Patients in the GD group also received a larger amount of intraoperative and total perioperative fluid than patients in the non-goal-directed group, and this was accounted for by a larger amount of intraoperative colloid (MD 467 mL, 95% CI 331 to 603). There was significant heterogeneity in the length of hospital stay between the included trials, and when pooled, patients in the GD group had a shorter hospital stay than those managed without using specific hemodynamic goals (MD 2 days, 95% CI 1 to 3) (Fig. 4b). Pneumonia (RR 0.7, 95% CI 0.6 to 0.9) and renal complications (RR 0.7, 95% CI 0.5 to 0.9) were also less common in the GD groups (Figs. 6A and 6B), and the time taken to first bowel movement (MD 1 day, 95% CI 0.8 to 1.2) and resumption of normal diet (MD 1.4 days, 95% CI 0.8 to 1.9) was also shorter after GD therapy (Figs. 7A and 7B). The incidence of noninfective pulmonary complications, wound infection, sepsis, myocardial infarction, pulmonary edema, arrhythmias, transfusion requirements, anastomotic leak, or mortality (RR 1.1, 95% CI 0.9 to 1.4) were similar between the 2 groups (Fig. 5B). There were no differences in most outcomes, including risk of acute renal failure, between studies that used different hemodynamic goals of GD therapy (Fig. 8).
When the 2 strata of trials were compared indirectly, liberal use of perioperative fluid without using any hemodynamic goal was associated with an increased length of hospital stay (MD 4 days, 95% CI 3.4 to 4.4), time to first bowel movement (MD 2 days, 95% CI 1.3 to 2.3), and risk of pneumonia (RRR 3, 95% CI 1.8 to 4.8) compared to using GD therapy. Mortality (RRR 2, 95% CI 0.6 to 6.5), wound infection (RRR 2, 95% CI 0.8 to 3.9), and renal failure (RRR 0.8, 95% CI 0.2 to 3.2) were, however, not significantly different between liberal and GD therapy. Restricting the analysis to trials studying open abdominal procedures only did not alter the results significantly (mortality: RRR 3, 95% CI 0.6 to 18; acute renal failure: RRR 1, 95% CI 0.1 to 18).
Restricting the analysis of the LVR stratum to higher-quality studies did not change the mortality results (RR 0.6, 95% CI 0.1 to 15) or wound infection (RR1.1, 95% CI 0.4, 2.8). Difference in hospital stay did, however, become insignificant after excluding lower-quality studies (MD −0.1 day, 95% CI −1 to 0.9; P = 0.9).
Restricting the analysis of the GD stratum to higher-quality studies did not change the results of GD fluid therapy on mortality (RR 0.7, 95% CI 0.3 to 1.7) or wound infection (RR1.1, 95% CI 0.3 to 4.7) compared to the non-GD therapy. Hospital stay remained significantly shorter for those patients who received GD fluid therapy (MD −0.1 day, 95% CI −1 to 0.9; P = 0.9) compared to non-GD fluid therapy.
Using pneumonia as an end-point, the funnel plot suggests that there may be a small publication bias favoring small positive studies using GD therapy (Fig. 9), but the beneficial effect of GD therapy on risk of pneumonia remained unchanged after the trim and fill adjustment (RR 0.7, 95% CI 0.5 to 0.9, P = 0.026). Publication bias was not apparent among the LVR studies, and the risk of pneumonia remained unchanged after the trim and fill adjustment, favoring restricted fluid therapy (RR 0.43, 95% CI 0.2 to 0.9).
The principal findings of this meta-analysis were that (i) GD fluid therapy reduced renal complications, pneumonia, time to first bowel movement, resumption of normal diet and length of stay compared to non-GD therapy; (ii) a restrictive fluid strategy reduced the incidence of pulmonary edema and pneumonia, time to first bowel movement, and the length of stay compared to liberal fluid therapy without using hemodynamic goals; (iii) both patients randomized to have GD fluid strategy and liberal fluid therapy without hemodynamic goals received more perioperative fluid than those managed with non-GD therapy and a restrictive fluid strategy, respectively; (iv) although both GD and liberal fluid therapy both used a large amount of perioperative fluid, their effects on perioperative outcomes were different; patients in the GD groups had a shorter length of stay, time to recovery of gastrointestinal function, and a lower incidence of pneumonia compared to those in the liberal groups; (v) no specific fluid management strategy was associated with an improvement in mortality; and (vi) significant heterogeneity in continuous outcome was observed, but publication bias was not apparent.
The cardinal discrepancy in perioperative outcomes between studies using GD and liberal fluid strategies requires careful consideration. In the first instance, our results suggest that some form of GD therapy may be better than liberal use of IV fluid without hemodynamic goals. Restricting our analysis to higher-quality studies did not change the positive association between GD therapy and improvement in perioperative outcomes. This result is, perhaps, not surprising, because individualized fluid therapy according to the clinical condition of the patients should, at least theoretically, avoid the problem of excessive resuscitation or underresuscitation. It may also be that GD monitoring gives information on fluid responsiveness, hence indicating when a fluid bolus is needed for organ perfusion,63 as opposed to the risk of fluid accumulation from unnecessary excessive fluid.64 The ability to avoid both hyper- and hypovolemia is challenging,10,65 and our limited data did not suggest that one form of hemodynamic goal is better than the other.
Second, studies that used GD strategies administered a larger amount of colloid, and liberal strategies used more crystalloid fluids. Although a large RCT on critically ill patients has shown that outcomes after using crystalloid were comparable to albumin-based colloid fluid,22 a similar conclusion cannot be reached for patients undergoing major surgery, because trials comparing colloids and crystalloids on perioperative patients are all underpowered to detect clinically important benefits and risks. Third, although our results showed that GD therapy may be superior to not using hemodynamic goals by simply using a liberal amount of fluids, we must interpret these results with caution because the primary outcome, hospital mortality, was not different despite reduced complications.
This study has several methodological strengths. First, previous meta-analyses have restricted their focus to a specific GD modality or surgical subgroup. Meta-analyses of the use of esophageal Doppler as a component of GD therapy has suggested an improvement in outcomes when applied to a subgroup of patients undergoing colonic surgery13,66–68 or a broader group of patients undergoing major elective, cardiac, or trauma surgery.69 Our results differ from these previous meta-analyses. We sought to exclude studies on procedures (e.g., trauma, cardiac, sepsis) that would induce a very strong inflammatory response than that observed in elective or emergent surgical procedure. A dramatic perturbation of hemodynamic physiology is an important confounder that may undermine meta-analysis of this intervention.10 Second, we have included data from the gray literature, used a conservative random-effects model analysis, and did not amalgamate the total numbers of complications as a composite end-point to reduce the risk of double-counting and false positive results.70 Third, we have included studies that used any form of advanced hemodynamic monitoring as part of the GD therapy. Apart from a slightly more precise signal in the reduction of length of hospital stay with the use of esophageal Doppler, we found that all forms of hemodynamic monitoring appeared to be equally effective in the reductions in perioperative complications.
This meta-analysis also has some limitations. First, there was significant heterogeneity in the continuous outcomes. This is not unexpected because, in general, continuous outcomes are associated with a larger variance. Furthermore, heterogeneity in the continuous outcomes can also be explained by the differences in case mix, standard management of the patients, and the trial design among the included studies. For example, of the GD trials examined, the interventions began preoperatively in 7 trials, intraoperatively in 14 and postoperatively in 2 trials. Second, although many promising trials were initially identified, most were excluded for failing to meet the strict inclusion criteria of this study. Furthermore, many trials were single-center trials, and the total sample size may still have been too small to detect a clinically important difference in mortality. With 3800 patients, the sample size only had a power of 72% to detect a reduction in hospital mortality from 2% to 1%. Third, the types of fluid used between the 2 strata of studies were different. GD therapy trials used predominantly colloids, whereas LVR trials used predominantly crystalloids. Concern has been expressed in relation to the potential toxicity of certain colloids,7 with some authorities advising against their use outside of the context of clinical trials.71 Finally, we have assumed that the large amount of fluid used in the GD therapy and liberal therapy was the only common denominator between the 2 strata of studies so that they could be compared indirectly. Such extrapolations will have some inherent limitations, and the RRRs obtained should be interpreted as hypothesis generating.
In summary, our study has shown that both GD fluid therapy and liberal use of fluid without using hemodynamic goals used a large amount of perioperative fluid, but the perioperative outcomes after such therapies differed significantly, favoring the use of specific hemodynamic goals to titrate fluid therapy. With the limited data available, significant uncertainty remains concerning the relative benefits of GD and restrictive fluid strategies, or the superiority of one modality of hemodynamic monitoring over another. An adequately powered factorial-designed RCT of GD versus non-GD and liberal versus restrictive fluid strategies, controlling for specific subgroups of surgery, will be needed to resolve the controversial issue of optimal perioperative fluid management strategy.
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