Perioperative Liberal and Restrictive Fluid Strategies and Postoperative Outcomes

Messina et al. Crit Care (2021) 25:205 https://doi.org/10.1186/s13054-021-03629-y

RESEARCH Open Access Perioperative liberal versus restrictive fuid strategies and postoperative outcomes: a systematic review and metanalysis on randomised‑controlled trials in major abdominal elective surgery Antonio Messina1,2* , Chiara Robba3, Lorenzo Calabrò1, Daniel Zambelli1, Francesca Iannuzzi3,4, Edoardo Molinari3,4, Silvia Scarano3,4, Denise Battaglini3, Marta Baggiani5, Giacomo De Mattei6, Laura Saderi7, Giovanni Sotgiu7, Paolo Pelosi3,4 and Maurizio Cecconi1,2

Abstract Background: Postoperative complications impact on early and long-term patients’ outcome. Appropriate perioperative fuid management is pivotal in this context; however, the most efective perioperative fuid management is still unclear. The enhanced recovery after surgery pathways recommend a perioperative zero-balance, whereas recent fndings suggest a more liberal approach could be benefcial. We conducted this trial to address the impact of restrictive vs. liberal fuid approaches on overall postoperative complications and mortality. Methods: Systematic review and meta-analysis, including randomised controlled trials (RCTs). We performed a systematic literature search using MEDLINE (via Ovid), EMBASE (via Ovid) and the Cochrane Controlled Clinical trials register databases, published from 1 January 2000 to 31 December 2019. We included RCTs enrolling adult patients undergoing elective abdominal surgery and comparing the use of restrictive/liberal approaches enrolling at least 15 patients in each subgroup. Studies involving cardiac, non-elective surgery, paediatric or obstetric surgeries were excluded. Results: After full-text examination, the metanalysis fnally included 18 studies and 5567 patients randomised to restrictive (2786 patients; 50.0%) or liberal approaches (2780 patients; 50.0%). We found no diference in the occurrence of severe postoperative complications between restrictive and liberal subgroups [risk diference (95% CI) 0.009 ( 0.02; 0.04); p value 0.62; I2 (95% CI) 38.6% (0–66.9%)]. This result was confrmed also in the subgroup of fve= studies− having a low overall= risk of bias. The liberal= approach was associated with lower overall renal major events, as compared to the restrictive [risk diference (95% CI) 0.06 (0.02–0.09); p value 0.001]. We found no difference in either early (p value 0.33) or late (p value 0.22) =postoperative mortality between= restrictive and liberal subgroups = =

*Correspondence: [email protected] 1 Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center – IRCCS, Via Alessandro Manzoni, 56, 20089 Rozzano, MI, Italy Full list of author information is available at the end of the article

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Conclusions: In major abdominal elective surgery perioperative, the choice between liberal or restrictive approach did not afect overall major postoperative complications or mortality. In a subgroup analysis, a liberal as compared to a restrictive perioperative fuid policy was associated with lower overall complication renal major events, as compared to the restrictive. Trial Registration: CRD42020218059; Registration: February 2020, https://www.crd.york.ac.uk/prospero/display_ record.php?RecordID 218059. = Keywords: Liberal, Restrictive, Fluid therapy, Postoperative complications, Postoperative mortality

Introduction mortality, predefned postoperative organ-related com- A worldwide efort aims to reduce postoperative complications and hospital length of stay. Finally, we stratifed plications[1], which are recognised as partially prevent- the studies according to preoperative severity score and able events afecting long-term morbidity and impacting the reported rate of complications [i.e. American Society health and fnancial systems [2, 3]. Several perioperative of Anaesthesiologists (ASA) physical status score]. strategies have been proposed to optimise intraoperative management and postoperative care [4]. Among them, Materials and methods perioperative fuid therapy is a core concept. Te ideal We adhered to the Preferred Reporting Items for System- perioperative approach has been debated for decades, atic Reviews and Meta-Analysis—Protocols (PRISMA- having the crucial role of balancing oxygen supply and P) guidelines [21] (Additional fle 1: Table 1) and the demand, maintaining fuid and electrolyte homeostasis study protocol was registered [(International Pro- and avoiding inadequate tissue perfusion and fuid over- spective Register of Systematic Reviews—PROSPERO load [5–12]. (CRD42020218059)]. Te most efective perioperative fuid management is still unclear [13–15]. It has been classifed as restric- Data sources and search strategy tive (< 1.75 L per day), balanced (1.75 to 2.75 L per day) A systematic literature search was performed by using and liberal (> 2.75 L per day)[16]. However, the literature the following databases to identify relevant studies provides diferent, somewhat overlapping defnitions (i.e. in indexed scientifc journals: MEDLINE (via Ovid), from 1.0 to 2.7 L for restrictive, compared with 2.8 to 5.4 EMBASE (via Ovid) and the Cochrane Controlled Clini- L for liberal fuid regimens) [17] and conficting evidence cal trials register, by using the terms: [(“liberal” OR [13–15]. Te enhanced recovery after surgery (ERAS) “restrictive” OR “zero-balance” AND (“surgery”/exp OR pathways to support early recovery among patients surgery)] with flters for humans, age (< 18 years), lan- undergoing major surgery recommend a restrictive guage (English) and time of publication (1 January 2000 approach aiming at the perioperative “zero-balance”[13]. to 31 December 2019). In contrast, recent fndings suggest that excessively We included RCTs 1) enrolling adult patients under- restrictive approaches could be detrimental, indicating going elective abdominal surgery; 2) comparing two that a moderately liberal fuid regimen (i.e. positive fuid diferent regimes of fuid administration defned as balance of 1 to 2 L at the end of surgery) might be the “restrictive” and “liberal” or “conventional” or “standard”; best approach[14]. 3) starting the study protocol intraoperatively; 4) report- Interestingly, a recent large randomised controlled trial ing postoperative complications or mortality or as pri- (RCT) assigning 2983 patients to either zero-balance mary or secondary outcomes. or liberal strategy showed comparable disability-free Te restrictive approach was defned as a modality of survival outcome, although the zero-balance approach perioperative (i.e. intraoperative and during the frst 24 h was associated with a higher rate of acute kidney injury after surgery) treatment employing a specifc and prede- [16]. As a matter of fact, this single study enrolled more fned treatment protocol to obtain in one of the enrolled patients than several previous RCTs regarding this topic, populations an overall negative or zero fuid balance, insofar, partially challenging previous results [18–20]. as compared to the other. Accordingly, trials showing Terefore, we conducted an up-to-date meta-analysis no statistically signifcant diference in the overall fuid of RCTs to assess the association between restrictive and intake or balance, between restrictive and liberal sub- liberal strategies and major adverse surgical outcomes in groups, were also excluded. elective surgery. Studies involving cardiac, non-elective surgery, pae- Secondarily, we appraised the association between diatric or obstetric surgeries were excluded. We also restrictive and liberal approaches on perioperative excluded editorials, commentaries, letters to the editor, Messina et al. Crit Care (2021) 25:205 Page 3 of 13

opinion articles, reviews, meeting abstracts and original Secondary outcomes were: to evaluate the association articles lacking abstract and/or quantitative details, or between restrictive and liberal approaches on periop- those enrolling less than 15 patients in each subgroup. erative early (≤ 30 postoperative days) and late (i.e. > 30 Te references of all included papers, review articles, postoperative days) mortality and predefned postoper- commentaries and editorials on this topic were also ative major complications: renal (i.e. worsening of renal reviewed to identify other studies of interest missed dur- function, according to the trial defnition); cardiovas- ing the primary search. cular [i.e. pulmonary not infective complications, cardiac ischemic dysfunction/failure, cardiac arrhythmias; Data extraction and quality assessment acute neurological events); infections (i.e. all infective Tree couples of examiners (S.S., E.M., D.B., F.I., M.B., complications reported, including the occurrence of G.D.M.) independently evaluated titles and abstracts. either sepsis or septic shock). We also evaluated the Te articles were then subdivided into three subgroups: length of hospital stay and stratifed the studies accord- “included” and “excluded” (if the two examiners agreed ing to the enrolled patients’ ASA classifcation. with the selection) or “uncertain” (in case of disagree- ment). In the case of “uncertain” classifcation, discrepancies were resolved by further examination performed Statistical analysis by two expert authors (A.M. and C.R.). We used a stand- Statistical analysis was conducted on the summary sta- ardised electronic spreadsheet (Microsoft Excel, V 14.4.1; tistics described in the selected articles (e.g. means, Microsoft, Redmond, WA) to extract the data from all medians, proportions) and, therefore, the statistical included studies, recording trial characteristics (the com- unit of observation for all the selected variables was the plete data reporting sheet is provided in Additional fle 1: single study and not the patient. Descriptive statistics Table 2). When necessary, the included studies’ corre- of individual studies used diferent statistical indica- sponding authors were contacted to obtain missing data tors for central tendency and variability, such as means related to trial demographics, methods and outcomes. and standard deviations, whereas absolute and relative frequencies were adopted for qualitative variables. To Risk of bias assessment in the included studies show one single indicator for the quantitative variables Two examiners (L.C. and D.Z.) independently assessed we collected means with standard deviations (SD) or the internal validity of the included studies and discrep- medians and inter-quartile ranges (IQR) were used, as ancies were resolved by a third senior author (A.M. or appropriate. C.R.), by using the RoB 2 (a revised Cochrane Collabo- Te metanalysis included only those studies report- ration’s risk of bias tool for randomised trials) [22]. Te ing mortality and rate of complications, according to RoB 2 considers fve bias domains: 1) the randomisation the defnition adopted in each study and expressed as process; 2) the deviations from intended interventions; 3) rate with respect of the enrolled populations. For ASA missing outcome data; 4) measurement of the outcome; subgroup analysis, we grouped studies with at least 5) selection of the reported results. Finally, the overall 50% of the included population classifed as ASA I/II, risk of bias was calculated and, accordingly, studies were compared to those having at least 50% of the included included in either high-risk/ some concerns /low-risk population classifed as ASA III/IV. We, fnally, strati- groups. fed the studies according to three tertiles of the overall amount of perioperative fuid given (day 0 and day 1) The strength of the body of evidence and the rate of major events. Te strength of the body of evidence was assessed We assessed publication bias using a funnel plot for according to the Grading of Recommendations, Assess- the considered outcomes. Statistical heterogeneity and 2 ment, Development and Evaluations (GRADE) evidence inconsistency were measured using Q and I tests and 2 system[23]. were deemed to be signifcant when p < 0.1 and I > 50%. According to heterogeneity, random or fxed-efect Outcomes defnitions models were used to perform metanalysis. According to 2 Our primary outcome was to appraise the efect of Higgins et al. [24], I values around 25, 50 and 75% were restrictive vs liberal approaches on the overall rate of considered representing, respectively, low, moderate and severe statistical inconsistency. major complications. Tis outcome was assessed both ® considering all the studies reporting it, and those in the Te statistical software STATA 13 (StataCorp, Col- subgroup having a low-risk of bias, according to the RoB lege Station, TX, USA) was used to perform all the 2 scale. computations. Messina et al. Crit Care (2021) 25:205 Page 4 of 13

Results Primary outcome: rate of major complications We identifed 26 potentially eligible studies after the Pooling data from the 13 studies, we found no diference title and abstract assessment (Fig. 1 and Additional in the occurrence of major postoperative complications fle 1: Table 3). After full-text examination, the meta- between restrictive and liberal subgroups [pooled risk nalysis fnally included 18 studies and 5567 patients diference (95% CI) = 0.009 (− 0.02; 0.04); Chi2 = 0.24; (male/female ratio 1.1:1) randomised to restrictive (2786 p value = 0.62; I2 (95% CI) = 38.6% (0–66.9%)] (Fig. 3). patients; 50.0%) and liberal approaches (2780 patients; In the subgroup of fve studies [16, 25, 30–32] report- 50.0%). All the studies, except one [25], have been con- ing the outcome of major postoperative events and hav- ducted on non-obese patients, the vast majority being ing a low overall risk of bias, we found no diference scheduled for laparotomic (3925 patients, 70.5%) surgery. between restrictive and liberal subgroups [pooled risk All the studies, except two [25, 26], were conducted on diference (95% CI) = 0.013 (−0.02; 0.05); Chi2 = 0.42; p patients with a median age > 60 years old (Table 1). Inter- value = 0.51; I2 (95% CI) = 1.0% (0–64.5%)]. estingly, in 5 studies (27.7%), including the largest one [16], the perioperative fuid administration algorithm was Secondary outcomes guided by the optimisation of predefned or fow haemo- Postoperative mortality dynamic pressure variables, by means of a goal-directed We found no diference in either early [data pooled therapy [16, 25, 27–29] (Additional fle 1: Table 4). from the 10 studies—pooled risk diference = − 0.005 Te risk of bias assessment reported: “low risk” for (95% CI − 0.016 to 0.005); Chi2 = 0.95; p value = 0.33; 8 (44.4%) and “some concerns” for 11 10 (55.5%) of the I2 = 0% (95% CI 0% to 52.7%)] or late [data pooled from included studies, mostly (9 of these 11; 81.8%) related to the 8 studies—pooled risk diference = 0.005 (95% CI the selection of the reported results (Fig. 2). − 0.003 to 0.012); Chi2 = 1.51; p value = 0.22; I2 (incon- Following the GRADE system, the quality of evidence sistency) = 0% (95% CI 0–56.3%)] postoperative mortal- was defned as high for 8 studies [16, 25, 30–35] and ity between restrictive and liberal subgroups (Additional moderate for all the others. fle 1: Figures 1–2).

Postoperative organ‑related major complications and length Perioperative fuid administration, balance and weight of stay gain Pooling data from the 8 studies, the liberal approach Intraoperatively, patients in the restrictive subgroup was associated with lower overall complication renal overall received a median (IQR) of 1925 (1482–2470) of major events, as compared to the restrictive [pooled risk fuids, as compared to 3878 (3000–4400) of the liberal diference (95% CI) = 0.06 (0.02–0.09); Chi 2 = 10.3; p subgroup. On day 0 (i.e. considering the overall amount value = 0.001] (Fig. 4). In this subgroup, a sub-analysis of fuids received on the day of the operation, including regarding the use of type of fuid used intraoperatively intraoperative fuid therapy), patients in the restrictive (colloids vs. crystalloids) showed a borderline statistical subgroup overall received a median (IQR) of 2341 ml signifcance regarding an increased incidence of major (1635–3530) of fuids, as compared to 4,350 ml (3095– renal events in the restrictive populations receiving col- 5326) in the liberal subgroup. Finally, considering day 0 loids, as compared to the liberal ones [mean (SD) major and day 1, a median of 3617 (2897–5291) of fuids was renal events 8.0% (4.7) vs. 1.7% (1.9); p = 0.05]. administered to the restrictive subgroups, as compared On the contrary, we found no diference between to 5820 (5038–7000) to the liberal subgroups (Table 2 restrictive and liberal subgroups in the occurrence of and Additional fle 1: Table 4). either severe postoperative cardiovascular (9 studies; Only two studies reported the mean postoperative p value = 0.88) or infective (10 studies; p value = 0.10) overall fuid balance among restrictive and liberal sub- complications (Additional fle 1: Figures 3–4), or the groups [16, 33]. Nine studies (50.0%) did not report length of hospital stay [7 days (6–9) vs. 7 days (5–8); p postoperative weight gain [25, 26, 29–31, 33, 34, 36, 37], value = 0.49]. moreover, in Myles et al.’s study, data regarding this varia- ble were missing for 1,036 (69.5%) patients in the restric- Subgroup analyses tive fuid group and 999 (66.9%) in the liberal fuid group As reported in Additional file 1: Table 5, preoperative [16]. ASA risk score did not impact the postoperative com- Five studies (27.7%) [16, 28, 35, 38, 39] reported a plications rate, among restrictive/liberal subgroups. median (IQR) weight gain of 0.3 kg (− 0.1 to 0.65) and No difference in the overall rate of major complica- 2.0 kg (1.7–2.6) in restrictive and liberal groups on post- tions was found by stratifying the in tertiles of overall operative day 1, respectively. perioperative fluid administered (Fig. 5). Messina et al. Crit Care (2021) 25:205 Page 5 of 13

Fig. 1 Flow of the studies. * Not ftting eligibility criteria full-text articles excluded are reported in Additional fle 1: Table 3. ROB, risk of bias = Messina et al. Crit Care (2021) 25:205 Page 6 of 13 37 (45) 932 (62.4) NA 68 (41.5) NA NA 25 (26) 84 (65.6) 26 (22.0) 8 (10.1) 17 (30.9) 30 (34.9) 7 (20.6) 18 (24) 9 (56.2) 19 (25.3) 34 (26.4) 1 (1.4) LIB 31 (37) 923 (61.9) NA 71 (42.8) NA NA 23 (25.8) 83 (63.4) 23 (19.0) 11 (14.4) 19 (36.5) 33 (35.5) 8 (22.2) 24 (31.6) 8 (50) 20 (26) 30 (24.2) 2 (2.9) RES ASA III–IV, n (%) ASA III–IV, 46 (55) 540 (36.2) NA 90 (54.9) NA NA 41 (42.7) NA 75 (63.6) 53 (67.1) 38 (69.1) 24 (27.9) 6 (17.6) 54 (72) 5 (31.2) 37 (49.3) 86 (66.7) 39 (54.2) LIB 52 (63) 542 (36.4) NA 88 (53) NA NA 37 (41.6) NA 70 (57.9) 49 (59.7) 33 (63.5) 27 (29) 9 (25) 50 (65.8) 2 (12.5) 42 (54.5) 81 (65.3) 33 (47.8) RES ASA II, n (%) 0 (0.0) 21 (1.4) NA 6 (3.7) NA NA 30 (31.3) NA 17 (14.4) 21 (26.6) 0 (0.0) 32 (37.2) 20 (58.8) 3 (4.0) 3 (18.8) 19 (25.3) 9 (7.0) 32 (44.4) LIB 0 (0.0) 25 (1.7) NA 7 (4.2) NA NA 29 (32.6) NA 28 (23.1) 19 (23.1) 0 (0.0) 33 (35.5) 19 (52.8) 2 (2.6) 5 (31.2) 15 (19.5) 13 (10.5) 34 (49.3) RES ASA I, n (%) 24 NA NA 27 NA 25 22 25 26 25 43 22 24 26 24 25 NA 25 LIB ) 2 24 NA NA 26 NA 25 22 27 26 25 44 22 25 24 26 26 NA 25 RES BMI (kg/m 68 66 66 65 NA 69 65 68 70 69 42 73 60 59 77 59 52 69 LIB 69 66 67 65 NA 69 65 67 70 68 40 72 62 62 74 63 53 64 RES Age (years) 83 (50.0) 1493 (50.1) 25 (50) 164 (49.7) 24 (44.4) 30 (50) 96 (51.9) 128 (51.2) 118 (49.4) 79 (49.1) 55 (51.4) 86 (48) 34 (48.6) 75 (49.7) 16 (50) 75 (49.3) 129 (51) 72 (51.1) LIB n (%) 83 (50.0) 1490 (49.9) 25 (50) 166 (50.3) 30 (55.6) 30 (50) 89 (48.1) 131 (52.4) 121 (50.6) 82 (50.9) 52 (48.6) 93 (52) 36 (51.4) 76 (50.3) 16 (50) 77 (50.7) 124 (49) 69 (48.9) RES n (%) 166 2983 50 330 54 60 185 250 239 161 107 179 70 151 32 152 253 141 Pt. analysed n (%) 2014 2018 2016 2016 2015 2015 2014 2014 2013 2012 2012 2012 2010 2009 2007 2005 2005 2003 Year Summary of the included studies: general characteristics population of the enrolled Wuethrich [ 35 ] Wuethrich Myles [ 16 ] Kassim [ 29 ] Grant [ 31 ] van Samkar [ 47 ] Piljic [ 34 ] Piljic Hong-Ying [ 49 ] Hong-Ying Lavu [ 33 ] Lavu Kalyan [ 32 ] Abraham [ 38 ] Matot [ 25 ] Gao [ 30 ] Futier [ 36 ] Futier Muller [ 37 ] Holte [ 39 ] Holte Nisanevich [ 28 ] Kabon [ 26 ] Brandstrup [ 46 ] 1 Table References and body mass Age respectively. strategy, or liberal restrictive who received those patients to RES/LIB refers status; ASA: American Society physical not available; of Anaesthesiologists NA: data N : number of patients; in each study report recorded (BMI) columns index of the LIB/RES populations the mean/median values Messina et al. Crit Care (2021) 25:205 Page 7 of 13

Fig. 2 The internal validity of the included studies was assessed by two expert authors, by using the Rob2: a revised Cochrane Collaboration’s risk of bias tool for randomised trials [22] Messina et al. Crit Care (2021) 25:205 Page 8 of 13 9900) D1 2515) D1 4245) D1 RES 500 (0–5000) D1 NA 2170 (476) D1 NA 1200 (3900– NA 2100 (340) D1 NA NA 1944(1354– 3042 2090 (360) D1 2006 (549) D1 2500 1436 (1000– NA 2056 2100 (800–4000) D1 9100) D1 3894) D1 6500) D1 4100) FLUIDS DAY 1 DAY FLUIDS (ml) LIB 1500 (0–6000) NA 2012 (475) D1 NA 2700 (1800– NA 2730 (560) D1 NA NA 3315(2645– 3312 2750 (570) D1 2613 (549) D1 2500 2577 (1650– NA 3100 2050 (1000– 8050) (935–2250) 6700) 3328) (550–4791) + PO) RES 2740 (1100– 3100 (300) 1408 (946) 1640 1925 (1100– 3380 (1114) 1555 (410) NA 3050 (2662– NA 5731 NA 4038 NA 1178 NA 2737 NA 11,083) 8050 6400) 6700) 4856) FLUIDS DAY 0 (IO DAY FLUIDS (ml) LIB 5388 (2700– 5000 (400) 3878 (1170) 5050 (3563– 2950 (1600– 5588 (1463) 3050 (800) NA 5775 (5050– NA 8789 NA 5017 NA 2151 (1030– NA 4300 NA 6700) 480–3100) (690–1500) (700–4000) RES NA NA 1408 (946) NA 1925 (1100– NA 1555 (410) 1325( NA 1000 4812 1620 1977 (528) NA NA NA NA 1700 6400) 14,000) 2500) 6200) TOTAL FLUIDS IO FLUIDS TOTAL IO FLUIDS TOTAL (ml) (ml) LIB NA NA 3878 (1170) NA 2950 (1600– NA 3050 (800) 3300 (1500– NA 2033 (1576– 6694 3110 2598 (505) NA NA NA NA 4300 (2800– (580–1500) 2500) (650–5130) 2294) (700–4000) RES NA 2500 (1300) NA 1140 NA 3040 (769) 1320 (220) NA 575 (452–800) NA 4812 NA 1662 (655) 2100 (1600– 2050 1219 (140) 1677 (1173– 1700 6500) 3070) 6000) 7550) 3850) 6200) CRYSTALLOIDS IO CRYSTALLOIDS IO (ml) CRYSTALLOIDS (ml) LIB NA 3900 (1900) NA 3900 (2722– NA 5266 (1340) 1450 (310) NA 2500 (2000– NA 6694 NA 1923 (593) 3400 (2500– 3563 (1050– 3586 (473) 3000 (2100– 4300 (2800– RES NA 0 NA 500 (341–850) NA 854 (547) 210 (300) NA 0 (0–200) NA 0 NA 315 (409) 1400 (0.6) 390 (0–2500) 1219 (268) 500 (250–800) 0 1000) COLLOIDS IO COLLOIDS (ml) LIB NA 0 NA 500 (350–750) NA 316 (311) 1240 (410) NA 0 (0–500) NA 0 NA 675 (513) 1000 (0.6) 363 (0–4000) 920 (206) 500 (400– 0 RES NA 0 NA 30.4 NA 25.2 13.5 NA 0 NA 0 NA 15.9 40.0 15.9 50.0 22.9 0 LIB IO COLLOIDS (%) NA 0 NA 11.3 NA 5.6 40.6 NA 0 NA 0 NA 25.9 22.7 9.2 20.4 14.2 0 Summary 1 0 and day of the included studies: fuid infused on day [ 47 ] 2 Table References PO, intraoperative; IO, RES, restrictive; liberal; LIB, reported data in the study. obtained from are without ranges Data in the included studies. those present to according ranges, reported with the appropriate are Data of rate reports frst column The the overall not available. NA, data after the operation; 1, frst day unit); DAY care or intensive room either in recovery spent (including the whole period after the operation postoperative of fuids amount intraoperative the overall to as compared administration, of colloids rate intraoperative Brandstrup [ 46 ] Kabon [ 26 ] Nisanevich [ 28 ] Holte [ 39 ] Holte Muller [ 37 ] Futier [ 36 ] Futier Gao [ 30 ] Matot [ 25 ] Abraham [ 38 ] Kalyan [ 32 ] Lavu [ 33 ] Lavu Hong-Ying [ 49 ] Hong-Ying Piljic [ 34 ] Piljic van Samkar Grant [ 31 ] Kassim [ 29 ] Myles [ 16 ] Wuethrich [ 35 ] Wuethrich Messina et al. Crit Care (2021) 25:205 Page 9 of 13

Fig. 3 Forest and bias assessment plots of postoperative major events

Fig. 4 Forest and bias assessment plots of postoperative major renal events

Discussion found no diference between the two approaches in the Tis metanalysis conducted on RCTs in major abdomi- occurrence of the overall major postoperative complica- nal elective surgery regarding the efect of perioperative tions or mortality. On the contrary, the liberal fuid policy liberal or restrictive approach on postoperative outcomes Messina et al. Crit Care (2021) 25:205 Page 10 of 13

Fig. 5 Liberal / restrictive classifcation of the subgroups of patients in the included studies. Data are reported according to the tertiles of overall fuid amount (in ml) reported in the days 0 (day of the operation) and 1 (frst postoperative day)

was associated with lower overall complication renal single trial enrolled more patients than 17 RCTs com- major events, as compared to the restrictive. bined in the previous 15 years (Table 1). Te weight Postoperative complications are common after major of this trial specifcally impacts on postoperative surgery and represent a signifcant fnancial and social major renal events of the present metanalysis, which burden [2, 3]. Optimisation of fuid management has were lower in the liberal subgroup as compared to the been extensively studied as a potentially modifable peri- restrictive (Fig. 4). Interestingly, renal events did not operative factor by adopting specifc protocols focused impact on overall mortality, despite the fact that acute on modality of fuid administration and cumulative fuid kidney injury is recognised as an independent risk fac- balance [9–11, 40]. Te analysis of the literature in this tor for mortality [41]. However, postoperative mortality feld is rather complex due to the number of variables is greatly afected by the results of the study of Myles potentially afecting the fnal outcomes, which includes et al. [16]. Moreover, the present metanalysis did not the overall complexity and the intrinsic risks of each spe- include trials on cardiac surgery, which is a clinical cifc type of the surgery. setting specifcally associated with an increased risk On the one hand, a tendency towards a more restric- of death in those patients who develop postoperative tive approach (as supported by the ERAS pathways [13]) acute kidney injury [41–43]. has been reported. In fact, a previous metanalysis [19] Considering the impact of crystalloids/colloids use on showed that fewer patients had a lower total complica- the renal postoperative outcome, this metanalysis only tion rate and risk of infection in the restrictive group as suggests a possible additive efect of the colloids use in a compared to the liberal group. restrictive approach. However, a recent large RCT com- On the other, the recent large RCT performed by paring the use of low molecular weight hydroxyethyl- Myles et al. challenged this concept, showing that dis- starch vs. 0.9% saline for intravascular volume expansion ability-free survival at 1 year did not change in patients in high-risk surgical patients showed no signifcant dif- randomised to a zero-balance vs a liberal approach, ference in a composite outcome of death or signifcant with the frst strategy being associated with higher rates postoperative [27]. For this reason, this result should be of acute kidney injury, surgical site infection and need considered with extreme caution. for renal-replacement therapy [16]. Interestingly, this Messina et al. Crit Care (2021) 25:205 Page 11 of 13

In the feld of perioperative fuid administration, sum- However, despite the lack of statistical signifcance, marising the evidence available in the literature into we found the highest rates of major complications in straightforward clinical suggestions for daily clinical the highest and lowest tertiles of our sub-analysis. practice is rather complicated, and our updated results Finally, the included studies all report overall low basically indicate an equivalence between the two peri- perioperative mortality rates; thus, as expected, the operative fuid policies, suggesting a “third way”. Te impact of liberal vs. restrictive strategies on periopera- overall amount of fuid (perioperative target) should tive mortality was not signifcant. be integrated into an individualised goal-directed fuid replacement strategy (perioperative policy), to prevent fuid overload and fuid shortage by closely monitor- Limitations ing the efects of each bolus administered, as long as the Some limitations of this study should be acknowledged. individual plateau of the impact on predefned fow or First, as concern the data obtained from the included pressure variables is achieved [12, 44]. Interestingly, this studies: 1) the defnition of postoperative complica- approach was incorporated into the intraoperative pro- tions and the timing in mortality assessment may vary tocol of 5 studies [16, 25, 27–29], including the study of among the included studies, implying a bias in the Myles et al. who assessed central venous pressure and reported outcomes’ comparability. In fact, some com- stroke volume variation in case of intraoperative hypo- plications (i.e. pneumonia, wound abscess/infection/ tension to guide resuscitation (supplementary appendix dehiscence, pneumothorax) have been considered of the trial [16]). Moreover, a recent metanalysis showed either as minor or major, according to study-specifc a trend towards the reduction of postoperative compli- criteria, which have been respected in the data analysis; cations when a goal-directed therapy is used in patients 2) we computed major/minor complications accord- receiving large amounts of perioperative fuids [45]. ing to either the criteria adopted in the study or (only Tus, rather than choosing between a fxed-volume regi- for subgroup analysis) defnitions clearly indicating the men and a goal-directed concept, an alternative approach gravity degree (i.e. peritonitis and anastomotic leak has could be to combine the two strategies. Of note, in the been always considered as severe complications); 3) the study of Myles et al. [16] restrictive fuid therapy had impact of restrictive/liberal policies on specifc sub- similar efects in patients treated with or without a goal- groups of patients is overall lacking (i.e. patients with directed device. pre-existing renal or diastolic cardiac dysfunction), lim- As shown by our qualitative analysis, neither the perio- iting the generalisability of data; 4) this is not a meta- perative intakes nor the fuid balance or the bodyweight analysis based on individual data and the main author gain has been consistently reported in the considered of each study (whenever needed) has been contacted RCTs. Surprisingly, the overall fuid balance or the post- only to provide more specifc information regard- operative weight diference, which should be, in principle, ing the results on the overall population enrolled. the most efective perioperative variables depicting the Tis is specifcally important for colloids/crystalloids fuid paths of restrictive and liberal subgroups, has been sub-analysis. reported only in 5 studies (27.7%) [16, 33, 35, 46, 47]. Te Tird, the overall quality of the included stud- heterogeneity in actual overall fuid balance computation, ies reported “some concerns” in the majority of them as long the defnition of postoperative complications (see (55.5%), mostly related to the selection of the reported further) greatly afects the comparability of the RCTs, results due to drawbacks in the trial registration. Tis is soliciting clear standards in data reporting. mainly due to the criteria imposed by the RoB 2 scale [22] Considering the fuid intake alone, our data sug- for the trial registration. Te International Committee of gest that an overall median administration of about 4 L Medical Journal Editors policy regarding prospective trial on days 0 and 1 may be considered restrictive, whereas registration was started in 2005 [48], and most of the trial about 6 L may be considered liberal. However, as pointed published before 2010 do not fulfl the RoB 2 criteria for out by previous metanalysis [18, 19], these cut-ofs are “low-risk” report. Moreover, a monitoring of the study associated with large inter-quartile ranges due to the protocol is reported only in three studies [16, 26, 33]. lack of consistency in perioperative fuid regimen defni- Finally, we adopted a database combination search tion. Consequently, some subgroups of RCTs classifed strategy, including PUBMED®, EMBASE® and the as restricted would be considered liberal in some other Cochrane Controlled Clinical trials register, excluding trials (see Fig. 5), because of overlapping perioperative diferent sources (i.e. Web of Science®). Although this volumes. choice should allow a reliable coverage of the published studies for the topic of interest, some RCTs could not be identifed. Messina et al. Crit Care (2021) 25:205 Page 12 of 13

Conclusions Author details 1 Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical In major abdominal elective surgery perioperative, the and Research Center – IRCCS, Via Alessandro Manzoni, 56, 20089 Rozzano, choice between liberal or restrictive approach did not MI, Italy. 2 Department of Biomedical Sciences, Humanitas University, Pieve 3 afect overall major postoperative complications or Emanuele, MI, Italy. Anaesthesia and Intensive Care, IRCCS for Oncology and Neuroscience, San Martino Policlinico Hospital, Genoa, Italy. 4 Department mortality. In a subgroup analysis, a liberal fuid policy of Surgical Sciences and Integrated Diagnostic (DISC), University of Genoa, was associated with lower overall complication renal Genoa, Italy. 5 Anesthesia and Intensive Care Medicine, Maggiore Della Carità 6 major events, as compared to the restrictive. University Hospital, Novara, Italy. Anesthesia and Intensive Care Medicine, Azienda Sanitaria Universitaria Integrata Udine, Udine, Italy. 7 Clinical Epidemi- Te lack of consistency in perioperative overall fuid ology and Medical Statistics Unit, Department of Medical, Surgical and Experi- balance and in the defnitions of clinical outcomes still mental, University of Sassari, Sassari, Italy. afects the comparability of the results of RTCs, solicit- Received: 9 April 2021 Accepted: 6 June 2021 ing clear standards in data reporting.

Abbreviations ASA: American Society of Anaesthesiologists (ASA) physical status score; RCT References : Randomised controlled trial; ERAS: Enhanced recovery after surgery; SD: 1. de Vries EN, Prins HA, Crolla RM, den Outer AJ, van Andel G, van Helden Standard deviation; 95%CI: 95% Confdence intervals. SH, et al. Efect of a comprehensive surgical safety system on patient outcomes. N Engl J Med. 2010;363:1928–37. Supplementary Information 2. Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumb- hani DJ, et al. Determinants of long-term survival after major surgery The online version contains supplementary material available at https://doi. and the adverse efect of postoperative complications. Ann Surg. org/10.1186/s13054-021-03629-y. 2005;242:326–41. 3. Healy MA, Mullard AJ, Campbell DA Jr, Dimick JB. Hospital and payer costs associated with surgical complications. JAMA Surg. 2016;151:823–30. Additional fle 1. Supplementary materials including supplementary 4. Kang SH, Lee Y, Min SH, Park YS, Ahn SH, Park DJ, et al. Multimodal tables and fgures. enhanced recovery after surgery (eras) program is the optimal perioperative care in patients undergoing totally laparoscopic distal gastrectomy for gastric cancer: A prospective, randomized, clinical trial. Ann Surg Acknowledgements Oncol. 2018;25:3231–8. None declared. 5. Holte K, Kehlet H. Fluid therapy and surgical outcomes in elective surgery: a need for reassessment in fast-track surgery. J Am Coll Surg. Authors’ contributions 2006;202:971–89. A.M. and C.R. designed the study, conducted the primary data search, solved 6. Cecconi M, Corredor C, Arulkumaran N, Abuella G, Ball J, Grounds RM, the classifcation discrepancies in data collection and drafted the manuscript; et al. Clinical review: goal-directed therapy-what is the evidence in surgi- L.C., D.Z., F.I., E.M., S.S., D.B. and M.B. performed the evaluation of titles and cal patients? The efect on diferent risk groups. Crit Care. 2013;17:209. abstracts and helped in data collection and the manuscript preparation, L.S. 7. Hamilton MA, Cecconi M, Rhodes A. A systematic review and meta- and G.S. conducted the data analysis and helped in manuscript preparation; analysis on the use of preemptive hemodynamic intervention to improve P.P. substantially contributed in manuscript preparation and data interpre- postoperative outcomes in moderate and high-risk surgical patients. tation; M.C. helped in designing the study and in the primary search and Anesth Analg. 2011;112:1392–402. substantially contributed in manuscript preparation and data interpreta- 8. Lobo SM, de Oliveira NE. Clinical review: What are the best hemodynamic tion. All the authors approved the fnal version of the paper and agree to targets for noncardiac surgical patients? Crit Care. 2013;17:210. be accountable for all aspects of the work thereby ensuring that questions 9. Marik PE. Perioperative hemodynamic optimization: a revised approach. J related to the accuracy or integrity of any part of the work are appropriately Clin Anesth. 2014;26:500–5. investigated and resolved. 10. Voldby AW, Brandstrup B. Fluid therapy in the perioperative setting-a clinical review. J Intensive Care. 2016;4:27. Funding 11. Thacker JK, Mountford WK, Ernst FR, Krukas MR, Mythen MM. Periopera- This work has not been funded by an external source. tive fuid utilization variability and association with outcomes: considera- tions for enhanced recovery eforts in sample us surgical populations. Availability of data and materials Ann Surg. 2016;263:502–10. The datasets used and/or analysed during the current study are available from 12. Heming N, Moine P, Coscas R, Annane D. Perioperative fuid management the corresponding author on reasonable request. for major elective surgery. Br J Surg. 2020;107:e56–62. 13. Gustafsson UO, Scott MJ, Schwenk W, Demartines N, Roulin D, Francis Declarations N, et al. Guidelines for perioperative care in elective colonic surgery: Enhanced recovery after surgery (eras((r))) society recommendations. Ethical approval and consent to participate World J Surg. 2013;37:259–84. Not applicable. 14. Miller TE, Myles PS. Perioperative fuid therapy for major surgery. Anesthe- siology. 2019;130:825–32. Consent for publication 15. Wrzosek A, Jakowicka-Wordliczek J, Zajaczkowska R, Serednicki WT, Not applicable. Jankowski M, Bala MM, et al. Perioperative restrictive versus goal-directed fuid therapy for adults undergoing major non-cardiac surgery. Cochrane Competing interests Database Syst Rev. 2019;12:CD012767. Dr. Messina received travel expenses and registration for meetings, congresses, 16. Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, et al. Restric- and courses and lecture fees from Vygon; Prof. Cecconi is a consultant for tive versus liberal fuid therapy for major abdominal surgery. N Engl J Edwards Lifesciences, LiDCO and Cheetah Medical. 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