ProMISe
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.
Publications
Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, Canter R, Coats TJ, Delaney A, Gimbel E, Grieve RD, Harrison DA, Higgins AH, Howe B, Huang DT, Kellum JA, Mouncey PR, Music E, Peake SL, Pike F, Reade MC, Sadique MZ, Singer M, Yealy DM. Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. N Engl J Med 2017; . http://dx.doi.org/10.1056/NEJMoa1701380
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Tan JC, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess 2015; 19(97):1-150. http://dx.doi.org/10.3310/hta19970
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372(14):1301-11. http://dx.doi.org/10.1056/NEJMoa1500896
Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, Davies A, Delaney A, Harrison DA, Holdgate A, Howe B, Huang DT, Iwashyna T, Kellum JA, Peake SL, Pike F, Reade MC, Rowan KM, Singer M, Webb SA, Weissfeld LA, Yealy DM, Young JD. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015; 41(9):1549-60. http://dx.doi.org/10.1007/s00134-015-3822-1
Power GS, Harrison DA, Mouncey PR, Osborn TM, Harvey SE, Rowan KM. The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan. Crit Care Resusc 2013; 15(4):311-7.
Huang DT, Angus DC, Barnato A, Gunn SR, Kellum JA, Stapleton DK, Weissfeld LA, Yealy DM, Peake SL, Delaney A, Bellomo R, Cameron P, Higgins A, Holdgate A, Howe B, Webb SA, Williams P, Osborn TM, Mouncey PR, Harrison DA, Harvey SE, Rowan KM. Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe. Intensive Care Med 2013; 39(10):1760-75. http://dx.doi.org/10.1007/s00134-013-3024-7
Reade MC, Delaney A, Bailey MJ, Harrison DA, Yealy DM, Jones PG, Rowan KM, Bellomo R, Angus DC. Prospective meta-analysis using individual patient data in intensive care medicine. Intensive Care Med 2010; 36(1):11-21. http://dx.doi.org/10.1007/s00134-009-1650-x
Delaney A, Angus DC, Bellomo R, Cameron P, Cooper DJ, Finfer S, Harrison DA, Huang DT, Myburgh JA, Peake SL, Reade MC, Webb SA, Yealy DM. Bench-to-bedside review: the evaluation of complex interventions in critical care. Crit Care 2008; 12(2):210. http://dx.doi.org/10.1186/cc6849
