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, http://links.lww.com/JCM/A115, Forest Plot of Mortality for Modern GDT). These benefits persisted across subgroup analysis in the highest risk patients (OR 0.60; 95% CI, 0.42 to 0.85; P = 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, http://links.lww.com/JCM/A115). In the context of TSA, this suggests that the cumulative sample size is inadequate to definitively determine the impact of GDT on peri-operative mortality and that further trials have the potential to alter the magnitude and/or direction of effect.
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).
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).
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.
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%).
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).
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, http://links.lww.com/JCM/A115, Forest Plot of Mortality for PAC-guided GDT), but this effect did not persist in the largest and most rigorously conducted study.28 There were no other differences in any of the other secondary outcomes among the PAC studies, including morbidity and LoS (Tables 4 and 5).
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.
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
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.
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.
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
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
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 (http://optimiseii.org/). 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.
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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