British Journal of Anaesthesia, 119 (S1): i63–i71 (2017)

doi: 10.1093/bja/aex293
Clinical Practice

Are we close to the ideal intravenous fluid?

N. MacDonald1 and R. M. Pearse2,*
1
Department of Perioperative and Pain Medicine, Barts Health NHS Trust, London E1 1BB, UK and 2Barts and
The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
*Corresponding author. E-mail: r.pearse@qmul.ac.uk

Abstract
The approach to i.v. fluid therapy for hypovolaemia may significantly influence outcomes for patients who experience a
systemic inflammatory response after sepsis, trauma, or major surgery. Currently, there is no single i.v. fluid agent that
meets all the criteria for the ideal treatment for hypovolaemia. The physician must choose the best available agent(s) for
each patient, and then decide when and how much to administer. Findings from large randomized trials suggest that some
colloid-based fluids, particularly starch-based colloids, may be harmful in some situations, but it is unclear whether they
should be withdrawn from use completely. Meanwhile, crystalloid fluids, such as saline 0.9% and Ringer’s lactate, are more
frequently used, but debate continues over which preparation is preferable. Perhaps most importantly, it remains unclear
how to select the optimal dose of fluid in different patients and different clinical scenarios. There is good reason to believe
that both inadequate and excessive i.v. fluid administration may lead to poor outcomes, including increased risk of infection
and organ dysfunction, for hypovolaemic patients. In this review, we summarize the current knowledge on this topic and
identify some key pitfalls and some areas of agreed best practice.

Key words: colloids; Crystalloid solutions; fluid therapy

During the past 100 yr, i.v. fluid therapy has become an integral
part of perioperative care, and yet the question of the ‘ideal’
fluid remains elusive. For both the intensive care physician and
the anaesthetist, i.v. fluid resuscitation is considered a core skill,
which we expect to deliver safely and effectively. Despite this,
the evidence base for fluid therapy remains a hotly debated
topic. In this review, we explore the reasons behind these
debates and provide an objective summary of the current
knowledge on this topic. The scope of this review includes man-
ufactured i.v. fluid solutions used for fluid resuscitation. With
the exception of albumin solution, we do not cover the use of
blood products or the use of i.v. fluids for specialized indica-
tions, such as traumatic brain injury.
Historical context
In 1831, William O’Shaughnessy wrote to The Lancet to report
some fascinating and remarkably detailed observations on the
blood drawn from cholera sufferers.1 His account included a
detailed description of reduction in water content, low bicar-
bonate concentrations, and uraemia ‘. . . where suppression of
urine has been a marked symptom’. A few months later,
Thomas Latta achieved some success with the i.v. administra-
tion of a solution of saline and sodium bicarbonate to moribund
cholera victims in Sunderland. In another detailed letter to The
Lancet, he provided a fascinating account of the clinical response
to fluid therapy.2 We can trace the history of fluid therapy as
modern medicine itself has evolved. Hartmann used a modified
Ringer’s solution to rehydrate children suffering from gastroen-
teritis in the 1930s, and by World War II the benefits of i.v. fluid
in the treatment of haemorrhagic shock were widely acknowl-
edged.3 Four million bottles of i.v. fluid solutions were pur-
chased by the US Army during this period.4 The improvement in
outcome associated with the use of fluid therapy during surgery
for combat casualties was subsequently reported during the
Korean War.5 Improvement in patient outcomes remains the

Editorial decision: August 2, 2017; Accepted: August 21, 2017

C The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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 i64 | MacDonald and Pearse

driving factor in fluid therapy research, which continues to need for haemorrhage control may greatly complicate resuscita-
highlight the importance of choosing the optimal type and dose tion for victims of trauma.
of fluid for each individual patient.

Concepts and misconceptions in the

Relevant physiology
It is important to separate fluid therapy into fluid maintenance
and fluid resuscitation (or volume replacement). This is helpful
because there is comparatively little debate about maintenance
fluid therapy. The daily requirements for water and electrolytes
are well described6 and easily delivered either enterally or intra-
venously. It is usually best to view replacement of fluid deficits
after prolonged preoperative fasting as part of the maintenance
fluid strategy, by calculating water and electrolyte needs based
on body mass and the time since last intake. Most controversies
around fluid therapy centre on the replacement of hypovolae-
mia or significant fluid losses (i.e. fluid resuscitation). Each doc-
tor’s approach to fluid resuscitation is heavily influenced by
their beliefs about the pathophysiology of the acute disease
states characterized by significant fluid loss and the pharmaco-
kinetics and pharmacodynamics of the fluid agents used to
replace this loss. The major causes of hypovolaemia are dehy-
dration, haemorrhage, sepsis, and the systemic inflammatory
response to other acute disease, such as trauma or pancreatitis.
The pathophysiology of the main categories of hypovolaemia is
summarized in Table 1. The immediate purpose of fluid resusci-
tation is quickly to replace circulating volume to restore organ
perfusion. However, the heterogeneity of acute illness results in
wide variation in the precise nature and volume of fluid lost,
from whole blood in acute haemorrhage to almost pure water in
some forms of gastroenteritis. Fluid resuscitation is further
complicated by the presence or absence of continued fluid loss
and the associated mechanism. In the event of dehydration,
this may be simple to treat, whereas continued bleeding and the
pathophysiology of hypovolaemia
Fluid compartments and the pharmacokinetics of i.v.
fluid
The intravascular half-life of i.v. fluid is thought to vary depend-
ing on the pharmacokinetic and pharmacodynamic properties
of the fluid. All fluids will redistribute throughout the body
eventually, but longer intravascular half-lives may make effec-
tive fluid resuscitation easier. Dextrose solutions are thought to
remain in the circulation for only a very short period because
the small amount of sugar is rapidly metabolized, leaving free
water to diffuse throughout the fluid compartments. Thus,
although dextrose 5% and similar solutions may be suitable as
part of a calculated maintenance fluid regimen, they are of lim-
ited value in fluid resuscitation, where maintaining the intra-
vascular volume is important. The sodium, chloride, and other
electrolyte content in isotonic fluids is believed to help retain
water in the circulation, resulting in a volume expansion effect
lasting between 20 and 100 min depending on the concentration
and quantity of fluid.7 8 In the case of colloid solutions, expan-
sion effects of 2–5 h have been quoted.7 9 However, it is impor-
tant to understand that much of this teaching is based on
theoretical principles or the effects of fluids on healthy volun-
teers.10 The actions of i.v. fluids may differ widely between
patients and disease states, or the differential effects of solu-
tions may be much less than previously thought. It is essential
to balance theoretical benefits of any given fluid against what
we know about potential harm. Important examples include the
risk of coagulopathy11 12 and nephrotoxicity13 14 associated with
hydroxyethyl starch solutions, and the endocrine effects of total

Table 1 Summary of principal causes of hypovolaemia, current understanding of pathophysiology, and treatment

Cause of Examples Pathophysiology Mechanism of continued fluid Common beliefs about

hypovolaemia loss fluid therapy

Dehydration Vomiting Normal regulation Ongoing fluid loss outstrips Replace with fluid that will
Gastroenteritis mechanisms homeostatic mechanisms rehydrate intra- and
Burns overwhelmed extravascular space.
Electrolyte replacement
is required
Haemorrhage Trauma Breech of vascula- Ongoing bleeding or failure in Replace with blood prod-
Major surgery ture leading to haemorrhage control ucts at 1:1:1 ratio of
obvious or con- packed red cells/fresh
cealed blood loss frozen plasma/platelets
in massive haemorrhage
Sepsis Pneumonia Infection resulting in Abnormal vascular permeabil- Early goal-directed therapy
Body cavity a systemic inflam- ity, leading to fluid loss from is as effective as usual
infection matory response circulation. Pathological vas- care; excessive fluid may
odilation, causing relative be harmful
hypovolaemia
Systemic All of the above Inflammatory Abnormal vascular permeabil- Early goal-directed therapy
inflammatory response to any of ity, leading to fluid loss from is as effective as usual
response the major insults circulation. Pathological vas- care; excessive fluid may
described above odilation, causing relative be harmful
hypovolaemia

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 How do we select the right fluid for the right patient?
body sodium and chloride excess associated with hypertonic
crystalloids, such as saline 0.9%.15
Stress response to injury and surgery
The stress response to surgery and trauma is an evolutionary
response to injury that involves a complex interaction of bio-
chemical and humoral mediators, including vasopressin and
the renin–angiotensin system.16 17 In the initial response, these
combine to ensure the retention of fluid and electrolytes with
reduced urine output. This can be understood by recognizing
the need to recover from injury before being able to search for
water and food. This response varies between individuals and
may be less pronounced with minimally invasive surgical tech-
niques, where the volume of tissue injury is less. Maintenance
fluid and electrolyte requirements will be reduced after major
surgery, and this is one important reason why patients are vul-
nerable to fluid and electrolyte overload in the early postopera-
tive period.16 Monitoring of urine output is an important tool,
but we must recognize that the healthy normal output is
reduced during and after surgery. In patients with healthy kid-
neys, a urine output of 0.5 ml kg1 h1 should not cause concern
in the context of carefully monitored fluid and electrolyte bal-
ance. Fluid prescriptions thoughtfully tailored to individual
patients, and reviewed by experienced doctors on a daily basis,
will reduce harm.
Third space loss and capillary leak
For many years, anaesthetists were taught that large volumes of
fluid leaked into the extracellular space during surgery. This so
called ‘third space’ loss was thought to be a widespread cause of
hypovolaemia.18 However, detailed calculations have shown
that these and other insensible fluid losses, such as evaporation
from exposed viscera, were significantly overestimated.19 The
consequent administration of large volumes of i.v. fluid resulted
in accumulation of fluid in the interstitial space (tissue oedema),
which may have resulted in worse patient outcomes. It now
seems likely that the observed fluid losses were attributable to
increased capillary permeability caused by the systemic inflam-
matory response to surgery. Importantly, this inflammatory
response, and the associated fluid loss from the circulation, are
likely to vary from patient to patient, especially in major body
cavity surgery. For many procedures, the inflammatory
response will be mild and will not result in a significant fluid
deficit. However, these patients will still require replacement of
fluid deficits because of preoperative fasting, ongoing fluid
maintenance, and replacement of any estimated blood loss.
Confusion around the indication for fluid is a common cause of
suboptimal fluid therapy, because the clinician is unclear what
the successful treatment end point should be.
Endothelial glycocalyx
The discovery of the endothelial glycocalyx demonstrated that
fluid movement in the human vascular system is much more
complex than Starling’s original description of fluid dynamics
across blood vessel walls.20 The glycocalyx consists of glycopro-
teins bound to the vascular luminal surface of the endothelium,
providing a semi-permeable membrane between circulating
blood and the cell surface.21 The glycocalyx has several impor-
tant functions, especially in the initiation of tissue inflamma-
tion, but it also plays a key role in the regulation of vascular
permeability. In health, the glycocalyx functions as a barrier to
large molecules, but in illness the glycocalyx can be severely
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| i65
compromised, particularly by active inflammatory states
including sepsis, trauma, and surgery. When damaged, the pas-
sage of fluid and larger molecules is not regulated, and fluid is
lost from the microcirculation.22 23
Theoretical properties of the ideal fluid
The concept of the ‘ideal’ fluid is a popular topic for anaesthesia
teaching and examinations. The acute illness will determine
the nature of the fluid lost, from whole blood to almost pure
water. Thus, the ideal fluid will also vary from patient to patient,
a fact not well understood by doctors who seek a one-size-fits-
all formulation for fluid therapy. The ideal resuscitation fluid
should remain within the intravascular space for several hours.
The chemical composition should be similar to that of extracel-
lular fluid, and any constituents should be readily metabolized
and excreted by the body. The fluid must be safe, sterile, and
not prone to cause allergic reactions, organ toxicity, or other
side-effects. From a practical perspective, we may also want the
fluid to be easy to transport and store, easy to administer, and
modestly priced. The reader will appreciate that no such fluid
yet exists.
The fluids that are used in perioperative care are commonly
classified into crystalloids and colloids. Crystalloids can further
be categorized into hypertonic, hypotonic, and isotonic (or bal-
anced) fluids. Saline 0.9% (also termed normal saline) is the
most commonly used hypertonic solution. Hypotonic solutions,
such as dextrose 5% and saline 0.45%, are mostly appropriate
for maintenance rather than resuscitation. The fluid developed
by Hartmann from Ringer’s solution can be termed isotonic or
‘balanced’, and many commercially available fluids are based
on this formulation. Although these fluids are closest to the
physiological norm, none is identical to plasma. Colloids consist
of large molecules dispersed in a crystalloid solvent. The first
colloid to be used in perioperative care was albumin solution
fractionated from autologous blood. The high oncotic pressure
of colloid molecules is thought to ensure that the fluid remains
in the intravascular space for longer periods, providing more
effective resuscitation with smaller fluid volumes. In blinded
studies, clinicians do indeed prescribe smaller volumes of col-
loid solution when compared with crystalloids.13 24 However, if
the endothelial glycocalyx is disrupted by an acute inflamma-
tory response, the intravascular half-life may not be much
greater than that of crystalloid solutions. There are many differ-
ent colloid solutions, but succinylated gelatins, hydroxyethyl
starches, and human albumin solution account for the great
majority of colloid prescriptions. Table 2 summarizes the more
commonly used fluids and their composition.
Controversies: choosing the correct type of
fluid for resuscitation
Crystalloid solutions
Crystalloids have traditionally been categorized as hypertonic,
isotonic, and hypotonic solutions to contrast their composition
with that of plasma. Most hypertonic solutions in common use
have a slightly higher osmotic load than plasma, with the
exception of hypertonic saline solutions used in neurocritical
care to control elevated intracranial pressure. Hartmann’s and
similar balanced solutions are widely used in anaesthesia and
critical care, although saline 0.9% is also popular in many coun-
tries. The choice of saline 0.9% is debated by many because the
high concentrations of sodium and chloride (154 mmol litre1)
 i66 | MacDonald and Pearse

Table 2 Commonly used fluid solutions. Note that use of different solutions varies widely between countries

Fluid solution Category Chemical constituents Common uses Notes

þ 1
Ringer’s lactate/ Isotonic crystalloid Na 130 mmol litre
Hartmann’s Cl 109 mmol litre1
solution Lactate 28 mmol litre1
Kþ 4 mmol litre1
Ca2þ 2 mmol litre1
Plasmalyte Isotonic crystalloid Naþ 140 mmol litre1
Cl 98 mmol litre1
Acetate 27 mmol litre1
Gluconate 23 mmol litre1
Kþ 5 mmol litre1
Mg2þ 1.5 mmol litre1
Normal saline Hypertonic crystalloid Naþ 154 mmol litre1
Cl 154 mmol litre1
Dextrose 5% Hypotonic crystalloid Dextrose 50 g litre1
Dextrose 5% in Hypertonic crystalloid Naþ 77 mmol litre1
saline 0.45%
Cl 77 mmol litre1
Dextrose 50 g litre1
Hydroxyethyl Starch-based colloid Naþ 154 mmol litre1
starch Cl 154 mmol litre1
Starch 60 g litre1
Gelatin Gelatin-based colloid Naþ 151 mmol litre1
Cl 103 mmol litre1
Kþ 4 mmol litre1
Ca2þ 1 mmol litre1
Mg2þ 1 mmol litre1
Acetate 24 mmol litre1
Gelatin 40 g litre1
Human albumin 5% Derived blood product Albumin 50 g litre1
Naþ 145 mmol litre1
Used as both resuscita- Composition can vary
tion and maintenance slightly between differ-
fluid ent commercial
products.
Lactate is metabolized to
bicarbonate
Used as both resuscita- Aims to mimic ‘normal
tion and maintenance physiology’ as much as
fluid possible
Still commonly used as Concerns about develop-
a resuscitation fluid. ment of metabolic acido-
Being superseded in sis with continued use
some areas by more
‘physiological’
solutions
Part of maintenance Overuse can lead to
regimen. hyponatraemia
Used to rehydrate
whole-body water
loss
Part of maintenance Various strengths of dex-
regimen. trose in various
Used to replace carbo- strengths of saline are
hydrates and available
electrolytes
Resuscitation fluid No longer licensed for use
in critically ill patients in
many countries
Resuscitation fluid Composition varies
between products. Move
towards carrier fluid
being more physiologi-
cal. Anaphylaxis rate
appears to be less than
thought
Resuscitation fluid in Varying compositions
specific available
circumstances

lead to salt overload and hyperchloraemic acidosis.15 25 This
may also occur less frequently with any solution containing
supraphysiological doses of electrolytes, including several pop-
ular colloid solutions. However, at present there is only circum-
stantial evidence that this phenomenon leads to permanent
harm.26
Colloids
Many different i.v. colloid solutions, with a diverse range of
properties, have been developed for clinical practice. However,
most of these have fallen from use. Human albumin solution,
hydroxyethyl starch, and succinylated gelatins are the only
types of colloid solutions still in widespread use, and their clini-
cal value is hotly debated. The CHEST and 6S trials have pro-
vided very high-quality data on the effects of hydroxyethyl
starch in critically ill patients.13 14 Both trials included two
active treatment arms comparing starch solutions with crystal-
loids, it being unethical to withhold fluid resuscitation as a ‘con-
trol’ therapy. Taken together, the findings of these trials suggest
that starch solutions are associated with an excess rate of acute
kidney injury requiring renal replacement therapy, which may
lead to a higher mortality rate.27 In the USA, hydroxyethyl
starch solutions are no longer licensed for use in critically ill
patients and those with renal dysfunction, whereas they have
been completely withdrawn in the UK. However, the European
Medicines Agency has permitted ongoing use of these agents to
treat haemorrhage in surgical patients and victims of major
trauma. A systematic review did not identify any excess mortal-
ity associated with hydroxyethyl starch solutions in surgical
patients, but did not suggest benefit either.28 Multicentre trials
are planned to confirm the safety of these solutions to treat

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haemorrhage in surgical and trauma patients, but many clini-
cians are sceptical of this strategy. Succinylated gelatins are not
available in all countries because of data suggesting a high inci-
dence of anaphylaxis.29 However, in one recent major trial of
goal-directed haemodynamic therapy there were no reported
instances of anaphylaxis despite widespread use of these solu-
tions within the trial.30 We are not aware of any recent major
studies specifically evaluating gelatin solutions,31 but given the
general concern about harm from colloid solutions, there may
be limited equipoise for the pragmatic trials needed to confirm
safety and effectiveness.
Albumin
The use of albumin is better supported by published clinical trial
evidence. The SAFE trial confirmed that albumin 4% was equiv-
alent to normal saline in terms of safety and clinical outcomes
amongst critically ill patients, and the ALBIOS trial demon-
strated no difference in survival rates amongst patients suffer-
ing from severe sepsis and septic shock.32 The updated
Cochrane systematic review of trials of albumin solution still
includes a very heterogeneous selection of trials, many of which
are small and methodologically poor.33 This review includes tri-
als from the 1970s with potentially significant bias, and conse-
quently, we would not recommend basing clinical practice on
its findings.
Controversies: choosing the correct dose in
fluid resuscitation
Routine or usual care
Although we may debate at length the choice of resuscitation
fluid, the differences in outcomes achieved with the commonly
used agents are often modest. In large trials, relative risk reduc-
tions of between 10 and 20% are considered important, as are
absolute risk reductions as small as 1%. Indeed, the purpose of
large, simple trials is to detect these small but important differ-
ences in outcomes between alternative treatments. At a global
level, the cumulative patient benefit of implementing such evi-
dence is reflected in a gradual and sustained decrease in control
group mortality in major trials. However, such evidence must be
seen in the context of the huge variations in volumes of fluid
administered. Clinical trials frequently demonstrate wide varia-
tions in the volume of fluid resuscitation between patients, and
there is evidence of differences at an institutional level that is
hard to explain on the basis of casemix alone. These differences
are the likely dominant factor in the profile of side-effects expe-
rienced by individual patients. Not all side-effects of resuscita-
tion fluids are dose related, but most are. If the difference in
routine practice of two doctors results in one giving 50% more
fluid than the other, the patients in their care are likely to expe-
rience important differences in harm that outweigh any differ-
ences in the types of fluids used. Nonetheless, even differences
in outcomes between clinicians will be hard to identify in daily
practice because they in turn are much smaller than the varia-
tion between patients. The absence of clear guidance on fluid
dose in drug formularies is notable. Our community must
accept that the variations in the routine practice of fluid therapy
cannot all be appropriate, and some will be associated with
harm.
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How do we select the right fluid for the right patient? | i67
Chronic disease
As the population ages, the incidence of co-morbidity in the
population is increasing.34 This manifests in a patient popula-
tion with not only more advanced cardiac and kidney disease
but also an increase in baseline cognitive dysfunction and frailty
scores. Currently, there is not a clear consensus on the best fluid
therapy for the patient with multiple co-morbidities who is at
risk of more than one organ dysfunction. For these patients, it is
important that a patient-specific fluid strategy is decided,
agreed upon, and followed by all members of the team responsi-
ble for the patient’s perioperative care.
Restrictive vs liberal fluid management formulae
The stress response to surgery, trauma, or critical illness will
result in salt and water retention.16 Such patients should there-
fore receive lower doses of maintenance fluid during the period
of this response. Anecdotal evidence suggests that most
patients receive more fluid than they need. A ‘restrictive’
approach to fluid therapy is therefore an attractive concept.
There is an extensive literature comparing restrictive and liberal
fluid regimens during and after surgery, but with inconsistent
findings.35 Much of this apparent contradiction can be explained
by differences in the fluid algorithms used. Regimens described
as restrictive in one trial will meet the definition of liberal in
another. Most algorithms were developed from expert opinion
and not experimental observation, but the opinions of experts
may be prejudicial and often vary widely. The major limitation
of current restrictive fluid algorithms is that they combine fluid
maintenance and resuscitation into a single algorithm based on
body mass. The prescription of maintenance fluid is very simple
and should indeed be determined by body mass (Table 3).
However, the optimal dose of resuscitation fluid will have a
weak relationship with body mass and should primarily be
determined by physiology. Nonetheless, the concept of a restric-
tive approach to fluid therapy is valuable, and UK guidelines on
postoperative fluid maintenance therapy promote this
approach.6
Cardiac output-guided fluid or ‘goal-directed therapy’
algorithms
One possible solution to the challenge of finding the optimal
dose of resuscitation fluid is the use of cardiac output monitor-
ing to guide the administration of i.v. fluid and inotropic drugs
as part of a haemodynamic therapy algorithm.36 Many terms
have been used to describe this technique, including goal-
directed therapy, fluid optimization, and flow-directed therapy.
This therapeutic approach has been shown to modify inflam-
matory pathways and to improve tissue perfusion and oxygena-
tion.37 38 Importantly, modern cardiac output-guided fluid
algorithms do not apply an absolute haemodynamic end point
that must be attained regardless of the circumstances. Instead,
they use haemodynamic monitoring to inform whether a fluid
bolus has achieved a physiological response. This information
can then be used to predict more accurately whether further
fluid resuscitation will be beneficial. The use of algorithms
guided by cardiac output monitoring has been recommended in
a report commissioned by the Centers for Medicare and
Medicaid Services in the USA39 and by the National Institute for
Health and Care Excellence (NICE) in the UK.40 However, the
majority of the evidence base consists of small trials, and this is
insufficient to resolve controversies regarding potential harm
associated with fluid excess, myocardial injury, and invasive
 i68 | MacDonald and Pearse

Table 3 Fluid therapy guidance, based on the National Institute for Health and Care Excellence guidelines and statement from the
International Fluid Optimization group. *No definitive haemodynamic end point has been identified. Most algorithms state either cardiac
output or stroke volume end points, although dynamic parameters, such as pulse pressure variation, have been used

Type of fluid Maintenance dose Resuscitation dose Reported side-

effects
Intraoperative Postoperative Intraoperative Postoperative

Saline 0.9% 1 ml kg1 h1 1 ml kg1 h1 200–300 ml bolus. 200–300 ml bolus. Hyperchloraemic
metabolic
acidosis
Titrate to haemody- Titrate to haemody- Hypernatraemia
namic end point* namic end point
‘Balanced’ 1ml kg1 h1 1ml kg1 h1 200–300 ml bolus. 200–300 ml bolus. Hypernatraemia
solutions Titrate to haemody- Titrate to haemody-
namic end point namic end point
Hypotonic 1ml kg1 h1 1 ml kg1 h1 Not recommended Not recommended Hyponatraemia
solutions
Gelatin-based Not recommended Not recommended 200–300 ml bolus. 200–300 ml bolus. Anaphylaxis.
colloids Titrate to haemody- Titrate to haemody- Others related to
namic end point namic end point carrier fluid
Starch-based Not recommended Not recommended 200–300 ml bolus. 200–300 ml bolus. Nephrotoxicity.
colloids Titrate to haemody- Titrate to haemody- Coagulopathy.
namic end point namic end point Others related to
carrier fluid

forms of monitoring. More recently, the findings of the largest
trial did not confirm the clinical benefit of this approach, which
may have related to a lack of statistical power; but this trial did
provide important evidence that this treatment approach is
safe.30 41 It seems likely that cardiac output-guided fluid therapy
will offer most benefit to patients with fluid deficits that are
hard to estimate. This might explain the stronger signals of ben-
efit in major gut surgery, whereas the evidence for efficacy in
vascular surgery is much weaker.
Haemodynamic end points
Several haemodynamic end points have been used in attempts
to optimize fluid delivery objectively. Before the pulmonary
artery catheter (PAC), end points such as urine output, periph-
eral perfusion, and capillary refill time had all been suggested.
In addition to the variation in clinician interpretation, the vary-
ing physiological responses to insults such as surgery, trauma,
and sepsis make these variables unreliable to guide fluid ther-
apy, although they can be used as a fall back in the absence of
more objective parameters. Central venous pressure (CVP),
when available, was commonly used to guide fluid therapy in
hospital, but research has demonstrated that neither CVP nor
changes in CVP accurately predict fluid responsiveness.42
Central venous pressure is no longer first line in fluid therapy
guidelines, although it can be used in the absence of other
parameters. The introduction of the PAC allowed accurate
measurement of cardiac output and stroke volume, amongst
other indices, and this monitor was initially used to guide fluid
therapy in major surgical procedures and intensive care unit
patients. The suggestion that the PAC itself was associated with
harm43 led to a decline in its use, and although two subsequent
papers44 45 suggested no difference in outcomes associated with
use of the PAC, this technology has been largely superseded by
less invasive monitoring that derives haemodynamic indices
including cardiac output and stroke volume.
Most fluid therapy algorithms now use stroke volume rather
than cardiac output as an end point for fluid therapy. More
recently, dynamic parameters, such as pulse pressure variation
(PPV) and stoke volume variation (SVV), have been used as indi-
cators of the fluid responsiveness of the patient.
Dynamic predictors of fluid responsiveness
There has been a great deal of interest in so-called ‘dynamic
indices of fluid responsiveness’, such as PPV and SVV.46 These
indices reflect the variation in cardiac output during the respira-
tory cycle and provide an attractive concept of a simple number
that tells us whether the patient is or is not fluid responsive.
However, these indices should be interpreted with caution.
Spontaneous ventilation, irregular cardiac rhythm or frequent
extrasystoles, pneumoperitoneum, and low-tidal-volume venti-
lation may all affect the predictive accuracy of PPV and SVV.47
The principal value of these indices may be as a guide for when
not to give fluid. A patient is highly unlikely to be hypovolaemic
when the value of either parameter is <5%, even in the presence
of spontaneous ventilation or irregular rhythm.
Closed-loop fluid administration
An interesting emerging technology in this field is the ‘closed-
loop’ automated fluid management system, which uses com-
puter software to interpret haemodynamic physiology on a sec-
ond-by-second basis to determine the optimal rate of fluid
administration.48 Such technologies have passed the proof-of-
concept stage and are now being tested in clinical trials.
Patients may receive comparable amounts of fluid when driven
by a closed-loop system, whilst spending more time in the opti-
mal haemodynamic target zone.49 This is an exciting develop-
ment, but we must avoid the errors of previous research on i.v.
fluid therapy and ensure that the safety and efficacy of

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 How do we select the right fluid for the right patient? | i69

Table 4 Some key principles that can help to ensure safe i.v. fluid prescribing

Take-home message Explanation

Question yourself No-one has all the answers. Safe prescribing involves recognition that our clinical decision could be
wrong, so we are better able to change the strategy if required
Context Context is key. Patients generally need additional fluid during and early after major surgery. In the days
that follow, they generally need less than the standard maintenance dose. A similar principle applies
to critically ill patients
Do they need it? Why are you giving the fluid? Consider each indication separately, even if you administer the fluid at the
same time. This applies especially to maintenance and resuscitation fluids. Vasoactive drugs may be a
better treatment for vasodilation associated with anaesthesia
Dose The dose of fluid you give is likely to be more important than the type of fluid you give. Aim to prescribe
the lowest effective dose of fluid. When we give a drug that is not indicated, we can only do harm
Observation If a patient genuinely needs fluid, they also need continued observation. Many errors in fluid prescribing
relate to a failure to adapt fluid therapies to the needs of the patient

closed-loop systems are robustly evaluated before proceeding to
larger clinical effectiveness trials.
Has clinical research defined safe and effective
fluid therapy?
Challenges of fluid research
Some commentators debate the value of large multicentre trials,
which frequently fail to confirm the clinical effectiveness of
study treatments. This may be because of the numerous chal-
lenges of designing and completing a trial to provide high-qual-
ity data. Clinical trials of fluid therapy are very heterogeneous
because they are designed to answer different questions in dif-
ferent patient populations. Trials use a variety of clinical out-
come measures, from safety end points and explanatory
mechanisms through to patient-centred outcomes, such as
morbidity and mortality. It is often difficult to identify a simple
well-defined population who may benefit from the fluid treat-
ment in an easily measurable way. The indications for fluid,
and its dose, are almost always subjective, making the trial
intervention hard to standardize and adding further variability.
This is a particular problem when so many randomized trials of
i.v. fluid therapy have been conducted in only one hospital,
where clinical practice may not fully reflect wider international
standards. These differences can make comparison of studies
difficult. In many instances, however, randomized trials have
failed because the researchers failed to pose a relevant question
or design a trial appropriately to answer it, or both. Our under-
standing of the purpose of large trials may also be poor. The
purpose of clinical effectiveness (or pragmatic) trials is to bal-
ance the benefits of a treatment that has shown promise in
smaller efficacy (or explanatory) trials with the practicalities of
widespread use in the clinical environment. It is therefore very
important that we do not progress to large clinical effectiveness
trials until efficacy trials have established a sound biological
basis for our treatment strategy in a given patient population.
Clinical effectiveness trials must focus on a small number of
clinical outcomes that may realistically be modified by the
study treatment and are of direct relevance to patients. Clinical
effectiveness trials are not designed to extend knowledge into
new areas but to enhance the acuity of clinical evidence on an
existing question. Well-conceived and well-designed clinical
effectiveness trials improve patient care regardless of findings;
they prove the value of some treatments, demonstrate the mar-
ginal benefit and hence lack of utility of others, and confirm the
importance of harms that were previously thought insignificant.
The findings of successful multicentre trials may deliver more
value than excitement.
Poor interpretation of good research
Clinicians commonly dispute outcome data from studies, not
because of limitations in trial design, but because the findings
do not fit their own pre-existing understanding and knowledge
base. In anaesthesia and intensive care, we are taught about
fluid therapy from the very start of our careers. Not unreason-
ably, we have each come to firmly believe in our own under-
standing of the topic. However, these physiological teachings
can be outdated and incorrect, and frequently, differ widely
between doctors. Sometimes, the findings of high-quality
research may strongly challenge our beliefs.50 We place empha-
sis on certain harms but ignore others. We must learn to accept
the unexpected or even unwelcome findings of large trials that
have been well designed and conducted. Instead of dismissing
results we cannot explain, we must seek to identify and under-
stand the alternative mechanisms by which fluid can benefit or
harm patients. We must also be prepared to accept that some
benefits or harms are simply not as important as we previously
thought.
Making sense of i.v. fluid prescribing
Sadly, there is no single ideal i.v. fluid preparation, either overall
or for specific situations. It seems easy to demonstrate the flaws
in any given approach to fluid prescribing, but increasingly diffi-
cult to define best clinical practice. What hope then, for rational
harmonized clinical practice? The key to safe fluid prescribing
may have much more to do with general principles than with the
finer detail. Despite the uncertainty of many of our conclusions,
there remain some simple dos and don’ts that can promote safe
and effective patient care. These are summarized in Table 4.
Conclusions
The evidence base for fluid therapy will continue to be debated
for some years to come, and the ‘ideal’ fluid remains elusive.
We do not appear to be close to the ideal i.v. fluid, and given the

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 i70 | MacDonald and Pearse
complexity and heterogeneous disease states that require fluid
therapy, it appears unlikely that the ideal fluid for all situations
exists. Nonetheless, we know that our approach to i.v. fluid
therapy for hypovolaemia may significantly influence outcomes
for our patients. Best practice will involve the use of a variety of
different fluids, carefully chosen for each specific indication. We
continue to use large, simple trials to explore the relative merits
of different fluids, and different methods of choosing the dose
of fluids. Meanwhile, we must remember that both inadequate
and excessive i.v. fluid administration may lead to poor out-
comes for hypovolaemic patients. There are some simple princi-
ples for safe prescribing that allow us to be confident we are
providing the best possible care for our patients.
Authors’ contributions
Concept of the article: R.M.P.
Design, initial drafting, and final version of the article: N.M.,
R.M.P.
Declaration of interests
R.M.P. holds research grants and has given lectures, performed
consultancy work, or both, for Nestle Health Sciences, BBraun,
Medtronic, Glaxo Smithkline, and Edwards Lifesciences, and is a
member of the Associate editorial board of the British Journal of
Anaesthesia. N.M. has no conflicts of interest.
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