Our search strategy resulted in 1062 articles, of which 588 remained after excluding duplicates (Fig. 1). Of those, 525 were animal studies, pediatric studies, not in English, not available as full-text, or compared different fluid types and were excluded. After reading all full-text articles for eligibility, we excluded another 34 studies because either the hemodynamic parameters were not defined in the conventional arm or no data on ARF were presented. One study, which did report ARF,24 was excluded because it was not possible to distinguish new occurrences of ARF in each group from those with ARF at randomization. Table 1 shows the characteristics of the resulting 28 included studies, and Table 2 shows the hemodynamic monitoring used in each of the selected studies. Twelve studies25–36 did not include oliguria reversal as a target in either of the treatment protocols, GDT and CFM, and were allocated to the GDT− versus CFM− group; 7 studies in which only the CFM protocol included oliguria reversal were allocated to the GDT− versus CFM+ group37–43; and 9 studies that included oliguria reversal as a target in both the GDT and the CFM protocol were assigned to the GDT+ versus CFM+ group.44–52 We did not find studies comparing GDT with oliguria reversal as a target with CFM without oliguria reversal as a target, studies comparing GDT with and without oliguria reversal as a target, or studies comparing CFM with and without oliguria reversal as a target. Eight of the 28 studies had a score of <3 on the Jadad scale (Table 3). The allocation of the studies to the subgroups is shown in Table 4. None of the selected studies reported the use of nephrotoxic medication, and only 5 reported the use of diuretics for reasons other than oliguria reversal.36,40,47,49,52
Meta-analysis of all 28 studies showed that overall, GDT was associated with a lower occurrence of ARF than CFM (OR, 0.58; 95% CI, 0.44–0.76; P < 0.001; I2 = 34.3%; n = 28). In the GDT− versus CFM+ group, patients who received GDT were less likely to develop ARF than those treated with CFM (OR, 0.45; 95% CI, 0.34–0.61; P < 0.001; I2 = 7.1%; n = 7). The studies in the other 2 protocol groups did not provide enough evidence to conclude a superiority of GDT compared with CFM. Forest plots of the primary analysis are shown in Figure 2. The heterogeneity in this analysis ranged from low to moderate. The funnel plot of the overall analysis showed no marked asymmetry, suggesting the absence of publication bias (Figure 1, Supplemental Digital Content 2, http://links.lww.com/AA/B266, showing the funnel plot of studies reporting the occurrence of ARF when comparing GDT with CFM).
Results from the meta-analysis of those studies that targeted oliguria reversal during the pre- and intraoperative setting are shown in Figure 3. Here, the combined analysis showed that GDT was associated with a lower occurrence of ARF compared with CFM (OR, 0.62; 95% CI, 0.42–0.89; P = 0.01; I2 = 25.1%; n = 21). All 3 protocol group-specific meta- analyses estimated ORs smaller than 1; however, none of the estimates were significantly different from 1.00.
Meta-analysis of the studies that used fluid management protocols during the postoperative and ICU setting showed that GDT reduced the number of ARF cases (OR, 0.56; 95% CI, 0.39–0.80; P = 0.004, I2 = 42.6%; n = 14). The corresponding forest plot is displayed in Figure 4. Here, the OR in the GDT− versus CFM+ group was significantly smaller than 1.00 (OR, 0.46; 95% CI, 0.31–0.70; P = 0.015; I2 = 1.2%; n = 3), whereas results in the other 2 groups were inconclusive. Funnel plots for the secondary analyses showed no asymmetry, and hence suggested no publication bias (Figures 2 and 3, Supplemental Digital Content 3 and 4, http://links.lww.com/AA/B267 and http://links.lww.com/AA/B268, showing the funnel plots corresponding to the secondary analysis).
Because we did not find any studies directly comparing targeting oliguria reversal with not targeting oliguria reversal in each treatment, we conducted additional, pooled analyses based on the subgroups of studies described earlier (Table 4). The results from this analysis are reported in detail in Table 5.
In the present study, we performed meta-analyses on 28 studies and found that GDT is superior to CFM with regard to preventing ARF. This effect was the strongest in studies that included oliguria reversal as a target in CFM but not in GDT. Although the comparison of GDT with CFM where both treatments included or excluded oliguria reversal as a target suggested superiority of GDT, available evidence was inadequate to allow a definite conclusion. This lack of clarity may partially be because of the small number of studies that were available for analysis.
Several reasons are possible for why urine output may have limited effectiveness as a hemodynamic management goal. Urine output is a parameter that takes time to change and is influenced by factors other than the hemodynamic status. Thus, oliguria can be because of causes that are unaffected by fluid administration or have already been resolved. Therefore, patients may be at risk for fluid overload because of superfluous fluid administration targeted only at urine output. However, strategies that do not target oliguria reversal may limit fluid overload by more precisely targeting variables related to cardiac output or oxygen delivery. Once the hemodynamic status has been optimized, any subsequent occurrence of oliguria is unlikely to be because of hemodynamic causes, favoring the exclusion of oliguria reversal as a target.
GDT patients received a similar or larger volume of fluids than CFM patients in most of the included studies (Table 4); and even in the GDT− versus CFM+ group, most studies used an equal or larger fluid volume in GDT than in CFM. However, in the subset of trials where GDT resulted in less fluid administered than in CFM, targeting oliguria reversal had a larger impact in the CFM than in the GDT group. These data suggest that in GDT trials that focus on limiting fluid administration, targeting oliguria reversal may play a role. For example, additional fluid resuscitation targeted at increasing urine output may result in hypervolemia and subsequent ARF. In contrast, when GDT results in equal or larger fluid volumes than CFM to achieve the predefined hemodynamic targets, any effects of targeting oliguria reversal on the occurrence of ARF may be relatively minor, possibly because of the volume of fluids already administered.
On the basis of our findings, GDT is better suited than CFM for preventing ARF in the preoperative or intraoperative setting. Furthermore, GDT might reduce ARF in the postoperative or ICU setting, but when we excluded studies in which GDT and CFM were already started during the preoperative or intraoperative setting, the data were too limited to draw a definite conclusion. Similar to our findings, the meta-analysis performed by Brienza et al.12 reported that patients treated with GDT in the postoperative setting had less ARF. However, their meta-analysis differed from ours in several ways. First, they assigned studies according to the commencement of hemodynamic optimization. Second, they pooled the intraoperative and postoperative commencement into one analysis.12 Finally, they excluded studies with late optimization (i.e., >12 hours postoperative or after the onset of organ failure). It has been suggested that intraoperative and postoperative optimization should be separated because of differences in etiology and hemodynamic goals.53 Consequently, although our study supports the findings of Brienza et al.12 for the early postoperative phase, our findings also suggest that GDT may prevent ARF when used during the late postoperative phase or in the ICU.
Although we found that GDT was associated with less ARF when oliguria reversal was not included as a target, the effects of such strategies on mortality remain unclear. Because of the relatively low numbers of available studies reporting both ARF and mortality, we considered the risk of selection bias too high and therefore did not perform analyses to investigate the effects of targeting oliguria reversal on mortality.
Second, the hemodynamic parameters targeted in the GDT protocols and the methods used to evaluate them varied greatly among the included studies (Table 2). This variance was partly because of the large timespan between some studies, which has led to pulmonary artery catheters and esophageal Doppler monitoring being replaced by calibrated or uncalibrated arterial pressure-derived continuous cardiac output devices. Our subgroup analyses suggest that although all these methods assess parameters related to cardiac output or oxygen delivery, the differences between these devices and their practical limitations could have affected patient management and treatment options. Even when using similar devices, the correct interpretation of these indices is also important. Starting treatments based on an erroneous interpretation of hemodynamic parameters could result in more harm to patients in terms of ARF or other outcomes rather than the intended benefit. Furthermore, the potential change in the risk of ARF from earlier studies might also be attributable to improvements in conventional health care practice throughout the decades.
Another limitation of our meta-analysis is the different underlying conditions in the included studies. It is likely, for example, that surgical and septic patients differ regarding goals for hemodynamic optimization. Nevertheless, achieving an optimal hemodynamic state through intensive monitoring of cardiac output or oxygen delivery-derived parameters should result in a similar benefit, despite the underlying conditions. Thus, once hemodynamic status has been optimized, the development of ARF should mostly be determined by risk factors associated with the underlying condition. Furthermore, any additional fluids given after the hemodynamic status has been optimized can lead to deleterious effects because of fluid overload, which in turn increases the risk of developing ARF.
Finally, the methods used to optimize hemodynamic status differed among the studies. As shown in Table 2, the use of vasopressors and inotropic drugs as well as the type of fluid was not consistent. Colloids such as hetastarch, for example, have been associated with an increased risk for acute kidney injury.56,57 In most of the selected studies, colloids were used as the primary intervention fluid to achieve and maintain hemodynamic goals, including urine output. Although unlikely, it is possible that asymmetry in colloid use between groups may have affected our results. In recent years, an association between hyperchloremic solutions and an increased risk for acute kidney injury has also been suggested.58,59 This effect also could have influenced our findings because of differences in fluid compositions used within or between studies. Furthermore, it is important to note that standard random-effects meta-analysis methods may not accurately estimate the between-study variation when only few studies are included in the analysis. We attempted to minimize this problem by using a more robust estimator; nevertheless, results from analyses with only few studies should be interpreted with great care.
Collectively, our data favor targeting circulatory optimization by GDT without targeting oliguria reversal to prevent ARF. This effect of GDT on ARF is present even during the perioperative period or in the ICU. Our findings support the hypothesis that ARF is not prevented by striving toward a predefined urine output target. However, randomized controlled trials are needed to investigate whether targeting oliguria reversal has a deleterious effect on the occurrence of ARF and whether—as our findings suggest—resuscitation protocols that prioritize cardiac output and oxygen delivery are better able to reduce the risk of ARF than those including oliguria reversal as a target.
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