The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.

Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.

In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes.

To define the terms "sepsis" and "organ failure" in a precise manner.

Christian S. Scheer, Christian Fuchs, Matthias Gründling, Marcus Vollmer, Juliane Bast, Jürgen A. Bohnert, Kathrin Zimmermann, Klaus Hahnenkamp, Sebastian Rehberg, Sven-Olaf Kuhn

Sepsis guidelines recommend obtaining blood cultures before starting anti-infective therapy in patients with sepsis. However, little is known how antibiotic treatment prior to sampling affects bacterial growth. The aim of this study was to compare the results of blood cultures drawn prior to and under antibiotic therapy.

To the Editor: Seasonal patterns of presentations to intensive care units (ICUs) in the Southern Hemisphere can inform health care planning for critically ill patients worldwide, as was seen during the H1N1 influenza pandemic in 2009. During the late winter and early spring of 2017, ICUs in……

Abstract Background Development of sepsis is a process with significant variation among individuals. The precise elements of this variation need to be defined. This study was designed to define the way in which comorbidities contribute to sepsis development. Methods Three thousand five hundred nine patients with acute pyelonephritis (AP), community-acquired pneumonia (CAP), intraabdominal infections (IAI) or primary bacteremia (BSI) and at least two signs of the systemic inflammatory response syndrome were analyzed. The study primary endpoint was to define how comorbidities as expressed in the Charlson’s comorbidity index (CCI) and the underlying type of infection contribute to development of organ dysfunction. The precise comorbidities that mediate sepsis development and risk for death among 18 comorbidities recorded were the secondary study endpoints. Results CCI more than 2 had an odds ratio of 5.67 for sepsis progression in patients with IAI between significantly higher than AP and BSI. Forward logistic regression analysis indicated seven comorbidities that determine transition into sepsis in patients with AP, four comorbidities in CAP, six comorbidities in IAI and one in BSI. The odds ratio both for progression to sepsis and death with one comorbidity or with two and more comorbidities was greater than in the absence of comorbidities. Conclusions The study described how different kinds of infection vary in the degree to which they lead to sepsis. The number of comorbidities that enhances the risk of sepsis and death varies depending on the underlying infections.

Adhikari NJ, Rubenfeld GD.

In the past 2 years, sepsis has received considerable attention from the global community. In 2017, the World Health Assembly passed a resolution urging all 194 UN Member States to implement actions to reduce the burden of sepsis, and for the World Health Organization to report on the public health implications of sepsis and its global consequences. It has become clear that early resuscitation targeted to hemodynamic goals is more expensive and no more effective than routine care in high-income countries. In Zambia, a protocolized resuscitation strategy actually increased mortality. These data and other studies continue to suggest that some evidence on sepsis therapy does not generalize on a global scale.

McHale, Tony M.; Garciarena, Carolina D.; Fagan, Robert P.; Smith, Stephen G. J.; Martin-Loches, Ignacio; Curley, Gerard F.; Fitzpatrick, Fidelma; Kerrigan, Steve W.

Objectives: The vascular endothelium is a major target of sepsis-induced events, and endothelial activation accounts for much of the pathology of sepsis. Urinary tract infections and pneumonia caused by Escherichia coli are among of the most common infections causing sepsis in both community and hospital settings. Currently, there are no approved drugs on the market to treat the underlying pathophysiology of sepsis. The aim of this study is to elucidate the molecular mechanism by which E. coli induces endothelial injury as a result of attachment. Design: Laboratory research using a hemodynamic perfusion ex vivo model. Setting: Research Laboratories of Royal College of Surgeons in Ireland and Beaumont Hospital. Patients: Ex vivo human vascular endothelial cells. Interventions: Addition of αVβ3 antagonist, cilengitide. Measurements and Main Results: Clinical strains of E. coli isolated from patients with sepsis bound to sheared human endothelial cells under static and hemodynamic shear conditions. Binding was dependent on E. coli cell membrane protein outer membrane protein A attaching directly to endothelial cell integrin αVβ3. Attachment resulted in disturbances in endothelial barrier integrity, as determined by loss of tight junction protein staining, permeability changes, and ultimately cell death by apoptosis. Using a low concentration of the αVβ3 antagonist cilengitide or using a strain deficient in outer membrane protein A resulted in a significant reduction in endothelial dysfunction following infection. Conclusions: Inhibition of E. coli binding to endothelial cell αVβ3 by cilengitide prevents endothelial dysfunction and may, therefore, present as a novel early therapeutic for the treatment of sepsis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by Science Foundation Ireland Grant Number 13/CDA/2119 (to Dr. Kerrigan) and Health Research Board Grant Number HRA-POR-2010–33 (to Dr. Smith). Drs. Fagan’s and Smith’s institutions received funding from Health Research Board Ireland (a PhD studentship awarded to Dr. Smith who supported the start-up costs and PhD stipend and consumables for Dr. Fagan). Dr. Fagan received support for article research from the Health Research Board Ireland. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: skerrigan@rcsi.ie Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Lima, Alexandre; van Rooij, Tom; Ergin, Bulent; Sorelli, Michele; Ince, Yasin; Specht, Patricia A. C.; Mik, Egbert G.; Bocchi, Leonardo; Kooiman, Klazina; de Jong, Nico; Ince, Can

Objectives: We developed quantitative methods to analyze microbubble kinetics based on renal contrast-enhanced ultrasound imaging combined with measurements of sublingual microcirculation on a fixed area to quantify early microvascular alterations in sepsis-induced acute kidney injury. Design: Prospective controlled animal experiment study. Setting: Hospital-affiliated animal research institution. Subjects: Fifteen female pigs. Interventions: The animals were instrumented with a renal artery flow probe after surgically exposing the kidney. Nine animals were given IV infusion of lipopolysaccharide to induce septic shock, and six were used as controls. Measurements and Main Results: Contrast-enhanced ultrasound imaging was performed on the kidney before, during, and after having induced shock. Sublingual microcirculation was measured continuously using the Cytocam on the same spot. Contrast-enhanced ultrasound effectively allowed us to develop new analytical methods to measure dynamic variations in renal microvascular perfusion during shock and resuscitation. Renal microvascular hypoperfusion was quantified by decreased peak enhancement and an increased ratio of the final plateau intensity to peak enhancement. Reduced intrarenal blood flow could be estimated by measuring the microbubble transit times between the interlobar arteries and capillary vessels in the renal cortex. Sublingual microcirculation measured using the Cytocam in a fixed area showed decreased functional capillary density associated with plugged sublingual capillary vessels that persisted during and after fluid resuscitation. Conclusions: In our lipopolysaccharide model, with resuscitation targeted at blood pressure, the contrast-enhanced ultrasound imaging can identify renal microvascular alterations by showing prolonged contrast enhancement in microcirculation during shock, worsened by resuscitation with fluids. Concomitant analysis of sublingual microcirculation mirrored those observed in the renal microcirculation. Drs. Lima and van Rooij contributed equally as first authors. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by an Innovation Grant of the Dutch Kidney Foundation (14 OI 11), NanoNextNL, a micro- and nanotechnology consortium of the Government of the Netherlands and by the European Erasmus + Traineeship program. Dr. Lima’s, de Jong’s, and Ince’s institution received funding from the Dutch Kidney Foundation. Dr. van Rooij’s institution received funding from NanoNextNL, and he received support for article research from NanoNextNL and the Dutch Kidney Foundation. Dr. Ince received funding from the Dutch Kidney Foundation (Innovation Grant), and he received support for article research from the Dutch Kidney Foundation. Dr. Mik disclosed he is a founder and shareholder of Photonics Healthcare B.V. (Utrecht, The Netherlands); this company build a device for measuring mitochondrial oxygen tension, but this is not related to the subject of the article. Dr. Kooiman’s institution received funding from NanoNextNL; a Veni grant from Dutch Scientific Organization, division Toegepaste en Technische Wetenschappen; a fellowship grant from Erasmus MC Foundation; and a Grant from Phospholipid Research Center. Dr. Kooiman received funding from Erasmus MC (employer). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: a.pintolima@erasmusmc.nl Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Xu F, Lin S, Yan X, et al.

AbstractBackgroundIL-38 is the most recently characterized cytokine of the IL-1 family. However, its role in sepsis remains unknown.MethodsCirculating IL-38 was measured in two cohorts of adult and pediatric patients with sepsis. Using two murine models of lipopolysaccharide (LPS)-induced endotoxinemia and cecal ligation and puncture (CLP)-induced sepsis, the effects of IL-38 on survival, inflammation, tissue injury, or bacterial clearance were assessed.ResultsSerum IL-38 concentrations were significantly elevated in adult and pediatric patients with sepsis relative to corresponding healthy adult and pediatric controls, respectively. Increased IL-38 negatively correlated with the number of blood leukocytes, and the level of inflammatory cytokines including IL-6 and TNF-α in clinical sepsis. Anti-IL-38 antibody impaired survival, while recombinant IL-38 improved survival, in the two murine models of LPS-induced endotoxinemia and CLP-induced sepsis. IL-38 administration decreased inflammatory response, as reflected by lower levels of cytokines/chemokines (including IL-6, TNF-α, IL-10, IL-17, IL-27, CXCL1, and CCL2), and less tissue damage (including lung, liver, and kidney) in CLP-induced sepsis. Furthermore, IL-38 augmented bacterial clearance in CLP-induced polymicrobial sepsis.ConclusionsThese findings suggest that IL-38 attenuates sepsis by decreasing inflammation and increasing bacterial clearance, thus providing a novel tool for anti-sepsis therapy.

Lee, Si-Huei; Hsu, Tzu-Chun; Lee, Meng-tse Gabriel; Chao, Christin Chihh-Ting; Lee, Wan-Chien; Lai, Chi-Cheng; Lee, Chien-Chang; for the National Taiwan University Health Economics and Outcome Research Group

Objective: We aimed to compare the sepsis incidence, mortality rates, and primary sites of infection among adult, elderly, and octogenarian patients with sepsis. Design: Population-based cohort study. Setting: The entire health insurance claims data of Taiwan, which enrolled 99.8% of the 23 million Taiwanese population. Patients: Sepsis patients were identified by International Classification of Diseases, 9th Edition, Clinical Modification codes for both infection and organ dysfunction from January 1, 2002, to December 31, 2012. Patients were categorized into three age groups: 1) adults (18–64 yr); 2) elderly (65–84 yr); and 3) oldest old (≥ 85 yr). The 30-day all-cause mortality was verified by a linked national death certificate database. Interventions: None. Measurements and Main Results: From 2002 to 2012, we identified 1,259,578 patients with sepsis, of which 417,328 (33.1%) were adults, 652,618 (51.8%) were elderly, and 189,632 (15.1%) were oldest old. We determined that the incidence of sepsis in the oldest old was 9,414 cases per 100,000 population on 2012, which was 31-fold greater than the adult incidence (303 cases per 100,000 population) and three-fold greater than the elderly incidence (2,908 cases per 100,000 population). Despite the increasing trend in incidence, the mortality decreased by 34% for adults, 24% for elderly, and 22% for oldest old. However, systemic fungal infection was disproportionately increased in oldest old patients (1.76% annual increase) and the elderly patients (1.00% annual increase). Conclusion: The incidence of sepsis is disproportionately increased in elderly and oldest old patients. Despite the increasing trend in incidence, the mortality rate in geriatric patients with sepsis has decreased. However, the increased incidence of fungal infections in the geriatric population warrants further attention. Additional members of the National Taiwan University Health Economics and Outcome Research Group are: Meng-Che Wu, Shyr-Chyr Chen, Wan-Ting Hsu, Szu-Ta Chen, and Ke-ying Su. No funding bodies had any role in the study design, data collection and analysis, decision to publish, or preparation of the article. The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health, or National Health Research Institutes. Dr. S.-H. Lee drafted the analytical plan, guided the statistical analysis, interpreted the data, and wrote the draft. Ms. Hsu and Ms. W.-C. Lee conducted all the statistical analysis. Dr. M.-t.G. Lee interpreted the results, and wrote the final draft and point-to-point response. Dr. Chao helped with language editing and provided critical comments. Dr. Lai analyzed the data, provided critical feedback, and authorized the final article. Dr. C.-C. Lee designed the study, obtained funding, drafted the analytical plan, guided the statistical analysis, interpreted the data, and wrote the draft. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Taiwan National Science Foundation Grant NSC 102-2314-B-002 -131 -MY3, National Taiwan University Hospital Grant NTUH.106-P04, and Taiwan National Ministry of Science and Technology Grants MOST 104-2314-B-002 -039 -MY3 and MOST 106-2811-B-002-048. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: cclee100@gmail.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Estenssoro, Elisa; Kanoore Edul, Vanina S.; Loudet, Cecilia I.; Osatnik, Javier; Ríos, Fernando G.; Vázquez, Daniela N.; Pozo, Mario O.; Lattanzio, Bernardo; Pálizas, Fernando; Klein, Francisco; Piezny, Damián; Rubatto Birri, Paolo N.; Tuhay, Graciela; Díaz, Anatilde; Santamaría, Analía; Zakalik, Graciela; Dubin, Arnaldo; on behalf of SATISEPSIS Investigators

Objectives: The new Sepsis-3 definitions have been scarcely assessed in low- and middle-income countries; besides, regional information of sepsis outcomes is sparse. Our objective was to evaluate Sepsis-3 definition performance in Argentina. Design: Cohort study of 3-month duration beginning on July 1, 2016. Settings: Forty-nine ICUs. Patients: Consecutive patients admitted to the ICU with suspected infection that triggered blood cultures and antibiotic administration. Interventions: None. Measurements and Main Results: Patients were classified as having infection, sepsis (infection + change in Sequential Organ Failure Assessment ≥ 2 points), and septic shock (vasopressors + lactate > 2 mmol/L). Patients on vasopressors and lactate less than or equal to 2 mmol/L (cardiovascular dysfunction) were analyzed separately, as those on vasopressors without serum lactate measurement. Systemic inflammatory response syndrome was also recorded. Main outcome was hospital mortality. Of 809 patients, 6% had infection, 29% sepsis, 20% cardiovascular dysfunction, 40% septic shock, and 3% received vasopressors with lactate unmeasured. Hospital mortality was 13%, 20%, 39%, 51%, and 41%, respectively (p = 0.000). Independent predictors of outcome were lactate, Sequential Organ Failure Assessment score, comorbidities, prior duration of symptoms (hr), mechanical ventilation requirement, and infection by highly resistant microorganisms. Area under the receiver operating characteristic curves for mortality for systemic inflammatory response syndrome and Sequential Organ Failure Assessment were 0.53 (0.48–0.55) and 0.74 (0.69–0.77), respectively (p = 0.000). Conclusions: Increasing severity of Sepsis-3 categories adequately tracks mortality; cardiovascular dysfunction subgroup, not included in Sepsis-3, has distinct characteristics. Sequential Organ Failure Assessment score shows adequate prognosis accuracy─contrary to systemic inflammatory response syndrome. This study supports the predictive validity of Sepsis-3 definitions. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by a grant of the National Ministry of Health (2014) given to the Sociedad Argentina de Terapia Intensiva. Dr. Pálizas disclosed government work and disclosed that this research was organized by a Committee of the Argentine Society of Critical Care Medicine (SATI); SATI received some funding from the Ministry of Health due to the epidemiologic importance of the study. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: estenssoro.elisa@gmail.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abu-Kaf, Heba; Mizrakli, Yuval; Novack, Victor; Dreiher, Jacob

Objectives: Sepsis remains a disease with a high mortality rate. The study goal was to assess long-term survival of severe sepsis in young patients. Design: Retrospective cohort study. Setting: Patients admitted with sepsis to ICUs in seven tertiary hospitals between 2003 and 2011. Patients: A total of 409 patients less than 45 years who survived to hospital discharge were age and sex matched with 818 patients with infectious disease without sepsis selected from internal medicine or surgical department admissions. Interventions: None. Measurements and Main Results: The median age in sepsis patients and the comparison group was 31 and 32 years, respectively. The proportions of patients surviving after hospital discharge were significantly lower in the sepsis group compared with the control group; among survivors, 6-month, 1-year, and 3-year mortality rates were 0.7% versus 0%, 4.5% versus 0.7%, 7.9% versus 1.2%, and 10.8% versus 1.8%, respectively (p < 0.001 for all). In a multivariate Cox proportional hazards regression model, sepsis was associated with an increased risk of mortality (hazard ratio, 3.79; 95% CI, 2.27–6.32), while controlling for age, Charlson Comorbidity Index, history of stroke, and congestive heart failure. Past the 24-month landmark, sepsis was not found to be an independent risk for mortality (hazard ratio, 1.79; 95% CI, 0.67–4.79). Based on cause of death analysis, chronic underlying comorbidities might explain the excess mortality in patients with sepsis. Conclusions: Young patients experiencing an episode of severe sepsis continue to be at higher risk of long-term mortality. The highest mortality rates were observed during the first 24 months following discharge. Drs. Abu-Kaf and Mizrakli contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Novack received consulting fees (unrelated to the manuscript) from CardioMed Consultants, LLC. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: jacod@bgu.ac.il Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mearelli, Filippo; Fiotti, Nicola; Giansante, Carlo; Casarsa, Chiara; Orso, Daniele; De Helmersen, Marco; Altamura, Nicola; Ruscio, Maurizio; Castello, Luigi Mario; Colonetti, Efrem; Marino, Rossella; Barbati, Giulia; Bregnocchi, Andrea; Ronco, Claudio; Lupia, Enrico; Montrucchio, Giuseppe; Muiesan, Maria Lorenza; Di Somma, Salvatore; Avanzi, Gian Carlo; Biolo, Gianni

Objectives: To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. Design: Multicenter prospective study. Setting: At emergency department admission in five University hospitals. Patients: Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. Interventions: None. Measurements and Main Results: A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholypase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as “likely” or “unlikely” to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholypase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. Conclusions: We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Italian Ministry of Health. Drs. Mearelli, Fiotti, Giansante, Casarsa, De Helmersen, Altamura, Barbati, and Bregnocchi disclosed government work. Dr. Orso received support for article research from the Italian Ministry of Education, Universities and Research. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: filippome@libero.it Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abbasi J.

A new laboratory test in development may help identify patients with sepsis, a life-threatening condition that remains difficult to diagnose. The work, published in Nature Biomedical Engineering, builds on previous research implicating neutrophil dysfunction as a key player in sepsis.

Stefanova, D., Raychev, A., Deville, J., Humphries, R., Campeau, S., Ruchala, P., Nemeth, E., Ganz, T., Bulut, Y.

Iron is an essential micronutrient for most microbes and their hosts. Mammalian hosts respond to infection by inducing the iron-regulatory hormone hepcidin, which causes iron sequestration and a rapid decrease in plasma and extracellular iron concentration (hypoferremia). Previous studies showed that hepcidin regulation of iron is essential for protection from infection-associated mortality with the siderophilic pathogens Yersinia enterocolitica and Vibrio vulnificus. However, the evolutionary conservation of the hypoferremic response to infection suggests that not only rare siderophilic bacteria but also common pathogens may be targeted by this mechanism. We tested 10 clinical isolates of E. coli from children with sepsis and found that both genetic (hepcidin knockout, HKO) and iatrogenic iron overload (IV iron) potentiated infection with 8 out of 10 studied isolates: after peritoneal injection of E. coli, iron-loaded mice developed sepsis with 60% to 100% mortality within 24h while control wild type mice suffered 0% mortality. Using one strain for more detailed study, we show that iron overload allowed rapid bacterial multiplication and dissemination. We further found that the presence of non-transferrin bound iron (NTBI) in circulation is more important than total plasma or tissue iron in rendering mice susceptible to infection and mortality. Post infection treatment of HKO mice with just two doses of the hepcidin agonist PR73 abolished NTBI and completely prevented sepsis-associated mortality. We demonstrate that siderophilic phenotype extends to clinically common pathogens. The use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism.

A. Heffernan, J. Lipman, J. Roberts

We read with interest the comments from Ong et al. [1] regarding the need for a well-designed randomized controlled trial (RCT) to provide evidence to guide clinicians regarding the use of combined β-lactam antibiotic and aminoglycoside therapy for the management of critically ill patients with sepsis or septic shock. We would like to highlight the importance of appropriate dosing strategies and the inclusion of pharmacokinetic/pharmacodynamic (PK/PD) sub-studies to provide further evidence about the potential utility of combination therapy.

Lewis, Anthony J.; Zhang, Xianghong; Griepentrog, John E.; Yuan, Du; Collage, Richard D.; Waltz, Paul K.; Angus, Derek C.; Zuckerbraun, Brian S.; Rosengart, Matthew R.

Objectives: The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. Design: Laboratory animal research, pilot human feasibility trial. Setting: University basic science laboratory and tertiary care hospital. Subjects: Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. Interventions: Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. Measurements and Main Results: Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. Conclusions: Modifying the spectrum of light may offer therapeutic utility in sepsis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by a Basic/Translational Research Training Fellowship Grant awarded by the Surgical Infection Society (to Dr. Rosengart), R01 GM082852 (to Dr. Rosengart), R01 GM116929 (to Dr. Rosengart), and T32GM008516 (to Dr. Lewis) from the National Institutes of Health. Drs. Lewis, Griepentrog, Zuckerbraun, and Rosengart received support for article research from the National Institutes of Health. Dr. Zuckerbraun disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: rosengartmr@upmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

J. Rello, T.S.R. van Engelen, E. Alp, T. Calandra, V. Cattoir, W.V. Kern, M.G. Netea, S. Nseir, S.M. Opal, F.L. van de Veerdonk, M.H. Wilcox, W.J. Wiersinga

Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored.

Timothy Barkham, Anna Sheppard, Nicola Jones, Swaine Chen

Abstract Raoultella ornithinolytica is increasingly being isolated as a causative organism in human infections. Most of the infections caused by R. ornithinolytica are hospital acquired and occur in patients who are immunocompromised, had invasive procedures or have indwelling catheters. This is a first report of early onset neonatal sepsis caused by multi-drug-resistant R. ornithinolytica. The infection was not very severe and was characterised by generalized flushing of the skin. Patient made complete recovery once appropriate antibiotics were started.

Vichaya Suttisunhakul, Phireak Hip, Pidor Ouch, Piseth Ly, Chonthida Supaprom, Agus Rachmat, Michael Prouty, Andrew Vaughn, Ahreej Eltayeb, Sim Kheng, Danielle V. Clark, James V. Lawler, Narisara Chantratita, Mary N. Burtnick, Paul J. Brett and Kevin L. Schully

Abstract. Burkholderia pseudomallei, the etiologic agent of melioidosis, is predicted to be ubiquitous in tropical regions of the world with areas of highest endemicity throughout Southeast Asia (SEA). Nevertheless, the distribution of B. pseudomallei and the burden of melioidosis in many SEA countries remain unclear. In Cambodia, only two human endemic cases of melioidosis were reported through 2008 and since then only a few hundred cases have been described in the literature. This is in sharp contrast to the annual burden of thousands of cases in surrounding areas. To further investigate the prevalence of melioidosis in Cambodia, we used a recently developed O-polysaccharide–based rapid enzyme-linked immunosorbent assay to detect B. pseudomallei–specific antibodies in serum samples obtained from 1,316 febrile illness or sepsis patients from 10 different provinces. Based on a cutoff value derived through culture-confirmed melioidosis cases, the proportion of positive samples in our cohort was approximately 12%. Regression analysis indicated that the odds of obtaining a positive result were 2.2 times higher for males than females controlling for age and province (95% confidence interval: 1.6–3.2, P < 0.001). Consistent with this, 9.2% of females were positive versus 18.2% of males (P < 0.001). Notably, 22.5% of grain or rice farmers were positive versus 10.1% of subjects with occupations not involving regular contact with soil. Positive results varied significantly by province. Collectively, the results of this study suggest that the true burden of melioidosis in Cambodia is greater than has previously been reported.

Brendon P. Scicluna

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 8, Page 1070-1073, April 15, 2018.