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Publication Date: September 2005
Welcome to "Sepsis".
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Course Details
Course Length: Approximately 2 hours. Your time may vary based on modem speed, prerequisite knowledge and other factors.
Date Published: September 2005
Sepsis is an exaggerated systemic inflammatory response to infection that leads to widespread tissue destruction in areas remote from the original site of injury. It is a source of considerable morbidity and mortality in hospitalised patients. This course, "Sepsis", gives basic medical background information about the pathophysiology of sepsis, and presents a summary of the spectrum of clinical presentation
The first section, AETIOLOGY (and Mechanisms), first discusses the roles of different pathogens that can cause infection, and the various types of hosts that are susceptible. It then introduces the mechanisms underlying the body’s response to various pathogens, and demonstrates how the systemic response that ensues can cause disease.
The second section, EPIDEMIOLOGY, reviews the epidemiology of sepsis including the prevalence and associated mortality.
The third section, PROGNOSIS, discusses the prognosis of disease, particularly as it relates to organ failure.
The fourth section, DIAGNOSIS, defines various ways in which sepsis can affect the body. Diagnostic criteria are also presented. Symptoms, signs and haemodynamic monitoring in the hospital are discussed.
The fifth section, PREVENTION AND TREATMENT, first discusses some of the treatment options available for sepsis, and the supportive therapies that are employed. Finally, a discussion on preventative strategies is employed.
Early attention focused on inflammation as the dominant process in the aetiology of sepsis. One of the new concepts that have radically changed the view of sepsis is the current understanding of the impact of inflammation, coagulation, and fibrinolysis acting simultaneously in the disease process. This section introduces these processes and their proposed role in sepsis.
These are the objectives for this section. You will be tested on these objectives in the final assessment.
After you finish this section, you should be able to:
Bacteria are the most common cause of sepsis although viral and fungal infections can also lead to sepsis. This lesson describes the microbes that can invade normally sterile tissue to induce an inflammatory response, and the structural components that elicit septic response.
Bacteria are the most common causative agents of both hospital and community-acquired sepsis. There are two types of bacteria, which stain differently with Gram stain due to differences in the structure of their cell wall, which are shown here. Gram-negative bacteria outnumber Gram-positive bacteria in sepsis by a ratio of 2:1.
Viruses and fungi are less frequently identified causes of sepsis. However, the number of sepsis cases associated with fungal infection has grown to 5-10% of all sepsis patients.
This table shows the community acquired, and nosocomial or hospital derived bacteria that have been associated with sepsis and their common organ target. When you are ready click on continue.
Different components of bacteria have been implicated in the pathogenesis of sepsis. Endotoxin, a lipopolysaccharide on the cell wall of Gram-negative bacteria is one of the most important contributors. The level of endotoxin in the blood may predict a poor outcome in sepsis.
Other factors that have been identified include components of bacterial cell walls such as peptidoglycan, formyl peptides, muramyl dipeptide and lipoteichoic acid. Some bacteria may produce exotoxins that may lead to sepsis and shock. One form of septic shock, toxic shock syndrome, can be initiated by exotoxins of Staphylococcus aureus, called superantigens, and Streptococcus pyogenes, called SpeA.
There are several host factors that may predispose particular patients to become septic as well as increase their likelihood of dying. These factors are reviewed in this lesson.
Most sepsis or septic shock cases occur in patients with underlying conditions that make them immunosuppressed or otherwise predisposed to infections.
This table shows pro-sepsis factors, which include underlying diseases, surgery, prior drug therapy, age, miscellaneous conditions, and genetic factors.
Roll your cursor over each section to view more information.
Rollover Text: Underlying Disease
Patients with underlying diseases such as neutropaenia, solid tumours, leukemia, dysproteinemias, cirrhosis of the liver, diabetes, AIDS, or other serious chronic conditions are susceptible to sepsis.
Rollover Text: Surgery
Patients who have undergone a surgical procedure are prone to bacterial exposure and sepsis. Infection after surgery can be related to the surgery itself, or be an infection of the wound (called surgical site infection). The chance of developing an infection after surgery is related to many factors, including the type of surgery. For example, if the large bowel is opened, because the risk of bacterial contamination of the peritoneum is increased even with careful surgical technique, the chance of post-surgical infection is higher. Higher risks of infection also occur when a foreign piece of material is left in the body e.g. prosthetic joints and intravascular catheters, or in situations where repeated surgery is warranted. Patients undergoing major surgery are also prone to other infections such as pneumonia.
Rollover Text: Prior Drug Therapy
Patients who are immuno-compromised by immuno-suppressive drugs are prone to infection and subsequent sepsis. Prior treatment with antibiotics, especially broad spectrum ones, may cause a patient to become colonised with bacteria which may be resistant to antibiotics. This does not require antibiotic treatment. However, in some situations, patients may go on to become infected with these organisms (called a superinfection), which requires treatment with appropriate antibiotics.
Rollover Text: Age
Age is a contributing factor with newborn, especially premature infants, males above 40 years of age, and females 20 to 45 years of age being more susceptible.
Rollover Text: Miscellaneous Conditions
Miscellaneous conditions where sepsis may occur include childbirth, septic abortion, trauma and widespread burns, and intestinal ulceration.
Rollover Text: Genetics
The human major histocompatibility complex (MHC) is a region on the short arm of chromosome 6 that encodes many immune related proteins. Many of these are polymorphic and alleles are often associated with diseases particularly autoimmune diseases such as diabetes, multiple sclerosis, and rheumatoid arthritis. The tumour necrosis factor alpha (TNF-α) gene is located in the MHC, and the TNF2 allele has been strongly associated with higher susceptibility and mortality associated with septic shock. This is one example of a number of genetically acquired conditions that predispose the infection.
Early attention focused on inflammation as the dominant process in the cascade of sepsis events leading to organ dysfunction. A new paradigm on the pathophysiology of sepsis is developing - one that views the loss of homeostasis as an uncontrolled cascade of coagulation, fibrinolysis, and inflammation. This lesson introduces this paradigm.
When a microbe infects tissue, there is an immediate cascade of proinflammatory mediators liberated. Simultaneously, this is kept in check by the release of anti-inflammatory agents. It is this balance that allows mobilization of defense and microbe killing mediators, while permitting tissue repair and healing. In sepsis this equilibrium is upset and the proinflammatory mediators are favoured to cause endothelial damage.
More recently, investigations into the extent of coagulation and fibrinolysis abnormalities in sepsis have shown that the endothelial damage promotes coagulation. Normally, natural modulators promote fibrinolysis to counteract thrombosis. In sepsis, it is now proposed that the endothelial damage suppresses fibrinolysis further contributing to the loss of control.
Endogenous modulators of homeostasis are consumed and their levels become deficient as the body attempts to return to a normal functional state.
Concurrently, the endothelial damage causes further exacerbation of inflammation.
Left unopposed, the endothelial damage accumulates and so in turn does coagulation.
This uncontrolled cascade of inflammation and coagulation fuels the progression of sepsis, resulting in hypoxia, widespread ischaemia, organ dysfunction, and ultimately death for a large number of patients.
Inflammation is intended to be a localised, nonspecific response to tissue injury. It can be triggered by mechanical (such as trauma), chemical or microbial (such as bacterial endotoxin) stimuli. This lesson shows how a normal inflammatory response occurs in response to a toxic stimulus, and how an exaggerated inflammatory response can cause sepsis.
When a bacterium infects a person and enters a part of the systemic circulation, the initial toxic insult triggers a pro-inflammatory state by stimulating adjacent monocytes to produce proinflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor alpha (TNF-α), and interleukin-8 (IL-8).
Monocytes are circulating white blood cells that are important for destroying and removing bacteria as well as producing cytokines. Cytokines are small proteins that have important roles in cell-to-cell communication and behaviour.
Activated neutrophils are attracted to the area of inflammation by cytokines such as IL-8. These cytokines as well as bacterial toxins also up-regulate endothelial cell adhesion molecules such as E-selectin and P-selectin, which promote the attachment of activated neutrophils that have trafficked to the area. The activated neutrophils then facilitate vascular injury by the release of proteases and other inflammatory mediators such prostaglandins, and leukotrienes. The coagulation cascade is also activated.
At the same time, anti-inflammatory cytokines such as IL-4 and IL-10 act as negative feedback and provide balance. Normally, this is continued until the wound is healed and infection is controlled. However, loss of this local control or an overly activated response results in an exaggerated systemic response.
The processes of inflammation and coagulation are intimately linked. The end result of the coagulation pathway is the production of thrombin, which transforms soluble fibrinogen into a fibrin tangle to form a clot. This process is finely regulated, and also counterbalanced by fibrinolysis, which breaks down a clot. This lesson outlines the important role of the coagulation pathway and fibrinolysis in the pathogenesis of sepsis.
The processes of inflammation and coagulation are intimately linked. Pro-inflammatory cytokines TNF-α, IL-1 and IL-8 together with bacterial toxins also facilitate the release of tissue factor from a variety of sources.
Tissue Factor is a key mediator between the immune system and coagulation, and is the principal activator of coagulation. Tissue Factor interacts with factor VIIa, forming the factor VIIa-TF complex, which activates factors X. Factors X and V then combine to activate the conversion of prothrombin to thrombin. Thrombin accumulates and catalyses the generation of fibrin threads that clump with activated platelets to form a thrombus or clot. Amplification of coagulation via thrombin-mediated processes then occurs by activating factors XI, VIII, and V, which feed back into the cascade to generate more thrombin and more coagulation.
The coagulation cascade is normally counterbalanced by three anticoagulant mechanisms. Tissue factor pathway inhibitor or TFPI is a regulatory protease inhibitor, which is a potent inhibitor of the initial step in the extrinsic pathway. It acts by binding to Factor Xa to form a complex, which in turn binds to, and inhibits, the Factor VIIa tissue-factor complex.
Factor Xa and thrombin are inhibited by a naturally occurring plasma serine protease inhibitor called antithrombin III or AT3.
Finally, Protein C is a naturally occurring plasma protein, which is converted to its activated form -Activated Protein C, or APC which cleaves Factors Va and Factor VIIIa to inactive forms that have no coagulant activity.
Coagulation is also counterbalanced by fibrinolysis. Plasmin is the principal effector of fibrinolysis, and is formed when tissue plasminogen activating factor (t-PA) triggers the conversion of plasminogen to plasmin. Plasmin then breaks down the fibrin strands that hold a clot together.
Fibrinolysis is in turn regulated by two key inhibitors called plasminogen activator inhibitor 1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI).
In sepsis, several of the anticoagulant systems are inactivated. Hold your cursor over the "Sepsis" button to view the effects of sepsis on these mechanisms.
Proteins such as Protein C tend to be depleted or consumed, and their already decreased activity is lower still in patients who progress to severe sepsis and septic shock. This means Factors VIII and V are not downregulated.
In parallel, fibrinolysis is suppressed through increased PAI-1 activity; decreased t-PA activity, and decreased plasminogen levels. Endotoxins released by Gram-negative pathogens increase the activity of PAI-1.
Ultimately, the suppression of fibrinolysis in conjunction with activation of coagulation creates a dynamic process of coagulopathy in patients with sepsis.
This lesson summarises the combined role of inflammation, increased coagulation and reduced fibrinolysis in sepsis. It also covers the key proteins that are involved in tilting the balance toward sepsis.
In simplified terms, sepsis can be conceptualised as a dysfunction of the opposing mechanisms that normally maintain homeostasis.
On one side are increased inflammation and coagulation, which are driven by proinflammatory mediators, endothelial injury, tissue factor expression, and thrombin production.
On the opposite side is suppressed fibrinolysis, which normally counters procoagulant forces. This occurs through multiple mechanisms, most notably increased levels of PAI-1 and TAFI, and decreased levels of Protein C and endogenous Activated Protein C.
This lesson summarises the combined role of inflammation, increased coagulation and reduced fibrinolysis in sepsis. It also covers the key proteins that are involved in tilting the balance toward sepsis.
In simplified terms, sepsis can be conceptualised as a dysfunction of the opposing mechanisms that normally maintain homeostasis.
On one side are increased inflammation and coagulation, which are driven by proinflammatory mediators, endothelial injury, tissue factor expression, and thrombin production.
On the opposite side is suppressed fibrinolysis, which normally counters procoagulant forces. This occurs through multiple mechanisms, most notably increased levels of PAI-1 and TAFI, and decreased levels of Protein C and endogenous Activated Protein C.
This “drag and drop” progress check will test your knowledge of the information presented in this section. Because your score will not be recorded, you may take the progress check as many times as you would like.
Please feel free to review the lessons as often as required to successfully complete the progress check.
Use the terms to label the diagram. Not all terms are used. Use the “rewind” button to reset.
Match the terms with the appropriate groups. Not all terms are used. Use the “rewind” button to reset.