LISBON — After decades of controversy, a consensus has emerged that corticosteroids provide major benefits in patients with severe sepsis or septic shock, Dr. Djillali Annane said at the 12th International Congress on Infectious Diseases.
The benefits, as demonstrated in multiple randomized placebo-controlled trials, are improved 28-day mortality, shorter shock duration, improved hemodynamics, reduced organ dysfunction, and less systemic inflammation.
It should be emphasized that these benefits accrue only with low-dose corticosteroids administered for at least 5 days, and only in the sizable patient subsets having adrenal insufficiency or refractory septic shock, said Dr. Annane of the University of Versailles, France.
Much of the lengthy controversy in this field was the result of great heterogeneity in clinical trials, particularly those before 1992. For example, steroids for septic shock fell into disfavor in the 1980s and 1990s because multiple trials before 1992 showed no benefit because the negative studies used short-course, high-dose corticosteroids, Dr. Annane explained. Today, with the benefit of hindsight, no evidence supports the use of such therapy, he said at the congress, which was sponsored by the International Society for Infectious Diseases.
Dr. Annane was first author of a 2006 Cochrane Collaboration systematic review of corticosteroids for treatment of severe sepsis and septic shock (Cochrane Library ISSN 1464-780X).
In 15 randomized trials of more than 2,000 children and adults included in the analysis, steroid therapy didn't change 28-day all-cause mortality. But the results varied according to dosing strategy. In nine trials of replacement-dose corticosteroids—the equivalent of hydrocortisone at 200–300 mg/day intravenously for 5 days or longer—there was a highly significant 20% reduction in the relative risk of 28-day mortality, compared with placebo, and a greater proportion of patients experiencing shock reversal by day 7. Patients on high-dose, short-course corticosteroids did not benefit.
Several new trials have been published since completion of the Cochrane review. An updated analysis incorporating these studies shows a significant 12% reduction in all-cause mortality with steroid therapy when all trials are considered. For only those involving low-dose therapy for at least 5 days, the relative risk reduction in mortality is now an even more robust 23%.
The Cochrane review found no significant increase in rates of superinfection, GI bleeding, or hyperglycemia linked to steroid therapy, but Dr. Annane found those trial results inconsistent with real-world practice. These adverse events are common with steroids, he cautioned, adding that only patients likely to obtain therapeutic benefit should be exposed to such risks.
That's why American College of Critical Care Medicine guidelines, which were coauthored by Dr. Annane, recommend low-dose steroids only in septic shock that is refractory or accompanied by adrenal insufficiency, as defined by an increase in cortisol of 9 mcg/dL or less in response to a corticotropin test (Crit. Care Med. 2004;32:1928–48).
The rationale behind low-dose steroid therapy in septic shock is that systemic inflammation is a hallmark of sepsis. Inflammatory cytokines suppress the hypothalamic-adrenal-pituitary axis, resulting in adrenal insufficiency in about half of septic shock patients. Steroids induce immune modulation through numerous cellular mechanisms of action. Indications for steroids in septic shock may soon rise.
The benefits accrue only in patients with adrenal insufficiency or refractory septic shock. DR. ANNANE