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1.
The use of glucocorticoids (corticotherapy) in severe sepsis is one of the main controversial issues in critical care medicine.
These agents were commonly used to treat sepsis until the end of the 1980s, when several randomized trials casted serious
doubt on any benefit from high-dose glucocorticoids. Later, important progress in our understanding of the role played by
the hypothalamic–pituitary–adrenal axis in the response to sepsis, and of the mechanisms of action of glucocorticoids led
us to reconsider their use in septic shock. The present review summarizes the basics of the physiological response of the
hypothalamic–pituitary–adrenal axis to stress, including regulation of glucocorticoid synthesis, the cellular mechanisms of
action of glucocorticoids, and how they influence metabolism, cardiovascular homeostasis and the immune system. The concepts
of adrenal insufficiency and peripheral glucocorticoid resistance are developed, and the main experimental and clinical data
that support the use of low-dose glucocorticoids in septic shock are discussed. Finally, we propose a decision tree for diagnosis
of adrenal insufficiency and institution of cortisol replacement therapy. 相似文献
2.
Nicolas Nesseler Yoann Launey Caroline Aninat Fabrice Morel Yannick Mallédant Philippe Seguin 《Critical care (London, England)》2012,16(5):235
During sepsis, the liver plays a key role. It is implicated in the host response, participating in the clearance of the infectious agents/products. Sepsis also induces liver damage through hemodynamic alterations or through direct or indirect assault on the hepatocytes or through both. Accordingly, liver dysfunction induced by sepsis is recognized as one of the components that contribute to the severity of the disease. Nevertheless, the incidence of liver dysfunction remains imprecise, probably because current diagnostic tools are lacking, notably those that can detect the early liver insult. In this review, we discuss the epidemiology, diagnostic tools, and impact on outcome as well as the pathophysiological aspects, including the cellular events and clinical picture leading to liver dysfunction. Finally, therapeutic considerations with regard to the weakness of the pertinent specific approach are examined. 相似文献
3.
The present review discusses the hemodynamic effects of hypertonic saline in experimental shock and in patients with sepsis. We comment on the mechanisms of action of hypertonic saline, calling upon data in hemorrhagic and septic shock. Specific actions of hypertonic saline in severe sepsis and septic shock are highlighted. Data are available that support potential benefits of hypertonic saline infusion in various aspects of the pathophysiology of sepsis, including tissue hypoperfusion, decreased oxygen consumption, endothelial dysfunction, cardiac depression, and the presence of a broad array of proinflammatory cytokines and various oxidant species. The goal of research in this field is to identify reliable therapies to prevent ischemia and inflammation, and to reduce mortality. 相似文献
4.
Sepsis is the primary cause of death in the intensive care unit. Extracorporeal blood purification therapies have been proposed
for patients with sepsis in order to improve outcomes since these therapies can alter the host inflammatory response by non-selective
removal of inflammatory mediators or bacterial products or both. Recent technological progress has increased the number of
techniques available for blood purification and their performance. In this overview, we report on the latest advances in blood
purification for sepsis and how they relate to current concepts of disease, and we review the current evidence for high-volume
hemofiltration, cascade hemofiltration, hemoadsorption, coupled plasma filtration adsorption, high-adsorption hemofiltration,
and high-cutoff hemofiltration/hemodialysis. Promising results have been reported with all of these blood purification therapies,
showing that they are well tolerated, effective in clearing inflammatory mediators or bacterial toxins (or both) from the
plasma, and efficacious for improvement of various physiologic outcomes (for example, hemodynamics and oxygenation). However,
numerous questions, including the timing, duration, and frequency of these therapies in the clinical setting, remain unanswered.
Large multicenter trials evaluating the ability of these therapies to improve clinical outcomes (that is, mortality or organ
failure), rather than surrogate markers such as plasma mediator clearance or transient improvement in physiologic variables,
are required to define the precise role of blood purification in the management of sepsis. 相似文献
5.
Sepsis and septic shock are the leading causes of acute renal failure, multiple organ system dysfunction, and death in the intensive care unit. The pathogenesis of sepsis is complex and comprises a mosaic of interconnected pathways. Several attempts to improve patient outcomes by targeting specific components of this network have been unsuccessful. For these reasons, the ideal immunomodulating strategy would be one that restores immunologic stability rather than blindly inhibiting or stimulating one or another component of this complex network. Hence, the recent focus of immunomodulatory therapy in sepsis has shifted to nonspecific methods of influencing the entire inflammatory response without suppressing it. Here, we discuss the various modalities of extracorporeal blood purification, the existing evidence, and future prospects. 相似文献
6.
Myocardial dysfunction frequently accompanies severe sepsis and septic shock. Whereas myocardial depression was previously considered a preterminal event, it is now clear that cardiac dysfunction as evidenced by biventricular dilatation and reduced ejection fraction is present in most patients with severe sepsis and septic shock. Myocardial depression exists despite a fluid resuscitation-dependent hyperdynamic state that typically persists in septic shock patients until death or recovery. Cardiac function usually recovers within 7-10 days in survivors. Myocardial dysfunction does not appear to be due to myocardial hypoperfusion but due to circulating depressant factors, including the cytokines tumor necrosis factor alpha and IL-1beta. At a cellular level, reduced myocardial contractility seems to be induced by both nitric oxide-dependent and nitric oxide-independent mechanisms. The present paper reviews both the clinical manifestations and the molecular/cellular mechanisms of sepsis-induced myocardial depression. 相似文献
7.
In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation.
Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms
that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically
be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the
available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation.
Preclinical research has demonstrated partial interference of heparin – administered even at low doses – with the therapeutic
effects of antithrombin, and has confirmed – at the level of cellular mechanisms – a regulatory role for antithrombin in DIC.
Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest
that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there
is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms
of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment
of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled
studies. 相似文献
8.
Wiedermann CJ 《Critical care (London, England)》2006,10(1):209
In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin – administered even at low doses – with the therapeutic effects of antithrombin, and has confirmed – at the level of cellular mechanisms – a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies. 相似文献
9.
Sheldon Magder 《Critical care (London, England)》2009,13(1):202-12
In septic patients increased central drive and increased metabolic demands combine to increase energy demands on the ventilatory
muscles. This occurs at a time when energy supplies are limited and energy production hindered, and it leads to an energy
supply-demand imbalance and often ventilatory failure. Problems related to contractile function of the ventilatory muscles
also contribute, especially when the clinical course is prolonged. The increased ventilatory activity increases interactions
between the ventilatory and cardiovascular systems, and when ventilatory muscles fail and mechanical ventilatory support is
required a new set of problems emerges. In this review I discuss factors related to ventilatory muscle failure, giving emphasis
to mechanical and supply demand aspects. I also review the implications of changes in ventilatory patterns for heart-lung
interactions. 相似文献
10.
Etienne de Montmollin Jerome Aboab Arnaud Mansart Djillali Annane 《Critical care (London, England)》2009,13(5):230
Sepsis, despite recent therapeutic progress, still carries unacceptably high mortality rates. The adrenergic system, a key modulator of organ function and cardiovascular homeostasis, could be an interesting new therapeutic target for septic shock. β-Adrenergic regulation of the immune function in sepsis is complex and is time dependent. However, β2 activation as well as β1 blockade seems to downregulate proinflammatory response by modulating the cytokine production profile. β1 blockade improves cardiovascular homeostasis in septic animals, by lowering myocardial oxygen consumption without altering organ perfusion, and perhaps by restoring normal cardiovascular variability. β-Blockers could also be of interest in the systemic catabolic response to sepsis, as they oppose epinephrine which is known to promote hyperglycemia, lipid and protein catabolism. The role of β-blockers in coagulation is less clear cut. They could have a favorable role in the septic pro-coagulant state, as β1 blockade may reduce platelet aggregation and normalize the depressed fibrinolytic status induced by adre-nergic stimulation. Therefore, β1 blockade as well as β2 activation improves sepsis-induced immune, cardiovascular and coagulation dysfunctions. β2 blocking, however, seems beneficial in the metabolic field. Enough evidence has been accumulated in the literature to propose β- adrenergic modulation, β1 blockade and β2 activation in particular, as new promising therapeutic targets for septic dyshomeostasis, modulating favorably immune, cardiovascular, metabolic and coagulation systems. 相似文献
11.
Clinical review: Role of triggering receptor expressed on myeloid cells-1 during sepsis 总被引:2,自引:0,他引:2 下载免费PDF全文
Gibot S 《Critical care (London, England)》2005,9(5):485-489
Triggering receptor expressed on myeloid cells (TREM)-1 is a recently identified molecule that is involved in monocytic activation and in the inflammatory response. It belongs to a family related to the natural killer cell receptors and is expressed on neutrophils, mature monocytes and macrophages. The inflammatory response mediated by Toll-like receptor-2 and -4 stimulation is amplified by the engagement of TREM-1. The expression of membrane-bound TREM-1 is greatly increased on monocytes during sepsis. Moreover, infection induces the release of a soluble form of this receptor, which can be measured in biological fluid and may be useful as a diagnostic tool. Modulation of the TREM-1 signalling pathway by the use of small synthetic peptides confers interesting survival advantages during experimental septic shock in mice, even when this teatment is administered late after the onset of sepsis. 相似文献
12.
13.
This paper reviews several recent, randomized, double-blind, placebo-controlled trials of monoclonal antibodies against endotoxin, interleukin-1 receptor antagonist (IL-1 ra), and monoclonal antibody against tumor necrosis factor (TNF) in sepsis. 相似文献
14.
Helen F Galley 《Critical care (London, England)》2010,14(4):230
Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. Under normal circumstances, complex interacting antioxidant defense systems control oxidative stress within mitochondria. However, no studies have yet provided conclusive evidence of the beneficial effect of antioxidant supplementation in patients with sepsis. This may be because the antioxidants are not accumulating in the mitochondria, where they are most needed. Antioxidants can be targeted selectively to mitochondria by several means. This review describes the in vitro studies and animal models of several diseases involving oxidative stress, including sepsis, in which antioxidants targeted at mitochondria have shown promise, and the future implications for such approaches in patients. 相似文献
15.
The present report highlights the most important papers appearing in Critical Care and other major journals about severe sepsis, the systemic inflammatory response and multiorgan dysfunction over the past
year. A number of these clinical and laboratory studies will have a considerable impact on the sepsis research agenda for
years to come. The steroid controversy, the debate over tight glycemic control, the colloid versus crystalloid issue, the
value of selective decontamination of the digestive tract, the enlarging role of biomarkers, the value of genomics and rapid
diagnostic techniques have all been prominently featured in recent publications. Basic research into novel predictive assays,
genetic polymorphisms, and new molecular methods to risk-stratify and to determine treatment options for sepsis have occupied
much of the Critical Care publications relating to sepsis pathophysiology in 2008. We will attempt to briefly summarize what we consider to be the
most significant contributions to the sepsis literature over the last year, and their likely ramifications in the future,
for critical care clinicians, clinical investigators and basic researchers alike. 相似文献
16.
This paper reviews several recent, randomized, double-blind, placebo-controlled trials of monoclonal antibodies against endotoxin, interleukin-1 receptor antagonist (IL-1 ra), and monoclonal antibody against tumor necrosis factor (TNF) in sepsis. 相似文献
17.
Sepsis is a complex syndrome that develops when the initial, appropriate host response to an infection becomes amplified, and is then dysregulated. Among other factors, the innate immune system is of central importance to the early containment of infection. Death from infection is strongly heritable in human populations. Hence, genetic variations that disrupt innate immune sensing of infectious organisms could explain the ability of the immune system to respond to infection, the diversity of the clinical presentation of sepsis, the response to current medical treatment, and the genetic predisposition to infection in each individual patient. Such genetic variations may identify patients at high risk for the development of sepsis and organ dysfunction during severe infections. Single base variations, known as single nucleotide polymorphisms (SNPs), are the most commonly used variants. There has been great interest in exploring SNP in those genes involved in the inflammatory cascade resulting from the systemic inflammatory response to micro organisms. The rationale for studying gene SNPs in critical illnesses seeks to identify potential markers of susceptibility, severity, and clinical outcome; seeks to identify potential markers for responders and non-responders in clinical trials, and seeks to identify targets for therapeutic intervention. In this review, we focus on the current state of association studies of those genes governing the powerful bacterial infection-induced inflammation and provide guidelines for future studies describing disease associations with genetic variations based on current recommendations. We envision a time in the near future when genotyping will be include in the standard evaluation of critically ill patients and will help to prioritize a therapeutic option. 相似文献
18.
19.
Cellular apoptosis and organ injury in sepsis: a review 总被引:6,自引:0,他引:6
20.
Cellular signaling by proteases of the blood coagulation cascade through members of the protease-activated receptor (PAR) family can profoundly impact on the inflammatory balance in sepsis. The coagulation initiation reaction on tissue factor expressing cells signals through PAR1 and PAR2, leading to enhanced inflammation. The anticoagulant protein C pathway has potent anti-inflammatory effects, and activated protein C signals through PAR1 upon binding to the endothelial protein C receptor. Activation of the coagulation cascade and the downstream endothelial cell localized anticoagulant pathway thus have opposing effects on systemic inflammation. This dichotomy is of relevance for the interpretation of preclinical and clinical data that document nonuniform responses to anticoagulant strategies in sepsis therapy. 相似文献