Perioperative liberal versus restrictive fluid strategies and postoperative outcomes: a systematic review and metanalysis on randomised-controlled trials in major abdominal elective surgery

A worldwide effort aims to reduce postoperative complications[1], which are recognised as partially preventable events affecting long-term morbidity and impacting health and financial systems [2, 3]. Several perioperative strategies have been proposed to optimise intraoperative management and postoperative care [4]. Among them, perioperative fluid therapy is a core concept. The ideal perioperative approach has been debated for decades, having the crucial role of balancing oxygen supply and demand, maintaining fluid and electrolyte homeostasis and avoiding inadequate tissue perfusion and fluid overload [5‐12].

The most effective perioperative fluid management is still unclear [13‐15]. It has been classified as restrictive (< 1.75 L per day), balanced (1.75 to 2.75 L per day) and liberal (> 2.75 L per day)[16]. However, the literature provides different, somewhat overlapping definitions (i.e. from 1.0 to 2.7 L for restrictive, compared with 2.8 to 5.4 L for liberal fluid regimens) [17] and conflicting evidence [13‐15]. The enhanced recovery after surgery (ERAS) pathways to support early recovery among patients undergoing major surgery recommend a restrictive approach aiming at the perioperative “zero-balance”[13]. In contrast, recent findings suggest that excessively restrictive approaches could be detrimental, indicating that a moderately liberal fluid regimen (i.e. positive fluid balance of 1 to 2 L at the end of surgery) might be the best approach[14].

Interestingly, a recent large randomised controlled trial (RCT) assigning 2983 patients to either zero-balance or liberal strategy showed comparable disability-free survival outcome, although the zero-balance approach was associated with a higher rate of acute kidney injury [16]. As a matter of fact, this single study enrolled more patients than several previous RCTs regarding this topic, insofar, partially challenging previous results [18‐20].

Therefore, we conducted an up-to-date meta-analysis of RCTs to assess the association between restrictive and liberal strategies and major adverse surgical outcomes in elective surgery.

We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis—Protocols (PRISMA-P) guidelines [21] (Additional file 1: Table 1) and the study protocol was registered [(International Prospective Register of Systematic Reviews—PROSPERO (CRD42020218059)].

We identified 26 potentially eligible studies after the title and abstract assessment (Fig. 1 and Additional file 1: Table 3). After full-text examination, the metanalysis finally included 18 studies and 5567 patients (male/female ratio 1.1:1) randomised to restrictive (2786 patients; 50.0%) and liberal approaches (2780 patients; 50.0%). All the studies, except one [25], have been conducted on non-obese patients, the vast majority being scheduled for laparotomic (3925 patients, 70.5%) surgery. All the studies, except two [25, 26], were conducted on patients with a median age > 60 years old (Table 1). Interestingly, in 5 studies (27.7%), including the largest one [16], the perioperative fluid administration algorithm was guided by the optimisation of predefined or flow haemodynamic pressure variables, by means of a goal-directed therapy [16, 25, 27‐29] (Additional file 1: Table 4).

The risk of bias assessment reported: “low risk” for 8 (44.4%) and “some concerns” for 11 10 (55.5%) of the included studies, mostly (9 of these 11; 81.8%) related to the selection of the reported results (Fig. 2).

Following the GRADE system, the quality of evidence was defined as high for 8 studies [16, 25, 30‐35] and moderate for all the others.

This metanalysis conducted on RCTs in major abdominal elective surgery regarding the effect of perioperative liberal or restrictive approach on postoperative outcomes found no difference between the two approaches in the occurrence of the overall major postoperative complications or mortality. On the contrary, the liberal fluid policy was associated with lower overall complication renal major events, as compared to the restrictive.

Postoperative complications are common after major surgery and represent a significant financial and social burden [2, 3]. Optimisation of fluid management has been extensively studied as a potentially modifiable perioperative factor by adopting specific protocols focused on modality of fluid administration and cumulative fluid balance [9‐11, 40]. The analysis of the literature in this field is rather complex due to the number of variables potentially affecting the final outcomes, which includes the overall complexity and the intrinsic risks of each specific type of the surgery.

On the one hand, a tendency towards a more restrictive approach (as supported by the ERAS pathways [13]) has been reported. In fact, a previous metanalysis [19] showed that fewer patients had a lower total complication rate and risk of infection in the restrictive group as compared to the liberal group.

On the other, the recent large RCT performed by Myles et al. challenged this concept, showing that disability-free survival at 1 year did not change in patients randomised to a zero-balance vs a liberal approach, with the first strategy being associated with higher rates of acute kidney injury, surgical site infection and need for renal-replacement therapy [16]. Interestingly, this single trial enrolled more patients than 17 RCTs combined in the previous 15 years (Table 1). The weight of this trial specifically impacts on postoperative major renal events of the present metanalysis, which were lower in the liberal subgroup as compared to the restrictive (Fig. 4). Interestingly, renal events did not impact on overall mortality, despite the fact that acute kidney injury is recognised as an independent risk factor for mortality [41]. However, postoperative mortality is greatly affected by the results of the study of Myles et al. [16]. Moreover, the present metanalysis did not include trials on cardiac surgery, which is a clinical setting specifically associated with an increased risk of death in those patients who develop postoperative acute kidney injury [41‐43].

Considering the impact of crystalloids/colloids use on the renal postoperative outcome, this metanalysis only suggests a possible additive effect of the colloids use in a restrictive approach. However, a recent large RCT comparing the use of low molecular weight hydroxyethyl-starch vs. 0.9% saline for intravascular volume expansion in high-risk surgical patients showed no significant difference in a composite outcome of death or significant postoperative [27]. For this reason, this result should be considered with extreme caution.

In the field of perioperative fluid administration, summarising the evidence available in the literature into straightforward clinical suggestions for daily clinical practice is rather complicated, and our updated results basically indicate an equivalence between the two perioperative fluid policies, suggesting a “third way”. The overall amount of fluid (perioperative target) should be integrated into an individualised goal-directed fluid replacement strategy (perioperative policy), to prevent fluid overload and fluid shortage by closely monitoring the effects of each bolus administered, as long as the individual plateau of the impact on predefined flow or pressure variables is achieved [12, 44]. Interestingly, this approach was incorporated into the intraoperative protocol of 5 studies [16, 25, 27‐29], including the study of Myles et al. who assessed central venous pressure and stroke volume variation in case of intraoperative hypotension to guide resuscitation (supplementary appendix of the trial [16]). Moreover, a recent metanalysis showed a trend towards the reduction of postoperative complications when a goal-directed therapy is used in patients receiving large amounts of perioperative fluids [45]. Thus, rather than choosing between a fixed-volume regimen and a goal-directed concept, an alternative approach could be to combine the two strategies. Of note, in the study of Myles et al. [16] restrictive fluid therapy had similar effects in patients treated with or without a goal-directed device.

As shown by our qualitative analysis, neither the perioperative intakes nor the fluid balance or the bodyweight gain has been consistently reported in the considered RCTs. Surprisingly, the overall fluid balance or the postoperative weight difference, which should be, in principle, the most effective perioperative variables depicting the fluid paths of restrictive and liberal subgroups, has been reported only in 5 studies (27.7%) [16, 33, 35, 46, 47]. The heterogeneity in actual overall fluid balance computation, as long the definition of postoperative complications (see further) greatly affects the comparability of the RCTs, soliciting clear standards in data reporting.

Considering the fluid intake alone, our data suggest that an overall median administration of about 4 L on days 0 and 1 may be considered restrictive, whereas about 6 L may be considered liberal. However, as pointed out by previous metanalysis [18, 19], these cut-offs are associated with large inter-quartile ranges due to the lack of consistency in perioperative fluid regimen definition. Consequently, some subgroups of RCTs classified as restricted would be considered liberal in some other trials (see Fig. 5), because of overlapping perioperative volumes.

However, despite the lack of statistical significance, we found the highest rates of major complications in the highest and lowest tertiles of our sub-analysis.

In major abdominal elective surgery perioperative, the choice between liberal or restrictive approach did not affect overall major postoperative complications or mortality. In a subgroup analysis, a liberal fluid policy was associated with lower overall complication renal major events, as compared to the restrictive.

The lack of consistency in perioperative overall fluid balance and in the definitions of clinical outcomes still affects the comparability of the results of RTCs, soliciting clear standards in data reporting.