HYPRESS: Hydrocortisone for the Prevention of Septic Shock (2016)

“Among adults with severe sepsis who were not in shock, a continuous infusion of hydrocortisone did not reduce the risk of septic shock at 14 days.”

  • The HYPRESS Investigators

1. Publication Details

  • Trial Title: Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial
  • Citation: Keh D, Trips E, Marx G, et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016;316(17):1775-1785. DOI: 10.1001/jama.2016.16946
  • Published: November 1, 2016, in The Journal of the American Medical Association (JAMA)
  • Author: Didier Keh, M.D.
  • Funding: German Federal Ministry of Education and Research.

2. Keywords

  • Sepsis, Septic Shock, Prevention, Corticosteroids, Hydrocortisone, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients with severe sepsis who are not yet in shock (Population), does a continuous infusion of hydrocortisone (Intervention) compared to placebo (Comparison) reduce the incidence of septic shock within 14 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Corticosteroids were a controversial therapy for established septic shock, with trials showing conflicting results. It was hypothesized that the inflammatory cascade in sepsis was a key driver of progression from sepsis to the more life-threatening state of septic shock.
  • Knowledge Gap: It was unknown if administering corticosteroids earlier in the course of severe sepsis, before the onset of shock, could prevent this progression and improve outcomes. This was a novel “preemptive” or prophylactic strategy that had not been tested in a large randomized trial.
  • Proposed Hypothesis: The authors hypothesized that a continuous infusion of hydrocortisone would be superior to placebo in preventing the development of septic shock in patients with severe sepsis.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 34 intensive care units (ICUs) in Germany.
  • Trial Period: Enrollment ran from March 2009 to June 2013.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with severe sepsis (Sepsis-2 criteria) for less than 48 hours, who did not have septic shock (i.e., did not require vasopressors).
    • Exclusion Criteria: Included an expected survival of less than 24 hours, pregnancy, and contraindications to corticosteroids.
  • Intervention: Patients received a continuous intravenous infusion of hydrocortisone (200 mg per day) for 5 days, followed by a taper.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All patients received standard care for severe sepsis according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 1200 patients would be required to have 80% power to detect a 6% absolute risk reduction in the primary outcome. (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: The incidence of septic shock within 14 days.
    • Secondary Outcomes: Included time to onset of septic shock, mortality at 28 and 180 days, and the incidence of adverse events like secondary infections.

6. Key Results

  • Enrollment and Baseline: 380 patients were randomized (190 to hydrocortisone and 190 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early for futility by the data and safety monitoring board after an interim analysis showed a very low probability of finding a significant benefit with hydrocortisone.
  • Primary Outcome: There was no significant difference in the primary outcome. Septic shock developed in 36 of 188 patients (19%) in the hydrocortisone group and in 46 of 190 patients (24%) in the placebo group (p=0.23).
  • Secondary Outcomes: There were no significant differences between the groups in 28-day or 180-day mortality.
  • Adverse Events: The incidence of serious adverse events was similar in both groups. However, hyperglycemia and hypernatremia were more common in the hydrocortisone group.

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 patients who developed septic shock between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for developing septic shock: 0.79 (95% CI, 0.53 to 1.18; P-value: 0.25).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.79.
      • Clinical Meaning: An RR of 0.79 suggests a non-significant 21% lower relative risk of developing septic shock in the hydrocortisone group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.53 to 1.18.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 47% benefit to an 18% harm.
    • P-value: The p-value of 0.25 is much higher than the 0.05 threshold, indicating the result is 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 multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 34 diverse ICUs increases the applicability of the findings.
  • Patient-Centered Outcomes: The study included the important patient-centered outcome of mortality, in addition to its primary outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study used the older Sepsis-2 definition of severe sepsis, which may limit its direct applicability to populations defined by the current Sepsis-3 criteria.
  • Other: The trial was stopped early for futility and was therefore underpowered to definitively rule out a smaller, but still potentially important, treatment effect.

10. Conclusion of the Authors

  • The authors concluded that among adults with severe sepsis who were not in shock, a continuous infusion of hydrocortisone did not reduce the risk of septic shock at 14 days.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against the strategy of preemptive corticosteroid use in severe sepsis.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe sepsis who have not yet developed shock.
    • Actionable Intervention: Do not administer hydrocortisone with the expectation of preventing the progression to septic shock.
  • What This Trial Does NOT Mean: This trial does NOT mean that corticosteroids have no role in established septic shock. Its findings are specific to the prophylactic use of steroids in the pre-shock phase.
  • Implementation Caveats: The findings of this trial support the de-adoption of an ineffective therapy and reinforce the principle of avoiding unnecessary corticosteroid use and its associated side effects (like hyperglycemia).

12. Context and Related Studies

  • Building on Previous Evidence: The HYPRESS trial (2016) was designed to test a novel, preemptive strategy for corticosteroid use, moving the intervention earlier in the disease course than in previous trials like CORTICUS (2008).
  • Influence on Subsequent Research: The definitive neutral result of this trial has been influential in shaping sepsis guidelines, which do not recommend the use of corticosteroids in patients with sepsis in the absence of shock.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: The failure of this and other broad, untargeted therapies in sepsis has shifted the focus of research towards more personalized approaches, aiming to identify specific inflammatory phenotypes that might respond to targeted immunomodulatory therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, testing a novel prophylactic strategy for a deadly condition.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological limitation is the early termination for futility, which underpowered the study to rule out a smaller effect.
  • Results: The study reported a clear neutral finding for its primary outcome and all major secondary outcomes.
  • 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 is a classic example of a high-quality “negative” trial that was practice-changing by providing strong evidence to not adopt a new, plausible-sounding therapy.

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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