About The Trial

Research Question

In patients aged 50 and over undergoing emergency laparotomy surgery, does cardiac output-guided haemodynamic therapy during and for six hours following surgery increase days alive and out of hospital when compared to standard care?

Background

Outcomes from emergency bowel surgery (laparotomy) represent a major healthcare problem. More than 30,000 patients in England and Wales undergo this surgery annually, with over 3,000 patients dying within 30 days of surgery ¹. One treatment with the potential to improve outcomes is peri-operative intravenous fluid administration guided by cardiac output monitoring. Large recent trials, and a Cochrane review, have suggested - but not confirmed - that this treatment may be effective in reducing postoperative complications after major elective bowel surgery ^2,3. However, the Cochrane review found that there were insufficient data to support its routine use in emergency surgery. Emergency surgical patients have major haemodynamic differences from elective patients, so it is possible that this treatment may either be more or less effective in this group. Improving outcomes for patients undergoing emergency surgery was one of the top ten research priorities resulting from the 2015 James Lind Alliance Priority Setting Partnership, underlining the importance of this area to clinicians, patients and the public. If this treatment had a similar beneficial mortality effect to that suggested in elective surgical populations and was adopted into routine practice, hundreds of lives each year could be saved in England and Wales.

Study design

Pragmatic multicentre open randomised trial supported by data from the ongoing National Emergency Laparotomy Audit (NELA), with internal feasibility phase.

Inclusion criteria

All patients aged 50+ requiring emergency bowel surgery in line with NELA criteria, with or without capacity to consent.

Intervention

Protocolised cardiac output-guided haemodynamic therapy during surgery, and for six hours after in patients admitted to an area capable of delivering this intervention. Clinician discretion on choice of cardiac output monitor and isotonic fluid for boluses.

Control group

Intravenous fluid administration without the use of cardiac output monitoring or protocol.

A set of basic standards of care will be applied to both groups, in line with best current evidence. All elements of control or intervention group care will be delivered by the patient’s clinical team.

Primary outcome

Number of days spent alive and out of hospital within 90 days of trial randomisation (DAOH-90).

Secondary outcomes

90 days and one-year mortality; length of stay in hospital and intensive care; hospital readmission within 90 days; cost effectiveness.

Sample size and recruitment rate

Participant recruitment started in 2017 with an aim to complete recruitment within three years. 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 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.

For the new primary outcome of DAOH-90, we calculated that 3138 participants (1569 per group) would be required 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), with 90% power, a 5% alpha level, and a 2% dropout rate.

Efficient trial design features

This proposal has been funded through the NIHR Health Technology Assessment programme through their Efficient Study Designs stream. To deliver this trial in a timely fashion and without excessive cost this trial has an efficient design, featuring:

NELA support

Data on patient baseline characteristics, details of surgery, peri-operative events and postoperative outcomes will be restricted to those collected by the National Emergency Laparotomy Audit by the treating clinicians as part of routine care, and NHS datasets.

Minimal requirement for additional research staff

Clinicians will deliver the intervention or control group care. Anaesthetists and intensive care teams are familiar with cardiac output-guided fluid therapy and the presence of additional research staff during the intervention will not be required.

The EPOCH trial, examining the effect of an integrated care pathway and quality improvement package in this patient group, has shown the success of a similar study design. It has used NELA data for outcomes measures, and an intervention that is delivered by clinicians.

Adoption by trainee research networks

Trainees in anaesthesia and surgery have a major input to the care of patients undergoing emergency laparotomy. They are extremely well-placed to assist in patient recruitment - particularly out of hours - and the trial intervention. National adoption of this trial by the surgical and anaesthetic trainee research networks will harness the success these networks have had with recent multicentre and randomised trials, and help embed this trial within clinicians’ daily practice.

No additional cost from the trial intervention

Nearly all UK Trusts have cardiac output monitors available for use during surgery. We will seek industry support to contribute consumables for cardiac output monitoring. The intervention typically only involves a minor additional volume of intravenous fluid to be given.

Network support

FLO-ELA has been adopted by the UK Perioperative Medicine Clinical Trials Network. This network was recently formed to develop, support and co-ordinate the efficient delivery of large scale perioperative clinical trials. This has given the trial access to an organised network of trained, experienced local principal investigators with a strong focus on delivering trials such as this to target. This collaborative network will also strengthen links between FLO-ELA and stakeholder groups including trainees, surgeons, anaesthetists and clinical research networks, further supporting its successful uptake and delivery.

References

• NELA project team. First Patient Report of the National Emergency Laparotomy Audit. Royal College of Anaesthetists; 2015.
• Grocott MPW, Dushianthan A, Hamilton MA, Mythen MG, Harrison D, Rowan K. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. Cochrane Database Syst Rev Online. 2012;11:CD004082.
• Pearse RM, Harrison DA, MacDonald N, Gillies MA, Blunt M, Ackland G, et al. Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA J Am Med Assoc. 2014 May 19;311(21):2181-90.