Sprung et al: High-Dose Corticosteroids in Septic Shock (1984)

“We were unable to show an improvement in the overall survival of patients with severe, late septic shock who were treated with high-dose corticosteroids.”

  • Sprung CL, et al.

1. Publication Details

  • Trial Title: The Effects of High-Dose Corticosteroids in Patients with Septic Shock: A Prospective, Controlled Study
  • Citation: Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984;311(18):1137-1143. DOI: 10.1056/NEJM198411013111801
  • Published: September 27, 1984, in The New England Journal of Medicine
  • Author: Charles L. Sprung, M.D.
  • Funding: The Upjohn Company; Veterans Administration.

2. Keywords

  • Sepsis, Septic Shock, Corticosteroids, Methylprednisolone, Dexamethasone

3. The Clinical Question

  • In adult patients with severe septic shock (Population), does treatment with high-dose corticosteroids (Intervention) compared to placebo (Comparison) improve short-term survival and shock reversal (Outcome)?

4. Background and Rationale

  • Existing Knowledge: In the 1970s and early 1980s, the use of high-dose corticosteroids for septic shock was common but highly controversial. The practice was supported by animal studies and some smaller, non-randomized human studies, but the true clinical benefit was unknown.
  • Knowledge Gap: There was a critical need for high-quality, randomized controlled trial evidence to determine if high-dose steroids were truly beneficial or potentially harmful in this critically ill population.
  • Proposed Hypothesis: The authors hypothesized that high-dose corticosteroids would improve the survival of patients with septic shock.

5. Study Design and Methods

  • Design: A prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: Two Veterans Administration medical centers in the United States.
  • Trial Period: Enrollment period not explicitly stated in the publication.
  • Population:
    • Inclusion Criteria: Patients with clinical evidence of infection, a systolic blood pressure <90 mm Hg, and evidence of inadequate organ perfusion.
    • Exclusion Criteria: Included age <18 years, pregnancy, and prior steroid use.
  • Intervention: Patients received either high-dose methylprednisolone (30 mg/kg) or dexamethasone (6 mg/kg).
  • Control: Patients received a matching placebo (5% dextrose in water).
  • Management Common to Both Groups: All patients received standard care for septic shock at the time, which included intravenous fluids and antibiotics.
  • Power and Sample Size: A formal power calculation was not reported in the publication, which was common for trials of that era.
  • Outcomes:
    • Primary Outcome: Overall mortality.
    • Secondary Outcomes: Included reversal of shock and the development of complications.

6. Key Results

  • Enrollment and Baseline: 59 patients were randomized (29 to corticosteroids and 30 to placebo). The groups were generally well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no statistically significant difference in overall mortality between the groups. 11 of 29 patients (38%) in the steroid group died, compared with 9 of 30 patients (30%) in the placebo group.
  • Secondary Outcomes: Patients treated with corticosteroids had a significantly higher rate of shock reversal within 24 hours (79% vs. 43%; p<0.01). However, this did not translate to a survival benefit.
  • Adverse Events: There was a trend towards more complications, particularly secondary infections, in the corticosteroid group, although this was not statistically significant. A key finding was in a subgroup of patients with renal insufficiency, where mortality was significantly higher in the steroid group (78% vs. 25%; p<0.05).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed according to the treatment received.
  • Statistical Tests Used: Proportions were compared using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of mortality proportions between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value for the difference in overall mortality was not reported but was stated as not significant. The p-value of <0.01 for shock reversal indicates a statistically significant difference for that secondary outcome.
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 38% – 30% = 8%.
      • Clinical Meaning: For every 100 patients treated with high-dose steroids, there was a non-significant trend towards 8 additional deaths.
  • Subgroup Analyses: A post-hoc subgroup analysis showed a significant increase in mortality among patients with renal insufficiency who received corticosteroids.

8. Strengths of the Study

  • Study Design and Conduct: For its time, the randomized, double-blind, placebo-controlled design was a major strength and represented a high level of evidence.
  • Patient-Centered Outcomes: The study focused on the crucial outcome of mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted for its era with a low risk of bias.
  • External Validity (Generalizability): The findings are specific to high-dose steroid regimens and cannot be extrapolated to the low-dose “stress-dose” regimens studied in modern trials.
  • Other: The sample size was very small by modern standards, meaning the study was underpowered to definitively rule out either a small benefit or a small harm.

10. Conclusion of the Authors

  • The authors concluded that high-dose corticosteroids are not beneficial in the treatment of severe, late septic shock. They noted that while steroids may aid in the early reversal of shock, this does not translate to improved survival and may be harmful in some patients.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided the first strong, randomized evidence against the routine use of high-dose corticosteroids in septic shock. It was instrumental in shifting practice away from this common but harmful therapy.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe septic shock.
    • Actionable Intervention: Do not administer high-dose corticosteroids (e.g., methylprednisolone 30 mg/kg).
  • What This Trial Does NOT Mean: This trial does NOT mean that all steroids are bad in sepsis. Its findings are specific to high-dose regimens and do not apply to the physiologic or “stress-dose” steroids studied in later trials.
  • Implementation Caveats: The finding of faster shock reversal highlights the powerful physiological effects of steroids but underscores the critical lesson that improving a physiological number does not always translate to improved patient-centered outcomes.

12. Context and Related Studies

  • Building on Previous Evidence: The Sprung et al. trial (1984) was one of the first high-quality RCTs to challenge the prevailing dogma, which was based on weaker, non-randomized data.
  • Influence on Subsequent Research: The negative findings of this trial, along with others from the same era (e.g., Bone et al. 1987), led to the abandonment of high-dose steroids for sepsis. This shifted the research focus towards investigating whether lower, more physiologic “stress-doses” of steroids could be beneficial, which led to the next generation of trials, including Annane et al. (2002) and CORTICUS (2008).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial helped to resolve the question of high-dose steroids but opened the door to the next major question: is there a role for low-dose steroids in septic shock?
  • Future Directions: The entire subsequent history of steroid research in sepsis, from the Annane (2002) trial to the APROCCHSS (2018) and ADRENAL (2018) trials, can be seen as the future direction that followed from this study’s pivotal findings.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and addressed a very common and controversial practice at the time.
  • Methods: The randomized, double-blind, placebo-controlled design was a major strength for its era. The main limitation was the small sample size, which made the study underpowered to detect anything other than a very large effect.
  • Results: The study reported a clear neutral finding for its primary outcome of mortality. The secondary finding of faster shock reversal without a survival benefit was a critical lesson for the field of critical care. The signal of harm in patients with renal failure was an important safety concern.
  • Conclusions and Applicability: The authors’ conclusion was a fair and important interpretation of their data. Despite its small size, this trial was highly influential because it provided strong evidence to stop a common and potentially harmful practice, paving the way for more nuanced research into the role of corticosteroids in sepsis.

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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