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Excerpt
Significant advances in the treatment of many different types of disease processes have occurred over the last several decades. For example, our ability to care for patients who suffer severe injury, develop malignancy, or suffer organ failure and require solid organ or bone marrow transplantation has increased to the point where successful outcome is the norm. The underpinnings of these successes, however, consist of the widespread use of a number of therapeutic modalities. These therapeutic approaches include the use of physiologic monitoring in the intensive care unit to assess the adequacy of fluid resuscitation and tissue oxygenation, ventilatory and metabolic support, various forms of aggressive surgical intervention, chemotherapy for the treatment of malignancy, and immunosuppression for the maintenance of solid organ and bone marrow allograft function. Unfortunately, most if not all of these advances appear to be associated with the unrelenting occurrence of many different types of nosocomial infection. Perhaps this observation is not surprising when one recognizes that these life-prolonging forms of therapy are increasingly being employed in very young and elderly individuals and patients with underlying diseases such as diabetes mellitus, and that certain forms of therapy (e.g., chemotherapy, exogenous immunosuppression) impair endogenous host defenses against infection to a considerable degree. In particular, infection that is associated with what is now termed ``sepsis syndrome'' is associated with significant morbidity and mortality. Virtually every clinical trial recently performed in this area indicates that the mortality rate of this disease process remains approximately 40%. This high mortality rate continues unabated despite the judicious use of potent antimicrobial agents, fluid resuscitation, intensive care, and metabolic support. What can be done to ameliorate the effects of this lethal disease process?
It would seem patent that significant advances in the treatment of sepsis syndrome will be made only after the pathophysiology of the disease process itself is better characterized. Although studies performed in experimental animal models have been helpful in this regard, assessment of data obtained in the clinical setting probably will prove more valuable. Overall, great strides have been made in this area of clinical research over the last several years. Foremost, the pathophysiologic response to systemic infection has been defined such that most investigators now can discuss sepsis syndrome scientifically, using specific criteria as reference points. Concurrently, investigators are attempting to ascertain those factors that are associated with morbidity and mortality. Unfortunately, much more research needs to be undertaken in this area. Thus far, paradigms that seem obvious based on studies performed in experimental animal models or human volunteers have been more difficult to discern in the clinical arena. For example, it has been established that endotoxin administration provokes the release of cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interleukin-8 with subsequent alterations in host physiology ensuing. However, in composite there has been poor correlation of increased cytokine concentrations with mortality in septic patients. This poor correlation probably has occurred for a number of reasons, all of which are related to the complexity of the clinical situation: a) the precise time at which the initial septic insult occurs very rarely is known in an individual patient; b) the magnitude of the insult is unknown; c) individuals assuredly differ in their response to a specific type of insult; d) repeated episodes of infection that provoke cytokine release probably routinely occur in the clinical setting; and e) the sampling frequency will assuredly influence the results.
