Endotoxemia and Endotoxin Shock

Disease, Diagnosis and Therapy

C. Ronco, P. Piccinni, M. H. Rosner, Claudio Ronco

• Publisher: S. Karger
• Year: 2010
• Print ISBN:
  9783805594844
• eBook ISBN:
  9783805594851
• Topic: Medicine
• Subtopic: Medical Technology & Supplies

The presence of endotoxin in the bloodstream is the consequence of an immunological response triggered by bacterial invasion of the host. This condition leads to altered cardiovascular function, lung dysfunction and acute kidney injury. Removing as much as possible of the circulating endotoxin is therefore imperative to mitigate its biological and clinical effects at the cellular, tissue and organ levels. The publication at hand summarizes the basic mechanisms, rationale and clinical results of a new therapeutic approach that promises to attain this goal: It consists of a specific hemoperfusion process that utilizes cartridges with immobilized polymixin B in an extracorporeal circuit.Containing contributions by renowned researchers, this book represents as a milestone in the field of extracorporeal therapies in sepsis. It will be a valuable reference work for both basic scientists and clinical professionals who want to keep abreast of current developments.

Endotoxemia: Pathophysiological Background

Ronco C, Piccinni P, Rosner MH (eds): Endotoxemia and Endotoxin Shock: Disease, Diagnosis and Therapy. Contrib Nephrol. Basel, Karger, 2010, vol 167, pp 14–24

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Endotoxins and Other Sepsis Triggers

Steven M. Opal

Infectious Disease Division, Memorial Hospital of Rhode Island, Pawtucket, R.I., USA

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Abstract

Endotoxin, or more accurately termed bacterial lipopolysaccharide (LPS), is recognized as the most potent microbial mediator implicated in the pathogenesis of sepsis and septic shock. Yet despite its discovery well over a century ago, the fundamental role of circulating endotoxin in the blood of most patients with septic shock remains enigmatic and a subject of considerable controversy. LPS is the most prominent 'alarm molecule' sensed by the host's early warning system of innate immunity presaging the threat of invasion of the internal milieu by Gram-negative bacterial pathogens. In small doses within a localized tissue space, LPS signaling is advantageous to the host in orchestrating an appropriate antimicrobial defense and bacterial clearance mechanisms. Conversely, the sudden release of large quantities of LPS into the bloodstream is clearly deleterious to the host, initiating the release of a dysregulated and potentially lethal array of inflammatory mediators and procoagulant factors in the systemic circulation. The massive host response to this single bacterial pattern recognition molecule is sufficient to generate diffuse endothelial injury, tissue hypoperfusion, disseminated intravascular coagulation and refractory shock. Numerous attempts to block endotoxin activity in clinical trials with septic patients have met with inconsistent and largely negative results. Yet the groundbreaking discoveries within the past decade into the precise molecular basis for LPS-mediated cellular activation and tissue injury has rekindled optimism that a new generation of therapies that specifically disrupt LPS signaling might succeed. Other microbial mediators found in Gram-positive bacterial and viral and fungal pathogens are now appreciated to activate many of the same host defense networks induced by LPS. This information is providing novel interventions in the continuing effots to improve the care of septic patients.

Copyright © 2010 S. Karger AG, Basel

Sepsis and the multiorgan failure that frequently accompanies severe infection remains a leading cause of mortality in the intensive care unit [1]. It is estimated that about 650,000 750,000 patients develop sepsis annually in the United States with similar incidences in Europe and around the world [2]. Nearly half of septic patients develop severe sepsis and septic shock. The mortality for septic shock remains approximately 30-45%, despite advances in supportive care and numerous efforts to improve patient outcome [1-3].

The microbiology of sepsis has significantly evolved over the past 25 years. The principal microbial pathogens in the 1970s were enteric Gram-negative bacilli and Pseudomonas aeruginosa. In the late 1980s, a transition to predominantly Gram-positive bacterial pathogens was observed [3]. The rapid transmission and acquisition of antibiotic resistance genes among Gram-positive bacteria, and their propensity to adhere and persist on vascular catheter surfaces and other implantable medical devices have contributed to the increasing incidence of Gram-positive pathogens as a cause of sepsis. Opportunistic fungal pathogens are also increasing in frequency as a cause of sepsis [3].

Remarkably, Gram-negative bacterial pathogens now appear to be staging a comeback as the predominant causative microorganisms of ICU infections in recent surveys [4].

Endotoxin, Microbial Mediators and the Recognition of Sepsis

The consensus working definitions for such clinical terms as sepsis, septic shock, systemic inflammatory response syndrome and multiple organ dysfunction syndrome have been recently updated by the surviving sepsis campaign [2]. These definitions take into account the myriad of infectious agents and microbial mediators implicated in the pathogenesis of sepsis. Actual bloodstream infection by these pathogens at the time sepsis is recognized by the clinician is documented in only about one third of patients, but the evidence of generalized inflammation and procoagulant activity is almost invariably present. The systemic inflammatory response in human sepsis is primarily initiated by micro-bial-derived, highly conserved, macromolecules that feature surface patterns not found in human tissues. The most potent of all the pathogen-associated molecular pattern (PAMP) molecules is bacterial lipopolysaccharide (LPS), also known as endotoxin. A large number of other PAMPs are expressed on Gram-positive bacteria, fungi, parasites and viral pathogens. These molecules serve as ligands for the pattern recognition receptors expressed on immune effector cells known as the Toll-like receptors (TLRs) [5, 6]. A summary of the major pathogen-derived mediators of sepsis and their respective Toll-like receptors (TLRs) is found in table 1.

The TLR family is the most important, but not the only PAMP recognition receptor complex, within the human innate immune system. TLRs are type 1 transmembrane receptors for the detection of LPS and many other microbial mediators, such as peptidoglycan, lipopeptides, flagellins, microbial nucleic acids, multiple fungal cell wall components, viral proteins and lipoteichoic acid. Ten TLRs have been identified by human genome searches thus far [5].

Table 1. PAMPs and DAMPs (danger-associated molecular patterns) and their primary pattern recognition receptors in humans

	Origin	TLR
Bacterial PAMPs
LPS-MD2	Gram-negative bacteria	TLR4
Lipoteichoic acid	Gram-positive bacteria	TLR2^a
Peptidoglycan	Gram-pos./neg. bacteria	TLR2
Triacyl lipopeptides	Gram-pos./neg. bacteria	TLR1/TLR2
Diacyl lipopeptides	Mycoplasma spp.	TLR2/TLR6
Porins, OMPs	Neisseria spp.	TLR2
Flagellin	motile Gram-pos./neg. bacteria	TLR5
CpG DNA	bacteria, some DNA viruses	TLR9
Viral PAMPs
dsRNA	double-stranded RNA virus	TLR3
ssRNA	single-stranded RNA virus	TLR7/8
Fungal PAMPs
Zymosan	Saccharomyces cerevisiae	TLR2/TLR6
Phospholipomannan	Candida albicans	TLR2
Mannan	Candida albicans	TLR4
O-linked mannosyl residues	Candida albicans	TLR4
β-glucans	Candida albicans	TLR2/dectin-1
DAMPs
S 100a proteins	host	RAGE
Heat shock proteins	host	TLR4
Fibrinogen, fibronectin	host	TLR4
Hyaluronan	host	TLR4
Biglycans	host	TLR4
HMGB1	host	TLR4, TLR2
OMP = Outer membrane protein CpG = cytosine-phosphate-guanine motifs RAGE = receptor for advanced glycation endproducts HMGB1 = high mobility group box-1. ^a For detection of LTA from some pathogens TLR6 functions as a coreceptor for TLR2.

Microbial Virulence and the Causative Microorganisms of Sepsis

It is important to recognize that most microorganisms lack the requisite capacity to successfully invade humans. Most encounters between microbes and the human immune system results in rapid inhibition and microbial clearance by our innate and adaptive immune systems. Only a select few microbial pathogens possess a highly organized and sophisticated set of virulence properties needed to evade host defenses, invade tissues and detect stress signals within the host. Pathogens also process a series of delivery systems capable of distributing toxins to their cellular targets [7, 8]. These microorganisms have mechanisms for packaging and exchanging favorable gene arrays (e.g. antibiotic resistance ...

Table of contents

• Cover Page
• Front Matter
• Endotoxin in the Pathogenesis of Sepsis
• Endotoxins and Other Sepsis Triggers
• Rationale of Extracorporeal Removal of Endotoxin in Sepsis: Theory, Timing and Technique
• Extracorporeal Removal of Endotoxin: The Polymyxin B-Immobilized Fiber Cartridge
• Mechanisms of Polymyxin B Endotoxin Removal from Extracorporeal Blood Flow: Molecular Interactions
• Mechanisms of Polymyxin B Endotoxin Removal from Extracorporeal Blood Flow: Hydrodynamics of Sorption
• Endotoxin Removal by Polymyxin B Immobilized Cartridge Inactivates Circulating Proapoptotic Factors
• Polymyxin-B Hemoperfusion and Endotoxin Removal: Lessons from a Review of the Literature
• PMX Endotoxin Removal in the Clinical Practice: Results from the EUPHAS Trial
• Early Management of Endotoxemia Using the Endotoxin Activity Assay and Polymyxin B-Based Hemoperfusion
• Endotoxin Activity Level and Septic Shock: A Possible Role for Specific Anti-Endotoxin Therapy?
• Endotoxin Removal: How Far from the Evidence? From EUPHAS to EUPHRATES
• Endotoxin Removal: How Far from the Evidence? The EUPHAS 2 Project
• Author Index
• Subject Index