Author: Vanessa I. Petrak, M.D.


Septic Shock is a dysregulated host response to infection, resulting in life-threatening circulatory, cellular, and metabolic abnormalities. Sepsis is associated with a dysregulated response of the hypothalamic-pituitary-adrenal axis that may involve any of the steps from cortisol production to cortisol use by cells. Short term mortality is approximately 45-50%, and 50% of those survivors may have long term cognitive decline.

Corticosteroids improve cardiovascular function by restoring effective blood volume through increased mineralocorticoid activity and by increasing systemic vascular resistance.

The benefit-to-risk ratio of corticosteroids in sepsis remains controversial.

  • Quantitative analysis of trials studying this has variably confirmed or refuted survival benefit leading to substantial heterogeneity in physicians’ clinical practice
  • Approximately 1/3rd of physicians believe that corticosteroids improve survival, 1/3rd believe they don’t, and 1/3rd are unsure
  • The uncertainty is based on two studies with only one demonstrating benefit. Of note, the one that demonstrated benefit combined hydrocortisone with fludrocortisone as opposed to the other study which was just hydrocortisone.

This discrepancy led to this trial to test the hypothesis that hydrocortisone-plus-fludrocortisone therapy or drotrecogin alfa (activated) would improve the clinical outcome in patients with septic shock. Fludrocortisone was added to provide additional mineralocorticoid potency. Drotrecogin alpha (activated) is a human recombinant activated protein C. It initially showed a survival benefit in sepsis, but subsequent studies failed to reproduce this result and it was taken off the market

In this article, they only reported on the effects of hydrocortisone-plus-fludrocortisone therapy


Septic shock was defined as:

  •  Presence of a clinically or microbiologically documented infection
  • A sequential organ failure assessment (SOFA) score of 3 or 4 for a least 2 organs and at least 6 hours
  • Receipt of vasopressor therapy for at least 6 hours to maintain systolic bp of 90mmHg or MAP >65mmHg

STUDY TYPE: Double blind randomized trial with a 2×2 factorial design


INCLUSION CRITERIA: Patients in the ICU that had indisputable or probable septic shock for less than 24 hours


  • Presence of septic shock for at least 24 hours
  • High risk of bleeding
  • Pregnancy or lactation
  • Underlying conditions that could affect short term survival
  • Known hypersensitivity to drotrecogin alfa (activated)
    • (later removed after this was taken off the market)
  •  Previous treatment with corticosteroids

SAMPLE SIZE: 1,241 patients, recruited between September 2,2008-June 23rd, 2015

Patient allocation:

  • Arm A: Hydrocortisone placebo (iv every 6 h) and fludrocortisone placebo (po once daily) for 7 days, and placebo of activated protein C for 4 days.
  • Arm B: Hydrocortisone (iv every 6 h) and fludrocortisone (po once daily) for 7 days, and placebo of activated protein C for 4 days.
  • Arm C: Hydrocortisone placebo (iv every 6 h) and fludrocortisone placebo (po once daily) for 7 days, and activated protein C for 4 days
  • Arm D: Hydrocortisone (iv every 6 h) and fludrocortisone (po once daily) for 7 days, and activated protein C for 4 days.

Study design:

Picture 1

Patients were allocated to groups of hydrocortisone plus fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. After deotrecogin alfa was removed from the market, the study continued with a two-group parallel design (Hydro + Fludro vs. placebo)

Before randomization, plasma total cortisol levels were measured before, and 30 and 60 minutes after, an IV bolus of 250µg of corticotropin (Synacthen). Nonexperimental interventions (anti-infective treatments, hemodynamic and respiratory management, and blood glucose control) were harmonized across centers according to the 2008 Surviving Sepsis Campaign guidelines


PRIMARY OUTCOME: 90-day all-cause mortality was 43% (264 of 614 patients in the hydro + fludro group) and 49.1% (308 of 627 of placebo) with P=0.03

Picture 1


  • Mortality at ICU discharge
    • Significantly lower in hydro-plus-fludro group (35.4% vs 41%, P=0.04)
  •  Mortality at hospital discharge:
    • Significantly lower in hydro-plus-fludro group (39% vs 45.3%, P=0.02)
  •  Mortality at day 28
    • NOT significantly lower in hydro-plus-fludro group (33.7 and 38.9%, P=0.06)
  • Mortality at day 180
    • Significantly lower in hydro-plus-fludro group (46.6% vs 52.5%, P=0.04)
  • Number of days alive and free of vasopressors
    • Significantly higher in hydro-plus-fludro group (17 vs. 15 days, P<0.05)
  • Number of days alive free of mechanical ventilation
    • Similar between the 2 groups (11 vs 10 days, P=0.07)
  • Number of days alive free of organ failure
    • Significantly higher in hydro-plus-fludro group (14 vs 12 days, P=0.003)

Adverse Events: There were no difference between the groups in GI bleeding, superinfection, new sepsis, or neurologic sequelae. However, as expected, there was an increased risk of hyperglycemia in the hydro-plus-fludro group.



  • Large sample size
  • Study was conducted across multiple centers (34)
  • Baseline characteristics were similar between the two groups
  • Multiple secondary outcomes were evaluated
  • Double-blind randomized trial


  • This study used a 90-day outcome, while no statistically significant difference was noted at 28-day. At that far out, there are possible other causes for mortality unrelated to treatment.
  • There was no data on comorbidities (particularly COPD and diabetes)
  • The study was suspended twice
  • 1st after the withdrawal of Xigris from the market
  • 2nd at the request of the data and safety monitoring board to check the quality of the trial agents and the distribution of serious adverse events
  • They calculated that 320 patients were needed in each group (total number of 1280 patients) were needed to detect an absolute difference of 10 percentage points in 90-day mortality (power of 95%).
  • They had 97% of the expected sample size


7-day treatment with a 50mg IV bolus of hydrocortisone every 6 hours and a daily dose of 50µg of oral fludrocortisone resulted in lower mortality at day 90 and at ICU and hospital discharge than placebo among adults with septic shock. Due to increased hyperglycemia, may want to be cautious with brittle diabetics.


 Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (PMID 29490185)

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