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

Abdominal Surgery Clinical Trial

— RELIEF  

Official title:

Restrictive Versus Liberal Fluid Therapy in Major Abdominal Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01424150
• Other study ID #: 164/11 Pilot - 544/12 Main
• Status: Completed
• Phase: Phase 4
• First received: August 25, 2011
• Last updated: February 11, 2018
• Start date: July 2013
• Est. completion date: October 22, 2017

Study information

• Verified date: August 2017
• Source: Bayside Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3000
• Est. completion date: October 22, 2017
• Est. primary completion date: September 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Abdominal Surgery

Intervention

Other:
• Liberal fluid therapy
Liberal protocol group is designed to provide approximately 6.0L per day.
• Restrictive fluid therapy
Restrictive protocol group is designed to provide less than 2.0 L water and 120 mmol sodium per day.

Locations

Country	Name	City	State
Australia	Alfred Hospital	Melbourne	Victoria

Sponsors (2)

Lead Sponsor	Collaborator
Bayside Health	National Health and Medical Research Council, Australia

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Preplanned substudies (for mechanistic understanding)	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.; Cost-effectiveness, to include hospital stay and complications as we have done previously; Hyperchloraemic acidosis (to measure strong ion difference, Cl-, lactate, albumin …); Pulmonary oedema and acute lung injury (to measure FiO2/PaO2 ratio, CT/CXR-confirmed atelectasis …); Perioperative oliguria and acute kidney injury 5. Obesity and perioperative risk 6. BNP and risk prediction 7. Goal directed therapy - decision analysis 8. Perioperative diabetes and HbA1C	3 years
Primary	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	Death		90 days, then up to 12 months after surgery
Secondary	A composite (pooled) and individual septic complications: sepsis, surgical site infection, anastomotic leak, and pneumonia	As per individual definitions	30 days postoperative
Secondary	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
Secondary	Surgical site infection	using CDC criteria (http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf):	30 days postoperative
Secondary	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
Secondary	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
Secondary	Pulmonary oedema	respiratory distress or impaired oxygenation AND radiological evidence of pulmonary oedema	30 days postoperative
Secondary	Total ICU stay and mechanical ventilation time	including initial ICU admission and readmission times	30 day postoperative
Secondary	Hospital stay	from the start (date, time) of surgery until actual hospital discharge	30 days postoperative
Secondary	Quality of recovery	15-item Quality of recovery score (QoR-15)	days 1, 3 and day 30 postoperative
Secondary	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
Secondary	Inflammation	plasma C-reactive protein (CRP, using site-specific assay) concentration on Day 3	Day 3 postoperative
Secondary	Tissue perfusion	peak serum lactate within 24 hours of surgery	24 hours post surgery
Secondary	Any blood transfusion	including red cell, fresh frozen plasma or platelet transfusion, from the commencement of surgery	From surgery to Day 3 postoperative
Secondary	Total ICU stay and unplanned ICU admission to ICU	additive, including initial ICU admission and readmission times up to Day 30	30 days postoperative