International Sepsis Forum Research Articles

Editorial introductions.

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned to a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Matteo BassettiMatteo BassettiMatteo Bassetti is Head of the Infectious Diseases Clinic of the Policlinico San Martino University Hospital in Genoa and Full Professor of Infectious Diseases of the University of Genoa, Italy. Dr Bassetti studied at the University of Genoa School of Medicine and continued his medical education at the Yale University School of Medicine, New Haven, USA with an Infectious Diseases fellowship. Dr Bassetti is Chair of the Critically Ill Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), president of the Italian Society of Anti-infective Therapy (SITA) and member of executive committee for the battle against antimicrobial resistance of the Italian Minister of Health (PNCAR). He is member-elected (2018-2022) of International Council of the Immunocompromised Host Society (ICHS). From 2019, he is member of the council of International Sepsis Forum (ISF). He serves on the editorial board of several prestigious international journals. He is author or co-author of 750 papers (H index 85; 30000 citations) published in International peer-review journals and several chapter's book on antibiotic therapy, fungal infections, antimicrobial resistances, infections in immunocompromised patients and critically ill patients. Wei Shen LimWei Shen LimProfessor Wei Shen Lim is consultant respiratory physician at Nottingham University Hospitals NHS Trust and Honorary Professor of Respiratory Medicine, University of Nottingham, UK. He is Chair of COVID-19 Immunisation on the Joint Committee of Vaccination and Immunisation (JCVI), UK and a member of various national advisory groups including the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) to the Chief Medical Officer for England. He was Chief Investigator of the hibernated ASAP Trial of Dexamethasone in Pandemic Influenza (2012-2022), and co-led the evaluation of Dexamethasone for COVID-19 in the RECOVERY TRIAL He has been involved with the British Thoracic Society (BTS) and the National Institute for Health and Care Excellence (NICE) in the development of various national clinical management guidelines for acute respiratory infections including community acquired pneumonia, pandemic influenza and COVID-19. He developed the CURB-65 severity assessment score for community acquired pneumonia and the BTS community acquired pneumonia care bundle. He was awarded the British Thoracic Society Meritorious Award in 2016 for contributions towards respiratory infections, and in 2021 the Moxon Medal by the Royal College of Physicians (London).

Surviving Sepsis Campaign.

Surviving Sepsis Campaign.

Definitions, rates and associated mortality of ICU-acquired pneumonia: A multicenter cohort study

IntroductionWe aimed to analyze intensive care unit (ICU)-acquired pneumonia according to 7 definitions, estimating associated hospital mortality. MethodsThis cohort study was nested within an international randomized trial, evaluating the effect of probiotics on ICU-acquired pneumonia in 2650 mechanically ventilated adults. Each clinically suspected pneumonia was adjudicated by two physicians blinded to allocation and center. The primary outcome was ventilator-associated pneumonia (VAP) informed by ventilation for ≥2 days, new, progressive or persistent infiltrate plus 2 of: temperature > 38 °C or < 36 °C; leukopenia (<3 × 10(Fernando et al., 20206)/L) or leukocytosis (>10 × 10(Fernando et al., 20206)/L); and purulent sputum. We also used 6 other definitions estimating the risk of hospital mortality. ResultsThe frequency of ICU-acquired pneumonia varied by definition: the trial primary outcome VAP (21.6%), Clinical Pulmonary Infection Score (CPIS) (24.9%), American College Chest Physicians (ACCP) (25.0%), International Sepsis Forum (ISF) (24.4%), Reducing Oxidative Stress Study (REDOXS) (17.6%), Centers for Disease Control (CDC) (7.8%), and invasively microbiologically confirmed (1.9%). The trial primary outcome VAP (HR 1.31 [1.08, 1.60]), ISF (HR 1.32 [1.09,1.60]), CPIS (HR 1.30 [1.08,1.58]) and ACCP definitions (HR 1.22 [1.00,1.47]) were associated with hospital mortality. ConclusionsRates of ICU-acquired pneumonia vary by definition and are associated with differential increased risk of death.

Досвід лікування новонародженого з раннім колі-клебсіельозним сепсисом, що ускладнився некрозом м’яких тканин волосистої поверхні голови

According to the modern epidemiology of sepsis, early newborn sepsis is bacterial in 84% of cases. According to the materials of the last congresses of the International Sepsis Forum (ISF), and in particular ISF 2021, among severe forms of neonatal sepsis, colie and klebsiella sepsis, closely associated with intrauterine maternal infection, prevail. Purpose - to show efficiency of the pathogenic approach in the treatment of early newborn sepsis. The article presents the experience of treating a newborn child with early newborn sepsis caused by intrauterine colie infection and associated with klebsiella infection, which was complicated by necrosis of the skin and fiber of almost the entire surface of the scalp. The child was admitted to the newborn surgery department with signs of wound sepsis, an open infected wound covered with a necrotic soft tissue - hairy skin flap. The studied prenatal history demonstrated a close relationship of the disease with intrauterine coliе infection. The child was examined by laboratory (microbiological blood and wound surface, biochemical - total, procalcitonin, C-reactive protein, coagulogram and also immunological (T-, B-lymphocytes, CD-64-blood) and instrumental (ultrasound, computed tomography, X-ray) methods. On the basis of the obtained research results, pathogenetic therapy was carried out, the child was prepared for surgical intervention - necrectomy and subsequent transplantation of auto skin to close the soft tissue defect of the cranial vault. As a result of the treatment carried out by a multifunctional team of doctors, the child recovered, the skin of the cranial vault of the head was completely restored. Conclusions. The obtained research results and good treatment results demonstrated the effectiveness of the pathogenetic approach to the treatment of severe forms of neonatal sepsis. The research was carried out in accordance with the principles of the Declaration of Helsinki on Human Rights. The research protocol is approved by the Local Ethics Committee of all participating institutions. The consent of the child’s parents was obtained for the research. No conflict of interests was declared by the authors. Keywords: newborn, intrauterine sepsis, wound sepsis, colie-klebsiellosis sepsis, necrosis,

Editorial introductions

Editorial introductions

Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice.

An estimated 14.1 million patients survive sepsis each year. Many survivors experience poor long-term outcomes, including new or worsened neuropsychological impairment; physical disability; and vulnerability to further health deterioration, including recurrent infection, cardiovascular events, and acute renal failure. However, clinical trials and guidelines have focused on shorter-term survival, so there are few data on promoting longer-term recovery. To address this unmet need, the International Sepsis Forum convened a colloquium in February 2018 titled "Understanding and Enhancing Sepsis Survivorship." The goals were to identify gaps and limitations of current research and shorter- and longer-term priorities for understanding and enhancing sepsis survivorship. Twenty-six experts from eight countries participated. The top short-term priorities identified by nominal group technique culminating in formal voting were to better leverage existing databases for research, develop and disseminate educational resources on postsepsis morbidity, and partner with sepsis survivors to define and achieve research priorities. The top longer-term priorities were to study mechanisms of long-term morbidity through large cohort studies with deep phenotyping, build a harmonized global sepsis registry to facilitate enrollment in cohorts and trials, and complete detailed longitudinal follow-up to characterize the diversity of recovery experiences. This perspective reviews colloquium discussions, the identified priorities, and current initiatives to address them.

Performance of plasma measurement of neutrophil gelatinase-associated lipocalin as a biomarker of bacterial infections in the intensive care unit

PurposeTo assess the value of dimeric neutrophil-gelatinase associated lipocalin (NGAL) as an early marker of bacterial infection and its response to antibiotic therapy in intensive care unit (ICU) patients. Materials & methodsWe measured daily plasma dNGAL in 198 patients admitted to a mixed ICU. Likelihood of infection was determined with International Sepsis Forum criteria. We measured dNGAL in 145 healthy controls to establish normal values. ResultsICU patients had higher dNGAL than healthy controls. A suspected or confirmed infection was independently associated with 90% (95% CI 15–215%) higher dNGAL than absence of infection. We observed no association between acute kidney injury and dNGAL. Diagnostic accuracy at antibiotic treatment initiation, assessed with area under the receiver-operating characteristics curve (AUC-ROC), for dNGAL was 0.70 (95% CI 0.60–0.79). AUC-ROC for dNGAL 24 h before antibiotic treatment initiation was 0.54 (95% CI 0.41–0.66). The mean (95% CI) change of dNGAL in the first 2 days after appropriate antibiotic therapy initiation was −31 (−49,−13)%. ConclusionsIn our cohort of ICU patients, plasma dNGAL was associated with presence of bacterial infections independent of AKI but it performed poor as a predictor of infections. Following antibiotic therapy, dNGAL markedly decreased–supporting further exploration of dNGAL-guided antibiotic de-escalation.

Editorial introductions

Editorial introductions

Interrater Variability in Identifying Ventilator Associated Pneumonia Using Six Different Definitions

Objective: There is no widely accepted standard definition for Ventilator Associated Pneumonia (VAP). The reliability of the current definitions in use remains controversial. Our objective was to assess the reliability of six commonly used VAP definitions: The Loose, The Rigorous, The Modified Clinical Pulmonary Infection Score (CPIS), The Canadian Critical Care Trials Group (CCCTG), The International Sepsis Forum Consensus (ISFC) and The Center for Disease Control and Prevention (CDC). Design: We examined the electronic health records of all the consecutively admitted adult patients at our institution who received invasive mechanical ventilation (IMV) for ≥ 48 hours, from January 2006 through December 2006.Patients were excluded if they developed pneumonia within the first 48 hours or if they had a tracheostomy before IMV. Two expert intensivists independently reviewed the following data for each patient: indications and duration of IMV, vital signs, oxygen requirements, the frequency of respiratory suctioning, amount, color and consistency of secretion, ventilator settings, leukocyte count, microbiologic and radiographic data. Interreviewer reliability in diagnosing VAP independently were compared using Cohen’sKappa statistics. Results: A total of 115 patients met the initial inclusion criteria of which 47 patients were excluded (40 had pneumonia on presentation, 6 developed pneumonia within 48 hours and 1 had a tracheostomy on admission). The inter-reviewer agreement Kappa for the Loose, the Rigorous, CPIS, CCCTG, ISFC and CDC definitions for VAP were 0.22, 0.49, 0.33, 0.41, 0.38 and 0.68 respectively. Conclusion: The CDC definition of VAP proved to be statistically more reliable than other tested definitions of VAP, as demonstrated by the lowest interrater variability between two independent reviewers.

Abdominal infections in the intensive care unit: characteristics, treatment and determinants of outcome.

BackgroundAbdominal infections are frequent causes of sepsis and septic shock in the intensive care unit (ICU) and are associated with adverse outcomes. We analyzed the characteristics, treatments and outcome of ICU patients with abdominal infections using data extracted from a one-day point prevalence study, the Extended Prevalence of Infection in the ICU (EPIC) II.MethodsEPIC II included 13,796 adult patients from 1,265 ICUs in 75 countries. Infection was defined using the International Sepsis Forum criteria. Microbiological analyses were performed locally. Participating ICUs provided patient follow-up until hospital discharge or for 60 days.ResultsOf the 7,087 infected patients, 1,392 (19.6%) had an abdominal infection on the study day (60% male, mean age 62 ± 16 years, SAPS II score 39 ± 16, SOFA score 7.6 ± 4.6). Microbiological cultures were positive in 931 (67%) patients, most commonly Gram-negative bacteria (48.0%). Antibiotics were administered to 1366 (98.1%) patients. Patients who had been in the ICU for ≤2 days prior to the study day had more Escherichia coli, methicillin-sensitive Staphylococcus aureus and anaerobic isolates, and fewer enterococci than patients who had been in the ICU longer. ICU and hospital mortality rates were 29.4% and 36.3%, respectively. ICU mortality was higher in patients with abdominal infections than in those with other infections (29.4% vs. 24.4%, p < 0.001). In multivariable analysis, hematological malignancy, mechanical ventilation, cirrhosis, need for renal replacement therapy and SAPS II score were independently associated with increased mortality.ConclusionsThe characteristics, microbiology and antibiotic treatment of abdominal infections in critically ill patients are diverse. Mortality in patients with isolated abdominal infections was higher than in those who had other infections.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-420) contains supplementary material, which is available to authorized users.

Characteristics of AIDS patients in Dutch intensive care units

Background: Infection with HIV enhances the risk to develop invasive bacterial infection, often resulting in sepsis. Both HIV infection and sepsis are associated with activation of the coagulation system. The influence of HIV infection on the sepsis-induced disturbance of the hemostatic balance is unknown. We aimed to determine the impact of HIV infection on coagulation activation during sepsis. Methods & Materials: We performed a prospective observational study in Lambarene, Gabon, and included all patients that were hospitalized with either fever or hypothermia and at least one other SIRS (Systemic Inflammatory Response Syndrome) criterion. Blood cultures, HIV testing and malaria diagnostics were performed. Patients with evidence of infection (based on adapted Centers for Disease Control and Prevention, and International Sepsis Forum Consensus Conference definitions) were classified as sepsis cases. Citrated plasma was obtained on admission, as well as in asymptomatic controls with or without HIV infection from the same region. Statistical analyses were done using the KruskalWallis test followed by a post-hoc Mann-Whitney U test. Results: We included113 sepsis patients (34 HIV positive), and 95 asymptomatic controls (60 HIV positive). Both asymptomatic HIV infection and sepsis were associated with activation of coagulation, as reflected by elevated levels of D-dimer and fibrinogen, and endothelial cell activation, as evidenced by elevated levels of Von Willebrand factor. Sepsis was associated with similar changes albeit to a greater extent; in addition, sepsiswas accompaniedwith downregulation of anticoagulant pathways, as reflected by reduced antithrombin and protein S levels. In asymptomatic HIV infection protein S was downregulated, whereas antithrombin levels were increased. Sepsis, but not HIV infection, resulted in prolonged prothrombin time and activated partial thromboplastin time. Coinfection with HIV did not impact on activation of coagulation during sepsis. Importantly, however, HIV co-infection did aggravate perturbations in VonWillebrand and protein S levels in sepsis patients. Conclusion: Both HIV infection and sepsis cause a net procoagulant state. HIV co-infection augments impairment of the anticoagulant system and activation of endothelium during sepsis. These mechanisms may play a role in enhanced sepsis related morbidity of HIV patients.

The influence of HIV infection on coagulation activation during sepsis

Background: Infection with HIV enhances the risk to develop invasive bacterial infection, often resulting in sepsis. Both HIV infection and sepsis are associated with activation of the coagulation system. The influence of HIV infection on the sepsis-induced disturbance of the hemostatic balance is unknown. We aimed to determine the impact of HIV infection on coagulation activation during sepsis. Methods & Materials: We performed a prospective observational study in Lambarene, Gabon, and included all patients that were hospitalized with either fever or hypothermia and at least one other SIRS (Systemic Inflammatory Response Syndrome) criterion. Blood cultures, HIV testing and malaria diagnostics were performed. Patients with evidence of infection (based on adapted Centers for Disease Control and Prevention, and International Sepsis Forum Consensus Conference definitions) were classified as sepsis cases. Citrated plasma was obtained on admission, as well as in asymptomatic controls with or without HIV infection from the same region. Statistical analyses were done using the KruskalWallis test followed by a post-hoc Mann-Whitney U test. Results: We included113 sepsis patients (34 HIV positive), and 95 asymptomatic controls (60 HIV positive). Both asymptomatic HIV infection and sepsis were associated with activation of coagulation, as reflected by elevated levels of D-dimer and fibrinogen, and endothelial cell activation, as evidenced by elevated levels of Von Willebrand factor. Sepsis was associated with similar changes albeit to a greater extent; in addition, sepsiswas accompaniedwith downregulation of anticoagulant pathways, as reflected by reduced antithrombin and protein S levels. In asymptomatic HIV infection protein S was downregulated, whereas antithrombin levels were increased. Sepsis, but not HIV infection, resulted in prolonged prothrombin time and activated partial thromboplastin time. Coinfection with HIV did not impact on activation of coagulation during sepsis. Importantly, however, HIV co-infection did aggravate perturbations in VonWillebrand and protein S levels in sepsis patients. Conclusion: Both HIV infection and sepsis cause a net procoagulant state. HIV co-infection augments impairment of the anticoagulant system and activation of endothelium during sepsis. These mechanisms may play a role in enhanced sepsis related morbidity of HIV patients.

Editorial introductions

Current Opinion in Critical Care was launched in 1995. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of critical care is divided into 13 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the journal's Editor and Section Editor for this issue. EDITOR-IN-CHIEF Jean-Louis VincentJean-Louis VincentDr Vincent is Professor of intensive care at the University of Brussels, Belgium, and Head of the Department of Intensive Care at the Erasme University Hospital in Brussels, Belgium. He earned his medical degree from the Universite Libre de Bruxelles, Belgium, with magna cum laude, with a specialty in Internal Medicine and Intensive Care Medicine. His training included two years of fellowship in critical care medicine at the University of Southern California, USA with Prof. Max Harry Weil. Dr Vincent has signed more than 700 original articles, more than 280 book chapters and review articles, and around 800 original abstracts. He has edited 86 books including 63 in his own series Update in Intensive Care and Emergency Medicine and Yearbook in Intensive Care and Emergency Medicine published by Springer-Verlag (Heidelberg, Berlin, New York). He is co-editor of the Textbook of Critical Care (Elsevier Saunders, 5th Edition). He has also written a French Manual of Intensive Care and Emergency Medicine (Springer, France), and is the co-editor of the series Le point sur… (Springer, France). Dr Vincent is the editor-in-chief of Critical Care, Current Opinion in Critical Care, and ICU Management. He is member of the Editorial Boards of about 30 journals including Critical Care Medicine (senior editor), PLoS Medicine, Lancet Infectious Diseases, Intensive Care Medicine, Chest, Shock, and Journal of Critical Care. Dr Vincent is presently Secretary General of the World Federation of Societies of Intensive and Critical Care Medicine. He is a Past-President of the European Society of Intensive Care Medicine and the European Shock Society, and the Past-Chairman of the International Sepsis Forum. For 31 years he has organized an International Symposium on Intensive Care and Emergency Medicine which is held every March in Brussels. This symposium, which gathers 5,000 participants, has become one of the largest meetings in the field. He received the Foundation André Loicq award in 1986, the Foundation De Kerckheer award in 2000, the Distinguished Investigator award of the Society of Critical Care Medicine in 2001 and the College Medalist Award of the American College of Chest Physicians in 2003. He was the Recipient of the "Society Medal” (lifetime award) of the European Society of Intensive Care Medicine in 2009 and he received “ Prix Scientifique Joseph Maison-Sciences biomédicales cliniques” (scientific award of the FRS-FNRS) in 2010. SECTION EDITOR Arthur P. WheelerArthur P. WheelerArthur Wheeler is a Professor in the Division of Allergy, Pulmonary and Critical Care Medicine at Vanderbilt University, USA, and serves as the Director of the Vanderbilt ICU. He is a graduate of the University Of Maryland School Of Medicine, USA, then completed training programs in Internal Medicine, Pulmonary Disease and Critical Care at Vanderbilt University. Dr Wheeler's research interest in severe sepsis, acute lung injury and thromboembolic disease has resulted in more than 100 publications. He is also the co-author of a successful textbook of Critical Care Medicine now in its fourth edition. He has delivered hundreds of national and international lectures and is the recipient of numerous teaching awards. Most recently Dr Wheeler has been developing and testing the effectiveness of alternative care delivery models in critical care including the use of nurse practitioners.

Immunomodulation in Sepsis: State of the Art and Future Perspective

Despite advances in supportive care of critically ill patients, sepsis remains an important cause of death worldwide. More than 750,000 individuals develop severe sepsis in North America annually, with a mortality rate varying between 35 and 50%. Over recent years, numerous efforts have been committed to understanding the pathophysiology of septic syndrome, as well as attempts to intervene in the inflammatory cascade with the aim of altering the outcome of the syndrome and to improve survival. Not all of these attempts have been successful. Issued guidelines by the International Sepsis Forum have incorporated only the use of corticosteroids, tight glycemic control and the use of recombinant activated protein C as recommendations for the management of the septic patient along with the initial resuscitation and infection-site control measures. These strategies along, with novel attempts of immunomodulation, are thoroughly reviewed in this article.

Early Recognition of Sepsis in the Emergency Department: An Evidence-based Project

Sepsis is a complex clinical syndrome that is challenging to diagnose and treat. Severe sepsis (acute organ dysfunction resulting from infection) is a major health problem that affects millions of persons globally. Severe sepsis has a reported inpatient mortality rate from 30% to 35%. 1 The Surviving Sepsis Campaign was developed by the European Society of Critical Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine to help meet the challenges of sepsis and to improve its management, diagnosis, and treatment. 2 This campaign developed guidelines that are of practical use for the bedside clinician in the diagnosis and treatment of severe sepsis. The purpose of this evidence-based early sepsis recognition project was to implement a sepsis screening measure for improving the identification, communication, and treatment of patients with sepsis.

The Surviving Sepsis Campaign: A History and a Perspective

The Surviving Sepsis Campaign (SSC) was launched in 2002 as a collaborative initiative of the European Society of Intensive Care Medicine (ESICM), the International Sepsis Forum (ISF), and the Society of Critical Care Medicine (SCCM). Its objective was, through the development and promulgation of evidence-based guidelines that facilitated the application of knowledge derived from clinical trials to bedside practice, to effect a 25% reduction in the relative risk of death from severe sepsis and septic shock. The evolution and content of the SSC is summarized and the scientific basis of the conclusions is reviewed from the literature. The SSC developed evidence-based management guidelines and undertook a broad educational program to implement them by integrating their recommendations into resuscitation and management bundles. The process engaged practitioners in North America, Europe, and South America and was supported by professional societies around the world. It also engendered controversy based on accusations of undue industry influence and some dissatisfaction among individuals who were antagonistic toward protocolization of care. By its conclusion, more than 22,000 patients with sepsis had been entered in the SSC database, and analysis of the results showed that participation in the SSC was associated with a 5.4% absolute survival benefit. The SSC has impacted the care of septic patients and catalyzed changes that are likely to persist and evolve.

Developments in the management of patients with sepsis

Sepsis is associated with a high incidence of mortality and morbidity, however with appropriate strategies for monitoring and early targeted intervention mortality rates decline. This article examines the basic pathophysiology of the inflammatory response to tissue injury and the effects this has on circulation. A partnership of the Society of Critical Care Medicine, the European Society of Intensive Care Medicine and the International Sepsis Forum has developed the surviving sepsis strategy, which includes the sepsis six treatment pathway and early goal-directed therapy incorporating the six-hour care bundle.

The new Surviving Sepsis Campaign recommendations on glucose control should be reconsidered

Sir: Dellinger et al. are to be congratulated on their new Surviving Sepsis Campaign recommendations as published recently in this journal [1]. The efforts of Dellinger and his group are of great value for all of us who take care of patients with sepsis. Indeed, guidelines like those from the Surviving Sepsis Campaign, an initiative of the European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine, are very much welcomed and appreciated by the intensive care community. They have been and continue to be an important tool in improving care of septic patients globally. However, in our opinion, the new recommendations are flawed with respect to glucose control. The new recommendations for septic patients advise maintaining the blood glucose concentration (BGC) below 150 mg/dl (8.3 mmol/l) instead of adhering to the more strict thresholds as in the two randomized controlled trials by van den Berghe et al. (BGC 80–110 mg/dl, 4.0–6.1 mmol/l) [2, 3]. The Surviving Sepsis Campaign justifies this departure on several grounds: new studies show conflicting results incidence of severe hypoglycemia with lower BGC thresholds, with a presumed association between severe hypoglycemia and death. We disagree with the advised thresholds, and argue against the reasoning for not retaining the original stricter BGC thresholds. First, the evidence. Simply, there are no studies that provide evidence for glucose control in sepsis using the now recommended threshold of 150 mg/dl. Using the 150 mg/dl upper limit, more septic patients will be in the higher BGC range. However, with more successful glucose control (i. e., BGC closer to 80 mg/dl) more benefit is achieved [4, 5]. Indeed, the lowered BGC rather than the insulin dose is related to reduced mortality, critical illness polyneuropathy, bacteremia, and inflammation [4]. Second, the conflicting information that comes from new (yet unpublished) studies [6, 7]. Unfortunately, the multicenter VISEP trial on glucose control in Germany by the SepNet group was discontinued prematurely because of identical mortality rates in the treatment groups but a higher incidence of hypoglycemia in the glucose control group (12.1% vs. 2.1%) [6]. Another study, the European GLUControl trial, was also stopped before inclusion was completed [7]. As in the VISEP study, the primary reason for stopping inclusion of patients was the relatively high incidence of hypoglycemia in the glucose control group. Due to the early termination of these studies we are left with two underpowered randomized controlled trials which can by no means be used as evidence in the discussion on potential benefit of glucose control. Third, blood glucose control with insulin carries the risk of hypoglycemia. Indeed, the incidence of severe hypoglycemia (defined as a blood glucose concentration < 40 mg/dl) is 5 to 10 times higher than with a conventional blood glucose strategy [2, 3]. Thus, the rise in incidence of hypoglycemia in the glucose control groups in the two newer studies as mentioned above was not surprising. Similar findings came from numerous other studies reporting on some form of glucose control (merely studies with a before–after design) [8]. Fear of severe hypoglycemia has, at least in part, hampered broad implementation of glucose control [8]. Although many ICUs have adopted some form of glucose control, frequently the applied glucose control regimens have higher thresholds than those used in the original studies. Of note, with higher BGC thresholds, the incidence of severe hypoglycemia does not differ greatly from that with more strict BGC thresholds [8]. Fourth, the assumed association between hypoglycemia and poor outcome. We recently analyzed the short-term consequences (seizures, coma, and death) of hypoglycemia [9]. The hazard ratio for in-hospital death was 1.03 (95% confidence interval 0.68–1.56; P = 0.88) in patients with a first occurrence of hypoglycemia relative to the controls without hypoglycemia. Results were corrected for duration of intensive care unit admittance before hypoglycemia, age, sex, and Acute Physiology, Age and Chronic Health Evaluation II score at admission. In addition, no cases of hypoglycemia-associated death were reported. Although the evidence for glucose control with strict thresholds does not yet support a grade A recommendation (based on the highest level of evidence), it does appear to be stronger than the evidence in support of a strategy of tolerating higher BGC thresholds. Most importantly, however, the only evidence we have supports a BGC threshold of 110 mg/dl, not 150 mg/dl.

Severe community acquired pneumonia update: mortality, mechanisms and medical intervention

Severe community-acquired pneumonia (CAP) in the intensive care unit (ICU) is associated with a high mortality rate of about 30% [1], and this rate has remained largely unaltered since the discovery of antibiotics in the 1950s [2]. Until now, no therapies have been designed specifically as adjunct agents for the treatment of severe CAP. In the majority of cases, broad-spectrum antibiotics or pathogen-directed therapies are effective in eradicating the causative organism(s), but they do not address causative effects from pathways of inflammation and coagulation, which are characteristic of the host response to infection. Initially activated as a protective host response, these inflammatory and coagulation pathways may become unregulated and paradoxically may cause tissue damage in the setting of severe CAP. A major component of both of these pathways is tissue factor (TF), a microvascular endothelial glycoprotein that becomes exposed to the systemic circulation after tissue damage. TF is an attractive therapeutic target for adjunctive treatment in severe CAP because it is the initiating factor in the TF coagulation pathway (which ultimately results in thrombin generation and fibrin deposition) [3] and has been shown to stimulate directly the production and release of proinflammatory cytokines (through the protease-activated receptor system) [4]. The largest phase III randomized, placebo-controlled study ever undertaken in patients with severe CAP is currently underway to investigate whether targeting the TF pathway with a specific TF pathway inhibitor can significantly reduce 28-day all-cause mortality in the primary target population. The objective of this symposium is to review the epidemiology of severe CAP, examine current clinical practice and treatment guidelines, and investigate the evidence supporting the potentially central role of TF in the pathophysiology of severe CAP. Jordi Rello MD, PhD is Chief of the Critical Care Department at the Joan XXIII University Hospital in Tarragona, Spain. Professor Rello has been actively involved in clinical research for the past 20 years, focusing on the prevention and control of hospital-acquired infections, severe CAP and treatment of infections in critically ill patients. His presentation focused on the epidemiology, diagnosis and severity scoring of severe CAP, and the impact that treatment guidelines have had [5]. Tom van der Poll MD, PhD is Head of the Centre for Experimental and Molecular Medicine in the Academic Medical Centre in Amsterdam. His research is based in the Centre for Infection and Immunity Amsterdam (CINIMA) and focuses on innate immune responses to bacterial and myco-bacterial infection. He also serves on the Steering Committee of the International Sepsis Forum. His presentation focused on the pathogenesis of severe CAP, in particular covering the roles played by TF as a critical component of the infectious, inflammatory and coagulation pathways [6]. Pierre-Francois Laterre MD is Head of the Intensive Care Unit at St. Luc University Hospital, Universite Catholique de Louvain in Brussels, Belgium. Professor Laterre's professional and scientific activities have focused on the diagnosis, investigation and treatment of sepsis, particularly its interaction with the coagulation cascade. As Co-Chair for the symposium, his presentation focused on the rationale for TF as a therapeutic target in severe CAP and reviewed the design of the ongoing phase III CAPTIVATE study of tifacogin [7]. Jean-Paul Mira MD is Professor of Critical Care Medicine and Chair of the Medical Intensive Care Unit at the Cochin University Hospital; he is also Head of the Variability of Innate Immunity Research Laboratory at the Cochin Institute, both in Paris, France. His research interests are cellular responses to micro-organisms, Toll-like receptor signalling, functional genomics, genetic predisposition to sepsis and sepsis-induced immunosuppression. His presentation focused on the potential for biomarkers to assist physicians in the diagnosis of severe CAP and their possible future role in directing appropriate treatment [8]. The second Co-Chair, Steve Opal MD, who is Professor of Medicine from the Brown Medical School, Pawtucket, Rhode Island, USA, hosted the questions from the audience and directed responses from faculty.

The Use of Gene-Expression Profiling to Identify Candidate Genes in Human Sepsis

Our understanding of the pathophysiology of sepsis remains incomplete. Genomewide study offers an unbiased, system biology approach to examine the expression patterns of circulating leukocytes and may reveal novel insights into the host response to sepsis. We examined whether gene-expression profiling of neutrophils could identify signature genes and important pathways in the clinical syndrome of sepsis. Gene-expression profiling was performed using oligonucleotide microarrays on peripheral blood samples of 94 critically ill patients (71 septic and 23 nonseptic). Using a supervised learning algorithm based on support vector machine, a molecular signature of sepsis was generated from a training set of 44 samples and validated in an independent set of 50 samples. The diagnostic performance of the signature genes was assessed against a reference standard based on the International Sepsis Forum Consensus Conference definition of infection. A set of 50 signature genes correctly identified sepsis with a prediction accuracy of 91 and 88% in the training and validation sets, respectively. The diagnostic performance remained high regardless of patient's age, comorbidities, or prior antibiotic treatment. Compared with controls, genes involved in immune modulation and inflammatory response had reduced expression in patients with sepsis. In particular, the activation of nuclear factor-kappaB pathway was reduced, whereas its inhibitor gene, NFKBIA, was significantly up-regulated. The signature genes reflect suppression of neutrophils' immune and inflammatory function by sepsis. Gene-expression profiling therefore provides a novel approach to advance our understanding of the host response in sepsis.