CLINICAL DETECTION OF LPS AND ANIMAL-MODELS OF ENDOTOXEMIA

The interest in the study of endotoxemia in the clinical area has incr eased recently as a result of a) improved and simplified endotoxin det ermination e.g. chromogenic-kinetic microplate methods (also an improv ed blood sampling tool is available), b) incidence of sepsis has incre ased due to improvement in early (e.g. posttraumatic) survival, c) int erest in and good evidence for gut translocation as a source of endoto xemia, d) agents have developed, which can antagonize endotoxins. Ther e is evidence that patients with positive endotoxin test in the ICU ha ve a higher incidence of organ failure. To study the pathophysiologica l consequences of endotoxemia and possible ways of intervention animal models are necessary. The choice of the experimental setting depends on the aim of the study e.g. whether prolonged observation is necessar y in survival studies or whether hemodynamic variables have to be meas ured or whether therapeutic agents only crossreact with primates. Sinc e LPS levels are quite low in clinical studies, an important factor fo r selection of a relevant animal might be LPS sensitivity, or the use of additional sensitization techniques e.g. galactosamine. Another imp ortant aspect in this context is whether LPS is given as bolus or infu sed up to several days. In this review the dose, time, and route of LP S administration is also discussed. For screening purposes rodents are usually used, or sometimes rabbits due to their higher LPS sensitivit y. Another very sensitive animal model is the sheep, which can be chro nically instrumented and as a specialty allows lung lymph drainage and thus studies of LPS effects on pulmonary permeability. Pigs are used for hemodynamic studies and often in therapeutical studies if species- specificity of the drug tested is not important, in cases where a larg e animal is necessary. Finally the non-human primates offer a number o f advantages due to human-like physiology, due to the cross-reactivity of human assay systems and accordingly also cross-reactivity of human therapeutic agents. While the chimpanzee also shares the LPS sensitiv ity of humans, baboons are insensitive like rodents. Thus each model s erves to provide some useful purpose and the selection must be made to meet the requirements of the specific questions to be asked, with spe cial emphasis of the chosen endotoxin model on relevance for the human sepsis state.