results in a
hyperchloraemic metabolic acidosis.19,20 In contrast, balanced
crystalloids substitute a portion of the chloride anion with
other (organic) anions, which are rapidly metabolized and lead
to bicarbonate generation. Examples of balanced crystalloids
are Ringer’s solution, which contains lactate, and Plas-
maeLyte, which contains acetate and gluconate. Chloride-rich
fluids have been implicated in increased risk of hyper-
chloraemic metabolic acidosis, longer hospital stays, renal
injury, and mortality.6,21e30 There are several randomized-
controlled trials that show no overall difference in the inci-
dence of acute kidney injury between critically-ill patients
given balanced or unbalanced crystalloids.31 However, in the
recent large randomized, multiple-crossover trial by Semler
and colleagues,31 patients who received higher volumes of 0.9%
saline had a higher incidence of acute kidney injury and were
more likely to receive renal replacement therapy compared
with those who received balanced crystalloids.
Proposed mechanisms of renal injury associated with
hyperchloraemia are reduced renal blood flow because of
afferent arteriolar vasoconstriction, inflammation, and
oedema.22 These effects have been replicated in a study that
compared starch solutions suspended in balanced crystalloids
or saline.32
Crystalloids vs colloids
There is an ongoing debate regarding the choice between
colloids and crystalloids in i.v. fluid therapy. In the 1990s, an
association was identified between hypoalbuminaemia and
mortality in critically ill patients.33 The proposed mechanism
for the protective effects of albumin have been free-radical
scavenging,34 improved water retention in the intravascular
compartment, and water reabsorption from the interstitium.
However, the physiology of stress in surgery and critical illness
results in disruption of the endothelial glycocalyx, which may
render some of these theoretical benefits of colloids less
effective.3
The demonstrated benefit of colloids varies between
studies. A small study of 100 hypoalbuminaemic critically-ill

patients who were randomized to receive albumin or not as
part of their therapy showed a decrease in Sequential Organ
Failure Assessment scores in the group that received albu-
min.35 However, a much larger study by Finfer and col-
leagues36 did not demonstrate a difference in 28-day mortality
or renal outcomes in 6997 critically-ill patients who were
randomized to receive 4% albumin or 0.9% saline.
Two widely reported studies from Australasia and Scandi-
navia suggest an association between synthetic colloid
administration and renal injury. Myburgh and colleagues5
compared 6% HES in 0.9% saline with 0.9% saline in critically
ill patients. They found no difference in 90-day mortality, but
patients who received HES were more likely to require renal
replacement therapy [relative risk, 1.21; 95% confidence in-
terval (CI), 1.00e1.45; P¼0.04]. Perner and colleagues4
compared 6% HES in Ringer’s acetate with Ringer’s acetate.
They found an increase in 90-day mortality (relative risk, 1.17;
95% CI, 1.01e1.36; P¼0.03) and need for renal replacement
therapy (relative risk, 1.35; 95% CI, 1.01e1.80; P¼0.04) in the
HES group. The proposed mechanisms of colloid-induced
renal injury include direct toxicity to the nephron,37 and
hyperoncotic plasma at the glomerulus leading to reduced
glomerular ultrafiltration.38 HES molecules greater than
50 kDa must be enzymatically degraded in the reticuloendo-
thelial system before renal excretion. This process is slow, and
can lead to vacuolization and oedema in the proximal tubules
of the nephron, a process referred to as osmotic nephrosis.
Goal-directed fluid therapies
After the 2001 study by Rivers and colleagues,39 which sug-
gested that early goal-directed fluid resuscitation improved
clinical outcomes in critically-ill patients with sepsis, there
have been several studies that further explored the associa-
tion between early goal-directed therapies (EGDT) and patient
outcomes. Three large, multicentre, randomized, controlled
trials each evaluated the effectiveness of EGDT with regards to
reducing mortality and adverse renal outcomes as identified
by the need for renal-replacement therapy.
The Protocolized Care for Early Septic Shock (ProCESS) trial,
the Australasian Resuscitation in Sepsis Evaluation (ARISE)
trial, and the Protocolised Management in Sepsis (ProMISe)
trials each found no reduction in mortality or need for renal-
replacement therapy with utilization of EGDT.40e42
A recent meta-analysis of the ProCESS, ARISE, and ProMISe
studies performed by the Protocolized Resuscitation in Sepsis
Meta-Analysis (PRISM) Investigators43 showed that EGDT does
not improve outcomes for patients with sepsis when
compared with usual care. It is possible that in the years since
the Rivers study,39 ‘usual care’ has improved, and earlier
identification of sepsis, antibiotic administration, and superior
supportive therapies result in improved patient outcomes,
therefore reducing the potential impact of EGDT.
The previously mentioned EGDT trials all focus on the
critical care population. There is a relative paucity of data for
intraoperative goal-directed therapy (GDT) with a specific
focus on renal outcomes. However, a recent meta-analysis of
2099 patients over 23 studies by Rollins and Lobo44 showed
that while there is no mortality benefit to intraoperative GDT,
there is a reduction in morbidity in patients receiving intra-
operative GDT. Interestingly, no morbidity benefit is demon-
strated with intraoperative GDT in patients who are on an
enhanced-recovery protocol. The goals used to direct therapy
in these studies were transoesophageal Doppler
I.V. fluids - 399
ultrasonography, lithium dilution, and arterial pressure wave
contour analysis. There was no significant difference in total
fluid volume administered between patients receiving GDT or
standard care, although the total amount of fluid decreased in
more recent studies. The GDT group in an early study included
in the meta-analysis received 4405 ml of crystalloid compared
with 4375 ml in the control group, whereas a more recent
study reports 1500 ml crystalloid in the GDT group compared
with 1400 ml in the control group.
Renal outcome measures
Composite outcomes
Renal outcome measures in clinical research are typically indi-
vidual events or composite variables that combine several spe-
cific outcomes into one group variable. There are risks and
benefits to either approach. Whilst using individual outcomes
can reduce the risk of confounding, rare outcomes can be missed
and larger sample sizes are required. Using a composite outcome
measure increases the overall event rate (and thus makes it
easier to find evidence of an effect of an intervention) but is not
without problems, such as that of competing risk. In the com-
posite outcome described later [Major Adverse Kidney Events in
the first 30 days (MAKE30)], patients cannot experience the
sustained worsened renal function component if they die before
Day 30. This conceptecompeting riskemust be minimized if a
composite outcome measure is used for a clinical trial.
In perioperative clinical trials that study renal function, we
advocate use of MAKE30.45 This outcome is defined as the
occurrence of any of the following: in-hospital mortality, new
renal replacement therapy, or sustained worsened renal
function at 30 days after intensive care unit (ICU) admission.
Persistent renal dysfunction can be defined as a 200% increase
in serum creatinine from admission to discharge.46 Such a
large increase in creatinine has the potential to miss cases of
milder renal impairment, however this reduced sensitivity is
accompanied by increased specificity, and there is no doubt of
its clinical relevance. Although a timeframe of 30 days reso-
nates with physicians, assessment at 90 days (MAKE90) pro-
vides a more logical link to the incidence (or progression) of
chronic kidney disease. The overall incidence of MAKE30 in
adult ICU populations is in the 15e20% range depending on the
severity of the acute illness and underlying cause of disease.
The Risk, Injury, Failure, Loss and End-stage kidney disease
(RIFLE),47 Acute Kidney Injury Network (AKIN),48 and Kidney
Disease: Improving Global Outcomes (KDIGO)49 classifications
are all systems that define several strata of acute kidney injury
based on proportional increases in serum creatinine and de-
creases in urine output. Urine output is a potentially prob-
lematic element of these criteria, as it is recorded
inconsistently, particularly in patients who are not in a
critical-care setting, and therefore less likely to have a urinary
catheter. Whilst serum creatinine likely offers a more robust
metric for kidney injury, it is also imperfect as it is affected by
ethnicity, body-mass, age, sex, diet, and medications.
Biomarkers
The traditional biomarker for renal injury is serum creatinine,
and is often assessed in conjunction with urine output. Both of
these measures are insufficiently sensitive, are confounded by
factors such as muscle mass, and usually alert the physician to
kidney injury after significant damage has occurred.
 400 - D.J. McLean, A.D. Shaw

Therefore, there has been a desire to identify biomarkers for Edited subsequent versions, accept responsibility for the
early kidney injury. The three biomarkers with the most data content of the manuscript: both authors.
currently are tissue inhibitor of metalloproteinase 2 (TIMP2)50, Any opinions expressed are the authors’, and not necessarily
insulin-like growth factor-binding protein 7 (IGFBP7),50 and those of their respective institutions.
neutrophil gelatinase-associated lipocalin (NGAL).51 However,
there are several issues relating to these biomarkers.
TIMP2 and IGFBP7 are released during the G1 arrest portion Acknowledgements
of renal tubular cell cycles, which occurs during renal tubular
Both authors acknowledge the support of their Department
stress. NGAL is released after either renal ischaemia or direct
Chairmen, Dr Michael Eaton and Dr Warren Sandberg.
nephrotoxicity, and has been suggested to be most effective in
predicting radiocontrast-induced kidney injury. NGAL can
only predict kidney injury in patients with previously healthy
Declaration of interest
kidneys. Kidney injury is usually a multifactorial process, so
these markers might not have sufficient sensitivity or speci- A.D.S. reports previously working as a consultant for Baxter
ficity when used in isolation. Healthcare, and as an advisory board member for FAST
When planning future clinical trials, it is important to agree BioMedical, Astute, and Edwards Lifesciences. D.J.M. reports
upon standardized and validated clinical endpoints so that no conflicts of interest.
clinically meaningful comparisons can be made between
studies.52 We believe that MAKE3045 is a reasonable start,
particularly in view of its patient-centred nature. Funding
Supported entirely by departmental resources.

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Handling editor: H.C Hemmings Jr