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JOURNAL ARTICLE
MULTICENTER STUDY
RANDOMIZED CONTROLLED TRIAL

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock

Djillali Annane, Alain Renault, Christian Brun-Buisson, Bruno Megarbane, Jean-Pierre Quenot, Shidasp Siami, Alain Cariou, Xavier Forceville, Carole Schwebel, Claude Martin, Jean-François Timsit, Benoît Misset, Mohamed Ali Benali, Gwenhael Colin, Bertrand Souweine, Karim Asehnoune, Emmanuelle Mercier, Loïc Chimot, Claire Charpentier, Bruno François, Thierry Boulain, Franck Petitpas, Jean-Michel Constantin, Gilles Dhonneur, François Baudin, Alain Combes, Julien Bohé, Jean-François Loriferne, Roland Amathieu, Fabrice Cook, Michel Slama, Olivier Leroy, Gilles Capellier, Auguste Dargent, Tarik Hissem, Virginie Maxime, Eric Bellissant
New England Journal of Medicine 2018 March 1, 378 (9): 809-818
29490185

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized 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.

METHODS: 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. 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. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design.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).

RESULTS: Among the 1241 patients included in the trial, 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). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). 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.

CONCLUSIONS: 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. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Comments

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Varun Shetty wrote:

5

This study will probably change the way we treat septic shock going forward. Great work!

Ephraim Tang wrote:

0

Agreed.

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