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The past four decades have added greatly to our recognition that sepsis, originally defined as a syndrome induced by actively dividing microorganisms in the circulation, is, in fact, a complex and diverse disorder. The term has now come to encompass a constellation of abnormalities that reflect disordered or dysregulated inflammation. As such, sepsis may be initiated by infection; however, it may also occur in the absence of microbial invasion, for example, in response to extensive trauma, uninfected pancreatitis, ruptured aortic aneurysm, or some distinctly unusual entities, such as amniotic fluid embolism. All such patients may develop multiple organ dysfunction syndrome (MODS) and a newly recognized state currently called “chronic critical illness (CCI).” What is now apparent is that our ability to manage shock and to support organ function has unmasked a common ­family of disorders that have a high mortality and significant morbidity. Familiarity with sepsis is essential for all medical practitioners.

This chapter defines the clinical findings that constitute sepsis, MODS, and CCI. The disorders are described as a function of their position on a continuum of clinical, organ system–specific, cellular, and, indeed, even subcellular, changes that include abnormal biochemistry, metabolism, and energetics. Several pathogenic hypotheses, management strategies, and intriguing new forms of therapy are addressed.

Definitions, Natural History, and Epidemiology

The characteristic response to inflammatory stimuli, including surgery and trauma, has been referred to as the stress response, the evolutionary importance of which lies in facilitation of survival and tissue repair.1

Initially in the stress response, an orchestrated neuro-hormonal-humoral mechanism directs substrate delivery to the most vital organs—the heart and brain. Enabling of the mechanism requires rapid development of vasoconstriction, fluid retention, and translocation of intracellular water into the vasculature. In the absence of exogenous life support, death from shock ensues when these endogenous mechanisms are inadequate.

Resuscitation from the initial phase of shock is followed by a period during which cardiovascular function and global metabolism are markedly enhanced.2 The driving force behind this second phase is repair of damaged tissue, with white blood cells serving as the primary effectors of the process.3 To support the increased white blood cell mass, substrate is mobilized from endogenous sources and glucose reserves are rapidly depleted. Because white blood cells are obligate glucose users, muscle (both skeletal and smooth) is broken down to provide precursors for increases in hepatic gluconeogenesis. Nonglucogenic amino acids are used to synthesize structural proteins and enzymes. Energy to support the liver, heart, and other organs is derived from fat and amino acids, since utilization of glucose by tissues other than blood cells and neurons is blocked. Generalized capillary recruitment and leak allow substrate delivery to the avascular area where tissue is damaged. The amount of fluid in the extracellular compartment, particularly in the extracellular, extravascular matrix, increases dramatically. Continued fluid retention and movement of water out of cells ...

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