In the early 2000s, there was an emergence in the use of low-dose steroids in patients with sepsis. This was based on various trials showing the benefit of the use of low-dose steroids in the reversal of septic shock without significant side effects, discussed further below.
Pathophysiology
Steroids improve hemodynamic parameters. In an animal model, Hinshaw and colleagues induced septic shock in adrenalectomized dogs by infusing lethal doses of E. coli. The untreated dogs died within hours, whereas the dogs treated with antibiotics and steroids had a complete recovery from shock, and survived more than 100 hours.9
During sepsis, endotoxins induce nitric oxide synthase, which produces relaxation of vascular smooth muscle tone, with resultant hypotension and reduced contractility response to norepinephrine.10 Corticosteroids prevent induction of nitric oxide synthase and enhance the vaso-active response to catecholamines through the glucocorticoid receptors. In vascular endothelial cells, glucocorticoids also inhibit serum phospholipase A2, reducing the production of vasodilators, such as prostacyclin and prostaglandin E1.11,12
Steroids reduce inflammation. Sepsis is driven by a systemic inflammatory response, in which components of the outer-cell membrane of both gram-positive and gram-negative bacteria and endotoxins induce the production of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1).13 These cytokines have a direct toxic effect on various tissues. In addition, inflammatory cytokines suppress adrenal response to adrenocorticotropic hormone (ACTH), which results in decreased endogenous cortisol production, and compete with glucocorticoids for their receptors, inducing resistance to the action of steroids at the tissue level.14
In healthy volunteers challenged with bacterial endotoxins, low-dose steroids (~10 mg of prednisolone) suppress the release of proinflammatory cytokines and prevent the activation of endothelial cells and neutrophils.15 Steroids also inhibit the release of toxic enzymes, such as lysozymes and superoxides from neutrophils.16,17
Data Supporting Steroid Use in Septic Shock
Mortality data. Two major studies evaluated the effect of low-dose steroids in patients with septic shock. Annane and colleagues conducted a placebo-controlled, blinded trial and divided the study population into “responders” and “nonresponders” based on their response to ACTH stimulation test. Within the “nonresponder” group, steroids reduced the risk of mortality by 16% (63% mortality in the placebo group and 53% mortality in the corticosteroid group, P=0.02).16 Steroids also significantly reduced ICU mortality (70% versus 58%), hospital mortality (72% versus 61%) and one-year mortality (77% versus 68%) compared with placebo. No statistically significant difference in mortality between steroids and placebo was seen in the “responder” group.16
The CORTICUS trial, a multicenter, randomized, double-blind, placebo-controlled trial, showed no significant difference in 28-day mortality between those treated with corticosteroids (39.2%) and those receiving a placebo (36%, P=0.069).17 There was also no significant difference in either hospital or ICU mortality in this study.
A recent meta-analysis demonstrated no significant effect of corticosteroid treatment on 28-day mortality, ICU mortality, or hospital mortality in septic shock. However, subanalysis of trials using a prolonged course (>5 days) of low-dose steroids (300 mg of hydrocortisone or equivalent) showed a significant reduction in 28-day all-cause mortality (P=0.02) and hospital mortality (P =0.05), and a decrease in ICU length of stay.18
Reversal of shock. Various studies have shown a decrease in the time necessary to reverse septic shock with the use of low-dose steroids. Annane and colleagues showed the median time to vasopressor therapy withdrawal was seven days in the group treated with steroids versus nine days in the placebo group (P=0.01).16 The CORTICUS study demonstrated significantly shorter times to reversal of shock in the group treated with hydrocortisone compared with the placebo group—3.3 days versus 5.8 days (P<0.001).17 In a smaller study, 68% of hydrocortisone-treated patients achieved seven-day shock reversal compared with 21% in the placebo group, a difference of 47% in the rate of reversal of shock.18
