intraoperative goal-directed fluid therapy in elective ... goal... · intraoperative goal-directed...

META-ANALYSIS

Intraoperative Goal-directed Fluid Therapy in ElectiveMajor Abdominal Surgery

A Meta-analysis of Randomized Controlled Trials

Katie E. Rollins, MRCS and Dileep N. Lobo, DM, FRCS, FACS, FRCPE

Objectives: To compare the effects of intraoperative goal-directed fluid

therapy (GDFT) with conventional fluid therapy, and determine whether

there was a difference in outcome between studies that did and did not use

Enhanced Recovery After Surgery (ERAS) protocols.

Methods: Meta-analysis of randomized controlled trials of adult patients

undergoing elective major abdominal surgery comparing intraoperative

GDFT versus conventional fluid therapy. The outcome measures were post-

operative morbidity, length of stay, gastrointestinal function and 30-day

mortality.

Results: A total of 23 studies were included with 2099 patients: 1040 who

underwent GDFT and 1059 who received conventional fluid therapy. GDFT

was associated with a significant reduction in morbidity (risk ratio [RR] 0.76,

95% confidence interval [CI] 0.66–0.89, P¼ 0.0007), hospital length of stay

(LOS; mean difference �1.55 days, 95% CI �2.73 to �0.36, P¼ 0.01),

intensive care LOS (mean difference �0.63 days, 95% CI �1.18 to �0.09,

P¼ 0.02), and time to passage of feces (mean difference �0.90 days, 95% CI

�1.48 to �0.32 days, P¼ 0.002). However, no difference was seen in

mortality, return of flatus, or risk of paralytic ileus. If patients were managed

in an ERAS pathway, the only significant reductions were in intensive care

LOS (mean difference �0.63 days, 95% CI �0.94 to �0.32, P< 0.0001) and

time to passage of feces (mean difference �1.09 days, 95% CI �2.03 to

�0.15, P¼ 0.02). If managed in a traditional care setting, a significant

reduction was seen in both overall morbidity (RR 0.69, 95% CI 0.57 to

�0.84, P¼ 0.0002) and total hospital LOS (mean difference �2.14, 95% CI

�4.15 to �0.13, P¼ 0.04).

Conclusions: GDFT may not be of benefit to all elective patients undergoing

major abdominal surgery, particularly those managed in an ERAS setting.

Keywords: complications, goal-directed fluid therapy, intraoperative, meta-

analysis, outcome

Copyright © 2015 Wolters Kluw

From Gastrointestinal Surgery, National Institute for Health Research NottinghamDigestive Diseases Biomedical Research Unit, Nottingham University Hos-pitals and University of Nottingham, Queen’s Medical Centre, Nottingham,UK.

Disclosure: Supported by a Research Fellowship awarded by the European Societyfor Clinical Nutrition and Metabolism (ESPEN; to KER). The sponsors had norole in the design, execution, and reporting of the study. DNL has receivedunrestricted research funding and speaker’s honoraria from Fresenius Kabi, B.Braun Medical, and Baxter Healthcare for unrelated work. DNL is Chairmanof the Scientific Committee of the Enhanced Recovery After Surgery(ERAS1) Society. KER declares no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citationsappear in the printed text and are provided in the HTML and PDF versions ofthis article on the journal’s Web site (www.annalsofsurgery.com).

This is an open-access article distributed under the terms of the Creative CommonsAttribution-Non Commercial-No Derivatives License 4.0, where it is permiss-ible to download and share the work provided it is properly cited. The workcannot be changed in any way or used commercially.

Reprints: Dileep N. Lobo, DM, FRCS, FACS, FRCPE, Nottingham Digestive DiseasesCentre, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham NG72UH, United Kingdom. E-mail: [email protected].

Copyright � 2015 Wolters Kluwer Health, Inc. All rights reserved.ISSN: 0003-4932/14/26105-0821DOI: 10.1097/SLA.0000000000001366

Annals of Surgery � Volume 263, Number 3, March 2016

(Ann Surg 2016;263:465–476)

I ntraoperative hypovolemia caused by loss of as little as 10% to15% of blood volume can result in an appreciable fall in splanch-

nic perfusion, which often outlasts the period of hypovolemia.1 Thisresults in an intramucosal acidosis of the gut,2 leading to a cascade ofevents that impair postoperative gastrointestinal function and causecomplications. 3 Postoperative gastrointestinal morbidity in the formof an inability to tolerate oral or enteral tube feeding, nausea,vomiting, and abdominal distension can be responsible for over halfof delayed discharges.4 This concept led to the use of intraoperativegoal-directed fluid therapy (GDFT) in which relatively small-volume(200–250 mL) boluses of fluid (usually a colloid) over backgroundcrystalloid infusions have been used to increase stroke volume andcardiac output, improve gut perfusion,1 and decrease gut mucosalacidosis.

A number of methods, including transesophageal Doppler(TED), lithium dilution, arterial pulse contour analysis, thoracicelectrical bioimpedance, partial non-rebreathing systems, and trans-pulmonary thermodilution techniques have been used to measureintraoperative stroke volume and cardiac output and, thereby, helpdirect fluid therapy.5 The methods used most frequently in clinicalpractice are the TED and lithium dilution techniques. The commonestalgorithm assesses the change in stroke volume in response to a fluidbolus of 200 to 250 mL infused over 5 to 10 minutes. An increase instroke volume of more than 10% in response to this bolus signifieshypovolemia and indicates the need for a further bolus. An increase instroke volume of 10% or less suggests adequate filling and continu-ation of the background crystalloid infusion without the need foranother fluid bolus. A reduction in stroke volume by more than 10%during continued monitoring necessitates a further bolus and repetitionof the cycle. Variations in this methodology include monitoring ofstroke volume variation and corrected flow time (FTc).6,7

Randomized controlled trials and meta-analyses8–11 pub-lished in the first decade of the twenty-first century suggested thatintraoperative GDFT resulted in a statistically significant reductionin postoperative complication rates and length of stay (LOS) whencompared with patients receiving conventional intraoperative fluidtherapy. This led to intraoperative GDFT being recommended as astandard of care by the UK National Institute for Health and ClinicalExcellence (NICE).12 However, postoperative fluid therapy regimenswere not clear in most of the early studies, and perioperative care wasnot standardized. Avoidance of postoperative salt and water overloadand maintaining patients in as near a state to zero fluid balance aspossible has been shown to reduce both complication rates and lengthof hospital stay even in patients not receiving GDFT.13–16 Inaddition, the use of fast-track or Enhanced Recovery After Surgery(ERAS) protocols,17,18 which are multimodal perioperative carepathways designed to reduce the metabolic stress of surgery andaccelerate postoperative recovery, have resulted in fewer compli-cations [risk ratio 0.5, 95% confidence interval (CI) 0.4–0.7] and

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Rollins and Lobo Annals of Surgery � Volume 263, Number 3, March 2016

reduction in LOS by 2.5 (95% CI�3.5 to�1.5) days after colorectalsurgery when compared with patients managed with traditionalcare.19 More recent trials14,17,18 in which patients have been managedwithin ERAS protocols with avoidance of postoperative fluid over-load have suggested that, although intraoperative GDFT resulted inimprovement of cardiovascular variables when compared with con-ventional fluid therapy, there was no significant difference in clinicaloutcomes.14,20,21

The aims of this meta-analysis of randomized clinical trials ofintraoperative GDFT versus conventional fluid therapy in patientsundergoing elective major abdominal surgery were to

�

46

compare the effects of intraoperative GDFT with conventionalfluid therapy on postoperative complications, length of hospitalstay, gastrointestinal function, and mortality.

�
determine whether there was a difference in outcome betweenstudies that used ERAS protocols for perioperative care and thosethat did not.
METHODS

Search StrategyA search of the PubMed, MEDLINE, Web of Science,

GoogleTM Scholar, and Cochrane Library databases was con-ducted to identify studies evaluating the impact of intraoperativegoal-directed fluid therapy on postoperative elective surgical out-comes in all branches of surgery published in all languagesbetween January 1995 and December 2014. Electronic searchterms used were [‘‘goal-directed fluid therapy’’ OR ‘‘flow-directed fluid therapy’’] AND [‘‘surgery’’ OR ‘‘intraoperative’’]and the search was limited to adult patients undergoing electivesurgery. The bibliography of studies that met the inclusion criteriawere also searched for other relevant articles and conferenceabstracts to ensure study inclusion was as comprehensive aspossible. The meta-analysis was conducted according to thePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.22

Selection of ArticlesFull-text articles were screened after exclusion of citations on

the basis of article title and abstract. We selected studies if theyincluded adult patients undergoing elective major abdominal surgerywho were randomized to receive either GDFT or conventional intra-operative fluid therapy and if the study reported at least 1 relevantpostoperative outcome. ‘‘Major abdominal surgery’’ included general,vascular, gynecologic, and urologic procedures where the bowel washandled. We excluded studies if they involved patients undergoingnon-abdominal surgery such as cardiac, orthopedic, or peripheralvascular surgery, included emergency surgical procedures, did notreport any relevant clinical outcome measures, or if both groupsreceived GDFT. One study23 was excluded due to retraction of a largenumber of articles by 1 of the authors. We discussed studies where theinclusion criteria were not clear and made a final decision.

Data ExtractionData were extracted by 1 author (KER) and checked by

another (DNL). The primary outcome measure was postoperativemorbidity with secondary outcome measures being 30-day mortality,hospital and intensive care LOS, time to return of gastrointestinalfunction (flatus and feces), and incidence of paralytic ileus. Datawere also collated on patient demographics (age, sex, AmericanSociety of Anesthesiology [ASA] grade), surgical variables (surgicalprocedure, number of laparoscopic cases, and estimated blood loss),and intraoperative fluid administration (overall, colloid and


6 | www.annalsofsurgery.com

crystalloid, and inotrope administration). We noted the method ofadministration of GDFT and whether patients were managedusing ERAS principles (eg, if stated by the authors or having acombination of 4 or more elements such as avoidance of prolongedpreoperative starvation, provision of preoperative carbohydrate load-ing, use of thoracic epidural analgesia, avoidance of premedication,opioids and postoperative fluid overload, and early postoperativefeeding and mobilization)17,18 or traditional care. We contacted thecorresponding author on 3 occasions over a 6-week period if the datarequired were not available in the article. If the authors did notprovide the data, the medians and interquartile ranges (IQR) wereconverted to means and standard deviations (SDs) using the tech-nique described by Hozo et al.24 This technique uses the median asthe best estimate of the mean, and the SD is calculated by thefollowing formula:

SD ¼ Upper limit of IQR� Lower limit of IQR

1:35

The risk of bias was assessed using the Cochrane Collabor-ation tool in RevMan 5.3,25 which focuses upon random sequencegeneration (selection bias), allocation concealment (selection bias),blinding of participants and personnel (performance bias), blindingof outcome assessment (detection bias), incomplete outcome data(attrition bias), and selective reporting (reporting bias).

Statistical AnalysisRevMan 5.3 software25 was used for data analysis. Dichoto-

mous variables were quoted as a risk ratio (RR) with 95% CI andanalyzed using the Mantel–Haenszel random effects model. Continu-ous variables were quoted as a mean difference using a random effectsmodel with 95% CI and analyzed using the inverse-variance randomeffects model. Forest plots were constructed and a P value less than0.05 on 2-tailed testing signified a statistically significant difference.Study heterogeneity and inconsistency was assessed using the I2

statistic26: less than 25%—low heterogeneity, 25% to 50%—moderateheterogeneity, and more than 50%—high heterogeneity. A predeter-mined secondary analysis was conducted on results obtained when theintervention was delivered within or without ERAS protocols. Thequality of the evidence for each outcome was comprehensivelyassessed and graded using GRADEpro software.27

Protocol RegistrationWe registered the protocol for this meta-analysis with the

PROSPERO database (www.crd.york.ac.uk/prospero)—registrationno. CRD42014015595.

RESULTS

From 294 studies identified, 23 studies were eligible for inclu-sion (Fig. 1).6,7,21,28–47 There were 8 studies based in colorectal sur-gery,6,21,36–39,45,46 1 in upper gastrointestinal surgery,29 2 in urology,34,40

1 in abdominal vascular surgery,47 1 in gynecology,35 and 10 ina range of abdominal procedures.7,28,30–33,41–44 The risk of bias inthe studies included was low and, in general, study quality was high (seeSupplemental Digital Content Table 1, available at http://links.lww.com/SLA/A853). The quality of the evidence for each outcome in the meta-analysis is summarized in Supplemental Digital Content Table 2,available at http://links.lww.com/SLA/A854. Although there was norisk of bias or indirectness for all end-points, therewas inconsistency andimprecision for hospital and intensive therapy unit (ITU) LOS.

DemographicsThe 23 randomized controlled trials included a total of 2099

patients, of whom 1040 had been randomized to intraoperative


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http://www.crd.york.ac.uk/prospero

http://links.lww.com/SLA/A853



FIGURE 1. PRISMA diagram showing identification of relevantstudies from initial search.

Annals of Surgery � Volume 263, Number 3, March 2016 Goal-directed Fluid Therapy in Abdominal Surgery

GDFT and 1059 to traditional intraoperative fluid managementstrategies. GDFT was administered as part of an ERAS programin 10 studies6,21,30,34,36–40,45 and as part of a traditional recoverypathway in 13.7,28,29,31–33,35,41–44,46,47 The method for administeringGDFT in the studies was: TED in 12,6,7,21,34–40,45,46 hemodynamicparameters from radial arterial line (including lithium dilution) in9,29–33,42–44,47 pleth variability index from the pulse oximeter in 1,41

and a noninvasive cardiac output monitoring device in 1.28 Patientdemographics are detailed in Table 1.

Fluid TherapyThere was some variation in fluid therapy over time (Table 2).

One of the earliest studies7 infused 4405� 2650 mL lactated Ringersolution and 847� 373 mL 6% hydroxyethyl starch (HES) intra-operatively in the GDFT group versus 4375� 2452 mL Ringer and282� 470 mL HES in the control group. In contrast, the mostrecently published study21 administered 1500 mL (1000–2000 mL) intraoperative crystalloid and 500 mL (250–750 mL)colloid in the GDFT group versus 1400 mL (1000–1900 mL) and0 mL (0–300 mL) in the control group.

MorbidityEighteen studies6,7,21,28,31,32,35–39,41,42,44–47 on 899 patients

managed with GDFT versus 914 patients with traditional fluidmanagement reported morbidity rates (Fig. 2). These were furtherdivided by whether the patients had been managed as part of anERAS pathway (866 patients) or as part of a traditional care pathway(947 patients). One study30 focused on cardiac morbidity alone, butthese data are included in the overall analysis. Overall morbiditywas significantly lower in patients managed with GDFT versusthose in the control group (RR 0.76, 95% CI 0.66–0.89,P¼ 0.0007). When just those managed with GDFT in a traditionalcare pathway setting were considered, morbidity rates were alsosignificantly lower in the GDFT group when compared with controls(RR 0.69, 95% CI 0.57–0.84, P¼ 0.0002). However, when theGDFT was administered in conjunction with an ERAS pathway,it did not result in a reduction in morbidity risk (RR 0.86, 95% CI0.70–1.05, P¼ 0.14). The funnel plot for the primary outcomemeasure of morbidity showed no major asymmetry to indicate asignificant bias in either group.



MortalityMortality rates were detailed in 18 studies6,7,21,28,29,32,35,37–47

that included 855 patients in the GDFT group and 870 in thetraditional group (Fig. 3). Overall, there was no statistically signifi-cant difference in the incidence of mortality between GDFT andcontrol patients, nor was there any difference in those managed withan ERAS pathway or traditional care.

Hospital Length of StayOverall hospital LOS was reported in all studies except one32

included in the meta-analysis (Fig. 4). However, 2 studies30,34

reported only median (IQR) data, and we were unable to obtainthe mean�SD from the authors. These data were estimated using thetechnique described by Hozo et al.24 and all data were included in theanalysis of hospital LOS. There were 1043 patients managed in anERAS setting and 1014 in a traditional setting (Fig. 4). GDFTresulted in a significant decrease in hospital length of stay in theoverall group (mean difference�1.55 days, 95% CI�2.73 to�0.36,P¼ 0.01). If patients managed in a traditional care setting werespecifically examined, GDFT again resulted in a significantreduction in overall hospital LOS (mean difference �2.14 days,95% CI �4.15 to �0.13, P¼ 0.04). However, there was no signifi-cant difference in hospital LOS in those managed with an ERASpathway (mean difference �0.71 days, 95% CI �1.91 to 0.49,P¼ 0.25).

Intensive Care Length of StayPostoperative LOS in the ITU was reported in 8 stud-

ies28,30,32,41–44,46 (Fig. 4). Again, 3 studies30,44,46 provided only median(IQR) data; therefore, estimated mean�SD data were included forthese studies. Only 1 study in an ERAS setting reported intensive careLOS,30 whereas 7 studies in a traditional setting reported this. GDFTresulted in a significant reduction in intensive care LOS (Fig. 4) in allpatients (mean difference �0.63 days, 95% CI �1.18 to �0.09,P¼ 0.02) and in the 1 study in which patients were managed withan ERAS pathway (mean difference �0.63 days, 95% CI �0.94 to�0.32, P< 0.0001). GDFT, however, made no significant difference tointensive care LOS in those patients managed within a traditionalcare setting.

Return of Gastrointestinal FunctionEleven studies examined time to return of gastrointestinal

function postoperatively, in the form of passage of flatus,28,31,38

feces,6,29,33,35,45 or both.30,39,40 First, considering time to passage flatusin all studies including those with calculated data (Fig. 5), there were334 patients who were managed with GDFT and 345 in the controlgroup. There was no significant difference in the time to passage offlatus in either the overall group or in those managed in combinationwith traditional care or an ERAS pathway.

When time to passage of feces was considered, 365 patientswere managed with GDFT and 370 with control intraoperative fluid(Fig. 5). GDFT resulted in a significant reduction in time to passageof feces in the overall group (mean difference �0.90 days, 95%CI �1.48 to �0.32 days, P¼ 0.002) as well as those managed withGDFT in combination with an ERAS pathway (mean difference�1.09 days, 95% CI �2.03 to �0.15, P¼ 0.02). However, thisdifference was not significant in patients managed in a traditionalcare setting.

Incidence of Postoperative IleusSeven studies (707 patients) included data on the incidence of

postoperative ileus in 345 patients managed with intraoperative



Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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.


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GDFT versus 362 patients in the control group6,21,28,36–38,40 (Fig. 5).The use of GDFT did not affect the incidence of postoperative ileussignificantly in either the overall group or in those managed incombination with either traditional care or an ERAS pathway.

DISCUSSION

This meta-analysis of 23 randomized controlled trials including2099 patients has demonstrated that, in patients undergoing electivemajor abdominal surgery, GDFT was associated with a significantreduction in overall morbidity, LOS (both hospital and intensive care),and time to passage of feces when compared with conventionalintraoperative fluid therapy when all studies were considered. How-ever, there were no significant differences in short-term mortality, timeto passage of flatus, or risk of paralytic ileus.

When the effect of GDFT was considered in the setting ofERAS pathways, which are being implemented increasingly interna-tionally, there was no statistically significant impact on morbidityand mortality, hospital LOS, time to passage of flatus, or incidence ofparalytic ileus. A significant reduction in intensive care LOS withGDFT was seen, but this was based on a single study.30 When theimpact of GDFT was considered in the setting of a traditional carepathway, a significant reduction in morbidity and overall hospitalLOS was seen when compared with controls, but there was nosignificant difference in any other outcome considered.

The studies included in this meta-analysis were conductedover a 12-year period during which significant advances have beenmade in the concept and implementation of ERAS principles andthere is evidence that ERAS programs are associated with reducedhospital LOS,19,48,49 decreased morbidity, and improved cost-effec-tiveness.50 The studies were conducted in a variety of surgical special-ties which have differing expected LOS; however, if the studiesexamining colorectal surgery alone are analyzed,6,21,36–39,45 LOShas declined progressively over a temporal scale from 12.0� 7.5 daysin 2005 45 to 7.48� 3.8 days in 2014.21 With the ongoing push fordecreasing LOS, reinforced by recent reports of 2-day51 and 23-hour52

hospital stays for laparoscopic colorectal resection, the margin foroverall improvement in LOS provided by GDFT may decrease.Overall heterogeneity was high for LOS (90%) and, although itreduced to 61% for the ERAS group, it was still high. Therefore, itis not certain whether the lack of difference in the LOS in the ERASsubgroup was a time-dependent effect or a reflection of the effect ofERAS pathways.

The other issue raised by the temporal spread of the results isthat of the volume of fluid infused intraoperatively. This volume haschanged drastically from the earliest to more recent papers, with aprogressively greater difference in volume infused between GDFTand conventional fluid management groups, suggesting that theconcept and impact of GDFT may have changed during this period.It is possible that, in the early phase of introduction of GDFT, patientswere being frequently fluid overloaded intraoperatively. Given thatpostoperative morbidity is associated in a U-shaped manner with thevolume of intraoperative fluid infused,51 excessive fluid adminis-tration in some of these studies may have attenuated some of thepotential benefits of GDFT. Further to this, the majority of earlystudies did not consider the importance of postoperative salt andwater overload, which may also have impacted negatively on out-come. In contrast, near-zero fluid balance is considered more care-fully in recent studies due to advancing knowledge of the importanceof these factors52 in the perioperative setting. The provision of high–chloride-containing fluids, with the resultant undesirable hyper-chloremic acidosis,53–55 may also have masked some benefits pro-vided by GDFT. Worldwide, there is now a move away from 0.9%saline-based fluids to balanced crystalloids and colloids, and this



FIGURE 2. Forest plot comparing overallmorbidity rate for patients receivingGDFT versus control, divided by thosemanaged using ERAS or traditional prin-ciples. A Mantel–Haenszel randomeffects model was used to conduct themeta-analysis, and risk ratios are quotedincluding 95% confidence intervals.(Zheng et al., 201330 considered cardiacmorbidity alone).


may lead to a further improvement in outcomes.56 One further factorto consider is that different studies have employed different goals forGDFT, and the emphasis of this has evolved over time. In the earlierstudies included in this meta-analysis, patients were given fluidboluses if they were fluid responsive, regardless of their hemody-namic status, to maximize stroke volume by pushing patients to thetop of their Frank–Starling curve. This approach is likely to result in



fluid overload by ‘‘optimizing’’ patients to a point where they are nolonger fluid responsive rather than assessing ‘‘good enough’’ resus-citation. In contrast, more contemporary studies administer bolusfluid only if patients were fluid responsive and had evidence ofhemodynamic compromise, which may be reflected in the overallsmaller volumes administered in more recent studies where a targetof near-zero fluid balance was employed.


FIGURE 3. Forest plot comparing in-hos-pital or 30-day mortality rate for patientsreceiving GDFT versus control, divided bythose managed using ERAS or traditionalprinciples. A Mantel–Haenszel randomeffects model was used to conduct themeta-analysis, and risk ratios are quotedincluding 95% confidence intervals.


FIGURE 4. Forest plot comparing overallhospital LOS (top) and intensive treat-ment unit (ITU) LOS (bottom) forpatients receiving GDFT versus controlincluding studies with estimated data,divided by those managed using ERASor traditional principles. An inverse-var-iance random effects model was used toconduct the meta-analysis, and meandifferences are quoted including 95%confidence intervals.


The present study was conducted using rigorous method-ology and represents the largest meta-analysis examining the role ofGDFT versus conventional intraoperative fluid management inpatients undergoing elective major abdominal surgery. Not onlydid we set out to establish the difference in clinical outcomemeasures but also at the outset a secondary outcome of comparingthose managed within ERAS pathways with those who were man-aged in traditional care setting was specified. This secondaryanalysis has resulted in some interesting observations in outcomesbetween the 2 settings, which appear to differ considerably. Afurther strength was that to ensure the data were as complete aspossible for all studies included, most importantly the mean�SDdata for continuous variables, all authors were contacted on 3separate occasions requesting the necessary raw data rather thanthe median (IQR). Unfortunately, not all authors responded to therequest for information, and data for several studies 30,34,40,44 wereestimated for inclusion in the meta-analysis. This estimation wasdone using an established method24 that has been employed in othermeta-analyses.

This meta-analysis had several weaknesses inherent in itsdesign and conduct. The methodology for conducting GDFTdiffered greatly between studies, including TED,6,7,21,34–40,45,46



hemodynamic parameters from an arterial line,29–33,42–44,47 plethvariability index from the pulse oximeter,41 and a noninvasivecardiac output monitoring device.28 Inclusion of all techniquesfor conducting GDFT was chosen purposefully to ensure that theconclusions of this meta-analysis were generalizable to differentGDFT methods. However, subgroup analyses comparing the variousmethods was not feasible because of the small numbers of patientswho were managed with techniques other than TED or monitoring ofhemodynamic parameters from arterial lines. One factor that wasnot measured consistently between the studies was that of post-operative fluid administration and overall balance, which maysignificantly impact upon some of the postoperative outcomes.The use of rescue therapy such as diuretics and inotropes is alsodifficult to discern from the studies. None of the ERAS pathwaystudies included an assessment of compliance with the ERASstandards, which is particularly important because of the correlationbetween compliance with the standards and clinical outcomes.57–59

There was a large degree of heterogeneity in the studiesincluded in this review. Using the I2 statistic26 for the 7 clinicaloutcomes, 1 outcome had low (I2< 25%), 3 had moderate (I2 25%–50%), and 3 had high heterogeneity (I2> 50%). This great variationmay have impacted upon the significance of the results. In addition,



FIGURE 5. Forest plot comparing time toreturn of flatus and feces and incidence ofparalytic ileus for patients receiving GDFTversus control including studies with esti-mated data, divided by those managedusing ERAS or traditional principles. Aninverse-variance random effects modelwas used to conduct the meta-analysis,and mean differences are quoted includ-ing 95% confidence intervals. The Man-tel-Haenszel random effects model withrisk ratios was used for postoperativeileus.


to improve generalizability, we included all studies that includedpatients who had major abdominal surgery where the bowel washandled. It was also not possible to differentiate the effects oftemporal changes in perioperative management algorithms and othertreatment interventions such as the use of vasopressors from theeffect of GDFT.

NICE guidance12 released in 2011 on the use of TED-guidedfluid therapy has recommended its use ‘‘in patients undergoing majoror high-risk surgery or other surgical patients in whom a clinicianwould consider using invasive cardiovascular monitoring.’’ However,this guidance was made mainly on the findings of older studies, some



of which were on patients undergoing cardiac and hip fracturesurgery and most of which were conducted within a traditionalsetting of perioperative care. All studies included in the presentmeta-analysis focused on patients who would meet the criteria formajor or high-risk surgery, making this meta-analysis an excellentsetting in which to examine the potential benefits of this technique.By comparing the older studies with newer studies that have beenconducted using multimodal enhanced recovery perioperative carepathways, we have shown in our meta-analysis that modern peri-operative care reduces the impact of GDFT on outcome. This couldhelp inform healthcare providers better and facilitate a more rational




decision-making process before recommending GDFT as ‘‘standardof care.’’ Given the unclear benefits of GDFT found in this study,particularly in those managed within an ERAS pathway, it isuncertain whether this recommendation ought to be adopted forall patients undergoing elective major abdominal surgery.

The bolus fluid administered as part of the GDFT protocol in theincluded studies was variable, with HES being the documented fluidadministered in 14 studies.7,21,28,29,32,34,35,37,39,41–44,46 However, therehas recently been a moratorium in Europe on the use of HES due toconcerns of increased risk of acute kidney injury requiring renal re-placement therapy,60–62 as well as mortality60,62 based on recentrandomized controlled trials in critically ill patients. Given that muchof the evidence in this study, as well as other meta-analyses, are basedupon the use of HES as the bolus fluid administered for GDFT, theimpact of GDFT using gelatin (or other colloid)-based fluid may differfrom current evidence. Further literature63 has examined the role ofbalanced crystalloid (Hartmann solution) versus colloid (6% HES) asthe bolus agent for GDFT, demonstrating no clinical benefit fromcolloid in terms of morbidity or coagulopathy. Only 2 of the studiesincluded in this meta-analysis30,47 administered crystalloid as the bolusagent. Crystalloids may be increasingly utilized in future studiesregarding GDFT due to suggested therapeutic equivalence of colloidand crystalloid in combination with concerns with regard to someforms of colloid.

An updated meta-analysis on perioperative administration offluids, with or without inotropes/vasoactive drugs, targeted to increaseblood flow (relative to control) against measured goals in patientsundergoing abdominal and extra-abdominal surgery, including emer-gency procedures showed that patients randomized to a hemodynamictherapy algorithm, had fewer complications and shorter LOS thancontrols.64 Nevertheless, the findings of the present meta-analysis forpatients managed within ERAS pathways are in agreement with aprevious meta-analysis of 6 trials of 691 patients undergoing electivecolorectal surgery in which it was shown that TED-guided GDFT didnot influence LOS or complications.65

However, although the benefits of GDFT on clinical outcomesmay be marginal, the presence of an important benefit such as costsavings cannot be ruled out on the basis of this meta-analysis. Furtherlarge-scale randomized trials addressing all the issues that we havehighlighted, including a cost-effectiveness analysis, are necessarybefore the real impact of GDFT in elective abdominal surgery is known.

CONCLUSIONS

This meta-analysis has shown that the benefits of GDFT maynot be as clear as has been suggested historically. The overall peri-operative management of patients has changed during the period ofinclusion of studies in this meta-analysis, including decreasingexpected hospital LOS, overall decreasing volumes of intraoperativefluid infusion, avoidance of postoperative salt and water overload, andintroduction and compliance with ERAS programs. Despite the NICEGuidance12 which recommends that GDFT technology should be used‘‘in patients undergoing major or high-risk surgery,’’ this studysuggests that GDFT may not be of use to all elective patients under-going major abdominal surgery. The benefit conveyed by GDFT isparticularly attenuated by its combination with ERAS pathways thatare being increasingly implemented internationally. GDFT may bemore of use in the intraoperative care of high-risk patients; however, asyet, there are no definitive data to support this belief.

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