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Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective.

ABSTRACT: INTRODUCTION: Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock. METHODS: RCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of Abstracts of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus. RESULTS: Corticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ?1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids. CONCLUSIONS: Although a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.

SUBMITTER: Moran JL

PROVIDER: S-EPMC2945102 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective.

Moran John L JL Graham Petra L PL Rockliff Sue S Bersten Andrew D AD

Critical care (London, England) 20100713 4

<h4>Introduction</h4>Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.<h4>Methods</h4>RCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Contr ...[more]

PMID: 20626892

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Project description:IntroductionThe benefits and use of low-dose corticosteroids (LDCs) in severe sepsis and septic shock remain controversial. Surviving sepsis campaign guidelines suggest LDC use for septic shock patients poorly responsive to fluid resuscitation and vasopressor therapy. Their use is suspected to be wide-spread, but paucity of data regarding global practice exists. The purpose of this study was to compare baseline characteristics and clinical outcomes of patients treated or not treated with LDC from the international PROGRESS (PROmoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis.MethodsPatients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups.ResultsA total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47).ConclusionsWidespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.

Project description:The role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the microcirculation during severe sepsis.Prospective observational study on patients admitted in a 12-beds intensive care unit of a university hospital from July 2010 to December 2011, with severe sepsis and at least two sepsis-induced organ failures occurring within 48 hours from the onset of sepsis, who received an infusion of aPC (24 mcg/kg/h for 96 hours) (aPC group). Patients with contraindications to aPC administration were also monitored (no-aPC group).At baseline (before starting aPC infusion, T0), after 24 hours (T1a), 48 hours (T1b), 72 hours (T1c) and 6 hours after the end of aPC infusion (T2), general clinical and hemodynamic parameters were collected and the sublingual microcirculation was evaluated with sidestream dark-field imaging. Total vessel density (TVD), perfused vessel density (PVD), De Backer score, microvascular flow index (MFIs), the proportion of perfused vessels (PPV) and the flow heterogeneity index (HI) were calculated for small vessels. The perfused boundary region (PBR) was measured as an index of glycocalyx damage. Variables were compared between time points and groups using non parametric or parametric statistical tests, as appropriate.In the 13 aPC patients mean arterial pressure (MAP), base excess, lactate, PaO2/FiO2 and the Sequential Organ Failure Assessment (SOFA) score significantly improved over time, while CI and ITBVI did not change. MFIs, TVD, PVD, PPV significantly increased over time and the HI decreased (p?<?0.05 in all cases), while the PBR did not change. No-aPC patients (n?=?9) did not show any change in the microcirculation over time. A positive correlation was found between MFIs and MAP. TVD, PVD and De Backer score negatively correlated with norepinephrine dose, and the SOFA score negatively correlated with MFIs, TVD and PVD.aPC significantly improves the microcirculation in patients with severe sepsis/septic shock.NCT01806428.

Project description:ObjectivesTo assess the prevalence of immunocompromised diagnoses among children with severe sepsis and septic shock, and to determine the association between immunocompromised diagnoses and clinical outcomes after adjustment for demographics and illness severity.DesignRetrospective multicenter cohort study.SettingEighty-three centers in the Virtual Pediatric Systems database.PatientsChildren with severe sepsis or septic shock admitted to a participating PICU between January 1, 2012, and December 31, 2016.InterventionsNone.Measurements and main resultsAcross 83 centers, we identified 10,768 PICU admissions with an International Classification of Diseases, 9th Revision, Clinical Modification code for severe sepsis or septic shock; 3,021 of these patients (28%) had an immunocompromised diagnosis. To evaluate variation across centers and determine factors associated with PICU mortality, we used mixed-effect logistic regression models. Among patients without hematopoietic cell transplant, congenital immunodeficiency (adjusted odds ratio, 1.90; 95% CI, 1.24-2.92), multiple prior malignancies (adjusted odds ratio, 1.86; 95% CI, 1.15-2.99), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 3.09; 95% CI, 1.91-4.98) were associated with an increased odds of PICU mortality. Among patients with prior hematopoietic cell transplant, liquid malignancy (adjusted odds ratio, 3.15; 95% CI, 2.09-4.74), congenital immunodeficiency (adjusted odds ratio, 6.94; 95% CI, 3.84-12.53), multiple prior malignancies (adjusted odds ratio, 3.54; 95% CI, 1.80-6.95), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 2.79; 95% CI, 1.36-5.71) were associated with an increased odds of PICU mortality. PICU mortality varied significantly by center, and a higher mean number of sepsis patients per month in a center was associated with lower PICU mortality (adjusted odds ratio, 0.94; 95% CI, 0.90-0.98). PICU resource utilization varied by immunocompromised diagnosis and history of hematopoietic cell transplant, and among survivors immunocompromised patients have shorter median PICU length of stay compared with patients without immunocompromised diagnoses (p < 0.001).ConclusionsImmunocompromised diagnoses are present in 28% of children with severe sepsis or septic shock. Multiple prior malignancies, hemophagocytic lymphohistiocytosis, congenital immunodeficiency, and hematopoietic cell transplant are independently associated with an increased odds of PICU mortality in children with severe sepsis or septic shock. Significant variation exists in PICU mortality among centers despite adjustment for immunocompromised diagnoses, known risk factors for sepsis-related mortality, and center-level sepsis volume.

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Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective.

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Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective.

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