Restrictive Versus Liberal Fluid Therapy in Major Abdominal Surgery
Phase: NA
Conditions: Abdominal Surgery
Sponsor: Bayside Health

 
 
 
 
 
The RELIEF Trial  
 
REstrictive versus LIbEral Fluid Therapy in Major Abdominal Surgery 
 
 
 
www.relief.org.au 
 
 
 
 
On behalf of the Australian and New Zealand College of Anaesthetists Clinical Trials Network (ANZCA CTN), and the Australian and New 
Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) 
 
 
 
ClinicalTrials.gov Identifier: NCT01424150 
 
 
 
 
Protocol Version 2: 3rd August 2016 
 
 
 
 
 
 
 
 
Study title: Restrictive versus liberal fluid therapy in major abdominal surgery 
 
Protocol Number: Anaesthesia Research 046 
 
Sponsor: Alfred Health, Melbourne 
 
 
Funding source: The Australian National Health and Medical Research Council (APP1043755) 
 
 
 
 
 

 
2
AGREEMENT 
 
This document is confidential.  The Investigators declare that they have read the final study protocol and any 
amendments.  The Investigators will conduct the study according to the procedures specified in the study protocol, and 
in accordance with ICH GCP notes for Guidance on Good Clinical Practice (CPMP/ICH/135/95) and the Australian 
NH&MRC National Statement on Ethical Conduct in Research Involving Humans. 
 
 
 
 
.......................................................................... 
 
............................ 
Investigator 
 
 
 
 
 
Date 

 
3
RELIEF: REstrictive versus LIbEral Fluid Therapy in Major Abdominal Surgery 
 
 
Principal Investigator 
Paul Myles, MB.BS, MPH, MD, FCAI, FANZCA, FRCA, FAHMS 
Director, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital and Monash University 
 
Intensive Care 
Rinaldo Bellomo, MB.BS, MD, FRACP, FCICM, PGDipEcho 
Co-Director of the ANZIC-RC and the Director of Intensive Care Research at Austin Health 
 
 
Anaesthesia 
Tomas Corcoran, MB, BCh, BAO, MRCPI, FCAI, MD, FCICM 
Department of Anaesthesia and Pain Medicine, Royal Perth Hospital; School of Medicine and Pharmacology, University 
of Western Australia 
 
Philip Peyton, MD, PhD, MB.BS, FANZCA, PGDipEcho 
Staff Anaesthetist, Department of Anaesthesia, Austin Health 
 
David Story, MBBS, MD, BMedSci, FANZCA 
Chair of Anaesthesia; and Head, Centre for Anaesthesia, Perioperative and Pain Medicine; The University of Melbourne 
 
Kate Leslie, MB.BS, MD, M Epi, FANZCA 
Staff Anaesthetist, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital; University of Melbourne; 
Monash University 
 
Surgery 
Chris Christophi, MB.BS, FRACS 
Director of Surgery, Austin Hospital and University of Melbourne 
 
Jonathan Serpell, MB.BS, MD, Med, FRACS, FACS 
Director, Department of General Surgery, Alfred Hospital and Monash University 
 
Statistician 
Andrew Forbes MSc, PhD 
Head, Biostatistics Unit, Department of Epidemiology & Preventive Medicine, Monash University 
 
 
Research Manager: Sophie Wallace 
 
Data and Safety Monitoring Committee 
Monty Mythen (Chair, intensivist, Smiths Medical Professor of Anaesthesia & Critical Care, University College London (UK); 
Russell Gruen (surgeon), Guy Ludbrook (anaesthetist), John McNeil (epidemiologist), Katherine Lee (statistician). 
 
Endpoint Adjudication Committee: David McIlroy, Mark Shulman, Jamie Cooper 
 
Governance and Data Quality Manager: Sophie Wallace 
 
 
 
 
 
 
 
ABBREVIATIONS 
 
ACE – angiotensin converting enzyme  
ANZCA TG – Australian and New Zealand College of Anaesthetists Trials Group 

 
4
ANZICS CTG – Australian and New Zealand Intensive Care Society Clinical Trials Group 
APTT – activated partial thromboplastin time 
ARB – angiotensin-II receptor blocker 
ASA – American Association of Anesthesiologists   
ATACAS – Aspirin and Tranexamic Acid for Coronary Artery Surgery trial 
BMI - Body Mass Index 
BP – Blood Pressure 
CXR – Chest X-Ray 
CRF – Case Report Form 
CT - computed tomography scan 
CVP – Central Venous Pressure 
CD - Compact Disc 
CDC - Centers for Disease Control and Prevention 
CRP - C-reactive protein 
DO2 – Tissue oxygen delivery 
DSMC – Data Safety and Monitoring Committee 
EAC – Endpoint Adjudication Committee 
ECG - Electrocardiography 
ENIGMA – Evaluation of Nitrous Oxide in the Gas mixture for Anaesthesia 
ENIGMA-II - Nitrous oxide anaesthesia and cardiac morbidity after major surgery 
ERAS – Enhanced Recovery After Surgery 
FiO2 – Fraction of Inspired Oxygen 
FTc – Flow Time Corrected 
GA – General Anaesthesia 
GCP – Good Clinical Practice 
GFR - Glomerular filtration Rate 
HR – Heart Rate 
HDU – High Dependency Unit 
INR - International Normalized Ratio 
ICP – Intracranial Pressure 
ICU – Intensive Care Unit 
IV - Intravenous 
IVRS – Interacive Voice Response System 
L - Litres 
PRN - as the occasion arises; as needed. 
RIFLE - Risk, Injury, Failure, Loss, and End-stage kidney classification 
NHMRC – Australian National Health and Medical Research Council 
NHSN - National Healthcare Safety Network 
mmol/L – Millimole per Litre 
mmHg - millimetres of mercury 
OR – Operating Room 
PA – Pulmonary Artery 
PaO2 – Arterial partial pressure of oxygen  
PI&CF – Patient Information and Consent form 
PPV - Positive Pressure Ventilation 
QoR-40 – 40-item Quality of Recovery score 
SAFE - Saline versus Albumin Fluid Evaluation study 
sBP – Systolic Blood Pressure 
SVV – Stroke Volume Variation 
TGA – Australian Therapeutic Goods Administration 
TOE – transoesophageal echocardiography, or TEE 
WCC – White Cell Count 
WHODAS - World Health Organization Disability Assessment Schedule 
 

 
5
TRIAL SUMMARY 
 
Design: This will be a large, randomized, parallel-group, controlled trial. After stratification by centre and planned 
ICU/HDU admission (or not), patients will be randomly assigned from a computer-generated list (1:1) to either a 
Restrictive or Liberal fluid Group.  
 
Group 1 = Restrictive fluid regimen (intraoperative and 1st 24 h ≈2.5 L) 
Group 2 = Liberal fluid regimen (intraoperative and 1st 24 h ≈5.5 L) 
 
Sample Size: 3000 patients  
 
Study Duration: 3 years 
 
Primary Endpoint 
Disability-free survival up to 1 year: survival and freedom from disability after surgery, the latter being a persistent (>6 
months) reduction in functional status as defined by a 4-point or greater reduction in the 12-item version of WHODAS. 
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. 
 
Interim analysis (& DSMC review): at n≈ 1500 patients 
 
 
 
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.  
 
 
1.1 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. 
 
 
 

 
6
2. BACKGROUND 
Anaesthetists typically manage perioperative hypotension in the first instance with an intravenous (IV) fluid bolus of a 
balanced salt crystalloid solution, or sometimes with one of several colloids. If persistent or more profound 
hypotension occurs, particularly in the intraoperative period when anaesthetic drug-induced vasodilation is common, 
an IV vasoconstrictor (typically metaraminol bolus prn) is used.  Similar approaches are used in the intensive care unit 
(ICU) and surgical wards.  We simply don’t know whether using a ‘liberal’ fluid strategy based primarily on 
supplemental IV fluids, or a ‘restrictive’ strategy based on altered haemodynamic goals and/or vasopressor drug 
therapy, is best for most patients undergoing major surgery.  The evidence base for fluid management in the 
postoperative setting is poor and is insufficient to guide our practice (1-4).  Anaesthetists, intensivists and surgeons 
differ in their approaches to perioperative fluid therapy (5, 6). 
 
Around 250 million people undergo major surgery each year around the world (7), with about 2 million being in 
Australia (1 in 10 Australians), and a growing proportion (now 40%) being elderly.  By 2056 in Australia, more than 8.5 
million anaesthetics (>50%) will be administered to patients over the age of 65 (8). These patients and many others 
have co-existent medical diseases that add risk to the procedure. The personal, social and economic consequences of 
postoperative complications, additional hospital stay, and long-term disability, are great. 
 
Both colloids and crystalloids are used for fluid resuscitation and maintenance, but it is the amount of fluids 
administered and the goals of resuscitation that need re-evaluation.  Since the 1950s, when it was first claimed that 
after surgery fluids are redistributed to a theoretical ‘third space’ (9), perioperative IV fluid replacement has included 
replacement of such third-space losses with crystalloid.  In fact there are many reasons why clinicians administer 
generous amounts of IV fluids during and after surgery.  Concerns about reversing preoperative dehydration, support 
ingthe circulation after general and regional anaesthesia, avoiding gut hypoperfusion and promoting tissue oxygen 
delivery, avoiding blood transfusion, and maintaining urine output are common (10-12).  Optimizing tissue perfusion 
typically requires more fluid than indicated by normal clinical criteria or with invasive monitoring (10). Occult 
hypovolaemia and intraoperative gut hypoperfusion occurs in around 60% of major surgery patients, both of which are 
linked to increases in morbidity and mortality (11). Further support for this comes from some studies showing that a 
liberal fluid strategy in patients undergoing minor surgery, mostly in the ambulatory setting, improves early recovery 
measures such as dizziness, nausea and thirst, and may improve pulmonary function, exercise capacity, and shorten 
hospital stay (13).  Similarly in the ICU setting, with some small trials suggest that fluid supplementation and optimized 
haemodynamics reduce organ dysfunction, postoperative morbidity and death (14, 15).   
 
If fluid administration is restricted it is likely that hypotension will be treated with vasopressor therapy.  Vasopressors 
may impair organ perfusion, threaten local tissues at the site of IV administration, cause arrhythmias, or be mistakenly 
used when hypovolaemia is the underlying cause. 
 
But excess fluid administration causes oedema, with increased pulmonary morbidity (16), impaired coagulation (17), 
bacterial translocation and sepsis (18), and poor wound healing .  In contrast to the above, other small trials of patients 
undergoing abdominal surgery have found that fluid restriction lead to reduced morbidity and hospital stay (12, 13). 
This conflicting evidence explains why there are diverse and varied practices around the world. Several expert 
guideline/consensus statements have been published, with most supporting restrictive fluid administration (2, 19). But 
all come to similar conclusions: High-grade evidence regarding the optimal fluid regimen is currently lacking (19). 
 
2.1 Liberal or Restrictive IV Fluid Resuscitation 
Traditional perioperative IV fluid regimens in abdominal surgery can lead to patients receiving 3 to 7 L of fluid on the 
day of surgery and more than 3 L/day for the following 3 to 4 days, leading to a 3- to 6-kg weight gain (20, 21).  Several 
small trials have compared restrictive and liberal fluid regimens (3, 22).  
 
Lobo et al (20)  did a tightly-controlled randomized trial in 20 adult patients having colonic surgery.  The liberal group, 
representing ‘standard’ care, received IV fluids in accordance with their present hospital practice (≥3 L/day) and the 
restrictive group received ≤2 L water and sodium 77 mmol per day. All patients had no comorbidity other than colonic 
cancer. The restrictive group had shorter median gastric emptying times, less complications (0 vs. 7, P=0.01) and 
shorter hospital stay (6 vs. 9 days, P=0.001). Brandstrup et al (23) did a randomized trial comparing similar fluid 
regimens in 172 colorectal surgical patients. The restrictive group had fewer postoperative complications (33% vs. 51%, 
P=0.013) and less deaths (0 vs. 4, P=0.12). Nisenavich et al (24) compared liberal and restrictive fluid regimens in 152 
patients undergoing elective abdominal surgery. The restrictive group had faster return of bowel function, less 
complications (P=0.046), and shorter hospital stay (P=0.01). Similar benefits were found in recent trials in colorectal 
and abdominal aortic surgery (25, 26) . 
 

 
7
However, Kabon et al (25) compared similar fluid regimens in 253 colorectal surgical patients and found no difference 
in the rates of wound infection, restrictive group 14% vs. liberal group 11% (P=0.46).  Holte et al (27) compared two 
fluid regimens with physiological recovery as the primary outcome measure in 32 patients undergoing fast-track 
colonic surgery. The rate of complications tended to be higher in the restrictive group (6 vs. 1, P = 0.08).  A meta-
analysis of the fluid trials up to 2007 (3) found restrictive regimens reduced overall complications, OR 0.41 (95% CI: 
0.22-0.77), P=0.005; but the authors noted the heterogeneity of fluid regimens and definitions of outcomes. Another 
two recent small trials found either no benefit (26) or harm (28). 
 
We have done an updated meta-analysis of relevant trials (12 trials, 1160 patients) to evaluate the overall effect of 
fluid restriction on mortality (see Fig 1) and some morbidities (22). We could not pool overall complications because of 
their variability and inconsistency of counting. About half the trials did not measure or report mortality, so this 
outcome is underpowered. We found some possible benefits of fluid restriction:  
 
Pneumonia: RR 0.43 (95% CI: 0.20-0.94); P=0.03 
 
Pulmonary oedema: RR 0.22 (95% CI: 0.06-0.78); P=0.02 
 
Hospital stay: restrictive groups 2 days less (95% CI: 0.5-3.4); P=0.009 
 
Hospital mortality: RR 0.59 (95% CI:0.2-2.0); P=0.40 
 
Figure 1. Mortality 
 
 
 
Our results show fluid restriction seems very promising and could lead to marked improvements in patient outcomes, 
but a large definitive trial is needed to generate the reliable evidence needed to change practice around the world. 
 
An earlier meta-analysis that included less relevant trials (4) found that the range of ‘liberal’ IV fluid replacement 
varied from 2,750 to 5,388 ml compared with 998 to 2,740 ml in the ‘restrictive’ regimen. Like others (3) they noted 
that the fluid regimens and outcomes were inconsistently defined and only two studies reported perioperative care 
principles and discharge criteria.  These and others have argued for a carefully designed trial that incorporates such 
details.  
 
2.2 Crystalloid or Colloid Fluid Resuscitation? 
Colloid proponents have argued that colloids lessen the risk of oedema because of the higher oncotic pressure, and 
textbooks typically recommend a 3-5 fold ratio of crystalloid to colloid volumes for acute fluid resuscitation.  But the 
oncotic pressure effect may be lost if colloids leak and remain in the interstitial spaces. This perhaps explains why 
recent large trials have found that CVP and pulmonary function are comparable with both crystalloids and colloids (29-
31) . The SAFE study found that the volume of crystalloid needed for resuscitation at 24 h was only 1.3-fold larger than 
that of 4% albumin (32). There is concern regarding the safety of colloids (29-31, 33) . 
 
The weight of evidence downplays the superiority of any particular IV fluid (crystalloid or colloid (32), type of colloid 
(3), or type of crystalloid. The main unresolved question is how much fluid to use, and whether haemodynamic- or 
flow-directed goals provide further benefit. However, in view of emerging evidence suggesting adverse effects of 
starch-based colloid solutions (30, 34), we recommend they NOT be used in this study. 
 
2.3 Goal-directed Therapy: fluids and/or inotropes 
CVP is an unreliable measure of intravascular status (35), but remains the most common monitor used to guide fluid 
resuscitation and vasopressor support. Relatively noninvasive monitors such as oesophageal Doppler and pulse 
contour analysis are becoming popular for intraoperative and ICU use (36), and there have been several positive trials 
(37-40), meta-analysis (22, 41), and guidelines (42) supporting their use. The strongest evidence is for oesphageal 
Doppler (42) but the device is infrequently used in Australian practice at present. Goal-directed strategies focus on 

 
8
fluid responsiveness and typically require additional IV fluid supplementation, usually giving an extra 800 ml per case, 
and more postoperatively(22). These findings are hard to resolve when considering the apparent success of fluid 
restriction regimens described above. 
 
One influential trial of ‘optimized’ care in the UK (15) in which 138 high-risk patients undergoing major abdominal 
surgery were randomly assigned to one of 3 groups: control, or ‘pre-optimized’ with either dopexamine or adrenaline. 
The control group remained on the general surgical ward with no preoperative fluid protocol. The intervention groups 
were admitted to the ICU for a minimum of 4 h before surgery, and had full haemodynamic monitoring including PA 
catheter. The two intervention groups were initially fluid optimized with colloid until pulmonary occlusion pressure 12 
mm Hg was reached; red cell transfusion was used for haemoglobin <110 g/L. Patients then received inotrope therapy 
titrated to reach a target DO2 of 600 ml/min/m2 for up to 12±24 h after surgery. Hospital mortality in the protocol 
groups was 3%, compared with 17% in the control (P=0.007), and morbidity and hospital stay were significantly 
reduced in the dopexamine group. Interpretation of this study is difficult.  It could be said that closer (and more expert) 
care in the ICU, compared with junior doctor-based ward care, was a key factor. Whether the target DO2 itself, 
inotrope therapy, additional fluids, or the combination of these factors is important is unclear. Two subsequent meta-
analyses of dopexamine in major surgery had conflicting findings (43, 44) , and a recent trial using FloTrac-guided fluid 
supplementation found (45) no effect on complication rate (45).  
 
The most recent meta-analysis (46) of 29 trials involved 4805 patients found pre-emptive perioperative haemodynamic 
intervention significantly reduced mortality, OR 0.48 [95% CI:0.33–0.78]; P<0.0002; and surgical complications, OR 0.43 
[0.34–0.53]; P< 0.0001. That is, supplemental fluids seem to improve outcome.  Sub-group analyses showed similar 
effects with each type of intervention, including use of supplemental IV fluids alone: 
 
 
 
A later trial in 179 patients found no outcome benefit of goal-directed therapy, and possibly longer hospital stay (47). 
 
One of the reasons for the varied results is that the focus should not be on the amount of IV fluid, but the timing and 
individualisation of such therapy.  There may be an optimal amount, probably better targeted using a goal-directed 
approach (48). 
 
2.4 “Fast-track” or “enhanced recovery from surgery” (ERAS) programs  
There is a growing interest in facilitating recovery and earlier hospital discharge after colorectal and other abdominal 
surgery (44-46).  ERAS programs typically include avoidance of bowel preparation, nasogastric and drain tubes; non-
opioid analgesia; and promoting early postoperative mobilization and oral nutrition.  A randomized trial comparing an 
ERAS program with traditional care in 156 patients undergoing colorectal surgery was stopped early because of 
apparent benefit (46), with less complications (21% vs. 50%, P=0.001) and a shorter hospital stay (5 vs. 9 days, 
P<0.001). A regression analysis revealed excess IV fluids (OR 4.2 [95% CI 1.7–10]; P=0.002) as an independent predictor 
of postoperative complications. A recent meta-analysis of ERAS studies has similarly found a significant reduction in 
complications and hospital stay (49). Most of the above fluid trials did not employ ERAS principles (4), and so we plan 
to include these in our study.  
 
2.5 Measuring Outcome after Major Abdominal Surgery? 
Most of the above-quoted studies pooled a variety of postoperative adverse outcomes into a single composite 
outcome (“complications”), for which there was often an imbalance in severity and duration, and with questionable 
long-term relevance to patients.  Composite outcomes can be valid and important but only if properly constructed 
(50).  Of course a hard endpoint after surgery is survival, but none of the above studies was sufficiently powered to 
detect a clinically important difference.  Mortality is low after most types of surgery (49, 51) and so is an unattractive 
primary endpoint on which to base a sample size calculation.   

 
9
 
It is unclear which of many adverse postoperative outcomes dominates any other.  There is a strong argument to use 
patient-centred outcome measures.  Quality of life is often used, but these instruments were not designed to be 
responsive after major surgery.  Our 40-item quality of recovery score (QoR-40) has undergone psychometric 
evaluation, including utility and responsiveness testing (51, 52), and has been externally validated and used in many 
perioperative studies (53-55) .  But the QoR-40 is designed to measure outcome up to 30 days after surgery.  Survival, 
and avoiding long-term disability, are likely to be the most important and highly valued outcomes for patients 
undergoing major surgery (56, 57) .  We thus plan to measure disability-free survival up to 1 year after surgery in this 
study.   
 
Interim Long-term Outcome Data for ENIGMA-II and ATACAS trials: Our experience to date with 1-year follow-up for 
death/disability (using Katz ADLs) in our two current large international trials across >30 sites (58, 59) has had excellent 
follow-up, with <1% missing data (24 of 2,570 patients).  For noncardiac surgery (n=1800) there have been 242 deaths 
and 286 with new disability (a combined rate of 31%). This event rate, from a lower risk study population, exceeds our 
assumptions used in our sample size calculation. Clearly, disability should not be ignored in perioperative outcome 
trials, and its inclusion can enhance study power.   
 
2.6 Feasibility: Pilot Study 
To ascertain current practices and support for this trial, we surveyed all members of both ANZCA and ANZICS Trials 
Groups (n=238) and found that >90% were comfortable with the proposed Group fluid regimens and were interested 
in participating in the trial (60). 
We undertook a feasibility pilot study of the proposed trial at 3 centres.  After ethics approval and patient consent, and 
surgeon, anaesthetist and intensivist support, we have demonstrated that we can successfully implement the fluid 
regimens both intraoperatively and postoperatively: 
 
 
variable 
Restrictive 
(n=41) 
Liberal 
(n=41) 
 
P value 
Age, y 
IV fluid (crystalloid + colloid) 
   Intraoperative 
   Total at 24 h postoperative 
Postoperative 
Haemoglobin, g/L 
Albumin, g/L 
CRP, mg/L 
Quality of recovery score 
Median ICU stay, h 
Median Hospital stay, days 
65 ± 12 
 
1746 ± 748 
3167 ± 1625 
 
110 ± 18 
31 ± 6.7 
108 ± 80 
159 ± 20 
0 (0-15) 
8.1 (5.6-14) 
67 ± 12 
 
2730 ± 1309 
5133 ± 2138 
 
101 ± 17 
27 ± 7.0 
128 ± 75 
154 ± 26 
0 (0-19) 
8.4 (6.9-16) 
- 
 
<0.0005 
<0.0005 
 
0.014 
0.030 
0.33 
0.34 
0.86 
0.30 
 
To date there is no evidence of any adverse haemodynamic or renal effects with restrictive therapy (61). 
 
In addition, we are currently undertaking a cohort study of 400 patients undergoing a range of elective surgeries to 
accurately measure and define rates of comorbidity, wellbeing and disability at 1, 3, 6, and 12 months after surgery.  
This will validate our follow-up and disability measurement techniques. 
 

 
10 
3. STUDY DESIGN 
3.1 Experimental design 
Large, multicentre, randomized, single blind, pragmatic trial, with patients randomly assigned to either Restrictive or 
Liberal fluid, stratified by site and planned HDU/ICU admission.  
 
This is an effectiveness trial (62, 63)  – some elements of the trial are deliberately left to the anaesthetist’s discretion in 
order to reflect usual practice and maximise generalisability.  
 
 
3.2 Subject Selection 
 
3.2.1 Definition of Disease State 
We are targeting patients undergoing planned major abdominal or pelvic surgery that includes a skin incision and 
operative duration expected to exceed two hours. 
 
3.2.2 Source and Number 
We will use similar procedures to those used by us successfully in previous multicentre studies. Simple eligibility 
criteria, and research nurse-screening and enrolment, ensure that recruitment is maximized. 
 
3000 patients in total will be required for this study (1500 in each group). 
 
3.2.3 Entrance 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: 
a) age ≥70 years 
b) known or documented history of coronary artery disease  
c) known or documented history of heart failure  
d) diabetes currently treated with an oral hypoglycaemic agent and/or insulin  
e) preoperative serum creatinine >200 mol/L (>2.8 mg/dl) 
f) 
morbid obesity (BMI ≥35 kg/m2) 
g) preoperative serum albumin <30 g/L 
h) anaerobic threshold (if done) <12 mL/kg/min 
i) 
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 mol/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. 
 

 
11 
3.3 Study Procedures 
 
3.3.1 General Description 
 
 
Study Flow Chart  
 
All procedures are based on successful strategies used in each of our previous large multicentre trials. Ethics 
Committee approval and informed consent will be obtained at all study centres.  After enrolment, on the day of 
surgery, patients will be randomly assigned (1:1) to groups via either (both established) 24-hr freecall telephone or 
web-based service using a computer-generated code. All other perioperative clinical care will be according to standard 
practice. All relevant factors will be recorded on a trial case report form (CRF). 
 
3.3.2 Perioperative Management 
Preoperative period 
ERAS perioperative care principles will be emphasized.  All patients will receive prophylactic antibiotics according to 
established guidelines. Medications will be continued perioperatively unless or at the clinicians discretion, but we will 
recommend withholding ACE-inhibitors and ARBs on the day of surgery. We will record preoperative use of bowel 
preparation, fasting times, ERAS data, medications, and biochemistry and haematology results on the CRF. 
 
Intraoperative period 
Choice of anaesthetic agents and perioperative analgesia will be left to the discretion of the anaesthetist; such data will 
be recorded. We will emphasize the need to avoid hypothermia (<36 oC). Epidural use will be recorded as this may 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
 
Preadmiss
ion Clinic/ 
preoperati
ve visit 
Day of 
Surgery 
Post op  
day 1 
Post op day 
3 
Day of 
discharge 
30 day 
follow up 
phone 
call 
3 month 
phone 
follow-up 
6 month 
phone 
follow-up 
12 month 
phone 
follow-up 
Entry Criteria 
х 
 
 
 
 
 
 
 
 
Informed 
Consent 
x       or       x 
 
 
 
 
 
 
 
Demographics, 
Medical History 
x       or       x 
 
 
 
 
 
 
 
ECG 
x       or       x 
x 
if chest pain or elevated troponin 
 
 
 
Randomisation 
 
х 
 
 
 
 
 
 
 
Blood tests 
Electrolytes 
x       or       x 
х 
х 
 
 
 
 
 
Liver function 
tests 
If clinically  indicated 
 
If clinically  indicated 
 
 
 
 
 
 
HbA1C 
Recommended in ALL 
diabetics 
 
 
 
 
 
 
 
CRP 
 
 
X 
 
 
 
 
 
Blood tests 
Troponin 
Lactate 
 
If clinically  indicated 
 
 
 
 
 
 
IV fluids 
 
х 
x 
x 
 
 
 
 
 
Web-based 
data entry 
 
х 
 
 
х 
х 
х 
х 
х 
Wound 
inspection 
 
 
If change of 
dressing 
х 
х 
Medical 
record 
review 
 
 
 
QoR-15 
 
 
x 
x 
 
х 
 
 
 
WHODAS 
х 
 
 
 
 
х 
х 
х 
х 
Adverse Events 
 
х 
х 
х 
 
х 
 
 
 
 
Outcomes 
 
 
 
 
 
х 
 
 
 
Blood products 
 
х 
х 
х 
х 
 
 
 
 

 
12 
increase the risk of hypotension and need for IV fluids (64, 65), but such effects are likely to be small (66). We will 
record usage of all “advanced” monitoring devices (CVP, pulse contour analysis, TOE, oesophageal Doppler).  
 
The acceptable limits of low BP, and a definition of ‘hypotension’, vary widely (67), though such a definition will be 
modified by older age, pre-existing hypertension, and cerebrovascular disease.  We will use a general guideline of  
systolic BP <90 mmHg for more than 5 mins, but also ask the attending anaesthetist to modify their acceptable lower 
limit of sBP at the commencement of surgery, and, according to randomly-assigned group, treat hypotension with 
additional IV fluid or vasopressor therapy (see below).  For example, in younger patients or those with pre-existing low 
BP it may be acceptable to tolerate a sBP of 85-95 mmHg, but in older patients, particularly those with pre-existing 
hypertension, a higher lower limit may be required.  Such modification to the acceptable lower sBP will be recorded. 
For patients managed in a high dependency or ICU environment after surgery, hypotension will be similarly treated for 
the first 24 h after surgery. 
 
Postoperative period 
Patients will be followed daily and outcomes will be recorded until discharge. We will recommend that 
antihypertensive medications should be withheld until sBP is consistently at or above preoperative levels. Serum 
electrolytes, haemoglobin/haematocrit, and a 12-lead ECG will be ordered preoperatively and on day 1 after surgery. 
CRP will be measured on postoperative Day 3 and whenever sepsis is suspected (68, 69) . Additional laboratory tests 
will be ordered if clinically indicated. On day 3 all patients will complete the 15-item quality of recovery score (QoR-15). 
On day 30 all patients will be contacted by phone to ascertain if they have experienced any outcomes, and if detected, 
further testing will be arranged. Documentation for such events will be sought in the hospital medical record and 
doctor’s records. The QoR-15 will be repeated on day 30 along with WHODAS, and the WHODAS will be repeated at 3-, 
6- and 12-month follow-up to ascertain survival status and new-onset disability. 
 
 
3.3.3 Clinical Observations 
 
3.3.3.1 Primary Endpoint 
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 (70) 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 (71). 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. 
 
 
3.3.3.2 Secondary Endpoints 
Secondary endpoints include an a priori composite of 30-day mortality or major septic complications (sepsis, surgical 
site infection, anastomotic leak, and pneumonia), plus each individually, serum lactate (at 6 and 24 h), CRP (Day 3), 
blood transfusion, acute kidney injury, ICU and hospital stay, unplanned admission to ICU, and quality of recovery 
(QoR-15).  We will use the following definitions: 
1. Death: all-cause mortality at 90 days, then up to 12 months after surgery 
2. A composite (pooled) and individual septic complications: sepsis, surgical site infection, anastomotic leak, and 
pneumonia 
3. Sepsis: using Centers for Disease Control and Prevention (CDC) with National Healthcare Safety Network (NHSN) 
criteria:(72): 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):  
i) 
Core temperature > 38°C or <36°C (core temperature was rectal or tympanic). If oral, inguinal or axillary 
temperatures were used, 0.5°C to be added to the measured value  
ii) Heart rate > 90 beats per minute. If patient had an atrial arrhythmia, record the ventricular rate. If patients have a 
known medical condition or are receiving treatment that would prevent tachycardia (for example, heart block or 
beta blockers), they must meet two of the remaining three (a,b,c) SIRS criteria  
a) Respiratory rate > 20 breaths per minute  
b) PaCO2 < 32 mmHg (4.3 kPa)  
c) mechanical ventilation for an acute process 
iii) White cell count of >12,000 mm3 or < 4,000 mm3 
4. Surgical site infection: using CDC criteria  (http://www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf): 
i) 
Superficial – This includes one or more of the following:  

 
13 
(1) purulent drainage from the superficial incision, 
(2) organisms isolated 
(3) diagnosis by surgeon or other physician or one of the signs or symptoms of infection- (pain or tenderness, 
localised swelling, redness or heat, superficial incision and is deliberately opened by surgeon.) (Unless 
culture negative) 
ii) Deep Incisional – This includes one of the following : 
(1) Purulent discharge from deep incision but not from organ/space component of the surgical site  
(2) A deep incision spontaneously dehisces or is deliberately opened by surgeon with one addition sign 
(Temperature >38°C, localised pain, tenderness) 
(3) An abscess or other evidence of infection 
(4) Diagnosis by surgeon or other physician  
iii) Organ/space - Occurred within 30 days with no implant or within 1 year if an implant is in place – this includes one 
or more of the following 
(1) Purulent discharge  
(2) Organisms identified  
(3) Abscess or evidence of infection involving the organ/space on examination  
(4) Diagnosis by surgeon or other physician 
5. 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. 
6. 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.  
(1) Grade A - anastomotic leakage results in no change in patients' management 
(2) Grade B - leakage requires active therapeutic intervention but is manageable without re- laparotomy 
(3) Grade C - anastomotic leakage requires re-laparotomy 
7. 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), 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]) 
8. Pulmonary oedema: respiratory distress or impaired oxygenation AND radiological evidence of pulmonary oedema 
9. Duration of mechanical ventilation: additive, for all episodes up to 90 days after surgery 
10. Inflammation: plasma C-reactive protein (CRP, using site-specific assay) concentration on Day 3 
11. Tissue perfusion: peak serum lactate within 24 hours of surgery 
12. Any blood transfusion: including red cell, fresh frozen plasma or platelet transfusion, from the commencement of 
surgery 
13. Unplanned admission to ICU within 30 days of surgery 
14. Total ICU stay: additive, including initial ICU admission and readmission times up to Day 30 
15. Hospital stay: additive, from the start (date, time) of surgery until actual hospital discharge , plus readmission(s) up to 
Day 30 
16. Quality of recovery: QoR-15 score(76) on days 1, 3, and 30. 
17.  
 
Fluid Therapy and Blood Transfusion: General Guidelines  

 
14 
Excessive fluid resuscitation can cause haemodilution (64) and dilutional coagulopathy, and this may increase the need 
for red cell and other blood transfusion (32). Blood transfusion is, of itself, associated with increased rates of sepsis 
and other postoperative complications (3, 24). All patients will have the same red cell transfusion trigger of 70 g/L, but 
this can be modified after assessment of cardiovascular risk (77, 78) or concern for active bleeding. Normal Saline, 
containing 154 mmol of sodium and 154 mmol of chloride per litre, is non-physiological and can lead to 
hyperchloraemic acidosis (33) and perhaps poorer outcome (79, 80).  We will use a balanced salt solution as the 
routine fluid therapy in this study.  The questionable value of urine output as a measure of kidney or other tissue 
perfusion will be emphasized (81). 
 
Our study Group fluid regimens are aimed at distinct volume differences and according to recent recommendations(4, 
72) . The group-assigned fluid regimens will continue for at least 24 hours after surgery, or until cessation of IV fluid 
therapy (whichever occurs first). If the patient’s clinical condition warrants modification to the type or rate of fluid 
administration, then such modifications can be made immediately. This does NOT imply that the patient is removed 
from the trial because we will analyze according to the intention-to-treat principle, but we will collect such data for 
secondary per-protocol and sensitivity analyses.  
 
Management of Oliguria 
It is a normal response of the body to attempt to conserve fluid in times of physiological stress. Oliguria (low urine 
output) is part of this homeostatic mechanism; there is no evidence it is harmful in the short term (first 24-48 h after 
surgery is common and not abnormal) (81).  Nor is there any evidence that diuretics protect against AKI (82).  We will 
however provide guidance to ward medical and nursing staff (see Procedures Manual).  
 
 
4. Experimental control 
 
4.1 Group assignment 
This will be a large, randomized, parallel-group, controlled trial. After stratification by centre and planned ICU/HDU 
admission (or not), patients will be randomly assigned from a computer-generated list (1:1) to either a Restrictive or 
Liberal fluid Group. 
 
A 24-hr interactive voice recognition system (IVRS) will be available.  An alternative web-based randomisation service 
will also be available during the conduct of the trial. 
 
This is an intention to treat trial.  Any participant who is randomised will be followed for the duration of the trial 
(unless they withdraw consent) even if they are withdrawn from the active phase of the trial.  Patients who do not 
complete the active phase of the study will not be replaced. 
 
 
Liberal Protocol 
The Liberal protocol group reflects common contemporary practices in Australia(29, 82), and is consistent with 
previous international trials (20, 24, 83) – see Appendix.  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 – the latter can 
be further down-titrated after 4 hours if clinically indicated.  Important: for the purposes of calculations of bolus and 
maintenance fluids in patients exceeding 100 kg, the maximal body weight will be set at 100 kg.  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.  For a 75-kg adult, the 
intraoperative volume (for a 4 h operation) will be 3150 ml (+colloid/blood replacement for blood loss), and then 
around 2700 ml per day.  That is, the first (intraoperative + postoperative) 24-h fluid administration will be about 5400 
ml (P.T.O).   
 
 
Restrictive Protocol 
The Restrictive protocol group is designed to provide less than 2.0 L water and 120 mmol sodium per day.  Induction of 
anaesthesia will be accompanied by an IV fluid bolus limited 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 0.8 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 

 
15 
be increased if there is hypotension AND evidence of hypovolaemia.  For a 75-kg patient and 4 h operation, 
intraoperative fluid volume will be 1875 ml (+colloid/blood replacement for blood loss). The first 24-h fluid 
administration will be around half that of the liberal group (P.T.O).   
 
 
Hypotension will be initially treated with fluid boluses in the liberal protocol group, and with a vasoconstrictor in the 
restrictive protocol group. The latter will consist of metaraminol or phenylephrine bolus/infusion and/or noradrenaline 
infusion during surgery, and a noradrenaline infusion postoperatively if in a HDU or ICU environment.  The lower limit 
of acceptable sBP in the restrictive group can be further reduced by the attending anaesthetist or intensivist in order to 
limit fluid replacement or potentially unnecessary inotropic support (as per above). We have laminated instructional 
flowcharts for the anaesthetists and postoperative (ward or ICU/HDU) medical and nursing staff caring for the study 
patients (see Appendix). Research staff will be present at or soon after all handover steps, and be contactable at all 
hours. 
 
 
 
4.2 Goal-directed Therapy 
For anaesthetists employing advanced monitoring (eg. CVP or goal-directed device), we allow additional colloid fluid 
supplementation to augment a haemodynamic target.  It is likely to lead to additional colloid administration during and 
after surgery (3, 4, 45). Some hospitals use pulse contour analysis to direct perioperative or ICU fluid therapy in surgical 
patients, and some use oesophageal Doppler. Most rely upon conventional monitoring (HR, BP, urine output).  We plan 
to test the effectiveness of each approach according to their local availability and use.  The statistical analysis will focus 
R a n d o m i s a t i o n 
Restrictive 
At induction 
Hartmanns ≤5 ml/kg 
During surgery 
Hartmanns 5 ml/kg/h 
After surgery 
IV fluids, ≤0.8 ml/kg/h 
Cease IV fluids ASAP, 
aim for early oral fluids 
At induction 
Hartmanns 10 ml/kg 
During surgery 
Hartmanns 8 ml/kg/h 
After surgery 
IV fluids ≥1.5 ml/kg/h 
Continue IV fluids ≥24hrs 
Total fluid in first 24 h for 75 kg adult undergoing 4 h operation 
≤3000 ml 
≥5400 ml 
Both groups 
Blood loss may be replaced with 
colloid / blood 
Liberal 
RELIEF Methods 
Modifications can be made to 
type or rate of fluid if warranted 
by patient’s condition* 

 
16 
on a test for interaction, to determine whether the effects of a fluid regimen work differently in those with and 
without any advanced monitoring. We anticipate that more than half will use (only) clinical measures. 
 
For each of the goal-directed techniques, pulse/stroke volume variation or FTc will be measured before 
commencement of surgery and repeated at regular (say, 10-30 min) intervals intraoperatively.  For those in the liberal 
protocol group, goal-directed therapy can continue postoperatively at 4 hourly intervals, for up to 24 hours after 
surgery.  If there is evidence of fluid responsiveness (eg. systolic pressure/volume variation of ≥13% (77)) at any of 
these times then IV colloid or crystalloid 3-5 ml/kg can be given.  Such data will be collected on the CRF. 
 
Colloid* (recommended) or crystalloid 
(3 ml/kg) 
 
Liberal 
 
Restrictive 
Colloid/blood (using a transfusion 
threshold) bolus if acute bleeding 
Yes 
Yes 
If normotensive but monitoring suggests 
hypovolaemia 
   (eg. CVP<5 or oliguria) 
 
Yes 
 
No 
If normotensive but goal-directed device 
suggests hypovolaemia 
   (eg. FTc <0.33, ∆SV ≥10%, or  SVV≥13%) 
 
Yes 
 
Consider 
If hypotensive 
(1) and hypovolaemia 
(2) but not hypovolaemic 
 
Colloid* 
 
Colloid* ± vasoactive 
 
Colloid* (but limit) + vasoconstrictor 
 
vasoactive therapy 
* starch-based colloids are not recommended (30, 34) 
 
 
 
4.3 Blinding Procedure 
Patients will be blinded to Group allocation.  Anaesthetists, surgeons, and intensivists will have knowledge of Group 
identity. Similarly, it is expected that other surgical and nursing staff, and research staff conducting the in-hospital daily 
reviews, cannot be properly blinded to Group identity. But research staff conducting 1-12 mth follow-ups MUST be 
blinded to Group allocation.   
 
 
 
4.4 Case Report Forms  
For each form on which information is entered, the patient's initials, allocation number and the date of the visit must 
be entered in the appropriate space. The CRFs must be neatly handwritten with a black-ink ballpoint pen. Errors must 
be corrected by drawing a single line through the incorrect entry and writing in the new value positioned as close to 
the original as possible.  
 
The correction must then be initialled and dated by the authorised individual making the change. Do not obliterate, 
write over, or erase the original entry when making a correction. 
Case report forms should be opened as soon as possible following the start of screening and kept up to date as the 
patient continues the study. 
 
As soon as possible after the end of each patient's participation in the study the CRF must be completed. All centres 
must store the paper based CRF according to GCP/ICP guidelines.  
 
 
4.5 Web-based data entry 
Following completion of the paper-based CRF, data will need to be entered by research staff to the database through a 
web-based data entry system. Further information can be found in the Procedures Manual. The system will audit the 
timeliness of data entry and reports will be generated the data monitoring committee regularly. 
 
4.6 Data Base Production and Verification 
Study data will be collected via the internet, monitored by the trial data management centre where all data fields are 
checked and automatically downloaded onto a database.  At the end of the trial site-specific data will be sent to each 
site investigator on a CD, for long-term storage. 
 

 
17 
Study data will be collected in a paper based CRF, for transcription onto a web-database. We will maximize data quality 
and protocol standardization by arranging a start-up meeting at local scientific meetings or live streamed web based 
sessions, and will provide regular feedback to each centre via phone and the trial web-site, along with a monthly 
newsletter.  A complete procedures manual will be produced. All study personnel will have 24-h access to the study 
coordinating centre to resolve any questions that arise.  Further information can be found in the Procedures Manual. 
 
 
4.7 Compliance Checks 
Random audits of centres will be undertaken, to access the accuracy and legitimacy of the trial data. 
Statistical monitoring of the data completeness, data variance, and risk-appropriate endpoint rates will be done for all 
patient data. 
 
 
4.8 Patient Completion/Withdrawal 
All participants who are randomised will and undergo GA for surgery must be followed for the duration of the study 
(unless they withdraw consent) even if they are withdrawn from the active phase of the trial. 
 
 
4.9 Repeat and Special Laboratory Tests 
Serum electrolytes, haemoglobin/haematocrit, and a 12 lead ECG will be ordered preoperatively and if clinically 
indicated  after surgery. All diabetics should have their HbA1C measured before surgery. Further tests will be ordered if 
clinically indicated. 
 
4.10 Adverse Experiences 
Serious adverse effects, serious adverse reactions, or suspected unexpected serious adverse reactions (SUSARs) are 
serious adverse events judged to be related to therapy.  
 
At each visit/assessment, all adverse experiences either observed by the investigator or one of the clinical staff, or 
reported by the patient spontaneously or in response to a direct question will be evaluated by the investigator and 
noted in the adverse experience section of the patient's CRF.  The nature of each experience, time of onset after 
surgery, duration, severity and relationship to treatment will be established. Any corrective treatment should be 
recorded on the appropriate pages of the CRF. 
 
Adverse events should be documented at each assessment point throughout the study. Maximum intensity should be 
assigned to one of the following categories: 
 
Mild - an adverse event which is easily tolerated by the patient, causing minimal discomfort and not interfering with 
everyday activities. 
 
Moderate - an adverse event which is sufficiently discomforting to interfere with normal everyday activities. 
 
Severe - an adverse event which is incapacitating and prevents normal everyday activities and/or requires therapeutic 
intervention (i.e. use of a prescription drug or hospitalisation). 
 
Any serious adverse event should be reported by the local site investigator or research assistant within 24 hours by 
telephone or email to the local site investigator.  Note that study endpoints do not need to be included as serious 
adverse events. 
 
A preliminary telephone report should be followed by a full report which includes copies of relevant hospital case 
records, autopsy reports and other documents, where applicable. 
 
A serious adverse experience is defined as any event which is fatal, life-threatening, permanently disabling or 
incapacitating or results in hospitalisation, prolongs a hospital stay or is associated with congenital abnormality, 
carcinoma or overdose.   
 
Life threatening means that the patient was at immediate risk of death from the event as it occurred, ie. it does not 
include a reaction that, had it occurred in a more serous form, might have caused death. For example, drug induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life threatening, even though drug 
induced hepatitis can be fatal. 

 
18 
 
Permanent disability means a permanent and substantial disruption of a patient's ability to carry out normal life 
functions. 
 
More details for Adverse Event reporting will be found in the procedures manual. 
 
 
5. BIAS CONTROL 
This is a large trial, randomised with permuted blocks (by centre and ICU). Anaesthetists, surgeons, and intensivists will 
have knowledge of Group identity. Similarly, it is expected that other surgical and nursing staff, and research staff 
conducting the in-hospital daily reviews, cannot be properly blinded to Group identity. But research staff conducting 
Day 3, 1-12 mth follow-ups MUST be blinded to Group allocation.  Secondary outcomes are clearly defined in the 
protocol; disputes will be resolved by blinded assessors (endpoint adjudication committee). 
 
 
6. SAMPLE SIZE AND STATISTICAL ANALYSIS 
All statistical analysis will be overseen by Prof Andrew Forbes, Monash University Department of Epidemiology and 
Preventive Medicine.  The intention-to-treat population will include all patients randomly assigned to groups AND 
undergoing induction of anaesthesia. 
 
Our initial sample size calculation was based primarily on our own data and other published studies. Our ENIGMA-II 
trial (n>5000 enrolled to date), with a lower risk study population, has a disability-free survival rate of 70% (15% 
mortality, 15% new disability) at 1 year after surgery).  The most recent large data comes from the UK, where the 1-
year mortality for open colorectal surgery was 17% in the 31,847 patients with pre-existing comorbidity (84). 
Reductions in serious complication rates have exceeded 25% in pooled analyses of similar studies(3, 82) , and pre-
existing major comorbidity increases mortality risk up to 16-fold (83). Using a type I error of 0.05 and survival analysis, 
with an expected one year disability-free survival probability of 65% (65) and a hazard ratio of ≥1.25, 1300 patients in 
each group will provide 90% power.  Target recruitment was set at 2800 patients to account for losses due to follow-
up. The Trial Steering Committee met on the 30th June, 2016, to discuss the results of a data quality committee review 
and statistician’s report of the accruing incidence of disability. With near-complete information on 2,578 enrolled 
patients there were 300 events (disability or death); that is, a 12-month event rate of 14.6% - this is lower than 
expected. An increase in the trial sample size to 3,000 (≈380 events), which provides 80% power to detect HR≤0.75. 
This protocol amendment was accepted by the Steering Committee. 
 
Analyses will be intention-to-treat. For analysis of the composite death-disability endpoint, we will use the Cox 
proportional hazards regression model  with treatment as the only covariate to produce an unadjusted hazard ratio 
with a 95% confidence interval, together with Kaplan-Meier survival curves for graphical display; Analysis of secondary 
outcomes measured on a binary scale will be performed using log-binomial regression to estimate risk ratios with 95% 
confidence intervals, or exact logistic regression to approximate risk ratios if the number of events in either arm is 
fewer than 10.  Time to event outcomes will use Cox proportional hazards regression as above.  For analysis of the 
primary composite death-disability endpoint we will use the Cox proportional hazards regression model with 
treatment as the only covariate to produce an unadjusted hazard ratio with a 95% confidence interval, together with 
Kaplan-Meier survival curves for graphical display.  
 
Outcomes measured on a continuous scale with a right skewed distribution will be log transformed and analysed using 
linear regression with robust standard errors, and outcomes with a left skewed distribution will be analysed with 
median regression with standard errors estimated using 1000 bootstrap replications.  
 
 
Sensitivity Analysis 
Sensitivity analyses for all outcomes will use regression models with additional adjustment for the stratification 
variables of site and planned HDU/ICU destination status, plus any variables exhibiting substantial imbalance across 
treatment arms at baseline.   
 
Sensitivity to missing outcome data will be performed using multiple imputation if the proportion of missing outcome 
data is greater than 5%. This will use baseline and auxiliary post-baseline information to inform the imputations under 
a missing at random assumption. 
 
Subgroup Analysis  

 
19 
Planned sub-group analyses will assess patient sex, age groups (approximate quintiles), country, bowel surgery 
(yes/no), and use of any goal-directed techniques (yes/no). The latter include invasive or non-invasive cardiac output, 
stroke volume or pulse pressure variation, and oesophageal Doppler; but not include CVP monitoring. For these we will 
undertake tests for interaction by adding treatment-by-covariate terms to the regression models.  
 
Additional prespecified subgroups will be tested for heterogeneity of effect, and their results considered exploratory 
(only): country, body mass index (BMI) categories (underweight, normal, overweight, obese, ≥super obese), ASA 
physical status (1/2, 3, 4), planned HDU/ICU destination status, and duration of surgery (approximate quintiles). 
 
 
7. INTERIM ANALYSIS 
Interim analyses will consider the defined study endpoints, but include a specific consideration of 90-day mortality 
(because the primary endpoint is not finalised until 1 year after study entry) after enrolment of 1,445 patients, using 
the boundaries of O'Brien and Fleming. Results will be made available to the Data and Safety Monitoring Committee.  
 
8. SECONDARY ANALYSIS 
 
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. 
 
   8.1 Cost-effectiveness, to include hospital stay and complications as we have done previously (85)   
   8.2 Hyperchloraemic acidosis (to measure strong ion difference, Cl-, lactate, albumin) 
   8.3 Pulmonary oedema (to measure FiO2/PaO2 ratio, CT/CXR-confirmed atelectasis) 
   8.4 Coagulopathy (to measure blood loss, platelet count, fibrinogen, INR, APTT, Hb flux, transfusion) 
   8.5 Sepsis (to measure fever, WCC, CRP and possibly other biomarkers) 
   8.6 AKI and hepatic injury  
   8.7 Postoperative cognitive deficit  
   8.8 Feeding and return of bowel function 
   8.9 Wound healing and anastomotic leak 
 
9. PERSONNEL RESPONSIBILITIES 
 
9.1 Investigators 
The Steering Committee will consist of the principal investigator (PSM [Chair]), and other clinician-researchers in 
anaesthesia, surgery and intensive care medicine, plus the trial statistician – see below. 
 
Each site investigator must ensure that all staff conducting the study are qualified to do so. 
 
Each site investigator must submit the study protocol to the Ethics Committee or equivalent regulatory body and obtain 
approval prior to commencing the study. 
 
Each site investigator must ensure that all staff involved with the study are fully instructed on the study procedures and 
are given access to the study protocol and other information relating to the study. 
 
Each site investigator must ensure that the study is conducted in accordance with this protocol, ICH GCP notes for 
Guidance on Good Clinical Practice (CPMP/ICH/135/95) and in Australia with the NHMRC National Statement on Ethical 
Conduct in Research Involving Humans.  
 
It is each site investigator’s responsibility to ensure that written, informed consent is obtained from each patient prior to 
entering the study. 
 
Each site investigator must ensure that the web-based CRFs are complete and accurate on completion of the study.  
Each site investigator will ensure that the quality control procedures are performed on both the CRFs and the data base. 
 
It is the principal investigator’s responsibility, in conjunction with the chief investigators, to write the Study Report at the 
completion of the study.  Authorship guidelines are described in Section 11. 
 
9.2 Monitor 

 
20 
Not applicable. 
 
9.3 Sponsor 
Alfred Health, as an investigator initiated study. 
 
9.4 Steering Committee 
The steering committee will include Paul Myles (chair), Rinaldo Bellomo, Tomas Corcoran, Chris Christophi, Andrew 
Forbes, Phil Peyton, David Story,, Kate Leslie, Jonathan Serpell, Shay McGuinness, Rachel Parke and Sophie Wallace (trial 
manager) 
 
9.5 Endpoint Adjudication Committee (EAC) 
Confirmation reports of all detected outcomes will be de-identified and re-labelled with study number.  The committee 
will consist of experienced perioperative physicians. Details are provided in the Procedures Manual. Their role will be 
to resolve any uncertainty as to any of the above outcomes: additional advice can be sought by consultation with sub-
specialists.  
 
10. DATA SAFETY MONITORING COMMITTEE  
The committee consists of Prof Monty Mythen (Chair, intensivist, Smiths Medical Professor of Anaesthesia & Critical 
Care, University College London (UK); Co-Director, Surgical Outcomes Research Centre), Prof Russell Gruen (surgeon, 
Professor of Surgery and Public Health, The Alfred & Monash University Director, National Trauma Research 
Institute; Melbourne), Prof John McNeil (epidemiologist and triallist, Professor of Epidemiology and Preventive 
Medicine; Head, School of Applied Clinical and Public Health Sciences; Monash University), Prof Guy Ludbrook 
(anaesthetist, Professor of Anaesthesia, Flinders University), and Dr Katherine Lee (independent statistician, MCRI). 
 
The DMSC will discuss the interim results and vote for continuation or stopping the trial.  A majority vote to stop the 
trial will be communicated to the Steering Committee at the Trial Coordinating Centre according to predetermined 
stopping rules (as above) and consideration of other relevant evidence. Their conduct is to be guided by the paper by 
DeMets et al. (86). Further details are provided in the DSMC charter. 
 
 
11. ADMINISTRATIVE PROCEDURES 
 
11.1 Amendments to the Protocol 
RELIEF Trial participating 
centres 
Endpoint 
Adjudication 
Committee 
Steering 
Committee 
Data Safety Monitoring 
Committee 
Biostatistician 
Data Management Centre 

 
21 
All modifications of the study will be written and filed as amendments to this protocol, maintaining original section 
identification. Such modification(s) will be made by the principal investigator, with endorsement by the Steering 
Committee and with the approval of the Ethics Committee (where applicable). 
 
Any modifications to the study will be applied for all subsequent patients 
 
11.2 
 Early Termination or Extension of the Study 
The investigator (with Ethics Committee approval) may discontinue or extend the study at any time. 
 
 
11.3 
Confidentiality/Publication of Study Results 
Interim and preliminary results should not be discussed or presented outside the Trial Group, unless authorised by the 
chair of the Trial Steering Committee. The investigators plan to publish the results in a peer-reviewed journal.  
 
11.4 
Retention of Records 
All CRFs and all other documents associated with this study must be archived for at least 7 years following the 
completion of the trial, in accordance with TGA requirements.   
 
11.5 
Audits 
For the purpose of compliance with ICH GCP notes for Guidance on Good Clinical Practice (CPMP/ICH/135/95), it may be 
necessary for a regulatory agency to conduct a site audit. 
 
Random audits may be conducted throughout the trial at the discretion of the Trial Steering Committee. 
 
12. ETHICAL PROCEDURES 
 
12.1 
Guidelines for Good Clinical Practice 
This study is to be performed in accordance with ICH GCP notes for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95). 
 
12.2 
Precautionary Advice 
None specifically required. 
 
12.3 
Participant Information Sheet and Consent Form 
The investigator or delegate will explain the study verbally to the patient.  The patient will then be given a copy of the 
PI&CF and given an opportunity to read it and ask any questions of the investigator.  The patient will be encouraged to 
obtain additional information about the study from an independent source.  Once the patient is satisfied with the 
information they have received, has had an opportunity to ask questions and obtain additional information, and the 
investigator is satisfied that the patient truly understands the nature of the study, the patient will be asked to sign the 
consent form. 
 
The signing of the consent form must take place in front of a witness and that witness must also be satisfied that the 
patient has a good understanding of the study.  Each patient’s signed consent form will be retained by the investigator.    
 
Patients will be advised that they are free to refuse to participate in, or to withdraw from the study at any time.  The 
medical care provided will not be affected by agreement or refusal to participate in this study.  The original Consent 
Form for each subject will be stored in the Investigators file and a copy of the consent form will be placed in the 
patient’s medical record. 
 
12.4 
Ethics Committee 
This protocol will be submitted to the Ethics Committee (or relevant regulatory body) at each site and their approval 
obtained. 

 
22 
13. AUTHORSHIP PLAN 
 
RELIEF Trial  
Authorship & Agreement 
 
 
Target Journal: Lancet, New England Journal of Medicine, or JAMA 
 
Planned Authorship: The RELIEF Trial Investigators 
 
The trial will be described as a collaboration of the Australian and New Zealand College of Anaesthetists (ANZCA) Trials 
Group and the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. 
 
The planned writing committee will include Paul Myles, Rinaldo Bellomo, Tomas Corcoran, Andrew Forbes, Philip Peyton, David 
Story, Chris Christophi, Andrew Davies, Kate Leslie, and Jonathan Serpell.  This list may be extended or altered, according to a 
majority vote of the Trial Steering Committee. 
 
Committee members and Site investigators at centres recruiting more than 250 patients will be offered co-authorship 
on at least one of the secondary publications.  A more extensive participation and higher rate of patient enrolment may 
support a claim for authorship on the main publication (above), subject to a majority vote of the Trial Steering 
Committee.  
 
Following acceptance for publication, all co-investigators (site investigators at each centre) can have access to all trial 
data if they would like to plan secondary analysis (and follow-up publication or presentation).  A separate protocol 
should be developed and will require approval by the Trial Steering Committee before the presentation is made or 
submitted for publication.    
 
An Authorship Agreement document will be produced before commencement of the trial, and all site investigators will 
be asked to sign their acknowledgement of this.   
 
All site investigators listed in the appendix of the final publication(s) can be considered an author and so can list the 
publication(s) on their CVs.    
 
Agreement to Participation 
I have read the trial protocol and agree to conduct the study according to the procedures outlined, and in accordance 
with Good Clinical Research Practice (GCRP) guidelines.  Any information related to this trial will be kept confidential 
until publication or presentation at a scientific meeting.  I have read and accept the proposed authorship plan. 
 
 
 
 
Site Coordinator (print): ………………………………. 
 
 
 
 
 
Signature: ……………………………….……  
Date: ……/..…/……… 
 

 
23 
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