Clinical trial NCT01424150: REstrictive Versus LIbEral Fluid Therapy in Major Abdominal Surgery: RELIEF Study
Official title: Restrictive Versus Liberal Fluid Therapy in Major Abdominal Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Abdominal Surgery
Keywords: Postoperative fluid
surgery
anaesthesia
fluid
mortality
morbidity
Lead sponsor: Bayside Health
Sponsor class: OTHER_GOV
Collaborators: name: National Health and Medical Research Council, Australia
First posted: 2011-08-26
Enrollment: 3000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: The optimal fluid regimen, haemodynamic (or other) targets and fluid choice (colloid or crystalloid) for patients undergoing major surgery are based on rationales that are not supported by strong evidence. Practices vary substantially, guidelines are vague, small trials and meta-analyses are contradictory. The strongest and most consistent evidence, and biological plausibility because of tissue edema, supports a restrictive fluid strategy. But other evidence supports goal-directed therapy, requiring additional IV fluid. There is no good evidence that use and choice of colloids improves outcome. RELIEF will study the effects of fluid restriction, and the possible effect-modification of goal-directed therapy and colloids. The first will be randomly assigned; the latter will be measured covariates dictated by local practices and beliefs.

Study Hypotheses A restrictive fluid regimen for adults undergoing major abdominal surgery leads to reduced complications and improved disability-free survival when compared with a liberal fluid regimen.

Secondary hypothesis: The effects of fluid restriction are similar whether or not goal-directed therapy is used (assessed as a statistical test of interaction). A restrictive fluid regimen will reduce a composite of 30-day septic complications and mortality.

Detailed description: The investigators have completed a pilot study of 82 subjects to test the feasibility of the trial (2011), and are currently doing a cost-effectiveness substudy (2012-13)

1. AIM OF THE TRIAL To investigate the effectiveness of fluid restriction (vs. liberal), and the possible effect-modification of goal-directed therapy (eg. oesophageal Doppler, Flotrac®). The first will be randomly assigned; the latter will be measured covariates according to local practices and beliefs.

The optimal fluid regimen and haemodynamic (or other) targets for patients undergoing major surgery are based on rationales that are not supported by strong evidence. Practices vary substantially; guidelines are vague, small trials and meta-analyses are contradictory. The strongest and most consistent evidence, and biological plausability regarding tissue oedema, supports a restrictive fluid strategy. There is less (and more contradictory) evidence supporting goal-directed therapy using a flow-directed device and/or dopexamine, and use and choice of colloids. A large, definitive clinical trial evaluating perioperative fluid replacement in major surgery is required.

Study Hypotheses A restrictive fluid regimen for adults undergoing major abdominal surgery leads to reduced complications and improved disability-free survival when compared with a liberal fluid regimen.

Secondary hypotheses: The effects of fluid restriction are similar whether or not goal-directed therapy is used (assessed as a statistical test of interaction). A restrictive fluid regimen will reduce a composite of 30-day septic complications and mortality.

Eligibility criteria: Inclusion criteria:

1. Adults (≥18 years) undergoing elective major surgery and providing informed consent
2. All types of open or lap-assisted abdominal or pelvic surgery with an expected duration of at least 2 hours, and an expected hospital stay of at least 3 days (for example, oesophagectomy, gastrectomy, pancreatectomy, colectomy, aortic or aorto-femoral vascular surgery, nephrectomy, cystectomy, open prostatectomy, radical hysterectomy, and abdominal incisional hernia repair)
3. At increased risk of postoperative complications, defined as at least one of the following criteria:

   * age ≥70 years
   * known or documented history of coronary artery disease
   * known or documented history of heart failure
   * diabetes currently treated with an oral hypoglycaemic agent and/or insulin
   * preoperative serum creatinine \>200 µmol/L (\>2.8 mg/dl)
   * morbid obesity (BMI ≥35 kg/m²)
   * preoperative serum albumin \<30 g/L
   * anaerobic threshold (if done) \<12 mL/kg/min
   * or two or more of the following risk factors:

     * ASA 3 or 4
     * chronic respiratory disease
     * obesity (BMI 30-35 kg/m²)
     * aortic or peripheral vascular disease
     * preoperative haemoglobin \<100 g/L
     * preoperative serum creatinine 150-199 µmol/L (\>1.7 mg/dl)
     * anaerobic threshold (if done) 12-14 mL/kg/min

Exclusion Criteria

1. Urgent or time-critical surgery
2. ASA physical status 5 - such patients are not expected to survive with or without surgery, and their underlying illness is expected to have an overwhelming effect on outcome (irrespective of fluid therapy)
3. Chronic renal failure requiring dialysis
4. Pulmonary or cardiac surgery - different pathophysiology, and thoracic surgery typically have strict fluid restrictions
5. Liver resection - most units have strict fluid/CVP limits in place and won't allow randomisation
6. Minor or intermediate surgery, such as laparoscopic cholecystectomy, transurethral resection of the prostate, inguinal hernia repair, splenectomy, closure of colostomy - each of these are typically "minor" surgery with minimal IV fluid requirements, generally low rates of complications and mostly very good survival.

Primary outcomes:
measure: Disability-free Survival
timeFrame: 1 year postoperative
Secondary outcomes:
measure: Death
timeFrame: 90 days, then up to 12 months after surgery
measure: Composite Septic Outcome or Death
timeFrame: 30 days postoperative
measure: Sepsis
timeFrame: 30 days postoperative
measure: Surgical Site Infection
timeFrame: 30 days postoperative
measure: Pneumonia
timeFrame: 30 Days postoperative
measure: Acute Kidney Injury
timeFrame: 30 days postoperative
measure: Pulmonary Oedema
timeFrame: 30 days postoperative
measure: Total Duration of Time Spend in the ICU or HDU (in Days)
timeFrame: 30 day postoperative
measure: Hospital Stay
timeFrame: 30 days postoperative
measure: Quality of Recovery
timeFrame: days 3
measure: Anastomotic Leak
timeFrame: 30 days postoperative
measure: C-reactive Protein
timeFrame: Day 3 postoperative
measure: mmol/L
timeFrame: 24 hours post surgery
measure: Total ICU Stay and Unplanned ICU Admission to ICU
timeFrame: 30 days postoperative
Other outcomes:
measure: Preplanned Substudies (for Mechanistic Understanding)
timeFrame: 5 years
Locations:
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
Study officials:
affiliation: Alfred Hospital, Monash University
name: Paul S Myles, MB.BS, MPH, MD, FANZCA
role: STUDY_CHAIR
References:
citation: Bihari S, Dixon DL, Painter T, Myles P, Bersten AD. Understanding Restrictive Versus Liberal Fluid Therapy for Major Abdominal Surgery Trial Results: Did Liberal Fluids Associate With Increased Endothelial Injury Markers? Crit Care Explor. 2021 Jan 25;3(1):e0316. doi: 10.1097/CCE.0000000000000316. eCollection 2021 Jan.
citation: Gurunathan U, Rapchuk IL, Dickfos M, Larsen P, Forbes A, Martin C, Leslie K, Myles PS. Association of Obesity With Septic Complications After Major Abdominal Surgery: A Secondary Analysis of the RELIEF Randomized Clinical Trial. JAMA Netw Open. 2019 Nov 1;2(11):e1916345. doi: 10.1001/jamanetworkopen.2019.16345.
citation: Myles PS, McIlroy DR, Bellomo R, Wallace S. Importance of intraoperative oliguria during major abdominal surgery: findings of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery trial. Br J Anaesth. 2019 Jun;122(6):726-733. doi: 10.1016/j.bja.2019.01.010. Epub 2019 Feb 16.
citation: Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, Christophi C, Leslie K, McGuinness S, Parke R, Serpell J, Chan MTV, Painter T, McCluskey S, Minto G, Wallace S; Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. N Engl J Med. 2018 Jun 14;378(24):2263-2274. doi: 10.1056/NEJMoa1801601. Epub 2018 May 9.
citation: Myles P, Bellomo R, Corcoran T, Forbes A, Wallace S, Peyton P, Christophi C, Story D, Leslie K, Serpell J, McGuinness S, Parke R; Australian and New Zealand College of Anaesthetists Clinical Trials Network, and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Restrictive versus liberal fluid therapy in major abdominal surgery (RELIEF): rationale and design for a multicentre randomised trial. BMJ Open. 2017 Mar 3;7(3):e015358. doi: 10.1136/bmjopen-2016-015358.