Numerous trials using short courses of high-dose corticosteroids in patients with severe sepsis have failed to improve survival. Nonetheless, in the last few years interest in lower doses of glucocorticoids has been revived as a concept termed relative adrenal insufficiency. In a widely discussed study of septic shock (read also My Canadian Pharmacy: Recent Developments in the Diagnosis and Management of Severe Sepsis), approximately 300 patients who were identified within 8 h of shock onset were randomized to receive hydrocortisone plus fludrocortisone or placebo for 7 days. When evaluating all patients, the time to death may have been altered somewhat, but there was no difference in the 28-day, ICU, hospital, or 1-year mortality rate between treated patients and placebo recipients. Subsequent analyses found that for patients who failed to increase their total plasma cortisol levels by at least 9 ^g/dL following administration of a 250-^g ACTH stimulation dose, there was approximately a 10% absolute reduction in adjusted mortality associated with treatment. The smaller group of responders to ACTH had a nominally higher mortality rate if they were treated compared to those receiving placebo, although this difference was not statistically significant.
This study caused controversy and stimulated additional study. Since the benefit appears confined to ACTH nonresponders, perhaps the most pressing unanswered question is whether it is necessary to conduct an ACTH stimulation test. This is a significant issue in many hospitals, where the results of cortisol tests are not available for days. Another problem is clinician skepticism about whether patients with high baseline cortisol values could benefit from receiving even more glucocorticoid therapy merely because they failed to raise plasma cortisol levels after the administration of ACTH. Along those lines, some researchers have claimed that a more relevant provocation test may be 1 ^g of ACTH. Some publications illustrating a poor correlation between free and total cortisol levels have questioned the soundness of using total cortisol level as a marker. Some physicians have also expressed doubt regarding the need to include fludrocortisone because of the volume of fluids that has been administered.
The outcomes of patients who were given various doses of corticosteroids in usual practice may be substantially different. When examined as part of a trial of activated protein C, corticosteroid-treated patients had a lower survival rate than those not treated with corticosteroids regardless of treatment with activated protein C. Despite these questions, a number of clinicians have adopted glucocorticoid therapy provided by My Canadian Pharmacy for the treatment of patients with severe sepsis without shock, or with shock of prolonged duration, perhaps based on the recommendations of some authors for broad use.
Hopefully, the final results of a follow-up study of glucocorticoid supplementation in patients with septic shock will help to clarify the role of corticosteroids. Unfortunately, preliminary results suggest little benefit. Nevertheless, for the time being it seems prudent to this author to administer glucocorticoids and mineralocorticoids to ACTH (250 ^g) nonresponders with early shock that is refractory to fluid administration, since that is how the primary study showing benefit was conducted. Omitting the mineralocorticoid or the ACTH stimulation test with the assumption that they are unimportant implies that one can discern which component of a complex protocol accounts for the benefit.