Critical Care Medicine 978-1-4963-0291-5 chapter 27

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SECTION II • Medical and Surgical Crises

For example, in some parts of the Southeastern United States, half of all Pneumococcus isolates are at least of intermediate resistance to penicillin. In addition, now in many ICUs, the single most com- mon organism causing severe episodes of sepsis is a highly resistant nosocomial pathogen, typically methicillin-resistant S. aureus (MRSA) or vanco- mycin-resistant Enterococcus (VRE). Regardless, in most circumstances, critically ill patients require prompt empiric therapy for all reasonably likely organisms until culture data are available. PATHOPHYSIOLOGY The severity of sepsis is determined more by the specificity and ferocity of the host response than by the inciting organism. Ironically, the same inflam- matory and coagulopathic mechanisms that are detrimental when intense, unrestrained, and undi- rected in the septic patient usually act as beneficial and effective defenses. Certainly, both confined inflammation and accelerated coagulation limit spread of local infection or injury. It is only when rogue, diffuse, unbridled inflammation, or coagu- lation occurs that they are counterproductive and organ damaging. Adverse host responses impair car-

diovascular, neuronal, autonomic, hormonal, bioen- ergetic metabolic, and coagulation functions. Historically, excessive inflammation was con- sidered the major, if not sole, pathogenetic factor in severe sepsis. This paradigm envisioned a multistage inflammatory “cascade” in which an initial trigger caused production of a few “early” mediators, followed over hours by a larger number of secondary media- tors (Table 27-2). Moreover, a linear progression from health to septic shock was envisioned, based primarily on the intensity of inflammation. It is now clear that inflammation, though extremely important and cen- tral to the sepsis syndrome, is but one of at least three important pathophysiologic pathways that includes enhanced coagulation and impaired thrombolysis. The trigger for severe sepsis is often a protein, lipid, or carbohydrate toxin shed from a microbe but may be activated complement, a clotting cas- cade component, or dead host tissue. The most notorious inciting factor is endotoxin, the integral cell wall lipopolysaccharide component of gram- negative bacteria. However, it is far from being the only important toxin; staphylococcal toxic shock syndrome toxin (TSST-1) and group B streptococ- cal (GBS) toxin are other well-recognized triggers. The triggering compound usually is only present

Table 27-2.  Common Mediators of Sepsis and Their Actions Agent Action CELLULAR ELEMENTS Monocytes and macrophages Neutrophils Cytokine production, tissue factor expression Tissue destruction via oxidant and protease mechanisms

EICOSANOIDS Prostaglandins  Prostacyclin  Thromboxane  E-series prostaglandins Leukotrienes

Vasodilation, inhibition of platelet aggregation Vasoconstriction, platelet aggregation Renal vasodilation, inhibition of cytokine generation Vasodilation, increased vascular permeability, leukocyte chemotaxis

CYTOKINES Tumor necrosis factor

Activates neutrophils; causes IL-1, IL-6, and IL-8 production; promotes leukocyte/vessel wall adhesion Copyright © 2019 Wolter Kluwer, Inc. Unauthorized reproduction of the content is prohibited.

Interleukin-1 Interleukin-6 Interleukin-8 OXIDANTS H 2 O 2 , HOCl 2 PROTEASES

Neutrophil chemoattractant

2 −

− , O

Direct injury of lipids, nucleotides, and proteins

Destruction of vital cellular proteins, including antioxidants

CLOTTING PROTEINS Thrombin

Microvascular thrombosis, leukocyte activation, inhibition of fibrinolysis

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