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 catecholamines 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 depression 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.
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.
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 production. 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.
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 T-lymphocyte activators that induce the release of high levels of cytokines that result in a variety of clinical manifestations, ranging from a diffuse rash to vasodilation, hypotension, shock, and death.
Shock is a progressive disorder that leads to death if the underlying problems are not corrected. The exact mechanisms 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 hypovolemic shock but are common to other forms as well:
An initial nonprogressive stage during which reflex compensatory mechanisms are activated and vital organ perfusion is maintained,
A progressive stage characterized by tissue hypo-perfusion and onset of worsening circulatory and metabolic derangement, including acidosis,