EVERE SEPSIS REMAINS AN IMPORtant cause of death, accounting for 9.3% of all deaths in the United States in 1995. 1 If our understanding of the mechanisms of host response to stress has strongly progressed during the last 2 decades, 2 the various drugs developed for specific targets of the cytokine cascade have failed to improve patient survival. 3,4 Corticosteroids were the first antiinflammatory drugs tested in randomized trials. At high doses during short courses, they did not induce favorable effects. 5,6 However, the observation that severe sepsis may be associated with relative adrenal insufficiency 7,8 or systemic inflammation-induced glucocorticoid receptor resistance 9 prompted renewed interest of a replacement therapy

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.