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Eur J Anaesthesiol 2018; 35:1–15

ORIGINAL ARTICLE

Does goal-directed haemodynamic and fluid therapy

improve peri-operative outcomes?
A systematic review and meta-analysis
Matthew A. Chong, Yongjun Wang, Nicolas M. Berbenetz and Ian McConachie

BACKGROUND Much uncertainty exists as to whether peri-
operative goal-directed therapy is of benefit.
OBJECTIVES To discover if peri-operative goal-directed
therapy decreases mortality and morbidity in adult surgical
patients.
interval (CI) 0.50 to 0.87; number needed to treat ¼ 59; N ¼
52; I2 ¼ 0.0%]. In subgroup analysis, there was no mortality
benefit for fluid-only goal-directed therapy, cardiac surgery
patients or nonelective surgery. Contemporary goal-directed
therapy also reduced pneumonia (OR 0.69; 95% CI, 0.51 to
0. 92; number needed to treat ¼ 38), acute kidney injury (OR

F
DESIGN An updated systematic review and random effects 0. 73; 95% CI, 0.58 to 0.92; number needed to treat ¼ 29),
meta-analysis of randomised controlled trials. wound infection (OR 0.48; 95% CI, 0.37 to 0.63; number
needed to treat ¼ 19) and hospital length of stay (days)
DATA SOURCES Medline, Embase and the Cochrane
O (0.90; 95% CI, 1.32 to 0.48; I2 ¼ 81. 2%). No impor-
Library were searched up to 31 December 2016.
tant differences in outcomes were found for the pulmonary
ELIGIBILITY CRITERIA Randomised controlled trials enroll- artery catheter studies, after accounting for advances in the
O
ing adult surgical patients allocated to receive goal-directed standard of care.
therapy or standard care were eligible for inclusion. Trauma
CONCLUSION Peri-operative modern goal-directed therapy
patients and parturients were excluded. Goal-directed therapy
reduces morbidity and mortality. Importantly, the quality of
was defined as fluid and/or vasopressor therapy titrated to
PR

evidence was low to very low (e.g. Grading of Recommen-

haemodynamic goals [e.g. cardiac output (CO)]. Outcomes
included mortality, morbidity and hospital length of stay. Risk of
bias was assessed using Cochrane methodology.
RESULTS Ninety-five randomised trials (11 659 patients)
were included. Only four studies were at low risk of bias.
Modern goal-directed therapy reduced mortality compared
with standard care [odds ratio (OR) 0.66; 95% confidence
dations, Assessment, Development and Evaluation scoring),
and there was much clinical heterogeneity among the goal-
directed therapy devices and protocols. Additional well
designed and adequately powered trials on peri-operative
goal-directed therapy are necessary.
Published online xx month 2018

Introduction
The concept of peri-operative goal-directed haemody-
namic and fluid therapy (GDT) has its origins in the
seminal study by Shoemaker et al.1, where patients who
received preoperative haemodynamic optimisation
titrated to explicit goals of end organ blood flow had
improved outcomes. Over the decades, GDT has
remained a high area of interest in peri-operative study,
with the publication of nearly 100 randomised controlled
trials (RCTs) since the 1990s alone.1–95 In contrast to care
guided by traditional vital signs, the principle underlying
GDT is that the administration of fluid and vasopressors
be guided by explicit targets that reflect end organ blood
flow, such as cardiac index (CI), stroke volume (SV)
variation (SVV) or oxygen delivery (DO2).96 Historically,
such indices were measured by pulmonary artery cathe-
ters (PAC), but recently less invasive technologies have
become widely available.97 Such contemporary GDT
devices derive measurements using a variety of methods

From the Department of Anesthesia and Perioperative Medicine (MAC, YW, IMC) and Department of Medicine, Western University, London, Ontario, Canada (NB)
Correspondence to Dr Matthew A. Chong, MD, Department of Anesthesia and Perioperative Medicine, University Hospital – London Health Sciences Centre, 339
Windermere Road, C3-108, London, ON, Canada N6A 5A5
E-mail: matthew.a.chong@gmail.com

0265-0215 Copyright ß 2018 European Society of Anaesthesiology. All rights reserved. DOI:10.1097/EJA.0000000000000778

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2 Chong et al.

Table 1 Overview of contemporary goal-directed haemodynamic and fluid therapy devices

Technology Measurements derived Sample manufacturer(s) or brand(s)

Transpulmonary indicator dilution Cardiac output LiDCO and PiCCOß
Arterial waveform-derived Stroke volume variation and cardiac output FloTracTM, LiDCO and PiCCOß
Oesophageal Doppler Flow corrected time and stroke volume CardioQTM
Echocardiography Cardiac output, stroke volume and contractility assessment Philipsß and SonositeTM
Partial CO2 rebreathing Cardiac output NICOß
Bioreactance Cardiac output NICOMß

GDT can be guided by a variety of modern technologies to derive haemodynamic indices, such as cardiac output and measures of volume responsiveness.97 LiDCO,
lithium dilution cardiac output (LiDCO Ltd, Lake Villa, Illinois, USA); NICOß, noninvasive cardiac output (Novametrix Medical Systems, Wallingford, Connecticut, USA);
NICOMß, noninvasive cardiac output monitor (Cheetah Medical, Vancouver, Washington, USA); PiCCOß, pulse contour cardiac output. (PULSION Medical Systems SE,
Feldkirchen, Germany). For reference, the rest of the systems used as examples in this table are manufactured by the following companies: FloTracTM (Edwards Life
Sciences, Irvine, California, USA), CardioQTM (Deltex Medical, Chichester, United Kingdom), Philips Ultrasound Machines (Philips Ultrasound Inc., Reedsville,
Pennsylvania, USA) and SonositeTM (Sonosite Inc., Bothell, Washington, USA).

from transpulmonary indicator dilution to arterial wave- care and that reported at least one clinical outcome
form analysis. These are summarised in Table 1.97 of interest.
Given the clinical importance of GDT and its potential to
Study selection
improve patient outcomes, investigating whether or not
Patient groups
these interventions are truly effective is worthwhile.
For inclusion, studies had to recruit adult surgical
However, existing reports and meta-analyses have dem-
patients having elective, urgent or emergency surgery.
onstrated conflicting results.98–101 Significantly, several
Although both cardiac and noncardiac surgery were of
significant limitations of methodology have been

F
interest, we excluded studies recruiting exclusively
repeated across these older reports, such as missed stud-
trauma patients, parturients and nonsurgical critical
ies,98,99 pooled complications as an artificial composite
care patients.
with the risk of double-counting of events98,102 and
O
exclusion of certain types of surgery or patient
Intervention
groups.98–101 Finally, several authors have pooled
Subjects had to be randomised to either a standard of care
PAC-guided GDT studies with those using contempo-
O
or GDT. We defined GDT as any fluid and/or vasopressor
rary GDT devices.98,103
therapy titrated to haemodynamic targets that included
To address the limitations of existing publications, we the following: SVV, pulse pressure variation (PPV), CO or
performed an updated systematic review and meta-anal- CI, SV or SV index, central venous oxygen saturation,
PR

ysis of peri-operative GDT. We hypothesised that peri-
operative GDT would improve mortality (primary out-
come) and morbidity (secondary outcomes) in adult sur-
gical patients when compared with standard care.
Although use of PAC is historically of interest with regard
to GDT, we postulated that those generally older studies
would have significant methodological differences from
modern studies, such as the initiation of GDT preopera-
tively, and would not reflect current practice.1 Under
these more rigorous methodological conditions, we won-
dered whether the benefits of GDT identified in older
analyses would persist.98,103
Methods
The current systematic review and meta-analysis com-
plies with the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) statement.104 Our
institutional research ethics board does not require
approval for systematic reviews and meta-analyses.
Literature search
MEDLINE, EMBASE and the Cochrane Library were
searched without language restriction from inception to
31 December 2016 for RCTs that recruited adult surgical
patients receiving peri-operative GDT versus standard
DO2 or DO2 index, oesophageal Doppler flow corrected
time, echocardiography assessment and oxygen extrac-
tion ratio (O2ER). These targets were chosen as they
are well studied and, in the context of the conflicting
evidence base, there is some suggestion that their opti-
misation improves outcome.97,103 If investigators used an
Enhanced Recovery After Surgery (ERAS) Programme,
both study arms must have been receiving the ERAS
care. With regard to the control arm therapy, we
excluded studies where the control arm was also
receiving a form of GDT, such as trials comparing two
different GDT devices or those comparing different
GDT targets. We accepted standard care in the form
of protocol-driven standard care (e.g. maintain mean
arterial pressure > 65 mmHg), care at the discretion of
the attending physicians with no formal protocol or pro-
tocols involving restrictive fluid strategies.
Outcomes
The primary outcome was in-study mortality. Secondary
outcomes included organ-specific morbidity, such as
myocardial infarction (MI), arrhythmia, cardiac arrest,
congestive heart failure (CHF), acute kidney injury
(AKI), pulmonary embolus, infections, stroke or transient
ischaemic attack (TIA) and surgical complications.

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Furthermore, exposure to allogenic packed red blood cell
transfusion and hospital and ICU length of stay (LoS)
were of secondary interest.
Search strategy
The full search strategy is available online (Supplemental
Digital Content 1, Search Strategy Appendix, http://
links.lww.com/JCM/A115). The search used a compre-
hensive combination of medical subject heading terms
and free-text terms and synonyms. The reference lists of
included articles and older reviews were manually
searched for additional studies. Unpublished data were
not sought. To avoid publication bias, grey literature (e.g.
conference abstracts) was included in the systematic
review.
Article screening, data extraction and risk of
bias assessment
Studies were screened independently by MC and YW
and any discrepancies resolved by consensus with IM. A
similar process was used for the data extraction. Extracted
data included baseline demographic data, study descrip-
tors and predefined clinical outcomes. The risk of bias
assessment was conducted using the Cochrane Risk of
Bias Tool.105 The tool defines several sources of bias and
provides a standardised approach for assessment. The
O provided excellent descriptions of TSA, and full discus-
specific domains include random sequence generation
(selection bias), allocation concealment (selection bias),
O
blinding of participants and personnel (performance
bias), blinding of outcome assessment (performance
bias), complete reporting of data and with low-to-minimal
loss to follow-up (attrition bias), selective reporting bias
PR
and other bias.105 Studies were considered to be at low
risk of bias if they adequately met the first five criteria
with no evidence of significant selective reporting bias or
any other major sources of bias. Grading of Recommen-
dations, Assessment, Development and Evaluation
(GRADE) methodology was used to appraise the overall
evidence base quality for each outcome.106
Statistical analysis
Stata (Version 13.1; StataCorp, College Station, Texas,
USA) was used for statistical analysis. Binary outcomes
were reported as odds ratios (ORs). Continuous outcomes
were reported as the weighted mean difference (WMD)
or standardised mean difference, where appropriate. Both
types of data were presented with their corresponding
95% confidence intervals (95% CI). We anticipated clini-
cal heterogeneity among the devices and methods used to
provide GDT, and therefore, a random-effects analysis
model was selected. For statistically significant outcomes,
the number needed to treat to benefit one patient
(NNTB) or number needed to treat to harm one patient
(NNTH) were calculated, where appropriate. All data are
reported with a significance level of a ¼ 0.05. Heteroge-
neity was estimated using the I2 statistic and the x2 test
for statistical significance. We considered an I2 value from
Eur J Anaesthesiol 2018; 35:1–15
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Meta-analysis of peri-operative goal-directed therapy 3
50 to 70% to be moderate heterogeneity and 70% or
higher to be high heterogeneity. Stratification of out-
comes based on PAC versus other technologies was
planned a priori. Furthermore, all subgroup analyses were
prespecified according to hypothesised sources of hetero-
geneity and included: type of surgery (e.g. cardiac versus
noncardiac surgery), type of fluid (e.g. colloid versus
crystalloid), fluid versus fluid and vasopressors to achieve
goals, presence of ERAS program, risk of bias and tech-
nology used to achieve the GDT. Publication bias was
assessed via Egger’s regression and visual inspection of
the data on a funnel plot.
In the context of many meta-analyses, repeated signifi-
cance testing of pooled data can lead to the possibility of
Type 1 errors.107,108 Trial sequential analysis (TSA) is a
statistical technique that allows the creation of trial
sequential boundaries within a cumulative meta-analysis
to determine whether a P value is sufficiently small to
show an effect or futility.107,108 TSA was used to assess
the maturity of the evidence base for the primary out-
come of mortality. To perform the TSA, we assumed a
two-tailed a of 0.05, b of 80% and a relative risk reduction
F
of 20% from the control group event rate. The TSA was
performed with version 0.9.5.5 Beta. Other authors have
sion is beyond the scope of this systematic review.108
Results
Literature search and study selection
The search initially retrieved 1945 citations with 95
RCTs (11 659 patients) meeting the inclusion criteria
(PRISMA Flowchart, Fig. 1).1–95 Eight small RCTs
(400 patients) did not report extractable outcomes and,
therefore, could not be pooled for meta-analy-
sis.2,8,17,19,49,54,86,95 A description of excluded studies is
provided in the supplemental content (Supplemental
Digital Content 2, Table of Excluded Studies, http://
links.lww.com/JCM/A115).
Baseline characteristics of included randomised
controlled trials
The salient baseline characteristics of included RCTs are
shown in Table 2. Only four of 95 studies were consid-
ered to be at low risk of bias, given the challenge in
blinding participants during the performance of GDT in
the peri-operative period (Risk of Bias Assessment, Sup-
plemental Digital Content 3, Risk of Bias Assessment
and Risk of Bias Distribution, http://links.lww.com/JCM/
A115, Fig. 2).36,51,76,84 Notably, 12 studies recruited car-
diac surgery patients, with the rest recruiting noncardiac
surgery patients.19,22,31,38,40,42,47,57,58,60,66,70 Thirteen
studies used a PAC to guide therapy.1,3,11,12,18,25,28,31,60,83,
87,90,93
The remaining studies of more modern
GDT devices/technologies used oesophageal Doppler
(23 studies),10,13,14,17,20,21,23,24,32,33,41 –43,46,47,68,71,74,76,78,
79,82,86
noninvasive CO monitoring (e.g. arterial
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4 Chong et al.

Fig. 1

Records identified through Additional records

Identification
database searching identified through other
(n = 1945) sources
(n = 8)

Records after duplicates

removed (n = 1529)
Screening

Records screened Records excluded

(n = 1529) (n = 1426)

Full-text articles Full-text articles excluded,

Eligibility

assessed for with reasons

eligibility (n = 8)
(n = 103)
• Wrong intervention (n = 1)
• Wrong outcomes (n = 5)
• Duplicate of included

F
Studies included in study (n = 2)
qualitative
O
synthesis (n = 95)
Included

Studies included in
O
quantitative
synthesis (meta-
analysis)
(n = 87)
PR

PRISMA flow chart. The study selection process is described in detail. Excluded studies are listed with their reasons for exclusion in Supplemental
Digital Content 2, http://links.lww.com/JCM/A115. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

waveform-derived CI or SVV; 52 studies),2,4–6,8,9,15,
16,19,22,26,27,29,30,34–40,44,48,49,51–55,57–59,61–67,69,70,73,75,77,80,
81,84,85,88,91,92,95
and miscellaneous technologies (e.g.
PPV, laboratory measurements of O2ER or echocardiog-
raphy; seven studies).7,45,50,56,72,89,94 All results are pre-
sented according to the predefined analysis plan and
stratified by PAC use versus the more contemporary
technologies.
Results for contemporary goal-directed
haemodynamic and fluid therapy
Primary outcome: in-study mortality
GDT guided by modern technology resulted in lower in-
study mortality compared with standard care (OR 0.66;
95% CI, 0.50 to 0.87; P ¼ 0.004; NNTB ¼ 59 or 18 events
prevented per 1000 patients; I2 ¼ 0.0%; N ¼ 52; Supple-
mental Digital Content 4, http://links.lww.com/JCM/
A115, Forest Plot of Mortality for Modern GDT). These
benefits persisted across subgroup analysis in the highest
risk patients (OR 0.60; 95% CI, 0.42 to 0.85; P ¼ 0.004;
NNTB ¼ 34), the highest risk procedures (OR 0.69; 95%
CI, 0.51 to 0.95; P ¼ 0.02; NNTB ¼ 75), and among
studies where the GDT was initiated intra-operatively
(OR 0.65; 95% CI, 0.47 to 0.89; P ¼ 0.007; NNTB ¼ 59).
A full summary of the sensitivity analyses is shown in
Table 3. Notably, the mortality reduction was not sta-
tistically significant in the subgroup of studies employing
fluid-only GDT, but remained significant among studies
where no industry relationship was apparent (Table 3).
Given that only four studies overall could be definitively
judged at low risk of bias, subgroup analysis by risk of bias
was insufficiently powered.36,51,76,84 With regard to TSA,
the cumulative z-curve did not cross the trial sequential
monitoring boundaries nor enter the region of futility
(Supplemental Digital Content 5, Trial Sequential Anal-
ysis, http://links.lww.com/JCM/A115). In the context of
TSA, this suggests that the cumulative sample size is
inadequate to definitively determine the impact of GDT
on peri-operative mortality and that further trials have the
potential to alter the magnitude and/or direction of effect.

Eur J Anaesthesiol 2018; 35:1–15

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 Table 2 Baseline data

Patients Intervention
Trial Year Sample size Patient risk Type of surgery Initiation of GDT GDT technology Control group
Ackland et al.84 2015 204 High risk General and vascular Postoperative Noninvasive Cardiac Output Monitor Protocol-driven standard care
surgery
Bartha et al.85 2013 150 High risk Orthopaedic surgery Preoperative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Ben Romdhane et al.86 2014 30 High risk General surgery Unclear Oesophageal Doppler Standard care
Bender et al.87 1997 104 High risk Vascular surgery Preoperative PAC Standard care
Benes et al.88 2010 120 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Benes et al.89 2015 80 Low risk Orthopaedic surgery Intra-operative PPV Restrictive fluid therapy
Berlauk et al.90 1991 89 High risk Vascular surgery Preoperative PAC Standard care
Bisgaard et al.92 2013 70 High risk Vascular surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Bisgaard et al.91 2013 40 High risk Vascular surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
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Bonazzi et al.93 2002 100 Low risk Vascular surgery Preoperative PAC Standard care
Boyd et al.83 1993 107 High risk Abdominal surgery Preoperative PAC Protocol-driven standard care
Brandstrup et al.82 2012 150 Low risk General surgery Intra-operative Oesophageal Doppler ‘Zero balance’/‘Normal bodyweight’
Broch et al.81 2016 79 Low risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Buettner et al.80 2008 80 Low risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Bundgaard-Nielsen et al.79 2013 42 Low risk Urological surgery Intra-operative Oesophageal Doppler Standard care
Calvo Vecino et al.78 2014 121 Unclear General surgery, urology, Intra-operative Oesophageal Doppler Standard care
gynacology and
orthopaedic surgery
Cecconi et al.77 2011 40 Low risk Orthopaedic surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Challand et al.76 2012 179 Low risk General surgery Intra-operative Oesophageal Doppler Standard care
PR
Cordero-Rochet et al.2 2014 80 Low risk ENT surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Colantonio et al.75 2015 80 Low risk Oncological surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
EJA-D-17-00516

Conway et al.74 2002 57 Low risk General surgery Intra-operative Oesophageal Doppler Standard care
Correa-Gallego et al.73 2015 135 Low risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Donati et al.72 2007 135 High risk
O
General and vascular
surgery
Intra-operative Oxygen delivery or extraction Protocol-driven standard care

El Sharkawy et al.71 2013 59 Low risk General surgery Intra-operative Oesophageal Doppler Protocol-driven standard care
Fellahi et al.70 2015 100 High risk Cardiac surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Forget et al.94
Funk et al.69
2010
2015
82
40
Low risk
High risk
General surgery
Vascular surgery
O
Intra-operative
Intra-operative
PPV
Noninvasive Cardiac Output Monitor
Protocol-driven standard care
Standard care
Gan et al.68 2002 100 Low risk General, gynaecological, Intra-operative Oesophageal Doppler Protocol-driven standard care
and urological surgery
Gerent et al.67 2015 125 High risk General surgery Postoperative Noninvasive Cardiac Output Monitor Standard care
Goepfert et al.66 2013 100 High risk Cardiac surgery
F
Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Han et al.62 2016 40 Low risk Orthopaedic surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Hand et al.63 2016 94 High risk ENT surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Harten et al.64 2008 30 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Hughes et al.65 2013 30 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Jammer et al.61 2015 30 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Jerez Gomez-Coronado et al.60 2001 390 High risk Cardiac surgery Postoperative PAC Protocol-driven standard care
Jhanji et al.59 2010 135 High risk General surgery Postoperative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Kapoor et al.57 2008 30 High risk Cardiac surgery Postoperative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Kapoor et al.58 2016 130 High risk Cardiac surgery Postoperative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Kellman et al.56 2014 60 High risk Urological surgery Intra-operative TEE Standard care
Khambalia et al.55 2015 60 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Kulkarni et al.54 2012 31 Unclear ENT surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Kumar et al.52 2015 40 High risk General and vascular Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
surgery
Kumar et al.53 2016 60 Low risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care

Eur J Anaesthesiol 2018; 35:1–15

Meta-analysis of peri-operative goal-directed therapy 5

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 Table 2 (continued )

Patients Intervention
Trial Year Sample size Patient risk Type of surgery Initiation of GDT GDT technology Control group
Lai et al.51 2015 220 Low risk General and urological Intra-operative Noninvasive Cardiac Output Monitor Standard care
surgery
6 Chong et al.

Lopes et al.50 2007 33 High risk General surgery Intra-operative PPV Standard care
Martini et al.49 2009 59 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Liberal and restrictive fluid controls
Mayer et al.48 2010 60 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
McKendry et al.47 2004 174 High risk Cardiac surgery Postoperative Oesophageal Doppler Standard care
McKenny et al.46 2013 102 Low risk Gynaeological surgery Intra-operative Oesophageal Doppler Standard care
Mikor et al.45 2015 79 High risk General, urological, and Intra-operative Oxygen delivery or extraction Protocol-driven standard care
vascular surgery
Moppett et al.44 2015 130 High risk Orthopaedic surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
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Munoz et al.43 2012 250 High risk General surgery Intra-operative Oesophageal Doppler Standard care
Mythen et al.42 1995 60 High risk Cardiac surgery Intra-operative Oesophageal Doppler Standard care
Noblett et al.41 2006 108 Low risk General surgery Intra-operative Oesophageal Doppler Standard care
Osawa et al.40 2016 126 High risk Cardiac surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Oubaha et al.95 2009 29 Unclear General surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Park et al.39 2016 47 Low risk ENT surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care

Eur J Anaesthesiol 2018; 35:1–15

Parke et al.38 2015 144 High risk Cardiac surgery Postoperative Noninvasive Cardiac Output Monitor Standard care
Pearse et al.36 2005 122 High risk General surgery Postoperative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Pearse et al.37 2014 734 Low risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Peng et al.35 2014 80 Low risk Orthopaedic surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Pestana et al.34 2014 142 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
PR
Phan et al.33 2014 100 Low risk General surgery Intra-operative Oesophageal Doppler Restrictive fluid therapy
EJA-D-17-00516

Pillai et al.32 2011 66 Low risk Urological surgery Intra-operative Oesophageal Doppler Standard care
Polonen et al.31 2000 403 High risk Cardiac surgery Postoperative PAC Protocol-driven standard care
Ramsingh et al.30 2013 38 Low risk General, urological, Intra-operative Noninvasive Cardiac Output Monitor Standard care
O
gynaecological surgery
Salzwedel et al.29 2013 160 Low risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Sandham et al.28 2003 1994 High risk General, thoracic, vascular, Preoperative PAC Standard care
orthopaedic surgery
Scheeren et al.27 2013 64 High risk General and urological
surgery
O Intra-operative Noninvasive Cardiac Output Monitor Standard care

26
Schmid et al. 2016 180 High risk General surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Schultz et al.25 1985 70 High risk Orthopaedic surgery Preoperative PAC Standard care
Senagore et al.24 2009 64 Low risk General surgery Intra-operative Oesophageal Doppler Protocol-driven standard care
Shoemaker et al.1 1988 88 High risk General surgery
F
Preoperative PAC Protocol-driven standard care
Sinclair et al.23 1997 40 Low risk Orthopaedic surgery Intra-operative Oesophageal Doppler Standard care
Smetkin et al.22 2009 40 High risk Cardiac surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Srinivasa et al.21 2014 85 Low risk General surgery Intra-operative Oesophageal Doppler Restrictive fluid therapy
Szturz et al.20 2010 230 Low risk Urological surgery Intra-operative Oesophageal Doppler Protocol-driven standard care
Tolstova et al.19 2010 47 High risk Cardiac surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Valentine et al.18 1998 120 High risk Vascular surgery Preoperative PAC Standard care
Van Dellen et al.17 2013 84 High risk General surgery Postoperative Oesophageal Doppler Standard care
Van Der Linden et al.16 2010 60 High risk Vascular surgery Intra-operative Noninvasive Cardiac Output Monitor Protocol-driven standard care
Vanakas et al.15 2012 20 High risk Orthopaedic surgery Intra-operative Noninvasive Cardiac Output Monitor Standard care
Venn et al.14 2002 90 High risk Orthopaedic surgery Intra-operative Oesophageal Doppler Standard care arm and CVP arm
Wakeling et al.13 2005 128 Low risk General surgery Intra-operative Oesophageal Doppler Protocol-driven standard care
Wilson et al.12 1999 138 High risk General, vascular, and Preoperative PAC Standard care
urological surgery
Yassen et al.11 2012 60 High risk General surgery Postoperative PAC Protocol-driven standard care
Zakhaleva et al.10 2013 91 High risk General surgery Intra-operative Oesophageal Doppler Protocol-driven standard care

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Meta-analysis of peri-operative goal-directed therapy 7

methods. Studies recruiting cardiac surgery patients, critical care patients requiring surgery or more than 50% of patients with ASA class 3 or higher were classified as having ‘high risk’ patients. ASA class, American Society of
Key patient groups and intervention details of included studies are presented. The noninvasive cardiac output monitor group includes monitors that derive cardiac output from arterial waveform analysis, lithium ion dilution or other
Secondary outcomes: organ-specific morbidity
All binary secondary outcomes are listed in detail in

Anesthesiologists’ classification; ENT, ear, nose, throat; GDT, goal-directed haemodynamic and fluid therapy; PAC, pulmonary artery catheter; PPV, pulse pressure variation; TEE, transoesophageal echocardiography.
care
care
care

care
care
care
Table 4.
standard
standard
standard

standard
standard
standard
Cardiovascular outcomes
Control group

Contemporary GDT reduced rates of arrhythmia (OR

Protocol-driven
Protocol-driven
Protocol-driven

Protocol-driven
Protocol-driven
Protocol-driven
Standard care 0.70; 95% CI, 0.55 to 0.91; P ¼ 0.006; NNTB ¼ 34). MI,
CHF and cardiac arrest were not significantly different
between groups (Table 4).

Respiratory outcomes
Cardiac Output Monitor
Cardiac Output Monitor

Cardiac Output Monitor

Cardiac Output Monitor
Cardiac Output Monitor

Rates of respiratory failure and prolonged mechanical

Intervention

ventilation were reduced in patients receiving GDT (OR

0.54; 95% CI, 0.35 to 0.84; P ¼ 0.006; NNTB ¼ 26).
Furthermore, rates of pneumonia were reduced with
GDT compared with standard care (OR 0.69; 95% CI,
GDT technology

0.51 to 0.92; P ¼ 0.01; NNTB ¼ 38).

Noninvasive
Noninvasive

Noninvasive
Noninvasive
Noninvasive

Other infectious outcomes

PAC
PPV

Wound infection (OR 0.48; 95% CI, 0.37 to 0.63;

NNTB ¼ 19) and intra-abdominal infection (OR 0.65;
95% CI, 0.45 to 0.93; NNTB ¼ 35) rates were reduced
Initiation of GDT

F
in patients receiving GDT. In addition, rates of sepsis
Intra-operative
Intra-operative
Intra-operative
Intra-operative
Intra-operative
Intra-operative
Preoperative

were also reduced in the GDT arm compared with

standard care, but only 13 studies reported this outcome
O (OR 0.55; 95% CI, 0.33 to 0.91; P ¼ 0.02; NNTB ¼ 43).
The incidence of urinary tract infection was similar
between groups (Table 4).
O
Other outcomes
Type of surgery

GDT patients had reduced rates of AKI versus standard

Thoracic surgery

Vascular surgery
General surgery

General surgery

General surgery
General surgery
Neurosurgery

care (OR 0.73; 95% CI, 0.58 to 0.92; P ¼ 0.007;

PR

NNTB ¼ 29). No significant difference was detected

for stroke or pulmonary embolism between groups. Like-
wise, surgical complications were similar between groups
in terms of anastomotic leak and ileus or bowel obstruc-
Patient risk

tion. Finally, exposure to allogenic blood was not differ-

High risk
High risk
High risk
Low risk
Low risk
Low risk
Low risk

ent between arms.

Secondary outcomes: healthcare length of stay and

other continuous outcomes
Sample size
Patients

Continuous outcomes are summarised in Table 5.

60
40
60
80
60
90
72

Length of stay
Across the 62 RCTs reporting hospital LoS, contempo-
rary GDT reduced LoS (days) compared with standard
2014
2012
2012
2013
2013
2016
1997
Year

care by 0.90 (95% CI, 1.32 to 0.48), with very high

statistical heterogeneity (I2 ¼ 81.2%). Similarly, ICU LoS
was also reduced (0.69; 95% CI, 1.00 to 0.37;
I2 ¼ 83.8%).

Time to recovery of bowel function

Table 2 (continued )

The time to first flatus (days) was reduced by modern

GDT by 0.37 (95% CI, 0.59 to 0.14; I2 ¼ 74.1%), but
Ziegler et al.3
Zheng et al.4
Zheng et al.5
Zhang et al.8
Zhang et al.7
Zhang et al.6
Zeng et al.9

there were no differences in the time to first oral intake or

bowel movement detected. Statistical heterogeneity was
Trial

high among all these analyses (Table 5).

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8 Chong et al.

Fig. 2

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel

(performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting bias (reporting bias)

Other bias

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

F
Risk of bias distribution. The bar chart shows the breakdown of scores for each domain of the Cochrane Risk of Bias Tool. There were significant
deficits in meeting the criteria for most of the studies, particularly with the performance of blinding participants and study personnel and the reporting
of allocation concealment method. The full risk of bias scoring is shown in Supplemental Digital Content 3, http://links.lww.com/JCM/A115, due to
the large size of that figure.
O
O
Results for pulmonary artery catheter-guided goal- ‘major abdominal complications’,49 reduced mortality
directed haemodynamic and fluid therapy (albeit statistical analysis is not presented)54 and reduced
Mortality was reduced among all 13 studies that used a lactate levels.95
PR

PAC to guide the GDT (OR 0.53; 95% CI, 0.30 to 0.92;
P ¼ 0.004; Supplemental Digital Content 6, http://
links.lww.com/JCM/A115, Forest Plot of Mortality for
PAC-guided GDT), but this effect did not persist in
the largest and most rigorously conducted study.28 There
were no other differences in any of the other secondary
outcomes among the PAC studies, including morbidity
and LoS (Tables 4 and 5).
Publication bias
The primary outcome (in-study mortality) was assessed
for publication bias with Egger’s regression, and a funnel
plot was constructed and inspected for asymmetry.
Egger’s regression was not significant (P ¼ 0.59) and
the funnel plot appeared symmetrical on visual inspec-
tion, which suggests a low probability of publication bias.
Results of nonmeta-analysable studies
Eight small RCTs (400 patients) could not be pooled due
to lack of extractable outcomes, and all of these studies
were conference abstracts not yet published at the time of
our literature search.2,8,17,19,49,54,86,95 Of these, some
found no difference between GDT and standard care.2,19
Others found modest differences such as decreased hos-
pital LoS,8,86 faster recovery of bowel function,17 reduced
Discussion
Contemporary goal-directed haemodynamic and fluid
therapy
This comprehensive systematic review and meta-analysis
of 95 RCTs demonstrates that contemporary GDT mod-
estly improves in-study mortality in non-trauma and
nonpregnant adult surgical patients (OR 0.60; 95% CI,
0.50 to 0.87; NNTB ¼ 59; P ¼ 0.004; N ¼ 52). The overall
results are found in the Summary of Findings Table,
with the corresponding GRADE recommendations
(Table 6).106 Based on the articles included in this
analysis, these numbers suggest that for every 1000
patients treated with GDT, 18 (95% CI, 7 to 26) deaths
would be prevented. In reference to the subgroup anal-
yses performed, the mortality benefits were most pro-
nounced in high-risk patients (NNTB ¼ 34), present
among trials where the GDT was initiated intra-opera-
tively (NNTB ¼ 59), and persisted among large trials
recruiting more than 100 patients (NNTB ¼ 59). In con-
trast and perhaps in part due to lack of statistical power,
the benefits were not statistically significant in cardiac
surgery trials or studies involving emergency surgery, and
they seemed to be reliant on the use of vasoactive agents
as part of the GDT. Furthermore, with regard to the

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Meta-analysis of peri-operative goal-directed therapy 9

Table 3 Summary of subgroup analyses for in-study mortality for contemporary goal-directed haemodynamic and fluid therapy

Subgroup OR (95% CI) NNTB or (NNTH) N of studies P value

Overall pooled; I2 U 0.0% 0.66 (0.50 to 0.87) 59 52 0.004
Patient risk
High 0.60 (0.42 to 0.85) 34 28 0.004
Low 0.79 (0.50 to 1.24) – 24 0.30
Surgical risk
High 0.69 (0.51 to 0.95) 75 43 0.02
Intermediate 0.55 (0.30 to 1.02) – 9 0.06
Industry ties
Yes 0.83 (0.56 to 1.22) – 23 0.34
No 0.52 (0.35 to 0.77) 35 29 0.001
Surgical type
Noncardiac 0.67 (0.50 to 0.91) 60 44 0.009
Cardiac 0.59 (0.27 to 1.27) – 8 0.18
Elective surgery
Elective only 0.66 (0.48 to 0.92) 73 45 0.01
Includes emergency cases 0.66 (0.39 to 1.12) – 7 0.13
Start of GDT
Preoperative – – 1 –
Intraoperative 0.65 (0.47 to 0.89) 59 45 0.007
Postoperative 0.72 (0.38 to 1.33) – 6 0.29
Use of vasopressors
If required per protocol 0.59 (0.40 to 0.89) 44 26 0.01
Not per protocol (fluid-based intervention only) 0.65 (0.41 to 1.05) – 23 0.08
Per protocol (mandatory) – – 2 0.85
Unclear – – 1 0.55

F
Technology
Cardiac output monitors 0.68 (0.49 to 0.95) 56 29 0.02
Oesophageal Doppler 0.71 (0.39 to 1.28) – 16 0.26
Pulse pressure variation
Oxygen delivery or extraction
O
0.54 (0.14 to 2.05)
–
–
–
4
2
0.37
–
Echocardiography – – 1 –
Study size
Large trials (n> 100) 0.69 (0.50 to 0.95) 59 24 0.02
O
–
Small trials (n<100) 0.59 (0.34 to 1.03) – 28 0.06

Adequately powered prespecified subgroup analyses are shown in the table with the corresponding numbers needed to treat for benefit or harm values. Bold results
achieved statistical significance. 95% CI, 95% confidence interval; GDT, goal-directed haemodynamic and fluid therapy; I2, heterogeneity statistic; N of studies, total
PR

number of trials; n ¼ number of subjects within a trial; NNTB, number needed to treat for benefit; NNTH, number needed to treat for harm; OR, odds ratio.

device used to achieve the GDT, the minimally invasive
CO monitor category was the only significant modern
subgroup. Finally, although statistical heterogeneity was
low (I2 ¼ 0.0% for the primary outcome), clinical hetero-
geneity is still a real concern given the variety of GDT
technologies, haemodynamic goals and protocols
employed. Taken together with the high risk of bias,
modest absolute risk reduction and inconclusive TSA,
the results should be interpreted with caution.
Secondary benefits of modern GDT included 30 (95%
CI, 10 to 47) fewer cases of arrhythmia, 27 (95% CI, 7 to
43) fewer cases of pneumonia, 55 (95% CI, 39 to 67) fewer
cases of wound infection and 35 (95% CI, 11 to 55) fewer
cases of AKI per 1000 patients treated with GDT (Table
6). Significantly, the rate of AKI was reduced despite 71
of 95 GDT studies using colloid boluses (Table 1), which
have been demonstrated to be harmful in critical care
patients.109 Despite increased fluid administration in the
GDT group overall, there was no difference in CHF or
MI. Hospital and ICU LoS were also reduced with GDT,
albeit the statistical heterogeneity in this analysis was
very high.
Pulmonary artery catheter-guided goal-directed
haemodynamic and fluid therapy
Given the significant limitations among the trials that
used PAC-guided GDT, together with improvements in
the conduct of clinical care and trial design that have
taken place over recent decades, it is perhaps not surpris-
ing that data for the PAC studies were systemically
different from modern studies. It is for this reason that
these data were presented separately. In this context,
PAC-guided GDT reduced in-study mortality in older
trials that mainly involved preoperative optimisation –
but not in the most rigorous and well conducted study.28
With regard to secondary outcomes, there were no differ-
ences for the PAC-guided GDT studies.
In addition to being more invasive than contemporary
GDT technologies, there is a lag time between the deci-
sion to place a PAC and actual insertion; furthermore, the
plethora of haemodynamic data derived from a PAC must
be integrated, interpreted and then applied to patient
care.97 For all these reasons, reinforced by our findings,
contemporary practice does not place a great value on the
role of PAC for intra-operative monitoring.110,111

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10 Chong et al.

Table 4 Binary secondary outcomes summary

Outcome OR (95% CI) NNTB (NNTH) Heterogeneity (I2) N of studies P value

Arrhythmia
Modern 0.70 (0.55 to 0.91) 34 0.0% 33 0.006
PAC 0.93 (0.70 to 1.24) – 0.0% 7 0.64
Myocardial infarction
Modern 0.79 (0.49 to 1.28) – 0.0% 23 0.34
PAC 1.12 (0.76 to 1.65) – 0.0% 9 0.58
CHF
Modern 0.61 (0.33 to 1.12) – 0.0% 17 0.11
PAC 1.08 (0.84 to 1.38) – 0.0% 9 0.57
Cardiac arrest
Modern 1.01 (0.51 to 1.99) – 0.0% 5 0.98
PAC 0.45 (0.15 to 1.37) – 0.0% 3 0.16
Pneumonia
Modern 0.69 (0.51 to 0.92) 38 0.0% 29 0.01
PAC 0.88 (0.65 to 1.21) – 0.0% 5 0.43
Respiratory failure or prolonged need for mechanical ventilation
Modern 0.54 (0.35 to 0.84) 26 0.0% 19 0.006
PAC 0.77 (0.19 to 3.19) – 58.7% 4 0.72
Wound infection
Modern 0.48 (0.37 to 0.63) 19 0.0% 32 <0.001
PAC 0.80 (0.58 to 1.10) – 0.0% 5 0.17
Intra-abdominal infection
Modern 0.65 (0.45 to 0.93) 35 0.0% 16 0.02
PAC 0.42 (0.09 to 1.87) – 0.0% 3 0.25
UTI

F
Modern 0.72 (0.48 to 1.08) – 0.0% 18 0.11
PAC – – – 2 –
Sepsis
Modern
PAC
0.55 (0.33 to 0.91)
0.77 (0.40 to 1.48)
43
–
O 0.0%
0.0%
13
5
0.02
0.43
Stroke
Modern 0.80 (0.36 to 1.78) – 0.0% 15 0.58
PAC 0.37 (0.08 to 1.69) – 0.0% 5 0.20
O
Ileus or bowel obstruction
Modern 0.75 (0.52 to 1.08) – 0.0% 17 0.13
PAC – – – 1 –
Anastomotic leak
PR

Modern 0.67 (0.44 to 1.02) – 0.0% 17 0.06

PAC – – – 1 –
Nausea/vomiting
Modern 0.36 (0.24 to 0.52) 7 0.0% 12 <0.001
PAC – – – 0 –
AKI
Modern 0.73 (0.58 to 0.92) 29 6.6% 37 0.007
PAC 0.65 (0.36 to 1.15) – 13.9% 7 0.14
Pulmonary embolus
Modern 0.87 (0.41 to 1.84) – 0.0% 19 0.71
PAC 1.12 (0.14 to 8.71) – 51.4% 4 0.92
Allogenic blood transfusion exposure
Modern 1.11 (0.83 to 1.49) – 36.3% 26 0.47
PAC – – – 2 –

Dichotomous outcomes are listed in the table with data reported by PAC-guided versus modern GDT. Bold outcomes achieved statistical significance. 95% CI, 95%
confidence interval; AKI, acute kidney injury; GDT, goal-directed haemodynamic and fluid therapy; I2, heterogeneity statistic; N of studies, total number of trials; NNTB,
number needed to treat for benefit; NNTH, number needed to treat for harm; OR, odds ratio; PAC, pulmonary artery catheter; UTI, urinary tract infection.

Differences from previous reviews
Given the clinical importance of peri-operative GDT, it
is important that any systematic review be comprehen-
sive and that the meta-analysis accounts for inherent
sources of heterogeneity as best as possible. Our work
improves upon the previous published reviews that have
significant limitations of methodology. For example, we
have included studies that were excluded in other reports
with narrower inclusion criteria, allowing for the ability to
comment on important subgroups such as cardiac surgery
patients.40,98,99,112 In addition, we avoided pooling com-
plications as an artificial composite,98,102,113,114 mixing
GDT trials with those exploring liberal versus restrictive
fluid administration,102 and pooling both PAC-guided
and contemporary GDT studies together.98,99,103 With
reference to the latter, it was our opinion that certain PAC
studies generally did not reflect contemporary practice
and were of lower methodological quality, which would

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Meta-analysis of peri-operative goal-directed therapy 11

Table 5 Continuous secondary outcomes summary

Outcome WMD (days) 95% CI (days) I2 N of studies P value

Hospital LoS
Modern S0.90 S1.32 to S0.48 81.2%M 62 <0.001
PAC 0.26 1.03 to 0.51 86.5%M 8 0.52
ICU LoS
Modern S0.69 S1.00 to S0.37 83.8%M 23 <0.001
PAC 0.20 0.86 to 0.45 86.7%M 6 0.54
Time to first oral intake
Modern 0.54 1.11 to 0.03 95.7%M 13 0.06
PAC – – – 0 –
Time to first flatus
Modern S0.37 S0.59 to S0.14 74.1%M 10 0.002
PAC – – – 0 –
Time to first bowel movement
Modern 0.21 0.65 to 0.23 86.4%M 10 0.35
PAC – – – 0 –

Secondary outcomes are stratified by use of PAC versus modern technologies to guide the GDT. Bold outcomes achieved statistical significance. 95% CI, 95%
confidence interval; GDT, goal-directed haemodynamic and fluid therapy; I2, heterogeneity statistic; LoS, length of stay; N of studies, total number of trials; PAC, pulmonary
artery catheter; WMD, weighted mean difference. M Denotes statistically significant I2 values with P < 0.05.

decrease the external validity of the results had they been Another important consideration is the comparability
pooled with the data from more contemporary trials.1 between different GDT devices; indeed, studies explor-
ing the correlation between different GDT monitors for

F
reflecting haemodynamic status have demonstrated
mixed results.115–117 Significantly, in subgroup analysis
Study limitations
by type of technology, the mortality benefit of modern
Despite the low statistical heterogeneity in our morbidity
O GDT only persisted in the minimally invasive CO moni-
and mortality analyses, the main limitation of this meta-
tor subgroup, which reduces the ability to generalise the
analysis is the clinical heterogeneity among the different
primary outcome results.
GDT devices, goals and algorithms employed by
O
included studies. Although such clinical heterogeneity In addition, although our analysis identified several
can never be fully mitigated by statistical means, we took secondary benefits of peri-operative GDT, the second-
several measures to address this issue, such as the use of a ary outcomes should be interpreted with caution because
PR

random effects model, stratification of the results by not all studies reported each outcome, and the timing of
PAC-guided GDT versus modern GDT, and finally follow-up varied between studies. Furthermore, another
subgroup analysis by other important sources of hetero- significant limitation is the high risk of bias among
geneity (e.g. type of GDT monitor). included studies. For example, only four of 95 studies

Table 6 Summary of findings table for contemporary goal-directed haemodynamic and fluid therapy

Illustrative comparative risks (95% CI)

Assumed risk Corresponding risk Quality of the
(standard care reduction in GDT Relative effect Number of subjects evidence
Outcomes group) group (95% CI) (95% CI) (number of studies) (GRADE)
Mortality 52 per 1000 patients 18 (7 to 26) events avoided per 0.66 (0.50 to 0.87) 5550 (52)  lowa
1000 patients
Arrhythmia 109 per 1000 patients 30 (10 to 47) events avoided per 0.70 (0.55 to 0.91) 3269 (33)  lowa
1000 patients
CHF 28 per 1000 patients Not significantly different 0.61 (0.33 to 1.12) 2125 (17)  lowa
Pneumonia 93 per 1000 patients 27 (7 to 43) events avoided per 0.69 (0.52 to 0.92) 2776 (29)  lowa
1000 patients
Wound infection 111 per 1000 patients 55 (39 to 67) events avoided per 0.48 (0.37 to 0.63) 3593 (32)  lowa
1000 patients
AKI 141 per 1000 patients 35 (11 to 55) events avoided per 0.73 (0.58 to 0.92) 4310 (37)  lowa
1000 patients
Hospital LoS The mean hospital LoS The mean hospital LoS was 0.90 8797 (62)  very lowa,b
ranged across (0.48 to 1.32) days shorter in the
control groups from GDT group
1.2 to 29 days

, low quality evidence rating using the GRADE recommendations; , very low-quality evidence rating using the GRADE recommendations; 95% CI, 95% confidence
interval; AKI, acute kidney injury; CHF, congestive heart failure; GDT, goal-directed haemodynamic and fluid therapy; GRADE, Grading of Recommendations, Assessment,
Development and Evaluation; LoS, length of stay. a High risk of bias due to lack of blinding and unclear method of allocation concealment for the majority of studies. b Very
high statistical heterogeneity.

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12 Chong et al.
performed blinding and more than half of the studies
had an unclear description of allocation concealment
(Fig. 2). Regarding other sources of bias, study investi-
gators had relationships with industry in 31 of 95
trials.10,12,13,16,24,27,29,30,36,37,40,45,47,48,51,59,63,64,66,68,76,77,
80 – 82,84,88,91,92,94,114
Previous work has demonstrated
that industry influence in a trial increases the chance
that the results will favour the intervention.118 There-
fore, we cannot exclude the effect that such heavy
industry involvement may have increased the effect
sizes observed here, which is compounded by the other
deficiencies in methodology of the evidence base.118
Conclusion
In summary, this systematic review and meta-analysis of
RCTs demonstrates reduced mortality, morbidity and
hospital LoS with contemporary GDT in non-trauma
and non-pregnant adult surgical patients. For every
1000 patients treated with modern GDT, 18 (95% CI,
7 to 26) deaths are prevented and organ-specific morbid-
ity is reduced. Importantly, the benefits of GDT seem to
be reliant on the use of vasoactive agents and the mor-
tality results were not statistically significant in some
important subgroups, such as cardiac surgery patients.
Nonetheless, the results are relevant to anaesthetic prac-
O 9
tice; the performance of intra-operatively initiated GDT
still yielded clinically important benefits. However, cau-
tion is warranted due to the significant flaws in the
O
existing evidence base, the overall GRADE scoring of
low to very low for the most important outcomes, and
clinical heterogeneity among the haemodynamic goals
PR
and GDT monitoring devices studied.
Given the deficits in the current evidence base, it is
fortunate that higher quality trials are currently in prog-
ress, such as the international OPTIMISE-II Study
(http://optimiseii.org/). Large trials such as OPTI-
MISE-II are important for clarifying the magnitude of
benefit of peri-operative GDT, particularly given the
inconclusive TSA and the fact that the existing literature
has a predominance of small trials (less than 100 patients).
In addition, further study is required in clinically impor-
tant subgroups, such as cardiac and emergency surgery
patients. Finally, the best GDT protocols and haemody-
namic targets still remain to be identified. Given the
benefits found here and the potential for GDT to trans-
form peri-operative anaesthetic care, this field will prob-
ably remain an active area of research.
Acknowledgements relating to this article
Assistance with the study: we thank fellow department members Dr
Rudy Noppens (MD) and Dr Maurico Geraldo (MD) for their
assistance in interpreting non-English language articles for this
systematic review and meta-analysis. In addition, we are grateful
for Brie McConnell’s assistance in retrieving full-text copies of
certain study articles.
Financial support and sponsorship: none.
Eur J Anaesthesiol 2018; 35:1–15
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Conflicts of interest: none.
Presentation: preliminary data from this review was presented as an
oral presentation at the 2017 Canadian Anesthesiologists’ Society
meeting in Niagara Falls, Ontario, Canada (24 to 26 June 2017).
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