Steroids Redux: Targeting the Mineralocorticoid Axis in Sepsis*

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The role of corticosteroids in the management of septic shock has been a defining and durable controversy in critical care. Early studies by Schumer (1) suggested that the use of large doses of corticosteroids could dramatically improve survival in septic shock, a hypothesis that was soundly rejected following the publication of two landmark multicenter trials that showed no evidence of benefit, and even a signal for harm (2, 3). Yet, the idea that steroids might favorably modulate the course of sepsis remained a tenacious one, with evolving evidence that while high-dose therapy was inefficacious, physiologic doses might be beneficial, particularly when glucocorticoid agonists were administered in conjunction with mineralocorticoids (4). The impending completion of the 3,800 patients ADjunctive coRticosteroid trEatment iN criticAlly ilL patients with septic shock (ADRENAL) trial of pharmacologic dose of glucocorticoids for the treatment of sepsis will provide the most compelling evidence of the value of glucocorticoids in sepsis (5).
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.

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