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Objective: The mineralocorticoid receptor (MR) has two ligands, aldosterone and cortisol. Hydroxysteroid 11-beta dehydrogenase (HSD11B) isoenzymes regulate which ligand will bind to MR. In this study we aimed to evaluate the expression of the MR and the HSD11B isozymes in peripheral polymorphonuclear cells (PMNs) in critical illness for a 13-day period. Design: Prospective study Setting: One multi-disciplinary intensive care unit (ICU) Participants: Forty-two critically ill patients Methods: Messenger RNA (mRNA) expression of MR, HSD11B1, and HSD11B2, aldosterone levels, and plasma renin activity (PRA) were measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age and sex-matched healthy subjects were used as controls. Results: Compared to healthy controls, MR expression in critically ill patients was lower during the entire study period. HSD11B1 expression was also lower, while HSD11B2 expression was higher. In patients, PRA, aldosterone, the aldosterone:renin ratio, and cortisol remained unaltered during the study period. Conclusion: Our results suggest that, in our cohort of critically ill patients, local endogenous cortisol availability is diminished, pointing towards glucocorticoid resistance. Aldosterone probably occupies the MR, raising the possibility that PMNs might be useful to study to gain insights into MR functionality during pathological states. [ABSTRACT FROM AUTHOR]

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing's syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cor tisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilat eral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy. [ABSTRACT FROM AUTHOR]

Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circula tion. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) exp ected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-clea ved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry con firmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that al ter epitopes recognized by specific monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Desmopressin is a vasopressin analogue selective for type 2 vasopressin receptors that mediate renal water retention. In contrast to the native hormone arginine vasopressin, a well-known ACTH secretagogue, desmopressin, exerts minimal or no activity on ACTH excretion. However, in a substantial proportion of patients with ACTH-dependent Cushing's syndrome (CS), desmopressin elicits an ACTH and cortisol response, which contrasts with the minimal responses obtained in healthy subjects. The mechanism underlying this paradoxical response involves upregulation of vasopressin type 3 and/or the aberrant expression of type 2 receptors by neoplastic ACTH-producing cells. This makes desmopressin administration a suitable test enabling the distinction between neoplastic from functional (formerly termed 'pseudo-Cushing syndrome') ACTH-dependent cortisol excess. Several studies have now established an adjunctive role of desmopressin in the initial diagnostic workup of CS. Despite some early data indicating that this test may also have a role in distinguishing between Cushing's disease (CD) and ectopic ACTH secretion, subsequent studies failed to confirm this observation. The ability of the paradoxical response to desmopressin to depict the presence of neoplastic ACTH-secreting cells was also exploited in the follow-up of patients with CD undergoing surgery. Loss of the desmopressin response, performed in the early postoperative period, was a good predictor for a favorable long-term outcome. Moreover, during follow-up, reappearance of desmopressin paradoxical response was an early indicator for recurrence. In conclusion, the desmopressin test is a valid tool in both the diagnosis and follow-up of patients with CD and should be more widely applied in the workup of these patients. [ABSTRACT FROM AUTHOR]

Endocrine glands are among the organs that most frequently harbor incidentally discovered lesions. Pituitary, thyroid, parathyroid and adrenal incidentalomas are increasingly encountered in everyday practice with variable clinical implications. The major concerns are the risks of malignancy and hormonal hypersecretion mostly in the form of subclinically functioning tumors. Pituitary incidentalomas are usually microadenomas and most of the time clinically unimportant; however, incidentally discovered larger lesions require a more careful diagnostic and therapeutic approach. Thyroid incidentalomas are extremely common; exclusion of malignancy is the main concern in this clinical setting. Although parathyroid adenomas are not uncommon, these lesions are frequently missed owing to their small size and due to clinical unawareness. Adrenal incidentalomas carry a small but finite risk of malignancy. An intriguing challenge regarding incidentally discovered adrenal lesions is that a substantial proportion is associated with hormonal alterations, mainly in the form of subtle cortisol excess. Although still largely controversial, evidence is emerging that so-called subclinical hypercortisolism may not be completely harmless. The best biochemical criterion of subtle cortisol excess remains elusive. Surgical intervention in selected cases results in some beneficial effects, but more data are required in order to routinely support surgery in this clinical setting. This Review provides a brief overview of the prevalence, clinical effect and management of endocrine incidentalomas with a focus on data regarding the diagnostic and therapeutic challenges imposed by incidentally discovered adrenal lesions. [ABSTRACT FROM AUTHOR]

Long-acting somatostatin analogues (SSA) are widely used for the treatment of acromegaly; however, they also alter β-cell function by inhibiting insulin secretion. In this study, we assess the effect of SSA on glucose homeostasis in patients with acromegaly treated with SSAs, compared to patients treated with surgery. We studied four groups of patients with acromegaly: at the time of diagnosis (group I, n = 53), after successful transsphenoidal surgery (TSS, group II, n = 30) and under successful SSA treatment (group III, n = 20); 22 patients were studied only before treatment, 19 only post-treatment, while 31 patients (group IV) were studied before and after the treatment. Patients underwent an oral glucose tolerance test. Insulin sensitivity and β-cell insulin secretion were estimated using appropriate mathematical models. Control of acromegaly with either TSS or SSA improved insulin sensitivity as evident by significantly lower fasting and postglucose insulin levels and HOMA-IR. In addition, patients of group III compared to patients of group II demonstrated significantly lower HOMA-β% (52·5 ± 10·9 vs 189·6 ± 86·7, P < 0·05) and lower first and second phase insulin release (443 ± 83·5 vs 1077 ± 140·8, P < 0·05 and 150 ± 18·2 vs 285 ± 33·3, P < 0·05), respectively. Also, lower fasting glucose levels and a lower prevalence of diabetes were noted in group II compared to group III (5·1 ± 0·2 vs 6·2 ± 0·2 m, P < 0·05, and 13·3% vs 40%, P < 0·0031, respectively). Control of acromegaly with SSA seems to exhibit a negative effect on pancreatic β-cell function. Whether this has long-term clinical implications remains to be established. Nevertheless, careful monitoring of glucose metabolism in patients under SSA is beneficial for their optimal management. [ABSTRACT FROM AUTHOR]

The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. Observational retrospective study in a single secondary/tertiary centre. One hundred and seventy-two patients with adrenal incidentalomas (41 with BI). Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA-S), midnight F, 24-h urine collection for cortisol (UFC), low-dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F-post-LDDST>70 nmol/l and one more abnormality; several diverse cut-offs were also examined. No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F-post-LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P < 0·001) and lower DHEA-S (1·6 ± 1·5 vs 2·5 ± 2·3 μmol/l, P = 0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5% vs 12·2%, P < 0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F-post-LDDST ( P = 0·008) and a decrease in midnight F ( P = 0·015) levels. Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management. [ABSTRACT FROM AUTHOR]

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR). [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late‐ night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH‐dependent and non‐ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non‐ACTH dependent forms. Differentiation between the ACTH‐dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100 years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS. [ABSTRACT FROM AUTHOR]

Background: this prospective observational study aims to assess serum levels of glial fibrillary acidic protein (GFAP), s100b, and total Tau in long-COVID patients, exploring correlations with symptoms, cognitive decline, mental health, and quality of life. Methods: Long-COVID patients visiting our outpatient clinic (February 2021–December 2022) were screened alongside age- and sex-matched controls. GFAP, s100b, and total Tau in serum were measured with ELISA. Cognitive function, depression, anxiety, post-traumatic stress disorder, and quality of life were evaluated using MoCA, HADS (depression and anxiety), IES-R, and SF-36, respectively. Results: Sixty-five long-COVID patients and 20 controls were included. GFAP levels were significantly higher in long-COVID patients (p = 0.031), though not correlating with the presence of long-COVID symptoms. S100b and total Tau showed no significant differences between patients and controls. Nervous system-related symptoms were reported in 47% of patients. High rates of cognitive decline (65.9%), depression (32.2%), anxiety (47.5%), and post-traumatic stress disorder (44.1%) were observed. Over 80% of the study population scored below normative cutoffs for SF-36, indicating a significant impact on quality of life. Conclusions: in this long-COVID cohort with substantial psychological and cognitive symptoms, GFAP levels were elevated compared to controls, though not correlating with the presence of long-COVID symptoms. [ABSTRACT FROM AUTHOR]

Posterior reversible encephalopathy syndrome (PRES) represents a distinct neurological entity characterized by a range of neurological signs and symptoms (seizures, headache, visual abnormalities, altered consciousness, and/or focal neurological signs) and typical neuroimaging findings reflecting reversible subcortical vasogenic edema, usually in the setting of blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and eclampsia. Here we present a case of a 61-year-old woman, with a history of recent total thyroidectomy and postoperative hypoparathyroidism, who was admitted to the Emergency Department with generalized seizures. Although in this clinical setting, hypocalcemia is expected as the most possible underlying pathogenic factor for triggering seizures, the patient was diagnosed with iatrogenic hypercalcemia and milk-alkali syndrome. A brain magnetic resonance imaging (MRI) demonstrated cortical swelling and fluid-attenuated inversion recovery (FLAIR) signal abnormalities in both occipital, parietal, and right frontal lobes, consistent with PRES. The patient's encephalopathy resolved after resolution of hypercalcemia; she had no neurological deficits on discharge, while she was restarted on lower doses of calcium for hypoparathyroidism. This case illustrates the challenges imposed by postoperative hypoparathyroidism and highlights that PRES is a rare but serious complication of hypercalcemia of which endocrinologists should be aware. [ABSTRACT FROM AUTHOR]

Objective: Visceral adiposity index (VAI), initially developed for the assessment of cardiometabolic risk, has been also proposed for the detection of nonalcoholic fatty liver disease (NAFLD); however, its diagnostic performance for NAFLD is still under investigation. We evaluated VAI as a marker of NAFLD and compared its diagnostic performance with that of three other NAFLD indices - fatty liver index (FLI), lipid accumulation product (LAP) and hepatic steatosis index (HSI) - in premenopausal women with and without polycystic ovary syndrome (PCOS) assessed for NAFLD by ultrasonography.Design: Cross-sectional case-control study.Methods: Anthropometric measurements, biochemical testing and abdominal ultrasonography after excluding causes of secondary liver disease were performed in 145 premenopausal women with PCOS (Rotterdam criteria) and 145 healthy control women within the same age range and matched for body mass index (BMI). The diagnostic performance of the four indices was assessed with receiver operating characteristic (ROC) analysis.Results: NAFLD by ultrasonography was detected in 132 of the total sample of 290 women (45.5%). VAI, FLI, LAP and HSI values were significantly higher in women with NAFLD than those without. The areas under the curve (AUROCs) for VAI, FLI, LAP and HSI were 0.77 ± 0.03, 0.87 ± 0.02, 0.84 ± 0.02 and 0.83 ± 0.02, respectively, in the whole group, showing an adequate discriminatory ability for NAFLD of the four indices. AUROCs of the four indices calculated separately for PCOS and control women showed a similar performance of all indices in the two groups.Conclusions: These data show that VAI is useful for detecting NAFLD in premenopausal women with and without PCOS. However, VAI had a lower diagnostic performance in this cohort than FLI, LAP and HSI. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. Methods: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. Results: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52–0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52–0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. Conclusions: We estimate there is a 67–68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition. [ABSTRACT FROM AUTHOR]

The unprecedented scale of the current SARS-CoV-2/COVID-19 pandemic has led to an extensive—yet fragmented—assessment of its endocrine repercussions; in many reports, the endocrine aspects of COVID-19 are lumped together in intensive care unit (ICU) patients and non-ICU patients. In this brief review, we aimed to present endocrine alterations in ICU-hospitalized patients with COVID-19. There are tangible endocrine disturbances that may provide fertile ground for COVID-19, such as preexisting diabetes. Other endocrine disturbances accompany the disease and more particularly its severe forms. Up to the time of writing, no isolated robust endocrine/hormonal biomarkers for the prognosis of COVID-19 have been presented. Among those which may be easily available are admission glycemia, thyroid hormones, and maybe (OH)25-vitamin D3. Their overlap among patients with severe and less severe forms of COVID-19 may be considerable, so their levels may be indicative only. We have shown that insulin-like growth factor 1 may have prognostic value, but this is not a routine measurement. Possibly, as our current knowledge is expanding, the inclusion of selected routine endocrine/hormonal measurements into artificial intelligence/machine learning models may provide further information. [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]

Objectives: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking.Design: Prospective observational study.Setting: One academic multidisciplinary ICU.Subjects: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free.Interventions: None.Measurements and Main Results: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 μg/dL, p < 0.01) compared with the control group.Conclusions: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins. [ABSTRACT FROM AUTHOR]

Purpose: Endothelial protein C receptor (EPCR) is expressed mainly in endothelial cells and is involved in regulation of the cytoprotective and anticoagulant pathways of protein C. We assessed whether haplotypes in the EPCR gene modify the risk of severe sepsis and/or septic shock (SS/SS) development in critically ill patients. Methods: Three polymorphisms in the EPCR gene were genotyped in 389 Caucasian critically ill patients, hospitalized in the intensive care units of two major hospitals in Athens, Greece. Multivariate logistic regression analysis controlling for age, acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, sex, and diagnosis was performed to determine the effect of haplotypes H1 and H3 in the EPCR gene on the development of SS/SS. Results: H2 carriers versus all other genotypes combined had a nonsignificant excess of SS/SS ( p = 0.087). SS/SS occurred in 38.8 % of critically ill patients carrying minor alleles belonging to both H1 and H3 haplotypes, in 58.0 % of H1 carriers, 64.3 % of H3 carriers, and 65.2 % of patients carrying all common alleles (H2). Compared with H2 carriers, the odds ratios (OR) for developing SS/SS were 0.34 [95 % confidence interval (CI) 0.16-0.76, p = 0.008] for simultaneous H1 and H3 carriers, 0.65 (95 % CI 0.37-1.13, p = 0.123) for H1 carriers, and 0.82 (95 % CI 0.39-1.70, p = 0.590) for H3 carriers. Conclusions: Our results indicate that simultaneous carriers of minor alleles belonging to both the H1 and H3 haplotypes may be at reduced risk of developing SS/SS in this cohort of critically ill patients. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore the effect of red blood cell (RBC) transfusion on microdialysis-assessed interstitial fluid metabolic parameters in septic patients. Methods: We conducted a retrospective study of 37 patients with severe sepsis/septic shock requiring transfusion of one to two RBC units. Interstitial fluid metabolic alterations were monitored by a microdialysis catheter inserted in the subcutaneous adipose tissue. Samples were collected before (T0) and after transfusion at two time-points: T1a and T1b; median post-transfusion times of 120 [interquartile range (IQR); 45-180] and 360 (IQR; 285-320) min. Lactate, pyruvate, glycerol and glucose concentrations were measured with a bedside analyzer, and the lactate/pyruvate (LP) ratio was calculated automatically. Results: RBC transfusions decreased the LP ratio from (T0) 18.80 [interquartile range (IQR); 14.85-27.45] to (T1a) 17.80 (IQR; 14.35-25.20; P < 0.05) and (T1b) 17.90 (IQR; 14.45-22.75; P < 0.001), while there was also significant interindividual variation. Post-transfusion LP ratio changes at T1a [ r = −0.42; 95 % confidence interval (CI), −0.66 to −0.098; P = 0.01] and T1b ( r = −0.68; 95 % [CI], −0.82 to −0.44; P < 0.001) were significantly correlated with the pre-transfusion LP ratio, but not with baseline demographic characteristics, vital signs, severity scores, hemoglobin level and blood lactate. RBC storage time and leukocyte reduction had no influence on the tissue metabolic response to transfusion. Conclusions: Tissue oxygenation is affected by RBC transfusion in critically ill septic patients. Monitoring of tissue LP ratio by microdialysis may represent a useful method for individual clinical management. [ABSTRACT FROM AUTHOR]

Glucocorticoid actions are mediated by the glucocorticoid receptor (GCR) whose dysfunction leads to glucocorticoid tissue resistance. Our objective was to evaluate GCR-α and GCR-β expression and key steps in the GCR signalling cascade in critical illness. Expression of GCR and major GCR-target genes, cortisol, adrenocorticotropin (ACTH) and cytokines was measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age- and sex-matched subjects were used as controls. Acutely, mRNA expression of GCR-α was 10-fold and of GCR-β 3-fold the expression of controls, while during the sub-acute phase expression of both isoforms was lower compared to controls. Expression of FKBP5 and GILZ decreased significantly. Cortisol levels remained elevated and ACTH increased during the 13-day period. GCR expression and hypothalamic-pituitary-adrenal axis function undergo a biphasic response during critical illness. The dissociation between low GCR expression and high cortisol implies an abnormal stress response. • GCR expression and HPA axis function undergo a biphasic response. • Acutely, GCR expression is increased. • No trans-activation or trans-repression of GCR-target genes occurs. • Sub-acutely, dissociation between low GCR expression and high cortisol. • Abnormal stress response. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]