Hydrocortisone in combination with fludrocortisone significantly reduced 90-day mortality in septic shock patients in a double-blind, randomized, controlled trial.
Prior to this study, two large trials had displayed that corticosteroids were beneficial in improvingand but little was known about corticosteroids’ ability to increase survival in sepsis patients.
The study, named the Activated Protein C and Corticosteroids for Human Septic Shock () trial, was designed to assess the benefit/risk ratio of using activated protein C – drotrecogin alfa (activated) – and corticosteroids together or separately in septic shock patients. The original design of the study included Xigris (drotrecogin alfa) and was composed of four parallel groups, but Xigris was removed from the market in October of 2011, so the study continued with only two parallel groups.
A total of 1,241 patients experiencing chronic septic shock were recruited into the two double-blind, parallel groups, with patients in one group receiving hydrocortisone plus fludrocortisone and the other receiving placebos. The placebos used in this study were similar in appearance to the actual treatment drugs. The placebos for hydrocortisone and fludrocortisone were either parenteral mannitol (133.6 mg), disodium phosphate (8.73 mg), and sodium phosphate (0.92 mg) or tablets of microcrystalline cellulose (59.098 mg), respectively.
Hydrocortisone was given intravenously every 6 hours as a 50-mg intravenous bolus, and fludrocortisone was given once a day as a 50-mcg tablet through a nasogastric tube. Patients in ICUs who had septic shock for less than 24 hours were included in the study. Septic shock was identified by the presence of a clinically or microbiologically documented infection, a Sequential Organ Failure Assessment score of 3 or 4 for at least two organs and for at least 6 hours, and receipt of vasopressor therapy for at least 6 hours.
After 90 days, 264 of 614 of the patients (43%) in the hydrocortisone/fludrocortisone group and almost half (49.1%) of 627 patients in the placebo group had died (P = .03). The relative risk of death was 0.88 (95% confidence interval, 0.78-0.99), which favored the hydrocortisone/fludrocortisone group. The researchers also observed that death was significantly lower in the hydrocortisone/fludrocortisone group, compared with the placebo group, at time of ICU discharge (35.4% vs. 41.0%, respectively; P = .04).
While mortality was reduced, patients still experienced adverse events. 326 of 614 (53.1%) patients in the hydrocortisone/fludrocortisone group and 363 of 626 patients (58.0%) in the placebo group experienced at least one serious adverse event by day 180 (P = 0.08).
“Seven-day treatment with a 50-mg intravenous bolus of hydrocortisone every 6 hours and a daily dose of 50 mcg of oral fludrocortisone resulted in lower mortality at day 90 and at ICU and hospital discharge than placebo among adults with septic shock,” concluded Dr. Annane and his coauthors.
The majority of researchers had no relevant financial disclosures to report, while some doctors received grants and personal fees unrelated to this study. This study was funded in part by public grants from the French Ministry of Health.
SOURCE: Annana A et al. NEJM. 2018 Feb 28. .