Faculty Opinions recommendation of Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic shock; clinical implications.

Abstract Context Corticosteroid-binding globulin (CBG) transports cortisol and other steroid hormones1,2. High-affinity CBG (haCBG) undergoes proteolysis of the reactive centre loop (RCL) by neutrophil elastase (NE) at inflammatory sites, liberating immunomodulatory cortisol and altering conformation to low-affinity CBG (laCBG). Pyrexia reduces CBG:cortisol binding affinity, an interaction at the RCL is speculated3. Objective To measure the equilibrium binding constants of a panel of steroids to glycosylated haCBG and laCBG over temperature and pH ranges mimicking the pathophysiological conditions of septic shock. Design Surface plasmon resonance was used to determine the binding profiles of 19 steroid ligands to haCBG and laCBG at temperatures 25°C, 37°C and 39°C and pH 7.4 and 7.0. The RCL-recognizing 9G12 antibody was used to assess cleavage and epitope availability of the RCL across conditions. Results A 4–8 fold reduction in affinity for cortisol, cortisone, corticosterone, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone and prednisolone occurred with NE-mediated haCBG-to-laCBG conversion, cortisol expectedly displayed the highest binding affinity. Binding affinity consistently decreased at higher temperatures and at acidic pH for both haCBG and laCBG. 9G12 antibody RCL binding was preserved for haCBG across temperatures. Conclusions These studies reveal that steroid binding to CBG is selective and in all cases reduced upon NE-mediated haCBG-to-laCBG transition. Moreover, reduced CBG:cortisol binding affinity at elevated temperature occurs with an intact and accessible RCL epitope, suggesting a non-RCL mechanism for the delivery of anti-inflammatory cortisol in pyrexia. Synergy of NE cleavage and pyrexia/acidosis may serve for local inflammatory site cortisol delivery and increase free cortisol. These findings demonstrate the modifiable hormone binding characteristics of CBG in (patho-)physiological conditions, supporting its significance in cortisol delivery in obviating systemic inflammation and multiorgan-organ failure in patients with septic shock and its association with mortality4. 1. Pemberton PA, Stein PE, Pepys MB, et al. Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988;336(6196):257–258. 2. Pugeat MM, Dunn JF, Nisula BC. Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):69–75. 3. Cameron A, Henley D, Carrell R, et al. Temperature-responsive release of cortisol from its binding globulin: a protein thermocouple. J Clin Endocrinol Metab. 2010;95(10):4689–4695. 4. Meyer EJ, Nenke MA, Rankin W, et al. Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality. Clin Endocrinol (Oxf). 2019;90(1):232–240.

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Clinical implications of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Canadian Medical Association Journal ◽

10.1503/cmaj.170149 ◽

2018 ◽

Vol 190 (36) ◽

pp. E1058-E1059 ◽

Cited By ~ 19

Author(s):

Shannon M. Fernando ◽

Bram Rochwerg ◽

Andrew J.E. Seely

Keyword(s):

Septic Shock ◽

Clinical Implications ◽

International Consensus ◽

The Third ◽

Sepsis And Septic Shock

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Altered hepatic vasopressin and alpha 1-adrenergic receptors after chronic endotoxin infusion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.252.5.e699 ◽

1987 ◽

Vol 252 (5) ◽

pp. E699-E702 ◽

Cited By ~ 2

Author(s):

B. L. Roth ◽

J. A. Spitzer

Keyword(s):

Septic Shock ◽

Plasma Membrane ◽

Adrenergic Receptors ◽

Endotoxin Infusion ◽

Human Sepsis ◽

High Affinity ◽

Altered Glucose ◽

Vasopressin Receptors ◽

Receptor Number ◽

Sepsis And Septic Shock

Sepsis and septic shock are complicated by a number of hemodynamic and metabolic aberrations. These include catecholamine refractoriness and altered glucose metabolism. Recently, a nonshock rat model of continuous endotoxin infusion via an implanted osmotic pump was developed that reproduces some of the metabolic and cardiovascular findings of human sepsis. By using this model, we have found a decreased number of hepatic plasma membrane alpha 1-adrenergic and [Arg8]vasopressin receptors in rats continuously infused with endotoxin. There was a significant decrease in [3H]prazosin (35 +/- 7%) and [3H] [Arg8]vasopressin (43 +/- 8%) receptors after 30 h of continuous endotoxin infusion with no change in affinity. The ability of norepinephrine to form the high-affinity complex with alpha 1-adrenergic receptors was not altered after chronic endotoxin infusion. The results are consistent with the concept that alterations in receptor number might underlie certain of the metabolic consequences of chronic sepsis.

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Effect of fluid bolus triggers and their combination on fluid responsiveness in optimization phase of severe sepsis and septic shock resuscitation

MedPharmRes ◽

10.32895/ump.mpr.2.3.27 ◽

2018 ◽

Vol 2 (3) ◽

pp. 27-32

Author(s):

Bien Le ◽

Dai Huynh ◽

Mai Tuan ◽

Minh Phan ◽

Thao Pham ◽

...

Keyword(s):

Blood Pressure ◽

Septic Shock ◽

Severe Sepsis ◽

Fluid Responsiveness ◽

Statistical Significance ◽

Venous Pressure ◽

Fluid Bolus ◽

Low Blood Pressure ◽

Low Central Venous Pressure ◽

Sepsis And Septic Shock

Objectives: to evaluate the fluid responsiveness according to fluid bolus triggers and their combination in severe sepsis and septic shock. Design: observational study. Patients and Methods: patients with severe sepsis and septic shock who already received fluid after rescue phase of resuscitation. Fluid bolus (FB) was prescribed upon perceived hypovolemic manifestations: low central venous pressure (CVP), low blood pressure, tachycardia, low urine output (UOP), hyperlactatemia. FB was performed by Ringer lactate 500 ml/30 min and responsiveness was defined by increasing in stroke volume (SV) ≥15%. Results: 84 patients were enrolled, among them 30 responded to FB (35.7%). Demographic and hemodynamic profile before fluid bolus were similar between responders and non-responders, except CVP was lower in responders (7.3 ± 3.4 mmHg vs 9.2 ± 3.6 mmHg) (p 0.018). Fluid response in low CVP, low blood pressure, tachycardia, low UOP, hyperlactatemia were 48.6%, 47.4%, 38.5%, 37.0%, 36.8% making the odd ratio (OR) of these triggers were 2.81 (1.09-7.27), 1.60 (0.54-4.78), 1.89 (0.58-6.18), 1.15 (0.41-3.27) and 1.27 (0.46-3.53) respectively. Although CVP < 8 mmHg had a higher response rate, the association was not consistent at lower cut-offs. The combination of these triggers appeared to raise fluid response but did not reach statistical significance: 26.7% (1 trigger), 31.0% (2 triggers), 35.7% (3 triggers), 55.6% (4 triggers), 100% (5 triggers). Conclusions: fluid responsiveness was low in optimization phase of resuscitation. No fluid bolus trigger was superior to the others in term of providing a higher responsiveness, their combination did not improve fluid responsiveness as well.

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