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1.  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.
doi:10.1186/2110-5820-3-15
PMCID: PMC3673822  PMID: 23718252
Delirium; Brain dysfunction; Sepsis
2.  Design, conduct, and analysis of a multicenter, pharmacogenomic, biomarker study in matched patients with severe sepsis treated with or without drotrecogin Alfa (activated) 
Background
A genomic biomarker identifying patients likely to benefit from drotrecogin alfa (activated) (DAA) may be clinically useful as a companion diagnostic. This trial was designed to validate biomarkers (improved response polymorphisms (IRPs)). Each IRP (A and B) contains two single nucleotide polymorphisms that were associated with a differential DAA treatment effect.
Methods
DAA is typically given to younger patients with greater disease severity; therefore, a well-matched control group is critical to this multicenter, retrospective, controlled, outcome-blinded, genotype-blinded trial. Within each center, DAA-treated patients will be matched to controls treated within 24 months of each other taking into account age, APACHE II, cardiovascular, respiratory, renal, and hematologic dysfunction, mechanical ventilation status, medical/surgical status, and infection site. A propensity score will estimate the probability that a patient would have received DAA given their baseline characteristics. Two-phase data transfer will ensure unbiased selection of matched controls. The first transfer will be for eligibility and matching data and the second transfer for outcomes and genotypic data. The primary analysis will compare the effect of DAA in IRP + and IRP − groups on in-hospital mortality through day 28.
Discussion
A design-based approach matching DAA-free to DAA-treated patients in a multicenter study of patients who have severe sepsis and high risk of death will directly compare control to DAA-treated groups for mortality by genotype. Results, which should be available in 2012, may help to identify the group of patients who would benefit from DAA and may provide a model for future investigation of sepsis therapies.
doi:10.1186/2110-5820-2-15
PMCID: PMC3403963  PMID: 22694772
Drotrecogin alfa (activated); Pharmacogenomics biomarker; Predictive marker; Propensity score; Severe sepsis; Treatment selection; Sepsis; Drotrecogin alfa activated (DAA); Activated protein C; Genome wide association study; Survival
3.  Corticosteroids for severe sepsis: an evidence-based guide for physicians 
Septic shock is characterized by uncontrolled systemic inflammation that contributes to the progression of organ failures and eventually death. There is now ample evidence that the inability of the host to mount an appropriate hypothalamic-pituitary and adrenal axis response plays a major in overwhelming systemic inflammation during infections. Proinflammatory mediators released in the inflamed sites oppose to the anti-inflammatory response, an effect that may be reversed by exogenous corticosteroids. With sepsis, via nongenomic and genomic effects, corticosteroids restore cardiovascular homeostasis, terminate systemic and tissue inflammation, restore organ function, and prevent death. These effects of corticosteroids have been consistently found in animal studies and in most recent frequentist and Bayesian meta-analyses. Corticosteroids should be initiated only in patients with sepsis who require 0.5 μg/kg per minute or more of norepinephrine and should be continued for 5 to 7 days except in patients with poor hemodynamic response after 2 days of corticosteroids and with a cortisol increment of more than 250 nmol/L after a standard adrenocorticotropin hormone (ACTH) test. Hydrocortisone should be given at a daily dose of 200 mg and preferably combined to enteral fludrocortisone at a dose of 50 μg. Blood glucose levels should be kept below 150 mg/dL.
doi:10.1186/2110-5820-1-7
PMCID: PMC3224490  PMID: 21906332

Results 1-3 (3)