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Background. Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. Methods. This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7–14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Results. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). Conclusions. Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

Sepsis, a complex physiological and metabolic response to infection, is a common reason for admission to an intensive care unit. This review examines the basis, diagnosis, and current treatment of this disorder. Sepsis is one of the oldest and most elusive syndromes in medicine. Hippocrates claimed that sepsis (σήψις) was the process by which flesh rots, swamps generate foul airs, and wounds fester. 1 Galen later considered sepsis a laudable event, necessary for wound healing. 2 With the confirmation of germ theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infection, often described as “blood poisoning,” and assumed to be the result of the host's invasion by pathogenic organisms that then spread in the bloodstream. However, with the advent of modern antibiotics, germ theory did not fully explain the pathogenesis of . . .

In patients with severe sepsis, albumin replacement in addition to crystalloid administration conferred no benefit, as compared with crystalloids alone, with respect to mortality at 28 or 90 days. Post hoc analysis suggested a possible benefit in patients with septic shock. For decades, human albumin has been administered to patients to provide adequate oncotic pressure and intravascular volume. 1 In 1998, however, a report from the Cochrane Injuries Group Albumin Reviewers indicated that the administration of albumin may be potentially harmful in critically ill patients, as compared with the administration of crystalloid solutions. 2 Subsequent meta-analyses reported contradictory findings. 3 , 4 To clarify this issue, a large, double-blind, randomized trial (the Saline versus Albumin Fluid Evaluation [SAFE] study) 5 was conducted, in which 4% albumin solution was compared with normal saline as fluid replacement in critically ill patients, with results indicating that albumin administration was . . .

Procalcitonin is a promising marker for identification of bacterial infections. We assessed the accuracy and clinical value of procalcitonin for diagnosis of sepsis in critically ill patients. We searched Medline, Embase, ISI Web of Knowledge, the Cochrane Library, Scopus, BioMed Central, and Science Direct, from inception to Feb 21, 2012, and reference lists of identified primary studies. We included articles written in English, German, or French that investigated procalcitonin for differentiation of septic patients—those with sepsis, severe sepsis, or septic shock—from those with a systemic inflammatory response syndrome of non-infectious origin. Studies of healthy people, patients without probable infection, and children younger than 28 days were excluded. Two independent investigators extracted patient and study characteristics; discrepancies were resolved by consensus. We calculated individual and pooled sensitivities and specificities. We used I2 to test heterogeneity and investigated the source of heterogeneity by metaregression. Our search returned 3487 reports, of which 30 fulfilled the inclusion criteria, accounting for 3244 patients. Bivariate analysis yielded a mean sensitivity of 0·77 (95% CI 0·72–0·81) and specificity of 0·79 (95% CI 0·74–0·84). The area under the receiver operating characteristic curve was 0·85 (95% CI 0·81–0·88). The studies had substantial heterogeneity (I2=96%, 95% CI 94–99). None of the subgroups investigated—population, admission category, assay used, severity of disease, and description and masking of the reference standard—could account for the heterogeneity. Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients. Nevertheless, the results of the test must be interpreted carefully in the context of medical history, physical examination, and microbiological assessment. Ministry of Education and Research, the Deutsche Forschungsgemeinschaft, Thuringian Ministry for Education, Science and Culture, the Thuringian Foundation for Technology, Innovation and Research, and the German Sepsis Society.

Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion—a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis.

Observational data had suggested that statin treatment may improve outcomes in patients with the acute respiratory distress syndrome from sepsis. This randomized trial showed no benefit to statin treatment in such patients. Despite progress in supportive care strategies for the acute respiratory distress syndrome (ARDS), mortality remains high, especially among patients with sepsis. 1 Inflammation leading to cellular damage and cellular death contributes to both pulmonary and nonpulmonary organ failure. Therapies that attenuate inflammation may improve outcomes in patients with ARDS. 2 Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, known collectively as statins, are commonly prescribed for hypercholesterolemia. However, statins also reduce inflammation and have been shown to prevent ARDS in murine models. 3 – 13 Several (but not all) large observational studies, a small randomized, controlled trial, and meta-analyses before study initiation have suggested that patients . . .

Mortality from severe sepsis and septic shock differs across continents, countries, and regions. We aimed to use data from the Surviving Sepsis Campaign (SSC) to compare models of care and outcomes for patients with severe sepsis and septic shock in the USA and Europe. The SSC was introduced into more than 200 sites in Europe and the USA. All patients identified with severe sepsis and septic shock in emergency departments or hospital wards and admitted to intensive care units (ICUs), and those with sepsis in ICUs were entered into the SSC database. Patients entered into the database from its launch in January, 2005, through January, 2010, in units with at least 20 patients and 3 months of enrolment of patients were included in this analysis. Patients included in the cohort were limited to those entered in the first 4 years at every site. We used random-effects logistic regression to estimate the hospital mortality odds ratio (OR) for Europe relative to the USA. We used random-effects linear regression to find the relation between lengths of stay in hospital and ICU and geographic region. 25 375 patients were included in the cohort. The USA included 107 sites with 18 766 (74%) patients, and Europe included 79 hospital sites with 6609 (26%) patients. In the USA, 12 218 (65·1%) were admitted to the ICU from the emergency department whereas in Europe, 3405 (51·5%) were admitted from the wards. The median stay on the hospital wards before ICU admission was longer in Europe than in the USA (1·0 vs 0·1 days, difference 0·9, 95% CI 0·8–0·9). Raw hospital mortality was higher in Europe than in the USA (41·1% vs 28·3%, difference 12·8, 95% CI 11·5–14·7). The median length of stay in ICU (7·8 vs 4·2 days, 3·6, 3·3–3·7) and hospital (22·8 vs 10·5 days, 12·3, 11·9–12·8) was longer in Europe than in the USA. Adjusted mortality in Europe was not significantly higher than that in the USA (32·3% vs 31·3%, 1·0, −1·7 to 3·7, p=0·468). Complete compliance with all applicable elements of the sepsis resuscitation bundle was higher in the USA than in Europe (21·6% vs 18·4%, 3·2, 2·2–4·4). The significant difference in unadjusted mortality and the fact that this difference disappears with severity adjustment raise important questions about the effect of the approach to critical care in Europe compared with that in the USA. The effect of ICU bed availability on outcomes in patients with severe sepsis and septic shock requires further investigation. Eli Lilly Co, Baxter Lifesciences, Philips Medical Systems, the Society of Critical Care Medicine, and the European Society of Intensive Care Medicine.

Abstract Rationale Observational studies link statin therapy with improved outcomes in patients with severe sepsis. Objectives To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. Methods Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. Measurements and Main Results There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87–191] vs. 244 [187–317] pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). Conclusions Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).

In this study, patients with severe sepsis were assigned to fluid resuscitation with starch (HES 130/0.4) or Ringer's acetate. The starch group had an increased risk of death at day 90 and increased use of renal-replacement therapy, as compared with the Ringer's acetate group. Intravenous fluids are the mainstay of treatment for patients with hypovolemia due to severe sepsis. Colloid solutions are used to obtain rapid and lasting circulatory stabilization, but there are limited data to support this practice. 1 The Surviving Sepsis Campaign guidelines recommend the use of either colloids or crystalloids, 2 but high-molecular-weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis, as observed in two randomized trials. 3 , 4 Those trials had substantial limitations, and participants received HES solutions with a molecular weight of 200 kD and a substitution ratio (the number of hydroxyethyl groups per glucose molecule) of . . .