Porth's Essentials of Pathophysiology, 4e

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Heart Failure and Circulatory Shock

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in leukocyte adhesion, local inflammation, neutrophil activation, generation of fever, tachycardia, lactic acido- sis, ventilation–perfusion abnormalities, and other signs of sepsis. Although activated neutrophils kill microor- ganisms, they also injure the endothelium (endothelial dysfunction) by releasing mediators that increase vas- cular permeability. In addition, injured endothelial cells release an excess of nitric oxide, a potent vasodilator that acts as a key mediator of septic shock. Another important aspect of sepsis that is also related to endothelial dysfunction is an alteration of the procoagulation–anticoagulation balance with an increase in procoagulation factors and a decrease in anticoagulation factors. Lipopolysaccharide on the sur- face of microorganisms stimulates endothelial cells lin- ing blood vessels to increase their production of tissue factor, thus activating coagulation 67 (see Chapter 12). Fibrinogen is then converted to fibrin, leading to the formation of microvascular thrombi that further amplify tissue injury. In addition, sepsis lowers levels of protein C, protein S, antithrombin III, and tissue factor pathway inhibitor, substances that modulate and inhibit coagulation. 67 Sepsis and septic shock are typically manifested by hypotension and warm, flushed skin. Whereas other forms of shock (i.e., cardiogenic, hypovolemic, and obstructive) are characterized by a compensatory increase in systemic vascular resistance, septic shock often presents with a decrease in systemic vascular resistance. Hypovolemia is due to arterial and venous dilatation, plus leakage of plasma into the interstitial spaces. Abrupt changes in cognition or behavior are due to reduced cerebral blood flow and may be early indications of septic shock. Regardless of the underly- ing cause, fever and increased leukocytes are present. An elevated serum lactate or metabolic acidosis indicates anaerobic metabolism due to tissue hypoxia or cellular dysfunction and altered cellular metabolism. 70 Tissue hypoxia produces continued production and activation of inflammatory mediators, resulting in further increases in vascular permeability, impaired vascular regulation, and altered hemostasis. As sepsis continues, organ sys- tem failure can occur. Multiple organ dysfunction is the major cause of death in sepsis. Early recognition of the signs and symptoms of con- ditions that could lead to sepsis is key to optimizing outcomes and decreasing sepsis-related mortality. The treatment of sepsis and septic shock focuses on con- trol of the causative agent, support of the circulation and the failing organ systems. 68 The administration of antibiotics that are specific for the infectious agent is essential. However, antibiotics do not treat inflamma- tion; thus, the cardiovascular status of the patient must be supported to increase oxygen delivery to the cells and prevent further cellular injury. Swift and aggressive fluid administration is needed to compensate for third spacing, though which type of fluid is optimal remains controversial. 71 Equally aggressive use of vasopressor agents, such as norepinephrine or epinephrine, is needed to counteract the vasodilation caused by inflammatory mediators. 67

Microorganisms

Suspected or confirmed infection

Systemic inflammatory response

Diffuse endothelium disruption and impaired microvascular function

Severe sepsis with organ dysfunction

Hypotension, hypoxemia, oliguria, metabolic acidosis, thrombocytopenia

Septic shock

FIGURE 20-10. Pathogenic mechanisms leading from infection to septic shock.

enhanced awareness of the diagnosis, increased number of resistant organisms, growing number of immunocom- promised and elderly persons, and greater use of inva- sive procedures. 69 With early intervention and advances in treatment methods, the mortality rate has decreased; however, the number of deaths has increased because of the increased prevalence. The pathogenesis of sepsis involves a complex process of cellular activation resulting in release of proinflam- matory mediators such as cytokines; recruitment of neu- trophils and monocytes; involvement of neuroendocrine reflexes; and activation of complement, coagulation, and fibrinolytic systems. 66 Initiation of the response begins with activation of the innate immune system and release of a number of proinflammatory and anti-inflammatory mediators (Chapter 15). Two of these mediators, tumor necrosis factor (TNF)- α and interleukin-1, are involved