Introduction
Sepsis is defined as acomplex activation of immune system with a documented infection, systemic inflammatory response syndrome (SIRS) as acomplex activation of immune system regardless of eatiology ,infection ,trauma ,burns ,or asterile inflammatory process ,Sever sepsis is as sepsis plus organ dysfunction and Septic shock is as sepsis plus unexplained acute circulatory collapse with organ dysfunction, hypotention, and tissue hypoperfusion. (Browser 2008)
Sepsis has been referred to as aprocess of malignant intravascular inflammation .It is considered malignant because it is uncontrolled ,unregulated,and self sustaining .It is considered intravascular because it represents the blood –borne spread of what is usually acell-to-cell interaction in the interstitial space .It is considered inflammatory because all characteristics of the septic response are exaggerations of the normal inflammatory response. (Mesiner 2002)
When tissue is injured or infected, there is simultaneous release of pro-inflammatory and anti- inflammatory elements .The balance of these contrasting signals helps to facilitate tissue repair and healing .However ,remote tissue injury may ensue when this equilibrium in the inflammatory process is lost ,and these mediators exert systemic effects .The significant consequences of a systemic pro-inflammatory reaction include endothelial damage ,microvascular dysfunction ,and impaired tissue oxygenation and organ injury .The significant consequences of an excessive anti- inflammatory process include immunosuppression .In addition, pro-and anti-inflammatory process may interfere with each other, creating a state of destructive immunologic process. (Mesiner 2001)
The occurrence of sepsis in the united states from 1979 to 2000 using representive samples showed that the incidence and the number of sepsis related deaths increased ,despite a decline in the overall in hospital mortality among sepsis patients. (Hebert 2008)
Sepsis is associated with increased hospital and ICU stays ,expensive antimicrobial therapies ,and prolonged duration of mechanical ventilation .As such, the economic impact of sepsis is considerable.
(Angus 2004)
Sepsis is clearly associated with high morbidity and mortality. Importantly, the prognosis of septic patients is influenced not only by the severity of infection ,but also by the previous health status and the host response and diagnosis of sepsis affects not only immediate mortality, but has an effect on longer-term death rates as well. (Mesiner 2000)
Studies in the past year have documented sepsis rate in cancer patients to be 10 times higher than non cancer patients ,making cancer potentially the greatest contributor to the risk for sepsis among co- morbid conditions greater even than HIV and diabetes. (Luce 2008)
The lungs are the most commen source of infection .The most commonly isolated organisms in nosocomial infections ,an important cause of sepsis in ICU patients ,are staphylococcus aureus, klebesilla ,pseudomonas aregenosa, Ecoli.Over recent years , there has been a change in the eatiology of septic shock with chest related infection becoming more important than abdominal infection ,possibly related to increased and often prolonged use of mechanical ventilation.
(Martin 2004)
In the last half of the 20th century, the use of antibiotics for the treatment of bacterial infections transformed the practice of medicine, resulting in sharp reductions in morbidity and mortality from acute and chronic infections. However, mortality has remained high when an acute bacterial infection induces sepsis with shock, metabolic acidosis, oliguria, or hypoxemia. In fact, in the United States alone, there are at least 500,000 episodes of sepsis annually, and the resultant mortality rate ranges from 30 to 50 percent, even with intensive medical care, including antibiotics, intravenous fluids, nutrition, mechanical ventilation for respiratory failure, and surgery when indicated to eradicate the source of the infection. (Rangel Frausto ,et al 2003)
In the past 15 years several treatments designed to reduce the mortality rate associated with sepsis have been unsuccessful, leading some investigators to conclude that any adjunctive therapy is destined to fail because once the clinical signs of severe sepsis are present, irreversible organ injury has already occurred. At last, however, there has been progress in finding an effective new therapy for sepsis. It is reported the results of a large clinical trial in which recombinant human activated protein C significantly reduced mortality in patients with severe sepsis.
(Bernard ,et aL 2000)
Activated protein C, a component of the natural anticoagulant system, is a potent antithrombotic serine protease with substantial anti inflammatory properties. What has the efficacy of this treatment taught us about the pathogenesis of sepsis, and what are the strengths and limitations of this important clinical trial. (Gandrel ,et al 2001)
AIM OF THE WORK
The aim of this work is to determine the effect of intravenous activated protein C therapy in the treatment of patients with severe sepsis and septic shock in the ICU.
Chapter I
The pathophysiology of sepsis
Sepsis has been referred to as a process of malignant intravascular inflammation .It is considered malignant because it is uncontrolled, unregulated, and self-sustaining. It is considered intravascular because it represents the blood-borne spread of what is usually a cell-to-cell interaction in the interstitial space. It is considered inflammatory because all characteristics of the septic response are exaggerations of the normal inflammatory response. (pinsky, et al 2008)
When tissue is injured or infected, there is simultaneous release of pro-inflammatory and anti-inflammatory elements. The balance of these contrasting signals helps to facilitate tissue repair and healing. However, remote tissue injury may ensue when this equilibrium in the inflammatory process is lost, and these mediators exert systemic effects . (Bone 2008)
The significant consequences of a systemic pro-inflammatory reaction include endothelial damage, microvascular dysfunction, and impaired tissue oxygenation and organ injury. The significant consequences of an excessive anti-inflammatory response include immunosuppression. In addition, pro- and anti-inflammatory processes may interfere with each other, creating a state of destructive immunologic dissonance. (Bone 2008)
Normal inflammation:
Inflammation is intended to be a local and contained response to infection. While initiating insults may be numerous, the inflammatory processes are qualitatively similar. At the site of injury, the endothelium expresses adherence molecules to attract leukocytes. At the same time, polymorphonuclear leukocytes (PMNs) are activated and express adhesion molecules that cause their aggregation and margination to the vascular endothelium. A prerequisite for subsequent phagocytosis of invading bacteria and debris from injured tissue is diapedesis and then migration of these PMNs to the site of injury. (Movat ,et al 2008).
The release of mediators by PMNs at the site of injury or infection is responsible for the cardinal signs of local inflammation e.g Local vasodilation and hyperemia ,Increased microvascular permeability, resulting in protein-rich edema. (Monatt ,et al 2005)
The primitive, but effective, local inflammatory processes (adherence, chemotaxis, phagocytosis, bacterial killing) are highly regulated at various levels, mainly through the production of cytokines by macrophages. Once a macrophage has been triggered and activated during the invasion of tissue by bacteria, it secretes cytokines (eg, tumor necrosis factor, interleukins) and other mediators into the cell's microenvironment . (Michard ,et al 2008).
Tumor necrosis factor (TNF) release becomes self-stimulating (an autocrine process), and cytokine levels are further increased by the release of other inflammatory mediators, including table (3). This leads to continued activation of PMNs, macrophages and lymphocytes. In addition, the proinflammatory mediators recruit more PMNs and macrophages (a paracrine process). The net effect is clearing of bacteria and debris, which is followed by tissue repair (Fekety , et al 2008).
Table (1): Inflammatory mediators in sepsis
Mediator Source Main Effect
Histamine Mast cells, basophils, platelets Vasodilatation, increased vascular permeability
Serotonin Platelets Increased vascular permeability, platelet aggregation
Prostaglandins All leucocytes, platelets, endothelial cells Most cause vasodilatation Thromboxane – vasoconstriction
Leukotrienes All leucocytes Vasoconstriction, bronchospasm, increased vascular permeability
Platelet activating factor (PAF) All leucocytes, platelets, endothelial cells Platelet aggregation and degranulation, vasodilatation, increased vascular permeability, leukocyte adherence
Nitric oxide (NO) Endothelial cells, macrophages, platelets Vasodilatation
Cytokines (interleukin eg IL1, Tumour necrosis factor TNF) Macrophages, lymphocytes Vasodilatation, fever, lethargy, attracts leucocytes
Kinin system
(Bradykinin) Circulates in plasma inactive Increased vascular permeability, vasodilatation
Complement System Cascade of inactive plasma proteins Leukocyte activation, phagocytosis
C3a and C5a cause increased vascular permeability and vasodilatation
In some cases, mediator release exceeds the boundaries of the local environment. This may lead to a more generalized response that affects otherwise normal tissue fig 1). This process is referred to as sepsis when it occurs in association with infection, and as SIRS when it is induced by noninfectious conditions, such as pancreatitis, severe trauma, and aspiration.
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