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Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock

Hicks, Caitlin W. MS; Sweeney, Daniel A. MD; Danner, Robert L. MD; Eichacker, Peter Q. MD; Suffredini, Anthony F. MD; Feng, Jing BS; Sun, Junfeng PhD; Behrend, Ellen N. VMD, PhD; Solomon, Steven B. PhD; Natanson, Charles MD

doi: 10.1097/CCM.0b013e31822efa14
Laboratory Investigations

Objective: Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock.

Design, Setting, Subjects, and Interventions: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia.

Measurements and Main Results: Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression.

Conclusions: In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.

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From the Cleveland Clinic Lerner College of Medicine (CWH), Cleveland, OH; Howard Hughes Medical Institute (CWH), National Institutes of Health Research Scholar, Bethesda, MD; the Critical Care Medicine Department (CWH, RLD, PQE, AFS, JF, JS, SBS, CN), Clinical Center, National Institutes of Health, Bethesda, MD; the Medical Intensivist Program (DAS), Washington Hospital, Fremont, CA; and the Department of Clinical Sciences (ENB), College of Veterinary Medicine, Auburn University, Auburn, AL.

This study was funded, in part, by the National Institutes of Health and the Howard Hughes Medical Institute. All work pertaining to this manuscript was performed at the National Institutes of Health (NIH). The study was supported by NIH intramural funds but the opinions expressed herein do not necessarily represent the opinions of the US Government.

The authors have not disclosed any potential conflicts of interest.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins