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Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of sepsis, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol by enzymes such as 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body's ability to mount an appropriate inflammatory response. The actions of cortisol are mediated through two types of corticosteroid receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GCR). In sepsis, the expression and activity of GCR is altered, contributing to the pathophysiology of the disease. GCR expression and activity are typically downregulated in sepsis, impairing the body's ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment for sepsis. The rationale for steroid-based treatment is to supplement the body's endogenous cortisol production, restore normal cortisol levels, and improve the body's ability to mount an appropriate inflammatory response. However, the use of steroids in sepsis remains controversial, and clinical trials have yielded mixed results. Some studies have shown that steroid-based treatment can improve shock reversal, reduce the need for vasopressors, and improve overall survival in patients with septic shock, whereas other studies have found no benefit or even harm from steroid-based treatment in sepsis.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury characterized by an acute inflammatory response in the lung parenchyma. Hence, it is considered as the most appropriate clinical syndrome to study pathogenic mechanisms of lung inflammation. ARDS is associated with increased morbidity and mortality in the intensive care unit (ICU), while no effective pharmacological treatment exists. It is very important therefore to fully characterize the underlying pathobiology and the related mechanisms, in order to develop novel therapeutic approaches. In vivo and in vitro models are important pre-clinical tools in biological and medical research in the mechanistic and pathological understanding of the majority of diseases. In this review, we will present data from selected experimental models of lung injury/acute lung inflammation, which have been based on clinical disorders that can lead to the development of ARDS and related inflammatory lung processes in humans, including ventilation-induced lung injury (VILI), sepsis, ischemia/reperfusion, smoke, acid aspiration, radiation, transfusion-related acute lung injury (TRALI), influenza

Pulmonary Arterial Hypertension is regarded as a devastating disease, complicating Connective Tissue Diseases. Although much progress has been achieved in the last 20 years, several unfulfilled needs in diagnosis and management of PAH in these patients may still be identified. After a systematic review of the literature and integrating results from the latest research articles, key clinical issues for the screening and diagnosis of Pulmonary Arterial Hypertension in Connective Tissue Disorder Patients and specifically Scleroderma patients are described in this article, allowing physicians to contribute to early diagnosis of patients with Scleroderma-associated Pulmonary Arterial Hypertension.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.\ud \ud Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.\ud \ud Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.\ud \ud Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.\ud \ud Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.\ud \ud Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Background: Aging is associated with physiological changes in respiratory mechanical properties. In elderly patients an increased incidence of Acute Respiratory Distress Syndrome (ARDS) resulting in increased number of elderly patients treated in Intensive Care Units (ICUs), along with increased mortality has been reported. Aim of the present study was to identify potential age-related differences in respiratory mechanics, gas exchange and ventilator settings in patients with early ARDS. The relationship between age and ICU mortality was additionally assessed. Methods: In 58 consecutive early ARDS patients demographic and anthropometric characteristics, ventilatory settings, pulmonary physiologic measurements (arterial blood gases and static respiratory mechanics) and outcome within ICU setting were recorded. Patients were divided into three age groups, those

To evaluate whether tentative prognostic models for intensive care unit survival of multiple trauma patients could be improved by including endocrine parameters.Prospective study.Eighty-three male and 11 female multiple trauma patients.Upon admission, severity of trauma was assessed with the Acute Physiology and Chronic Health Evaluation II (APACHE II), the Sequential Organ Failure Assessment (SOFA) score and the Injury Severity Score (IS). Concurrently, blood was drawn to measure thyrotropin (TSH), free thyroxine (fT4), trioodothyronine (T3), corticotropin (ACTH), prolactin (PRL), cortisol and dehydroepiandrosterone sulphate (DHEAS). Adrenal reserve was assessed with the Synacthen test.Seventy-five of the 83 men and 8 of the 11 women survived. APACHE II and SOFA scores were higher in non-survivors compared to survivors (with considerable overlap). From the baseline endocrine work-up, survivors had higher ACTH and DHEAS values compared to non-survivors (also with considerable overlap). No differences between survivors and non-survivors were noted in the Synacthen test or in thyroid function tests. Nevertheless, a multivariate logistic regression model that incorporated the APACHE II score and hormonal parameters (Cortisol post-Synacthen, DHEAS, TSH*age) was well-fitted to assess survival/non-survival as an endpoint and better than APACHE II, SOFA or IS scores alone to predict ICU survival or death.In critically ill multiple trauma patients, age, TSH, Cortisol post-Synacthen and DHEAS values upon admission to the ICU, combined with the APACHE II score, may predict outcome more accurately than the APACHE II score alone.an the APACHe II score alone.

The chemotactic factor formyl-methionyl-leucyl-phenylalanine (FMLP) when injected in rabbits causes dose-dependent transient hypotension, as well as neutropenia, thrombocytopenia and a decrease in systemic vascular resistance, as previously shown. Since both FMLP and endotoxin are elaborated at sites of infection by certain bacteria, whether they act in concert to produce shock was examined. Animals were pretreated with 380 microg/kg of E. coli endotoxin, 24 hours before the infusion of 10(-9) moles FMLP and were compared with animals pretreated only with saline and administered FMLP. Within 3 min after FMLP, endotoxin-pretreated animals developed a significant fall in MAP (p0.001) and neutrophils (p0.001) compared to controls. Statistically significant lactic acidemia, with reduced HCO(-)3 levels also developed in the endotoxin-pretreated group after FMLP injection. These results indicate that endotoxin apparently induces a prepared state, thus facilitating the hemodynamic and cellular effects of FMLP in this model.