Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Early dexamethasone treatment for septic shock patients: a prospective randomized clinical trial. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. Steroids in the treatment of clinical septic shock. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Effectiveness of betamethasone in management of severe infections. A double-blind study. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Hydrocortisone therapy for patients with septic shock. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. The Veterans Administration Systemic Sepsis Cooperative Study Group. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial.
To investigate the effects of stress doses of hydrocortisone on the duration of vasopressor therapy in human septic shock.
                Prospective, randomized, double-blind, single-center study.
                Twenty-bed multidisciplinary intensive care unit in a 1400-bed university hospital.
                Forty consecutive patients who met the ACCP/SCCM criteria for septic shock. An additional criterion for inclusion in the study was vasopressor support and high-output circulatory failure with a cardiac index of >4 L/min/m2 after fluid resuscitation (pulmonary capillary wedge pressure: 12-15 mm Hg) and without the use of positive inotropes such as dobutamine or dopexamine. The primary study end point was the time to cessation of vasopressor support (norepinephrine or epinephrine in any dose, dopamine > or = 6 microg/kg/min). Secondary study end points were the evolution of hemodynamics and the multiple organ dysfunction syndrome (MODS). The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. MODS was described by the Sepsis-related Organ Failure Assessment score.
                All eligible patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started with a loading dose of 100 mg given within 30 mins and followed by a continuous infusion of 0.18 mg/ kg/hr. When septic shock had been reversed, the dose of hydrocortisone was reduced to 0.08 mg/kg/hr. This dose was kept constant for 6 days. As soon as the underlying infection had been treated successfully or sodium serum concentrations had increased to >155 mmol/L, the hydrocortisone infusion was tapered in steps of 24 mg/day. Physiologic saline solution was the placebo.
                Hemodynamic and oxygen-derived variables were measured at previously defined time points over a study period of 5 days. Relevant clinical and laboratory measurements were registered for a study period of 14 days to assess the evolution of organ dysfunction. Baseline data at recruitment did not differ between the two groups. Shock reversal was achieved in 18 of the 20 patients treated with hydrocortisone vs. 16 of the 20 patients treated with placebo. Hydrocortisone significantly reduced the time to cessation of vasopressor support. The median time of vasopressor support was 2 days (1st and 3rd Quartiles, 1 and 6 days) in the hydrocortisone-treated group and 7 days (1st and 3rd Quartiles, 3 and 19 days) in the placebo group (p = .005 Breslow test). There was a trend to earlier resolution of the organ dysfunction syndrome in the hydrocortisone group.
                Infusion of stress doses of hydrocortisone reduced the time to cessation of vasopressor therapy in human septic shock. This was associated with a trend to earlier resolution of sepsis-induced organ dysfunctions. Overall shock reversal and mortality were not significantly different between the groups in this low-sized single-center study. Preliminary studies have suggested that low doses of corticosteroids might rapidly improve hemodynamics in late septic shock treated with catecholamines. We examined the effect of hydrocortisone on shock reversal, hemodynamics, and survival in this particular setting.
                Prospective, randomized, double-blind, placebo-controlled study.
                Two intensive care units of a University hospital.
                Forty-one patients with septic shock requiring catecholamine for >48 hrs.
                Patients were randomly assigned either hydrocortisone (100 mg i.v. three times daily for 5 days) or matching placebo.
                Reversal of shock was defined by a stable systolic arterial pressure (>90 mm Hg) for > or =24 hrs without catecholamine or fluid infusion. Of the 22 hydrocortisone-treated patients and 19 placebo-treated patients, 15 (68%) and 4 (21%) achieved 7-day shock reversal, respectively, a difference of 47% (95% confidence interval 17% to 77%; p = .007). Serial invasive hemodynamic measurements for 5 days did not show significant differences between both groups. At 28-day follow-up, reversal of shock was higher in the hydrocortisone group (p = .005). Crude 28-day mortality was 7 (32%) of 22 treated patients and 12 (63%) of 19 placebo patients, a difference of 31% (95% confidence interval 1% to 61%; p = .091). Shock reversal within 7 days after the onset of corticosteroid therapy was a very strong predictor of survival. There were no significant differences in outcome in responders and nonresponders to a short corticotropin test. The respective rates of gastrointestinal bleeding and secondary infections did not differ between both groups.
                Administration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock for a mean of >96 hrs resulted in a significant improvement in hemodynamics and a beneficial effect on survival. These beneficial effects do not appear related to adrenocortical insufficiency. To determine the effect of moderate dose dexamethasone administered before antibiotics on the outcome of African children with sepsis.
                The design was a randomized, double blinded, placebo-controlled trial of dexamethasone (0.2 mg/kg) vs. placebo given intravenously before antibiotic therapy. Patients were recruited from the patient populations at two missionary hospitals. Primary outcome variables were determined before analysis of data.
                Seventy-two children with sepsis were enrolled in the study. Treatment with dexamethasone was not associated with improved outcome for any of six outcome variables: survival to discharge (83%, dexamethasone group; 89%, placebo group); hemodynamic stability at 48 h (33%, dexamethasone group; 49%, placebo group); median length of hospital stay (11 days, dexamethasone group; 11 days, placebo group); normal at discharge (90%, dexamethasone group; 75%, placebo group); normal at follow-up (90%, dexamethasone group; 72%, placebo group); and afebrile at 48 to 72 h (61%, dexamethasone group; 44%, placebo group).
                These data indicate that a moderate dose of dexamethasone given before antibiotic therapy did not improve outcome in the pediatric patients with sepsis whom we studied. Sepsis and septic shock are very common conditions among critically ill patients that lead to multiple organ dysfunction syndrome (MODS) and death. Our purpose was to investigate the efficacy of early administration of dexamethasone for patients with septic shock, with the aim of halting the progression towards MODS and death.
                Prospective, randomized, double-blind, single-center study, developed in a surgical intensive care unit at Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo.
                The study involved 29 patients with septic shock. All eligible patients were prospectively randomized to receive either a dose of 0.2 mg/kg of dexamethasone (group D) or placebo (group P), given three times at intervals of 36 hours. The patients were monitored over a seven-day period by means of the sequential organ failure assessment score.
                Patients treated with dexamethasone did not require vasopressor therapy for as much time over the seven-day period as did the placebo group (p = 0.043). Seven-day mortality was 67% in group P (10 out of 15) and 21% in group D (3 out of 14) (relative risk = 0.31, 95% confidence interval 0.11 to 0.88). Dexamethasone enhanced the effects of vasopressor drugs.
                Early treatment with dexamethasone reduced the seven-day mortality among septic shock patients and showed a trend towards reduction of 28-day mortality. We hypothesize that hydrocortisone infusion in severe community-acquired pneumonia attenuates systemic inflammation and leads to earlier resolution of pneumonia and a reduction in sepsis-related complications. In a multicenter trial, patients admitted to the Intensive Care Unit (ICU) with severe community-acquired pneumonia received protocol-guided antibiotic treatment and were randomly assigned to hydrocortisone infusion or placebo. Hydrocortisone was given as an intravenous 200-mg bolus followed by infusion at a rate of 10 mg/hour for 7 days. Primary end-points of the study were improvement in Pa(O(2)):FI(O(2)) (Pa(O(2)):FI(O(2)) > 300 or >/= 100 increase from study entry) and multiple organ dysfunction syndrome (MODS) score by Study Day 8 and reduction in delayed septic shock. Forty-six patients entered the study. At study entry, the hydrocortisone group had lower Pa(O(2)):FI(O(2)), and higher chest radiograph score and C-reactive protein level. By Study Day 8, treated patients had, compared with control subjects, a significant improvement in Pa(O(2)):FI(O(2)) (p = 0.002) and chest radiograph score (p < 0.0001), and a significant reduction in C-reactive protein levels (p = 0.01), MODS score (p = 0.003), and delayed septic shock (p = 0.001). Hydrocortisone treatment was associated with a significant reduction in length of hospital stay (p = 0.03) and mortality (p = 0.009). 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 proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a 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, cardiac index, 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 (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory 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. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression. Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock.
                To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.
                Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999.
                Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test.
                Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.
                Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test).
                One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups.
                In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events. To determine whether corticosteroids are efficacious in severe septic shock, we conducted a prospective study of 59 patients randomly assigned to a methylprednisolone, dexamethasone, or control group. Patients were treated 17.5 +/- 5.4 hours (mean +/- S.E.M.) after the onset of shock, and 55 patients required vasopressor agents. Early in the hospital course, reversal of shock was more likely in patients who received corticosteroids than in those who did not. Four (19 per cent) of 21 methylprednisolone-treated, 7 (32 per cent) of 22 dexamethasone-treated, and none of 16 control patients had reversal of shock 24 hours after drug administration (corticosteroid groups vs. control group, P less than 0.05). Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal (P less than 0.05). At 133 hours after drug administration, 17 (40 per cent) of 43 corticosteroid-treated patients had died, and 11 (69 per cent) of 16 control patients had died (P less than 0.05). However, these differences in reversal of shock and survival disappeared later in the course. Overall, 16 (76 per cent) of 21 patients receiving methylprednisolone, 17 (77 per cent) of 22 patients receiving dexamethasone, and 11 (69 per cent) of 16 controls in the hospital died. We conclude that corticosteroids do not improve the overall survival of patients with severe, late septic shock but may be helpful early in the course and in certain subgroups of patients. A prospective (Part I) and a retrospective (Part II) study were used to determine the safety and efficacy of corticosteroids in the treatment of septic shock. In Part I, 172 consecutive patients in septic shock admitted over an 8-year period were treated with either steroid or saline: 43 received dexamethasone (DMP), 43 received methylprednisolone (MPS), and 86 received saline. The study was double-blind and randomized, and the three groups were compared for age, severity of shock, presence of underlying disease, and year of study. In the 86 saline-treated patients, the mortality rate was 38.4% (33/86); in the steroid-treated patients, it was 10.4% (9/86). With MPS the mortality rate was 11.6% (5/43), and with DMP it was 9.3% (4/43). Thus, overall mortality was significantly less in the steroid-treated group than in the control group. Further, there was no significant difference in mortality rate between the DMP- and the MPS-treated patients. In Part II, 328 patients were studied retrospectively. One-hundred sixty were treated without steroid, and 168 were treated with either DMP or MPS. Again, the two groups of patients were compared for severity of shock, underlying disease, age, and year of study. Mortality among patients treated without steroid was 42.5% (68/160) and among patients treated with steroid was 14% (24/168); there was no significant difference in mortality rate between DMP- and MPS-treated patients. In Parts I and II combined, complications occurred in 6% of steroid-treated patients with no significant difference between DMP- and MPS-treated groups. To determine the effects of low-dose prolonged methylprednisolone infusion on lung function in patients with early severe ARDS.
                Randomized, double-blind, placebo-controlled trial.
                ICUs of five hospitals in Memphis.
                Ninety-one patients with severe early ARDS (</= 72 h), 66% with sepsis.
                Patients were randomized (2:1 fashion) to methylprednisolone infusion (1 mg/kg/d) vs placebo. The duration of treatment was up to 28 days. Infection surveillance and avoidance of paralysis were integral components of the protocol.
                The predefined primary end point was a 1-point reduction in lung injury score (LIS) or successful extubation by day 7.
                In intention-to-treat analysis, the response of the two groups (63 treated and 28 control) clearly diverged by day 7, with twice the proportion of treated patients achieving a 1-point reduction in LIS (69.8% vs 35.7%; p = 0.002) and breathing without assistance (53.9% vs 25.0%; p = 0.01). Treated patients had significant reduction in C-reactive protein levels, and by day 7 had lower LIS and multiple organ dysfunction syndrome scores. Treatment was associated with a reduction in the duration of mechanical ventilation (p = 0.002), ICU stay (p = 0.007), and ICU mortality (20.6% vs 42.9%; p = 0.03). Treated patients had a lower rate of infections (p = 0.0002), and infection surveillance identified 56% of nosocomial infections in patients without fever.
                Methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extrapulmonary organ dysfunction and reduction in duration of mechanical ventilation and ICU length of stay. The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial. Our study was designed as a prospective, randomized, double-blind, placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock. Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia (rectal temperature greater than 38.3 degrees C [101 degrees F] or less than 35.6 degrees C [96 degrees F]), tachypnea (greater than 20 breaths per minute), tachycardia (greater than 90 beats per minute), and the presence of one of the following indications of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels, or oliguria. Three hundred eighty-two patients were enrolled. Treatment--either methylprednisolone sodium succinate (30 mg per kilogram of body weight) or placebo--was given in four infusions, starting within two hours of diagnosis. No significant differences were found in the prevention of shock, the reversal of shock, or overall mortality. In the subgroup of patients with elevated serum creatinine levels (greater than 2 mg per deciliter) at enrollment, mortality at 14 days was significantly increased among those receiving methylprednisolone (46 of 78 [59 percent] vs. 17 of 58 [29 percent] among those receiving placebo; P less than 0.01). Among patients treated with methylprednisolone, significantly more deaths were related to secondary infection. We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock. The effects of massive doses of steroids on septic shock were tested in 48 patients being treated for extensive cellulitis, wet gangrene, or severe peritonitis. From diagnosis until maximum weight gain (average, 47 hours), they received an average of 17.7 L of crystalloid solution and 1.0 L of blood and voided 3.1 L of urine. Of the 48 patients, 23 were selected in random fashion to receive dexamethasone sodium phosphate (6 mg/kg) over 48 hours. The average age (55 years), duration of shock (36 minutes), and insult were similar for both groups. Each group received similar volumes of fluid and blood. Steroid therapy was associated with a statistically significant rise in diastolic pressure (88 v 78 mm Hg), mean arterial pressure (105 v 95 mm Hg), and central venous pressure (16 v 10 cm H2O). Concomitant blood volume was lower in patients treated with steroids (5.2 v 6.1 L). All differences between the two groups disappeared after 48 hours when steroid therapy was discontinued. No differences were noted in morbidity and five patients in each group died. We conducted a prospective, randomized, double-blind study to determine whether high-dose methylprednisolone could prevent parenchymal lung injury, including the adult respiratory distress syndrome (ARDS), or improve mortality when administered early in septic shock. All patients already hospitalized in or newly admitted to the medical and surgical intensive care units at San Francisco General Hospital between September 1, 1983 and August 29, 1986 were eligible for admission to the study if they had either (1) an increase in temperature of 1.5 degrees C and a decrease in systolic blood pressure of 20 mm Hg or more from baseline values (in already hospitalized patients), or (2) a temperature greater than 38.5 degrees C or less than 35.5 degrees C and a systolic blood pressure of less than 90 mm Hg (in newly admitted patients). Patients meeting these criteria were excluded if they (1) had severe immunodeficiency, (2) were less than 18 or greater than 76 yr of age, (3) had multilobar roentgenographic infiltrates, or (4) were already receiving corticosteroids. Eighty-seven patients enrolled in the study received either methylprednisolone, 30 mg/kg per dose, or mannitol placebo for a total of 4 doses every 6 h, following the presumptive diagnosis of septic shock. Of these patients, 75 ultimately were determined on the basis of culture results to have actually had septic shock at the time of entry. Thirteen of the patients who received methylprednisolone developed ARDS, compared to 14 patients who received placebo. Lesser degrees of parenchymal lung injury did not differ between the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS) The aim of the study was to assess the prognostic importance of basal cortisol concentrations and cortisol response to corticotropin, and to determine the effects of physiological dose steroid therapy on mortality in patients with sepsis.
                Basal cortisol level and corticotropin stimulation test were performed within 24 hours in all patients. One group (20 patients) received standard therapy for sepsis and physiological-dose steroid therapy for 10 days; the other group (20 patients) received only standard therapy for sepsis. Basal cortisol level was measured on the 14th day in patients who recovered. The outcome of sepsis was compared.
                Only Sequential Organ Failure Assessment (SOFA) score was found related to mortality, independent from other factors in multivariate analysis. No significant difference was found between the changes in the percentage of SOFA scores of the steroid therapy group and the standard therapy group in survivors, nor between the groups in basal and peak cortisol levels, cortisol response to corticotropin test and mortality. The mortality rates among patients with occult adrenal insufficiencies were 40% in the steroid therapy group and 55.6% in the standard therapy group.
                There was a trend towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy. In the advancing process from sepsis to septic shock, adrenal insufficiency was not frequent as supposed. There was a trend (that did not reach significance) towards a decrease in the mortality rates of the patients with sepsis who received physiological-dose steroid therapy. nan To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock.
                Prospective, randomized, double-blind, single-center study.
                Medical intensive care unit of a university hospital.
                Forty-one consecutive patients with early hyperdynamic septic shock.
                After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score.
                Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p < .02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group.
                Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve. Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin.
                In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test.
                Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock.
                Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.)
                2008 Massachusetts Medical Society We conducted a multicenter randomized, double-blind, placebo-controlled trial of early short-term, high-dose methylprednisolone sodium succinate in 223 patients with clinical signs of systemic sepsis and a normal sensorium (112 received glucocorticoid and 111 placebo). Patients also received antibiotics and intravenous fluids. Glucocorticoid or placebo was administered intravenously by a bolus (30 mg per kilogram of body weight over 15 minutes) followed by infusion of 5 mg per kilogram per hour for nine hours. The average time between the diagnosis of sepsis and infusion was 2.8 hours. The principal end point was 14-day mortality, which was similar in the placebo (22 percent) and glucocorticoid (21 percent) groups (P = 0.97). Mortality was also not significantly different between those receiving placebo and those receiving glucocorticoid in subgroups with evidence of sepsis (21 vs. 19 percent), gram-negative bacteremia (27 vs. 7 percent), gram-positive bacteremia (18 vs. 26 percent), or all gram-negative infections (25 vs. 17 percent). Resolution of secondary infection within 14 days was significantly higher in patients receiving placebo (12 of 23) than in those receiving glucocorticoid (3 of 16) (P = 0.03), but mortality rates were similar in both treatment groups for those with unresolved infection (36 vs. 31 percent). We conclude that early high-dose glucocorticoid therapy does not reduce mortality significantly in patients with systemic sepsis who have a normal sensorium, and therefore should not be used as adjunctive therapy. Corticosteroid therapy induces potentially detrimental hyperglycemia in septic shock. In addition, the benefit of adding fludrocortisone in this setting is unclear.
                To test the efficacy of intensive insulin therapy in patients whose septic shock was treated with hydrocortisone and to assess, as a secondary objective, the benefit of fludrocortisone.
                A multicenter, 2 x 2 factorial, randomized trial, involving 509 adults with septic shock who presented with multiple organ dysfunction, as defined by a Sequential Organ Failure Assessment score of 8 or more, and who had received hydrocortisone treatment was conducted from January 2006 to January 2009 in 11 intensive care units in France.
                Patients were randomly assigned to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone, continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone, conventional insulin therapy with hydrocortisone alone, or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered in a 50-mg bolus every 6 hours, and fludrocortisone was administered orally in 50-microg tablets once a day, each for 7 days.
                In-hospital mortality.
                Of the 255 patients treated with intensive insulin, 117 (45.9%), and 109 of 254 (42.9%) treated with conventional insulin therapy died (relative risk [RR], 1.07; 95% confidence interval [CI], 0.88-1.30; P = .50). Patients treated with intensive insulin experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) than those in the conventional-treatment group, with a difference in mean number of episodes per patient of 0.15 (95% CI, 0.02-0.28; P = .003). At hospital discharge, 105 of 245 patients treated with fludrocortisone (42.9%) died and 121 of 264 (45.8%) in the control group died (RR, 0.94; 95% CI, 0.77-1.14; P = .50).
                Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality.
                clinicaltrials.gov Identifier: NCT00320099.
Overall, corticosteroids did not change mortality in severe sepsis and septic shock. A long course of low dose corticosteroids reduced 28-day mortality without inducing major complications; metabolic disorders were increased.