Sepsis-associated delirium: the pro and con of C5a blockade

The intimate mechanisms of sepsis-induced delirium are unknown. Among the potential contributing factors, the breakdown of the blood–brain barrier is considered a key determinant of brain dysfunction. The complement activation is paramount to an appropriate activation of the central nervous system during stress. C3a and C5a have been extensively studied and may be involved in sepsis-induced delirium. Here we discuss the pro and con for inhibiting C5a to attenuate brain damage during sepsis. In particular, we discuss the hypothesis that C5a increased blood–brain barrier permeability amy ease the brain to mount an appropriate response to sepsis. Thus, blockade of C5a may be detrimental, resulting in an attenuated response of the stress system

Corticosteroids for community-acquired pneumonia: time to act!

The use of corticosteroids for the treatment of community-acquired pneumonia has been reported for almost 50 years. A recent systematic analysis of the relevant literature suggested that corticosteroids reduce the critical illness associated with community-acquired pneumonia. There is little doubt that a prolonged administration of a moderate dose of corticosteroids may alleviate the systemic inflammatory response and subsequent organ dysfunction in severe infection. Whether these favorable effects on morbidity may translate into better survival and quality of life needs to be addressed in additional adequately powered randomized controlled trials

Robust Virtual Keyboard for Brain-Computer Interface (ROBIK): An Halfway Update on the Project

International audienceThe principle of a Brain-Computer Interface or BCI is to control a device through the extraction and interpretation of signal features from electroencephalograms (EEG) collected either from the surface of the scalp or through invasive measurements. This late idea of communication technique (Vidal 1973), offers the advantage of bypassing the need for muscle activity in the control chain and is therefore presented as a promising alternative to restore communication and control in severely disabled patients (Wolpow, et al. 2002). However, the lack of robustness and ergonomics of both available software and EEG measurement techniques have delayed the transfer of this technology to patients bedsides. The French Research Agency has funded a 3-year project gathering national leaders in microelectronics (CEA-Leti), EEG signal processing (Gipsa-Lab) and clinical management of severely disabled people (Raymond Poincar hospital). The aim of the project is the development and the clinical validation of a Brain-Computer Interface prototype for communication. As an initial step, a survey was carried out to assess patients' and users (family and caretakers) needs, which were translated into specifications, on the basis of which software and hardware were developed. The survey (n=45) highlighted the need for easy-to-setup systems (installation time=15min), which stresses the importance of mechanical comfort and customization of application. The development of signal processing techniques has led to improvements of the P3Speller paradigm. A first prototype of a 32-channel EEG recording system is under development. To ease the EEG measurements and reduce installation time, the system has a reduced size. It includes the analog amplification and digital conversion of 32 channels sampled at 1 kHz, as well as the wireless data transmission to a computer. First in vivo validations were performed on small animals. This system will be optimized and connected to a headset specifically designed to provide a comfortable and handy interface with dry electrodes. The present project will still run for one and a half years ,ending with its clinical validation in a population of severely disabled patients, which will compare performances of the system with existing assistive technologies. At this stage, the proposed system yields very promising results, and outperforms the current state-of-the-art. If such a system is shown to perform better than current users assistive technology, it could reach the commercial availability for severely disabled patients within the next 5 years

Targeting skeletal muscle tissue oxygenation (StO(2)) in adults with severe sepsis and septic shock:a randomised controlled trial (OTO-StS Study)

Objective Evaluation of the ratio of oxyhaemoglohin to total haemoglobin in skeletal muscle (StO(2)) using near-infrared spectroscopy may aid in the monitoring of patients with sepsis. This study assessed the benefits and risks of targeting StO(2) in adults with severe sepsis or septic shock. Design A European randomised controlled trial was performed on two parallel groups. Setting Five intensive care units (ICU) in France, Greece, Spain and Germany were used for the study. Participants A total of 103 adults with severe sepsis or septic shock on ICU admission were randomised (54 subjects in the experimental arm and 49 subjects in the control arm). Interventions Haemodynamic management using an algorithm that was adapted from the 2004 Surviving Sepsis Campaign guidelines with (experimental arm) or without (control arm) targeting an StO(2) value greater than 80% at a minimum of two different sites. Outcomes The primary outcome was a composite: 7-day all-cause mortality or worsening of organ function, defined as a positive difference in Sepsis-related Organ Failure Assessment (SOFA) score between day 7 and randomisation (ie, delta SOFA >0). Secondary endpoints: 30-day mortality, duration of mechanical ventilation and vasopressor therapy up to 30 days from randomisation. Results The study ended prematurely due to lack of funding after enrolment of 103/190 patients. Eighteen patients (33.3%) in the experimental arm and 14 (28.6%, P=0.67) in the control arm died or exhibited delta SOFA >0 on day 7. The mean number of days on mechanical ventilation was 12.2 +/- 10.6 in the experimental group and 7.6 +/- 7.9 in the control group (P=0.03). Thirty-one (57%) patients in the experimental arm and 14 (29%) patients in the control arm received red cells by day 7 (P=0.01). Conclusion Despite the limitation related to premature termination, this study provides no data to support the routine implementation of resuscitation protocols incorporating StO(2) >80% at two or more muscle sites as a target. StO(2)-guided therapy may be associated with prolonged use of mechanical ventilation and an increased number of red blood cell transfusions

Understanding brain dysfunction in sepsis

Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood–brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis of brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke’s encephalopathy. Modulation of microglial activation, prevention of blood–brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors

Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoid access to target cells (i.e. peripheral tissue resistance). Irreversible anatomical damages to the hypothalamus, pituitary, or adrenal glands rarely occur. Conversely, transient functional impairment in hormone synthesis may be a common complication of severe sepsis. Glucocorticoids interact with a specific cytosolic glucocorticoid receptor, which undergoes conformational changes, sheds heat shock proteins and translocates to the nucleus. Glucocorticoids may also interact with membrane binding sites at the surface of the cells. The molecular action of glucocorticoids results in genomic and nongenomic effects. Direct and indirect transcriptional and post-transcriptional effects related to the cytosolic glucocorticoid receptor account for the genomic effects. Nongenomic effects are probably subsequent to cytosolic interaction between the glucocorticoid receptor and proteins, or to interaction between glucocorticoids and specific membrane binding sites