Journal of Critical Care 29 (2014) 204209

Contents lists available at ScienceDirect

Journal of Critical Care

journal homepage: www.jccjournal.org

A systematic review of goal directed uid therapy: Rating of evidence

for goals and monitoring methods
Heath Wilms, BCom, MBus, Anubhav Mittal, BHB, MBChB, PhD, FRACS, Matthew D. Haydock,
Marc van den Heever, BCA, BSc, Marcello Devaud, MBChB, John A. Windsor, BSc, MBChB, MD, FRACS, FACS
The University Of Auckland, Auckland, New Zealand

a r t i c l e

i n f o

Keywords:
Goals
Fluid therapy
Endpoint
Treatment outcome
Physiologic monitoring

a b s t r a c t
Purpose: To review the literature on goal directed uid therapy and evaluate the quality of evidence for each
combination of goal and monitoring method.
Materials and Methods: A search of major digital databases and hand search of references was conducted. All
studies assessing the clinical utility of a specic uid therapy goal or set of goals using any monitoring method
were included. Data was extracted using a pre-determined pro forma and papers were evaluated using GRADE
principles to assess evidence quality.
Results: Eighty-one papers met the inclusion criteria, investigating 31 goals and 22 methods for monitoring uid
therapy in 13052 patients. In total there were 118 different goal/method combinations. Goals with high evidence
quality were central venous lactate and stroke volume index. Goals with moderate quality evidence were sublingual
microcirculation ow, the oxygen extraction ratio, cardiac index, cardiac output, and SVC collapsibility index.
Conclusions: This review has highlighted the plethora of goals and methods for monitoring uid therapy. Strikingly,
there is scant high quality evidence, in particular for non-invasive G/M combinations in non-operative and nonintensive care settings. There is an urgent need to address this research gap, which will be helped by methodologies
to compare utility of G/M combinations.
2014 Elsevier Inc. All rights reserved.

1. Introduction
Almost 40 years ago, Shoemaker and colleagues published a
landmark study introducing the use of physiological goals to guide
uid therapy [1]. They demonstrated that mortality could be reduced
by titrating uid therapy to pre-determined cardiorespiratory variables. This was the birth of goal directed uid therapy (GDFT).
Since then many goals have been promoted to direct uid therapy,
both invasive and non-invasive [2]. Despite evidence demonstrating the
potential benet of GDFT in a number of disease states [3], there remains
no consensus about the most effective goals for uid therapy or the most
appropriate monitoring methods. As such, GDFT remains a well-accepted
concept that has not yet translated to an established standard of care.
Formal evaluation of the different goal/method (G/M) combinations for
GDFT has been hampered by the many different goals, the number of
methods to monitor uid therapy, the variation in study design, and the
lack of comparable controls. A new approach to evaluating G/M
Conicts of Interest and Sources of Funding: the authors have had no nancial
support in the preparation of this manuscript. The authors have no conicts of
interest to declare.
Corresponding author. Pancreas Research Group, Surgical Research Network,
Department of Surgery, School of Medicine, Faculty of Medical and Health Sciences,
University of Auckland, Private Bag 92019, Auckland 1023 (New Zealand). Tel.: +64
9 373 7599.
E-mail address: j.windsor@auckland.ac.nz (J.A. Windsor).
0883-9441/$ see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcrc.2013.10.019

combinations is required so that the leading options can be formally

studied to establish an evidence based standard of care for GDFT.
The aim of this study was to conduct a systematic review of the
literature and evaluate the quality of evidence for each G/M
combination using the established GRADE methodology [49].
2. Materials and methods
2.1. Literature search
A systematic and comprehensive search of major reference
databases (PubMed, MEDLINE, Embase, and the Cochrane Library)
was undertaken with no constraint on publication date (all available
entries to Feb 2013 were searched) or language using the search
string: (uid and (goal-directed or endpoint)).mp. [mp = protocol
supplementary concept, rare disease supplementary concept, title,
original title, abstract, name of substance word, subject heading word,
unique identier]. The reference lists of articles selected for inclusion
as well as all relevant review articles were hand searched to ensure
inclusion of all relevant studies.
2.2. Inclusion and exclusion criteria
Articles were assessed for inclusion by 2 reviewers (HW and MH). All
laboratory studies, observational studies and clinical trials that directly

H. Wilms et al. / Journal of Critical Care 29 (2014) 204209

assessed the efcacy of a specic uid therapy goal or set of goals in

combination were identied. Randomized controlled trials (RCTs),
cohort studies, case control studies, case series and historical control
studies were all included. Review papers were excluded (although their
reference lists were hand searched) as well as any papers that did not
investigate the benets of at least one goal for uid therapy. The
concurrent use of inotropes and vasopressors was permitted.
2.3. Data extraction
Four authors (HW, MH, MV and MD) were involved in data
extraction and checking the data for accuracy, which was done using a
pre-dened pro forma. The data elds in the template included title,
authors, date of publication, study type, setting, participant numbers,
participant description, goal(s) assessed, outcomes assessed, exposure
and comparison interventions, outcomes and precision of outcomes.
2.4. Data denitions
The term uid therapy included any form of intravenous uid
encompassing resuscitation, maintenance, replacement and nutrition
uid therapy. The publications were identied as human or animal
studies. As each goal could be measured by several different methods,
and thus there could be several G/M combinations. The methodology
used to measure each goal was further categorized as invasive or noninvasive. Invasive was dened as requiring a monitoring method that
involved puncture of the skin (excluding peripheral venous blood
sampling), use of an indwelling catheter or an endoscope. Invasive
methods were further subdivided into those that required the patient
to be ventilated or those that could be used in non-ventilated patients.
Non-invasive techniques were dened as those that were monitored
by an entirely external methodology.

205

Table 1
Rating of evidence quality and usefulness
Factor

Descriptors

Study design

+1 Paper is an RCT
1 Paper is an observational study
0 Negligible limitations likely to cause biases in the
body of evidence
Study bias
1 Serious limitations likely to cause biases in the
body of evidence
2 Very serious limitations likely to cause biases in the
body of evidence
+1 Paper nds benet by targeting goal
Inconsistency
0 Paper nds no benet by targeting goal
1 Paper nds harm done by targeting goal
0 Negligible doubts about directness of measures used
in body of evidence
Indirectness
1 Serious doubts about directness of measures used
in body of evidence
2 Very serious doubts about directness of measures
used in body of evidence
0 No signicant result, or signicant results have
clinically signicant CI margins
Imprecision
1 Some key signicant results with questionably
clinically signicant CI margins
2 Signicant results with no clinically signicant
CI margins
0 No evidence of publication bias for body of evidence
(peer reviewed journal)
Publication bias
1 High probability of publication bias (non peer
reviewed journal)
2 Very high probability of bias (known previous non
publication of results)
Large effect
+2 Relative risk ratio N5 or b0.20
+1 Relative Risk Ratio 2-5 or 0.5-0.2
0 = Relative Risk Ratio 0.5-2 or not presented in
paper/not calculable
Bias causing conservatism +1 All possible biases are likely to cause conservative
estimation of effects
0 All possible biases are not likely to have this effect.

2.5. Rating the quality of evidence

The body of evidence from clinical studies supporting each G/M
combination was assessed using the GRADE methodology [49]. The
GRADE method identies several qualities that either decrease or
increase the quality of a body of evidence. The factors decreasing
evidence quality are poor study design (for example observational
studies rather than RCTs), study bias (for example, an RCT with
inadequate blinding), inconsistency of results between studies (if more
than 33% of studies investigating a particular G/M combination are found
to have opposing ndings), indirectness of measures (if a secondary
measure is used to proxy for a main study outcome), imprecision in
outcome measurement and publication bias. Factors increasing evidence
quality include; a large intervention effect, the presence of a dose
response gradient and when confounding variables are present that
would likely cause a conservative estimate of the true effect.
Each clinical paper was evaluated in the same fashion as done by the
GRADEPro software [10] and all factors were included excepting the
presence of a dose response gradient as this was deemed not applicable
to the outcomes assessed in our sample of papers. The reason for this
being that the outcomes investigated are not consistently reported as
continuous variables and therefore it is not possible to demonstrate a
doseresponse gradient. The rating rubric used is shown in Table 1. In
line with the GRADE method, an evidence score of 1 equates to high
quality evidence, 0 equates to moderate quality, -1 equates to low
quality and 2 equates to very low quality.

studies is summarized in Fig. 1. A total of 81 studies were included.

These included six laboratory studies (Supplementary Table 1) and 75
clinical studies comprising 13,052 patients. Of the 81 studies, 42 were
obtained by hand searching reference lists. The entire sample of studies
investigated 31 unique goals, and 22 methods of monitoring to give a
total of 118 G/M combinations. Of these combinations, 96 were invasive
and 22 non-invasive. Table 2 shows the 108 different combinations of
goals and methods for monitoring uid therapy evaluated by the 75
clinical studies. Three G/M combinations were only investigated by
laboratory studies and as a result are not included in Table 2. The 6
laboratory studies investigated 10 G/M combinations between them
(see Supplementary Table 1). The most frequently investigated goal for
monitoring uid therapy was stroke volume as determined by
oesophageal Doppler (n = 14).
3.2. Clinical endpoints
The studies covered a large number of different clinical endpoints
making quantitative analysis (i.e. a meta analysis) impossible. Studies
generally investigated either clinical endpoints or the accuracy of
measurement of a specic G/M combination.

3.3. Rating the evidence around goals and methods of monitoring

uid therapy

3. Results
3.1. Data overview
A total of 1118 articles published between 1984 and 2013 were
identied by the initial literature search. The inclusion and exclusion of

Fig. 2 shows a breakdown of the evidence quality behind the

108 G/M combinations from the clinical studies. The most striking
nding is that very little high quality evidence exists in any category.
Table 2 further subdivides clinical studies into individual G/M
combinations within the non-invasive, invasive non-ventilated and

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H. Wilms et al. / Journal of Critical Care 29 (2014) 204209

3.5. Invasive non-ventilated G/M combinations

Only 2 goals in this category had an evidence base of high or
moderate quality (central venous lactate and the oxygen extraction
ratio respectively).
3.6. Invasive ventilated G/M combinations
Goals in this category were investigated more often than any other,
and four goals achieved high (stroke volume index) or moderate evidence quality (cardiac index, cardiac output and SVC collapsibility
index). In this group, oesophageal Doppler was the most frequently
investigated method but the quality of the evidence was low to very low.
4. Discussion

Fig. 1. PRISMA ow diagram.

invasive ventilated categories and states the quality of evidence for

each combination as a whole.

3.4. Non-invasive G/M combinations

Generally the quality of evidence investigating non-invasive G/M
combinations is poor. No goal had a high quality evidence base and
only a single goal (sublingual microcirculation ow) was found to
have moderate quality.

Goal directed uid therapy has a rapidly expanding literature base

and is a well-accepted concept. This is the rst comprehensive systematic review of the many non-invasive and invasive G/M combinations used to guide uid therapy. It demonstrates that despite the
plethora of studies there is no consensus on which approach is best, or
worthy of further investigation. Direct comparison between studies is
hampered by the large range of goals and methods for monitoring,
inconsistent study design and the lack of a common control group.
This review found that most studies have investigated invasive
techniques to monitor the effects of uid therapy (96 invasive G/M
combinations compared with 22 noninvasive), even though the vast
majority of patients receiving intravenous uid therapy are neither
anaesthetized nor ventilated. This is a surprising result given the widespread availability of simple and inexpensive monitoring methods, and
the low level of training required for non-invasive GDFT. There is a clear
need for further research to evaluate non-invasive G/M combinations to
direct uid therapy in non-operative and non-intensive care settings.
The lack of a common control group around GDFT prevented a
formal comparison of different G/M combinations for clinical utility.
This means that it is not possible to provide clear guidance to
clinicians about which goals or monitoring methods are more
clinically useful or to researchers as to which should be prioritized
for further study. Future research efforts may focus on developing an
index of utility to allow comparison between diverse goals, settings,
disease states and outcomes.

Fig. 2. Publications by category and evidence quality.

H. Wilms et al. / Journal of Critical Care 29 (2014) 204209

207

Table 2
Clinical studies and evidence quality by goal/method combination

Non invasive

Invasive
Non-ventilated

Goal

Monitoring method

Evidence quality Number of papers References

Sublingual microcirculation ow
Mean arterial pressure
Urine output
Stroke volume
Maintenance of normal uid balance
Lactate clearance
Pulse oximeter-derived pleth variability index
Skeletal muscle O2 saturation
Lactate
Cerebral O2 saturation
Central venous pressure
Central venous lactate
Oxygen extraction ratio
Oxygen delivery index
Cardiac index
Mixed venous O2 saturation
Central venous O2 saturation

Sidestream Darkeld Imaging

BP Cuff
Urinary catheter
Finometer nger pressure cuff
Fluid balance monitoring
Peripheral blood sample
Pulse oximeter with PVI capability
NIRS optode
Peripheral blood sample
NIRS optode
Ultrasound
Central line sampling
Central line + arterial line sampling
Invasive CO measurement + arterial sampling
Transpulmonary dilution
Pulmonary artery catheter
Central line

Moderate
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
High
Moderate
Low
Low
Low
Very low

2
2
2
1
4
1
3
1
2
1
1
1
1
4
3
1
10

Pulmonary artery catheter + VoLEF + PiCCO

Central line + pressure transducer
Central line + arterial line sampling
Transpulmonary dilution
Transpulmonary dilution
Pulmonary artery catheter
Self calibrating pulse contour analysis
Self calibrating pulse contour analysis
Oesophageal doppler
Oesophageal doppler
Self calibrating pulse contour analysis
Calibrated pulse contour analysis (PiCCO/LiDCO)
Oesophageal doppler
Calibrated pulse contour analysis (PiCCO/LiDCO)
Oesophageal doppler
Arterial line + monitoring equipment
Oesophageal doppler
Calibrated pulse contour analysis (PiCCO/LiDCO)
Self calibrating pulse contour analysis
Oesophageal doppler
Oesophageal doppler

Very low
Very low
Very low
Very low
Very low
Very low
High
Moderate
Moderate
Low
Low
Low
Low
Low
Very low
Very low
Very low
Very low
Very low
Very low
Very low

1
7
5
4
2
3
1
3
1
13
7
2
2
2
1
4
4
2
2
1
1

Left ventricle end diastolic volume index

Central venous pressure
Arterio-venous CO2 pressure difference
Intrathoracic blood volume
Global end diastolic volume index
Pulmonary wedge pressure
Invasive ventilated Stroke volume index
Cardiac index
SVC collapsibility index
Stroke volume
Stroke volume variation
Cardiac output
Stroke volume index
Stroke volume
IVC diameter change
Pulse pressure variation
Corrected aortic ow time
Cardiac index
Stroke volume
Cardiac output
Aortic blood ow variation

In conclusion, this systematic review of the literature relating to

goal directed uid therapy has highlighted the weak evidential base
for this well-accepted concept. The published research in this area is
slanted towards more invasive and technology dependent methods in
ventilated patients. However, the majority of patients receiving uid
therapy are ward patients who are not appropriate for invasive
methods. Therefore, the research priority must be to evaluate goals
and monitoring methods that are appropriate to the awake nonventilated ward patient. The development of a pragmatic utility rating
index may in the future permit comparison of different G/M
combinations. Most important is the need for undertaking better
designed and powered studies to provide evidence in support of
different goals and methods of monitoring uid therapy.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.jcrc.2013.10.019.
Acknowledgments
The authors have had no nancial assistance in preparing this
review and have no conicts of interest to declare.
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Further Reading
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haemodilution in the pig. Acta Anaesthesiol Scand 2005;49:114956.
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