FLO-ELA: FLuid Optimisation in Emergency LAparotomy. Open, multi-centre, randomised controlled trial of cardiac output-guided haemodynamic therapy compared to usual care in patients undergoing emergency bowel surgery

DESIGN Open multi-centre randomised controlled trial with internal pilot study SETTING Surgical services of 50 NHS hospitals PATIENTS Patients aged 50 years and over undergoing an expedited, urgent or emergency major abdominal procedure on the gastrointestinal tract eligible for inclusion within the National Emergency Laparotomy Audit (NELA). Exclusion criteria: Refusal of patient consent, clinician refusal, abdominal procedure outside the scope of NELA, previous enrolment in the FLO-ELA trial, previous inclusion in the NELA audit within the same hospital admission, current participation in another clinical trial of a treatment with a similar biological mechanism. INTERVENTION Goal-directed haemodynamic therapy (GDHT): use of cardiac output monitoring to determine the dose & timing of intravenous fluid administration according to a suggested algorithm, during and up to six hours after emergency laparotomy. CONTROL Usual care, with intravenous fluid given according to conventional clinical assessment without the use of cardiac output monitoring or associated treatment algorithm. MEASUREMENT OF OUTCOMES & COSTS Primary outcome: Number of days spent alive and out of hospital within 90 days of trial randomisation (DAOH-90). Secondary outcome: 90 days and one-year mortality; length of stay in hospital and intensive care; hospital readmission within 90 days; cost effectiveness. Process outcomes: Length of stay in hospital; length of stay in critical care; hospital re-admission within 90 days. Economic outcomes: Secondary care costs within 90 days and one year; within-trial cost-effectiveness of intervention based on mortality and quality-adjusted life years, from a secondary care perspective. SAMPLE SIZE With a 5% alpha level and 90% power, and assuming a 2% dropout rate, we require 1569 patients in each arm (3138 total) to detect a 3.2-day increase in DAOH-90 (from mean 64.5 (SD 28.0) days in the control group to 67.7 (SD 27.1) days in the intervention group). ECONOMIC EVALUATION Time horizon: 90 days and one year following randomisation. Perspective: secondary care, focusing on anticipated drivers of total costs. Cost-effectiveness: costs linked with primary outcome (mortality) Cost-utility: costs linked with quality-adjusted life years (mapped from NIHR EPOCH trial) EFFICIENT STUDY DESIGN The trial is set up to be efficient and economical by: -using an established, ongoing database (National Emergency Laparotomy Audit) and existing NHS sources for all data on clinical details and outcomes; no additional data collection from patients. -reducing the need for research staff. Clinicians will deliver the study interventions; they are familiar with the intervention and have indicated their support through research prioritisation exercises and clinician surveys. Front-line anaesthetic and surgical trainees will support study recruitment round the clock through trainee research networks. These have a proven track record in delivering trials and are partners in this proposal. -no excess intervention costs, as nearly all hospitals already own the cardiac output monitors required for the intervention. PROJECT TIMETABLES & RECRUITMENT RATE Participant recruitment started in 2017 with an aim to complete recruitment within three years across 100 hospitals within NELA that submit data on >10,000 emergency laparotomies annually. Based on a 30% patient uptake rate among eligible patients, three years were needed to recruit the required sample size, followed by a one-year follow-up period with six months for final data analysis & dissemination. The original primary outcome planned was mortality at 90-days after randomisation, with a required sample size of 7646 participants. Due to slower than anticipated recruitment rates and the impact of the COVID-19 pandemic, we were no longer able to achieve the originally planned sample size. A revised primary outcome and sample size was agreed with oversight committees and the trial funder. These changes were made without any access to or knowledge of unblinded data. EXPERTISE IN TEAM Internationally leading expertise with outstanding track record in completing large multi-centre trials in perioperative medicine. The Clinical Trials Unit has methodological expertise and experience of working with NELA. The group includes diverse representation of all relevant professional groups (surgeons, anaesthetists & intensive care physicians), the NELA Project Team, clinical trialists and of patients and carers.