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Djillali Annane, MD, PhD; Véronique Sébille, PhD; Claire Charpentier, MD; Pierre-Edouard Bollaert, MD, PhD; Bruno François, MD; Jean-Michel Korach, MD; Gilles Capellier, MD, PhD; Yves Cohen, MD, PhD; Elie Azoulay, MD; Gilles Troché, MD; Philippe Chaumet-Riffaut, MD; Eric Bellissant, MD, PhD

JAMA. 2002;288:862-871.

Context  Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock.

Objective  To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.

Design and Setting  Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999.

Patients  Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test.

Intervention  Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50-µg tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.

Main Outcome Measure  Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test).

Results  One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P = .02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P = .001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups.

Conclusion  In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.

Author Affiliations: Service de Réanimation Médicale, Hôpital Raymond Poincaré, Université de Paris V, Faculté de Médecine Paris-Ouest, Garches (Dr Annane); Service de Pharmacologie, Unité de Pharmacologie Clinique, Hôpital de Pontchaillou, Université de Rennes I, Rennes (Drs Sébille and Bellissant); Service de Réanimation Chirurgicale (Dr Charpentier) and de Réanimation Médicale (Dr Bollaert), Hôpital Central, Nancy; the Service de Réanimation Polyvalente, Hôpital Dupuytren, Limoges (Dr François); Service de Réanimation Polyvalente, Centre Hospitalier, Chalons en Champagne (Dr Korach); Service de Réanimation Médicale, Hôpital Jean Minjoz, Besançon (Dr Capellier); Service de Réanimation Médico-Chirurgicale, Hôpital Avicenne, Bobigny (Dr Cohen); Service de Réanimation Médicale (Dr Azoulay) and Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris (Dr Chaumet-Riffaut), Hôpital Saint-Louis, Paris; and the Service de Réanimation Chirurgicale, Hôpital Antoine Béclère, Clamart (Dr Troché), France. Dr Sébille is now at the Loboratoire de Biostatistiques at the Faculté de Pharmacie at the Université de Nantes, France.

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