Steroids Redux: Targeting the Mineralocorticoid Axis in Sepsis*
However, a key residual question remains. The most impressive evidence of benefit for steroids came from a French trial that showed that a combination of hydrocortisone and fludrocortisone could reduce the mortality of septic shock by 10% (6). To what extent was the enhanced benefit seen in this study driven by different patient selection, differences in supportive care, differences in trial design or conduct, or the independent effects of the mineralocorticoid agonist, fludrocortisone? We will not know the answer definitively without a head-to-head trial comparing glucocorticoids to the combination of a glucocorticoid and a mineralocorticoid. In the absence of that trial, however, an enhanced understanding of the biology of the response to steroids in experimental sepsis may provide a framework within which to address the question.
Adrenal corticosteroids exert complex and varied effects on systemic homeostasis. A clear mechanism for the apparent benefit for low-dose glucocorticoids (4) has been elusive; however, it is generally believed that treatment comprises replacement therapy for an acute state of relative adrenal insufficiency. The dominant focus on the activity of aldosterone has been its role in the regulation of sodium and water homeostasis in the kidney. It is now clear, however, that mineralocorticoid receptors are also present on vascular smooth muscle and endothelial cells, and that aldosterone can induce both vasoconstriction and vascular inflammation and remodeling independent of its renal effects (7, 8). In chronic diseases such as hypertension and heart failure, the effects of aldosterone on vascular reactivity are detrimental, and the focus has been on the development of pharmacologic inhibitors of the mineralocorticoid receptor (9). A beneficial role in sepsis, therefore, assumes effects that are highly context-dependent. du Cheyron et al (10) reported that plasma aldosterone concentrations are low in some patients with septic shock, and that a low aldosterone concentration is associated with increased fluid requirements and an increased risk of acute kidney injury requiring renal replacement therapy. Thus, the hypothesis that a mineralocorticoid deficit accompanies the relative glucocorticoid deficit is biologically plausible.
In this issue of Critical Care Medicine, Fadel et al (11) report a series of experiments that show that mineralocorticoids can augment blood pressure in experimental endotoxemia. In a murine model of endotoxic shock, they show that the administration of aldosterone increases blood pressure and protects against endotoxin-mediated lethality. Aldosterone administration in vivo increased the blood pressure response to phenylephrine, both in vivo, and in mesenteric arterial rings isolated from treated animals.