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Drotrecogin alfa (activated) is approved for use in patients with sepsis who are at high risk for death. This controlled trial found no benefit in patients at a low risk for death (relative risk of death with drotrecogin alfa, 1.08). The rate of serious bleeding was higher with drotrecogin alfa. Drotrecogin alfa should not be used in patients with sepsis who have a low risk of death, such as those with single-organ failure or an APACHE II score below 25. Drotrecogin alfa should not be used in patients with sepsis who have a low risk of death, such as those with single-organ failure or an APACHE II score below 25. Severe sepsis contributes to approximately 10 percent of admissions to the intensive care unit worldwide, with resultant in-hospital mortality of 20 to 52 percent. 1 – 9 The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, involving adult patients with severe sepsis, showed a 19.4 percent reduction in the relative risk of death from all causes and an absolute reduction of 6.1 percent at 28 days among patients treated with drotrecogin alfa (activated) (DrotAA; Xigris, Eli Lilly) as compared with placebo. 10 Exploratory analyses of subgroups in the PROWESS trial indicated a consistent treatment effect in the majority of . . .

Drotrecogin alfa (activated) (DrotAA) is used for the treatment of adults with severe sepsis who have a high risk of dying. A phase 1b open-label study has indicated that the pharmacokinetics and pharmacodynamics of DrotAA are similar in children and adults. We initiated the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE) trial to investigate the efficacy and safety of the drug in children. Children aged between 38 weeks' corrected gestational age and 17 years with sepsis-induced cardiovascular and respiratory failure were randomly assigned to receive placebo or DrotAA (24 μg/kg/h) for 96 h. We used a prospectively defined, novel primary endpoint of Composite Time to Complete Organ Failure Resolution (CTCOFR) score. Secondary endpoints were 28-day mortality, major amputations, and safety. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov, number NCT00049764. 477 patients were enrolled; 237 received placebo, and 240 DrotAA. Our results showed no significant difference between groups in CTCOFR score (p=0·72) or in 28-day mortality (placebo 17·5%; DrotAA, 17·2%; p=0·93). Although there was no difference in overall serious bleeding events during the 28-day study period (placebo 6·8%; DrotAA 6·7%; p=0·97), there were numerically more instances of CNS bleeding in the DrotAA group (11 [4·6%], vs 5 [2·1%] in placebo, p=0·13), particularly in children younger than 60 days. For CTCOFR score days 1–14, correlation coefficient was −0·016 (95% CI −0·106 to 0·74); relative risk for 28-day mortality was 1·06 (95% CI 0·66 to 1·46) for DrotAA compared with placebo. Although we did not record any efficacy of DrotAA in children with severe sepsis, serious bleeding events were similar between groups and the overall safety profile acceptable, except in children younger than 60 days. However, we gained important insights into clinical and laboratory characteristics of childhood severe sepsis, and have identified issues that need to be addressed in future trials in critically ill children.

To compare the mortality of critically ill patients given either enteral feeding with an immune-enhancing formula or parenteral nutrition (PN). We report the results of a planned interim analysis on patients with severe sepsis which was undertaken earlier than planned once a meta-analysis suggested excess mortality in patients with severe sepsis given enteral immunonutrition. Randomised multicentre unblinded controlled clinical trial. Thirty-three General Intensive Care Units in Italy. Among the 237 recruited patients, 39 had severe sepsis or septic shock; 21 of them received PN. Eligible patients received either total PN or enteral nutrition, the latter containing extra L-arginine, omega-3 fatty acids, vitamin E, beta carotene, zinc, and selenium. The primary endpoint for the subgroup analysis on patients with severe sepsis was mortality on Intensive Care Unit (ICU). The ICU mortality of patients with severe sepsis given enteral nutrition (EN) was higher than for those given PN (44.4% vs 14.3%; p=0.039). More patients given EN than patients given PN still had severe sepsis when they died (38.9% vs 9.5%, p=0.055). Recruitment of patients with severe sepsis was subsequently stopped. Our results show that enteral immunonutrition, compared to PN, may be associated with excess mortality in patients with severe sepsis.

Sepsis remains a major global cause of morbidity and death. This investigation from Australia and New Zealand ICUs challenges the utility of the two criteria of the systemic inflammatory response syndrome as a key element in defining severe sepsis. Severe sepsis is a major cause of admission to the intensive care unit (ICU) and death. 1 , 2 The criteria according to the systemic inflammatory response syndrome (SIRS) were described 23 years ago as a clinical expression of the host response to inflammation. 3 In this context and in the presence of symptoms meeting two or more SIRS criteria, severe sepsis was seen as evolving from infection to sepsis, severe sepsis, and septic shock, in order of increasing severity. This approach was codified by the consensus statement of the American College of Chest Physicians and Society of Critical Care Medicine in 1992 . . .

To determine the accuracy of hospital discharge diagnoses in identifying severe infections among intensive care unit (ICU) patients, and estimate the impact of misclassification on incidence and 1-year mortality. Sepsis, pneumonia, and central nervous system (CNS) infections among 7,615 ICU admissions were identified using ICD-9 and ICD-10 diagnoses from the Swedish hospital discharge register (HDR). Sensitivity, specificity, and likelihood ratios were calculated using ICU database diagnoses as reference standard, with inclusion in sepsis trials (IST) as secondary reference for sepsis. CNS infections were accurately captured (sensitivity 95.4% [confidence interval (CI) = 86.8–100] and specificity 99.6% [CI = 99.4–99.8]). Community-acquired sepsis (sensitivity 51.1% [CI = 41.0–61.2] and specificity 99.4% [CI = 99.2–99.6]) and primary pneumonia (sensitivity 38.2% [CI = 31.2–45.2] and specificity 98.6% [CI = 98.2–99.0]) were more accurately detected than sepsis and pneumonia in general. One-year mortality was accurately estimated for primary pneumonia but underestimated for community-acquired sepsis. However, there were only small differences in sensitivity and specificity between HDR and ICU data in the ability to identify IST. ICD-9 appeared more accurate for sepsis, whereas ICD-10 was more accurate for pneumonia. Accuracy of hospital discharge diagnoses varied depending on diagnosis and case definition. The pattern of misclassification makes estimates of relative risk more accurate than estimates of absolute risk.

Sepsis remains a leading cause of morbidity and mortality in the neonatal population, and at present, there is no unified definition of neonatal sepsis. Existing consensus sepsis definitions within paediatrics are not suited for use in the NICU and do not address sepsis in the premature population. Many neonatal research and surveillance networks have criteria for the definition of sepsis within their publications though these vary greatly and there is typically a heavy emphasis on microbiological culture. The concept of organ dysfunction as a diagnostic criterion for sepsis is rarely considered in neonatal literature, and it remains unclear how to most accurately screen neonates for organ dysfunction. Accurately defining and screening for sepsis is important for clinical management, health service design and future research. The progress made by the Sepsis-3 group provides a roadmap of how definitions and screening criteria may be developed. Similar initiatives in neonatology are likely to be more challenging and would need to account for the unique presentation of sepsis in term and premature neonates. The outputs of similar consensus work within neonatology should be twofold: a validated definition of neonatal sepsis and screening criteria to identify at-risk patients earlier in their clinical course.ImpactThere is currently no consensus definition of neonatal sepsis and the definitions that are currently in use are varied.A consensus definition of neonatal sepsis would benefit clinicians, patients and researchers.Recent progress in adults with publication of Sepsis-3 provides guidance on how a consensus definition and screening criteria for sepsis could be produced in neonatology.We discuss common themes and potential shortcomings in sepsis definitions within neonatology.We highlight the need for a consensus definition of neonatal sepsis and the challenges that this task poses.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Abstract Rationale The Sepsis-3 Task Force updated the clinical criteria for sepsis, excluding the need for systemic inflammatory response syndrome (SIRS) criteria. The clinical implications of the proposed flowchart including the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) and SOFA scores are unknown. Objectives To perform a clinical decision-making analysis of Sepsis-3 in patients with community-acquired pneumonia. Methods This was a cohort study including adult patients with community-acquired pneumonia from two Spanish university hospitals. SIRS, qSOFA, the Confusion, Respiratory Rate and Blood Pressure (CRB) score, modified SOFA (mSOFA), the Confusion, Urea, Respiratory Rate, Blood Pressure and Age (CURB-65) score, and Pneumonia Severity Index (PSI) were calculated with data from the emergency department. We used decision-curve analysis to evaluate the clinical usefulness of each score and the primary outcome was in-hospital mortality. Measurements and Main Results Of 6,874 patients, 442 (6.4%) died in-hospital. SIRS presented the worst discrimination, followed by qSOFA, CRB, mSOFA, CURB-65, and PSI. Overall, overestimation of in-hospital mortality and miscalibration was more evident for qSOFA and mSOFA. SIRS had lower net benefit than qSOFA and CRB, significantly increasing the risk of over-treatment and being comparable with the “treat-all” strategy. PSI had higher net benefit than mSOFA and CURB-65 for mortality, whereas mSOFA seemed more applicable when considering mortality/intensive care unit admission. Sepsis-3 flowchart resulted in better identification of patients at high risk of mortality. Conclusions qSOFA and CRB outperformed SIRS and presented better clinical usefulness as prompt tools for patients with community-acquired pneumonia in the emergency department. Among the tools for a comprehensive patient assessment, PSI had the best decision-aid tool profile.