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

Abstract

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