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

BackgroundEarly 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.ObjectivesThe 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.DesignA pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation.SettingFifty-six NHS hospitals in England.ParticipantsA total of 1260 patients who presented at EDs with septic shock.InterventionsEGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1.Main outcome measuresAll-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year.ResultsFollowing 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.LimitationsRecruitment was lower at weekends and out of hours. The intervention could not be blinded.ConclusionsThere 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%.Future workThe 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.Trial registrationCurrent Controlled Trials ISRCTN36307479.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.

A systematic review of human and veterinary applications of noninvasive tissue oxygen monitoring

“…EGDT in sepsis, trauma, and critically ill patients has become standard of care in human medicine. Recently, ProMISe ARISE, and ProCESS trials have cast doubts as to the utility of EGDT in patients with septic shock . The EGDT groups in these studies not only had no difference in 90 day mortality but also were found to have increased costs of treatment …”

Bacterial sepsis

“…Prospective investigations, e. g., the International Multicentre Prevalence Study on Sepsis (IMPreSS) by Rhodes et al, achieved a reduction in in-hospital mortality of up to 36-40% by implementing bundle measures [45]. This has also been confirmed by other studies [18,19,40].…”

“…Mortality in this collective was 34.3% during the stay in the ICU and 40.4% for the hospital stay. Data from international studies vary within a comparable range [14,[18][19][20][21][22]. Whereas sepsis is the third most common cause of death in non-surgical ICUs [23,24], it is the primary cause of death in surgical ICUs [15].…”

“…By dictating a strict treatment algorithm and strictly adhering to this path, Rivers et al were able to significantly reduce mortality in sepsis patients for the first time. However, subsequent studies on sepsis treatment optimization revealed that more flexible "sepsis bundles" were not inferior to strict EGDT [18,19,39,40]. Consequently, treatment moved away from EGDT according to Rivers et al, and the sepsis bundles defined by the Surviving Sepsis Campaign (SSC) were implemented [7].…”

The Emperor Has no Clothes? Searching for Dysregulation in Sepsis

“…Still, the concept of early goal directed therapy itself was not tested until three randomized controlled trials conducted during this decade. The ProCESS, ARISE and proMISe were three large scale randomized controlled trials of EGDT independently conducted on three continents [36][37][38]. In each study, EGDT failed to improve survival compared to usual care.…”