title: 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.
abstract: BACKGROUND
  Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness.
  
  
  OBJECTIVE
  The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness.
  
  
  METHODS
  A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation.
  
  
  METHODS
  Fifty-six NHS hospitals in England.
  
  
  METHODS
  A total of 1260 patients who presented at EDs with septic shock.
  
  
  METHODS
  EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1.
  
  
  METHODS
  All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year.
  
  
  RESULTS
  Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events.
  
  
  CONCLUSIONS
  Recruitment was lower at weekends and out of hours. The intervention could not be blinded.
  
  
  CONCLUSIONS
  There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%.
  
  
  CONCLUSIONS
  The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN36307479.
  
  
  BACKGROUND
  This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mouncey
authors.affiliation: Departments of Surgery and Emergency Medicine, Washington University, St Louis, MO, USA.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Osborn
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: G Sarah
authors.initials: GS
authors.lastname: Power
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Harrison
authors.affiliation: Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: M Zia
authors.initials: MZ
authors.lastname: Sadique
authors.affiliation: Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Grieve
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: Rahi
authors.initials: R
authors.lastname: Jahan
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: Jermaine C K
authors.initials: JC
authors.lastname: Tan
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Harvey
authors.affiliation: Faculty of Medicine, Imperial College London, London, UK.|Department of Acute Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Bell
authors.affiliation: Department of Intensive Care Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Julian F
authors.initials: JF
authors.lastname: Bion
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Coats
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.affiliation: Nuffield Division of Anaesthetics, University of Oxford, Oxford, UK.
authors.forename: J Duncan
authors.initials: JD
authors.lastname: Young
authors.affiliation: Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Rowan
mesh_terms: D000328:Adult; D003362:Cost-Benefit Analysis; D019468:Disease Management; D004636:Emergency Service, Hospital; D004739:England; D019983:Guideline Adherence; D006801:Humans; D012151:Resuscitation / Q000191:economics / Q000379:methods*; D012772:Shock, Septic / Q000191:economics / Q000401:mortality / Q000628:therapy*; D013673:Technology Assessment, Biomedical; D016896:Treatment Outcome