CHAPTER 7: HEMODYNAMIC DISORDERS | SHOCK
Recognition of Genetic Polymorphisms in TollLike Receptors and Tumor Necrosis Factor Has Helped Elucidate the Pathogenesis of Sepsis Gene mutations in several cytokines, cell surface receptors and other circulating markers have been associated with variability in susceptibility to sepsis. TLR-pattern recognition receptors recognize pathogen-associated microbial patterns and thus are critical in triggering innate immune responses. Toll-like receptor-4 (TLR4) is critical in recognizing LPS of gram-negative bacteria. A mutation, from aspartic acid to glycine at amino acid 299 of TLR4, leads to reduced inflammatory responses in a variety of clinical settings. Thus, TLR4 appears to be important in magnifying responses to endotoxin and in sepsis. Polymorphisms in TLRs and other pattern recognition receptors may help to explain why patients respond so differently to specific infectious agents. Similarly, recently discovered mutations in the TNF-! gene have improved our understanding of the role of TNF! in sepsis. For example, a G to A base change at base 308 of the TNF-! promoter leads to enhanced promoter activity
and increased expression of TNF-! and is associated with increased risk of sepsis and shock. Other gene mutations associated with worse prognosis in sepsis are found in IL-1 receptor agonist, CD14 and plasminogen activator inhibitor-1.
Multiple Organ Dysfunction Syndrome Is the End-Result of Shock Improvements in the early treatment of shock and sepsis have allowed patients to survive long enough to manifest a new problem, progressive deterioration of organ function. Almost all septic shock patients suffer from dysfunction of at least one organ. However, multiple organ dysfunction occurs in one third of patients with septic shock, trauma or burns and in a quarter of those with acute pancreatitis. Whatever the cause, the clinical deterioration of MODS is held to result from common mechanisms of tissue injury subsumed under the rubric of SIRS. Mortality of SIRS/MODS exceeds 50%, making it responsible for most deaths in noncoronary intensive care units in the United States. In most cases inflammatory reactions and the progression from sepsis to organ dysfunction reflect a balance between proinflammatory and anti-inflammatory factors. As mentioned above, TNF-!, IL-1 and NO• have systemic effects. Also, reactive oxygen species are important triggers of end-organ dysfunction. The acute response to sepsis is characterized by release of adrenocorticotropic hormone, cortisol, adrenaline and noradrenaline, vasopressin, glucagon and growth hormone. The net result is shutdown of noncritical systems and an overall catabolic state. Although proinflammatory mediators predominate in SIRS, anti-inflammatory factors play an important role in some patients. The result is compensated anti-inflammatory response syndrome (CARS), in which paralysis of the immune system leads to a poor outcome. It is now thought that following bacterial infection, there is an initial response of excessive inflammation and septic shock characteristic of SIRS. Such uncontrolled cytokine induction is preceded by a stage of anergy and immune repression or CARS. Septic patients who cycle between SIRS and CARS are susceptible to increased mortality. Persons with a heterogeneous response are said to have a “mixed anti-inflammatory response syndrome” (MARS).
Vascular Compensatory Mechanisms Changes in the macrovascular and microvascular circulation are at least partly responsible for variable organ injury in SIRS. Compensatory mechanisms in shock shift blood flow away from the periphery, so as to maintain flow to the heart and the brain. These responses involve the sympathetic nervous system, release of endogenous vasoconstrictors and hormonal substances, and local vasoregulation. The result is increased cardiac output achieved by increasing heart rate and myocardial contractility while constricting arteries and arterioles. ■
Increased sympathetic discharge augments catecholamine release by the adrenal medulla. Skeletal muscle, splanchnic bed and skin arterioles respond to increased sympathetic discharge; cardiac and cerebral arterioles are less reactive. Thus, increased sympathetic tone shifts blood flow from the periphery to the heart and brain. The marked arteriolar
7 | Hemodynamic Disorders
during sepsis. TNF is also central to the pathogenesis of shock that is not associated with endotoxemia (e.g., cardiogenic shock). While LPS is the most potent stimulus, other antigens also promote TNF release. These include toxin-1 of the toxic shock syndrome; enterotoxin; antigens of mycobacteria, fungi, parasites and viruses; and products of complement activation. When macrophages are exposed to LPS in septic shock, large amounts of TNF are suddenly released, often with lethal consequences. Administering anti-TNF antibody before exposing an animal to endotoxin or to gramnegative bacteria completely protects from septic shock. Unfortunately, comparable studies in humans have not been as successful. TNF released by monocyte/macrophages exerts a direct toxic effect on endothelial cells by compromising membrane permeability and inducing endothelial cell apoptosis. It also acts indirectly by (1) initiating a cascade of other mediators that amplify its deleterious effects, (2) promoting adhesion of polymorphonuclear leukocytes to endothelial surfaces and (3) activating the extrinsic coagulation pathway. TNF stimulates release of IL-1 and IL-6, PAF and other eicosanoids that may mediate tissue injury. Interestingly, in animal studies, nonlethal doses of TNF may become fatal if administered together with IL-1. TNF also increases expression of adhesion molecules, such as intercellular adhesion molecules (ICAMs), vascular cell adhesion molecules (VCAMs), P-selectin and endothelial-leukocyte adhesion molecules (ELAMs) on endothelial surfaces, thereby promoting leukocyte adhesion and leukostasis. This mechanism presumably plays a role in the respiratory distress syndrome, in which activated neutrophils are sequestered in the pulmonary circulation and damage alveoli. Other vasoactive peptides include the vasodilatory prostacyclins and endothelin (ET)-1, a potent vasoconstrictor (Fig. 7-32). Note that the term septic syndrome refers to the physiologic and metabolic response characteristic of sepsis in the absence of an infection.
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