Title: 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
Funder: Department of Health and Social Care

Abstract: DESIGN Open multi-centre randomised controlled trial with internal pilot study SETTING Surgical services of 100 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: Mortality within 90 days of randomisation. Secondary outcome: Mortality within one year of randomisation. 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; 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 3823 patients in each arm (7646 total) to detect a risk ratio of 0.85 (equivalent to an absolute decrease from 19% to 16.15%) for the primary outcome. ECONOMIC EVALUATION Time horizon: 90 days 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 Recruitment will take place in 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 will be needed to recruit the required sample size, followed by a one-year follow-up period with six months for final data analysis & dissemination. 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.

Lay abstract: RESEARCH AIMS We aim to trial a treatment used to guide the dose and timing of fluid administered into the bloodstream to patients during and shortly after surgery. We will trial this treatment, called “goal-directed haemodynamic therapy” (GDHT), in patients undergoing emergency bowel surgery (laparotomy). BACKGROUND Emergency laparotomy is a common major emergency surgical procedure, performed to treat life-threatening conditions caused by cancer, infections or previous surgery. Over 30,000 people in England & Wales undergo this surgery annually at a cost of over £650m. Outcomes from emergency bowel surgery are poor; 14% of patients aged over 50 die within a month of surgery, rising to 20% within three months. As this surgery is so common, treatments that reduce death rates even slightly could save hundreds of lives. Major surgery and critical illness (both features of emergency bowel surgery) reduce blood flow to vital organs. This can cause serious complications and death after surgery. Fluids are given into the bloodstream to improve blood flow. Giving the right amount of fluid at the right time has a major impact on outcomes after surgery, but is hard to gauge accurately. Clinicians normally use signs such as heart rate and blood pressure to guide them, but these can be unreliable. GDHT aims to address this. It lets clinicians determine the dose and timing of fluid to give patients, guided by a monitor measuring the blood flow pumped by the heart. GDHT may be beneficial in planned surgery, but has not been properly tested in the complex setting of emergency bowel surgery. PRIMARY OBJECTIVE To determine whether GDHT given to patients aged 50+ during and for up to six hours after emergency laparotomy reduces the number of deaths within 90 days of surgery. SECONDARY OBJECTIVES To determine whether GDHT: -reduces deaths within one year of surgery -reduces time spent in intensive care and in hospital after surgery -is good value for money DESIGN Trial of 7646 patients randomly assigned to GDHT or usual care in 100 hospitals over three years. This will tell us whether GDHT reduces mortality from 19% to 16% within 90 days of surgery. This would equate to >700 lives saved annually in the UK. The trial is designed to be efficient and economical by: -using an ongoing database (National Emergency Laparotomy Audit) for all trial data; NO extra data collection from patients. -reducing the need for research staff. Clinical staff will be responsible for trial procedures. They are familiar with GDHT and have shown support for the trial through surveys on research priorities and their views on this treatment. Front-line anaesthetic and surgical trainee doctors will recruit patients round the clock. Their research networks have a proven track record in trial recruitment and are partners in this proposal. PATIENT & PUBLIC INVOLVEMENT We have had active patient involvement from the outset. A 2015 James Lind Alliance project ranked this topic in the ten most important research questions in perioperative medicine. Our lay member will attend trial meetings and be involved in key decisions. DISSEMINATION FLO-ELA will provide definitive evidence on the value of this treatment. The results will be widely disseminated to front-line NHS staff, patients and healthcare policy makers. The trial will be carried out in a “real world” NHS setting so we expect widespread uptake of GDHT for this group if found to be beneficial.

Research activity codes: 6.4 SURGERY
Health categories: ORAL AND GASTROINTESTINAL