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Perioperative medicine

Targeting oliguria reversal in perioperative restrictive fluid management does not influence the occurrence of renal dysfunction

A systematic review and meta-analysis

Egal, Mohamud; de Geus, Hilde R.H.; van Bommel, Jasper; Groeneveld, A.B. Johan

Author Information
European Journal of Anaesthesiology: June 2016 - Volume 33 - Issue 6 - p 425-435
doi: 10.1097/EJA.0000000000000416

Abstract

Introduction

Interest in restrictive fluid management has increased over the past decade, mainly because of increasing evidence of adverse events associated with positive fluid balance in surgical and critically ill patients.1–4 The large fluid volumes in standard perioperative fluid management were intended to compensate for hypovolaemia because of nonanatomical third-space loss and preoperative fasting,5 although in recent years, both these concepts have been called into question.6–8 Although several meta-analyses have associated restrictive fluid management with lower mortality and complication rates after abdominal and major surgery,9–11 the main argument against reducing intraoperative fluid intake was that it would lead to persistence of hypovolaemia and thereby induce or aggravate renal injury. However, a recent meta-analysis by Boland et al.12 concluded that perioperative fluid restriction in major abdominal surgery had no effect on postoperative acute renal failure (ARF).

Nevertheless, clinicians widely use urine output as a surrogate for renal perfusion to guide perioperative fluid therapy.13,14 Many perioperative care protocols include oliguria reversal as a resuscitation target to maintain urine output above a specific predefined threshold and advocate additional fluid boluses when oliguria occurs, in an attempt to improve diuresis. However, the relationship between perioperative urine output and postoperative ARF is weak at best.15 Oliguria does not always occur because of a decrease in renal perfusion pressure or glomerular perfusion and therefore will not necessarily benefit from fluid therapy aimed at improving cardiac output and systemic blood pressure. Intra-abdominal pressure during abdominal surgery and neurohormonal regulation because of surgical stress are likely fluid-unresponsive causes of oliguria during surgery,16 and administering fluids to increase urine output in these patients may lead to fluid overload without any renal benefits. Conversely, if fluid boluses are withheld when oliguria occurs in a hypovolaemic patient, the persistence of renal hypoperfusion may, over time, induce damage leading to ARF. Even though the rationale behind targeting oliguria reversal is often questioned, especially when haemodynamic monitoring tools which can estimate cardiac output are available, it still remains widely used.

We investigated whether perioperative restrictive fluid management had an effect on the occurrence of oliguria, ARF, fluid intake and fluid balance. We also investigated whether targeting oliguria reversal influenced these parameters. We hypothesised that excluding oliguria reversal as a target does not affect these parameters when used in a restrictive fluid management protocol.

Methods

We performed a systematic literature search to identify all studies investigating restrictive fluid management and also reporting the occurrence of ARF. We included studies with adult surgical patients, performed as randomised controlled trials and comparing restrictive with conventional fluid management in the perioperative period. Studies using only restrictive fluid management in the postoperative setting were also eligible for inclusion; however, the intraoperative data – if available – were not pooled with the intraoperative data from the other studies. We excluded articles which were not in English and those unavailable as full-text. We excluded studies directly comparing restrictive fluid management strategy with a goal-directed therapy strategy, because, whereas goal-directed therapy leads to the infusion of a fluid volume equal to conventional fluid management,17 the additional haemodynamic measurements would introduce bias. However, studies in which both the restrictive and the control group were treated using a goal-directed therapy strategy were included, and the control group was allocated to the conventional fluid management group. We excluded studies with protocols in which diuretics were administered to increase urine output when oliguria occurred; however, studies that used a diuretic for indications outside the fluid management protocol or for indications unrelated to the reversal of oliguria were not excluded.

We used the definitions of restrictive and conventional fluid management as provided by the individual studies. We defined targeting oliguria reversal as the concept of achieving and maintaining urine output above a previously defined threshold by additional fluid boluses, in combination with vasoactive medication, guided by the occurrence of oliguria. Because the currently used term acute kidney injury is specifically linked to the RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) and later criteria,18 we used the term ARF for all definitions using a relative or absolute increase in serum creatinine concentration, need for renal replacement therapy or any combination of these with any severity and length of oliguria, as defined in the selected studies.

We searched the MEDLINE (1966 to present) database via PubMed and the EMBASE (1980 to present) database (last search August 2015) using combinations of the following Medical Subject Headings terms and keywords; a full search strategy for the MEDLINE database is presented in Supplemental Digital Content Table S1 and for the EMBASE database in Supplemental Digital Content Table S2, http://links.lww.com/EJA/A83. We hand-searched references of studies considered for inclusion and references of the review articles for eligible studies. We screened the title and abstract of the studies found in the search to identify whether the study fulfilled our inclusion criteria, and if the occurrence of ARF was not reported in the abstract, we screened the full-text article.

Using a predefined study form, one author (M.E.) scored the following variables: total study population; group sizes; type of patients; presence or absence of oliguria reversal in treatment protocols; urine output threshold to define oliguria; occurrence of oliguria; definition of ARF; duration of postoperative period in which ARF was assessed; occurrence of ARF; intraoperative fluid intake; postoperative fluid intake; postoperative fluid balance; and operative periods in which the study was performed. Once included, the studies were scored according to the Jadad scale19 on: reporting whether randomised or not and by which method; the method of blinding used and whether this was appropriate; and adequate reporting of withdrawals and dropouts.

To investigate whether targeting oliguria reversal had an effect on oliguria, ARF occurrence, fluid intake and fluid balance, we assigned all included studies to one of two groups based on whether oliguria reversal was included as a target in the study protocol: restrictive fluid management compared with conventional fluid management without oliguria reversal as a target in both protocols; and restrictive fluid management compared with conventional fluid management with oliguria reversal as a target in both protocols.

We first analysed whether there was a difference in the occurrence of intraoperative study-defined oliguria between restrictive and conventional fluid management. The second analysis was to investigate the difference in ARF occurrence between restrictive and conventional fluid management. We also performed a sensitivity analysis based on whether ARF was defined as a need for renal replacement therapy or as an increase in serum creatinine concentration. We then pooled studies reporting intraoperative fluid intake to investigate whether the mean fluid difference between restrictive and conventional fluid management differed between studies targeting and not targeting oliguria reversal. We similarly pooled studies reporting postoperative fluid intake and postoperative fluid balance. In studies reporting postoperative fluid balance as a change from preoperative weight, we made the assumption that 1 kg of weight gain was equal to a volume increase of 1 l.

Owing to the lack of studies directly comparing the inclusion and exclusion of oliguria reversal as a target in a perioperative restrictive fluid management protocol, we performed an indirect comparison to assess the effects of targeting oliguria reversal. We compared the cumulative ARF occurrence of studies including oliguria reversal as a target with those without oliguria reversal as a target, grouped according to the use of either restrictive or conventional fluid management protocols.

Statistical analysis

We calculated the odds ratio (OR) and corresponding 95% confidence intervals (CIs) of each study for occurrence of ARF using the available dichotomous data. In studies with a count of zero in one of the treatment arms, 0.5 was added to all frequencies in that study. For continuous data, we used mean with SD. If mean with SD was not present, we calculated it from the median and range using the methods described by Hozo et al.20 When only median with interquartile range (IQR) was presented in the study, we assumed a normal distribution to approximate mean with SD and used the median as mean. We calculated SD for each side of the IQR as

wherein 0.67 is the Z-range for the 25th to 75th percentiles, a is the lower IQR value, and b equals the upper IQR value. Then we used the formula

to calculate the SD of the study population. In an indirect comparison, we calculated an OR and 95% CI, for the difference in ARF occurrence in studies with and without oliguria reversal as a target based on the cumulative number of patients with ARF and the cumulative total number of patients in each fluid management protocol. We calculated the respective P value using Fisher's exact test.

All meta-analyses were performed as a random effects meta-analysis, and because of the expected heterogeneity between studies and the small number of included studies, we used the Sidik–Jonkman estimator21 in combination with the Knapp and Hartung adjustment22 to obtain better estimates of the heterogeneity variance. Heterogeneity was analysed using the I2 statistic and the thresholds for interpretation were used as defined in the Cochrane Handbook. We used a random effects meta-regression model with a heteroscedastic compound symmetry variance structure using targeting oliguria reversal as the moderator to test for subgroup differences in ARF occurrence and mean differences in intraoperative fluid intake and postoperative fluid balance between studies targeting and those not targeting oliguria reversal. We did not perform a meta-regression analysis for oliguria and postoperative fluid intake because of the small number of studies in one group and changes in postoperative fluid management strategies in both groups. We used R (version 3.2.1)23 with the metafor package (version 1.9.7)24 for the analyses and to create the forest and funnel plots. In case the funnel plot for the analysis on ARF occurrence suggested publication bias, we performed a trim-and-fill analysis to identify missing studies. We subsequently performed a new analysis which compensates for any missing trials identified and compared the results with the analysis on ARF occurrence with a meta-regression model. Pooled outcome data are presented as OR and 95% CI, and exact P values are given unless P < 0.001. Statistical significance was defined as a 95% CI, which did not include 1.00 and a P value less than 0.05.

Results

We found 477 articles, of which 30 full-text articles remained after removing duplicates and articles which met our exclusion criteria (Fig. 1). We included 15 studies and the characteristics are reported in Table 1. Six studies included oliguria reversal as a target in both the restrictive and conventional fluid management protocols25–30 and nine studies excluded oliguria reversal as a target in both protocols.31–39 One study used only restrictive fluid management during the postoperative period.34 Three studies27,28,32 did not exclude patients with chronic kidney disease or preoperative ARF. Only one of the included studies28 had a score of less than 3 on the Jadad scale (Table 2).

Fig. 1
Fig. 1:
Flow chart of study selection. ARF, acute renal failure; GDT, goal-directed therapy.
Table 1
Table 1:
Characteristics of included studies
Table 1
Table 1:
(Continued) Characteristics of included studies
Table 2
Table 2:
Risk of bias assessment in selected studies

Four studies34,35,37,38 reported no difference in intraoperative urine output between restrictive and conventional fluid management, and in three studies,25,32,36 intraoperative urine output was lower in patients with restrictive fluid management. Five studies25,33,34,37,38 reported the occurrence of study-defined oliguria when using restrictive and conventional fluid management, ranging from urine output less than 0.5 ml kg−1 h−1 to less than 1.0 ml kg−1 h−1. There was insufficient evidence to associate restrictive fluid management with an increase in study-defined oliguria (Fig. 2). Because of the limited number of studies in the targeting oliguria reversal subset, we did not test for differences in oliguria between targeting and not targeting oliguria reversal.

Fig. 2
Fig. 2:
Forest plot of studies reporting occurrence of study-defined oliguria when comparing restrictive with conventional fluid management. CI, confidence interval; IV, inverse variance.

The frequency of ARF in restrictive and conventional fluid management was 2.5 and 2.5%, respectively. In two studies targeting oliguria reversal25,29 and five studies not targeting oliguria reversal,31,33,35,37,38 serum creatinine concentration did not significantly increase from baseline during the following postoperative days. The overall analysis did not provide enough evidence to conclude that restrictive fluid management increased ARF occurrence (Fig. 3). Although the heterogeneity in this analysis was low, six studies reported no occurrence of ARF in either restrictive or conventional fluid management. The funnel plot suggested possible publication bias (Supplementary Digital Content Figure S1, http://links.lww.com/EJA/A83). The trim-and-fill analysis suggested three missing studies, which are included in the funnel plot and forest plot in Supplementary Digital Content Figure S1 and Figure S2, http://links.lww.com/EJA/A83, respectively. The overall OR was 1.07 (95% CI, 0.60 to 1.92; P = 0.84; I2 = 17.5%; Nstudies = 18), which does not significantly differ from the analysis in Figure 2 (P = 1.00).

Fig. 3
Fig. 3:
Forest plot of studies reporting occurrence of acute renal failure when comparing restrictive with conventional fluid management. CI, confidence interval; IV, inverse variance.

The sensitivity analysis to investigate whether different ARF definitions influenced the results is reported in Supplemental Digital Content Figure S3, http://links.lww.com/EJA/A83. The estimated OR for need for renal replacement therapy was 0.89 (95% CI, 0.22 to 3.61; P = 0.82; I2 = 24.7%; Nstudies = 5) and for serum creatinine concentration 0.75 (95% CI, 0.19 to 2.96; P = 0.62; I2 = 22.4%; Nstudies = 6) when comparing restrictive with conventional fluid management.

In studies with oliguria reversal as a target, the estimated OR for ARF occurrence was 0.58 favouring restrictive fluid management, and in studies not targeting oliguria reversal, the estimated OR for ARF occurrence was 1.8 favouring conventional fluid management; however, neither was significantly different from 1.00 (Fig. 3). There was also insufficient evidence to suggest that targeting oliguria reversal decreased the occurrence of ARF (OR 0.31; 95% CI 0.08 to 1.22; P = 0.088).

The fluid management protocols for each study are shown in Table 1. Two studies25,28 reported that 15 and 22%, respectively, of the patients in the restrictive fluid management protocol had received more fluids than intended, and one study34 reported that the actual volume administered during surgery was higher than intended in either protocol. One study26 reported that restrictive fluid management was associated with more additional fluid boluses, and one study29 reported no difference in additional fluid boluses between protocols.

The mean difference in intraoperative fluid intake could be extracted and calculated for 12 studies (Fig. 4). Less fluid was infused during the intraoperative period in patients receiving restrictive fluid management than in those with conventional fluid management, irrespective of targeting oliguria. There was insufficient evidence to suggest that targeting oliguria reversal was associated with a smaller difference in fluid intake between restrictive and conventional fluid management (OR 1.32; 95% CI, 0.47 to 3.77; P = 0.56).

Fig. 4
Fig. 4:
Forest plot of the mean difference in infused fluids in litres between restrictive and conventional fluid management during the intraoperative and postoperative period. *Mean and SD derived from median and interquartile range. **Mean and SD derived from median and range. CI, confidence interval; IV, inverse variance.

The mean difference in postoperative fluid intake could be extracted and calculated for seven studies (Fig. 4). The studies without oliguria reversal as a target continued the use of the restrictive fluid management protocol into the postoperative period, whereas the studies with oliguria reversal as a target had the same postoperative fluid regimen for both restrictive and conventional arms (Table 1). Postoperative fluid intake was lower in restrictive fluid management than in conventional fluid management in studies without oliguria reversal as a target and in studies with oliguria reversal as a target; however, the differences were not statistically significant, suggesting that factors other than postoperative fluid restriction affect fluid intake.

Nine studies25–27,30–33,36,39 reported on postoperative fluid balance either in terms of volume or weight increase (Fig. 4). Postoperative fluid balance was lower in patients receiving restrictive fluid management than in those with conventional fluid management, irrespective of targeting oliguria. There was insufficient evidence to suggest that targeting oliguria reversal was associated with a smaller difference in postoperative fluid balance between restrictive and conventional fluid management (OR 1.07; 95% CI, 0.33 to 3.55; P = 0.88). The heterogeneities in the fluid intake and fluid balance analyses were high.

Because there were no studies investigating targeting oliguria reversal with not targeting oliguria reversal, we performed an indirect comparison to analyse the effects of including targeting oliguria reversal or excluding targeting oliguria reversal on the occurrence of ARF (Table 3). Targeting oliguria reversal in a restrictive protocol does not appear to affect the occurrence of ARF, whereas targeting oliguria reversal in a conventional protocol may possibly increase the occurrence of ARF.

Table 3
Table 3:
Indirect comparison of the effect of targeting oliguria reversal in restrictive and conventional fluid management

Discussion

In this meta-analysis, we found insufficient evidence to associate restrictive fluid management with an increase in oliguria and ARF occurrence. The difference in intraoperative fluid intake between conventional and restrictive fluid management was similar whether oliguria reversal was targeted or not. In line with our initial hypothesis, excluding targeting oliguria reversal in a restrictive fluid management protocol does not seem to be associated with an increase in ARF occurrence when compared with including oliguria reversal as a target.

Similar to the findings from the meta-analysis of major abdominal surgery by Boland et al.,12 we were unable to demonstrate an association between restrictive fluid management and an increase in the occurrence of postoperative ARF. Additionally, the FACCT trial40 in patients with acute lung injury was unable to demonstrate a difference in renal failure-free days between a restrictive and conventional fluid management strategy, although the restrictive fluid management strategy utilised diuretics when oliguria occurred. Even when looking at more specific ARF definitions, we found insufficient evidence that restrictive fluid management was associated with an increase in the need for renal replacement therapy or with a postoperative increase in serum creatinine concentration. The latter, however, could be explained by a positive postoperative fluid balance diluting any increase to near preoperative levels.

We were unable to demonstrate an increase in the occurrence rate of oliguria because of the restrictive fluid management protocols, and targeting oliguria reversal did not seem to influence fluid intake. It is likely that patients given restrictive fluid management were already normovolaemic during surgery as most postoperative fluid balances were near zero. This suggests that oliguria is the result of a physiological stress response during surgery to maintain an adequate intravascular volume through activity of several neurohormonal systems such as the renin-angiotensin-aldosterone axis and antidiuretic hormone.16,41 Hence, oliguria does not necessarily reflect absolute hypovolaemia and additional fluid administration could increase urine output, but probably without any true benefit in terms of renal function.

Our findings suggest that excluding targeting oliguria reversal does not seem to increase ARF occurrence when using a restrictive fluid management protocol. However, since the postoperative fluid intake did not noticeably differ between restrictive and conventional fluid management in studies either targeting or not targeting oliguria reversal, we cannot exclude the possibility that the postoperative fluid protocols could have had an effect on the occurrence of ARF. It may be that protocols which restrict postoperative fluid intake do not compensate for patients being unable to manage their own fluid balance. Without an adequate postoperative fluid protocol to compensate for this fluid deficit, this may eventually lead to an increase in ARF occurrence by prolonged and recurrent episodes of hypovolaemia. Moreover, intravascular volume could change during the postoperative period, whereas the physiological stress response from surgery may continue and influence the activity of neurohormonal systems. It is therefore possible that to maintain an adequate intravascular volume during the postoperative period requires more fluids because of vasodilatation-mediated volume redistribution.

Lastly, it is important to note that the indirect comparison groups are treated as a cohort based on the cumulative ARF occurrence in each fluid management protocol with or without targeting oliguria reversal, therefore lacking the benefit of randomisation. This indirect comparison is the best available surrogate effect estimate, since there were no trials available which either directly compared targeting with not targeting oliguria reversal, or compared restrictive fluid management without against conventional fluid management with targeting oliguria reversal. As a result, we recommend future studies to prospectively investigate the effects of targeting oliguria reversal on the occurrence of ARF.

The meta-analysis has several limitations. The low event rates in the selected studies can be a cause for bias and are most likely caused by excluding patients with preoperative chronic kidney disease, and by the inconsistent ARF definition among the included studies as reported in Table 1. The funnel plot for ARF occurrence suggested possible publication bias. This may be because of the lack of published studies with ARF as an investigated outcome leading to selection bias or perhaps because of language bias from excluding trials not published in English. Since most of the studies included only patients with normal preoperative serum creatinine concentration and undergoing elective surgery, the a priori risk of ARF in these patients was lower than for patients with chronic kidney disease or undergoing emergency surgery.42,43 Nevertheless, the incidence of postoperative ARF in this meta-analysis is well within the margins reported in current literature.15,43,44 However, it must be noted that the incidence of ARF may be an underestimate. The latest diagnostic criteria for acute kidney injury – the consensus definition which incorporates the whole spectrum of renal dysfunction18 – incorporated small increases in serum creatinine concentration.45 These small increases have been associated with an increased mortality rate,46,47 although it remains unknown whether these small changes are merely a marker of underlying disorder which are the cause of the mortality increase or whether these changes in serum creatinine concentration represent fluctuations in renal function with clinical importance.45

Second, the fluid administration protocols greatly differed among the included studies. As described by the I2 in Figure 4, the heterogeneity of the fluid intake comparisons was very high. In addition, the adherence to the protocols during the study might have been poor. Although only three studies actively reported deviations from protocol, it can be assumed that other studies had similar issues, which bias our findings. Nevertheless, restrictive fluid management reduced intraoperative fluid intake irrespective of the use of oliguria reversal as a target.

It is also important to note that unlike earlier meta-analyses,9,10 we did not redefine restrictive and conventional fluid management, but rather used the study definitions. This may introduce some bias because some restrictive fluid management protocols were considered to be either too restrictive or not restrictive enough. However, most of the restrictive fluid management protocols infused roughly 2 l during surgery, which in the meta-analysis by Varadhan et al.10 was defined as a state of fluid balance for the average patient without ongoing fluid deficits or losses. Additionally, most of the studies reporting postoperative fluid management had a neutral fluid balance with restrictive fluid management, suggesting that in these studies restrictive fluid management was closer to an optimal fluid strategy than the conventional fluid management.

Conclusion

Even though event numbers were small, we found insufficient evidence to associate restrictive fluid management with an increased occurrence of oliguria and risk of ARF. Intraoperative fluid intake and postoperative fluid balances remained lower with restrictive fluid management. Similarly, adding targeting oliguria reversal in both protocols did not influence ARF occurrence, fluid intake or fluid balance. There was insufficient evidence to suggest that restrictive fluid management in combination with oliguria reversal as a target influences ARF occurrence in either direction. However, this may be because of postoperative rather than intraoperative fluid management when oliguria occurs. Future studies are needed to confirm the effects of targeting oliguria reversal, although restrictive fluid management seems to be a safe and viable perioperative fluid strategy for the kidney, considering the currently available evidence.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: none.

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