Multiple Organ Dysfunction Syndrome in Sepsis Background, Pathophysiology, Epidemiology. Malignant intravascular inflammation. Sepsis has been referred to as a process of malignant intravascular inflammation. Normally, a potent, complex, immunologic cascade ensures a prompt protective response to microorganism invasion in humans. A deficient immunologic defense may allow infection to become established however, an excessive or poorly regulated response may harm the host through maladaptive release of indigenously generated inflammatory compounds see the image below. Lipid A and other bacterial products release cytokines and other immune modulators that mediate the clinical manifestations of sepsis. Gta Iv Hot Coffee Mod How To Install. Interleukins, tumor necrosis factor TNF, interferon gamma IFN, and other colony stimulating factors are produced rapidly within minutes or hours after interactions of monocytes and macrophages with lipid A. Inflammatory mediator release becomes a self stimulating process, and release of other such mediators, including interleukin IL 1, platelet activating factor, IL 2, IL 6, IL 8, IL 1. NO, further increases cytokine levels. Sepsis Online Medical Reference from definition and diagnosis through risk factors and treatments. Authored by Steven P. LaRosa of the Cleveland Clinic. Systemic. This leads to continued activation of polymorphonuclear leukocytes PMNs, macrophages, and lymphocytes proinflammatory mediators recruit more of these cells. All of these processes create a state of destructive immunologic dissonance. Sepsis is described as an autodestructive process that permits extension of the normal pathophysiologic response to infection to involve otherwise normal tissues and results in MODS. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune from the consequences of the inflammatory excesses of sepsis. Mortality increases as organ failure increases. Although uncontrolled, once MODS develops systemic evidence of both proinflammatory and anti inflammatory up regulation are usually present, suggesting that failure of host defense homeostasis is the final pathway from sepsis to MODS, rather than simple hypotension induced end organ injury, as may occur with hemorrhagic shock. Survival from severe sepsis with MODS is usually associated with a generalized reduction in both the proinflammatory and anti inflammatory response. A novel hypothesis has recently emerged that survival from severe sepsis requires a generalized down regulation of the bodys immune response, energetic functions, and associated organ performance. Thus, MODS may by the hosts adaptive response to overwhelming inflammation, allowing inflammation to clear without causing permanent end organ harm. As discussed below, all organs reveal a generalized hyporesponsiveness that is clearly abnormal in health but may mark a survival strategy in severe sepsis. Dysfunction of organ systems. ISepsis Vitamin C, Hydrocortisone and Thiamine QA. A_Molekularis_terapiak_en_book/images/image084.png' alt='Activated Protein C For Sepsis Treatment' title='Activated Protein C For Sepsis Treatment' />Circulatory derangement. Significant derangement in autoregulation of circulation is typical of sepsis. Vasoactive mediators cause vasodilatation and increase microvascular permeability at the site of infection. NO plays a central role in the vasodilatation of septic shock. Also, impaired secretion of vasopressin may occur, which may permit persistence of vasodilatation. Changes in both systolic and diastolic ventricular performance occur in sepsis. Through the use of the Frank Starling mechanism, cardiac output often is increased to maintain blood pressure in the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac output appropriately. Regionally, sepsis interferes with the normal distribution of systemic blood flow to organ systems. Consequently, core organs may not receive appropriate oxygen delivery, and the result is what is known as regional hypoperfusion. Microcirculation is the key target organ for injury in sepsis since vascular endothelium is universally affected by the circulating inflammatory mediators. Although it is unclear if microcirculatory abnormalities are the cause or an innocent bystander of the end organ injury, clear microvascular dysfunction is seen. A decrease in the number of perfused capillaries is seen, although with application of vasodilator therapies, full microvascular recruitment occurs. Mitochondrial dysfunction also occurs and is often associated with reduced mitochondrial transmembrane potential gradients, which are necessary to drive oxidative phosphorylation. The end result is an apparent inability of end organs to extract oxygen maximally. Debate continues as to whether this failure of energy metabolism is an adaptive cytoprotective mechanism similar to hibernation or reflects primary mitochondrial pathology. These are areas of active research but do not presently translate into clear clinical practice guidelines. Increased capillary endothelial permeability leads to widespread protein rich tissue edema. Septic shock and SIRS are characterized by reversible myocardial depression, which can prove resistant to catecholamine and fluid administration. Circulating myocardial depressant factorprobably representing the synergistic effects of TNF, IL 1, other cytokines, and NOis implicated in pathogenesis. The two characteristics of this acute stress myocardial depression are impaired adrenergic responsiveness and diastolic dysfunction leading to relative catecholamine resistance and small rather than dilated hearts. Firewall Client Is Not Installed Properly. Macrovascular myocardial ischemia and hypoperfusion are unlikely contributors. In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression cause regional tissue distress, and regional dysoxia therefore persists. This condition is termed microcirculatory and mitochondrial distress syndrome MMDS. Sepsis induced inflammatory autoregulatory dysfunction persists, and oxygen need is not matched by supply, leading to MODS. Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances causes hypotension. Pulmonary dysfunction. Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and enhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membranes. Acute lung injury and acute respiratory distress syndrome ARDS are frequent manifestations of these effects. Indeed, sepsis and pneumonia are the most common causes of ARDS. Gastrointestinal dysfunction. The gastrointestinal GI tract may help propagate the injury of sepsis. Overgrowth of bacteria in the upper GI tract may be aspirated into the lungs, producing nosocomial or aspiration pneumonia. The normal barrier function of the gut may be affected, allowing translocation of bacteria, endotoxins, and normal digestive proteases into the systemic circulation and extending the septic response. Septic shock can cause paralytic ileus that can lead to a delay in the institution of enteral feeding. Excess NO production is thought to be the causative agent of sepsis induced ileus. The optimal level of nutritional intake is interfered with in the face of high protein and calorie requirements. Narcotics and muscle relaxants can further worsen GI tract motility. Liver dysfunction. As a consequence of the role the liver plays in host defense, the abnormal synthetic functions caused by liver dysfunction can contribute to both the initiation and progression of sepsis. The reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria and their products liver dysfunction leads to a spillover of these products into systemic circulation. Liver failure shocked liver can be manifested by elevations in liver enzymes and bilirubin, coagulation defects, and failure to excrete toxins such as ammonia, which lead to worsening encephalopathy. Renal dysfunction. Acute kidney injury AKI often accompanies sepsis.