Two recent small randomized trials evaluating a 5- to 12-day course of low dose
hydrocortisone in patients with
septic shock have reported a significant clinical improvement and a reduction in mortality. Recent studies indicate that an overaggressive and unregulated systemic inflammatory response is a major determinant of outcome in
sepsis. In
septic shock, nonsurvivors as opposed to survivors have over time: (1) significantly higher
NF-kB activity in peripheral mononuclear cells, (2) persistent elevation in circulating inflammatory
cytokine levels, and (3) elevated
ACTH and
cortisol levels. Current research recognizes that
cytokines can cause a concentration-dependent resistance to endogenous
glucocorticoids (GC). It is postulated that an excess of
cytokine-induced
transcription factors, such as
NF-kB, may form complexes with activated
glucocorticoid receptors (GCR), preventing GCR interaction with
DNA. When T cells are incubated with a combination of
cytokines, GC resistance is induced in a
cytokine concentration-dependent fashion and reversed by removal of
cytokines. Prolonged treatment with physiological doses of exogenous GCs may be necessary to compensate adequately for the inability of target organs to respond to endogenous
cortisol and for the inability of the host to produce appropriately elevated levels of GCs. This hypothesis is supported by the laboratory findings of a recent randomized study of patients with unresolving acute respiratory disease.