March 1, 2018
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.
What was the research question?
Does therapy with hydrocortisone plus fludrocortisone improve the clinical outcomes of patients with septic shock?
How did they do it?
Multicenter, double-blind, randomized trial at 34 centers in France.
Included patients with septic shock who are requiring vasopressor therapy of at least 0.25 mcg/kg/min for at least 6 hours in the first 24 hours.
1241 patients were randomized to receive hydrocortisone (50 mg IV every 6 hours) and fludrocortisone (50 mcg orally daily) (614 patients), compared to placebo (627 patients) for 7 days.
The primary outcome was 90-day all-cause mortality.
Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure.
What did they find?
90-day mortality was lower in the intervention group compared to placebo (43.0%vs. 49.1%; P=0.03).
Mortality was also significantly lower in the intervention group than in the placebo group at ICU discharge (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) but not at day 28 (33.7% and 38.9%, respectively; P=0.06).
Vasopressor-free days at day 28 were higher in the intervention group compared to the placebo group (17 vs. 15 days, P<0.001), as was organ-failure–free days (14 vs. 12 days, P=0.003).
Ventilator-free days were similar in the two groups (11 vs 10 days; P=0.07).
The rate of serious adverse events did not differ significantly between the two groups for GI bleed, new infection, or myopathy; however, it was associated with higher rate of hyperglycemia in the intervention group.
What are the limitations of the study?
The study is smaller than the ADRENAL trial and perhaps the mortality benefit would have vanished should the trial expanded further as an interim analysis of the ADRENAL study at almost a similar number of enrolled patients revealed a mortality benefit.
The withdrawal of drotrecogin alfa may have impacted the statistical power of the trial.
High proportion of very sick patients with higher doses of vasopressors and higher mortality rate compared to similar other studies which limits external validity.
What does it mean?
Therapy with hydrocortisone plus fludrocortisone reduces 90-day mortality in patients with septic shock.
Hydrocortisone is associated with a faster shock reversal and is continued to be given (without fludrocortisone) at 50 mg every 6 hours for ongoing requirement of vasopressor therapy in septic shock patients.