الفهرس 
The Pathophysiology of Septic ShockOnly 14 pages are availabe for public view
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Abstract
Septic shock remains a significant challenge for clinicians. Recent advances in cellular and molecular biology have significantly improved our understanding of its pathogenetic mechanisms. Important advances in the pathophysiology of sepsis have led directly to new effective therapies. Severe sepsis and septic shock are the end result of complex interactions between infecting organisms and several elements of the host response, and reflect a primarily inappropriate response by the host to a microbial pathogenic insult.
The key term that describes the pathophysiologic events in septic shock at any point in time is the‘‘mismatch’’ of the host response to the intensity of the pathogenic stimuli ultimately leading to organ injury or dysfunction with or without hypotension. The nature of the interactions between the microbial pathogen and the host is complex and, at the tissues, results in excessive inflammation or immunosuppression, abnormal coagulation and blood flow, and microcirculatory dysfunction leading to organ injury and cell death.
The complex events that occur in septic shock can be broadly divided into microorganism-related components and host-related components. Concerning the host-related events in septic shock, multiple derangements involving several biologic systems contribute to different degrees to the development of septic shock, and include aspects of microbial pathogenicity, key cellular and humoral aspects of the maladaptive immunoinflammatory response, the interactions between the immunoinflammatory and coagulation systems, and their cardiocirculatory consequences, resulting in the clinical picture of septic shock.
Emerging research suggests a role for neural modulation of inflammation. One of the earliest documented observations supporting the existence of central autonomic interaction with the immunoinflammatory response involved a serendipitous finding that, with central administration of a TNF inhibitor, efferent vagal activity was stimulated with systemic anti-inflammatory action.
It is now understood that these cytokine-suppressive effects of vagal stimulation are mediated by the release of its neurotransmitter acetylcholine (ACh) and its subsequent interaction with ACh receptors expressed by macrophages and other immune effector cells.
Early uncomplicated sepsis is characterized by high circulating catecholamine levels with significant metabolic (catabolic state), immunomodulaory (excessive inflammation), and cardiocirculatory (increased cardiac output) consequences. Prolonged elevation of circulating catecholamines is toxic to host cells, predisposing the patient to cardiocirculatory failure with hypotension resulting from peripheral vasodilatation and compromised myocardial contractility.
A number of organ abnormalities may occur in septic shock. The lungs may develop low-pressure pulmonary edema, or adult respiratory distress syndrome (ARDS). Disseminated intravascular coagulopathy is not infrequent and carries a high mortality. Renal impairment and gastrointestinal dysfunction may occur secondary to regional ischemia. Central nervous system dysfunction is also common.
The diagnosis and management of severe sepsis and septic shock is a complex and dynamic process. Newer evidence-based interventions are constantly being developed and implemented with the purpose of improving morbidity and mortality. With the recent updated guidelines, medical institutions frequently follow sepsis protocols incorporating early empiric antibiotics, restoration of tissue perfusion, initiation of vasopressor support, and other supportive measures that have been shown to improve patient outcomes, including overall mortality.
A recent study assessing the value of a standardized protocol for patients who have severe sepsis and septic shock demonstrated that those patients who received care adherent to standardized protocols were more likely to starting antibiotics within 1 h and within 6–8 h after diagnosis, respectively and receive appropriate initial antimicrobial treatment, and have a shorten mean length of stay.
Numerous adjunctive treatments (that is, other than antibiotics and hemodynamic supports) for severe sepsis and septic shock have been tested in clinical trials. These include neutralisation of microbial toxins such as lipopolysaccharide, non¬specific anti¬inflammatory and immunosuppressive drugs, neutralisation of pro-inflammatory cytokines, and correction of abnormalities in coagulation. The results have been mixed, although several recent clinical trials have given encouraging results.
Protein C, has anti¬thrombotic, pro¬fibrinolytic, and anti¬inflammatory effects, Treatment with activated protein C reduces mortality from severe sepsis at the price of a slight increase in bleeding events. Glucocorticoids exert broad metabolic and immuno modulating effects, and it has been found that a seven day course of low doses of hydrocortisone and fludrocortisone reduced mortality in patients with septic shock and relative adrenal insufficiency.
Severe sepsis and septic shock are associated with myocardial involvement characterized by systolic and diastolic dysfunction. The sepsis associated cardiomyopathy is due to many pathophysiological causes that act synergistically, while a single determinant is still not identifiable. Early diagnosis of heart dysfunction is mandatory in order to implement a correct therapeutic regimen in septic patients. Measurements of biochemical markers, as troponin and BNP is now recognized as an useful tool for early identification and subsequent monitoring of sepsis related myocardial dysfunction.
Current experimental and clinical data suggest that high catecholamine plasma levels and over-stimulation of the sympathoadrenergic system may relevantly contribute to the pathogenesis of heart failure in patients suffering from septic shock. Since several therapeutic interventions influence catecholamine plasma levels in septic shock patients, treatment strategies aiming at the reduction of endogenous or exogenous catecholamine exposure may protect the heart during septic shock and could facilitate patient survival.
Calcium desensitisation could be a potential component in septic myocardial depression. Levosimendan acts via calcium sensitisation, this would be a more logical choice of inotrope in septic myocardial depression rather than dobutamine.
Continuous infusion of vasopressin restores vascular tone in vasoplegic (catecholamine- resistant) shock states by several mechanisms including activation of vasopressin1 receptors (V1R’s), modulation of KATP channels, modulation of nitric oxide, and potentiation of adrenergic and other vasoconstrictor agents.