OBJECTIVES: To develop, optimize, and validate a generalized mass action, equilibrium solution that incorporates measured concentrations of albumin as well as cortisol binding globulin (CBG) to estimate free cortisol. DESIGN AND METHODS: Free cortisol was estimated by Coolens method or by cubic equilibrium equation and compared to measured free cortisol, determined by ultrafiltration method, in subjects with septic shock (n=45), sepsis (n=19), and healthy controls (n=10) at 0, 30, and 60 min following administration of cosyntropin (250 mcg). The data set also included repeat testing in 30 subjects following recovery from sepsis/septic shock. The equilibrium dissociation constant for cortisol binding to albumin (K(A)) was optimized by non-linear regression. The cubic equilibrium solution was also used to model the influence of cortisol, CBG, and albumin concentration on free cortisol. RESULTS: Compared to measured free cortisol, the cubic solution, using an optimized K(A) of 137,800 nM, was less biased than Coolens solution, with mean percent error of -23.0% vs. -41.1% (paired t test, P<0.001). Standard deviation values were also significantly lower (Wilks' test, P<0.001) for the cubic solution (SD 35.8% vs. 40.8% for cubic vs. Coolens, respectively). Modeling studies using the cubic solution suggest an interaction effect by which low concentrations of CBG and albumin contribute to a greater increase in free cortisol than the sum of their independent effects. CONCLUSIONS: Mass action solutions that incorporate the measured concentration of albumin as well as CBG provide a reasonably accurate estimate of free cortisol that generalizes to conditions of health as well as a setting of hypercortisolism and low CBG and albumin concentrations associated with septic shock. Modeling studies emphasize the significant contribution of albumin deficiency and albumin-bound cortisol under conditions of CBG-deficiency, and identify a synergistic effect by which combined CBG and albumin deficiency contribute to elevation of free cortisol in septic shock.
OBJECTIVES: To develop, optimize, and validate a generalized mass action, equilibrium solution that incorporates measured concentrations of albumin as well as cortisol binding globulin (CBG) to estimate free cortisol. DESIGN AND METHODS: Free cortisol was estimated by Coolens method or by cubic equilibrium equation and compared to measured free cortisol, determined by ultrafiltration method, in subjects with septic shock (n=45), sepsis (n=19), and healthy controls (n=10) at 0, 30, and 60 min following administration of cosyntropin (250 mcg). The data set also included repeat testing in 30 subjects following recovery from sepsis/septic shock. The equilibrium dissociation constant for cortisol binding to albumin (K(A)) was optimized by non-linear regression. The cubic equilibrium solution was also used to model the influence of cortisol, CBG, and albumin concentration on free cortisol. RESULTS: Compared to measured free cortisol, the cubic solution, using an optimized K(A) of 137,800 nM, was less biased than Coolens solution, with mean percent error of -23.0% vs. -41.1% (paired t test, P<0.001). Standard deviation values were also significantly lower (Wilks' test, P<0.001) for the cubic solution (SD 35.8% vs. 40.8% for cubic vs. Coolens, respectively). Modeling studies using the cubic solution suggest an interaction effect by which low concentrations of CBG and albumin contribute to a greater increase in free cortisol than the sum of their independent effects. CONCLUSIONS: Mass action solutions that incorporate the measured concentration of albumin as well as CBG provide a reasonably accurate estimate of free cortisol that generalizes to conditions of health as well as a setting of hypercortisolism and low CBG and albumin concentrations associated with septic shock. Modeling studies emphasize the significant contribution of albumin deficiency and albumin-bound cortisol under conditions of CBG-deficiency, and identify a synergistic effect by which combined CBG and albumin deficiency contribute to elevation of free cortisol in septic shock.
Authors: Marissa N Smith; William C Griffith; Shirley A A Beresford; Melinda Vredevoogd; Eric M Vigoren; Elaine M Faustman Journal: J Expo Sci Environ Epidemiol Date: 2013-12-04 Impact factor: 5.563
Authors: Nienke Molenaar; A B Johan Groeneveld; Hilde M Dijstelbloem; Margriet F C de Jong; Armand R J Girbes; Annemieke C Heijboer; Albertus Beishuizen Journal: Intensive Care Med Date: 2011-08-18 Impact factor: 17.440
Authors: Laura E Dichtel; Melanie Schorr; Claudia Loures de Assis; Elizabeth M Rao; Jessica K Sims; Kathleen E Corey; Puja Kohli; Patrick M Sluss; Michael J McPhaul; Karen K Miller Journal: J Clin Endocrinol Metab Date: 2019-10-01 Impact factor: 5.958
Authors: J Yu; N A Cilfone; E M Large; U Sarkar; J S Wishnok; S R Tannenbaum; D J Hughes; D A Lauffenburger; L G Griffith; C L Stokes; M Cirit Journal: CPT Pharmacometrics Syst Pharmacol Date: 2015-10-05