Fluid Overload

Michael E. OConnor, MBBS, BSc, MRCP, FRCAa,b,

John R. Prowle, MA, MB BChir, MSc, MD, FRCP, FFICMa,b,c,*

KEYWORDS
 Fluid overload  Edema  Critical illness  Diuretics  Ultrafiltration

KEY POINTS
 Fluid overload is an almost universal finding in the critically ill, despite little evidence to
justify fluid therapy within the intensive care unit after initial resuscitation.
 Hemodynamic responses to fluid administration are unpredictable and short lived, which
may contribute to recurrent fluid administration.
 Positive fluid balances have been consistently associated with adverse outcomes and or-
gan dysfunction in critical illness.
 Structural and functional changes in the endothelium and extracellular matrix during
systemic inflammation leads to sequestration of administered fluid outside the circulation,
promoting fluid accumulation and impeding its removal.
 Strategies to manage fluid balances in the critically ill require close attention to true need
for fluid administration and active prevention or management of fluid overload.

INTRODUCTION: ASSOCIATION BETWEEN FLUID OVERLOAD AND ADVERSE

OUTCOMES IN CRITICAL ILLNESS

When delivered correctly for the right reasons and at the appropriate time, intravenous
fluid can be lifesaving. However, in established critical illness, a combination of increased
fluid intake and relatively reduced urine output frequently results in accumulation of
excess fluid within the body (Table 1). In particular, critically ill patients with sepsis
frequently receive very large volumes of fluid resulting in significantly positive fluid bal-
ances; for example, in a retrospective analysis of data from the Vasopressin in Septic
Shock Trial (VASST), the mean fluid balance was on average 14.2 L at 12 hours after

Disclosures: Dr J.R. Prowle has received speakers and consultants fees from Baxter and institu-
tional funding from NIKKISO Europe GmbH, both manufactures of continuous renal replace-
ment therapy technology.
a
Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS Trust, Whitechapel
Road, London E1 1BB, UK; b Centre for Translational Medicine & Therapeutics, William Harvey
Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M
6BQ, UK; c Department of Renal and Transplant Medicine, The Royal London Hospital, Barts
Health NHS Trust, Whitechapel Road, London E1 1BB, UK
* Corresponding author. Adult Critical Care Unit, The Royal London Hospital, Barts Health NHS
Trust, Whitechapel Road, London E1 1BB, UK.
E-mail address: j.prowle@qmul.ac.uk

Crit Care Clin - (2015) --

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2 OConnor & Prowle

Table 1
Contributions to positive fluid balances in critical illness

Early in Admission to Intensive Care Later in Admission to Intensive Care

Excessive intake Need for blood products Obligate daily fluid needs in terms
of fluid Intravenous fluid resuscitation of drug therapies and nutrition
Intercurrent clinical events requiring
fluid resuscitation
Inadequate fluid Acute or chronic kidney disease Ongoing renal impairment
elimination Acute hemodynamic instability Cardiac and liver dysfunction
Fluid losses from circulation to Sequestration of fluid in the
interstitial space interstitium and body cavities

presentation with severe sepsis and 111.0 L by day 4 after enrollment.1 Crucially, in this
analysis, the upper 2 quartiles of fluid balance were associated with progressively worse
survival than patients with less positive fluid balance, even after adjustment for baseline
illness severity and demographics. It is pertinent to consider the magnitude of fluid
excess we are dealing with here. The fluid balance in the mid upper quartile of the VASST
analysis at 4 days was 120.5 L; that is about 50% of the normal total body water, clearly
far in excess of any plausible volume deficit at baseline. Despite clinicians apparent will-
ingness to administer very large volumes of fluid over several days to the sickest critically
ill patients, when the relationship between fluid balance and outcome has been examined
a consistent association has been demonstrated between positive fluid balance and pro-
longed intensive care unit (ICU) stay, development or worsening of organ dysfunction
and excess mortality.211 A recent systematic review considered 17 observational
studies reporting fluid balances in relation to clinical outcomes including data from
more than 5000 ICU patients; in these results, nonsurvivors (48% mortality) had a
more positive cumulative fluid balance by day 7 of their ICU stay than survivors by, on
average, 4.35 L.12 In parallel to the adverse effects of fluid overload, patients instead
achieving a negative fluid balance in the ICU have an increased survival from septic
shock13 and in acute kidney injury (AKI) treated with continuous renal replacement ther-
apy8 and have a shorter duration of mechanical ventilation and ICU stay.6,14 Of course,
demonstration of an association between positive fluid balance and adverse outcomes
does not prove a causative role of fluid overload in mediating adverse outcomes; un-
doubtedly, positive fluid balances are a marker of severity critical illness both as a reflec-
tion of the degree of physiologic instability and physician response to it.15 However, the
authors think there are strong biological arguments, supported by a wealth of observa-
tional evidence, that fluid overload does worsen organ function; therefore, excessive fluid
accumulation is an avoidable source of iatrogenic morbidity and mortality in at least a
proportion of patients. Many causative mechanisms could mediate a direct association
between the development of interstitial edema and the development of progressive or-
gan dysfunction; these include impaired oxygen and metabolite diffusion, distorted tis-
sue architecture, obstruction of organ perfusion, venous outflow and lymphatic
drainage, and disturbed cell-cell interaction.
Evidence of the adverse effects of fluid overload can be found in almost all organ
systems (Fig. 1), including the gastrointestinal tract,16 the liver,17,18 the cardiovascular
system,1922 the central nervous system,23,24 and skin and soft tissues.2528 In partic-
ular, fluid overload and the resultant visceral edema is a risk factor for intra-abdominal
hypertension (IAH). In an ICU population, positive fluid balances have been associated
with an increased risk of IAH,2931 which in turn is strongly associated with the devel-
opment of other organ dysfunction, particularly the development of AKI.12,29,3134 The
 Fluid Overload 3

Fig. 1. Pathologic sequelae of fluid overload in organ systems. GFR, glomerular filtration
rate; RBF, renal blood flow. (From Prowle JR, Echeverri JE, Ligabo EV, et al. Fluid balance
and acute kidney injury. Nat Rev Nephrol 2010;6(2):110; with permission.)

effects of fluid overload are perhaps most well recognized in the respiratory system
where the development or worsening of pulmonary edema can lead to impaired gas
exchange, reduced lung compliance, and increased work of breathing.35 Positive fluid
balances and liberal fluid strategies have been associated with decreased survival,
greater duration of mechanical ventilation, and an increased ICU length of stay in
retrospective analyses of patient outcomes in acute lung injury7,36 and prospective
studies.37 Importantly, the only multicenter prospective randomized controlled study
examining fluid management strategies in the ICU focused on a group with severe
lung injury, the Fluid And Catheter Treatment Trial (FACTT).6 FACTT compared a liberal
versus conservative fluid management strategy in patients with acute respiratory
distress syndrome. Fluid restriction and diuretics were used to maintain lower central
venous or pulmonary capillary wedge pressure in patients in the conservative arm of
4 OConnor & Prowle

the study; over 7 days, this strategy achieved a neutral fluid balance in the conserva-
tive arm compared with, on average, a positive fluid balance of 17 L in the liberal arm.
The conservative fluid management strategy led to fewer ventilator days,6 and a post
hoc analysis indicated that achieving a negative fluid balance with diuretics was asso-
ciated with improved survival.14
Finally, the relationship between fluid overload and AKI is of particular interest given
the role of the kidney in maintaining salt and water homeostasis. Traditional teaching
has emphasized the need for fluid resuscitation aiming to maintain renal perfusion and
maintain urine output in patients with or at risk of AKI. However, the clinical literature
has consistently demonstrated the fluid overload is particularly harmful in AKI; in a pre-
vious review,38 the authors identified 17 observational studies examining fluid balance
and outcomes in patients with AKI from 2008 to 13,8,9,11,14,3950 and all demonstrated
evidence of harm from fluid overload and/or benefit from its resolution. Prospective
evidence supporting improved renal outcome with active avoidance of fluid overload
is also available from the FACTT study whereby conservative fluid management was
associated with a strong trend toward a lower need for renal replacement therapy6 and
a lower incidence of AKI in a post hoc analysis adjusted for fluid balance.51 Strong
physiologic arguments support a causative role for fluid overload in the persistence
of AKI whereby increased venous pressure, extrarenal compression, and intrarenal
interstitial pressure all potentially act to oppose renal blood flow and reduce glomer-
ular ultrafiltration gradient,38 in-line with an observed association between more pos-
itive fluid balance at initiation of renal replacement therapy (RRT) and poorer renal
outcomes in severe AKI.39

DEVELOPMENT OF FLUID OVERLOAD: A PATIENT-PHYSICIAN INTERACTION

Given very significant adverse associations of fluid overload, the authors think there is
a clinical imperative to minimize the extent and impact of fluid overload in the ICU. To
achieve this, clinicians need to appreciate how and why such degrees of fluid overload
occur. Because almost all fluid inputs are under direct control of the clinical team, we
first have to consider how and why we give fluid therapy in the ICU and the evidence
underlying this practice.
Conventional management of patients with signs of inadequate tissue perfusion is to
ensure adequate circulating volume by rapid administration of intravenous fluids.
Although the administration of an initial bolus of fluid in shocked patients is considered
an essential feature of emergency management, continued or repeated fluid therapy
beyond the very initial phase of management may not be beneficial. Three large ran-
domized controlled trials5254 have now demonstrated that, in the first 6 hours after
presentation with sepsis, management strategies including administration of intrave-
nous fluids targeting the restoration of surrogate end points for tissue perfusion (central
venous oxygen saturation) and volume status (central venous pressure [CVP]) are not
associated with improved outcomes. Thus, even during the earliest phase of critical
illness, the rationale and indications for fluid therapy, beyond an initial bolus, are not
well established. In light of these findings, the Surviving Sepsis Campaign has, in March
2015, revised their 2012 guidelines55 to remove the use of CVP and central venous ox-
ygen saturation as targets for hemodynamic therapy, including intravenous fluids.56
Once in the ICU, bolus fluid therapy is frequently continued provided with the inten-
tion of improving systemic hemodynamics and tissue perfusion. The rationale of bolus
fluid is to augment cardiac output in the context of presumed inadequate ventricular
preload. However, routine hemodynamic targets of resuscitation (blood pressure,
heart rate, CVP) are poorly predictive of cardiac output and much less indicative of
 Fluid Overload 5

adequate tissue perfusion; the effects of acute illness, chronic disease, and drug ther-
apy can unpredictably alter the response of the cardiovascular system to fluid admin-
istration. In particular, there are no clinical data to support a link between CVP and
circulating volume or hemodynamic response to fluid therapy,57 as the relationship be-
tween CVP, cardiac performance, and fluid responsiveness is highly variable depend-
ing on the clinical context.58 Generally in critical illness, the cardiovascular response to
fluid is modified by diverse factors, including myocardial function,19,59,60 arterial resis-
tance, regional perfusion,61,62 venous reservoir capacity, and capillary permeability,63
making the clinical assessment of the response to fluid therapy very challenging
resulting in considerable clinical practice variation. Importantly, although fluid therapy
will only effectively treat hypovolemic shock,6466 it is frequently used in the context of
cardiogenic and vasodilatory shock to rule out a hypovolemic component, with little
regard to the substantial risks of fluid accumulation in these conditions. Measure-
ments of cardiac output do provide information on global tissue perfusion and allow
fluid and other inotropic therapies to be titrated against cardiac response and should
be considered if there is any uncertainty about the potential response to fluid therapy;
however, in practice, these are not routinely used in contemporary ICUs.67 However,
indiscriminate use of intravenous fluid to maximize cardiac output in established crit-
ical illness might not be beneficial if the effects are short lived or do not correlate with
improvement in tissue oxygenation. For instance, in a large animal model, intravenous
fluid boluses caused short-lived increases in cardiac output and blood pressure68 but
no change in renal oxygen delivery. Similarly, in a rat model of hemorrhagic shock,
fluid resuscitation with crystalloids could restore systemic blood pressure but had
no effect on renal microvascular oxygenation.69
The natural consequence of exploratory fluid therapy and persistent boluses given
to achieve short-lived hemodynamic responses is fluid accumulation.68,70 This fluid
accumulation is particularly pronounced in systematic inflammatory states. In sepsis,
rapid fluid redistribution from damaged and leaky capillaries means only 5% of the vol-
ume of fluid infused is estimated to remain in the intravascular compartment after
90 minutes71; even in an intact circulation, only around 20% of infused crystalloid re-
mains in the vascular compartment after redistribution.72 These effects, combined
with obligate fluid input, are from a multitude of sources73; the relative inability of
the kidney to manage salt and water homeostasis in the context of critical illness
means that almost all critically ill patients are at risk of fluid overload.17 As the adverse
effects of fluid overload and limited clinical effects of fluid therapy are increasingly
recognized,74 clinical fluid administration is likely to shift from ensuring adequacy of
fluid resuscitation to focus much more on the prevention and treatment of fluid over-
load. However, in order to confidently make this paradigm shift from a deeply
engrained culture of repeated fluid boluses, a sound understanding of the pathophys-
iology of the development of fluid overload, its adverse effects on organ systems, and
the therapeutic strategies for its resolution are required.

PATHOGENESIS OF FLUID OVERLOAD

Fluid overload can be defined as a pathologic accumulation of water and dissolved

electrolytes in the body beyond that seen in healthy individuals. In general, this excess
fluid accumulates as extracellular fluid in expandable interstitial compartments as
interstitial edema and as macroscopic fluid collections in the thorax (pleural effusions)
or abdomen (ascites). Thus, fluid overload is predominantly a syndrome of interstitial
edema and total of body sodium excess (the predominant extracellular cation). As dis-
cussed, interstitial edema is likely to mediate many of the adverse effects of fluid
6 OConnor & Prowle

overload.17 At an organ level, tissue edema impedes capillary blood flow and
lymphatic drainage, especially in encapsulated organs, such as the kidneys and liver,
where additional volume cannot be accommodated without an increase in interstitial
pressure,75 causing further impairment of organ perfusion and function.
The dynamic role of vascular integrity in maintaining vascular volume means that it is
crucial to consider key structures, such as the endothelial glycocalyx, when consid-
ering the development and treatment of fluid overload.76,77 In recent years, our under-
standing of the vascular biology of edema formation in the capillary bed has
progressed from a balance of pressure-driven plasma ultrafiltration across the capil-
lary wall and colloid-osmotic pressuremediated plasma reabsorption, in the classic
Starling model, to a revised model incorporating our knowledge of the structure and
function of the glycocalyx.78,79 The glycocalyx is a complex network of cell-bound pro-
teoglycans, glycosaminoglycan side chains, and sialo-proteins that envelop the
luminal side of intact endothelium including the intercellular endothelial cleft where
intercellular transcapillary water fluxes occur.80 The glycocalyx participates in
numerous physiologic functions from regulating vascular permeability to storing a
large proportion of noncirculating plasma volume and modulating inflammation and
hemostasis. An important functional role of the glycocalyx is to bind plasma proteins;
this effectively excludes proteins from the subendothelial cleft (ETC) resulting in a local
oncotic gradient between the plasma and cleft opposing transcapillary water
efflux.78,79 An understanding of the glycocalyx function has, thus, led to a revised Star-
ling model whereby a local oncotic gradient that remains fairly constant along the
capillary and opposes and attenuates pressure-mediated plasma water efflux without
ever causing reabsorption of fluid from the interstitium, except in specialized vascular
beds in the renal tubules and the intestines.78 This model has several important phys-
iologic implications. Firstly, the primary pathology resulting in increased capillary
permeability in inflammatory states is the disruption of the glycocalyx, which is a phys-
ical process that will not be rapidly reversible once established. Secondly, rates of fluid
loss from capillaries will be determined by capillary pressure (increased by increased
venous pressure and the extent of precapillary arteriolar vasodilation, which transmits
systemic pressure to the capillary bed) but relatively little by plasma oncotic pressure,
as the oncotic gradient in the small ETC is chiefly determined by glycocalyx integrity.
Finally, as transcapillary fluxes are smaller than previously predicted and unidirec-
tional, almost all vascular refilling from the interstitium occurs via lymphatic chan-
nels.78,79 These observations have corresponding clinical implications: Firstly, once
the glycocalyx is disrupted, patients will be at ongoing risk of fluid interstitial accumu-
lation. Secondly, manipulation of the colloid concentration in plasma is not likely to
provide much more effective vascular filling and certainly will not encourage vascular
refilling form the capillary bed findings consistent with the limited hemodynamic
benefit of colloids over crystalloids in resuscitation72 and absence of any fluid sparing
effect in patients with severe sepsis.81 Finally, vascular refilling during fluid removal is
likely to be slow and relatively fixed; therefore, tolerance of rapid rates of fluid removal
in critically ill patients will be poor and a little offset by elevating colloid-osmotic pres-
sure. Evidence of widespread alteration and breakdown of the endothelial glycocalyx
has been demonstrated in disease states, such as sepsis,8285 major surgery,85
trauma,86 and postischemic states87; this process occurs both because of the direct
effect of ischemia, oxidative stress, and pathogen-host responsemediated injury or
because of the effect of circulating toxins, such as lipopolysaccharide and inflamma-
tory mediators, particularly tumor necrosis factor (TNF) a.82,84,88 Acute hyperglycemia,
a common finding in critical illness, has also been associated with loss of glycocalyx
integrity.89 As well as leading to plasma water and protein extravasation, loss of
 Fluid Overload 7

glycocalyx potentiates ongoing inflammatory responses by of exposure of endothelial

cell adhesion molecules.76,90 Such mechanisms may mediate important pathologic
events associated with interstitial edema, such as acute lung injury.84
In combination, loss of fluid from the vascular space and loss of glycocalyx volume
itself, which causes an increase vascular fluid capacitance, create a potential need for
fluid replacement, but in a context whereby further interstitial edema may rapidly arise.
This circumstance presents a clinical dilemma of providing enough fluid to avoid overt
hypovolemia while avoiding a vicious cycle whereby volume expansion leads to wors-
ening tissue edema impairing further organ function. Although squaring this circle may
by impossible in many patients, an awareness of these mechanisms should prompt
fluid therapy to be regarded not as an obligation but as a powerful drug therapy to
be carefully titrated.
In addition to a clear role in the development of edema in systemic inflammation,
glycocalyx dysfunction seems to play a central role in edematous states more gener-
ally, emphasizing the key importance of this mechanism. For instance, in nephrotic
syndrome, the primary processes driving edema are now thought to be primary renal
salt and water retention and systemic inflammation involving TNF a91 rather than
hypoalbuminemia, which, in isolation, does not cause edema. Similarly, atrial natri-
uretic peptide release, stimulated by mechanical wall stress cardiac atria, has been
shown to cause acute deterioration of the glycocalyx and is associated with increased
vascular permeability and intestinal fluid shift.92,93 Perioperatively, volume expansion
has been shown to mediate atrial natriuretic peptide (ANP) release and shedding of
glycocalyx,94 raising the possibility that fluid therapy can indirectly compromise
vascular integrity and worsen fluid shifts to the interstitium. These mechanisms sug-
gest that there may be an unappreciated, long-lasting effect of strategies to elevate
CVP or maximize cardiac output with volume expansion in the critically ill if this triggers
ANP release.
Another underappreciated mechanism of edema formation is alteration of structure
and function of the extracellular matrix (ECM) in systemic inflammation and critical
illness.95 Normally, fluid loss from capillaries leads to increased interstitial pressure
opposing transcapillary ultrafiltration and promoting lymphatic filling, which is the
initial process in lymphatic drainage. However, after local tissue injury or exposure
to inflammatory mediators, interstitial pressure has been noted to decrease, despite
rapid efflux of fluid to the interstitium. Decreased interstitial pressure is thought to arise
because of the release of cellular tension exerted on the collagen and microfibril net-
works in the ECM by mechanisms including release of collagen-binding b1-integrins.96
In addition to the loss of ECM mechanical integrity, the resultant exposure of glycos-
aminoglycan ground substance, which is normally compressed and underhydrated,
expands and takes up fluid.95 Local injury97 and a wide range of local and systemic
inflammatory mediators98 and toxins, including lipopolysaccharide,99 have been
shown to mediate such ECM changes with a decrease in interstitial pressure, which
promotes the development and retention of tissue edema. Finally, low interstitial pres-
sure in combination with disruption of local lymphatic architecture and the direct effect
of inflammatory mediators and immobility on lymphatic function will result in impaired
lymphatic drainage of accumulated tissue fluid, further contributing to interstitial fluid
accumulation.100
Overall, the current understanding of the vascular biology of interstitial edema em-
phasizes the structural changes in the capillaries and endothelium that predispose to
interstitial fluid accumulation, which are mechanisms that are not directly related to
plasma protein loss or colloid osmotic pressure (Fig. 2). These changes may actually
be worsened by excessive volume loading through direct and endocrine mechanisms.
8 OConnor & Prowle

Fig. 2. Systemic inflammation results in disruption of endothelial glycocalyx and changes in

the ECM and lymphatic drainage that promote loss of plasma fluid to the extracellular space
and its retention in the interstitial compartment. These processes have implications for the
magnitude and duration of response to fluid therapy and ability to resolve fluid overload
once it has arisen. LPS, lipopolysaccharide.

An important consequence of the modified Starling model incorporating understand-

ing of the role of the glycocaylx is that as return of fluid to the circulation is predomi-
nantly by lymphatic drainage, the ability to rapidly resolve fluid accumulation by
diuresis or ultrafiltration will be limited. Thus, although the prevention of fluid overload
in critical illness will be very challenging, every fluid administration should be carefully
considered, as resolution of the resultant interstitial edema is likely to be very difficult.

MANAGEMENT OF FLUID OVERLOAD

Controlling Fluid Intake
Equipped with an appreciation of the causes and consequences of fluid overload, cli-
nicians can adopt a more systematic approach to fluid management in the ICU. Thus,
the process has to commence with the rationale management of fluid resuscitation to
minimization initial fluid accumulation. In brief, recent conceptual models of resuscita-
tion of the critically ill have emphasized sequential phases of fluid resuscitation.101 In
this approach, fluid therapy is provided emergently during very acute clinical instability
(rescue phase) but is rapidly tempered to judicious use of intravenous fluid to optimize
the hemodynamic status and thence to a stabilization phase whereby clinicians aim for
an even or slightly negative fluid balance. Finally, in the de-escalation phase, the clini-
cian aims to mobilize accumulated fluid during the initial resuscitation. This approach
places the consideration of fluid overload at the center of the hemodynamic manage-
ment of shock rather than as an after thought and emphasizes the need to consider the
need for fluid therapy in the context of clinical response and fluid balance at all stages
 Fluid Overload 9

of critical illness. In line with this concept, the authors have suggested an approach
whereby, beyond the initial first few hours of acute critical illness, evidence of inade-
quate organ function should prompt the assessment of the cardiac output and bolus
fluid therapy should be considered only in the context of inadequate cardiac output
and evidence of volume responsiveness, with an end point of an acceptable level of
cardiac output and system perfusion and not with the intention to maximize stroke vol-
ume.38 This strategy sets several hurdles to justify fluid therapy, reflecting the
complexity of the assessment of volume status in critical illness, the short-lived effect
of fluid therapy, the longer-term adverse effects of fluid overload, and the great diffi-
culty of removing fluid once it has been lost to the interstitium.

Fluid Removal: Diuretics, Ultrafiltration, and Monitoring

The more rigorous approach to the assessment of need for fluid therapy described
earlier is then accompanied by a process of continued assessment and management
of fluid balance, with the intention of preventing or resolving fluid overload once sta-
bility has been achieved. A schematic approach to this process has been sug-
gested38,73; if signs of fluid overload are present, then steps to resolve this should
be undertaken, whereas if a patient is perceived to be euvolemic, then fluid balance
should be actively managed to prevent the acquisition of fluid overload, particularly
if prescribed fluid inputs is high (Fig. 3). Choice of diuretic therapy over mechanical
fluid removal will depend on renal function, baseline urine output, and severity of fluid
overload; however, the response to therapy should be regularly reassessed. Although
evidence suggests that the use of diuretics to treat established AKI is ineffective102
and may delay definitive AKI management with RRT,103 their use in a large population
of patients with AKI in the ICU has not been associated with increased mortality104;
thus the use of diuretics to manage fluid balance, paying close attention to clinical
response, is logical and clinically supportable.105 A diuretic challenge at an adequate
dose of 1.0 to 1.5 mg/kg furosemide may be useful in making an early assessment of
patients likely to respond and those that may require RRT to avoid definite fluid man-
agement in those likely to require it.106,107
When using an active fluid management strategy with diuretics or mechanical ultra-
filtration, it is important to distinguish between the overall level of fluid overload (the
eventual target) and the ability to remove fluid from the circulation without inducing he-
modynamic instability. In the sickest patients, these two factors may be disassociated
necessitating a slow transition from prevention of further accumulation of fluid to slow
fluid removal. Different forms of monitoring inform clinicians on these differing aspects
of therapy; static assessments of fluid status inform on the extent of fluid accumula-
tion, whereas dynamic assessments of cardiac output and tissue perfusion provide in-
formation on tolerance of rate of removal (Table 2).
Determining the total quantity of fluid overload and the goal of therapy is chal-
lenging, as charted fluid balances are often inaccurate and do not account for unmea-
sured fluid losses or change in flesh weight during prolonged critical illness. However,
charted daily fluid balance do seem to be a more useful guide in determining the risk of
fluid overload than daily weights in the ICU, which can be inaccurate in guiding fluid
management in the critical care setting.108 Bioelectrical impedance body-
composition analysis (BIA), a noninvasive method of fluid assessment, can provide es-
timates of total-body, extracellular, and intracellular water to allow the quantification of
fluid overload and setting of dry weight109,110; BIA is used widely in determining the
fluid status in patients with end-stage renal failure on hemodialysis or peritoneal dial-
ysis. However, this technology has not been extensively validated in critical care; its
benefit over use of a well-kept fluid balance has not yet been established.
 10
OConnor & Prowle
Fig. 3. A clinical approach to prevention and treatment of fluid overload after the initial phase of critical illness. Many different technologies for
hemodynamic and fluid balance assessment can be applied within this philosophy. ECMO, extracorporeal membrane oxygenation; FB, fluid balance;
UF, ultrafiltration. (Adapted from Rosner MH, Ostermann M, Murugan R, et al. Indications and management of mechanical fluid removal in critical
illness. Br J Anaesth 2014;113(5):76471; with permission.)
 Fluid Overload 11

Table 2
Methodology for assessment of response to changes in circulating volume and quantification
fluid overload in critically ill patients

Measure Characteristics
Measures of fluid responsiveness and tolerance of fluid removal
Stroke volume variation Requires mandatory mechanical ventilation
Pulse pressure variation Indicates position on Frank-Starling curve not extent
of tissue fluid overload
Echocardiography Subjective impression of right ventricular filling and
inferior vena cava collapse
Requires technical expertise
Poor windows in critically ill
Passive straight leg raise Provides impression of fluid responsiveness without
requirement for fluid challenge
Difficult or impossible in some patients
Stroke volume or other hemodynamic Require administration of fluid
response to fluid challenge Positive response does not imply fluid is clinically
indicated or that response will be sustained
Fluid responsiveness is normal physiologic state
Central venous or pulmonary artery No evidence that absolute values or relative changes
wedge pressure correlate with cardiac output or fluid
responsiveness
Very low values may imply right ventricular preload
could be increased with fluid therapy
Blood volume monitoring A monitor of reverse fluid responsiveness, the
(continuous hematocrit) hemodynamic effect of fluid removal
Currently available during hemodialysis only
May be too imprecise to preempt hypotension during
ultrafiltration in the critically ill
Measures of fluid overload
Clinical examination Significant volume overload can occur without edema
(peripheral and pulmonary Edema and intravascular volume depletion may
edema) coexist
Wide range of addition contributing causes
Serial weight Quantifies extent of fluid overload
Difficult to perform in critically ill
Loss of muscle and fat mass may mask fluid gain
Cumulative fluid balance Quantifies extent of fluid overload
Often imprecisely recorded
Difficult to account for insensible losses
Chest radiograph Gives impression of pulmonary edema only
Wide differential diagnosis
Oxygenation indices Nonspecific for fluid overload depending on clinical
Ventilatory requirements context
Lung ultrasound More sensitive for early pulmonary congestion before
chest radiograph, oxygenation, and symptomatic
changes116
Requires technical expertise
May be confounded by other pulmonary pathology
Echocardiography Subjective impression of right ventricular or inferior
vena cava distension
Requires technical expertise
Poor windows in critically ill

(continued on next page)

12 OConnor & Prowle

Table 2
(continued )
Measure Characteristics
Intra-abdominal pressure Only significant if abnormal
Cause may be primary or secondary (fluid overload)
Bioimpedance analysis of body Noninvasive
composition Enables separate estimate of extracellular volume
over hydration and intracellular (muscle) volume
Quantifies extent of fluid overload
Methodology not validated in critically ill
May be difficult to perform good-quality
measurements at bedside in ICU
Requires accurate weight measurement
Range of algorithms to calculate volume
measurements, which are device specific and may
not be applicable to critically ill

Adapted from Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the prevention and atten-
uation of acute kidney injury. Nat Rev Nephrol 2014;10(1):42; with permission.

Given the difficulty in determining the true extent of fluid overload and the uncertain
tolerance of fluid removal even when significant overload is present, dynamic moni-
toring of fluid removal should not be neglected. The commencement of fluid removal
could be considered a reverse fluid challenge using the same clinical and hemody-
namic monitoring that would be used to assess the response to fluid administration.
These considerations are important in assessing the outcomes of fluid removal strate-
gies. A follow-up of a sample of patients from the FACCT study demonstrated that pa-
tients in the conservatively managed group tended to have poorer cognitive function
after recovery from critical illness; hypothetically, this could be linked to transient epi-
sodes of hypoperfusion during fluid management.111 In line with this, although patients
in FACCT only received fluid removal when strict criteria for hemodynamic stability
were present, there was a higher incidence of new shock in the conservative arm. A
recent follow-up nonrandomized study examined a FACCT-Lite conservative fluid
strategy,112 which resulted in an approximately 2-L positive fluid balance over
7 days (compared with even and 17-L balances, respectively, with conservative and
liberal strategies in FACCT); this approach demonstrated similar respiratory and renal
outcomes to the conservative group in FACCT but with a new shock incidence similar
to the liberal arm, suggesting this may be a safer approach. Further evidence for the
importance of hemodynamic stability during fluid removal is found in the large body
of observation evidence suggesting that the use of continuous renal replacement ther-
apy for the treatment of AKI in the ICU is associated with improved long-term renal out-
comes compared with intermittent dialysis.113,114 This observation is potentially related
to lower rates of hemodynamic instability and recurrent renal ischemia associated with
slower fluid removal that allows for the slow vascular refilling during continuous or
extended ultrafiltration.115 Related to improved tolerance of fluid removal, continuous
therapy has been shown to better allow negative fluid balances to be achieved in the
ICU compared with intermittent therapy, which was associated with progressive fluid
accumulation.11 Thus, continuous use of extended RRT modalities may be beneficial
to long-term organ function both by avoiding recurrent hemodynamic instability and
by achieving better resolution of fluid overload. Collectively, this evidence suggests
that fluid removal strategies do need to be carefully titrated and monitored and that
 Fluid Overload 13

futures trials considering such approaches will have to consider measures on longer-
term organ functions as well as short-term ICU outcomes.

SUMMARY

In the critically ill, fluid overload is widely prevalent and has been consistently associ-
ated with adverse outcomes and organ dysfunction. Although some degree of fluid
accumulation is an almost inevitable consequence of early resuscitation requirements
and obligate fluid intakes, many patients receive multiple fluid boluses to ill-defined in-
dications and with, at best, very short-term hemodynamic effects. Once accrued, fluid
overload is challenging to resolve, as structural changes in the vascular bed and the
ECM promote fluid sequestration in the interstitial compartment. Thus, any approach
to fluid management requires careful attention to the true requirement for fluid thera-
pies; fluids should be regarded as powerful drugs with serious potential adverse ef-
fects rather than a default low-risk response to clinical changes.
Critical care should involve the regular assessment, management, and prevention of
fluid overload. When fluid removal is attempted, careful and continued monitoring is
essential, as vascular refilling is likely to be slow and the extent of total fluid accumu-
lation and tolerance of fluid removal may be poorly correlated. As yet there is little pro-
spective evidence to guide clinicians in this area, and therapy should be tailored to
individual patient requirements.

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