revista brasileira de anestesiologia … · líquidos em cirurgia não ... 2015 sociedade...

Rev Bras Anestesiol. 2016;66(5):513---528

REVISTABRASILEIRA DEANESTESIOLOGIA Publicação Oficial da Sociedade Brasileira de Anestesiologia

www.sba.com.br

REVIEW ARTICLE

Intraoperative goal directed hemodynamic therapyin noncardiac surgery: a systematic reviewand meta-analysis

Javier Ripollésa,∗, Angel Espinosab, Eugenio Martínez-Hurtadoa,Alfredo Abad-Gurumetac, Rubén Casans-Francésd, Cristina Fernández-Péreze,Francisco López-Timonedaf, José María Calvo-Vecinoa,EAR Group (Evidence Anestesia Review Group)

a Departamento de Anestesia, Hospital Universitario Infanta Leonor, Universidad Complutense de Madrid, Madrid, Spainb Department of Anesthesia, Blekinge County Council Hospital, WämöCenter, Karlskrona, Swedenc Departamento de Anestesia, Hospital Universitario la Paz, Madrid, Spaind Departamento de Anestesia, Hospital Universitario Lozano Blesa, Zaragoza, Spaine Departamento de Medicina Preventiva y Salud Pública, Hospital Clínico San Carlos, Madrid, Spainf Departamento de Anestesia, Hospital Clinico San Carlos, Universidad Complutense de Madrid, Madrid, Spain

Received 23 December 2014; accepted 18 February 2015Available online 14 September 2015

KEYWORDSGoal directed fluidtherapy;Meta-analysis;Hemodynamic goal;Noncardiac surgery

AbstractBackground: The goal directed hemodynamic therapy is an approach focused on the use ofcardiac output and related parameters as end-points for fluids and drugs to optimize tissueperfusion and oxygen delivery. Primary aim: To determine the effects of intraoperative goaldirected hemodynamic therapy on postoperative complications rates.Methods: A meta-analysis was carried out of the effects of goal directed hemodynamic ther-apy in adult noncardiac surgery on postoperative complications and mortality using PreferredReporting Items for Systematic Reviews and Meta-Analyses methodology. A systematic searchwas performed in Medline PubMed, Embase, and the Cochrane Library (last update, October2014). Inclusion criteria were randomized clinical trials in which intraoperative goal directedhemodynamic therapy was compared to conventional fluid management in noncardiac surgery.Exclusion criteria were trauma and pediatric surgery studies and that using pulmonary artery
catheter. End-points were postoperative complications (primary) and mortality (secondary).
he entry criteria were examined in full and subjected to quantifiableup analysis (stratified by type of monitor, therapy, and hemodynamictivity analysis.

Those studies that fulfilled tanalysis, predefined subgrogoal), and predefined sensi

∗ Corresponding author.E-mail: [email protected] (J. Ripollés).

http://dx.doi.org/10.1016/j.bjane.2015.02.0010104-0014/© 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

dx.doi.org/10.1016/j.bjane.2015.02.001

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dx.doi.org/10.1016/j.bjane.2015.02.001

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514 J. Ripollés et al.

Results: 51 RCTs were initially identified, 24 fulfilling the inclusion criteria. 5 randomized clin-ical trials were added by manual search, resulting in 29 randomized clinical trials in the finalanalysis, including 2654 patients. A significant reduction in complications for goal directedhemodynamic therapy was observed (RR: 0.70, 95% CI: 0.62---0.79, p < 0.001). No significantdecrease in mortality was achieved (RR: 0.76, 95% CI: 0.45---1.28, p = 0.30). Quality sensitiveanalyses confirmed the main overall results.Conclusions: Intraoperative goal directed hemodynamic therapy with minimally invasive mon-itoring decreases postoperative complications in noncardiac surgery, although it was not ableto show a significant decrease in mortality rate.© 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is anopen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALAVRAS-CHAVEFluidoterapiaalvo-dirigida;Metaanálise;Objetivohemodinâmico;Cirurgia não cardíaca

Terapia hemodinâmica alvo-dirigida no intraoperatório de cirurgia não cardíaca:revisão sistemática e meta-análise

ResumoJustificativa: A terapia hemodinâmica alvo-dirigida (THAD) é uma abordagem focada no uso dodébito cardíaco (DC) e parâmetros relacionados, como desfechos para fluidos e medicamentospara otimizar a perfusão tecidual e o fornecimento de oxigênio. Objetivo primário: determinaros efeitos da THAD sobre as taxas de complicacões no pós-operatório.Métodos: Meta-análise dos efeitos da THAD em cirurgias não cardíacas de adultos sobre ascomplicacões pós-operatórias e mortalidade, usando a metodologia PRISMA. Uma busca sis-temática foi realizada no Medline PubMed, Embase e Biblioteca Cochrane (última atualizacão,outubro de 2014). Os critérios de inclusão foram estudos clínicos randômicos (ECRs) nosquais a THAD no intraoperatório foi comparada com a terapia convencional de reposicão delíquidos em cirurgia não cardíaca. Os critérios de exclusão foram traumatismo e estudos decirurgia pediátrica e aqueles usando cateter de artéria pulmonar. Os desfechos, primário esecundário, foram complicacões pós-operatórias e mortalidade, respectivamente. Os estudosque atenderam aos critérios de inclusão foram examinados na íntegra e submetidos à análisequantitativa, análise de subgrupo pré-definido (estratificada por tipo de monitor, terapia eobjetivo hemodinâmico) e análise de sensibilidade pré-definida.Resultados: 51 ECRs foram identificados inicialmente, 24 atenderam aos critérios de inclusão.Cinco ECRs foram adicionados por busca manual, resultando em 29 ECRs para análise final,incluindo 2.654 pacientes. Uma reducão significativa das complicacões para a THAD (RR: 0,70,IC de 95%: 0,62-0,79, p < 0,001). Nenhuma diminuicão significativa na mortalidade foi observada(RR: 0,76, IC de 95%: 0,45-1,28, p = 0,30). Análises de sensibilidade qualitativa confirmaram osprincipais resultados gerais.Conclusões: THAD no intraoperatório com monitoracão minimamente invasiva diminui ascomplicacões no pós-operatório de cirurgia não cardíaca, embora não tenha mostrado umareducão significativa da taxa de mortalidade.© 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. Este e umartigo Open Access sob uma licenca CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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ntroduction

he perioperative management of high-risk surgical patientsontinues to be a challenge for the anesthesiologists.espite advances in perioperative management, the inci-ence of serious complications after major surgery remainsigh.1,2 A decrease in perioperative oxygen transport is
losely related to the development of organ failure andeath.3 It has also been demonstrated that a large high-riskurgical population accounts for 12.5% of surgical proce-ures and for more than 80% of deaths.4 Surgical patients
aoac

an be classified as high risk based on surgical factors oratient-related factors.5 Goal directed hemodynamic ther-py (GDHT) is based on the optimization of preload with these of algorithms based on fluids, inotropes and/or vasopres-ors to achieve a certain goal in stroke volume (SV), cardiacndex (CI), or oxygen delivery (DO2). The ultimate goal of thisptimization is to avoid fluid overload, tissue hypoperfusion,

6
nd hypoxia. All the studies of perioperative hemodynamicptimization had the same starting point, fluid loading,nd the same endpoint, achieving adequate DO2. However,linical heterogeneity between studies of GDHT cannot be




















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Goal directed hemodynamic therapy

ignored, with regard to type of surgery, patient’s character-istics, therapeutic goals, methods for achieving these goalsand monitoring. The pulmonary arterial catheter (PAC) hasbeen considered to be the ‘‘gold standard’’ for monitor-ing preload, afterload, contractility, and tissue oxygenation.The invasiveness and high rate of complications associatedwith this device render it as unsuitable for routine use inmost cases. The use of minimally invasive monitoring hasgained popularity in the past few years; these devices havebeen validated intraoperatively. Currently PAC is not rec-ommended in most surgeries, and for this reason it was notanalyzed in this meta-analysis. There are no data to supportthe practice of using central venous pressure to guide fluidtherapy,7 therefore, central venous pressure-guided fluidtherapy was not included in analysis.

Yet there are no studies in which different algorithmsor different objectives are compared. The best method forassessing tissue oxygenation and intravascular volume hasnot yet been defined. The present review was designed toupdate the published evidence and determine the effective-ness of intraoperative GDHT with regard to complicationsand mortality with different types of algorithms and moni-tors used.

Material and methods

Selection criteria

The Preferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) methodology8 was used to identifythe studies, based on the following inclusion criteria:

1. Participants: Adult patients (over 18 years) undergoingelective noncardiac surgery were included. The studieswere not limited in terms of surgical risk.

2. Types of intervention: Intraoperative goal directedhemodynamic therapy: defined as hemodynamic moni-toring that allows to perform a hemodynamic optimiza-tion algorithm based on the use of fluids, inotropesand/or vasopressors to achieve normal or supranormalhemodynamic values. GDHT guided by pulmonary arterycatheter, transesophageal echocardiography or centralvenous pressure-guided GDHT were excluded.

3. Types of comparison: The studies that were selectedfor analysis included those that compared GDHT withconventional fluid management (monitoring of bloodpressure, electrocardiogram, heart rate, urine outputand/or central venous pressure).

4. Results: RCTs reporting any of the following outcomes:postoperative complications and/or mortality.

5. Types of studies: RCTs where intraoperative GDHT wasperformed in adult patients scheduled for noncardiacmajor surgery. Only peer-reviewed manuscripts wereincluded.

Sources of information

Following the PRISMA protocol8 different search strategies(last updated in October 2014) were used to iden-tify relevant studies that met inclusion criteria usingEMBASE, MEDLINE and the Cochrane Library. There were no

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515

estrictions on the publication date or language. In addi-ion to electronic searching, industry representatives wereontacted for additional material. All identified review arti-les and evidence-based guidelines were hand-searched fordditional references.

earch itemshe search was conducted using the following key words:urgery, fluid, goal directed, end point, hemodynamic, tar-et, goal and randomized controlled trial.

tudy selection and data extraction

wo independent investigators assessed each title andbstract in order to discard any irrelevant RCTs and identifyhose potentially relevant. These RCTs were analyzed select-ng those that met the inclusion criteria outlined above.CT data extraction was performed by two different inves-igators and any discrepancy required further analysis andonfirmation by a third investigator. The authors reviewedhe data analysis in order to avoid errors in data transcrip-ion.

ssessment of risk of bias in included studies

ias assessment risk was performed using the Cochrane riskf bias tool. From this tool, we used seven domains to assesshe methodological quality of the studies included in thenalysis.

utcome variableshe primary outcome was the overall postoperativeomplications. The results were stratified according to theollowing variables: monitor utilized, therapy used to reach

hemodynamic goal and the hemodynamic goal. For theredefined subgroup analysis, studies were grouped:

1) Monitor: (a) Arterial pulse contour analysis methods(Vigileo/Flotrac®, Edwards Lifesciences Corporation,USA; ProAQT®, Pulsion medical systems SE, Germany;LiDCO Plus®, LiDCO Ltd., UK); (b) oesophageal DopplerMonitoring-ODM (CardioQ®, Deltex Medical, UK); (c)noninvasive methods (Masimo®, Masimo Corporation;CNAP® PPV, CNSystems Medizintechnik AG) and (d)measures of oxygen delivery and extraction methods.

2) Therapy: (a) Fluids; (b) fluids and inotropes; (c)vasopressors and fluids and (4) fluids, inotropes andvasopressors.

3) Hemodynamic goals: (a) SV maximization; (b)CI > 2.5 mL/min/m2; (c) preload responsiveness (includ-ing stroke volume variation, Pulse pressure variationand Pleth Variability Index®) and (d) ScvO2.

The secondary outcome was mortality.

tatistical analysis

eview manager (‘‘Revman’’) 10 for MAC (Cochrane col-aboration, Oxford, UK) was used for statistical analysis.eta-analysis was carried out using the Mantel---Haenszel


Records identified throughdatabase searching

(n=14 160)

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clud

edRecords after duplicates removed

(n=10 475)

Records screened(n=1003)

Full-text articles assessedfor eligibility

(n=51)

Studies included inqualitative synthesis

(n=29)

Records excluded(n=9472)

Full-text articles excluded,

Outcomes not reportedn=2

Perioperative (n=6)Cardiac surgery (n=5)

Emergency surgery (n=1)Sepsis (n=2)

Both groups GDT (n=6)

Studies included inquantitative synthesis

(meta-analysis)(n=29)

Additional records identifiedthrough other sources

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Figure 1 Flow diagram

andom-effects model, with results presented as risk ratioRR) with a 95% confidence interval (CI). Forest plotsere then constructed, considering p < 0.050 as statistically

ignificant effect. Statistical heterogeneity was evaluatedsing I2 statistics; I2 values of less than 25% were defineds low heterogeneity, 25---50% as moderate heterogeneitynd greater than 50% as high heterogeneity. A �2 test for

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Random sequence generation (selection b

Allocation concealment (selection b

Blinding of participants and personnel (performance b

Blinding of outcome assessment (detection b

Incomplete outcome data (attrition b

Selective reporting (reporting b

Other b

Low risk of bias Unclear risk of bia

igure 2 Review authors’ judgements about each risk of bias itemow risk of bias; white, unclear risk of bias; red, high risk of bias.

strating search strategy.

eterogeneity was performed, with p < 0.100 regarded astatistically significant. A priori sensitivity analyses wereonducted on both the primary and the secondary out-
omes by restricting the analysis to high quality trials: tohose studies that showed no allocation bias and thoseithout randomization/allocation bias. Publication bias wasssessed using funnel plot techniques.
ias)

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Bartha et al. 2012

Benes et al. 2010

Brandstrup et al. 2012

Buettner et al. 2008

Cecconi et al. 2011

Challand et al. 2012

Conway et al. 2002

Donati et al. 2007

Forget et al. 2010

Forget et al. 2013

Gan et al. 2002

Jammer et al. 2010

Lopes et al. 2007

Mayer et al. 2010

McKenny et al. 2013

Nobblet et al. 2006

Peng et al. 2014

Salzwedel et al. 2013

Scheeren et al. 2013

Senagore et al. 2009

Sinclair et al. 1997

Srinivasa et al. 2013

Van der Linden et al. 2010

Venn et al. 2002

Walkening et al. 2005

Zakhaleva et al. 2013

Zhang et al. 2012

Zhang et al. 2013

Zheng et al. 2013

Figure 3 Review authors’ judgements about each risk of biasitem for each included study.


Results

Study selection

There were 14,160 references in electronic databases, ofwhich 1003 were screened. Of those, 55 RCTs were analyzedand 24 of them were included for systematic review andmeta-analysis, excluding those who did not meet the inclu-sion criteria. Finally a total of 29 RCTs were included9---37;5 RCTs were added by manual search. 2654 patients wereincluded. Fig. 1 shows the flowchart used for item selection.

Assessment of risk of bias in individual studies

Bias risk was analyzed with the Cochrane tool. This was per-formed by two authors independently and we resolved anydisparity by discussion and the involvement of a third per-son. We present the methodological quality in a summarytable and a graph (Figs. 2 and 3).

Characteristics of the studies included in theanalysis

The selected articles describe the results of RCTs that eval-uated the use of intraoperative GDHT in noncardiac electivesurgery, and that included postoperative complicationsand/or mortality as outcome. The characteristics of theincluded RCTs are shown in Table 1.

Primary results

1. Total complicationsAnalyzing the 29 RCTs, 26 describe the total associated

complications10---37 GDHT was associated with a significantreduction in overall complication compared with patientstreated in the control group (RR: 0.70, 95% CI: 0.62---0.79,p < 0.001) (Fig. 4).

2. Complications by monitorA significant decrease in complications was found in

subgroup based on pulse contour analysis (RR: 0.78, 95%CI: 0.59---0.99, p = 0.04) and subgroup ODM (RR: 0.67, 95%CI: 0.53---0.85, p < 0.001). However, it was not shown inthe subgroup of noninvasive monitoring (RR: 0.57, 95%CI: 0.28---1.15, p = 0.12) and was based on measures ofoxygen delivery and extraction methods (RR: 0.59, 95%CI: 0.20---1.80, p = 0.36) (Fig. 5).

3. Complications by hemodynamic therapyA significant decrease in complications was observed

in the fluids as monotherapy subgroup (RR: 0.69, 95%CI: 0.57---0.84, p < 0.001), fluids and vasopressors sub-group (RR: 0.76, 95% CI: 0.68---0.85, p < 0.001), and fluids,vasopressors and inotropes subgroup (RR: 0.54, 95% CI:0.32---0.89, p = 0.02). However, the use of fluids andinotropes showed no decrease in complications (RR. 0.66,95% CI: 0.34---1.28, p = 0.22) (Fig. 6).

4. Complications by hemodynamic goal
A decrease in complications was associated with the
use of GDHT in the following subgroups: Svmaximization(RR: 0.73, 95% CI: 0.61---0.89, p < 0.001), in the subgrouppreload responsiveness (RR: 0.73, 95% CI: 0.59---0.95),


Table 1 PICO characteristic of included studies.

Study Year Patients Intervention Comparator Outcomes Studydesign

Sinclairet al.

1997 Patients over 55years undergoinghip replacementsurgery

CardioQ-guided GDHTby optimizing SV andcFT with fluidsn 20

Standard caren 20

Length of stay,hemodynamicparameters

RCT

Conwayet al.

2002 ASA I---III patientsundergoingcolorectal surgery

CardioQ-guided GDHTby optimizing SV withfluidsn 29

Standard caren 28

Hemodynamicparameters, bowelfunctionparameters,complications

RCT

Gan et al. 2002 ASA I---III patientsundergoing majorsurgery


Standard caren 50

Length of stay,complications

RCT

Vennet al.

2002 Patients undergoinghip replacementsurgery


Standard caren 29

Length of stay,hemodynamicparameters

RCT

Walkelinget al.

2005 ASA I---III patientsundergoingcolorectal surgery inan ERAS protocol


Standard care(CVP12---15 mmHg)n 64

Length of stay,oral tolerance,complications,quality of recovery

RCT

Nobbletet al.

2006 Patients undergoingcolorectal surgery


Standard caren 54

Length of stay,complications,bowel functionrecovery

RCT

Donatiet al.

2007 High-risk patientsundergoing majorabdominal surgery

GDHT by optimizingERO2 with fluids andinotropesn 68

Standard caren 67

Hemodynamicparameters,complications,length of stay

RCT

Lopeset al.


CNAP-guided GDHTby optimizing�PP < 10%n 17

Standard caren 16

Hemodynamicparameters,complications, ICUstay, length of stay

RCT

Buettneret al.

2008 ASA I---III patientsundergoing majorabdominal surgery(general,gynecological)

PPV-guided GTHDwith fluids andvasopressorsn 40

Standard caren 40

Tissue oxygenationparameters,hemodynamicparameters,length of stay

RCT

Senagoreet al.

2009 Low- andmoderate-riskpatients undergoinglaparoscopic bowelresection in an ERASprotocol

CardioQ-guided GDHTby optimizing SV withfluids n 21(LR) or HES6%n 21

Standard caren 22

Complications,length of stay

RCT

Jammeret al.

2010 Patients undergoingcolorectal surgery

ScvO2-guided GDHTwith fluidsn 121

Standard caren 120

Complications RCT

Van derLindenet al.

2010 ASA II---III patientsundergoing low limbarterial by-pass

Flotrac-guided GDHTmaintaining aCI > 2.5 mL/min/m2

and CVP < 15 mmHgwith fluids andinotropes.Sevofluraneanesthesian 20

Standard careguided byAPm and CVPn 17

Hemodynamicparameters,Complications,length of stay

RCT

Goal directed hemodynamic therapy 519

Table 1 (Continued)


Forgetet al.

2010 Patients undergoingmajor abdominalsurgery

Masimo-guided GDHTby optimizing PVIwith fluids andvasopressorsn 41

Standard caren 41

Amount of fluidadministered,lactate levels,complications,length of stay,mortality

RCT

Mayeret al.


Flotrac-guided GDHTmaintaining aCI > 2.5 mL/min/m2

with fluids, inotropesand vasopressorsn 30

Standard care(restrictive)n 30


RCT

Beneset al.

2010 High-risk patients(ASA III---IV)undergoing majorabdominal surgery

Flotrac-guided GDHTby optimizing SVVwith fluids andinotropesn 60

Standard caren 60

Complications,length of stay, ICUstay, mortality

RCT

Cecconiet al.

2011 Patients undergoinghip replacement.Regional Anesthesia

Flotrac-guided GDHTby optimizing SV andDOI > 600 mL/min/m2


Standard caren 20

Amount of fluidsadministered,vasoactive use,complications,length of stay

RCT

Challandet al.

2012 Patients undergoingcolorectal surgery inan ERAS protocol.All patients


Standard caren 90

Length of stay,readmission,complications

RCT

Brandstrupet al.

2012 ASA I---III patientsundergoingcolorectal surgery


Standardcare. Zerobalancen 79


RCT

Barthaet al.

2013 Patients over 70years undergoinghip replacement inan ERAS protocol

LiDCO plus guidedGDHT by optimizingSV andDOI > 600 mL/min/m2

with fluids andinotropesn 74

Standard caren 75

Complications,amount of fluidsadministered,hemodynamicresponse, lengthof stay

RCT

Zhanget al.

2013 ASA I---II patientsundergoinggastrointestinalsurgery

PPV-guided GDHTwith fluids: LR n 20;and HES 6%n 20

Standard caren 20

Length of stay,bowel functionparameters,complications,hemodynamicparameters

RCT

Salzwedelet al.

2013 ASA II---III patientsundergoing majorabdominal surgery

ProAQT-guided GDHTmaintaining aCI > 2.5 mL/min/m2


Standard caren 81


RCT

Scheerenet al.

2013 ASA III---IVundergoing majorabdominal surgery

Flotrac-guided GDHTby optimizing SV andSVV with fluidsn 26

Standard caren 26

Complications,SOFA score, ICUstay, mortality

RCT


Table 1 (Continued)


Zhanget al.

2013 ASA I---II undergoinglobectomy surgery

Flotrac-guided GDHTby optimizing SVVand maintaining aCI > 2.5 mL/min/m2

with fluids andinotropesn 30

Standard caren 30


RCT

Forgetet al.

2013 Low- andmoderate-riskpatients undergoingcolorectal surgery inan ERAS protocol

Masimo-guided GDHTby optimizing PVIwith fluids (IPV < 13)n 10

Standard caren 11

Amount of fluidsadministered,complications,mortality, lengthof stay

RCT

Zakhalevaet al.

2013 Patients undergoingcolorectal surgery inan ERAS protocol


Standard caren 40

Time of surgery,amount of fluidsadministered,bowel functionrecovery,complications,length of stay,mortality

RCT

Srinivasaet al.

2013 ASA I---III patientsundergoingcolorectal surgerywithout an ERASprotocol

CardioQ-guided GDTby optimizing SV andcFT with fluidsn 37

Standard caren 37

Hemodynamicparameters,complications

RCT

McKennyet al.

2013 Patients undergoingmajor gynecologicalsurgery


Standard caren 50


RCT

Zhenget al.

2013 Elderly high-riskpatients undergoingmajor abdominalsurgery

Flotrac-guided GDHTby maintaining aCI > 2.5 mL/min/m2

with fluids andvasopressorsn 30

Standard caren 30

Cardiovascularcomplications,bowel functionparameters, ICUstay, length of stay

RCT

Penget al.

2014 Adult patientsundergoing majororthopedic surgery

Flotrac-guided GDHTto maintain SVV < 10or <14% in pronepositionn 40

Standard caren 40

Splanchnic organfunctions,postoperativecomplications

RCT

GDHT, goal directed hemodynamic therapy; SV, stroke volume; Cft, corrected flow time; RCT, randomized controlled trial; ASA, AmericanSociety of Anesthesiologist; CVP, central venous pressure; ERAS, enhanced recovery after surgery; ERO2, oxygen extraction index; �PP,increment of pulse pressure; PPV, pressure pulse variation; LR, lactate of ringer; HES, hydroxyethyl starch; CI, cardiac index; PVI, ple-

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Ni

SsN((rc

thysmography variation index; SVV, stroke volume variation; DOI,

ScvO2, central venous oxygen saturation.

p < 0.001), and with a CI target, CI > 2.5 mL/min/m2 (RR:0.58, 95% CI: 0.44---0.76, p < 0.001), whereas in the sub-group that utilized measures of oxygen delivery andextraction methods no significant decrease was observed(Fig. 7).

ortality

o significant differences were found with regard to mortal-ty (RR: 0.76, 95% CI: 0.45---1.28, p = 0.30) (Fig. 8).

hwpp

n delivery index; SVI, indexed stroke volume; PP, pulse pressure;

ensitivity analysis, assessment risk of bias acrosstudies and publication biaso changes in the results with regard to complications[RR: (CI 95%) 0.71 (0.61---0.82), p < 0.01]) or mortality ([RR:CI 95%) 0.77 (0.42---1.40), p = 0.39]) were observed whenestricting the analysis to those studies that had no allo-ation bias; or when restricting the analysis to those that
ad no allocation and/or randomization bias in the resultsith regard to complications [RR (CI 95%) 0.69 (0.59---0.81),
< 0.01] and mortality ([RR (CI 95%) 0.95 (0.45---1.85), = 0.87]) On the other hand, a prespecified group analysis


Gan et al. 2002Venn et al. 2002Conway et al. 2002Walkening et al. 2005Nobblet et al. 2006Donati et al. 2007Lopes et al. 2007Senagore et al. 2009Mayer et al. 2010Forget et al. 2010Jammer et al. 2010Van der Linden et al. 2010Benes et al. 2010Cecconi et al. 2011Zhang et al. 2012Brandstrup et al. 2012Challand et al. 2012Bartha et al. 2012Zhang et al. 2013McKenny et al. 2013Scheeren et al. 2013Salzwedel et al. 2013Forget et al. 2013Srinivasa et al. 2013Zakhaleva et al. 2013Zheng et al. 2013Peng et al. 2014

0.54 [0.37, 0.81]0.51 [0.30, 0.85]

0.54 [0 .20, 1.40]0.63 [0.43 , 0.92]0.13 [0.02, 0.97]

0.33 [0 .17, 0.64]0.55 [0 .29, 1.04]2.10 [0.68, 6.44]0.40 [0.18, 0.89]0.78 [0.66, 0.93]0.99 [0.74, 1.33]

1.27 [0 .24, 6.76]0.43 [0.28, 0.66]

0.80 [0 .64, 1.02]1.20 [0.59, 2.45]0.96 [0.60, 1.53]

0.78 [0 .36, 1.68]1.04 [0 .79, 1.36]0.56 [0.30, 1.07]

0.52 [0.24 , 1.12]0.54 [0.31, 0.94]0.74 [0.62, 0.88]

0.14 [0 .02, 0.96]0.96 [0.72 , 1.28]0.46 [0.22, 0.96]0.64 [0.49, 0.84]0.78 [0.59, 1.04]

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1541512

352010241343161516727

27193032

59292864546716443041

12017502040719075305026811037403040

4.7%3.5%1.4%5.0%0.3%2.4%2.6%1.0%1.9%7.9%6.0%0.5%4.4%7.0%2.2%3.9%2.0%6.4%2.6%2.0%3.2%7.8%0.4%6.2%2.1%6.3%6.2%

200220022002200520062007200720092010201020102010201020112012201220122012201320132013201320132013201320132014

Total (95% CI)Total eventsHeterogeneity: Tau2=0.04 ; Chi2=54.70, df=26 ( P=.0008); I2=52%Test for overall effect: Z=5.71 (P<.00001)

1275

StudyGDHT

Events Total Weight YearRisk Ratio

M-H, Random, 95% CIRisk Ratio

M-H, Random, 95% CIControl

Events Total

1259 100.0% 0.70 [0.62, 0.79]460 645

0.01Favours GDHT Favours control 0.1 1 10 100

roup

ruwavsascawwtftbAaasdcOar

Figure 4 Effect of GDHT in the protocol g

has been conducted and described above. A funnel plot wasdrawn for the primary outcome comparison to explore thepossibility of publication bias. The symmetry of the funnelplot was assessed visually and did not suggest publicationbias (Fig. 9).

Discussion

Numerous studies have reported differences betweentechnologies, especially in their response to typical sur-gical interventions such as fluid and vasoactive drugadministration.38 The results obtained with one type ofmonitoring cannot be extrapolated to those obtained withother monitors.39 RCTs using noninvasive monitors werelimited both in number of patients studied and meth-odological quality. How minimal invasive cardiac outputmonitoring techniques can be used to guide individ-ualized fluid management40 needs to be sustained byvalidation studies that adhere to the proposed methodologi-cal considerations41 as well as large-scale clinical outcomestudies.

There is some evidence that SV maximization strategiescould be harmful in aerobically fit patients by lead-ing to volume overload,25 and recent evidence suggests
that this goal does not provide the benefits previouslydescribed.42
However, the results of our meta-analysis show thatthis hemodynamic goal remains valid. The use of dynamic

tp

s

vs control group on overall complications.

esponse parameters to volume may decrease the risk of vol-me overload. A CI > 2.5 mL/min/m2 as hemodynamic targetithin algorithms in which fluids, vasopressors and inotropesre used avoid the risk of hypotension due to decreasedasomotor tone. The use of inotropes increases the CO inituations where the patient is nonresponsive to the volumend does not present a reduced vasomotor tone. Inotropicupport with dobutamine can result in changes in microvas-ular flow related to direct effects on the microcirculations well as global CO.43 With the exception of ScvO2, thatas only evaluated in one RCT,19 and was not associatedith better outcomes, this meta-analysis has not been able

o detect significant differences between subgroups. There-ore it seems reasonable to adapt GDHT to risk patient,ype of surgery as well as its duration44 as recommendedy recent European Society of Anaesthesiology guidelines.45

multicenter observational trial in patients with intra-bdominal surgery found that low ScvO2 was associated withn increased risk of postoperative complications in high-riskurgery. In this trial, the optimal value of mean ScvO2 toiscriminate between patients who did or did not developomplications was 73% (sensitivity 72%, specificity 61%)46

ne of the major limitations of venous oximetry is that,s a global marker of demand-supply balance, it does noteflect organ-specific malperfusion. Whether ScvO2 moni-
oring improves outcomes in surgical patients remains to beroven in large RCTs.
Unlike our results, a recent meta-analysis has shown aignificant benefit of GDHT in patients receiving fluids and


SubgroupPulse contour devices

Oesophageal Doppler Monitoring

Measures of Oxygen Delivery and Extraction

Non invasive

Total (95% CI)

GDHTEvents Total Weight

Risk RatioM-H, Random, 95% CI


ControlEvents Total


Bartha et al. 2012Benes et al. 2010Cecconi et al. 2011Mayer et al. 2010Peng et al. 2014Salzwedel et al. 2013Scheeren et al. 2013Van der Linden et al. 2010Zhang et al. 2012Zhang et al. 2013Zheng et al. 2013Subtotal (95% CI)

Brandstrup et al. 2012Challand et al. 2012Conway et al. 2002Gan et al. 2002McKenny et al. 2013Nobblet et al. 2006Senagore et al. 2009Srinivasa et al. 2013Venn et al. 2002Walkening et al. 2005Zakhaleva et al. 2013Subtotal (95% CI)

Donati et al. 2007Jammer et al. 2010Subtotal (95% CI)

Forget et al. 2010Forget et al. 2013Lopes et al. 2007Subtotal (95% CI)

Total eventsHeterogeneity: Tau2=0.11 ; Chi2=42.20, df=10 ( P=.00001); I2=76%Test for overall effect: Z=2.02 (P<.04)

Total eventsHeterogeneity: Tau2=0.05 ; Chi2=17.18, df=10 ( P=.07); I2=42%Test for overall effect: Z=3.39 (P<.0007)

Total eventsHeterogeneity: Tau2=0.57 ; Chi2=9.05, df=1 (P=.003); I2=89%Test for overall effect: Z=0.92 (P<.36)


Total eventsHeterogeneity: Tau2=0.07 ; Chi2=74.18, df=26 ( P=.00001); I2=65%Test for overall effect: Z=4.50 (P<.00001)Test for subgroup differences: Chi2=1.21, df=3 ( P=.75); I2=0%

272216

216142

7860

6040

626458

1.04 [0.79, 1.36]0.43 [0.28, 0.66]0.80 [0.64, 1.02]0.40 [0.18, 0.89]2.40 [1.48, 3.90]

0.74 [0.62 , 0.88]0.54 [0.31, 0.94]1.27 [0.24, 6.76]1.20 [0.59, 2.45]0.56 [0.30, 1.07]0.64 [0.49, 0.84]

0.78 [0.61,0.99]

0.96 [0.60, 1.53]0.78 [0.36, 1.68]0.54 [0.20, 1.40]0.54 [0.37, 0.81]0.52 [0.24, 1.12]

0.13 [0.02 , 0.97]1.57 [0.48, 5.18]0.96 [0.72, 1.28]0.51 [0.30, 0.85]0.63 [0.43, 0.92]0.46 [0.22, 0.96]

0.67 [0.53, 0.85]

0.33 [0.17, 0.64]0.99 [0.74, 1.33]

0.59 [0.20, 1.80

0.78 [0.66, 0.93]0.14 [0.02, 0.96]0.55 [0.29, 1.04]

0.57 [0.28, 1.15]

0.72 [0.62,0.83]

4418166

2552123

129

19

7460203032793620403030

451

433520151372162

101630

7550203040812617403030

439

6.0%4.6%6.3%2.3%4.1%6.8%3.6%0.7%2.7%3.1%6.0%

46.1%

23105

21816

2611247

7189296051544237306432

559

24139

381584

27213819

7190285950544437296440

566

4.2%2.4%1.8%4.9%2.4%0.5%1.2%5.8%3.8%5.0%2.6%

34.7%

951

68121189

2751

67 120

187

2.9%5.8%

8.6%

3217

41101768

417

12

41101667

6.9%0.5%3.1%

10.5%

1267 1259 100.0%

Figure 5 Effect of GDHT in the protocol group vs control group on overall complications grouped by monitor. Pulse contourd : CN

io

cetm

lfi

evices: Vigileo/Flotrac®, ProAQT, and LiDCO Plus®. No invasive

notropes in order to achieve supraphysiological targets forxygen delivery in high-risk patients.47

This meta-analysis was unable to demonstrate a signifi-
ant reduction in mortality. There are a number of reasons toxplain why the control mortality may have decreased overime. These include: (1) better overall care thus decreasingortality for similar patients; (2) clinicians’ awareness,
atte

AP® PPV and Masimo®.

earning from previous early published studies and there-ore drifting their practice toward lower risk groups; (3)mprovement in technology, that has become less invasive

48
nd therefore, gaining more credibility. Another reason forhis may be that the most recent studies are not poweredo assess mortality; in earlier studies, mortality was consid-red the most relevant endpoint, but this has changed to


Fluids

Fluids and inotropes

Fluids and vasopressor

Fluids, inotropes and vasopressor

Total (95% CI)


Total eventsHeterogeneity: Tau2= 0.06 ; Chi2=27.25, df=15 (P=.02); I2=46%Test for overall effect: Z=3.65 (P=.0003)

Total eventsHeterogeneity: Tau2=0.31 ; Chi2=12.69, df=3 (P=.005); I2=76%Test for overall effect: Z=1.22 (P=.22)


Total eventsHeterogeneity: Tau2=0.14 ; Chi2=8.64, df=2 (P=.01); I2=77%Test for overall effect: Z=2.41 (P=.02)

Total eventsHeterogeneity: Tau2=0.04 ; Chi2=53.21, df=26 (P=.001); I2=51%Test for overall effect: Z=5.82 (P<.00001)Test for subgroup differences: Chi2=2.31, df=3 (P=.51); I2=0%

6454580.70 [0.62,0.79]1275 1259 100.0%

312225

8865

12392

12276

0.54 [0 .37, 0.81]0.51 [0.30, 0.85]0.54 [0 .20, 1.40]0.63 [0.43, 0.92]0.13 [0.02, 0.97]0.55 [0.29, 1.04]1.57 [0.48 , 5.18]0.99 [0 .74, 1.33]0.96 [0.60, 1.53]0.78 [0 .36, 1.68]1.20 [0.59, 2.45]0.54 [0 .31, 0.94]0.46 [0.22, 0.96]

0.14 [O.Q2 , 0.96]0.52 [0 .24, 1.12]0.96 [0.72, 1.28]0.69 [0.57, 0.84]

0.33 [0 .17, 0.64]1.27 [0.24, 6.76]1.04 [0.79, 1.36]0.56 [0 .30, 1.07]0.66 [0.34, 1.28]

0.78 [0.66, 0.93]0.80 [0 .64, 1.02]0.64 [0.49, 0.84]0.78 [0.59, 1.04]0.76 [0.68, 0.85]

0.43 [0.28, 0.66]0.40 [0.18, 0.89]0.74 [0.62, 0.88]0.54 [0.32, 0.89]

21115

24176

5123101212718

26

60302964541742

1217189403632105137

783

38219

388

124

5124131016197

1527

59292864541644

1207190402640105037

778

4.7%3.4%1.3%5.0%0.3%2.6%0.9%6.1%3.9%1.9%2.2%3.2%2.1%0.4%2.0%6.2%

46.3%

93

449

68207430

192

272

4316

67177530

189

2.4%0.5%6.4%2.6%

11.9%

32161925

41203040

131

41203032

41203040

131

8.1%7.0%6.4%6.2%

27.7%

186

52

603079

169

351572

503081

161

4.3%1.8%7.9%

14.1%

2002200220022005200620072009201020122012201220132013201320132013

2007201020122013

2010201120132014

201020102013

GDHTEvents Total Weight Year



ControlEvents TotalSubgroup

Gan et al. 2002Venn et al. 2002Conway et al . 2002Walkening et al. 2005Nobblet et al . 2006Lopes et al . 2007Senagore et al. 2009Jammer et al. 2010Brandstrup et al. 2012Challand et al . 2012Zhang et al . 2012Scheeren et al . 2013Zakhaleva et al . 2013Forget et al. 2013McKenny et al . 2013Srinivasa et al. 2013Subtotal (95% CI)

Donati et al . 2007Van der Linden et al. 2010Bartha et al . 2012Zhang et al . 2013Subtotal (95% CI)

Forget et al. 2010Cecconi et al . 2011Zheng et al . 2013Peng et al. 2014Subtotal (95% CI)

Benes et al . 2010Mayer et al. 2010Salzwedel et al . 2013Subtotal (95% CI)

Figure 6 Effect of GDHT in the protocol group vs control group on overall complications grouped by therapy.

wrsb

length of stay and morbidity endpoints with less high-riskpatient group, and as a result, have very low or no mortal-ity. However, a reduction in mortality associated with GDHTwas demonstrated in groups of extremely high-risk patients

49
(baseline mortality rate of >20%) as well as with long-termfollow-up.50
Unlike previous meta-analysis, we have not includedthose studies in which PAC was used, since these studies

opic

ere published over 10 years, and do not reflect cur-ent practice. Grocott et al. meta-analysis51 included 31tudies with 5292 participants. The results are dominatedy a single large RCT with a weight of more than 60%

52
f the overall population in which PAC was used. Theresent meta-analysis confirms that the use of minimallynvasive monitoring is effective and reduces postoperativeomplications. Postsurgical complications have a dramatic


Conway et al. 2002Gan et al. 2002Venn et al. 2002Walkening et al. 2005Nobblet et al. 2006Senagore et al. 2009Cecconi et al. 2011Challand et al. 2012Brandstrup et al. 2012Bartha et al. 2012Srinivasa et al. 2013McKenny et al. 2013Zakhaleva et al. 2013Subtotal (95% CI)Total events

Lopes et al. 2007Forget et al. 2010Zhang et al. 2012Scheeren et al. 2013Forget et al. 2013Peng et al. 2014Subtotal (95% CI)Total events

Donati et al. 2007Van der linden et al. 2010Mayer et al. 2010Benes et al. 2010Zheng et al. 2013Zhang et al. 2013Salzwedel et al. 2013Subtotal (95% CI)Total events

936

1819

952

110

68203060303079

287

272

1535301672

182

67173050303081

275

2.4%0.5%

4.4%6.6%2.6%8.2%

24.6%

Jammer et al. 2010Subtotal (95% CI)Total eventsHeterogeneity: Not applicableTest for overall effect: Z=0.06 (P=.96)

Total (95% CI)Total events

51

51

452

51

51

630

121121

1245

120120

1229

6.2%6.2%

100.0%

ScVO2>75%

CI>2.5m/min/m2

0.33 [0.17, 0.64]1.27 [0.24, 6.76]

Not estimable0.43 [0.28, 0.66]0.64 [0.49, 0.84]0.56 [0.30, 1.07]0.74 [0.62. 0.88]0.58 [0.44, 0.76]

0.99 [0.74, 1.33]0.99 [0.74, 1.33]

2010

0.71 [0.63.0.80]

Favours GDHT Favours control

0.01 0.1 10 1001

2007201020102010201320132013

0.55 [0.29, 1.04]0.78 [0.66, 0.93]1.20 [0.59, 2.45]0.54 [0.31, 0.94]0.14 [0.02, 0.96]0.78 [0.59, 1.04]0.73 [0.59, 0.91]

7321212

125

89

174140361040

184

12411016

732

118

164140261040

173

2.6%8.4%2.2%3.2%0.4%6.4%

23.1%

200720102012201320132014

SV maximizationSubgroup

GDHTEvents Total Events Total Weight M–H, Random, 95% CI M–H, Random, 95% CIYear

Control Risk ratio Risk ratio

5211124

16

1610234426

87

202

29603064544220897174375132

653

9382138

84

20132443271519

279

28592964544420907175375040

661

1.3%4.8%3.4%5.0%0.3%0.9%7.3%1.9%4.0%6.6%6.3%2.0%2.1%

46.0%

0.54 [0.20, 1.40]0.54 [0.37, 0.81]0.51 [0.30, 0.85]0.63 [0.43, 0.92]0.13 [0.02, 0.97]1.57 [0.48, 5.18]0.80 [0.64, 1.02]0.78 [0.36, 1.68]0.96 [0.60, 1.53]1.04 [0.79, 1.36]0.96 [0.72, 1.28]0.52 [0.24, 1.12]0.46 [0.22, 0.96]0.73 [0.61, 0.89]

2002200220022005200620092011201220122012201320132013

Heterogeneity: Tau2=0.05; Chi2=23.67, df=12 (P=.02); I2=49%Test for overall effect: Z=3.21 (P=.001)

Heterogeneity: Tau2=0.02; Chi2=7.76, df=5 (P=.17); I2 =36%Test for overall effect: Z=2.78 (P=.005)

Heterogeneity: Tau2=0.06; Chi2=12.59, df=5 (P=.03); I2 =60%Test for overall effect: Z=3.90 (P<.0001)

Preload responsiveness (SVV, PPV, PVI)

Heterogeneity: Tau2=0.04; Chi2=50.42, df=25 (P=.002); I2=50%Test for overall effect: Z=5.66 (P<.00001)Test for subgroup differences: Chi2=6.94, df=3 (P=0.07), I2=56.8%

Figure 7 Effect of GDHT in the protocol group vs control group on overall complications grouped by hemodynamic goal. (SV,stroke volume; CI, cardiac index, SVV, stroke volume variation; PPV, pulse pressure variation, PVI®, Pleth Variability Index).

iGwnCdQ

R

M

mpact on costs. Potential costs savings resulting fromDHT are substantial53 and seem to be cost effective evenith moderate clinical effect.54 Particularly, ODM tech-
ology has been considered favorably by both the NHSenter for evidence-based purchasing in the United King-om and United States Agency for Healthcare Research anduality.55,56
daat

esearch implications

ore studies in which different types of monitoring and
ifferent types of algorithms and hemodynamic therapiesre compared in patients with different risk in order tochieve optimal hemodynamic goals are needed. In addi-ion, outcome report should be standardized. In this regard,


Study

Sinclair et al. 1997Venn et al. 2002Conway et al. 2002Walkening et al. 2005Nobblet et al. 2006Donati et al. 2007Lopes et al. 2007Buettner et al. 2008Senagore et al. 2009Mayer et al. 2010Benes et al. 2010Forget et al. 2010Van der Linden et al. 2010Jammer et al. 2010Cecconi et al. 2011Challand et al. 2012Brandstrup et al. 2012Zhang et al. 2012Bartha et al. 2012McKenny et al. 2013Srinivasa et al. 2013Scheeren et al. 2013Forget et al. 2013Zheng et al. 2013Zakhaleva et al. 2013Zhang et al. 2013Peng et al. 2014

Total (95% CI)Total events

0.50 [0.05, 5.08]1.45 [0.26, 8.06]0.32 [0.01, 7.59]

Not estimable0.33 [0.01, 8.01]0.99 [0.14, 6.79]0.38 [0.08, 1.67]0.33 [0.01, 7.95]0.21 [0.01, 4.24]1.00 [0.15, 6.64]0.42 [0.04, 4.46]

5.00 [0.25, 101.04]Not estimableNot estimableNot estimable

1.26 [0.35, 4.55]1.00 [0.06, 15.68]

Not estimable0.76 [0.18, 3.28]

Not estimableNot estimable

0.15 [0.01, 2.92]Not estimableNot estimableNot estimableNot estimable

3.00 [0.13, 71.51]

0.76 [0.45, 1.28]

199720022002200520062007200720082009201020102010201020102011201220122012201220132013201320132013201320132014

130002200212000510300000001

23

20302964546817404230604120

12120897140745137361030323040

1196

20292864546716404430504117

12020907140755037261030403040

1179

5.1%9.3%2.8%

2.7%7.4%

12.4%2.7%3.0%7.7%4.9%3.0%

16.7%3.6%

12.9%

3.1%

2.7%

100.0%

221012512220000410400200000

31

GDHTEvents Total Events Total Weight M–H, Random, 95% CI M–H, Random, 95% CIYear

Control Risk ratio Risk ratio

Favours GDHT Favours control

0.01 0.1 10 1001Heterogeneity: Tau2 =0.00; Chi2 =7.47, df=15 (P=.94); I2 =0%Test for overall effect: Z=1.05 (P=.30)

tocol

asrra

Figure 8 Effect of GDHT in the pro

recommendations for the evaluation and standardization ofperioperative complications have been recently published.57

In summary, more studies are needed to demonstrate a sig-nificant reduction in mortality associated with GDHT.

Weaknesses in study

The study by Mayer et al.22 has been under investigationfor ethical reasons, the manuscript has not been withdrawn

0

0.5

1.5

1

20.01 0.1 1 10 100

RR

SE(log[RR])

Figure 9 Funnel plot of the published studies in relation tothe primary outcome. The measure of precision used is thestandard error (SE) of the log RR.

iisoa

ctiderra

dhntt

p

group vs control group on mortality.

nd remains part of the scientific record at the time weearched the literature. To verify potential biases in ouresults, both the primary and the secondary outcome weree-examined without including the Mayer et al.22 manuscriptnd no differences were found.

Many trials were single center trials and only one hasnvestigated more than 100 patients per group.19 Differencesn methodological quality may cause heterogeneity. Smallertudies tend to be conducted and analyzed with less method-logical rigor than larger studies, and trials of lower qualitylso tend to show larger intervention effects.

The major limitation of our analysis is that overallomplications were analyzed, regardless of the severity ofhese and their impact on length of stay and/or mortal-ty. Furthermore, the use of different surgical interventions,ifferent monitoring systems and algorithms adds more het-rogeneity to the analysis. Thus, study heterogeneity mayeduce the precision of treatment effect estimates andeduce the generalizability of the results of this meta-nalysis.

The present meta-analysis is based on studies thatescribe the incidence of postoperative complications. Itas to be recognized that the reporting of complications isot consistent and that the definitions used can differ inype, definition and importance between studies, limiting
he applicability of some of our findings.
Furthermore, and unlike previous meta-analysis, theresent meta-analysis conducted a global analysis of total

5

csrwq

C

Toisdt

C

T

F

Tp

A

TfM

Gb

R

1

1

1

1

1

1

1

1

1

1

2

2

2

26

omplications, without conducting an organ-specific47,58 ortratified by risk49 analysis. Despite these limitations, theesults are consistent in most subgroups analyzed and evenhen the analysis is restricted to those studies with higheruality.

onclusions

he results of this meta-analysis show that the usef intraoperative GDHT with minimally invasive monitor-ng decreases postoperative complications in noncardiacurgery, although it was not possible to show a significantecrease in mortality rate. ScvO2 monitoring was not ableo decrease the frequency of complications.

onflicts of interest

he authors declare no conflicts of interest.

unding

his study had no funding. EAR group is a collaborative inde-endent nonprofit group, endless external funding.

cknowledgements

he authors wish to thank the professionals of the Pro-essional Library of the University Hospital Infanta Leonor,adrid.

The authors wish to thank Drs. Angela Camps, Susanaonzález and Miriam de Nadal for their invaluable contri-ution in training and interest in this area.

eferences

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0. Conway DH, Mayall R, Abdul-Latif MS, et al. Randomised con-trolled trial investigating the influence of intravenous fluidtitration using oesophageal Doppler monitoring during bowelsurgery. Anaesthesia. 2002;57:845---9.

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6. Lopes MR, Oliveira MA, Pereira VOS, et al. Goal-directed fluidmanagement based on pulse pressure variation monitoring dur-ing high-risk surgery: a pilot randomized controlled trial. CritCare. 2007;11:R100.

7. Buettner M, Schummer W, Huettemann E, et al. Influence ofsystolic-pressure-variation guided intraoperative fluid manage-ment on organ function and oxygen transport. Br J Anaesth.2008;101:194---9.

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