An historical review of glucocorticoid treatment in sepsis. Disease pathophysiology and the design of treatment investigation

摘要: This review provides an historical perspective on events that have shaped our pathophysiological understanding of sepsis during this century and, as a result, influenced the design glucocorticoid treatment trials. A structured format to evaluate clinical investigation in patients with is presented. From early 1950s late 1980s, methodological quality randomized trials improved, while science dictating protocols overlooked prior observations and relied almost exclusively findings experimental model misrepresented human sepsis. As daily dose escalated up 140 fold duration decreased 24-hours or less. Bedside observation was foundation for evaluating response studies, later trials, survival principle outcome measure these reports frequently did not include serial recordings biological, clinical, physiological variables over time. Today, we appreciate excessive activation host defense septic shock acute respiratory distress syndrome (ARDS) may induce noncompensated resistance target organs, thereby negating beneficial suppressive influence inadequately secreted endogenous cortisol. Recent studies shown dysregulated characterized by exaggerated protracted immune cells nuclear factor-kB persistent elevation biological markers (inflammatory cytokine levels, etc.) disease activity Within new sepsis, prolonged increased doses exogenous glucocorticoids theory modify intracellular balance among activated transcription factors, convert initially into regulated one. Supporting evidence provided results recent controlled uncontrolled unresolving ARDS showing associated rapid, significant, sustained reduction circulating levels activity, progressive improvement. No other intervention has yet level evidence.