ICNARC played a key role in establishing whether a new treatment protocol for critically ill patients with sepsis improved patient outcomes, both nationally and internationally. 

UK delivery 

Sepsis is a global health priority, affecting millions of people worldwide, with critical care sepsis admissions costing in excess of £100 million annually. EGDT is a structure treatment plan for the early management of sepsis that involves more ‘aggressive’ use of interventions. Based on low quality evidence its implementation was widely recommended and practiced internationally. The Protocolised Management In Sepsis (ProMISe) evaluation investigated the effectiveness of early goal directed therapy (EGDT) in patients with sepsis. 

Prior to the ProMISe study, the evidence for benefit from EGDT was derived from observational studies and small trials, in particular one small single-centre trial published in the New England Journal of Medicine, which observed a 16% reduction in mortality when EGDT was initiated. The ProMISe randomised clinical trial enrolled 1260 septic patients from 56 hospitals in the UK to evaluate the effect of EGDT on patient outcomes. The trial reported that EGDT did not result in better patient outcomes, including mortality or quality of life, compared with usual care, and was associated with higher costs across a broad range of patient and hospital characteristics.  

This provided high quality evidence to clinicians, policy makers and the community that adoption of EGDT from usual care was not appropriate, leading to immediate changes in international guidelines including those from the international Surviving Sepsis Campaign and the UK’s National Institute for Clinical Excellence. Overall, the publication in the New England Journal of Medicine, has been cited over 1000 times, is included in 10 policy documents. With an estimated 6,500 critical care admissions from sepsis, de-implementation of EGDT would save the NHS approximately, £6.5 million/year, returning the grant investment within months.  

International collaboration 

The results of ProMISe were combined with the two other similar large randomised clinical trials of EGDT carried out in Australia/New Zealand (ARISE) and in the United States (ProCESS). This pre-planned individual patient data meta-analysis, led by ICNARC, included a total of 3763 patients across the three studies confirmed that there was no benefit of EGDT. This also allowed further understanding about whether particular patient groups may benefit from the more aggressive treatment (e.g. higher illness severity), but confirmed there was no such benefit. This was able to alleviate concerns that important treatment effects in patient subgroups or particular settings may have been missed in the individual RCTs due to a lack of statistical power. This analysis also included cost-effectiveness analyses, finding that the average incremental net monetary benefit for EGDT versus usual care was negative, and the probability that EGDT is cost-effective was less than 25%, providing further support to the conclusion that EGDT is not superior to usual care. The results were also published in NEJM and have been cited >300 times.  


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