Annals of medicine
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Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. ⋯ In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.
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Severe sepsis is a common disease process affecting some 2-11% of hospital admissions in the US. Severe sepsis and septic shock are associated with considerable morbidity and mortality, and account for a large part of intensive care unit costs. ⋯ In the last couple of years these advances have come to fruition with the development of a drug, drotrecogin alfa, which specifically reduces mortality from this all too often fatal disease. While intensive early resuscitation remains the cornerstone of management, new approaches are beginning to form part of sepsis management protocols and will lead to improved outcomes for patients with this disease process.
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Several preclinical models for sepsis have been used in the last decades to successfully unravel the pathophysiologic processes during sepsis. Furthermore, these models for sepsis revealed promising immunomodulating agents for the treatment of sepsis. Nevertheless, several clinical trials evaluating the efficacy of these new anti-inflammatory agents in septic patients showed disappointing results. ⋯ Importantly, investigations studying the effects of several immunomodulating strategies have demonstrated strikingly opposite results when using models for sepsis lacking an infectious focus and when using models for sepsis with a more natural route of infection. These differences will be discussed in this article. In general, it is advised to use a combination of models to test a new therapeutic agent, before starting a clinical study evaluating this new therapy.
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During sepsis or acute respiratory distress syndrome, the hypothalamic pituitary adrenal axis is rapidly activated through a systemic pathway, i.e. by circulating pro-inflammatory cytokines and through the vagus nerve. Subsequently, the adrenal glands release cortisol, a hormone which will likely counteract the inflammatory process and restore cardiovascular homeostasis. Both experimental models and studies in humans suggest that inadequate hypothalamic pituitary adrenal axis response to stress accounts, at least partly, for the genesis of shock and organ dysfunction in sepsis and acute respiratory distress syndrome. ⋯ These trials showed consistently that, in these patients, the use of low dose of corticosteroids alleviated inflammation, restored cardiovascular homeostasis, reduced organ dysfunction, improved survival and was safe. Further studies are ongoing to better identify the target population. In the meantime, cortisol replacement (i.e. 200 to 300 mg daily of hydrocortisone or equivalent) should be considered as standard care for these patients.
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Glucose transport, the rate limiting step in glucose metabolism in skeletal muscle, is mediated by insulin-sensitive glucose transporter 4 (GLUT4) and can be activated in skeletal muscle by two separate and distinct signalling pathways: one stimulated by insulin and the second by muscle contractions. Skeletal muscle is the principal tissue responsible for insulin-stimulated glucose disposal and thus the major site of peripheral insulin resistance. Impaired glucose transport in skeletal muscle leads to impaired whole body glucose uptake, and contributes to the pathogenesis of Type 2 diabetes mellitus. ⋯ Intense efforts are underway to define the molecular mechanisms that regulate glucose metabolism in insulin sensitive tissues. This review will present our current understanding of mechanisms regulating glucose transport in skeletal muscle in humans. Elucidation of the pathways involved in the regulation of glucose homeostasis will offer insight into the pathogenesis of insulin resistance and Type 2 diabetes mellitus and may lead to the identification of biochemical entry points for drug intervention to improve glucose homeostasis.