The prevalence of sepsis-induced coagulopathy in patients with sepsis - a secondary analysis of two German multicenter randomized controlled trials.

BACKGROUND: Sepsis and septic shock are frequently accompanied by coagulopathy. Since the sepsis-induced coagulopathy (SIC) score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, however, SIC prevalence in patients fulfilling sepsis criteria according to the third international consensus definition (SEPSIS-3) has not yet been evaluated. METHODS: The Critical Care Trials Group of the German Sepsis Competence Network (SepNet) conducted a secondary analysis of two randomized controlled trials. Only patients fulfilling sepsis criteria according SEPSIS-3 were included in this secondary analysis. In a two step approach, SIC prevalence was determined in 267 patients with sepsis but not septic shock (at the time of inclusion) from the "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis" (HYPRESS) trial. Then, we estimated SIC prevalence in 1,018 patients from the "Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock" (SISPCT) trial using a simplified SIC score based on the platelet-SIC-subscore (PSSC). Study aims were to assess (i) the prevalence of SIC in patients with SEPSIS-3, (ii) the association of SIC with 90-day mortality and morbidity, (iii) the time when patients become SIC positive during the course of sepsis, and (iv) the value of the PSSC for predicting SIC. RESULTS: In the HYPRESS trial, SIC prevalence was 22.1% (95% confidence interval [CI] 17.5-27.5%). The estimated SIC prevalence in the SISPCT trial was 24.2% (95% CI 21.6-26.9%). In the HYPRESS trial, SIC was associated with significantly higher 90-day mortality (13.9% vs. 26.8%, p = 0.027) and morbidity. Logistic regression analysis adjusted for age, sex, treatment arm, and (SIC-adapted) SOFA score confirmed the negative association of SIC with survival (p = 0.011). In the SISPCT trial, increased PSSCs were associated with higher 90-day mortality (PSSC 0: 34.4%, PSSC 1: 40.5%, PSSC 2: 53.3%; p < 0.001). In both trials, SIC was already present at sepsis diagnosis or occurred during the following 4 days. CONCLUSIONS: SIC is a clinically relevant complication of sepsis. Although it might be less frequent than previously reported, its occurrence is associated with higher morbidity and mortality and should be interpreted as an early warning sign.

Patient-Level Meta-Analysis of Low-Dose Hydrocortisone in Adults with Septic Shock.

Low-Dose Hydrocortisone and Septic ShockCorticosteroids have been evaluated as a therapy for septic shock for more than 50 years. However, uncertainty persists about their effects on mortality. Pirracchio and colleagues undertake a patient-level meta-analysis to answer this important question.

Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study.

RATIONALE: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. OBJECTIVES: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. METHODS: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. CONCLUSIONS: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .

Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock.

Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.

Treatment and Mortality of Hemophagocytic Lymphohistiocytosis in Adult Critically Ill Patients: A Systematic Review With Pooled Analysis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis is a cytokine release syndrome caused by uncontrolled immune activation resulting in multiple organ failure and death. In this systematic review, we aimed to analyze triggers, various treatment modalities, and mortality in critically ill adult hemophagocytic lymphohistiocytosis patients. DATA SOURCES: MEDLINE database (PubMed) at October 20, 2019. STUDY SELECTION: Studies and case series of patients greater than or equal to 18 years old, of whom at least one had to be diagnosed with hemophagocytic lymphohistiocytosis and admitted to an ICU. DATA EXTRACTION: Source data of studies and case series were summarized and analyzed on an individual basis. Multivariable logistic regression analysis was performed adjusting for age, sex, and trigger groups. Each single treatment agent was entered as a dichotomous variable to determine treatments associated with survival, regardless if given alone or in combination. DATA SYNTHESIS: In total, 661 patients from 65 studies and case series were included. Overall mortality was 57.8%. Infections were the most frequent trigger (49.9%), followed by malignancies (28.0%), autoimmune diseases (12.1%), unknown triggers (9.4%), and drugs (0.6%). Treatment with IV immunoglobulins was associated with improved survival (odds ratio, 0.548; 95% CI, 0.337-0.891; p = 0.015), while treatment with cyclosporine was associated with increased risk of death (odds ratio, 7.571; 95% CI, 3.702-15.483; p < 0.001). Considering different trigger groups separately, same results occurred only for infection-triggered hemophagocytic lymphohistiocytosis. No information was available on disease severity and other confounding factors. CONCLUSIONS: Mortality of hemophagocytic lymphohistiocytosis in the ICU is high. Most common triggers were infections. Results of survival analyses may be biased by treatment indication and disease severity. Future studies prospectively investigating treatment tailored to critically ill hemophagocytic lymphohistiocytosis patients are highly warranted.

Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare though often fatal hyperinflammatory syndrome mimicking sepsis in the critically ill. Diagnosis relies on the HLH-2004 criteria and HScore, both of which have been developed in pediatric or adult non-critically ill patients, respectively. Therefore, we aimed to determine the sensitivity and specificity of HLH-2004 criteria and HScore in a cohort of adult critically ill patients. METHODS: In this further analysis of a retrospective observational study, patients ≥ 18 years admitted to at least one adult ICU at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with hyperferritinemia of ≥ 500 µg/L were included. Patients' charts were reviewed for clinically diagnosed or suspected HLH. Receiver operating characteristics (ROC) analysis was performed to determine prediction accuracy. RESULTS: In total, 2623 patients with hyperferritinemia were included, of whom 40 patients had HLH. We found the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria (95.0% sensitivity and 93.6% specificity) and HScore cutoff of 168 (100% sensitivity and 94.1% specificity). By adjusting HLH-2004 criteria cutoffs of both hyperferritinemia to 3000 µg/L and fever to 38.2 °C, sensitivity and specificity increased to 97.5% and 96.1%, respectively. Both a higher number of fulfilled HLH-2004 criteria [OR 1.513 (95% CI 1.372-1.667); p <  0.001] and a higher HScore [OR 1.011 (95% CI 1.009-1.013); p <  0.001] were significantly associated with in-hospital mortality. CONCLUSIONS: An HScore cutoff of 168 revealed a sensitivity of 100% and a specificity of 94.1%, thereby providing slightly superior diagnostic accuracy compared to HLH-2004 criteria. Both HLH-2004 criteria and HScore proved to be of good diagnostic accuracy and consequently might be used for HLH diagnosis in critically ill patients. CLINICAL TRIAL REGISTRATION: The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Hyperferritinemia in Critically Ill Patients.

OBJECTIVE: Hyperferritinemia is frequently seen in critically ill patients. A rather rare though life-threatening condition related to severely elevated ferritin is hemophagocytic lymphohistiocytosis. We analyze ferritin levels to differentiate hemophagocytic lymphohistiocytosis from other causes of hyperferritinemia in a mixed cohort of critically ill patients. DESIGN: Retrospective observational study. SETTING: Adult surgical, anesthesiologic, and medical ICUs of a university hospital. PATIENTS: Critical care patients (≥ 18 yr old) admitted to any of the adult ICUs at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with at least one ferritin value and hyperferritinemia (≥ 500 µg/L). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized into hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other diagnoses. These were further categorized into 17 subgroups. Hemophagocytic lymphohistiocytosis diagnosis was based on Hemophagocytic Lymphohistiocytosis-2004 criteria and the HScore. Of 2,623 patients with hyperferritinemia, 40 were considered to have hemophagocytic lymphohistiocytosis (1.52%). Maximum ferritin levels were highest in hemophagocytic lymphohistiocytosis patients compared with all other disease groups (each p < 0.001). Sepsis and septic shock patients had higher maximum ferritin levels than patients with other diagnoses (each p < 0.001). A maximum ferritin value of 9,083 µg/L was at 92.5% sensitivity and 91.9% specificity for hemophagocytic lymphohistiocytosis (area under the curve, 0.963; 95% CI, 0.949-0.978). Of all subgroups with other diagnoses, maximum ferritin levels were highest in patients with varicella-zoster virus, hepatitis, or malaria (median, 1,935, 1,928, and 1,587 µg/L, respectively). Maximum ferritin levels were associated with increased in-hospital mortality (odds ratio, 1.518 per log µg/L [95% CI, 1.384-1.665 per log µg/L]; p < 0.001). CONCLUSIONS: This is the largest study of patients with ferritin available in a mixed ICU cohort. Ferritin levels in patients with hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other conditions were distinctly different, with the highest ferritin levels observed in hemophagocytic lymphohistiocytosis patients. Maximum ferritin of 9,083 µg/L showed high sensitivity and specificity and, therefore, may contribute to improved diagnosis of hemophagocytic lymphohistiocytosis in ICU. The inclusion of ferritin into the sepsis laboratory panel is warranted.

Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH), an uncontrolled overactivation of the immune system, is well characterized in pediatric patients, yet, much less is known about this life-threatening condition in adult patients. As HLH is often complicated by organ failure, patients will require admission to the intensive care unit for organ support therapy. However, recognition of HLH patients in the intensive care unit (ICU) is challenged by the clinical overlap with sepsis. Here, we analyze HLH patients to better understand its clinical presentation, diagnosis, and treatment. METHODS: For the purpose of this retrospective observational study, we searched for suspected and diagnosed adult HLH of all patients admitted to at least one adult surgical, anesthesiological or medical ICU between January 2006 and August 2018 at the university hospital Charité - Universitätsmedizin Berlin. All cases were reviewed by two HLH experts, who confirmed or declined the diagnosis. RESULTS: Of 6,340 ICU patients with ferritin measurement, 40 suffered from HLH (0.63%). Of these, in-hospital mortality was 60.0% over all cases, which was highest in malignancy-associated HLH (71.4%). Infections were identified as most common triggers (42.5%). A variety of 19 different treatment strategies were applied. Non-survivors showed higher ferritin at diagnosis compared with survivors (P = 0.021), which was also seen in multivariable analyses. A minimum ferritin of 4083 µg/L after diagnosis was most predictive for 30-day mortality (AUC 0.888, 95% CI 0.771-1.000; sensitivity 93.8%, specificity 78.9%). CONCLUSIONS: Mortality in adult HLH patients in the ICU is high, particularly in malignancy-associated HLH. Infections are the most frequent HLH triggers in critically ill patients. At present, there is no standardized treatment for HLH in adult patients available. Assessment of ferritin is valuable for diagnosis, prognosis, and treatment monitoring. TRIAL REGISTRATION: The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Corticosteroids for treating sepsis in children and adults.

BACKGROUND: Sepsis occurs when an infection is complicated by organ failure. Sepsis may be complicated by impaired corticosteroid metabolism. Thus, providing corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and 2015 prior to this update. OBJECTIVES: To examine the effects of corticosteroids on death in children and adults with sepsis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, ISRCTN, and the WHO Clinical Trials Search Portal, on 25 July 2019. In addition, we conducted reference checking and citation searching, and contacted study authors, to identify additional studies as needed. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of corticosteroids versus placebo or usual care (antimicrobials, fluid replacement, and vasopressor therapy as needed) in children and adults with sepsis. We also included RCTs of continuous infusion versus intermittent bolus of corticosteroids. DATA COLLECTION AND ANALYSIS: All review authors screened and selected studies for inclusion. One review author extracted data, which was checked by the others, and by the lead author of the primary study when possible. We obtained unpublished data from the authors of some trials. We assessed the methodological quality of trials and applied GRADE to assess the certainty of evidence. Review authors did not contribute to assessment of eligibility and risk of bias, nor to data extraction, for trials they had participated in. MAIN RESULTS: We included 61 trials (12,192 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Nine studies are ongoing and will be considered in future versions of this review. We judged 19 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably slightly reduce 28-day mortality (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.84 to 0.99; 11,233 participants; 50 studies; moderate-certainty evidence). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 6236 participants; 7 studies; low-certainty evidence) and probably slightly reduce hospital mortality (RR 0.90, 95% CI 0.82 to 0.99; 8183 participants; 26 trials; moderate-certainty evidence). Corticosteroids reduced length of intensive care unit (ICU) stay for all participants (mean difference (MD) -1.07 days, 95% CI -1.95 to -0.19; 7612 participants; 21 studies; high-certainty evidence) and resulted in a large reduction in length of hospital stay for all participants (MD -1.63 days, 95% CI -2.93 to -0.33; 8795 participants; 22 studies; high-certainty evidence). Corticosteroids increase the risk of muscle weakness (RR 1.21, 95% CI 1.01 to 1.44; 6145 participants; 6 studies; high-certainty evidence). Corticosteroids probably do not increase the risk of superinfection (RR 1.06, 95% CI 0.95 to 1.19; 5356 participants; 25 studies; moderate-certainty evidence). Corticosteroids increase the risk of hypernatraemia (high-certainty evidence) and probably increase the risk of hyperglycaemia (moderate-certainty evidence). Moderate-certainty evidence shows that there is probably little or no difference in gastroduodenal bleeding, stroke, or cardiac events, and low-certainty evidence suggests that corticosteroids may result in little to no difference in neuropsychiatric events. Continuous infusion of corticosteroids versus intermittent bolus We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration. Three studies reported data for this comparison, and the certainty of evidence for all outcomes was very low. AUTHORS' CONCLUSIONS: Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day and hospital mortality among patients with sepsis. Corticosteroids result in large reductions in ICU and hospital length of stay (high-certainty evidence). There may be little or no difference in the risk of major complications; however, corticosteroids increase the risk of muscle weakness and hypernatraemia, and probably increase the risk of hyperglycaemia. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.

Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol.

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS: The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. ETHICS AND DISSEMINATION: The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité - Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03510650.

Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial.

Importance: 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. Objective: To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock. Design, Setting, and Participants: 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. Interventions: 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). Main Outcomes and Measures: 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]). Results: 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. Conclusions and Relevance: 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. Trial Registration: clinicaltrials.gov Identifier: NCT00670254.

Corticosteroids for treating sepsis.

BACKGROUND: Sepsis occurs when an infection is complicated by organ failures as defined by a sequential organ failure assessment (SOFA) score of two or higher. Sepsis may be complicated by impaired corticosteroid metabolism. Giving corticosteroids may benefit patients. The original review was published in 2004 and was updated in 2010 and again in 2015. OBJECTIVES: To examine the effects of corticosteroids on death at one month in patients with sepsis, and to examine whether dose and duration of corticosteroids influence patient response to this treatment. SEARCH METHODS: We searched the Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (October 2014), EMBASE (October 2014), Latin American Caribbean Health Sciences Literature (LILACS; October 2014) and reference lists of articles, and we contacted trial authors. The original searches were performed in August 2003 and in October 2009. SELECTION CRITERIA: We included randomized controlled trials of corticosteroids versus placebo or supportive treatment in patients with sepsis. DATA COLLECTION AND ANALYSIS: All review authors agreed on the eligibility of trials. One review author extracted data, which were checked by the other review authors, and by the primary author of the paper when possible. We obtained some missing data from trial authors. We assessed the methodological quality of trials. MAIN RESULTS: We identified nine additional studies since the last update, for a total of 33 eligible trials (n = 4268 participants). Twenty-three of these 33 trials were at low risk of selection bias, 22 were at low risk of performance and detection bias, 27 were at low risk of attrition bias and 14 were at low risk of selective reporting.Corticosteroids reduced 28-day mortality (27 trials; n = 3176; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 1.00; P value = 0.05, random-effects model). The quality of evidence for this outcome was downgraded from high to low for imprecision (upper limit of 95% CI = 1) and for inconsistency (significant heterogeneity across trial results). Heterogeneity was related in part to the dosing strategy. Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (22 trials; RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01, fixed-effect model). The quality of evidence was downgraded from high to moderate for inconsistency (owing to non-significant effects shown by one large trial). Corticosteroids also reduced mortality rate in the intensive care unit (13 trials; RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04, random-effects model) and at the hospital (17 trials; RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03, random-effects model). Quality of the evidence for in-hospital mortality was downgraded from high to moderate for inconsistency and imprecision (upper limit of 95% CI for RR approaching 1). Corticosteroids increased the proportion of shock reversal by day seven (12 trials; RR 1.31, 95% CI 1.14 to 1.51; P value = 0.0001) and by day 28 (seven trials; n = 1013; RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) and reduced the SOFA score by day seven (eight trials; mean difference (MD) -1.53, 95% CI -2.04 to -1.03; P value < 0.00001, random-effects model) and survivors' length of stay in the intensive care unit (10 trials; MD -2.19, 95% CI -3.93 to -0.46; P value = 0.01, fixed-effect model) without inducing gastroduodenal bleeding (19 trials; RR 1.24, 95% CI 0. 92 to 1.67; P value = 0.15, fixed-effect model), superinfection (19 trials; RR 1.02, 95% CI 0.87 to 1.20; P value = 0.81, fixed-effect model) or neuromuscular weakness (three trials; RR 0.62, 95% CI 0.21 to 1.88; P value = 0.40, fixed-effect model). Corticosteroid increased the risk of hyperglycaemia (13 trials; RR 1.26, 95% CI 1.16 to 1.37; P value < 0.00001, fixed-effect model) and hypernatraemia (three trials; RR 1.64, 95% CI 1.28 to 2.09; P value < 0.0001, fixed-effect model). AUTHORS' CONCLUSIONS: Overall, low-quality evidence indicates that corticosteroids reduce mortality among patients with sepsis. Moderate-quality evidence suggests that a long course of low-dose corticosteroids reduced 28-day mortality without inducing major complications and led to an increase in metabolic disorders.

High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial.

IMPORTANCE: Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE: To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS: High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES: The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS: There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE: Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION: trialregister.nl Identifier: NTR2181.

Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study.

INTRODUCTION: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. METHODS: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. RESULTS: Median time to AT was 2.1 (IQR 0.8 - 6.0) hours and 3 hours (-0.1 - 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). CONCLUSIONS: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality.

Risk factors in critical illness myopathy during the early course of critical illness: a prospective observational study.

INTRODUCTION: Non-excitable muscle membrane indicates critical illness myopathy (CIM) during early critical illness. We investigated predisposing risk factors for non-excitable muscle membrane at onset of critical illness. METHODS: We performed sequential measurements of muscle membrane excitability after direct muscle stimulation (dmCMAP) in 40 intensive care unit (ICU) patients selected upon a simplified acute physiology (SAPS-II) score >OR= 20 on 3 successive days within 1 week after ICU admission. We then investigated predisposing risk factors, including the insulin-like growth factor (IGF)-system, inflammatory, metabolic and hemodynamic parameters, as well as suspected medical treatment prior to first occurrence of abnormal dmCMAP. Nonparametric analysis of two-factorial longitudinal data and multivariate analysis were used for statistical analysis. RESULTS: 22 patients showed abnormal muscle membrane excitability during direct muscle stimulation within 7 (5 to 9.25) days after ICU admission. Significant risk factors for the development of impaired muscle membrane excitability in univariate analysis included inflammation, disease severity, catecholamine and sedation requirements, as well as IGF binding protein-1 (IGFBP-I), but did not include either adjunctive hydrocortisone treatment in septic shock, nor administration of neuromuscular blocking agents or aminoglycosides. In multivariate Cox regression analysis, interleukin-6 remained the significant risk factor for the development of impaired muscle membrane excitability (HR 1.006, 95%-CI (1.002 to 1.011), P = 0.002). CONCLUSIONS: Systemic inflammation during early critical illness was found to be the main risk factor for development of CIM during early critical illness. Inflammation-induced impairment of growth-factor mediated insulin sensitivity may be involved in the development of CIM.

Perioperative gene expression analysis for prediction of postoperative sepsis.

BACKGROUND: Postoperative sepsis is one of the main causes of death after major abdominal surgery; however, the immunologic factors contributing to the development of sepsis are not completely understood. In this study, we evaluated gene expression in patients who developed postoperative sepsis and in patients with an uncomplicated postoperative course. METHODS: We enrolled 220 patients in a retrospective matched-pair, case-control pilot study to investigate the perioperative expression of 23 inflammation-related genes regarding their properties for predicting postoperative sepsis. Twenty patients exhibiting symptoms of sepsis in the first 14 days after surgery (case group) were matched with 20 control patients with an uncomplicated postoperative course. Matching criteria were sex, age, main diagnosis, type of surgery, and concomitant diseases. Blood samples were drawn before surgery and on the first and second postoperative days. Relative gene expression was analyzed with real-time reverse-transcription PCR. RESULTS: Significant differences (P < 0.005) in gene expression between the 2 groups were observed for IL1B (interleukin 1, beta), TNF [tumor necrosis factor (TNF superfamily, member 2)], CD3D [CD3d molecule, delta (CD3-TCR complex)], and PRF1 [perforin 1 (pore forming protein)]. Logistic regression analysis and a subsequent ROC curve analysis revealed that the combination of TNF, IL1B, and CD3D expression had a specificity and specificity of 90% and 85%, respectively, and predicted exclusion of postoperative sepsis with an estimated negative predictive value of 98.1%. CONCLUSIONS: These data suggest that gene expression analysis may be an effective tool for differentiating patients at high and low risk for sepsis after abdominal surgery.

Multicenter comparison of cortisol as measured by different methods in samples of patients with septic shock.

PURPOSE: To compare inter-laboratory and inter-assay measurements of total cortisol in patients with septic shock and to evaluate current recommendations for diagnosis of corticosteroid insufficiency in septic shock. METHODS: In the multinational CORTICUS study duplicate serum samples were taken before and after corticotropin stimulation tests in patients with septic shock. Serum cortisol was measured in paired samples, one being measured by the chemical laboratory of each participating site and the other by a central laboratory using an electrochemiluminescence immunoassay. Cortisol levels measured by tandem mass spectrometry were used as a 'gold standard' reference method in a subset of samples. RESULTS: A total of 425 corticotropin tests (850 cortisol samples) were available for comparison of local and central laboratory measurements. The concordance correlation coefficient between central laboratory immunoassay and local hospital assays was 0.98 (CI 0.97-0.99) when the immunoassay of one manufacturer was used and 0.60 (CI 0.54-0.65) when immunoassays of different manufacturers were used. The comparison with the reference method of mass spectrometry showed concordance correlation coefficients ranging from 0.43 to 0.97 depending on the assay under study. Diagnosis of corticosteroid insufficiency was diverging due to inter-assay variations in up to 27% of cases. CONCLUSION: In samples taken from patients in septic shock, there was a high inter-assay variation of total serum cortisol. Comparisons with a reference method revealed both over- and underestimations of true cortisol levels. These inter-assay variations in samples of patients with septic shock complicate the diagnosis of corticosteroid insufficiency.