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Does goal-directed haemodynamic and fluid therapy improve peri-operative outcomes?

A systematic review and meta-analysis

Chong, Matthew A.; Wang, Yongjun; Berbenetz, Nicolas M.; McConachie, Ian

Author Information
European Journal of Anaesthesiology: July 2018 - Volume 35 - Issue 7 - p 469-483
doi: 10.1097/EJA.0000000000000778


This article is accompanied by the following Invited Commentary:

Gillies MA, Pearse R, Chew MS. Peri-operative goal-directed therapy: A definitive answer remains elusive. Eur J Anaesthesiol 2018; 35:467–468.


The concept of peri-operative goal-directed haemodynamic 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 catheters (PAC), but recently less invasive technologies have become widely available.97 Such contemporary GDT devices derive measurements using a variety of methods from transpulmonary indicator dilution to arterial waveform analysis. These are summarised in Table 1.97

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

Given the clinical importance of GDT and its potential to improve patient outcomes, investigating whether or not these interventions are truly effective is worthwhile. However, existing reports and meta-analyses have demonstrated conflicting results.98–101 Significantly, several significant limitations of methodology have been repeated across these older reports, such as missed studies,98,99 pooled complications as an artificial composite with the risk of double-counting of events98,102 and exclusion of certain types of surgery or patient groups.98–101 Finally, several authors have pooled PAC-guided GDT studies with those using contemporary GDT devices.98,103

To address the limitations of existing publications, we performed an updated systematic review and meta-analysis of peri-operative GDT. We hypothesised that peri-operative GDT would improve mortality (primary outcome) and morbidity (secondary outcomes) in adult surgical 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 preoperatively, and would not reflect current practice.1 Under these more rigorous methodological conditions, we wondered whether the benefits of GDT identified in older analyses would persist.98,103


The current systematic review and meta-analysis complies 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 care and that reported at least one clinical outcome of interest.

Study selection

Patient groups

For inclusion, studies had to recruit adult surgical patients having elective, urgent or emergency surgery. Although both cardiac and noncardiac surgery were of interest, we excluded studies recruiting exclusively trauma patients, parturients and nonsurgical critical care patients.


Subjects had to be randomised to either a standard of care or GDT. We defined GDT as any fluid and/or vasopressor therapy titrated to haemodynamic targets that included the following: SVV, pulse pressure variation (PPV), CO or CI, SV or SV index, central venous oxygen saturation, DO2 or DO2 index, oesophageal Doppler flow corrected time, echocardiography assessment and oxygen extraction 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 optimisation 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 protocols involving restrictive fluid strategies.


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. 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, The search used a comprehensive 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 descriptors 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 specific domains include random sequence generation (selection bias), allocation concealment (selection bias), 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 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 Recommendations, 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 clinical 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 α = 0.05. Heterogeneity was estimated using the I2 statistic and the χ2 test for statistical significance. We considered an I2 value from 50 to 70% to be moderate heterogeneity and 70% or higher to be high heterogeneity. Stratification of outcomes based on PAC versus other technologies was planned a priori. Furthermore, all subgroup analyses were prespecified according to hypothesised sources of heterogeneity 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 technology 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 significance 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 outcome of mortality. To perform the TSA, we assumed a two-tailed α of 0.05, β of 80% and a relative risk reduction of 20% from the control group event rate. The TSA was performed with version Beta. Other authors have provided excellent descriptions of TSA, and full discussion is beyond the scope of this systematic review.108


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-analysis.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,

Fig. 1
Fig. 1:
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, PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

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 considered 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, Supplemental Digital Content 3, Risk of Bias Assessment and Risk of Bias Distribution,, Fig. 2).36,51,76,84 Notably, 12 studies recruited cardiac 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 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 echocardiography; seven studies).7,45,50,56,72,89,94 All results are presented according to the predefined analysis plan and stratified by PAC use versus the more contemporary technologies.

Table 2
Table 2:
Baseline data
Fig. 2
Fig. 2:
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,, due to the large size of that figure.

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 = 0.004; NNTB = 59 or 18 events prevented per 1000 patients; I2 = 0.0%; N = 52; Supplemental Digital Content 4,, 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 = 0.004; NNTB = 34), the highest risk procedures (OR 0.69; 95% CI, 0.51 to 0.95; P = 0.02; NNTB = 75), and among studies where the GDT was initiated intra-operatively (OR 0.65; 95% CI, 0.47 to 0.89; P = 0.007; NNTB = 59). A full summary of the sensitivity analyses is shown in Table 3. Notably, the mortality reduction was not statistically 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 Analysis, 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.

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

Secondary outcomes: organ-specific morbidity

All binary secondary outcomes are listed in detail in Table 4.

Table 4
Table 4:
Binary secondary outcomes summary

Cardiovascular outcomes

Contemporary GDT reduced rates of arrhythmia (OR 0.70; 95% CI, 0.55 to 0.91; P = 0.006; NNTB = 34). MI, CHF and cardiac arrest were not significantly different between groups (Table 4).

Respiratory outcomes

Rates of respiratory failure and prolonged mechanical ventilation were reduced in patients receiving GDT (OR 0.54; 95% CI, 0.35 to 0.84; P = 0.006; NNTB = 26). Furthermore, rates of pneumonia were reduced with GDT compared with standard care (OR 0.69; 95% CI, 0.51 to 0.92; P = 0.01; NNTB = 38).

Other infectious outcomes

Wound infection (OR 0.48; 95% CI, 0.37 to 0.63; NNTB = 19) and intra-abdominal infection (OR 0.65; 95% CI, 0.45 to 0.93; NNTB = 35) rates were reduced in patients receiving GDT. In addition, rates of sepsis were also reduced in the GDT arm compared with standard care, but only 13 studies reported this outcome (OR 0.55; 95% CI, 0.33 to 0.91; P = 0.02; NNTB = 43). The incidence of urinary tract infection was similar between groups (Table 4).

Other outcomes

GDT patients had reduced rates of AKI versus standard care (OR 0.73; 95% CI, 0.58 to 0.92; P = 0.007; NNTB = 29). No significant difference was detected for stroke or pulmonary embolism between groups. Likewise, surgical complications were similar between groups in terms of anastomotic leak and ileus or bowel obstruction. Finally, exposure to allogenic blood was not different between arms.

Secondary outcomes: healthcare length of stay and other continuous outcomes

Continuous outcomes are summarised in Table 5.

Table 5
Table 5:
Continuous secondary outcomes summary

Length of stay

Across the 62 RCTs reporting hospital LoS, contemporary GDT reduced LoS (days) compared with standard care by −0.90 (95% CI, −1.32 to −0.48), with very high statistical heterogeneity (I2 = 81.2%). Similarly, ICU LoS was also reduced (−0.69; 95% CI, −1.00 to −0.37; I2 = 83.8%).

Time to recovery of bowel function

The time to first flatus (days) was reduced by modern GDT by −0.37 (95% CI, −0.59 to −0.14; I2 = 74.1%), but there were no differences in the time to first oral intake or bowel movement detected. Statistical heterogeneity was high among all these analyses (Table 5).

Results for pulmonary artery catheter-guided goal-directed haemodynamic and fluid therapy

Mortality was reduced among all 13 studies that used a PAC to guide the GDT (OR 0.53; 95% CI, 0.30 to 0.92; P = 0.004; Supplemental Digital Content 6,, 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 = 0.59) and the funnel plot appeared symmetrical on visual inspection, 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 hospital LoS,8,86 faster recovery of bowel function,17 reduced ‘major abdominal complications’,49 reduced mortality (albeit statistical analysis is not presented)54 and reduced lactate levels.95


Contemporary goal-directed haemodynamic and fluid therapy

This comprehensive systematic review and meta-analysis of 95 RCTs demonstrates that contemporary GDT modestly improves in-study mortality in non-trauma and nonpregnant adult surgical patients (OR 0.60; 95% CI, 0.50 to 0.87; NNTB = 59; P = 0.004; N = 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 analyses performed, the mortality benefits were most pronounced in high-risk patients (NNTB = 34), present among trials where the GDT was initiated intra-operatively (NNTB = 59), and persisted among large trials recruiting more than 100 patients (NNTB = 59). In contrast 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 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 = 0.0% for the primary outcome), clinical heterogeneity 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.

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

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 surprising 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 differences for the PAC-guided GDT studies.

In addition to being more invasive than contemporary GDT technologies, there is a lag time between the decision 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

Differences from previous reviews

Given the clinical importance of peri-operative GDT, it is important that any systematic review be comprehensive 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 complications 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 decrease the external validity of the results had they been pooled with the data from more contemporary trials.1

Study limitations

Despite the low statistical heterogeneity in our morbidity and mortality analyses, the main limitation of this meta-analysis is the clinical heterogeneity among the different GDT devices, goals and algorithms employed by included studies. Although such clinical heterogeneity can never be fully mitigated by statistical means, we took several measures to address this issue, such as the use of a random effects model, stratification of the results by PAC-guided GDT versus modern GDT, and finally subgroup analysis by other important sources of heterogeneity (e.g. type of GDT monitor).

Another important consideration is the comparability between different GDT devices; indeed, studies exploring the correlation between different GDT monitors for reflecting haemodynamic status have demonstrated mixed results.115–117 Significantly, in subgroup analysis by type of technology, the mortality benefit of modern GDT only persisted in the minimally invasive CO monitor subgroup, which reduces the ability to generalise the primary outcome results.

In addition, although our analysis identified several secondary benefits of peri-operative GDT, the secondary outcomes should be interpreted with caution because not all studies reported each outcome, and the timing of follow-up varied between studies. Furthermore, another significant limitation is the high risk of bias among included studies. For example, only four of 95 studies performed blinding and more than half of the studies had an unclear description of allocation concealment (Fig. 2). Regarding other sources of bias, study investigators 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 Therefore, 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


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 morbidity is reduced. Importantly, the benefits of GDT seem to be reliant on the use of vasoactive agents and the mortality results were not statistically significant in some important subgroups, such as cardiac surgery patients. Nonetheless, the results are relevant to anaesthetic practice; the performance of intra-operatively initiated GDT still yielded clinically important benefits. However, caution is warranted due to the significant flaws in the existing evidence base, the overall GRADE scoring of low to very low for the most important outcomes, and clinical heterogeneity among the haemodynamic goals and GDT monitoring devices studied.

Given the deficits in the current evidence base, it is fortunate that higher quality trials are currently in progress, such as the international OPTIMISE-II Study ( Large trials such as OPTIMISE-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 important subgroups, such as cardiac and emergency surgery patients. Finally, the best GDT protocols and haemodynamic targets still remain to be identified. Given the benefits found here and the potential for GDT to transform peri-operative anaesthetic care, this field will probably 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.

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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