Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock

Abstract

Background Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock, but have variable effects on survival. Objective and Methods To determine if exogenous mineralocorticoid and glucocorticoid stimulation have distinct effects, and whether the timing on such stimulation alters their effects, in septic shock. Desoxycorticosterone (DOC), a selective mineralocorticoid agonist; dexamethasone (DEX), a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 h in 74 canines with staphylococcal pneumonia. Measurements and Main Results Effects of DOC and DEX were different and opposite depending on timing of administration for survival (p=0.05); fluid requirements (p=0.05); central venous pressures (p≤0.007); indicators of hemoconcentration [i.e. sodium (p=0.0004), albumin (p=0.05), and platelet counts (p=0.02)]; IL-6 levels (p=0.04); and cardiac dysfunction (p=0.05). Prophylactic DOC treatment significantly improved survival, shock, and all the other outcomes above, but therapeutic DOC did not. Conversely, prophylactic DEX was much less effective for improving these outcomes compared to therapeutic DEX, with the exception of shock reversal. Prophylactic DEX given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared to therapeutic DEX (p≤0.05), consistent with adrenal suppression. Conclusions In septic shock, mineralocorticoids are only beneficial if given prophylactically, while 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.

Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia

“…Transfusing 42-day-old washed stored blood lessened the degree of lung and liver injury when compared with unwashed controls, decreased vasopressor requirements (reversed shock), and improved cardiac performance (Figures 2 and 3). 28,29 In contrast, transfusing washed fresher blood had a different and opposite effect that made these same parameters worse when compared with unwashed controls.…”

“…The LIS in a previously published scoring system increases our ability to find the abnormalities in the lungs, which includes mean pulmonary artery pressure, alveolar-arterial oxygen gradient, plateau pressure, O 2 saturation, and respiratory rate. 1,28,29 (B,D) The LIS is plotted in the same fashion as the shock score for old and fresh blood. In each of these panels, unwashed blood is represented by a solid line and washed blood by a dashed line.…”

Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia

“…However, this test is cumbersome, and its clinical utility during sepsis has not been established (9,20,39). Furthermore, no consensus exists for what random cortisol value defines relative adrenal insufficiency in septic shock or indicates the need for exogenous therapy (3,6,17,20,23,25,(33)(34)(35). This lack of reliable diagnostic criteria has led to skepticism regarding the existence of CIRCI and hampered trials evaluating corticosteroid replacement therapy.…”

“…In a canine model of severe septic shock due to Staphylococcus aureus pneumonia, we previously demonstrated that desoxycorticosterone pivalate, a selective mineralocorticoid agonist, started 72 h before sepsis (25), or therapeutic dexamethasone, a selective glucocorticoid agonist, given at the onset of sepsis either alone or with desoxycorticosterone (26), reversed shock and improved survival. How-ever, dexamethasone started 48 h before sepsis, and desoxycorticosterone started at the onset of infection, were not beneficial in this S. aureus pneumonia model (25). Thus, the effect of selective corticosteroids on outcomes in this model of septic shock has been previously fully described (25,26).…”

“…How-ever, dexamethasone started 48 h before sepsis, and desoxycorticosterone started at the onset of infection, were not beneficial in this S. aureus pneumonia model (25). Thus, the effect of selective corticosteroids on outcomes in this model of septic shock has been previously fully described (25,26). In these studies, total, bound, and free cortisol, ACTH, and aldosterone were serially measured, and low-and high-dose ACTH stimulation tests were performed daily.…”