Cardiovascular & Haematological Disorders - Drug Targets - Volume 15, Issue 1, 2015

The process of blood coagulation is mediated by activation of a series of serine-protease zymogens. The protein C (PC) anticoagulant pathway, one of the important pathways related to physiological thrombosis formation, includes PC, thrombomodulin (TM), endothelial PC receptor (EPCR), protein S (PS) and C4b-binding protein (C4BP). TM, mainly present in endothelial cells, is a cofactor for thrombin-catalyzed activation of PC, and the resulting activated PC (aPC) inactivates the blood coagulation cofactors factor Va and factor VIIIa in the presence of PS. PS, mainly synthesized in hepatocytes and endothelial cells, plays a critical role as a cofactor of anticoagulant aPC in the regulation of blood coagulation. The cofactor activity of PS for aPC is regulated by C4BP, a multimeric protein whose structure consists of seven α-chains (C4BPα) and a β-chain (C4BPβ). Sepsis is generally caused by infection by microorganisms, and patients with sepsis undergo drastic hemostatic changes, thought to be induced by lipopolysaccharide (LPS) and inflammatory cytokines. In this review, based primarily on our previous studies, we describe the LPS- and cytokine-induced changes in various proteins in the PC anticoagulant pathway that are related to the increased risk of thrombosis under sepsis. Furthermore, we discuss the potential of recombinant soluble TM (rsTM) as a possible remedy for sepsis.

Sepsis-associated delirium (SAD) is a clinical manifestation of the involvement of the central nervous system (CNS) during sepsis. The purpose of this review is to provide a concise overview of SAD including the epidemiology and current diagnostic criteria for SAD. We present in detail the pathophysiology with regards to blood-brain-barrier breakdown, cytokine activation and neurotransmitter deregulation. Treatment and prognosis for SAD are also briefly discussed. SAD is the most common form of delirium acquired in the ICU (Intensive Care Unit), and is described in about 50% of septic patients. Clinical features include altered level of consciousness, reduced attention, change in cognition and perceptual disturbances. Symptoms can reversible, but prolonged deficits can be observed in older patients. Pathophysiology of SAD is poorly understood, but involves microvascular, metabolic and, not least, inflammatory mechanisms leading to CNS dysfunction. These mechanisms can be different in SAD compared to ICU delirium associated with other conditions. SAD is diagnosed clinically using validated tools such as CAM-ICU (Confusion Assessment Method for the Intensive Care Medicine) or ICDSC (The Intensive Care Delirium Screening Checklist), which have good specificity but low sensitivity. Neuroimaging studies and EEG (Electroencephalography) can be useful complement to clinical evaluation to define the severity of the condition. Prompt diagnosis and eradication of septic foci whenever possible is vital. Preventive measures for SAD in the critically ill patient requiring long-term sedation include maintaining light levels of sedation using non-benzodiazepine sedatives (either propofol or dexmedetomidine). Early mobilization of patients in the ICU is also recommended. Antipsychotic drugs (haloperidol and atypical antipsychotics) are widely used to treat SAD, but firm evidence of their efficacy is lacking.

Neutrophil migration is critical for pathogen clearance and host survival during severe sepsis. Interaction of neutrophil adhesion receptors with ligands on endothelial cells results in firm adhesion of the circulating neutrophils, followed by neutrophil activation and directed migration to sites of infection through the basement membrane and interstitial extracellular matrix. Proteolytic enzymes and reactive oxygen species are produced and released by neutrophils in response to a variety of inflammatory stimuli. Although these mediators are important for host defense, they also promote tissue damage. Excessive neutrophil migration during the early stages of sepsis may lead to an exaggerated inflammatory response with associated tissue damage and subsequent organ dysfunction. On the other hand, dysregulation of migration and insufficient migratory response that occurs during the latter stages of severe sepsis contributes to neutrophils’ inability to contain and control infection and impaired wound healing. This review discusses the major steps and associated molecules involved in the balance of neutrophil trafficking, the precise regulation of which during sepsis spells life or death for the host.

Sepsis is a state of infection with serious systemic manifestations, and if severe enough, can be associated with multiple organ dysfunction and systemic hypotension, which can cause tissues to be hypoxic. Inflammation, as part of the multifaceted biological response to injurious stimuli, such as pathogens or damaged tissues and cells, underlies these biological processes. Prolonged and persistent inflammation, also known as chronic inflammation, results in progressive alteration in the various types of cells at the site of inflammation and is characterized by the simultaneous destruction and healing of tissue during the process. Tissue hypoxia during inflammation is not just a simple bystander process, but can considerably affect the development or attenuation of inflammation by causing the regulation of hypoxia-dependent gene expression. Indeed, the study of transcriptionally regulated tissue adaptation to hypoxia requires intense investigation to help control hypoxia-induced inflammation and organ failure. In this review, I have described the pathophysiology of sepsis with respect to oxygen metabolism and expression of hypoxia-inducible factor 1.

The mortality rate among patients suffering acute respiratory distress syndrome (ARDS) remains high despite implementation at clinical centers of the lung protective ventilatory strategies recommended by the International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. This suggests that such strategies are still sub-optimal for some ARDS patients. For these patients, tailored use of ventilator settings should be considered, including: further reduction of tidal volumes, administration of neuromuscular blocking agents if the patient’s spontaneous breathing is incompatible with mechanical ventilation, and adjusting positive end-expiratory pressure (PEEP) settings based on transpulmonary pressure levels.

Acute respiratory distress syndrome (ARDS) is one of the major causes of ICU deaths. Extracorporeal lung assist (ECLA) has been used as a rescue therapy for most severe form of ARDS. However, its survival benefit had not been shown until CESAR trial in 2009. This has been because the concept of lung protective ventilation strategy had not yet known. Since CESAR trial, the clinical application of ECLA for ARDS as a method to achieve lung rest has wide spread. The effectiveness is further appreciated during the 2009 H1N1 influenza pandemic. The succeeded countries achieved building the transportation systems to collect ECLA patients. With the accumulating evidences of survival benefit, the long-term outcome such as pulmonary function and quality of life are in concern. PumplessECLA which is a newly developed form of ECLA is also reviewed. In this essay we will firstly review the basics of ARDS and ECLA. Then the historical development of ECLA evidences for ARDS are reviewed.

Sepsis remains to be a significant health care issue associated with high mortality and healthcare cost, despite the extensive effort to better understand the pathophysiology of the sepsis. Recently updated clinical guideline for severe sepsis and septic shock, “Surviving Sepsis Campaign 2012”, emphasizes the importance of early goal-directed therapy, which can be implemented in intraoperative management of sepsis patients. Herein, we review the updates of current guideline and discuss its application to anesthesic management. Furthermore, we review the recent advance in knowledge of sepsis pathophysiology, focusing on immune modulation, which may lead to new clinical therapeutic approach to sepsis.

Gingivitis and periodontitis are both highly prevalent gum diseases characterized by an accumulation of a polymicrobial biofilm (dental plaque) around teeth and inflammation in adjacent soft tissues. During dental procedures, even tooth brushing, these bacteria and their components, such as endotoxin, can easily disseminate into the systemic circulation through minor or major gingival injuries. Particularly in immuno-compromised subjects or patients with preexisting pathologic conditions, bacteremia may lead to bacterial infection of distant organs, which may cause immunological reactions. Oral bacteria and endotoxins have been found in sepsis, infective endocarditis, lung infection, liver disease and many other potentially lethal disorders. This article presents a review of the possible pathologic consequences of bacteremia originating in the oral cavity and points out the most commonly affected organs as well as preventive and treatment measures. At the present time, plaque control by subjects and/or dental professionals is one of the most effective means to prevent the onset and progression of oral bacteremia-induced systemic diseases.