Annane D, et al. - This trial was designed to test the hypothesis that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. Researchers found that compared with placebo, hydrocortisone plus fludrocortisone lowered 90-day all-cause mortality in septic shock patients.

Methods

• In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, researchers assessed the impact of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos.
• Ninety-day all-cause mortality was primary outcome.
• 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.
• The trial continued with a two-group parallel design after drotrecogin alfa (activated) was withdrawn from the market.
• A comparison was carried out between patients who received hydrocortisone plus fludrocortisone vs those who did not (placebo group).

Results

• This trial included a total of 1241 patients.
• Findings demonstrated that the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03).
• Researchers reported that the relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99).
• They noted significantly lower mortality 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).
• In the hydrocortisone-plus-fludrocortisone group vs in the placebo group, the number of vasopressor-free days to day 28 was significantly higher (17 vs 15 days, P<0.001), as was the number of organ-failure–free days (14 vs 12 days, P=0.003).
• In addition, data revealed similar number of ventilator-free days in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07).
• Both groups did not differ significantly in terms of the rate of serious adverse events, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.