Infectious disease clinics of North America
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Infect. Dis. Clin. North Am. · Jun 1999
ReviewClinical trials for severe sepsis. Past failures, and future hopes.
Recent clinical trials with experimental immunotherapeutic agents for severe sepsis and septic shock have been largely unsuccessful despite seemingly convincing preclinical evidence of significant benefit of these antisepsis therapies. This article reviews basic therapeutic rationale, preclinical evaluation, and clinical trial design of past clinical trials of innovative sepsis treatments. Lessons learned from past failures should provide insights into the design and implementation of successful clinical trials for new anti-sepsis agents in the future.
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The treatment of severe sepsis and septic shock remains a challenge as we approach the next millennium. Although more attention is being given to guidelines and care pathways for sepsis, these are unfortunately based primarily on consensus opinion. Additional research into supportive interventions in this potentially devastating disease is needed. ⋯ A wide variety of adrenergic agents may be useful in sepsis. Initial therapy for hypoperfusion, however, should be targeted toward establishing adequate intravascular volume and left ventricular preload. Adjunctive therapy to prevent complications during the intensive care unit stay is important.
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As a result of better understanding of pathogenesis, new definitions of sepsis have been proposed, and the complexity of this syndrome is clearer. Population-based studies of bloodstream infections--what now is called sepsis--have helped us to understand the natural history of this very frequent problem. The mortality and morbidity of each of the systemic inflammatory response syndrome stages have been described; our ability to better understand and predict these stages will help us to make better therapeutic decisions.
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Any delay in the management of infection is deleterious, especially in patients whose illness is severe. It is of paramount importance to shorten this delay. This article emphasizes the different ways to reach this goal, including the use of new biologic markers, such as cytokines or procalcitonin.
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In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L-arginine. The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult. Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states. This article reviews the biology of NO in sepsis and discusses strategies for neutralization of the increased NO production, in the setting of severe sepsis and septic shock.