APROCCHSS: Steroids for Septic Shock (2018)

“In patients with septic shock, treatment with hydrocortisone plus fludrocortisone resulted in lower 90-day mortality compared to placebo.”

  • The APROCCHSS Investigators

1. Publication Details

  • Trial Title: Hydrocortisone plus Fludrocortisone for Adults with Septic Shock
  • Citation: Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. DOI: 10.1056/NEJMoa1705716
  • Published: March 1, 2018, in The New England Journal of Medicine
  • Author: Djillali Annane, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

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

3. The Clinical Question

  • In adult patients with septic shock (Population), does treatment with low-dose hydrocortisone plus fludrocortisone (Intervention) compared to placebo (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The use of corticosteroids in septic shock has been a subject of intense debate for decades. Previous major trials like CORTICUS (2008) had failed to show a clear mortality benefit and raised concerns about side effects, leading to conflicting recommendations in clinical guidelines.
  • Knowledge Gap: There was a need for a modern, adequately powered trial to reassess the effect of low-dose corticosteroids in a contemporary cohort of patients defined by the new Sepsis-3 criteria.
  • Proposed Hypothesis: The authors hypothesized that treatment with low-dose hydrocortisone plus fludrocortisone would be superior to placebo in reducing 90-day mortality in patients with septic shock.

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 France.
  • Trial Period: Enrollment ran from March 2008 to June 2015.
  • Population:
    • Inclusion Criteria: Adult patients with septic shock, defined by the Sepsis-3 criteria as suspected infection plus a vasopressor requirement to maintain a mean arterial pressure of ≥65 mm Hg and a serum lactate of ≥2 mmol/L.
    • Exclusion Criteria: Included contraindications to corticosteroids, pregnancy, and treatment with etomidate.
  • Intervention: Patients received intravenous hydrocortisone (50 mg every 6 hours) plus oral fludrocortisone (50 μg once daily) for 7 days.
  • Control: Patients received matching intravenous and oral placebos for 7 days.
  • Management Common to Both Groups: All patients received standard care for septic shock according to international guidelines, including early antibiotics and fluid resuscitation.
  • Power and Sample Size: The trial was designed to have 80% power to detect an absolute risk reduction of 8 percentage points 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 day 90.
    • Secondary Outcomes: Included mortality at other time points (ICU, hospital, day 28, day 180), vasopressor-free days, and organ-failure-free days.

6. Key Results

  • Enrollment and Baseline: 1,241 patients were randomized (614 to the steroid group and 627 to the placebo group). The baseline characteristics were well-balanced between the two groups, with a median SOFA score of 12.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: 90-day mortality was significantly lower in the steroid group: 264 of 614 patients (43.0%) died, compared with 308 of 627 patients (49.1%) in the placebo group (p=0.03).
  • Secondary Outcomes: Patients in the steroid group had an early resolution of shock and organ dysfunction, with significantly more vasopressor-free days by day 28 (17 vs 15 days; p<0.001) and more organ-failure-free days (14 vs 12 days; p<0.001).
  • Adverse Events: The overall incidence of serious adverse events was similar between the groups. However, hyperglycemia was more common in the steroid 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, and time-to-event data were analyzed with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of proportions of death between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio for death at 90 days: 0.82 (95% CI, 0.69 to 0.98; P-value: 0.03).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR = (Hazard Rate in Intervention Group) / (Hazard Rate in Control Group).
      • Calculation: The paper reports the result as 0.82.
      • Clinical Meaning: The HR of 0.82 means that patients in the steroid group had an 18% lower risk of death at any given time point compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.69 to 0.98.
      • Clinical Meaning: Since this range is entirely below the line of no effect (1.0), it confirms that the result is statistically significant. Clinically, this means we can be 95% confident that the true benefit is a risk reduction of somewhere between 2% and 31%.
    • P-value: The p-value of 0.03 is below the 0.05 threshold, indicating the result is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 49.1% – 43.0% = 6.1%.
      • Clinical Meaning: For every 100 patients with septic shock treated with this steroid regimen, about 6 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.061 = 16.4, which is rounded down to 16.
      • Clinical Meaning: You would need to treat 16 patients with this regimen to prevent one additional death.
  • Subgroup Analyses: No significant differences in treatment effect were found in the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing selection and performance bias, leading to a high degree of internal validity.
  • Generalizability: The inclusion of 34 centers increases the external validity, making the results more applicable to a broad range of clinical settings.
  • Statistical Power: The study was adequately powered for its primary outcome, with over 1200 patients enrolled.
  • Patient-Centered Outcomes: The study focused on 90-day mortality, which is a robust, objective, and highly relevant outcome for patients.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias. The main point of discussion is the modest treatment effect.
  • External Validity (Generalizability): The use of fludrocortisone is a key component of the intervention; therefore, the results may not be applicable to regimens using hydrocortisone alone.
  • Other: The upper bound of the confidence interval (0.98) was very close to 1.0. While statistically significant, this suggests the true benefit, while real, may be small.

10. Conclusion of the Authors

  • In adult patients with septic shock, a 7-day course of intravenous hydrocortisone plus oral fludrocortisone resulted in lower 90-day all-cause mortality compared to placebo.

11. To Summarize

  • Impact on Current Practice: This trial provided important evidence supporting the use of corticosteroids in septic shock, helping to resolve some of the long-standing clinical uncertainty on the topic.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock requiring vasopressor support.
    • Actionable Intervention: Consider treatment with low-dose hydrocortisone (200mg/day) and fludrocortisone.
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 16 patients treated.
  • 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: Clinicians should be prepared to actively manage hyperglycemia, a common and expected side effect of this treatment.

12. Context and Related Studies

  • Building on Previous Evidence: The APROCCHSS trial (2018) was designed to address the conflicting results of the earlier CORTICUS trial (2008) by using more modern sepsis definitions and including fludrocortisone.
  • Influence on Subsequent Research: The findings of this trial must be considered alongside the concurrent ADRENAL trial (2018), which was published at the same time and found no mortality benefit with hydrocortisone alone. This has led to an ongoing debate and further research into whether the mineralocorticoid effect of fludrocortisone is a crucial component of the benefit seen in APROCCHSS.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the benefit is from the hydrocortisone, the fludrocortisone, or the combination. It does not clarify if hydrocortisone alone is sufficient.
  • Future Directions: Future research is focused on identifying which specific subgroups of septic shock patients benefit most from corticosteroids, and clarifying the role of mineralocorticoid therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing one of the most persistent controversies in critical care. The hypothesis was clear and testable.
  • Methods: The study design was robust (multicenter RCT with blinding), which is a key strength. The use of modern Sepsis-3 criteria makes the patient population relevant to current practice. The control group was appropriate.
  • Results: The result was statistically significant, but the effect size was modest (NNT of 16). The fact that the 95% CI approached 1.0 (0.98) means that while the result is statistically significant, the true benefit might be quite small. The positive secondary outcomes (faster shock resolution) add to the plausibility of the finding.
  • Conclusions and Applicability: The authors’ conclusion is justified by their primary outcome data. The main point for discussion in the wider community is how to reconcile this positive result with the neutral result of the ADRENAL trial. This suggests the mineralocorticoid effect of fludrocortisone may be an important component, and the results of APROCCHSS may not be generalizable to hydrocortisone-only strategies.

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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