Protocolised Management In Sepsis (ProMISe): a multicentre, randomised controlled trial of the clinical and cost-effectiveness of early protocolised resuscitation for emerging septic shock

Severe sepsis is a syndrome characterised by a systemic inflammatory response to infection that often leads to rapid acute organ failure and death. In 2006, ICNARC reported an increasing incidence of severe sepsis in UK adult critical care units, rising from 50 to 70 cases per 100,000 population over the last decade (equating to 31,000 patient episodes per year). 29% of all admissions to adult, general critical care units were associated with severe sepsis in the first 24 hours and had a hospital mortality of 45% (equating to 15,000 deaths per year). 21% of all severe sepsis cases (equating to 6,500 patients per year) were admitted for critical care via the emergency department (ED). Acute hospital mortality for these patients was 35% with average lengths of stay of 9 days in the critical care unit and a further 14 days in acute hospital following critical care. In 2001, Rivers et al. reported the results of a randomised controlled trial (RCT) that delivered six hours of early, goal-directed, protocolised resuscitation to patients presenting at a single US ED with emerging septic shock. Early, goal-directed, protocolised resuscitation, compared with usual resuscitation, significantly reduced hospital mortality (from 46.5% to 30.5%) and shortened hospital length of stay for survivors. ProMISe is an RCT of a six-hour, early, goal-directed resuscitation protocol (akin to the Rivers' protocol), compared with usual resuscitation (standard UK resuscitation practice), for patients presenting in the ED with early signs of severe sepsis/septic shock (systemic inflammatory response, known or presumed infection and hypotension or hypoperfusion). ProMISe is a pragmatic, multi-centre, open, parallel-groups RCT. Allocation to one of the two arms will be stratified by recruiting centre. All care, either after six hours of the early, goal-directed, resuscitation protocol or in the usual resuscitation arm, will be at the discretion of the treating clinician(s). All recruited patients will be followed-up for one year. To achieve 80% power to detect a reduction in 90-day mortality from 40% to 32% (P<0.05), ProMISe will recruit 630 patients per arm (allowing for refusal of consent, or loss to follow-up at 90 days). Based on an observed rate of 24 admissions per year, ProMISe anticipates that each participating hospital will be able to recruit 14 patients per year. At this recruitment rate, ProMISe will be completed with 48 hospitals recruiting for 26 months and allowing for centres commencing recruitment incrementally over the first six months of patient recruitment. The primary objectives are: - to compare early, goal-directed, protocolised resuscitation, compared with usual resuscitation, on mortality at 90 days; - to compare incremental cost-effectiveness of early, goal-directed, protocolised resuscitation, compared with usual resuscitation, at one year. The secondary objectives are to compare early, goal-directed, protocolised resuscitation, compared with usual resuscitation, on: - mortality at one year; - health-related quality of life at 90 days and one year; - resource use and costs at 90 days and one year; - requirement for, and duration of, critical care unit organ support; - length of stay in the ED, critical care unit and acute hospital; and - to estimate lifetime, incremental cost-effectiveness. A full cost-effectiveness analysis (CEA) will be undertaken. All analyses will be lodged in a statistical analysis plan, a priori, before the investigators are unblinded to any trial outcomes. All analyses will be performed according to the intention-to-treat principle, and results will be reported in accordance with the CONSORT statement. ProMISe liaises with two similar trials, internationally, ProCESS (USA) and ARISE (Australasia). An individual patient data meta-analysis is planned for the three trials.