This was a multi-centre, prospective, randomised, controlled trial conducted in four Scottish hospitals, coordinated from the Centre for Healthcare Randomised Trials in the Health Services Research Unit, University of Aberdeen [20]. The trial was designed as a partial 2*2 factorial design with initial randomisation to fluid loading versus no fluid loading, with a secondary randomisation (if an ICU bed was available at the time of recruitment) to intensive care (level 3) versus high dependency (level 2) care [20]. The second randomisation had to be abandoned, however, due to a continuing lack of ICU beds at the time of patient recruitment (this decision was agreed upon with the funder, the Data Monitoring Committee (DMC) and the Trial Safety Committee (TSC). As such, this paper presents the results for the single comparison of fluid loading versus no fluid loading. The design features and estimates used in this protocol were informed by the results of a 15-week pilot program undertaken in the Aberdeen Royal Infirmary during which 23 patients were recruited (not included in this analysis). The main study was undertaken in three university hospitals (Aberdeen Royal Infirmary, Glasgow Royal Infirmary and Glasgow Western Infirmary) and one district general hospital (Royal Alexandra Hospital, Paisley).
Participants were recruited from the elective operating schedules in the recruiting hospitals and informed consent was obtained. Patients were, in general, identified following a pre-assessment visit at a local hospital or following their initial appointment with the surgeon. They were sent an information leaflet prior to their hospital admission whenever possible. Informed consent was sought from these patients on their admission to hospital. Patients were fasted according to local hospital fasting policies and always for at least six hours before surgery. No hospital in the study allowed consumption of carbohydrate rich fluids up to two hours before surgery.
Inclusion criteria included patients undergoing major elective intra-abdominal surgery including major intra-peritoneal surgery, major open aortic surgery, major renal and bladder surgery and hysterectomy and oophorectomy for cancer. Patients were required to fulfil two high-risk surgical criteria according to the Revised Cardiac Risk Index (RCRI); these include a high risk type of surgery, presence of ischaemic heart disease, history of congestive heart failure, history of cerebrovascular disease, insulin therapy for diabetes and pre-operative serum creatinine > 160 μmol/L [21]. Patients who underwent open or laparoscopically-assisted surgery were eligible. Clinical exclusion criteria included clinician concern about the safety of interventions, New York Heart Association grade IV heart failure, emergency surgery, chronic renal failure/creatinine > 300 μmol/L, lack of informed consent, age < 16 years, pregnancy, major hepatic surgery, and expected survival < 6 months.
Participants were randomised through an interactive voice response automated telephone randomisation service on the day before surgery. A minimisation algorithm was used, incorporating centre, age, sex and type of surgery [22]. POSSUM (Pre-Operative and Operative Physiological and Operative Severity Score for Enumeration of Mortality and Morbidity) scores were measured to derive physiological disturbance and operative severity [23].
Fluid interventions
Patients were randomised to ward-based intravenous pre-operative fluid loading or no pre-operative fluid loading. The pre-operative fluid loading group patients were electively commenced on 25 ml/kg Ringer's lactate solution over the six-hour period in the ward setting before surgery [5]. In the standard fluid regimen no routine pre-operative fluid loading was given. All patients receiving bowel preparation were given 10 ml/kg Ringer's lactate solution in the 12- to 6-hour period before surgery irrespective of trial group allocation as this is deemed to be the best clinical practice. Fluids were not warmed during administration. This meant that fluid loading patients who received bowel preparation would receive 35 ml/kg in the 12 hours before surgery.
All non-protocol fluid prescriptions and other management decisions were made by the clinically responsible surgical team. We did not control or protocolise the time of discharge from hospital. Due to the nature of the interventions no blinding of the interventions was possible.
All participants were followed up daily for one week for major morbidity and mortality, then at hospital discharge and then one, three and six months after surgery for survival and quality of life. The decision to discharge the patient from hospital was made by the caring team with no involvement of the study personnel. Study outcomes measured during hospital stay were measured by study personnel not blinded to the intervention. Outcomes assessed after hospital discharge were measured using postal participant questionnaires.
Outcomes
The primary outcome was the number of days in hospital after surgery [9–13] Secondary outcomes included cost-effectiveness at six months, measured by the Net Benefit statistic, which is calculated using the following equation: ((λ * quality adjusted life year (QALY)) - costs) where λ indicates society's 'willingness to pay' (λ is typically set at £20,000) [24], QALY are calculated using EQ-5D scores and costs included both primary and secondary care costs [25]. Other secondary outcomes, including measures of health status, included changes in health status and quality of life over 6 months after surgery and quality of life at 48 hours, 1, 3 and 6 months after surgery, measured using SF-36 and EQ-5D [25–27]; health care costs including full hospital costs and primary care costs; mortality measured using time-to-event analysis; and the level of major morbidities in hospital using the Post-Operative Morbidity Survey at days 1, 3 and 7 after surgery (POMS) [28] Serious adverse events were assessed by clinical leads defined according to standard definitions, (that is, an untoward occurrence that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, consists of a congenital anomaly or birth defect, or is otherwise considered medically significant by the investigator) [29].
Sample size
The full power calculation is presented in the trial protocol paper [20]. For the fluid comparison, we aimed to be able to detect a 0.5 SD difference in the primary outcome of number of days in hospital following surgery, with 80% power and 5% significance. This resulted in a target sample size of 128 patients. Data on number of days in hospital were available for all patients in the trial.
Statistical analysis
The statistical analysis was based on all people randomised, irrespective of subsequent compliance to treatment allocation. Trial analysis was undertaken using standard methods for two-group comparisons for continuous, binary and time-to-event outcomes using intention to treat principles. All statistical analyses were pre-specified in a Statistical Analysis Plan which was agreed upon before the analysis was undertaken. The primary analysis was adjusted for the minimisation variables using analysis of covariance. A significance level of P < 0.05 was considered as evidence of statistical significance for the primary outcome and confidence intervals presented. An a priori secondary subgroup analysis was investigated through tests for interaction and included patients with high cardiac risk [21]; patients with high-grade functional limitation due to heart failure and type of surgery. Stricter levels of statistical significance (P < 0.01) were sought, reflecting the exploratory nature of these subgroup analyses.
Economic analysis
A within trial economic analysis was conducted from the UK National Health Services' perspective. Discounting was not used since the follow-up was only six months. Benefits in the economic analysis were reported in terms of QALYs estimated from the responses to the EQ-5D questionnaire at five time points - baseline (before surgery), 48 hours, 1 month, 3 months and 6 months after surgery. These responses were converted to utility values using the EQ-5D social tariff, which has been estimated from a representative sample of the UK population [25]. The utility scores obtained at these time points were transformed into QALYs using the area under the curve method by assuming linear extrapolation between subsequent data collection time points.
Patient specific data for the use of NHS resources were retrieved using patient case notes (post-operative inpatient length of stay and outpatient visits) as well as six months' questionnaires to participants (primary care contacts and medicines consumed). Unit costs were retrieved from a number of publicly available sources [30–32]. Intervention cost for base case analysis considered no extra time for pre-operative fluid loading, 30 minutes doctor's time and 42 minutes nurse's time.
Sensitivity analyses were performed for cost and QALYs by alternatively excluding from the analysis participants with 5% and 10% highest and lowest total cost or QALYs. Moreover, the intervention cost was adjusted by adding 12 hours inpatient time in the surgical ward. This scenario would be relevant if normal practice (in the absence of fluid loading) was to conduct surgery on the day of admission. In this situation, patients who receive the fluid intervention would be required to be admitted to hospital earlier to allow time for pre-operative fluid loading to take place. Furthermore, alternative bed-ridden EQ-5D scores were used as baseline utility scores for all participants (that is, -0.402). Finally, missing data were not regarded a priori as an issue for the base case analysis. However, this was tested by imputing mean EQ-5D and mean costs for those categories with missing data within each study group and this was further explored using multiple imputation techniques. A base case analysis and sensitivity analyses were performed. For every analysis, differences in mean total cost and mean QALY data were bootstrapped (1,000 repetitions) adjusting for minimisation variables as well as baseline EQ-5D score [33].
Trial oversight
The Multicentre Research Ethics Committee for Scotland approved the study (Ref 04/MRE10/76). The trial was registered in a public trials registry (registry number ISRCTN32188676). The trial was overseen by a TSC with an independent Chair and an independent DMC reviewed accruing data at regular intervals.
Role of the funding source
The study sponsor and funding source had no role in the collection, analysis and interpretation of data, or in the writing of the report, or in the decision to submit the paper for publication.