Six subphenotypes in septic shock: Latent class analysis of the PROWESS Shock study.

PURPOSE: Septic shock is a highly heterogeneous condition which is part of the challenge in its diagnosis and treatment. In this study we aim to identify clinically relevant subphenotypes of septic shock using a novel statistic al approach. METHODS: Baseline patient data from a large global clinical trial of septic shock (n = 1696) was analysed using latent class analysis (LCA). This approach allowed investigators to identify subgroups in a heterogeneous population by estimating a categorical latent variable that detects relatively homogeneous subgroups within a complex phenomenon. RESULTS: LCA identified six different, clinically meaningful subphenotypes of septic shock each with a typical profile: (1) "Uncomplicated Septic Shock, (2) "Pneumonia with adult respiratory distress syndrome (ARDS)", (3) "Postoperative Abdominal", (4) "Severe Septic Shock", (5): "Pneumonia with ARDS and multiple organ dysfunction syndrome (MODS)", (6) "Late Septic Shock". The 6-class solution showed high entropy approaching 1 (i.e., 0.92), indicating there was excellent separation between estimated classes. CONCLUSIONS: LCA appears to be an applicable statistical tool in analysing a heterogenous clinical cohort of septic shock. The results may lead to a better understanding of septic shock complexity and form a basis for considering targeted therapies and selecting patients for future clinical trials.

Severe sepsis and systemic inflammatory response syndrome in emergency department patients with suspected severe infection.

BACKGROUND: Severe sepsis is a common condition with a reported high mortality, but most studies have been confined to intensive care unit (ICU) populations. The systemic inflammatory response syndrome (SIRS) has been used to define sepsis, however its usefulness has been questioned. Our aim was to describe the prevalence and clinical impact of severe sepsis and SIRS in patients admitted from the emergency department (ED) with a suspected serious infection. METHODS: Four hundred and four adult patients were enrolled prospectively from the ED. Variables defining severe sepsis and SIRS were measured and the relationship between severe sepsis, SIRS, and the clinical course was analyzed. RESULTS: Infections were diagnosed in 344 patients (85%). The overall mortality rate at 28 days was 2.7%, and 4.5% of patients were treated in the ICU. Patients with severe sepsis within 24 h of admission (42%) were more likely to suffer a critical course (ICU admission 9.0%, death 5.1%; p < 0.001). While SIRS was observed in 72% of the subjects at presentation, it was not associated with severe sepsis within 24 h or a subsequent critical course. Furthermore, 23% of patients with severe sepsis within 24 h did not present with SIRS. CONCLUSIONS: Severe sepsis was a common condition among ED patients with a clinically suspected serious infection. Mortality was low compared with results from the ICU setting, suggesting that severe sepsis is a more benign disease than earlier reported. As a tool for the definition of sepsis and for the selection of patients for clinical sepsis trials, SIRS lacks acceptable discriminative ability in an ED population with a high prevalence of serious infections.

Circulating monocytes are not the major source of plasma cytokines in patients with sepsis.

In sepsis, large quantities of inflammatory cytokines are released into the bloodstream. The cellular source of these cytokines is unclear, and we have here investigated to what extent circulating cells in blood contributed to this production. We used the enzyme-linked immunospot technique to study the spontaneous as well as the lipopolysaccharide (LPS)-induced secretion of the proinflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), granulocyte-macrophage colony-stimulating factor, IL-1ß, IL-12p40, and the anti-inflammatory cytokine IL-10 from whole-blood cells. The study comprised 32 septic patients (24 with septic shock) and 30 healthy controls. Despite significantly increased plasma cytokine levels in the septic patients, the number of spontaneous cytokine-secreting cells was small or nonexistent and did not differ between the two groups. Lipopolysaccharide stimulation of cells from the same samples triggered substantially increased numbers of cytokine-producing cells in both patients and controls. However, although the numbers of IL-6- and tumor necrosis factor α-secreting monocytes were very similar in both groups, significantly fewer IL-1ß-, IL-10-, IL-12p40-, and granulocyte-macrophage colony-stimulating factor-secreting monocytes were seen in samples from septic patients as compared with healthy controls. The reduced number of cytokine-secreting cells in response to LPS stimulation correlated with disease severity, as expressed by Sequential Organ Failure Assessment score and the stage of sepsis. In summary, circulating leukocytes did not appear to be responsible for the increased plasma levels of cytokines observed in sepsis. A selective sepsis-induced downregulation of cytokine secretion in response to LPS underscores the complexity of cytokine regulation in sepsis.

Clinical and laboratory variables identifying bacterial infection and bacteraemia in the emergency department.

BACKGROUND: While early antimicrobial treatment is of critical importance to patients with severe infections, excessive use of antibiotics has caused escalating bacterial resistance. Better diagnostic tools are needed to secure antibiotic stewardship. METHODS: The diagnostic value of clinical and laboratory variables in predicting infections that require antibiotic treatment was evaluated in a prospective observational study of 404 adult patients admitted from the emergency department (ED) with suspected severe infections. We also investigated the association of these variables with bacteraemia and severe sepsis. RESULTS: In a univariate analysis, increased levels of C-reactive protein (CRP), procalcitonin (PCT), interleukin 6 (IL-6), lipopolysaccharide binding protein (LBP), white blood cell count (WBC), neutrophils, respiratory rate (RR) (p ≤ 0.001), and a decreased haemoglobin (Hb) level (p = 0.005) were associated with an indicated demand for antibiotics (n = 286). In a multivariate analysis, only WBC, Hb, RR, and CRP remained independent predictors. When compared to the clinician's ability to make accurate antibiotic decisions, all variables tested had inferior diagnostic accuracy except CRP. Increased levels of PCT, IL-6, LBP, CRP, bilirubin, and RR were significantly associated with bacteraemia (n = 68) (p ≤ 0.001). Of these, PCT and IL-6 were also associated with severe sepsis (n = 156) (p < 0.001). In a multivariate analysis, CRP, RR, PCT, and bilirubin remained associated with bacteraemia. CONCLUSIONS: Special attention should be directed to CRP, WBC, RR, and Hb when selecting patients for antibiotic treatment in the emergency department. PCT, IL-6, and LBP did not provide additional guidance on antibiotic decisions and better tests are required in order to improve antibiotic stewardship.

Drotrecogin alfa (activated) in adults with septic shock.

BACKGROUND: There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 µg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS: At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).

ELISpot analysis of LPS-stimulated leukocytes: human granulocytes selectively secrete IL-8, MIP-1beta and TNF-alpha.

Granulocytes and monocytes/macrophages represent key effector cells of the innate immune system. While human monocytes have been recognized as capable of secreting a broad spectrum of cytokines, the situation has been less clear in granulocytes with studies often showing conflicting results. In this study, lipopolysaccharide (LPS)-induced cytokine secretion from polymorphonuclear cells (PMN) and peripheral blood mononuclear cells (PBMC) was analyzed at the single cell level with the enzyme-linked immunospot (ELISpot) assay. This method allowed us to establish the cytokine profiles for both PBMC and PMN based on the frequency and pattern of cytokine secreting cells, rather than on the amount of produced cytokine detectable in solution by ELISA. As a result, low levels of contaminating mononuclear cells present in our PMN preparations could be discriminated from granulocytes. Using this technique, neutrophils were found to secrete the two chemokines, IL-8 and MIP-1beta in response to LPS. Also TNF-alpha was secreted but in lower amounts and by significantly fewer cells. However, and as opposed to several other reports, we were unable to detect secretion of IL-1beta, IL-6, IL-10, IL-12 and GM-CSF. In contrast to the limited cytokine production by PMN, PBMC secreted considerably larger amounts of the investigated cytokines with CD14(+) monocytes being the primary source of production. Finally, we believe that the cytokine ELISpot technique may provide a powerful tool by which cells of the innate immune system can be studied from a functional perspective at the single cell level.

Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock.

The role of drotrecogin alfa (activated) (DAA) in severe sepsis remains controversial and clinicians are unsure whether or not to treat their patients with DAA. In response to a request from the European Medicines Agency, Eli Lilly will sponsor a new placebo-controlled trial and history suggests the results will be subject to great scrutiny. An academic steering committee will oversee the conduct of the study and will write the study manuscripts. The steering committee intends that the study will be conducted with the maximum possible transparency; this includes publication of the study protocol and a memorandum of understanding which delineates the role of the sponsor. The trial has the potential to provide clinicians with valuable data but patients will only benefit if clinicians have confidence in the conduct, analysis and reporting of the trial. This special article describes the process by which the trial was developed, major decisions regarding trial design, and plans for independent analysis, interpretation and reporting of the data.

Swedish guidelines for diagnosis and treatment of infective endocarditis.

Swedish guidelines for diagnosis and treatment of infective endocarditis (IE) by consensus of experts are based on clinical experience and reports from the literature. Recommendations are evidence based. For diagnosis 3 blood cultures should be drawn; chest X-ray, electrocardiogram, and echocardiography preferably transoesophageal should be carried out. Blood cultures should be kept for 5 d and precede intravenous antibiotic therapy. In patients with native valves and suspicion of staphylococcal aetiology, cloxacillin and gentamicin should be given as empirical treatment. If non-staphylococcal etiology is most probable, penicillin G and gentamicin treatment should be started. In patients with prosthetic valves treatment with vancomycin, gentamicin and rifampicin is recommended. Patients with blood culture negative IE are recommended penicillin G (changed to cefuroxime in treatment failure) and gentamicin for native valve IE and vancomycin, gentamicin and rifampicin for prosthetic valve IE, respectively. Isolates of viridans group streptococci and enterococci should be subtyped and MIC should be determined for penicillin G and aminoglycosides. Antibiotic treatment should be chosen according to sensitivity pattern given 2-6 weeks intravenously. Cardiac valve surgery should be considered early, especially in patients with left-sided IE and/or prosthetic heart valves. Absolute indications for surgery are severe heart failure, paravalvular abscess, lack of response to antibiotic therapy, unstable prosthesis and multiple embolies. Follow-up echocardiography should be performed on clinical indications.

Postoperative surgical site infections in cardiac surgery--an overview of preventive measures.

Postoperative surgical site infections are a major cause of postoperative morbidity and mortality in cardiac surgery. A surgical site infection occurs when the contaminating pathogens overcome the host defense systems and an infectious process begins. Bacteria may enter the operating site either by direct contamination from the patient's skin or internal organs, through the hands and instruments of the surgical staff or by bacteria-carrying particles that float around in the operating theatre and may land in the wound. The ability to withstand the contaminating bacteria depends on both local and systemic host defense. Successful preventive strategies are multiple and must include: 1) Minimizing the bacterial contamination of the surgical site (skin preparation, operating room ventilation, scrubbing, double gloving, etc.), 2) Minimizing the consequences of virulent contaminating bacteria by antibiotic prophylaxis (adequate dose, sort, timing, duration), 3) Minimizing injury to local host defense (atraumatic surgery, no excessive electrocautery, meticulous hemostasis, etc.), and 4) Optimizing general host defense (nutrition, tobacco smoking, weight loss, etc.). Compliance with these preventive procedures must be enforced through regular reviews of performance. Non-compliance with hygiene routines is often due to ignorance and poor planning. Education of personnel in these issues is a continuous process.

Nosocomial pneumonia in the ICU: a prospective cohort study.

Ventilator-associated pneumonia (VAP) is the most common intensive care unit (ICU)-acquired infection among patients requiring mechanical ventilation. A prospective surveillance programme of all patients has been implemented at the ICU, Karolinska University Hospital, Sweden since 2001. Within this programme, incidence and risk factors for ICU-acquired pneumonia and associated death over a 2-y period have been studied. Of 329 patients enrolled in the study, 221 required mechanical ventilation. 33 of 221 patients (15%) developed VAP, corresponding to a rate of 29 VAP/1000 ventilator d. Risk factors for VAP were aspiration (hazard ratio 3.79; 95% CI 1.48-9.68), recent surgery (HR 3.58; 95% CI 1.15-11.10) and trauma (HR 3.00; 95% CI 1.03-8.71). 11 patients of 33 (33%) with VAP died within 28 d compared to 46 of 288 (16%) without ICU-acquired pneumonia (odds ratio 2.73; 95% CI 0.97-7.63). We conclude that: 1) incidence of VAP was 15% and the most important risk factor was aspiration; 2) APACHE II score > or = 20 is a stronger predictor for poor outcome than VAP; 3) a minority of patients with APACHE II score > or = 20 develop VAP; and 4) continuous surveillance programmes are feasible and provide valuable data for improvement of quality of care.

[13 cases of cervical necrotizing fasciitis--all patients survived. Surgery, antibiotics and hyperbaric oxygenation give the best results]. / 13 fall av cervikal nekrotiserande fasciit--alla överlevde. Kirurgi, antibiotika och hyperbar oxygenbehandling ger bästa resultat.

Cervical necrotizing fasciitis is a serious, rapidly progressive infection along fascia planes that sometimes involves skin, subcutaneous tissue and muscle (myositis). The condition, often of dental or pharyngeal origin, is associated with high morbidity and mortality. Thirteen consecutive cases of cervical necrotizing fasciitis treated with hyperbaric oxygen at the Karolinska Hospital during the period 1997-2003 were reviewed. Eight male and five female patients, 33 to 78 years old, were treated according to the Karolinska Hospital guidelines for severe soft tissue infections. All patients recovered. Eleven of thirteen patients required intensive care and eight inotropic drugs. Streptococcus milleri was the predominant pathogen found in initial cultures. Three case reports are presented. Our findings lend further support to the literature on the importance of a prompt multidisciplinary approach with aggressive surgical intervention, broad-spectrum antibiotic therapy and hyperbaric oxygen therapy.

[Septic shock--a condition with great potential for improvement. Management and therapy]. / Septisk chock--ett sjukdomstillstånd med betydande förbättringspotential. Omhändertagande och terapi.

There is a recent focus upon treatment of septic shock, related to the publication of a number of interesting studies during the last two years. These studies indicate that patient outcome can be improved, provided care is organized so as to optimize and expedite initial treatment of the patient in septic shock. In parallel, new drugs have been launched using rather aggressive marketing, which calls for recommendations and advice from professional experts who are independent of the pharmaceutical industry. This article reviews the studies that have engendered a new optimism in the treatment of septic shock. These "new" therapies are presented in a total context with a temporal perspective. It is suggested that emergency sepsis teams be instituted at hospitals.

[Activated protein C--recent addition to therapy of sepsis]. / Aktiverat protein C--ett nytillskott i sepsisbehandlingen.

Human recombinant activated protein C (Xigris) represents a new concept in adjuvant therapy for patients with severe sepsis. In the large randomized controlled trial on which the registration is based, 28 day mortality was significantly reduced by 6.1% from 30.8% in the placebo group to 24.7% in the treatment group. Treatment benefit seemed to be restricted to those patients with the most severe disease. Side effects in terms of intracerebral hemorrhage and procedure related bleeding were seen during the 4 day infusion period. Until further data becomes available from ongoing studies, we recommend that treatment be restricted to those patients for whom benefit has been shown in the clinical trial, i.e. adult patients with septic shock and at least one additional sign of organ dysfunction as defined in the study. Patients with septic organ dysfunctions with a longer duration than 24 h were not evaluated in the study.