Hydrocortisone plus fludrocortisone decreases mortality in adults with septic shock

1. Patients with septic shock in the intensive care unit (ICU) undergoing mechanical ventilation receiving hydrocortisone plus fludrocortisone had a lower 90-day all-cause mortality compared to placebo treated patients.

2. The mortality rate at ICU and hospital discharge, and day 180 were significantly lower in the hydrocortisone plus fludrocortisone group, and the number of vasopressor-free days was significantly higher compared to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Sepsis is a significant cause of mortality and morbidity, and while hemodynamic, respiratory, and antibiotic directed therapies are well defined, there is no approved adjunctive treatment. Corticosteroids have been used but supporting evidence for this treatment is controversial. Additionally, human recombinant activated protein C (drotrecogin alpha) has shown some benefit in patients with septic shock by modulating host response. Given the uncertainty of corticosteroid use, this randomized controlled trial (RCT) aimed to compare hydrocortisone-plus-fludrocortisone or drotrecogin alpha to placebo to determine their effect on clinical outcomes. Drotrecogin was removed from the market during the trial so the study continued with two study arms. Patients in the treatment group who were mechanically ventilated had a lower 90-day all-cause mortality rate compared to placebo. The mortality rate at ICU and hospital discharge, and day 180 was significantly lower in the hydrocortisone plus fludrocortisone group.  Further, the number of vasopressor-free and organ-failure free days were significantly higher in the treatment group compared to placebo.  The rate of adverse events did not differ significantly between groups.

Strengths of this study were the RCT design and inclusion of many patients across multiple ICUs thus providing sufficient power to detect a difference in the primary outcome. A limitation includes lack of reported data on drotrecogin alpha treated patients.

Click to read the study, published in NEJM

Relevant Reading: JAMA clinical guidelines synopsis: management of sepsis and septic shock

In-Depth [randomized controlled trial]: This was a multicenter, double blind, randomized trial with a 2 x 2 factorial design.  Patients were randomly assigned to either receiving hydrocortisone plus fludrocortisone, drotrecogin alpha, both, or placebo. Eligible patients had probable septic shock for less than 24 hours, and excluded patients had high bleeding risk or conditions that could affect survival. The primary outcome was 90-day all-cause mortality. There were 34 centers involved in the trial between September 2008 and June 2015.  The trial was temporarily stopped in 2011-2012 when drotrecogin alpha was withdrawn from the market.

Ultimately, 1241 patients were randomized to either hydrocortisone-plus-fludrocortisone (n = 614) or placebo (n = 626).  At day 90, there were significantly fewer deaths in the treatment group compared to placebo group (43.0% vs 49.1%; relative risk of death [RR], 0.88; 95% confidence interval [CI], 0.78 to 0.99, p = 0.03). Mortality at ICU discharge was significantly lower in the treatment group compared to placebo (35.4% vs 41.0%, P=0.04), hospital discharge (39.0% vs 45.3%, p = 0.02) and day 180 (46.6% vs 52.5%, p = 0.04).  Patients in the treatment group had significantly fewer vasopressor-free days up to day 28 than those in the placebo group (17d vs 15d, p < 0.001), and significantly more organ-free-failure days to day 28 compared to the placebo group (14 days vs 12 days, p = 0.003). One serious adverse event by day 180 was experienced by 53.1% and 58.0% of patients in the treatment and placebo groups, respectively (p = 0.08).

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