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REstrictive Versus LIbEral Fluid Therapy in Major Abdominal Surgery: RELIEF Study (RELIEF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Bayside Health
Sponsor:
Collaborator:
Australian and New Zealand College of Anaesthetists Clinical Trials Network
Information provided by (Responsible Party):
Bayside Health
ClinicalTrials.gov Identifier:
NCT01424150
First received: August 25, 2011
Last updated: August 3, 2016
Last verified: August 2016
  Purpose

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.


Condition Intervention Phase
Abdominal Surgery
Other: Liberal fluid therapy
Other: Restrictive fluid therapy
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: Restrictive Versus Liberal Fluid Therapy in Major Abdominal Surgery

Further study details as provided by Bayside Health:

Primary Outcome Measures:
  • Disability-free survival [ Time Frame: 1 year postoperative ] [ Designated as safety issue: No ]
    Disability-free survival up to 1 year: survival and freedom from disability. The latter is defined as a persistent (≥6 months) reduction in health status as measured by a 12-item version of WHODAS score of at least 24 points, reflecting a disability level of at least 25% and being the threshold point between "disabled" and "not disabled" as per WHO guidelines. Disability will be assessed by the participant, but if unable then we will use the proxy's report. The date of onset of new disability will be recorded. Further details are provided in the Procedures Manual and the Statistical Analysis Plan.


Secondary Outcome Measures:
  • Death [ Time Frame: 90 days, then up to 12 months after surgery ] [ Designated as safety issue: No ]
  • A composite (pooled) and individual septic complications: sepsis, surgical site infection, anastomotic leak, and pneumonia [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    As per individual definitions

  • Sepsis [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    using Centers for Disease Control and Prevention (CDC) with National Healthcare Safety Network (NHSN) criteria, two or more features of the systematic inflammatory response syndrome (SIRS) plus evidence of a source or site of infection (can be positive blood culture or purulence from any site)

  • Surgical site infection [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    using CDC criteria (http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf):

  • Pneumonia [ Time Frame: 30 Days postoperative ] [ Designated as safety issue: No ]

    The presence of new and/or progressive pulmonary infiltrates on chest radiograph plus two or more of the following:

    1. Fever ≥ 38.5°C or postoperative hypothermia <36°C
    2. Leukocytosis ≥ 12,000 WBC/mm3 or leukopenia < 4,000 WBC/mm3
    3. Purulent sputum and/or
    4. New onset or worsening cough or dyspnoea.

  • Acute kidney injury [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    according to The Kidney Disease: Improving Global Outcomes (KDIGO) group criteria, but not urine output - for Stage 2 or worse AKI defined as at least 2-fold increase in creatinine, or estimated GFR decrease >50%.(73) We also plan to report renal replacement therapy up to 90 days after surgery. Because a restrictive IV fluid regimen may artificially elevate serum creatinine due to a smaller dilutional effect from less IV fluids, we therefore calculated adjusted creatinine by first estimating the volume of distribution for creatinine as equal to total body water (assumed to be 60% of body weight, expressed in mL), and assuming that 50% of IV fluid was still accumulated as tissue oedema at the time of postoperative creatinine measurements.(74, 75) That is: adjusted Cr = SCr x (1+ [0.5 x fluid balance/total body water])

  • Pulmonary oedema [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    respiratory distress or impaired oxygenation AND radiological evidence of pulmonary oedema

  • Total ICU stay and mechanical ventilation time [ Time Frame: 30 day postoperative ] [ Designated as safety issue: No ]
    including initial ICU admission and readmission times

  • Hospital stay [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    from the start (date, time) of surgery until actual hospital discharge

  • Quality of recovery [ Time Frame: day 3 and day 30 postoperative ] [ Designated as safety issue: No ]
    Quality of recovery score

  • Anastomotic leak [ Time Frame: 30 days postoperative ] [ Designated as safety issue: No ]
    A defect of the intestinal wall at the anastomotic site (including suture and staple lines of neorectal reservoirs) leading to a communication between the intra- an extra luminal compartments.

  • Inflammation [ Time Frame: Day 3 postoperative ] [ Designated as safety issue: No ]
    plasma C-reactive protein (CRP, using site-specific assay) concentration on Day 3

  • Tissue perfusion [ Time Frame: 24 hours post surgery ] [ Designated as safety issue: No ]
    peak serum lactate within 24 hours of surgery

  • Any blood transfusion [ Time Frame: From surgery to Day 3 postoperative ] [ Designated as safety issue: No ]
    including red cell, fresh frozen plasma or platelet transfusion, from the commencement of surgery

  • Unplanned ICU stay [ Time Frame: 30 days postoperative ] [ Designated as safety issue: Yes ]
    additive, including initial ICU admission and readmission times up to Day 30


Other Outcome Measures:
  • Preplanned substudies (for mechanistic understanding) [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

    We plan several substudies (to be funded from other sources), each of which will have a separate protocol and authorship plan (using an expanded list of contributors). Additional blood tests and other investigations will be done at selected hospitals according to local interest and expertise.

    1. Cost-effectiveness, to include hospital stay and complications as we have done previously (80)
    2. Hyperchloraemic acidosis (to measure strong ion difference, Cl-, lactate, albumin …)
    3. Pulmonary oedema (to measure FiO2/PaO2 ratio, CT/CXR-confirmed atelectasis …)
    4. Coagulopathy (to measure blood loss, plt count, fibrinogen, INR, APTT, Hb flux, transfusion …)
    5. Sepsis (to measure fever, WCC, CRP …).


Estimated Enrollment: 3000
Study Start Date: July 2013
Estimated Study Completion Date: November 2018
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Liberal
At the commencement of surgery a bolus of Hartmann's balanced salt crystalloid 10 ml/kg followed by 8 ml/kg/h will be administered until the end of surgery. A maintenance infusion will then continue at 1.5 ml/kg/h, for at least 24 hours, but this can be reduced postoperatively if there is evidence of fluid overload and no hypotension, and increased if there is evidence of hypovolaemia or hypotension. Alternative fluid types (crystalloid, dextrose, colloid) and electrolyte supplements will be allowed postoperatively in order to account for local preferences and patient biochemistry, for which we will collect data.
Other: Liberal fluid therapy
Liberal protocol group is designed to provide approximately 6.0L per day.
Experimental: Restrictive
Will provide less than 2.0 L water and 120 mmol sodium per day. Induction of anaesthesia will limit IV bolus fluid to ≤5 ml/kg; no other IV fluids will be used at the commencement of surgery (unless indicated by goal-directed device [see below]). Hartmann's balanced salt crystalloid 5 ml/kg/h will be administered until the end of surgery, and bolus colloid/blood used intraoperatively to replace blood loss (ml for ml); then an infusion at 1 ml/kg/h until expedited cessation of IV fluid therapy within 24 hours. The rate of postoperative fluid replacement can be reduced if there is evidence of fluid overload and no hypotension, and can be increased if there is hypotension AND evidence of hypovolaemia.
Other: Restrictive fluid therapy
Restrictive protocol group is designed to provide less than 2.0 L water and 120 mmol sodium per day.

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

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01424150

Contacts
Contact: Paul S Myles, MB.BS, MPH, MD, FANZCA +61 3 9076 3176 p.myles@alfred.org.au
Contact: Sophie KA Wallace, BHS RN, MPH + 61 3 9076 3176 ext 2651 s.wallace@alfred.org.au

Locations
Australia, Victoria
Alfred Hospital Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Sophie Wallace, MPH    +61390762651 ext 62651    s.wallace@alfred.org.au   
Principal Investigator: Paul S Myles, MB.BS, MPH, MD,FCARCSI,FANZC         
Sponsors and Collaborators
Bayside Health
Australian and New Zealand College of Anaesthetists Clinical Trials Network
Investigators
Study Chair: Paul S Myles, MB.BS, MPH, MD, FANZCA Alfred Hospital, Monash University
  More Information

Responsible Party: Bayside Health
ClinicalTrials.gov Identifier: NCT01424150     History of Changes
Other Study ID Numbers: 164/11 Pilot - 544/12 Main 
Study First Received: August 25, 2011
Last Updated: August 3, 2016
Health Authority: Australia: National Health and Medical Research Council
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Bayside Health:
Postoperative fluid
surgery
anaesthesia
fluid
mortality
morbidity

ClinicalTrials.gov processed this record on December 08, 2016