Toll-like Receptor 4 Modulation as a Strategy to Treat Sepsis

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock

Spontaneous Cervical Epidural Hematoma

Background: A 65-year-old woman was admitted to the emergency department for sudden onset of neck pain and dysesthesia of both upper limbs. The pain occurred spontaneously, without any history of recent trauma. Rapidly after her admission, she developed tetraparesia. The patient had a past medical history of long standing hypertension correctly controlled as confirmed at admission. Neurological examination confirmed the tetraparetic status with a sensory level at Th3. Moreover, a saddle anesthesia with impaired bladder control was observed. Cranial nerve examination and consciousness of the patient remained normal. Laboratory coagulation tests and platelets count were all within normal limits

Teamwork enables high level of early mobilization in critically ill patients

Additional file 2. Physiological responses of physiotherapy session. Values expressed as mean ± standard deviation; IB = In bed, IC = In chair, * different from baseline, ≈ different from 0 min

AMP-activated protein kinase controls liposaccharide-induced hyperpermeability

Organ dysfunction determines the severity of sepsis and is correlated to mortality. Endothelial increased permeability contributes to the development of organ failure. AMP-activated protein kinase (AMPK) has been shown to modulate cytoskeleton and could mediate endothelial permeability. Our hypothesis is that AMPK controls sepsis-induced hyperpermeability in the heart and is involved in septic cardiomyopathy. Sepsis was induced by intraperitoneal injection of liposaccharide, 10 mg/kg (LPS). Alpha-1 AMPK knockout mice (α1KO) were compared with wild-type. Vascular permeability was characterized by Evans blue extravasation. Inflammatory cytokine mRNA expression was determined by qPCR analysis. Left ventricular mass was assessed by echocardiography. In addition, to emphasize the beneficial role of AMPK on heart vascular permeability, AMPK activator (acadesine) was administered to C57Bl6 mice before LPS injection. The ANOVA test with Bonferroni's post hoc test and the log-rank test were used. P < 0.05 was considered as significant. Increased cardiac vascular permeability was observed in the LPS group in comparison to untreated animals (2.5% vs. 16%; P < 0.05). The α1KO mice exhibited an increase vascular permeability after LPS injection in comparison to wild-type mice (41.5% vs. 16%; P < 0.05). α1KO animals had a significant mortality increase after LPS injection (70% vs. 10%; P < 0.05). LPS markedly induced the production of proinflammatory cytokines (TNFα, IL-1β, IL-6) that were significantly higher in the α1KO animals. More importantly, LPS treatment leads to an increased left ventricular mass in the α1KO mice within 24 hours, suggesting the onset of edema. Finally LPS-induced vascular hyperpermeability was greatly reduced after AMPK activation by acadesine (13.2% vs. 40%; P < 0.05). AMPK importantly regulates cardiac vascular permeability and could control the sepsis-induced cardiomyopathy. AMPK could represent a new pharmacological target of sepsis

The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a Multicenter, Multinational, 14-Day Inception Cohort Study

PURPOSE: In this prospective, multicenter, 14-day inception cohort study, we investigated the epidemiology, patterns of infections, and outcome in patients admitted to the intensive care unit (ICU) as a result of severe acute respiratory infections (SARIs). METHODS: All patients admitted to one of 206 participating ICUs during two study weeks, one in November 2013 and the other in January 2014, were screened. SARI was defined as possible, probable, or microbiologically confirmed respiratory tract infection with recent onset dyspnea and/or fever. The primary outcome parameter was in-hospital mortality within 60 days of admission to the ICU. RESULTS: Among the 5550 patients admitted during the study periods, 663 (11.9 %) had SARI. On admission to the ICU, Gram-positive and Gram-negative bacteria were found in 29.6 and 26.2 % of SARI patients but rarely atypical bacteria (1.0 %); viruses were present in 7.7 % of patients. Organ failure occurred in 74.7 % of patients in the ICU, mostly respiratory (53.8 %), cardiovascular (44.5 %), and renal (44.6 %). ICU and in-hospital mortality rates in patients with SARI were 20.2 and 27.2 %, respectively. In multivariable analysis, older age, greater severity scores at ICU admission, and hematologic malignancy or liver disease were independently associated with an increased risk of in-hospital death, whereas influenza vaccination prior to ICU admission and adequate antibiotic administration on ICU admission were associated with a lower risk. CONCLUSIONS: Admission to the ICU for SARI is common and associated with high morbidity and mortality rates. We identified several risk factors for in-hospital death that may be useful for risk stratification in these patients

INTENSIFIED HOME-MANAGEMENT FOR WORRISOME COVID-19 ADULT PATIENTS

In many countries facing the COronaVIrus Disease 2019 (COVID-19) outbreak, the healthcare system was progressively stretched to capacity, emergency departments were overwhelmed and a lack of hospitalbeds threatened to occur.[1, 2] Belgium was no exception and the hospital admissions due to COVID-19 peaked a first time in early April 2020, followed by a second even higher peak in early November 2020. During this second wave of the COVID-19 epidemic, the overstretched capacity of the Intensive Care Units (ICU) was a matter of concern. Patients from some overburdened hospitals had to be transferred to other hospitals within Belgium and even abroad. In order to relieve hospital overloading and save intensive care beds for the most severe cases, the option to treat highly selected patients at home with intensified monitoring and therapy emerged. A decision-aid tool for the home-based management of COVID-19 adult patients was elaborated by the Outbreak Support Team in Liège (OST-Liège) (see Figure 1, version as of 01/11/2020). It aims at helping the General Practitioners (GPs) with a number of crucial considerations to decide which patient with a (confirmed or highly suspected) COVID-19, is eligible for intensified home-based care (monitoring and treatment) in the context of hospital saturation. Such an approach is in line with the WHO interim guidance on home care[3] which recommends that: • COVID-19 care pathways be established at local, regional and national levels. COVID-19 care pathways are for persons with suspected or confirmed COVID-19. • Hospitals and health systems at local, regional, national and global level plan and be ready to surge clinical care capacity (staff, structure, supplies and systems) in order to be able to provide appropriate care of all COVID-19 patients and maintain essential health services. • Each institution should establish a plan for what to do in situations of resource scarcity to cover the allocation or access to critical medical interventions (such as oxygen, intensive care beds and/or ventilators). Such a plan should establish a clear overall aim. The OST-Liège decision-aid tool was inspired by other existing algorithms/tools and was discussed with emergency teams and hospital physicians in four hospitals in Liège. A first diffusion towards the French-speaking GPs was performed in November 2020 in a webinara. At the end of October 2020, the Collège de Médecine Générale (CMG) and the Cellule d’Appui Scientifique Universitaire (CASU) asked KCE to validate the various components of this decision-aid tool

Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

yesInflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes. AMPK activation inhibited IL-1β-stimulated CXCL10 secretion, associated with reduced interleukin-1 receptor associated kinase-4 (IRAK4) phosphorylation and downregulated MKK4/JNK and IKK/IκB/NFκB signalling. AMPK activation inhibited TNF-α-stimulated IKK/IκB/NFκB signalling but had no effect on JNK phosphorylation. The JAK/STAT3 pathway was also suppressed by AMPK after IL-6 stimulation and during adipogenesis. Adipose tissue from AMPKα1−/− mice exhibited increased JNK and STAT3 phosphorylation, supporting suppression of these distinct proinflammatory pathways by AMPK in vivo. The inhibition of multiple pro-inflammatory signalling pathways by AMPK may underlie the reported beneficial effects of AMPK activation in adipose tissue.British Heart Foundatio