Endotoxin septic shock

Endotoxins are the lipopolysaccharides (LPS) of the outer membrane of Gram-negative bacteria. They trigger inflammatory reactions in the infected organism, activate complement and cause fever or even a septic shock. They act on toll-like receptors. 

The fluid and protein shift into the abdomen (called third-spacing) may be so dramatic that circulating blood volume is decreased, which causes decreased cardiac output and hypovolemic shock. Accompanying fever, vomiting, or diarrhea may worsen the fluid imbalance. A reflex sympathetic response, manifested by sweating, tachycardia, and vasoconstriction, may be evident. With an inflamed peritoneum, bacteria and endotoxins are absorbed easily into the bloodstream (translocation), and this may result in septic shock. Other foreign substances present in the peritoneal cavity potentiate peritonitis, notably feces, dead tissues, barium, mucus, bile, and blood. 

The alternative pathway may become activated by lipopolysaccharides, endotoxin (sepsis), virus, fungi, immunoglobulin A-antigen (IgA-Ag) immunocom-plexes, and foreign material. These activate C3, after which the common pathway of complement activation takes place (Fig. 4). There are also a number of inhibitors that regulate and control complement activation. The most important are the Cl-esterase inhibitor (Cl-Inh) and the membrane attack complex inhibitor factor (MACIF CD59). In sepsis a relative deficiency of Cl-Inh has been reported. Administration of Cl-Inh to patients with septic shock attenuates complement acti-... 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

Relatively few data are available on the response of ANP to endotoxemia or septic shock. In an ovine model, a 13-fold increase in blood ANP concentration has been found 2 hours after endotoxin administration in a dose of 1.5 pg/kg body weight (LI7). The ANP level remained elevated during the first 6 hours and was associated with marked diuresis and natriuresis and with decreased cardiac output and increased peripheral resistence (LI7). In human studies, a significantly higher ANP blood level was observed in ARDS (E4) and in patients with acute respiratory failure associated with sepsis (M30). In a longitudinal study, we found that plasma ANP levels were increased in patients with sepsis, but the ANP levels showed no relation to the severity of disease or to the presence of shock (B8). 

C5, Cannon, J. G Tompkins, R. G., and Gelfland, J. A., Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J. Infect. Dis. 161, 79-84 (1990). 

E7. Endo, S., Inada, K., Inoue, Y., Kuwata, Y Suzuki, M., Yamashita, H., Hoshi, S and Yoshida, M T vo types of septic shock classified by the plasma levels of cytokines and endotoxin. Circ. Shock 38,264-274(1992). 

The biomedical importance of infections by gram-negative pathogens and the consequences of septic shock have drawn much attention to lipid A, the toxic subcomponent of the lipopolysaccharide endotoxin of these organisms. A comprehensive account of the chemical structures and biological behavior of the lipid A structures is presented here by Zahrihnger, Lindner, and Rietschel. The chapter incorporates much of their own work from the... 

One of the most serious consequences of (Gram-negative) bacterial infection is the possible development of septic shock. This is caused by the release of lipopolysaccharide (LPS endotoxin) from the bacterial cell surface. Various anti-LPS monoclonals (mainly targeted at its lipid A component Chapter 3) have been developed. It is hoped that administration of such monoclonals to affected individuals would effectively mop up free LPS, hence ameliorating the severity of the condition. Most trial results to date have proved disappointing in this regard. 

Endotoxaemia. - Exposure to bacterial endotoxin (lipopolysaccharide) can induce the production of pro-inflammatory mediators (e.g. tumour necrosis factor a and interleukin 1), culminating in septic shock profound vasodilation... 

A bactericidal permeability increasing protein found inside human neutrophils has been investigated as a potent endotoxin neutralizing agent in the treatment of septic shock. It has also been shown to enhance the activity of antibiotics, suggesting a potential use in treating antibiotic-resistant infections (28). 

The absorption of drugs in solution from intramuscular and subcutaneous sites of injection is limited by the perfusion rate. Failure to recognize this important concept has resulted in patient death. For example, morphine sulfate is often administered subcutaneously in a dose of 10 mg per 70 kg of body weight. This dose is sufficient to produce analgesia in 70% of patients with moderate to severe pain. However, in the setting of circulatory collapse and shock (e.g., septic shock in bacteremia due to release of endotoxin) in which the peripheral circulation may be impaired, morphine is not absorbed. Cases have been reported in which the lack of analgesia prompted the additional injection of morphine, all of which remained at the injection site and in the subcutaneous capillary bed. When the peripheral circulation improved, the massive amount of morphine that had collected became absorbed and death ensued, which was primarily due to respiratory depression. 

Ziegler, E.J., Fisher, C.J.Jr, Sprung, C. L. etal. (1991). Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin A randomized, double-blind, placebo-controlled trial. N. Eng.]. Med. 324, 429-436. 

Derkx, B., Wittes, J., McCloskey R. et al. (1999). Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. Clin. Infect. Dis. 28, 770-777. 

Cortiveau, C.C., Danner, R.L. Endotoxin as a therapeutic target in septic shock. Infect Agents Dis 2 (1993) 35-43. 

Keywords Sepsis Septic shock Endotoxin Lipopolysaccharide Lipopolyamine Alkylpolyamine Polymyxin B Pharmacokinetics Pharmacodynamics Cytokine p38MAPK Prodrug... 

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