Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between pro inflammatory and anti inflammation, 40 patients with septic shock were randomized in a double-blind cross-over study to receive either the first 100 mg of hydrocortisone asimprovea loading dose and 10 mg per hour until Day 3 (n 20) or placebo(n 20), followed by the opposite medication until Day 6.Hydrocortisone infusion induced an increase of mean arterial pressure,systemic vascular resistance, and a decline of heart rate, cardiacindex, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (solubleE-selectin) and neutrophil activation (expression of CD11b, CD64),and anti inflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes,human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. Inconclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of anti inflammation rather than immuno suppression.
During sepsis, the systemic in?ammatory response comprises reciprocal communication between the neuroendocrine and the peripheral immune system (1). Proin?ammatory media¬tors recruit the hypothalamic–pituitary–adrenal axis to counter-regulate in?ammation through the synthesis of the stress hormone cortisol. The fundamental roles of glucocorticoids in stress response to infection and increasing knowledge of the antiin?ammatory and immunosuppressive pharmacody¬namic pro?le have been the rationale for its use in sepsis trials for decades. Timing, dosage, and duration of glucocorticoid administration were adapted to different disease pathophysi¬ologic models and probably had a major impact on outcome (2). Several randomized controlled trials unequivocally revealed that short-time (1 to 2 days) administration of high doses of glucocorticoids (up to 40 g of hydrocortisone equiva¬lent per day) in early septic shock was without effect on outcome or was even harmful—most probably because of immunosuppression and increased incidence of secondary infections (3, 4). Only one study showed an initial improve¬ment of survival and shock reversal with high-dose methyl¬prednisolone, but with ongoing disease, the differences were no longer signi?cant (5).
In contrast to these former approaches, recent randomized controlled trials indicate that prolonged (5 days or more) administration of “low” doses (compared with the doses above) of hydrocortisone (240–300 mg per day) in early or late septic shock improves shock reversal (6, 7) and outcome (8, 9). These results are in agreement with the concept of impaired adrenocortical reserve in septic shock (2, 10–13). However, the diagnosis and predictive value of relative adre¬nal insuf?ciency in septic shock is still a matter of current discussions (14). Although it was reported that shock reversal and outcome were independent from adrenal reserve (8), other reports indicate that the degree of adrenal dysfunction correlates with outcome (15) and that hydrocortisone therapy reduces mortality only in patients with impaired adrenal reserve (9).
Overall, the encouraging results of the recent low-dose hydrocortisone trials evoked a reassessment of the role of glucocorticoids in septic shock. It is well established that glucocorticoids modulate the stress response to sepsis dose dependently through permissive (e.g., enhancing the cardio¬vascular response to vasopressors) and suppressive (e.g., inhi¬bition of cytokine synthesis) effects (16). However, there is little known about the immunologic effects of continuously infused low doses of hydrocortisone in septic shock. In partic¬ular, protection from overshooting in?ammatory response has to be weighted against the risk of aggravated immunosup¬pression, which gained increasing importance in understand¬ing of sepsis pathophysiology and multiple organ failure (17). Because low doses of glucocorticoids are increasingly used as an adjunctive therapy to stabilize blood pressure in septic shock patients, knowledge of immune reactions is of clinical importance to elucidate possible risks accompanied with this therapeutic approach. Therefore, we investigated the effects of a 3-day hydrocortisone treatment on hemodynamic and immunologic parameters, comparing the response with the application and the withdrawal of hydrocortisone in a two-period crossover design.
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