Download New aspects of perioperative fluid therapy

Vol. 2, No. 1 2005
Drug Discovery Today: Therapeutic Strategies
Editors-in-Chief
Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK
Eliot Ohlstein – GlaxoSmithKline, USA
DRUG DISCOVERY
TODAY
THERAPEUTIC
STRATEGIES
Pain and anaesthesia
New aspects of perioperative fluid
therapy
Edward Burdett1,*, Mike James2
1
2
UCL Centre for Anaesthesia, First Floor Crosspiece, Middlesex Hospital, London W1T 3AA, UK
Department of Anaesthesia, University of Cape Town, South Africa
Fluid therapy is perhaps the most important nonsurgical determinant of postoperative outcome. There are
many new and emerging developments in periopera-
Section Editors:
Brigitta Brandner and Lesley Bromley – University College
London Hospital’s Trust, London, UK
tive fluid therapy. This article describes the current
controversies in the area and puts them into context
with existing practice. In particular, we describe new
aspects of monitoring and goal-directed therapy, as
In spite of the general acceptance of the importance of fluid
therapy, the optimal strategy is still debated [2]. In this
review, we shall outline the new developments in perioperative fluid therapy and discuss what the future might bring.
well as updating the colloid–crystalloid debate. We also
and their role in future therapy.
Pharmacological advances in fluid therapy
The ideal fluid
Introduction and background
Later we will show that in considering fluid therapy the ‘how’,
‘when’ and ‘how much’ are as important as the ‘what’, but it is
helpful at this point to list the properties of the ideal fluid:
describe the development of oxygen-containing fluids,
Modern intravenous fluid therapy has its origins in the cholera
epidemics of the mid-19th century, although the physiological
importance of maintenance of circulating volume was not
recognized until five decades later. The beginning of evidence-based medicine was responsible for the incorporation
of fluid therapy into everyday perioperative practice because
survival benefit was proven in the 1960s in animal models of
haemorrhage. Colloid solutions were introduced in the 1920s,
and successful fractionation of blood into its constituent
components led to the use of human albumin solution to treat
hypovolaemic soldiers in the Second World War [1].
Technology to monitor end points of fluid therapy, such as
cardiac output flow and oxygen delivery has been available
since the 1970s. Refinement of these techniques has led to
our ability to provide dynamic monitoring of physiological
variables, and to direct our therapy accordingly.
*Corresponding author: E. Burdett ([email protected])
1740-6773/$ ß 2005 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2005.05.013
Physicochemical properties:
cheap and easy to manufacture;
stable in storage;
nonreactive with equipment;
nonviscous.
Pharmacological properties:
stays in the required body compartment as long as necessary;
maintains and normalizes electrolyte and acid/base homeostasis;
facilitates delivery of oxygen to the tissues;
non-allergenic;
no interactions with other drugs or fluids;
physiologically inert, especially with regard to coagulation,
immunological or renal function;
completely eliminated from the body with no long-term
side-effects.
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Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
Vol. 2, No. 1 2005
It is preferable to use a balanced, low-chloride fluid where
possible. Lactated Ringer’s (Hartmann’s) solution is a more
physiological crystalloid, which has a lower level of chloride
than normal saline, the ionic balance being maintained with
anionic lactate, which is hepatically metabolized to bicarbonate. Perioperative infusion of Lactated Ringer’s solution
leads to less metabolic acidosis than infusion of normal saline
[10], and less perturbation of renal variables and less blood
loss [11]. However, Ringer’s lactate is significantly hypotonic
(osmolarity 274 mOsm/L; osmolality 253 mOsm/L), and this
can also be disadvantageous, particularly where the integrity
of the blood–brain barrier is compromised.
Because of the relatively recent identification of the adverse
effects of normal saline and products formulated with it, most
colloid solutions in everyday clinical use are suspended in it. A
high molecular weight starch suspended in a balanced electrolyte vehicle is available for clinical use in America [12], and
various similar products are undergoing Phase III trials at
present. Their use will no doubt increase as their availability
increases.
Glossary
Abdominal compartment syndrome: fluid build-up in the
abdomen leading to an increase in pressure so that blood cannot flow to
the vital organs.
Coagulopathy: an inability of the blood to clot normally. The term
describes blood, which clots too readily or not readily enough.
Doppler principle: the principle whereby sound pitch increases as the
source moves toward the listener and decreases as it moves away.
Hyperchloraemic metabolic acidosis: a condition whereby the pH
of the plasma is too low, and in addition there is an excess of chloride in
the plasma.
Microanastamotic graft: a graft whose blood supply is maintained by
very small and delicate vessels which are stitched together under
microscopy.
Preoperative hypovolaemia: inadequate circulating volume
preoperatively.
Thrombocytopaenia: a low level of platelets in the blood.
The ‘ideal fluid’ does not exist at present. The various
classes of available fluids vary in their physical and biological
properties, each with their relative advantages and disadvantages. Data are increasing as to whether these translate into
clinical outcome differences, and new formulations are soon
to be available which might improve therapy (Table 1).
Advances in colloids
Intravenous fluids, which incorporate colloid components
into their formulation has several theoretical advantages,
some of which are being demonstrated at a clinical level.
Broadly speaking, colloids fall into four categories.
Advances in crystalloids
Normal saline, the most commonly used intravenous fluid
worldwide, causes HYPERCHLORAEMIC METABOLIC ACIDOSIS (see
glossary) when given in high dose. This phenomenon has
been demonstrated in animal models in healthy volunteer
studies and clinically [3,4], and it has been linked to impairment in renal and coagulation variables in perioperative
patients [5,6] as well as impaired renal function and cognitive
function in volunteers [7]. The mechanism by which this
acidosis occurs is not fully understood but it is related to an
excess of plasma chloride causing an increased base deficit [8].
Balanced fluids which contain more physiological levels of
chloride, along with a bicarbonate-precursor buffer and small
amounts of other electrolytes, such as calcium, magnesium
and potassium do not cause hyperchloraemic metabolic
acidosis [9].
Hydroxyethyl starch (HES)
Hydroxyethyl starches are a group of colloids, which have a
sustained intravascular colloid action. They continue to
provide a volume expanding effect in the circulation longer
and more effectively than any other synthetic fluid [13],
and are the colloid of choice for many practitioners in sepsis
and extensive blood loss surgery. The use of these drugs has
been limited in the past by their adverse effects, in particular their interference with normal coagulation which may
be associated with increased perioperative blood loss [14]
and with their long-term accumulation, which may manifest as itching [15]. As a result, their maximum licensed
dose is limited.
Table 1. Constituents of commonly available fluids
Contents (mmol/L)
Sodium
Chloride
Bicarbonate
Potassium
Magnesium
Calcium
Glucose
Colloid
0.9% saline
154
154
–
–
–
–
–
–
Lactated Ringer’s
(Hartmanns solution)
131
111
29
5
–
4
–
–
Hespan
154
154
–
–
–
–
–
Hetastarch
Hextend
143
124
28
3
0.4
2
1
Hetastarch
Gelofusine
154
120
–
–
–
–
–
Gelatin
Plasma
140
100
26
4
1.2
2
5
Plasma proteins
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There have been advances in the formulations of these
starches recently. Low molecular weight starches with a lower
degree of substitution are associated with less COAGULOPATHY
(see glossary) but a similarly effective volume expansion
compared with the older products with higher molecular
weights and degree of substitution [16]. The latest of these
exerts an in vivo molecular weight close to the ideal size of
70 kDa. In addition, new products are reaching the market,
which incorporate starch molecules suspended in a balanced
electrolyte solution [12].
The ideal colloid solution would probably be a low to
medium molecular weight starch with a low degree of substitution, suspended in a balanced electrolyte solution. At
present, no such solution exists commercially but there are
several interesting products undergoing Phase III trials.
Dextrans
These colloids, because of their inhibition of normal coagulation and their capacity to reduce the viscosity of blood and
red cell aggregation, have only a niche role in intraoperative
fluid therapy, such as in the maintenance of MICROANASTAMOTIC
GRAFTS (see glossary) in plastics and maxillofacial surgery. The
availability of dextran I hapten inhibition treatment has
reduced the risk of anaphylaxis that was previously associated
with these colloids [17].
Gelatins
There have been few recent developments with gelatins.
There are some data, however, to show that gelatins provide
little effective advantage in terms of plasma volume expansion over crystalloid therapy. These data, coupled with the
increased rate of anaphylactic reactions to the gelatins compared to other colloids, and the theoretical risk of contracting
bovine spongiform encephalopathy from cattle bone products [18] has led to decreased use in some centres.
Albumin
Because its safety was called into question by a systematic
review [19], there has been a large body of literature recently
regarding the effectiveness of human albumin solution. As a
result of this and a more recent trial showing no outcome
advantage over normal saline [20], the use of this relatively
expensive product is not popular.
Colloids versus crystalloids
The debate over which type of fluid is better is ongoing. Most
modern practitioners use a mixture of crystalloids and colloids perioperatively to maintain intravascular volume, the
proportion of each depending on the clinical situation and
the individual.
The theoretical benefit of colloid therapy over crystalloid is
related to the avoidance of the tissue oedema associated with
large volume crystalloid resuscitation, but until recently this
Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
was not borne out by convincing clinical data. There is now
animal evidence that fluid overload with crystalloids leads to
a decrease in tissue oxygenation, and human data that crystalloid excess leads to deterioration of pulmonary function,
ABDOMINAL COMPARTMENT SYNDROME (see glossary) and poor gut
function. Clinically, the use of colloid intraoperatively
improves some postoperative variables. Morretti et al. [21]
in a prospective randomized controlled trial of 90 patients
showed significantly less incidence of nausea and vomiting,
use of rescue antiemetics and severe pain, when comparing
hydroxyethyl starch with lactated Ringer’s solution intraoperatively. Lang et al. showed better tissue oxygenation in
patients receiving a colloid as opposed to a crystalloid during
major abdominal surgery [22].
There are now some data to suggest that large volume
haemodilution with crystalloid causes a hypercoagulable
state [23,24]. Whether this translates into an increase in
thrombotic events clinically is not yet known, although
one early study has suggested a link [25].
Three meta-analyses comparing overall outcome between
crystalloid and colloid therapy have not favoured either arm
[26,27], and we are still awaiting a large rigorously conducted
randomized controlled trial.
New aspects of data collection and study design
Few anaesthetists follow protocols or evidence-based practice
because there have been no consistent data showing an outcome advantage, either one way or the other.
Traditionally ‘hard’ end points, especially mortality, are now
so rare with elective major surgery that there are considerable
logistical difficulties in designing studies with enough power.
Conversely, studies investigating outcome in emergency and
intensive care work face multiple confounding variables. Over
the last decade, however, several more subtle and detailed
postoperative morbidity scales have been designed, which take
into account the quality of the patient experience, as well as
other ‘harder’ end points [28]. Thus, data are emerging quantifying postoperative pain, mobility, nausea and tissue oedema
after major surgery, which can be used as tools to identify
differences in outcome after different fluid therapies.
Healthcare costs have inexorably risen over the past halfcentury, and there is no reason to suppose that this trend will
reverse. As patient expectation rises, so will the lengths that
the hospital practitioner will go to ensure that outcomes are
favourable.
The incorporation of clinical audit into the culture of
hospital medicine and advances in information technology
has allowed more comprehensive data on fluid therapy practices to be available on an intra-departmental level. Protocoldriven fluid therapy has advantages with regards to manpower and audit, and over the next decade this will expand as
the correlation between hospital practice and outcome
increasingly guides our treatment.
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Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
How, when, and how much
Much effort has been invested in optimizing the administration strategy of fluids. Below, we outline some recent developments.
Pre-optimization
Fluid therapy is ultimately aimed at ensuring adequate oxygen supply to meet the demand in the tissues that need it most.
An acceptable outcome following elective surgery requires
optimization of the patient preoperatively. Frustratingly, this
is often not the case as PREOPERATIVE HYPOVOLAEMIA (see glossary)
is an inevitable result of prolonged fasting or decontamination
of the bowel. Some interesting data are now emerging, revealing the advantage that the high-risk patient can have if invasively monitored and optimized in a high-dependency setting
overnight before the operation. Identification of patients at
risk and appropriate stratification of resources deliver a more
appropriate level of care and a rationalization of cost [29].
Aggressive treatment of these high-risk groups preoperatively
with fluids, with or without inotropes to achieve predefined
targets, such as serum lactate, oxygen extraction ratio and
urine output can improve outcome [30].
Physiological monitoring and goal-directed therapy
The medical practitioner traditionally directs therapy to meet
physiological targets and perioperative fluid therapy is no
exception. In the past, these targets were clinical signs but
over the last quarter of a century, technological advances
have made monitoring response to therapy more accurate;
monitoring of clinical signs is less sensitive than invasive
monitoring of other variables.
The balance between risk and benefit has been difficult to
maintain – there are significant morbidities associated with
invasive monitoring [31]. Other less invasive forms of monitoring now exist which have enabled the perioperative practitioner to direct therapy toward specific goals. At the same
time, the importance of dynamic monitoring of response to
therapeutic interventions has been acknowledged.
Flow of blood through the aorta can be measured using
the DOPPLER PRINCIPLE (see glossary) via the oesophagus or
transcutaneously. From this, cardiac output can be derived
and response to treatment measured. This noninvasive
approach is easy to learn, and has morbidity benefits when
used to maintain physiological targets in high-risk surgery
[32,33].
The introduction of a device, which monitors end-organ
perfusion via gastric pH sampling, offers another monitoring
parameter. This appliance, the gastric tonometer, uses perfusion data from the upper GI tract as a surrogate for systemic
blood flow and oxygen delivery [34]. Clinical data suggests
outcome advantages with the perioperative use of these
devices when used in conjunction with fluid therapy plus
or minus inotropes to achieve physiological goals. There have
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been no data as yet, however, to show a mortality advantage
with the use of perfusion-targeted strategies.
Other modalities of monitoring have been evaluated in the
intensive care setting but have yet to crossover successfully
into perioperative care. Analysis of intra-arterial blood pressure waveforms, in particular systolic pressure variation,
pulse pressure variation and stroke volume variation yields
information about response to fluid therapy [35]. This is
accurate and less invasive than traditional measures. Perioperative outcome data for these devices are not yet forthcoming but it is a potentially exciting avenue for the future.
Wet or dry?
It is not justifiable to invasively monitor most patients, and
indeed the vast majority of procedures are performed without
cardiac output monitoring [36], so how do we know how
much to give and when? It is generally accepted that outcomes are improved in minor procedures if fasted patients are
given fluid [37], but the literature is not clear regarding ‘wet or
dry’ strategies when the procedure causes a major physiological upset. Some centres advocate a liberal fluid regime [38],
and some a restrictive one [39]. On reflection, this is not
surprising; patients and procedures vary widely, and it is
preferable to tailor fluid strategies to individual needs rather
than to adopt a blanket strategy. The right amount of fluid to
give is the amount, which makes the patient respond favourably.
Artificial oxygen carriers and blood substitutes
Artificial oxygen carriers aim to reproduce the oxygen carrying capacity of intact red cells without the potential adverse
effects. They can be used in place of allergenic blood transfusion or to augment it. Without the need for crossmatching,
they have a potential perioperatively and elsewhere, for
example in pre-hospital resuscitation and with Jehovah’s
Witness populations [40].
These products are not in widespread clinical use but some
experience with them has now begun to yield results. The two
most promising categories of oxygen carriers are:
modified haemoglobin solutions and
perflurocarbon emulsions.
Initially, the development of these products was hampered
by systemic toxicity and unfavourable oxy-haemoglobin dissociation characteristics, but while not in widespread clinical
use as yet, they have undergone several clinical trials and
their formulations have improved. Their potential is enormous, and their improvement is a priority in the pharmaceutical industry.
Modified haemoglobin solutions improve oxygen transport and tissue oxygenation in animal models and some
encouraging phase III data now exists [41].
Boldt, J. et al. [44]
Department of Anesthesiology and
Intensive Care Medicine, Klinikum der Stadt
Ludwigshafen, Bremserstrasse 79, D-67063
Ludwigshafen, Germany
Avoidance of coagulopathy
New developments in low
molecular weight starches
Outcome advantage
unproven
Balanced low-molecular
weight starches
Gan, T.J. et al. [33]
Duke University Medical Centre,
North Carolina, USA http://www.mc.duke.edu/
Outcome advantages shown
Goal-directed therapy
Resource implications
Trials in progress
Kaplan, L.J. et al. [43]
Clinic of Anesthesiology,
Ludwig-Maximilians-University, Munich, Germany
Evidence for acidosis with
normal saline administration
Avoidance of hyperchloraemic
metabolic acidosis
Balanced fluid therapy
Outcome advantage
unproven
Intensive Care, Western Hospital,
Melbourne, Australia http://www.cpxtesting.com/
Noninvasive cardiac
output monitoring
Rationalization of resources
Presurgical optimization
High initial cost,
infrastructure implications
Who is working on this strategy
(group/institute/company)
Pros
Cons
Latest developments
Sinclair, S. et al. [32]
Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
Strategies
Table 2. Comparison summary table of key fluid administration strategies
Refs
Vol. 2, No. 1 2005
The haemoglobin molecules in these solutions are crosslinked, and do not have ABO antigens. However their systemic side-effects are significant. Nephrotoxicity is less of a
problem with new formulations but systemic vasoconstriction is often seen, either as a direct antagonism of nitric
oxide action on the endothelium or via alpha-1 adrenoceptor
activation. Transient hyperbilirubinaemia is seen as the result
of haemoglobin breakdown and is self-limiting.
Perflurocarbons are hydrophobic carbon fluorides, which
are good solvents for oxygen and carbon dioxide. Emulsifying
these substances has rendered them into highly effective
carriers of oxygen with relatively few adverse affects.
Animal studies have shown remarkable effects in tissue
oxygenation and microperfusion, whereas Phase III data
suggest that less transfusion is required in perfluorocarbontreated patients undergoing major cardiac [42] and noncardiac surgery.
Side-effects include altered coagulation variables and
THROMBOCYTOPAENIA (see glossary), both undesirable in these
groups of patients.
None of these oxygen-carrying fluids are licensed for
intraoperative use as yet; their considerable problems require
solving before they can be used as anything more than a
research tool but they offer a realistic alternative to mainstream fluid therapies in the future.
Conclusions
Perioperative fluid therapy as a technique has evolved considerably over the past three decades. There have been several
exciting new developments with regards to different formulations of fluids, both with respect to crystalloids and the
different colloid solutions and oxygen delivery substances. In
particular, a new generation of balanced fluids will soon
appear, including low molecular weight starches. (Table 2).
Monitoring techniques to ensure the optimum use of these
fluids has also advanced considerably. There are now several
relatively noninvasive devices, which measure dynamic physiological variables upon which we can base our therapy.
Preoperative optimization and risk-stratification is beginning to enter the culture of perioperative care worldwide. This
together with the improvement in monitoring may form the
basis of a rationalization of resources to where they are needed
the most.
Whether these new aspects of fluid therapy will deliver
significant improvements in patient outcome remains to be
seen. The future will yield a significant improvement in our
knowledge as high-quality clinical trials and audit generate
further data to guide our practice.
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