JAC Sup-B 13-Finch

Serious sepsis is a major medical problem. Studies from the USA and Europe attest to its importance and possibly increasing incidence. Annually, an estimated 400,000– 600,000 persons develop sepsis in the USA and, of these, approximately 35% die. Although surgery, transplantation, cytotoxic chemotherapy, immunomodulation and other advances in the management of disease increase longevity, these techniques are often complicated by sepsis. Pre-existing disease of the heart, lungs, kidneys, liver and other organs clearly predisposes to infection and sepsis. It is also clear that current management strategies for dealing with serious sepsis have intrinsic limitations. Despite the plethora of available antibiotics, the mortality rate for Gram-negative bacteraemia complicated by shock ranges from 50% to 80%, while the increasing problem of drug resistance is further threatening our ability to deal effectively with this infection. The economic burden of serious sepsis is enormous but poorly defined. The past decade has witnessed impressive advances in our knowledge of the pathophysiology of sepsis. 7 The role of microbial products such as endotoxin and peptidoglycan have been extensively investigated. Likewise, the host response to sepsis at the cellular and molecular level is better understood. Clarification of host cytokine expression, interaction and regulation has rapidly led to opportunities for novel therapeutic intervention. These and other investigational approaches are summarized in Table I. Some will be discussed further in relation to the problems and pitfalls that have arisen when these interventions have been studied in clinical trials. In parallel with advances in knowledge concerning the basic science of sepsis has been the recognition that clinical definitions of disease expression and severity assessment are essential for an accurate and reproducible evaluation of host response to sepsis. The standardization of terms such as sepsis, sepsis syndrome, septic shock and refractory septic shock has been a significant advance and has been complemented by the introduction of such terms as the ‘systemic inflammatory response’ and ‘multiple organ dysfunction syndrome’. Likewise severity and chronic health indices such as the acute physiology and chronic health evaluation (APACHE) scoring systems have been widely adopted as indicators of severity and prognosis and