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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Restrictive Versus Liberal Fluid Therapy in Major Abdominal Surgery

Conditions
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Abdominal Surgery

Intervention / Treatment
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* Other: Liberal fluid therapy
* Other: Restrictive fluid therapy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Adults (≥18 years) undergoing elective major surgery and providing informed consent 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) 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 Urgent or time-critical surgery 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) Chronic renal failure requiring dialysis Pulmonary or cardiac surgery - different pathophysiology, and thoracic surgery typically have strict fluid restrictions Liver resection - most units have strict fluid/CVP limits in place and won't allow randomisation 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liberal<br>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<br>* Liberal protocol group is designed to provide approximately 6.0L per day.<br>|
| Experimental: Restrictive<br>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<br>* Restrictive protocol group is designed to provide less than 2.0 L water and 120 mmol sodium per day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disability-free survival | 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. | 1 year postoperative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death |  | 90 days, then up to 12 months after surgery | 
| A composite (pooled) and individual septic complications: sepsis, surgical site infection, anastomotic leak, and pneumonia | As per individual definitions | 30 days postoperative | 
| Sepsis | 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) | 30 days postoperative | 
| Surgical site infection | using CDC criteria (http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf): | 30 days postoperative | 
| Pneumonia | The presence of new and/or progressive pulmonary infiltrates on chest radiograph plus two or more of the following: Fever ≥ 38.5°C or postoperative hypothermia <36°C Leukocytosis ≥ 12,000 WBC/mm3 or leukopenia < 4,000 WBC/mm3 Purulent sputum and/or New onset or worsening cough or dyspnoea. | 30 Days postoperative | 
| Acute kidney injury | 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). | 30 days postoperative | 
| Pulmonary oedema | respiratory distress or impaired oxygenation AND radiological evidence of pulmonary oedema | 30 days postoperative | 
| Total ICU stay and mechanical ventilation time | including initial ICU admission and readmission times | 30 day postoperative | 
| Hospital stay | from the start (date, time) of surgery until actual hospital discharge | 30 days postoperative | 
| Quality of recovery | 15-item Quality of recovery score (QoR-15) | days 1, 3 and day 30 postoperative | 
| Anastomotic leak | 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. | 30 days postoperative | 
| Inflammation | plasma C-reactive protein (CRP, using site-specific assay) concentration on Day 3 | Day 3 postoperative | 
| Tissue perfusion | peak serum lactate within 24 hours of surgery | 24 hours post surgery | 
| Any blood transfusion | including red cell, fresh frozen plasma or platelet transfusion, from the commencement of surgery | From surgery to Day 3 postoperative | 
| Total ICU stay and unplanned ICU admission to ICU | additive, including initial ICU admission and readmission times up to Day 30 | 30 days postoperative | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postoperative fluid, surgery, anaesthesia, fluid, mortality, morbidity