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Tissue vulnerability to hypoxia. Neurons undergo irre- versible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells, although hardier than neurons, still die after only 20 to 30 minutes of ischemia. By contrast, fibroblasts within myocardium remain viable after many hours of ischemia. #352 | | |
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Infarcts are areas of ischemic necrosis most commonly caused by arterial occlusion (typically resulting from thrombosis or embolization); venous outflow obstruction is a less frequent cause. #355 | | |
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Infarcts caused by venous occlusion or occurring in spongy tissues typically are hemorrhagic (red); those caused by arterial occlusion in compact tissues typically are pale (white). #357 | | |
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Whether or not vascular occlusion causes tissue infarction is influenced by collateral blood supplies, the rate at which an obstruction develops, intrinsic tissue susceptibility to ischemic injury, and blood oxygenation. #359 | | |
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Shock is a state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia. At the outset, the cellular injury is reversible; however, prolonged shock even- tually leads to irreversible tissue injury and is often fatal. #361 | | |
Shock may complicate severe hemorrhage, extensive trauma or burns, myocardial infarction, pulmonary embolism, and microbial sepsis. Its causes fall into three general categories (Table 4.3): #362 | | |
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Cardiogenic shock results from low cardiac output as a result of myocardial pump failure. It may be caused by myocardial damage (infarction), ventricular arrhythmias, extrinsic compression (cardiac tampon- ade) (Chapter 12), or outflow obstruction (e.g., pulmo- nary embolism). #364 | | |
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Hypovolemic shock results from low cardiac output due to loss of blood or plasma volume (e.g., resulting from hemorrhage or fluid loss from severe burns). #366 | | |
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Septic shock is triggered by microbial infections and is associ- ated with severe systemic inflammatory response syndrome (SIRS). In addition to microbes, SIRS may be triggered by a variety of insults, including burns, trauma, and/or pancreatitis. The common pathogenic mechanism is a massive outpouring of inflammatory mediators from innate and adaptive immune cells that produce arterial vasodilation, vascular leakage, and venous blood pooling. These cardiovascular abnormalities result in tissue hypoperfusion, cellular hypoxia, and metabolic derangements that lead to organ dysfunction and, if severe and persistent, organ failure and death. The pathogenesis of shock is discussed in detail below. #368 | | |
Less commonly, shock can result from a loss of vascular tone associated with anesthesia or secondary to a spinal cord injury (neurogenic shock). Anaphylactic shock results from systemic vasodilation and increased vascular perme- ability that is triggered by an immunoglobulin E–mediated hypersensitivity reaction (Chapter 5). #369 | | |
Pathogenesis of Septic Shock #370 | | |
Septic shock is responsible for 2% of all hospital admis- sions in the United States. Of these, 50% require treatment in intensive care units. The number of cases in the United States exceeds 750,000/year and the incidence is rising, which is ironically due to improvements in life support for critically ill patients, as well as the growing ranks of immu- nocompromised hosts (because of chemotherapy, immu- nosuppression, advanced age, or human immunodeficiency virus infection) and the increasing prevalence of multidrug- resistant organisms in the hospital setting. Despite improvements in care, the mortality remains at a stagger- ing 20% to 30%. #371 | | |
Septic shock is most frequently triggered by gram- positive bacterial infections, followed by gram-negative bacteria and fungi. Hence, an older synonym, “endotoxic shock,” is no longer appropriate. #372 | | |
The ability of diverse microorganisms to cause septic shock is consistent with the idea that a variety of microbial constituents can trigger the process. As mentioned in Chapter 3, macrophages, neutrophils, dendritic cells, endo- thelial cells, and soluble components of the innate immune system (e.g., complement) recognize and are activated by several substances derived from microorganisms. After activation, these cells and factors initiate a number of inflammatory responses that interact in a complex, incom- pletely understood fashion to produce septic shock and multiorgan dysfunction (Fig. 4.19). #373 | | |
Factors believed to play major roles in the pathophysiol- ogy of septic shock include the following: #374 | | |
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Inflammatory and counterinflammatory responses. In sepsis, various microbial cell wall constituents engage recep- tors on cells of the innate immune system, triggering proinflammatory responses. Likely initiators of inflam- mation in sepsis are signaling pathways that lie down- stream of Toll-like receptors (TLRs) (Chapter 5), which recognize a host of microbe-derived substances contain- ing so-called “pathogen-associated molecular patterns” (PAMPs), as well as G-protein–coupled receptors that detect bacterial peptides, and C-type lectin receptors such as Dectins. On activation, innate immune cells produce numerous cytokines, including TNF, IL-1, IFN- γ, IL-12, and IL-18, as well as other inflammatory media- tors such as high-mobility group box 1 protein (HMGB1). Markers of acute inflammation such as C-reactive protein and procalcitonin are also elevated. The latter is a clinically useful indicator of septic shock. Reactive oxygen species and lipid mediators such as prostaglan- dins and platelet-activating factor (PAF) are also elabo- rated. These effector molecules induce endothelial cells (and other cell types) to upregulate adhesion molecule expression and further stimulate cytokine and chemo- kine production. The complement cascade is also activated by microbial components, both directly and through the proteolytic activity of plasmin (Chapter 3), resulting in the production of anaphylotoxins (C3a, C5a), chemotac- tic fragments (C5a), and opsonins (C3b), all of which contribute to the proinflammatory state. In addition, microbial components can activate coagulation directly through factor XII and indirectly through altered endo- thelial function (discussed later). The accompanying widespread activation of thrombin may further augment inflammation by triggering protease activated receptors on inflammatory cells. #376 | | |
The hyperinflammatory state, initiated by sepsis, triggers counterregulatory immunosuppressive mecha- nisms, which may involve both innate and adaptive immune cells. As a result, septic patients may oscillate between hyperinflammatory and immunosuppressed states during their clinical course. Proposed mecha- nisms for the immune suppression include a shift from proinflammatory (TH1) to anti-inflammatory (TH2) cyto- kines (Chapter 5), production of anti-inflammatory mediators (e.g., soluble TNF receptor, IL-1 receptor antagonist, and IL-10), lymphocyte apoptosis, the immunosuppressive effects of apoptotic cells, and the induction of cellular anergy. In some patients the coun- terregulatory mechanisms overshoot the inflammatory responses and the resultant immune suppression renders such patients susceptible to superinfections. #377 | | |
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Endothelial activation and injury. The proinflammatory state and endothelial cell activation associated with sepsis lead to widespread vascular leakage and tissue #379 | | |
edema, which have deleterious effects on both nutrient delivery and waste removal. One effect of inflammatory cytokines is to loosen endothelial cell tight junctions, making vessels leaky and resulting in the accumulation of protein-rich edema fluid throughout the body. This alteration impedes tissue perfusion and may be exacer- bated by attempts to support the patient with intrave- nous fluids. Activated endothelium also upregulates production of nitric oxide (NO) and other vasoactive inflammatory mediators (e.g., C3a, C5a, and PAF), which may contribute to vascular smooth muscle relax- ation and systemic hypotension. #380 | | |
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Induction of a procoagulant state. The derangement in coagulation is sufficient to produce the formidable com- plication of disseminated intravascular coagulation in up to half of septic patients. Sepsis alters the expression of many factors so as to favor coagulation. Proinflamma- tory cytokines increase tissue factor production by monocytes and possibly endothelial cells as well, and decrease the production of endothelial anti-coagulant factors, such as tissue factor pathway inhibitor, throm- bomodulin, and protein C (see Fig. 4.11). They also dampen fibrinolysis by increasing plasminogen activa- tor inhibitor-1 expression (see Fig. 4.10). The vascular leak and tissue edema decrease blood flow at the level of small vessels, producing stasis and diminishing the washout of activated coagulation factors. Acting in #382 | | |
concert, these effects lead to systemic activation of thrombin and the deposition of fibrin-rich thrombi in small vessels, often throughout the body, further com- promising tissue perfusion. In full-blown disseminated intravascular coagulation, the consumption of coagula- tion factors and platelets is so great that deficiencies of these factors appear, leading to concomitant bleeding and hemorrhage (Chapter 12). #383 | | |
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Metabolic abnormalities. Septic patients exhibit insulin resistance and hyperglycemia. Cytokines such as TNF and IL-1, stress-induced hormones (such as glucagon, growth hormone, and glucocorticoids), and catechol- amines all drive gluconeogenesis. At the same time, the proinflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues, likely by impairing the surface expression of GLUT-4, a glucose transporter. Hyperglycemia decreases neutrophil function—thereby suppressing bactericidal activity—and causes increased adhesion molecule expression on endothelial cells. Although sepsis is initially associated with an acute surge in glucocorticoid production, this phase may be followed by adrenal insufficiency and a functional deficit of glucocorticoids. This may stem from depres- sion of the synthetic capacity of intact adrenal glands or frank adrenal necrosis resulting from disseminated intravascular dissemination (Waterhouse-Friderichsen syndrome) (Chapter 20). Finally, cellular hypoxia and diminished oxidative phosphorylation lead to increased lactate production and lactic acidosis. #385 | | |
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Organ dysfunction. Systemic hypotension, interstitial edema, and small vessel thrombosis all decrease the delivery of oxygen and nutrients to the tissues that, because of cellular hypoxia, fail to properly use those nutrients that are delivered. Mitochondrial damage resulting from oxidative stress impairs oxygen use. High levels of cytokines and secondary mediators diminish myocardial contractility and cardiac output, and increased vascular permeability and endothelial injury can lead to the acute respiratory distress syndrome (Chapter 13). Ultimately, these factors may conspire to cause the failure of multiple organs, particularly the kidneys, liver, lungs, and heart, culminating in death. #387 | | |
The severity and outcome of septic shock are likely dependent on the extent and virulence of the infection; the immune status of the host; the presence of other comorbid conditions; and the pattern and level of mediator produc- tion. The multiplicity of factors and the complexity of the interactions that underlie sepsis explain why most attempts to intervene therapeutically with antagonists of specific mediators have not been effective and may even have had deleterious effects in some cases. The standard of care remains antibiotics to treat the underlying infection and intravenous fluids, pressors, and supplemental oxygen to maintain blood pressure and limit tissue hypoxia. Suffice it to say that even in the best of clinical centers, septic shock remains an obstinate clinical challenge. #388 | | |
An additional group of secreted bacterial proteins called superantigens also cause a syndrome similar to septic shock (e.g., toxic shock syndrome). Superantigens are polyclonal #389 | | |
T-lymphocyte activators that induce the release of high #390 | | |
levels of cytokines that result in a variety of clinical mani- festations, ranging from a diffuse rash to vasodilation, hypotension, shock, and death. #391 | | |
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Shock is a progressive disorder that leads to death if the underlying problems are not corrected. The exact mecha- nisms of sepsis-related death are still unclear; aside from increased lymphocyte and enterocyte apoptosis, cellular necrosis is minimal. Death typically follows the failure of multiple organs, which usually offer no morphological clues to explain their dysfunction. For hypovolemic and cardiogenic shock, however, the pathways leading to a patient’s demise are reasonably well understood. Unless the insult is massive and rapidly lethal (e.g., exsanguination from a ruptured aortic aneurysm), shock tends to evolve through three general (albeit somewhat artificial) stages. These stages have been documented most clearly in hypo- volemic shock but are common to other forms as well: #393 | | |
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An initial nonprogressive stage during which reflex compensatory mechanisms are activated and vital organ perfusion is maintained, #395 | | |
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A progressive stage characterized by tissue hypo- perfusion and onset of worsening circulatory and meta- bolic derangement, including acidosis, #397 | | |
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An irreversible stage in which cellular and tissue injury is so severe that even if the hemodynamic defects are corrected, survival is not possible. #399 | | |
In the early nonprogressive phase of shock, various neu- rohumoral mechanisms help maintain cardiac output and blood pressure. These mechanisms include baroreceptor reflexes, release of catecholamines and anti-diuretic hormone, activation of the renin-angiotensin-aldersterone axis, and generalized sympathetic stimulation. The net effect is tachycardia, peripheral vasoconstriction, and renal fluid conservation; cutaneous vasoconstriction causes the characteristic “shocky” skin coolness and pallor (notably, septic shock can initially cause cutaneous vasodilation, so the patient may present with warm, flushed skin). Coro- nary and cerebral vessels are less sensitive to sympathetic signals and maintain relatively normal caliber, blood flow, and oxygen delivery. Thus, blood is shunted away from the skin to the vital organs such as the heart and the brain. #400 | | |
