Effects of hydrocortisone stress-dose therapy in septic shock (part I): influence on hemodynamic stability and plasma nitrite/nitrate levels

A renaissance of the `glucocorticoid discussion' emerged during the last years with reports of `stress dose' or `low-dose' hydrocortisone (HO replacement therapy in patients with septic shock, assuming relative adrenal insufficiency, improving hemodynamic stability, modulating the inflammatory response, and probably improving outcome [1,2]. Here we present results from an interim analysis for the first 20 patients enrolled in a double blinded, randomized, placebo controlled, cross-over study to investigate the effects of HC infusion on 40 patients in septic shock [3] who needed norepinephrine (NE) for hemodynamic support. Patients were randomized to receive either HC 10 mg/h after an initial bolus of 100 mg, or placebo (PL). After 3 days, the medication was switched, i.e. patients who had HC for the first 3 days received PL for another 3 days, and vice versa. Plasma nitrite/nitrate (Griess reaction) was measured before the study and daily for 6 days, hemodynamic monitoring was performed before and every 8 h throughout the study period. No differences between the two group were found for age, sex, cause of sepsis, and severity of illness at time of study entry established by SAPS II and SOFA. HC treatment allowed marked reduction of NE infusion within 48 h after study began (Fig. 1). Systemic vascular resistance (SVR) increased with HC infusion but remained unchanged in the PL-group during the first study period (Fig. 2). When HC was switched to the other group, SVR decreased despite increased NE requirement in patients who received HC before, whereas in the other group SVR increased and NE could be reduced. Mean arterial blood pressure, but not cardiac index, paralleled changes of SVR. Plasma nitrite/nitrate decreased with HC infusion, indicating suppression of endogenous nitric oxide (NO) production (Fig. 3). Interestingly, rebound phenomenon after cessation of HC was not accompanied by increased nitrite/nitrate concentrations.

Conclusions

In patients with septic shock, stress-dose HC infusion improves hemodynamic stability, reduces NE, requirement and increases SVR. Improvement of SVR may be due to HC-induccd suppression of inducible NO synthases (iNOS) and/or suppression of the synthesis of iNOS stimulating cytokines. Cessation of HC. infusion induces rebound effects which seem to be NO-independent.

Figure 1-3.

Norepinephrine administration (1), systemic vascular resistance (SVR) (2), and plasma nitrite/nitrate concentrations (3) in patients with septic shock who received stress-dose hydrocortisone (HC) therapy (see text). Day 0: values before study. Triangles, HC during day 1-3; squares, HC during day 4-6. Note that the medication was switched on day 3. Data are presented as mean ± SEM, n = 10 for each data point.