Advertisement

Goal-directed hemodynamic therapy versus restrictive normovolemic therapy in major open abdominal surgery: A randomized controlled trial

Open AccessPublished:October 31, 2020DOI:https://doi.org/10.1016/j.surg.2020.09.035

      Abstract

      Background

      The aim of this study was to compare the occurrence of postoperative complications in patients undergoing elective open abdominal surgery and receiving intraoperative goal-directed hemodynamic therapy or restrictive normovolemic therapy.

      Methods

      A total of 401 patients were randomized in the goal-directed hemodynamic therapy or restrictive normovolemic therapy groups. A cardiac output monitor was used in all goal-directed hemodynamic therapy patients and was left at the discretion of anesthetists in charge of patients in the restrictive normovolemic therapy group. The primary outcome was a composite morbidity endpoint (30-day mortality and complications grade 2–4 according to Dindo-Clavien classification). Secondary outcomes were the hospital duration of stay, the incidence of pulmonary, cardiovascular, and renal complications up to 30 days after surgery, and midterm survival.

      Results

      Intraoperatively, the goal-directed hemodynamic therapy group received higher intravenous fluid volumes (mean of 10.8 mL/kg/h and standard deviation of 4.0) compared with the restrictive normovolemic therapy group (mean of 7.2 mL/kg/h and standard deviation of 2.0; P < .001). On the first postoperative day, similar fluid volumes were infused in the 2 groups. The primary outcome occurred in 57.7% of goal-directed hemodynamic therapy and 53.0% of restrictive normovolemic therapy (relative risk, 1.09 [95% confidence interval, 0.91–1.30]), and there was no significant difference between groups for any secondary outcomes.

      Conclusion

      Among patients undergoing major open abdominal surgery, the goal-directed hemodynamic therapy and the restrictive normovolemic therapy were associated with similar incidence of moderate-to-severe postoperative complications and hospital resource use.

      Introduction

      Fluid therapy is an important cornerstone in perioperative management, and it may influence clinical outcome and the use of health care resources, particularly after major surgery.
      • Shin C.H.
      • Long D.R.
      • McLean D.
      • et al.
      Effects of intraoperative fluid management on postoperative outcomes: A hospital registry study.
      ,
      • Eng O.S.
      • Dumitra S.
      • O'Leary M.
      • et al.
      Association of fluid administration with morbidity in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
      Fluid overload results in interstitial edema, increased cardiorespiratory workload, and body weight gain, whereas insufficient fluid loading leads to poor peripheral blood flow and low tissue oxygen delivery. Both strategies have been associated with impaired wound healing and poor outcomes.
      • Chawla L.S.
      • Ince C.
      • Chappell D.
      • et al.
      and the ADQI XII Fluids Workgroup. Vascular content, tone, integrity, and haemodynamics for guiding fluid therapy: a conceptual approach.
      ,
      • Kulemann B.
      • Timme S.
      • Seifert G.
      • et al.
      Intraoperative crystalloid overload leads to substantial inflammatory infiltration of intestinal anastomoses-a histomorphological analysis.
      The traditional “liberal” fluid strategy assumes that anesthesia-induced vasoplegia causes a reduction of the “stressed” circulatory volume, whereas surgery-induced inflammation generates a capillary leak that allows fluids to move from the intravascular to the interstitial compartment. Both mechanisms implicate that additional intravenous fluids are required to restore the intravascular volume and maintain oxygen transport capacity.
      • Strunden M.S.
      • Heckel K.
      • Goetz A.E.
      • Reuter D.A.
      Perioperative fluid and volume management: physiological basis, tools and strategies.
      Nevertheless, the importance of the so-called nonanatomical surgical “third space” has been exaggerated, since the disturbances in vascular permeability are transient and mostly localized around the injured tissues.
      • Chan S.T.
      • Kapadia C.R.
      • Johnson A.W.
      • Radcliffe A.G.
      • Dudley H.A.
      Extracellular fluid volume expansion and third space sequestration at the site of small bowel anastomoses.
      ,
      • Voldby A.W.
      • Brandstrup B.
      Fluid therapy in the perioperative setting-a clinical review.
      Nowadays, Enhanced Recovery After Surgery (ERAS) programs have been widely implemented to provide cost-efficient perioperative care, and much emphasis has been placed on fluid management to facilitate physiological recovery.
      • Makaryus R.
      • Miller T.E.
      • Gan T.J.
      Current concepts of fluid management in enhanced recovery pathways.
      ,
      • Carmichael J.C.
      • Keller D.S.
      • Baldini G.
      • et al.
      Clinical Practice Guidelines for Enhanced Recovery After Colon and Rectal Surgery from the American Society of Colon and Rectal Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons.
      Vivid scientific debates are focusing on the amount of fluids to be given, the indications of vasopressors and/or inotropes, and the physiologic targets to be achieved.
      • Miller T.E.
      • Myles P.S.
      Perioperative fluid therapy for major surgery.
      The goal-directed hemodynamic therapy (GDHT) requires a close monitoring of the stroke volume for guiding fluids and cardiovascular drugs. On the other hand, restrictive normovolemic therapy (RNT) simply requires a fixed-rate infusion of crystalloids coupled with the administration of vasopressors to mitigate the vasodilatory effects of anesthetic agents and/or neuraxial block.
      • Voldby A.W.
      • Brandstrup B.
      Fluid therapy in the perioperative setting-a clinical review.
      From more than 45 randomized controlled studies (RCT),
      • Sun Y.
      • Chai F.
      • Pan C.
      • Romeiser J.L.
      • Gan T.J.
      Effect of perioperative goal-directed hemodynamic therapy on postoperative recovery following major abdominal surgery-a systematic review and meta-analysis of randomized controlled trials.
      • Calvo-Vecino J.M.
      • Ripolles-Melchor J.
      • Mythen M.G.
      • et al.
      and the FEDORA Trial Investigators Group
      Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
      • Giglio M.
      • Dalfino L.
      • Puntillo F.
      • Brienza N.
      Hemodynamic goal-directed therapy and postoperative kidney injury: an updated meta-analysis with trial sequential analysis.
      there is some evidence that the GDHT is associated with less postoperative morbidity compared with the liberal strategy, although recent well-controlled trials have failed to demonstrate favorable clinical effects.
      • Schmid S.
      • Kapfer B.
      • Heim M.
      • et al.
      Algorithm-guided goal-directed haemodynamic therapy does not improve renal function after major abdominal surgery compared to good standard clinical care: a prospective randomised trial.
      ,
      • Pearse R.M.
      • Harrison D.A.
      • MacDonald N.
      • et al.
      and the OPTIMISE Study Group
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      Fewer studies using RNT have reported beneficial effects,
      • Schol P.B.
      • Terink I.M.
      • Lance M.D.
      • Scheepers H.C.
      Liberal or restrictive fluid management during elective surgery: a systematic review and meta-analysis.
      ,
      • Wuethrich P.Y.
      • Burkhard F.C.
      • Thalmann G.N.
      • Stueber F.
      • Studer U.E.
      Restrictive deferred hydration combined with preemptive norepinephrine infusion during radical cystectomy reduces postoperative complications and hospitalization time: a randomized clinical trial.
      although concerns have been raised regarding the risk of acute kidney injury.
      • Myles P.S.
      • Bellomo R.
      • Corcoran T.
      • et al.
      and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
      So far, 4 small studies comparing GDHT to RNT did not report any difference in the occurrence of complications after intra-abdominal surgery.
      • Zhang J.
      • Qiao H.
      • He Z.
      • Wang Y.
      • Che X.
      • Liang W.
      Intraoperative fluid management in open gastrointestinal surgery: goal-directed versus restrictive.
      • Srinivasa S.
      • Taylor M.H.
      • Singh P.P.
      • Yu T.C.
      • Soop M.
      • Hill A.G.
      Randomized clinical trial of goal-directed fluid therapy within an enhanced recovery protocol for elective colectomy.
      • Phan T.D.
      • D'Souza B.
      • Rattray M.J.
      • Johnston M.J.
      • Cowie B.S.
      A randomised controlled trial of fluid restriction compared to oesophageal Doppler-guided goal-directed fluid therapy in elective major colorectal surgery within an Enhanced Recovery After Surgery program.
      • Brandstrup B.
      • Svendsen P.E.
      • Rasmussen M.
      • et al.
      Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance?.
      Given uncertainties related to the beneficial impact of GDHT and RNT along with the recent improvements in overall perioperative care, we carried out an RCT to compare the clinical impact of intraoperative GDHT versus RNT in patients undergoing major abdominal surgery.

      Material and methods

      The trial was approved by the Ethics Committee of the University Hospital of Geneva (NAC 09–022) and registered at ClinicalTrials.gov (NCT02625701), and it was conducted between 2010 and 2018 in a single academic center. All patients provided written informed consent at least 1 day before surgery.

       Study population

      Eligible adult patients were scheduled for major abdominal, urological, or vascular surgery via open laparotomy under general anesthesia (≥2 hours). Patients undergoing emergency procedures, those with end-stage organ failure (with Child-Pugh class C or model for end-stage liver disease score >22, on hemodialysis or hemofiltration, with forced expiratory lung volume in 1 second <30% of predicted values), those with psychiatric disorders, and those unable to give an independent consent were all excluded.

       Study design

      This was a randomized, controlled, parallel-arm, and superiority trial. Patients were randomly allocated to 1 of 2 groups (GDHT versus RNT) in a 1:1 ratio using a computer-generated list with blocks of 4. Allocation details were concealed in sequentially numbered, sealed, and stapled envelopes. The randomization sequence was developed before initiation of the trial and concealed until after enrollment. The investigator opened envelopes on the day of surgery. Patients, health care professionals in intensive care (ICU), intermediate care, and postanesthesia care units (PACU), as well as the assessors who recorded data during the postoperative period, were all blinded to the treatment allocation. Investigators who collected the intraoperative data had knowledge of the group assignment.

       Perioperative anesthesia conduct

      All included patients were allowed solid foods up to 6 hours before surgery and fluids up to 2 hours before surgery. Bowel preparation was not performed in most patients, and an enhanced recovery after surgery program was not implemented during the study period. Prophylactic antibiotics were administered to all patients.
      A multicomponent monitoring system (IntelliVue MP70; Philips Medical Systems, Philips Healthcare, Amsterdam, The Netherlands) was applied and included a 5-lead electrocardiogram, an oxygen pulse oximeter, invasive radial arterial pressure, a nasopharyngeal temperature, as well as processed electroencephalography (BIS Monitor; Aspect Medical Systems, Norwood, MA) and electromyographic response to nerve stimulations. Pulse pressure variation (PPV) was obtained online from the analysis of the pressure waveform.
      An epidural catheter was placed in most patients to provide continuous intra and postoperative analgesia, and neuraxial analgesia was performed in some patients with a single intrathecal injection of morphine (5–10 mcg/kg), particularly in vascular surgery.
      • Licker M.
      • Ellenberger C.
      • Cartier V.
      • et al.
      Impact of anesthesia technique on the incidence of major complications after open aortic abdominal surgery: a cohort study.
      Anesthesia was induced intravenously with sufentanil (10–15 μg) and propofol (2–3 mg·kg-1). After completion of neuromuscular blockade, the trachea was intubated, and the lungs were mechanically ventilated with low tidal volume (6–8 mL·kg-1 of predicted body weight), a positive end-expiratory pressure of 5 to 10 cm of water, hourly alveolar recruitment maneuvers, and respiratory rate adjusted to keep the end-tidal carbon dioxide close to 4.5% to 5%. The fractional inspiratory oxygen concentration was adjusted to maintain SpO2 above 94%. The administration of neuromuscular blocking agents was titrated to maintain 1 to 2 mechanical twitches in response to supramaximal stimulation of the ulnar nerve at the wrist. Anesthesia was maintained with inhaled sevoflurane to target bispectral index values between 40 and 60, whereas analgesia was ensured with neuraxial analgesia. In the absence of central neuraxial analgesic block, lidocaine, ketamine, or dexmedetomidine were infused intravenously to minimize the administration of intravenous opiate and facilitate weaning from the ventilator at the end of surgery. Normothermia was maintained with forced-air warming blankets, a heated infusion system, and rewarming intra-abdominal irrigating fluids. During surgery, arterial blood gas samples were obtained hourly. A bladder catheter was inserted in all patients.
      Postoperatively, patients were transferred to the PACU, intermediate care unit, or ICU, where local practice guidelines entailed multimodal analgesia, intravenous hypotonic solutions (5% dextrose/0.40% sodium chloride between 0.8–1.2 mL/kg/h) as well as early resumption of oral intake, mobilization, and removal of indwelling catheters and drains.

       Hemodynamic management

      During anesthesia induction, all patients received 5 to 8 mL·kg-1 of a balanced crystalloid solution (Ringerfundin; B. Braun Medical AG, Sempach, Switzerland) to compensate for preoperative fasting and vasodilation associated with general anesthesia and central neuraxial block. Throughout surgery, balanced crystalloids were given at a rate of 2 to 4 mL·kg-1·h-1. Surgery-related blood losses were compensated by infusing balanced crystalloids in a 2:1 ratio or by infusing colloids (hydroxyethyl starch [HES balanced]; Fresenius Kabi AG, Stans, Switzerland) in a 1:1 ratio. Packed red cells were transfused when the hemoglobin level dropped below 90 to 100 g·L-1 in the elderly and in subjects with cardiac comorbidities or below 80 g·L-1 in those without cardiac comorbidities.
      In the GDHT group, the arterial line was connected to a dedicated monitor (LiDCO Ltd, Cambridge, United Kingdom) to estimate stroke volume index and cardiac index (non-calibrated) based on the pulse contour analysis of the pressure wave and to guide the hemodynamic interventions. A fluid challenge of 250 mL (colloids or crystalloids) given over 10 minutes was initiated before incision and repeated until the gain in stroke volume index was less than 10% and whenever mean arterial pressure (MAP) decreased (>20% or < 65–70 mmHg) and PPV was higher than 10% (Fig 1).
      Figure thumbnail gr1
      Fig 1Intraoperative anesthetic and hemodynamic management.
      In the RNT group, besides the basal infusion of crystalloids, supplemental fluids were given in a 1:2 ratio to compensate any fluid losses (blood, urinary output, effusions from the gastrointestinal tract) and to support circulatory homeostasis in cases of metabolic acidosis or hypotension that showed a poor response to vasopressors (Fig 1). A cardiac output monitor (LiDCO Ltd) was available at the discretion of the anesthetists in charge of the patient.
      In both groups, MAP was kept above 65 to 70 mmHg with either ephedrine and/or phenylephrine boluses. Norepinephrine was used as a continuous infusion in patients requiring repeated doses of ephedrine or phenylephrine and when local anesthetics were administered through the epidural catheter. Moderate oliguria (0.3–0.8 mL·kg-1·h-1) was not considered an indication for fluid loading.

       Data collected and study endpoints

      On the day of enrolment, collected data included demographic and clinical information as well as the results of blood laboratory tests and other investigations. The revised cardiac risk index was computed for each patient. Surgical and anesthetic data were directly recorded during the procedure. Postoperatively, patients were followed until hospital discharge to report any adverse events. Blood samples were taken on the day before surgery and daily within the first 3 days after surgery to measure plasma concentrations of N terminal pro-B type natriuretic peptide (NT-proBNP) and Troponin I (from 2010 to 2014) or high sensitive Troponin T (from 2015 to 2018; Elecys immunoassay, Roche Diagnostics, Basel, Switzerland) to detect myocardial injury after noncardiac surgery.
      • Biccard B.M.
      • Scott D.J.A.
      • Chan M.T.V.
      • et al.
      Myocardial injury after noncardiac surgery (MINS) in vascular surgical patients: A prospective observational cohort study.
      ,
      • Writing Committee for the V.S.I.
      • Devereaux P.J.
      • Biccard B.M.
      • et al.
      Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery.
      After hospital discharge, follow-up was performed by phone calls after surgery. Data were collected by 2 assessors with more than 2 years of work experience in clinical research.
      The primary endpoint was a composite morbidity endpoint (30-day mortality and complications of grade 2–4, according to Dindo-Clavien classification
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      ).
      Secondary endpoints included the incidence of specific complications such as atelectasis, pneumonia, acute respiratory distress failure, myocardial infarction, acute heart failure, arrhythmias, myocardial injury after noncardiac surgery, pulmonary thromboembolism, stroke, wound infection, acute kidney injury, delirium as well as unplanned ICU admission, ICU and hospital durations of stay, and midterm survival. We also analyzed the amount of fluids (crystalloids, colloids, blood products) and cardiovascular drugs administered as well as hemodynamic parameters (MAP, PPV, heart rate, cardiac index, and blood lactate levels).

       Statistical analysis

      According to previous published data,
      • Sun Y.
      • Chai F.
      • Pan C.
      • Romeiser J.L.
      • Gan T.J.
      Effect of perioperative goal-directed hemodynamic therapy on postoperative recovery following major abdominal surgery-a systematic review and meta-analysis of randomized controlled trials.
      • Calvo-Vecino J.M.
      • Ripolles-Melchor J.
      • Mythen M.G.
      • et al.
      and the FEDORA Trial Investigators Group
      Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
      • Giglio M.
      • Dalfino L.
      • Puntillo F.
      • Brienza N.
      Hemodynamic goal-directed therapy and postoperative kidney injury: an updated meta-analysis with trial sequential analysis.
      • Schmid S.
      • Kapfer B.
      • Heim M.
      • et al.
      Algorithm-guided goal-directed haemodynamic therapy does not improve renal function after major abdominal surgery compared to good standard clinical care: a prospective randomised trial.
      • Pearse R.M.
      • Harrison D.A.
      • MacDonald N.
      • et al.
      and the OPTIMISE Study Group
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      • Schol P.B.
      • Terink I.M.
      • Lance M.D.
      • Scheepers H.C.
      Liberal or restrictive fluid management during elective surgery: a systematic review and meta-analysis.
      • Wuethrich P.Y.
      • Burkhard F.C.
      • Thalmann G.N.
      • Stueber F.
      • Studer U.E.
      Restrictive deferred hydration combined with preemptive norepinephrine infusion during radical cystectomy reduces postoperative complications and hospitalization time: a randomized clinical trial.
      • Myles P.S.
      • Bellomo R.
      • Corcoran T.
      • et al.
      and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
      we assumed that the primary outcome would occur in about 35% of patients in the RNT group and that the GDHT would reduce the proportion of patients experiencing this primary outcome by one-third (from 35% to 22%). Therefore, a sample size of 200 patients in each group was needed for a 0.05 difference (2-sided) with a power of 80%. After recruiting the first 100 and then 200 and 300 patients, interim analyses were planned.
      Continuous variables were reported as mean with standard deviation (SD) or median with interquartile range and categorical variables as frequencies (%). Continuous variables were compared using a Student’s t test or Mann-Whitney U test and categorical variables using χ2 test or Fisher exact test. Standardized differences were used to assess imbalances between baseline characteristics between the 2 groups. Repeated-measures 2-way analysis of variance with Greenhouse-Geisser correction was used to estimate between group differences of intraoperative hemodynamic and respiratory parameters. Kaplan-Meier curves were built for survival probability up to 6 years after surgery.
      As the trial included 3 types of surgery and evolved over a 9-year period of time, a post hoc sensitivity analysis using generalized linear models was carried out to assess the effect of fluid therapy after adjusting for type of surgery and time period.
      All analyses were performed using STATA 14 software (Stata Corp, College Station, TX).

      Results

      A total of 558 subjects were assessed, and 401 were randomized between 2010 and 2018, with 200 allocated to GDHT and 201 to RNT algorithm; data from 198 and 196 patients were analyzed in the GDHT and RNT groups, respectively (Fig 2). Since 2014, given concerns raised by the Committee on Pharmacovigilance Risk Assessment of the European Medicines Agency regarding the use of 6% HES in septic, burned, and critically ill patients, cardiac output (CO) optimization and compensation of fluid losses were preferably performed with crystalloids, although the administration of HES was not formerly forbidden.
      Figure thumbnail gr2
      Fig 2Consolidated Standards of Reporting Trials flow diagram.
      Baseline demographic and clinical characteristics were similar between the 2 groups (Table I). Patients in the GDHT group included a higher proportion of visceral operations and lower proportion of urologic procedures than the RNT group, although the Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity scores were comparable. As reported in Table II, the duration of surgery and the conduct of anesthesia were comparable in both groups. A cardiac output monitor was used in 185 of patients (93%) in the RNT group. A fluid challenge was given in all GDHT patients (median of 4, range 2 to 10). The mean (SD) volumes of fluids infused intraoperatively were higher in the GDHT than in the RNT group (10.8 [4.0] vs 7.2 [2.0] mL·kg-1·h-1; P < .001), whereas the intraoperative doses of ephedrine, phenylephrine, and norepinephrine were lower. Intraoperatively, the time course of MAP and cardiac index was comparable in both groups whereas toward the end of surgery, heart rate and PPV increased in the RNT group and remained unchanged in the GDHT group (Fig 3). The control of ventilatory parameters and oxygenation indices did not differ between the 2 groups (Fig 4).
      Table IDemographic, clinical, biological, and surgical characteristics of patients
      VariablesGDHT groupRNT groupSTD
      (n = 196)(n = 198)
      Age, y65(14)64(12)0.1127
      Female sex71(36.2)71(35.9)0.0076
      Height, cm170(9)169(9)0.0294
      Weight, kg71.9(15.6)72.5(15.0)–0.0427
      BMI, kg/m224.9(5.1)25.2(4.6)–0.0599
      Comorbidities
      Hypertension97(49.5)85(42.9)0.1319
      Hypercholesterolemia60(30.6)43(21.7)0.2034
      Diabetes mellitus32(16.3)25(12.6)0.1053
      Vascular disease28(14.3)26(13.1)0.0336
      Coronary heart disease23(11.7)19(9.6)0.0693
      Heart insufficiency16(8.2)12(6.1)0.0819
      Arrhythmia15(7.7)16(8.1)0.0159
      COPD38(19.4)35(17.7)0.0440
      Current smoker74(37.8)64(32.3)0.1140
      Cancer surgery83(42.3)85(42.9)0.0118
      Renal dysfunction24(12.2)27(13.6)0.0415
      Revised cardiac risk index ≥277(39.2)73(36.8)0.0645
      ASA-PS classes III & IV98(50.0)85(42.9)0.1421
      POSSUM physiologic score15.6(7.1)15.5(6.1)0.0115
      POSSUM operative severity score15.2(3.3)14.7(3.8)0.1226
      Preoperative medications
      Beta-adrenergic blockers44(22.4)40(20.2)0.0549
      Calcium channel blockers33(16.8)16(8.1)0.2675
      Statins52(26.5)41(20.7)0.1374
      ACEI or ARB67(34.2)47(23.7)0.2318
      Antiplatelets53(27.0)44(22.2)0.1120
      Anticoagulants32(16.3)21(10.6)0.1682
      Corticoids1(0.5)5(2.5)0.1654
      Laboratory
      Hemoglobin, g/L120.7(18.1)121.3(18.3)–0.0292
      Creatinine, mmol/L80.6(22.2)85.9(74.8)–0.0968
      NT-pro-BNP, pg/mL69(35–159)56(29–128)0.1931
      Surgery
      Visceral surgery100(51.0)135(68.2)0.3552
      Urologic surgery43(21.7)20(10.1)0.3270
      Vascular surgery53(27.0)43(21.7)0.1242
      Data are presented as mean (SD), number (percentage) or median (interquartile range).
      ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ASA-PS, American Society of Anesthesiologists physical status; BMI, body mass index; COPD, chronic obstructive pulmonary disease; POSSUM, Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity; STD, standardized difference.
      Table IIAnesthetic and hemodynamic management
      VariableGDHT groupRNT groupSTD
      (n = 196)(n = 198)
      Anesthesia
      GA alone35(17.9)40(20.2)0.05976
      GA + epidural analgesia121(61.7)128(64.6)0.06040
      GA + spinal analgesia40(20.4)30(15.2)0.13781
      Inhalational anesthetics193(98.5)196(99.0)0.04649
      Total iv anesthesia3(1.5)2(1.0)0.04649
      Duration of anesthesia, min399.0(141.7)388.5(123.5)0.70791
      Duration of surgery, min313.1(135.8)297.5(122.7)0.12098
      Intraoperative variablesP value
      Fluid administration, mL4,868(2033)3,294(1,384)< .001
      Fluid administration, mL/kg/h10.8(4.0)7.2(2.0)< .001
      Crystalloids, mL4,478(2157)3,081(1,427)< .001
      Colloids
      Patients, n73(37.2)65(32.8)< .358
      χ2 tests.
      Volume, mL1,046(623)650(475)< .001
      Diuresis, mL658(527)501(315)< .001
      Ephedrine administration
       Patients, n145(74)154(78)< .378
      χ2 tests.
       Dose, mg18(12)22(13)< .002
      Phenylephrine administration
       Patients, n136(69)148(75)< .236
      χ2 tests.
       Dose, mg473(373)583(400)< .018
      Norepinephrine administration
       Patients, n94(48.0)109(55.1)< .159
      χ2 tests.
       Dose, mg791(568)993(790)< .041
      Blood transfusion
       Patients, n31(15.8)29(14.6)< .747
      χ2 tests.
       Packed red blood cells, unit2(1–3)2(1–2)< .160
      Wilcoxon rank sum tests.
      Hemoglobin end of surgery, g/L104.8(14.3)111.7(17.2)< .001
      Lactate end of surgery, mmol/L1.4(0.9)1.5(0.9)< .391
      Postoperative
      Fluids on first postoperative day, mL2,920(1,281)2,780(1,299)< .289
      Peak NT-pro-BNP, pg/L240(102–429)158(85–313)< .004
      Wilcoxon rank sum tests.
      Peak creatinine, mmol/L91.3(39.9)91.8(41.1)< .892
      Lowest hemoglobin, g/L96.9(14.2)98.3(15.4)< .373
      Postoperative blood transfusion
      Patients30(15.3)30(15.2)< .966
      χ2 tests.
      Packed red blood cells, unit1(1–2)2(1–2)< .226
      Wilcoxon rank sum tests.
      Maximal postoperative weight gain, kg4.9(2.6–7.1)3.4(1.1–5.9)< .001
      Wilcoxon rank sum tests.
      Data are presented as mean (SD), number (percentage) or median (interquartile range).
      Student’s t tests are used for statistical tests unless otherwise indicated.
      GA, general anesthesia; iv, intravenous; STD, standardized difference.
      χ2 tests.
      Wilcoxon rank sum tests.
      Figure thumbnail gr3
      Fig 3Intraoperative hemodynamic changes in patients receiving intraoperative GDHT compared to RNT. Repeated-measures 2-way analysis of variance with Greenhouse-Geisser correction was used to estimate the trend differences between the 2 groups.
      Figure thumbnail gr4
      Fig 4Respiratory parameters in patients receiving intraoperative GDHT compared to RNT. Repeated-measures 2-way analysis of variance with Greenhouse-Geisser correction was used to estimate the trend differences between the 2 groups.
      Postoperatively, the GDHT group presented higher peak values of NT-proBNP and larger weight gain compared with the RNT group.
      As shown in Table III, a total of 210 patients reached the composite postoperative mortality-morbidity end point: 113 patients (57.7%) in the GDHT group and 105 (53.0%) in the RNT group. Regarding the primary outcome, there was no difference among subgroups stratified according to sex, age, revised cardiac risk index, Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity score, as well as study time, types of fluids, surgery, and anesthesia (Fig 5). The incidence of any postoperative complications, as well as the rate of unplanned admission in the ICU and the hospital duration of stay, did not differ between the 2 groups.
      Table IIIPrimary and secondary endpoints
      VariableGDHT groupRNT groupP value
      (n = 196)(n = 198)
      Composite index of major complications
      Dindo-Clavien classification (grade ≥2): 30-d mortality, acute respiratory distress syndrome, pneumonia, atelectasis, arrhythmias, MINS, myocardial infarct, acute kidney injury, wound infection.
      113(57.7)105(53.0).356
      Mortality
       30-days mortality2(1.0)1(0.5).556
      Fisher exact tests.
      Postoperative pulmonary complications41(20.9)44(22.2).753
       Acute respiratory distress syndrome2(1.0)6(3.0).284
      Fisher exact tests.
       Reintubation1(0.5)1(0.5)1.000
      Fisher exact tests.
       Pneumonia7(3.6)12(6.1).249
       Atelectasis3417.3)33(16.7).857
      Cardiovascular complications58(29.6)57(28.8).861
       Myocardial infarct3(1.5)3(1.5)1.000
      Fisher exact tests.
       MINS51(26.0)44(22.2).378
       Arrhythmias5(2.6)4(2.0).750
      Fisher exact tests.
       Heart failure11(5.6)12(6.1).849
       Thromboembolism7(3.6)9(4.5).624
      Surgical complications
       Reoperation9(4.6)5(2.5).268
       Bleeding14(7.1)10(5.1).385
      Wound infection17(8.7)25(12.6).204
      Systemic inflammatory response syndrome32(16.3)36(18.2).626
      Acute kidney injury (≥ 25% eGFR decrease)48(24.5)37(18.7).161
      Postoperative delirium8(4.1)11(5.6).495
      Admission in ICU10(5.1)13(6.6).536
       Planned9(4.5)14(7.1).298
       Unplanned10(5.1)13(6.6).536
      Hospital duration of stay, d12(8–20)13(8–19).779
      Wilcoxon rank sum tests.
      Data are presented as number (percentage) or median (interquartile range).
      χ2 tests were used for statistical tests unless otherwise indicated.
      ARDS, acute respiratory distress syndrome; eGFR, estimated glomerular filtration rate; MINS, myocardial injury after noncardiac surgery.
      Dindo-Clavien classification (grade ≥2): 30-d mortality, acute respiratory distress syndrome, pneumonia, atelectasis, arrhythmias, MINS, myocardial infarct, acute kidney injury, wound infection.
      Fisher exact tests.
      Wilcoxon rank sum tests.
      Figure thumbnail gr5
      Fig 5Effect of intraoperative fluid therapy on the primary outcome in prespecified subgroups. GA, general anesthesia; POSSUM, Physiologic and Operative Severity Score for the Enumeration of Mortality and Morbidity; RCRI, revised cardiac risk index.
      Postoperative actuarial survival did not differ according to the intraoperative fluid strategy (Fig 6). The 30-day and 1-year overall mortality rates were respectively 1.0% and 11.7% in the GDHT group and 0.5% and 10.6% in the RNT group.
      Figure thumbnail gr6
      Fig 6Postoperative survival in patients receiving intraoperative GDHT compared to RNT. No significant difference between groups (log-rank test for equality of survivor functions, P = .523).
      The post hoc sensitivity analysis (supplemental file) demonstrated that adjusting for the study period and the type of surgery had no significant effect on the primary study endpoint (relative risk [RR] 1.06 [95% confidence interval (CI), 0.89–1.28] vs RR 1.09 [95% CI, 0.91–1.30] unadjusted) and any secondary study endpoints (pulmonary complications: RR 0.97 [95% CI, 0.67–1.41] vs RR 0.94 [95% CI, 0.65–1.37] unadjusted; cardiovascular complications: RR 1.01 [95% CI, 0.74–1.38] vs RR 1.03 [95% CI, 0.76–1.40] unadjusted; surgical complications: RR 1.06 [95% CI, 0.69–1.63] vs RR 0.98 [95% CI, 0.63–1.51] unadjusted; acute kidney injury: RR 1.19 [95% CI, 0.81–1.75] vs RR 1.31 [95% CI, 0.90–1.92] unadjusted).

      Discussion

      In this single center trial evaluating a 30-day composite morbidity index among patients undergoing major open abdominal surgery, we compared the intraoperative application of GDHT to RNT. Within 30 days after surgery, the composite morbidity index and the occurrence of any specific complication were similar in the 2 groups, as was postoperative survival.
      Perioperative fluid and cardiovascular drug therapies have been studied extensively, but the optimal strategy remains controversial and uncertain given the heterogeneity of patient populations and different surgical approaches, along with variable tissue injuries (open and laparoscopic procedures), different algorithms for fluid therapy, and poorly controlled conditions in the usual-care and liberal groups.
      • Rahbari N.N.
      • Zimmermann J.B.
      • Schmidt T.
      • Koch M.
      • Weigand M.A.
      • Weitz J.
      Meta-analysis of standard, restrictive and supplemental fluid administration in colorectal surgery.
      ,
      • Ripolles-Melchor J.
      • Chappell D.
      • Espinosa A.
      • et al.
      Perioperative fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part I: Physiological background.
      When compared with a liberal fluid regimen, both GDHT and RNT have shown favorable effects on early postoperative morbidity and hospital duration of stay.
      • Schol P.B.
      • Terink I.M.
      • Lance M.D.
      • Scheepers H.C.
      Liberal or restrictive fluid management during elective surgery: a systematic review and meta-analysis.
      ,
      • Feng S.
      • Yang S.
      • Xiao W.
      • Wang X.
      • Yang K.
      • Wang T.
      Effects of perioperative goal-directed fluid therapy combined with the application of alpha-1 adrenergic agonists on postoperative outcomes: a systematic review and meta-analysis.
      The few small trials directly comparing GDHT with RNT did not demonstrate any significant differences regarding postoperative clinical outcome.
      • Zhang J.
      • Qiao H.
      • He Z.
      • Wang Y.
      • Che X.
      • Liang W.
      Intraoperative fluid management in open gastrointestinal surgery: goal-directed versus restrictive.
      • Srinivasa S.
      • Taylor M.H.
      • Singh P.P.
      • Yu T.C.
      • Soop M.
      • Hill A.G.
      Randomized clinical trial of goal-directed fluid therapy within an enhanced recovery protocol for elective colectomy.
      • Phan T.D.
      • D'Souza B.
      • Rattray M.J.
      • Johnston M.J.
      • Cowie B.S.
      A randomised controlled trial of fluid restriction compared to oesophageal Doppler-guided goal-directed fluid therapy in elective major colorectal surgery within an Enhanced Recovery After Surgery program.
      • Brandstrup B.
      • Svendsen P.E.
      • Rasmussen M.
      • et al.
      Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance?.
      Likewise, in the context of ERAS, recent trials comparing GDHT with a more evidence-based fluid approach also failed to replicate the positive results reported in earlier studies where GDHT was compared to a liberal strategy that often resulted in fluid overload.
      • Schmid S.
      • Kapfer B.
      • Heim M.
      • et al.
      Algorithm-guided goal-directed haemodynamic therapy does not improve renal function after major abdominal surgery compared to good standard clinical care: a prospective randomised trial.
      ,
      • Corcoran T.
      • Rhodes J.E.
      • Clarke S.
      • Myles P.S.
      • Ho K.M.
      Perioperative fluid management strategies in major surgery: a stratified meta-analysis.
      A recent systematic review of 112 RCTs on perioperative GDHT concluded that a meta-analysis was inappropriate, given the overall high risk of bias in many trials, large heterogeneity in patients populations, different hemodynamic devices and target physiologic endpoints, and the variable type and timing of interventions (type of fluids, with or without inotropes/vasopressor).
      • Kaufmann T.
      • Clement R.P.
      • Scheeren T.W.L.
      • Saugel B.
      • Keus F.
      • van der Horst I.C.C.
      Perioperative goal-directed therapy: A systematic review without meta-analysis.
      Furthermore, merging all data from earlier trials and more recent trials into one pooled intervention effect estimate is highly questionable owing to the recent advancements in perioperative care (eg, protective lung ventilation) that have led to better clinical outcomes in both the intervention and control groups.
      In contrast with previous trials, the current study is the largest ever conducted involving exclusively high-risk procedures (open laparotomy, duration ≥120 minutes) and comparing 2 individualized active interventions (GDHT versus RNT), one aiming to optimize cardiac output and the other to match fluid administration with ongoing fluid losses while controlling hemodynamics with vasopressors.
      Although we did not officially adhere to an ERAS program, some key processes were already implemented, namely preoperative patient optimization, intraoperative lung protective ventilation, low-dose opiate anesthesia, and standardized fast-track postoperative care.
      In both groups, treatment goals were flexibly defined to match with evidence-based scientific knowledge and to avoid local practice misalignment. Before the start of this study, cardiac output monitors and arterial pressure wave analysis with PPV were routinely used in our hospital during high-risk surgery, and anesthetists were all trained to identify low-flow conditions and to correct relative hypovolemia resulting from anesthesia- and inflammation-induced vasorelaxation. Therefore, hemodynamic parameters reflecting blood flow and volume responsiveness (cardiac output and PPV) were available in the majority of RNT patients and in all GDHT patients for individualized administration of fluids or/and vasopressors to optimize intravascular volume and blood flow based on the Franck-Starling relationship.
      Restricting fluid administration in the RNT group was associated with increased vasopressor requirement and resulted in lower weight gain. In the GDHT group, the higher volume of intraoperative fluids resulted in lower PPV along with greater postoperative weight gain and higher blood NT-proBNP values compared with the RNT. Besides surgery-mediated inflammation, anesthetic agents and neuraxial analgesia led to reduce vascular muscular tone within the arterial and venous compartment and, in turn, to reduce venous return and to lower the arterial pressure. Consequently, fluids infused in GDHT protocols were partly redistributed within the unstressed venous compartment, the remaining part contributing to maximize cardiac output.
      • Gelman S.
      • Bigatello L.
      The physiologic basis for goal-directed hemodynamic and fluid therapy: the pivotal role of the venous circulation.
      Alternatively, administration of vasopressors to stabilize the unstressed blood volume in the RNT group represented a sound physiologically evidence-based approach to maintain vascular venous tone and avoid fluid overload while promoting optimal blood flow. Notably, dynamic indices such as PPV are known to be unreliable to predict fluid responsiveness under vasopressor treatment, owing to alteration in venous capacitance and compliance.
      • Bouchacourt J.P.
      • Riva J.A.
      • Grignola J.C.
      The increase of vasomotor tone avoids the ability of the dynamic preload indicators to estimate fluid responsiveness.
      Our standardized protocols for fluids and hemodynamic management differed from those used in 3 multicenter trials
      • Calvo-Vecino J.M.
      • Ripolles-Melchor J.
      • Mythen M.G.
      • et al.
      and the FEDORA Trial Investigators Group
      Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
      ,
      • Pearse R.M.
      • Harrison D.A.
      • MacDonald N.
      • et al.
      and the OPTIMISE Study Group
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      ,
      • Myles P.S.
      • Bellomo R.
      • Corcoran T.
      • et al.
      and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
      that included patients with similar preoperative risk profiles but with less extensive surgical tissue trauma given the shorter duration of abdominal procedures and the higher rates of laparoscopic surgeries.
      In the OPTIMIZE
      • Pearse R.M.
      • Harrison D.A.
      • MacDonald N.
      • et al.
      and the OPTIMISE Study Group
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      and FEDORA
      • Calvo-Vecino J.M.
      • Ripolles-Melchor J.
      • Mythen M.G.
      • et al.
      and the FEDORA Trial Investigators Group
      Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
      trials, patients in the GDHT group were all equipped with a cardiac output monitor to guide fluid loading with colloids to maximize stroke volume, whereas patients in the usual-care group had no cardiac output monitor and were treated according to undefined local practices (OPTIMIZE) or received a continuous infusion of balanced crystalloids at 3 to 5 mL/kg/h for laparoscopic surgery or 5 to 7 mL/kg/h for open procedures (FEDORA trial). In the RELIEF trial,
      • Myles P.S.
      • Bellomo R.
      • Corcoran T.
      • et al.
      and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
      neither a CO monitor nor dynamic indices of fluid responsiveness were available, and a “restrictive” fluid regimen designed to provide “near-zero fluid balance” was compared to a liberal fluid regimen with crystalloids infused at a rate of 8 to 11 mL/kg/h. The GDHT was associated with a nonsignificant decrease in postoperative mortality-morbidity index in the OPTIMIZE trial
      • Pearse R.M.
      • Harrison D.A.
      • MacDonald N.
      • et al.
      and the OPTIMISE Study Group
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      and with fewer complications only in patients undergoing laparoscopic surgeries (not laparotomies) in the FEDORA trial.
      • Calvo-Vecino J.M.
      • Ripolles-Melchor J.
      • Mythen M.G.
      • et al.
      and the FEDORA Trial Investigators Group
      Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
      In contrast, the fixed-rate of intraoperative fluid regimen in the RELIEF trial was associated with comparable disability-free survival at 1 year, although a higher rate of acute kidney injury was experienced in patients treated with the restrictive regimen.
      • Myles P.S.
      • Bellomo R.
      • Corcoran T.
      • et al.
      and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
      Taken together, these findings indicate that a single algorithm for fluids and drug administration does not fit in all perioperative situations. The optimal hemodynamic goals remain unclear, depending on a patient’s baseline physiological conditions and variable responses to surgical stress that require individualized adjustments to fit the metabolic needs. Maximizing intraoperative CO with GDHT does not represent the sole method of improving postoperative clinical outcome in most patients with a low-risk profile and undergoing minimally invasive surgery. However, in patients with limited cardio-respiratory reserve and in unstable hemodynamic conditions, the GDHT likely represents a suitable approach by targeting CO and oxygen delivery to match the individual patient requirements while maintaining circulatory volume and arterial blood pressure using inotropes or vasopressors. In line with this proposal, the 2018 ERAS guidelines in elective colorectal surgery have been modified by strongly recommending GDHT only in high-risk patients, not in “all patients” as ascertained in the 2012 guidelines.
      • Gustafsson U.O.
      • Scott M.J.
      • Hubner M.
      • et al.
      Guidelines for Perioperative Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations: 2018.
      Our trial has certain limitations. First, the generalization of our findings is limited owing to the single-center settings and the inclusion of patients undergoing extensive, open intra-abdominal procedures. Hence, our results could not be translated to lesser invasive and laparoscopic procedures that elicit an attenuated stress response. Second, the trial intervention dictated the administration of fluids only during the intraoperative period when most fluids were administered, whereas the prescription of fluids in the PACU or ICU were left at the discretion of the attending physicians who were blinded to the group assignment. Third, the event rate of major adverse events was higher than expected, and it was likely related to the inclusion of higher-risk open laparotomies with prolonged duration of anesthesia and mechanical ventilation, while patient age and comorbidity burden were comparable to those reported in recent trials.
      • Calvo-Vecino J.M.
      • Ripolles-Melchor J.
      • Mythen M.G.
      • et al.
      and the FEDORA Trial Investigators Group
      Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
      ,
      • Pearse R.M.
      • Harrison D.A.
      • MacDonald N.
      • et al.
      and the OPTIMISE Study Group
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      ,
      • Wuethrich P.Y.
      • Burkhard F.C.
      • Thalmann G.N.
      • Stueber F.
      • Studer U.E.
      Restrictive deferred hydration combined with preemptive norepinephrine infusion during radical cystectomy reduces postoperative complications and hospitalization time: a randomized clinical trial.
      ,
      • Myles P.S.
      • Bellomo R.
      • Corcoran T.
      • et al.
      and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
      Fourth, the discharge criteria were not predefined, which can limit the interpretation of hospital duration of stay. This secondary endpoint is not only influenced by objective criteria of functional recovery but also by structural, social, and logistical aspects inherent to the patient’s environment and the local health care system. Finally, anesthetists were allowed to administer either crystalloids or colloids to replace blood losses and optimize cardiac output despite controversy surrounding the potential adverse effects of HES in critically ill patients.
      • Zarychanski R.
      • Abou-Setta A.M.
      • Turgeon A.F.
      • et al.
      Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis.
      ,
      • Raiman M.
      • Mitchell C.G.
      • Biccard B.M.
      • Rodseth R.N.
      Comparison of hydroxyethyl starch colloids with crystalloids for surgical patients: A systematic review and meta-analysis.
      From experimental and recent clinical studies, we can expect a reduction in the overall amount of fluid infused if only colloids are administered for volume loading in GDHT patients.
      In conclusion, a goal-directed hemodynamic strategy and a restrictive normovolemic regimen were associated with comparable effects on the incidence of moderate or severe complications in patients undergoing high-risk open intra-abdominal surgery.

      Conflict of interest/Disclosure

      ML received travel funding for lectures from Getinge and Fresenius Kabi. JD, SL, PG, CE, RS, GB, and ES claim no conflict of interest.

      Funding/Support

      The trial was supported by an institutional grant from the department of anesthesiology, pharmacology intensive care, and emergency medicine at the University Hospital of Geneva (Geneva, Switzerland). The funding bodies had no role in the design and conduct of the study; data collection, management, analysis, or interpretation; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

      Acknowledgments

      The authors would like to thank all of the administrative staff who were involved in the patients’ screening and the clinical and surgical staff who provided care to all the patients included in this study.

      Supplementary materials

      References

        • Shin C.H.
        • Long D.R.
        • McLean D.
        • et al.
        Effects of intraoperative fluid management on postoperative outcomes: A hospital registry study.
        Ann Surg. 2018; 267: 1084-1092
        • Eng O.S.
        • Dumitra S.
        • O'Leary M.
        • et al.
        Association of fluid administration with morbidity in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
        JAMA Surg. 2017; 152: 1156-1160
        • Chawla L.S.
        • Ince C.
        • Chappell D.
        • et al.
        and the ADQI XII Fluids Workgroup. Vascular content, tone, integrity, and haemodynamics for guiding fluid therapy: a conceptual approach.
        Br J Anaesth. 2014; 113: 748-755
        • Kulemann B.
        • Timme S.
        • Seifert G.
        • et al.
        Intraoperative crystalloid overload leads to substantial inflammatory infiltration of intestinal anastomoses-a histomorphological analysis.
        Surgery. 2013; 154: 596-603
        • Strunden M.S.
        • Heckel K.
        • Goetz A.E.
        • Reuter D.A.
        Perioperative fluid and volume management: physiological basis, tools and strategies.
        Ann Intensive Care. 2011; 1: 2
        • Chan S.T.
        • Kapadia C.R.
        • Johnson A.W.
        • Radcliffe A.G.
        • Dudley H.A.
        Extracellular fluid volume expansion and third space sequestration at the site of small bowel anastomoses.
        Br J Surg. 1983; 70: 36-39
        • Voldby A.W.
        • Brandstrup B.
        Fluid therapy in the perioperative setting-a clinical review.
        J Intensive Care. 2016; 4: 27
        • Makaryus R.
        • Miller T.E.
        • Gan T.J.
        Current concepts of fluid management in enhanced recovery pathways.
        Br J Anaesth. 2018; 120: 376-383
        • Carmichael J.C.
        • Keller D.S.
        • Baldini G.
        • et al.
        Clinical Practice Guidelines for Enhanced Recovery After Colon and Rectal Surgery from the American Society of Colon and Rectal Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons.
        Dis Colon Rectum. 2017; 60: 761-784
        • Miller T.E.
        • Myles P.S.
        Perioperative fluid therapy for major surgery.
        Anesthesiology. 2019; 130: 825-832
        • Sun Y.
        • Chai F.
        • Pan C.
        • Romeiser J.L.
        • Gan T.J.
        Effect of perioperative goal-directed hemodynamic therapy on postoperative recovery following major abdominal surgery-a systematic review and meta-analysis of randomized controlled trials.
        Crit Care. 2017; 21: 141
        • Calvo-Vecino J.M.
        • Ripolles-Melchor J.
        • Mythen M.G.
        • et al.
        • and the FEDORA Trial Investigators Group
        Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial).
        Br J Anaesth. 2018; 120: 734-744
        • Giglio M.
        • Dalfino L.
        • Puntillo F.
        • Brienza N.
        Hemodynamic goal-directed therapy and postoperative kidney injury: an updated meta-analysis with trial sequential analysis.
        Crit Care. 2019; 23: 232
        • Schmid S.
        • Kapfer B.
        • Heim M.
        • et al.
        Algorithm-guided goal-directed haemodynamic therapy does not improve renal function after major abdominal surgery compared to good standard clinical care: a prospective randomised trial.
        Crit Care. 2016; 20: 50
        • Pearse R.M.
        • Harrison D.A.
        • MacDonald N.
        • et al.
        • and the OPTIMISE Study Group
        Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
        JAMA. 2014; 311: 2181-2190
        • Schol P.B.
        • Terink I.M.
        • Lance M.D.
        • Scheepers H.C.
        Liberal or restrictive fluid management during elective surgery: a systematic review and meta-analysis.
        J Clin Anesth. 2016; 35: 26-39
        • Wuethrich P.Y.
        • Burkhard F.C.
        • Thalmann G.N.
        • Stueber F.
        • Studer U.E.
        Restrictive deferred hydration combined with preemptive norepinephrine infusion during radical cystectomy reduces postoperative complications and hospitalization time: a randomized clinical trial.
        Anesthesiology. 2014; 120: 365-377
        • Myles P.S.
        • Bellomo R.
        • Corcoran T.
        • et al.
        and the Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Austrialian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy for major abdominal surgery.
        N Engl J Med. 2018; 378: 2263-2274
        • Zhang J.
        • Qiao H.
        • He Z.
        • Wang Y.
        • Che X.
        • Liang W.
        Intraoperative fluid management in open gastrointestinal surgery: goal-directed versus restrictive.
        Clinics (Sao Paulo). 2012; 67: 1149-1155
        • Srinivasa S.
        • Taylor M.H.
        • Singh P.P.
        • Yu T.C.
        • Soop M.
        • Hill A.G.
        Randomized clinical trial of goal-directed fluid therapy within an enhanced recovery protocol for elective colectomy.
        Br J Surg. 2013; 100: 66-74
        • Phan T.D.
        • D'Souza B.
        • Rattray M.J.
        • Johnston M.J.
        • Cowie B.S.
        A randomised controlled trial of fluid restriction compared to oesophageal Doppler-guided goal-directed fluid therapy in elective major colorectal surgery within an Enhanced Recovery After Surgery program.
        Anaesth Intensive Care. 2014; 42: 752-760
        • Brandstrup B.
        • Svendsen P.E.
        • Rasmussen M.
        • et al.
        Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance?.
        Br J Anaesth. 2012; 109: 191-199
        • Licker M.
        • Ellenberger C.
        • Cartier V.
        • et al.
        Impact of anesthesia technique on the incidence of major complications after open aortic abdominal surgery: a cohort study.
        J Clin Anesth. 2013; 25: 296-308
        • Biccard B.M.
        • Scott D.J.A.
        • Chan M.T.V.
        • et al.
        Myocardial injury after noncardiac surgery (MINS) in vascular surgical patients: A prospective observational cohort study.
        Ann Surg. 2018; 268: 357-363
        • Writing Committee for the V.S.I.
        • Devereaux P.J.
        • Biccard B.M.
        • et al.
        Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery.
        JAMA. 2017; 317: 1642-1651
        • Dindo D.
        • Demartines N.
        • Clavien P.A.
        Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
        Ann Surg. 2004; 240: 205-213
        • Rahbari N.N.
        • Zimmermann J.B.
        • Schmidt T.
        • Koch M.
        • Weigand M.A.
        • Weitz J.
        Meta-analysis of standard, restrictive and supplemental fluid administration in colorectal surgery.
        Br J Surg. 2009; 96: 331-341
        • Ripolles-Melchor J.
        • Chappell D.
        • Espinosa A.
        • et al.
        Perioperative fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part I: Physiological background.
        Rev Esp Anestesiol Reanim. 2017; 64: 328-338
        • Feng S.
        • Yang S.
        • Xiao W.
        • Wang X.
        • Yang K.
        • Wang T.
        Effects of perioperative goal-directed fluid therapy combined with the application of alpha-1 adrenergic agonists on postoperative outcomes: a systematic review and meta-analysis.
        BMC Anesthesiol. 2018; 18: 113
        • Corcoran T.
        • Rhodes J.E.
        • Clarke S.
        • Myles P.S.
        • Ho K.M.
        Perioperative fluid management strategies in major surgery: a stratified meta-analysis.
        Anesth Analg. 2012; 114: 640-651
        • Kaufmann T.
        • Clement R.P.
        • Scheeren T.W.L.
        • Saugel B.
        • Keus F.
        • van der Horst I.C.C.
        Perioperative goal-directed therapy: A systematic review without meta-analysis.
        Acta Anaesthesiol Scand. 2018; 62: 1340-1355
        • Gelman S.
        • Bigatello L.
        The physiologic basis for goal-directed hemodynamic and fluid therapy: the pivotal role of the venous circulation.
        Can J Anaesth. 2018; 65: 294-308
        • Bouchacourt J.P.
        • Riva J.A.
        • Grignola J.C.
        The increase of vasomotor tone avoids the ability of the dynamic preload indicators to estimate fluid responsiveness.
        BMC Anesthesiol. 2013; 13: 41
        • Gustafsson U.O.
        • Scott M.J.
        • Hubner M.
        • et al.
        Guidelines for Perioperative Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations: 2018.
        World J Surg. 2019; 43: 659-695
        • Zarychanski R.
        • Abou-Setta A.M.
        • Turgeon A.F.
        • et al.
        Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis.
        JAMA. 2013; 309: 678-688
        • Raiman M.
        • Mitchell C.G.
        • Biccard B.M.
        • Rodseth R.N.
        Comparison of hydroxyethyl starch colloids with crystalloids for surgical patients: A systematic review and meta-analysis.
        Eur J Anaesthesiol. 2016; 33: 42-48