Accepted Manuscript Guiding principles of fluid and volume therapy Dita Aditianingsih, M.D. Yohanes W.H. George, M.D.

PII:

S1521-6896(14)00050-0

DOI:

10.1016/j.bpa.2014.07.002

Reference:

YBEAN 813

To appear in:

Best Practice & Research Clinical Anaesthesiology

Received Date: 4 May 2014 Revised Date:

20 June 2014

Accepted Date: 4 July 2014

Please cite this article as: Aditianingsih D, George YWH, Guiding principles of fluid and volume therapy, Best Practice & Research Clinical Anaesthesiology (2014), doi: 10.1016/j.bpa.2014.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Guiding principles of fluid and volume therapy

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Dita Aditianingsih, M.D.*, Yohanes W.H. George, M.D.

Department of Anaesthesia and Intensive Care, University of Indonesia, Cipto

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Mangunkusumo Hospital, Jakarta, Indonesia

*Corresponding author. Department of Anaesthesia and Intensive Care, University of

City, 10430, Indonesia.

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Indonesia, Cipto Mangunkusumo Hospital, Diponegoro St. No. 71, Central Jakarta

Tel: 62-21-3143736/ 62-815-1819244 Fax: 62-21-3912526

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E-mail address: [email protected] (D. Aditianingsih).

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[email protected] (Y. George)

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Abstract

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Fluid therapy is a core concept in the management of peri-operative and critically ill patients for maintenance of intravascular volume and organ perfusion. Recent evidence regarding the vascular barrier and its role in terms of vascular

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leakage has led to a new concept for fluid administration. The choice of fluid used should be based on the fluid composition and the underlying pathophysiology of the

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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 remains a challenge. Liberal vs restrictive fluid management has been challenged by

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recent evidence, and the ideal approach appears to be goal-directed fluid therapy.

Keywords:

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‘double-barrier concept’

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crystalloids colloids

liberal vs restrictive fluid management preload responsiveness goal-directed fluid therapy

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Introduction

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Fluid therapy is a core concept in the management of peri-operative and critically ill patients. Several aspects influence the benefits and side effects of fluid administration. Recent evidence regarding the vascular barrier, its physiological

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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,

function of the vascular barrier.

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it has been suggested that endothelial glycocalyx may play a pivotal role in the

Traditionally, high volumes of crystalloids have been administered to patients undergoing major surgery, based on presumptions of pre-operative dehydration and

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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

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hypovolaemia results in reduced cardiac output (CO) and decreased oxygen delivery

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(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

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ACCEPTED MANUSCRIPT 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

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intravenous solutions. Therapeutic goals will be highlighted, along with critical

for clinicians.

Physiology and pathophysiological basics

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evaluation of haemodynamic parameters to guide fluid therapy, and recommendations

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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 compartment consists of the interstitial space, blood plasma and small amounts of secreted transcellular fluid (e.g. intra-ocular,

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cerebrospinal, 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.

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Intravenous fluid therapy targets the intravascular fluid volume (IVFV, blood

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volume), the extracellular 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 difference between the intra-operative, peri-operative, postoperative 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 contains colloid osmotic components, that is both iso-oncotic and isotonic. Fluid replacement aims to offset any impending or existing ECFV deficit

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ACCEPTED MANUSCRIPT 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

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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

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compartment across the vascular endothelial barrier, and movement is classified as physiological and pathological. Physiological fluid movement occurs continuously

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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

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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

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Ernest Starling described fluid movement as a net balance of colloid osmotic

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pressure and hydrostatic 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 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

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ACCEPTED MANUSCRIPT 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 endothelial glycocalyx may act as a primary molecular filter, generating an effective

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oncotic gradient at the endothelial microstructural level, with the intravascular– interstitial protein gradient concentration playing a minor role.5,6 This new ‘doublebarrier concept’ suggests that the ‘first-line’ endothelial glycocalyx layer and

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endothelial cells comprising the endothelial surface layer maintain the vascular barrier. Together, these layers have a thickness of 0.4–1.2 µm, and function in

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dynamic equilibrium with approximately 800–1000 ml of circulating and noncirculating plasma in humans. A normal level of plasma albumin is required for optimal function. 7-9 The endothelial surface layer/glycocalyx layer is the first contact surface between blood and tissue. It addition to its role as a vascular barrier, it is

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involved in processes such as inflammation, haemostasis, coagulation and regulation of vasomotor tone. If damaged, glycocalyx loses much of its ability to act as a barrier, and causes platelet aggregation, leukocyte adhesion and increased transendothelial

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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

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ACCEPTED MANUSCRIPT takes 25–35 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 65–70% after

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infusion of 1.1 l of acetated Ringer’s solution over 10 min and 2 l of acetated Ringer’s solution over 20 min.11-13 In patients undergoing general anaesthesia, up to 60% of acetated Ringer’s solution was located in the plasma during continuous infusion.14 In

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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

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increase in plasma volume after 30 min of infusion is 50–75%. 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

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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

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within fluid compartments. The decrease in albumin level lasted for more than 6 h

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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 bicarbonate and sustained hyperchloraemia for more than 6 h.18

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ACCEPTED MANUSCRIPT 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 more than 1 l of NS in 1 h or less. There is a strong likelihood of hyperchloraemic acidosis if patients receive a high volume (at least 4 l)

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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 patients with normal organ function. Healthy human

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volunteers need more than 2 days to excrete a salt and water load of 2 l of NS.16,18,20,21 Worse outcomes were observed in patients with acute illness or critical illness,

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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 solutions including NS were avoided.22,23 The mechanism of renal toxicity caused by NS or other hyperchloraemic

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solutions remains unclear, but a high chloride load could reduce renal function by brief provocation of the tubule–glomerular system. NS worsened sepsis-induced AKI due to increased inflammation, and this outcome was confirmed by decreased

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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, 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

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ACCEPTED MANUSCRIPT 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

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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 30–60 min for

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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

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therefore intravascular volume remains increased for longer.27 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

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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

fluid.28,29

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patients tend to retain more fluid, and need days or weeks to excrete the excess

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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 4– 5% 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 vs 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

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ACCEPTED MANUSCRIPT 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.30-32 In 2013, a Cochrane review found no evidence that colloid

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resuscitation (including albumin) reduces the risk of morbidity or mortality compared with crystalloid resuscitation in heterogenous critically ill patients.33

Gelatins are polydispersed polypeptides from degraded bovine collagen. The

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average molecular weight of gelatins is 30–35 kDa, they have comparable volumeexpanding capability, and they are relatively safe in terms of coagulation and organ

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integrity except for kidney function. Patients undergoing 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

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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

impairment.35

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for nephrotoxicity, the use of gelatins should be limited in patients with renal

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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 semisynthetic colloid is available with various concentrations, molecular weights, molar substitutions, C2/C6 ratios, solvents 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

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ACCEPTED MANUSCRIPT 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 increased incidence of AKI and need for

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RRT.37 Hyperoncotic colloids induce glomerular filtration of hyperoncotic molecules, resulting in hyperviscous urine and stasis of tubular flow, causing ‘osmotic nephrosislike lesions’ in the kidneys.38

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Newer HESs have a lower molecular weight (130 kDa) and molar substitution ratios of 0.38–0.45. The recommended maximum daily dose of HES 130/0.4 is 33–50

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ml.kg-1.39 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 patients

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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

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increased incidence of AKI (Kidney Disease Improving Global Outcome stage 2–3 criteria), increased need for RRT, increased overall mortality at 30 days and

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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 use of HES was associated with increased urine output in patients with low risk for AKI, but increased levels of serum creatinine in patients with higher risk for AKI.43 Both the 6S trial and the CHEST trial found a significant increase in the need

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ACCEPTED MANUSCRIPT for RRT associated with HES administration, and no significant difference in shortterm 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

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cases of shock. The HES:crystalloid ratio in the CHEST trial was 1:1.3, which is similar to the albumin: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

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better state to deal with hazards, while patients in the 6S trial were sicker, had been resuscitated adequately prior to study enrolment, and the 6S trial was designed to use

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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

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risk of AKI and mortality. HES is contra-indicated for use in patients with severe coagulopathy, and patients with renal impairment or needing RRT, and use of HES must be discontinued at the first sign of coagulopathy or AKI. HES should only be

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used for rapid volume replacement due to acute blood loss at the lowest effective dose

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for the shortest period of time, when crystalloids alone are not considered sufficient. Administration should be guided by continuous haemodynamic monitoring, and infusion should be stopped as soon as appropriate haemodynamic goals have been achieved.44

Liberal vs restrictive fluid administration Traditionally, in peri-operative settings, a large volume of crystalloid solution is infused routinely to achieve an adequate intravascular volume. This approach is

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ACCEPTED MANUSCRIPT based on the concept that patients tend to be hypovolaemic pre-operatively 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

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be treated by vasoactive agents.45,46

In minor surgery, peri-operative fluid shifts are small and the risk of organ dysfunction is low. Pre-operative fasting accounts for fluid deficits, and more liberal

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administration of crystalloids to healthy patients undergoing moderate-risk surgery led to a better recovery profile compared with patients who received restricted

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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, many postoperative patients have a positive fluid balance, and the risk of complications increases. No significant data exist to support the concept of the ‘third

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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

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is difficult to define ‘liberal’ or ‘restrictive’ protocols in clinical practice, because the

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studies varied in terms of design, types of fluid administered, additional fluids administered, outcome variables, definitions of intra- and postoperative 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

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ACCEPTED MANUSCRIPT administration, while patients 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

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hydrostatic pressure due to reduced precapillary 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 endpoint as well as

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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 overall fluid

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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

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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

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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

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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

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ACCEPTED MANUSCRIPT 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 increased risk of mortality in patients with septic shock.58 Despite

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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

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sepsis. In patients with septic shock and acute respiratory distress syndrome, higher initial intravenous fluid volumes followed by a negative fluid balance for 2

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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

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correcting hypovolaemia with GDT.

Goal-directed volume therapy

An imbalance between DO2 and oxygen consumption (VO2) is common in

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patients undergoing high-risk surgery and critically ill patients. Tissue oxygen supply

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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

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ACCEPTED MANUSCRIPT of left ventricular preload. Targets are achieved by fluid infusion and combinations of inotropes. Shoemaker et al. introduced the concept of targeting supranormal values of CO and DO2–VO2 using a pulmonary arterial catheter in patients undergoing highrisk surgery, and this was found to be associated with better outcomes in these

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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

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parameters for initial fluid resuscitation in patients with severe sepsis and septic shock.53 Unfortunately, both CVP and PAOP are poor markers of intravascular

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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

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The first step in a fluid resuscitation strategy is the assessment of CO and preload. The Frank–Starling curve is used to determine the relationship between ventricular preload and stroke volume in individual patients, and refers to static

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volumetric parameters such as cardiac preload and dynamic parameters to predict

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preload responsiveness of patients (Fig. 1).65,70 The parameters can be evaluated best using continuous monitoring methods, ranging from classical thermodilution techniques 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 parameters, 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

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ACCEPTED MANUSCRIPT Dynamic 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 mechanical ventilation. Arterial PPV is the variation in arterial pulse pressure during positive-pressure-controlled ventilation, and SVV is the

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variation in stroke volume during positive-pressure-controlled ventilation; both are calculated using pulse contour analysis of the area beneath the arterial waveform curve or by oesophageal Doppler monitoring measurements. PPV and SVV use the

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magnitude of the respiratory change in arterial pulse pressure and stroke volume index as indicators of preload dependence, and are reliable predictors of preload

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responsiveness. PVI is calculated continuously by a non-invasive device that measures change in the perfusion index (ratio of non-pulsatile to pulsatile blood flow through the peripheral capillary bed) during a respiratory cycle. Variations in PPV, SVV ≥10–13% and PVI ≥15% are highly predictive of preload responsiveness. SVV,

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PPV and PVI are unreliable in the presence of spontaneous breathing, cardiac arrhythmia, open chest, tidal volume 7–10 ml.kg-1) 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

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predictor in critically ill patients.

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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. In 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 microcirculatory alterations and shunting, and is characterized by persistent regional dysoxia as signified by elevated lactate levels, increased P(cv-a)CO2 (difference between arterial PaCO2 and central venous PvCO2) and high ScvO2. Lactate is the product of anaerobic

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ACCEPTED MANUSCRIPT metabolism when tissues are being hypoperfused.53,60 Several studies have shown a significantly lower lactate level in the GDT arm postoperatively.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

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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(cv-

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a)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

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flow or CO to wash out CO2 from the tissue. Therefore, increased P(cv-a)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,

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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

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fluids might be a good target for fluid therapy. Targeting the microcirculation in fluid

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resuscitation with direct bedside observations using near-infrared spectroscopy, orthogonal polarization spectral and sidestream darkfield imaging can evaluate and guide GDT at 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 conservative fluid

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ACCEPTED MANUSCRIPT management strategies use macro- and microcirculatory parameters as the targets of resuscitation, and aim to match the increased oxygen demands during stress and systemic inflammatory responses, and avoid further complications. Therapeutic interventions should be made early to restore fluid balance, preserve tissue perfusion

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and tissue oxygenation. It is achieved by optimizing macrocirculatory haemodynamic targets such as static pressure targets (e.g. MAP, CVP, PAOP), volumetric targets (CO, SV, GEDV, ITBV), dynamic parameter targets (e.g. PPV, SVV, PVI), organ-

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function target (e.g. EVLW), in parallel with improvement of microcirculatory targets (lactate, ScvO2, P(cv-a)CO2) and microcirculatory flow. When performed early during

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or after surgery, or after recognition of shock, in appropriate patients, and using welldefined targets, GDT has been shown to improve the outcomes of patients undergoing high-risk surgery and critically ill patients.

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Practice points

The new ‘double-barrier concept’ and fluid kinetics of endothelial glycocalyx suggest that glycocalyx degradation may lead to increased capillary

High chloride solutions should be avoided in high volume resuscitation due to

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permeability and interstitial oedema.

hyperchloraemic metabolic acidosis and nephrotoxicity. It is advisable to use balanced electrolyte solutions for volume replacement.

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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.

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Both hypo- and hypervolaemia have an adverse effect on patient outcome.

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ACCEPTED MANUSCRIPT GDT based on the patient’s underlying pathophysiology, guided by volumetric parameters (e.g. GEDV, ITBV), dynamic parameters (e.g. PPV, SVV, PVI, PLR test, EEO test), and organ function target (e.g. EVLW), represents the ideal macrocirculatory approach. Bedside

observations

using

near-infrared

spectroscopy,

orthogonal

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polarization spectral and sidestream darkfield imaging can guide GDT at

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microcirculatory level and result in more optimal resuscitation.

Research agenda

Future high-quality trials are needed to determine whether colloids,

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crystalloids or a combination 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

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strategy can improve outcomes, and the optimum time for implementation, especially in specific populations of critically ill patients. -

Large multicentre trials are needed to compare various peri-operative GDT

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protocols in terms of peri-operative morbidity and mortality among patients in

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all risk strata.

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Fig. 1. Frank–Starling 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),

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stroke volume variation (SVV) and pulse variability index (PVI) are high, and end-expiratory occlusion (EEO) and passive leg raise (PLR) tests are positive.

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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 unresponsiveness, where PPV, SVV and PVI are low, and EEO

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and PLR tests are negative. Volume loading has little effect on stroke volume and

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leads to a large increase in EVLW. (Reproduced with Permission from [65])70

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