Low-dose hydrocortisone prolongs survival in a lethal sepsis model in adrenalectomized rats.

BACKGROUND: Controversial clinical findings of low-dose hydrocortisone supplementation in septic shock led us to investigate the impact of administration in lethal septic shock in adrenalectomized rats. MATERIALS AND METHODS: After preliminary experiments, to define the intravenous dose of hydrocortisone delivered in bilaterally adrenalectomized rats with serum cortisol level similar to sham rats, survival experiments were run in 75 rats after intraperitoneal challenge with Escherichia coli. Rats were treated with placebo, ertapenem, hydrocortisone, and a combination. Sacrifice experiments were run to measure gene transcripts in whole blood and in the liver and to assess cytokine stimulation of splenocytes and tissue overgrowth. RESULTS: The combination of hydrocortisone and ertapenem was superior to any single treatment and mandatory to achieve survival benefit. Splenocytes from infected rats had decreased production of tumor necrosis factor-alpha (TNFα); this was reversed with hydrocortisone treatment. Hydrocortisone increased the expression of TNF, Il1r2, and Hdac4 and decreased that of Dnmt3a. Bacterial burden of E. coli in kidney was decreased after hydrocortisone treatment. CONCLUSIONS: Low dose of hydrocortisone is a mandatory adjunctive to antimicrobial therapy in a rat model of septic shock after bilateral adrenalectomy. The mechanism of action is related to reversal of sepsis-induced immunosuppression through interaction with histone deacetylases and de novo DNA methyltransferases.