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

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CHAPTER 27 • Sepsis and Septic Shock

transiently in the circulation and commonly escapes detection, even when sophisticated monitoring is performed. For example, less than one half of patients exhibiting septic shock ever have detect- able endotoxin in plasma. This fact may help to explain the failure of antidotes developed to bind and neutralize circulating toxins. Development of sepsis does not require bacteremia or endovascular infection; toxic products may be released into the bloodstream from localized sites (e.g., abscesses) or directly from the colon (gut translocation), even when viable organisms do not circulate. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) have received the most attention as targets for modifying the septic response because they are potent, rapidly produced inflammatory compounds found in the tissues and circulation of many septic patients (Table 27-3). However, controversy exists regarding the significance of these circulating cyto- kines, and clinical trials designed to lessen levels of these compounds have not reduced mortality. That controversy notwithstanding, these cytokines are major stimulants for generation and release of other mediators, including IL-6, IL-8, enzymes,

prostaglandins, leukotrienes, oxidant radicals, plate- let-activating factor, and nitric oxide. Some activate coagulation (Fig. 27-3). Simultaneously with the dominant proinflammatory agents, anti-inflammatory mediators ramp up their activity. There is growing appreciation that abnormal coagulation is nearly universal in severe sepsis and that a complex interplay exists between clot- ting and inflammation. At the outset of the syn- drome, tissue factor expressed by leukocytes and endothelium and cytokines lead to the production of thrombin by stimulating clotting factors V and VIII. Initially, the natural anticlotting systems (e.g., protein C, protein S, antithrombin) counteract the accelerated clotting. In this process, clotting proteins are consumed forming thrombi, and anti- clotting proteins are depleted trying to inhibit clot formation. Because sepsis also impairs the host’s ability to convert inactive anticlotting precursors to functioning proteins, clotting proceeds unopposed. As a second line of defense, endogenous fibrino- lytic systems (e.g., plasminogen) are activated to dissolve the microvessel clogging thrombi, increas- ing plasma levels of clot degradation products.

Table 27-3.  Experimental and Unverified Therapies for Sepsis Category Proposed Action Result Corticosteroids Nonspecific anti-inflammatory

Multiple failed human trials, possibly increases infection risk Inconsistent data from clinical trials

Replacement of relative adrenal insufficiency

Naloxone

Opioid receptor antagonist

May transiently raise blood pressure, no effect on survival

Cyclooxygenase inhibitors

Reduce thromboxane and prostacyclin Improved vital signs, no effect on survival, overall safe

Antiendotoxins

Inactivate gram-negative toxins

Several failed trials, possible harm suspected from one agent; trials ongoing

IL-1 receptor antagonist

Block IL-1 action Inactivate TNF Block TNF action

No improvement in physiology or survival

TNF antibodies Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproductio of the content is prohibited. No clear benefit

TNF receptor antagonists

Dose-dependent increase in mortality

Antioxidants Prevent oxidant-mediated cellular injury Trials ongoing Toll-like receptor antagonists Block inflammatory signal transduction Positive phase II human trails, studies ongoing Tissue factor pathway inhibitor Inhibit tissue factor activation of coagulation Studies ongoing Activated protein C Antithrombotic, anti-inflammatory serine protease No benefit in several trials. Possible harm

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