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Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock.

ABSTRACT: 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.

SUBMITTER: Hicks CW

PROVIDER: S-EPMC3242885 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock.

Hicks Caitlin W CW Sweeney Daniel A DA Danner Robert L RL Eichacker Peter Q PQ Suffredini Anthony F AF Feng Jing J Sun Junfeng J Behrend Ellen N EN Solomon Steven B SB Natanson Charles C

Critical care medicine 20120101 1

<h4>Objective</h4>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 ...[more]

PMID: 21926575

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Project description:IntroductionThe present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20% in the microvascular flow index of small vessels among groups.MethodsThe design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 μg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization.ResultsTP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 μg/kg/minute (0.29 to 1.04) vs. 0.16 μg/kg/minute (0.03 to 0.37) for TP and 0.40 μg/kg/minute (0.20 to 1.05) vs. 0.23 μg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7% (2.6 to 19.8) for TP, 8.9% (0.0 to 17.8) for AVP, and 6.9% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6% (8.6 to 36.9) for TP, 20.2% (-3.0 to 37.2) for AVP, and 11.4% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison).ConclusionsThe present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se.Trial registrationClinicalTrial.gov NCT00995839.

Project description:BackgroundPrevious studies have suggested that β1-receptor blockers benefit septic shock patients. This study aimed to determine whether β1-receptor blockers benefit tissue perfusion in sepsis and to identify parameters to reduce the risk of this drug in sepsis.MethodsConsecutive septic shock patients were recruited from the Intensive Care Unit of Peking Union Medical College Hospital within 48 h of diagnosis. All patients were hemodynamically stable and satisfactorily sedated with a heart rate (HR) ≥100 beats/min. Esmolol therapy achieved the target HR of 10-15% lower than the baseline HR. Clinical and physiological data of patients were collected prospectively within 1 h prior to esmolol therapy and 2 h after achieving the targeted HR.ResultsSixty-three patients were recruited. After esmolol therapy, blood pressure was unaltered, whereas stroke volume (SV) was increased compared with before esmolol therapy (43.6 ± 22.7 vs. 49.9 ± 23.7 ml, t = -2.3, P = 0.047). Tissue perfusion, including lactate levels (1.4 ± 0.8 vs. 1.1 ± 0.6 mmol/L, t = 2.6, P = 0.015) and the central venous-to-arterial carbon dioxide difference (5.6 ± 3.3 vs. 4.3 ± 2.2 mmHg, t = 2.6 P = 0.016), was also significantly decreased after esmolol therapy. For patients with increased SV (n = 42), cardiac efficiency improved, and esmolol therapy had a lower risk for a decrease in cardiac output (CO). Therefore, pretreatment cardiac systolic and diastolic parameters with (n = 42)/without (n = 21) an increase in SV were compared. Mitral lateral annular plane systolic excursion (MAPSElat) in patients with increased SV was significantly higher than that in those without increased SV (1.3 ± 0.3 vs. 1.1 ± 0.2 cm, t = 2.4, P = 0.034).ConclusionsSV of septic shock patients is increased following esmolol therapy. Although CO is also decreased with HR, tissue perfusion is not worse. MAPSElat can be used to predict an increase in SV before esmolol use.Trial registrationClinicalTrials.gov, NCT01920776; https://clinicaltrials.gov/ct2/show/NCT01920776?term=NCT01920776&rank=1.

Project description:INTRODUCTION: V(2)-receptor (V(2)R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V(2)R-antagonist (Propionyl(1)-D-Tyr(Et)(2)-Val(4)-Abu(6)-Arg(8,9))-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V(1a)R/V(2)R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic shock. METHODS: After the onset of septic shock, chronically instrumented sheep were randomly assigned to receive first-line treatment with the selective V(2)R-antagonist (1 ?g/kg per hour), AVP (0.05 ?g/kg per hour), or normal saline (placebo, each n = 7). In all groups, open-label norepinephrine was additionally titrated up to 1 ?g/kg per minute to maintain mean arterial pressure at 70 ± 5 mmHg, if necessary. RESULTS: Compared to AVP- and placebo-treated animals, the selective V(2)R-antagonist stabilized cardiopulmonary hemodynamics (mean arterial and pulmonary artery pressure, cardiac index) as effectively and increased intravascular volume as suggested by higher cardiac filling pressures. Furthermore, left ventricular stroke work index was higher in the V(2)R-antagonist group than in the AVP group. Notably, metabolic (pH, base excess, lactate concentrations), liver (transaminases, bilirubin) and renal (creatinine and blood urea nitrogen plasma levels, urinary output, creatinine clearance) dysfunctions were attenuated by the V(2)R-antagonist when compared with AVP and placebo. The onset of septic shock was associated with an increase in AVP plasma levels as compared to baseline in all groups. Whereas AVP plasma levels remained constant in the placebo group, infusion of AVP increased AVP plasma levels up to 149 ± 21 pg/mL. Notably, treatment with the selective V(2)R-antagonist led to a significant decrease of AVP plasma levels as compared to shock time (P < 0.001) and to both other groups (P < 0.05 vs. placebo; P < 0.001 vs. AVP). Immunohistochemical analyses of lung tissue revealed higher hemeoxygenase-1 (vs. placebo) and lower 3-nitrotyrosine concentrations (vs. AVP) in the V(2)R-antagonist group. In addition, the selective V(2)R-antagonist slightly prolonged survival (14 ± 1 hour) when compared to AVP (11 ± 1 hour, P = 0.007) and placebo (11 ± 1 hour, P = 0.025). CONCLUSIONS: Selective V(2)R-antagonism may represent an innovative therapeutic approach to attenuate multiple organ dysfunction in early septic shock.

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Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock.

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Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock.

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