Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260

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Best Practice & Research Clinical

Anaesthesiology
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Guiding principles of fluid and volume therapy

Dita Aditianingsih, M.D., Consultant Anaesthetist and
Intensivist a, c, *,
Yohanes W.H. George, M.D., Consultant Intensivist b, c
a
Head of Emergency Intensive Care Unit, Cipto Mangunkusumo Hospital, Diponegoro St. no. 71,
Central Jakarta City, 10430, Indonesia
b
Head of Emergency and Intensive Care Unit, Pondok Indah Hospital, Metroduta Kav UE, South Jakarta City,
12310, Indonesia
c
Department of Anaesthesia and Intensive Care, University of Indonesia, Jakarta, Indonesia

Keywords:
Fluid therapy is a core concept in the management of perioperative
‘double-barrier concept’ and critically ill patients for maintenance of intravascular volume
crystalloids and organ perfusion. Recent evidence regarding the vascular bar-
colloids rier and its role in terms of vascular leakage has led to a new
liberal versus restrictive fluid management concept for fluid administration. The choice of fluid used should be
preload responsiveness based on the fluid composition and the underlying pathophysi-
goal-directed fluid therapy ology of the patient. Avoidance of both hypo- and hypervolaemia is
essential when treating circulatory failure. In daily practice, the
assessment of individual thresholds in order to optimize cardiac
preload and avoid hypovolaemia or deleterious fluid overload re-
mains a challenge. Liberal versus restrictive fluid management has
been challenged by recent evidence, and the ideal approach ap-
pears to be goal-directed fluid therapy.
© 2014 Elsevier Ltd. All rights reserved.

Introduction

Fluid therapy is a core concept in the management of perioperative and critically ill patients. Several
aspects influence the benefits and side effects of fluid administration. Recent evidence regarding the

* Corresponding author. Department of Anaesthesia and Intensive Care, University of Indonesia, Cipto Mangunkusumo
Hospital, Diponegoro St. No. 71, Central Jakarta City, 10430, Indonesia. Tel.: þ62 21 3143736, þ62 815 1819244; Fax: þ62 21
3912526.
E-mail addresses: ditaaditia@yahoo.com, dita1506@yahoo.com (D. Aditianingsih).

http://dx.doi.org/10.1016/j.bpa.2014.07.002
1521-6896/© 2014 Elsevier Ltd. All rights reserved.
250 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260

vascular barrier, its physiological relevance and its role in terms of vascular leakage has led to a new
concept for intravascular fluid administration. In contrast to Starling's principle of fluid exchange, it has
been suggested that endothelial glycocalyx may play a pivotal role in the function of the vascular
barrier.
Traditionally, high volumes of crystalloids have been administered to patients undergoing major
surgery, based on presumptions of preoperative dehydration and overestimation of intra-operative
fluid loss due to the ‘third space’. The Surviving Sepsis Campaign recommends goal-directed fluid
therapy (GDT) in the case of persistent hypoperfusion within 6 h. Inadequate fluid replacement in cases
of hypovolaemia results in reduced cardiac output (CO) and decreased oxygen delivery (DO2) to tissues,
leading to organ dysfunction. However, excessive fluid administration and a positive fluid balance are
associated with various complications and increased risk of mortality. Studies have compared
restrictive fluid administration with liberal fluid administration for volume management, and tried to
find an association between the physiological function of the vascular barrier and the type of fluid
administered (i.e., crystalloid or colloid). However, the results of these studies are conflicting. Recent
studies have focused on the use of advanced haemodynamic monitoring and proposed the rational
concept of GDT to improve outcomes in critically ill patients and those undergoing high-risk surgery.
This brief review will summarize the relevant physiology of body fluid distribution, the role of the
endothelial vascular barrier, and the effects of various intravenous solutions. Therapeutic goals will be
highlighted, along with critical evaluation of haemodynamic parameters to guide fluid therapy and
recommendations for clinicians.

Physiology and pathophysiological basics

The human body consists of 60% water; approximately two-thirds is located in the intracellular
compartment and one-third is located in the extracellular compartment. The extracellular compart-
ment consists of the interstitial space, blood plasma and small amounts of secreted transcellular fluid
(e.g., intra-ocular, cerebrospinal, and gastrointestinal). The capillary endothelium is freely permeable to
water, electrolytes, nutriments and glucose, but is impermeable to large molecules such as proteins and
colloids, which are confined to the intravascular space.
Intravenous fluid therapy targets the intravascular fluid volume (IVFV, blood volume), the extra-
cellular fluid volume (ECFV, extracellular space) or both. The composition and differential use of
intravenous fluids should be determined by the fluid space targeted, and there appears to be no dif-
ference between the intra-operative, perioperative, post-operative and intensive care settings. Volume
replacement aims to replace a reduction in IVFV and to correct hypovolaemia in order to maintain
haemodynamics and vital signs. This is achieved with an essentially physiological solution that con-
tains colloid osmotic components, that is both iso-oncotic and isotonic. Fluid replacement aims to
offset any impending or existing ECFV deficit due to loss of cutaneous, enteral or renal fluid. This is
achieved with a physiological solution that contains all osmotically active components and is isotonic.
Electrolyte replacement or osmotherapy aims to restore the physiological total body fluid volume
(intracellular fluid volume (ICFV) plus ECFC) when loss of cutaneous, enteral or renal fluid has altered
the composition and/or volume of either or both fluid spaces (ICFV and/or ECFV) [1].
Fluid moves between the intravascular compartment and the extravascular compartment across the
vascular endothelial barrier, and movement is classified as physiological and pathological. Physiolog-
ical fluid movement occurs continuously through an intact vascular endothelial barrier. Fluid is
redistributed slowly between the interstitial and intracellular compartments, and returns to the
intravascular compartment via the lymphatic system. Physiological fluid movement does not cause
interstitial oedema, but fluid loss can result in dehydration. Pathological fluid movement occurs when
the vascular endothelial barrier is damaged. This type of movement allows fluid accumulation leading
to interstitial oedema, and can lead to acute hypovolaemia if the fluid loss is excessive [2].
Ernest Starling described fluid movement as a net balance of colloid osmotic pressure and hydro-
static pressure between the intravascular and interstitial compartments. The fluid components of the
intravascular compartment are mainly pulled inwards due to the colloid osmotic pressure produced by
the protein content of plasma. This pressure opposes the high intravascular hydrostatic pressure, which
has a tendency to push fluid out of the vessels into the interstitium. This principle suggests that both
 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260 251

the interstitial colloid osmotic pressure and hydrostatic pressure are far below the intravascular
pressure, and the net result of these forces is a small outward leak of fluid and proteins from the
vasculature into the interstitium; this is returned to the blood vessels continually via the lymphatic
system [3]. This classic principle suggests that the endothelial cell layer alone is responsible for the
function of the vascular barrier [4]. In contrast to Starling's principle, it has been suggested that the
endothelial glycocalyx may act as a primary molecular filter, generating an effective oncotic gradient at
the endothelial microstructural level, with the intravasculareinterstitial protein gradient concentra-
tion playing a minor role [5,6]. This new ‘double-barrier concept’ suggests that the ‘first-line’ endo-
thelial glycocalyx layer and endothelial cells comprising the endothelial surface layer maintain the
vascular barrier. Together, these layers have a thickness of 0.4e1.2 mm, and function in dynamic
equilibrium with approximately 800e1000 ml of circulating and non-circulating plasma in humans. A
normal level of plasma albumin is required for optimal function [7e9]. The endothelial surface layer/
glycocalyx layer is the first contact surface between blood and tissue. In addition to its role as a vascular
barrier, it is involved in processes such as inflammation, haemostasis, coagulation and regulation of
vasomotor tone. If damaged, the glycocalyx loses much of its ability to act as a barrier and causes
platelet aggregation, leucocyte adhesion and increased transendothelial permeability, resulting in
interstitial oedema [10].

Fluids for volume therapy: crystalloids or colloids

Crystalloids

Crystalloids are distributed freely across the vascular endothelial barrier. A paradigm exists that four
times as much crystalloid compared with colloid is needed for the same volume effect, and several
studies have shown comparable results. Isotonic or near-isotonic crystalloids, such as normal saline
(NS), lactated Ringer's (LR) solution and acetated Ringer's solution, have shown that the distribution
phase takes 25e35 min. The increase in plasma volume during infusion is greater than commonly
suggested. Following infusion of 2 l of acetated Ringer's solution over 30 min, 50% was located in the
plasma at the end of infusion in normovolaemic volunteers; other studies have reported an increase in
plasma volume of 65e70% after infusion of 1.1 l of acetated Ringer's solution over 10 min and 2 l of
acetated Ringer's solution over 20 min [11e13]. In patients undergoing general anaesthesia, up to 60%
of acetated Ringer's solution was located in the plasma during continuous infusion [14]. In healthy
female volunteers, the fraction of infused Ringer's solution that remains in the plasma is higher for
slower infusion rates and decreases with infusion time. The increase in plasma volume after 30 min of
infusion is 50e75%. A relatively long period of time is required for crystalloid fluids to distribute; as
such, slow infusions are more effective than bolus administrations [15].
The effects of different types of crystalloids have been studied in healthy volunteers. LR solution
decreased serum osmolality briefly, with a return to baseline after 1 h. NS did not affect serum
osmolality but caused metabolic acidosis [16]. Serum albumin was decreased by dilution but returned
to baseline, indicating redistribution within fluid compartments. The decrease in albumin level lasted
for >6 h with NS, but returned to normal within 1 h with dextrose 5%. Haemoglobin was also decreased
by dilution; the water content from the dextrose 5% infusion was excreted after 2 h, but NS had a
longer-lasting effect with only 30% of sodium and water excreted after 6 h [17]. The increase in plasma
volume, as estimated by dilution of haemoglobin and albumin, was shown to be more sustained with
NS (56% of infused volume at 6 h) compared with Hartmann's solution (30%). There were no significant
differences in serum potassium, sodium, urea or total osmolality, but NS resulted in a decrease in bi-
carbonate and sustained hyperchloraemia for >6 h [18].
The use of large volumes of NS causes hyperchloraemic metabolic acidosis. Twenty-nine percent of
patients with shock developed hyperchloraemic acidosis within 24 h of infusion of >1 l of NS in 1 h.
There is a strong likelihood of hyperchloraemic acidosis if patients receive a high volume (at least 4 l) of
NS at a high infusion rate [19]. In short-term interventions, limiting NS administration with the use of
colloids in any carrier has a moderate hyperchloraemic effect, and this is relatively transient for pa-
tients with normal organ function. Healthy human volunteers need >2 days to excrete a salt and water
load of 2 l of NS [16,18,20,21].
252 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260

Worse outcomes were observed in patients with acute illness or critical illness, where the ability to
excrete a salt and water load is impaired. A significant decrease in the incidence of acute kidney injury
(AKI) and the need for renal replacement therapy (RRT) were observed when hyperchloraemic solu-
tions including NS were avoided [22,23]. The mechanism of renal toxicity caused by NS or other
hyperchloraemic solutions remains unclear, but a high chloride load could reduce renal function by
brief provocation of the tubuleeglomerular system. NS worsened sepsis-induced AKI due to increased
inflammation, and this outcome was confirmed by decreased function, increased levels of injury
biomarkers and histological results [24].

Colloids

Colloids are fluids that contain macromolecules exceeding 40 kDa and are classified as natural (e.g.,
albumin) and artificial (e.g., starches, dextrans and gelatins). Colloids are dissolved in either saline or
more balanced salt solutions. Colloid gelatins of low-to-medium molecular weight and albumin are
more likely to leak into the interstitial compartment compared with hydroxyethyl starch (HES), which
has a higher molecular weight. HES is retained intravascularly for longer, and the duration of retention
in the circulatory system differs between colloids [25].
Colloids are believed to increase plasma oncotic pressure. Due to their higher molecular weight,
colloids may interact and adsorb to the glycocalyx layer, and restrict ultrafiltration, while crystalloids
equilibrate rapidly between the intravascular and interstitial compartments [26]. In healthy, intact
vascular barriers, colloids remain in the intravascular compartment for up to 16 h, compared with
30e60 min for crystalloids such as LR solution and NS. The colloid volume required to achieve a
haemodynamic target is less compared with the crystalloid volume (1:4), and therefore intravascular
volume remains increased for longer [27]. The endothelial glycocalyx is often damaged in injured and
critically ill patients, and therefore capillary leakage is more likely. When a colloid solution diffuses into
the interstitium, it reduces the oncotic pressure gradient between the capillary barriers and results in
further fluid extravasation. At best, colloids can restore intravascular volume within minutes or hours,
but their effect on total body water is cumulative and persists. Critically ill patients tend to retain more
fluid, and need days or weeks to excrete the excess fluid [28,29].
Albumin is the main molecule used to preserve intravascular osmotic pressure and is an ideal
colloid to restore protein deficits in the vasculature. Human albumin 4e5% in saline is a natural colloid
for volume resuscitation. It is produced by the fractionation of blood, and is heat-treated to prevent
transmission of pathogens; as such, it may cause allergic and immunological complications. The Saline
versus Albumin Fluid Evaluation (SAFE) study showed no significant benefits in terms of mortality rate
at 28 days or development of new organ failure. Additional analysis in predefined subgroups showed
that, in patients with traumatic brain injury, there was a significant association between albumin
administration and higher mortality rate at 2 years; and, in patients with severe sepsis, there was an
association between decreased mortality rate at 28 days and albumin administration, suggesting a
potential benefit of albumin resuscitation [30e32]. In 2013, a Cochrane review found no evidence that
colloid resuscitation (including albumin) reduces the risk of morbidity or mortality compared with
crystalloid resuscitation in heterogeneous critically ill patients [33].
Gelatins are polydispersed polypeptides from degraded bovine collagen. The average molecular
weight of gelatins is 30e35 kDa, they have comparable volume-expanding capability and they are
relatively safe in terms of coagulation and organ integrity except for kidney function. Patients un-
dergoing aortic aneurysm surgery who were resuscitated with 4% gelatin demonstrated more distinct
tubular damage with a higher level of serum urea and creatinine compared with patients resuscitated
with HES, and concern regarding the risk of AKI associated with the use of gelatins was raised [34]. The
use of gelatins has not been studied in a high-quality randomized controlled trial (RCT). Consequently,
given the lack of clinical benefits and potential for nephrotoxicity, the use of gelatins should be limited
in patients with renal impairment [35].
HES is an artificial polymer derived from hydroxyethyl substitution of amylopectin obtained from
sorghum, waxy maize or potatoes. Hydroxyethylation of the glucose unit protects against hydrolysis
degradation by non-specific amylases and water solubility in the blood. This semi-synthetic colloid is
available with various concentrations, molecular weights, molar substitutions, C2/C6 ratios, solvents
 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260 253

and pharmacological profiles. HES with a high molecular weight (>200 kDa) and a molar substitution
ratio >0.5 (200/0.6) is associated with coagulopathy due to a reduction in von Willebrand factor and
factor VIII, leading to decreased platelet adhesion, changes in viscoelasticity and fibrinolysis [36]. HES
with a higher molecular weight is metabolized more slowly and causes prolonged intravascular
expansion, but may accumulate in subcutaneous tissue, liver and kidney. The use of 10% HES 200/0.5 in
patients with sepsis was associated with an increased incidence of AKI and need for RRT [37].
Hyperoncotic colloids induce glomerular filtration of hyperoncotic molecules, resulting in hyper-
viscous urine and stasis of tubular flow, causing ‘osmotic nephrosis-like lesions’ in the kidneys [38].
Newer HESs have a lower molecular weight (130 kDa) and molar substitution ratios of 0.38e0.45.
The recommended maximum daily dose of HES 130/0.4 is 33e50 ml kg1 [39]. HES 130/0.4 has been
shown to attenuate inflammatory responses when administered as a resuscitation fluid in a septic
shock and haemorrhagic shock rat model, by decreasing the levels of tumour necrosis factor-alpha,
interleukins and oxidative stress [40,41]. Two large RCTs have evaluated the safety of HES for pa-
tients with severe sepsis and septic shock. The 6S trial is an RCT involving 800 patients with severe
sepsis and septic shock. The investigators reported that the use of 6% HES (130/0.42), compared with
acetated Ringer's solution, was associated with an increased incidence of AKI (Kidney Disease
Improving Global Outcome stage 2e3 criteria), increased need for RRT, increased overall mortality at
30 days and significantly increased mortality at 90 days [42]. The CHEST trial is an RCT involving 7000
patients with severe sepsis. The investigators found that the use of 6% HES (130/0.4), compared with
NS, was associated with lower incidence of AKI, and was not associated with a significant difference in
mortality at 90 days. However, this trial found that the use of HES was associated with increased urine
output in patients with low risk of AKI, but increased levels of serum creatinine in patients with higher
risk of AKI [43]. Both the 6S trial and the CHEST trial found a significant increase in the need for RRT
associated with HES administration, and no significant difference in short-term haemodynamic
resuscitation targets between HES and crystalloids. The CHEST trial found that the use of HES was
associated with the use of approximately 30% less fluid, faster elevation of central venous pressure
(CVP) and lower incidence of new cases of shock. The HES-to-crystalloid ratio in the CHEST trial was
1:1.3, which is similar to the albumin-to-saline ratio in the SAFE study. The different results from these
two trials are likely to be due to the fact that patients in the CHEST trial were in a better state to deal
with hazards, while patients in the 6S trial were sicker and had been resuscitated adequately prior to
study enrolment, and the 6S trial was designed to use the same volume of fluid and did not allow a
decrease in resuscitation volume in both arms [20,30,42,43]. The Pharmacovigilance Risk Assessment
Committee of the European Medicines Agency concluded that, until further evidence is available, HES
must no longer be used in patients with sepsis, burn injuries or critical illness because of the risk of AKI
and mortality. HES is contraindicated for use in patients with severe coagulopathy, and patients with
renal impairment or needing RRT, and the use of HES must be discontinued at the first sign of coa-
gulopathy or AKI. HES should only be used for rapid volume replacement due to acute blood loss at the
lowest effective dose for the shortest period of time, when crystalloids alone are not considered suf-
ficient. Administration should be guided by continuous haemodynamic monitoring, and infusion
should be stopped as soon as appropriate haemodynamic goals have been achieved [44].

Liberal versus restrictive fluid administration

Traditionally, in perioperative settings, a large volume of crystalloid solution is infused routinely to

achieve an adequate intravascular volume. This approach is based on the concept that patients tend to
be hypovolaemic preoperatively due to prolonged fasting, cathartic bowel preparation, perspiration
and urinary output. General anaesthesia and neuraxial blockade result in hypotension, and this often
triggers liberal fluid administration to achieve the haemodynamic target. This should be treated by
vasoactive agents [45,46].
In minor surgery, perioperative fluid shifts are small and the risk of organ dysfunction is low.
Preoperative fasting accounts for fluid deficits, and more liberal administration of crystalloids to
healthy patients undergoing moderate-risk surgery led to a better recovery profile compared with
patients who received restricted amounts of the same crystalloid [47,48]. The concept of the ‘third
space’ in surgical exposure leads to aggressive fluid replacement of the insensible loss. As a result,
254 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260

many post-operative patients have a positive fluid balance, and the risk of complications increases. No
significant data exist to support the concept of the ‘third space’, and a positive fluid balance was
associated with poorer outcome [49]. A review of patients undergoing major abdominal surgery and
knee arthroplasty, excluding high-risk patients, compared liberal and restrictive fluid regimens; it
concluded that it is difficult to define ‘liberal’ or ‘restrictive’ protocols in clinical practice, because the
studies varied in terms of design, types of fluid administered, additional fluids administered, outcome
variables, definitions of intra- and post-operative periods and the fact that a restrictive regimen in one
study may be liberal in another [50,51]. Liberal fluid administration in patients undergoing major
surgery was associated with increased risk of pneumonia, longer time to bowel movement and
increased length of hospital stay, compared with the restrictive therapy and GDT groups [52]. Patients
undergoing moderate-risk surgery seem to benefit from more liberal fluid administration, while pa-
tients undergoing high-risk or major surgery seem to benefit from restrictive or conservative strategies.
In sepsis, distributive shock and oedema are attributed to a combination of increased capillary
permeability to proteins and increased net transcapillary hydrostatic pressure due to reduced pre-
capillary vasoconstriction. Early GDT is a stepwise approach that improved 30-day mortality in patients
with sepsis, using central venous oxygen saturation (ScvO2) >70% as an additional end point as well as
optimized CVP and mean arterial pressure (MAP) [53]. The GDT arm received, on average, 2 l more fluid
than the control arm in the first 6 h, although the overall fluid volume in the first 72 h was similar in
both groups. In a subset analysis, patients with sepsis who had renal support including fluid removal at
enrolment had a lower mortality rate and a shorter duration of mechanical ventilation despite
administration of equal volumes [53,54]. The Fluids and Catheter Treatment Trial determined that
conservative fluid management 24 h after the establishment of acute respiratory distress syndrome
could significantly improve lung and central nervous system function, decrease the need for sedation,
reduce the duration of mechanical ventilation and reduce the length of stay in an intensive care unit
(ICU). However, the study suggested that a conservative fluid management strategy should be applied
cautiously during the resuscitation phase [55]. An early adequate fluid management strategy in the
resuscitation phase corrects global tissue hypoxia (reflected by decreased lactate and increased ScvO2)
and decreases the incidence of mechanical ventilation in the first 72 h. Fluid resuscitation improves
microcirculation and modulates certain distinct biomarkers in the early phase of sepsis, but not in the
late phase of sepsis [56]. The Sepsis Occurrence in Acutely Ill Patients (SOAP) study and Vasopressin
and Septic Shock Trial (VASST) favour a conservative fluid management strategy. The SOAP study
showed that a positive fluid balance within 72 h was associated with severity and mortality in the
subgroup of patients with severe sepsis and septic shock [57]. The VASST indicated that higher CVP at
12 h and a higher positive fluid balance on day 4 was associated with an increased risk of mortality in
patients with septic shock [58]. Despite potential biases such as indications, time dependencies,
repeated exposure of interventions, competing risks and exclusion of the most sick and least sick
patients, most studies found that a positive fluid balance was a risk factor in patients with sepsis. In
patients with septic shock and acute respiratory distress syndrome, higher initial intravenous fluid
volumes followed by a negative fluid balance for 2 consecutive days within the first 7 days of shock
resulted in a lower mortality rate [59]. However, rather than relying on ‘liberal’ or ‘restrictive’ terms, it
is more important to focus on the precise volume and timing of fluid administration based on targets
for correcting hypovolaemia with GDT.

Goal-directed volume therapy

An imbalance between DO2 and oxygen consumption (VO2) is common in patients undergoing
high-risk surgery and critically ill patients. Tissue oxygen supply can be determined by DO2, whereas
optimization of CO is the primary factor to match metabolic demands. Fluid resuscitation has been
regarded as the first step in optimizing CO, but numerous studies have reported that only 50% of
haemodynamically unstable patients responded to fluid challenges [60,61].
MAP, heart rate and diuresis are measured routinely but cannot assess haemodynamic instability or
differentiate its causes accurately. Traditionally, for perioperative fluid administration, the predefined
values of CVP and pulmonary arterial occlusion pressure (PAOP) are used to estimate left atrial pressure
as an assumption of left ventricular preload. Targets are achieved by fluid infusion and combinations of
 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260 255

inotropes. Shoemaker et al. introduced the concept of targeting supranormal values of CO and
DO2eVO2 using a pulmonary arterial catheter in patients undergoing high-risk surgery, and this was
found to be associated with better outcomes in these patients [62]. However, increased mortality was
observed in critically ill patients treated with supranormal target values; therefore, ScvO2 and oxygen
extraction ratio were added as resuscitation targets [63]. Early GDT used CVP, MAP and ScvO2 as target
parameters for initial fluid resuscitation in patients with severe sepsis and septic shock [53]. Unfor-
tunately, both CVP and PAOP are poor markers of intravascular volume, primarily due to non-linear
variations in vascular compliance, and do not correlate with circulating blood volume. A systematic
review verified that CVP and PAOP were poor indicators of preload and volume responsiveness to
changes in stroke volume or CO [64].
The first step in a fluid resuscitation strategy is the assessment of CO and preload. The Frank-
eStarling curve is used to determine the relationship between ventricular preload and stroke volume
in individual patients, and refers to static volumetric parameters such as cardiac preload and dynamic
parameters to predict preload responsiveness of patients (Fig. 1) [65,70]. The parameters can be
evaluated best using continuous monitoring methods, ranging from classical thermodilution tech-
niques with a pulmonary artery catheter and transpulmonary indicator dilution to less invasive non-
calibrated pulse contour analysis of arterial pressure signal, and oesophageal Doppler. Static param-
eters, such as global end-diastolic volume (GEDV) and intrathoracic blood volume (ITBV), can be
determined by transpulmonary thermodilution techniques. These parameters are not limited by
spontaneous breathing, and have been shown to be valuable indicators of cardiac preload [66]. Dy-
namic parameters, such as pulse pressure variation (PPV), stroke volume variation (SVV) and pulse
variability index (PVI), are derived from interactions between the heart and the lungs during me-
chanical ventilation. Arterial PPV is the variation in arterial pulse pressure during positive-pressure-
controlled ventilation, and SVV is the variation in stroke volume during positive-pressure-controlled
ventilation; both are calculated using pulse contour analysis of the area beneath the arterial wave-
form curve or by oesophageal Doppler monitoring measurements. PPV and SVV use the magnitude of
the respiratory change in arterial pulse pressure and stroke volume index as indicators of preload
dependence, and are reliable predictors of preload responsiveness. PVI is calculated continuously by a
non-invasive device that measures change in the perfusion index (ratio of non-pulsatile to pulsatile

Preload reserve No Preload reserve

High PPV/SVV/PVI Low PPV/SVV/PVI ≤10-13%
≥10-13% Negative PLR/EEO test
Positive PLR/EEO test Large increase of EVLW
Normal or small increase Negative response to volume
Stroke of EVLW loading Normal
Positive response to
Volume volume loading Heart

Failing Heart

0
0
Cardiac Preload

Fig. 1. FrankeStarling curves are influenced by ventricular contractility. There is preload reserve when the ventricle is functioning on
the steep part of the curve. This indicates preload responsiveness, where pulse pressure variation (PPV), stroke volume variation
(SVV) and pulse variability index (PVI) are high, and end-expiratory occlusion (EEO) and passive leg raise (PLR) tests are positive.
Volume loading induces a significant increase in stroke volume, and results in a small increase in extravascular lung water (EVLW).
When the ventricle is functioning near the flat part of the curve, there is no preload reserve. This indicates preload unrespon-
siveness, where PPV, SVV and PVI are low, and EEO and PLR tests are negative. Volume loading has little effect on stroke volume and
leads to a large increase in EVLW. (Reproduced with Permission from Ref. [65]) [70].
256 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260

blood flow through the peripheral capillary bed) during a respiratory cycle. Variations in PPV, SVV
10e13% and PVI 15% are highly predictive of preload responsiveness. SVV, PPV and PVI are unre-
liable in the presence of spontaneous breathing, cardiac arrhythmia, open chest, tidal volume
<7 ml kg1, intra-abdominal hypertension and right ventricular failure [67,68], and end-expiratory
occlusion (EEO) test and passive leg raise (PLR) test can be used as alternatives. The EEO test is
based on the concept that, during mechanical ventilation, each insufflation increases intra-thoracic
blood pressure and impedes venous return. If interrupting mechanical insufflation during EEO for
15 s increases CO and arterial pulse pressure by >5%, it could predict preload responsiveness. The PLR
test can be performed in patients who are breathing spontaneously, by elevating the legs in order to
evaluate whether the shift of blood from the lower extremities to the central circulation is able to
increase left cardiac preload and improve CO by 10% in order to assess preload responsiveness [69].
The adverse effect of fluid overload is pronounced, especially in the lungs. Lungs receive the maximum
CO and are greatly exposed to the inflammation cascade. Consequently, lungs will provide clinical insight
into dynamic microcirculatory alterations, and bedside monitoring to detect pulmonary oedema with
extravascular lung water (EVLW), performed by transpulmonary thermodilution, is valuable. EVLW will
estimate the extent of capillary leak and fluid overload. During fluid infusion, preload-responsive patients
are likely to have a large increase in stroke volume and a small increase in EVLW. If there is a small in-
crease, or no increase, in stroke volume and a large increase in EVLW, the patient is not fluid responsive
[70]. In cardiac surgery, a goal-directed treatment algorithm using GEDV, SVV and EVLW could reduce the
need for vasoactive agents, mechanical ventilation and length of ICU stay compared with a goal-directed
algorithm using MAP, CVP and PAOP [71]. Critically ill patients receiving mechanical ventilation
demonstrated a significant correlation between increased EVLW and a positive fluid balance and organ
dysfunction and poor outcomes [72]. Higher EVLW (>7e10 ml kg1) values were found in non-survivors,
and this was an independent risk factor for mortality at 28 days [73,74]. EVLW is a valuable tool to guide
fluid management, and appears to be a good predictor in critically ill patients.
Three forms of shock (hypovolaemic, obstructive and cardiogenic) are associated with reduced CO;
therefore, these conditions have a positive effect on overall outcome after normalization of CO. By
contrast, in cases of distributive shock (e.g., septic shock), inadequate tissue perfusion and cellular
dysfunction persist in the presence of normal or even elevated CO. This defect occurs due to micro-
circulatory alterations and shunting, and is characterized by persistent regional dysoxia as signified by
elevated lactate levels, increased P(cva)CO2 (difference between arterial PaCO2 and central venous
PvCO2) and high ScvO2. Lactate is the product of anaerobic metabolism when tissues are being
hypoperfused [53,60]. Several studies have shown a significantly lower lactate level in the GDT arm
post-operatively [75]. GDT guided by close lactate monitoring showed that a fluid-restricted regime in
patients undergoing major elective gastrointestinal surgery may lead to fluid insufficiency and low
tissue perfusion in up to 28% of patients. Close monitoring of serum lactate levels and lactate clearance
to guide fluid administration may improve early detection of hypoperfusion and evaluation of the
patient's response to fluid therapy [53,76]. P(cvas)CO2 is a blood-flow-related blood gas parameter.
Arterial PaCO2 is dependent on pulmonary gas exchange, but central venous PvCO2 is dependent on the
ability of the flow or CO to wash out CO2 from the tissue. Therefore, increased P(cva)CO2 may help the
early detection of hypoperfusion and can guide fluid administration [77,78].
In patients with sepsis, microcirculatory impairment and tissue hypoxia persist despite systemic
haemodynamic optimization, such as normal or increased CO, normal blood flow and normal DO2.
Microcirculatory alterations are a significant risk factor in this population. A study in patients with
septic shock found reduced microcirculatory perfusion, and improvement of the microcirculatory flow
response to fluids might be a good target for fluid therapy. Targeting the microcirculation in fluid
resuscitation with direct bedside observations using near-infrared spectroscopy, orthogonal polari-
zation spectral and sidestream darkfield imaging can evaluate and guide GDT at the microcirculatory
level, and result in more optimal resuscitation [79].

Conclusions

The choice and timing of administration of different types of fluid, and the amount, should be based
on the fluid composition and the underlying pathophysiology of the patient. Early adequate and late
 D. Aditianingsih, Y.W.H. George / Best Practice & Research Clinical Anaesthesiology 28 (2014) 249e260 257

conservative fluid management strategies use macro- and microcirculatory parameters as the targets
of resuscitation, and aim to match the increased oxygen demands during stress and systemic in-
flammatory responses, and avoid further complications. Therapeutic interventions should be made
early to restore fluid balance, and preserve tissue perfusion and tissue oxygenation. It is achieved by
optimizing macrocirculatory haemodynamic targets such as static pressure targets (e.g., MAP, CVP and
PAOP), volumetric targets (CO, SV, GEDV and ITBV), dynamic parameter targets (e.g., PPV, SVV and PVI)
and organ-function target (e.g., EVLW), in parallel with improvement of microcirculatory targets
(lactate, ScvO2, and P(cva)CO2) and microcirculatory flow. When performed early during or after
surgery, or after recognition of shock, in appropriate patients, and using well-defined targets, GDT has
been shown to improve the outcomes of patients undergoing high-risk surgery and critically ill
patients.

Practice points

- The new double-barrier concept’ and fluid kinetics of the endothelial glycocalyx suggest that
glycocalyx degradation may lead to increased capillary permeability and interstitial oedema.
- High-chloride solutions should be avoided in high-volume resuscitation due to hyper-
chloraemic metabolic acidosis and nephrotoxicity. It is advisable to use balanced electrolyte
solutions for volume replacement.
- HES solutions must be avoided in critically ill patients at high risk of AKI and coagulopathy,
and should only be used for the treatment of hypovolaemia due to acute blood loss, at the
lowest effective dose for the shortest period of time, when crystalloids alone are not
considered sufficient.
- Both hypo- and hypervolaemia have an adverse effect on patient outcome. GDT based on the
patient's underlying pathophysiology, guided by volumetric parameters (e.g., GEDV and
ITBV), dynamic parameters (e.g., PPV, SVV, PVI, PLR test and EEO test) and organ function
target (e.g., EVLW), represents the ideal macrocirculatory approach.
- Bedside observations using near-infrared spectroscopy, orthogonal polarization spectral and
sidestream darkfield imaging can guide GDT at the microcirculatory level and result in more
optimal resuscitation.

Research agenda

- Future high-quality trials are needed to determine whether colloids, crystalloids or a com-
bination of the two fluid types could produce better outcomes, especially in particular clinical
conditions.
- Further prospective RCTs are needed to evaluate whether a late conservative strategy can
improve outcomes, and the optimum time for implementation, especially in specific pop-
ulations of critically ill patients.
- Large multicentre trials are needed to compare various perioperative GDT protocols in terms
of perioperative morbidity and mortality among patients in all risk strata.

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