Four-Compartment Diffusion Model of Cortisol Disposition: Comparison With 3 Alternative Models in Current Clinical Use.

Context: Estimated rates of cortisol elimination and appearance vary according to the model used to obtain them. Generalizability of current models of cortisol disposition in healthy humans is limited. Objective: Development and validation of a realistic, mechanistic model of cortisol disposition that accounts for the major factors influencing plasma cortisol concentrations in vivo (Model 4), and comparison to previously described models of cortisol disposition in current clinical use (Models 1-3). Methods: The 4 models were independently applied to cortisol concentration data obtained for the hydrocortisone bolus experiment (20 mg) in 2 clinical groups: healthy volunteers (HVs, n = 6) and corticosteroid binding globulin (CBG)-deficient (n = 2). Model 4 used Fick's first law of diffusion to model free cortisol flux between vascular and extravascular compartments. Pharmacokinetic parameter solutions for Models 1-4 were optimized by numerical methods, and model-specific parameter solutions were compared by repeated measures analysis of variance. Models and respective parameter solutions were compared by mathematical and simulation analyses, and an assessment tool was used to compare performance characteristics of the four models evaluated herein. Results: Cortisol half-lives differed significantly between models (all P < .001) with significant model-group interaction (P = .02). In comparative analysis, Model 4 solutions yielded significantly reduced free cortisol half-life, improved fit to experimental data (both P < .01), and superior model performance. Conclusion: The proposed 4-compartment diffusion model (Model 4) is consistent with relevant experimental observations and met the greatest number of empiric validation criteria. Cortisol half-life solutions obtained using Model 4 were generalizable between HV and CBG-deficient groups and bolus and continuous modes of hydrocortisone infusion.

Decreased maximal cortisol secretion rate in patients with cirrhosis: Relation to disease severity.

BACKGROUND & AIMS: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. METHODS: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). RESULTS: Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24-0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33-0.46), and CSRmax was negatively correlated with CP score (r = -0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min-1) compared with that in the CP ≤8 group (0.21 ± 0.21 min-1), and free cortisol elimination rates were negatively correlated with CP score (r = -0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p <0.001) was observed. CONCLUSIONS: CSRmax and free cortisol elimination rates were significantly reduced according to severity of cirrhosis. In contrast to stimulated total cortisol concentrations, CSRmax estimates were independent of cortisol-binding protein concentrations. Results provide additional evidence of subnormal adrenocortical function in patients with cirrhosis. LAY SUMMARY: We applied numerical analytic methods to characterise adrenocortical function in patients with varying stages of chronic liver disease. We found that patients with more severe cirrhosis have decreased rate of free cortisol elimination and decreased maximal cortisol secretion rate, which is a measure of adrenocortical function. In contrast to conventional measures of adrenocortical function, those obtained using numerical methods were not affected by variation in corticosteroid binding globulin and albumin concentrations. We conclude that patients with cirrhosis demonstrate measurable abnormalities of adrenocortical function, evidence of which supports aspects of the hepatoadrenal syndrome hypothesis.

Characterization of Cortisol Secretion Rate in Secondary Adrenal Insufficiency.

CONTEXT: In secondary adrenal insufficiency (SAI), chronic deficiency of adrenocorticotropin (ACTH) is believed to result in secondary changes in adrenocortical function, causing an altered dose-response relationship between ACTH concentration and cortisol secretion rate (CSR). OBJECTIVE: We sought to characterize maximal cortisol secretion rate (CSRmax) and free cortisol half-life in patients with SAI, compare results with those of age-matched healthy controls, and examine the influence of predictor variables on ACTH-stimulated cortisol concentrations. DESIGN: CSRmax was estimated from ACTH1-24 (250 µg)-stimulated cortisol time-concentration data. Estimates for CSRmax and free cortisol half-life were obtained for both dexamethasone (DEX) and placebo pretreatment conditions for all subjects. SETTING: Single academic medical center. PATIENTS: Patients with SAI (n = 10) compared with age-matched healthy controls (n = 21). INTERVENTIONS: The order of DEX vs placebo pretreatment was randomized and double-blind. Cortisol concentrations were obtained at baseline and at intervals for 120 minutes after ACTH1-24. MAIN OUTCOME MEASURES: CSRmax and free cortisol half-life were obtained by numerical modeling analysis. Predictors of stimulated cortisol concentrations were evaluated using a multivariate model. RESULTS: CSRmax was significantly (P < 0.001) reduced in patients with SAI compared with controls for both placebo (0.17 ± 0.09 vs 0.46 ± 0.14 nM/s) and DEX (0.18 ± 0.13 vs 0.43 ± 0.13 nM/s) conditions. Significant predictors of ACTH1-24-stimulated total cortisol concentrations included CSRmax, free cortisol half-life, and baseline total cortisol, corticosteroid-binding globulin, and albumin concentrations (all P < 0.05). CONCLUSIONS: Our finding of significantly decreased CSRmax confirms that SAI is associated with alterations in the CSR-ACTH dose-response curve. Decreased CSRmax contributes importantly to the laboratory diagnosis of SAI.

Reversible increase in maximal cortisol secretion rate in septic shock.

OBJECTIVE: Cortisol clearance is reduced in sepsis and may contribute to the development of impaired adrenocortical function that is thought to contribute to the pathophysiology of critical illness-related corticosteroid insufficiency. We sought to assess adrenocortical function using computer-assisted numerical modeling methodology to characterize and compare maximal cortisol secretion rate and free cortisol half-life in septic shock, sepsis, and healthy control subjects. DESIGN: Post hoc analysis of previously published total cortisol, free cortisol, corticosteroid-binding globulin, and albumin concentration data. SETTING: Single academic medical center. PATIENTS: Subjects included septic shock (n = 45), sepsis (n = 25), and healthy controls (n = 10). INTERVENTIONS: I.v. cosyntropin (250 µg). MEASUREMENTS AND MAIN RESULTS: Solutions for maximal cortisol secretion rate and free cortisol half-life were obtained by least squares solution of simultaneous, nonlinear differential equations that account for free cortisol appearance and elimination as well as reversible binding to corticosteroid-binding globulin and albumin. Maximal cortisol secretion rate was significantly greater in septic shock (0.83 nM/s [0.44, 1.58 nM/s] reported as median [lower quartile, upper quartile]) compared with sepsis (0.51 nM/s [0.36, 0.62 nM/s]; p = 0.007) and controls (0.49 nM/s [0.42, 0.62 nM/s]; p = 0.04). The variance of maximal cortisol secretion rate in septic shock was also greater than that of sepsis or control groups (F test, p < 0.001). Free cortisol half-life was significantly increased in septic shock (4.6 min [2.2, 6.3 min]) and sepsis (3.0 min [2.3, 4.8 min] when compared with controls (2.0 min [1.2, 2.6 min]) (both p < 0.004). CONCLUSIONS: Results obtained by numerical modeling are consistent with comparable measures obtained by the gold standard stable isotope dilution method. Septic shock is associated with generally not only higher levels but also greater variance of maximal cortisol secretion rate when compared with control and sepsis groups. Additional studies would be needed to determine whether assessment of cortisol kinetic parameters such as maximal cortisol secretion rate and free cortisol half-life is useful in the diagnosis or management of critical illness-related corticosteroid insufficiency.

Multiband optical absorption controlled by lattice strain in thin-film LaCrO3.

Experimental measurements and ab initio modeling of the optical transitions in strained G-type antiferromagnetic LaCrO(3) resolve two decades of debate regarding the magnitude of the band gap and the character of the optical absorption spectrum in the visible-to-ultraviolet (up to ∼5 eV) range in this material. Using time-dependent density functional theory and accounting for thermal disorder effects, we demonstrate that the four most prominent low-energy absorption features are due to intra-Cr t(2g)-e(g) (2.7, 3.6 eV), inter-Cr t(2g)-t(2g) (4.4 eV), and interion O 2p-Cr 3d (from ∼5 eV) transitions and show that the excitation energies of the latter type can be strongly affected by the lattice strain.

Estimation of maximal cortisol secretion rate in healthy humans.

CONTEXT: Cortisol secretion is related to ACTH concentration by a sigmoidal dose-response curve, in which high ACTH concentrations drive maximal cortisol secretion rates (CSR(max)). OBJECTIVE: We sought to estimate CSR(max) and free cortisol half-life in healthy humans (n = 21) using numerical methods applied to data acquired during cosyntropin (250 µg) stimulation. We also evaluated the effect of overnight dexamethasone (DEX; 1 mg) vs. placebo on estimates of CSR(max) and free cortisol half-life. DESIGN: This study was a double-blind, placebo-controlled, randomized order of overnight DEX vs. placebo, cosyntropin (250 µg) stimulation with frequent serum cortisol sampling and computer-assisted numerical analysis. SETTING: The study was conducted at a single academic medical center. PARTICIPANTS: Twenty-one healthy adult subjects (15 females and six males), mean aged 46 yr, participated in the study. INTERVENTION: Intervention in the study included DEX vs. placebo pretreatment, cosyntropin (250 µg) iv with frequent cortisol sampling. MAIN OUTCOME MEASURES: CSR(max) and free cortisol half-life estimates, R² for goodness of fit, were measured. RESULTS: Mean ± sd CSR(max) was 0.44 ± 0.13 nm/second, with free cortisol half-life of 2.2 ± 1.1 min. DEX did not significantly affect estimates of CSR(max) or free cortisol half-life. Our model accounts for most of the variability of measured cortisol concentrations (overall R² = 90.9 ±11.0%) and was more accurate (P = 0.004) during DEX suppression (R² = 94.6 ± 4.6%) compared with placebo (R² = 87.2 ± 8.7%). CONCLUSIONS: Application of a mass-action model under conditions of cosyntropin stimulation provides a relatively simple method for estimation CSR(max) that accurately predicts measured cortisol concentrations. DEX administration did not significantly affect estimates of CSR(max) or free cortisol half-life.

Validation of a simple method of estimating plasma free cortisol: role of cortisol binding to albumin.

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.