Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis

Objective To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock.Data sources Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group''s trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS.Review method Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them. We obtained some missing data from authors of trials and assessed methodological quality of trials.Results 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (≥ 5 days) with low dose (≤ 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects.Conclusions For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low doses of corticosteroids, however, mortality at 28 days and hospital morality was reduced.     

Interleukin-6 and procalcitonin in children with sepsis and septic shock

Objectives. To examine the behavior of interleukin-6 (IL-6) and procalcitonin (PCT) and verify whether they can be used to differentiate children with septic conditions. Methods. Septic children aged between 28 days and 14 years, prospectively enrolled from 01/2004 to 12/2005, were divided into sepsis (SG; n = 47) and septic shock (SSG; n = 43) groups. IL-6 and PCT were measured at admission (T0) and 12 h later (T12h). PCT results were classed as: 0.5 ng/mL = sepsis unlikely; 0.5 to <2 = sepsis possible; 2 to <10 = systemic inflammation; 10 = septic shock. Results. Ninety children were included. At T0, there was a higher frequency of SSG with higher PCT compared with SG [SSG: 30 (69.7%) > SG: 14 (29.8%); p < 0.05]. Similar results were observed at T12h. PRISM was significantly higher for SSG patients with higher PCT than SG patients. At T0, IL-6 levels were higher in SSG [SSG: 213.10 (10.85–396.70) > SG: 63.21 (0.86–409.82); p = 0.001], but not statistically different at T12h. IL-6 levels positively correlated with PRISM score in SSG patients at admission (p = 0.001; r = 0.86). Conclusion. PCT and IL-6 appear to be helpful in early assessment of pediatric sepsis, are of diagnostic value at admission, and are related to disease severity.     

Simultaneous activation of apoptosis and inflammation in pathogenesis of septic shock: a hypothesis

Sepsis, a widely prevalent disease with increasing morbidity and mortality, is thought to result from uncontrolled inflammatory responses to microbial infection and/or components. However, failure of several experimental anti-inflammatory therapies has necessitated re-evaluation of the paradigm underlying the pathogenesis of this complex disorder. Apoptotic cell death forms a second dominant feature of septic shock in patients and animal models. Anti-apoptotic strategies may protect animals from septic death. However, simultaneous occurrence of apoptosis and inflammation is necessary for septic death. At the cellular level, apoptosis plays a central role in the development of the lymphoid system and regulation of immune responses. Immune activation renders cells refractory to apoptosis while apoptosis of activated lymphocytes is an important immunoregulatory mechanism. Factors such as complement factor 5a, caspase-1 and mitogen-activated protein kinase, which participate in apoptosis as well as pro-inflammatory pathways, may be responsible for simultaneous activation of apoptosis and inflammation in sepsis. Further identification of other similar biochemical events capable of co-activating inflammation and apoptosis may provide new targets for therapy of this hitherto untreatable disease.     

Comparing the prognostic performance of ASSIST to interleukin-6 and procalcitonin in patients with severe sepsis or septic shock

Abstract

Context: We recently derived and validated a multi-biomarker-based model (ASSIST) to stratify patients with sepsis based on initial mortality risk.

Objective: The objective of this study was to compare the performance of ASSIST to interleukin-6 (IL6) and procalcitonin (PCT).

Methods: The area-under-the-receiver operating characteristic curve for predicting 28-d mortality using ASSIST was compared with that of IL6 (n?=?452) and PCT (n?=?235).

Results: The area under the curve for ASSIST was greater than that of IL6 and PCT.

Conclusions: ASSIST estimated the probability of mortality more reliably than IL6 and PCT in this cohort of patients with sepsis.     

The original biotechnology: brewing an undergraduate education

The increasing number of microbreweries and brewpubs and the popularity of homebrewing present a heady opportunity for undergraduate projects that blend together theory, practice and job opportunities in the realm of fermentation science. However, a perception of prohibitive regulation on campus and other concerns has led many instructors to abandon that most practical demonstration of fermentation, the production of ethanol by Saccharomyces cerevisiae. We present our success in introducing fermentation using homebrewing in a microbiology laboratory. Virtually all fundamental topics of microbiology are remarkably easy to demonstrate with this project: growth and replication, physiology, limitation of growth by sterilization and other methods, competition, energy conservation and utilization, consequences and uses of mutations, and genetic engineering are among the topics which dovetail with this activity. Further, this activity also represents a natural introduction to a number of industrial topics: issues of scaling-up, pilot tests and environmental conditions. Journal of Industrial Microbiology & Biotechnology (2000) 24, 327–333. Received 07 March 1999/ Accepted in revised form 23 November 1999     

Tumor Necrosis Factor gene polymorphism results in high TNF level in sepsis and septic shock

IntroductionSystemic sepsis releases several cytokines among which tumor necrosis factor alfa (TNFα) has emerged as key cytokine causing septic shock. Single Nucleotide Polymorphisms (SNPs) at positions ?238, ?308, ?376 and +489 in the promoter region of TNF gene exhibit differential association to inflammation and increased TNF production in sepsis.Materials and MethodsThis research work was carried out in 278 critically ill patients and 115 controls. The patients were divided into four groups: Healthy controls, SIRS, Sepsis and Septic shock. Plasma cytokine level was evaluated by ELISA. Specific sequences of TNF gene (?238, ?308, ?376, +489) were amplified using polychromase chain reaction (PCR). SNP detected by BamHiI, NcoI, FokI, TaiI restriction enzymes.ResultsMean plasma TNFα level in healthy Control group was 8.37 ± 2.23 pg/ml, in SIRS group, the mean plasma TNFα level was 77.99 ± 5.51 pg/ml, in Sepsis patients 187.1 ± 14.33 pg/ml and in septic shock 202.2 ± 14.85 pg/ml; range 56.17–417.1 pg/ml. SNP was studied among different patient groups, which showed a higher frequency of mutants among sepsis and shock patients as compared to control.ConclusionPlasma TNF alpha level was significantly high in patients with sepsis and septic shock. SNP of TNF gene showed significant association between polymorphism and development of severe sepsis and septic shock, this would help us in evaluating patients at high risk for septic shock and such patients needed to obtain a rational basis for therapy.     

A rationale for the prophylactic use of monophosphoryl lipid A in sepsis and septic shock.

Monophosphoryl lipid A (MLA), a substructure of bacterial lipopolysaccharide (LPS), is being developed as a prophylactic for sepsis and septic shock. In the present study it was shown that MLA induced a rapid accumulation of IFN-gamma in mice that correlated with an in vivo priming of macrophages. Primed macrophages could be induced in vitro to synthesize nitric oxide, a key mediator of macrophage cytotoxicity. Due to its rapid clearance, MLA was not present in circulation at the time when IFN-gamma accumulated, suggesting that MLA could not synergize with IFN-gamma to systemically activate macrophages in vivo. MLA treatment tolerized mice against the IFN-gamma response--ie., treatment of mice with MLA on day 1 blocked LPS from inducing IFN-gamma on days 2-4. The significance of these results in relation to MLA's ability to enhance non-specific resistance and block LPS lethality in animals is discussed.     

The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax

Inhalation anthrax is often described as a toxin‐mediated disease. However, the toxaemia model does not account for the high mortality of inhalation anthrax relative to other forms of the disease or for the pathology present in inhalation anthrax. Patients with inhalation anthrax consistently show extreme bacteraemia and, in contrast to animals challenged with toxin, signs of sepsis. Rather than toxaemia, we propose that death in inhalation anthrax results from an overwhelming bacteraemia that leads to severe sepsis. According to our model, the central role of anthrax toxin is to permit the vegetative bacteria to escape immune detection. Other forms of B. anthracis infection have lower mortality because their overt symptoms early in the course of disease cause patients to seek medical care at a time when the infection and its sequelae can still be reversed by antibiotics. Thus, the sepsis model explains key features of inhalation anthrax and may offer a more complete understanding of disease pathology for researchers as well as those involved in the care of patients.     

Phagocytosis and digestion of pH-sensitive fluorescent dye (Eos-FP) transfected E. coli in whole blood assays from patients with severe sepsis and septic shock

The function of phagocytic and antigen presenting cells is of crucial importance to sustain immune competence against infectious agents as well as malignancies. We here describe a reproducible procedure for the quantification of phagocytosis by leukocytes in whole blood. For this, a pH-sensitive green-fluorescent protein- (GFP) like dye (Eos-FP) is transfected into infectious microroganisms. After UV-irradiation, the transfected bacteria emit green (≈5160 nm) and red (≈581 nm) fluorescent light at 490 nm excitation. Since the red fluorescent light is sensitive to acidic pH, the phagocytosed bacteria stop emitting red fluorescent light as soon as the phagosomes fuse with lysosomes. The green fluorescence is maintained in the phagolysosome until pathogen degradation is completed. Fluorescence emission can be followed by flow cytometry with filter settings documenting fluorescence 1 (FL 1, FITC) and fluorescence 2 (FL 2, phycoerythrin, PE). Eos-FP transfected bacteria can also be traced within phagocytes using microscopical techniques. A standardized assay has been developed which is suitable for clinical studies by providing clinicians with syringes pre-filled with fixed and appropriately UV-irradiated Eos-FP E. coli (TruCulture™). After adding blood or body fluids to these containers and starting the incubation at 37°C, phagocytosis by granulocytes proceeds over time. Cultures can be terminated at a given time by lysing red blood cells followed by flow cytometry. A pilot study demonstrated that Eos-FP E. coli phagocytosis and digestion was up-regulated in the majority of patients with either severe sepsis or septic shock as compared to healthy donors (p < 0.0001 after o/n incubation). Following treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in selected patients with sepsis, phagolysosome fusion appeared to be accelerated.     

Urine catecholamines in children with severe Enterovirus A71 infection: comparison with paediatric septic shock

Purpose: Hypercatecholaminemia-related heart failure has been proposed as the main cause of enterovirus A71-related (EV-A71) early mortality. The purpose of this study was to measure urine catecholamine concentrations in severe EV-A71-infected children.

Methods: A total of 35 children, aged 2.5?±?2.1 years, were divided into three groups. Group I: 15 septic shock patients, group II: 17?EV-A71-stage-2 patients, and group III: 3?EV-A71-stage-4 patients. The laboratory results, cardiac biomarkers and urine catecholamine concentrations were statistically analysed.

Results: Group I had the highest C-reactive protein (CRP) levels and group II had the lowest B-type natriuretic peptide (BNP) and its N-terminal prohormone among the groups (p?=?0.039, <0.01 and <0.01, respectively). Group III patients had significantly higher urine catecholamine and troponin-I values among the groups. If urine epinephrine (Epi) >134 ug/gCr, norepinephrine (NE) >176 ug/gCr and vanillylmandelic acid (VMA) >11.7?mg/gCr were used as the cutoff points to differentiate groups II and III, the sensitivities and specificity were all 100%.

Conclusions: The significantly elevated urine catecholamine concentrations in EV-A71-stage-4 patients support the hypothesis that hypercatecholaminemia-related heart failure is involved in severe EV-A71 infection. Urine catecholamines could be used as reliable biomarkers for differentiation of severe EV-A71 infection with or without heart failure and septic shock.     

A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis

Identification of patients at increased risk of death is dramatically important in severe sepsis. Cytokines have been widely assessed as potential biomarkers in this disease, but none of the cytokines studied has evidenced a sufficient specificity or sensitivity to be routinely employed in clinical practice. In this pilot study, we profiled 17 immune mediators in the plasma of 29 consecutively recruited patients with severe sepsis or septic shock, during the first 24h following admission to the ICU, by using a Bio-Plex Human Cytokine 17-Plex Panel (Bio-Rad). Patients were 66.1year old in average. Twelve patients of our cohort died during hospitalization at the ICU, eight of them in the first 72h due to multiorganic dysfunction syndrom (MODS). Levels in plasma of three pro-inflammatory mediators (IL-6, IL-8, MCP-1) and of an immunosuppressive one (IL-10) were higher in those patients with fatal outcome. We developed a combined score with those cytokines showing to better predict mortality in our cohort based on the results of Cox regression analysis. This way, IL-6, IL-8 and IL-10 were included in the score. Patients were split into two groups based on the percentile 75 (P75) of the plasma levels of these three interleukins. Those patients showing at least one interleukin value higher than P75 were given the value "1". Those patients showing IL-6, IL-8, IL-10 levels below P75 were given the value "0". Hazard ratios for mortality at day 3 and day 28th obtained with the combined score were 2-3-fold higher than those obtained with the individual interleukins values. In conclusion, we have described a combined cytokine score associated with a worse outcome in patients with sepsis, which may represent a new avenue to be explored for guiding treatment decisions in this disease.     

Exogenous heat shock protein 70 mediates sepsis manifestations and decreases the mortality rate in rats

Mammalian responses to bacterial lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria can lead to an uncontrolled inflammatory reaction that can be deadly for the host. We checked whether heat shock protein 70 (Hsp70) protein is able to protect animals from the deleterious effects of bacterial LPS by monitoring the effect of exogenous Hsp70 injections before and after LPS administration. Our research with rats demonstrates for the first time that administration of exogeneous Hsp70 before and after LPS challenges can reduce mortality rates and modify several parameters of hemostasis and hemodynamics. Hsp70 isolated from bovine muscles showed significant protective effects against the impaired coagulation and fibrinolytic systems caused by LPS, and reduced the mortality caused by Escherichia coli and Salmonella typhimurium LPS injections significantly. Characteristically, Hsp70 preparations used in the experiments result in different effects when administered before and after an LPS challenge, and the effects of Hsp70 injections also differ significantly depending on the origin of the LPS (E coli vs S typhimurium). Based on our data, mammalian Hsp70 appears to be an attractive target in therapeutic strategies designed to stimulate endogenous protective mechanisms against many deleterious consequences of septic shock by accelerating the functional recovery of susceptible organs in humans.     

Absenteeism among hospital staff during an influenza epidemic: implications for immunoprophylaxis.

The 1980-81 epidemic of influenza A/Bangkok 79 was responsible for increased absenteeism (1.7 times the rate for the corresponding period of the subsequent nonepidemic year) among selected hospital staff in Winnipeg''s Health Sciences Centre. Retrospective study of employment records for 25 of the centre''s largest departments showed excess sick-leave costs of about $24 500 during the 2-week period of peak absenteeism that included the epidemic. Although the centre was sampling prospectively for the virus the first positive results became available too late for chemoprophylactic measures to have been effective. The greater increase in absenteeism among nursing staff caring for patients with chronic respiratory disease and nurses working on general medical or pediatric acute infection/isolation wards suggested that these groups be targeted for influenza vaccination in hospitals.     

Immunoregulatory biological response modifiers: effect of cytokines on septic shock

Whole bacteria or bacterial components or their extracts were employed to restore or augment the immune system. Beneficial effects were attained with these agents in treating various diseases. These agents were named biological response modifiers (BRMs) because they regulated certain cellular components of the immune system. The cellular regulation induced by these BRMs was found to be due to cytokines. The cytokines were shown to act directly on the various cellular components and to provide therapeutic benefit in various autoimmune and immune deficiency diseases. Overproduction of specific cytokines however leads to a deleterious effect on the host. Overproduction of tumour necrosis factor (endotoxin, lipopolysaccharide) leads to septic shock. Bacteraemia is the leading cause of overproduction of tumour necrosis factor (TNF). Septic shock in many cases leads to death. Several monoclonal antibodies to lipopolysaccharide (LPS) and anticytokines have demonstrated protection against septic shock.     

Mortality after fluid bolus in children with shock due to sepsis or severe infection: a systematic review and meta-analysis

Introduction

Sepsis is one of the leading causes of childhood mortality, yet controversy surrounds the current treatment approach. We conducted a systematic review to assess the evidence base for fluid resuscitation in the treatment of children with shock due to sepsis or severe infection.

Methods

We searched 3 databases for randomized trials, quasi-randomized trials, and controlled before-after studies assessing children with septic shock in which at least one group was treated with bolus fluids. The primary outcome was mortality at 48 hours. Assessment of methodological quality followed the GRADE criteria. Relative risks (RRs) and 95% confidence intervals (CI) were calculated and data pooled using fixed-effects method.

Results

13 studies met our inclusion criteria. No bolus has significantly better mortality outcomes at 48 hours for children with general septic shock (RR 0.69; 95%CI 0.54–0.89), and children with malaria (RR 0.64; 95%CI 0.45–0.91) when compared to giving any bolus. This result is largely driven by a single, high quality trial (the FEAST trial). There is no evidence investigating bolus vs no bolus in children with Dengue fever or severe malnutrition. Colloid and crystalloid boluses were found to have similar effects on mortality across all sub-groups (general septic shock, malaria, Dengue fever, and severe malnutrition).

Conclusions

The majority of all randomized evidence to date comes from the FEAST trial, which found that fluid boluses were harmful compared to no bolus. Simple algorithms are needed to support health-care providers in the triage of patients to determine who could potentially be harmed by the provision of bolus fluids, and who will benefit.