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Context: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based., Objective: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress., Design and Participants: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration)., Main Outcome Measure: We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress., Results: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range., Conclusions: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress., (© Endocrine Society 2020.)

Introduction: In critically ill patients, the hypothalamic-pituitary-adrenal axis is activated, resulting in increased serum cortisol concentrations. However, in some patients, especially those with sepsis, cortisol levels are relatively low for the degree of illness severity. Therefore, in the present project, we aim to characterize the time course of glucocorticoid receptor (GCR) alpha and beta expression in peripheral polymorphonuclear cells of critically ill septic or nonseptic patients using real-time PCR., Design: A prospective observational study conducted on 32 critically ill adults not receiving steroids, in a university-affiliated, multidisciplinary intensive care unit (ICU). Blood samples were collected for measurement of glucocorticoid receptor expression within 24-48 hours of admission to the ICU and at days 4, 8 and 13 after admission, reflecting the acute and chronic phase of the illness., Results: During ICU stay, patients expressed over time reduced levels of both GCR-α and GCR-β mRNA. More specifically, GCR-α mRNA expression was decreased fourfold 4 days after admission (P < 0.0001) and remained low up to 2 weeks after admission (P < 0.001). On the other hand, GCR-β mRNA levels remained stable shortly after admission, but approx. one week after admission, its levels decreased threefold (P < 0.01) and remained reduced up to 2 weeks after admission (P < 0.001)., Discussion: Our results suggest that critically ill patients have highly variable expression of alpha and beta GCR, and moreover, the levels of both receptors decrease during ICU stay. Taken together, these might explain the differential responsiveness of patients to exogenous steroid administration or to endogenous cortisol secretion., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Purpose: The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels., Materials and Methods: An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls., Results: The patients had higher adiponectin (10.9 ± 6.1 μg/mL vs 6.0 ± 2.9 μg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted., Conclusions: Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to measure subcutaneous tissue cortisol obtained by microdialysis (MD) in 35 mechanically ventilated septic patients. Materials and Methods: Upon intensive care unit admission, an MD catheter was inserted into the subcutaneous tissue of the thigh. Cortisol (CORT) was determined in a 5:00 to 9:00 AM microdialysate sample collected within 72 hours. Concurrently, serum total (T-CORT) and free CORT (F-CORT) were measured. The Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment scores were calculated. Both T-CORT less than 10 μg/dL and F-CORT less than 0.8 μg/dL were considered as indicating critical illness-related corticosteroid insufficiency. Adrenal adequacy was defined as T-CORT greater than 20 μg/dL or F-CORT greater than 2.0 μg/dL. Results: Total CORT correlated significantly with F-CORT (rs=+0.8, P < .0001).Microdialysis CORT had a lower correlation with T-CORT (rs = +0.6, P < .0001) and F-CORT (rs = +0.7, P < .0001) and a weak correlation with APACHE II score (rs=+0.4, P < .01). On the basis of MD-CORT, the patients were divided in quartiles. Although the median F-CORT and T-CORT levels were significantly different (P < .001) among the MD-CORT quartiles, there was a considerable overlap between the subgroups. All patientswith T-CORT less than 10 μg/dL and all but 3 patients with F-CORT less than 0.8 μg/dL had tissue CORT in the lower quartile. However, only 50%and 58% of patients with adequate T-CORT and F-CORT levels, respectively, had concordant MD-CORT in the highest quartile. Conclusions: Microdialysis CORT levels correlate moderately with circulating T-CORT and F-CORT. Of note, several patients presented with discrepant measurements between interstitial and circulating CORT concentrations. Thus, interstitial CORT measurements represent an additional tool to investigate the tissue CORT availability in critically ill patients. [ABSTRACT FROM AUTHOR]

Purpose: More than a disorder of macrocirculation, sepsis is a disease affecting the microcirculation and the tissue metabolism. In vivo microdialysis (MD) is a bedside technique that can monitor tissue metabolic changes. We conducted this study aiming (1) to assess whether patients at different sepsis stages present with different MD-assessed tissue metabolic profiles and (2) to determine if different underlying types of infections and implicated pathogens are associated with dissimilar metabolic alterations. Methods: We studied 90 mechanically ventilated patients, 65 with septic shock and 25 with severe sepsis. An MD catheter was inserted in the subcutaneous adipose tissue of the upper thigh and interstitial fluid samples were collected along with arterial blood samples every 4 h for a maximum of 6 days. Lactate, pyruvate, glycerol, and glucose concentrations were measured. Results: During the study period, patients with septic shock had higher MD-assessed glycerol ( P = 0.009), glycerol gradient ( P = 0.016), and glucose ( P = 0.004) than patients with severe sepsis, whereas tissue lactate, lactate gradient, and pyruvate dropped significantly with time ( P = 0.007, <0.001, and <0.001, respectively) in both patient groups without any observed between-group difference. In addition, there was no between-group difference in their tissue lactate/pyruvate ratio on any day, nor did the ratio decrease significantly with time. Compared with pneumonia patients, and despite similar baseline clinical characteristics, those suffering from intra-abdominal infections showed a pattern of higher and progressively increasing tissue levels of glucose ( P = 0.001) and glycerol ( P = 0.001). Finally, patients harboring Gram-positive infections had higher tissue levels of glycerol ( P = 0.027) and glycerol gradient ( P = 0.029) than patients with Gram-negative infections. Conclusions: MD can detect tissue metabolic abnormalities that differ in relation to the sepsis stage and the type of underlying infection or responsible pathogen. Some of the MD-assessed abnormalities are not reflected by conventional blood measurements and possess prognostic potential. It remains to be determined if this type of metabolic monitoring can find clinical applications in the wide population of septic critically ill patients. [ABSTRACT FROM AUTHOR]

No study has directly measured tissue lactate clearance in patients with sepsis during the post-resuscitation period. In this study we aimed to assess in ICU patients with sepsis (n = 32) or septic shock (n = 79)—during the post-resuscitation phase—the relative kinetics of blood/tissue lactate clearances and to examine whether these are associated with outcome. We measured serially—over a 48-h period—blood and adipose tissue interstitial fluid lactate levels (with microdialysis) and we calculated lactate clearance. Statistics included mixed model analysis, Friedman’s analysis of variance, Wilcoxon’s test, Mann-Whitney’s test, receiver operating characteristics curves and logistic regression. Forty patients died (28-day mortality rate = 28%). Tissue lactate clearance was higher compared to blood lactate clearance at 0–8, 0–12, 0–16, 0–20 and 0–24 h (all p < 0.05). Tissue lactate clearance was higher in survivors compared to non-survivors at 0–12, 0–20 and 0–24 h (all p = 0.02). APACHE II along with tissue lactate clearance <30% at 0–12, 0–20 and 0–24 h were independent outcome predictors. We did not find blood lactate clearance to be related to survival. Thus, in critically ill septic patients, elevated tissue (but not blood) lactate clearance, was associated with a favorable clinical outcome. [ABSTRACT FROM AUTHOR]