BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.
METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group).
RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.
CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).
<b>BACKGROUND: </b>Whether hydrocortisone reduces mortality among patients with septic shock is unclear.<b>METHODS: </b>We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.<b>RESULTS: </b>From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia.<b>CONCLUSIONS: </b>Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).
<b>Importance: </b>Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial.<b>OBJECTIVE: </b>To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock.<b>Design, Setting, and Participants: </b>Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock.<b>INTERVENTIONS: </b>Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190).<b>Main Outcomes and Measures: </b>The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]).<b>RESULTS: </b>The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, -4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia.<b>Conclusions and Relevance: </b>Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These findings do not support the use of hydrocortisone in these patients.<b>Trial Registration: </b>clinicaltrials.gov Identifier: NCT00670254.
The aim of our study was to evaluate the clinical impact of the administration of intravenous steroids, alone or in conjunction with drotrecogin-alfa (activated) (DrotAA), on the outcomes in septic shock patients. Methods: We performed a sub-study of the PROWESS-Shock trial (septic shock patients who received fluids and vasopressors above a predefined threshold for at least 4 hours were randomized to receive either DrotAA or placebo for 96 hours). A propensity score for the administration of intravenous steroids for septic shock at baseline was constructed using multivariable logistic regression. Cox proportional hazards model using inverse probability of treatment weighting of the propensity score was used to estimate the effect of intravenous steroids, alone or in conjunction with DrotAA, on 28-day and 90-day all-cause mortality. Results: A total of 1695 patients were enrolled of which 49.5% received intravenous steroids for treatment of septic shock at baseline (DrotAA + steroids N = 436; DrotAA + no steroids N = 414; placebo + steroids N = 403; placebo + no steroids N = 442). The propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo (interaction p-value = 0.38 and p = 0.27, respectively) nor was a difference detected within each randomized treatment. Similarly, the course of vasopressor use and cardiovascular SOFA did not appear to be influenced by steroid therapy. In patients with lung infection (N = 744), abdominal infection (N = 510), Gram-positive sepsis (N = 420) and Gram-negative sepsis (N = 461), the propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo nor was a difference detected within each randomized treatment. Conclusions: In the present study of septic shock patients, after adjustment for treatment selection bias, we were unable to find noticeable positive impact from intravenous steroids for treatment of septic shock at baseline either in patients randomized for DrotAA or placebo. Trial registration: Clinicaltrials.gov NCT00604214. Registered 24 January 2008.
Objective: To observe the effect of low-dose hydrocortisone on the requirement of norepinephrine and lactate clearance in patients with refractory septic shock, and to investigate the effect of stress dose corticosteroids in reversing septic shock and improving tissue oxygen supply. Methods: Seventy-seven septic shock patients with hypotension refractory to fluids and administration of norepinephrine were randomly divided into control and treatment groups. In treatment group intravenous injection of low-dose hydrocortisone was given on top of the treatment given in control group for 14 days. The mean arterial pressure (MAP), lactate clearance and the data of norepinephrine use were compared between two groups during the course of treatment. Results: The number of patients requiring norepinephrine was significantly lower and the MAP was significantly higher in 24 hours, 7 days, 14 days than those at the beginning of treatment in both groups (all P<0.01). Compare to the control group, the course of using norepinephrine was shorter and the number of using norepinephrine was smaller in 7 days in treatment group (both P<0.05) (the MAP and lactate clearance were higher in 24 hours and 7 days in treatment group (P<0.05 or P<0.01). But there were no differences in mortality and the length of stay in intensive care unit (ICU). Conclusion: For the patients with septic shock with refractory hypotension, low-dose hydrocortisone can decrease the time course and dosage of vasopressors, improve tissue oxygen supply, thus can reverse septic shock more rapidly.
BACKGROUND: idrocortisone è ampiamente usato in pazienti con shock settico, anche se un beneficio di sopravvivenza è stata riportata solo in pazienti che sono rimasti hypotensive after fluido e rianimazione vasopressori e la cui livelli plasmatici di cortisolo non aumenterà in modo appropriato dopo la somministrazione di corticotropin.
METODI: In questo studio multicentrico, randomizzato, in doppio cieco, controllato con placebo, abbiamo assegnato 251 pazienti a ricevere 50 mg di idrocortisone per via endovenosa e 248 pazienti a ricevere placebo ogni 6 ore per 5 giorni, la dose è stata poi è diminuito durante un 6 - giorni. A 28 giorni, l'esito primario era la mortalità tra i pazienti che non hanno una risposta a un test corticotropin.
RISULTATI: Dei 499 pazienti nello studio, 233 (46,7%) non ha avuto una risposta alla corticotropin (125 nel gruppo idrocortisone e 108 nel gruppo placebo). A 28 giorni, non vi era alcuna differenza significativa nella mortalità tra i pazienti nei due gruppi di studio che non hanno una risposta alle corticotropin (39,2% nel gruppo Idrocortisone e 36,1% nel gruppo placebo, p = 0,69) o tra coloro che avevano una risposta alla corticotropin (28,8% nel gruppo idrocortisone e 28,7% nel gruppo placebo, P = 1.00). A 28 giorni, 86 su 251 pazienti nel gruppo idrocortisone (34,3%) e 78 di 248 pazienti nel gruppo placebo (31,5%) era morto (P = 0,51). Nel gruppo idrocortisone, shock è stata invertita più velocemente rispetto al gruppo placebo. Tuttavia, ci sono stati più episodi di superinfezione, inclusa la sepsi nuova e shock settico.
CONCLUSIONI: L'idrocortisone non ha migliorato la sopravvivenza o l'inversione di shock nei pazienti con shock settico, sia generale o nei pazienti che non hanno una risposta a corticotropin, anche se idrocortisone affrettò inversione di shock nei pazienti in cui si è invertito shock. (Numero ClinicalTrials.gov, NCT00147004.)
CONTESTO E OBIETTIVO: sepsi e dello shock settico sono condizioni molto comuni tra i pazienti in condizioni critiche che portano alla sindrome da disfunzione d'organo multipla (MODS) e la morte. Il nostro scopo era di esaminare l'efficacia della precoce somministrazione di desametasone per i pazienti con shock settico, con l'obiettivo di arrestare la progressione verso MODS e la morte.
Progettazione e la realizzazione: prospettico, randomizzato, in doppio cieco, unico centro di studio, sviluppato in una unità di terapia intensiva chirurgica presso l'Ospedale das Clínicas, Faculdade de Medicina da Universidade de São Paulo.
Metodi: Lo studio ha coinvolto 29 pazienti con shock settico. Tutti i pazienti eleggibili sono stati prospettici randomizzati a ricevere una dose di 0,2 mg / kg di desametasone (gruppo D) o placebo (gruppo P), tre volte ad intervalli di 36 ore. I pazienti sono stati controllati per un periodo di sette giorni per mezzo del punteggio di valutazione sequenziale insufficienza d'organo.
RISULTATI: I pazienti trattati con desametasone non ha richiesto terapia con vasopressori per tutto il tempo nel periodo di sette giorni come ha fatto il gruppo placebo (p = 0,043). Sette giorni di mortalità è stata del 67% nel gruppo P (10 su 15) e il 21% nel gruppo D (3 su 14) (rischio relativo = 0,31, intervallo di confidenza 95% 0,11-0,88). Desametasone aumentato gli effetti dei farmaci vasopressori.
CONCLUSIONI: Il trattamento precoce con desametasone ha ridotto la sette giorni mortalità tra i pazienti con shock settico e ha mostrato una tendenza verso la riduzione della mortalità a 28 giorni.
Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.
METHODS:
In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group).
RESULTS:
Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.
CONCLUSIONS:
In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).
