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.

Brendon P. Scicluna

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 936-938, April 15, 2019. …

Corl, Keith A.; Prodromou, Michael; Merchant, Roland C.; Gareen, Ilana; Marks, Sarah; Banerjee, Debasree; Amass, Timothy; Abbasi, Adeel; Delcompare, Cesar; Palmisciano, Amy; Aliotta, Jason; Jay, Gregory; Levy, Mitchell M.

Objectives: It is unclear if a low- or high-volume IV fluid resuscitation strategy is better for patients with severe sepsis and septic shock. Design: Prospective randomized controlled trial. Setting: Two adult acute care hospitals within a single academic system. Patients: Patients with severe sepsis and septic shock admitted from the emergency department to the ICU from November 2016 to February 2018. Interventions: Patients were randomly assigned to a restrictive IV fluid resuscitation strategy (≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care. Measurements and Main Results: We enrolled 109 patients, of whom 55 were assigned to the restrictive resuscitation group and 54 to the usual care group. The restrictive group received significantly less resuscitative IV fluid than the usual care group (47.1 vs 61.1 mL/kg; p = 0.01) over 72 hours. By 30 days, there were 12 deaths (21.8%) in the restrictive group and 12 deaths (22.2%) in the usual care group (odds ratio, 1.02; 95% CI, 0.41–2.53). There were no differences between groups in the rate of new organ failure, hospital or ICU length of stay, or serious adverse events. Conclusions: This pilot study demonstrates that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared with usual care. Although limited by the sample size, we observed no increase in mortality, organ failure, or adverse events. These findings further support that a restrictive IV fluid strategy should be explored in a larger multicenter trial. 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 Division of Pulmonary and Critical Care and the Department of Emergency Medicine, Alpert Medical School of Brown University. Dr. Merchant’s institution received funding from the National Institutes of Health. Dr. Jay disclosed he is a Covidien scientific advisory board member. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Keith Corl, MD, ScM, Department of Medicine, Division of Pulmonary, Critical Care & Sleep, The Rhode Island Hospital, 593 Eddy St, 4th floor, Providence, RI 02903. E-mail: keith_corl@brown.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

David B. Antcliffe

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 980-986, April 15, 2019. …

Higgins, Alisa M.; Peake, Sandra L.; Bellomo, Rinaldo; Cooper, D. Jamie; Delaney, Anthony; Harris, Anthony H.; Howe, Belinda D.; Nichol, Alistair D.; Webb, Steve A.; Williams, Patricia J.; on behalf of the Australasian Resuscitation in Sepsis Evaluation (ARISE) Investigators and the ANZICS Clinical Trials Group

Objectives: To examine long-term survival and quality of life of patients with early septic shock. Design: Prospective, randomized, parallel-group trial. Setting: Fifty-one hospitals in Australia, New Zealand, Finland, Hong Kong, and the Republic of Ireland. Patients: One-thousand five-hundred ninety-one patients who presented to the emergency department with early septic shock between October 2008 and April 2014, and were enrolled in the Australasian Resuscitation in Sepsis Evaluation trial. Interventions: Early goal-directed therapy versus usual care. Measurements and Main Results: Long-term survival was measured up to 12 months postrandomization. Health-related quality of life was measured using the EuroQoL-5D-3L, Short Form 36 and Assessment of Quality of Life 4D at baseline, and at 6 and 12 months following randomization. Mortality data were available for 1,548 patients (97.3%) and 1,515 patients (95.2%) at 6 and 12 months, respectively. Health-related quality of life data were available for 85.1% of survivors at 12 months. There were no significant differences in mortality between groups at either 6 months (early goal-directed therapy 21.8% vs usual care 22.6%; p = 0.70) or 12 months (early goal-directed therapy 26.4% vs usual care 27.9%; p = 0.50). There were no group differences in health-related quality of life at either 6 or 12 months (EuroQoL-5D-3L utility scores at 12 mo early goal-directed therapy 0.65 ± 0.33 vs usual care 0.64 ± 0.34; p = 0.50), with the health-related quality of life of both groups being significantly lower than population norms. Conclusions: In patients presenting to the emergency department with early septic shock, early goal-directed therapy compared with usual care did not reduce mortality nor improve health-related quality of life at either 6 or 12 months. Investigators in the Australasian Resuscitation in Sepsis Evaluation (ARISE) study and their affiliations are listed in Supplemental Digital Content 1 (http://links.lww.com/CCM/E509). 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). The Australasian and Resuscitation in Sepsis Evaluation trial was funded by the National Health and Medical Research Council of Australia (numbers 491075 and 1021165). Additional funding to support the long-term mortality and health-related quality of life assessments was provided by the Intensive Care Foundation. Ms. Higgins was supported to complete this work by a National Health and Medical Research Council postgraduate scholarship (number 579709). The remaining authors have disclosed that they do not have any potential conflicts of interest. Clinical trial registration: ClinicalTrials.gov number, NCT00975793. For information regarding this article, E-mail: lisa.higgins@monash.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mark Trinder

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 7, Page 854-862, April 1, 2019. …

Tiffanie K. Jones

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 7, Page 812-814, April 1, 2019. …

Kohoutova, Michaela; Horak, Jan; Jarkovska, Dagmar; Martinkova, Vendula; Tegl, Vaclav; Nalos, Lukas; Vistejnova, Lucie; Benes, Jan; Sviglerova, Jitka; Kuncova, Jitka; Matejovic, Martin; Stengl, Milan

Objectives: To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis. Design: Prospective, controlled, randomized trial. Setting: University animal research laboratory. Subjects: Twenty-five domestic pigs were divided into three groups: 1) sepsis group (eight pigs), 2) sepsis + vagus nerve stimulation group (nine pigs), and 3) control sham group (eight pigs). Interventions: Sepsis was induced by cultivated autologous feces inoculation in anesthetized, mechanically ventilated, and surgically instrumented pigs and followed for 24 hours. Electrical stimulation of the cervical vagus nerve was initiated 6 hours after the induction of peritonitis and maintained throughout the experiment. Measurements and Main Results: Measurements of hemodynamics, electrocardiography, biochemistry, blood gases, cytokines, and blood cells were collected at baseline (just before peritonitis induction) and at the end of the in vivo experiment (24 hr after peritonitis induction). Subsequent in vitro analyses addressed cardiac contractility and calcium handling in isolated tissues and myocytes and analyzed mitochondrial function by ultrasensitive oxygraphy. Vagus nerve stimulation partially or completely prevented the development of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathovagal balance toward sympathetic dominance, and cardiac mitochondrial dysfunction, and reduced the number of activated monocytes. Sequential Organ Failure Assessment scores and vasopressor requirements significantly decreased after vagus nerve stimulation. Conclusions: In a clinically-relevant large animal model of progressive sepsis, vagus nerve stimulation was associated with a number of beneficial effects that resulted in significantly attenuated multiple organ dysfunction and reduced vasopressor and fluid resuscitation requirements. This suggests that vagus nerve stimulation might provide a significant therapeutic potential that warrants further thorough investigation. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 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). Drs. Kohoutova’s, Horak’s, Jarkovska’s, Martinkova’s, Tegl’s, Nalos’s, Vistejnova’s, Benes’s, Sviglerova’s, Kuncova’s, Matejovic’s, and Stengl’s institutions received funding from Grant Agency of the Czech Republic (project No. 15-15716S). Dr. Benes received funding from Edwards Lifesciences (consulting) and CNSystems Medizintechnik Graz (consulting and open access publication grant) (unrelated to this study). For information regarding this article, E-mail: milan.stengl@lfp.cuni.cz Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Bourcier, Simon; Hindlet, Patrick; Guidet, Bertrand; Dechartres, Agnès

Objectives: Many recent randomized controlled trials in the field of septic shock failed to demonstrate a benefit on mortality. Randomized controlled trials increasingly report organ support duration and organ support-free days as primary or secondary outcomes. We conducted a methodologic systematic review to assess how organ support outcomes were defined and reported in septic shock randomized controlled trials. Data Sources: MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science. Study Selection: We included randomized controlled trials published between January 2004 and March 2018 that involved septic shock adults and assessed organ support duration and/or organ support-free days for hemodynamic support, respiratory support, or renal replacement therapy. Data Extraction: For each randomized controlled trial, we extracted the definitions of organ support duration and organ support-free days. We particularly evaluated how nonsurvivors were accounted for. Study authors were contacted to provide any missing information regarding these definitions. Data Synthesis: We included 28 randomized controlled trials. Organ support duration and organ support-free days outcomes were reported in 17 and 15 randomized controlled trials, respectively, for hemodynamic support, 15 and 15 for respiratory support, and five and nine for renal replacement therapy. Nonsurvivors were included in the organ support duration calculation in 13 of 14 randomized controlled trials (93%) for hemodynamic support and nine of 10 (90%) for respiratory support. The organ support-free days definition for hemodynamic support, respiratory support, and renal replacement therapy was reported in six of 15 randomized controlled trials (40%), eight of 15 randomized controlled trials (53%), and six of nine randomized controlled trials (67%) reporting an organ support-free days outcome, respectively. Of these, one half assigned “0” to nonsurvivors, and the other half attributed one point per day alive free of organ support up to a predefined time point. Conclusions: This study highlights the heterogeneity and infrequency of organ support duration/organ support-free days outcome reporting in septic shock trials. When reported, the definitions of these outcome measures and methods of calculation are also infrequently reported, in particular how nonsurvivors were accounted for, which may have an important impact on interpretation. Drs. Bourcier and Hindlet was involved in the study conception, selection of randomized controlled trials (RCTs), data extraction, data analysis, interpretation of results, and drafting of the article. Dr. Guidet was involved in the study conception, selection of RCTs, interpretation of results, and drafting of the article. Dr. Dechartres was involved in the study conception, data extraction, data analysis, interpretation of results, and drafting of the article. 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). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: simon.bourcier@aphp.fr Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background Brucella is high-consequence pathogen and one of the most common seen laboratory- acquired infection pathogens. Quick and accurate detection of the pathogen will be of great important to reducing laboratory- acquired infection. Traditional biomedical reaction based method is time consumption, and mass spectrometry based method greatly reduces time consumption in pathogen identification. In the case presented here, we shared our experience in identification of Brucella directly from positive blood culture with mass spectrometry based method. Case presentation The patient is a 6-year boy with a history of three weeks fever accompanied with sweating and a pain at right patella. The patient also has a history of thalassemia and blood transfusion was performed previously admitted to our hospital. Two bottles of marrow culture and one bottle of blood culture were positive, and direct mass spectrometry from positive culture material revealed Brucella infection within 1 h. Conclusion Clinical characters and laboratory findings of the patient presented here might help clinician in non-endemic region to made suspected brucellosis diagnose. Our experience in rapid identification of Brucella from positive blood culture with MALDI-TOF SP could help preventing laboratory-acquired infection of Brucella.…

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 5, Page 669-669, March 1, 2019. …

Kim Westerdijk, Koen S. Simons, Marissa Zegers, Peter C. Wever, Peter Pickkers, Cornelis P. C. de Jager

by Kim Westerdijk, Koen S. Simons, Marissa Zegers, Peter C. Wever, Peter Pickkers, Cornelis P. C. de Jager Background Early diagnosis and treatment has proven to be of utmost importance in the outcome of sepsis patients. We compared the accuracy of the neutrophil-lymphocyte count ratio (NLCR) to conventional inflammatory markers in patients admitted to the Intensive Care Unit (ICU). Methods We performed a retrospective cohort study consisting of 276 ICU patients with sepsis and 388 ICU patients without sepsis. We compared the NLCR as well as C-reactive protein (CRP) level, procalcitonin (PCT) level, white blood cell (WBC) count, neutrophil count and lymphocyte count on ICU admission between sepsis and non-sepsis ICU patients. To evaluate the sensitivity and specificity, we constructed receiver operating characteristics (ROC) curves. Results Significant differences in NLCR values were observed between sepsis and non-sepsis patients (15.3 [10.8–38.2] (median [interquartile range] vs. 9.3 [6.2–14.5]; p

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.