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.

Kushimoto, Shigeki; Abe, Toshikazu; Ogura, Hiroshi; Shiraishi, Atsushi; Saitoh, Daizoh; Fujishima, Seitaro; Mayumi, Toshihiko; Hifumi, Toru; Shiino, Yasukazu; Nakada, Taka-aki; Tarui, Takehiko; Otomo, Yasuhiro; Okamoto, Kohji; Umemura, Yutaka; Kotani, Joji; Sakamoto, Yuichiro; Sasaki, Junichi; Shiraishi, Shin-ichiro; Takuma, Kiyotsugu; Tsuruta, Ryosuke; Hagiwara, Akiyoshi; Yamakawa, Kazuma; Masuno, Tomohiko; Takeyama, Naoshi; Yamashita, Norio; Ikeda, Hiroto; Ueyama, Masashi; Fujimi, Satoshi; Gando, Satoshi;

Objectives: To investigate the impact of body temperature on disease severity, implementation of sepsis bundles, and outcomes in severe sepsis patients. Design: Retrospective sub-analysis. Setting: Fifty-nine ICUs in Japan, from January 2016 to March 2017. Patients: Adult patients with severe sepsis based on Sepsis-2 were enrolled and divided into three categories (body temperature < 36°C, 36–38°C, > 38°C), using the core body temperature at ICU admission. Interventions: None. Measurements and Main Results: Compliance with the bundles proposed in the Surviving Sepsis Campaign Guidelines 2012, in-hospital mortality, disposition after discharge, and the number of ICU and ventilator-free days were evaluated. Of 1,143 enrolled patients, 127, 565, and 451 were categorized as having body temperature less than 36°C, 36–38°C, and greater than 38°C, respectively. Hypothermia—body temperature less than 36°C—was observed in 11.1% of patients. Patients with hypothermia were significantly older than those with a body temperature of 36–38°C or greater than 38°C and had a lower body mass index and higher prevalence of septic shock than those with body temperature greater than 38°C. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores on the day of enrollment were also significantly higher in hypothermia patients. Implementation rates of the entire 3-hour bundle and administration of broad-spectrum antibiotics significantly differed across categories; implementation rates were significantly lower in patients with body temperature less than 36°C than in those with body temperature greater than 38°C. Implementation rate of the entire 3-hour resuscitation bundle + vasopressor use + remeasured lactate significantly differed across categories, as did the in-hospital and 28-day mortality. The odds ratio for in-hospital mortality relative to the reference range of body temperature greater than 38°C was 1.760 (95% CI, 1.134–2.732) in the group with hypothermia. The proportions of ICU-free and ventilator-free days also significantly differed between categories and were significantly smaller in patients with hypothermia. Conclusions: Hypothermia was associated with a significantly higher disease severity, mortality risk, and lower implementation of sepsis bundles. 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 funds of the Japanese Association for Acute Medicine. Dr. Gando’s institution received funding from Japan Society for the Promotion of Science (Grant-in-aid for Scientific Research); he received funding from Asahi Kasei Pharma (lecture fee); and he disclosed that this article is supported by the Japanese Association for Acute Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Shigeki Kushimoto, MD, Division of Emergency and Critical Care Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980–8574, Japan. E-mail: kussie@emergency-medicine.med.tohoku.ac.jp Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Pepper, Dominique J.; Demirkale, Cumhur Y.; Sun, Junfeng; Rhee, Chanu; Fram, David; Eichacker, Peter; Klompas, Michael; Suffredini, Anthony F.; Kadri, Sameer S.

Objectives: Observational studies suggest obesity is associated with sepsis survival, but these studies are small, fail to adjust for key confounders, measure body mass index at inconsistent time points, and/or use administrative data to define sepsis. To estimate the relationship between body mass index and sepsis mortality using detailed clinical data for case detection and risk adjustment. Design: Retrospective cohort analysis of a large clinical data repository. Setting: One-hundred thirty-nine hospitals in the United States. Patients: Adult inpatients with sepsis meeting Sepsis-3 criteria. Exposure: Body mass index in six categories: underweight (body mass index < 18.5 kg/m2), normal weight (body mass index = 18.5–24.9 kg/m2), overweight (body mass index = 25.0–29.9 kg/m2), obese class I (body mass index = 30.0–34.9 kg/m2), obese class II (body mass index = 35.0–39.9 kg/m2), and obese class III (body mass index ≥ 40 kg/m2). Measurements: Multivariate logistic regression with generalized estimating equations to estimate the effect of body mass index category on short-term mortality (in-hospital death or discharge to hospice) adjusting for patient, infection, and hospital-level factors. Sensitivity analyses were conducted in subgroups of age, gender, Elixhauser comorbidity index, Sequential Organ Failure Assessment quartiles, bacteremic sepsis, and ICU admission. Main Results: From 2009 to 2015, we identified 55,038 adults with sepsis and assessable body mass index measurements: 6% underweight, 33% normal weight, 28% overweight, and 33% obese. Crude mortality was inversely proportional to body mass index category: underweight (31%), normal weight (24%), overweight (19%), obese class I (16%), obese class II (16%), and obese class III (14%). Compared with normal weight, the adjusted odds ratio (95% CI) of mortality was 1.62 (1.50–1.74) for underweight, 0.73 (0.70–0.77) for overweight, 0.61 (0.57–0.66) for obese class I, 0.61 (0.55–0.67) for obese class II, and 0.65 (0.59–0.71) for obese class III. Results were consistent in sensitivity analyses. Conclusions: In adults with clinically defined sepsis, we demonstrate lower short-term mortality in patients with higher body mass indices compared with those with normal body mass indices (both unadjusted and adjusted analyses) and higher short-term mortality in those with low body mass indices. Understanding how obesity improves survival in sepsis would inform prognostic and therapeutic strategies. The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the National Institutes of Health. Drs. Pepper, Demirkale, Sun, and Kadri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. Drs. Pepper, Demirkale, Sun, Rhee, Fram, Eichacker, Klompas, Suffredini, and Kadri contributed substantially to the study design, data analysis, and interpretation. Drs. Pepper and Kadri drafted the article. Drs. Demirkale, Sun, Rhee, Fram, Eichacker, Klompas, and Suffredini revised it critically for important intellectual content. Drs. Pepper, Demirkale, Sun, Rhee, Fram, Eichacker, Klompas, Suffredini, and Kadri approve the final version to be published. 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 National Institutes of Health Intramural Research Program, Clinical Center. Dr. Pepper received other support from intramural funding from the National Institutes of Health (NIH). Drs. Pepper, Demirkale, Sun, Fram, Eichacker, Suffredini, and Kadri received support for article research from the NIH. Drs. Pepper, Demirkale, Sun, Suffredini, and Kadri disclosed government support. Dr. Rhee’s institution received support for article research from Agency for Healthcare Research and Quality (AHRQ) (grant number K08HS025008), and he received support for article research from AHRQ. Dr. Fram’s institution received funding from the NIH; he received funding from Commonwealth Informatics (stockholder); and he disclosed work for hire. Dr. Klompas’ institution received funding from the Centers for Disease Control and Prevention. Address requests for reprints to: Dominique J. Pepper, MD, MBChB, Critical Care Medicine Department, National Institutes of Health, Building 10, Room 2C145 Bethesda, MD 20892. E-mail: dominiquepepper@gmail.com Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

These two cases encapsulate a common dilemma for clinicians who are trying to implement the recommendation of the Surviving Sepsis Campaign to administer broad-spectrum antibiotics within 1 hour after a patient’s presentation with possible sepsis. Both patients meet Surviving Sepsis Campaign……

Hotchkiss, Richard S.; Colston, Elizabeth; Yende, Sachin; Angus, Derek C.; Moldawer, Lyle L.; Crouser, Elliott D.; Martin, Greg S.; Coopersmith, Craig M.; Brakenridge, Scott; Mayr, Florian B.; Park, Pauline K.; Ye, June; Catlett, Ian M.; Girgis, Ihab G.; Grasela, Dennis M.

Objectives: To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559, Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression. Design: Randomized, placebo-controlled, dose-escalation. Setting: Seven U.S. hospital ICUs. Study Population: Twenty-four participants with sepsis, organ dysfunction (hypotension, acute respiratory failure, and/or acute renal injury), and absolute lymphocyte count less than or equal to 1,100 cells/μL. Interventions: Participants received single-dose BMS-936559 (10–900 mg; n = 20) or placebo (n = 4) infusions. Primary endpoints were death and adverse events; key secondary endpoints included receptor occupancy and monocyte human leukocyte antigen-DR levels. Measurements and Main Results: The treated group was older (median 62 yr treated pooled vs 46 yr placebo), and a greater percentage had more than 2 organ dysfunctions (55% treated pooled vs 25% placebo); other baseline characteristics were comparable. Overall mortality was 25% (10 mg dose: 2/4; 30 mg: 2/4; 100 mg: 1/4; 300 mg: 1/4; 900 mg: 0/4; placebo: 0/4). All participants had adverse events (75% grade 1–2). Seventeen percent had a serious adverse event (3/20 treated pooled, 1/4 placebo), with none deemed drug-related. Adverse events that were potentially immune-related occurred in 54% of participants; most were grade 1–2, none required corticosteroids, and none were deemed drug-related. No significant changes in cytokine levels were observed. Full receptor occupancy was achieved for 28 days after BMS-936559 (900 mg). At the two highest doses, an apparent increase in monocyte human leukocyte antigen-DR expression (> 5,000 monoclonal antibodies/cell) was observed and persisted beyond 28 days. Conclusions: In this first clinical evaluation of programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition in sepsis, BMS-936559 was well tolerated, with no evidence of drug-induced hypercytokinemia or cytokine storm, and at higher doses, some indication of restored immune status over 28 days. Further randomized trials on programmed cell death protein-1/programmed cell death-ligand 1 pathway inhibition are needed to evaluate its clinical safety and efficacy in patients with 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 by Bristol-Myers Squibb. Drs. Hotchkiss’s, Yende’s, Angus’s, Moldawer’s, Crouser’s, Martin’s, Coopersmith’s, Brakenridge’s, Mayr’s, and Park’s institution received funding from Bristol-Myers Squibb. Drs. Hotchkiss, Colston, Yende, Angus, and Moldawer received support for article research from Bristol-Myers Squibb. Drs. Hotchkiss, Colston, Moldawer, Crouser, Martin, Coopersmith, Brakenridge, Mayr, Park, Catlett, and Grasela disclosed off-label product use of antiprogrammed cell death-ligand 1 inhibitor (BMS-936559) for the treatment of immune suppression in the context of severe sepsis. Drs. Colston and Grasela disclosed they are shareholders of Bristol-Myers Squibb. Dr. Hotchkiss receives research grant support and serves on advisory boards to Bristol-Myers Squibb. Dr. Yende received grant support from Bristol-Myers Squibb for the design of this study. Dr. Angus received consulting fees from Bristol-Myers Squibb for advice on study design. Dr. Martin’s institution received funding from the National Institutes of Health. Dr. Coopersmith’s institution received funding from the Society of Critical Care Medicine (president in 2015). Dr. Park’s institution received funding from the National Institutes of Health, and she received other support from the U.S. Food and Drug Administration/Biomedical Advanced Research and Development Authority and Atox Bio. Drs. Colston, Ye, Catlett, Girgis, and Grasela disclosed that they are employees of Bristol-Myers Squibb. Study registration number (ClinicalTrials.gov): NCT02576457. Data sharing: BMS policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. For information regarding this article, E-mail: richardshotchkiss@wustl.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background In the new Sepsis-3 definition, sepsis is defined as “life-threatening organ dysfunction due to a dysregulated host response to infection.” We tested the predictive validity of the systematic inflammatory response syndrome (SIRS) criteria in patients in the Sepsis-3 cohort. Methods Among 1243 electronic health records from 1 January to 31 December 2015 at Sichuan University West China Hospital, we identified patients with sepsis and septic shock according to the Sepsis-3 definition and divided them into 2 subsets: SIRS-positive and SIRS-negative. We compared their characteristics and outcomes as well as the predictive validity of the SIRS criteria for in-hospital mortality. Results Of the 1243 patients, 631 were enrolled. Among these, 538 (85.3%) patients had SIRS-positive sepsis or septic shock, 168 (31.2%) of whom died, and 93 (14.7%) had SIRS-negative sepsis or septic shock, 20 (21.5%) of whom died (p = 0.06). Over a 1-year period, these groups had similar characteristics and changes in mortality. Among patients of the Sepsis-3 cohort admitted to the intensive care unit, the predictive validity for in-hospital mortality was lower for the SIRS criteria (area under the receiver operating characteristic curve [AUROC], 0.53; 95% confidence interval [95% CI], 0.49–0.57) than for the sequential (sepsis-related) organ failure assessment (SOFA) criteria (AUROC, 0.70; 95% CI, 0.66–0.74; p ≤ 0.01 for both). The SIRS score had poor predictive validity for the risk of in-hospital mortality. Conclusions In this cohort study of the new Sepsis-3 definition, we found that the SIRS criteria are weaker than the SOFA criteria with respect to their predictive efficacy for in-hospital death.…

Kraft, Bryan D.; Chen, Lingye; Suliman, Hagir B.; Piantadosi, Claude A.; Welty-Wolf, Karen E.

Objectives: Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes. Design: Prospective case-control study. Setting: Academic Medical Center and Veterans Affairs Hospital. Patients: Uninfected control patients (n = 20) and septic ICU patients (n = 37). Interventions: Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates. Measurements and Main Results: Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-α and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week. Conclusions: Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery. Drs. Kraft and Chen contributed equally. Dr. Welty-Wolf conceived of the overall experimental design. Drs. Kraft and Chen drafted the article. All authors performed data analysis and interpretation, revised the article, and approved of the final 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). All authors received support for article research from the National Institutes of Health (NIH). Dr. Kraft’s institution received funding from the NIH/National Heart, Lung, and Blood Institute, and the National Institute of General Medical Sciences, and he received funding from Shionogi Pharmaceuticals (Advisory Board). Dr. Kraft receives funding from the National Institutes of Health (K08HL130557) and has received honoraria from Shionogi Pharmaceuticals and La Jolla Pharmaceutical Company. Dr. Suliman receives funding from the National Institutes of Health (R01-HL135239-01A1). Dr. Piantadosi receives funding from the National Institutes of Health (R01-HL135239-01A1) and the Office of Naval Research (ONR N00014011240). Dr. Welty-Wolf received funding from the National Institutes of Health (R01GM084116). Drs. Chen’s and Welty-Wolf’s institutions received funding from the NIH. For information regarding this article, E-mail: bryan.kraft@duke.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Granja, Tiago; Körner, Andreas; Glück, Christian; Hohmann, Jan David; Wang, Xiaowei; Köhler, David; Streißenberger, Ariane; Nandurkar, Harshal H.; Mirakaj, Valbona; Rosenberger, Peter; Peter, Karlheinz; Straub, Andreas

Objectives: Sepsis is associated with a systemic inflammatory reaction, which can result in a life-endangering organ dysfunction. Pro-inflammatory responses during sepsis are characterized by increased activation of leukocytes and platelets, formation of platelet-neutrophil aggregates, and cytokine production. Sequestration of platelet-neutrophil aggregates in the microvasculature contributes to tissue damage during sepsis. At present no effective therapeutic strategy to ameliorate these events is available. In this preclinical pilot study, a novel anti-inflammatory approach was evaluated, which targets nucleoside triphosphate hydrolase activity toward activated platelets via a recombinant fusion protein combining a single-chain antibody against activated glycoprotein IIb/IIIa and the extracellular domain of CD39 (targ-CD39). Design: Experimental animal study and cell culture study. Setting: University-based experimental laboratory. Subjects: Human dermal microvascular endothelial cells 1, human platelets and neutrophils, and C57BL/6NCrl mice. Interventions: Platelet-leukocyte-endothelium interactions were evaluated under inflammatory conditions in vitro and in a murine lipopolysaccharide-induced sepsis model in vivo. The outcome of polymicrobial sepsis was evaluated in a murine cecal ligation and puncture model. To evaluate the anti-inflammatory potential of activated platelet targeted nucleoside triphosphate hydrolase activity, we employed a potato apyrase in vitro and in vivo, as well as targ-CD39 and as a control, nontarg-CD39 in vivo. Measurements and Main Results: Under conditions of sepsis, agents with nucleoside triphosphate hydrolase activity decreased platelet-leukocyte-endothelium interaction, transcription of pro-inflammatory cytokines, microvascular platelet-neutrophil aggregate sequestration, activation marker expression on platelets and neutrophils contained in these aggregates, leukocyte extravasation, and organ damage. Targ-CD39 had the strongest effect on these variables and retained hemostasis in contrast to nontarg-CD39 and potato apyrase. Most importantly, targ-CD39 improved survival in the cecal ligation and puncture model to a stronger extent then nontarg-CD39 and potato apyrase. Conclusions: Targeting nucleoside triphosphate hydrolase activity (CD39) toward activated platelets is a promising new treatment concept to decrease systemic inflammation and mortality of sepsis. This innovative therapeutic approach warrants further development toward clinical application. Prof. Peter and Dr. Straub contributed equally and share senior authorship. 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 grants from the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG], Bonn, Germany) to Dr. Straub (grant number STR-687/4-1); Prof. Rosenberger (grant number DFG-RO 3672/6-2); and Prof. Mirakaj (MI-1506/4-1) and the Interdisciplinary Center for Clinical Research (IZKF) program of the University of Tübingen, Germany (grant number IZKF-No. PK 2015-1-05; granted to Prof. Rosenberger and Mr. Glück); by a grant of the Dr. Karl Kuhn Foundation to Dr. Straub; and Dr. Xang was supported by a future leader fellowship of the National Heart Foundation of Australia). Mr. Glück received scholarship support for 1 year and travel support for visits at scientific meetings (German Anaesthesiology Congress and German Intensive Care and Emergency Medicine Congress) by the “IZKF—Promotionskolleg” University of Tübingen (Germany). Mr. Glück and Dr. Straub disclosed targ-CD39 as an experimental agent. Prof. Peter was supported by a principal research fellowship from the National Health and Medical Research Council of Australia. Dr. Straub’s institution received funding from Deutsche Forschungsgemeinschaft (German Research Foundation) and Interdisciplinary Center for Clinical Research (IZKF) program of the University of Tübingen, Germany, and he received speaker honoraria from CSL Behring GmbH Munich, Germany and Schöchl Medical Education GmbH Mattsee, Austria. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Andreas Straub, MD, Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University Tübingen, Waldhörnlestr. 22, 72072 Tübingen, Germany. E-mail: andreas.straub@uni-tuebingen.de Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ilko, Steven A.; Vakkalanka, J. Priyanka; Ahmed, Azeemuddin; Harland, Karisa K.; Mohr, Nicholas M.

Objectives: Severe sepsis is a complex, resource intensive, and potentially lethal condition and rural patients have worse outcomes than urban patients. Early identification and treatment are important to improving outcomes. The objective of this study was to identify hospital-specific factors associated with inter-hospital transfer. Design: Mixed method study integrating data from a telephone survey and retrospective cohort study of state administrative claims. Setting and Subjects: Survey of Iowa emergency department administrators between May 2017 and June 2017 and cohort of adults seen in Iowa emergency departments for severe sepsis and septic shock between January 2005 and December 2013. Interventions: None. Measurements and Main Results: Multivariable logistic regression was used to identify independent predictors of inter-hospital transfer. We included 114 institutions that provided data (response rate = 99%), and responses were linked to a total of 150,845 visits for severe sepsis/septic shock. In our adjusted model, having the capability to place central venous catheters or having a subscription to a tele-ICU service was independently associated with lower odds of inter-hospital transfer (adjusted odds ratio, 0.69; 95% CI, 0.54–0.86 and adjusted odds ratio, 0.69; 95% CI, 0.54–0.88, respectively). A facility’s participation in a sepsis-specific quality improvement initiative was associated with 62% higher odds of transfer (adjusted odds ratio, 1.62; 95% CI, 1.10–2.39). Conclusions: The insertion of central venous catheters and access to a critical care physician during sepsis treatment are important capabilities in hospitals that transfer fewer sepsis patients. In the future, hospital-specific capabilities may be used to identify institutions as regional sepsis centers. This work was performed at the University of Iowa Carver College of Medicine, Iowa City, IA. Mr. Ilko and Drs. Ahmed and Mohr conceived the study, designed the data collection tool, and obtained research funding. Mr. Ilko undertook participant recruitment and data collection with data collection oversight and quality control from Dr. Ahmed. Ms. Vakkalanka and Dr. Harland were responsible for management of the datasets. Ms. Vakkalanka and Drs. Harland and Mohr provided statistical advice on study design and analyzed the data. Mr. Ilko, Ms. Vakkalanka, and Dr. Mohr drafted the article. Dr. Mohr takes responsibility for the article as a whole. All authors contributed substantially to its revision. 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). This was delivered as an oral presentation, in part, at the Medical Student Research Conference at the University of Iowa, Carver College of Medicine, Iowa City, IA, on September 14, 2017. It was delivered as a poster presentation at Society for Academic Emergency Medicine Great Plains Regional Meeting in Columbia, MO, on October 7, 2017. Dr. Mohr disclosed that this research was funded by the HL007485 from the National Heart, Lung, and Blood Institute (Short Term Training for Students in the Health Professions) and support from the Department of Emergency Medicine, University of Iowa Carver College of Medicine. Mr. Ilko, Ms. Vakkalanka, and Dr. Mohr received support for article research from the NIH. Dr. Ahmed received funding from UptoDate. Dr. Harland disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: nicholas-mohr@uiowa.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kim, Joohae; Kim, Young Ae; Hwangbo, Bin; Kim, Min Jeong; Cho, Hyunsoon; Hwangbo, Yul; Lee, Eun Sook

Objectives: Although the effect of antihypertensive agents on sepsis has been studied, evidence for survival benefit was limited in the literature. We investigated differences in sepsis-related outcomes depending on the antihypertensive drugs given prior to sepsis in patients with hypertension. Design: Population-based cohort study. Setting: Sample cohort Database of the National Health Insurance Service from 2003 to 2013 in South Korea. Patients: Patients over 30 years old who were diagnosed with sepsis after receiving hypertension treatment. Interventions: None. Measurements and Main Results: Primary outcomes, 30-day and 90-day mortality rates, were analyzed for differences among three representative antihypertensive medications: angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, calcium channel blockers, and thiazides. In total, 4,549 patients diagnosed with hypertension prior to hospitalization for sepsis were identified. The 30-day mortality was significantly higher among patients who did not receive any medications within 1 month before sepsis (36.8%) than among patients who did (32.0%; p < 0.001). The risk for 90-days mortality was significantly lower in prior angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker users (reference) than in other drug users (odds ratio, 1.27; 95% CI, 1.07–1.52). There was no difference in the risk for 30-day and 90-day mortality depending on whether calcium channel blockers or thiazides were used. Use of calcium channel blockers was associated with a decreased risk for inotropic agent administration, compared with those of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (odds ratio, 1.23; 95% CI, 1.05–1.44) and thiazides (odds ratio, 1.33; 95% CI, 1.12–1.58). Conclusions: In patients with sepsis, lower mortality rate was associated with prior use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers not with use of calcium channel blockers or thiazides. The requirement of inotropic agents was significantly lower in prior use of calcium channel blockers, although the survival benefits were not prominent. Drs. J. Kim and Y. A. Kim equally contributed 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). Supported, in part, by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1520240). Dr. Lee disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hbb@ncc.re.kr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Carlton, Erin F.; Kohne, Joseph G.; Shankar-Hari, Manu; Prescott, Hallie C.

Objectives: Severe sepsis is a significant cause of healthcare use and morbidity among pediatric patients, but little is known about readmission diagnoses. We sought to determine the most common readmission diagnoses after pediatric severe sepsis, the extent to which post-sepsis readmissions may be potentially preventable, and whether patterns of readmission diagnoses differ compared with readmissions after other common acute medical hospitalizations. Design: Observational cohort study. Setting: National Readmission Database (2013–2014), including all-payer hospitalizations from 22 states. Patients: Four-thousand five-hundred twenty-eight pediatric severe sepsis hospitalizations, matched by age, gender, comorbidities, and length of stay to 4,528 pediatric hospitalizations for other common acute medical conditions. Interventions: None. Measurements and Main Results: We compared rates of 30-day all cause, diagnosis-specific, and potentially preventable hospital readmissions using McNemar’s chi-square tests for paired data. Among 5,841 eligible pediatric severe sepsis hospitalizations with live discharge, 4,528 (77.5%) were matched 1:1 to 4,528 pediatric hospitalizations for other acute medical conditions. Of 4,528 matched sepsis hospitalizations, 851 (18.8% [95% CI, 16.0–18.2]) were rehospitalized within 30 days, compared with 775 (17.1% [95% CI, 17.1–20.0]) of matched hospitalizations for other causes (p = 0.02). The most common readmission diagnoses were chemotherapy, device complications, and sepsis, all of which were several-fold higher after sepsis versus after matched nonsepsis hospitalization. Only 11.5% of readmissions were for ambulatory care sensitive conditions compared with 23% of rehospitalizations after common acute medical conditions. Conclusions: More than one in six children surviving severe sepsis were rehospitalized within 30 days, most commonly for maintenance chemotherapy, medical device complications, or recurrent sepsis. Only a small proportion of readmissions were for ambulatory care sensitive conditions. The views expressed in this publication are those of the author(s) not of the National Health Service, the National Institute for Health Research or the Department of Health or Department of Veterans Affairs or the U.S. government. 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. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Prescott’s institution received funding from the National Institutes of Health (NIH) (K08 GM115859)/National Institute of General Medical Sciences; she received support for article research from the NIH; and she 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: ecarlton@med.umich.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Gardner, Anna K.; Ghita, Gabriela L.; Wang, Zhongkai; Ozrazgat-Baslanti, Tezcan; Raymond, Steven L.; Mankowski, Robert T.; Brumback, Babette A.; Efron, Philip A.; Bihorac, Azra; Moore, Frederick A.; Anton, Stephen D.; Brakenridge, Scott C.

Objectives: This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness. Design: Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes. Setting: Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center. Patients: Adult critically ill patients that survived 14 days or longer after sepsis onset. Interventions: None. Measurements and Main Results: Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures. Conclusions: Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after 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 National Institute of General Medical Sciences (NIGMS) grants: R01 GM-113945 (to Dr. Efron), and P50 GM-111152 (to Drs. Gardner, Brumback, Efron, Bihorac, Moore, Anton, and Brakenridge) awarded by the NIGMS. Support was also provided by National Institute on Aging grants R03 AG056444 (to Dr. Brakenridge), and P30 AG028740 (to Drs. Gardner, Anton, and Brakenridge). In addition, this work was supported, in part, by a postgraduate training grant T32 GM-008721 (to Dr. Raymond) in burns, trauma, and perioperative injury by NIGMS. Drs. Gardner, Wang, Ozrazgat-Baslanti, Raymond, Brumback, Efron, Bihorac, Moore, Anton, and Brakenridge received support for article research from the National Institutes of Health (NIH). Drs. Gardner’s and Brakenridge’s institutions received funding from National Institute of General Medical Sciences (NIGMS) R01, NIGMS T32, and National Institute on Aging (NIA) R03. Dr. Brakenridge’s institution also received funding from NIA P30 and NIGMS P50. Drs. Wang’s, Ozrazgat-Baslanti’s, Raymond’s, Brumback’s, and Moore’s institutions received funding from the NIH. Dr. Raymond’s institution received funding from NIGMS P50. Dr. Bihorac’s institution received funding from the NIH R01, and she received funding from ATOX Bio. The remaining authors have disclosed that they do not have any potential conflicts of interest. ClinicalTrials.gov Identifier: NCT02276417. For information regarding this article, E-mail: Scott.Brakenridge@surgery.ufl.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Christopher Hansen

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 232-234, January 15, 2019. …

Abstract Purpose The management of early- (EOS) and late-onset sepsis (LOS) and neonatal intensive care units (NICUs) has not been extensively evaluated. Methods 231 highly specialized level 1 and level 2 NICUs in Germany were asked to participate in an internet-based survey. Results The final analysis of anonymized datasets from 80 NICUs (response rate 34.6 %) compared university hospitals and regional neonatal referral centers. The survey describes potential areas of improvement concerning empirical treatment of infants with LOS with vancomycin and 3rd generation cephalosporins, minimal volume of blood sampling for aerobic culture, consideration of lumbar tap in any child with blood culture positive LOS and drug monitoring details for gentamicin and vancomycin. Conclusion In summary, this survey reveals a significant gap between recent national German guidelines and daily practices in German NICUs.…

Asner S, Agyeman P, Gradoux E, et al.

AbstractBackgroundPopulation-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study.MethodsThe Swiss Pediatric Sepsis Study (09/2011–12/2015) prospectively recruited children

Johnson J, Milstone A.

infection prevention and controlneonatal sepsislow resource settings…

Adriana Cabal, Daniela Schmid, Sarah Lepuschitz, Anna Stöger, Marion Blaschitz, Franz Allerberger, Werner Ruppitsch, Markus Hell

In July 2018 four female patients hospitalized in the same maternal ward were diagnosed with puerperal sepsis caused by Steptococcus pyogenes.All were assisted by the same midwife in their deliveries. For active case finding diverse specimens were taken from the patients and the staff. By using a new core genome Multilocus Sequence Typing scheme, we confirmed here the transmission of a GAS strain by the only midwife involved in all deliveries that suffered from a panaritium. Still, proper hand hygiene before, during and after delivery assistance is of utmost importance.

Barbash, Ian J.; Davis, Billie; Kahn, Jeremy M.

Objectives: The Centers for Medicare and Medicaid Services requires hospitals to report compliance with a sepsis treatment bundle as part of its Inpatient Quality Reporting Program. We used recently released data from this program to characterize national performance on the sepsis measure, known as SEP-1. Design: Cross-sectional study of United States hospitals participating in the Centers for Medicare and Medicaid Services Hospital Inpatient Quality Reporting Program linked to Centers for Medicare and Medicaid Services’ Healthcare Cost Reporting Information System. Setting: General, short-stay, acute-care hospitals in the United States. Measurements and Main Results: We examined the hospital factors associated with reporting SEP-1 data, the hospital factors associated with performance on the SEP-1 measure, and the relationship between SEP-1 performance and performance on other quality measures related to time-sensitive medical conditions. A total of 3,283 hospitals were eligible for the analysis, of which 2,851 (86.8%) reported SEP-1 performance data. SEP-1 reporting was more common in larger, nonprofit hospitals. The most common reason for nonreporting was an inadequate case volume. Among hospitals reporting SEP-1 performance data, overall bundle compliance was generally low, but it varied widely across hospitals (mean and SD: 48.9% ± 19.4%). Compared with hospitals with worse SEP-1 performance, hospitals with better SEP-1 performance tended to be smaller, for-profit, nonteaching, and with intermediate-sized ICUs. Better hospital performance on SEP-1 was associated with higher rates of timely head CT interpretation for stroke patients (rho = 0.16; p < 0.001), more frequent aspirin administration for patients with chest pain or heart attacks (rho = 0.24; p < 0.001) and shorter median time to electrocardiogram for patients with chest pain (rho = –0.12; p < 0.001). Conclusions: The majority of eligible hospitals reported SEP-1 data, and overall bundle compliance was highly variable. SEP-1 performance was associated with structural hospital characteristics and performance on other measures of hospital quality, providing preliminary support for SEP-1 performance as a marker of timely hospital sepsis care. Supported, in part, by Agency for Healthcare Research and Quality (to Dr. Barbash, K08HS025455), National Institutes of Health (to Dr. Kahn, K24HL133444). Dr. Barbash received support for article research from the Agency for Healthcare Research and Quality. Dr. Kahn’s institution received funding from the NIH, and he received support for article research from the NIH. Dr. Davis has disclosed that she does not have any potential conflicts of interest. For information regarding this article, E-mail: barbashij@upmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Emanuele Rezoagli

American Journal of Respiratory and Critical Care Medicine, Volume 198, Issue 12, Page 1570-1572, December 15, 2018. …

Legrand M, Kellum JA.

Following esophageal resection for cancer, a 73-year-old man was admitted to the ICU with pneumonia and progressive acute respiratory failure, and he was placed on mechanical ventilation. At day 5, his creatinine level continued to increase. How would you proceed?…