Adjunctive therapies in a clinical revelant ovine model of septic shock

Sepsis has been defined as a systemic response to an infection. With an incidence of 3 per 1000 population per year or about 750 000 cases a year, this syndrome ranks as the 10th leading cause of death in the United States (1). Increasing severity of sepsis correlates with increasing mortality, which rises from 30-40% for severe sepsis up to 40-60% for septic shock. This thesis examines the effectiveness of adjunctive therapies, including activated protein C, hypercapnia and acidosis, and sodium selenite, in a clinically relevant ovine model of septic shock. The results from these studies can provide valuable information for future clinical trials on sepsis. This thesis is divided into four sections: 1) sepsis overview; 2) an autologous fecal peritonitis model in sheep and its evaluation; 3) the series of studies on adjunctive therapeutics; and 4) ongoing studies and future perspective. In the first section, a broad overview gives a rough introduction to delineate many aspects of sepsis syndrome such as terminology, etiology, epidemiology, pathophysiology and current guidelines for management. Hemodynamics in sepsis are especially elaborated since these are major observations throughout the studies presented later. In the second section, the general characteristics of the sepsis models used in this thesis are elucidated. Data on hemodynamics, lung mechanics, gas exchange, etc. are presented to feature the ovine peritonitis model. The results of laboratory examinations for hematology, coagulation, bacteriology, biochemistry and hormonology are also presented. And then, I review currently used sepsis models with regards to their advantages and disadvantages. The third section discusses three studies with their objectives, the methods used, the major findings, and the potential clinical implications. 9 1) Beneficial effects of recombinant human activated protein C in experimental septic shock. Activated protein C has a multitude of beneficial effects in severe sepsis and septic shock, including anti-inflammation, anti-coagulation, profibrinolysis, anti-apoptosis and endothelial protection. A clinical Phase III trial demonstrated that the administration of recombinant human activated protein C improved survival in patients with severe sepsis. However, doubts on the protective effects of activated protein C have persisted and been refueled by the recently published negative trials in less severely ill patients and in children. In the light of these ambiguities and uncertainties, we reinvestigated the effects of activated protein C in experimental septic shock. 2) Acute hypercapnia improves indices of tissue oxygenation more than dobutamine in septic shock. Hepercapnia has been found to possess beneficial effects in diverse acute inflammatory states independent of protective lung mechanics. To prove the hypothesis that acute hypercapnia has similar or superior hemodynamic effects to those of a dobutamine infusion, which may be particularly relevant in the presence of hemodynamic instability associated with respiratory failure, we investigated the effects of hypercapnia, which induced by inspiring extrinsic carbon dioxide in experimental septic shock. 3) High bolus dose of sodium selenite prolongs survival in an ovine model of septic shock. Selenite has both pro- and anti-oxidant effects. The administration of high dose sodium selenite may improve survival in septic shock patients. The benefit may be greater with the administration of a bolus (to achieve higher concentrations) rather than a continuous infusion. To test this hypothesis, we examined the effects of a high dose bolus administration of sodium selenite in experimental septic shock. The fourth and final section talks about currently ongoing studies and offers some perspective on future direction.