This is a major trial evaluating the usefulness of hydrocortisone and fludrocortisone during septic shock. About 12,000 patients were followed for 30-120 days. Compared to placebo, high doses of adrenal hormone equivalents improved 90-day death rates significantly. This is a step forward in improving the care of the deadly condition.
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Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone + fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.
In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos.
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.
After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group).
Among the 1,241 patients included in the trial, the 90-day mortality was 43.0% in the hydrocortisone-plus-fludrocortisone group and 49.1% in the placebo group (p=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was (RR) 0.88, p<0.05.
Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone 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).
The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure–free days (14 vs. 12 days, P=0.003).
The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.
In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo.