Sepsis: from basics to clinical practice - Editorial

Abstract

Severe sepsis and septic shock are common clinical problems from the newborn to elderly people. The patients often need to be treated in intensive care units. The mortality in septic shock is high. It has been estimated that about 150,000 and 200,000 yearly deaths are due to sepsis in the European Union and the United States, respectively. New developments in the treatment possibilities of sepsis have, however, been achieved during the last few years, and it may be easier to tackle this major clinical problem more effectively than before. This issue of the Journal includes a special section on sepsis. In the seven articles, both molecular and clinical aspects are discussed in the light of recent discoveries and modern clinical practice. Animal models for sepsis have revealed promising immunomodulating agents for the treatment of sepsis. Most models for sepsis lack an infectious focus. Many studies have addressed a variety of immunomodulating strategies, but the results have often been discouraging. The differences in the sepsis models as well as their advantages and disadvantages are discussed by Schultz and van der Poll (p. 573±81). They conclude that the use of a combination of models to test new therapeutic agents would be the most likely successful route for preclinical studies. Of the new molecules studied, activated protein C has been shown to be particularly effective in preventing microvascular thrombosis. Dr. Esmon provides a comprehensive review of the biology of the protein C pathway and of the features making it unique in controlling both microvascular coagulation and acute in ammatory response (p. 598±605). The review describes the complex molecular pathways, in which protein C is involved in these two contexts. Recent data suggest that activated protein C reduces the death rate from sepsis. Some concerns have also been raised, and the clinical studies published need further support. Accordingly, several such studies are underway. Another potential concern is the high cost, which may restrict the world-wide use of activated protein C. We may expect that the next few years will clarify the role of activated protein C in clinical practice. Both the in ammatory reaction and concurrent activation of the anti-in ammatory mechanisms in the host are central to the pathophysiology of sepsis. The balance between the two opposing groups of reactions may be critical for the outcome of the sepsis patient. Activated phagocytes and high circulating levels of pro-in ammatory cytokines occur in patients at risk for multi-organ failure. Impaired natural (innate) and adaptive immune reactions also predispose the patients to the development of secondary infections. As well as therapies aiming at modifying the natural course of in ammatory responses, the in ammatory markers may also offer tools for the diagnosis of sepsis and the degree of organ failure associated with it. Takala et al. (p. 614± 23) summarize their own results and provide evidence that markers like CD11b on phagocytes and serum interleukin-8 can discriminate patients at high risk for organ dysfunction. Such discrimination would be useful in targeting treatment for severe infections and in focusing anti-in ammatory therapies on the right type of patients. Severe sepsis is today a common disease accounting for up to 10% of hospital admissions. Dr. Vincent and co-workers give a practical view on sepsis and septic shock covering the supportive measures such as uid resuscitation and vasopressors (p. 606±13). They also review the use of activated protein C in the world-wide PROWESS trial. Three other articles focus on more speci®c issues in the treatment of sepsis, namely the treatment of impaired perfusion of the affected organs (Ruokonen et al. (p. 590±7)), the use of corticosteroids (Chadda and Annane (p. 582± 9)) and the management of meningoccocal disease (Wall (p. 624±34)). The main causes of septic death are multiple organ failure and concurrent hypotension. The treatment of haemodynamics consists of appropriate uid therapy and vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output (Ruokonen et al. (p. 590±7)). While norepinephrine is the drug of choice for low vascular resistance, insuf®cient myocardial function is commonly treated with dobutamine. The use of norepi-