ProMISe: Protocolised Management in Sepsis (2015)

“In this multicenter trial in England, we found that early goal-directed therapy did not improve outcomes in patients with septic shock and led to an increase in health care costs.”

  • The ProMISe Trial Investigators

1. Publication Details

  • Trial Title: Trial of early, goal-directed resuscitation for septic shock
  • Citation: The ProMISe Trial Investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301-1311. DOI: 10.1056/NEJMoa1500896
  • Published: April 2, 2015, in The New England Journal of Medicine
  • Author: The ProMISe Trial Investigators
  • Funding: UK National Institute for Health Research.

2. Keywords

  • Sepsis, Septic Shock, Early Goal-Directed Therapy (EGDT), Resuscitation, Protocolized Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with early septic shock in the emergency department (Population), does a 6-hour protocol of early goal-directed therapy (EGDT) (Intervention) compared to standard, non-protocolized usual care (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark single-center trial by Rivers et al. (2001) showed a dramatic mortality benefit for a complex resuscitation protocol called Early Goal-Directed Therapy (EGDT). This led to the widespread adoption of EGDT in international sepsis guidelines.
  • Knowledge Gap: Despite its inclusion in guidelines, the dramatic findings of the single-center Rivers trial had not been replicated in a large, multicenter setting. The ProCESS and ARISE trials, published just before this one, had also shown no benefit. A definitive answer from a UK-based trial was needed to confirm these findings.
  • Proposed Hypothesis: The authors hypothesized that EGDT would be superior to standard care in reducing 90-day mortality in patients with early septic shock.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 56 National Health Service (NHS) hospitals in England.
  • Trial Period: Enrollment ran from February 2011 to July 2014.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) presenting to the emergency department with early septic shock, defined by suspected or confirmed infection, evidence of refractory hypotension or hypoperfusion (e.g., lactate ≥4 mmol/L).
    • Exclusion Criteria: Included contraindications to central venous catheterization and situations where the treating clinician believed EGDT was either mandatory or contraindicated.
  • Intervention: Patients received a 6-hour protocol of EGDT, which included the placement of a central venous catheter for CVP and ScvO2 monitoring and guided the use of fluids, vasopressors, inotropes, and blood transfusions to meet specific physiological targets.
  • Control: Patients received “usual care,” where all treatment decisions, including the type and extent of hemodynamic monitoring, were at the discretion of the treating clinicians.
  • Management Common to Both Groups: All patients were managed in the emergency department and ICU according to the standard practices of the participating hospitals.
  • Power and Sample Size: The authors calculated that a sample size of 1260 patients would provide 80% power to detect a 9% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included mortality at other time points, duration of organ support, length of hospital stay, and cost-effectiveness.

6. Key Results

  • Enrollment and Baseline: 1260 patients were randomized (630 to the EGDT group and 630 to the usual-care group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 184 of 623 patients (29.5%) in the EGDT group died, compared with 181 of 620 patients (29.2%) in the usual-care group (p=0.90).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including duration of organ support or length of stay. Patients in the EGDT group did receive more intravenous fluids and more frequent use of dobutamine. The mean cost of care was significantly higher in the EGDT group.
  • Adverse Events: The incidence of serious adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.90 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled trial design provided a high level of evidence.
  • Generalizability: The pragmatic design across 56 diverse NHS hospitals makes the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference if one existed.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint. The inclusion of a cost-effectiveness analysis was a major strength.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded to clinicians, which is a potential source of performance bias.
  • External Validity (Generalizability): The “usual care” provided in the control group was of a very high standard, including rapid administration of antibiotics and fluids. This may have improved outcomes in the control group and reduced the potential for the protocolized arm to show a benefit.
  • Other: The overall mortality rate was lower than in the original Rivers trial, suggesting the study population or the standard of care had changed significantly over time.

10. Conclusion of the Authors

  • The authors concluded that in patients with early septic shock, EGDT did not lead to an improvement in 90-day mortality, and it was associated with higher costs than usual care.

11. To Summarize

  • Impact on Current Practice: This trial, as the third of the three large “sepsis trials,” provided the final, definitive evidence that the full, complex, and resource-intensive EGDT protocol is not superior to modern, high-quality standard care for septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with early septic shock.
    • Actionable Intervention: The results do not support the routine implementation of the full EGDT protocol.
  • What This Trial Does NOT Mean: This trial does NOT mean that the core principles of early sepsis care (early recognition, early antibiotics, and adequate fluid resuscitation) are not important. It suggests that these principles had become part of “usual care,” making the additional, complex components of the EGDT protocol unnecessary and more costly.
  • Implementation Caveats: The focus of early sepsis resuscitation should be on the timely administration of fluids and antibiotics, with vasopressors as needed, guided by careful clinical assessment rather than rigid physiological targets.

12. Context and Related Studies

  • Building on Previous Evidence: The ProMISe trial (2015) was the third of three large, multicenter trials designed to validate the findings of the original single-center EGDT trial by Rivers et al. (2001).
  • Influence on Subsequent Research: The consistent neutral findings of the “big three” sepsis trials (ProCESS (2014), ARISE (2014), and ProMISe) led to a significant simplification of international sepsis guidelines, moving away from the rigid EGDT protocol and towards a more streamlined approach to early resuscitation.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not identify which, if any, individual components of the original EGDT protocol might be beneficial on their own.
  • Future Directions: The results of this trial have shifted the focus of sepsis resuscitation research towards more nuanced questions, such as the optimal type and volume of fluid, and the best way to personalize vasopressor therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, seeking to validate a practice that had become a widespread standard of care based on single-center evidence.
  • Methods: The multicenter RCT design was of high quality. A key strength is that the “usual care” arm represented a high standard of modern sepsis care, making the comparison very relevant. The main methodological weakness is the open-label design.
  • Results: The study reported a clear neutral finding for its primary outcome, with no significant difference in mortality between the two groups. The finding of increased costs with no clinical benefit in the EGDT group is a critical secondary outcome.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This trial, as the third in a series of consistent “negative” trials, was profoundly practice-changing by providing definitive evidence to de-adopt a complex and resource-intensive intervention.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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