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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 in_uenced 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 ~ndings 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 bene~cial suppressive in_uence 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 (in_ammatory 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, signi~cant, 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.

Corticosteroids and ICU Course of Community Acquired Pneumonia in Egyptian Settings

“…The response to hydrocortisone treatment observed in the present study and in other randomized trials of patients with septic shock [28,[38][39][40][41] and severe pneumocystis pneumonia [42] contrasts with the negative findings of older trials. These negative finding may be related to the short duration of treatment [14,15]. Among a number of studies in support of this hypothesis [14], a randomized trial of patients with severe CAP found that a single dose of hydrocortisone (10 mg/kg) before antibiotic administration showed no effect on plasma TNFlevels [43].…”

“…These negative finding may be related to the short duration of treatment [14,15]. Among a number of studies in support of this hypothesis [14], a randomized trial of patients with severe CAP found that a single dose of hydrocortisone (10 mg/kg) before antibiotic administration showed no effect on plasma TNFlevels [43].…”

“…Corticosteroids, the most important natural inhibitors of inflammation, are not always effective in suppressing life-threatening systemic inflammation. The presence of systemic inflammation-induced tissue resistance to glucocorticoids and/or inadequate adrenal output might explain why older clinical trials found no efficacy with a time-limited course of massive doses of glucocorticoids [14,15]. On the other hand, other studies have shown that prolonged treatment with moderate doses of corticosteroids might improve intracellular down-regulation of inflammatory cytokine transcription and hasten the resolution of the illness [16,17].…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…There are many variables to consider, including the type of GC to be used, timing, dosage, mode of delivery, co-interventions, duration, and tapering. Over the last 40 years, multiple randomized trials investigating GC treatment in critical illness have clearly shown that the design of a treatment protocol has a profound impact on treatment response and outcome (304,305). The CONSORT (306) and GRADE (307) systems, while useful in evaluating the quality of a randomized trial, unfortunately lack a position on two fundamental elements of a trial design, namely the disease pathophysiology and the pharmacological principles applicable to the investigated drug.…”

Guía de práctica clínica para el diagnóstico y tratamiento de la sepsis en el servicio de urgencias de adultos

“…El papel fundamental de los esteroides en la sepsis se consideró originalmente con base en su perfil farmacodinámico como inmunosupresores y antiinflamatorios. 98 La dosificación y la duración de la terapia han sido motivo de muchos estudios, y con base en sus resultados hay varios elementos para resaltar:…”