Abdominal Surgery
Conditions
Keywords
Postoperative fluid, surgery, anaesthesia, fluid, mortality, morbidity
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.
Interventions
Liberal protocol group is designed to provide approximately 6.0L per day.
Restrictive protocol group is designed to provide less than 2.0 L water and 120 mmol sodium per day.
Sponsors
Bayside Health
National Health and Medical Research Council, Australia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disability-free Survival | 1 year postoperative | 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 (12-60 points) of World Health Organisation Disability Assessment Schedule score (WHODAS) of 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
| Measure | Time frame | Description |
|---|---|---|
| Death | 90 days, then up to 12 months after surgery | deceased within 12 months |
| Composite Septic Outcome or Death | 30 days postoperative | composite of 1 or more of:sepsis, surgical site infection, anastomotic leak, death and pneumonia |
| Sepsis | 30 days postoperative | 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 | 30 days postoperative | using CDC criteria (http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf): |
| Pneumonia | 30 Days postoperative | 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 | 30 days postoperative | 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). |
| Pulmonary Oedema | 30 days postoperative | respiratory distress or impaired oxygenation AND radiological evidence of pulmonary oedema |
| Total Duration of Time Spend in the ICU or HDU (in Days) | 30 day postoperative | including initial ICU admission and readmission times up to 30 days post operatively |
| Hospital Stay | 30 days postoperative | from the start (date, time) of surgery until actual hospital discharge |
| Quality of Recovery | days 3 | 15-item Quality of Recovery Score. The score is a patient reported outcome measure to score the individuals recovery following anaesthesia and surgery. Minimum value is 0 and maximum value is 150. The score of 150 is good. The higher the score the better |
| Anastomotic Leak | 30 days postoperative | 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. |
| C-reactive Protein | Day 3 postoperative | plasma C-reactive protein (CRP, using site-specific assay) concentration on Day 3 |
| mmol/L | 24 hours post surgery | peak serum lactate within 24 hours of surgery |
| Total ICU Stay and Unplanned ICU Admission to ICU | 30 days postoperative | additive, including initial ICU admission and readmission times up to Day 30 |
Countries
Australia
Contacts
STUDY_CHAIRPaul S Myles, MB.BS, MPH, MD, FANZCA
Alfred Hospital, Monash University
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Liberal fluid therapy: Liberal protocol group is designed to provide approximately 6.0L per day. | 1,493 |
| 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.
Restrictive fluid therapy: Restrictive protocol group is designed to provide less than 2.0 L water and 120 mmol sodium per day. | 1,490 |
| Total | 2,983 |
Baseline characteristics
| Characteristic | Restrictive | Total | Liberal |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 13 | 66 years STANDARD_DEVIATION 13 | 66 years STANDARD_DEVIATION 13 |
| American Society Anesthesiologists (ASA) Physical Status ASA 1 | 25 Participants | 46 Participants | 21 Participants |
| American Society Anesthesiologists (ASA) Physical Status ASA 2 | 542 Participants | 1082 Participants | 540 Participants |
| American Society Anesthesiologists (ASA) Physical Status ASA 3 | 849 Participants | 1717 Participants | 868 Participants |
| American Society Anesthesiologists (ASA) Physical Status ASA 4 | 74 Participants | 138 Participants | 64 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Australia | 836 participants | 1677 participants | 841 participants |
| Region of Enrollment Canada | 250 participants | 497 participants | 247 participants |
| Region of Enrollment Hong Kong | 111 participants | 227 participants | 116 participants |
| Region of Enrollment Italy | 32 participants | 64 participants | 32 participants |
| Region of Enrollment New Zealand | 46 participants | 94 participants | 48 participants |
| Region of Enrollment United Kingdom | 141 participants | 275 participants | 134 participants |
| Region of Enrollment United States | 74 participants | 149 participants | 75 participants |
| Sex: Female, Male Female | 719 Participants | 1429 Participants | 710 Participants |
| Sex: Female, Male Male | 771 Participants | 1554 Participants | 783 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 96 / 1,493 | 95 / 1,490 |
| other Total, other adverse events | 78 / 1,493 | 79 / 1,490 |
| serious Total, serious adverse events | 295 / 1,493 | 323 / 1,490 |
Outcome results
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 (12-60 points) of World Health Organisation Disability Assessment Schedule score (WHODAS) of 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.
Time frame: 1 year postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Disability-free Survival | 165 Participants |
| Restrictive | Disability-free Survival | 172 Participants |
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).
Time frame: 30 days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Acute Kidney Injury | 72 Participants |
| Restrictive | Acute Kidney Injury | 124 Participants |
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.
Time frame: 30 days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Anastomotic Leak | 35 Participants |
| Restrictive | Anastomotic Leak | 49 Participants |
Secondary
Composite Septic Outcome or Death
composite of 1 or more of:sepsis, surgical site infection, anastomotic leak, death and pneumonia
Time frame: 30 days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Composite Septic Outcome or Death | 295 Participants |
| Restrictive | Composite Septic Outcome or Death | 323 Participants |
Secondary
C-reactive Protein
plasma C-reactive protein (CRP, using site-specific assay) concentration on Day 3
Time frame: Day 3 postoperative
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liberal | C-reactive Protein | 133 mg/L |
| Restrictive | C-reactive Protein | 136 mg/L |
Secondary
Death
deceased within 12 months
Time frame: 90 days, then up to 12 months after surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Death | 96 Participants |
| Restrictive | Death | 95 Participants |
Secondary
Hospital Stay
from the start (date, time) of surgery until actual hospital discharge
Time frame: 30 days postoperative
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liberal | Hospital Stay | 5.6 days |
| Restrictive | Hospital Stay | 6.4 days |
Secondary
mmol/L
peak serum lactate within 24 hours of surgery
Time frame: 24 hours post surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liberal | mmol/L | 1.6 mmol/L |
| Restrictive | mmol/L | 1.6 mmol/L |
Secondary
Pneumonia
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.
Time frame: 30 Days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Pneumonia | 54 Participants |
| Restrictive | Pneumonia | 57 Participants |
Secondary
Pulmonary Oedema
respiratory distress or impaired oxygenation AND radiological evidence of pulmonary oedema
Time frame: 30 days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Pulmonary Oedema | 32 Participants |
| Restrictive | Pulmonary Oedema | 20 Participants |
Secondary
Quality of Recovery
15-item Quality of Recovery Score. The score is a patient reported outcome measure to score the individuals recovery following anaesthesia and surgery. Minimum value is 0 and maximum value is 150. The score of 150 is good. The higher the score the better
Time frame: days 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liberal | Quality of Recovery | 107 score on a scale |
| Restrictive | Quality of Recovery | 106 score on a scale |
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)
Time frame: 30 days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Sepsis | 129 Participants |
| Restrictive | Sepsis | 157 Participants |
Secondary
Surgical Site Infection
using CDC criteria (http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf):
Time frame: 30 days postoperative
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liberal | Surgical Site Infection | 245 Participants |
| Restrictive | Surgical Site Infection | 202 Participants |
Secondary
Total Duration of Time Spend in the ICU or HDU (in Days)
including initial ICU admission and readmission times up to 30 days post operatively
Time frame: 30 day postoperative
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liberal | Total Duration of Time Spend in the ICU or HDU (in Days) | 1.8 days |
| Restrictive | Total Duration of Time Spend in the ICU or HDU (in Days) | 1.4 days |
Secondary
Total ICU Stay and Unplanned ICU Admission to ICU
additive, including initial ICU admission and readmission times up to Day 30
Time frame: 30 days postoperative
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liberal | Total ICU Stay and Unplanned ICU Admission to ICU | 1.4 days |
| Restrictive | Total ICU Stay and Unplanned ICU Admission to ICU | 1.8 days |
Other Pre-specified
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. 1. Cost-effectiveness, to include hospital stay and complications as we have done previously 2. Hyperchloraemic acidosis (to measure strong ion difference, Cl-, lactate, albumin …) 3. Pulmonary oedema and acute lung injury (to measure FiO2/PaO2 ratio, CT/CXR-confirmed atelectasis …) 4. 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 9. CKD follow-up
Time frame: 5 years